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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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DASATINIB


Dasatinib.svg
2D chemical structure of 863127-77-9

DASATINIB

ダサチニブ水和物

BMS 354825

863127-77-9 HYDRATE, USAN, BAN INN, JAN
UNII: RBZ1571X5H

302962-49-8 FREE FORM Dasatinib anhydrous USAN, INN

Molecular Formula, C22-H26-Cl-N7-O2-S.H2-O, Molecular Weight, 506.0282T6N DNTJ A2Q D- DT6N CNJ B1 FM- BT5N CSJ DVMR BG F1[WLN]X78UG0A0RNдазатиниб [Russian] [INN]دازاتينيب [Arabic] [INN]达沙替尼 [Chinese] [INN]1132093-70-9[RN]302962-49-8[RN]5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-87129966762[Beilstein]

A pyrimidine and thiazole derived ANTINEOPLASTIC AGENT and PROTEIN KINASE INHIBITOR of BCR-ABL KINASE. It is used in the treatment of patients with CHRONIC MYELOID LEUKEMIA who are resistant or intolerant to IMATINIB.

An orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations. SRC-family protein-tyrosine kinases interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways; tumorigenic forms can occur through altered regulation or expression of the endogenous protein and by way of virally-encoded kinase genes. (NCI Thesaurus)

5-Thiazolecarboxamide, N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)-1-piperazinyl)-2-methyl-4-pyrimidinyl)amino)-, monohydrate

Synthesis ReferenceUS6596746

DASATINIB ANHYDROUS

  • KIN 001-5
  • NSC 759877
  • Sprycel
  • 302962-49-8 Dasatinib anhydrous
  • 5-THIAZOLECARBOXAMIDE, N-(2-CHLORO-6-METHYLPHENYL)-2-((6-(4-(2-HYDROXYETHYL)-1-PIPERAZINYL)-2-METHYL-4-PYRIMIDINYL)AMINO)-
  • BMS-354825
  • DASATINIB [INN]
  • DASATINIB [MI]
  • DASATINIB [WHO-DD]
  • DASATINIB ANHYDROUS
No.NDA No.Major Technical ClassificationPatent No.Estimated Expiry DateDrug Substance ClaimDrug Product ClaimPatent Use Code
All list
1N021986Formula65967462020-06-28YYU – 748
2N021986Formula65967462020-06-28YYU – 780
3N021986Uses(Indication)71258752020-04-13  U – 779
4N021986Uses(Indication)71258752020-04-13  U – 780
5N021986Uses(Indication)71538562020-04-28  U – 780
6N021986Crystal74917252026-03-28YY 
7N021986Formulation86801032025-02-04 Y

SPRYCEL (dasatinib) is an inhibitor of multiple tyrosine kinases.

The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2- methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate).

The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure: Dasatinib is a white to off-white powder and has a melting point of 280°–286° C.

The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol

DASATINIBDASATINIB (DASATINIB) | ANDA #202103 | TABLET;ORAL | Discontinued | APOTEX INC
SPRYCELSPRYCEL (DASATINIB) | NDA #021986 | TABLET;ORAL | Prescription | BRISTOL MYERS SQUIBBSPRYCEL (DASATINIB) | NDA #022072 | TABLET; ORAL | Prescription | BRISTOL MYERS SQUIBB

Clip

https://www.pharmainbrief.com/files/2017/09/A-106-17-20170918-Reasons.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/202103Orig1s000ltr.pdfU.S. Patent Number Expiration Date 6,596,746 (the ‘746 patent) June 28, 20207,125,875 (the ‘875 patent) April 13, 20207,153,856 (the ‘856 patent) April 28, 20207,491,725 (the ‘725 patent) March 28, 20268,680,103 (the ‘103 patent) February 4, 2025

Drug Name:Dasatinib HydrateResearch Code:BMS-354825Trade Name:Sprycel®MOA:Kinase inhibitorIndication:Acute lymphoblastic leukaemia (ALL); Chronic myeloid leukemia (CML )Status:ApprovedCompany:Bristol-Myers Squibb (Originator)Sales:$1,620 Million (Y2015); 
$1,493 Million (Y2014);
$1,280 Million (Y2013);
$1,019 Million (Y2012);
$803 Million (Y2011);ATC Code:L01XE06Approved Countries or Area

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2006-06-28Marketing approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coatedEq. 20 mg/50 mg/70 mg/80 mg/100 mg/140 mg DasatinibBristol-Myers SquibbPriority; Orphan
2006-06-28Additional approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated70 mgBristol-Myers SquibbPriority

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2006-11-20Marketing approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated20 mg/50 mg/70 mg/80 mg/100 mg/140 mgBristol-Myers SquibbOrphan

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2011-06-16Modified indicationSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated20 mg/50 mgBristol-Myers Squibb, Otsuka 
2009-01-21Marketing approvalSprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet, Film coated20 mg/50 mgBristol-Myers Squibb, Otsuka 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2013-09-17Marketing approval Acute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mg南京正大天晴制药 
2013-09-17Marketing approval Acute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mg南京正大天晴制药 
2013-09-17Marketing approval Acute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mg南京正大天晴制药 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet50 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet20 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet70 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet100 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet100 mgBristol-Myers Squibb 
2011-09-07Marketing approval施达赛/SprycelAcute lymphoblastic leukaemia (ALL), Chronic myeloid leukemia (CML )Tablet100 mgBristol-Myers Squibb 

SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:

SPRYCEL (dasatinib) tablets, for oral use Structural Formula - Illustration

Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol.

SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

Dasatinib hydrate was first approved by the U.S. Food and Drug Administration (FDA) on June 28, 2006, then approved by European Medicine Agency (EMA) on Nov 20, 2006, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jan 21, 2009. It was developed and marketed as Sprycel® by Bristol Myers Squibb in the US.

Dasatinibhydrate is a kinase inhibitor.It is indicated for the treatment ofchronic myeloid leukemia and acutelymphoblastic leukemia.

Sprycel® is available as film-coatedtabletfor oral use, containing 20, 50, 70, 80, 100 or 140 mg offreeDasatinib. The recommended dose is 100 mg once daily forchronic myeloid leukemia. Another dose is 140 mg once daily for accelerated phase chronic myeloid leukemia, myeloid or lymphoid blast phase chronic myeloid leukemia, or Ph+ acutelymphoblastic leukemia.

Dasatinib, also known as BMS-354825, is an orally bioavailable synthetic small molecule-inhibitor of SRC-family protein-tyrosine kinases. Dasatinib binds to and inhibits the growth-promoting activities of these kinases. Apparently because of its less stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to overcome the resistance to imatinib of chronic myeloid leukemia (CML) cells harboring BCR-ABL kinase domain point mutations.

Dasatinib, sold under the brand name Sprycel among others, is a targeted therapy medication used to treat certain cases of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL).[3] Specifically it is used to treat cases that are Philadelphia chromosome-positive (Ph+).[3] It is taken by mouth.[3]

Common adverse effects include low white blood cellslow blood plateletsanemiaswelling, rash, and diarrhea.[3] Severe adverse effects may include bleeding, pulmonary edemaheart failure, and prolonged QT syndrome.[3] Use during pregnancy may result in harm to the baby.[3] It is a tyrosine-kinase inhibitor and works by blocking a number of tyrosine kinases such as Bcr-Abl and the Src kinase family.[3]

Dasatinib was approved for medical use in the United States and in the European Union in 2006.[3][2] It is on the World Health Organization’s List of Essential Medicines.

Medical uses

Dasatinib is used to treat people with chronic myeloid leukemia and people with acute lymphoblastic leukemia who are positive for the Philadelphia chromosome.[5]

In the EU dasatinib is indicated for children with

  • newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukaemia in chronic phase (Ph+ CML CP) or Ph+ CML CP resistant or intolerant to prior therapy including imatinib.[2]
  • newly diagnosed Ph+ acute lymphoblastic leukaemia (ALL) in combination with chemotherapy.[2]
  • newly diagnosed Ph+ CML in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib.[2]

and adults with

  • newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myelogenous leukaemia (CML) in the chronic phase;[2]
  • chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib mesilate;[2]
  • Ph+ acute lymphoblastic leukaemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy.[2]

Adverse effects

The most common side effects are infectionsuppression of the bone marrow (decreasing numbers of leukocyteserythrocytes, and thrombocytes),[6] headache, hemorrhage (bleeding), pleural effusion (fluid around the lungs), dyspnea (difficulty breathing), diarrheavomitingnausea (feeling sick), abdominal pain (belly ache), skin rashmusculoskeletal paintirednessswelling in the legs and arms and in the facefever.[2] Neutropenia and myelosuppression were common toxic effects. Fifteen people (of 84, i.e. 18%) in the above-mentioned study developed pleural effusions, which was a suspected side effect of dasatinib. Some of these people required thoracentesis or pleurodesis to treat the effusions. Other adverse events included mild to moderate diarrhea, peripheral edema, and headache. A small number of people developed abnormal liver function tests which returned to normal without dose adjustments. Mild hypocalcemia was also noted, but did not appear to cause any significant problems. Several cases of pulmonary arterial hypertension (PAH) were found in people treated with dasatinib,[7] possibly due to pulmonary endothelial cell damage.[8]

On October 11, 2011, the U.S. Food and Drug Administration (FDA) announced that dasatinib may increase the risk of a rare but serious condition in which there is abnormally high blood pressure in the arteries of the lungs (pulmonary hypertension, PAH).[9] Symptoms of PAH may include shortness of breath, fatigue, and swelling of the body (such as the ankles and legs).[9] In reported cases, people developed PAH after starting dasatinib, including after more than one year of treatment.[9] Information about the risk was added to the Warnings and Precautions section of the Sprycel drug label.[9]

Pharmacology

Crystal structure[10] (PDB 2GQG) of Abl kinase domain (blue) in complex with dasatinib (red).

Dasatinib is an ATP-competitive protein tyrosine kinase inhibitor. The main targets of dasatinib are BCR/Abl (the “Philadelphia chromosome”), Srcc-Kitephrin receptors, and several other tyrosine kinases.[11] Strong inhibition of the activated BCR-ABL kinase distinguishes dasatinib from other CML treatments, such as imatinib and nilotinib.[11][12] Although dasatinib only has a plasma half-life of three to five hours, the strong binding to BCR-ABL1 results in a longer duration of action.[12]

History

See also: Discovery and development of Bcr-Abl tyrosine kinase inhibitors

Dasatinib was developed by collaboration of Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd,[13][14][15] and named for Bristol-Myers Squibb research fellow Jagabandhu Das, whose program leader says that the drug would not have come into existence had he not challenged some of the medicinal chemists‘ underlying assumptions at a time when progress in the development of the molecule had stalled.[16]

Society and culture

Legal status

Dasatinib was approved for used in the United States in June 2006 and in the European Union in November 2006[17][2]

In October 2010, dasatinib was approved in the United States for the treatment of newly diagnosed adults with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (CP-CML).[18]

In November 2017, dasatinib was approved in the United States for the treatment of children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase.[19]

Approval was based on data from 97 pediatric participants with chronic phase CML evaluated in two trials—a Phase I, open-label, non-randomized, dose-ranging trial and a Phase II, open-label, non-randomized trial.[19] Fifty-one participants exclusively from the Phase II trial were newly diagnosed with chronic phase CML and 46 participants (17 from the Phase I trial and 29 from the Phase II trial) were resistant or intolerant to previous treatment with imatinib.[19] The majority of participants were treated with dasatinib tablets 60 mg/m2 body surface area once daily.[19] Participants were treated until disease progression or unacceptable toxicity.[19]

Economics

The Union for Affordable Cancer Treatment objected to the price of dasatinib, in a letter to the U.S. trade representative. The average wholesale price in the U.S. is $367 per day, twice the price in other high income countries. The price in India, where the average annual per capita income is $1,570, and where most people pay out of pocket, is Rs6627 ($108) a day. Indian manufacturers offered to supply generic versions for $4 a day, but, under pressure from the U.S., the Indian Department of Industrial Policy and Promotion refused to issue a compulsory license.[20]

Bristol-Myers Squibb justified the high prices of cancer drugs with the high R&D costs, but the Union of Affordable Cancer Treatment said that most of the R&D costs came from the U.S. government, including National Institutes of Health funded research and clinical trials, and a 50% tax credit. In England and Wales, the National Institute for Health and Care Excellence recommended against dasatinib because of the high cost-benefit ratio.[20]

The Union for Affordable Cancer Treatment said that “the dasatinib dispute illustrates the shortcomings of US trade policy and its impact on cancer patients”[20]

Brand names

In Bangladesh dasatinib is available under the trade name Dasanix by Beacon Pharmaceuticals.In India, It is marketed by brand name NEXTKI by EMCURE PHARMACEUTICALS[medical citation needed]

Research

Dasatinib has been shown to eliminate senescent cells in cultured adipocyte progenitor cells.[21] Dasatinib has been shown to induce apoptosis in senescent cells by inhibiting Src kinase, whereas quercetin inhibits the anti-apoptotic protein Bcl-xL.[21] Administration of dasatinib along with quercetin to mice improved cardiovascular function and eliminated senescent cells.[22] Aged mice given dasatinib with quercetin showed improved health and survival.[22]

Giving dasatinib and quercetin to mice eliminated senescent cells and caused a long-term resolution of frailty.[23] A study of fourteen human patients suffering from idiopathic pulmonary fibrosis (a disease characterized by increased numbers of senescent cells) given dasatinib and quercetin showed improved physical function and evidence of reduced senescent cells.[21]Route 1

Reference:1. WO2005077945A2 / US2012302750A1.Route 2

Reference:1. WO0062778A1 / US6596746B1.Route 3

Reference:1. J. Med. Chem. 200447, 6658-6661.

2. J. Med. Chem. 200649, 6819-6832.Route 4

Reference:1. CN104292223A.Route 5

Reference:1. CN103420999A.

Syn 1

Reference

Balaji, N.; Sultana, Sayeeda. Trace level determination and quantification of potential genotoxic impurities in dasatinib drug substance by UHPLC/infinity LC. International Journal of Pharmacy and Pharmaceutical Sciences. Department of Chemistry. St. Peter’s University. Tamil Nadu, India 600054. Volume 8. Issue 10. Pages 209-216. 2016

SYN 2

Reference

Zhang, Shaoning; Wei, Hongtao; Ji, Min. Synthesis of dasatinib. Zhongguo Yiyao Gongye Zazhi. Dept. of Pharmaceutical Engineering, School of Chemistry & Chemical Engineering. Southeast University. Nanjing, Jiangsu Province, Peop. Rep. China 210096. Volume 41. Issue 3. Pages 161-163. 2010

SYN 3

Reference

Suresh, Garbapu; Nadh, Ratnakaram Venkata; Srinivasu, Navuluri; Yennity, Durgaprasad. A convenient new and efficient commercial synthetic route for dasatinib (Sprycel). Synthetic Communications. Division of Chemistry, Department of Science and Humanities. Vignan’s Foundation for Science Technology and Research University. Guntur, India. Volume 47. Issue 17. Pages 1610-1621. 2017

SYN 4

Reference

Chen, Bang-Chi; Zhao, Rulin; Wang, Bei; Droghini, Roberto; Lajeunesse, Jean; Sirard, Pierre; Endo, Masaki; Balasubramanian, Balu; Barrish, Joel C. A new and efficient preparation of 2-aminothiazole-5-carbamides: applications to the synthesis of the anticancer drug dasatinib. ARKIVOC (Gainesville, FL, United States). Discovery Chemistry. Bristol-Myers Squibb Research and Development. Princeton, USA 08543. Issue 6.Pages 32-38. 2010

SYN 5

Reference

An, Kang; Guan, Jianning; Yang, Hao; Hou, Wen; Wan, Rong. Improvement on the synthesis of Dasatinib. Jingxi Huagong Zhongjianti. College of Science. Nanjing University of Technology. Nanjing, Jiangsu Province, Peop. Rep. China 211816. Volume 41. Issue 2. Pages 42-44. 2011

PATENT

https://patents.google.com/patent/US7491725B2/en

EXAMPLESExample 1Preparation of Intermediate:

(S)-1-sec-Butylthiourea

Figure US07491725-20090217-C00048

To a solution of S— sec-butyl-amine (7.31 g, 0.1 mol) in chloroform (80 mL) at 0° C. was slowly added benzoyl isothiocyanate (13.44 mL, 0.1 mol). The mixture was allowed to warm to 10° C. and stirred for 10 min. The solvent was then removed under reduced pressure, and the residue was dissolved in MeOH (80 mL). An aqueous solution (10 mL) of NaOH (4 g, 0.1 mol) was added to this solution, and the mixture was stirred at 60° C. for another 2 h. The MeOH was then removed under reduced pressure, and the residue was stirred in water (50 mL). The precipitate was collected by vacuum filtration and dried to provide S-1-sec-butyl-thiourea (12.2 g, 92% yield). mp 133-134° C.; 1H NMR (500 MHz, DMSO-D6) δ 7.40 (s, 1H), 7.20 (br s, 1H), 6.76 (s, 1H), 4.04 (s, 1H), 1.41 (m, 2H), 1.03 (d, J=6.1 Hz, 3H), 0.81 (d, J=7.7 Hz, 3H); 13C NMR (125 MHz, DMSO-D6) δ 182.5, 50.8, 28.8, 19.9, 10.3; LRMS m/z 133.2 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.49; H, 8.88; N, 21.32; S, 24.27.

Example 2Preparation of Intermediate:

(R)-1-sec-Butylthiourea

Figure US07491725-20090217-C00049

(R)-1-sec-Butylthiourea was prepared in 92% yield according to the general method outlined for Example 1. mp 133-134° C.; 1H NMR(500 MHz, DMSO) δ 0.80(m, 3H, J=7.7), 1.02(d, 3H, J=6.1), 1.41(m, 2H), (3.40, 4.04)(s, 1H), 6.76(s, 1H), 7.20(s, br, 1H), 7.39(d, 1H, J=7.2); 13C NMR (500 MHz, DMSO) δ: 10.00, 19.56, 28.50, 50.20, 182.00; m/z 133.23 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.32; H, 9.15; N, 21.14; S, 24.38.

Example 3Preparation of:

Figure US07491725-20090217-C00050

To a solution of 3-amino-N-methyl-4-methylbenzamide hydrochloride (1.0 g, 5 mmol) in acetone (10 mL) at 0° C. was added pyridine (1.2 mL, 15 mmol) dropwise via syringe. 3-Methoxyacryloyl chloride (0.72 mL. 6.5 mmol) was added and the reaction stirred at room temperature for 1 h. The solution was cooled again to 0° C. and 1N HCl (1.5 mL) was added dropwise via pipet. The reaction mixture was stirred for 5 min, then water (8.5 mL) was added via an addition funnel. The acetone was removed in vacuo and the resulting solution stirred for 4h. Crystallization began within 15 min. After stirring for 4 h, the vessel was cooled in an ice bath for 30 min, filtered, and rinsed with ice cold water (2×3 mL) to give compound 3A (0.99 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.12 (br s, 1H), 7.76 (s, 1H), 7.29 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 5.47 (d, J=12.3 Hz, 1H), 3.48 (s, 3H), 2.54 (d, J=4.7 Hz, 3H), 2.03 (s, 3H); HPLC rt 2.28 min (Condition A).

3B. Example 3To a 50 mL RBF containing the above compound 3A (0.5 g, 2.0 mmol) was added THF (2.5 mL) and water (2 mL), followed by NBS (0.40 g, 2.22 mmol), and the solution was stirred for 90 min. R-sec-butylthiourea (Ex. 2) (267 mg), was added, and the solution was heated to 75° C. for 8 h. Conc. NH4OH was added to adjust the pH to 10 followed by the addition of EtOH (15 mL). Water (15 mL) was added and the slurry stirred for 16 h, filtered, and washed with water to give Example 3 as a light brown solid (0.48 g, 69% yield, 98% purity). MS 347.1; HPLC 2.59.

Example 4Preparation of:

Figure US07491725-20090217-C00051

Example 4 is prepared following the methods of Example 3 but using the appropriate acryl benzamide and Example 1.

Example 5Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (The Compound of Formula (IV))

Figure US07491725-20090217-C00052

5A. 1-(6-Chloro-2-methylpyrimidin-4-yl)thiourea

Figure US07491725-20090217-C00053

To a stirring slurry of 4-amino-5-chloro-2-methylpyrimidine (6.13 g, 42.7 mmol) in THF (24 mL) was added ethyl isothiocyanatoformate (7.5 mL, 63.6 mmol), and the mixture heated to reflux. After 5h, another portion of ethyl isothiocyanato formate (1.0 mL, 8.5 mmol) was added and after 10h, a final portion (1.5 mL, 12.7 mmol) was added and the mixture stirred 6h more. The slurry was evaporated under vacuum to remove most of the solvent and heptane (6 mL) added to the residue. The solid was collected by vacuum filtration and washed with heptane (2×5 mL) giving 8.01 g (68% yield) of the intermediate ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate.A solution of ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (275 mg, 1.0 mmol) and 1N sodium hydroxide (3.5 eq) was heated and stirred at 50° C. for 2h. The resulting slurry was cooled to 20-22° C. The solid was collected by vacuum filtration, washed with water, and dried to give 185 mg of 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea (91% yield). 1H NMR (400 MHz, DMSO-d6): δ2.51 (S, 3H), 7.05 (s, 1H), 9.35 (s,1H), 10.07 (s, 1H), 10.91 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 25.25, 104.56, 159.19, 159.33, 167.36, 180.91.

5B. (E)-N-(2-Chloro-6-methylphenyl)-3-ethoxyacrylamide

Figure US07491725-20090217-C00054

To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5° C. The mixture was then warmed and stirred for 2 h. at 20° C. Hydrochloric acid (1N, 115 mL) was added at 0-10° C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22° C. then 1 h. at 0° C. The solid was collected by vacuum filtration, washed with water (2×75 mL) and dried to give 74.1 g (73.6% yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (400 Hz, DMSO-d6) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45(d, 1H, J=12.4 Hz), 9.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.57, 18.96, 67.17, 97.99, 126.80, 127.44, 129.07, 131.32, 132.89, 138.25, 161.09, 165.36.

5C. 2-Amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US07491725-20090217-C00055

To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at −10 to 0° C. The slurry was warmed and stirred at 20-22° C. for 3h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80° C. After 2h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02.

5D. 2-(6-Chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US07491725-20090217-C00056

To a stirring solution of compound 5C (5.00 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (3.65 g 22.4/mmol) in THF (65 mL) was added a 30% wt. solution of sodium t-butoxide in THF (21.1 g, 65.36 mmol) slowly with cooling to keep the temperature at 10-20° C. The mixture was stirred at room temperature for 1.5 h and cooled to 0-5° C. Hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture stirred 1.75 h at 0-5° C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4% yield) of compound 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).

5E. Example 5To a mixture of compound 5D (4.00 g, 10.14 mmol) and hydroxyethylpiperazine (6.60 g, 50.69 mmol) in n-butanol (40 mL) was added DIPEA (3.53 mL, 20.26 mmol). The slurry was heated at 118° C. for 4.5 h, then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with n-butanol (5 mL), and dried. The product (5.11 g) was dissolved in hot 80% EtOH—H2O (80 mL), and the solution was clarified by filtration. The hot solution was slowly diluted with water (15 mL) and cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with 50% ethanol-water (5 mL) and dried affording 4.27 g (83.2% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide as monohydrate. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.40 (s, 3H), 2.42 (t, 2H, J=6), 2.48 (t, 4H, J=6.3), 3.50 (m, 4H), 3.53 (q, 2H, J=6), 4.45 (t, 1H, J=5.3), 6.04 (s, 1H), 7.25 (t, 1H, J=7.6), 7.27 (dd, 1H, J=7.6, 1.7), 7.40 (dd, 1H, J=7.6, 1.7), 8.21 (s, 1H), 9.87 (s, 1H), 11.47.

Example 6Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide

Figure US07491725-20090217-C00057

To a slurry of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide 5B (120 mg, 0.50 mmol) in THF (0.75 ml) and water (0.5 mL) was added NBS (98 mg, 0.55 mmol) at 0° C. The mixture was warmed and stirred at 20-22° C. for 3h. To this was added 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea 5A (100 mg, 0.49 mmol), and the slurry heated and stirred at reflux for 2h. The slurry was cooled to 20-22° C. and the solid collected by vacuum filtration giving 140 mg (71% yield) of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).Compound 5D was elaborated to N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, following Step 5E.

Example 7Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide7A. 2-[4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanol

Figure US07491725-20090217-C00058

2-piperazin-1-yl-ethanol (8.2 g, 63.1 mmol) was added to a solution of 4,6-dichloro-2-methylpyrimidine (5.2 g, 31.9 mmol) in dichloromethane (80 ml) at rt. The mixture was stirred for two hours and triethylamine (0.9 ml) was added. The mixture was stirred at rt for 20h. The resultant solid was filtered. The cake was washed with dichloromethane (20 ml). The filtrate was concentrated to give an oil. This oil was dried under high vacuum for 20h to give a solid. This solid was stirred with heptane (50 ml) at rt for 5h. Filtration gave 7C (8.13 g) as a white solid

7B. Example 7

Figure US07491725-20090217-C00059


To a 250 ml of round bottom flask were charged compound 5C (1.9 g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2CO(16 g, 115.7 mmol), Pd (OAc)(52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and flushed with nitrogen. Toluene was added (60 ml). The suspension was heated to 100-110° C. and stirred at this temperature for 20h. After cooling to room temperature, the mixture was applied to a silica gel column. The column was first eluted with EtOAC, and then with 10% of MeOH in EtOAC. Finally, the column was washed with 10% 2M ammonia solution in MeOH/90% EtOAC. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g).

Analytical MethodsSolid State Nuclear Magnetic Resonance (SSNMR)All solid-state C-13 NMR measurements were made with a Bruker DSX-400, 400 MHz NMR spectrometer. High resolution spectra were obtained using high-power proton decoupling and the TPPM pulse sequence and ramp amplitude cross-polarization (RAMP-CP) with magic-angle spinning (MAS) at approximately 12 kHz (A. E. Bennett et al, J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and S. O. Smith, J. Magn. Reson. A., 1994, 110, 219-227). Approximately 70 mg of sample, packed into a canister-design zirconia rotor was used for each experiment. Chemical shifts (δ) were referenced to external adamantane with the high frequency resonance being set to 38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn. Reson., 1982, 48, 35-54).X-Ray Powder DiffractionOne of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X-ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.X-Ray powder diffraction data for the crystalline forms of Compound (IV) were obtained using a Bruker GADDS (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) (General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of 1 mm or less in diameter; the capillary was rotated during data collection. The sample-detector distance was 17 cm. The radiation was Cu Kα (45 kV 111 mA, λ=1.5418 Å). Data were collected for 3<2θ<35° with a sample exposure time of at least 300 seconds.Single Crystal X-RayAll single crystal data were collected on a Bruker-Nonius (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) Kappa CCD 2000 system using Cu Kα radiation (λ=1.5418 Å) and were corrected only for the Lorentz-polarization factors. Indexing and processing of the measured intensity data were carried out with the HKL2000 software package (Otwinowski, Z. & Minor, W. (1997) in Macromolecular Crystallography, eds. Carter, W. C. Jr & Sweet, R. M. (Academic, NY), Vol. 276, pp. 307-326) in the Collect program suite (Data collection and processing user interface: Collect: Data collection software, R. Hooft, Nonius B. V., 1998).The structures were solved by direct methods and refined on the basis of observed reflections using either the SDP (SDP, Structure Determination Package, Enraf-Nonius, Bohemia NY 11716 Scattering factors, including f′ and f″, in the SDP software were taken from the “International Tables for Crystallography”, Kynoch Press, Birmingham, England, 1974; Vol IV, Tables 2.2A and 2.3.1) software package with minor local modifications or the crystallographic package, MAXUS (maXus solution and refinement software suite: S. Mackay, C. J. Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland. maXus: a computer program for the solution and refinement of crystal structures from diffraction data).The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were varied.The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were variedDifferential Scanning CalorimetryThe DSC instrument used to test the crystalline forms was a TA Instruments® model Q1000. The DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about +/−1° C., and the heat of fusion can be measured within a relative error of about +/−5%. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. At least 2 mg of sample powder was placed into the bottom of the pan and lightly tapped down to ensure good contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10° C. per minute in the temperature range between 25 and 350° C.The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram (“W/g”). The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.Thermogravimetric Analysis (TGA)The TGA instrument used to test the crystalline forms was a TAInstruments® model Q500. Samples of at least 10 milligrams were analyzed at a heating rate of 10° C. per minute in the temperature range between 25° C. and about 350° C.

Example 8Preparation of:

crystalline monohydrate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)An example of the crystallization procedure to obtain the crystalline monohydrate form is shown here:

  • Charge 48 g of the compound of formula (IV).
  • Charge approximately 1056 mL (22 mL/g) of ethyl alcohol, or other suitable alcohol.
  • Charge approximately 144 mL of water.
  • Dissolve the suspension by heating to approximately 75° C.
  • Optional: Polish filter by transfer the compound of formula (IV) solution at 75° C. through the preheated filter and into the receiver.
  • Rinse the dissolution reactor and transfer lines with a mixture of 43 mL of ethanol and 5 mL of water.

Heat the contents in the receiver to 75-80° C. and maintain 75-80° C. to achieve complete dissolution.Charge approximately 384 mL of water at a rate such that the batch temperature is maintained between 75-80° C.Cool to 75° C., and, optionally, charge monohydrate seed crystals. Seed crystals are not essential to obtaining monohydrate, but provide better control of the crystallization.

  • Cool to 70° C. and maintain 70° C. for ca. 1 h.
  • Cool from 70 to 5 C over 2 h, and maintain the temperature between 0 at 5° C. for at least 2 h.
  • Filter the crystal slurry.
  • Wash the filter cake with a mixture of 96 mL of ethanol and 96 mL of water.
  • Dry the material at ≦50° C. under reduced pressure until the water content is 3.4 to 4.1% by KF to afford 41 g (85 M %).
    Alternately, the monohydrate can be obtained by:
    • 1) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate and heated at 80° C. to give bulk monohydrate.
    • 2) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate. On standing several days at room temperature, bulk monohydrate had formed.
    • 3) An aqueous suspension of compound IV was seeded with monohydrate and heated at 70° C. for 4 hours to give bulk monohydrate. In the absence of seeding, an aqueous slurry of compound IV was unchanged after 82 days at room temperature.
    • 4) A solution of compound IV in a solvent such as NMP or DMA was treated with water until the solution became cloudy and was held at 75-85° C. for several hours. Monohydrate was isolated after cooling and filtering.
    • 5) A solution of compound IV in ethanol, butanol, and water was heated. Seeds of monohydrate were added to the hot solution and then cooled. Monohydrate was isolated upon cooling and filtration.

One of ordinary skill in the art will appreciate that the monohydrate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 1 or by a representative sampling of peaks as shown in Table 1.Representative peaks taken from the XRPD of the monohydrate of the compound of formula (IV) are shown in Table 1.TABLE 1 2-Theta d(Å) Height 17.994 4.9257 915 18.440 4.8075 338 19.153 4.6301 644 19.599 4.5258 361 21.252 4.1774 148 24.462 3.6359 250 25.901 3.4371 133 28.052 3.1782 153The XRPD is also characterized by the following list comprising 2θ values selected from the group consisting of: 4.6±0.2, 11.2±0.2, 13.8±0.2, 15.2±0.2, 17.9±0.2, 19.1±0.2, 19.6±0.2, 23.2±0.2, 23.6±0.2. The XRPD is also characterized by the list of 2θ values selected from the group consisting of: 18.0±0.2, 18.4±0.2, 19.2±0.2, 19.6±0.2, 21.2±0.2, 24.5±0.2, 25.9±0.2, and 28.0±0.2.Single crystal x-ray data was obtained at room temperature (+25° C.). The molecular structure was confirmed as a monohydrate form of the compound of Formula (IV).The following unit cell parameters were obtained for the monohydrate of the compound of formula (IV) from the x-ray analysis at 25° C.:a(Å)=13.8632(7); b(Å)=9.3307(3); c(Å)=38.390(2);V(Å3) 4965.9(4); Z′=1; Vm=621Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.354Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).Single crystal x-ray data was also obtained at −50° C. The monohydrate form of the compound of Formula (IV) is characterized by unit cell parameters approximately equal to the following:Cell dimensions:

  • a(Å)=13.862(1);
  • b(Å)=9.286(1);
  • c(Å)=38.143(2);

Volume=4910(1) Å3Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.369wherein the compound is at a temperature of about −50° C.The simulated XRPD was calculated from the refined atomic parameters at room temperature.The monohydrate of the compound of formula (IV) is represented by the DSC as shown in FIG. 2. The DSC is characterized by a broad peak between approximately 95° C. and 130° C. This peak is broad and variable and corresponds to the loss of one water of hydration as seen in the TGA graph. The DSC also has a characteristic peak at approximately 287° C. which corresponds to the melt of the dehydrated form of the compound of formula (IV).The TGA for the monohydrate of the compound of Formula (IV) is shown in FIG. 2 along with the DSC. The TGA shows a 3.48% weight loss from 50° C. to 175° C. The weight loss corresponds to a loss of one water of hydration from the compound of Formula (IV).The monohydrate may also be prepared by crystallizing from alcoholic solvents, such as methanol, ethanol, propanol, i-propanol, butanol, pentanol, and water.

Example 9Preparation of:

crystalline n-butanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)The crystalline butanol solvate of the compound of formula (IV) is prepared by dissolving compound (IV) in 1-butanol at reflux (116-118° C.) at a concentration of approximately 1 g/25 mL of solvent. Upon cooling, the butanol solvate crystallizes out of solution. Filter, wash with butanol, and dry.The following unit cell parameters were obtained from the x-ray analysis for the crystalline butanol solvate, obtained at room temperature:a(Å)=22.8102(6); b(Å)=8.4691(3); c(Å)=15.1436(5); β=95.794(2);V(Å3) 2910.5(2); Z′=1; Vm=728Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.283Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the butanol solvate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 3 or by a representative sampling of peaks. Representative peaks for the crystalline butanol solvate are 2θ values of: 5.9±0.2, 12.0±0.2, 13.0±0.2, 17.7±0.2, 24.1±0.2, and 24.6±0.2.

Example 10Preparation of:

crystalline ethanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)

Figure US07491725-20090217-C00060

To a 100-mL round bottom flask was charged 4.00 g (10.1 mmol) of 5D (contained 2.3 Area % 5C) 6.60 g (50.7 mmol) of 7B, 80 mL of n-butanol and 2.61 g (20.2 mmol) of DIPEA. The resulting slurry was heated to 120° C. and maintained at 120° C. for 4.5 h whereby HPLC analysis showed 0.19 relative Area % of residual 5D to compound IV. The homogeneous mixture was cooled to 20° C. and left stirring overnight. The resulting crystals were filtered. The wet cake was washed twice with 10-mL portions of n-butanol to afford a white crystalline product. HPLC analysis showed this material to contain 99.7 Area % compound IV and 0.3 Area % 5C.The resulting wet cake was returned to the 100-mL reactor, and charged with 56 mL (12 mL/g) of 200 proof ethanol. At 80° C. an additional 25 mL of ethanol was added. To this mixture was added 10 mL of water resulting in rapid dissolution. Heat was removed and crystallization was observed at 75-77° C. The crystal slurry was further cooled to 20° C. and filtered. The wet cake was washed once with 10 mL of 1:1 ethanol: water and once with 10 mL of n-heptane. The wet cake contained 1.0% water by KF and 8.10% volatiles by LOD. The material was dried at 60° C./30 in Hg for 17 h to afford 3.55 g (70 M %) of material containing only 0.19% water by KF, 99.87 Area % by HPLC. The 1H NMR spectrum, however revealed that the ethanol solvate had been formed.The following unit cell parameters were obtained from the x-ray analysis for the crystalline ethanol solvate (di-ethanolate, E2-1), obtained at −40° C.:a(Å)=22.076(1); b(Å)=8.9612(2); c(Å)=16.8764(3); β=114.783(1);V(Å3) 3031.1(1); Z′=1; Vm=758Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.271Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 4 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 5.8±0.2, 11.3±0.2, 15.8±0.2, 17.2±0.2, 19.5±0.2, 24.1±0.2, 25.3±0.2, and 26.2±0.2.In addition, during the process to form the ethanolate (diethanolate) the formation of another ethanol solvate (½ ethanolate, T1E2-1) has been observed. To date this additional ethaonol solvate is known strictly as a partial desolvation product of the original diethanolate form E2-1, and has only been observed on occasion during crystallization of E2-1The following unit cell parameters were obtained from the x-ray analysis for the crystalline ½ ethanol solvate T1E2-1, obtained at −10° C.:a(Å)=22.03(2); b(Å)=9.20(1); c(Å)=12.31(1);β=93.49(6)V(Å3) 2491(4)); Z′=1; Vm=623;Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.363Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (T1E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 7 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 7.20±0.2, 12.01±0.2, 12.81±0.2, 18.06±0.2, 19.30±0.2, and 25.24±0.2.

Example 11Preparation of:

crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (Neat form N-6)To a mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL) was added DIPEA (155 mL, 0.89 mol). The suspension was heated at 110° C. (solution obtained) for 25 min., then cooled to about 90° C. The resulting hot solution was added dropwise into hot (80° C.) water (8010) mL, keeping the temperature at about 80° C. The resulting suspension was stirred 15 min at 80° C. then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with water (2×1600 mL) and dried in vacuo at 55-60° C. affording 192.45 g (88.7% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 2.41 (s, 3H), 2.43 (t, 2H, J=6), 2.49 (t, 4H, J=6.3), 3.51 (m, 4H), 3.54 (q, 2H, J=6), 4.46 (t, 1H, J=5.3), 6.05 (s, 1H), 7.26 (t, 1H, J=7.6), 7.28 (dd, 1H, J=7.6, 1.7), 7.41 (dd, 1H, J=7.6, 1.7), 8.23 (s, 1H), 9.89 (s, 1H), 11.48. KF0.84; DSC: 285.25° C. (onset), 286.28° C. (max).The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline compound IV, obtained at 23° C.:a(Å)=22.957(1); b(Å)=8.5830(5); c(Å)=13.803(3); β=112.039(6);V(Å3)=2521.0(5); Z′=1; Vm=630Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.286Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the crystalline form of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 5 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (N-6) are 2θ values of: 6.8±0.2, 11.1±0.2, 12.3±0.2, 13.2±0.2, 13.7±0.2, 16.7±0.2, 21.0±0.2, 24.3±0.2, and 24.8±0.2.

Example 12Preparation of:

crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (neatform T1H1-7)The title neat form may be prepared by heating the monohydrate form of the compound of formula (IV) above the dehydration temperature.The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline (T1H1-7) compound IV, obtained at 25° C.:a(Å)=13.4916; b(Å)=9.3992(2); c(Å)=38.817(1);V(Å3)=4922.4(3); Z′=1; Vm=615Space group PbcaDensity (calculated) (g/cm3) 1.317Wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the neat crystalline form (T1H1-7) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 6 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (T1H1-7)) are 2θ values of: 8.0±0.2, 9.7±0.2, 11.2±0.2, 13.3±0.2, 17.5±0.2, 18.9±0.2, 21.0±0.2, 22.0±0.2.Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.PATENThttps://patents.google.com/patent/US8680103B2/enAminothiazole-aromatic amides of formula I

Figure US08680103-20140325-C00002


wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase. They are expected to be useful in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncological disorders [see, U.S. Pat. No. 6,596,746 (the ‘746 patent), assigned to the present assignee and incorporated herein by reference], and p38 kinase-associated conditions such as inflammatory and immune conditions, as described in U.S. patent application Ser. No. 10/773,790, filed Feb. 6, 2004, claiming priority to U.S. Provisional application Ser. No. 60/445,410, filed Feb. 6, 2003 (hereinafter the ‘410 application), both of which are also assigned to the present assignee and incorporated herein by reference.The compound of formula (IV), ′N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, is an inhibitor of SRC/ABL and is useful in the treatment of oncological diseases.

Figure US08680103-20140325-C00003

Other approaches to preparing 2-aminothiazole-5-carboxamides are described in the ‘746 patent and in the ‘410 application. The ‘746 patent describes a process involving treatment of chlorothiazole with n-BuLi followed by reaction with phenyl isocyanates to give chlorothiazole-benzamides, which are further elaborated to aminothiazole-benzamide final products after protection, chloro-to-amino substitution, and deprotection, e.g.,

Figure US08680103-20140325-C00004

The ‘410 application describes a multi-step process involving first, converting N-unsubstituted aminothiazole carboxylic acid methyl or ethyl esters to bromothiazole carboxylic acid esters via diazotization with tert-butyl nitrite and subsequent CuBrtreatment, e.g.,

Figure US08680103-20140325-C00005


then, hydrolyzing the resulting bromothiazole esters to the corresponding carboxylic acids and converting the acids to the corresponding acyl chlorides, e.g.,

Figure US08680103-20140325-C00006


then finally, coupling the acyl chlorides with anilines to afford bromothiazole-benzamide intermediates which were further elaborated to aminothiazole-benzamide final products, e.g.,

Figure US08680103-20140325-C00007

Other approaches for making 2-aminothiazole-5-carboxamides include coupling of 2-aminothiazole-5-carboxylic acids with amines using various coupling conditions such as DCC [Roberts et al, J. Med. Chem. (1972), 15, at p. 1310], and DPPA [Marsham et al., J. Med. Chem. (1991), 34, at p. 1594)].The above methods present drawbacks with respect to the production of side products, the use of expensive coupling reagents, less than desirable yields, and the need for multiple reaction steps to achieve the 2-aminothiazole-5-carboxamide compounds.Reaction of N,N-dimethyl-N′-(aminothiocarbonyl)-formamidines with α-haloketones and esters to give 5-carbonyl-2-aminothiazoles has been reported. See Lin, Y. et al, J. Heterocycl. Chem. (1979), 16, at 1377; Hartmann, H. et al, J. Chem. Soc. Perkin Trans. (2000), 1, at 4316; Noack, A. et al; Tetrahedron (2002), 58, at 2137; Noack, A.; et al. Angew. Chem. (2001), 113, at 3097; and Kantlehner, W. et al., J. Prakt. Chem./Chem.-Ztg. (1996), 338, at 403. Reaction of β-ethoxy acrylates and thioureas to prepare 2-aminothiazole-5-carboxylates also has been reported. See Zhao, R., et al., Tetrahedron Lett. (2001), 42, at 2101. However, electrophilic bromination of acrylanilide and crotonanilide has been known to undergo both aromatic bromination and addition to the α,β-unsaturated carbon-carbon double bonds. See Autenrieth, Chem. Ber. (1905), 38, at 2550; Eremeev et al., Chem. Heterocycl. Compd. Engl. Transl. (1984), 20, at 1102.New and efficient processes for preparing 2-aminothiazole-5-carboxamides are desired.

SUMMARY OF THE INVENTION

This invention is related to processes for the preparation of 2-aminothiazole-5-aromatic amides having the formula (I),

Figure US08680103-20140325-C00008


wherein L, Ar, R2, R3, R4, R5, and m are as defined below, comprising reacting a compound having the formula (II),

Figure US08680103-20140325-C00009


wherein Q is the group —O—P*, wherein P* is selected so that, when considered together with the oxygen atom to which P* is attached, Q is a leaving group, and Ar, L, R2, R3, and m are as defined below,
with a halogenating reagent in the presence of water followed by a thiourea compound having the formula (III),

Figure US08680103-20140325-C00010


wherein, Rand Rare as defined below,
to provide the compound of formula (I),

Figure US08680103-20140325-C00011


wherein,Ar is the same in formulae (I) and (II) and is aryl or heteroaryl;L is the same in formulae (I) and (II) and is optionally-substituted alkylene;Ris the same in formulae (I) and (II), and is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;Ris the same in formulae (I) and (II), and is selected from hydrogen, halogen, cyano, haloalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;Ris (i) the same in each of formulae (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclo, or alternatively, Ris taken together with R5, to form heteroaryl or heterocyclo;Ris (i) the same in each of formulae (I) and (III), and (ii) is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclo, or alternatively, Ris taken together with R4, to form heteroaryl or heterocyclo; andm is 0 or 1.Applicants have surprisingly discovered said process for converting β-(P*)oxy acryl aromatic amides and thioureas to 2-aminothiazole derivatives, wherein the aromatic amides are not subject to further halogenation producing other side products. Aminothiazole-aromatic amides, particularly, 2-aminothiazole-5-benzamides, can thus be efficiently prepared with this process in high yield.In another aspect, the present invention is directed to crystalline forms of the compound of formula (IV).

EXAMPLESExample 1Preparation of Intermediate:

(S)-1-sec-Butylthiourea

Figure US08680103-20140325-C00049

To a solution of S-sec-butyl-amine (7.31 g, 0.1 mol) in chloroform (80 mL) at 0° C. was slowly added benzoyl isothiocyanate (13.44 mL, 0.1 mol). The mixture was allowed to warm to 10° C. and stirred for 10 min. The solvent was then removed under reduced pressure, and the residue was dissolved in MeOH (80 mL). An aqueous solution (10 mL) of NaOH (4 g, 0.1 mol) was added to this solution, and the mixture was stirred at 60° C. for another 2 h. The MeOH was then removed under reduced pressure, and the residue was stirred in water (50 mL). The precipitate was collected by vacuum filtration and dried to provide S-1-sec-butyl-thiourea (12.2 g, 92% yield). mp 133-134° C.; 1H NMR (500 MHz, DMSO-D6) δ 7.40 (s, 1H), 7.20 (br s, 1H), 6.76 (s, 1H), 4.04 (s, 1H), 1.41 (m, 2H), 1.03 (d, J=6.1 Hz, 3H), 0.81 (d, J=7.7 Hz, 3H); 13C NMR (125 MHz, DMSO-D6) δ 182.5, 50.8, 28.8, 19.9, 10.3; LRMS m/z 133.2 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.49; H, 8.88; N, 21.32; S, 24.27.

Example 2Preparation of Intermediate:

(R)-1-sec-Butylthiourea

Figure US08680103-20140325-C00050

(R)-1-sec-Butylthiourea was prepared in 92% yield according to the general method outlined for Example 1. mp 133-134° C.; 1H NMR (500 MHz, DMSO) δ 0.80 (m, 3H, J=7.7), 1.02 (d, 3H, J=6.1), 1.41 (m, 2H), (3.40, 4.04) (s, 1H), 6.76 (s, 1H), 7.20 (s, br, 1H), 7.39 (d, 1H, J=7.2); 13C NMR (500 MHz, DMSO) δ: 10.00, 19.56, 28.50, 50.20, 182.00; m/z 133.23 (M+H); Anal. Calcd for C5H12N2S: C, 45.41; H, 9.14; N, 21.18; S, 24.25. Found: C, 45.32; H, 9.15; N, 21.14; S, 24.38.

Example 3Preparation of:

Figure US08680103-20140325-C00051

To a solution of 3-amino-N-methyl-4-methylbenzamide hydrochloride (1.0 g, 5 mmol) in acetone (10 mL) at 0° C. was added pyridine (1.2 mL, 15 mmol) dropwise via syringe. 3-Methoxyacryloyl chloride (0.72 mL 6.5 mmol) was added and the reaction stirred at room temperature for 1 h. The solution was cooled again to 0° C. and 1N HCl (1.5 mL) was added dropwise via pipette. The reaction mixture was stirred for 5 min, then water (8.5 mL) was added via an addition funnel. The acetone was removed in vacuo and the resulting solution stirred for 4 h. Crystallization began within 15 min. After stirring for 4 h, the vessel was cooled in an ice bath for 30 min, filtered, and rinsed with ice cold water (2×3 mL) to give compound 3A (0.99 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.12 (br s, 1H), 7.76 (s, 1H), 7.29 (m, 2H), 7.05 (d, J=7.9 Hz, 1H), 5.47 (d, J=12.3 Hz, 1H), 3.48 (s, 3H), 2.54 (d, J=4.7 Hz, 3H), 2.03 (s, 3H); HPLC rt 2.28 min (Condition A).

3B. Example 3To a 50 mL RBF containing the above compound 3A (0.5 g, 2.0 mmol) was added THF (2.5 mL) and water (2 mL), followed by NBS (0.40 g, 2.22 mmol), and the solution was stirred for 90 min. R-sec-butylthiourea (Ex. 2) (267 mg), was added, and the solution was heated to 75° C. for 8 h. Conc. NH4OH was added to adjust the pH to 10 followed by the addition of EtOH (15 mL). Water (15 mL) was added and the slurry stirred for 16 h, filtered, and washed with water to give Example 3 as a light brown solid (0.48 g, 69% yield, 98% purity). MS 347.1; HPLC 2.59.

Example 4Preparation of:

Figure US08680103-20140325-C00052

Example 4 is prepared following the methods of Example 3 but using the appropriate acryl benzamide and Example 1.

Example 5Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (The compound of Formula (IV))

Figure US08680103-20140325-C00053

5A. 1-(6-Chloro-2-methylpyrimidin-4-yl)thiourea

Figure US08680103-20140325-C00054

To a stirring slurry of 4-amino-5-chloro-2-methylpyrimidine (6.13 g, 42.7 mmol) in THF (24 mL) was added ethyl isothiocyanatoformate (7.5 mL, 63.6 mmol), and the mixture heated to reflux. After 5 h, another portion of ethyl isothiocyanato formate (1.0 mL, 8.5 mmol) was added and after 10 h, a final portion (1.5 mL, 12.7 mmol) was added and the mixture stirred 6 h more. The slurry was evaporated under vacuum to remove most of the solvent and heptane (6 mL) added to the residue. The solid was collected by vacuum filtration and washed with heptane (2×5 mL) giving 8.01 g (68% yield) of the intermediate ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate.A solution of ethyl 6-chloro-2-methylpyrimidin-4-ylcarbamothioylcarbamate (275 mg, 1.0 mmol) and 1N sodium hydroxide (3.5 eq) was heated and stirred at 50° C. for 2 h. The resulting slurry was cooled to 20-22° C. The solid was collected by vacuum filtration, washed with water, and dried to give 185 mg of 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea (91% yield). 1H NMR (400 MHz, DMSO-d6): δ2.51 (S, 3H), 7.05 (s, 1H), 9.35 (s, 1H), 10.07 (s, 1H), 10.91 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 25.25, 104.56, 159.19, 159.33, 167.36, 180.91.

5B. (E)-N-(2-Chloro-6-methylphenyl)-3-ethoxyacrylamide

Figure US08680103-20140325-C00055

To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5° C. The mixture was then warmed and stirred for 2 h. at 20° C. Hydrochloric acid (1N, 115 mL) was added at 0-10° C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22° C. then 1 h. at 0° C. The solid was collected by vacuum filtration, washed with water (2×75 mL) and dried to give 74.1 g (73.6% yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (400 Hz, DMSO-d6) δ 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27-7.37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz), 9.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.57, 18.96, 67.17, 97.99, 126.80, 127.44, 129.07, 131.32, 132.89, 138.25, 161.09, 165.36.

5C. 2-Amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US08680103-20140325-C00056

To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at −10 to 0° C. The slurry was warmed and stirred at 20-22° C. for 3 h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80° C. After 2 h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02.

5D. 2-(6-Chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

Figure US08680103-20140325-C00057

To a stirring solution of compound 5C (5.00 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (3.65 g 22.4/mmol) in THF (65 mL) was added a 30% wt. solution of sodium t-butoxide in THF (21.1 g, 65.36 mmol) slowly with cooling to keep the temperature at 10-20° C. The mixture was stirred at room temperature for 1.5 h and cooled to 0-5° C. Hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture stirred 1.75 h at 0-5° C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4% yield) of compound 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).

5E. Example 5To a mixture of compound 5D (4.00 g, 10.14 mmol) and hydroxyethylpiperazine (6.60 g, 50.69 mmol) in n-butanol (40 mL) was added DIPEA (3.53 mL, 20.26 mmol). The slurry was heated at 118° C. for 4.5 h, then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with n-butanol (5 mL), and dried. The product (5.11 g) was dissolved in hot 80% EtOH—H2O (80 mL), and the solution was clarified by filtration. The hot solution was slowly diluted with water (15 mL) and cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with 50% ethanol-water (5 mL) and dried affording 4.27 g (83.2% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide as monohydrate. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.40 (s, 3H), 2.42 (t, 2H, J=6), 2.48 (t, 4H, J=6.3), 3.50 (m, 4H), 3.53 (q, 2H, J=6), 4.45 (t, 1H, J=5.3), 6.04 (s, 1H), 7.25 (t, 1H, J=7.6), 7.27 (dd, 1H, J=7.6, 1.7), 7.40 (dd, 1H, J=7.6, 1.7), 8.21 (s, 1H), 9.87 (s, 1H), 11.47.

