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ORGANIC SPECTROSCOPY

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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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Fedratinib


Fedratinib structure.svgFedratinib.png

ChemSpider 2D Image | Fedratinib | C27H36N6O3SFigure imgf000121_0001

FEDRATINIB

SAR-302503; TG-101348, 6L1XP550I6, 936091-26-8 [RN], WHO 9707

Molecular Formula: C27H36N6O3S
Molecular Weight: 524.684 g/mol

FLT3, JAK2

http://www.ama-assn.org//resources/doc/usan/fedratinib.pdf

Fedratinib had been in phase III clincial trials by Sanofi for the treatment of myelofibrosis.

However, Sanofi had discontinued this research because of the safety issues. Orphan drug designation was assigned in the U.S. and in Japan for this indication. In 2017, the clinical hold was lifted in the U.S. by Impact Biomedicines.

MYELOFIBROSIS (MF), SANOFI , phase 3

Benzenesulfonamide, N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]-

N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzenesulfonamide

N-tert-butyl-3-[[5-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]pyrimidin-4-yl]amino]benzenesulfonamide

USAN (AB-104) FEDRATINIB
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. Benzenesulfonamide, N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-
pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]-
2. N-tert-butyl-3-[(5-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]anilino}pyrimidin-4-
yl)amino]benzenesulfonamide

MOLECULAR FORMULA C27H36N6O3S
MOLECULAR WEIGHT 524.7
SPONSOR Sanofi
CODE DESIGNATIONS SAR302503; TG101348
CAS REGISTRY NUMBER……….936091-26-8

WHO 9707

TG-101348 , a dual-acting JAK2/FLT3 small molecule kinase inhibitor, has been evaluated in phase III clinical development at Sanofi (formerly known as sanofi-aventis) for the oral treatment of intermediate-2 or high risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly. However, development of the compound has been discontinued due to safety issues.

In preclinical models of myeloproliferative diseases, TG-101348, administered orally, was shown to reduce V617F-expressing cell populations in a dose-dependent manner without adversely impacting normal hematopoiesis. The reduction of V617F- expressing cell populations correlated with improved survival and reduced morbidity. Orphan drug designation was assigned in the U.S. and in Japan for the treatment of secondary and primary myelofibrosis. In July 2010, TargeGen was acquired by Sanofi. In 2013, orphan drug designation was assigned by the FDA for the treatment of polycythemia vera.

Fedratinib is an orally bioavailable, small-molecule, ATP-competitive inhibitor of Janus-associated kinase 2 (JAK2) with potential antineoplastic activity. Fedratinib competes with JAK2 as well as the mutated form AK2V617F for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and the induction of tumor cell apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders (MPDs); the mutated form JAK2V617F has a valine-to-phenylalanine modification at position 617 and plays a key role in tumor cell proliferation and survival.

Fedratinib has been used in trials studying the treatment and basic science of Solid Tumor, Myelofibrosis, Renal Impairment, Neoplasm Malignant, and Hepatic Impairment, among others.

Fedratinib (TG101348SAR302503) is an orally available inhibitor of Janus kinase 2 (JAK-2) developed for the treatment of patients with myeloproliferative diseases including myelofibrosis. Fedratinib acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM).[1] In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to suppression of proliferation and induction of apoptosis.

Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor JAK-STAT activating mutations that are sensitive to TG101348. Phase I trial results focused on safety and efficacy of Fedratinib in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011.[2]

Fedratinib was originally discovered at TargeGen. In 2010, Sanofi-Aventis acquired TargeGen and continued development of fedratinib until 2013. In 2016, Impact Biomedicines acquired the rights to fedratinib from Sanofi and continued its development for the treatment of myelofibrosis and polycythemia vera. In January 2018, Celgene acquired Impact Biomedicines.[3]

Image result for Fedratinib SYNTHESIS

SYN

WO2007053452A1. +Bioorganic & Medicinal Chemistry Letters, 27(12), 2668-2673; 2017

Condensation of 3-bromo-N-tertbutylbenzylsulfonamide with 2-chloro-5-methyl-pyrimidin-4-ylamine  in the presence of Pd2(dba)3, Xantphos, Cs2CO3 in refluxing dioxane gives sulfonamide derivative , which is coupled with 4-[2-pyrrolidin-1-yl-ethoxy]phenylamine  in AcOH at 150°C to provide the title compound

PRODUCT PATENT

WO2007053452A1.

Inventors Jon Jianguo CaoJohn HoodDan LohseChi Ching MakPherson Andrew McGlenn NoronhaVed PathakJoel RenickRichard M. SollBinqi ZengLess «
Applicant Targegen, Inc.

https://encrypted.google.com/patents/WO2007053452A1?cl=en

EXAMPLE 90. 7V-fe^-Butyl-3-{5-methyl-2-14-(2-pyrrolidm-l-yl-ethoxy)-phenylaminol- pyrimidin-4-ylaminol-benzenesuIfonamide (Compound LVII)

Figure imgf000121_0001

LVII

[0203] A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-l-yl- ethoxy)-phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 °C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum atnount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).

[0204] 1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J= 5.8 Hz, 2H), 3.99 (t, J= 6.0 Hz, 2H), 6.79 (d, J= 9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, IH), 7.90 (s, IH), 8.10-8.15 (m, 2H), 8.53 (s, IH), 8.77 (s, IH). MS (ES+): m/z 525 (M+H)+. it ιr

PATENTS

WO 2013059548

PAPER

Bioorganic & Medicinal Chemistry Letters, 27(12), 2668-2673; 2017

PATENT

WO 2012061833

The compound and the pharmaceutical compositions described herein can be used for treating or delaying development of myelofibrosis in a subject. N-teft-Butyl-3-[(5-methyl-2-{ [4- (2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide has the following chemical structure:

Figure imgf000018_0001

Example 4. Synthesis of TG101348

Example 4.1 N-fer^-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)-benzenesulfonamide

(Intermediate)

Example 4.1(a)

Figure imgf000053_0001

1 2 Intermediate

[0162] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1) (0.4 g, 2.8 mmol), 3-bromo-N- teft-butyl-benzenesulfonamide (2) (1.0 g, 3.4 mmol), Pd2(dba¾ (0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate

concentrated in vacuo. The residue was dissolved in EtOAc and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was used in the next step without purification. MS (ES+): m/z 355 (M+H)+.