Example 6Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide

Figure US08680103-20140325-C00058

To a slurry of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide 5B (120 mg, 0.50 mmol) in THF (0.75 ml) and water (0.5 mL) was added NBS (98 mg, 0.55 mmol) at 0° C. The mixture was warmed and stirred at 20-22° C. for 3 h. To this was added 1-(6-chloro-2-methylpyrimidin-4-yl)thiourea 5A (100 mg, 0.49 mmol), and the slurry heated and stirred at reflux for 2 h. The slurry was cooled to 20-22° C. and the solid collected by vacuum filtration giving 140 mg (71% yield) of 2-(6-chloro-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).Compound 5D was elaborated to N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide, following Step 5E.

Example 7Preparation of:

N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide7A. 2-[4-(6-Chloro-2-methyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanol

Figure US08680103-20140325-C00059

2-Piperazin-1-yl-ethanol (8.2 g, 63.1 mmol) was added to a solution of 4,6-dichloro-2-methylpyrimidine (5.2 g, 31.9 mmol) in dichloromethane (80 ml) at rt. The mixture was stirred for two hours and triethylamine (0.9 ml) was added. The mixture was stirred at rt for 20 h. The resultant solid was filtered. The cake was washed with dichloromethane (20 ml). The filtrate was concentrated to give an oil. This oil was dried under high vacuum for 20 h to give a solid. This solid was stirred with heptane (50 ml) at rt for 5 h. Filtration gave 7C (8.13 g) as a white solid

7B. Example 7

Figure US08680103-20140325-C00060

To a 250 ml of round bottom flask were charged compound 5C (1.9 g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2CO(16 g, 115.7 mmol), Pd (OAc)(52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and flushed with nitrogen. Toluene was added (60 ml). The suspension was heated to 100-110° C. and stirred at this temperature for 20 h. After cooling to room temperature, the mixture was applied to a silica gel column. The column was first eluted with EtOAC, and then with 10% of MeOH in EtOAC. Finally, the column was washed with 10% 2M ammonia solution in MeOH/90% EtOAC. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g).

Analytical MethodsSolid State Nuclear Magnetic Resonance (SSNMR)All solid-state C-13 NMR measurements were made with a Bruker DSX-400, 400 MHz NMR spectrometer. High resolution spectra were obtained using high-power proton decoupling and the TPPM pulse sequence and ramp amplitude cross-polarization (RAMP-CP) with magic-angle spinning (MAS) at approximately 12 kHz (A. E. Bennett et al, J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and S. O, Smith, J. Magn. Reson. A, 1994, 110, 219-227). Approximately 70 mg of sample, packed into a canister-design zirconia rotor was used for each experiment. Chemical shifts (6) were referenced to external adamantane with the high frequency resonance being set to 38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn. Reson., 1982, 48, 35-54).X-Ray Powder DiffractionOne of ordinary skill in the art will appreciate that an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed. In particular, it is generally known that intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed. It should be further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account. Additionally, a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles. Consequently, it is to be understood that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X-ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention. The ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art.X-Ray powder diffraction data for the crystalline forms of Compound (IV) were obtained using a Bruker GADDS (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) (General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of 1 mm or less in diameter; the capillary was rotated during data collection. The sample-detector distance was 17 cm. The radiation was Cu Kα (45 kV 111 mA, λ=1.5418 Å). Data were collected for 3<2θ<35° with a sample exposure time of at least 300 seconds.Single Crystal X-RayAll single crystal data were collected on a Bruker-Nonius (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wis. 53711 USA) Kappa CCD 2000 system using Cu Kα radiation (λ=1.5418 Å) and were corrected only for the Lorentz-polarization factors. Indexing and processing of the measured intensity data were carried out with the HKL2000 software package (Otwinowski, Z. & Minor, W. (1997) in Macromolecular Crystallography, eds. Carter, W. C. Jr. & Sweet, R. M. (Academic, NY), Vol. 276, pp. 307-326) in the Collect program suite (Data collection and processing user interface: Collect: Data collection software, R. Hooft, Nonius B. V., 1998).The structures were solved by direct methods and refined on the basis of observed reflections using either the SDP (SDP, Structure Determination Package, Enraf-Nonius, Bohemia N.Y. 11716 Scattering factors, including f′ and f″, in the SDP software were taken from the “International Tables for Crystallography”, Kynoch Press, Birmingham, England, 1974; Vol IV, Tables 2.2A and 2.3.1) software package with minor local modifications or the crystallographic package, MAXUS (maXus solution and refinement software suite: S. Mackay, C. J. Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland. maXus: a computer program for the solution and refinement of crystal structures from diffraction data).The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were varied.The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Σw(|Fo|−|Fc|)2. R is defined as Σ∥Fo|−|Fc∥/Σ|Fo| while Rw=[Σw(|Fo|−|Fc|)2w|Fo|2]1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were variedDifferential Scanning CalorimetryThe DSC instrument used to test the crystalline forms was a TA INSTRUMENTS° model Q1000. The DSC cell/sample chamber was purged with 100 ml/min of ultra-high purity nitrogen gas. The instrument was calibrated with high purity indium. The accuracy of the measured sample temperature with this method is within about +/−1° C., and the heat of fusion can be measured within a relative error of about +/−5%. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. At least 2 mg of sample powder was placed into the bottom of the pan and lightly tapped down to ensure good contact with the pan. The weight of the sample was measured accurately and recorded to a hundredth of a milligram. The instrument was programmed to heat at 10° C. per minute in the temperature range between 25 and 350° C.The heat flow, which was normalized by a sample weight, was plotted versus the measured sample temperature. The data were reported in units of watts/gram (“W/g”). The plot was made with the endothermic peaks pointing down. The endothermic melt peak was evaluated for extrapolated onset temperature, peak temperature, and heat of fusion in this analysis.Thermogravimetric Analysis (TGA)The TGA instrument used to test the crystalline forms was a TA INSTRUMENTS® model Q500. Samples of at least 10 milligrams were analyzed at a heating rate of 10° C. per minute in the temperature range between 25° C. and about 350° C.

Example 8Preparation of:

Crystalline monohydrate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)An example of the crystallization procedure to obtain the crystalline monohydrate form is shown here:Charge 48 g of the compound of formula (IV).Charge approximately 1056 mL (22 mL/g) of ethyl alcohol, or other suitable alcohol.Charge approximately 144 mL of water.Dissolve the suspension by heating to approximately 75° C.Optional: Polish filter by transfer the compound of formula (IV) solution at 75° C. through the preheated filter and into the receiver.Rinse the dissolution reactor and transfer lines with a mixture of 43 mL of ethanol and 5 mL of water.Heat the contents in the receiver to 75-80° C. and maintain 75-80° C. to achieve complete dissolution.Charge approximately 384 mL of water at a rate such that the batch temperature is maintained between 75-80° C.Cool to 75° C., and, optionally, charge monohydrate seed crystals. Seed crystals are not essential to obtaining monohydrate, but provide better control of the crystallization.Cool to 70° C. and maintain 70° C. for ca. 1 h.Cool from 70 to 5 C over 2 h, and maintain the temperature between 0 at 5° C. for at least 2 h.Filter the crystal slurry.Wash the filter cake with a mixture of 96 mL of ethanol and 96 mL of water.Dry the material at ≦50° C. under reduced pressure until the water content is 3.4 to 4.1% by KF to afford 41 g (85 M %).Alternately, the monohydrate can be obtained by:1) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate and heated at 80° C. to give bulk monohydrate.2) An aqueous solution of the acetate salt of compound IV was seeded with monohydrate. On standing several days at room temperature, bulk monohydrate had formed.3) An aqueous suspension of compound IV was seeded with monohydrate and heated at 70° C. for 4 hours to give bulk monohydrate. In the absence of seeding, an aqueous slurry of compound IV was unchanged after 82 days at room temperature.4) A solution of compound IV in a solvent such as NMP or DMA was treated with water until the solution became cloudy and was held at 75-85° C. for several hours. Monohydrate was isolated after cooling and filtering.5) A solution of compound IV in ethanol, butanol, and water was heated. Seeds of monohydrate were added to the hot solution and then cooled. Monohydrate was isolated upon cooling and filtration.One of ordinary skill in the art will appreciate that the monohydrate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 1 or by a representative sampling of peaks as shown in Table 1.Representative peaks taken from the XRPD of the monohydrate of the compound of formula (IV) are shown in Table 1.TABLE 1 2-Theta d(Å) Height 17.994 4.9257 915 18.440 4.8075 338 19.153 4.6301 644 19.599 4.5258 361 21.252 4.1774 148 24.462 3.6359 250 25.901 3.4371 133 28.052 3.1782 153The XRPD is also characterized by the following list comprising 2θ values selected from the group consisting of: 4.6±0.2, 11.2±0.2, 13.8±0.2, 15.2±0.2, 17.9±0.2, 19.1±0.2, 19.6±0.2, 23.2±0.2, 23.6±0.2. The XRPD is also characterized by the list of 2θ values selected from the group consisting of: 18.0±0.2, 18.4±0.2, 19.2±0.2, 19.6±0.2, 21.2±0.2, 24.5±0.2, 25.9±0.2, and 28.0±0.2.Single crystal x-ray data was obtained at room temperature (+25° C.). The molecular structure was confirmed as a monohydrate form of the compound of Formula (IV).The following unit cell parameters were obtained for the monohydrate of the compound of formula (IV) from the x-ray analysis at 25° C.:a(Å)=13.8632(7); b(Å)=9.3307(3); c(Å)=38.390(2);V(Å3) 4965.9(4); Z′=1; Vm=621Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.354wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).Single crystal x-ray data was also obtained at −50° C. The monohydrate form of the compound of Formula (IV) is characterized by unit cell parameters approximately equal to the following:Cell dimensions: a(Å)=13.862(1);

  • b(Å)=9.286(1);
  • c(Å)=38.143(2);

Volume=4910(1) Å3Space group PbcaMolecules/unit cell 8Density (calculated) (g/cm3) 1.369wherein the compound is at a temperature of about −50° C.The simulated XRPD was calculated from the refined atomic parameters at room temperature.The monohydrate of the compound of formula (IV) is represented by the DSC as shown in FIG. 2. The DSC is characterized by a broad peak between approximately 95° C. and 130° C. This peak is broad and variable and corresponds to the loss of one water of hydration as seen in the TGA graph. The DSC also has a characteristic peak at approximately 287° C. which corresponds to the melt of the dehydrated form of the compound of formula (IV).The TGA for the monohydrate of the compound of Formula (IV) is shown in FIG. 2 along with the DSC. The TGA shows a 3.48% weight loss from 50° C. to 175° C. The weight loss corresponds to a loss of one water of hydration from the compound of Formula (IV).The monohydrate may also be prepared by crystallizing from alcoholic solvents, such as methanol, ethanol, propanol, i-propanol, butanol, pentanol, and water.

Example 9Preparation of:

Crystalline n-butanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)The crystalline butanol solvate of the compound of formula (IV) is prepared by dissolving compound (IV) in 1-butanol at reflux (116-118° C.) at a concentration of approximately 1 g/25 mL of solvent. Upon cooling, the butanol solvate crystallizes out of solution. Filter, wash with butanol, and dry.The following unit cell parameters were obtained from the x-ray analysis for the crystalline butanol solvate, obtained at room temperature:a(Å)=22.8102(6); b(Å)=8.4691(3); c(Å)=15.1436(5); β=95.794(2);V(Å3) 2910.5(2); Z′=1; Vm=728Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.283wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the butanol solvate of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 3 or by a representative sampling of peaks. Representative peaks for the crystalline butanol solvate are 2θ values of: 5.9±0.2, 12.0±0.2, 13.0±0.2, 17.7±0.2, 24.1±0.2, and 24.6±0.2.

Example 10Preparation of:

Crystalline ethanol solvate of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV)

Figure US08680103-20140325-C00061

To a 100-mL round bottom flask was charged 4.00 g (10.1 mmol) of 5D (contained 2.3 Area % 5C) 6.60 g (50.7 mmol) of 7B, 80 mL of n-butanol and 2.61 g (20.2 mmol) of DIPEA. The resulting slurry was heated to 120° C. and maintained at 120° C. for 4.5 h whereby HPLC analysis showed 0.19 relative Area % of residual 5D to compound IV. The homogeneous mixture was cooled to 20° C. and left stirring overnight. The resulting crystals were filtered. The wet cake was washed twice with 10-mL portions of n-butanol to afford a white crystalline product. HPLC analysis showed this material to contain 99.7 Area % compound IV and 0.3 Area % 5C.The resulting wet cake was returned to the 100-mL reactor, and charged with 56 mL (12 mL/g) of 200 proof ethanol. At 80° C. an additional 25 mL of ethanol was added. To this mixture was added 10 mL of water resulting in rapid dissolution. Heat was removed and crystallization was observed at 75-77° C. The crystal slurry was further cooled to 20° C. and filtered. The wet cake was washed once with 10 mL of 1:1 ethanol:water and once with 10 mL of n-heptane. The wet cake contained 1.0% water by KF and 8.10% volatiles by LOD. The material was dried at 60° C./30 in Hg for 17 h to afford 3.55 g (70 M %) of material containing only 0.19% water by KF, 99.87 Area % by HPLC. The 1H NMR spectrum, however revealed that the ethanol solvate had been formed.The following unit cell parameters were obtained from the x-ray analysis for the crystalline ethanol solvate (di-ethanolate, E2-1), obtained at −40° C.:a(Å)=22.076(1); b(Å)=8.9612(2); c(Å)=16.8764(3); β=114.783(1);V(Å3) 3031.1(1); Z′=1; Vm=758Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.271wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 4 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 5.8±0.2, 11.3±0.2, 15.8±0.2, 17.2±0.2, 19.5±0.2, 24.1±0.2, 25.3±0.2, and 26.2±0.2.In addition, during the process to form the ethanolate (diethanolate) the formation of another ethanol solvate (½ ethanolate, T1E2-1) has been observed. To date this additional ethanol solvate is known strictly as a partial desolvation product of the original diethanolate form E2-1, and has only been observed on occasion during crystallization of E2-1The following unit cell parameters were obtained from the x-ray analysis for the crystalline ½ ethanol solvate T1E2-1, obtained at −10° C.:a(Å)=22.03(2); b(Å)=9.20(1); c(Å)=12.31(1);β=93.49(6)V(Å3) 2491(4)); Z′=1; Vm=623;Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.363wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the ethanol solvate (T1E2-1) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 7 or by a representative sampling of peaks. Representative peaks for the crystalline ethanol solvate are 2θ values of: 7.20±0.2, 12.01±0.2, 12.81±0.2, 18.06±0.2, 19.30±0.2, and 25.24±0.2.

Example 11Preparation of:

Crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (Neat form N-6)To a mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL) was added DIPEA (155 mL, 0.89 mol). The suspension was heated at 110° C. (solution obtained) for 25 min., then cooled to about 90° C. The resulting hot solution was added dropwise into hot (80° C.) water (8010) mL, keeping the temperature at about 80° C. The resulting suspension was stirred 15 min at 80° C. then cooled slowly to room temperature. The solid was collected by vacuum filtration, washed with water (2×1600 mL) and dried in vacuo at 55-60° C. affording 192.45 g (88.7% yield) of N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 2.41 (s, 3H), 2.43 (t, 2H, J=6), 2.49 (t, 4H, J=6.3), 3.51 (m, 4H), 3.54 (q, 2H, J=6), 4.46 (t, 1H, J=5.3), 6.05 (s, 1H), 7.26 (t, 1H, J=7.6), 7.28 (dd, 1H, J=7.6, 1.7), 7.41 (dd, 1H, J=7.6, 1.7), 8.23 (s, 1H), 9.89 (s, 1H), 11.48. KF0.84; DSC: 285.25° C. (onset), 286.28° C. (max).The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline compound IV, obtained at 23° C.:a(Å)=22.957(1); b(Å)=8.5830(5); c(Å)=13.803(3); β=112.039(6);V(Å3)=2521.0(5); Z′=1; Vm=630Space group P21/aMolecules/unit cell 4Density (calculated) (g/cm3) 1.286wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the crystalline form of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 5 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (N-6) are 2θ values of: 6.8±0.2, 11.1±0.2, 12.3±0.2, 13.2±0.2, 13.7±0.2, 16.7±0.2, 21.0±0.2, 24.3±0.2, and 24.8±0.2.

Example 12Preparation of:

Crystalline N-(2-chloro-6-methylphenyl)-2-(6-(4-(3-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (IV) (neat form T1H1-7)The title neat form may be prepared by heating the monohydrate form of the compound of formula (IV) above the dehydration temperature.The following unit cell parameters were obtained from the x-ray analysis for the neat crystalline (T1H1-7) compound IV, obtained at 25° C.:a(Å)=13.4916; b(Å)=9.3992(2); c(Å)=38.817(1);V(Å3)=4922.4(3); Z′=1; Vm=615Space group PbcaDensity (calculated) (g/cm3) 1.317wherein Z′=number of drug molecules per asymmetric unit. Vm=V(unit cell)/(Z drug molecules per cell).One of ordinary skill in the art will appreciate that the neat crystalline form (T1H1-7) of the compound of formula (IV) may be represented by the XRPD as shown in FIG. 6 or by a representative sampling of peaks. Representative peaks for the crystalline neat form (T1H1-7)) are 2θ values of: 8.0±0.2, 9.7±0.2, 11.2±0.2, 13.3±0.2, 17.5±0.2, 18.9±0.2, 21.0±0.2, 22.0±0.2.Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 
 PAPERhttps://pubs.acs.org/doi/abs/10.1021/jm060727j

2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure−activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ∼ 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFα production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.

Abstract Image

PATENT

https://patents.google.com/patent/WO2019209908A1/enDasatinib (DAS), having the chemical designation N-(2-chloro-6-methylphenyl)-2- [[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide, monohydrate, is an orally bioavailable inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity. Dasatinib has the following structure:

Figure imgf000002_0001

Dasatinib is commercially marketed under the name SPRY CEL® and is indicated for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, for the treatment of patients chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome-positive chronic myeloid leukemia with resistance or intolerance to prior therapy and for the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.Solid forms of dasatinib are described in U.S. Patent Nos. 7491725 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 8680103 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 7973045 (anhydrous), 8067423 (isopropyl alcohol solvate), 8242270 (butanol solvate, monohydrate, diethanolate, hemi- ethanolate, anhydrous), 8884013 (monohydrates), 9249134 (amorphous), 9456992 (solid dispersion nanoparticles), 9556164 (saccharin salt crystal) and 9884857 (saccharinate, glutarate, nicotinate); in U.S. Publication Nos. 20160250153 (solid dispersion nanoparticles), 20160264565 (Form-SDI), 20160361313 (solid dispersion nanoparticles), 20170183334 (salts) and 20140031352 (anti-oxidative acid); in International Publication Nos.W02010067374 (solvated forms and Form I), W02010139980, W02010139981,W02013065063 (anhydrous), W02017103057, W02017108605 (solid dispersion),WO2017134617 (amorphous), WO2014086326 (NMP, isoamyl-OH, 1, 3-propanediol process), WO2015107545, WO2015181573, WO2017134615 (PG solvate), W02010062715 (isosorbide dimethyl ether, N,N’-dimethylethylene urea, N,N’-dimethyl-N,N’-propylene urea), WO2010139979 (DCM, DMSP, monohydrate), WO2011095588 (anhydrate, hydrochloride, hemi-ethanol), W02012014149 (N-methylformamide) and W02017002131 (propandiol, monohydrate); and in Chinese Patent Nos. CN102643275, CN103059013, CN103819469, CN104341410. None of the references describe an ethyl formate solvate of dasatinib.Dasatinib co-crystals are described in U.S. Patent No. 9,340,536 (co-crystals selected from methyl-4-hydroxybenzoate, nicotinamide, ethyl gallate, methyl gallate, propyl gallate, ethyl maltol, vanillin, menthol, and (lR,2S,5R)-(-)-menthol) and International Publication No. W02016001025 (co-crystal selected from menthol or vanillin). None of the references describe dasatinib co-crystal comprising dasatinib and a second compound, as a co-crystal former, wherein the second compound is selected from butyl paraben, propyl paraben and ethyl vanillin.Dasatinib (DAS), having the chemical designation N-(2-chloro-6-methylphenyl)-2- [[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide, monohydrate, is an orally bioavailable inhibitor of the receptor tyrosine kinase (RTK) epidermal growth factor receptor (ErbB; EGFR) family, with antineoplastic activity. Dasatinib has the following structure:

Figure imgf000002_0001

Dasatinib is commercially marketed under the name SPRY CEL® and is indicated for the treatment of patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, for the treatment of patients chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome-positive chronic myeloid leukemia with resistance or intolerance to prior therapy and for the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.Solid forms of dasatinib are described in U.S. Patent Nos. 7491725 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 8680103 (butanol solvate, monohydrate, diethanolate, hemi-ethanolate, anhydrous), 7973045 (anhydrous), 8067423 (isopropyl alcohol solvate), 8242270 (butanol solvate, monohydrate, diethanolate, hemi- ethanolate, anhydrous), 8884013 (monohydrates), 9249134 (amorphous), 9456992 (solid dispersion nanoparticles), 9556164 (saccharin salt crystal) and 9884857 (saccharinate, glutarate, nicotinate); in U.S. Publication Nos. 20160250153 (solid dispersion nanoparticles), 20160264565 (Form-SDI), 20160361313 (solid dispersion nanoparticles), 20170183334 (salts) and 20140031352 (anti-oxidative acid); in International Publication Nos.W02010067374 (solvated forms and Form I), W02010139980, W02010139981,W02013065063 (anhydrous), W02017103057, W02017108605 (solid dispersion),WO2017134617 (amorphous), WO2014086326 (NMP, isoamyl-OH, 1, 3-propanediol process), WO2015107545, WO2015181573, WO2017134615 (PG solvate), W02010062715 (isosorbide dimethyl ether, N,N’-dimethylethylene urea, N,N’-dimethyl-N,N’-propylene urea), WO2010139979 (DCM, DMSP, monohydrate), WO2011095588 (anhydrate, hydrochloride, hemi-ethanol), W02012014149 (N-methylformamide) and W02017002131 (propandiol, monohydrate); and in Chinese Patent Nos. CN102643275, CN103059013, CN103819469, CN104341410. None of the references describe an ethyl formate solvate of dasatinib.Dasatinib co-crystals are described in U.S. Patent No. 9,340,536 (co-crystals selected from methyl-4-hydroxybenzoate, nicotinamide, ethyl gallate, methyl gallate, propyl gallate, ethyl maltol, vanillin, menthol, and (lR,2S,5R)-(-)-menthol) and International Publication No. W02016001025 (co-crystal selected from menthol or vanillin). None of the references describe dasatinib co-crystal comprising dasatinib and a second compound, as a co-crystal former, wherein the second compound is selected from butyl paraben, propyl paraben and ethyl vanillin. hereafter. ClaimsHide Dependent  What is claimed is:1. A dasatinib co-crystal comprising dasatinib and a second compound, wherein the second compound is selected from butyl paraben, propyl paraben and ethyl vanillin.2. The dasatinib co-crystal according to claim 1, wherein a molar ratio of the dasatinib to the second compound is about 1: 1.3. The dasatinib co-crystal according to claim 1, wherein the second compound is butyl paraben.4. The dasatinib co-crystal according to claim 3, wherein a molar ratio of the dasatinib to the butyl paraben is about 1 : 1.5. The dasatinib co-crystal according to claim 1, which is Form I co-crystal of dasatinib and butyl paraben.6. The dasatinib co-crystal according to claim 5, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 4.9, 9.8, 11.3, 14.9, 17.5, 20.8, 21.6, 22.6 and 25.4° 2Q degrees.7. The dasatinib co-crystal according to claim 5, characterized by a thermal event at about 287.3 °C, as measured by differential scanning calorimetry.8. The dasatinib co-crystal according to claim 5, characterized by a weight loss of 8.1% from about 70 °C through about 165 °C, as measured by thermal gravimetric analysis.9. The dasatinib co-crystal of claim 5 monoclinic, P2i/C.10. The dasatinib co-crystal d of claim 5 which has single crystal parametersa = 18.630 (2) Ab = 8.725 (1) Ac = 22.331 (2) Aa = g = 90°, b = 104.575 (8)°.11. The dasatinib co-crystal of claim 5 which has a cell volume is about 3512.9 A3.12. The dasatinib co-crystal according to claim 1, wherein the second compound is ethyl vanillin.13. The dasatinib co-crystal according to claim 9, wherein a molar ratio of the dasatinib to the ethyl vanillin is about 1 : 1.14. The dasatinib co-crystal according to claim 1, which is Form II co-crystal of dasatinib and ethyl vanillin.15. The dasatinib co-crystal according to claim 14, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 5.7, 10.9, 13.5, 17.1, 18.4, 19.4, 23.7 and 26.3° 2Q degrees.16. The dasatinib co-crystal according to claim 14, characterized by one or more thermal events selected from about 140 °C, about 181 °C, and about 293 °C, as measured by differential scanning calorimetry.17. The dasatinib co-crystal according to claim 14, characterized by a weight loss of 24.3% from about 120 through 250 °C, as measured by thermal gravimetric analysis.18. The dasatinib co-crystal of claim 14 monoclinic, P2i/n.19. The dasatinib co-crystal d of claim 14 which has single crystal parametersa = 18.452 (1) Ab = 9.441 (6) Ac = 19.377 (1) Aa = g = 90°, b = 108.78 (1)°.20. The dasatinib co-crystal of claim 5 which has a cell volume is about 3195.71 A3.21. The dasatinib co-crystal according to claim 1, wherein the second compound is propyl paraben.22. The dasatinib co-crystal according to claim 21, wherein a molar ratio of the dasatinib to the propyl paraben is about 1 : 1.23. The dasatinib co-crystal according to claim 1, which is Form III co-crystal ofdasatinib and propyl paraben.24. The dasatinib co-crystal according to claim 23, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 4.8, 9.6, 11.9, 14.8, 18.4, 22.2, 23.9 and 26.1° 2Q degrees.25. The dasatinib co-crystal of claim 23 monoclinic, P2i/n.26. The dasatinib co-crystal of claim 23 which has single crystal parametersa = 18.859 (9) Ab = 8.131 (6) Ac = 22.473 (1) Aa = g = 90°, b = 103.87(1)°.27. The dasatinib co-crystal of claim 23 which has a cell volume is about 3345.51 A3.28. An ethyl formate solvate of dasatinib.29. The ethyl formate solvate of dasatinib according to claim 28, wherein a molar ratio of the dasatinib to the ethyl formate is about 1 : 1.30. The ethyl formate solvate of dasatinib according to claim 1, which is Form I of ethyl formate solvate of dasatinib.31. The ethyl formate solvate of dasatinib according to claim 30, characterized by having at least 2 or more X-ray powder diffraction peaks selected from about 6.0, 12.1, 15.1, 18.0, 23.8 and 24.8° 2Q degrees.32. The ethyl formate solvate of dasatinib according to claim 30, characterized by athermal event at about 287.3 °C, as measured by differential scanning calorimetry.33. The ethyl formate solvate of dasatinib according to claim 30, characterized by aweight loss of 8.1% from about 70 °C through about 165 °C, as measured by thermal gravimetric analysis.34. The ethyl formate solvate of dasatinib of claim 23 orthorhombic, P2i/c.35. The ethyl formate solvate of dasatinib of claim 23 which has single crystal parameters a = 14.8928 (5) Ab = 8.3299 (3) Ac = 22.18990 (6) Aa = g =b = 90°.36. The ethyl formate solvate of dasatinib of claim 23 which has a cell volume is about 2731.9 A3.37. A pharmaceutical composition comprising a pharmaceutically effective amount of the dasatinib co-crystal according to claim 1 and pharmaceutically acceptable excipient.38. A method of treating disease in a patient comprising administering a pharmaceutical formulation according to claim 37 to the patient in need thereof.39. A method of treating disease according to claim 38, wherein the disease ismyelogenous leukemia.40. A method of treating disease according to claim 38, wherein the disease isPhiladelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.41. A method of treating disease according to claim 38, wherein the disease Ph+ acute lymphoblastic leukemia (Ph+ ALL).42. A method of making the dasatinib co-crystal according to claim 1, comprisingdissolving dasatinib and a second compound, wherein the second compound is selected from the group consisting of butyl paraben, propyl paraben and ethyl vanillin, in heated methanol (-10: 1 – wt(mg)DAs:v(mL)MeOH and molD,\s:mohnci compound is 1 : 1.1) to form a clear solution, heating the solution under vacuum for about l8-20h to yield the dasatinib co-crystal.43. A process for the preparation Form II co-crystal of dasatinib and ethyl vanillin,according to claim 14, comprising: (g) dissolving Form I of ethyl formate solvate of dasatinib and ethyl vanillin in N-methyl-2-pyrrolidone to form a solution;(h) adding water to the solution;(i) stirring the solution for about 12-24 hours to form a slurry;(j) filtering the slurry to yield a precipitate;(k) washing the precipitate with water; and(l) drying the precipitate under vacuum with warming to yield Form II co crystal of dasatinib and ethyl vanillin.44. A process for the preparation of Form I of ethyl formate solvate of dasatinib,according to claim 30, comprising:(d) dissolving dasatinib in ethyl formate to form a solution;(e) stirring the solution for about 12-24 hours form a slurry;(f) filtering the slurry to yield Form I of ethyl formate solvate of dasatinib.45. A process for the preparation of Form I of ethyl formate solvate of dasatinib,according to claim 30, comprising:(g) dissolving dasatinib in N-Methyl-2-pyrrolidone to form a solution;(h) adding ethyl formate to the solution to form a slurry;(i) adding additional ethyl formate to the slurry;(j) stirring the slurry for about 2 hours;(k) filtering the slurry to yield a precipitate; and(l) washing the precipitate with ethyl formate to yield Form I of ethyl formate solvate of dasatinib. 

ATENThttps://patents.google.com/patent/WO2013065063A1/en
 Dasatinib, N-(2-chloro-6-methylphenyl)-2- [(6-[4-(2-hydroxyl)- 1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide compound having the following chemical structure of Formula (I)

Figure imgf000002_0001

Formula IAlso known as BMS-354825, it is a drug produced by Bristol Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after Imatinib treatment has failed and Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph + ALL). It is also being assessed for use in metastatic melanoma.A preparation of Dasatinib is described in US patent No. 6596746 (B l ), where the process is done by reacting compound of the following formula III with N-(2- hydroxyethyl) piperazine at 80° C.

Figure imgf000002_0002

Formula IIIThe compound of Formula (I) and its preparation is described in US Patent No. 6596746, US patent application No. 2005/0176965 Al , and US patent application No. 2006/0004067 Al .l Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, 1R etc. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR). Solvent medium and mode of crystallization play very important role in obtaining a crystalline form.The discovery of new polymorphic forms is a continuing goal of formulators. The new polymorphs may be advantageous for dosage form development and enhancing bioavailability owing to the altered physiochemical properties. Some form may turn out to be more efficacious. Discovering novel processes to prepare known polymorphic forms is also a primary goal of the pharmaceutical development scientists. New processes can provide novel intermediates or synthetic pathways that result in product with increased chemical and polymorphic purity in addition to providing cost and other advantages. There is thus a need to provide novel synthetic routes and intermediates that can realize these goals.Several crystalline forms of Dasatinib are described in the literature; these are designated as HI -7, BU-2, E2-1 , N-6, T1 H1 -7 and TIE2-1. Crystalline Dasatinib monohydrate (H I -7) and butanol solvate (BU-2) along with the processes for their preparation are described in WO 2005077945. In addition US 2006/0004067, which is continuation of US 2005215795 also describe two ethanol solvates (E2-1 ; TIE2-1) and two anhydrous forms (N-6 and T1 H1 -7).WO 2009053854 discloses various Dasatinib solvates including their crystalline form, amorphous form and anhydrous form.US patent No. 7973045 discloses the anhydrous form of Dasatinib and process for preparation thereof. The anhydrous form disclosed therein have typical characteristic XRD peaks at about 7.2, 1 1.9, 14.4, 16.5, 17.3, 19.1 , 20.8, 22.4, 23.8, 25.3 and 29.1 on the 2- theta value. WO 2010062715 discloses isosorbide dimethyl ether solvate, Ν,Ν’- dimethylethylene urea solvate and N,N’-dimethyl-N,N’-propylene urea solvate of Dasatinib.WO 2010067374 discloses novel crystalline form I, solvates of DMF, DMSO, toluene, isopropyl acetate and processes for their preparation.WO 2010139979 discloses MDC solvate and process of preparation, for use in the manufacture of pure Dasatinib.WO 2010139980 discloses a process for the preparation of crystalline Dasatinib monohydrate.The present invention is a step forward in this direction and provides a novel anhydrous form and process for its preparation, which can be used for the preparation of pure Dasatinib, in particularly Dasatinib monohydrate.The process for preparing Dasatinib monohydrate is described in US 2006/0004067. Further studies by the inventors have shown that the preparation of Dasatinib by using the method, which is disclosed in US 2006/0004067 yields the monohydrate with ~ 90% purity. Therefore the present invention provides a novel anhydrous form which can be used to get Dasatinib monohydrate with high yield and purity.Preparing API with increased purity is always an aim of the pharmaceutical development team. The inventors of the present invention have found that preparingDasatinib monohydrate using the novel anhydrous form of the present invention resulted in a highly pure product with a good yield.Scheme 1 shows a general process for the preparation of Dasatinib as disclosed in US 2006/0004067. Intermediate 3 and N-(2-hydroxyethyl) piperazine are heated together in a solvent system comprising n-butanol as a solvent and diisopropyl ethylamine (DIPEA) as a base. On cooling of the reaction mixture, Dasatinib precipitates out which is isolated by filtration.

Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003

DasatinibScheme 1Example – 1In a reaction vessel, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mmol) and N-(2- hydroxyethyl) piperazine (5.3 gm, 40.70 mmol) was added under stirring. The reaction mixture was heated at 80 °C for 2H. Acetonitrile was added into reaction mixture at 80 °C and stirred for 30 min. Cooled the suspension to room temperature and stirred for 30 min. Filtered, washed with acetonitrile and dried at 60 °C under vacuum to get 950 mg anhydrous N-(2-chloro-6-methylphenyl)-2-[(6-[4-(2-hydroxy 1)- 1 -piperaziny l]-2- methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide (76.73 % Yield).HPLC Purity 99.90 %M/C by KF 0.12 %DSC 278.17 °CTGA 2.05 %XRD as provided in Fig. 2

Patent

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dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactiCN103664929B *2012-08-302016-08-03石药集团中奇制药技术(石家庄)有限公司Dasatinib polycrystalline form medicament and preparation methodCN102838595B *2012-09-132014-09-24江苏奥赛康药业股份有限公司Preparation method of high-purity dasatinib and by-product of dasatinibCN103819469A *2012-11-162014-05-28重庆医药工业研究院有限责任公司Crystal form of dasatinib and preparation method for crystal form of dasatinibCZ306598B62012-12-062017-03-22Zentiva, K.S.A method of preparation and purification of new and known polymorphs and dasatinib solvatesCN105764502A2013-07-262016-07-13现代化制药公司Combinatorial methods to improve the therapeutic benefit of bisantrene and analogs and derivatives thereofCN103408542B *2013-08-132016-06-29南京优科生物医药研究有限公司A kind of preparation method of highly purified Dasatinib anhydrideWO2015049645A2 *2013-10-042015-04-09Alembic Pharmaceuticals LimitedAn improved process for the preparation of dasatinibCZ306732B62013-12-192017-05-31Zentiva, K.S.A method of preparation of the anhydrous polymorphic form of N-6 DasatinibCN104788445B *2015-04-102017-06-23山东新时代药业有限公司A kind of synthetic method of Dasatinib intermediateCN106668022B *2015-11-052020-09-15武汉应内药业有限公司Application of aminothiazole MyD88 specific inhibitor TJM2010-5* Cited by examiner, † Cited by third party, ‡ Family to family citation 

References[edit]

  1. ^ “Sprycel (Dasatinib)” (PDF). Therapeutic Goods Administration(TGA). Retrieved 18 July 2020.
  2. Jump up to:a b c d e f g h i j “Sprycel EPAR”European Medicines Agency(EMA). Retrieved 28 April 2020.  This article incorporates text from this source, which is in the public domain.
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  5. ^ Keating GM (January 2017). “Dasatinib: A Review in Chronic Myeloid Leukaemia and Ph+ Acute Lymphoblastic Leukaemia”. Drugs77 (1): 85–96. doi:10.1007/s40265-016-0677-xPMID 28032244S2CID 207489056.
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  10. ^ Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M, Kiefer SE, et al. (June 2006). “The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants”Cancer Research66 (11): 5790–7. doi:10.1158/0008-5472.CAN-05-4187PMID 16740718.
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  21. Jump up to:a b c Kirkland JL, Tchkonia T (2020). “Senolytic drugs: from discovery to translation”Journal of Internal Medicine288 (5): 518–536. doi:10.1111/joim.13141PMC 7405395PMID 32686219.
  22. Jump up to:a b Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz-Espín D (2019). “Targeting senescent cells in translational medicine”EMBO Molecular Medicine11 (12): e10234. doi:10.15252/emmm.201810234PMC 6895604PMID 31746100.
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Further reading[edit]

  • Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. (December 2004). “Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays”. Journal of Medicinal Chemistry47 (27): 6658–61. doi:10.1021/jm049486aPMID 15615512.

External links[edit]

  • “Dasatinib”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Trade namesSprycel, Dasanix
AHFS/Drugs.comMonograph
MedlinePlusa607063
License dataEU EMAby INNUS DailyMedDasatinibUS FDADasatinib
Pregnancy
category
AU: D
Routes of
administration
By mouth (tablets)
ATC codeL01EA02 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) [1]US: ℞-onlyEU: Rx-only [2]In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding96%
MetabolismLiver
Elimination half-life1.3 to 5 hours
ExcretionFecal (85%), kidney (4%)
Identifiers
showIUPAC name
CAS Number302962-49-8 
PubChem CID3062316
IUPHAR/BPS5678
DrugBankDB01254 
ChemSpider2323020 
UNIIX78UG0A0RN
KEGGD03658 
ChEBICHEBI:49375 
ChEMBLChEMBL1421 
CompTox Dashboard (EPA)DTXSID4040979 
ECHA InfoCard100.228.321 
Chemical and physical data
FormulaC22H26ClN7O2S
Molar mass488.01 g·mol−1
3D model (JSmol)Interactive image
hideSMILESCc1cccc(c1NC(=O)c2cnc(s2)Nc3cc(nc(n3)C)N4CCN(CC4)CCO)Cl
hideInChIInChI=1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27) Key:ZBNZXTGUTAYRHI-UHFFFAOYSA-N 

/////////////DASATINIB, BMS 35482503, KIN 001-5, NSC 759877, Sprycel, BMS, APOTEX, ダサチニブ水和物 , X78UG0A0RN, дазатиниб , دازاتينيب , 达沙替尼 , 

#DASATINIB, #BMS 35482503, #KIN 001-5, #NSC 759877, #Sprycel, #BMS, #APOTEX, #ダサチニブ水和物 , #X78UG0A0RN, #дазатиниб , #دازاتينيب , #达沙替尼 , 

O.Cc1nc(Nc2ncc(s2)C(=O)Nc3c(C)cccc3Cl)cc(n1)N4CCN(CCO)CC4

PATENT

https://patents.google.com/patent/US8884013B2/enDasatinib, with the trade name SPRYCEL™, is a oral tyrosine kinase inhibitor and developed by BMS Company. It is used to cure adult chronic myelogenous leukemia (CML), acute lymphatic leukemia (ALL) with positive Philadelphia chromosome, etc. Its chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl]amino]-5-thiazolformamide and its chemical structure is as following:

Figure US08884013-20141111-C00001

Five polymorphs of Dasatinib and the preparation methods thereof were described by Bristol-Myers Squibb in the Chinese Patent Application No. CN200580011916.6 (publication date is 13 Jun. 2007). The preparation methods instructed in this document are:Monohydrate: Dasatinib (48 g) was added into ethanol (1056 mL 22 ml/g) and water (144 mL), and dissolved by heating to 75° C.; the mixture was purified, filtrated and transferred to the receiver. The solution reactor and transferring pipes were washed with the mixture of ethanol (43 mL) and water (5 mL). The solution was heated to 75˜80° C. to be soluble completely and water (384 mL) was heated and the temperature of the solution was kept between 75° C. and 80° C. The seed crystal of monohydrate (preferable) was added when cooling to 75° C., and keep the temperature at 70° C. for 1 h; cooling to 5° C. within 2 h and keeping the temperature at 0˜5° C. for 2 h. The slurry was filtrated and the filter cake was washed by the mixture of ethanol (96 mL) and water (96 mL); after being dried under vacuum≦50° C. 41 g of solid was obtained.Butanol solvate: under refluxing (116° C.˜118° C.), Dasatinib was dissolved in 1-butanol (about 1 g/25 mL) to yield crystalline butanol solvate of Dasatinib. When cooling, this butanol solvate was recrystallized from solution. The mixture was filtrated and the filter cake was dried after being washed with butanol.Ethanol solvate: 5D (4 g, 10.1 mmol), 7B (6.6 g, 50.7 mmol), n-bubanol (80 mL) and DIPEA (2.61 g, 20.2 mmol)) were added into a 100 ml round flask. The obtained slurry was heated to 120° C. and kept the temperature for 4.5 h, and then cooled to 20° C. and stirred over night. The mixture was filtrate, and the wet filter cake was washed with n-butanol (2×10 mL) to yield white crystal product. The obtained wet filter cake was put back to the 100 ml reactor and 56 mL (12 mL/g) of 200 proof ethanol was added. Then additional ethanol (25 mL) was added at 80° C., and water (10 mL) was added into the mixture to make it dissolved rapidly. Heat was removed and crystallization was observed at 75° C.˜77° C. The crystal slurry was further cooled to 20° C. and filtrated. The wet filter cake was washed with ethanol:water (1:1, 10 mL) once and then washed with n-heptane (10 mL) once. After that it was dried under the condition of 60° C./30 in Hg for 17 h to yield 3.55 g of substance only containing 0.19% water.Neat form of N-6: DIPEA (155 mL, 0.89 mmol) was added into the mixture of compound 5D (175.45 g, 0.445 mol) and hydroxyethylpiperazine (289.67 g, 2.225 mol) in NMP (1168 mL). The suspension was heated at 110° C. for 25 min to be solution, which was then cooled down to about 90° C. The obtained solution was added dropwise into hot water (80° C., 8010 mL), and the mixture was stirred at 80° C. with heat preservation for 15 min and cooled to room temperature slowly. The solid was filtrated under vacuum and collected, washed by water (2×1600 mL) and dried under vacuum at 55° C.˜60° C. to give 192.45 of compound.Neat form of T1H1-7 (neat form and pharmaceutically acceptable carrier): monohydrate of Dasatinib was heated over dehydrate temperature to yield.Because Dasatinib is practically insoluble in water or organic solvent (e.g. methanol, ethanol, propanol, isopropanol, butanol, pentanol, etc.), even in the condition of heating, a large amount (over 100 times) of solvent is needed, which is disadvantageous in industrial production; in addition, with the method described in the Patent document of CN200580011916.6, the related substances in products can not be lowed effectively during the process of crystal preparation to improve the products quality.In terms of polymorphs of drug, each polymorph has different chemical and physical characteristics, including melting point, chemical stability, apparent solubility, rate of dissolution, optical and mechanical properties, vapor pressure as well as density. Such characteristics can directly influence the work-up or manufacture of bulk drug and formulation, and also affect the stability, solubility and bioavailability of formulation. Consequently, polymorph of drug is of great importance to quality, safety and efficacy of pharmaceutical preparation. When it comes to Dasatinib, there are still needs in the art for new polymorphs suitable for industrial production and with excellent physical and chemical properties as well.Example 1Preparation of the Polymorph IA. Dasatinib (10 g) and DMSO (40 ml) were added into a flask and heated up to 60˜70° C. by stirring, after dissolving, the mixture (120 mL) of water and acetone (1:1) was added under heat preservation. When crystal was precipitated, cooled it down to 0° C. to grow the grains for 10 minutes. Filtrate it and the cake was washed by water and then by the mixture of water and acetone (1:1). After that it was dried under −0.095 MPa at about 50° C. using phosphorus pentoxide as drying aid to give 7.7 g of white solid. Yield was 77%.Contrasts Index of raw material Items before transformation Index of Polymorph I Appearance off-white powder White crystal powder Related substance 0.85% 0.07% KF moisture 0.67% 3.59% 70~150 0.72% 3.63% TGA weight loss
The following items of products prepared by Method A were detected: microscope-crystal form (See. FIG. 1); XRPD Test (See. FIG. 2), IR Test (See. FIG. 3), DSC-TGA Test (See. FIG. 4-1, 42), 13C Solid-state NMR Test (See. FIG. 5).B. Dasatinib (10 g) and DMSO (40 ml) were added into a flask and heated slowly up to 60˜70° C. by stirring, after dissolving, the mixture (160 mL) of ethanol and water (1:1) was added under heat preservation. When crystal was precipitated, cooled it down to 0° C. to grow the grains for 10 minutes. Filtrate it and the cake was washed by the mixture of ethanol and water (1:1) and dried under −0.095 MPa at about 50° C. using phosphorus pentoxide as drying aid to give 7.7 g of white solid. Yield was 87%.Contrasts Index of raw material Items before transformation Index of Polymorph I Appearance off-white powder White crystal powder Related substance 0.85% 0.08% KF moisture 0.67% 3.58% 70~150 0.72% 3.67% TGA weight lossHPLC.Related Substances DeterminationHPLC conditions and system applicability: octadecylsilane bonded silica as the filler; 0.05 mol/L of potassium dihydrogen phosphate (adjusted to pH 2.5 by phosphoric acid, 0.2% triethylamine)-methanol (45:55) as the mobile phase; detection wavelength was 230 nm; the number of theoretical plates should be not less than 2000, calculated according to the peak of Dasatinib. The resolution of the peak of Dasatinib from the peaks of adjacent impurities should meet requirements.Determination method: sample was dissolved in mobile phase to be the solution containing 0.5 mg per milliliter. 20 μL of such solution was injected into liquid chromatograph, and chromatogram was recorded until the sixfold retention time of major component peak. If there were impurities peaks in the chromatogram of sample solution, total impurities and any single impurity were calculated by normalization method on the basis of peak area.Stability of Polymorph in the FormulationsThe XRPD patterns of capsules and tablets respectively prepared in the Example 3 and Example 4 have been tested, and compared with XRPD characteristic peaks of Polymorph I of Dasatinib prepared by the Method A in the Example 1 in the present invention, as listed in the following table:Bulk Drug Capsules 1 Capsules 2 Tablets 2 (Polymorph (Polymorph (Polymorph Tablets 1 (Polymorph I) I) I) (Polymorph I) I) 2θ 2θ 2θ 2θ 2θ 9.060 9.080 9.070 9.060 9.070 11.100 11.120 11.110 11.100 11.110 13.640 13.670 13.650 13.640 13.650 15.100 15.120 15.110 15.100 15.110 17.820 17.840 17.830 17.820 17.820 19.380 19.400 19.390 19.380 19.390 22.940 22.970 22.950 22.950 22.950The results in the above-mentioned comparative table have shown that the crystal form had substantially no change after Polymorph I of Dasatinib in the invention were prepared into capsules or tablets by the formulation process.In addition, The relative substances of capsules and tablets respectively prepared in the Example 3 and Example 4 have been tested, and compared with those of Polymorph I of Dasatinib prepared by the Method A in the Example 1 in the present invention, as listed in the following table:Bulk Drug (Polymorph I) Capsules 1 Capsules 2 Tablets 1 Tablets 2 0.07% 0.08% 0.08% 0.07% 0.08%The results in the above-mentioned comparative table have shown that the Polymorph I of Dasatinib was stable, and there were no significantly changes in respect to the relative substances, after Polymorph I of Dasatinib in the invention were prepared into capsules or tablets by the formulation process.INDUSTRIAL APPLICATIONThe present invention provides novel polymorphs of Dasatinib, preparing methods, and pharmaceutical composition comprising them. These polymorphs have better physicochemical properties, are more stable and are more suitable for industrial scale production, furthermore, are suitable for long-term storage, and are advantageous to meet the requirements of formulation process and long-term storage of formulations. The preparation technique of this invention was simple, quite easy for operation and convenient for industrial production, and the quality of the products was controllable with paralleled yields. In addition, by the methods of polymorph preparation in this invention, the amount of organic solvent used in crystal transformation could be reduced greatly, which led to reduced cost of products; organic solvents in Class III with low toxicity could be used selectively to prepare the polymorphs of this invention, reducing the toxic effects of the organic solvents potentially on human body to some extent.PATENThttps://patents.google.com/patent/WO2010067374A2/enDasatinib are antineoplastic agents, which were disclosed in WO Patent Publication No. 00/62778 and U.S. Patent No. 6,596,746. Dasatinib, chemically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide, is represented by the following structure:

Figure imgf000002_0001

Polymorphism is defined as “the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules”. Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other. Dasatinib can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.U.S. Patent Application No. 2005/0215795 A1 (herein after referred to as the 795 patent application) described five crystalline forms of dasatinib (monohydrate, butanol solvate, ethanol solvate, neat form (N-6) and neat form (T1H1-7)), characterized by powder X-ray diffraction (P-XRD) pattern.According to the ‘795 patent application, dasatinib monohydrate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 18.0, 18.4, 19.2, 19.6, 21.2, 24.5, 25.9 and 28.0 ± 0.2 degrees. As per the process exemplified in the ‘795 patent application, dasatinb monohydrate can be obtained in dasatinib, by heating and dissolving the dasatinib in an ethanol and water mixture. Crystallizing the monohydrate from the ethanol and water mixture and cooled to get dasatinib monohydrate.According to the ‘795 patent application, dasatinib crystalline butanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 5.9, 12.0, 13.0, 17.7, 24.1 and 24.6 ± 0.2 degrees.According to the 795 patent application, dasatinib crystalline ethanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 5.8, 11.3, 15.8, 17.2, 19.5, 24.1, 25.3 and 26.2 ± 0.2 degrees.According to the 795 patent application, dasatinib crystalline neat form (N-6) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 6.8, 11.1, 12.3, 13.2, 13.7, 16.7, 21.0, 24.3 and 24.8 ± 0.2 degrees.According to the 795 patent application, dasatinib crystalline neat form (T1H1-7) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 8.0, 9.7, 11.2, 13.3, 17.5, 18.9, 21.0 and 22.0 ± 0.2 degrees.U.S. Patent application No. 2006/0094728 disclosed ethanolate form (T1E2-1) of dasatinib, characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 7.2, 12.0, 12.8, 18.0, 19.3 and 25.2 ± 0.2 degrees. We have discovered novel crystalline form of dasatinib, dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate and dasatinib isopropyl acetate solvate.Another object of the present invention is to provide process for preparing the novel crystalline form of dasatinib, dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate, dasatinib isopropyl acetate solvate and known crystalline dasatinib monohydrate.Still another object of the present invention is to provide pharmaceutical compositions containing the novel crystalline form of dasatinib.Reference Example2-(6-Cholro-2-methylpyrimidin-4-yl-amino)-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (15 gm) was added to 1-(2-hydroxyethyl)piperazine at 250C and heated to 850C, stirred for 2 hours 30 minutes at 850C. To the solution was added water (500 ml) at 800C and slowly cooled to 250C, stirred for 1 hour at 250C. The solid was collected by filtration and the solid was washed with water (50 ml), and then dried the solid at 550C under vacuum to obtain 15 gm of dasatinib.Example 1Dasatinib (5 gm) obtained according to reference example was dissolved in ethyl acetate (300 ml) at 250C and heated to reflux temperature. To the solution was added methanol (100 ml) and stirred for 30 minutes at reflux temperature to form clear solution. The solution was slowly cooled to room temperature and then cooled to O0C, stirred for 1 hour at O0C. The solid was collected by filtration and the solid was washed with mixture of ethyl acetate and methanol (20 ml, 3:1), and then dried the solid at 500C under vacuum to obtain 3.5 gm of crystalline dasatinib form I.Example 2Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in acetone (100 ml) and methanol (250 ml) and heated to reflux temperature, stirred for 30 minutes at reflux temperature to form clear solution. The solution was cooled to room temperature and then cooled to 200C, stirred for 1 hour at 200C. The solid was collected by filtration and the solid was washed with mixture of acetone (10 ml) and methanol (25 ml), and then dried the solid at 500C under vacuum to obtain 4 gm of crystalline dasatinib form I (HPLC purity: 99.85%).Example 3Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) at 250C and heated to 650C to form clear solution. To the solution was slowly added acetone (50 ml) at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C and stirred for 1 hour at 250C. The contents are filtered and the solid obtained was washed with mixture of dimethylformamide and acetone (15 ml, 1:2), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.94%).Example 4Dasatinib (5 gm) was dissolved in dimethylformamide (25 ml) at 250C and heated to 650C to form clear solution. Ethyl acetate (50 ml) was added slowly to the solution at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C, stirred for 1 hour at 250C and filtered. The solid obtained was washed with mixture of dimethylformamide and ethyl acetate (30 ml, 1:2), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate.Example 5Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 650C to form a clear solution. The solution was cooled to 250C and then cooled to 50C, stirred for 4 hour at 50C. The solid was collected by filtration and the solid was washed with chilled dimethylformamide (10 ml), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.9%).Example 6Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 650C to form a clear solution. Water (50 ml) was added slowly to the solution at 650C and stirred for 1 hour at 650C. The solution was cooled to 250C and stirred for 30 minutes at 250C. The solid was collected by filtration and the solid was washed with mixture of dimethylformamide and water (15 ml, 1 :2), and then dried the solid at 500C under vacuum to obtain 4.7 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.93%).Example 7Dasatinib dimethylformamide solvate (4.7 gm) obtained as in example 6 was dissolved in water (50 ml) and heated to 750C, stirred for 4 hours at 750C. The solution was cooled to 250C, stirred for 30 minutes at 250C and filtered. The solid obtained was washed with water (15 ml), and then dried at 500C under vacuum to obtain 4.7 gm of dasatinib monohydrate.Example 8Dasatinib (20 gm) was dissolved in dimethyl sulfoxide (100 ml) at 250C and heated to 650C to form clear solution. To the solution was slowly added water (200 ml) at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C and stirred for 30 minutes at 250C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and water (30 ml, 1 :2), and then dried the solid at 500C under vacuum to obtain 19.5 gm of dasatinib monohydrate.Example 9Dasatinib (5 gm) was dissolved in isopropyl acetate (65 ml) and heated to 800C, stirred for 1 hour at 800C to form a clear solution. The solution was cooled to 250C, stirred for 1 hour at 250C and filtered. The solid obtained was washed with isopropyl acetate (15 ml) to obtain 5 gm of dasatinib isopropyl acetate solvate.Example 10Dasatinib (6 gm) was dissolved in toluene (100 ml) and heated to reflux temperature, stirred for 2 hours at reflux temperature to form a clear solution. The solution was slowly cooled to 250C. The contents are filtered and the solid obtained was washed with toluene (20 ml) to obtain 5.5 gm of dasatinib toluene solvate.Example 11Dasatinib (5 gm) was dissolved in dimethyl sulfoxide (20 ml) at 250C and heated to 650C. To the solution was slowly added ethyl acetate (200 ml) at 650C and the solution was slowly cooled to O0C, stirred for 2 hours at O0C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and ethyl acetate (55 ml, 1 :10), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethyl sulfoxide solvate.
PATENThttps://patents.google.com/patent/WO2014086326A1/enDasatinib, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1 -piperazinyl]-2- methyl-4-pyrimidmyl]amino]-5-thiazole carboxamide of formula I, also known as BMS- 354825, is a cancer treatment drug developed by Bristol-Myers Squibb and sold under the trade name Sprycel®. Dasatinib is a multi- BCR/ABL and Src family tyrosine kinase inhibitor and it is used for treatment of chronic myelogenous leukaemia (CML) as a secondary drug after primary treatment with imatinib (Gleevec®). It is also used for treatment of acute lymphoblastic leukaemia caused by mutation/translocation of chromosomes and development of the so-called Philadelphia chromosome (Ph+ ALL). However, its potential is so wide that the possibility of using it for treatment of other types of cancer, including advanced stages of prostate cancer, is still being investigated.

Figure imgf000002_0001

(I)In accordance with the basic patent WO2000062778A1, dasatinib is prepared by reaction of the key intermediate of formula II with l-(2-hydroxyethyl)piperazine in the presence of a base and a suitable solvent (Scheme 1). A similar preparation method was later used in a number of other process patents, only varying the corresponding base or solvent. Through the selection of a suitable solvent or procedure a great number of solvates or polymorphs can be prepared. Polymorphs have been one of the most frequently studied physical characteristics of active pharmaceutical substances (API) recently. Thus, different polymorphs of one API may have entirely different physical-chemical properties such as solubility, melting point, mechanical resistance of crystals but they may also influence the chemical and physical stability. Then, these properties may have an impact on further processes such as handling of the particular API, grinding or formulation method. These various physical-chemical characteristics of polymorphs influence the resulting bioavailability of the solid dosage form. Therefore, looking for new polymorphs and solvates is becoming an important tool for obtaining a polymorph form with the desired physical-chemical characteristics.

Figure imgf000003_0001

The process patent WO2005077945A2 describes preparation of the following solvates of dasatinib: monohydrate, butanol solvate, as well as two anhydrous forms (N-6 and T1H1- 7). A related patent also mentions two ethanol solvates, the hemi-ethanol and diethanol solvates (US 8 242 270 B2). Salts, various combinations of salts and their solvates have been described in detail in the patent application WO2007035874A1.Another process patent, WO2009053854A2, dealt with the preparation of a number of solvates or mixed solvates out of which especially the isopropanol and mixed isopropanol/dimethyl sulfoxide solvates, as well as a new solid form B, another anhydrous polymorph of dasatinib, are worth mentioning. Other patent applications have also dealt with the preparation of other solvates/mixed solvates (WO2010067374A2), or processes for the preparation and purification of the monohydrate/anhydrous form (WO2010139981A2) and its polymorphs (WO2011095059 Al).API solvates or salts are used in drug formulations in many cases. In the case of solvates the limits for individual solvents, their contents or maximum daily doses have to be strictly observed. Then, these limits can dramatically restrict their effective use. Thus, the clearly most convenient option is the use of sufficiently stable polymorphs of API that do not contain any solvents bound in the crystalline structure.Some of the above mentioned patent documents describe preparation of a stable anhydrous form of dasatinib (N-6). In accordance with individual patent documents the main disadvantages of the preparation of N-6 is the necessity of desolvation of the solvated form of the API at high temperatures (WO2009053854A2), or application of an increased temperature (50°C and more) and vacuum for a relatively long time (8-12h; WO2010139981A2 and WO2005077945A2). These procedures are very demanding from the point of view of general technology, energy and time, to say nothing of the necessity to work under an inert atmosphere to prevent possible oxidation-degradation reactions of the API. This is because dasatinib may be oxidized by atmospheric oxygen to the corresponding N-oxide (oxidation occurs in the piperazine ring), which may undergo the Cope elimination at increased temperatures. This secondary reaction may subsequently impair the purity of the prepared API.With a view to the above mentioned facts it is obvious that completely new methods and processes have to be developed even for polymorphs or solvates that are already well- known. Generally, the development of technologically and economically more efficient procedures is the main decisive parameter in their industrial utilization for the preparation of the API.Dasatinib of formula I is prepared by a reaction of the intermediate of formula II with l-(2- hydroxyethyl)piperazine in the presence of diisopropylethylamine (DIPEA) in an organic solvent from the group of dipolar aprotic solvents, higher alcohols or diols.If a dipolar aprotic solvent from the group of N-methyl-2-pyrrolidone (NMP), N^iV-dimethyl formamide (DMF), AyV-dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), formamide (FA), N,N -dimethyl propylene urea (DMPU) and l,3-dimethyl-2-imidazolidinone (DMI) is used, the reaction is carried out at 50-110°C under an inert atmosphere for 1/2-6 hours. In a preferable embodiment, NMP, DMSO, DMPU or DMI is used and the reaction is carried out at 90°C for 1-3 hours. The result of the reaction is crude dasatinib in the form of a solution in the corresponding solvent.If an alcohol from the group of isoamyl alcohol or 1,3-propanediol is used as a solvent for preparation of the crude dasatinib, the reaction mixture is heated at 120-160°C for 2-12 hours, in a preferable embodiment at 135°C for 3-6 hours.If dipolar aprotic solvents (NMP, DMF, DMA, DMSO, FA, DMPU and DMI) are used, in step a) a precipitant is added to the hot solution (90°C) under continuous stirring in an inert atmosphere in a 2- 15 fold, most preferably 4-10fold (by volume) amount with respect to the dipolar aprotic solvent. Suitable precipitants comprise especially acetonitrile, propionitrile, most preferably acetonitrile.After addition of the precipitant the obtained solution is withdrawn from the heating bath and is slowly left to cool down to 22°C under continuous stirring in an inert atmosphere. Crystallization occurs within 1-120 minutes (depending on the volume, until complete cooling). After having cooled down to 22°C (laboratory temperature), the suspension is stirred for another hour. The corresponding solvate of dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35 °C, most preferably at 22°C, and washed with the respective co-solvent.The solvate of dasatinib obtained this way can be directly used in the next step – recrystallization, without the necessity of drying. If necessary, the product may be dried at 10- 35°C, most preferably at 25°C, and at the pressure of 10-200 kPa, most preferably 50 kPa, for 6-24 hours, most preferably 12 hours.If NMP is used as the solvent in step a), the corresponding NMP solvate is isolated. The obtained dried crystalline NMP solvate (NM) of dasatinib has a characteristic XRPD pattern, which is presented in Figure no. 1. The NMP solvate (NM) has the following characteristic peaks: 5.88; 6.73; 10.73; 11.92; 13.39; 14.97; 16.72; 18.95; 20.17; 21.46; 22.81; 24.65; 25.18; 26.02 and 28.06 ± 0.2° 2-theta.If isoamyl alcohol or 1,3-propanediol are used as the solvents in step a), the reaction mixture is left to cool down to 22°C after expiration of the reaction time (3-6 h). Crystallization generally begins when the inner temperature of the reaction mixture drops to 100°C. After cooling down to 22°C (laboratory temperature), the suspension is further stirred for another 1 hour. Crystalline dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35°C, most preferably at 22°C, and washed with the corresponding solvent.The obtained product is dried at 10-35°C, most preferably at 25°C, and at the pressure of 10-200 kPa, most preferably 50 kPa, for 6-24 hours, most preferably 12 hours.The obtained crystalline isoamyl alcohol solvate (SI) of dasatinib has a characteristic XRPD pattern, which is shown in Figure no. 2. The solvate (SI) has the following characteristic peaks: 5.72; 10.35; 11.42; 12.61; 13.14; 14.27; 15.33; 17.18; 17.44; 17.97; 19.12; 19.95; 20.38; 22.05; 22.42; 23.01; 23.46; 23.68; 25.26; 26.20; 26.45; 26.62 and 27.78 ± 0.2° 2-theta.The obtained crystalline 1,3-propanediol solvate (SP) of dasatinib has a characteristic XRPD pattern, which is shown in Figure no. 3. The solvate (SP) has the following characteristic peaks: 6.04; 12.01; 15.10; 17.95; 18.35; 18.77; 21.25; 21.51; 22.96; 24.08; 24.62; 25.80; 26.16; 28.16 and 33.6578 ± 0.2° 2-theta.These solvates (or polymorph forms) are then easily converted to the desired anhydrous polymorph N-6 or another solvate in steps b) and c). All the forms prepared this way are sufficiently stable and can easily be isolated in the chemical purities of 99% and higher (in accordance with HPLC).The anhydrous polymorph form N-6 is prepared in the following way: any solvate or another polymorph is dissolved under an inert atmosphere at 90°C (reflux) in a 10-30 times, most preferably 20 times, the (weight) amount of the crystallization solvent. Suitable crystallization solvents include especially methanol, ethanol, isopropanol, most preferably methanol.A co-solvent is added in 0.1-10 times, most preferably ½-l times, the volume of the crystallization solvent used in an inert atmosphere at 90°C. The co-solvent can be, e.g., acetonitrile, propionitrile and their mixtures, most preferably acetonitrile. After addition of the co-solvent the obtained solution is withdrawn from the heating bath and is slowly left to cool down to 22°C under continuous stirring in an inert atmosphere. Crystallization occurs during 1-120 minutes (depending on the volume, until complete cooling). After having cooled down to 22°C (laboratory temperature), the suspension is stirred for another hour. Crystalline dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35°C, most preferably at 22°C, and washed with the corresponding co-solvent. The chemical purity of the obtained product is 99% (in accordance with HPLC); it is the polymorph form N-6 and its XRPD pattern is shown in Figure no. 4. The polymorph form N-6 has the following characteristic peaks: 6.77; 12.31; 13.16; 13.75; 16.70; 17.20; 18.54; 19.34; 20.25; 20.95; 21.94; 24.28; 24.82; and 27.80 ± 0.2° 2-theta.Brief Description of Drawings:Figure 1: shows an X-ray powder diffraction pattern of the crystalline solvate NM. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation.Figure 2: shows an X-ray powder diffraction pattern of the isoamyl alcohol crystalline solvate SI. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation. Figure 3: shows an X-ray powder diffraction pattern of the 1,3 propanediol crystalline solvate SP. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation.Figure 4: shows an X-ray powder diffraction pattern of the crystalline anhydrous form N-6. Individual axes: independently variable: reflection angle 2Θ, dependently variable: intensity of detected radiation.Examples: The following working examples illustrate methods for the preparation of dasatinib of formula I, its polymorph form N-6 and its solvates NM, SI, SP.The polymorph forms and solvates of dasatinib were characterized with X-ray powder diffraction using the following methods:The diffraction patterns were measured using an X’PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 – 40° 2Θ, increment: 0.01° 2Θ. The measurement was carried out using a flat powder sample that was placed on a Si plate. For the primary optic setting programmable divergence diaphragms with the irradiated sample area of 10 mm, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm ¼ were used. For the secondary optic setting an X’Celerator detector with the maximum opening of the detection slot, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used. HPLC method:Stock solution of samples: dissolve 5.0 mg of the sample in 10.0 ml of 50% acetonitrile R with water.Dimensions of the chromatographic HPLC column: / = 0.10 m, d= 3 mm- stationary phase: Zorbax Eclipse Plus Phenyl-Hexyl RRHD 1.8 μιη; temperature: 35 °C. Mobile phase: A: phosphate buffer (0.01 M sodium dihydrogen phosphate, pH treated by addition of sodium hydroxide to 7.00 ± 0.05); B: acetonitrile R.Gradient (A/B; flow 0.6 ml/min): 0 min 80/20; 10 min 50/50; 11 min 50/50; 12 min 80/20. Detection at the wavelength of 220 nm.Feed: 2 μΐ of the sample stock solution Example 1.Preparation of the NMP solvate (NM) of dasatinib:The intermediate of formula II (1.00 g; 2.54 mmol) and l-(2-hydroxyethyl)piperazine (1.66 g; 12.77 mmol) were dissolved in N-methylpyrrolidone (5 ml) under an inert atmosphere and diisopropylethylamine (0.9 ml, 5.18 mmol) was added to the reaction mixture. The reaction mixture was stirred and heated up to 90°C for 70 minutes and then acetonitrile (30 ml) was added to the reaction. The mixture was withdrawn from the heating bath and stirred intensively. Crystallization started after 5 minutes, the suspension was left to cool down under continuous stirring. After achieving the laboratory temperature it was stirred for another 2 hours. The crystalline substance was aspirated on frit S3, washed with acetonitrile (5 ml) and dried by suctioning under an inert nitrogen atmosphere for 15 minutes. The XRPD pattern of the sample obtained this way corresponds to the NMP solvate (NM) and can be used in the subsequent steps without the necessity of drying. Drying after 6 hours in an exsiccator at the laboratory temperature in vacuo (50 kPa) provided 1.2 g of crystalline dasatinib; 80% of the theoretical yield. HPLC purity 99.12%. The 1H NMR and 13C NMR spectra correspond to the data known from the literature. The XRPD pattern of the dried product corresponds to the NMP solvate (NM). The NM solvate is characterized by the reflections presented in Table 1 :Table 1 – NM forminterplanarpos. distance[°2Th.] [nm] rel. int. [%]5.88 1.5024 81.86.73 1.3131 100.010.73 0.8236 10.611.92 0.7420 59.213.39 0.6606 19.614.97 0.5915 38.416.72 0.5298 45.018.95 0.4679 10.920.17 0.4399 13.921.46 0.4138 13.422.81 0.3895 21.024.65 0.3608 13.325.18 0.3534 14.426.02 0.3422 11.928.06 0.3177 5.8 

Buspirone


Buspirone 200.svg
Buspirone

Buspirone

  • Molecular FormulaC21H31N5O2
  • Average mass385.503 Da
  • буспиронبوسبيرون丁螺酮

251-489-4[EINECS]253-072-2[EINECS]36505-84-7[RN]8-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione

  • 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione
  • Buspin
  • Buspirone
  • Spitomin

BuspironeCAS Registry Number: 36505-84-7CAS Name: 8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dioneMolecular Formula: C21H31N5O2Molecular Weight: 385.50Percent Composition: C 65.43%, H 8.11%, N 18.17%, O 8.30%Literature References: Non-benzodiazepine anxiolytic; 5-hydroxytryptamine (5-HT1) receptor agonist. Prepn: Y. H. Wu et al.,J. Med. Chem.15, 477 (1972); Y. H. Wu, J. W. Rayburn, DE2057845 (1971 to Bristol-Myers); eidem,US3717634 (1973 to Mead-Johnson). Pharmacology: L. E. Allen et al.,Arzneim.-Forsch.24, 917 (1974). Comparison with diazepam in treatment of anxiety: H. L. Goldberg, R. J. Finnerty, Am. J. Psychiatry136, 1184 (1979); A. F. Jacobson et al.,Pharmacotherapy5, 290 (1985). Nonsynergistic effect with alcohol: T. Seppala et al.,Clin. Pharmacol. Ther.32, 201 (1982). Disposition and metabolism: S. Caccia et al.,Xenobiotica13, 147 (1983). Series of articles on chemistry, pharmacology, addictive potential, and clinical trials: J. Clin. Psychiatry43, pp 1-116 (1982); on pharmacology, safety and clinical comparison with clorazepate: Am. J. Med.80, Suppl. 3B, 1-51 (1986). Review of pharmacology and therapeutic efficacy: K. L. Goa, A. Ward, Drugs32, 114-129 (1986). Review: M. W. Jann, Pharmacotherapy8, 100-116 (1988); D. P. Taylor, FASEB J.2, 2445-2452 (1988). 
Derivative Type: HydrochlorideCAS Registry Number: 33386-08-2Trademarks: Ansial (Vita); Ansiced (Abello); Axoren (Glaxo Wellcome); Bespar (BMS); Buspar (BMS); Buspimen (Menarini); Buspinol (Zdravlje); Buspisal (Lesvi); Narol (Almirall)Molecular Formula: C21H31N5O2.HClMolecular Weight: 421.96Percent Composition: C 59.77%, H 7.64%, N 16.60%, O 7.58%, Cl 8.40%Properties: Crystals from abs ethanol, mp 201.5-202.5°. LD50 i.p. in rats: 136 mg/kg (Allen).Melting point: mp 201.5-202.5°Toxicity data: LD50 i.p. in rats: 136 mg/kg (Allen) 
Therap-Cat: Anxiolytic.Keywords: Anxiolytic; Arylpiperazines; Serotonin Receptor Agonist.

Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder.[9][10] Benefits support its short term use.[11] It has not been found to be effective in treating psychosis.[9] It is taken by mouth, and it may take up to four weeks to have an effect.[9][10]

Common side effects of buspirone include nausea, headaches, dizziness, and difficulty concentrating.[9][11] Serious side effects may include hallucinationsserotonin syndrome, and seizures.[11] Its use in pregnancy appears to be safe but has not been well studied, while use during breastfeeding is not recommended.[11][12] It is a serotonin 5-HT1A receptor agonist.[2]

Buspirone was first made in 1968 and approved for medical use in the United States in 1986.[9][10] It is available as a generic medication.[11] In 2018, it was the 92nd most-commonly prescribed medication in the United States, with more than 8 million prescriptions.[13][14]

Medical uses

Anxiety

Buspirone is used for the short-term treatment of anxiety disorders or symptoms of anxiety.[15][16][17][18][19] It is generally less preferred than selective serotonin reuptake inhibitors (SSRIs).[10]

Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2–4 weeks to manifest itself.[20] The drug has been shown to be similarly effective in the treatment of generalized anxiety disorder (GAD) to benzodiazepines including diazepamalprazolamlorazepam, and clorazepate.[2] Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD,[21] although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).[2][22]

Other uses

Sexual dysfunction

There is some evidence that buspirone on its own may be useful in the treatment of hypoactive sexual desire disorder (HSDD) in women.[23]

Miscellaneous

Buspirone is not effective as a treatment for benzodiazepine withdrawalbarbiturate withdrawal, or alcohol withdrawal/delirium tremens.[24]

SSRI and SNRI antidepressants such as paroxetine and venlafaxine may cause jaw pain/jaw spasm reversible syndrome (although it is not common), and buspirone appears to be successful in treating bruxism on SSRI/SNRI-induced jaw clenching.[25][26]

Contraindications

Buspirone has these contraindications:[27][28]

Side effects

Main article: List of side effects of buspirone

Known side effects associated with buspirone include dizzinessheadachesnauseanervousness, and paresthesia.[2] Buspirone is relatively well tolerated, and is not associated with sedationcognitive and psychomotor impairmentmuscle relaxationphysical dependence, or anticonvulsant effects.[2] In addition, buspirone does not produce euphoria[20] and is not a drug of abuse.[16]

It is unclear if there is a risk of tardive dyskinesia or other movement disorders with buspirone.[9]

Overdose

Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available.[29] In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nauseavomitingdizzinessdrowsinessmiosis, and gastric distress.[15][16][18] In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisiatremor, and muscle rigidity observed.[30] Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals.[30] One death has been reported in association with 450 mg buspirone together with alprazolamdiltiazemalcoholcocaine.[30]

Interactions

Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4.[8] This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:[27]

Elevated blood pressure has been reported when buspirone has been administered to patients taking monoamine oxidase inhibitors (MAOIs).[27]

Pharmacology

Pharmacodynamics

SiteKi (nM)SpeciesRef
5-HT1A3.98–214
21 (median)
Human[33][34]
5-HT1B>100,000Rat[35]
5-HT1D22,000–42,700Human[36][37]
5-HT2A138
759–1,300
Human
Rat
[38]
[35][38]
5-HT2B214Human[38]
5-HT2C490
1,100–6,026
Human
Rat/pig
[38]
[35][38]
5-HT3>10,000Rat[39][40]
5-HT4>10,000Rat[40]
5-HT6398Mouse[41]
5-HT7375–381Rat[42][43]
α11,000Rat[35]
α26,000Rat[44]
α2A7.3 (1-PP)Human[35]
β8,800Rat[35]
D133,000Rat[35]
D2484
240
Human
Rat
[45]
[35]
D398Human[45]
D429Human[45]
mACh38,000Rat[35]
GABAA
(BDZ)
>100,000Rat[35]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity.[2][35] It is a partial agonist of both presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and postsynaptic 5-HT1A receptors.[2] It is thought that the main effects of buspirone are mediated via its interaction with the presynaptic 5-HT1A receptor, thus reducing the firing of serotonin-producing neurons.[2] Buspirone also has lower affinities for the serotonin 5-HT2A5-HT2B5-HT2C5-HT6, and 5-HT7 receptors.[33]

In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity.[2][35] It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses.[2] In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals.[2] Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.[45]

A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself and is known to act as a potent α2-adrenergic receptor antagonist.[44][46][47] This metabolite may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals.[46][48] In addition, 1-PP may play an important role in the antidepressant effects of buspirone.[48] Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor.[35][49] However, buspirone has been reported to have shown “significant and selective intrinsic efficacy” at the α1-adrenergic receptor expressed in a “tissue- and species-dependent manner”.[49]

Unlike benzodiazepines, buspirone does not interact with the GABAA receptor complex.[2][50]

Pharmacokinetics

Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism.[2] The time to peak plasma levels following ingestion is 0.9 to 1.5 hours.[2] It is reported to have an elimination half-life of 2.8 hours,[2] although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours.[4] Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed.[7][8] Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP.[4][5][6] 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans.[5] The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo.[5] As such, it is likely to play an important role in the therapeutic effects of buspirone.[5] 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.[46][48]

Phase I Metabolism of buspirone in humans[51][52][8]

History

Buspirone was first synthesized, by a team at Mead Johnson, in 1968,[21] but was not patented until 1975.[54][55] It was initially developed as an antipsychotic drug acting on the D2 receptor, but was found to be ineffective in the treatment of psychosis; it was then used as an anxiolytic instead.[2] In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD.[21][56] The patent placed on buspirone expired in 2001 and it is now available as a generic drug.

Society and culture

Buspar (buspirone) 10-mg tablets

Generic names

Buspirone is the INNBANDCF, and DCIT of buspirone, while buspirone hydrochloride is its USANBANM, and JAN.[1][57][58][59]

Brand name

Buspirone was primarily sold under the brand name Buspar.[57][59] Buspar is currently listed as discontinued by the US Federal Drug Administration.[60] In 2010, in response to a citizen petition, the US FDA determined that Buspar was not withdrawn for sale because of reasons of safety or effectiveness.[61]

2019 shortage

Due to interrupted production at a Mylan Pharmaceuticals plant in Morgantown, West Virginia, the United States experienced a shortage of buspirone in 2019.[62]

Research

Some tentative research supports other uses such as the treatment of depression and behavioral problems following brain damage.[2]

Chemistry

Buspirone is a member of the azapirone chemical class, and consists of azaspirodecanedione and pyrimidinylpiperazine components linked together by a butyl chain.

Analogues

Structural analogues of buspirone include other azapirones like gepironeipsapironeperospirone, and tandospirone.[53]

Synthesis

Buspirone synthesis:[54] DE 2057845 U.S. Patent 3,717,634 U.S. Patent 3,907,801 U.S. Patent 3,976,776

Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).

PAPERS

  1. Koziol, Anna E.; Acta Crystallographica, Section E: Structure Reports Online 2006, V62(12), Po5616-o5618 
  2. Mou, Jie; Organic Preparations and Procedures International 2008, V40(4), P391-394 
  3. Kairisalo, Pekka Juhani; FI 72975 B 1987 
  4. Journal of medicinal chemistry (1983), 26(2), 194-203
  5. Journal of medicinal chemistry (1986), 29(8), 1476-82.
  6. Medicinal research reviews (1990), 10(3), 283-326.
  7. Heterocycles (1993), 36(7), 1463-9
  8. Journal of medicinal chemistry (1996), 39(5), 1125-9.
  9. Journal of medicinal chemistry (1996), 39(16), 3195-202.
  10. Nature Catalysis, 3(10), 843-850; 2020

PAPER

https://pubs.rsc.org/en/content/articlelanding/2019/GC/C8GC03328E#!divAbstract

  1. Green Chemistry, 21(1), 59-63; 2019

Abstract

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.

Graphical abstract: Fast continuous alcohol amination employing a hydrogen borrowing protocol

http://www.rsc.org/suppdata/c8/gc/c8gc03328e/c8gc03328e2.pdf
8-(4-hydroxybutyl)-8-azaspiro[4.5]decane-7,9-dione (23): A solution of 3,3-tetramethyleneglutaric anhydride (0.25 mol/L in THF) was combined in a tee piece with a solution of 4-amino-1-butanol (0.25 mol/L in THF) and reacted in a 20 mL reactor coil (stainless steel, 20 min residence time) heated at 250 °C. The output was concentrated in vacuo and the residue purified by column chromatography on silica gel to afford the product in 84% yield (Rf = 0.31, 63% DCM/AcOEt). 1H NMR (400 MHz, CDCl3) δ = 3.78 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.58 (s, 4H), 1.77 – 1.64 (m, 4H), 1.64 – 1.53 (m, 4H), 1.53 – 1.43 (m, 4H). 13C NMR (100 MHz, CDCl3) δ = 172.33, 62.28, 44.87, 39.47, 39.14, 37.54, 29.81, 24.35, 24.17. HRMS for [C13H22NO3] + calculated 240.1594 found 240.1605. 

8-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)-8-azaspiro[4.5]decane-7,9-dione (Buspirone, 25): The flow system was flushed with THF, the back-pressure regulator was set to 50 bar, and the coil reactor heated to 250 °C. Then a solution (10 mL overall volume) containing 1-(2-pyrimidyl)piperazine (2 mmol), 8-(4-hydroxybutyl)- 8-azaspiro[4.5]decane-7,9-dione (23) (2 mmol), dichloro(p-cymene)ruthenium(II) dimer (0.08 mmol) and bis[(2- diphenylphosphino)phenyl] ether (DPEPhos, 0.17 mmol) was pumped at 0.8 ml/min through a heated coil (8 mL, Phoenix reactor). The output solution obtained in steady state (monitored using the FlowUV) was concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product in 76% yield (Rf = 0.29, 5% MeOH/DCM). 1H NMR (400 MHz, CDCl3) δ = 8.31 (d, J = 4.7 Hz, 2H), 6.48 (t, J = 4.7 Hz, 1H), 3.84 (t, J = 5.1 Hz, 4H), 3.79 (t, J = 6.8 Hz, 2H), 2.60 (s, 4H), 2.50 (t, J = 5.1 Hz, 4H), 2.40 (t, J = 6.8 Hz, 2H), 1.79 – 1.65 (m, 4H), 1.65 – 1.42 (m, 8H). 13C NMR (100 MHz, CDCl3) δ = 172.19, 161.63, 157.68, 109.77, 58.31, 53.06, 44.92, 43.60, 39.48, 39.35, 37.56, 26.04, 24.19, 24.19. HRMS for [C21H32N5O2] + calculated 386.2551 found 386.2570.

PAPER

Organic Preparations and Procedures International, 40(4), 391-394; 2008

https://www.tandfonline.com/doi/abs/10.1080/00304940809458099

PATENTS

US 3907801

ES 526304

EP 395192

EP 565274

EP 634411

EP 680961

US 5521313

Indian Pat. Appl., 2011MU01860,

PATENTS

WO 2014152737

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014152737

Syn

J Med Chem 1972,15(5),477-479

DE 2057845; FR 2073406; GB 1332194; US 3717634

The condensation of 1-(2-pyrimidinyl)piperazine (I) with 3-chloro-1-cyanopropane (II) by means of Na2CO3 in n-butanol gives 4-(2-pyrimidinyl)-1-(3-cyanopropyl)piperazine (III). This product is reduced with LiAlH4 or with H2 and Raney-Ni yielding 4-(2-pyrimidinyl)-1-(4-aminobutyl)piperazine (IV), which is finally condensed with 8-oxaspiro[4.5]decane-7,9-dione-(3,3-tetramethylene-glutaric anhydride) (V) in pyridine.

CLIP

Anxiolytics (Tranquilizers)

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Buspirone

Buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro [4,5] decan-7,9-dione (5.2.6), is synthesized by the reaction of 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) with 8-oxaspiro[4,5]decan-7,9-dione (5.2.5). In turn, 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) is synthesized by the reaction of 1-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile, giving 4-(2-pyrimidyl)-1-(3-cyanopropyl)piperazine (5.2.3), which is hydrogenated with Raney nickel into buspirone (5.2.4) [51–55].

Buspirone is an extremely specific drug that could possibly represent a new chemical class of anxiolytics—azaspirones. As an anxiolytic, its activity is equal to that of benzodiazepines; however, it is devoid of anticonvulsant and muscle relaxant properties, which are characteristic of benzodiazepines. It does not cause dependence or addiction. The mechanism of its action is not conclusively known. It does not act on the GABA receptors, which occurs in benzodiazepine use; however, it has a high affinity for seratonin (5-HT) receptors and a moderate affinity for dopamine (D2) receptors. Buspirone is effective as an anxiolytic. A few side effects of buspirone include dizziness, drowsiness, headaches, nervousness, fatigue, and weakness. This drug is intended for treatment of conditions of anxiety in which stress, muscle pain, rapid heart rate, dizziness, fear, etc. are observed; in other words, conditions of anxiety not associated with somewhat common, usual, and everyday stress. Synonyms for buspirone are anizal, axoren, buspar, buspimen, buspinol, narol, travin, and others.

CLIP

Applications of Biocatalysis for Pharmaceuticals and Chemicals

Ramesh N. Patel, in Organic Synthesis Using Biocatalysis, 2016

5.2 Enzymatic Preparation of 6-Hydroxybuspirone

Buspirone (Buspar®59, Figure 11.17) is a drug used for the treatment of anxiety and depression, thought to produce its effects by binding to the serotonin 5HT1A receptor [114–116]. Mainly as a result of hydroxylation reactions, it is extensively converted to various metabolites and blood concentrations return to low levels a few hours after dosing [117]. A major metabolite, 6-hydroxybuspirone, produced by the action of liver cytochrome P450 CYP3A4, was present at much higher concentrations in human blood than buspirone itself. For development of 6-hydroxybuspirone as a potential antianxiety drug, preparation and testing of the two enantiomers as well as the racemate was of interest. An enantioselective microbial reduction process was developed for the reduction of 6-oxobuspirone 60 to (R)-6-hydroxybuspirone 61a or (S)-6-hydroxybuspitone 61b. About 150 microbial cultures were screened for the enantioselective reduction of 60Rhizopus stolonifer SC 13898, Neurospora crassa SC 13816, Mucor racemosus SC 16198, and Pseudomonas putida SC 13817 gave >50% reaction yields and >95% ee of (S)-6-hydroxybuspirone 61a. The yeast strains Hansenula polymorpha SC 13845 and Candida maltosa SC 16112 gave (R)-6-hydroxybuspirone in >60% reaction yield and >97% ee [118]. The NADPH-dependent (R)-reductase (RHBR) from H. polymorpha SC 13845 was purified to homogeneity, its N-terminal and internal amino acid sequences were determined and the corresponding gene was cloned and expressed in E. coli. To regenerate the NADPH required for reduction, glucose-6-phosphate dehydrogenase gene from Saccharomyces cerevisiae was cloned and coexpressed in the same E. coli strain. Recombinant cultures coexpressing (R)-reductase (RHBR) and glucose 6-phosphate dehydrogenase catalyzed the reduction of 6-ketobuspirone to (R)-6-hydroxybuspirone 61a in 99% yield and 99.9% ee at 50 g/L substrate input [119].

The NADH-dependent (S)-reductase (SHBR) from P. putida SC 16269 was also purified to homogeneity, its N-terminal and internal amino acid sequences were determined and the corresponding gene was cloned and expressed in E. coli. To regenerate the NADH required for reduction, the NAD+ dependent formate dehydrogenase gene from Pichia pastoris was also cloned and co-expressed in the same E. coli strain. Recombinant E. coli coexpressing (S)-reductase and formate dehydrogenase was used to catalyze the reduction of 6-ketobuspirone to (S)-6-hydroxybuspirone 61b, in >98% yield and >99.8% ee at 50 g/L substrate input [119].

PATENT

https://patents.google.com/patent/US6686361

The present invention relates to methods of treating anxiety and depression using R-6-hydroxy-buspirone and pharmaceutical compositions containing R-6-hydroxy-buspirone.

Buspirone, chemically: 8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione, is approved for the treatment of anxiety disorders and depression by the United States Food and Drug Administration. It is available under the trade name BUSPAR® from Bristol-Myers Squibb Company.

Studies have shown that buspirone is extensively metabolized in the body. (See, for example, Mayol, et al., Clin. Pharmacol. Ther., 37, p. 210, 1985). One of the metabolites is 6-hydroxy-8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione having Formula I. This metabolite is also known as BMS 28674, BMS 442608, or

Figure US06686361-20040203-C00001

as 6-hydroxy-buspirone. This compound is believed to be the active metabolite of buspirone and its use in treating anxiety disorders and depression is disclosed in U.S. Pat. No. 6,150,365. The specific stereochemistry of 6-hydroxy-buspirone has not been described previously. Neither racemic 6-hydroxy-buspirone nor its enantiomers are commercially available at the present time.

Preclinical studies demonstrate that 6-hydroxy-buspirone, like buspirone, demonstrates a strong affinity for the human 5-HT1A receptor. In functional testing, 6-hydroxy-buspirone produced a dose-dependent anxiolytic response in the rat pup ultrasonic vocalization test, a sensitive method for assessment of anxiolytic and anxiogenic effects (Winslow and Insel, 1991, Psychopharmacology, 105:513-520).

Clinical studies in volunteers orally dosed with buspirone demonstrate that 6-hydroxy-buspirone blood plasma levels were not only 30 to 40 times higher but were sustained compared to buspirone blood plasma levels. The time course of 6-hydroxy-buspirone blood plasma levels, unlike buspirone blood plasma levels, correlate more closely with the sustained anxiolytic effect seen following once or twice a day oral dosing with buspirone.

Although buspirone is an effective treatment for anxiety disorders and depression symptomatology in a significant number of patients treated, about a third of patients get little to no relief from their anxiety and responders often require a week or more of buspirone treatment before experiencing relief from their anxiety symptomatology. Further, certain adverse effects are reported across the patient population. The most commonly observed adverse effects associated with the use of buspirone include dizziness, nausea, headache, nervousness, lightheadedness, and excitement. Also, since buspirone can bind to central dopamine receptors, concern has been raised about its potential to cause unwanted changes in dopamine-mediated neurological functions and a syndrome of restlessness, appearing shortly after initiation of oral buspirone treatment, has been reported in small numbers of patients. While buspirone lacks the prominent sedative effects seen in more typical anxiolytics such as the benzodiazepines, patients are nonetheless advised against operating potentially dangerous machinery until they experience how they are affected by buspirone.

It can be seen that it is desirable to find a medicament with buspirone’s advantages but which demonstrates more robust anxiolytic potency with a lack of the above described adverse effects.

Formation of 6-hydroxy-buspirone occurs in the liver by action of enzymes of the P450 system, specifically CYP3A4. Many substances such as grapefruit juice and certain other drugs; e.g. erythromycin, ketoconazole, cimetidine, etc., are inhibitors of the CYP3A4 isozyme and may interfere with the formation of this active metabolite from buspirone. For this reason it would be desirable to find a compound with the advantages of buspirone but without the drug—drug interactions when coadministered with agents affecting the activity level of the CYP3A4 isozyme.

EXAMPLE 3One-Step Synthesis of 6-Hydroxy-buspirone (I)

Buspirone (19.3 g, 50 mmole) was dissolved in dry THF (400 mL) and the resulting solution was cooled to −78° C. A solution of KN(SiMe3)in toluene (100 mL, 1 M) was added slowly. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent, prepared according to literature method: F. A. Davis, et al., Org. Synth., 1988, 66, 203) (17.0 g, 65 mmole) in dry THF (150 mL, precooled to −78° C.) was added quickly via a cannular. After stirred for 30 mins at −78° C., the reaction was quenched with 1 N HCl solution (500 mL). It was extracted with EtOAc (3×500 mL). The aqueous layer was separated, neutralized with saturated sodium bicarbonate solution, and extracted with EtOAc (3×500 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid residue which was subjected to column chromatography using CH2Cl2/MeOH/NH4OH (200:10:1) as the eluent to give pure 6-hydroxy-buspirone (I, 7.2 g) and a mixture of buspirone and 6-hydroxy-buspirone (I). The mixture was purified by above column chromatography to afford another 3.3 g of pure 6-hydroxy-buspirone (I).

1H NMR (CDCl3) δ8.30 (d, J=4.7 Hz, 2H), 6.48 (t, J=4.7 Hz, 1H), 4.20 (s, 1H), 3.83-3.72 (m, 5H), 3.55 (s, 1H), 2.80 (d, J=17.5 Hz, 1H), 2.55-2.40 (m, 7H), 2.09-2.03 (m, 1H), 1.76-1.54 (m, 10 H), 1.41-1.36 (m, 1H), 1.23-1.20 (m, 1H).

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External links

  •  Media related to Buspirone at Wikimedia Commons
  • “Buspirone”Drug Information Portal. U.S. National Library of Medicine.
Clinical data
Pronunciation/ˈbjuːspɪroʊn/ (BEW-spi-rohn)
Trade namesBuspar, Namanspin
Other namesMJ 9022-1[1]
AHFS/Drugs.comMonograph
MedlinePlusa688005
Pregnancy
category
AU: B1
Routes of
administration
By mouth
ATC codeN05BE01 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability3.9%[2]
Protein binding86–95%[3]
MetabolismLiver (via CYP3A4)[7][8]
Metabolites5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP[4][5][6]
Elimination half-life2.5 hours[7]
ExcretionUrine: 29–63%[3]
Feces: 18–38%[3]
Identifiers
showIUPAC name
CAS Number36505-84-7 
33386-08-2 (hydrochloride)
PubChem CID2477
IUPHAR/BPS36
DrugBankDB00490 
ChemSpider2383 
UNIITK65WKS8HL
KEGGD07593 
ChEBICHEBI:3223 
ChEMBLChEMBL49 
CompTox Dashboard (EPA)DTXSID2022707 
ECHA InfoCard100.048.232 
Chemical and physical data
FormulaC21H31N5O2
Molar mass385.512 g·mol−1
3D model (JSmol)Interactive image
hideSMILESO=C1N(CCCCN2CCN(CC2)C3=NC=CC=N3)C(CC4(CCCC4)C1)=O
hideInChIInChI=1S/C21H31N5O2/c27-18-16-21(6-1-2-7-21)17-19(28)26(18)11-4-3-10-24-12-14-25(15-13-24)20-22-8-5-9-23-20/h5,8-9H,1-4,6-7,10-17H2 Key:QWCRAEMEVRGPNT-UHFFFAOYSA-N 

////////////Buspirone, буспирон , بوسبيرون , 丁螺酮 , Anxiolytic,Arylpiperazines,  Serotonin Receptor Agonist, Ansial, Vita,  Ansiced,  Abello,  Axoren, Glaxo Wellcome,  Bespar, BMS,  Buspar, Buspimen, Menarini,  Buspinol, Zdravlje,  Buspisal, Lesvi,  Narol, Almirall,

#Buspirone, #буспирон , #بوسبيرون , #丁螺酮 , #Anxiolytic, #Arylpiperazines,  #Serotonin Receptor Agonist, #Ansial, #Vita,  #Ansiced,  #Abello,  #Axoren, #Glaxo Wellcome,  #Bespar, #BMS,  #Buspar, #Buspimen, Menarini,  Buspinol, Zdravlje,  Buspisal, Lesvi,  Narol, Almirall,

Tasimelteon, タシメルテオン


ChemSpider 2D Image | Tasimelteon | C15H19NO2

Tasimelteon.png

Tasimelteon

N-([(1R,2R)-2-(2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl)propanamide,

609799-22-6 [RN]
8985
Hetlioz [Trade name]
N-{[(1R,2R)-2-(2,3-Dihydro-1-benzofuran-4-yl)cyclopropyl]methyl}propanamide [ACD/IUPAC Name]
Propanamide, N-[[(1R,2R)-2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]- [ACD/Index Name]
SHS4PU80D9

609799-22-6 cas, BMS-214778; VEC-162, ATC:N05CH03

  • Use:Treatment of sleep disorder; Melatonin receptor agonist
  • (1R,2R)-N-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide
  • Formula:C15H19NO2, MW:245.3 g/mol
  • Hetlioz Vanda Pharmaceuticals, 2014

Approved fda 2014

EMA

Tasimelteon is a white to off-white crystalline powder, it is non hygroscopic, soluble in water across relevant pH values and freely soluble in alcohols, cyclohexane, and acetonitrile. Conducted in vivo studies demonstrate that tasimelteon is highly permeable substance. Photostability testing and testing on stress conditions demonstrated that the active substance degrades in light.

Tasimelteon exhibits stereoisomerism due to the presence of two chiral centres. Active substance is manufactured as a single, trans-1R,2R isomer. Enantiomeric purity is controlled routinely during manufacture of active substance intermediates by chiral HPLC/specific optical rotation and additionally controlled in the active substance. Stability data indicates tasimelteon is isomerically stable.

Polymorphism has been observed in polymorphic screening studies for tasimelteon and two forms have been identified. The thermodynamically more stable form has been chosen for development and the manufacturing process consistently yields active substance of single, desired polymorphic form. It was demonstrated that milling of the active substance does not affect polymorphic form. Polymorphism is additionally controlled in active substance release and shelf-life specifications using X-ray powder diffraction analysis.

Tasimelteon is synthesized in nine main steps using linear synthesis and using commercially available well-defined starting materials with acceptable specifications. Three intermediates are isolated for control of active substance quality including stereochemical control. The active substance is isolated by slow recrystallisation or precipitation of tasimelteon from an ethanol/water mixture which ensures the formation of desired polymorphic form. Up to two additional, optional recrystallisations may be performed for unmilled tasimelteon to ensure that milled tasimelteon active substance is of high purity. Seed crystals complying with active substance specifications can be used optionally. Active substance is jet milled (micronised) to reduce and control particle size, which is critical in finished product performance with regards to content uniformity and dissolution…….http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003870/WC500190309.pdf

launched in 2014 in the U.S. by Vanda Pharmaceuticals for the treatment of non-24-hour sleep-wake disorder in totally blind subjects. In 2015, the European Committee for Medicinal Products of the European Medicines Agency granted approval for the same indication.  In 2010 and 2011, orphan drug designations were assigned for the treatment of non-24 hour sleep/wake disorder in blind individuals without light perception in the U.S. and the E.U., respectively.

Tasimelteon (trade name Hetlioz) is a drug approved by the U.S. Food and Drug Administration (FDA)[2] in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD).[3] In June 2014, the European Medicines Agency accepted an EU filing application for tasimelteon[4] and in July 2015, the drug was approved in Europe for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults,[5] but not in the rarer case of non-24 in sighted people.

Tasimelteon is a selective agonist for the melatonin receptors MT1 and MT2, similar to other members of the melatonin receptor agonistclass of which ramelteon (2005) and agomelatine (2009) were the first approved.[6] As a treatment for N24HSWD, as with melatonin or other melatonin derivatives, the patient may experience improved sleep timing while taking the drug. Reversion to baseline sleep performance occurs within a month of discontinuation.[7]

Image result for TASIMELTEON DRUG FUTURE

Development

Tasimelteon (previously known as BMS-214,778) was developed for the treatment of insomnia and other sleep disorders. A phase II trial on circadian rhythm sleep disorders was concluded in March 2005.[8] A phase III insomnia trial was conducted in 2006.[9] A second phase III trial on insomnia, this time concerning primary insomnia, was completed in June 2008.[10] In 2010, the FDA granted orphan drug status to tasimelteon, then regarded as an investigational medication, for use in totally blind adults with N24HSWD.[11] (Through mechanisms such as easing the approval process and extending exclusivity periods, orphan drug status encourages development of drugs for rare conditions that otherwise might lack sufficient commercial incentive.)

On completion of Phase III trials, interpretations of the clinical trials by the research team concluded that the drug may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.[12] A year-long (2011–2012) study at Harvard tested the use of tasimelteon in blind subjects with non-24-hour sleep-wake disorder. The drug has not been tested in children nor in any non-blind people.

FDA approval

In May 2013 Vanda Pharmaceuticals submitted a New Drug Application to the Food and Drug Administration for tasimelteon for the treatment of non-24-hour sleep–wake disorder in totally blind people. It was approved by the FDA on January 31, 2014 under the brand name Hetlioz.[3] In the opinion of Public Citizen, an advocacy group, the FDA erroneously allowed it to be labelled without stating that it is only approved for use by totally blind people.[13] However, FDA updated its press release on Oct. 2, 2014 to clarify the approved use of Hetlioz, which includes both sighted and blind individuals. The update did not change the drug labeling (prescribing information).[14]

Toxicity

Experiments with rodents revealed fertility impairments, an increase in certain cancers, and serious adverse events during pregnancy at dosages in excess of what is considered the “human dose”.[15][16]

As expected, advisors to the US Food and Drug Administration have recommended approval of Vanda Pharmaceuticals’ tasimelteon, to be sold as Hetlioz, for the treatment of non-24-hour disorder in the totally blind.http://www.pharmatimes.com/Article/13-11-14/FDA_panel_backs_Vanda_body_clock_drug_for_blind.aspx

The master body clock controls the timing of many aspects of physiology, behavior and metabolism that show daily rhythms, including the sleep-wake cycles, body temperature, alertness and performance, metabolic rhythms and certain hormones which exhibit circadian variation. Outputs from the

suprachiasmatic nucleus (SCN) control many endocrine rhythms including those of melatonin secretion by the pineal gland as well as the control of Cortisol secretion via effects on the hypothalamus, the pituitary and the adrenal glands. This master body clock, located in the SCN, spontaneously generates rhythms of approximately 24.5 hours. These non-24-hour rhythms are synchronized each day to the 24-hour day-night cycle by light, the primary environmental time cue which is detected by specialized cells in the retina and transmitted to the SCN via the retino-hypothalamic tract. Inability to detect this light signal, as occurs in most totally blind individuals, leads to the inability of the master body clock to be reset daily and maintain entrainment to a 24-hour day.

Non-24-Hour Disorder, Non-24, also referred to as Non-24-Hour Sleep-Wake Disorder, (N24HSWD) or Non-24-Hour Disorder, is an orphan indication affecting approximately 65,000 to 95,000 people in the U.S. and 140,000 in Europe. Non- 24 occurs when individuals, primarily blind with no light perception, are unable to synchronize their endogenous circadian pacemaker to the 24-hour light/dark cycle. Without light as a synchronizer, and because the period of the internal clock is typically a little longer than 24 hours, individuals with Non-24 experience their circadian drive to initiate sleep drifting later and later each day. Individuals with Non-24 have abnormal night sleep patterns, accompanied by difficulty staying awake during the day. Non-24 leads to significant impairment, with chronic effects impacting the social and occupational functioning of these individuals.

In addition to problems sleeping at the desired time, individuals with Non-24 experience excessive daytime sleepiness that often results in daytime napping.

The severity of nighttime sleep complaints and/or daytime sleepiness complaints varies depending on where in the cycle the individual’s body clock is with respect to their social, work, or sleep schedule. The “free running” of the clock results in approximately a 1-4 month repeating cycle, the circadian cycle, where the circadian drive to initiate sleep continually shifts a little each day (about 15 minutes on average) until the cycle repeats itself. Initially, when the circadian cycle becomes desynchronous with the 24h day-night cycle, individuals with Non-24 have difficulty initiating sleep. As time progresses, the internal circadian rhythms of these individuals becomes 180 degrees out of synchrony with the 24h day-night cycle, which gradually makes sleeping at night virtually impossible, and leads to extreme sleepiness during daytime hours.

Eventually, the individual’s sleep-wake cycle becomes aligned with the night, and “free-running” individuals are able to sleep well during a conventional or socially acceptable time. However, the alignment between the internal circadian rhythm and the 24-hour day-night cycle is only temporary.

In addition to cyclical nighttime sleep and daytime sleepiness problems, this condition can cause deleterious daily shifts in body temperature and hormone secretion, may cause metabolic disruption and is sometimes associated with depressive symptoms and mood disorders.

It is estimated that 50-75% of totally blind people in the United States (approximately 65,000 to 95,000) have Non-24. This condition can also affect sighted people. However, cases are rarely reported in this population, and the true rate of Non-24 in the general population is not known.

The ultimate treatment goal for individuals with Non-24 is to entrain or synchronize their circadian rhythms into an appropriate phase relationship with the 24-hour day so that they will have increased sleepiness during the night and increased wakefulness during the daytime. Tasimelteon

Tasimelteon is a circadian regulator which binds specifically to two high affinity melatonin receptors, Mella (MT1R) and Mellb (MT2R). These receptors are found in high density in the suprachiasmatic nucleus of the brain (SCN), which is responsible for synchronizing our sleep/wake cycle. Tasimelteon has been shown to improve sleep parameters in prior clinical studies, which simulated a desynchronization of the circadian clock. Tasimelteon has so far been studied in hundreds of individuals and has shown a good tolerability profile.

Tasimelteon has the chemical name: tr ns-N-[[2-(2,3-dihydrobenzofuran- 4-yl)cycloprop-lyl] methyl] propanamide, has the structure of Formula I:

Figure imgf000008_0001

Formula I

and is disclosed in US 5856529 and in US 20090105333, both of which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about 78°C (DSC) and is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG- 400), and only slightly soluble in water. The native pH of a saturated solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times greater affinity for MT2R relative to MTIR. It’s affinity (¾) for MTIR is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in the practice of this invention because it is a melatonin agonist that has been demonstrated, among other activities, to entrain patients suffering from Non-24.

Metabolites of tasimelteon include, for example, those described in “Preclinical Pharmacokinetics and Metabolism of BMS-214778, a Novel

Melatonin Receptor Agonist” by Vachharajani et al., J. Pharmaceutical Sci., 92(4):760-772, which is hereby incorporated herein by reference. The active metabolites of tasimelteon can also be used in the method of this invention, as can pharmaceutically acceptable salts of tasimelteon or of its active metabolites. For example, in addition to metabolites of Formula II and III, above, metabolites of tasimelteon also include the monohydroxylated analogs M13 of Formula IV, M12 of Formula V, and M14 of Formula VI.