Example 4.1(b)

Figure imgf000053_0002

SM2 Intermediate[0163] The Intermediate was synthesized from 2,4-dichloro-5-methylpyrimidine (SMI) and N-t- butyl-3-aminobenzenesulfonamide (SM2) in the following steps: (1) Mix MeOH (6.7UOa) and SMI (Combi Blocks) (UOa); (2) Add SM2 (1.15UOa, 082eq) and H20 (8.5UOa); (3) Heat 45°C, 20h, N2, IPC CPL SM2<2%; (4) Cool 20°C; (5) Centrifuge, N2; (6) Wash H20 (2.1UOa) + MeOH (1.7UOa); (7) Mix solid in H20 (4.3UOa) + MeOH (3.4UOa); (8) Centrifuge, N2; (9) Wash H20 (2.1UOa) + MeOH (1.7UOa); and (10) Dry 45°C, vacuum, 15h. Obtained

Intermediate, mass 49.6kg (UOb); Yield 79%; OP: 99.6%.

Example 4.2 N-½ri-Butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide

Figure imgf000054_0001

Intermediate TG101348

Example 4.2(a)

[0164] A mixture of N-ieri-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)- benzenesulfonamide (Intermediate) (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-l-yl-ethoxy)- phenylamine (3) (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 °C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCC^ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2S04 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%). ]H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, /=5.8 Hz, 2H), 3.99 (t, 7=6.0 Hz, 2H), 6.79 (d, 7=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)+.

Example 4.2(b)

[0165] N-½ri-Butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate was prepared from 4-[2-(l- pyrrolidinyl)ethoxy] aniline dihydrochloride (SM3) and Intermediate following steps (A) and (B).

[0166] Step (A), preparation of free base of SM3 (3) from SM3, comprised steps (1) – (9): (1) Solubilize NaOH (0.42UOb) in H20 (9UOb); (2) Cool <20°C, N2; (3) Add TBME (6UOb) then SM3 (Malladi Drugs) (1.06UOb); (4) Mix >20mn then stop; (5) Drain Aq Ph then extract by TBME (3UOb); (6) Combine Or Ph; (7) Concentrate, vacuum, T<40°C, to an Oil; (8) Solubilize in IPA (2.5UOb); and (9) Calculate dry extract 23%.

[0167] Step (B) comprised the steps (1) – (6): (1) Mix IPA (10.5UOb) and Intermediate (UOb); (2) Add free base of SM3 (0.75UOb, 1.33eq/ interm); (3) add HC1 cone (0.413UOb); (4) Heat 70°C, 20h, N2, IPC CPL Interm<2%; (5) Cool <20°C; (2) Centrifuge, N2; (3) Wash IPA (3UOb); (4) Dry 50°C, vacuum, 26h; (5) De-lump in Fitzmill; and (6) polybag (x2) / poly drum. Obtained TG101348 dihydrochloride monohydrate, mass 83.8kg; Yield 98%; OP: 99.5%. Example 5 Capsule Form of TG101348 and Process of Making TG101348

PATENT

WO 2010017122

US 2007259904

WO 2007053452

Paper

JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasms.

Treliński J, Robak T.

Curr Med Chem. 2013;20(9):1147-61.

JAK2 inhibitors for myelofibrosis: why are they effective in patients with and without JAK2V617F mutation?

Santos FP, Verstovsek S.

Anticancer Agents Med Chem. 2012 Nov;12(9):1098-109. Review.

Octa-arginine mediated delivery of wild-type Lnk protein inhibits TPO-induced M-MOK megakaryoblastic leukemic cell growth by promoting apoptosis.

Looi CY, Imanishi M, Takaki S, Sato M, Chiba N, Sasahara Y, Futaki S, Tsuchiya S, Kumaki S.

PLoS One. 2011;6(8):e23640. doi: 10.1371/journal.pone.0023640. Epub 2011 Aug 10

PATENT

us2007191405

Example 90 N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide (Compound LVII)

Figure US20070191405A1-20070816-C00156

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCOsolution (30 mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SOand filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).

1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)+.

Example 76 N-tert-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)-benzenesulfonamide (Intermediate 33)

Figure US20070191405A1-20070816-C00142

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd2(dba)(0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was used in the next step without purification. MS (ES+): m/z 355 (M+H)+.

PATENT

https://encrypted.google.com/patents/US20090286789

    Example 90N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benenesulfonamide (Compound LVII)

  • [0308]
    Figure US20090286789A1-20091119-C00143
  • [0309]
    A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in aeetie acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaIICOsolution (30 mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SOand filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).
  • [0310]
    1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)+.

PATENT

WO 2015117053

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015117053&recNum=4&maxRec=26794&office=&prevFilter=&sortOption=&queryString=FP%3A%28%22cancer%22%29+AND+EN_ALL%3Anmr&tab=PCTDescription

References

  1. Jump up^ Pardanani, A.; Hood, J.; Lasho, T.; Levine, R. L.; Martin, M. B.; Noronha, G.; Finke, C.; Mak, C. C.; Mesa, R.; Zhu, H.; Soll, R.; Gilliland, D. G.; Tefferi, A. (2007). “TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations”. Leukemia21 (8): 1658–1668. doi:10.1038/sj.leu.2404750PMID 17541402.
  2. Jump up^ Pardanani, A.; Gotlib, J. R.; Jamieson, C.; Cortes, J. E.; Talpaz, M.; Stone, R. M.; Silverman, M. H.; Gilliland, D. G.; Shorr, J.; Tefferi, A. (2011). “Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis”Journal of Clinical Oncology29 (7): 789–796. doi:10.1200/JCO.2010.32.8021PMC 4979099Freely accessiblePMID 21220608.
  3. Jump up^ “Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies (NASDAQ:CELG)”ir.celgene.com. Retrieved 2018-01-18.