Formula IV

Figure imgf000010_0001

Formula V

MO

Figure imgf000010_0002

Formula VI

Thus, it is apparent that this invention contemplates entrainment of patients suffering free running circadian rhythm to a 24 hour circadian rhythm by administration of a circadian rhythm regulator (i.e., circadian rhythm modifier) capable of phase advancing and/or entraining circadian rhythms, such as a melatonin agonist like tasimelteon or an active metabolite oftasimelteon or a pharmaceutically acceptable salt thereof. Other MT1R and MT2R agonists, i.e., melatonin agonists, can have similar effects on the master body clock. So, for example, this invention further contemplates the use of melatonin agonists such as but not limited to melatonin, N-[l-(2,3-dihydrobenzofuran-4- yl)pyrrolidin-3-yl]-N-ethylurea and structurally related compounds as disclosed in US 6,211,225, LY-156735 ((R)-N-(2-(6-chloro-5-methoxy-lH-indol- 3yl) propyl) acetamide) (disclosed in U.S. Patent No. 4,997,845), agomelatine (N- [2-(7-methoxy-l-naphthyl)ethyl]acetamide) (disclosed in U.S. Patent No.

5,225,442), ramelteon ((S)-N-[2-(l,6,7,8-tetrahydro-2H-indeno- [5,4-b] furan-8- yl)ethyl]propionamide), 2-phenylmelatonin, 8-M-PDOT, 2-iodomelatonin, and 6- chloromelatonin.

Additional melatonin agonists include, without limitation, those listed in U.S. Patent Application Publication No. 20050164987, which is incorporated herein by reference, specifically: TAK-375 (see Kato, K. et al. Int. J.

Neuropsychopharmacol. 2000, 3 (Suppl. 1): Abst P.03.130; see also abstracts P.03.125 and P.03.127), CGP 52608 (l-(3-allyl-4-oxothiazolidine-2-ylidene)-4- met- hylthiosemicarbazone) (See Missbach et al., J. Biol. Chem. 1996, 271, 13515-22), GR196429 (N-[2-[2,3,7,8-tetrahydro-lH-fur-o(2,3-g)indol-l- yl] ethyl] acetamide) (see Beresford et al., J. Pharmacol. Exp. Ther. 1998, 285, 1239-1245), S20242 (N-[2-(7-methoxy napth-l-yl) ethyl] propionamide) (see Depres-Brummer et al., Eur. J. Pharmacol. 1998, 347, 57-66), S-23478 (see Neuropharmacology July 2000), S24268 (see Naunyn Schmiedebergs Arch. June 2003), S25150 (see Naunyn Schmiedebergs Arch. June 2003), GW-290569, luzindole (2-benzyl-N-acetyltryptamine) (see U.S. Patent No. 5,093,352), GR135531 (5-methoxycarbonylamino-N-acetyltrypt- amine) (see U.S. Patent Application Publication No. 20010047016), Melatonin Research Compound A, Melatonin Agonist A (see IMSWorld R&D Focus August 2002), Melatonin

Analogue B (see Pharmaprojects August 1998), Melatonin Agonist C (see Chem. Pharm. Bull. (Tokyo) January 2002), Melatonin Agonist D (see J. Pineal Research November 2000), Melatonin Agonist E (see Chem. Pharm. Bull. (Tokyo) Febrary 2002), Melatonin Agonist F (see Reprod. Nutr. Dev. May 1999), Melatonin Agonist G (see J. Med. Chem. October 1993), Melatonin Agonist H (see Famaco March 2000), Melatonin Agonist I (see J. Med. Chem. March 2000), Melatonin Analog J (see Bioorg. Med. Chem. Lett. March 2003), Melatonin Analog K (see MedAd News September 2001), Melatonin Analog L, AH-001 (2-acetamido-8- methoxytetralin) (see U.S. Patent No. 5,151,446), GG-012 (4-methoxy-2- (methylene propylamide)indan) (see Drijfhout et al., Eur. J. Pharmacol. 1999, 382, 157-66), Enol-3-IPA, ML-23 (N-2,4-dinitrophenyl-5-methoxy-tryptamine ) (see U.S. Patent No. 4,880,826), SL-18.1616, IP-100-9 (US 5580878), Sleep Inducing Peptide A, AH-017 (see U.S. Patent No. 5,151,446), AH-002 (8-methoxy- 2-propionamido-tetralin) (see U.S. Patent No. 5,151,446), and IP-101.

Metabolites, prodrugs, stereoisomers, polymorphs, hydrates, solvates, and salts of the above compounds that are directly or indirectly active can, of course, also be used in the practice of this invention.

Melatonin agonists with a MT1R and MT2R binding profile similar to that of tasimelteon, which has 2 to 4 time greater specificity for MT2R, are preferred.

Tasimelteon can be synthesized by procedures known in the art. The preparation of a 4-vinyl-2,3-dihydrobenzofuran cyclopropyl intermediate can be carried out as described in US7754902, which is incorporated herein by reference as though fully set forth.

Pro-drugs, e.g., esters, and pharmaceutically acceptable salts can be prepared by exercise of routine skill in the art.

In patients suffering a Non-24, the melatonin and Cortisol circadian rhythms and the natural day/night cycle become desynchronized. For example, in patients suffering from a free-running circadian rhythm, melatonin and Cortisol acrophases occur more than 24 hours, e.g., >24.1 hours, prior to each previous day’s melatonin and Cortisol acrophase, respectively, resulting in desynchronization for days, weeks, or even months, depending upon the length of a patient’s circadian rhythm, before the melatonin, Cortisol, and day /night cycles are again temporarily synchronized.

Chronic misalignment of Cortisol has been associated with metabolic, cardiac, cognitive, neurologic, neoplastic, and hormonal disorders. Such disorders include, e.g., obesity, depression, neurological impairments.

Structure-activity relationship
SAR
Figure : Melatonin receptor agonists. The applied colors indicate the mutual properties with the general melatonin receptor agonists pharmacophore.

INTRODUCTION

Tasimelteon has the chemical name: trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1yl]methyl]propanamide, has the structure of Formula I:

Figure US20130197076A1-20130801-C00001

and is disclosed in U.S. Pat. No. 5,856,529 and in US 20090105333, both of which are incorporated herein by reference as though fully set forth.

Tasimelteon is a white to off-white powder with a melting point of about 78° C. (DSC) and is very soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG-400), and only slightly soluble in water. The native pH of a saturated solution of tasimelteon in water is 8.5 and its aqueous solubility is practically unaffected by pH. Tasimelteon has 2-4 times greater affinity for MT2R relative to MT1R. It’s affinity (Ki) for MT1R is 0.3 to 0.4 and for MT2R, 0.1 to 0.2. Tasimelteon is useful in the practice of this invention because it is a melatonin agonist that has been demonstrated, among other activities, to entrain patients suffering from Non-24.

SYNTHESIS

(1R-trans)-N-[[2 – (2,3-dihydro-4 benzofuranyl) cyclopropyl] methyl] propanamide PATENT: BRISTOL-MYERS SQUIBB PRIORITY DATE: 1996 HYPNOTIC

Synthesis Tasimelteon

PREPARATION OF XV

XXIV D-camphorsulfonic acid IS REACTED WITH THIONYL CHLORIDE TO GIVE

…………XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

TREATED WITH

XXVI ammonium hydroxide

TO GIVE

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

TREATED WITH AMBERLYST15

….XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

TREATED WITH LAH, ie double bond is reduced to get

…..XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Intermediate

I 3-hydroxybenzoic acid methyl ester

II 3-bromo-1-propene

III 3 – (2-propenyloxy) benzoic acid methyl ester

IV 3-hydroxy-2-(2-propenyl) benzoic acid methyl ester

V 2,3-dihydro-4-hydroxy-2-benzofurancarboxylic acid methyl ester

VI benzofuran-4-carboxylic acid methyl ester

VII benzofuran-4-carboxylic acid

VIII 2,3-dihydro-4-benzofurancarboxylic acid

IX 2,3-dihydro-4-benzofuranmethanol

X 2,3-dihydro-4-benzofurancarboxaldehyde

XI Propanedioic acid

XII (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoic acid

XIII thionyl chloride

XIV (E) -3 – (2,3-dihydro-4-benzofuranyl) propenoyl chloride

XV (3aS, 6R, 7aR)-hexahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

XVI (3aS,6R,7aR)-1-[(E)-3-(2,3-dihydro-4-benzofuranyl)-1-oxo-2-propenyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVII (3aS,6R,7aR)-1-[[(1R,2R)-2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]carbonyl]hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide

XVIII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanol

XIX [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarboxaldehyde

XX hydroxylamine hydrochloride

XXI [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanecarbaldehyde oxime

XXII [R-(R *, R *)] -2 – (2,3-dihydro-4-benzofuranyl) cyclopropanemethanamine

XXIII propanoyl chloride

XXIV D-camphorsulfonic acid

XXV (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonyl chloride

XXVI ammonium hydroxide

XXVII (1S, 4R) -7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonamide

XXVIII (3aS, 6R) -4,5,6,7-tetrahydro-8 ,8-dimethyl-3H-3a ,6-methano-2 ,1-benzisothiazole-2 ,2-dioxide

Bibliography

– Patents: Benzofuran and dihydrobenzofuran melatonergic agents: US5856529 (1999)

Priority: US19960032689P, 10 Dec. 1996 (Bristol-Myers Squibb Company, U.S.)

– Preparation III (quinazolines): US2004044015 (2004) Priority: EP20000402845, 13 Oct. 2000

– Preparation of VII (aminoalkylindols): Structure-Activity Relationships of Novel Cannabinoid Mimetics Eissenstat et al, J.. Med. Chem. 1995, 38, 3094-3105

– Preparation XXVIII: Towson et al. Organic Syntheses, Coll. Vol. 8, p.104 (1993) Vol. 69, p.158 (1990)

– Preparation XV: Weismiller et al. Organic Syntheses, Coll. Vol. 8, p.110 (1993) Vol. 69, p.154 (1990).

– G. Birznieks et al. Melatonin agonist VEC-162 Improves sleep onset and maintenance in a model of transient insomnia. Sleep 2007, 30, 0773 Abstract.

-. Rajaratnam SM et al, The melatonin agonist VEC-162 Phase time immediately advances the human circadian system, Sleep 2006, 29, 0159 Abstract.

-. AK Singh et al, Evolution of a manufacturing route for a highly potent drug candidate, 229th ACS Natl Meet, March 13-17, 2005, San Diego, Abstract MEDI 576.

– Vachharajani NN et al, Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist, J Pharm Sci. 2003 Apr; 92 (4) :760-72.

. – JW Scott et al, Catalytic Asymmetric Synthesis of a melotonin antagonist; synthesis and process optimization. 223rd ACS Natl Meet, April 7-11, Orlando, 2002, Abstract ORGN 186.

SYNTHESIS CONSTRUCTION AS IN PATENT

WO1998025606A1

GENERAL SCHEMES

Reaction Scheme 1

Figure imgf000020_0001

The syntheses of the 4-aryl-propenoic acid derivatives, 2 and 3, are shown in Reaction Scheme 1. The starting aldehydes, 1 , can be prepared by methods well known to those skilled in the art. Condensation of malonic acid with the aldehydes, 1, in solvents such as pyridine with catalysts such as piperidine or pyrrolidine, gives the 4-aryl- propenoic acid, 2. Subsequent conversion of the acid to the acid chloride using reagents such as thionyl chloride, phosphoryl chloride, or the like, followed by reaction with N,0-dimethyl hydroxylamine gives the amide intermediate 3 in good yields. Alternatively, aldehyde 1 can be converted directly to amide 3 using reagents such as diethyl (N-methoxy- N-methyl-carbamoylmethyl)phosphonate with a strong base such as sodium hydride.

Reaction Scheme 2

Figure imgf000020_0002

The conversion of the amide intermediate 3 to the racemic, trans- cyclopropane carboxaldehyde intermediate, 4, is shown in Reaction Scheme 2. Intermediate 3 was allowed to react with cyclopropanating reagents such as trimethylsulfoxonium iodide and sodium hydride in solvents such as DMF, THF, or the like. Subsequent reduction using reagents such as LAH in solvents such as THF, ethyl ether, or the like, gives the racemic, trans-cyclopropane carboxaldehyde intermediates, 4.

Reaction Scheme 3

Figure imgf000021_0001

Racemic cyclopropane intermediate 5 (R = halogen) can be prepared from intermediate 2 as shown in Reaction Scheme 3. Intermediate 2 was converted to the corresponding allylic alcohol by treatment with reducing agents such as sodium borohydride plus iodine in solvents such as THF. Subsequent acylation using reagents such as acetic anhydride in pyridine or acetyl chloride gave the allylic acetate which was allowed to react with cyclopropanating reagents such as sodium chloro-difluoroacetate in diglyme to provide the racemic, trans- cyclopropane acetate intermediates, 5. Reaction Scheme 4

Figure imgf000022_0001

The conversion of the acid 2 to the chiral cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, is shown in Reaction Scheme 4. Intermediate 2 is condensed with (-)-2,10-camphorsultam under standard conditions, and then cyclopropanated in the presence of catalysts such as palladium acetate using diazomethane generated from reagents such as 1-methyl-3-nitro-1-nitrosoguanidine. Subsequent reduction using reagents such as LAH in solvents such as THF, followed by oxidation of the alcohol intermediates using reagents such as DMSO/oxalyl chloride, or PCC, gives the cyclopropane carboxaldehyde intermediate, (-)-(trans)-4, in good yields. The enantiomer, (+)-(trans)-4, can also be obtained employing a similar procedure using (+)-2,10- camphorsultam in place of (-)-2,10-camphorsultam.

When it is desired to prepare compounds of Formula I wherein m = 2, the alcohol intermediate may be activated in the conventional manner such as with mesyl chloride and treated with sodium cyanide followed by reduction of the nitrile group with a reducing agent such as LAH to produce the amine intermediate 6.

Reaction Scheme 5

Figure imgf000023_0001
Figure imgf000023_0002

Reaction Scheme 5 shows the conversion of intermediates 4 and 5 to the amine intermediate, 7, and the subsequent conversion of 6. or 7 to compounds of Formula I. The carboxaldehyde intermediate, 4, is condensed with hydroxylamine and then reduced with reagents such as LAH to give the amine intermediate, 7. The acetate intermediate 5 is hydrolyzed with potassium hydroxide to the alcohol, converted to the mesylate with methane sulfonyl chloride and triethyl amine in CH2CI2and then converted to the azide by treatment with sodium azide in solvents such as DMF. Subsequent reduction of the azide group with a reducing agent such as LAH produced the amine intermediate 7. Further reaction of 6 or 7 with acylating reagents gives compounds of Formula I. Suitable acylating agents include carboxylic acid halides, anhydrides, acyl imidazoles, alkyl isocyanates, alkyl isothiocyanates, and carboxylic acids in the presence of condensing agents, such as carbonyl imidazole, carbodiimides, and the like. Reaction Scheme 6

Figure imgf000024_0001

Reaction Scheme 6 shows the alkylation of secondary amides of Formula I (R2 = H) to give tertiary amides of Formula I (R2 = alkyl). The secondary amide is reacted with a base such as sodium hydride, potassium tert-butoxide, or the like, and then reacted with an alkylating reagent such as alkyl halides, alkyl sulfonate esters, or the like to produce tertiary amides of Formula I.

Reaction Scheme 7

Figure imgf000024_0002

Reaction Scheme 7 shows the halogenation of compounds of Formula I. The carboxamides, i (Q1 = Q2 = H), are reacted with excess amounts of halogenating agents such as iodine, N-bromosuccinimide, or the like to give the dihalo-compounds of Formula I (Q1 = Q2 = halogen). Alternatively, a stoichiometric amount of these halogenating agents can be used to give the monohalo-compounds of Formula I (Q1 = H, Q2 = halogen; or Q1 = halogen, Q2 = H). In both cases, additives such as lead IV tetraacetate can be used to facilitate the reaction. Biological Activity of the Compounds

The compounds of the invention are melatonergic agents. They have been found to bind human melatonergic receptors expressed in a stable cell line with good affinity. Further, the compounds are agonists as determined by their ability, like melatonin, to block the forskolin- stimulated accumulation of cAMP in certain cells. Due to these properties, the compounds and compositions of the invention should be useful as sedatives, chronobiotic agents, anxiolytics, antipsychotics, analgesics, and the like. Specifically, these agents should find use in the treatment of stress, sleep disorders, seasonal depression, appetite regulation, shifts in circadian cycles, melancholia, benign prostatic hyperplasia and related conditions

EXPERIMENTAL PROCEDURES

SEE ORIGINAL PATENT FOR CORECTIONS

Preparation 1

Benzofuran-4-carboxaldehyde

Step 1 : N-Methoxy-N-methyl-benzofuran-4-carboxamide

A mixture of benzofuran-4-carboxylic acid [Eissenstat, et al.. J. Medicinal Chemistry, 38 (16) 3094-3105 (1995)] (2.8 g, 17.4 mmol) and thionyl chloride (25 mL) was heated to reflux for 2 h and then concentrated in vacuo. The solid residue was dissolved in ethyl acetate (50 mL) and a solution of N,O-dimethylhydroxylamine hydrochloride (2.8 g) in saturated NaHC03(60 mL) was added with stirring. After stirring for 1.5 h, the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with saturated NaHCO3 and concentrated in vacuo to give an oil (3.2 g, 95.4%).

Step 2: Benzofuran-4-carboxaldehyde

A solution of N-methoxy-N-methyl-benzofuran-4-carboxamide (3.2 g, 16.6 mmol) in THF (100 mL) was cooled to -45°C and then LAH (0.7 g, 18.7 mmol) was added. The mixture was stirred for 15 min, allowed to warm to -5°C, and then recooled to -45°C. Saturated KHS04 (25 mL) was added with vigorous stirring, and the mixture was allowed to warm to room temperature. The precipitate was filtered and washed with acetone. The filtrate was concentrated in vacuo to give an oil (2.3 g, 94%). Preparation 2

2,3-Dihydrobenzofuran-4-carboxaldehyde

Step 1 : 2,3-Dihydrobenzofuran-4-carboxylic acid

Benzofuran-4-carboxylic acid (10.0 g, 61 .7 mmol) was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd/C (2 g) for 12 hr. The mixture was filtered and the filtrate was diluted with water (500 mL) to give 2,3- dihydrobenzofuran-4-carboxylic acid as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-187.5°C).

Step 2: (2,3-Dihydrobenzofuran-4-yl)methanol

A solution of 2,3-dihydrobenzofuran-4-carboxylic acid (10 g, 61 mmol) in THF (100 mL) was stirred as LAH (4.64 g, 122 mmol) was slowly added. The mixture was heated to reflux for 30 min. The mixture was cooled and quenched cautiously with ethyl acetate and then with 1 N HCI (150 mL). The mixture was then made acidic with 12 N HCI until all the inorganic precipitate dissolved. The organic layer was separated, and the inorganic layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, and then concentrated in vacuo. This oil was Kϋgelrohr distilled to a clear oil that crystallized upon cooling (8.53 g, 87.6%).

Step 3: 2.3-Dihydrobenzofuran-4-carboxaldehyde

DMSO (8.10 mL, 1 14 mmol) was added at -78°C to a stirred solution of oxalyl chloride in CH2CI2 (40 mL of a 2M solution). A solution of (2,3- dihydrobenzofuran-4-yl)methanol (8.53 g, 56.9 mmol) in CH2CI2 (35 mL) was added dropwise, and the solution stirred at -78°C for 30 min. Triethyl amine (33 mL, 228 mmol) was added cautiously to quench the reaction. The resulting suspension was stirred at room temperature for 30 min and diluted with CH2CI2 (100 mL). The organic layer was washed three times with water, and twice with brine, and then concentrated in vacuo to an oil (8.42 g, 100%) that was used without purification.

Preparation 16

(±)-(trans)-2-(2,3-Dihyd robenzofuran-4-yl)cyclopropane- carboxaldehyde

Step 1 : (±Htrans)-N-Methoxy-N-methyl-2-(2.3-dihydrobenzofuran-4- yhcyclopropanecarboxamide

Trimethylsulfoxonium iodide (9.9 g, 45 mmol) was added in small portions to a suspension of sodium hydride (1 .8 g, 45 mmol) in DMF (120 mL). After the foaming had subsided (10 min), a solution of (trans)- N-methoxy-N-methyl-3-(2,3-dihydrobenzofuran-4-yl)propenamide (3.5 g, 15 mmol) in DMF (60 mL) was added dropwise, with the temperature maintained between 35-40°C. The mixture was stirred for 3 h at room temperature. Saturated NH4CI (50 mL) was added dropwise and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with H2O and brine, dried over K2CO3, and concentrated in vacuo to give a white wax (3.7 g, 100%).

Step 2: (±)-(trans)- 2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde

A solution of (±)-(trans)-N-methoxy-N-methyl-2-(2,3-dihydrobenzofuran- 4-yl)cyclopropanecarboxamide (3.7 g, 15 mmol) in THF (10 mL) was added dropwise to a rapidly stirred suspension of LAH (683 mg, 18 mmol) in THF (50 mL) at -45°C, maintaining the temperature below -40°C throughout. The cooling bath was removed, the reaction was allowed to warm to 5°C, and then the reaction was immediately recooled to -45°C. Potassium hydrogen sulfate (3.4 g, 25.5 mmol) in H20 (50 mL) was cautiously added dropwise, the temperature maintained below – 30°C throughout. The cooling bath was removed and the suspension was stirred at room temperature for 30 min. The mixture was filtered through Celite and the filter cake was washed with ether. The combined filtrates were then washed with cold 1 N HCI, 1 N NaOH, and brine. The filtrates were dried over MgSO4, and concentrated in vacuo to give a clear oil (2.6 g, 99%).

Preparation 18

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde

Step 1 : (-Htrans)-N-[3-(2.3-Dihvdrobenzofuran-4-yl)-propenoyll-2.10- camphorsultam

To a solution of (-)-2,10-camphorsultam (8.15 g, 37.9 mmol) in 50 mL toluene at 0°C was added sodium hydride (1.67 g, 41.7 mmol). After stirring for 0.33 h at 0°C and 0.5 h at 20°C and recooling to 0°C, a solution of 3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl chloride
(37.9 mmol), prepared in situ from the corresponding acid and thionyl chloride (75 mL), in toluene (50 mL), was added dropwise. After stirring for 18 h at 20°C, the mixture was diluted with ethyl acetate and washed with water, 1 N HCI, and 1 N NaOH. The organic solution was dried and concentrated in vacuo to give 15.8 g of crude product. Recrystallization form ethanol-methanol (600 mL, 1 :1) gave the product (13.5 g, 92%, mp 199.5-200°C).

Step 2: (-)-N-[[(trans)-2-(2,3-Dihydrobenzofuran-4-yl)-cyclopropylj- carbonylj-2, 10-camphorsultam

1 -Methyl-3-nitro-1 -nitrosoguanidine (23.88g 163 mmol) was added in portions to a mixture of 10 N sodium hydroxide (60 mL) and ether (200 mL) at 0°C. The mixture was shaken vigorously for 0.25 h and the ether layer carefully decanted into a solution of (-)-N-[3-(2,3-dihydrobenzofuran-4-yl)-2-propenoyl]-2,10-camphorsultam (9.67 g, 25 mmol) and palladium acetate (35 mg) in methylene chloride (200 mL). After stirring for 18 h, acetic acid (5 mL) was added to the reaction and the mixture stirred for 0.5 h. The mixture was washed with 1 N HCI, 1 N NaOH and brine. The solution was dried, concentrated in vacuo and the residue crystallized twice from ethanol to give the product (6.67 g, 66.5%, mp 157-159°C).

Step 3: (-)-(trans)-2-(2,3-Dihydrobenzofuran-4-yl)cyclopropane- methanol

A solution of (-)-N-[(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclo-propanecarbonylj-2,10-camphorsultam (4.3 g, 10.7 mmol) in THF (50 mL) was added dropwise to a mixture of LAH (0.81 g, 21.4 mmol) in THF (50 mL) at -45°C. The mixture was stirred for 2 hr while it warmed to 10°C. The mixture was recooled to -40°C and hydrolyzed by the addition of saturated KHS0 (20 mL). The mixture was stirred at room temperature for 30 minutes and filtered. The precipitate was washed twice with acetone. The combined filtrate and acetone washes were concentrated in vacuo. The gummy residue was dissolved in ether, washed with 1 N NaOH and 1 N HCI, and then dried in vacuo to give the product (2.0 g, 98.4%).

Step 4: (-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane- carboxaldehyde DMSO (1.6 g, 21 mmol) was added to oxalyl chloride in CH2CI2(7.4 mL of 2 M solution, 14.8 mmole) at -78°C. The (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropylmethanol (2.0 g, 10.5 mmol) in CH2CI2(15 mL) was added. The mixture was stirred for 20 min and then triethylamine (4.24 g, 42 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min. The mixture was diluted with CH2CI2 and washed with water, 1 N HCI, and then 1 N NaOH. The organic layer was dried and concentrated iι> vacuo to give the aldehyde product (1.98 g, 100%).

Preparation 24

(-)-(trans)-2-(2.3-Dihydrobenzofuran-4-yl)cyclopropane-methanamine A mixture of (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-carboxaldehyde (1.98 g, 10.5 mmol), hydroxylamine hydrochloride (2.29 g, 33 mmol), and 30% NaOH (3.5 mL, 35 mmol), in 5:1
ethanol/water (50 mL) was heated on a steam bath for 2 h. The solution was concentrated in vacuo. and the residue mixed with water. The mixture was extracted with CH2CI2. The organic extracts were dried and concentrated in vacuo to give a solid which NMR analysis showed to be a mixture of the cis and trans oximes. This material was dissolved in THF (20 mL) and added to solution of alane in THF [prepared from LAH (1.14 g, 30 mmol) and H2S04 (1.47 g, 15 mmol) at 0°Cj. The reaction was stirred for 18 h, and quenched successively with water (1.15 mL), 15% NaOH (1.15 mL), and then water (3.45 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was mixed with ether and washed with water and then 1 N HCI. The acid washes were made basic and extracted with CH2CI . The extracts were dried and concentrated in vacuo to give the amine product (1.4 g, 70.5%). The amine was converted to the fumarate salt in ethanol (mp: 197-198°C).
Anal. Calc’d for C12H15NO • C4H404: C, 62.94; H, 6.27; N, 4.59.
Found: C, 62.87; H, 6.31 ; N, 4.52.

FINAL PRODUCT TASIMELTEON

Example 2

(-)-(trans)-N-[[2-(2,3-Dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl]propanamide

This compound was prepared similar to the above procedure using propionyl chloride and (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)- cyclopropanemethanamine to give an oil that solidified upon standing to an off-white solid (61 %, mp: 71-72°C). IR (NaCI Film): 3298, 1645, 1548, 1459, 1235 cm“1.

Mo5 : -17.3°

Anal. Calc’d for C15H19N02: C, 73.44; H, 7.87; N, 5.71 . Found: C, 73.28; H, 7.68; N, 5.58

SYNTHESIS

Synthesis Path

SYN

Tasimelteon (Hetlioz)Tasimelteon, which is marketed by Vanda Pharmaceuticals as Hetlioz and developed in partnership with Bristol-Myers Squibb,is a drug that was approved by the US FDA in January 2014 for the treatment of non-24-hour sleep–wake disorder (also called Non-24, N24 and N24HSWD).234 Tasimelteon is a melatonin MT1
and MT2 receptor agonist; because it exhibits a greater affinity to the MT2 receptor than MT1, is also known as Dual Melatonin
Receptor Agonist.234 Two randomized controlled trials (phases II
and III) demonstrated that tasimelteon improved sleep latency
and maintenance of sleep with a shift in circadian rhythms, and
therefore has the potential to treat patients with transient insomnia
associated with circadian rhythm sleep disorders.235 Preclinical
studies showed that the drug has similar phase-shifting properties
to melatonin, but with less vasoconstrictive effects.236 The most
likely scale preparation of the drug, much of which has been published
in the chemical literature, is described below in Scheme 44.
Activation of commercial bis-ethanol 250 with 2.5 equivalents
of the Vilsmeier salt 251 followed by treatment with base resulted
an intramolecular cyclization reaction with the proximal phenol
and concomitant elimination of the remaining imidate to deliver
the vinylated dihydrobenzofuran 252 in 76% yield.237 Interestingly,
this reaction could be performed on multi-kilogram scale, required
no chromatographic purification, and generated environmentallyfriendly
DMF and HCl as byproducts.237 Sharpless asymmetric
dihydroxylation of olefin 252 delivered diol 253 in 86% yield and
impressive enantioselectivity (>99% ee). This diol was then activated
with trimethylsilyl chloride and then treated with base to generate epoxide 254.238 Next, a modified Horner–Wadsworth–
Emmons reaction involving triethylphosphonoacetate (TEPA, 255)
was employed to convert epoxide 254 to cyclopropane 256.239
The reaction presumably proceeds through removal of the acidic
TEPA proton followed by nucleophilic attack at the terminal epoxide
carbon. The resulting alkoxide undergoes an intramolecular
phosphoryl transfer reaction resulting in an enolate, which then attacked the newly formed phosphonate ester in an SN2 fashion
resulting in the trans-cyclopropane ester, which was ultimately
saponified and re-acidified to furnish cyclopropane acid 256.239
Conversion of this acid to the corresponding primary amide preceded
carbonyl reduction with sodium borohydride. The resulting
amine was acylated with propionyl chloride to furnish tasimelteon
(XXXI) as the final product in 86% yield across the four-step
sequence.

PATENTS

US2010261786 10-15-2010 PREDICTION OF SLEEP PARAMETER AND RESPONSE TO SLEEP-INDUCING COMPOUND BASED ON PER3 VNTR GENOTYPE
US2009209638 8-21-2009 TREATMENT FOR DEPRESSIVE DISORDERS
US6060506 5-10-2000 Benzopyran derivatives as melatonergic agents
US5981571 11-10-1999 Benzodioxa alkylene ethers as melatonergic agents
WO9825606 6-19-1998 BENZODIOXOLE, BENZOFURAN, DIHYDROBENZOFURAN, AND BENZODIOXANE MELATONERGIC AGENTS
WO2007137244A1 * May 22, 2007 Nov 29, 2007 Gunther Birznieks Melatonin agonist treatment
US4880826 Jun 25, 1987 Nov 14, 1989 Nava Zisapel Melatonin antagonist
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extra info

Org. Synth.199069, 154
(−)-D-2,10-CAMPHORSULTAM
[3H-3a,6-Methano-2,1-benzisothiazole, 4,5,6,7-tetrahydro-8,8-dimethyl-2,2-dioxide, (3aS)-]
Submitted by Michael C. Weismiller, James C. Towson, and Franklin A. Davis1.
Checked by David I. Magee and Robert K. Boeckman, Jr..
1. Procedure
(−)-2,10-Camphorsultam. A dry, 2-L, three-necked, round-bottomed flask is equipped with a 1.5-in egg-shaped Teflon stirring bar, a 250-mL addition funnel, and a 300-mL Soxhlet extraction apparatus equipped with a mineral oil bubbler connected to an inert-gas source. The flask is charged with 600 mL of dry tetrahydrofuran (THF) (Note 1) and6.2 g (0.16 mol) of lithium aluminum hydride (Note 2). Into the 50-mL Soxhlet extraction thimble is placed 35.0 g (0.16 mol) of (−)-(camphorsulfonyl)imine (Note 3) and the reaction mixture is stirred and heated at reflux. After all of the(camphorsulfonyl)imine has been siphoned into the reaction flask (3–4 hr), the mixture is allowed to cool to room temperature. The unreacted lithium aluminum hydride is cautiously hydrolyzed by dropwise addition of 200 mL of 1 Nhydrochloric acid via the addition funnel (Note 4). After the hydrolysis is complete the contents of the flask are transferred to a 1-L separatory funnel, the lower, silver-colored aqueous layer is separated, and the upper layer placed in a 1-L Erlenmeyer flask. The aqueous phase is returned to the separatory funnel and washed with methylene chloride (3 × 100 mL). After the reaction flask is rinsed with methylene chloride (50 mL), the organic washings are combined with the THF phase and dried over anhydrous magnesium sulfate for 10–15 min. Filtration through a 300-mL sintered-glass funnel of coarse porosity into a 1-L round-bottomed flask followed by removal of the solvent on arotary evaporator gives 33.5 g (95%) of the crude (−)-2,10-camphorsultam. The crude sultam is placed in a 250-mL Erlenmeyer flask and crystallized from approximately 60 mL of absolute ethanol. The product is collected on a 150-mL sintered-glass funnel of coarse porosity and dried in a vacuum desiccator to give 31.1 g (88%) of the pure sultam. A second crop of crystals can be gained by evaporating approximately half the filtrate; the residue is crystallized as above to give 1.4 g (4%). The combined yield of white crystalline solid, mp 183–184°C, [α]D −30.7° (CHCl3, c 2.3) is92% (Note 5) and (Note 6).
2. Notes
1. Tetrahydrofuran (Aldrich Chemical Company, Inc.) was distilled from sodium benzophenone.
2. Lithium aluminum hydride was purchased from Aldrich Chemical Company, Inc.
3. (−)-(Camphorsulfonyl)imine, [(7S)-(−)-10,10-dimethyl-5-thia-4-azatricyclo[5.2.1.03,7]dec-3-ene 5,5-dioxide] was prepared by the procedure of Towson, Weismiller, Lal, Sheppard, and Davis, Org. Synth., Coll. Vol. VIII1993, 104.
4. The addition must be very slow at first (1 drop/5 sec) until the vigorous reaction has subsided.
5. The NMR spectrum of (−)-2,10-camphorsultam is as follows: 1H NMR (CDCl3) δ: 0.94 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.33 (m, 1 H), 1.47 (m,, 1 H), 1.80–2.05 (5 H), 3.09 (d, 1 H, J = 14), 3.14 (d, 1 H, J = 14), 3.43 (m, 1 H), 4.05 (br s, 1 H, NH); 13C NMR (CDCl3) δ: 20.17 (q, CH3), 26.51 (t), 31.55 (t), 35.72 (t), 44.44 (d), 47.15 (s), 50.08 (t), 54.46 (s), 62.48 (d).
6. Checkers obtained material having the same mp (183–184°C) and [α]D − 31.8° (CHCl3c 2.3).
3. Discussion
(−)-2,10-Camphorsultam was first prepared by the catalytic hydrogenation of (−)-(camphorsulfonyl)imine overRaney nickel.2 Lithium aluminum hydride reduction was used by Oppolzer and co-workers in their synthesis of the sultam.3,4 However, because of the low solubility of the sultam in tetrahydrofuran, a large amount of solvent was required.4 In the procedure described here the amount of solvent is significantly reduced by using a Soxhlet extractor to convey the imine slowly into the reducing medium.5
Oppolzer’s chiral auxiliary,6 (−)-2,10-camphorsultam, is useful in the asymmetric Diels–Alder reaction,3,4 and for the preparation of enantiomerically pure β-substituted carboxylic acids7 and diols,8 in the stereoselective synthesis of Δ2-isoxazolines,9 and in the preparation of N-fluoro-(−)-2,10-camphorsultam, an enantioselective fluorinating reagent.10

References and Notes
  1. Department of Chemistry, Drexel University, Philadelphia, PA 19104.
  2. Shriner, R. L.; Shotton, J. A.; Sutherland, H. J. Am. Chem. Soc.193860, 2794.
  3. Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Helv. Chim. Acta198467, 1397.
  4. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron198642, 4035.
  5. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, G.; Carroll,, P. J. J. Am. Chem. Soc.1988110, 8477.
  6. Oppolzer, W. Tetrahedron198743, 1969.
  7. Oppolzer, W.; Mills, R. J.; Pachinger, W.; Stevenson, T. Helv. Chim. Acta198669, 1542; Oppolzer, W.; Schneider, P. Helv. Chim. Acta198669, 1817; Oppolzer, W.; Mills, R. J.; Réglier, M. Tetrahedron Lett.198627, 183; Oppolzer, W.; Poli. G.Tetrahedron Lett.198627, 4717; Oppolzer, W.; Poli, G.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett.198829, 3559.
  8. Oppolzer, W.; Barras, J-P. Helv. Chim. Acta198770, 1666.
  9. Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Lett.198829, 3555.
  10. Differding, E.; Lang, R. W. Tetrahedron Lett.198829, 6087.

Org. Synth.199069, 158
(+)-(2R,8aS)-10-(CAMPHORYLSULFONYL)OXAZIRIDINE
[4H-4A,7-Methanooxazirino[3,2-i][2,1]benzisothiazole, tetrahydro-9,9-dimethyl-, 3,3-dioxide, [4aS-(4aα,7α,8aR*)]]
Submitted by James C. Towson, Michael C. Weismiller, G. Sankar Lal, Aurelia C. Sheppard, Anil Kumar, and Franklin A. Davis1.
Checked by David I. Magee and Robert K. Boeckman, Jr..
1. Procedure
A. (+)-(1S)-10-Camphorsulfonamide. Into a 2-L, two-necked, round-bottomed flask, equipped with a 250-mL dropping funnel, a magnetic stirring bar, and a reflux condenser fitted with an outlet connected to a disposable pipettedipped in 2 mL of chloroform in a test tube for monitoring gas evolution, were placed 116 g (0.5 mol) ofcamphorsulfonic acid (Note 1) and 750 mL of reagent-grade chloroform. The suspension of camphorsulfonic acid was heated to reflux and 71.4 g (43.77 mL, 0.6 mol, 1.2 equiv) of freshly distilled thionyl chloride was added dropwise over a 1-hr period. Heating was continued until gas evolution (sulfur dioxide and hydrogen chloride) had ceased (approximately 9–10 hr). The resultant solution of camphorsulfonyl chloride in chloroform was converted tocamphorsulfonamide without further purification.
In a 5-L, two-necked, round-bottomed flask fitted with a 250-mL dropping funnel and a mechanical stirrer was placed a solution of 1.6 L of reagent-grade ammonium hydroxide solution and the flask was cooled to 0°C in an ice bath. The solution of the crude camphorsulfonyl chloride, prepared in the preceding section, was added dropwise to the ammonium hydroxide solution at 0–10°C over a period of 1 hr. The reaction mixture was warmed to room temperature, stirred for 4 hr, the organic layer separated, and the aqueous layer was extracted with methylene chloride (3 × 250 mL). The combined organic layers were washed with brine (250 mL) and dried over anhydrousmagnesium sulfate. Removal of the solvent on the rotary evaporator gave 104.0 g (90%) of the crudecamphorsulfonamide (Note 2) and (Note 3).
B. (−)-(Camphorsulfonyl)imine. A 1-L, round-bottomed flask is equipped with a 2-in. egg-shaped magnetic stirring bar, a Dean–Stark water separator, and a double-walled condenser containing a mineral oil bubbler connected to an inert gas source. Into the flask are placed 5 g of Amberlyst 15 ion-exchange resin (Note 4) and 41.5 g of the crude(+)-(1S)-camphorsulfonamide in 500 mL of toluene. The reaction mixture is heated at reflux for 4 hr. After the reaction flask is cooled, but while it is still warm (40–50°C), 200 mL of methylene chloride is slowly added to dissolve any(camphorsulfonyl)imine that crystallizes. The solution is filtered through a 150-mL sintered glass funnel of coarse porosity an the reaction flask and filter funnel are washed with an additional 75 mL of methylene chloride.
Isolation of the (−)-(camphorsulfonyl)imine is accomplished by removal of the toluene on the rotary evaporator. The resulting solid is recrystallized from absolute ethanol (750 mL) to give white crystals, 34.5–36.4 g (90–95%), mp225–228°C; [α]D −32.7° (CHCl3, c 1.9) (Note 5).
C. (+)-(2R, 8aS)-10-Camphorylsulfonyloxaziridine. A 5-L, three-necked, round-bottomed Morton flask is equipped with an efficient mechanical stirrer, a 125-mm Teflon stirring blade, a Safe Lab stirring bearing (Note 6), and a 500-mL addition funnel. Into the flask are placed the toluene solution of (−)-(camphorsulfonyl)imine (39.9 g, 0.187 mol)prepared in Step B and a room-temperature solution of 543 g (3.93 mol, 7 equiv based on oxone) of anhydrouspotassium carbonate dissolved in 750 mL of water. The reaction mixture is stirred vigorously and a solution of 345 g (0.56 mol, 6 equiv of KHSO5) of oxone dissolved in 1250 mL of water is added dropwise in three portions over 45 min(Note 7) and (Note 8). Completion of the oxidation is determined by TLC (Note 9) and the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity to remove solids. The filtrate is transferred to a 3-L separatory funnel, the toluene phase is separated and the aqueous phase is washed with methylene chloride (3 × 100 mL). The filtered solids and any solids remaining in the Morton flask are washed with an additional 200 mL of methylene chloride. The organic extracts are combined and washed with 100 mL of saturated sodium sulfite, dried over anhydrousmagnesium sulfate for 15–20 min, filtered, and concentrated on the rotary evaporator. The resulting white solid is crystallized from approximately 500 mL of hot 2-propanol to afford, after drying under vacuum in a desiccator, 35.9 g(84%) of white needles, mp 165–167°C, [α]D +44.6° (CHCl3, c 2.2) (Note 10) and (Note 11).
(−)-(2S,8aR)-10-(camphorylsulfonyl)oxaziridine is prepared in a similar manner starting from (−)-10-camphorsulfonic acid; mp 166–167°C, [α]D +43.6° (CHCl3, c 2.2).
2. Notes
1. (1S)-(+)-10-Camphorsulfonic acid was purchased from Aldrich Chemical Company, Inc.
2. The crude sulfonamide is contaminated with 5–10% of the (camphorsulfonyl)imine, the yield of which increases on standing.
3. The 1H NMR spectrum of (+)-(1S)-10-camphorsulfonamide is as follows: (CDCl3) δ: 0.93 (s, 3 H, CH3), 1.07 (s, 3 H, CH3), 1.40–2.50 (m, 7 H), 3.14 and 3.53 (AB quartet, 2 H, CH2-SO2J = 15.1), 5.54 (br s, 2 H, NH2).
4. Amberlyst 15 ion-exchange resin is a strongly acidic, macroreticular resin purchased from Aldrich Chemical Company, Inc.
5. The spectral properties of (−)-(camphorsulfonyl)imine are as follows: 1H NMR (CDCl3) δ: 1.03 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.45–2.18 (m, 6 H), 2.65 (m, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH2-SO2J = 14.0); 13C NMR (CDCl3) δ: 19.01 (q, CH3), 19.45 (q, CH3), 26.64 (t), 28.44 (t), 35.92 (t), 44.64 (d), 48.00 (s), 49.46 (t), 64.52 (s), 195.52 (s); IR (CHCl3) cm−1: 3030, 2967, 1366. Checkers obtained material having identical melting point and [α]D−32.3° (CHCl3, c 1.8).
6. The SafeLab Teflon bearing can be purchased from Aldrich Chemical Company, Inc. A glass stirring bearing lubricated with silicone grease is unsatisfactory because the dissolved salts solidify in the shaft, causing freezing.
7. Efficient stirring is important and indicated by a milky white appearance of the solution.
8. Occasionally batches of oxone purchased from Aldrich Chemical Company, Inc., have exhibited reduced reactivity in this oxidation. Oxone exposed to moisture prior to use also gives reduced reactivity in this oxidation. If this occurs, oxone is added until oxidation is complete as determined by TLC (Note 9). Potassium carbonate is added as needed to maintain the pH at approximately 9.0. Oxone stored in the refrigerator under an inert atmosphere has shown no loss in reactivity for up to 6 months.
9. Oxidation is generally complete after addition of the oxone solution. The oxidation is monitored by TLC as follows. Remove approximately 0.5 mL of the toluene solution from the nonstirring solution, spot a 250-μm TLC silica gel plate, elute with methylene chloride, and develop with 10% molybdophosphoric acid in ethanol and heating(camphorsulfonyl)imine Rf = 0.28 and (camphorylsulfonyl)oxaziridine Rf = 0.62. If (camphorsulfonyl)imine is detected, stirring is continued at room temperature until the reaction is complete (see (Note 8)). If the reaction mixture takes on a brownish color after addition of oxone and has not gone to completion after 30 min, the reaction mixture is filtered through a 150-mL sintered-glass funnel of coarse porosity, and the solids are washed with 50 mL of methylene chloride. The aqueous/organic extracts are returned to the 5-L Morton flask and stirred vigorously and 52 g (0.08 mol, 1 equiv KHSO5) of oxone is added over 5 min and stirring continued until oxidation is complete (approximately 10–15 min).
10. The submitters employed a toluene solution of crude imine prepared in Part B and obtained somewhat higher yields (90–95%). However, the checkers obtained yields in this range on one half the scale using isolatedsulfonylimine.
11. The spectral properties of (+)-(camphorsulfonyl)oxaziridine are as follows: 1H NMR (CDCl3) δ: 1.03 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.45–2.18 (m, 6 H), 2.65 (d, 1 H), 3.10 and 3.28 (AB quartet, 2 H, CH2-SO2J = 14.0); 13C NMR (CDCl3) δ: 19.45 (q, CH3), 20.42 (q, CH3), 26.55 (t), 28.39 (t), 33.64 (t), 45.78 (d), 48.16 (s), 48.32 (t), 54.07 (s), 98.76 (s). The checkers obtained material (mp 165–167°C) having [α]D +44.7° (CHCl3, c 2.2).
3. Discussion
Camphorsulfonamide, required for the preparation of the (camphorsulfonyl)imine, was previously prepared in two steps. The first step involved conversion of camphorsulfonic acid to the sulfonyl chloride with PCl5 or SOCl2. The isolated sulfonyl chloride was converted in a second step to the sulfonamide by reaction with ammonium hydroxide. This modified procedure is more efficient because it transforms camphorsulfonic acid directly to camphorsulfonamide, avoiding isolation of the camphorsulfonyl chloride.
(Camphorsulfonyl)imine has been reported as a by-product of reactions involving the camphorsulfonamide.2,3,4,5Reychler in 1898 isolated two isomeric camphorsulfonamides,2 one of which was shown to be the(camphorsulfonyl)imine by Armstrong and Lowry in 1902.3 Vandewalle, Van der Eycken, Oppolzer, and Vullioud described the preparation of (camphorsulfonyl)imine in 74% overall yield from 0.42 mol of the camphorsulfonyl chloride.6 The advantage of the procedure described here is that, by using ammonium hydroxide, the camphorsulfonyl chloride is converted to the sulfonamide in >95% yield.7 The sulfonamide is of sufficient purity that it can be used directly in the cyclization step, which, under acidic conditions, is quantitative in less than 4 hr. These modifications result in production of the (camphorsulfonyl)imine in 86% overall yield from the sulfonyl chloride.
In addition to the synthesis of enantiomerically pure (camphorylsulfonyl)oxaziridine7 and its derivatives,8 the(camphorsulfonyl)imine has been used in the preparation of (−)-2,10-camphorsultam (Oppolzers’ auxiliary),6,9 (+)-(3-oxocamphorysulfonyl) oxaziridine,10 and the N-fluoro-2,10-camphorsultam, an enantioselective fluorinating reagent.11
The N-sulfonyloxaziridines are an important class of selective, aprotic oxidizing reagents.121314 Enantiomerically pure N-sulfonyloxaziridines have been used in the asymmetric oxidation of sulfides to sulfoxides (30–91% ee),15selenides to selenoxides (8–9% ee).16 disulfides to thiosulfinates (2–13% ee),5 and in the asymmetric epoxidation of alkenes (19–65% ee).17,18 Oxidation of optically active sulfonimines (R*SO2N=CHAr) affords mixtures of N-sulfonyloxaziridine diastereoisomers requiring separation by crystallization and/or chromatography.3
(+)-(Camphorylsulfonyl)oxaziridine described here is prepared in four steps from inexpensive (1S)-(+)- or (1R)-(+)-10-camphorsulfonic acid in 77% overall yield.7 Separation of the oxaziridine diastereoisomers is not required because oxidation is sterically blocked from the exo face of the C-N double bond in the (camphorsulfonyl)imine. In general, (camphorsulfonyl)oxaziridine exhibits reduced reactivity compared to other N-sulfonyloxaziridines. For example, while sulfides are asymmetrically oxidized to sulfoxides (3–77% ee), this oxaziridine does not react with amines or alkenes.7 However, this oxaziridine is the reagent of choice for the hydroxylation of lithium and Grignard reagents to give alcohols and phenols because yields are good to excellent and side reactions are minimized.19 This reagent has also been used for the stereoselective oxidation of vinyllithiums to enolates.20
The most important synthetic application of the (camphorylsulfonyl)oxaziridines is the asymmetric oxidation of enolates to optically active α-hydroxy carbonyl compounds.14,21,22,23,24 Chiral, nonracemic α-hydroxy carbonylcompounds have been used extensively in asymmetric synthesis, for example, as chiral synthons, chiral auxiliaries, and chiral ligands. This structural array is also featured in many biologically active natural products. This oxidizing reagent gives uniformly high chemical yields regardless of the counterion, and stereoselectivities are good to excellent (50–95% ee).9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 Since the configuration of the oxaziridine three-membered ring controls the stereochemistry, both α-hydroxy carbonyl optical isomers are readily available. Representative examples of the asymmetric oxidation of prochiral enolates by (+)-(2R,8aS)-camphorylsulfonyl)oxaziridine are given in Tables I and II.

This preparation is referenced from:

  • Org. Syn. Coll. Vol. 8, 110
  • Org. Syn. Coll. Vol. 9, 212
  • References and Notes
    1. Department of Chemistry, Drexel University, Philadelphia, PA 19104.
    2. Reychler, M. A. Bull. Soc. Chim. III188919, 120.
    3. Armstrong, H. E.; Lowry, T. M. J. Chem. Soc., Trans.190281, 1441.
    4. Dauphin, G.; Kergomard, A.; Scarset, A. Bull. Soc. Chim. Fr.1976, 862.
    5. Davis, F. A.; Jenkins, Jr., R. H.; Awad, S. B.; Stringer, O. D.; Watson, W. H.; Galloy, J. J. Am. Chem. Soc.1982104, 5412.
    6. Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetrahedron198642, 4035.
    7. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.; Carroll, P. J. J. Am. Chem. Soc.1988110, 8477.
    8. Davis, F. A.; Weismiller, M. C.; Lal, G. S.; Chen, B. C.; Przeslawski, R. M. Tetrahedron Lett.198930, 1613.
    9. Oppolzer, W. Tetrahedron198743, 1969.
    10. Glahsl, G.; Herrmann, R. J. Chem. Soc., Perkin Trans. I1988, 1753.
    11. Differding, E.; Lang, R. W. Tetrahedron Lett.198829, 6087.
    12. For recent reviews on the chemistry of N-sulfonyloxaziridines, see: (a) Davis, F. A.; Jenkins, Jr., R. H. in “Asymmetric Synthesis,” Morrison, J. D., Ed.; Academic Press: Orlando, FL, 1984, Vol. 4, Chapter 4;
    13. Davis, F. A.; Haque, S. M. in “Advances in Oxygenated Processes,” Baumstark, A. L., Ed.; JAI Press: London, Vol. 2;
    14. Davis, F. A.; Sheppard, A. C. Tetrahedron198945, 5703.
    15. Davis, F. A.; McCauley, Jr., J. P.; Chattopadhyay, S.; Harakal, M. E.; Towson, J. C.; Watson, W. H.; Tavanaiepour, I. J. Am. Chem. Soc.1987109, 3370.
    16. Davis, F. A.; Stringer, O. D.; McCauley, Jr., J. M. Tetrahedron198541, 4747.
    17. Davis, F. A.; Chattopadhyay, S. Tetrahedron Lett.198627, 5079.
    18. Davis, F. A.; Harakal, M. E.; Awad, S. B. J. Am. Chem. Soc.1983105, 3123.
    19. Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick S. Tetrahedron Lett.198728, 5115.
    20. Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett.198829, 4269.
    21. Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem.198651, 2402.
    22. Davis, F. A.; Haque, M. S. J. Org. Chem.198651, 4083; Davis, F. A.; Haque, M. S.; Przeslawski, R. M. J. Org. Chem.198954, 2021.
    23. Davis, F. A.; Ulatowski, T. G.; Haque, M. S. J. Org. Chem.198752, 5288.
    24. Davis, F. A.; Sheppard, A. C., Lal, G. S. Tetrahedron Lett.198930, 779.
    25. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M. S. J. Am. Chem. Soc.1990112, 6679.

a US 5 856 529 (Bristol-Myers Squibb; 5.1.1999; appl. 9.12.1997; USA-prior. 10.12.1996).