External links

Cited Patent Filing date Publication date Applicant Title
WO2009073575A2 * Nov 28, 2008 Jun 11, 2009 Oregon Health & Science University Methods for treating induced cellular proliferative disorders
US20090088410 * Dec 5, 2008 Apr 2, 2009 Celgene Corporation Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies
US20090286789 * Oct 14, 2008 Nov 19, 2009 Targegen, Inc. Bi-Aryl Meta-Pyrimidine Inhibitors of Kinases
Reference
1 * See also references of EP2635282A4
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US8604042 Aug 24, 2010 Dec 10, 2013 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
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Fedratinib
Fedratinib structure.svg
Names
IUPAC name

Ntert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide
Other names

SAR302503; TG101348
Identifiers
3D model (JSmol)
Properties
C27H36N6O3S
Molar mass 524.68 g·mol−1
Density 1.247 ± 0.06 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

////////////////FEDRATINIB, SAR-302503,  TG-101348, SANOFI, PHASE 3, TG101348,  SAR302503, TG 101348, SAR 302503, Orphan drug designation 

CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4

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Larotrectinib, ларотректиниб , 拉罗替尼 ,


Image result for LarotrectinibImage result for Larotrectinib

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib

ARRY-470, LOXO-101, PF9462I9HX

Molecular Formula: C21H22F2N6O2
Molecular Weight: 428.444 g/mol
(3S)-N-{5-[(2R)-2-(2,5-Difluorphenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidincarboxamid
(S)-N-{5-[(R)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carboxamide
10360
1223403-58-4 [RN]
UNII:PF9462I9HX
ларотректиниб [Russian] [INN]
拉罗替尼 [Chinese] [INN]
(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide
NTRK-fusion solid tumours
TRK inhibitor
orphan drug designation in the U.S
In 2013, Array Biopharma licensed the product to Loxo Oncology for development and commercialization in the U.S. In 2016, breakthrough therapy designation was received in the U.S. for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments. In 2017, Bayer acquired global co-development and commercialization rights from Loxo Oncology.
  • Originator Array BioPharma
  • Developer Array BioPharma; Loxo Oncology; National Cancer Institute (USA)
  • Class Antineoplastics; Pyrazoles; Pyrimidines; Pyrrolidines; Small molecules
  • Mechanism of Action Tropomyosin-related kinase antagonists
  • Orphan Drug Status Yes – Solid tumours; Soft tissue sarcoma

Highest Development Phases

  • Preregistration Solid tumours
  • Phase II Histiocytosis; Non-Hodgkin’s lymphoma
  • Phase I/II CNS cancer
  • Preclinical Precursor cell lymphoblastic leukaemia-lymphoma

Most Recent Events

  • 29 May 2018 FDA assigns PDUFA action date of 26/11/2018 for larotrectinib for Solid tumors
  • 29 May 2018 Larotrectinib receives priority review status for Solid tumors in the US
  • 29 May 2018 The US FDA accepts NDA for larotrectinib for Solid tumours for review

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib sulfate

(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;sulfuric acid

Larotrectinib (LOXO-101) sulfate is an oral potent and selective ATP-competitive inhibitor of tropomyosin receptor kinases (TRK).

    • Crystalline Form (I-HS) OF

SULFATE SALT REPORTED IN https://patents.google.com/patent/US20170165267

nmr  http://file.selleckchem.com/downloads/nmr/s796001-loxo-101-methanol-hnmr-selleck.pdf

Figure US20170165267A1-20170615-C00006Figure US20170165267A1-20170615-C00007

Molecular Weight 526.51
Formula C21H22F2N6O2.H2O4S
CAS No. 1223405-08-0
  1. LOXO-101 sulfate
  2. Larotrectinib sulfate
  3. LOXO-101 (sulfate)
  4. 1223405-08-0
  5. UNII-RDF76R62ID
  6. RDF76R62ID
  7. ARRY-470 sulfate
  8. LOXO-101(sulfate)
  9. Larotrectinib sulfate [USAN]
  10. PXHANKVTFWSDSG-QLOBERJESA-N
  11. HY-12866A
  12. s7960
  13. AKOS030526332
  14. CS-5314

LOXO-101 is a small molecule that was designed to block the ATP binding site of the TRK family of receptors, with 2 to 20 nM cellular potency against the TRKA, TRKB, and TRKC kinases. IC50 value: 2 – 20 nM Target: TRKA/B/C in vitro: LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. LOXO-101 is evaluated for off-target kinase enzyme inhibition against a panel of 226 non-TRK kinases at a compound concentration of 1,000 nM and ATP concentrations near the Km for each enzyme. In the panel, LOXO-101 demonstrates greater than 50% inhibition for only one non-TRK kinase (TNK2 IC50, 576 nM). Measurement of proliferation following treatment with LOXO-101 demonstrates a dose-dependent inhibition of cell proliferation in all three cell lines. The IC50 is less than 100 nM for CUTO-3.29 and less than 10 nM for KM12 and MO-91, consistent with the known potency of this drug for the TRK kinase family. [1] LOXO-101 demonstrates potent and highly-selective inhibition of TRKA, TRKB, and TRKC over other kinase- and non-kinase targets. LOXO-101 is a potent, ATP-competitive TRK inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members in binding and cellular assays, with 100x selectivity over other kinases. [2] in vivo: Athymic nude mice injected with KM12 cells are treated with LOXO-101 orally daily for 2 weeks. Dose-dependent tumor inhibition is observed, demonstrating the ability of this selective compound to inhibit tumor growth in vivo. [1]

Image result for Larotrectinib

DOI

https://doi.org/10.1038/nrd.2018.4

SYNTHESIS

WO 2010048314

Synthesis of larotrectinib

N-Boc-pyrrolidine as starting material The method involves enantioselective deprotonation, transmetalation with ZnCl2, Negishi coupling with 2-bromo-1,4-difluorobenzene,

N-arylation with 5-chloropyrazolo[1,5-a]pyrimidine, nitration, nitro reduction and condensation with CDI and 3(S)-pyrrolidinol.

PRODUCT Patent

WO 2010048314

https://patents.google.com/patent/WO2010048314A1

InventorJulia HaasSteven W. AndrewsYutong JiangGan Zhang

Original AssigneeArray Biopharma Inc.

Priority date 2008-10-22

Example 14


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide

[00423] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difiuorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (17 mg, 0.19 mmol) [purchased from Suven Life Sciences] was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (30 mg, 74% yield). MS (apci) m/z = 429.2 (M+H).

Example 14A


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolori,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide sulfate

[00424] To a solution of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-3 -hydroxypyrrolidine- 1 -carboxamide (4.5 mg, 0.011 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in MeOH (105 μL, 0.011 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3 -hydroxypyrrolidine- 1 -carboxamide sulfate (5.2 mg, 0.0099 mmol, 94 % yield) as a yellow solid.