    • b US 7 754 902 (Vanda Pharms.; 13.7.2010; appl. 18.5.2006).
  • treatment of circadian rhythm disorders:

    • US 8 785 492 (Vanda Pharms.; 22.7.2014; appl. 25.1.2013; USA-prior. 26.1.2012).
  • synthesis cis-isomer:

    • US 6 214 869 (Bristol-Myers Squibb; 10.4.2001; appl. 25.5.1999; USA-prior. 5.6.1998).

Patents

  1. USUS5856529 A
  2. USUS8785492 B2
  3. US5856529
  4. US8785492
  5. US9060995
  6. US9549913
  7. US9539234
  8. US9730910
  9. USRE46604
  10. US9855241

References

  1. Jump up^ “Tasimelteon Advisory Committee Meeting Briefing Materials”(PDF). Vanda Pharmaceuticals Inc. November 2013.
  2. Jump up^ “FDA transcript approval minutes” (PDF). FDA. November 14, 2013.
  3. Jump up to:a b Food and Drug Administration (January 31, 2014). “FDA approves Hetlioz: first treatment for non-24 hour sleep-wake disorder”. FDA.
  4. Jump up^ “tasimelteon (Hetlioz) UKMi New Drugs Online Database”. Retrieved August 6, 2014.
  5. Jump up^ “HETLIOZ® Receives European Commission Approval for the Treatment of Non-24-Hour Sleep-Wake Disorder in the Totally Blind”MarketWatch. PR Newswire. 7 July 2015. Retrieved 8 July 2015.
  6. Jump up^ Vachharajani, Nimish N.; Yeleswaram, Krishnaswamy; Boulton, David W. (April 2003). “Preclinical pharmacokinetics and metabolism of BMS-214778, a novel melatonin receptor agonist”. Journal of Pharmaceutical Sciences92 (4): 760–72. doi:10.1002/jps.10348PMID 12661062.
  7. Jump up^ Sack, R. L.; Brandes, R. W.; Kendall, A. R.; Lewy, A. J. (2000). “Entrainment of Free-Running Circadian Rhythms by Melatonin in Blind People”. New England Journal of Medicine343 (15): 1070–7. doi:10.1056/NEJM200010123431503PMID 11027741.
  8. Jump up^ “Safety and Efficacy of VEC-162 on Circadian Rhythm in Healthy Adult Volunteers”. ClinicalTrials.gov. |accessdate=May 15, 2014
  9. Jump up^ “VEC-162 Study in Healthy Adult Volunteers in a Model of Insomnia”. ClinicalTrials.gov. Retrieved May 15, 2014.
  10. Jump up^ “VEC-162 Study in Adult Patients With Primary Insomnia”. ClinicalTrials.gov. Retrieved May 15, 2014.
  11. Jump up^ Lynne Lamberg. “Improving Sleep and Alertness in the Blind (Part 5)”Matilda Ziegler Magazine for the Blind. Retrieved May 15, 2014.
  12. Jump up^ Shantha MW Rajaratnam; Mihael H Polymeropoulos; Dennis M Fisher; Thomas Roth; Christin Scott; Gunther Birznieks; Elizabeth B Klerman (2009-02-07). “Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials”The Lancet373 (9662): 482–491. doi:10.1016/S0140-6736(08)61812-7PMID 19054552. Retrieved 2010-02-23.
  13. Jump up^ Carome, Michael (1 July 2015). “Outrage of the Month: FDA Makes Major Blunder After Approving Drug for Rare Sleep Disorder”Huffington Post. Retrieved 8 July 2015.
  14. Jump up^ Food and Drug Administration (January 31, 2014). “FDA NEWS RELEASE: FDA approves Hetlioz: first treatment for non-24 hour sleep–wake disorder in blind individuals”. FDA.
  15. Jump up^ “Side Effects Drug Center: Hetlioz Clinical Pharmacology”. RxList. February 10, 2014.
  16. Jump up^ “Side Effects Drug Center: Hetlioz Warnings and Precautions”. RxList. February 10, 2014. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically.
Tasimelteon
Tasimelteon 2.svg
Tasimelteon ball-and-stick model.png
Clinical data
Trade names Hetlioz
License data
Pregnancy
category
  • US:C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability not determined in humans[1]
Protein binding 89–90%
Metabolism extensive hepatic, primarily CYP1A2 and CYP3A4-mediated
Elimination half-life 0.9–1.7 h / 0.8–5.9 h (terminal)
Excretion 80% in urine, 4% in feces
Identifiers
CAS Number
PubChemCID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ECHA InfoCard 100.114.889Edit this at Wikidata
Chemical and physical data
Formula C15H19NO2
Molar mass 245.32 g/mol
3D model (JSmol)

ANTHONY MELVIN CRASTO

DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

//////////////BMS-214778, VEC-162, Tasimelteon, Hetlioz, FDA 2014, 609799-22-6 , BMS-214778, VEC-162, ATC N05CH03, タシメルテオン , EU 2015, VANDA, BMS, orphan drug designations
CCC(=O)NCC1CC1C2=C3CCOC3=CC=C2

Chemical and physical properties 

Tasimelteon has two stereogenic centers. Besides the medically used trans-1 R , 2 R isomer (in the picture above left), there are thus three further stereoisomers that do not arise in the synthesis.

Tasimelteon stereoisomerism.svg

Tasimelteon is a white to off-white crystalline non-hygroscopic substance, soluble in water at physiologically relevant pH levels and readily soluble in alcohols, cyclohexane and acetonitrile. The compound occurs in two crystal forms. It is an anhydrate melting at 74 ° C and a hemihydrate . [4] The hemihydrate is from about 35 ° C the water of hydration and converts thereby in the anhydrate form to. [4] The anhydrate crystallizes in a monoclinic lattice with the space group P 2 1 , and the hemihydrate crystallizes in a tetragonal lattice with the space group P 4 3 21 2. [4]

4  Kaihang Liu, Zhou Xinbo, Zhejing Xu, Bai Hongzhen, Jianrong Zhu Jianming Gu, Guping Tang, Liu Xingang, Hu Xiurong: anhydrate and hemihydrate of Tasimelteon: Synthesis, structure, and pharmacokinetic study in J. Pharm. Biomed. Anal. 151 (2018) 235-243, doi : 10.1016 / j.jpba.2017.12.035 .

BMS-986118, for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)


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GKIUHMMLGAMMOO-OITFXXTJSA-N.png
BMS-986118
BMS compd for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)
Cas 1610562-74-7
1H-Pyrazole-5-acetic acid, 1-[4-[[(3R,4R)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)-
Molecular Weight, 540.96, C25 H28 Cl F3 N4 O4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid

(-)-[(4S,5S)-1-(4-[[(3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid

  • (4S,5S)-1-[4-[[(3R,4R)-1-(5-Chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-1H-pyrazole-5-acetic acid
  • 2-[(4S,5S)-1-[4-[[1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl]-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid isomer 2

BMS-986118 is a GPR40 full agonist. GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia

Image result for bms

NOTE CAS OF , 1H-Pyrazole-5-acetic acid, 1-[4-[[(3S,4S)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)- IS 1610562-73-6

str1

Image result for BMS-986118,

SYNTHESIS

WO 2014078610

PAPER

https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00982

Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

Abstract

Abstract Image

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitroIn vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

Compound 4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (4)

To a stirred solution of methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (5.5 g, 9.9 mmol) in THF (90 mL) and water (9 mL) at room temperature was added 2 N LiOH solution (12 mL, 24 mmol). The reaction mixture was stirred at room temperature for 16 h, and 1 N HCl (25 mL, 25 mmol) was added at 0 °C to pH = 4–5. The solvent was evaporated, and the residue was extracted three times with EtOAc. The organic extracts were dried over Na2SO4; the solution was filtered and concentrated. The residue was recrystallized from isopropanol to give 4(neutral form) as white solid (4.3 g, 7.7 mmol, 78% yield).
1H NMR (500 MHz, DMSO-d6) δ ppm 12.52 (br s, 1H), 8.01 (s, 1H), 7.05 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 6.40 (s, 1H), 4.49–4.33 (m, 1H), 4.02 (td, J = 8.8, 4.1 Hz, 1H), 3.80 (s, 3H), 3.56–3.39 (m, 2H), 3.37–3.29 (m, 1H), 2.94–2.85 (m, 1H), 2.72–2.66 (m, 1H), 2.64 (dd, J = 16.1, 2.9 Hz, 1H), 2.49–2.41 (m, 1H), 2.22–2.05 (m, 1H), 2.01–1.86 (m, 1H), 1.68–1.50 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H).
 
13C NMR (126 MHz, DMSO-d6) δ 171.5, 163.7, 157.1, 152.5, 146.3, 139.7 (q, J = 34.7 Hz), 136.2, 121.7 (q, J = 269.3 Hz), 117.3, 117.2, 116.0, 100.4, 78.9, 65.6, 54.2, 53.4, 47.8, 44.2, 36.0, 34.9, 29.5, 17.4, 15.3. 19F NMR (471 MHz, DMSO-d6) δ −61.94 (s, 3F).
 
Optical rotation: [α]D(20)−11.44 (c 2.01, MeOH).
 
HRMS (ESI/HESI) m/z: [M + H]+ Calcd for C25H29ClF3N4O4 541.1824; Found 541.1813. HPLC (Orthogonal method, 30% Solvent B start): RT = 11.9 min, HI: 97%. m/zobs 541.0 [M + H]+.
 
Melting point = 185.5 °C.
PAPER

Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

Chemical and Synthetic DevelopmentBristol-Myers Squibb CompanyOne Squibb Drive, New Brunswick, New Jersey08903, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00022

Abstract

Abstract Image

The final two steps used to prepare greater than 1 kg of a compound evaluated as a treatment for type 2 diabetes are reported. The application of a palladium-catalyzed C–O coupling presented significant challenges due to the nature of the reactants, impurities produced, and noncrystalline coupling intermediate. Process development was able to address these limitations and enable production of kilogram quantities of the active pharmaceutical ingredient (API) in greater efficiency than a Mitsunobu reaction for formation of the key bond. The development of a sequence that telescopes the coupling with the subsequent ester hydrolysis to yield the API and the workup and final product crystallization necessary to produce high-quality drug substance without the need of column chromatography are discussed.

Bruce Ellsworth

Bruce Ellsworth, Director, Head of Fibrosis Discovery Chemistry at Bristol-Myers Squibb

Rick EwingRick Ewing, Head, External Partnerships, Discovery Chemistry and Molecular Technologies at Bristol-Myers Squibb
str1 str2
PATENT
WO 2014078610
Original Assignee Bristol-Myers Squibb Company
Patent
Patent ID

Patent Title

Submitted Date

Granted Date

US9133163 DIHYDROPYRAZOLE GPR40 MODULATORS
2013-11-15
2014-05-22
US9604964 Dihydropyrazole GPR40 modulators
2013-11-15
2017-03-28
REF
1: Li Z, Qiu Q, Geng X, Yang J, Huang W, Qian H. Free fatty acid receptor
agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II
clinical development. Expert Opin Investig Drugs. 2016 Aug;25(8):871-90. doi:
10.1080/13543784.2016.1189530. PubMed PMID: 27171154.
2
Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
248th Am Chem Soc (ACS) Natl Meet (August 10-14, San Francisco) 2014, Abst MEDI 31
MEDI John Macor Sunday, August 10, 2014
Oral Session
General Oral Session – PM Session
Organizers: John Macor
Presiders: John Macor
Duration: 1:30 pm – 5:15 pm
1:55 pm 31 Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
Bruce A Ellsworth, Jun Shi, Elizabeth A Jurica, Laura L Nielsen, Ximao Wu, Andres H Hernandez, Zhenghua Wang, Zhengxiang Gu, Kristin N Williams, Bin Chen, Emily C Cherney, Xiang-Yang Ye, Ying Wang, Min Zhou, Gary Cao, Chunshan Xie, Jason J Wilkes, Heng Liu, Lori K Kunselman, Arun Kumar Gupta, Ramya Jayarama, Thangeswaran Ramar, J. Prasada Rao, Bradley A Zinker, Qin Sun, Elizabeth A Dierks, Kimberly A Foster, Tao Wang, Mary Ellen Cvijic, Jean M Whaley, Jeffrey A Robl, William R Ewing.

///////////BMS-986118, Preclinical, BMS, Bruce A. Ellsworth,  Jun Shi,  William R. Ewing,  Elizabeth A. Jurica,  Andres S. Hernandez,  Ximao Wu, DIABETES,

COc1cc(c(Cl)cn1)N4CCC(Oc2ccc(cc2)N3N=C([C@@H](C)C3CC(=O)O)C(F)(F)F)[C@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@H](C)C4

BMS-986195


img
BMS-986195
  • Molecular FormulaC20H23FN4O2
  • Average mass370.421 Da
  • CAS: 1912445-55-6
1H-Indole-7-carboxamide, 5-fluoro-2,3-dimethyl-4-[(3S)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]-
4-[(3S)-3-(2-Butynoylamino)-1-piperidinyl]-5-fluor-2,3-dimethyl-1H-indol-7-carboxamid
(S)-4-(3-(2-Butynoylamino)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide
(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide
  • Originator Bristol-Myers Squibb
  • Class Anti-inflammatories; Antirheumatics
  • Mechanism of Action Agammaglobulinaemia tyrosine kinase inhibitors

Highest Development Phases

  • Phase I Rheumatoid arthritis

Most Recent Events

  • 30 Jan 2018 Bristol-Myers Squibb completes a phase I trial in Rheumatoid arthritis (In volunteers, In adults, Combination therapy) in USA (PO) (NCT03262740)
  • 10 Nov 2017 Bristol-Myers Squibb completes a phase I drug-drug interaction trial in Healthy volunteers (NCT03131973)
  • 03 Nov 2017 Safety, pharmacokinetic, and pharmacodynamic data from a pharmacokinetic trial in healthy volunteers presented at the 81st American College of Rheumatology and the 52nd Association of Rheumatology Health Professionals Annual Scientific Meeting (ACR/ARHP-2017)
  • Image result for BMS-986195

BMS-986195 is a potent, covalent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases essential in antigen-dependent B-cell signaling and function. BMS-986195 is more than 5000-fold selective for BTK over all kinases outside of the Tec family, and selectivity ranges from 9- to 1010-fold within the Tec family. BMS-986195 inactivated BTK in human whole blood with a rapid rate of inactivation (3.5×10-4 nM-1·min-1) and potently inhibited antigen-dependent interleukin-6 production, CD86 expression and proliferation in B cells (IC50 <1 nM) without effect on antigen-independent measures in the same cells.

Bristol-Myers Squibb is developing BMS-986195, an oral candidate for the treatment of rheumatoid arthritis. A phase I clinical trial in healthy adult volunteers is ongoing.

Image result

Structure of BMS986195.
Credit: Tien Nguyen/C&EN

Presented by: Scott H. Watterson, principal scientist at Bristol-Myers Squibb

Target: Bruton’s tyrosine kinase (BTK)

Disease: Autoimmune diseases such as rheumatoid arthritis

Reporter’s notes: Completing another set of back-to-back presentations on the same target, Watterson revealed another BTK inhibitor also in Phase II clinical trials. Chemists made BMS-986195 in seven steps, and the molecule showed high levels of BTK inactivation in mice. The team aimed to develop an effective compound that required low doses and that had low metabolic degradation.

Patent

WO 2016065226

Inventor Saleem AhmadJoseph A. TinoJohn E. MacorAndrew J. TebbenHua GongQingjie LiuDouglas G. BattKhehyong NguScott Hunter WattersonWeiwei GuoBertrand Myra Beaudoin

Original Assignee Bristol-Myers Squibb Company

https://patents.google.com/patent/WO2016065226A1/en

PATENT

WO 2018045157

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E81EF2BDB127473D100AAA55455FC42B.wapp1nA?docId=WO2018045157&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

otein kinases, the largest family of human enzymes, encompass well over 500 proteins. Btk is a member of the Tec family of tyrosine kinases, and is a regulator of early B-cell development, as well as mature B-cell activation, signaling, and survival.

B-cell signaling through the B-cell receptor (BCR) leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell. The magnitude and duration of BCR signals must be precisely regulated. Aberrant BCR-mediated signaling can cause dysregulated B-cell activation and/or the formation of pathogenic auto-antibodies leading to multiple autoimmune and/or inflammatory diseases. Mutation of Btk in humans results in X-linked agammaglobulinaemia (XLA). This disease is associated with the impaired maturation of B-cells, diminished immunoglobulin production, compromised T-cell-independent immune responses and marked attenuation of the sustained calcium signal upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmune disease and/or inflammatory disease has been established in Btk-deficient mouse models. For example, in standard murine preclinical models of systemic lupus erythematosus (SLE), Btk deficiency has been shown to result in a marked amelioration of disease progression. Moreover, Btk deficient mice are also resistant to developing collagen-induced arthritis and are less susceptible to Staphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics (such as Rituxan) developed to deplete B-cells, represent an important approach to the treatment of a number of autoimmune and/or inflammatory diseases.

Because of Btk’s role in B-cell activation, inhibitors of Btk can be useful as inhibitors of B-cell mediated pathogenic activity (such as autoantibody production).

Btk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Btk deficiency in mice is associated with impaired IgE -mediated mast cell activation (marked diminution of T F-alpha and other inflammatory cytokine release), and Btk deficiency in humans is associated with greatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases including, but not limited to: SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, multiple sclerosis (MS), transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin diseases, Evan’s syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjogren’s syndrome, peripheral neuropathies (e.g., Guillain-Barre syndrome), pemphigus vulgaris, and asthma.

In addition, Btk has been reported to play a role in controlling B-cell survival in certain B-cell cancers. For example, Btk has been shown to be important for the survival of BCR-Abl-positive B-cell acute lymphoblastic leukemia cells. Thus inhibition of Btk activity can be useful for the treatment of B-cell lymphoma and leukemia.

In view of the numerous conditions that are contemplated to benefit by treatment involving modulation of protein kinases, it is immediately apparent that new compounds capable of modulating protein kinases such as Btk and methods of using these compounds should provide substantial therapeutic benefits to a wide variety of patients.

WO 2016/065226 discloses indole carboxamide compounds useful as Btk inhibitors, including (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (Example 223), which has the structure:

Also disclosed is multistep synthesis process for preparing (S)-4-(3-(but-2-ynamido) piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide.

There are difficulties associated with the adaptation of the multistep synthesis disclosed in WO 2016/065226 to larger scale synthesis, such as production in a pilot plant or a manufacturing plant for commercial production. Further, there is a continuing need to find a process that has few synthesis steps, provides higher yields, and/or generates less waste.

Applicants have discovered a new synthesis process for the preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide that has fewer synthesis steps and/or provides higher yields than the process disclosed in WO 2016/065226. Furthermore, this process contains no metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing.

EXAMPLE 1

(S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

Step 1 : Preparation of Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino)piperidin-l-yl)-5-fluorobenz

To a 250 mL ChemGlass reactor were charged methyl 2-amino-4,5-difluoro-benzoate (11.21 g, 59.90 mmol), tert-butyl N-[(3S)-3-piperidyl]carbamate (10 g, 49.930 mmol), potassium phosphate, dibasic (10.44 g, 59.94 mmol), and dimethyl sulfoxide (100 mL, 1400 mmol). The resulting thin slurry was heated to 95 to 100 °C and agitated at this temperature for 25 hours. The mixture was cooled to 50 °C. Methanol (100 mL) was added and followed by slow addition of water (50 mL). The mixture was aged at 50 °C for 30 minutes to result in a thick white slurry. Additional water (150 mL) was slowly charged to the above mixture and agitated at 50 °C for 1 hour. The slurry was cooled to 20 °C in 1 hour and aged at this temperature for 4 hours. The slurry was filtrated. The wet cake washed with 25% MeOH in water (30 mL), water (100 mL) and dried under vacuum at 60 °C for 24 h. Methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate was obtained as a white solid (7 g, yield: 72.5%). ¾ MR (400MHz, METHANOLS) δ 7.34 (d, J=14.6 Hz, 1H), 6.27 (d, J=7.3 Hz, 1H), 3.83-3.71 (s, 3H), 3.68-3.57 (m., 1H), 3.50 -3.40 (m 1H), 3.39 -3.31 (m, 1H), 3.31-3.26 (m, 1H), 2.86-2.70 (m, 1H), 2.64 (t, J=10.0 Hz, 1H), 1.97-1.84 (m, 1H), 1.84-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.44 (s, 9H), 1.38 (m, 1H). LC-MS [M+H] 368.

Step 2: Preparation of Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate

To a reactor were charged methyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (5.0 g), DPPOH (diphenyl phosphate, 6.81 g, 2 eq) and 3-hydroxybutanone (1.2 eq, 1.44 g), followed by addition of isopropyl acetate (100 mL, 20 mL/g). The mixture was allowed to warm up to 70 to 75 °C, resulting in a yellow solution. The solution was stirred at 70 to 75 °C for 30 h to complete the cyclization.

Water (2 mL) was added and the mixture was aged at 70 °C over 24 h to remove the Boc group. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (50 mL) was added and the mixture was stirred for 15 min. The organic layer was separated and washed with water (50 mL). The organic layer was then concentrated under vacuum (200 Torr) to -50 mL. The resulting slurry was stirred at 50 °C for 2 h and then heptane (100 mL) was added over 1 h. The mixture was cooled to room

temperature, stirred for 20 h, and then filtered. The cake was washed with heptane (50 mL). Methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate, DPPOH salt was obtained as a light yellow solid. The wet-cake was added to a reactor. Isopropyl acetate (100 mL) was added, followed by addition of aqueous K3PO4 solution (4 g in water 50 mL). The mixture was stirred at room temperature for -half-hour, resulting in a two phase clear solution (pH >10 for aqueous). The organic layer was separated and washed with water (50 mL), and then concentrated under vacuum to a volume of 15 mL. The resulting slurry was stirred at room temperature for 4 h, then heptane (75 mL) was added over 1 h. The mixture was aged at room temperature for 24 h, then concentrated to a volume to -50 mL. The slurry was filtered. The cake was washed with heptane 20 mL and dried under vacuum at 50 °C for 24 h. Methyl (S)-4-(3- aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate was obtained as a light yellow solid (2.76 g, yield: 69%). ¾ NMR (400MHz, DMSO-d6) δ 10.64 (s, 1H), 7.33 (d, J=13.7 Hz, 1H), 3.89 (s, 3H), 3.14 (br. m., 1H), 3.07-2.90 (m, 2H), 2.84 (br. m., 1H), 2.70 (br. m., 1H), 2.35 (s, 3H), 2.33 (s, 3H), 1.87 (br. m., 1H), 1.67 (br. m., 3H). LC-MS: M+H= 320.

Alternative Preparation

Step 2: Preparation of ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt

To a reactor were charged ethyl (S)-2-amino-4-(3-((tert-butoxycarbonyl)amino) piperidin-l-yl)-5-fluorobenzoate (1.0 g, limiting reagent), DPPOH (diphenyl phosphate, 1.97 g, 3.0 eq) and 3-hydroxybutanone (1.4 eq, 0.32 g), followed by addition of toluene (20 mL, 20 mL/g). The mixture was allowed to warm up to 80-90 °C, resulting in a yellow solution. The solution was stirred at 80-90 °C for 10 h to complete the

cyclization. Water (0.4 mL, 0.4 ml/g) was added and the mixture was aged at 80-90 °C for 8 hours. The mixture was cooled to room temperature. Next, aqueous 20% K3PO4 solution (15 mL, 15 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated and the aqueous layer was washed with toluene (7.5 mL, 7.5 mL/g). To combined organic layers water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. To the organic layer water (10 mL, 10 mL/g) was added and the mixture was stirred for 0.5 hour. The organic layer was separated. The organic layer was concentrated under vacuum (100 Torr) to 8 mL (8 ml/g). Following concentration the reaction mixture was cooled to 20-25 °C and MTBE (20 mL, 20 mL/g) was added. Trifluoroacetic acid (1.2 eq., 0.36 g) was slowly added to make the salt maintaining temperature at 20-25 °C. The resulting slurry was aged for 4 hours and then filtered. The filtered solids are washed with MTBE (8 mL, 8 mL/g) and the cake

was dried under vacuum at 50 °C. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt was obtained as a white to tan crystalline material (85% yield, 1.0 g). ¾ NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.16-7.88 (m, 2H), 7.37 (d, 7=13.6 Hz, 1H), 4.38 (q, 7=7.1 Hz, 2H), 3.18-3.01 (m, 3H), 2.96 (br s, 1H), 2.35 (s, 6H), 2.30 (s, 1H), 2.12 (br d, 7=9.3 Hz, 1H), 1.78 (br s, 2H), 1.45-1.31 (m, 4H), 1.10 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 165.1, 165.1, 158.4, 158.1, 135.4, 134.7, 134.6, 132.2, 128.8, 128.2, 126.9, 126.8, 118.7, 115.7, 110.6, 110.3,108.7, 108.6, 106.6, 106.5, 83.5, 79.8, 60.5, 54.9, 51.7, 48.7, 47.2, 28.4, 26.8, 23.6, 14.2, 11.1, 10.2

Step 3A: Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 40 mL vial was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by the addition of N,N-dimethylformamide (12.0 mL, 8.0 mL/g). The vial was purged with N2. Formamide (1.49 mL, 37.6 mmol) was added followed by sodium methoxide solution in methanol (35 wt%, 1.29 mL, 3.76 mmol). The resulting solution was heated at 50 °C over 8 hours. The reaction mixture was cooled down to room temperature and the reaction was quenched with water (12.0 mL, 8.0 mL/g). 2-methyltetrahydrofuran (30 mL, 20 mL/g) was added to the mixture. The mixture was shaken vigorously. The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL, 10 mL/g) two more times. Organic extracts were then washed with brine and water (15 mL each, 10 mL/g). The organic layer was evaporated. Solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow solid (1.04 g, 69% yield). ¾ NMR (500MHz, DMSO-d6) δ 10.60 (br. s.,

1H), 7.91 (br. s., 1H), 7.40 (d, 7=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Step 3B: Alternative Preparation of (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

A 100 mL Hastelloy high pressure EasyMax reactor was charged with methyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate (1.5 g, 4.70 mmol), followed by addition of 7 N ammonia solution in methanol (45.0 mL, 30.0 mL/g) followed by addition of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (1.33 g, 9.39 mmol). The reactor was sealed and purged with N2 three times. The reactor was then heated to 80 °C for 24 hrs. The reaction mixture was cooled to room temperature and the vessel contents were purged with N2 three times. Volatiles were concentrated to ~6 mL (4 mL/g) and water (24 mL, 16 mL/g) was added. The yellow precipitate was collected and filtered. The precipitate was washed with methanol/water mixture (20:80 v/v, 6 mL, 4 mL/g), and then water (18 mL, 12 mL/g). The solids were dried in vacuo at 60 °C to afford (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide as a yellow crystalline material (0.93 g, 62% yield). ¾ MR (500MHz, DMSO-de) δ 10.60 (br. s., 1H), 7.91 (br. s., 1H), 7.40 (d, J=14.0 Hz, 1H), 7.32 (br. s., 1H), 3.10 (br. s., 1H), 2.98 (br. s., 2H), 2.82 (br. s., 1H), 2.68 (br. s., 1H), 2.34 (br. s., 3H), 2.30 (br. s., 3H), 1.88 (br. s., 1H), 1.67 (br. s., 2H), 1.45 (br. s., 2H), 1.05 (br. s., 1H). LCMS [M+H] 305.24.

Alternative Preparation:

Step 3C: Preparation of (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt

Ethyl (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxylate trifluoroacetic acid salt (1.0 g, limiting reagent) and formamide (5 mL, 5 mL/g) were added to a nitrogen inerted reactor. The temperature was maintained at 20-25 °C. To the reactor was added a solution of 20 wt% potassium t-butoxide in THF. The reaction mixture was allowed to sit for 6 hours. To reaction mixture was added Me-THF (15 mL, 15 mL/g) and 12.5 wt % aqueous NaCl (5 mL, 5 mL/g). The reaction mixture was stirred for 0.5 hour. The organic layer was separated, 5 wt% aqueous NaCl (1 mL, 1 mL/g) and 0.25 N aqueous NaOH (4 mL, 4 mL/g) were added, and then stirred for 0.5 hour. The organic layer was separated and 5 wt% aqueous NaCl (5 mL, 5 mL/g) was added, the mixture was stirred for 0.5 hour, and organic phase was separated. The rich organic phase was dried distillation at a pressure of 100 mtorr with Me-THF to obtain KF in 1.5-4wt% range at 5 mL Me-THF volume. The volume was adjusted to 15 mL Me-THF by adding Me-THF (10 mL, 10 mL/g) and EtOH (4 mL, 4 mL/g). Next, 2-butynoic acid (1.0 eq., 0.19 g) was added and the mixture was agitated for 10 hrs. The resulting slurry was filtered. The cake was washed with Me-THF (10 mL, 10 mL/g) and dried under vacuum at 75 °C to afford (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (0.7 g, 80% yield) as white crystalline powder. ¾ NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.98 (br s, 1H), 7.50-7.32 (m, 2H), 3.32 (br d, J=8.6 Hz, 2H), 3.21 (br t, J=10.5 Hz, 1H), 3.13-2.89 (m, 3H), 2.32 (d, J=5.1 Hz, 5H), 2.11 (br d, J=10.9 Hz, 1H), 1.81-1.67 (m, 4H), 1.55-1.28 (m, 1H).

Step 4A: Preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF, 12.77 kg, 13.5 L). Reactor-1 was purged with N2 to inert. (S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide (3.0 kg, 1.0 equiv) was charged followed by 2-butynoic acid (0.854 kg, 1.04 equiv). Reactor-1 was rinsed with DMF (1.42 kg, 1.5 L). The mixture was sparged with N2 for 20 min. Triethylamine (2.99 kg, 3.0 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). TBTU (O-(Benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium tetrafluorob orate, 3.256 kg, 1.04 equiv) was charged followed by a DMF rinse (1.42 kg, 1.5 L). The reaction mixture was agitated for 1.5 h at 20 °C. MeTHF (46.44 kg, 60 L) was charged to the batch. The reaction was quenched with LiCl (20 wt%, 26.76 kg, 24 L) at 20 °C. The bottom aqueous layer was discharged as waste. The organic layer was washed with 2N HCl solution (24.48 kg, 24 L), 10 wt% sodium bicarbonate solution (25.44 kg, 24 L) and deionized water (24.0 kg, 24 L). THF (26.61 kg, 30 L) was charged into Reactor-1. The rich organic stream in MeTHF/TFIF was polish filtered. The stream was distilled down to 15 L at 75-100 Torn Constant volume distillation was carried out at 15 L with THF feed (39.92 kg, 45 L). The stream was heated to 60 °C for 1 hr and cooled to 50 °C. MTBE (33.30 kg, 45 L) was charged slowly over 2 h. The slurry was aged at 50 °C for 4 h and cooled to 20 °C over 2 h, and aged at 20 °C for >2 h. The 1st drop slurry was filtered and was rinsed with MTBE (8.88 kg, 12 L) twice. Wet cake was dried under vacuum 60 to 70 °C at 25 mbar overnight (>15 h). Reactor-1 was thoroughly cleaned with IPA. The dry cake was charged into Reactor-1 followed by the charge of IPA (47.10 kg, 60 L). The batch was heated to 60 °C to achieve full dissolution and cooled to 40 °C. Rich organic (24 L) was transferred to Reactor-2 for crystallization. The stream was distilled at 24 L constant volume and 100 mbar using remaining rich organic from reactor-1 as distillation feed. Following distillation completion, the batch was heated to 60 °C, aged at 60 °C for 2 h, cooled to 20 °C over 2 h, and aged at 20 °C over 2 h. The slurry was filtered. IPA (1.18 kg) was used to rinse the reactor and washed the cake. The wet cake was dried under vacuum at 70 °C and 25 mbar for >15 h. The dry cake (2.196 kg, 63.2% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C NMR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Step 4B: Alternative preparation of (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimeth -lH-indole-7-carboxamide

To Reactor-1 was charged N,N-dimethylformamide (DMF 4.5 mL, 4.5 mL/g). Reactor-1 was purged with N2 to inert. (,S)-4-(3-aminopiperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide 2-butynoic acid salt (1.0 g, limiting reagent) was charged followed by 2-butynoic acid (0.065g, 0.3 equiv.). The mixture was inerted with N2 for 20 min. N-methylmorpholine (0.78 g, 3.0 equiv) was charged. Next,

diphenylphosphinic chloride (0.79 g, 1.3 equiv) was charged over 0.5 h while maintaining the reaction temperature at 20-25 °C. The reaction mixture was agitated for 1.5 hour at 20 °C. Me-THF (14 mL, 14 mL/g) was charged to the reaction mixture. The reaction was quenched with the addition of aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C. The bottom aqueous layer was discharged as waste. Aqueous NaCl (12.5 wt%, 6 mL, 6 mL/g) at 20 °C was added to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. Deionized water (6 mL, 6 mL/g) was charged to the organic layer, stirred for 0.5 hour and the bottom aqueous layer was discharged to waste. THF (8 mL, 8 mL/g) was charged into Reactor-1 and the mixture was

concentrated under vacuum to remove Me-THF and water, and reconstituted in 4 L/kg of THF. The mixture was heated to 60 °C and stirred for 1 hour; the temperature was reduced to 50 °C and MTBE (12 mL, 12 mL/g) was added. The mixture was aged for 4 hours while maintaining the temperature of 50 °C and then cooled to room temperature. The solids were filtered and washed with MTBE (6.5 mL, 6.5 mL/g). The solids of crude were dried at 70 °C under vacuum for 12 hours.

Crude (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was charged to Reactor-2, followed by THF (12 mL, 12 mL/g). The mixture was stirred for 0.5 hour. The solution was polish filtered. The solution was concentrated under vaccuum to remove THF and reconstituted in EtOH (7 mL, 7 mL/g). (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide seeds (0.01 g, 0.01 g/g) were added, the mixture was heated to 60 °C and aged for 2 hours, n-heptane (21 mL, 21 mL/g) was added slowly over 4 hours. The mixture was aged for additional 2 hours at 60 °C, followed by cooldown to room temperature. The slurry was filtered, washed with n-heptane (6 mL, 6 mL/g), and dried under vacuum at 70 °C for 12 hours. The dry cake (0.68 g, 71% yield) was discharged as an off-white crystalline solid. ¾ NMR (400MHz, DMSO-d6): δ 10.62 (s, 1H), 8.48 (d, J= 7.1 Hz, 1H), 7.91 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33 (s, 1H), 3.88 (m, 1H), 3.11 (t, J= 8.0 Hz, 1H), 3.0 (m, 1H), 2.96 (m, 1H), 2.78 (t, J= 10.0 Hz, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 1.92 (s, 3H), 1.86 (m, 1H), 1.31 (m, 1H), 1.70 (m, 2H); 13C MR (400 MHz, DMSO-d6): δ 168.2, 153.2, 151.9, 134.4, 133.2, 132.1, 126.5, 112.3, 108.4, 106.0, 82.3, 75.7, 56.9, 51.9, 46.3, 29.7, 24.4, 11.1, 10.2, 3.0; LC-MS: M+H= 371.2.

Applicants have discovered a new synthesis process for the preparation of (S)-4- (3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide which offers significant advantages.

The new synthesis process utilizes fewer synthesis steps (4 vs 8) than the process disclosed in WO 2016/065226.

Additionally, the process of the present invention provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall

yield of 22% (step 1 : 73.%, step 2: 69%, step 3 : 69%, step 4: 63%). In comparison, (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide was prepared according to the process of WO 2016/065226, which provided (S)-4-(3-(but-2-ynamido)piperidin-l-yl)-5-fluoro-2,3-dimethyl-lH-indole-7-carboxamide at an overall yield of 2.9% yield (step 1 : 91%, step 2: 71%, step 3 : 35%, step 4: 88%, step 5: 80%, step 6: 29%, step 7: 99%, step 8: 63%).

Furthermore, the process of the present invention does not include any transition metal-catalyzed steps, no genotoxic intermediates, and is adaptable to large scale manufacturing. In comparison, the process disclosed in WO 2016/065226 employed lead (Pb) in process step (8) and included a potentially genotoxic hydrazine intermediate in process step 8.

The process of the present invention has an estimated manufacturing cycle time of approximately 6 months versus a estimated manufacturing cycle time of approximately 12 months for the process disclosed in WO 2016/065226.

REFERENCE

http://acrabstracts.org/abstract/bms-986195-is-a-highly-selective-and-rapidly-acting-covalent-inhibitor-of-brutons-tyrosine-kinase-with-robust-efficacy-at-low-doses-in-preclinical-models-of-ra-and-lupus-nephritis/

/////////////////BMS-986195, Phase I,  Rheumatoid arthritis, BMS

NC(=O)c2cc(F)c(c1c(C)c(C)nc12)N3CCC[C@@H](C3)NC(=O)C#CC

BMS-986020


imgImage result for BMS-986020

BMS-986020

AM-152; BMS-986020; BMS-986202

cas 1257213-50-5
Chemical Formula: C29H26N2O5
Molecular Weight: 482.536

(R)-1-(4′-(3-methyl-4-(((1-phenylethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1′-biphenyl]-4-yl)cyclopropane-1-carboxylic acid

Cyclopropanecarboxylic acid, 1-(4′-(3-methyl-4-((((1R)-1-phenylethoxy)carbonyl)amino)-5-isoxazolyl)(1,1′-biphenyl)-4-yl)-

1-(4′-(3-Methyl-4-(((((R)-1-phenylethyl)oxy)carbonyl)amino)isoxazol-5-yl)biphenyl-4-yl)cyclopropanecarboxylic acid

UNII: 38CTP01B4L

For treatment for pulmonary fibrosis, phase 2, The lysophosphatidic acid receptor, LPA1, has been implicated as a therapeutic target for fibrotic disorders

Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1-phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell-surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems.

Image result for Amira Pharmaceuticals

  • Originator Amira Pharmaceuticals
  • DeveloperB ristol-Myers Squibb; Duke University
  • Class Antifibrotics; Azabicyclo compounds; Carboxylic acids; Small molecules; Tetrazoles
  • Mechanism of Action Lysophosphatidic acid receptor antagonists
  • Orphan Drug Status Yes – Fibrosis
  • Phase II Idiopathic pulmonary fibrosis
  • Phase IPsoriasis

Most Recent Events

  • 05 May 2016 Bristol-Myers Squibb plans a phase I trial for Psoriasis in Australia (PO, Capsule, Liquid) (NCT02763969)
  • 01 May 2016 Preclinical trials in Psoriasis in USA (PO) before May 2016
  • 14 Mar 2016 Bristol-Myers Squibb withdraws a phase II trial for Systemic scleroderma in USA, Canada, Poland and United Kingdom (PO) (NCT02588625)

BMS-986020, also known as AM152 and AP-3152 free acid, is a potent and selective LPA1 antagonist. BMS-986020 is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis. BMS-986020 selectively inhibits the LPA receptor, which is involved in binding of the signaling molecule lysophosphatidic acid, which in turn is involved in a host of diverse biological functions like cell proliferation, platelet aggregation, smooth muscle contraction, chemotaxis, and tumor cell invasion, among others

Image result for BMS-986020

PRODUCT PATENT

GB 2470833, US 20100311799, WO 2010141761

Hutchinson, John Howard; Seiders, Thomas Jon; Wang, Bowei; Arruda, Jeannie M.; Roppe, Jeffrey Roger; Parr, Timothy

Assignee: Amira Pharmaceuticals Inc, USA

Image result for Hutchinson, John Howard AMIRA

John Hutchinson

PATENTS

WO 2011159632

WO 2011159635

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013025733&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

WO 2013025733

Synthesis of Compound 74

Synthetic Route (Scheme XLV)

Compound 74 Compound 74a

[0562] Compound XLV-1 was prepared by the same method as described in the synthesis of compound 1-4 (Scheme 1-A).

[0563] To a solution of compound XLV-1 (8 g, 28.08 mmol) in dry toluene (150 mL) was added compound XLV-2 (1.58 g, 10.1 mmol), triethylamine (8.0 mL) and DPPA (9.2 g, 33.6 mmol). The reaction mixture was heated to 80 °C for 3 hours. The mixture was diluted with EtOAc (50 mL), washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10 IX) to give compound XLV-3 (9.4 g, yield: 83 %). MS (ESI) m/z (M+H)+402.0.

[0564] Compound 74 was prepared analogously to the procedure described in the synthesis of Compound 28 and was carried through without further characterization.

[0565] Compound 74a was prepared analogously to the procedure described in the synthesis of Compound 44a. Compound 74a: 1HNMR (DMSO-d6 400MHz) δ 7.81 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.29-7.32 (m, 7 H), 5.78 (q, 1 H), 2.15 (s, 3 H), 1.52 (d, J = 6.0 Hz, 3H), 1.28 (br, 2 H), 0.74 (br, 2 H). MS (ESI) m/z (M+H)+ 483.1.

Paper

Development of a Concise Multikilogram Synthesis of LPA-1 Antagonist BMS-986020 via a Tandem Borylation–Suzuki Procedure

Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00301

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00301

Abstract Image

The process development for the synthesis of BMS-986020 (1) via a palladium catalyzed tandem borylation/Suzuki reaction is described. Evaluation of conditions culminated in an efficient borylation procedure using tetrahydroxydiboron followed by a tandem Suzuki reaction employing the same commercially available palladium catalyst for both steps. This methodology addressed shortcomings of early synthetic routes and was ultimately used for the multikilogram scale synthesis of the active pharmaceutical ingredient 1. Further evaluation of the borylation reaction showed useful reactivity with a range of substituted aryl bromides and iodides as coupling partners. These findings represent a practical, efficient, mild, and scalable method for borylation.

1H NMR (500 MHz, DMSO-d6) δ 1.19 (dd, J = 6.8, 3.8 Hz, 2H), 1.50 (dd, J = 6.8, 3.8 Hz, 2H), 1.56 (br s, 3H), 2.14 (br s, 3H), 5.78 (br s, 1H), 6.9–7.45 (br, 5H), 7.45 (br d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.79 (br d, 2H), 7.82 (br d, 2H), 8.87 (br s, 0.8H), 9.29 (s, 0.2H), 12.39 (br s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 9.2, 15.8, 22.4, 28.3, 72.8, 113.8, 125.4, 125.6, 126.2, 126.3, 127.1, 127.7, 128.4, 130.9, 137.4, 140.0, 141.5, 142.2, 154.4, 159.6, 160.8, 175.2. HRMS (ESI+) Calculated M + H 483.19145, found 483.19095.

REFERENCES

1: Kihara Y, Mizuno H, Chun J. Lysophospholipid receptors in drug discovery. Exp
Cell Res. 2015 May 1;333(2):171-7. doi: 10.1016/j.yexcr.2014.11.020. Epub 2014
Dec 8. Review. PubMed PMID: 25499971; PubMed Central PMCID: PMC4408218.

//////////////BMS-986020,  AM 152, BMS 986020, BMS 986202, Orphan Drug, BMS, Amira Pharmaceuticals, Bristol-Myers Squibb, Duke University, Antifibrotics, PHASE 2, pulmonary fibrosis

O=C(C1(C2=CC=C(C3=CC=C(C4=C(NC(O[C@H](C)C5=CC=CC=C5)=O)C(C)=NO4)C=C3)C=C2)CC1)O

BMS-986115


Figure imgf000170_0002

BMS-986115
CAS 1584647-27-7

(2R,3S)-N-((3S)-5-(3-Fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin- 3-yl)-2, -bis(3,3,3-trifluoropropyl)succinamide

MW: 574.4945,  C26-H25-F7-N4-O3, UNII: LSK1L593UU

10-Nitrooleate, CTK3B7458, CTK3C3167, 9-Octadecenoic acid, 10-nitro-, 875685-46-4, AG-L-63109, 9-Octadecenoic acid, 10-nitro-, (9E)-, 88127-53-1

FOR advanced solid tumors

  • Originator Bristol-Myers Squibb
  • Class Antineoplastics
  • Mechanism of Action Amyloid precursor protein secretase inhibitors; Notch signalling pathway inhibitors
  • Phase I Solid tumours

Most Recent Events

  • 30 Aug 2016Bristol-Myers Squibb terminates a phase I trial for Solid tumours (late-stage disease, second-line therapy or greater) in USA, Australia and Canada (NCT01986218)
  • 25 Jan 2016Bristol-Myers Squibb completes enrolment in its phase I trial for Solid tumours in USA, Australia and Canada (NCT01986218)
  • 31 Dec 2013Phase-I clinical trials in Solid tumours (late-stage disease) in Canada & Australia (Oral)

DETAILS WILL BE UPDATED SOON………….

BMS-986115 is an orally bioavailable, gamma secretase (GS) and pan-Notch inhibitor, with potential antineoplastic activity. Upon administration, GS/pan-Notch inhibitor BMS 986115 binds to GS and blocks the proteolytic cleavage and release of the Notch intracellular domain (NICD), which would normally follow ligand binding to the extracellular domain of the Notch receptor. This prevents both the subsequent translocation of NICD to the nucleus to form a transcription factor complex and the expression of Notch-regulated genes. This results in the induction of apoptosis and the inhibition of growth of tumor cells that overexpress Notch. Overexpression of the Notch signaling pathway plays an important role in tumor cell proliferation and survival

 

Bristol-Myers Squibb
Ashvinikumar V. Gavai, George V. Delucca,Daniel O’MALLEY, Patrice Gill, Claude A. Quesnelle, Brian E. Fink, Yufen Zhao,Francis Y. Lee,
Applicant Bristol-Myers Squibb Company

str2

Ashvinikumar Gavai

Claude Quesnelle

Claude Quesnelle
Senior Research Investigator/Chemist at Bristol-Myers Squibb

str2

RICHARD LEE

 

 

 

Patrice Gill

Patrice Gill

Research scientist at BMS

Dan O’Malley (Rice University)
Currently: Bristol-Myers Squibb

PICTURES WILL BE UPDATED………….

Useful for the treatment of conditions related to the Notch pathway, such as cancer and other proliferative diseases.

Notch signaling has been implicated in a variety of cellular processes, such as cell fate specification, differentiation, proliferation, apoptosis, and angiogenesis. (Bray, Nature Reviews Molecular Cell Biology, 7:678-689 (2006); Fortini, Developmental Cell 16:633-647 (2009)). The Notch proteins are single-pass heterodimeric transmembrane molecules. The Notch family includes 4 receptors, NOTCH 1-4, which become activated upon binding to ligands from the DSL family (Delta-like 1, 3, 4 and Jagged 1 and 2).

The activation and maturation of NOTCH requires a series of processing steps, including a proteolytic cleavage step mediated by gamma secretase, a multiprotein complex containing Presenilin 1 or Presenilin 2, nicastrin, APH1, and PEN2. Once NOTCH is cleaved, NOTCH intracellular domain (NICD) is released from the membrane. The released NICD translocates to the nucleus, where it functions as a transcriptional activator in concert with CSL family members (RBPSUH, “suppressor of hairless”, and LAG1). NOTCH target genes include HES family members, such as HES- 1. HES- 1 functions as transcriptional repressors of genes such as HERP 1 (also known as HEY2), HERP2 (also known as HEY1), and HATH1 (also known as ATOH1).

The aberrant activation of the Notch pathway contributes to tumorigenesis. Activation of Notch signaling has been implicated in the pathogenesis of various solid tumors including ovarian, pancreatic, as well as breast cancer and hematologic tumors such as leukemias, lymphomas, and multiple myeloma. The role of Notch inhibition and its utility in the treatment of various solid and hematological tumors are described in Miele, L. et al, Current Cancer Drug Targets, 6:313-323 (2006); Bolos, V. et al, Endocrine Reviews, 28:339-363 (2007); Shih, I.-M. et al, Cancer Research, 67: 1879- 1882 (2007); Yamaguchi, N. et al., Cancer Research, 68: 1881-1888 (2008); Miele, L., Expert Review Anti-cancer Therapy, 8: 1 197-1201 (2008); Purow, B., Current Pharmaceutical Biotechnology, 10: 154-160 (2009); Nefedova, Y. et al, Drug Resistance Updates, 1 1 :210-218 (2008); Dufraine, J. et al, Oncogene, 27:5132-5137 (2008); and Jun, H.T. et al, Drug Development Research, 69:319-328 (2008).

There remains a need for compounds that are useful as Notch inhibitors and that have sufficient metabolic stability to provide efficacious levels of drug exposure. Further, there remains a need for compounds useful as Notch inhibitors that can be orally or intravenously administered to a patient.

U.S. Patent No. 7,053,084 Bl discloses succinoylamino benzodiazepine compounds useful for treating neurological disorders such as Alzheimer’s Disease. The reference discloses that these succinoylamino benzodiazepine compounds inhibit gamma secretase activity and the processing of amyloid precursor protein linked to the formation of neurological deposits of amyloid protein. The reference does not disclose the use of these compounds in the treatment of proliferative diseases such as cancer.

Applicants have found potent compounds that have activity as Notch inhibitors and have sufficient metabolic stability to provide efficacious levels of drug exposure upon intravenous or oral administration. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

Image result for BMS 906024

Image result for BMS 906024 synthesis

PATENTS

US-20150166489-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=US137591635&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

US-20140087992-A1

https://www.google.com/patents/US20140087992

Example 1(2R,3S)—N-((3S)-5-(3-Fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamideFigure US20140087992A1-20140327-C00138

Intermediate 1A: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-(((S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoate

Figure US20140087992A1-20140327-C00139

In a 100 mL round-bottomed flask, a solution of Intermediate B-1 (1683 mg, 5.94 mmol), Et3N (1.656 mL, 11.88 mmol), and Intermediate S-1 in DMF (20 mL) was treated with o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3815 mg, 11.88 mmol) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and saturated aqueous NaHCO3. An off white precipitate formed and was filtered and washed with water. The resulting solid was dried on the filter under a stream of nitrogen to give Intermediate 1A (3.7 g, 99% yield). MS (ES): m/z=632.4[M+H+]; HPLC: RT=3.635 min Purity=98%. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm). 1H NMR (400 MHz, methanol-d4) δ 7.53 (t, J=4.5 Hz, 1H), 7.46-7.30 (m, 3H), 7.28-7.23 (m, 1H), 7.23-7.18 (m, 2H), 5.37 (s, 1H), 2.88 (td, J=10.4, 3.4Hz, 1H), 2.60 (td, J=10.2, 4.1 Hz, 1H), 2.54-2.40 (m, 1H), 2.47 (s, 3H), 2.33-2.12 (m, 3H), 1.98-1.69 (m, 4H), 1.51 (s, 9H).

Intermediate 1B: (2S,3R)-6,6,6-Trifluoro-3-(((S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure US20140087992A1-20140327-C00140

In a 250 mL round-bottomed flask, a solution of Intermediate 1A (3.7 g, 5.86 mmol) in DCM (25 mL) was treated with TFA (25 mL) and the resulting pale orange solution was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated to give Intermediate 1B. HPLC: RT=3.12 min (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm). MS (ES): m/z=576.3 (M+H)+. 1H NMR (400 MHz, methanol-d4) δ 7.54 (t, J=4.5 Hz, 1H), 7.49-7.29 (m, 3H), 7.28-7.15 (m, 3H), 5.38 (br. s., 1H), 2.89 (td, J=10.3, 3.7 Hz, 1H), 2.67 (td, J=9.9, 4.2Hz, 1H), 2.56-2.38 (m, 1H), 2.48 (s, 3H), 2.34-2.13 (m, 3H), 2.00-1.71 (m, 4H).

Example 1

In a 250 mL round-bottomed flask, a solution of Intermediate 1B (4.04 g, 5.86 mmol) in THF (50 mL) was treated with ammonia (2M in iPrOH) (26.4 mL, 52.7 mmol), followed by HOBT (1.795 g, 11.72 mmol) and EDC (2.246 g, 11.72 mmol). The resulting white suspension was stirred at room temperature overnight. The reaction mixture was diluted with water and saturated aqueous NaHCO3. The resulting solid was filtered, rinsed with water and then dried on the filter under a stream of nitrogen. The crude product was suspended in 20 mL of iPrOH and stirred at room temperature for 20 min and then filtered and washed with iPrOH and dried under vacuum to give 2.83 g of solid. The solid was dissolved in refluxing EtOH (100 mL) and slowly treated with 200 mg activated charcoal added in small portions. The hot mixture was filtered through CELITE® and rinsed with hot EtOH. The filtrate was reduced to half volume, allowed to cool and the white precipitate formed was filtered and rinsed with EtOH to give 2.57 g of white solid. A second recrystallization from EtOH (70 mL) afforded Example 1 (2.39 g, 70% yield) as a white solid. HPLC: RT=10.859 min (H2O/CH3CN with TFA, Sunfire C18 3.5 μm, 3.0×150 mm, gradient=15 min, wavelength=220 and 254 nm); MS (ES): m/z=575.3 [M+H+]; 1H NMR (400 MHz, methanol-d4) δ 7.57-7.50 (m, 1H), 7.47-7.30 (m, 3H), 7.29-7.15 (m, 3H), 5.38 (s, 1H), 2.85-2.75 (m, 1H), 2.59 (td, J=10.5, 4.0 Hz, 1H), 2.53-2.41 (m, 4H), 2.31-2.10 (m, 3H), 1.96-1.70 (m, 4H).

 

PATENT

WO-2014047372-A1

https://www.google.com/patents/WO2014047372A1?cl=en

Figure imgf000041_0001

Figure imgf000042_0001

Scheme 3

Figure imgf000044_0001
Figure imgf000045_0001

XII XI

Scheme 4

Figure imgf000047_0001

Intermediate S-l : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000053_0001

Intermediate S-IA: 3,3,3-Trifluoro ropyl trifluoromethanesulfonate

Figure imgf000053_0002

[00180] To a cold (-25 °C) stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf20 (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-l-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330g ISCO) and the product was eluted with DCM to afford Intermediate S-IA (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDC13) δ ppm 4.71 (2 H, t, J= 6.15 Hz), 2.49-2.86 (2 H, m).

Intermediate S-1B: (4S)-4-Benzyl-3-(5,5,5-trifluoropentanoyl)-l,3-oxazolidin-2-one

Figure imgf000054_0001

[00181] To a stirring solution of 5,5,5-trifluoropentanoic acid (14.76 g, 95 mmol) and DMF (0.146 rriL) in DCM (50 mL) was slowly added oxalyl chloride (8.27 mL, 95 mmol). After 2h, the mixture was concentrated to dryness. A separate flask was changed with (S)-4-benzyloxazolidin-2-one (16.75 g, 95 mmol) in THF (100 mL) and then cooled to -78 °C. To the solution was slowly added n-BuLi (2.5M, 37.8 mL, 95 mmol) over 10 min, stirred for 10 min, and then a solution of the above acid chloride in THF (50 mL) was slowly added over 5 min. The mixture was stirred for 30 min, and then warmed to room temperature. The reaction was quenched with sat aq NH4C1. Next, 10% aq LiCl was then added to the mixture, and the mixture was extracted with Et20. The organic layer was washed with sat aq NaHC03 then with brine, dried (MgSC^), filtered and concentrated to dryness. The residue was purified by Si02 chromatography (ISCO, 330 g column, eluting with a gradient from 100% hexane to 100% EtOAc) to afford the product Intermediate S-IB; (25.25 g, 85%): 1H NMR (400 MHz, CDC13) δ ppm 7.32-7.39 (2 H, m), 7.30 (1 H, d, J= 7.05 Hz), 7.18-7.25 (2 H, m), 4.64-4.74 (1 H, m), 4.17-4.27 (2 H, m), 3.31 (1 H, dd, J= 13.35, 3.27 Hz), 3.00-3.11 (2 H, m), 2.79 (1 H, dd, J= 13.35, 9.57 Hz), 2.16-2.28 (2 H, m), 1.93-2.04 (2 H, m).

Intermediate S-IC: tert- utyl (3R)-3-(((4S)-4-benzyl-2-oxo-l,3-oxazolidin-3- yl)carbonyl)-6,6,6-trifluoroh xanoate

Figure imgf000054_0002

[00182] To a cold (-78 °C), stirred solution of Intermediate S-IB (3.03 g, 9.61 mmol) in THF (20 mL) was added NaHMDS (1.0M in THF) (10.6 mL, 10.60 mmol) under a nitrogen atmosphere. After 2 hours, tert-butyl 2-bromoacetate (5.62 g, 28.8 mmol) was added neat via syringe at -78 °C and stirring was maintained at the same temperature. After 6 hours, the reaction mixture was warmed to room temperature. The reaction mixture was partitioned between saturated NH4C1 and EtOAc. The organic phase was separated, and the aqueous phase was extracted with EtOAc (3x). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO

CombiFlash Rf, 5% to 100% solvent A/B = hexanes/EtOAc, REDISEP® Si02 120g). Concentration of the appropriate fractions provided Intermediate S-1C (2.79 g, 67.6%) as a colorless viscous oil: 1H NMR (400 MHz, CDC13) δ ppm 7.34 (2 H, d, J= 7.30 Hz), 7.24-7.32 (3 H, m), 4.62-4.75 (1 H, m, J= 10.17, 6.89, 3.43, 3.43 Hz), 4.15-4.25 (3 H, m), 3.35 (1 H, dd, J= 13.60, 3.27 Hz), 2.84 (1 H, dd, J= 16.62, 9.57 Hz), 2.75 (1 H, dd, J = 13.35, 10.07 Hz), 2.47 (1 H, dd, J= 16.62, 4.78 Hz), 2.11-2.23 (2 H, m), 1.90-2.02 (1 H, m), 1.72-1.84 (1 H, m), 1.44 (9 H, s).

Intermediate S-ID: (2R)-2-( -tert-Butoxy-2-oxoethyl)-5,5,5-trifluoropentanoic acid

Figure imgf000055_0001

[00183] To a cool (0 °C), stirred solution of Intermediate S-1C (2.17 g, 5.05 mmol) in THF (50 mL) and water (15 mL) was added a solution of LiOH (0.242 g, 10.11 mmol) and H202 (2.065 mL, 20.21 mmol) in H20 (2 mL). After 10 min, the reaction mixture was removed from the ice bath, stirred for lh, and then cooled to 0 °C. Saturated aqueous NaHCC”3 (25 mL) and saturated aqueous Na2s03 (25 mL) were added to the reaction mixture, and the mixture was stirred for 10 min, and then partially concentrated. The resulting mixture was extracted with DCM (2x), cooled with ice and made acidic with cone. HC1 to pH 3. The mixture was saturated with solid NaCl, extracted with EtOAc (3x), and then dried over MgS04, filtered and concentrated to a colorless oil to afford Intermediate S-ID, 1.2514g, 92%): 1H NMR (400 MHz, CDCI3) δ ppm 2.83-2.95 (1 H, m), 2.62-2.74 (1 H, m), 2.45 (1 H, dd, J= 16.62, 5.79 Hz), 2.15-2.27 (2 H, m), 1.88-2.00 (1 H, m), 1.75-1.88 (1 H, m), 1.45 (9 H, s). Intermediate S-l : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and Intermediate S-1E: (2R,3R)-3-(tert-butoxycarbonyl)- 6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000056_0001

(S-1E)

[00184] To a cold (-78 °C) stirred solution of Intermediate S-1D (5 g, 18.50 mmol) in THF (60 mL) was slowly added LDA (22.2 mL, 44.4 mmol, 2.0M) over 7 min. After stirring for 2 hr, Intermediate S- 1 A (6.38 g, 25.9 mmol) was added to the reaction mixture over 3 min. After 60 min, the reaction mixture was warmed to -25 °C

(ice/MeOH/dry ice) and stirred for an additional 60 min at which time sat aq NH4C1 was added. The separated aqueous phase was acidified with IN HC1 to pH 3, and then extracted with Et20. The combined organic layers were washed with brine (2x), dried over MgS04, filtered and concentrated to provide a 1 :4 (II :I1E) mixture (as determined by 1H NMR) of Intermediate S-l and Intermediate S-1E (6.00 g, 89%) as a pale yellow solid. 1H NMR (500 MHz, CDC13) δ ppm 2.81 (1 H, ddd, J = 10.17, 6.32, 3.85 Hz), 2.63- 2.76 (1 H, m), 2.02-2.33 (4 H, m), 1.86-1.99 (2 H, m), 1.68-1.85 (2 H, m), 1.47 (9 H, s).

[00185] To a cold (-78 °C), stirred solution of a mixture of Intermediate S-l and Intermediate S-1E (5.97 g, 16.30 mmol) in THF (91 mL) was added LDA (19 mL, 38.0 mmol, 2.0M in THF/hexane/ethyl benzene) dropwise via syringe over 10 min (internal temperature never exceeded -65 °C, J-KEM® probe in reaction solution). The mixture was stirred for 15 min, and then warmed to room temperature (24 °C water bath), stirred for 15 min, and then cooled to -78 °C for 15 min. To the reaction mixture was added Et2AlCl (41 mL, 41.0 mmol, 1M in hexane) via syringe (internal temperature never exceeded -55 °C), and the mixture was stirred for 10 min, and then warmed to room temperature (24 °C bath) for 15 min and then back to -78 °C for 15 min. Meanwhile, a 1000 mL round bottom flask was charged with MeOH (145 mL) and precooled to -78 °C. With vigorous stirring the reaction mixture was transferred via cannula over 5 min to the MeOH. The flask was removed from the bath, ice was added followed by the slow addition of IN HC1 (147 mL, 147 mmol). Gas evolution was observed as the HC1 was added. The reaction mixture was allowed to warm to room temperature during which the gas evolution subsided. The reaction mixture was diluted with EtOAc (750 mL), saturated with NaCl, and the organic phase was separated, washed with a solution of potassium fluoride (8.52 g, 147 mmol) and IN HC1 (41 mL, 41.0 mmol) in water (291 mL), brine (100 mL), and then dried (Na2s04), filtered and concentrated under vacuum. 1H NMR showed the product was a 9: 1 mixture of Intermediate S-l and Intermediate S- 1E. The enriched mixture of Intermediate S-l and Intermediate S-1E (6.12 g, >99% yield) was obtained as a dark amber solid: 1H NMR (400 MHz, CDC13) δ ppm 2.64-2.76 (2 H, m), 2.04-2.35 (4 H, m), 1.88-2.00 (2 H, m), 1.71-1.83 (2 H, m), 1.48 (9 H, s).

Alternate procedure to make Intermediate S-l :

Intermediate S-IF: (2R,3 -1 -Benzyl 4-tert-butyl 2,3-bis(3,3,3-trifluoropropyl)succinate

Figure imgf000057_0001

[00186] To a stirred solution of a 9: 1 enriched mixture of Intermediate S-l and Intermediate S-1E (5.98 g, 16.33 mmol) in DMF (63 mL) were added potassium carbonate (4.06 g, 29.4 mmol) and benzyl bromide (2.9 mL, 24.38 mmol), the mixture was then stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (1000 mL), washed with 10% LiCl (3×200 mL), brine (200 mL), dried (Na2S04), filtered, concentrated, and then dried under vacuum. The residue was purified by Si02 chromatography using a toluene:hexane gradient. Diastereomerically purified

Intermediate S-IF (4.81g, 65%) was obtained as a colorless solid: 1H NMR (400 MHz, chloroform-d) δ 7.32-7.43 (m, 5H), 5.19 (d, J= 12.10 Hz, 1H), 5.15 (d, J= 12.10 Hz, 1H), 2.71 (dt, J= 3.52, 9.20 Hz, 1H), 2.61 (dt, J= 3.63, 9.63 Hz, 1H), 1.96-2.21 (m, 4H), 1.69-1.96 (m, 3H), 1.56-1.67 (m, 1H), 1.45 (s, 9H).

Intermediate S-l : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000058_0001

[00187] To a solution of Intermediate S-1F (4.81 g, 10.54 mmol) in MeOH (100 mL) was added 10% palladium on carbon (wet, Degussa type, 568.0 mg, 0.534 mmol) in a H2– pressure flask. The vessel was purged with N2 (4x), then purged with H2 (2x), and finally, pressurized to 50 psi and shaken overnight. The reaction vessel was

depressurized and purged with nitrogen. The mixture was filtered through CELITE®, washed with MeOH and then concentrated and dried under vacuum. Intermediate S-1 (3.81 g, 99% yield)) was obtained as a colorless solid: 1H NMR (400 MHz, chloroform-d) δ 2.62-2.79 (m, 2H), 2.02-2.40 (m, 4H), 1.87-2.00 (m, 2H), 1.67-1.84 (m, 2H), 1.48 (s, 9H).

Alternate procedure to make Intermediate S-1 :

Intermediate S-1 : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000058_0002

[00188] Intermediate S-1 as a mixture with Intermediate S-IE was prepared in a similar procedure as above from Intermediate S-1D to afford a 1 :2.2 mixture of

Intermediate S-1 and Intermediate S-IE (8.60 g, 23.48 mmol), which was enriched using LDA (2.0 M solution in THF, ethyl benzene and heptane, 28.2 mL, 56.4 mmol) and diethyl aluminum chloride (1.0 M solution in hexane, 59 mL, 59.0 mmol) in THF (91 mL). After workup as described above, the resulting residue was found to be a 13.2: 1 (by 1H NMR) mixture of Intermediate S-1 and Intermediate S-IE, which was treated as follows: The crude material was dissolved in MTBE (43 mL). Hexanes (26 mL) were slowly charged to the reaction mixture while maintaining a temperature below 30 °C. The reaction mixture was stirred for 10 min. Next, tert-butylamine (2.7 mL, 1.1 eq) was charged slowly over a period of 20 minutes while maintaining a temperature below 30 °C. This addition was observed to be exothermic. The reaction mixture was stirred for 2 hrs below 30 °C and then filtered. The solid material was washed with 5:3 MTBE: hexane (80 mL), and the filtrate was concentrated and set aside. The filtered solid was dissolved in dichloromethane (300 mL), washed with IN HC1 (lOOmL), and the organic layer was washed with brine (100 mL x 2), and then concentrated under reduced pressure below 45 °C to afford Intermediate S-l (5.46 g, 64%).

A second alternate procedure for preparing Intermediate S-l :

Intermediate S-1G: tert- utyl 5,5,5-trifluoropentanoate

Figure imgf000059_0001

[00189] To a stirred solution of 5,5,5-trifluoropentanoic acid (5 g, 32.0 mmol) in THF (30 mL) and hexane (30 mL) at 0 °C, was added tert-butyl 2,2,2-trichloroacetimidate (11.46 mL, 64.1 mmol). The mixture was stirred for 15 min at 0 °C. Boron trifluoride etherate (0.406 mL, 3.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. To the clear reaction mixture was added solid NaHC03 (5 g) and stirred for 30 min. The mixture was filtered through MgSC^ and washed with hexanes (200 mL). The solution was allowed to rest for 45 min, and the resulting solid material was removed by filtering on the same MgSC^ filter again, washed with hexanes (100 mL) and concentrated under reduced pressure without heat. The volume was reduced to about 30 mL, filtered through a clean fritted funnel, washed with hexane (5 mL), and then concentrated under reduced pressure without heat. The resulting neat oil was filtered through a 0.45μιη nylon membrane filter disk to provide Intermediate S-1G (6.6 g, 31.4 mmol 98% yield) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 1.38 (s, 9 H) 1.74-1.83 (m, 2 H) 2.00-2.13 (m, 2 H) 2.24 (t, J= 7.28 Hz, 2 H). Intermediate S-1H: (4S)-4-(Propan-2-yl)-3-(5,5,5-trifluoropentanoyl)-l,3-oxazolidin-2- one

Figure imgf000060_0001

[00190] To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-l,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 °C was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride, dissolved in THF (20 mL), was added via cannula over 15 min. The reaction mixture was warmed to 0 °C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4C1, and the mixture was extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B = hexanes/EtOAc, REDISEP® Si02 120g). Concentration of the appropriate fractions provided Intermediate S-1H (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 4.44 (1 H, dt, J= 8.31, 3.53 Hz), 4.30 (1 H, t, J= 8.69 Hz), 4.23 (1 H, dd, J= 9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J= 13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J= 7.05 Hz), 0.88 (3 H, d, J= 6.80 Hz).

Intermediate S-1I: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2- oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate, and Intermediate S-U: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2- (3 ,3 ,3 -trifluoropropyl)hexanoate

Figure imgf000061_0001

[00191] To a cold (-78 °C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol). The mixture was then warmed to 0 °C to give a 0.5M solution of LDA. A separate vessel was charged with Intermediate S-1H (2.45 g, 9.17 mmol). The material was azeotroped twice with benzene (the RotoVap air inlet was fitted with a nitrogen inlet to completely exclude humidity), and then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 °C, was added the LDA solution (21.0 mL, 10.5 mmol) and the mixture was stirred at -78 °C for 10 min, then warmed to 0 °C for 10 min., and then cooled to -78 °C. To a separate reaction vessel containing Intermediate S-1G (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 °C and LDA (37.0 mL, 18.5 mmol) was added. The resulting solution was stirred at -78 °C for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate and stirred at -78 °C for an additional 5 min, at which time the septum was removed and solid powdered bis(2- ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum was replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 °C) with rapid swirling and with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was then poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B = hexanes/EtOAc, REDISEP® Si02 120g). Concentration of the appropriate fractions provided a mixture of Intermediate S- II and Intermediate S-1J (2.87 g, 66%) as a pale yellow viscous oil. 1H NMR showed the product was a 1.6: 1 mixture of diastereomers S-1LS-1J as determined by the integration of the multiplets at 2.74 and 2.84 ppm: 1H NMR (400 MHz, CDC13) δ ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J= 9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J = 9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J= 10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m, J = 10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3 H, m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m). Intermediate S-1 : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and Intermediate S-IE: (2R,3R)-3-(tert-Butoxycarbonyl)- 6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000062_0001

(S-IE)

[00192] To a cool (0 °C), stirred solution of Intermediate S-1I and Intermediate S-1 J (4.54 g, 9.51 mmol) in THF (140 mL) and water (42 mL) were sequentially added hydrogen peroxide (30% in water) (10.3 g, 91 mmol) and LiOH (685.3 mg, 28.6 mmol). The mixture was stirred for 1 hr. At this time the reaction vessel was removed from the cold bath and then stirred for 1.5 hr. To the reaction mixture were added saturated NaHC03 (45 mL) and saturated Na2s03 (15 mL), and then the mixture was partially concentrated under reduced pressure. The resulting crude solution was extracted with DCM (3x). The aqueous phase was acidified to pH~l-2 with IN HC1, extracted with DCM (3x) and then EtOAc (lx). The combined organics were washed with brine, dried (Na2s04), filtered and concentrated under reduced pressure to provide a mixture of Intermediates S-1 and S-IE (3.00 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDC13) δ ppm 2.76-2.84 (1 H, m, diastereomer 2), 2.64-2.76 (3 H, m), 2.04-2.35 (8 H, m), 1.88- 2.00 (4 H, m), 1.71-1.83 (4 H, m), 1.48 (9 H, s, diastereomer 1), 1.46 (9 H, s,

diastereomer 2); 1H NMR showed a 1.7: 1 mixture of S-1E:S-1F by integration of the peaks for the t-butyl groups. Intermediate S-1 : (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and Intermediate S-IF: (2R,3R)-3-(fert-Butoxycarbonyl)- 6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000063_0001

[00193] To a cold (-78 °C) stirred solution of diisopropylamine (1.7 mL, 11.93 mmol) in THF (19 mL) under a nitrogen atmosphere was added n-BuLi (2.5M in hexanes) (4.8 mL, 12.00 mmol). The mixture was stirred for 5 min and then warmed to 0 °C. In a separate vessel, to a cold (-78 °C) stirred solution of the mixture of Intermediates S-1 and S-1E (1.99 g, 5.43 mmol) in THF (18 mL) was added the LDA solution prepared above via cannula slowly over 25 min. The mixture was stirred for 15 min, then warmed to room temperature (placed in a 24 °C water bath) for 15 min, and then again cooled to -78 °C for 15 min. To the reaction mixture was added Et2AlCl (1M in hexane) (11.4 mL, 11.40 mmol) via syringe. The mixture was stirred for 10 min, warmed to room

temperature for 15 min and then cooled back to -78 °C for 15 min. Methanol (25 mL) was rapidly added, swirled vigorously while warming to room temperature, and then concentrated to ~l/4 the original volume. The mixture was dissolved in EtOAc and washed with IN HC1 (50 mL) and ice (75 g). The aqueous phase was separated and extracted with EtOAc (2x). The combined organics were washed with a mixture of KF (2.85g in 75 mL water) and IN HC1 (13 mL) [resulting solution pH 3-4], then with brine, dried (Na2s04), filtered and concentrated under reduced pressure to give a 9: 1 (S-LS-1E) enriched diastereomeric mixture (as determined by 1H NMR) of Intermediate S-1 and Intermediate S-1E (2.13 g, >99%) as a pale yellow viscous oil: 1H NMR (400 MHz, CDC13) δ ppm 2.64-2.76 (2 H, m), 2.04-2.35 (4 H, m), 1.88-2.00 (2 H, m), 1.71-1.83 (2 H, m), 1.48 (9 H, s).

Intermediate S-2: (2R,3S)-3-(fert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3- fluoropropyl)hexanoic acid

Figure imgf000064_0001

Intermediate S-2: (2R,3S)-3-(tert-Butoxycarbonyl)-7,7,7-trifluoro-2-(3,3,3- trifluoropropyl)heptanoic acid, and Intermediate S-2A: (2R,3R)-3-(tert-Butoxycarbonyl)- 7,7,7-trifluoro-2-(3,3,3-trifluoropropyl)heptanoic acid

Figure imgf000064_0002

(S-2A)

[00194] To a cold (-78 °C), stirred solution of Intermediate S-1D (1.72 g, 6.36 mmol) in THF (30 mL) was slowly added LDA (7.32 mL, 14.6 mmol) over 7 min. After stirring for 1 h, 4,4,4-trifluorobutyltrifluoromethanesulfonate (2.11 g, 8.11 mmol) was added to the reaction mixture over 2 min. After 15 min, the reaction mixture was warmed to -25 °C (ice/MeOH/dry ice) for lh, and then cooled to -78 °C. After 80 min, the reaction was quenched with a saturated aqueous NH4C1 solution (10 mL). The reaction mixture was further diluted with brine and the solution was adjusted to pH 3 with IN HC1. The aqueous layer was extracted with ether. The combined organics were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide a mixture of Intermediates S-2 and S-2A (2.29 g, 95%) as a colorless oil. 1H NMR (400MHz, chloroform-d) δ 2.83-2.75 (m, 1H), 2.64 (ddd, J = 9.9, 6.7, 3.6 Hz, 1H), 2.32-2.03 (m, 5H), 1.98-1.70 (m, 3H), 1.69-1.52 (m, 3H), 1.50-1.42 (m, 9H). 1H NMR showed a 1 :4.5 mixture (S-2:S-2A) of diastereomers by integration of the peaks for the t- Bu groups.

Intermediate S-2: (2R,3S)-3-(fert-Butoxycarbonyl)-7,7,7-trifluoro-2-(3,3,3- trifluoropropyl)heptanoic acid, and Intermediate S-2A: (2R,3R)-3-(tert-Butoxycarbonyl)- 7,7,7-trifluoro-2-(3,3,3-trifluoropropyl)heptanoic acid

Figure imgf000065_0001

[00195] A mixture of Intermediate S-2 and Intermediate S-2A (2.29 g, 6.02 mmol) was dissolved in THF (38 mL) to give a colorless solution which was cooled to -78 °C. Then, LDA (7.23 mL, 14.5 mmol) (2.0M in heptane/THF/ethylbenzene) was slowly added to the reaction mixture over 3 min. After stirring for 15 min, the reaction mixture was placed in a room temperature water bath. After 15 min the reaction mixture was placed back in a -78 °C bath and then diethylaluminum chloride (14.5 mL, 14.5 mmol) (1M in hexane) was added slowly over 5 min. The reaction mixture was stirred at -78 °C. After 15 min, the reaction mixture was placed in a room temperature water bath for 10 min, and then cooled back to -78 °C. After 15 min, the reaction was quenched with MeOH (30.0 mL, 741 mmol), removed from the -78 °C bath and concentrated. To the reaction mixture was added ice and HC1 (60.8 mL, 60.8 mmol) and the resulting mixture was extracted with EtOAc (2x 200 mL). The organic layer was washed with potassium fluoride (3.50g, 60.3 mmol) in 55 mL H20 and 17.0 mL of IN HC1. The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide an enriched mixture of Intermediate S-2 and Intermediate S-2A (2.25g, 98% yield) as a light yellow oil. 1H NMR (400MHz, chloroform-d) δ 2.83-2.75 (m, 1H), 2.64 (ddd, J= 9.9, 6.7, 3.6 Hz, 1H), 2.32-2.03 (m, 5H), 1.98-1.70 (m, 3H), 1.69-1.52 (m, 3H), 1.50-1.42 (m, 9H). 1H NMR showed a 9: 1 ratio in favor of the desired diastereomer Intermediate S-2.

Intermediate S-2B: (2R,3S)-1 -Benzyl 4-tert-butyl 2,3-bis(4,4,4-trifluorobutyl)succinate

Figure imgf000065_0002

[00196] To a stirred 9: 1 mixture of Intermediate S-2 and Intermediate S-2A (2.24 g, 5.89 mmoL) and potassium carbonate (1.60 g, 11.58 mmoL) in DMF (30 mL) was added benzyl bromide (1.20 mL, 10.1 mmoL)). The reaction mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with 10% LiCl solution (3 x 100 mL), brine (50 mL), and then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash 0%> to 100% solvent A/B = hexane/EtOAc, REDISEP® Si02 220 g, detecting at 254 nm, and monitoring at 220 nm). Concentration of the appropriate fractions provided Intermediate S-2B (1.59 g, 57.5%). HPLC: RT = 3.863 min (CHROMOLITH® SpeedROD column 4.6 x 50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), 1H NMR (400MHz, chloroform-d) δ 7.40-7.34 (m, 5H), 5.17 (d, J= 1.8 Hz, 2H), 2.73-2.64 (m, 1H), 2.55 (td, J= 10.0, 3.9 Hz, 1H), 2.16-1.82 (m, 5H), 1.79-1.57 (m, 3H), 1.53-1.49 (m, 1H), 1.45 (s, 9H), 1.37-1.24 (m, 1H).

Intermediate S-2: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(4,4,4- trifluorobutyl)hexanoic acid

Figure imgf000066_0001

[00197] To a stirred solution of Intermediate S-2B (1.59 g, 3.37 mmoL) in MeOH (10 mL) and EtOAc (10 mL) under nitrogen was added 10%> Pd/C (510 mg). The atmosphere was replaced with hydrogen and the reaction mixture was stirred at room temperature for 2.5 h. The palladium catalyst was filtered off through a 4 μΜ polycarbonate film and rinsed with MeOH. The filtrate was concentrated under reduced pressure to give intermediate S-2 (1.28 g, 99%). 1H NMR (400MHz, chloroform-d) δ 2.76-2.67 (m, 1H), 2.65-2.56 (m, 1H), 2.33-2.21 (m, 1H), 2.17-2.08 (m, 3H), 1.93 (dtd, J= 14.5, 9.9, 5.2 Hz, 1H), 1.84-1.74 (m, 2H), 1.70-1.52 (m, 3H), 1.48 (s, 9H).

Intermediate A- 1 : (2-Amino-3 -methylphenyl)(3 -fluorophenyl)methanone

Figure imgf000067_0001

Intermediate A-1 A: 2-Amino- -methoxy-N,3-dimethylbenzamide

Figure imgf000067_0002

[00198] In a 1 L round-bottomed flask was added 2-amino-3-methylbenzoic acid (11.2 g, 74.1 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (14.45 g, 148 mmol) in DCM (500 mL) to give a pale brown suspension. The reaction mixture was treated with Et3N (35 mL), HOBT (11.35 g, 74.1 mmol) and EDC (14.20 g, 74.1 mmol) and then stirred at room temperature for 24 hours. The mixture was then washed with 10% LiCl, and then acidified with IN HCl. The organic layer was washed successively with 10%> LiCl and aq NaHC03. The organic layer was decolorized with charcoal, filtered, and the filtrate was dried over MgSC^. The mixture was filtered and concentrated to give 13.22 g (92% yield) of Intermediate A-1A. MS(ES): m/z = 195.1 [M+H+]; HPLC: RT = 1.118 min. (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm); 1H NMR (500MHz, chloroform-d) δ 7.22 (dd, J= 7.8, 0.8 Hz, 1H), 7.12-7.06 (m, 1H), 6.63 (t, J= 7.5 Hz, 1H), 4.63 (br. s., 2H), 3.61 (s, 3H), 3.34 (s, 3H), 2.17 (s, 3H).

Intermediate A- 1 : (2-Amino-3 -methylphenyl)(3 -fluorophenyl)methanone

Figure imgf000067_0003

[00199] In a 500 mL round-bottomed flask, a solution of l-fluoro-3-iodobenzene (13.61 mL, 116 mmol) in THF (120 mL) was cooled in a -78 °C bath. A solution of n- BuLi, (2.5M in hexane, 46.3 mL, 116 mmol) was added dropwise over 10 minutes. The solution was stirred at -78 °C for 30 minutes and then treated with a solution of

Intermediate A-1 A (6.43 g, 33.1 mmol) in THF (30 mL). After 1.5 hours, the reaction mixture was added to a mixture of ice and IN HCl (149 mL, 149 mmol) and the reaction flask was rinsed with THF (5 ml) and combined with the aqueous mixture. The resulting mixture was diluted with 10% aq LiCl and the pH was adjusted to 4 with IN NaOH. The mixture was then extracted with Et20, washed with brine, dried over MgS04, filtered and concentrated. The resulting residue was purified by silica gel chromatography (220g ISCO) eluting with a gradient from 10% EtOAc/hexane to 30% EtOAc/hexane to afford Intermediate A-l (7.11 g, 94% yield) as an oil. MS(ES): m/z = 230.1 [M+H+]; HPLC: RT = 2.820 min Purity = 99%. (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm).

Intermediate B-1 : (S)-3-Amino-5-(3-fluorophenyl)-9-methyl-lH-benzo[e][l,4]diazepin- 2(3H)-one

Figure imgf000085_0001

Intermediate B-1 A: (S)-Benzyl (5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro benzo[e] [ 1 ,4]diazepin-3-yl)carbamate

Figure imgf000085_0002

(B-1A)

[00225] In a 1 L round-bottomed flask, a solution of 2-(lH-benzo[d][l,2,3]triazol-l- yl)-2-((phenoxycarbonyl)amino)acetic acid (J. Org. Chem., 55:2206-2214 (1990)) (19.37 g, 62.0 mmol) in THF (135 mL) was cooled in an ice/water bath and treated with oxalyl chloride (5.43 mL, 62.0 mmol) and 4 drops of DMF. The reaction mixture was stirred for 4 hours. Next, a solution of Intermediate A- 1 (7.11 g, 31.0 mmol) in THF (35 mL) was added and the resulting solution was removed from the ice/water bath and stirred at room temperature for 1.5 hours. The mixture was then treated with a solution of ammonia, (7M in MeOH) (19.94 mL, 140 mmol). After 15 mins, another portion of ammonia, (7M in MeOH) (19.94 mL, 140 mmol) was added and the resulting mixture was sealed under N2 and stirred overnight at room temperature. The reaction mixture was then concentrated to ~l/2 volume and then diluted with AcOH (63 mL) and stir at room temperature for 4 hours. The reaction mixture was then concentrated, and the residue was diluted with 500 mL water to give a precipitate. Hexane and Et20 were added and the mixture was stirred at room temperature for 1 hour to form an orange solid. Et20 was removed under a stream of nitrogen and the aqueous layer was decanted. The residue was triturated with 40 mL of iPrOH and stirred at room temperature to give a white precipitate. The solid was filtered and washed with iPrOH, then dried on a filter under a stream of nitrogen to give racemic Intermediate B-1A (5.4 g, 41.7%yield).

[00226] Racemic Intermediate B-1A (5.9 g, 14.3 mmol) was resolved using the Chiral SFC conditions described below. The desired stereoisomer was collected as the second peak in the elution order: Instrument: Berger SFC MGIII, Column: CHIRALPAK® IC 25 x 3 cm, 5 cm; column temp: 45 °C; Mobile Phase: C02/MeOH (45/55); Flow rate: 160 mL/min; Detection at 220 nm.

[00227] After evaporation of the solvent, Intermediate B-1A (2.73 g, 46% yield) was obtained as a white solid. HPLC: RT = 3.075 min. (H20/MeOH with TFA,

CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm).

Chiral HPLC RT: 8.661 min (AD, 60% (EtOH/MeOH)/heptane) > 99%ee. MS(ES): m/z = 418.3 [M+H+];1H NMR (500MHz, DMSO-d6) δ 10.21 (s, 1H), 8.38 (d, J= 8.3 Hz, 1H), 7.57-7.47 (m, 2H), 7.41-7.29 (m, 8H), 7.25-7.17 (m, 2H), 5.10-5.04 (m, 3H), 2.42 (s, 3H).

Intermediate B-l : (S)-3-Amino-5-(3-fluorophenyl)-9-methyl-lH-benzo[e][l,4]diazepin- 2(3H)-one.

[00228] In a 100 mL round-bottomed flask, a solution of Intermediate B-1A (2.73 g, 6.54 mmol) in acetic acid (12 mL) was treated with HBr, 33% in HOAc (10.76 mL, 65.4 mmol) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with Et20 to give a yellow precipitate. The yellow solid was filtered and rinsed with Et20 under nitrogen. The solid was transferred to 100 mL round bottom flask and water was added (white precipitate formed). The slurry was slowly made basic with saturated NaHC03. The resulting tacky precipitate was extracted with EtOAc. The organic layer was washed with water, dried over MgS04, and then filtered and

concentrated to dryness to give Intermediate B-l (1.68 g, 91% yield) as a white foam solid. MS(ES): m/z = 284.2 [M+H+]; HPLC: RT = 1.72 min (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm). 1H NMR (400MHz, DMSO-d6) δ 10.01 (br. s., 1H), 7.56-7.44 (m, 2H), 7.41-7.26 (m, 3H), 7.22-7.11 (m, 2H), 4.24 (s, 1H), 2.55 (br. s., 2H), 2.41 (s, 3H). [00229] The compounds listed below in Table 6 (Intermediates B-2 to B-3) were prepared according to the general synthetic procedure described for Intermediate B-l , using the starting materials Intermediate A- 10 and Intermediate A-4, respectively.

 

Example 1

(2R,3S)-N-((3S)-5-(3-Fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-lH-l,4-benzodiazepin- 3-yl)-2, -bis(3,3,3-trifluoropropyl)succinamide

Figure imgf000098_0001

Intermediate 1A: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-(((S)-5-(3-fluorophenyl)-9-methyl- 2-0X0-2, 3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)carbamoyl)-2-(3,3 ,3- trifluoropropyl)hexanoat

Figure imgf000098_0002

[00240] In a 100 mL round-bottomed flask, a solution of Intermediate B-l (1683 mg, 5.94 mmol), Et3N (1.656 mL, 11.88 mmol), and Intermediate S-l in DMF (20 mL) was treated with o-benzotriazol-l-yl-A .A .N’.N’-tetramethyluronium tetrafluoroborate (3815 mg, 11.88 mmol) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and saturated aqueous NaHC03. An off white precipitate formed and was filtered and washed with water. The resulting solid was dried on the filter under a stream of nitrogen to give Intermediate 1A (3.7 g, 99% yield). MS(ES): m/z =

632.4[M+H+]; HPLC: RT = 3.635 min Purity = 98%. (H20/MeOH with TFA,

CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm). 1H NMR (400MHz, methanol-d4) δ 7.53 (t, J = 4.5 Hz, 1H), 7.46-7.30 (m, 3H), 7.28-7.23 (m, 1H), 7.23-7.18 (m, 2H), 5.37 (s, 1H), 2.88 (td, J = 10.4, 3.4 Hz, 1H), 2.60 (td, J =

10.2, 4.1 Hz, 1H), 2.54-2.40 (m, 1H), 2.47 (s, 3 H), 2.33-2.12 (m, 3H), 1.98-1.69 (m, 4H), 1.51 (s, 9H). Intermediate IB: (2S,3R)-6,6,6-Trifluoro-3-(((S)-5-(3-fluorophenyl)-9-methyl-2-oxo-

2,3-dihydro-lH-benzo[e][l,4]diazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000099_0001

[00241] In a 250 mL round-bottomed flask, a solution of Intermediate 1A (3.7 g, 5.86 mmol) in DCM (25 mL) was treated with TFA (25 mL) and the resulting pale orange solution was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated to give Intermediate IB. HPLC: RT = 3.12 min (H20/MeOH with TFA, CHROMOLITH® ODS S5 4.6 x 50 mm, gradient = 4 min, wavelength = 220 nm).

MS(ES): m/z = 576.3 (M+H)+. 1H NMR (400MHz, methanol-d4) δ 7.54 (t, J= 4.5 Hz, 1H), 7.49-7.29 (m, 3H), 7.28-7.15 (m, 3H), 5.38 (br. s., 1H), 2.89 (td, J= 10.3, 3.7 Hz, 1H), 2.67 (td, J= 9.9, 4.2 Hz, 1H), 2.56-2.38 (m, 1H), 2.48 (s, 3 H), 2.34-2.13 (m, 3H), 2.00-1.71 (m, 4H).

Example 1 :

[00242] In a 250 mL round-bottomed flask, a solution of Intermediate IB (4.04 g, 5.86 mmol) in THF (50 mL) was treated with ammonia (2M in iPrOH) (26.4 mL, 52.7 mmol), followed by HOBT (1.795 g, 11.72 mmol) and EDC (2.246 g, 11.72 mmol). The resulting white suspension was stirred at room temperature overnight. The reaction mixture was diluted with water and saturated aqueous NaHC03. The resulting solid was filtered, rinsed with water and then dried on the filter under a stream of nitrogen. The crude product was suspended in 20 mL of iPrOH and stirred at room temperature for 20 min and then filtered and washed with iPrOH and dried under vacuum to give 2.83 g of solid. The solid was dissolved in re fluxing EtOH(100 mL) and slowly treated with 200 mg activated charcoal added in small portions. The hot mixture was filtered through CELITE® and rinsed with hot EtOH. The filtrate was reduced to half volume, allowed to cool and the white precipitate formed was filtered and rinsed with EtOH to give 2.57 g of white solid. A second recrystallization from EtOH (70 mL) afforded Example 1 (2.39 g, 70% yield) as a white solid. HPLC: RT = 10.859 min (H20/CH3CN with TFA, Sunfire C18 3.5μπι, 3.0x150mm, gradient = 15 min, wavelength = 220 and 254 nm); MS(ES): m/z = 575.3 [M+H+]; 1H NMR (400MHz, methanol-d4) δ 7.57-7.50 (m, 1H), 7.47-7.30 (m, 3H), 7.29-7.15 (m, 3H), 5.38 (s, 1H), 2.85-2.75 (m, 1H), 2.59 (td, J= 10.5, 4.0 Hz, 1H), 2.53-2.41 (m, 4H), 2.31-2.10 (m, 3H), 1.96-1.70 (m, 4H).

 

SEE

WO2012129353A1 *Mar 22, 2012Sep 27, 2012Bristol-Myers Squibb CompanyBis(fluoroalkyl)-1,4-benzodiazepinone compounds

 

PAPER RELATED

Structure–activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors

Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
§ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,United States
ACS Med. Chem. Lett., 2015, 6 (5), pp 523–527
*Phone: 609-252-5091. E-mail: ashvinikumar.gavai@bms.com.
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Patent

http://www.google.co.in/patents/WO2012129353A1?cl=en

 

PATENT RELATED

US-20160060232-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159930181&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

 

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Clip RELATED

For some disease targets, an indirect approach may be best. Or so Ashvinikumar V. Gavai and his colleagues atBristol-Myers Squibbfound in their quest toward a potential cancer drug. Gavai unveiled BMS-906024, which is an experimental—and slightly roundabout—treatment for a number of cancers, including breast, lung, and colon cancers, and leukemia.

Cancers have a tendency to relapse or to become resistant to treatments that once worked. Research at BMS and elsewhere had suggested that a family of proteins called Notch is implicated in that resistance and in cancer progression more generally. Gavai, director of oncology chemistry at BMS in Princeton, N.J., and his team set out to block Notch family signaling.

Notch family members lack enzymatic activity, so blocking them directly is difficult. Instead, BMS developed inhibitors of an enzyme that is essential for activating Notch signaling—γ-secretase.

09116-cover-bms906024

Company: Bristol-Myers Squibb

Target: pan-Notch

Disease: breast, lung, colon cancer; leukemia

Interfering with Notch, even in this indirect way, can have detrimental effects on the gastrointestinal tract. Only two of the four Notch family members are linked to that side effect, Gavai says. But he and his team think their drug will be most effective if it acts on all four family members roughly equally—a so-called pan-Notch inhibitor. By selecting a molecule that’s well tolerated in animals and carefully scheduling doses of the drug in humans, it could be possible to minimize side effects, he says.

The BMS team relied on Notch signaling assays in leukemia and breast cancer cell lines to find leads. They soon learned that for their molecules to work, three chiral centers had to be in the S,R,Sconfiguration. After that, they strove to make the molecules last in the bloodstream. They removed an isobutyl group and tweaked some other parts of their candidate’s succinamide side chain. It was tough to retain both a long half-life and activity against Notch, Gavai told C&EN. “You’d optimize one and lose the other.”

His team threaded the needle with BMS-906024. Their studies with mice suggest that a dose of 4–6 mg once a week could be effective in people. That’s lower than doses being tested for other Notch-targeted agents, according to the website clinicaltrials.gov. The mouse studies also back the idea that Notch is involved in cancer drug resistance and suggest that Notch could be a target for taking on cancer stem cells, which are notoriously resistant to chemotherapy.

BMS-906024 is in Phase I clinical trials, both alone and in combination with other agents. Patients with colon, lung, breast, and other cancers are receiving intravenous doses of the compound to determine its safety and optimum dose ranges.

09116-cover-BMScxd

(From left, front row) Gavai, Weifeng Shan, (second row) Aaron Balog, Patrice Gill, Gregory Vite, (third row) Francis Lee, Claude Quesnelle, (rear row) Wen-Ching Han, Richard Westhouse.

Credit: Catherine Stroud Photography

http://cen.acs.org/articles/91/i16/BMS-906024-Notch-Signaling-Inhibitor.html

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PAPER RELATED

Abstract Image

An enantioselective synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (S1) is described. The key step in the sequence involved crystallization-induced dynamic resolution (CIDR) of compound 7 using Boc-d-phenylalanine as a chiral resolving agent and 3,5-dichlorosalicylaldehyde as a racemization catalyst to afford S1 in 81% overall yield with 98.5% enantiomeric excess.

Crystallization-Induced Dynamic Resolution toward the Synthesis of (S)-7-Amino-5H,7H-dibenzo[b,d]-azepin-6-one: An Important Scaffold for γ-Secretase Inhibitors

Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
Bristol-Myers Squibb Company, P.O Box 4000, Princeton, New Jersey 08543-4000, United States
Org. Process Res. Dev., Article ASAP
Cited Patent Filing date Publication date Applicant Title
WO2000007995A1 * Aug 7, 1999 Feb 17, 2000 Du Pont Pharmaceuticals Company SUCCINOYLAMINO LACTAMS AS INHIBITORS OF Aβ PROTEIN PRODUCTION
WO2000038618A2 * Dec 23, 1999 Jul 6, 2000 Du Pont Pharmaceuticals Company SUCCINOYLAMINO BENZODIAZEPINES AS INHIBITORS OF Aβ PROTEIN PRODUCTION
WO2001060826A2 * Feb 16, 2001 Aug 23, 2001 Bristol-Myers Squibb Pharma Company SUCCINOYLAMINO CARBOCYCLES AND HETEROCYCLES AS INHIBITORS OF Aβ PROTEIN PRODUCTION
US6737038 * May 17, 2000 May 18, 2004 Bristol-Myers Squibb Company Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
US7053084 Feb 17, 2000 May 30, 2006 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7456172 Jan 13, 2006 Nov 25, 2008 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US20030134841 * Nov 1, 2002 Jul 17, 2003 Olson Richard E. Succinoylamino lactams as inhibitors of A-beta protein production
US20120245151 * Mar 22, 2012 Sep 27, 2012 Bristol-Myers Squibb Company Bisfluoroalkyl-1,4-benzodiazepinone compounds

 

//////////BMS-986115, BMS 986115, 3,5-dichlorosalicylaldehyde, Alzheimer’s disease, Boc-D-phenylalanine, CIDR;dibenzoazepenone DKR; Notch inhibitorsNotch inhibitor, SAR T-acute lymphoblastic leukemia, triple-negative breast cancer, γ-secretase inhibitor, PHASE 1, BMS, Bristol-Myers Squibb,  Ashvinikumar Gavai1584647-27-7, UNII: LSK1L593UU

Cc1cccc2c1NC(=O)[C@H](N=C2c3cccc(c3)F)NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)N

BMS 906024


BMS-906024.pngBMS-906024.svg

 

Figure imgf000065_0001

BMS 906024

cas 1401066-79-2

  • MF C26H26F6N4O3
  • MW 556.500

(2R,3S)-N-[(3S)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinamide

Butanediamide, N1-((3S)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluorophenyl)-, (2R,3S)-

(2R,35)-N-((35)-l-Methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-3- (2,2,2-trifluoroethyl)-2-(3,3,3-trifluoropropyl)succinamide

Claude Quesnelle, Soong-Hoon Kim, Francis Lee, Ashvinikumar Gavai
Applicant Bristol-Myers Squibb Company

 

str2

Ashvinikumar Gavai

 

 

Claude Quesnelle

Claude Quesnelle
Senior Research Investigator/Chemist at Bristol-Myers Squibb

str2

RICHARD LEE

BMS-906024 is a novel, potent Notch receptor inhibitor . Cancers have a tendency to relapse or to become resistant to treatments that once worked. A family of proteins called Notch is implicated in that resistance and in cancer progression more generally. BMS-906024 is in Phase I clinical trials, both alone and in combination with other agents. Patients with colon, lung, breast, and other cancers are receiving intravenous doses of the compound to determine its safety and optimum dose ranges.

New Phase I drug structure by Bristol-Myers Squibb disclosed at the spring 2013 American Chemical Society meeting in New Orleans to treat breast, lung, and colon cancers and leukemia.[1] The drug works as an pan-Notch inhibitor. The structure is one of a set patented in 2012,[2] and it currently being studied in clinical trials.[3][4]

useful for the treatment of conditions related to the Notch pathway, such as cancer and other proliferative diseases.

Notch signaling has been implicated in a variety of cellular processes, such as cell fate specification, differentiation, proliferation, apoptosis, and angiogenesis. (Bray, Nature Reviews Molecular Cell Biology, 7:678-689 (2006); Fortini, Developmental Cell 16:633-647 (2009)). The Notch proteins are single-pass heterodimeric transmembrane molecules. The Notch family includes 4 receptors, NOTCH 1-4, which become activated upon binding to ligands from the DSL family (Delta-like 1, 3, 4 and Jagged 1 and 2).

The activation and maturation of NOTCH requires a series of processing steps, including a proteolytic cleavage step mediated by gamma secretase, a multiprotein complex containing Presenilin 1 or Presenilin 2, nicastrin, APH1, and PEN2. Once NOTCH is cleaved, NOTCH intracellular domain (NICD) is released from the membrane. The released NICD translocates to the nucleus, where it functions as a transcriptional activator in concert with CSL family members (RBPSUH, “suppressor of hairless”, and LAG1). NOTCH target genes include HES family members, such as HES- 1. HES- 1 functions as transcriptional repressors of genes such as HERP 1 (also known as HEY2), HERP2 (also known as HEY1), and HATH1 (also known as ATOH1).

The aberrant activation of the Notch pathway contributes to tumorigenesis. Activation of Notch signaling has been implicated in the pathogenesis of various solid tumors including ovarian, pancreatic, as well as breast cancer and hematologic tumors such as leukemias, lymphomas, and multiple myeloma. The role of Notch inhibition and its utility in the treatment of various solid and hematological tumors are described in Miele, L. et al, Current Cancer Drug Targets, 6:313-323 (2006); Bolos, V. et al, Endocrine Reviews, 28:339-363 (2007); Shih, I.-M. et al, Cancer Research, 67: 1879- 1882 (2007); Yamaguchi, N. et al., Cancer Research, 68: 1881-1888 (2008); Miele, L., Expert Review Anti-cancer Therapy, 8: 1 197-1201 (2008); Purow, B., Current Pharmaceutical Biotechnology, 10: 154-160 (2009); Nefedova, Y. et al, Drug Resistance Updates, 1 1 :210-218 (2008); Dufraine, J. et al, Oncogene, 27:5132-5137 (2008); and Jun, H.T. et al, Drug Development Research, 69:319-328 (2008).

There remains a need for compounds that are useful as Notch inhibitors and that have sufficient metabolic stability to provide efficacious levels of drug exposure. Further, there remains a need for compounds useful as Notch inhibitors that can be orally or intravenously administered to a patient.

U.S. Patent No. 7,053,084 Bl discloses succinoylamino benzodiazepine compounds useful for treating neurological disorders such as Alzheimer’s Disease. The reference discloses that these succinoylamino benzodiazepine compounds inhibit gamma secretase activity and the processing of amyloid precursor protein linked to the formation of neurological deposits of amyloid protein. The reference does not disclose the use of these compounds in the treatment of proliferative diseases such as cancer.

Applicants have found potent compounds that have activity as Notch inhibitors and have sufficient metabolic stability to provide efficacious levels of drug exposure upon intravenous or oral administration. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.

Image result for BMS 906024Image result for BMS 906024

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PAPER

Abstract Image

Structure–activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.

Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors

Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, United States
Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States
§ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,United States
ACS Med. Chem. Lett., 2015, 6 (5), pp 523–527
*Phone: 609-252-5091. E-mail: ashvinikumar.gavai@bms.com.
(2R,3S)-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4- benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide
colorless solid: HPLC: RT = 9.60 min (HPLC Method D). Chiral LC/Analytical SFC conditions: Column: LuxCellulose-2 (0.46 x 25cm), Mobile phase: 10% methanol in CO2, Flow rate: 3 mL/min, wavelength: 220 nm; Temp.: 35C. RT = 9.21 min, Purity = 99.95%.
MS (ES): m/z = 557 [M+H]+ ;
1H NMR (400 MHz, DMSO-d6)  9.54 (1H, d, J = 7.28 Hz), 7.71 – 7.80 (1H, m), 7.68 (2H, d, J = 8.78 Hz), 7.50 – 7.62 (3H, m), 7.45 (2H, t, J = 7.28 Hz), 7.29 – 7.40 (2H, m), 7.15 (1H, s), 5.30 (1H, d, J = 7.28 Hz), 3.39 (3H, s), 2.74 – 2.86 (1H, m), 2.02 -2.32 (3H, m), 1.45 – 1.79 (4H, m);
[]D = -107.0° (5.73 mg/mL, DMSO).
Elemental analysis: Theoretical: C: 54.11%; H: 4.70%; N: 10.06%; Actual: C: 54.06%; H: 4.90%; N: 10.08%.
Karl Fisher Moisture: 0.48.
HPLC Method D: Sunfire C18 3.5um, 3.0x150mm column, solvent A: 5% acetonitrile – 95% water – 0.05% TFA, solvent B: 95% acetonitrile – 5% water – 0.05% TFA, flow=0.5 mL/min, gradient from 10%B to 100%B over 15min, 254 nm detector.
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Patent

http://www.google.co.in/patents/WO2012129353A1?cl=en

Example 1

(2R,35)-N-((35′)-l-Methyl-2-oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3- b -trifluoropropy l)succinamide

Figure imgf000065_0001

Preparation 1A: tert-Butyl 5, -trifluoropentanoate

Figure imgf000065_0002

[00219] To a stirred solution of 5,5,5-trifluoropentanoic acid (5 g, 32.0 mmol) in THF (30 mL) and hexane (30 mL) at 0 °C, was added tert-butyl 2,2,2-trichloroacetimidate (11.46 mL, 64.1 mmol). The mixture was stirred for 15 min at 0 °C. Boron trifluoride etherate (0.406 mL, 3.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. To the clear reaction mixture was added solid aHC03 (5 g) and stirred for 30 min. The mixture was filtered through MgS04 and washed with hexanes (200 mL). The solution was allowed to rest for 45 min, and the resulting solid material was removed by filtering on the same MgS04 filter again, washed with hexanes (100 mL) and concentrated under reduced pressure without heat. The volume was reduced to about 30 mL, filtered through a clean fritted funnel, washed with hexane (5 mL), and then concentrated under reduced pressure without heat. The resulting neat oil was filtered through a 0.45μηι nylon membrane filter disk to provide tert-butyl 5,5,5- trifluoropentanoate (6.6 g, 31.4 mmol 98% yield) as a colorless oil: XH NMR (400 MHz, CDC13) δ ppm 1.38 (s, 9 H) 1.74-1.83 (m, 2 H) 2.00-2.13 (m, 2 H) 2.24 (t, J=7.28 Hz, 2 H).