PATENT

WO 2017201241 

Examples

Preparation of 10:

1)

(R,E)-N-(2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (17): Compound 16 and (R)-2-methylpropane-2-sulfinamide (1.05 eq.) were charged to a reactor outfitted with a mechanical stirrer, reflux condensor, J-Kem temperature probe under N2. DCM (3 mL/g of 14) was added (endothermic from 22 °C to about 5 °C) followed by addition of cesium carbonate (0.70 eq.) (exothermic to -50 °C). Once the addition was complete, the reaction mixture was stirred at room temperature for 3 h (slowly cools from about 40 °C). When the reaction was called complete (HPLC) the mixture was filtered through Celite. The Celite pad (0.3 wt eq) was equilibrated with DCM (1 mL/g of 16), and the reaction mixture was poured through the pad. The Celite cake was washed with DCM (2 x 1 mL/g), and the filtrate concentrated partially to leave about 0.5 to 1 mL/g DCM remaining. The orange solution was stored at room temperature (generally overnight) and used directly in the next reaction. (100% yield was assumed).

2)

(R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19): To a reactor equipped with overhead stirring, reflux condensor, under

nitrogen, was added magnesium turnings (2.0 eq), and THF (8 mL/g of 17). The mixture was heated to 40 °C. Dibal-H (25% wt in toluene, 0.004 eq) was added to the solution, and the suspension heated at 40 °C for 25 minutes. A solution of 2-(2-bromoethyl)-l,3-dioxane (18) (2 eq) in THF (4.6 mL/g of 17) was added dropwise to the Mg solution via addition funnel. The solution temperature was maintained < 55 °C. The reaction progress was monitored by GC. When the Grignard formation was judged complete, the solution was cooled to -30 °C, and 17 (1.0 eq, in DCM) was added dropwise via addition funnel. The temperature was kept between -30 °C and -20 °C and the reaction was monitored for completion (FIPLC). Once the reaction was called complete, the suspension (IT = -27.7 °C) was vacuum transferred to a prepared and cooled (10 °C) 10% aqueous citric acid solution (11 mL/g of 17). The mixture temperature rose to 20 °C during transfer. The milky solution was allowed to stir at ambient temperature overnight. MTBE (5.8 mL/g) was added to the mixture, and it was transferred to a separatory funnel. The layers were allowed to separate, and the lower aqueous layer was removed. The organic layer was washed with sat. NaHC03 (11 mL/g) and then sat. NaCl (5.4 mL/g). The organic layer was removed and concentrated to minimum volume via vacuum distillation. MTBE (2 mL/g) was added, and the mixture again concentrated to minimum volume. Finally MTBE was added to give 2 mL/g total MTBE (GC ratio of MTBE:THF was about 9: 1), and the MTBE mixture was heated to 50 °C until full dissolution occurred. The MTBE solution was allowed to cool to about 35 °C, and heptane was added portion -wise. The first portion (2 mL/g) is added, and the mixture allowed to stir and form a solid for 1-2 h, and then the remainder of the heptane is added (8 mL/g). The suspension was allowed to stir for >lh. The solids were collected via filtration through polypropylene filter cloth (PPFC) and washed with 10% MTBE in heptane (4 mL/g. The wet solid was placed in trays and dried in a vacuum oven at 55 °C until constant weight (3101 g, 80.5%, dense white solid, 100a% and 100wt%).

3)

(R)-2-(2,5-difluorophenyl)pyrrolidine (R)-2-hydroxysuccinate (10): To a flask containing 4: 1 TFA:water (2.5 mL/g, pre-mixed and cooled to <35 °C before adding 19) was added (R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19) (1 eq). The mixture temperature rose from 34 °C to 48 °C and was stirred at ambient temperature for 1 h. Additional TFA (7.5 mL/g) was added, followed by triethylsilane (3 eq) over 5 minutes. The biphasic mixture was stirred vigorously under nitrogen for 21 h until judged complete (by GC, <5% of imine). The mixture was then concentrated under vacuum until -10 kg target mass (observed 10.8 kg after concentration). The resulting concentrate was transferred to a separatory funnel and diluted with MTBE (7.5 mL/g), followed by water (7.5 mL/g). The layers were separated. The MTBE layer was back-extracted with 1M HC1 (3 mL/g). The layers were separated, and the aqueous layers were combined in a round-bottomed flask with DCM (8 mL/g). The mixture was cooled in an ice bath and 40% NaOH was charged to adjust the pH to >12 (about 0.5 mL/g; the temperature went from 24 °C to 27 °C, actual pH was 13), and the layers separated in the separatory funnel. The aqueous layer was back-extracted twice with DCM (2 x 4 mL/g). The organic layers were concentrated to an oil (<0.5 mL/g) under vacuum (rotovap) and EtOH (1 mL/g based on product) was added. The yellow solution was again concentrated to an oil (81% corrected yield, with 3% EtOH, 0.2% imine and Chiral HPLC showed 99.7%ee).

Salt formation: To a solution of (R)-2-(2,5-difluorophenyl)pyrrolidine 10 (1 eq) in EtOH (15 mL/g) was added Z)-(+)-Malic Acid (1 eq). The suspension was heated to 70 °C for 30 minutes (full dissolution had occurred before 70 °C was reached), and then allowed to cool to room temperature slowly (mixture was seeded when the temperature was < 40 °C). The slurry was stirred at room temperature overnight, then cooled to <5 °C the next morning. The suspension was stirred at <5 °C for 2h, filtered (PPFC), washed with cold EtOH (2 x 2 mL/g), and dried (50-55 °C) under vacuum to give the product as a white solid (96% based on 91% potency, product is an EtOH solvate or hemi- solvate).

Preparation of the compound of Formula I:

1)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3-nitropyrazolo[l,5-a]pyrimidine (11):

Compound 5 and 10 (1.05 eq) were charged to a reactor outfitted with a mechanical stirrer, J-Kem temperature probe, under N2. EtOH and THF (4: 1, 10 mL/g of 5) were added and the mixture was cooled to 15-25 °C. Triethylamine (3.5 eq) was added and the internal temp generally rose from 17.3 – 37.8 °C. The reaction was heated to 50 – 60 °C and held at that temperature for 7 h. Once the reaction is judged complete (HPLC), water (12 mL/g of 5) is added maintaining the temperature at 50 – 60 °C. The heat is removed and the suspension was slowly cooled to 21 °C over two h. After stirring at -21 °C for 2 h, the suspension was centrifuged and the cake was washed with water (3 x 3 mL/g of 5). The solid was transferred to drying trays and placed in a vacuum oven at 50 – 55 °C to give 11.