Preparation IB: (45)-4-(Propan-2- l)-3-(5,5,5-trifluoropentanoyl)-l,3-oxazolidin-2-one

Figure imgf000066_0001

[00220] To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (45)-4-(propan-2-yl)-l,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at -78 °C was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction mixture was warmed to 0 °C, and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4CI, and then extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP® S1O2 120g). Concentration of appropriate fractions provided Preparation IB (7.39 g, 86%) as a colorless oil: XH NMR (400 MHz, CDC13) δ ppm 4.44 (1 H, dt, J=8.31, 3.53 Hz), 4.30 (1 H, t, J=8.69 Hz), 4.23 (1 H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2 H, m), 2.32-2.44 (1 H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2 H, m), 1.88-2.00 (2 H, m), 0.93 (3 H, d, J=7.05 Hz), 0.88 (3 H, d, J=6.80 Hz). Preparation 1C: (25′,3R)-tert-Butyl 6,6,6-trifluoro-3-((5)-4-isopropyl-2-oxooxazolidine- 3 -carbonyl)-2-(3 ,3,3 -trifluoropropyl)hexanoate, and

Preparation ID: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3-((5)-4-isopropyl-2-oxooxazolidine- 3 -carbonyl)- -(3 ,3 ,3 -trifluoropropyl)hexanoate

Figure imgf000067_0001

(1 C) (1 D)

[00221] To a cold (-78 °C), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol), then warmed to 0 °C to give a 0.5M solution of LDA. A separate vessel was charged with Preparation IB (2.45 g, 9.17 mmol), the material was azeotroped twice with benzene (the RotoVap air inlet was fitted with nitrogen inlet to completely exclude humidity) then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to -78 °C, was added LDA solution (21.0 mL, 10.5 mmol) and stirred at -78 °C for 10 min, warmed to 0 °C for 10 min then recooled to -78 °C. To a separate reaction vessel containing Preparation 1A (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to -78 °C and LDA (37.0 mL, 18.5 mmol) was added, the resulting solution was stirred at -78° for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate, stirred at -78 °C for an additional 5 min at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40 °C) with rapid swirling with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP® S1O2 120g). Concentration of appropriate fractions provided Preparation 1C (2.87 g, 66%) as pale yellow viscous oil. XH NMR showed the product was a 1.6: 1 mixture of diastereoisomers 1C: 1D as determined by the integration of the multiplets at 2.74 & 2.84 ppm: XH NMR (400 MHz, CDC13) δ ppm 4.43-4.54 (2 H, m), 4.23-4.35 (5 H, m), 4.01 (1 H, ddd, J=9.54, 6.27, 3.51 Hz), 2.84 (1 H, ddd, J=9.41, 7.28, 3.64 Hz), 2.74 (1 H, ddd, J=10.29, 6.27, 4.02 Hz), 2.37-2.48 (2 H, m, J=10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3 H, m), 1.92-2.20 (8 H, m), 1.64-1.91 (5 H, m), 1.47 (18 H, s), 0.88-0.98 (12 H, m). Preparation IE: (2R,35)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and

Preparation IF: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000068_0001

(1 E) (1 F)

[00222] To a cool (0 °C), stirred solution of Preparation 1C and ID (4.54 g, 9.51 mmol) in THF (140 mL) and water (42 mL) was sequentially added hydrogen peroxide (30% in water) (10.3 g, 91 mmol) and LiOH (685.3 mg, 28.6 mmol) and the mixture was stirred for 1 hr. At this time the reaction vessel was removed from the cold bath and then stirred for 1.5 hr. The reaction was judged complete by HPLC. To the reaction mixture was added saturated NaHC03 (45 mL) and saturated a2S03(15 mL), and then partially concentrated under reduced pressure. The resulting crude solution was extracted with DCM (3x). The aqueous phase was acidified to pH~l-2 with IN HC1, extracted with DCM (3x) and EtOAc (lx). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure to provide a mixture of Preparation IE and IF (3.00 g, 86%) as colorless oil: XH NMR (400 MHz, CDC13) δ ppm 2.76-2.84 (1 H, m, diastereoisomer 2), 2.64-2.76 (3 H, m), 2.04-2.35 (8 H, m), 1.88-2.00 (4 H, m), 1.71-1.83 (4 H, m), 1.48 (9 H, s, diastereoisomer 1), 1.46 (9 H, s, diastereoisomer 2); XH NMR showed a 1.7: 1 mixture of 1E: 1F by integration of the peaks for the ?-butyl groups.

Preparation IE: (2R,35)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and

Preparation IF: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000069_0001

(1 E) (1 F)

[00223] To a cold (-78 °C), stirred solution of diisopropylamine (1.7 mL, 11.93 mmol) in THF (19 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexanes) (4.8 mL, 12.00 mmol). The mixture was stirred for 5 min and then warmed to 0 °C. In a separate vessel, to a cold (-78 °C) stirred solution of the mixture of Preparation IE and IF (1.99 g, 5.43 mmol) in THF (18 mL) was added the LDA solution prepared above via cannula slowly over 25 min. The mixture was stirred for 15 min, then warmed to room temperature (placed in a 24 °C water bath) for 15 min, and then again cooled to -78 °C for 15 min. To the reaction mixture was added Et2AlCl (1M in hexane) (11.4 mL, 1 1.40 mmol) via syringe, stirred for 10 min, warmed to room temperature for 15 min and then cooled back to -78 °C for 15 min. Methanol (25 mL) was rapidly added, swirled vigorously while warming to room temperature, then concentrated to ~l/4 original volume. The mixture was dissolved in EtOAc and washed with IN HCl (50 mL) and ice (75 g). The aqueous phase was separated, extracted with EtOAc (2x). The combined organics were washed with a mixture of KF (2.85g in 75 mL water) and IN HCl (13 mL) [resulting solution pH 3-4], then with brine, dried (Na2S04), filtered and concentrated under reduced pressure to give a 9: 1 (IE: IF) enriched diastereoisomeric mixture (as determined by XH NMR) of Preparation IE and Preparation IF (2.13 g, >99%) as a pale yellow viscous oil: XH NMR (400 MHz, CDC13) δ ppm 2.64-2.76 (2 H, m), 2.04-2.35 (4 H, m), 1.88-2.00 (2 H, m), 1.71-1.83 (2 H, m), 1.48 (9 H, s). Preparation 1 G: (35)-3 -Amino- 1 -methyl-5-phenyl- 1 ,3 -dihydro-2H- 1 ,4-benzodiazepin-2- one, and

Preparation 1H: (3R)-3 -Amino- 1 -methyl-5-phenyl- 1 ,3-dihydro-2H- 1 ,4-benzodiazepin-2- one

Figure imgf000070_0001

(1G) (1 H)

[00224] Racemic 3-amino-l-methyl-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2- one (Rittle, K.E. et al, Tetrahedron Letters, 28(5):521-522 (1987)) was prepared according to the literature procedure. The enantiomers were separated under chiral-SFC conditions using the following method: CHIRALPAK® AS-H 5×25; Mobile phase: 30% MeOH+ 0.1% DEA in C02; Flow rate: 280 mL/min; Pressure: 100 bar; Temperature: 35 °C.

[00225] Obtained the S-enantiomer (Preparation 1G): HPLC: RT=1.75 min (30% MeOH + 0.1% DEA in C02 on CHIRALPAK® AS-H 4.6×250 mm, 3 mL/min, 35 °C, 100 bar, 230 nm, ΙΟμΙ injection); ¾ NMR (400 MHz, CDC13) δ ppm 7.58-7.63 (2 H, m), 7.55 (1 H, ddd, J=8.50, 7.1 1, 1.76 Hz), 7.40-7.47 (1 H, m), 7.34-7.40 (3 H, m), 7.31 (1 H, dd, J=7.81, 1.51 Hz), 7.14-7.22 (1 H, m), 4.46 (1 H, s), 3.44 (3 H, s), 3.42 (2 H, s); [a]D= -155° (c=1.9, MeOH) (Lit. Rittle, K.E. et al, Tetrahedron Letters, 28(5):521-522 (1987): [a]D=-236°).

[00226] Also obtained the R-enantiomer (Preparation 1H): HPLC: RT=1.71 min; [a]D=+165° (c=2.1, MeOH) (Lit [a]D= +227°).

Alternate procedure to make Preparation 1 G:

Preparation 1G»CSA salt: (35)-3-Amino-l-methyl-5-phenyl-l,3-dihydro-2H-l,4- benzodiazepin-2-one, (15)-(+)-10-camphorsulfonic acid salt

Figure imgf000071_0001

[00227] Preparation lG’CSA was prepared from racemic 3-amino-l-methyl-5-phenyl- l,3-dihydro-2H-l,4-benzodiazepin-2-one (9.98g, 37.6 mmol) (prepared according to the literature as shown above) according to the literature procedure (Reider, P.J. et al, J. Org. Chem., 52:955-957 (1987)). Preparation lG’CSA (16.91g, 99%) was obtained as a colorless solid: Optical Rotation: [a]D = -26.99° (c=l, H20) (Lit. [a]D = -27.8° (c=l,

H20))

Preparation II: tert-Butyl (25,,3R)-6,6,6-trifluoro-3-(((35)-l-methyl-2-oxo-5-phenyl-2,3- dihydro- 1 H- 1 ,4-benzodiazepin-3 -yl)carbamoyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate, and Preparation 1J: tert-Butyl (2R,3R)-6,6,6-trifluoro-3-(((35)-l-methyl-2-oxo-5-phenyl-2,3- dihydro- 1 H- 1 ,4-benzodiazepin-3 -yl)carbamoyl)-2-(3 ,3 ,3-trifluoropropyl)hexanoate

Figure imgf000071_0002

(11) (U)

[00228] To a stirred solution of Preparation 1G (1.45 g, 5.47 mmol) and a 9: 1 mixture of Preparation IE and IF (1.989 g, 5.43 mmol) in DMF (19 mL) was added O- benzotriazol-l-yl-N,N,N’,N’-tetra-methyluronium tetrafluoroborate (1.79 g, 5.57 mmol) and triethylamine (3.0 mL, 21.52 mmol) and stirred overnight. The reaction was judged complete by LCMS. The reaction mixture was poured into water (125 mL) and the precipitated solid was collected by filtration, washed with water and air dried to provide an 8: 1 mixture of Preparation II and Preparation 1J (2.95 g, 89%) as a cream solid: MS (ES): m/z= 614 [M+H]+;XH NMR (400 MHz, CDC13) δ ppm 7.55-7.65 (3 H, m), 7.44- 7.52 (2 H, m), 7.35-7.45 (4 H, m), 5.52 (1 H, d, J=8.03 Hz), 3.48 (3 H, s), 2.63 (2 H, ddd, J=9.35, 3.95, 3.76 Hz), 2.14-2.25 (4 H, m), 1.90-2.03 (3 H, m), 1.69-1.82 (1 H, m), 1.51 (9 H, s).

Preparation IK: (25,,3R)-6,6,6-Trifluoro-3-(((35)-l-methyl-2-oxo-5-phenyl-2,3-dihydro- lH-l,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid, and

Preparation 1L: (2R,3R)-6,6,6-Trifluoro-3-(((35)-l-methyl-2-oxo-5-phenyl-2,3-dihydro- 1 H- 1 ,4-

Figure imgf000072_0001

(1 K) (1 L)

[00229] To a cool (0 °C), stirred solution of the above mixture of Preparation II and Preparation 1 J (2.95 g, 4.81 mmol) in DCM (20 mL) was added TFA (20 mL, 260 mmol). The reaction mixture was stirred for lhr, then allowed to warm to room temperature and stirred for 2.5 hr. The reaction was judged complete by LCMS. The reaction mixture was diluted with toluene (50 mL) and concentrated under reduced pressure. The residue mixture was redissolved in toluene (50 mL) and concentrated under reduced pressure then dried under high vacuum. The crude product was dissolved in DCM, S1O2 (15g) was added, concentrated, then was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 45% solvent A/B=DCM/EtOAc, REDISEP® S1O2 80g). Concentration of appropriate fractions provided a mixture of Preparation IK and Preparation 1L (2.00 g, 75%) as a cream solid: HPLC: RT=2.770 min

(CHROMOLITH® SpeedROD 4.6 x 50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z= 558 [M+H]+; XH NMR (400 MHz, CDC13) δ ppm 8.32 (1 H, d, J=8.03 Hz), 7.65-7.71 (1 H, m), 7.50-7.60 (3 H, m), 7.41-7.49 (2 H, m), 7.39 (1 H, dd, J=7.91, 1.63 Hz), 7.23-7.35 (2 H, m), 5.59 (1 H, d, J=8.03 Hz), 3.51 (3 H, s), 2.81 (1 H, ddd, J=10.54, 6.90, 3.64 Hz), 2.67-2.76 (1 H, m), 2.22-2.33 (3 H, m), 1.99-2.12 (3 H, m), 1.85-1.94 (1 H, m), 1.79 (1 H, ddd, J=13.87, 7.84, 3.64 Hz). Example 1 :

[00230] To a stirred solution of an 8: 1 mixture of Preparation IK and Preparation 1L (3.46 g, 6.21 mmol) in DMF (25 mL) under nitrogen atmosphere was added ammonium chloride (3.32 g, 62.1 mmol), EDC (3.55 g, 18.52 mmol), HOBT (2.85 g, 18.61 mmol), and triethyl amine (16 mL, 1 15 mmol) and stirred overnight. The reaction was judged complete by LCMS. The reaction mixture was poured into water (200 mL) with vigorous swirling and then allowed to sit. The solid was collected by filtration, washed with water, allowed to dry to afford 3.6 g colorless solid. The solid was purified by preparative SFC chromatography (Lux-Cellulose-2 (3x25cm), 8% methanol in CO2, 140ml/min @220nm and 35 °C; Sample: 3.6g in 50cc methanol, conc.=70mg/ml, Stack injection:

0.5cc/9.2min). Fractions containing product were concentrated, dried overnight under vacuum. Obtained Example 1 (2.74 g, 79%) as a colorless solid (Crystal Form -1): HPLC: RT=9.601 min (H20/CH3CN with TFA, Sunfire CI 8 3.5um, 4.6x150mm, 4.6x150mm, gradient = 15 min, wavelength = 220 and 254 nm). MS (ES): m/z= 557 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 9.54 (1 H, d, J=7.28 Hz), 7.71-7.80 (1 H, m), 7.68 (2 H, d, J=8.78 Hz), 7.50-7.62 (3 H, m), 7.45 (2 H, t, J=7.28 Hz), 7.29-7.40 (2 H, m), 7.15 (1 H, br. s.), 5.30 (1 H, d, J=7.28 Hz), 3.39 (3 H, s), 2.74-2.86 (1 H, m), 2.02-2.32 (3 H, m), 1.45-1.79 (4 H, m); [a]D = -107.0° (5.73 mg/mL, DMSO).

[00231] Crystal Form A-2 was prepared by adding approximately 1 mg of Example 1 to approximately 0.7 mL of acetone/acetonitrile/water solution (2:2: 1). A mixture of colorless needles and thin blades crystals were obtained after one day of slow evaporation of the solution at room temperature. The thin blade crystals were separated to provide crystal Form A-2.

[00232] Crystal Form EA-3 was prepared by adding approximately 1 mg of Example 1 to approximately 0.7 mL of ethyl acetate/heptane solution (1 : 1). Colorless blade crystals were obtained after three days of slow evaporation of the solution at room temperature.

[00233] Crystal Form THF-2 was obtained by adding approximately 5 mg of Example 1 to approximately 0.7 mL of THF/water solution (4: 1). Colorless blade-like crystals were obtained after one day of solvent evaporation at room temperature.

Alternate Procedure to Make Example 1 : Preparation 1M: 3,3,3-Trifluoropropyl trifluoromethanesulfonate

Figure imgf000074_0001

[00234] To a cold (-25 °C), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in CH2CI2 (120 mL) was added Tf20 (24.88 mL, 147 mmol) over 3 min, and stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-l-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half volume, then purified by loading directly on silica gel column (330g ISCO) and eluted with CH2C12. Obtained Preparation 1M (13.74 g, 53%) as a colorless oil. XH NMR (400 MHz, CDCI3) δ ppm 4.71 (2 H, t, J=6.15 Hz), 2.49-2.86 (2 H, m).

Preparation IN: (45)-4-Benzyl- -(5,5,5-trifluoropentanoyl)-l,3-oxazolidin-2-one

Figure imgf000074_0002

[00235] Preparation IN was prepared from 5,5,5-trifluoropentanoic acid (3.35 g, 21.46 mmol) and (45)-4-benzyl-l,3-oxazolidin-2-one (3.80 g, 21.46 mmol) by the general methods shown for Preparation IB. Preparation IN (5.67 g, 84%) was obtained as a colorless viscous oil: XH NMR (400 MHz, CDC13) δ ppm 7.32-7.39 (2 H, m), 7.30 (1 H, d, J=7.05 Hz), 7.18-7.25 (2 H, m), 4.64-4.74 (1 H, m), 4.17-4.27 (2 H, m), 3.31 (1 H, dd, J=13.35, 3.27 Hz), 3.00-3.1 1 (2 H, m), 2.79 (1 H, dd, J=13.35, 9.57 Hz), 2.16-2.28 (2 H, m), 1.93-2.04 (2 H, m).

Preparation 10: tert-Butyl (3R)-3-(((45)-4-benzyl-2-oxo-l,3-oxazolidin-3-yl)carbonyl)- 6,6,6-trifluorohexanoate

Figure imgf000075_0001

[00236] To a cold (-78 °C), stirred solution of Preparation IN (3.03 g, 9.61 mmol) in THF (20 mL) was added NaHMDS (1.0M in THF) (10.6 mL, 10.60 mmol) under nitrogen atmosphere. After 2 hours, tert-butyl 2-bromoacetate (5.62 g, 28.8 mmol) was added neat via syringe at -78 °C and stirring was maintained at the same temperature. After 6 hours, the reaction mixture was warmed to room temperature. The reaction mixture was partitioned between saturated NH4C1 and EtOAc. The organic phase was separated, and the aqueous was extracted with EtOAc (3x). The combined organics were washed with brine, dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 100% solvent A/B=hexanes/EtO Ac, REDISEP® Si02 120g). Concentration of appropriate fractions provided Preparation 10 (2.79 g, 67.6%) as a colorless viscous oil: XH NMR (400 MHz, CDC13) δ ppm 7.34 (2 H, d, J=7.30 Hz), 7.24-7.32 (3 H, m), 4.62- 4.75 (1 H, m, J=10.17, 6.89, 3.43, 3.43 Hz), 4.15-4.25 (3 H, m), 3.35 (1 H, dd, J=13.60, 3.27 Hz), 2.84 (1 H, dd, J=16.62, 9.57 Hz), 2.75 (1 H, dd, J=13.35, 10.07 Hz), 2.47 (1 H, dd, J=16.62, 4.78 Hz), 2.1 1-2.23 (2 H, m), 1.90-2.02 (1 H, m), 1.72-1.84 (1 H, m), 1.44 (9 H, s). -2-(2-tert-Butoxy-2-oxoethyl)-5,5,5-trifluoropentanoic acid

Figure imgf000075_0002

[00237] Preparation IP was prepared from Preparation 10 (2.79 g, 6.50 mmol) by the general methods shown for Preparation IE. Preparation IP (1.45 g, 83%) was obtained as a colorless oil: XH NMR (400 MHz, CDC13) δ ppm 2.83-2.95 (1 H, m), 2.62-2.74 (1 H, m), 2.45 (1 H, dd, J=16.62, 5.79 Hz), 2.15-2.27 (2 H, m), 1.88-2.00 (1 H, m), 1.75-1.88 (1 H, m), 1.45 (9 H, s). Preparation IE: (2R,35′)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and

Preparation IF: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000076_0001

(1 E) (1 F)

[00238] To a cold (-78 °C), stirred solution of Preparation IP (5.44 g, 20.13 mmol) in THF (60 mL) was slowly added LDA (24.60 mL, 44.3 mmol) over 7 min. After stirring for 2 hr, Preparation 1M (6.44 g, 26.2 mmol) was added to the reaction mixture over 3 min. After 45 min, the reaction mixture was warmed to -25 °C bath (ice/MeOH/dry ice) for 1 hr, and then warmed to 0 °C. After 45 min, Preparation 1M (lg) was added and the reaction mixture was stirred for 20 min. The reaction was quenched with water and IN NaOH and was extracted with (¾(¾. The organic layer was again extracted with IN NaOH (2x) and the aqueous layers were combined. The aqueous layer was cooled in ice/water bath and then acidified with concentrated HCl to pH 2. Next, the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was dried under high vacuum to provide a 1 :5 (IE: IF) mixture (as determined by XH NMR) of Preparation IE and Preparation IF (5.925 g, 80%) as a pale yellow solid. XH NMR (500 MHz, CDC13) 8 ppm 2.81 (1 H, ddd, J=10.17, 6.32, 3.85 Hz), 2.63-2.76 (1 H, m), 2.02- 2.33 (4 H, m), 1.86-1.99 (2 H, m), 1.68-1.85 (2 H, m), 1.47 (9 H, s).

Preparation IE: (2R,35)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid, and

Preparation IF: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000077_0001

(1 E) (1 F)

[00239] A mixture of Preparation IE and Preparation IF (64 mg, 1.758 mmol) was taken in THF (6 mL) to give a colorless solution which was cooled to -78 °C. Then, LDA (2.149 mL, 3.87 mmol) (1.8M in heptane/THF/ethylbenzene) was slowly added to the reaction mixture over 10 min. After stirring for 15 min the reaction mixture was placed in a room temperature water bath. After 15 min the reaction mixture was placed back in -78 °C bath and then diethylaluminum chloride (3.87 mL, 3.87 mmol) (1M in hexane) was added slowly over 5 min. The reaction mixture was stirred at -78 °C. After 15 min the reaction mixture was placed in a room temperature water bath for 10 min and then cooled back to -78 °C bath. After 15 min the reaction was quenched with MeOH (8 mL, 198 mmol), removed from the -78 °C bath and concentrated. To the reaction mixture was added ice and HC1 (16 mL, 16.00 mmol), followed by extraction with EtOAc (2x). The organic layer was washed with potassium fluoride (920 mg, 15.84 mmol) (in 25 mL FLO) and HC1 (4.5 mL, 4.50 mmol). The organics were dried over anhydrous magnesium sulphate and concentrated under reduced pressure to provide a 9: 1 (IE: IF) enriched mixture of Preparation IE and Preparation IF (540 mg, 1.583 mmol, 90% yield) as light yellow/orange solid. ¾ NMR (400 MHz, CDC13) δ ppm 2.64-2.76 (2 H, m), 2.04-2.35 (4 H, m), 1.88-2.00 (2 H, m), 1.71-1.83 (2 H, m), 1.48 (9 H, s). It was converted to Example 1 by the sequence of reactions as outlined above.

Alternate procedure to make Preparation IE:

Preparation 1Q: (2R,35)- -Benzyl 4-tert-butyl 2,3-bis(3,3,3-trifluoropropyl)succinate

Figure imgf000077_0002

(1Q) [00240] A clean and dry 5 L four neck round bottom flask equipped with mechanical stirring, thermometer socket and nitrogen bubbler at room temperature was charged with Ν,Ν-dimethyl formamide (2.07 L), a 1.2: 1 mixture of Preparation IE and Preparation IF (207 g, 0.5651 moles), potassium carbonate (1 17.1 g, 0.8476 moles) followed by benzyl bromide (116 g, 0.6781 moles) over 15-20 min. The reaction mixture was stirred for 2-3 hr. After completion of the reaction, the reaction mixture was concentrated to dryness at 50-55 °C under vacuum. Ethyl acetate (3.1 L, 30 Vol.) was charged into the concentrated reaction mass and then washed with water (2.07 L), brine (0.6 L) then dried over anhydrous sodium sulfate (207 g), filtered and concentrated to dryness at 40-45 °C under vacuum. The residue was dissolved in dichloromethane (1.035 L, 5 vol.) and then absorbed onto silica gel (60-120) (607 g, 3.0 w/w), then was purified with column chromatography using petroleum ether and ethyl acetate as solvents. After pooling several batches, Preparation 1Q (235 g) was obtained. HPLC purity: 99.77%, Preparation IE: (2R,35)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000078_0001

[00241] A clean and dry 2 L autoclave was charged with methanol (540 mL) and was purged with nitrogen for 5-10 minutes. To the autoclave was added 10% palladium on carbon (12 g, 20%), purged with nitrogen once again for 5-10 min then was charged with Preparation 1Q (60g, 0.1315 moles), the autoclave was flushed with methanol (60mL) and stirred for 4-6 hr at 20-25 °C under 5Kg hydrogen pressure. After completion of the reaction, the reaction mass was filtered through CELITE®, washed with methanol (180 mL), dried with anhydrous sodium sulfate (60 g), filtered and concentrated to dryness at 45-50 °C under vacuum. Obtained Preparation IE (45.8 g, 95%) as a colorless solid: HPLC purity: 98.9%.

Alternate procedure to make Preparation IE: Preparation IE: (2R,35)-3-(te^Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3- trifluoropropyl)hexanoic acid

Figure imgf000079_0001

[00242] Preparation IE was prepared in a procedure identical as above from a mixture of Preparations IE and IF (200g, 0.5460 moles) using LDA (1.8 M solution in THF, ethyl benzene and heptane) (698mL, 2.3equiv.) and diethyl aluminum chloride (1.0 M solution in hexane) (1256mL, 2.3equiv) in THF (2.0L). After workup as explained above, the resulting residue was treated as follows: The crude material was added to a 2L four neck round bottom flask, followed by the addition of MTBE (1.0L) charged below 30 °C. The resulting mixture was stirred for 5-10 minutes to obtain a clear solution.

Hexanes (600mL) was charged to the reaction mixture at a temperature below 30 °C. The reaction mixture was stirred for 10 min. Next, tert-butylamine (43.8g, l. leq) was charged slowly over a period of 15 minutes below 30 °C. This addition was observed to be exothermic. The reaction mixture was stirred for 2 hrs below 30 °C and filtered. The solid material was washed with 5:3 MTBE: hexane (200mL), the filtrate was

concentrated and transferred to an amber color bottle. The filtered solid was dissolved in dichloromethane (2.0L), washed with IN HC1 (2.0), the organic layer was washed with brine (1.0L x 2), then was concentrated under reduced pressure below 45 °C. This material was found to be 91.12% pure. The material was repurified by the above t- butylamine crystallization purification procedure. Obtained Preparation IE (78 g, 39%): HPLC purity: 99.54%.

Alternate procedure to make Example 1 :

Preparation II: tert-Butyl (25,,3R)-6,6,6-trifluoro-3-(((35)-l-methyl-2-oxo-5-phenyl-2,3- dihydro- 1 H- 1 ,4-benzodiazepin-3 -yl)carbamoyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate

Figure imgf000080_0001

[00243] A clean and dry 2 L four neck round bottom flask equipped with mechanical stirring, thermometer socket and nitrogen bubbler was charged with N,N- dimethylformamide (457 mL), Preparation IE (45.7g, 0.1248moles) and Preparation lG’CSA (62.08g, 0.1248moles) under nitrogen atmosphere at 20-25 °C. The reaction mixture was stirred for 15-20 minutes to make clear solution at 20-25 °C. To the reaction mixture was added TBTU (48.16g, 0.1498 moles) at 20-25 °C followed by triethylamine (50.51g, 0.4992 moles) over 15-20 minutes at 20-25 °C. The reaction mixture was stirred for 60-120 minutes at 20-25 °C under nitrogen atmosphere. After completion of the reaction, the reaction was quenched into water (1.37L, 30 Vol.) at 20-25 °C under stirring. The reaction mixture was stirred for 30 minutes at 20-25 °C. The reaction mixture was filtered and washed with water (228 mL). The resulting solid material was dissolved in ethyl acetate (457 mL), washed with water (2×137 mL), brine (137 mL), and then dried with anhydrous sodium sulfate (45.7g). Activated charcoal (9.14 g, 20%) was charged into the reaction mixture and stirred for 30 minutes. The mixture was filtered through CELITE® bed and 1 micron filter cloth, washed charcoal bed with ethyl acetate (137 mL), concentrated to 1.0 Vol. stage and then petroleum ether (457 mL, 10 Vol.) was charged and stirred for 30 minutes at 20-25 °C. The solid was collected by filtration, washed with petroleum ether (137 mL) and then dried under vacuum at 40-45 °C for 8 hr until loss on drying was less than 3.0%. Obtained Preparation II (65.2 g, 85%): HPLC purity: 98.26%.

Preparation IK: (25,,3R)-6,6,6-Trifluoro-3-(((35)-l-methyl-2-oxo-5-phenyl-2,3-dihydro- 1 H- 1 ,4-benzodiazepin-3 -yl)carbamoyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoic acid

Figure imgf000081_0001

[00244] A clean and dry 3 L four neck round bottom flask equipped with mechanical stirring, thermometer socket and nitrogen bubbler was charged with dichloromethane (980 mL) under nitrogen atmosphere followed by Preparation II (140 g, 0.2282 moles) at 20-25 °C. The reaction mixture was cooled to 0-5 °C and trifluoroacetic acid (980 mL) was charged slowly for 30-40 minutes. The resulting mixture was stirred for 2 hr at 0-5 °C under nitrogen atmosphere. The reaction temperature was raised to 20 to 25 °C, and the reaction mixture was stirred for 1-2 hr at 20 to 25 °C. After completion of the reaction, the reaction mixture was concentrated to dryness at 50 to 55 °C under vacuum. Toluene (3×700 mL,) was charged into the concentrated reaction mass, and then distilled off at 50 to 55 °C under vacuum. After complete concentration from toluene, ethyl acetate (280 mL) was charged into the reaction mass at 20 to 25 °C, stirred for 60 minutes, then the solid was collected by filtration, washed with ethyl acetate (140 mL), dried under vacuum at 50 to 55 °C for 12 hr until loss on drying was less than 2.0%. Obtained Preparation IK (106 g, 84%): HPLC purity: 98.43%.

Example 1 :

[00245] A reaction vessel was charged with Preparation IK (30 g, 53.81 mmol), HOBt (8.7g, 64.38 mmol), and THF (150 mL) at room temperature. To the homogeneous solution was added EDCI (12.4g, 64.68 mmol), stirred for 15 min, then cooled to 8 °C. To the reaction mixture was added ammonia (2M in IP A) (81 mL, 162 mmol) over 5 min so as to maintain a temperature below 10 °C. The resulting heavy slurry was stirred for 10 min, warmed to room temperature over 30 min, then stirred for 4 hr. At the completion of the reaction, water (230 mL) was slowly added over 15 min to maintain a temperature below 20 °C, and then stirred for 2 hr. The solid was collected by filtration, washed with water (3X60 mL), then dried under vacuum 48 hr at 55 °C. The above crude product was charged into a 1 L 3 -necked round flask. IP A (200 mL) was added, then heated to 80 °C resulting in a homogeneous solution. Water (170 mL) was slowly added (15 min) to maintain an internal temperature >75 °C. The resulting slurry was stirred and cooled to room temperature for 2 hr. The solid was collected by filtration, washed with water (2 X 50 mL), then dried under vacuum (55 °C for 24 h, and 30 °C for 48 h).

Obtained Example 1 (23.4 g, 78% yield): HPLC purity: 99.43%.

Example 2 NOT SAME

WITHOUT METHYL GROUP

(2R,35)-N-((35)-2-Oxo-5-phenyl-2,3-dihydro-lH-l,4-benzodiazepin-3-yl)-2,3-bis(3,3,3- trifluoropropyl)succinamide

Figure imgf000082_0001

Preparation 2A: (35)-3-Amino-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one, and Preparation 2B: -3-Amino-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one

Figure imgf000082_0002

(2A) (2B)

[00246] Racemic 3-amino-5-phenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one (J. Med. Chem., 49:231 1-2319 (2006), compound# 5) was prepared according to the literature procedure. The enantiomers were separated on Berger SFC MGIII Column: Lux 25X3 cm, 5cm; Mobile phase: 30% MeOH+ 0.1% DEA in C02; Flow rate: 150 mL/min;

Temperature: 40 °C; Detector wavelength: 250 nM. Obtained the S-enantiomer

Preparation 2A as a white solid: XH NMR (400 MHz, DMSO-d6) δ ppm 10.67 (1 H, br. s.), 7.58 (1 H, td, J=7.65, 1.76 Hz), 7.37-7.53 (5 H, m), 7.23-7.30 (2 H, m), 7.14-7.22 (1 H, m), 4.23 (1 H, s), 2.60 (2 H, br. s.); HPLC: RT=3.0625 min (30% MeOH + 0.1% DEA in C02 on OD-H Column, 3 mL/min, 35 °C, 96 bar, 230 nm, ΙΟμΙ inj); [a]D = -208.3° (5.05 mg/niL, MeOH). Also obtained the R-enantiomer Preparation 2B as an off white solid: HPLC: RT=3.970 min; [a]D = 182.1° (2.01 mg/mL, MeOH).

Preparation 2C: tert-Butyl (25,,3R)-6,6,6-trifluoro-3-(((35)-2-oxo-5-phenyl-2,3-dihydro- 1 H- 1 ,4-benzodiazepin-3 -yl)carbamoyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate, and

Preparation 2D: tert-Butyl (2R,3R)-6,6,6-trifluoro-3-(((35)-2-oxo-5-phenyl-2,3-dihydro- 1 H- -benzodiazepin-3 -yl)carbamoyl)-2-(3 ,3 ,3 -trifluoropropyl)hexanoate

Figure imgf000083_0001

(2C) (2D)

[00247] Preparation 2C was prepared from Preparation 2A (564 mg, 2.244 mmol) and a mixture of Preparation IE and Preparation IF (822 mg, 2.244 mmol) according to the general procedure shown for Preparation II. Obtained Preparation 2C and Preparation 2D (1.31 g, 97%): HPLC: RT=3.443 min (CHROMOLITH® ODS 4.6 x 50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm); MS (ES): m/z= 600.3 [M+H]+.

Preparation 2E: (25′,3R)-6,6,6-Trifluoro-3-(((35)-2-oxo-5-phenyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid, and

Preparation 2F: (2R,3R)-6,6,6-Trifluoro-3-(((35)-2-oxo-5-phenyl-2,3-dihydro-lH-l,4- benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid

Figure imgf000083_0002

(2E) (2F) [00248] A mixture of Preparation 2E and Preparation 2F was prepared from a mixture of Preparation 2C and Preparation 2D (1.3 lg, 2.185 mmol) by the general methods shown for Preparation IK. Obtained a mixture of Preparation 2E and Preparation 2F (1.18 g, 99%): HPLC: RT=2.885 min (CHROMOLITH® ODS 4.6 x 50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z= 544.2 [M+H]+.

Example 2:

[00249] Example 2 was prepared from a mixture of Preparation 2E and Preparation 2F (354 mg, 0.651 mmol) by the general methods shown for Example 1. After separation of the diastereoisomers, Example 2 was obtained (188 mg, 52%) as a white solid: HPLC: RT=9.063 min (H20/CH3CN with TFA, Sunfire C18 3.5um, 4.6x150mm, 4.6x150mm, gradient = 15 min, wavelength = 220 and 254 nm); MS (ES): m/z= 543 [M+H]+; XH NMR (400 MHz, DMSO-d6) δ ppm 10.87 (1 H, br. s.), 9.50-9.55 (1 H, m), 7.62-7.69 (2 H, m), 7.40-7.57 (5 H, m), 7.29-7.36 (2 H, m), 7.22-7.28 (1 H, m), 7.16 (1 H, br. s.), 5.25 (1 H, d), 3.30-3.32 (1 H, m), 2.75-2.86 (1 H, m), 2.44-2.48 (1 H, m), 2.06-2.34 (3 H, m), 1.51- 1.77 (4 H, m); [a]D = -114.4° (8.04 mg/mL, DMSO).

[00250] Crystal Form M2- 1 was prepared by adding approximately 1 mg of Example 2 to approximately 0.7 mL of MeOH/fluorobenzene solution (3 : 1). Colorless plate-like crystals were obtained after 2 days of solvent evaporation at room temperature.

PATENT

US-20160060232-A1

https://patentscope.wipo.int/search/en/detail.jsf?docId=US159930181&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 1

(2R,3S)—N-((3S)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinamide


Preparation 1A: tert-Butyl 5,5,5-trifluoropentanoate


      To a stirred solution of 5,5,5-trifluoropentanoic acid (5 g, 32.0 mmol) in THF (30 mL) and hexane (30 mL) at 0° C., was added tert-butyl 2,2,2-trichloroacetimidate (11.46 mL, 64.1 mmol). The mixture was stirred for 15 min at 0° C. Boron trifluoride etherate (0.406 mL, 3.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. To the clear reaction mixture was added solid NaHCO3 (5 g) and stirred for 30 min. The mixture was filtered through MgSO4 and washed with hexanes (200 mL). The solution was allowed to rest for 45 min, and the resulting solid material was removed by filtering on the same MgSO4 filter again, washed with hexanes (100 mL) and concentrated under reduced pressure without heat. The volume was reduced to about 30 mL, filtered through a clean fitted funnel, washed with hexane (5 mL), and then concentrated under reduced pressure without heat. The resulting neat oil was filtered through a 0.45 μm nylon membrane filter disk to provide tert-butyl 5,5,5-trifluoropentanoate (6.6 g, 31.4 mmol 98% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (s, 9H) 1.74-1.83 (m, 2H) 2.00-2.13 (m, 2H) 2.24 (t, J=7.28 Hz, 2H).

Preparation 1B: (4S)-4-(Propan-2-yl)-3-(5,5,5-trifluoropentanoyl)-1,3-oxazolidin-2-one


      To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min and the solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at −78° C. was added n-BuLi (2.5M in hexane) (13.0 mL, 32.5 mmol) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction mixture was warmed to 0° C., and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and then extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 60% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 120 g). Concentration of appropriate fractions provided Preparation 1B (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz).

Preparation 1C: (2S,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate, and

Preparation 1D: (2R,3R)-tert-Butyl 6,6,6-trifluoro-3-((S)-4-isopropyl-2-oxooxazolidine-3-carbonyl)-2-(3,3,3-trifluoropropyl)hexanoate


      To a cold (−78° C.), stirred solution of diisopropylamine (5.3 mL, 37.2 mmol) in THF (59 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexane) (14.7 mL, 36.8 mmol), then warmed to 0° C. to give a 0.5M solution of LDA. A separate vessel was charged with Preparation 1B (2.45 g, 9.17 mmol), the material was azeotroped twice with benzene (the RotoVap air inlet was fitted with nitrogen inlet to completely exclude humidity) then toluene (15.3 mL) was added. This solution was added to a flask containing dry lithium chloride (1.96 g, 46.2 mmol). To the resultant mixture, cooled to −78° C., was added LDA solution (21.0 mL, 10.5 mmol) and stirred at −78° C. for 10 min, warmed to 0° C. for 10 min then recooled to −78° C. To a separate reaction vessel containing Preparation 1A (3.41 g, 16.07 mmol), also azeotroped twice with benzene, was added toluene (15.3 mL), cooled to −78° C. and LDA (37.0 mL, 18.5 mmol) was added, the resulting solution was stirred at −78° for 25 min. At this time the enolate derived from the ester was transferred via cannula into the solution of the oxazolidinone enolate, stirred at −78° C. for an additional 5 min at which time the septum was removed and solid powdered bis(2-ethylhexanoyloxy)copper (9.02 g, 25.8 mmol) was rapidly added to the reaction vessel and the septum replaced. The vessel was immediately removed from the cold bath and immersed into a warm water bath (40° C.) with rapid swirling with a concomitant color change from the initial turquoise to brown. The reaction mixture was stirred for 20 min, was poured into 5% aqueous NH4OH (360 mL) and extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 60% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 120 g). Concentration of appropriate fractions provided Preparation 1C (2.87 g, 66%) as pale yellow viscous oil. 1H NMR showed the product was a 1.6:1 mixture of diastereoisomers 1C:1D as determined by the integration of the multiplets at 2.74 & 2.84 ppm: 1H NMR (400 MHz, CDCl3) δ ppm 4.43-4.54 (2H, m), 4.23-4.35 (5H, m), 4.01 (1H, ddd, J=9.54, 6.27, 3.51 Hz), 2.84 (1H, ddd, J=9.41, 7.28, 3.64 Hz), 2.74 (1H, ddd, J=10.29, 6.27, 4.02 Hz), 2.37-2.48 (2H, m, J=10.38, 6.98, 6.98, 3.51, 3.51 Hz), 2.20-2.37 (3H, m), 1.92-2.20 (8H, m), 1.64-1.91 (5H, m), 1.47 (18H, s), 0.88-0.98 (12H, m).

Preparation 1E: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid, and

Preparation 1F: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid


      To a cool (0° C.), stirred solution of Preparation 1C and 1D (4.54 g, 9.51 mmol) in THF (140 mL) and water (42 mL) was sequentially added hydrogen peroxide (30% in water) (10.3 g, 91 mmol) and LiOH (685.3 mg, 28.6 mmol) and the mixture was stirred for 1 hr. At this time the reaction vessel was removed from the cold bath and then stirred for 1.5 hr. The reaction was judged complete by HPLC. To the reaction mixture was added saturated NaHCO3(45 mL) and saturated Na2SO3 (15 mL), and then partially concentrated under reduced pressure. The resulting crude solution was extracted with DCM (3×). The aqueous phase was acidified to pH-1-2 with 1N HCl, extracted with DCM (3×) and EtOAc (1×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide a mixture of Preparation 1E and 1F (3.00 g, 86%) as colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 2.76-2.84 (1H, m, diastereoisomer 2), 2.64-2.76 (3H, m), 2.04-2.35 (8H, m), 1.88-2.00 (4H, m), 1.71-1.83 (4H, m), 1.48 (9H, s, diastereoisomer 1), 1.46 (9H, s, diastereoisomer 2); 1H NMR showed a 1.7:1 mixture of 1E:1F by integration of the peaks for the t-butyl groups.

Preparation 1E: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid, and

Preparation 1F: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid


      To a cold (−78° C.), stirred solution of diisopropylamine (1.7 mL, 11.93 mmol) in THF (19 mL) under nitrogen atmosphere was added n-BuLi (2.5M in hexanes) (4.8 mL, 12.00 mmol). The mixture was stirred for 5 min and then warmed to 0° C. In a separate vessel, to a cold (−78° C.) stirred solution of the mixture of Preparation 1E and 1F (1.99 g, 5.43 mmol) in THF (18 mL) was added the LDA solution prepared above via cannula slowly over 25 min. The mixture was stirred for 15 min, then warmed to room temperature (placed in a 24° C. water bath) for 15 min, and then again cooled to −78° C. for 15 min. To the reaction mixture was added Et2AlCl (1M in hexane) (11.4 mL, 11.40 mmol) via syringe, stirred for 10 min, warmed to room temperature for 15 min and then cooled back to −78° C. for 15 min. Methanol (25 mL) was rapidly added, swirled vigorously while warming to room temperature, then concentrated to ˜¼ original volume. The mixture was dissolved in EtOAc and washed with 1N HCl (50 mL) and ice (75 g). The aqueous phase was separated, extracted with EtOAc (2×). The combined organics were washed with a mixture of KF (2.85 g in 75 mL water) and 1N HCl (13 mL) [resulting solution pH 3-4], then with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give a 9:1 (1E:1F) enriched diastereoisomeric mixture (as determined by 1H NMR) of Preparation 1E and Preparation 1F (2.13 g, >99%) as a pale yellow viscous oil: 1H NMR (400 MHz, CDCl3) δ ppm 2.64-2.76 (2H, m), 2.04-2.35 (4H, m), 1.88-2.00 (2H, m), 1.71-1.83 (2H, m), 1.48 (9H, s).

Preparation 1G: (3S)-3-Amino-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, and

Preparation 1H: (3R)-3-Amino-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one


      Racemic 3-amino-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Rittle, K. E. et al., Tetrahedron Letters, 28(5):521-522 (1987)) was prepared according to the literature procedure. The enantiomers were separated under chiral-SFC conditions using the following method: CHIRALPAK® AS-H 5×25; Mobile phase: 30% MeOH+0.1% DEA in CO2; Flow rate: 280 mL/min; Pressure: 100 bar; Temperature: 35° C.
      Obtained the S-enantiomer (Preparation 1G): HPLC: RT=1.75 min (30% MeOH+0.1% DEA in CO2 on CHIRALPAK® AS-H 4.6×250 mm, 3 mL/min, 35° C., 100 bar, 230 nm, 10 μl injection); 1H NMR (400 MHz, CDCl3) δ ppm 7.58-7.63 (2H, m), 7.55 (1H, ddd, J=8.50, 7.11, 1.76 Hz), 7.40-7.47 (1H, m), 7.34-7.40 (3H, m), 7.31 (1H, dd, J=7.81, 1.51 Hz), 7.14-7.22 (1H, m), 4.46 (1H, s), 3.44 (3H, s), 3.42 (2H, s); [α]D=−155° (c=1.9, MeOH) (Lit. Rittle, K. E. et al.,Tetrahedron Letters, 28(5):521-522 (1987): [α]D=−236°).
      Also obtained the R-enantiomer (Preparation 1H): HPLC: RT=1.71 min; [α]D=+165° (c=2.1, MeOH) (Lit [α]D=+227°).

Alternate Procedure to Make Preparation 1G

Preparation 1G•CSA salt: (3S)-3-Amino-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, (1 S)-(+)-10-camphorsulfonic acid salt


      Preparation 1G•CSA was prepared from racemic 3-amino-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (9.98 g, 37.6 mmol) (prepared according to the literature as shown above) according to the literature procedure (Reider, P. J. et al., J. Org. Chem., 52:955-957 (1987)). Preparation 1G•CSA (16.91 g, 99%) was obtained as a colorless solid: Optical Rotation: [α]D=−26.99° (c=1, H2O) (Lit. [α]D=−27.8° (c=1, H2O))

Preparation 1I: tert-Butyl (2S,3R)-6,6,6-trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoate, and

Preparation 1J: tert-Butyl (2R,3R)-6,6,6-trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoate

      To a stirred solution of Preparation 1G (1.45 g, 5.47 mmol) and a 9:1 mixture of Preparation 1E and 1F (1.989 g, 5.43 mmol) in DMF (19 mL) was added 0-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (1.79 g, 5.57 mmol) and triethylamine (3.0 mL, 21.52 mmol) and stirred overnight. The reaction was judged complete by LCMS. The reaction mixture was poured into water (125 mL) and the precipitated solid was collected by filtration, washed with water and air dried to provide an 8:1 mixture of Preparation 1I and Preparation 1J (2.95 g, 89%) as a cream solid: MS (ES): m/z=614 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.55-7.65 (3H, m), 7.44-7.52 (2H, m), 7.35-7.45 (4H, m), 5.52 (1H, d, J=8.03 Hz), 3.48 (3H, s), 2.63 (2H, ddd, J=9.35, 3.95, 3.76 Hz), 2.14-2.25 (4H, m), 1.90-2.03 (3H, m), 1.69-1.82 (1H, m), 1.51 (9H, s).

Preparation 1K: (2S,3R)-6,6,6-Trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid, and

Preparation 1L: (2R,3R)-6,6,6-Trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid

      To a cool (0° C.), stirred solution of the above mixture of Preparation 1I and Preparation 1J (2.95 g, 4.81 mmol) in DCM (20 mL) was added TFA (20 mL, 260 mmol). The reaction mixture was stirred for 1 hr, then allowed to warm to room temperature and stirred for 2.5 hr. The reaction was judged complete by LCMS. The reaction mixture was diluted with toluene (50 mL) and concentrated under reduced pressure. The residue mixture was redissolved in toluene (50 mL) and concentrated under reduced pressure then dried under high vacuum. The crude product was dissolved in DCM, SiO2(15 g) was added, concentrated, then was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 45% solvent A/B=DCM/EtOAc, REDISEP® SiO2 80 g). Concentration of appropriate fractions provided a mixture of Preparation 1K and Preparation 1L (2.00 g, 75%) as a cream solid: HPLC: RT=2.770 min (CHROMOLITH® SpeedROD 4.6×50 mm (4 min grad) eluting with 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 254 nm); MS (ES): m/z=558 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (1H, d, J=8.03 Hz), 7.65-7.71 (1H, m), 7.50-7.60 (3H, m), 7.41-7.49 (2H, m), 7.39 (1H, dd, J=7.91, 1.63 Hz), 7.23-7.35 (2H, m), 5.59 (1H, d, J=8.03 Hz), 3.51 (3H, s), 2.81 (1H, ddd, J=10.54, 6.90, 3.64 Hz), 2.67-2.76 (1H, m), 2.22-2.33 (3H, m), 1.99-2.12 (3H, m), 1.85-1.94 (1H, m), 1.79 (1H, ddd, J=13.87, 7.84, 3.64 Hz).

Example 1

      To a stirred solution of an 8:1 mixture of Preparation 1K and Preparation 1L (3.46 g, 6.21 mmol) in DMF (25 mL) under nitrogen atmosphere was added ammonium chloride (3.32 g, 62.1 mmol), EDC (3.55 g, 18.52 mmol), HOBT (2.85 g, 18.61 mmol), and triethyl amine (16 mL, 115 mmol) and stirred overnight. The reaction was judged complete by LCMS. The reaction mixture was poured into water (200 mL) with vigorous swirling and then allowed to sit. The solid was collected by filtration, washed with water, allowed to dry to afford 3.6 g colorless solid. The solid was purified by preparative SFC chromatography (Lux-Cellulose-2 (3×25 cm), 8% methanol in CO2, 140 ml/min @220 nm and 35° C.; Sample: 3.6 g in 50 cc methanol, conc.=70 mg/ml, Stack injection: 0.5 cc/9.2 min). Fractions containing product were concentrated, dried overnight under vacuum. Obtained Example 1 (2.74 g, 79%) as a colorless solid (Crystal Form N-1): HPLC: RT=9.601 min (H2O/CH3CN with TFA, Sunfire C18 3.5 um, 4.6×150 mm, 4.6×150 mm, gradient=15 min, wavelength=220 and 254 nm). MS (ES): m/z=557 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (1H, d, J=7.28 Hz), 7.71-7.80 (1H, m), 7.68 (2H, d, J=8.78 Hz), 7.50-7.62 (3H, m), 7.45 (2H, t, J=7.28 Hz), 7.29-7.40 (2H, m), 7.15 (1H, br. s.), 5.30 (1H, d, J=7.28 Hz), 3.39 (3H, s), 2.74-2.86 (1H, m), 2.02-2.32 (3H, m), 1.45-1.79 (4H, m); [α]D=−107.0° (5.73 mg/mL, DMSO).
      Crystal Form A-2 was prepared by adding approximately 1 mg of Example 1 to approximately 0.7 mL of acetone/acetonitrile/water solution (2:2:1). A mixture of colorless needles and thin blades crystals were obtained after one day of slow evaporation of the solution at room temperature. The thin blade crystals were separated to provide crystal Form A-2.
      Crystal Form EA-3 was prepared by adding approximately 1 mg of Example 1 to approximately 0.7 mL of ethyl acetate/heptane solution (1:1). Colorless blade crystals were obtained after three days of slow evaporation of the solution at room temperature.
      Crystal Form THF-2 was obtained by adding approximately 5 mg of Example 1 to approximately 0.7 mL of THF/water solution (4:1). Colorless blade-like crystals were obtained after one day of solvent evaporation at room temperature.

Alternate Procedure to Make Example 1

Preparation 1M: 3,3,3-Trifluoropropyl trifluoromethanesulfonate

      To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in CH2Cl2 (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half volume, then purified by loading directly on silica gel column (330 g ISCO) and eluted with CH2Cl2. Obtained Preparation 1M (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2H, t, J=6.15 Hz), 2.49-2.86 (2H, m).

Preparation 1N: (4S)-4-Benzyl-3-(5,5,5-trifluoropentanoyl)-1,3-oxazolidin-2-one

      Preparation 1N was prepared from 5,5,5-trifluoropentanoic acid (3.35 g, 21.46 mmol) and (4S)-4-benzyl-1,3-oxazolidin-2-one (3.80 g, 21.46 mmol) by the general methods shown for Preparation 1B. Preparation 1N (5.67 g, 84%) was obtained as a colorless viscous oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.30 (1H, d, J=7.05 Hz), 7.18-7.25 (2H, m), 4.64-4.74 (1H, m), 4.17-4.27 (2H, m), 3.31 (1H, dd, J=13.35, 3.27 Hz), 3.00-3.11 (2H, m), 2.79 (1H, dd, J=13.35, 9.57 Hz), 2.16-2.28 (2H, m), 1.93-2.04 (2H, m).