2)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine fumarate Pt/C hydrogenation (12 fumarate): To a Parr reactor was charged 11 (1.0 eq), 5% Pt/C ~ 50 wt% water (2 mol% Pt / Johnson Matthey B 103018-5 or Sigma Aldrich 33015-9), and MeOH (8 mL/g). The suspension was stirred under hydrogen at 25-30 psi and the temperature was maintained below 65 °C for ~8 h. When the reaction was called complete (HPLC), the reaction was cooled to 15 – 25 °C and the hydrogen atmosphere was replaced with a nitrogen atmosphere. The reaction mixture was filtered through a 2 micron bag filter and a 0.2 micron line filter in series. The filtrate from the Pt/C hydrogenation was transferred to a reactor under nitrogen with mechanical stirring and then MTBE (8 mL/g) and fumaric acid (1.01 eq) were charged. The mixture was stirred under nitrogen for 1 h and solids formed after -15 min. The mixture was cooled to -10 to -20 °C and stirred for 3 h. The suspension was filtered (PPFC), washed with MTBE (-2.5 mL/g), and the solids was dried under vacuum at 20-25 °C with a nitrogen bleed to yield an off-white solid (83% yield).

3)

Phenyl (5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3,3a-dihydropyrazolo[l,5-a]pyrimidin-3-yl)carbamate (13): To a 5 to 15°C solution of 12-fumarate (1.0 eq) in 2-MeTHF (15 mL/g) was added a solution of potassium carbonate (2.0 eq.) in water (5 mL/g) followed by phenyl chloroformate (1.22 eq.) (over 22 min, an exotherm from 7 °C to 11 °C occurred). The mixture was stirred for 2 h and then the reaction was called complete (HPLC). The stirring ceased and the aqueous layer was removed. The organic layer was washed with brine (5 mL/g) and concentrated to ca. 5 mL/g of 2-MeTHF under vacuum and with heating to 40 °C. To the 2-MeTHF solution was added heptanes (2.5 mL/g) followed by seeds (20 mg, 0.1 wt%). This mixture was allowed to stir at room temperature for 2 h (until a solid formed), and then the remainder of the heptanes (12.5 mL/g) was added. The mixture was stirred at ambient temperature for 2 h and then the solids were collected via filtration (PPFC), washed with 4: 1 heptanes :MeTHF (2 x 2 mL/g), and dried to give 13 (96%).

4)

(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate: To a flask containing 13 (1.0 eq) was added a solution of (S)-pyrrolidin-3-ol (1.1 eq.) in EtOH (10 mL/g). The mixture was heated at 50 – 60 °C for 5 h, called complete (HPLC), and then cooled to 20-35 °C. Once <35°C, the reaction was polish-filtered (0.2 micron) into a clean reaction vessel and the mixture was cooled to -5 to 5 °C. Sulfuric acid (1.0 eq.) was added over 40 minutes, the temperature rose to 2 °C and the mixture was seeded. A solid formed, and the mixture was allowed to stir at -5 to 5 °C for 6.5 h. Heptanes (10 mL/g) was added, and the mixture stirred for 6.5 h. The

suspension was filtered (PPFC), washed with 1 : 1 EtOH:heptanes (2 x 2 mL/g), and dried (under vacuum at ambient temperature) to give Formula I (92.3%).

Preparation of the hydrogen sulfate salt of the compound of Formula I:

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)-N-(5- ((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (,S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1 : 1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5 :95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5 :95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate.

PATENT

US2017165267

https://patents.google.com/patent/US20170165267

Provided herein is a novel crystalline form of the compound of Formula I:

[0000]

Figure US20170165267A1-20170615-C00001

also known as (S)—N-(5-((R)-2-(2, 5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. In particular, the novel crystalline form comprises the hydrogen sulfate salt of the compound of Formula I in a stable polymorph form, hereinafter referred to as crystalline form (I-HS) and LOXO-101, which can be characterized, for example, by its X-ray diffraction pattern—the crystalline form (I-HS) having the formula:

[0000]

Figure US20170165267A1-20170615-C00002

In some embodiments of the above step (c), the base is an alkali metal base, such as an alkali metal carbonate, such as potassium carbonate.

Figure US20170165267A1-20170615-C00004

Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine Step A—Preparation of sodium pyrazolo[1,5-a]pyrimidin-5-olate

A solution of 1H-pyrazol-5-amine and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOH under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wt % solution in EtOH), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOH. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1.5 area % of 1H-pyrazol-5-amine was observed by TRK1PM1 HPLC to follow the progression of the reaction using 20 μL of slurry diluted in 4 mL deionized water and 5 μL injection at 220 nm.

After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mL/g) of heptane and then refluxed at 70° Celsius for 1 hour. The slurry was then cooled to room temperature overnight. The solid was collected by filtration on a tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4 mL/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[1,5-a]-pyrimidin-5-olate was obtained in 93-96% yield (corrected) and larger than 99.5 area % observed by HPLC (1 mg/mL dilution in deionized water, TRK1PM1 at 220 nm).

Step B—Preparation of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one

A tared round bottom flask was charged with sodium pyrazolo[1,5-a]pyrimidin-5-olate that was dissolved at 40-45° Celsius in 3.0 vol. (3.0 mL/g) of deionized water, and then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g deionized water content). Gas chromatography (GC) for residual EtOH (30 μL of solution dissolved in ˜1 mL MeOH) was performed showing less than 100 ppm with traces of ethyl nitrate fumes being observed below upon later addition of HNO3. In some cases, the original solution was charged with an additional 1.5 vol. (1.5 mL/g) of DI water, then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g DI water content). Gas chromatograph for residual EtOH (30 μL of solution dissolved in about 1 mL MeOH) was performed showing <<100 ppm of residual EtOH without observing any ethyl nitrate fumes below upon later addition of HNO3.