Preparation 1O: tert-Butyl (3R)-3-(((4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl)carbonyl)-6,6,6-trifluorohexanoate

      To a cold (−78° C.), stirred solution of Preparation 1N (3.03 g, 9.61 mmol) in THF (20 mL) was added NaHMDS (1.0M in THF) (10.6 mL, 10.60 mmol) under nitrogen atmosphere. After 2 hours, tert-butyl 2-bromoacetate (5.62 g, 28.8 mmol) was added neat via syringe at −78° C. and stirring was maintained at the same temperature. After 6 hours, the reaction mixture was warmed to room temperature. The reaction mixture was partitioned between saturated NH4Cl and EtOAc. The organic phase was separated, and the aqueous was extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 5% to 100% solvent A/B=hexanes/EtOAc, REDISEP® SiO2 120 g). Concentration of appropriate fractions provided Preparation 10 (2.79 g, 67.6%) as a colorless viscous oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.34 (2H, d, J=7.30 Hz), 7.24-7.32 (3H, m), 4.62-4.75 (1H, m, J=10.17, 6.89, 3.43, 3.43 Hz), 4.15-4.25 (3H, m), 3.35 (1H, dd, J=13.60, 3.27 Hz), 2.84 (1H, dd, J=16.62, 9.57 Hz), 2.75 (1H, dd, J=13.35, 10.07 Hz), 2.47 (1H, dd, J=16.62, 4.78 Hz), 2.11-2.23 (2H, m), 1.90-2.02 (1H, m), 1.72-1.84 (1H, m), 1.44 (9H, s).

Preparation 1P: (2R)-2-(2-tert-Butoxy-2-oxoethyl)-5,5,5-trifluoropentanoic acid

      Preparation 1P was prepared from Preparation 1O (2.79 g, 6.50 mmol) by the general methods shown for Preparation 1E. Preparation 1P (1.45 g, 83%) was obtained as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 2.83-2.95 (1H, m), 2.62-2.74 (1H, m), 2.45 (1H, dd, J=16.62, 5.79 Hz), 2.15-2.27 (2H, m), 1.88-2.00 (1H, m), 1.75-1.88 (1H, m), 1.45 (9H, s).

Preparation 1E: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid, and

Preparation 1F: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

      To a cold (−78° C.), stirred solution of Preparation 1P (5.44 g, 20.13 mmol) in THF (60 mL) was slowly added LDA (24.60 mL, 44.3 mmol) over 7 min. After stirring for 2 hr, Preparation 1M (6.44 g, 26.2 mmol) was added to the reaction mixture over 3 min. After 45 min, the reaction mixture was warmed to −25° C. bath (ice/MeOH/dry ice) for 1 hr, and then warmed to 0° C. After 45 min, Preparation 1M (1 g) was added and the reaction mixture was stirred for 20 min. The reaction was quenched with water and 1N NaOH and was extracted with CH2Cl2. The organic layer was again extracted with 1N NaOH (2×) and the aqueous layers were combined. The aqueous layer was cooled in ice/water bath and then acidified with concentrated HCl to pH 2. Next, the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The residue was dried under high vacuum to provide a 1:5 (1E:1F) mixture (as determined by 1H NMR) of Preparation 1E and Preparation 1F (5.925 g, 80%) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 2.81 (1H, ddd, J=10.17, 6.32, 3.85 Hz), 2.63-2.76 (1H, m), 2.02-2.33 (4H, m), 1.86-1.99 (2H, m), 1.68-1.85 (2H, m), 1.47 (9H, s).

Preparation 1E: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid, and

Preparation 1F: (2R,3R)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

      A mixture of Preparation 1E and Preparation 1F (64 mg, 1.758 mmol) was taken in THF (6 mL) to give a colorless solution which was cooled to −78° C. Then, LDA (2.149 mL, 3.87 mmol) (1.8M in heptane/THF/ethylbenzene) was slowly added to the reaction mixture over 10 min. After stirring for 15 min the reaction mixture was placed in a room temperature water bath. After 15 min the reaction mixture was placed back in −78° C. bath and then diethylaluminum chloride (3.87 mL, 3.87 mmol) (1M in hexane) was added slowly over 5 min. The reaction mixture was stirred at −78° C. After 15 min the reaction mixture was placed in a room temperature water bath for 10 min and then cooled back to −78° C. bath. After 15 min the reaction was quenched with MeOH (8 mL, 198 mmol), removed from the −78° C. bath and concentrated. To the reaction mixture was added ice and HCl (16 mL, 16.00 mmol), followed by extraction with EtOAc (2×). The organic layer was washed with potassium fluoride (920 mg, 15.84 mmol) (in 25 mL H2O) and HCl (4.5 mL, 4.50 mmol). The organics were dried over anhydrous magnesium sulphate and concentrated under reduced pressure to provide a 9:1 (1E:1F) enriched mixture of Preparation 1E and Preparation 1F (540 mg, 1.583 mmol, 90% yield) as light yellow/orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.64-2.76 (2H, m), 2.04-2.35 (4H, m), 1.88-2.00 (2H, m), 1.71-1.83 (2H, m), 1.48 (9H, s). It was converted to Example 1 by the sequence of reactions as outlined above.

Alternate Procedure to Make Preparation 1E

Preparation 1Q: (2R,3S)-1-Benzyl 4-tert-butyl 2,3-bis(3,3,3-trifluoropropyl)succinate

      A clean and dry 5 L four neck round bottom flask equipped with mechanical stirring, thermometer socket and nitrogen bubbler at room temperature was charged with N,N-dimethyl formamide (2.07 L), a 1.2:1 mixture of Preparation 1E and Preparation 1F (207 g, 0.5651 moles), potassium carbonate (117.1 g, 0.8476 moles) followed by benzyl bromide (116 g, 0.6781 moles) over 15-20 min. The reaction mixture was stirred for 2-3 hr. After completion of the reaction, the reaction mixture was concentrated to dryness at 50-55° C. under vacuum. Ethyl acetate (3.1 L, 30 Vol.) was charged into the concentrated reaction mass and then washed with water (2.07 L), brine (0.6 L) then dried over anhydrous sodium sulfate (207 g), filtered and concentrated to dryness at 40-45° C. under vacuum. The residue was dissolved in dichloromethane (1.035 L, 5 vol.) and then absorbed onto silica gel (60-120) (607 g, 3.0 w/w), then was purified with column chromatography using petroleum ether and ethyl acetate as solvents. After pooling several batches, Preparation 1Q (235 g) was obtained. HPLC purity: 99.77%,

Preparation 1E: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

      A clean and dry 2 L autoclave was charged with methanol (540 mL) and was purged with nitrogen for 5-10 minutes. To the autoclave was added 10% palladium on carbon (12 g, 20%), purged with nitrogen once again for 5-10 min then was charged with Preparation 1Q (60 g, 0.1315 moles), the autoclave was flushed with methanol (60 mL) and stirred for 4-6 hr at 20-25° C. under 5 Kg hydrogen pressure. After completion of the reaction, the reaction mass was filtered through CELITE®, washed with methanol (180 mL), dried with anhydrous sodium sulfate (60 g), filtered and concentrated to dryness at 45-50° C. under vacuum. Obtained Preparation 1E (45.8 g, 95%) as a colorless solid: HPLC purity: 98.9%.

Alternate Procedure to Make Preparation 1E

Preparation 1E: (2R,3S)-3-(tert-Butoxycarbonyl)-6,6,6-trifluoro-2-(3,3,3-trifluoropropyl)hexanoic acid

      Preparation 1E was prepared in a procedure identical as above from a mixture of Preparations 1E and 1F (200 g, 0.5460 moles) using LDA (1.8 M solution in THF, ethyl benzene and heptane) (698 mL, 2.3 equiv.) and diethyl aluminum chloride (1.0 M solution in hexane) (1256 mL, 2.3 equiv) in THF (2.0 L). After workup as explained above, the resulting residue was treated as follows: The crude material was added to a 2 L four neck round bottom flask, followed by the addition of MTBE (1.0 L) charged below 30° C. The resulting mixture was stirred for 5-10 minutes to obtain a clear solution. Hexanes (600 mL) was charged to the reaction mixture at a temperature below 30° C. The reaction mixture was stirred for 10 min. Next, tert-butylamine (43.8 g, 1.1 eq) was charged slowly over a period of 15 minutes below 30° C. This addition was observed to be exothermic. The reaction mixture was stirred for 2 hrs below 30° C. and filtered. The solid material was washed with 5:3 MTBE: hexane (200 mL), the filtrate was concentrated and transferred to an amber color bottle. The filtered solid was dissolved in dichloromethane (2.0 L), washed with 1N HCl (2.0), the organic layer was washed with brine (1.0 L×2), then was concentrated under reduced pressure below 45° C. This material was found to be 91.12% pure. The material was repurified by the above t-butylamine crystallization purification procedure. Obtained Preparation 1E (78 g, 39%): HPLC purity: 99.54%.

Alternate Procedure to Make Example 1

Preparation 1I: tert-Butyl (2S,3R)-6,6,6-trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoate

      A clean and dry 2 L four neck round bottom flask equipped with mechanical stirring, thermometer socket and nitrogen bubbler was charged with N,N-dimethylformamide (457 mL), Preparation 1E (45.7 g, 0.1248 moles) and Preparation 1G•CSA (62.08 g, 0.1248 moles) under nitrogen atmosphere at 20-25° C. The reaction mixture was stirred for 15-20 minutes to make clear solution at 20-25° C. To the reaction mixture was added TBTU (48.16 g, 0.1498 moles) at 20-25° C. followed by triethylamine (50.51 g, 0.4992 moles) over 15-20 minutes at 20-25° C. The reaction mixture was stirred for 60-120 minutes at 20-25° C. under nitrogen atmosphere. After completion of the reaction, the reaction was quenched into water (1.37L, 30 Vol.) at 20-25° C. under stirring. The reaction mixture was stirred for 30 minutes at 20-25° C. The reaction mixture was filtered and washed with water (228 mL). The resulting solid material was dissolved in ethyl acetate (457 mL), washed with water (2×137 mL), brine (137 mL), and then dried with anhydrous sodium sulfate (45.7 g). Activated charcoal (9.14 g, 20%) was charged into the reaction mixture and stirred for 30 minutes. The mixture was filtered through CELITE® bed and 1 micron filter cloth, washed charcoal bed with ethyl acetate (137 mL), concentrated to 1.0 Vol. stage and then petroleum ether (457 mL, 10 Vol.) was charged and stirred for 30 minutes at 20-25° C. The solid was collected by filtration, washed with petroleum ether (137 mL) and then dried under vacuum at 40-45° C. for 8 hr until loss on drying was less than 3.0%. Obtained Preparation 11 (65.2 g, 85%): HPLC purity: 98.26%.

Preparation 1K: (2S,3R)-6,6,6-Trifluoro-3-(((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamoyl)-2-(3,3,3-trifluoropropyl)hexanoic acid

      A clean and dry 3 L four neck round bottom flask equipped with mechanical stirring, thermometer socket and nitrogen bubbler was charged with dichloromethane (980 mL) under nitrogen atmosphere followed by Preparation 1I (140 g, 0.2282 moles) at 20-25° C. The reaction mixture was cooled to 0-5° C. and trifluoroacetic acid (980 mL) was charged slowly for 30-40 minutes. The resulting mixture was stirred for 2 hr at 0-5° C. under nitrogen atmosphere. The reaction temperature was raised to 20 to 25° C., and the reaction mixture was stirred for 1-2 hr at 20 to 25° C. After completion of the reaction, the reaction mixture was concentrated to dryness at 50 to 55° C. under vacuum. Toluene (3×700 mL,) was charged into the concentrated reaction mass, and then distilled off at 50 to 55° C. under vacuum. After complete concentration from toluene, ethyl acetate (280 mL) was charged into the reaction mass at 20 to 25° C., stirred for 60 minutes, then the solid was collected by filtration, washed with ethyl acetate (140 mL), dried under vacuum at 50 to 55° C. for 12 hr until loss on drying was less than 2.0%. Obtained Preparation 1K (106 g, 84%): HPLC purity: 98.43%.

Example 1

      A reaction vessel was charged with Preparation 1K (30 g, 53.81 mmol), HOBt (8.7 g, 64.38 mmol), and THF (150 mL) at room temperature. To the homogeneous solution was added EDCI (12.4 g, 64.68 mmol), stirred for 15 min, then cooled to 8° C. To the reaction mixture was added ammonia (2M in IPA) (81 mL, 162 mmol) over 5 min so as to maintain a temperature below 10° C. The resulting heavy slurry was stirred for 10 min, warmed to room temperature over 30 min, then stirred for 4 hr. At the completion of the reaction, water (230 mL) was slowly added over 15 min to maintain a temperature below 20° C., and then stirred for 2 hr. The solid was collected by filtration, washed with water (3×60 mL), then dried under vacuum 48 hr at 55° C. The above crude product was charged into a 1 L 3-necked round flask. IPA (200 mL) was added, then heated to 80° C. resulting in a homogeneous solution. Water (170 mL) was slowly added (15 min) to maintain an internal temperature>75° C. The resulting slurry was stirred and cooled to room temperature for 2 hr. The solid was collected by filtration, washed with water (2×50 mL), then dried under vacuum (55° C. for 24 h, and 30° C. for 48 h). Obtained Example 1 (23.4 g, 78% yield): HPLC purity: 99.43%.

PATENTS

US-20150284342-A1

US-20140357605-A1

US-20140100365-A1

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For some disease targets, an indirect approach may be best. Or so Ashvinikumar V. Gavai and his colleagues atBristol-Myers Squibbfound in their quest toward a potential cancer drug. Gavai unveiled BMS-906024, which is an experimental—and slightly roundabout—treatment for a number of cancers, including breast, lung, and colon cancers, and leukemia.

Cancers have a tendency to relapse or to become resistant to treatments that once worked. Research at BMS and elsewhere had suggested that a family of proteins called Notch is implicated in that resistance and in cancer progression more generally. Gavai, director of oncology chemistry at BMS in Princeton, N.J., and his team set out to block Notch family signaling.

Notch family members lack enzymatic activity, so blocking them directly is difficult. Instead, BMS developed inhibitors of an enzyme that is essential for activating Notch signaling—γ-secretase.

09116-cover-bms906024

Company: Bristol-Myers Squibb

Target: pan-Notch

Disease: breast, lung, colon cancer; leukemia

Interfering with Notch, even in this indirect way, can have detrimental effects on the gastrointestinal tract. Only two of the four Notch family members are linked to that side effect, Gavai says. But he and his team think their drug will be most effective if it acts on all four family members roughly equally—a so-called pan-Notch inhibitor. By selecting a molecule that’s well tolerated in animals and carefully scheduling doses of the drug in humans, it could be possible to minimize side effects, he says.

The BMS team relied on Notch signaling assays in leukemia and breast cancer cell lines to find leads. They soon learned that for their molecules to work, three chiral centers had to be in the S,R,Sconfiguration. After that, they strove to make the molecules last in the bloodstream. They removed an isobutyl group and tweaked some other parts of their candidate’s succinamide side chain. It was tough to retain both a long half-life and activity against Notch, Gavai told C&EN. “You’d optimize one and lose the other.”

His team threaded the needle with BMS-906024. Their studies with mice suggest that a dose of 4–6 mg once a week could be effective in people. That’s lower than doses being tested for other Notch-targeted agents, according to the website clinicaltrials.gov. The mouse studies also back the idea that Notch is involved in cancer drug resistance and suggest that Notch could be a target for taking on cancer stem cells, which are notoriously resistant to chemotherapy.

BMS-906024 is in Phase I clinical trials, both alone and in combination with other agents. Patients with colon, lung, breast, and other cancers are receiving intravenous doses of the compound to determine its safety and optimum dose ranges.

09116-cover-BMScxd

(From left, front row) Gavai, Weifeng Shan, (second row) Aaron Balog, Patrice Gill, Gregory Vite, (third row) Francis Lee, Claude Quesnelle, (rear row) Wen-Ching Han, Richard Westhouse.
Credit: Catherine Stroud Photography

http://cen.acs.org/articles/91/i16/BMS-906024-Notch-Signaling-Inhibitor.html

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Image result for BMS 906024

BMS-906024
Company: Bristol-Myers Squibb
Meant to treat: cancers including breast, lung, colon, and leukemia
Mode of action: pan-Notch inhibitor
Medicinal chemistry tidbit: The BMS team used an oxidative enolate heterocoupling en route to the candidate– a procedure from Phil Baran’s lab at Scripps Research Institute. JACS 130, 11546
Status in the pipeline: Phase I
Relevant documents: WO 2012/129353

PAPER

Abstract Image

An enantioselective synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one (S1) is described. The key step in the sequence involved crystallization-induced dynamic resolution (CIDR) of compound 7 using Boc-d-phenylalanine as a chiral resolving agent and 3,5-dichlorosalicylaldehyde as a racemization catalyst to afford S1 in 81% overall yield with 98.5% enantiomeric excess.

Crystallization-Induced Dynamic Resolution toward the Synthesis of (S)-7-Amino-5H,7H-dibenzo[b,d]-azepin-6-one: An Important Scaffold for γ-Secretase Inhibitors

Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India
Bristol-Myers Squibb Company, P.O Box 4000, Princeton, New Jersey 08543-4000, United States
Org. Process Res. Dev., Article ASAP
 1. Quesnelle, Claude; Kim, Soong-Hoon; Lee, Francis; Gavai, Ashvinikumar. Bis(fluoroalkyl)-1,4-benzodiazepinone compounds as Notch receptor inhibitors and their preparation and use in the treatment of cancer. PCT Int. Appl. (2012), WO 2012129353 A1 20120927.
Patent ID Date Patent Title
US2016060232 2016-03-03 BIS(FLUOROALKYL)-1, 4-BENZODIAZEPINONE COMPOUNDS
US2016022723 2016-01-28 COMBINATION THERAPY FOR THE TREATMENT OF PROLIFERATIVE DISEASES
US2016008316 2016-01-14 USE OF DIANHYDROGALACTITOL AND ANALOGS OR DERIVATIVES THEREOF IN COMBINATION WITH PLATINUM-CONTAINING ANTINEOPLASTIC AGENTS TO TREAT NON-SMALL-CELL CARCINOMA OF THE LUNG AND BRAIN METASTASES
US2016009785 2016-01-14 NOVEL FUSION MOLECULES AND USES THEREOF
US2015284342 2015-10-08 BIS(FLUOROALKYL)-1, 4-BENZODIAZEPINONE COMPOUNDS
US2015232491 2015-08-20 PRODRUGS OF 1, 4-BENZODIAZEPINONE COMPOUNDS
US8968741 2015-03-03 Anti-CD22 antibodies and immunoconjugates and methods of use
US2014357605 2014-12-04 BIS(FLUOROALKYL)-1, 4-BENZODIAZEPINONE COMPOUNDS
US8822454 2014-09-02 Bisfluoroalkyl-1, 4-benzodiazepinone compounds
US8629136 2014-01-14 Bisfluoroalkyl-1, 4-benzodiazepinone compounds
BMS-906024
BMS-906024.svg
Systematic (IUPAC) name
(2R,3S)-N-[(3S)-1-Methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-2,3-bis(3,3,3-trifluoropropyl)succinamide
Identifiers
PubChem CID 66550890
ChemSpider 28536138
Chemical data
Formula C26H26F6N4O3
Molar mass 556.500 g/mol

///////////////3,5-dichlorosalicylaldehyde, Alzheimer’s disease, Boc-D-phenylalanine, CIDR;dibenzoazepenone DKR; Notch inhibitorsNotch inhibitor, SAR T-acute lymphoblastic leukemia, triple-negative breast cancer, γ-secretase inhibitor, PHASE 1, BMS, Bristol-Myers Squibb, 1401066-79-2, Ashvinikumar Gavai

CN1c2ccccc2C(=N[C@@H](C1=O)NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)N)c3ccccc3

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Patent US8377886 – Use of gamma secretase inhibitors and notch …

www.google.com

Figure US08377886-20130219-C00003. gamma secretase inhibitor

Image result for γ-Secretase Inhibitors BMS

RO4929097 | γ-secretase inhibitor – Cellagen Technology

www.cellagentech.com

RO4929097 | γ-secretase inhibitor
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BMS 911543


 

BMS 911543

N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide

cas 1271022-90-2
Chemical Formula: C23H28N8O
Exact Mass: 432.23861

UNII-7N03P021J8;

N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide

Bristol-Myers Squibb Company  innovator

BMS-911543 is an orally available small molecule targeting a subset of Janus-associated kinase (JAK) with potential antineoplastic activity. JAK2 inhibitor BMS-911543 selectively inhibits JAK2, thereby preventing the JAK/STAT (signal transducer and activator of transcription) signaling cascade, including activation of STAT3. This may lead to an induction of tumor cell apoptosis and a decrease in cellular proliferation. JAK2, often upregulated or mutated in a variety of cancer cells, mediates STAT3 activation and plays a key role in tumor cell proliferation and survival.

 

The JAK2 selective compound BMS911543 (WO2011028864) is in phase II clinical trials for the treatment of m elofibrosis. BMS91 1543 is shown below.

BMS-911543.png

PAPER

ACS Medicinal Chemistry Letters (2015), 6(8), 850-855

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

Bristol-Myers Squibb R&D, US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States
ACS Med. Chem. Lett., 2015, 6 (8), pp 850–855
DOI: 10.1021/acsmedchemlett.5b00226
Publication Date (Web): July 12, 2015
Copyright © 2015 American Chemical Society
*Tel: +1-609-252-4320. E-mail: ashok.purandare@bms.com
Abstract Image

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile

str1

MS (ESI) m/z 434.3 (M+H). 1H NMR (CDCl3) δ: 7.96 (s, 1H), 7.65 (s, 1H), 6.83 (s, 1H), 4.67 (q, J = 7.1 Hz, 2H), 4.01 (s, 3H), 3.82 (s, 3H), 2.77 – 2.84 (m, 2H), 2.43 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H), 0.79 – 0.86 (m, 4H), 0.71 – 0.77 (m, 4H).

PAPER

Journal of Organic Chemistry (2015), 80(12), 6001-601

Click to access jo5b00572_si_001.pdf

Ni-Catalyzed C–H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543

Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States
J. Org. Chem., 2015, 80 (12), pp 6001–6011
DOI: 10.1021/acs.joc.5b00572
Publication Date (Web): April 7, 2015
Copyright © 2015 American Chemical Society
Abstract Image

BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. During the course of our studies, a Ni-mediated C–N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.

N,N-Dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, 1

 Amide 1(198.3 g, 89% yield) as off-white plates (mp 271–274 °C), which contained 0.13 wt % water by Karl Fisher analysis:
1H NMR (600 MHz, DMF-d7) δ 8.15 (br s, 1H), 8.07 (s, 1H), 7.30 (s, 1H), 6.96 (s, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.11 (s, 3H), 3.72 (s, 3H), 2.35 (s, 3H), 3.01 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 0.81–0.73 (m, 8H);
13C NMR (125 MHz, DMF-d7) δ 167.6, 148.5, 145.4, 144.7, 141.7, 139.7, 134.9, 128.0, 125.4, 102.9, 99.5, 96.9, 39.4, 36.0, 33.1, 32.0, 16.5, 11.6, 9.6;
HRMS-ESI (m/z) calcd for C23H29N8O [M + H]+ 433.2464, found 433.2457.

PATENT

WO 2015031562

These Schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein.

As shown below in Scheme 1, the general preparation of compound 7 is described. Trichloroacetyl pyrrole (Compound 1) is reacted with a halogenating agent to give the C4-bromo pyrrole (Compound 2). Alcoho lysis occurs in the presence of an alcohol and base to generate ester (Compound 3), which can be selectively nitrated through contact with an appropriate nitrating agent (defined as a species that generates N02 ), yielding C5-nitro pyrrole (Compound 4). Compound 4 can be isolated as its free form, or optionally as a salt with an appropriate base. Ethylation with an appropriate alkylating agent generates the N-ethyl pyrrole (Compound 5), which in the presence of an imidazole, base, palladium and an appropriate phosphine ligand, will undergo a coupling process to form Compound 6. Reduction of the nitro-group of Compound 6 in the presence of hydrogen, a metal catalyst and optionally a base will produce Compound 7.

Scheme 1

As shown below in Scheme 2, the preparation of Compound 13 is described. Trichloroacetyl pyrrole is treated with NBS in acetonitrile to produce Compound 8. Treatment with sodium ethoxide in EtOH yields the ethyl ester Compound 9. This may be treated with a range of nitrating systems, in this example, NaNC /SCVPy, to generate nitro-pyrrole Compound 10, which can be isolated directly or as a salt form with an appropriate base, preferably dibenzylamine. Ethylation with ethyl iodide generates Compound 11 which may be isolated, or optionally telescoped directly into the arylation with Compound 32. Arylation proceeds in the presence of palladium, Xantphos, potassium pivylate and Hunig’s base to generate Compound 12. Hydrogenation presence of Pt/C followed by cyclization with NaOEt yields Compound 13.

Scheme 2

Another process of the invention is disclosed in Scheme 3 shown below. Compound 14 is prepared from Compound 3 in the presence of an alkylating agent. Treatment with a suitable diboron reagent produces Compound 15, which can then be coupled with a suitably functionalized imidazole derivative to yield Compound 16. Amino lysis with a suitable nitrogen donor produces Compound 17, which can cyclize under appropriate conditions to produce Compound 7.

Scheme 3

Step 3 Step 4 Step 5

As shown below in Scheme 4, ethylation of Compound 9 with ethyl iodide produces Compound 18. This may be directly reacted with dipinacol-diboron in the presence of Pd(OAc)2 and tricyclohexylphosphin hexafluorophosphate and

tetramethylammonium acetate to yield Compound 19. Subsequent coupling with 5-Br-imidazole derivative yields Compound 20. Treatment with hydroxylamine hydrochloride in the presence of triethylamine yields the Compound 21. Subsequent cyclization with Piv20 in the presence of PRICAT™ and hydrogen yields Compound 13.

Scheme 4

77% isolated over 2-steps%

18

Step 5 Pd(OAc)2

PPh3

78%

As shown below in Scheme 5, Compound 23 may be converted to Compound 26 by two pathways. In one option, Compound 23 can be treated with palladium, ligand and a mild base to prepare Compound 25. Reaction of Compound 25 with a metal hydroxide produces Compound 26.

Alternately, Compound 23 can be treated with palladium and ligand in the presence of a soluble hydroxide base, followed by treatment with the metal counter-ion to prepare Compound 26 directly. Once Compound 26 is formed, it can be coupled to Compound 27 to form compound I.

A solution of Compound 1 in acetonitrile (1238.0 kg, 264.9 kg after correction) was charged into a 5000 L glass-lined reactor at a temperature of 20-30 °C. The mixture was added with stirring over about 2 h and then cooled to 0 °C. NBS (221.8 kg) was charged into the mixture at intervals of 20-30 min at 0-20 °C. The mixture was cooled to 0-5 °C and reacted until the content of Compound 8was < 1.0%. Additional NBS (4.0 kg) was charged into the mixture at 0-20 °C. The mixture was reacted over 3 h until the content of Compound 8 was < 1.0%. Purified water (2650.0 kg) was added over about 1.5 – 2.5 h at 0-20 °C. The mixture was cooled to 0-5 °C and then stirred for about 1 h for crystallization. The mixture was filtered and the filter cake was rinsed with water.

Example 2

While maintaining the temperature at 20-30 °C, anhydrous ethanol (950.0 kg) was charged into a 3000 L glass-lined reactor followed by Compound 8 (342.7 kg). The mixture was cooled to 0-5 °C over about 2 h. Sodium alcoholate solution in ethanol (21%, 36.4 kg) was added dropwise over about 1-1.5 h at 0-5 °C. The reaction mixture was then heated to about 25-30 °C and tested until the content of Compounds 8/9 was < 1.0%. The reaction mixture was concentrated at a temperature < 50 °C until about 1.3-1.4 volume of Compound 8 was left. The concentrated mixture was cooled at 25-30 °C. The mixture was quenched into cooled water (3427.0 kg) over about 2 h. After addition, the mixture was stirred at 0-5 °C over about 2 h for crystallization. The mixture was filtered and the filter cake was rinsed. The solid was dried at 30-40 °C over 40-45 h to afford 234.3 kg of Compound 9 , 99.9% purity and 91.3% yield.

Example 3

9 10

A mixture of NaN03, NaHS04, and Na2S04 in CH3CN is wet-milled to constant particle size of -50 micron. To the slurry of inorganic salts is added S03 -pyridine and Compound 9. The reaction mixture is agitated at 25 °C until 90-95% conversion is achieved. The reaction is quenched with aqueous sodium hydroxide and the spent inorganic salts are removed by filtration. The filtrate is passed through a carbon pad and distilled under constant volume distillation and diluted with water to a target 15

volumes/kg of Compound 9 and a target ratio 1.0:2.0 vol/vol MeCN to water. The resulting solids are deliquored, washed, and dried to afford Compound 10.

Example 4

Toluene (10 L/Kg)

65 °C

Compound 10 (1.0 eq) and TBABr (1.0 eq) were added to a biphasic mixture of toluene (8 L/kg 10) and potassium carbonate (1.5 eq) in water (5 L/kg 10). The batch temperature was held at 25 °C. The resulting triphasic slurry was heated to 60-65 °C and diethylsulfate (1.5 eq, in a solution of toluene 2 L/kg 10) was slowly added over ~ 1 h. The reaction was aged until less than 1 RAP of Compound 10 (10:11) remained. The resulting homogeneous biphasic mixture was cooled to 20 °C and the lean aq. phase was removed. The rich organic phase was washed with water (2×7 L/kg 10) and concentrated to 6 mL/g 10. The concentrated stream was dried via azeotropic, constant volume distillation with toluene until the water content of the stream was <0.1 wt %. The resulting stream was telescoped into the subsequent direct arylation reaction.

Example 5

11 28 12

To the toluene stream of Compound 11, with potassium pivalate (1.5 equiv.) was charged, followed by DIPEA (3 eq.), Compound 28 (3 eq.) and Pd(Xantphos)Cl2 (0.04 eq.). The vessel was evacuated to < 200 torr and backfilled with nitrogen (3 X) followed by heating to 95 °C until residual Compound 11 was less than 1 RAP (11: 12). The reaction mixture was cooled to 25 °C and diluted with ethyl acetate (15 mL/g vs input pyrrole) and aq. N-acetylcysteine (0.2 eq., 5 wt % solution, 1.8 mL/g vs. input pyrrole) and heated to 50 °C for 1 h. The biphasic mixture was cooled to 25 °C. The lower aqueous layer was removed. The ethyl acetate stream was washed with water (2×7 mL/g vs. input pyrrole). The rich organic phase was polish filtered followed by a vessel/polish filter rinse with ethyl acetate (2 mL/g vs. input pyrrole). The rich organic stream was concentrated to 4 mL/g vs. input pyrrole via vacuum distillation, while maintaining the batch temperature above 50 °C. If spontaneous nucleation did not occur, Compound 12 seeds (1 wt %) were charged, followed by aging for 30 min at temperature. MTBE (5 mL/g vs. 11) was charged to the slurry over 1 hour while maintaining the batch temperature above 40 °C, followed by aging at 40 °C for 1 h. The slurry was cooled to 0 °C over 6 h and aged at 0°C for 6 h. The slurry was filtered and washed with

EtO Ac : Toluene : MTBE (1.5: 1.0: 1.5, 2 mL/g vs. input 11 ). The wet cake was dried (50 °C, 100 torr) until LOD was < 1 wt %.

Example 6

Compound 12 (1 eq., limiting reagent (LR)) is dissolved in THF/NMP (20 Vol wrt LR, 9/1 ratio) and submitted to hydrogenation using 10 wt% (wrt LR) Pt/C (5 wt%) at 25 to 40° C for 5-10 h. The reaction containing the corresponding amine is filtered. The rich organic stream is concentrated to Compound 12 Vol (wrt LR) and subjected to 0.1 eq of 21 wt% NaOEt/EtOH for 5 h at 20-25 °C, upon which Compound 13 forms. The stream is cooled to 0-10 °C, and water (5L/Kg, wrt to LR) is added and then filtered to isolate Compound 13. The product is dried at 50 °C under vacuum.

Example 7

in toluene solution

9

18

Compound 18 was prepared by treating the pyrrole with ethyl iodide and pulverized potassium carbonate in DMF at 25-30°C under inert atmosphere. After the reaction was completed, the batch mass was cooled to 15°C to 20°C and quenched by slow addition of water then MTBE. The MTBE layer was separated and washed with water. The MTBE layer was distilled to 4 Vol and solvent swapped with toluene. The toluene stream was then taken into the next step.

Example 8

18 19

Tetra-methyl ammonium acetate in toluene slurry was heated to 75-80°C to get a clear solution. The mass was cooled to below 30°C and pyrrole in toluene and bis (pinacolato) diborane were added. The reactor was inerted by nitrogen purging then the reaction was heated to 75-80°C. A freshly prepared catalyst/ligand complex (0.0 leq of palladium acetate, 0.025eq of tricyclohexyl phosphino hexafluoroborate and 0.2eq of tetra methyl ammonium acetate in toluene) was charged under nitrogen atmosphere at RT and stirred for 2h. The mass was then stirred at 75-80°C under nitrogen atmosphere. After the reaction was completed, the mixture was cooled below 30°C and quenched with aq. sodium bisulphate solution. The organic layer was polish filtered through a Celite bed and the filtrate was washed with water. The solvent swapped to ethanol until the toluene content became less than 0.5 %. The solution was cooled to 0-5°C and water was added for crystallization. The product was then isolated by filtration.

Example 9

Compound 20 was prepared by treating Compound 19 with Compound 34 in the presence of palladium acetate, triphenyl phosphine and potassium carbonate in dimethyl acetamide with the water mixture as the solvent. Dimethyl acetamide, water, potassium carbonate and the two starting materials were charged into the reactor. The mixture was made inert with nitrogen for 30 min and then charged with freshly prepared catalyst mixture (palladium acetate, triphenyl phosphine and potassium carbonate in dimethyl acetamide). The temperature was raised to 78-83 °C then the mass was stirred at this temperature. After the reaction was completed, the reaction mass was cooled to ambient temperature and purified water was added slowly into the mass for product

crystallization. The mass was stirred for a period of 3 h and filtered. The wet cake was washed with purified water and dried in VTD at 50-55 °C under vacuum.

Example 10

Compound 21 was prepared by treating Compound 20 with hydroxylamine hydrochloride and triethyl amine using ethanol as the solvent. Compound 20 was added into ethanol (15 Vol) and the reaction mass was heated to 38-40 °C. Hydroxylamine hydrochloride was charged and stirred for 10 min, then triethyl amine was added slowly at 38-40 °C over a period of lh. The above mass was stirred at 38-40 °C until Compound 20 becomes less than 5.0%, typically in about 15 h. After the reaction was completed, the above reaction mass was cooled to ambient temperature (below 30 °C) and filtered. The wet cake was washed with purified water (4 Vol) and dried under vacuum in VTD at 55-60 °C.

Example 11

Initially Compound 21 was treated with pivalic anhydride using toluene and acetic acid mixture as solvent under inert atmosphere until Compound 21 becomes less than 3.0% with respect to Compound 21, typically in about 30 min. PRICAT Nickel was then added under nitrogen atmosphere. The reaction mass was inerted with nitrogen for three cycle times and then degassed with hydrogen gas for three cycle times. Following this, 3.0 kg/cm2 hydrogen pressure was applied to the reaction mass which was stirred for about 12h. After the reaction was completed, the reaction mixture was filtered through a sparkler filter. The filtrate was distilled and the solvent exchanged with toluene until the ratio of acetic acid & toluene reaches 1 :20. At this time, n-Heptane was charged and cooled to 15°C. Then the product was filtered and the wet cake was dried in VTD at 50-55°C under vacuum.

Compound 30 was prepared by the coupling of Compound 22 with Compound 29, 3 -bromo- 1,5 -dimethyl- lH-pyrazole in the presence of

Tris(dibenzylideneacetone)dipalladium chloroform adduct, t-Brettphos and potassium phosphate in tert-amyl alcohol at 98-103 °C under inert atmosphere. After completion of the reaction (typical level of Int.9 -5% & typical reaction hrs 20 h), the mass was cooled to ambient temperature and t-amyl alcohol (4 Vol) and 20 Vol of water were charged into the reaction mass. The reaction mass was stirred for 15 min. and then phase split. The organic layer was diluted with 10 Vol of MTBE and product was extracted with 20 Vol of 1M methane sulphonic acid. The MSA stream was treated with 15 wt % charcoal to reduce the residual palladium numbers. The filtrate was cooled to below 20 °C and the pH was adjusted to 1.7-1.9 using IN NaOH for product crystallization and then iltered. The wet cake was washed with purified water (3 x 5 Vol), followed by methanol (5 Vol). The cake was vacuum dried for 3 h. then the wet cake and dimethyl sulfoxide (20 Vol) were charged into a reactor. The mass was heated to 120-125 °C to get clear solution then the mass was cooled to ambient temperature and stirred for 2 h, then filtered. The wet cake was washed with methanol (3x 4.0 Vol) and vacuum dried for 2 h. The wet cake was dried in VTD at below 55°C under vacuum.

Example 13

Compound 30 , ethanol (16.5 Vol), water and aq sodium hydroxide solution were charged into a reactor then the mass was heated to 70-75 °C and stirred until Compound 30 becomes less than 1.0%. After the reaction was completed, the mass was diluted with ethanol for complete product precipitation at 65-75 °C. Then the mass was cooled to 50 °C for a period of lh and stirred for lh at 50 °C. The mass was further cooled to 20 °C and stirred for lh at 20 °C and then filtered. The wet cake was washed with 5 Vol of 15% aqueous ethanolic solution followed by THF. The wet cake was dried under vacuum at 70-75 °C till LOD comes to less than 5.0 %, typically in about 40 h.

Example 14

In a vessel 36.5 mmol (-42.6 mL) of Compound 29 solution in 2-methyl-2-butanol was combined with 30.7g (65.1 mmol) tetrabutylammonium hydroxide (55 wt% in water), 8.01g (27.0 mmol) Compound 13 , and 10 mL 2-methyl-2-butanol. The mixture was heated at 70 °C until hydrolysis of Compound 13 was complete (full dissolution, <15 min). The solution was cooled to 60 °C and 1.12g (2.22 mmol) of tBuBippyPhos followed by 384 mg (1.028 mmol) allylpalladium chloride dimer (L:Pd = 1 :1) was added. The mixture was heated to 80 °C and was aged at this temperature for 20h before cooling to 22 °C.

Water was added and the mixture concentrated, a constant volume distillation was then performed to swap to ethanol (40-55 °C, 150 mbar). The resulting solution was passed through a 5 micron filter to remove any particulates. The solution was heated to 55 °C and 8.10 mL (40.52 mmol, 1.5 equiv) 5N NaOH (aq) was added dropwise over a 3 h period. Crystals of Compound 31 began to form, and after aging for an additional lh, the mixture was cooled to 20 °C over 3 h. After an additional 6h of aging, crystals were collected on a frit and the cake was washed with 40 mL of 90: 10 ethanol: water, followed by 48 mL acetone. After drying at 80 °C in a vacu-oven for 16 h, Compound 31 was collected as an off-white solid (8.89g, 85%).

Example 15

Compound 31 was added into dichloromethane (20 Vol) and cooled to 15-20 °C. The reaction mass was charged with DMC in DCM solution (1.4 eq of DMC in 5.0 Vol of DCM). The mixture was stirred until Compound 31 becomes less than 2.0% with respect to the corresponding acid chloride, typically in about lh. After completion of the reaction, Compound 27 (1.4 eq) and N,N-diisopropylethyleneamine (3.0 eq) were charged and the mixture was stirred. After completion of the reaction, the mass was quenched with 12 Vol of water then the layers were separated. The organic layer was washed with water and filtered through a celite bed. The filtrate was concentrated to ~6.0 vol and then the mass was cooled to 35 °C. To the resulting solution was added THF, followed by seeds of product, then stirred for 3 h. The solvent was swapped with THF until

dichloromethane becomes less than 2 wt% (wrt THF). The mass was cooled to -5 to 0 °C over a period of 2 h and stirred for 2 h. The reaction mass was then filtered under a nitrogen atmosphere. The material was slurried with pre-cooled THF (2*2 Vol) and filtered. The wet cake was dried in VTD at 60 °C under vacuum till LOD becomes < 1%, typically in about 20 h.

Example 16

DC , RT

I

To a slurry of Compound 31 (15.00 g, 40.0 mmol) in dichloromethane (300 ml) was added diphenylphosphinic chloride (12.29 g, 51.9 mmol). The mixture was stirred at room temperature for 2 h and Ν,Ν-diisopropylethylamine ( 16.53 g, 127.9 mmol) was then added and stirred for another 30 min. Compound 27 (6.94 g, 51.9 mmol) and 4-dimethylaminopyridine (0.49 g, 4.0 mmol) were subsequently added and stirred for 16 h until the reaction was completed. The reaction mixture was treated with N-acetyl-L-cysteine (3.26 g, 20.0 mmol) and citric acid (10.10 g, 48.0 mmol) in deionized water (180 ml) for 2 h. After phase split, the dichloromethane phase was washed once with 0.42 N NaOH solution (180 ml) and washed twice with deionized water (180 ml each). The final dichloromethane phase was concentrated (to 90 ml) and acetone (30 ml) was added. The solution was cooled to 35 °C and N-2 form seed of Compound 1 ( 150 mg ) was added and aged for 1 h. The resulting slurry was solvent-swapped to acetone (DCM < 10% v/v), and cooled to 0 °C. The solid was filtered and washed with cold acetone and dried to afford 14.69 g (85%) of Compound I (HPLC AP 99.8) as off-white crystals.

Patent

WO 2011028864

http://www.google.com/patents/WO2011028864A1?cl=en

 

Compounds of general formula I in which the R group is thiazole (as in Ial) and R1 and R2 groups are CF3 or alkyl or cycloalkyl or combine to form a saturated carbocyclic or heterocyclic ring or where R2 group is COORb could be prepared using the general method depicted in Scheme 1. Dichloro intermediate II (prepared using procedure reported in WO200612237) could be combined with a 2,4-dimethoxybenzyl and the resulting secondary amine is capped with suitable protective group (Boc) (III). The second chlorine atom could be converted into the

corresponding amine (IV) through the benzophenone imine intermediate. The amino compound could be halogenated to intermediate V. V could be subjected to transition metal mediated indole ring formation and the resulting indole nitrogen is capped with ethyl iodide to afford VI. Ester hydrolysis followed by amide bond formation and cleavage of protective groups with acid treatment would yield amine VII. Amine VII could be converted into thiourea VIII by first coupling with benzoyl isothiocyanate followed treatment with aqueous base. Formation of thiazole could be achieved by condensation with an a-bromoketone derivative (R^HBrCOR2).

a) 2,4-dimethoxybenzylamine, heat; b) NaHMDS, Boc20; c) (Ph)2=NH; d) HCl; e) NIS; f) Pd2(dba)3, ethyl pyruvate; g) Etl, Cs2C03; h) NaOH (aq); i) dicyclopropylamine HCl, HATU, DIPEA; j) TFA; k) Benzoyl isothiocyanate;

1) NaOH (aq); m) I^CHBrCOR1

Scheme 1

Compounds of general formula Ia2 in which the R1 group is CONRaRa could be made using Scheme 2. Thiourea intermediate (VIII) could be combined with Et02CCHBrCOR1 to afford the thiazole ester (IX). The ester could be hydrolyzed and the acid could be coupled with amine to afford thiazole amide derivative (la)

a) Et02CCHBrCOR1; b) NaOH (aq); c) HNRaRa, HATU, DIPEA

Scheme 2

Similarly, compounds of general formula Ia3 in which the R1 group is CONRaRa could be prepared using the general protocol depicted in Scheme 3.

a) R2CHBrCOC02Me; b) NaOH (aq); c) HNRaRa, HATU, DIPEA

Scheme 3

Compounds of general formula la in which R1 is halogen (CI, Br or I) could be prepared by condensing an a,a’-dihaloketone as depicted in Scheme 4.

a) R2COCH(Hal)2

Scheme 4

Alternatively, thiourea derivative VIII could be converted to room temperature into C-5 un-substituted thiazole XI and then directly halogenated using electrophilic halogen source or through metallation followed by quenching with an electrophilic halogenating agent (Scheme 5).

a) BrCH2COR2; b) Selectfluor or NCS or NBS or NIS or tBuLi followed Selectfluor or NBS or NCS

Scheme 5

Compounds of general formula Ia5 in which R1 is S02Rb could be synthesized using the general synthetic approach shown in Scheme 6

a) Br2-acetic acid; b) EtOH, heat

Scheme 6

Compounds with general formula la in which R1 and R2 combine to form an aromatic or heteroaromatic ring could be prepared using Scheme 7.

X = hal, -S02Me

a) Pd(0) catalyst, NaOtBu, phosphine ligand, heat

Scheme 7

Alternatively, these compounds could be made by first coupling aniline or heteroaniline (XVI) with the isothiocyanate (XV) followed by oxidative cyclization (Scheme 8).

a) 1, 1 ‘-Thiocarbonyldi-2( 1 H)-pyridone; b) NaH; c) NIS

Scheme 8

Compounds of general formula Ibl could be prepared using the general synthetic approach depicted in Scheme 9. Aniline VII could be combined with γ-dithiomethylketone compound XVII, (prepared using the procedure reported at room temperature in Synlett, p 2331 (2008)) under basic condition to afford XVIII.

Stepwise condensation of the Boc-protected hydrazine derivative would give the required pyrazole Ibl.

a) NaH, THF; b) R1N(Boc)NH2, AcOH, 35-40°C; c) HCO2H or TFA, 60°C

Scheme 9

Compounds of general formula Ibl or Ifl and If could also be prepared by coupling C-4 halo derivative (XIX) with an appropriately substituted 2-aminopyrazole derivative (XX) using a transition metal catalyzed reaction (Scheme 10).

a) isoamyl nitrite, CH2I2 or isoamyl nitrite, CH2Br2; b) Pd2(dba)3, Xanphos, Cs2C03

Scheme 10

Compounds of general formula Ib2 in which R2 group is CONRaRa could be synthesized using Scheme 11. Aniline VII could be combined with γ-dithiomethylketone derivative XXII, (prepared using the procedure from

Tetrahedron, p 2631 (2003)) to afford intermediate XXIII. Stepwise condensation of Boc-protected hydrazine derivative would give the required pyrazole aldehyde XXIV. Aldehyde could be oxidized using oxone or sodium hypochlorite to furnish carboxylic acid XXV. Coupling of acid XXV with amine would give pyrazole amide Ib2.

a) NaH, THF, heat; b) R1N(Boc)NH2, AcOH; c) TFA; d) oxone or sodium hypochlorite; e) HNRaRa, HATU, DIPEA

Scheme 11

Compounds of general formula Icl could be prepared using the general protocol as shown in Scheme 12. Aniline VII could be coupled with chloroacetyl chloride and the resulting amide could be treated with thioamide (R2CS H2) to furnish thiazole Icl .

a) chloroacetyl chloride, base; b) R2CSNH2

Scheme 12

00120] Compounds of general formula ldl could be made as per Scheme 13. Previously described isothiocyanate derivative XV could be combined with amidine XXV under dehydrating reaction conditions to give 1,2,4-thiadiazole (ldl).

Scheme 13

Compounds of general formula lei could be prepared using a synthetic approach as shown in Scheme 14. Isothiocyanate XV could be combined with azide XXVI in the presence of phosphine to yield 1,3-oxazole Iel .

Scheme 14

Compounds of general formula lgl could be prepared using a synthetic approach as shown in Scheme 15. Amine VII could be combined with acyl isothiocyanate XXVII. The acylthioureaido could be condensed with hydrazine derivative to yield the 1,2,4-triazol derivative lgl.

igi

Scheme 15

 

without a methyl

Preparation of 7V,7V-dicyclopropyl-6-ethyl-l-methyl-4-(5-m ethyl- lH-pyrazol-3- ylamino)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide

[00437] Prepared using similar protocol as for example 72 from hydrazine.

[00438] MS (ESI) m/z 419.3 (M+H)

[00439] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.70 (br s, 1 H), 7.91 (br s, 1 H), 6.87 (s, 1 H), 6.09 (br s, 1 H), 4.64 (q, 2 H, J= 7.03 Hz), 4.08 (s, 3 H), 2.74 -2.95 (m, 2 H), 2.41 (s, 3 H), 1.51 (t, 3 H, J= 7.15 Hz), 0.81 – 0.95 (m, 4 H), 0.70 -0.81 (m, 4 H)

with an ethyl

7V,iV-dicyclopropyl-6-ethyl-4-(l-ethyl-5-methyl-lH-pyrazol-3-ylamino)-l-methyl- 1,6-dihydroimidazo [4,5-d] pyrrolo [2,3-b] pyridine-7-carboxamide

74A Preparation of fe/t-butyl l,3-dioxoisoindolin-2-yl(ethyl)carbamate

Diisopropyl azodicarboxylate (2.92 mL, 15.00 mmol) was added in one portion to a solution of tert-butyl l,3-dioxoisoindolin-2-ylcarbamate (2.62 g, 10 mmol, prepared following the procedure described by Nicolas Brosse et al. in Eur. J. Org. Chem. 4757-4764, 2003), triphenylphosphine (3.93 g, 15.00 mmol) and ethanol (0.691 g, 15.00 mmol) in THF (20 mL) at 0 °C and the reaction solution was stirred at room temperature for lh (monitored by TLC until completion). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate / hexanes) to provide tert-butyl l,3-dioxoisoindolin-2-yl(ethyl)carbamate (2.6 g, 90 % yield) as a white solid which was used as it in the next step

74B Preparation of fe/t-butyl l-ethylhydrazinecarboxylate

Boc

H2N-N

\

Methylhydrazine (1.415 niL, 26.9 mmol) was added to a solution oi tert-butyl l,3-dioxoisoindolin-2-yl(ethyl)carbamate (example 74A, 5.2 g, 17.91 mmol) in THF (40 mL) at 0 °C and the reaction mixture was stirred at room temperature overnight. A white precipitate formed and was filtered off through a pad of Celite, The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with IN HC1 (3×30 ml), the acid layer was washed with ethyl acetate (50 ml) and basified to pH 10 by addition of 20% NaOH. The basic solution was then extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 1 -ethylhydrazinecarboxylate (2.5 g, 87 % yield) as colorless oil.

XH NMR (400 MHz, CDC13) δ: 3.90 (br. s., 2H), 3.35 (q, J = 7.0 Hz, 2H), 1.42 (s, 9H), 1.07 (t, J = 7.0 Hz, 3H)

74 Preparation of N.N-dicyclopropyl-6-ethyl-4-(l-ethyl-5-methyl-lH-pyrazol-3-ylamino)-l-methyl-l ,6-dihydroimidazor4,5-d1pyrrolor2,3-b1pyridine-7-carboxamide

A mixture of (Z)-N,N-dicyclopropyl-6-ethyl- 1 -methyl-4-( 1 -(methylthio)-3-oxobut-l-enylamino)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 74B, 70 mg, 0.155 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (49.6 mg, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35 °C for 4 h (monitored by LC/MS until no starting material left). Formic acid (1 mL) was added and the reaction mixture stirred at 60 °C for 6 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol / dichloromethane). The material was further purified by preparative HPLC to afford N,N-dicyclopropyl-6-ethyl-4-( 1 -ethyl-5-methyl- lH-pyrazol-3-ylamino)- 1 -methyl- 1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (38 mg, 53.4 % yield) as an off-white solid.

MS (ESI) m/z 447.3 (Μ+Η).

XH NMR (500 MHz, CDC13) δ: 8.08 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H),

6.84 (s, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 2.79 – 2.85 (m, 2H), 2.34 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H), 0.82 -0.87 (m, 4H), 0.72 – 0.78 (m, 4H).

Patent

JAK2 INHIBITORS AND THEIR USE FOR THE TREATMENT OF MYELOPROLIFERATIVE DISEASES AND CANCER [US8202881]2011-03-102012-06-19

JAK2 inhibitors and their use for the treatment of myeloproliferative diseases and cancer [US8673933]2012-04-302014-03-18

: Purandare AV, McDevitt TM, Wan H, You D, Penhallow B, Han X, Vuppugalla R, Zhang Y, Ruepp SU, Trainor GL, Lombardo L, Pedicord D, Gottardis MM, Ross-Macdonald P, de Silva H, Hosbach J, Emanuel SL, Blat Y, Fitzpatrick E, Taylor TL, McIntyre KW, Michaud E, Mulligan C, Lee FY, Woolfson A, Lasho TL, Pardanani A, Tefferi A, Lorenzi MV. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280-8. doi: 10.1038/leu.2011.292. Epub 2011 Oct 21. PubMed PMID: 22015772.

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2011292a.html

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Click to access jo5b00572_si_001.pdf

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Bristol-Myers Squibb files NDA in Japan for all-oral hepatitis C treatment


Bristol-Myers Squibb has filed a new drug application (NDA) to Japan’s Pharmaceutical and Medical Devices Agency for the approval of an interferon-free and ribavirin-free treatment regimen for patients with chronic hepatitis C (HCV).

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Bristol-Myers Squibb files NDA in Japan for all-oral hepatitis C treatment