A round bottom vessel outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control was charged with 3 vol. (3 mL/g, 10 equiv) of >90 wt % HNOand cooled to about 10° Celsius under a nitrogen atmosphere using external ice-water cooling bath under a nitrogen atmosphere. Using a pressure equalizing addition funnel, the HNO3solution was charged with the 1.75-1.95 volumes of a deionized water solution of sodium pyrazolo[1,5-a]pyrimidin-5-olate (1.16-1.4 mL DI water/g of sodium pyrazolo[1,5-a]pyrimidin-5-olate) at a rate to maintain 35-40° Celsius internal temperature under cooling. Two azeotropes were observed without any ethyl nitrate fumes. The azeotrope flask, the transfer line (if applicable) and the addition funnel were rinsed with 2×0.1 vol. (2×0.1 mL/g) deionized water added to the reaction mixture. Once the addition was complete, the temperature was gradually increased to about 45-50° Celsius for about 3 hours with HPLC showing >99.5 area % conversion of sodium pyrazolo[1,5-a]pyrimidin-5-olate to 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one.

Step C—Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine

3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one was charged to a round bottom flask outfitted with a mechanical stirrer, a heating mantle, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive N2pressure control. Under mechanical stirring the solids were suspended with 8 volumes (8 mL/g) of CH3CN, and then charged with 2,6-lutitine (1.05 equiv) followed by warming the slurry to about 50° Celsius. Using a pressure equalizing addition funnel, the mixture was dropwise charged with 0.33 equivalents of POCl3. This charge yielded a thick, beige slurry of a trimer that was homogenized while stirring until a semi-mobile mass was observed. An additional 1.67 equivalents of POClwas charged to the mixture while allowing the temperature to stabilize, followed by warming the reaction mixture to a gentle reflux (78° Celsius). Some puffing was observed upon warming the mixture that later subsided as the thick slurry got thinner.

The reaction mixture was allowed to reflux until complete dissolution to a dark solution and until HPLC (20 μL diluted in 5 mL of CH3CN, TRK1PM1 HPLC, 5 μL injection, 268 nm) confirmed that no more trimer (RRT 0.92) was present with less than 0.5 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one (RRT 0.79) being observed by manually removing any interfering and early eluting peaks related to lutidine from the area integration. On a 1.9 kg scale, 0 area % of the trimer, 0.25 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one, and 99.5 area % of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine was observed after 19 hours of gentle reflux using TRK1PM1 HPLC at 268 [0000]

Figure US20170165267A1-20170615-C00005

Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate Step A—Preparation of tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate

2-bromo-1,4-difluorobenzene (1.5 eq.) was dissolved in 4 volumes of THF (based on weight of tert-butyl 2-oxopyrrolidine-1-carboxylate) and cooled to about 5° Celsius. A solution of 2.0 M iPrMgCl in THF (1.4 eq.) was added over 2 hours to the mixture while maintaining a reaction temperature below 25° Celsius. The solution was allowed to cool to about 5° Celsius and stirred for 1 hour (GC analysis confirmed Grignard formation). A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.0 eq.) in 1 volume of THF was added over about 30 min while maintaining a reaction temperature below 25° Celsius. The reaction was stirred at about 5° Celsius for 90 min (tert-butyl 2-oxopyrrolidine-1-carboxylate was confirmed to be less than 0.5 area % by HPLC). The reaction was quenched with 5 volumes of 2 M aqueous HCl while maintaining a reaction temperature below 45° Celsius. The reaction was then transferred to a separatory funnel adding 10 volumes of heptane and removing the aqueous layer. The organic layer was washed with 4 volumes of saturated aqueous NaCl followed by addition of 2×1 volume of saturated aqueous NaCl. The organic layer was solvent-switched to heptane (<1% wt THF confirmed by GC) at a distillation temperature of 35-55° Celsius and distillation pressure of 100-200 mm Hg for 2×4 volumes of heptane being added with a minimum distillation volume of about 7 volumes. The mixture was then diluted to 10 volumes with heptane while heating to about 55° Celsius yielded a denser solid with the mixture being allowed to cool to room temperature overnight. The slurry was cooled to less than 5° Celsius and filtered through polypropylene filter cloth. The wet cake was washed with 2×2 volumes of heptane. The solids were dried under vacuum at 55° Celsius until the weight was constant, yielding tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate as a white solid at about 75% to 85% theoretical yield.

Step B—Preparation of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole

tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate was dissolved in 5 vol. of toluene with 2.2 eq. of 12M HCl being added observing a mild exotherm and gas evolution. The reaction was heated to 65° Celsius for 12-24 hours and monitored by HPLC. Upon completion the reaction was cooled to less than 15° Celsius with an ice/water bath. The pH was adjusted to about 14 with 3 equivalents of 2M aqueous NaOH (4.7 vol.). The reaction was stirred at room temperature for 1-2 hours. The mixture was transferred to a separatory funnel with toluene. The aqueous layer was removed and the organic layer was washed with 3 volumes of saturated aqueous NaCl. The organic layer was concentrated to an oil and redissolved in 1.5 volumes of heptane. The resulting suspension was filtered through a GF/F filter paper and concentrated to a light yellow oil of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole with a 90% to 100% theoretical yield.

Step C—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine

Chloro-1,5-cyclooctadiene iridium dimer (0.2 mol %) and (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole (0.4 mol %) were suspended in 5 volumes of MTBE (based on 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole) at room temperature. The mixture was stirred for 1 hour and most of the solids dissolved with the solution turning dark red. The catalyst formation was monitored using an HPLC/PDA detector. The reaction was cooled to less than 5° Celsius and 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (1.0 eq.) was added using a 0.5 volumes of MTBE rinse. Diphenylsilane (1.5 eq.) was added over about 20 minutes while maintaining a reaction temperature below 10° Celsius. The reaction was stirred for 30 minutes below 10° Celsius and then allowed to warm to room temperature. The reaction was stirred overnight at room temperature. The completion of the reaction was confirmed by HPLC and then cooled to less than 5° Celsius. The reaction was quenched with 5 volumes of 2M aqueous HCl maintaining temperature below 20° Celsius. After 10 minutes the ice/water bath was removed and the reaction temperature was allowed to increase to room temperature while stirring for 2 hours. The mixture was transferred to a separatory funnel with 3 volumes of MTBE. The aqueous layer was washed with 3.5 volumes of MTBE followed by addition of 5 volumes of MTBE to the aqueous layer while adjusting the pH to about 14 by adding 0.75 volumes of aqueous 50% NaOH. The organic layer was washed with 5 volumes of aqueous saturated NaCl, then concentrated to an oil, and diluted with 3 volumes of MTBE. The solution was filtered through a polypropylene filter cloth and rinsed with 1 volume of MTBE. The filtrate was concentrated to an oil of (R)-2-(2,5-difluorophenyl)-pyrrolidine with a 95% to 100% theoretical yield and with 75-85% ee.

Step D—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate

(R)-2-(2,5-difluorophenyl)-pyrrolidine (1.0 eq.) was transferred to a round bottom flask charged with 15 volumes (corrected for potency) of EtOH (200 prf). D-malic acid (1.05 eq.) was added and the mixture was heated to 65° Celsius. The solids all dissolved at about 64° Celsius. The solution was allowed to cool to RT. At about 55° Celsius the solution was seeded with (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate (about 50 mg, >97% ee) and stirred at room temperature overnight. The suspension was then filtered through a polypropylene filter cloth and washed with 2×1 volumes of EtOH (200 prf). The solids were dried under vacuum at 55° Celsius, yielding (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate with a 75% to 90% theoretical yield and with >96% ee.

Referring to Scheme 1, suitable bases include tertiary amine bases, such as triethylamine, and K2CO3. Suitable solvents include ethanol, heptane and tetrahydrofuran (THF). The reaction is conveniently performed at temperatures between 5° Celsius and 50° Celsius. The reaction progress was generally monitored by HPLC TRK1PM1.

Figure US20170165267A1-20170615-C00006

Figure US20170165267A1-20170615-C00007

[0247]

Compounds II (5-chloro-3-nitropyrazolo[1,5-a]pyrimidine) and III ((R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate, 1.05 eq.) were charged to a round bottom flask outfitted with a mechanical stirrer, a J-Kem temperature probe and an Nadaptor for positive Npressure control. A solution of 4:1 EtOH:THF (10 mL/g of compound II) was added and followed by addition of triethylamine (NEt3, 3.50 eq.) via addition funnel with the temperature reaching about 40° Celsius during addition. Once the addition was complete, the reaction mixture was heated to 50° Celsius and stirred for 0.5-3 hours to yield compound IV.

To a round bottom flask equipped with a mechanical stirrer, a J-Kem temperature probe, and an Ninlet compound IV was added and followed by addition of tetrahydrofuran (10 mL/g of compound IV). The solution was cooled to less than 5° Celsius in an ice bath, and Zn (9-10 eq.) was added. 6M HCl (9-10 eq.) was then added dropwise at such a rate to keep the temperature below 30° Celsius (for 1 kg scale the addition took about 1.5 hours). Once the exotherm subsided, the reaction was allowed to warm to room temperature and was stirred for 30-60 min until compound IV was not detected by HPLC. At this time, a solution of potassium carbonate (K2CO3, 2.0 eq.) in water (5 mL/g of compound IV) was added all at once and followed by rapid dropwise addition of phenyl chloroformate (PhOCOCl, 1.2 eq.). Gas evolution (CO2) was observed during both of the above additions, and the temperature increased to about 30° Celsius after adding phenyl chloroformate. The carbamate formation was stirred at room temperature for 30-90 min. HPLC analysis immediately followed to run to ensure less than 1 area % for the amine being present and high yield of compound VI in the solution.

To the above solution amine VII ((S)-pyrrolidin-3-ol, 1.1 eq. based on theoretical yield for compound VI) and EtOH (10 mL/g of compound VI) was added. Compound VII was added before or at the same time as EtOH to avoid ethyl carbamate impurities from forming. The above EtOH solution was concentrated to a minimum volume (4-5 mL/g) using the batch concentrator under reduced pressure (THF levels should be <5% by GC), and EtOH (10 mL/g of compound VI) was back-added to give a total of 10 mL/g. The reaction was then heated at 50° Celsius for 9-19 hours or until HPLC shows that compound VI is less than 0.5 area %. The reaction was then cooled to room temperature, and sulfuric acid (H2SO4, 1.0 eq. to compound VI) was added via addition funnel to yield compound I-HS with the temperature usually exotherming at about 30° Celsius.

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

PATENT

CN 107987082

PATENT

https://patents.google.com/patent/US20170281632A1/en

WO 2010/048314 discloses in Example 14A a hydrogen sulfate salt of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. WO 2010/048314 does not disclose the particular form of the hydrogen sulfate salt described herein when prepared according to the method of Example 14A in that document. In particular, WO 2010/048314 does not disclose crystalline form (l-HS) as described below.

(S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I):

Figure US20170281632A1-20171005-C00001

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidi n-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1, 5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

References

External links

Larotrectinib
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US8865698 Method of treatment using substituted pyrazolo[1, 5-a]pyrimidine compounds
2013-07-16
2014-10-21
US8513263 Substituted Pyrazolo[1, 5-a]Pyrimidine Compounds as TRK Kinase Inhibitors
2011-08-11
US2017165267 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
2017-01-05
US2017260589 POINT MUTATIONS IN TRK INHIBITOR-RESISTANT CANCER AND METHODS RELATING TO THE SAME
2016-10-26
US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
2015-09-04
2016-08-11
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US9447104 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-a]PYRIMIDINE COMPOUNDS
2014-09-18
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US9127013 Method of treatment using substituted pyrazolo[1, 5-a] pyrimidine compounds
2015-01-14
2015-09-08
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US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
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US2015073036 NOVEL NTRK1 FUSION MOLECULES AND USES THEREOF
2014-08-29
2015-03-12
US2017114067 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
2017-01-05
US2016137654 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
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2016-05-19
US2015133429 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-a] PYRIMIDINE COMPOUNDS
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US2015366866 METHODS OF TREATING CHOLANGIOCARCINOMA
2014-01-17
2015-12-24
US8865698 Method of treatment using substituted pyrazolo[1, 5-a]pyrimidine compounds
2013-07-16
2014-10-21
US8513263 Substituted Pyrazolo[1, 5-a]Pyrimidine Compounds as TRK Kinase Inhibitors
2011-08-11
US2017165267 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
2017-01-05
US2017260589 POINT MUTATIONS IN TRK INHIBITOR-RESISTANT CANCER AND METHODS RELATING TO THE SAME
2016-10-26

///////////Larotrectinib, UNII:PF9462I9HX, ларотректиниб , 拉罗替尼 , ARRY-470, LOXO-101, PF9462I9HX, phase 3,  Array BioPharma, Loxo Oncology, National Cancer Institute, BAYER, orphan drug designation, breakthrough therapy designation

C1CC(N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CCC(C4)O)C5=C(C=CC(=C5)F)F.OS(=O)(=O)O

RG 7604,Taselisib


Taselisib skeletal.svgChemSpider 2D Image | Taselisib | C24H28N8O2  Taselisib.png

  • Molecular FormulaC24H28N8O2
  • Average mass460.531 Da

RG7604,Taselisib

GDC-0032, GDC0032;GDC 0032, RO5537381

1282512-48-4 [RN]
1H-Pyrazole-1-acetamide, 4-[5,6-dihydro-2-[3-methyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-d][1,4]benzoxazepin-9-yl]-α,α-dimethyl-
UNII:L08J2O299M
10.1021/jm4003632
2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide
POLYMORPHS almost A to Z, US9266903
Taselisib (GDC-0032) is an experimental cancer drug in development by Roche. Molecule is a complex heterocycle with no chiral centres, hazardous materials are used in synthesis, preparation of impurities is a challenge. Taselisib is in phase III with Roche , clinical trials for treatment of metastatic breast cancer and non-small cell lung cancer

Taselisib (GDC-0032) is an experimental cancer drug in development by Roche. It is a small molecule inhibitor targeting phosphoinositide 3-kinase subtype PIK3CA.[1]

Taselisib is in phase III with Roche , clinical trials for treatment of metastatic breast cancer and non-small cell lung cancer.[2]

Taselisib is a phosphatidylinositol 3-kinase (PI3Kalpha) inhibitor in phase III clinical studies at Roche for the treatment of postmenopausal women with histologically or cytologically confirmed locally advanced or metastatic estrogen-receptor positive (ER+) breast cancer.

Taselisib is an orally bioavailable inhibitor of the class I phosphatidylinositol 3-kinase (PI3K) alpha isoform (PIK3CA), with potential antineoplastic activity. Taselisib selectively inhibits PIK3CA and its mutant forms in the PI3K/Akt/mTOR pathway, which may result in tumor cell apoptosis and growth inhibition in PIK3CA-expressing tumor cells. By specifically targeting class I PI3K alpha, this agent may be more efficacious and less toxic than pan PI3K inhibitors. Dysregulation of the PI3K/Akt/mTOR pathway is frequently found in solid tumors and causes increased tumor cell growth, survival, and resistance to both chemotherapy and radiotherapy. PIK3CA, which encodes the p110-alpha catalytic subunit of the class I PI3K, is mutated in a variety of cancer cell types and plays a key role in cancer cell growth and invasion.

str1

PRODUCT PATENT

WO 2011036280

Inventors Nicole BlaquiereSteven DoDanette DudleyAdrian J. FolkesRobert HealdTimothy HeffronMark JonesAleksandr KolesnikovChudi NdubakuAlan G. OliveroStephen PriceSteven StabenLan WangLess «
Applicant F. Hoffmann-La Roche Ag

https://encrypted.google.com/patents/WO2011036280A1?cl=en

Discovery of 2-(3-(2-(1-Isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (GDC-0032): A -sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity
J Med Chem 2013, 56(11): 4597

Condensation of 4-bromo-2-hydroxybenzaldehyde  with glyoxal  in the presence of NH3 in MeOH gives 5-bromo-2-(1H-imidazol-2-yl)phenol

Which upon annulation with 1,2-dibromoethane  in the presence of Cs2CO3 in DMF at 90 °C yields 9-bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine .

Iodination of oxazepine  with NIS in DMF provides 9-bromo-2,3-diiodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine,

Which upon mono-deiodination by means of EtMgBr in THF at -15 °C affords 9-bromo-2-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine .

Amidation of iodide  with CO in the presence of PdCl2(PPh3)2 and HMDS in DMF at 70 °C produces the intermediate,

Which upon reaction with N,N-dimethylacetamide dimethyl acetal  in the presence of DME at 65 °C furnishes intermediate . Intramolecular cyclization of this compound with isopropylamine hydrochloride  in AcOH generates triazole derivative,

Which upon Suzuki coupling with dioxaborolane derivative in the presence of Pd(PPh3)4 and KOAc in CH3CN/H2O at 120 °C yields the target compound Taselisib.

Genentech BioOncology® logo

Taselisib has been used in trials studying the treatment and basic science of LYMPHOMA, Breast Cancer, Ovarian Cancer, Solid Neoplasm, and HER2/Neu Negative, among others.

Solubility (25°C)

In vitro DMSO 70 mg/mL warmed (151.99 mM)
Water Insoluble
Ethanol Insoluble warmed

Biological Activity

Description Taselisib (GDC 0032) is a potent, next-generation β isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with Ki of 0.29 nM/0.12 nM/0.97nM, >10 fold selective over PI3Kβ.
Features A beta isoform-sparing PI3K inhibitor.
Targets
PI3Kδ [1]
(Cell-free assay)
PI3Kα [1]
(Cell-free assay)
PI3Kγ [1]
(Cell-free assay)
PI3Kβ [1]
(Cell-free assay)
C2β [1]
(Cell-free assay)
View More
0.12 nM(Ki) 0.29 nM(Ki) 0.97 nM(Ki) 9.1 nM(Ki) 292 nM
In vitro GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3Kα, δ, and γ isoforms, with 30 fold less inhibition of the PI3K β isoform relative to the PI3Kα isoform. Preclinical data show that GDC-0032 has increased activity against PI3Kα isoform (PIK3CA) mutant and HER2-amplified cancer cell lines. GDC-0032 inhibits MCF7-neo/HER2 cells proliferation with IC50 of 2.5 nM. [1]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human MOLM16 cells Proliferation assay 72 h Antiproliferative activity against human MOLM16 cells after 72 hrs by Cell Titer-Blue assay 22727640
In vivo GDC-0032 pharmacokinetics is approximately dose proportional and time independent with a mean t1/2 of 40 hours. The combination of GDC-0032 enhances activity of fulvestrant resulting in tumor regressions and tumor growth delay (91% tumor growth inhibition (TGI)). In addition, the combination of GDC-0032 with tamoxifen enhances the efficacy of tamoxifen in vivo (102%TGI for GDC-0032). [1]

PATENT

WO 2014140073

The invention relates to methods of making the PI3K inhibitor I (GDC-0032), named as 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanamide, having the structure:

Figure imgf000003_0001

and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.

Another aspect of the invention includes novel intermediates useful for preparing GDC- 0032 and having the structures:

Figure imgf000003_0002
Figure imgf000004_0001
Figure imgf000005_0001

The following Schemes 1-15 illustrate the chemical reactions, processes, methodology for the synthesis of GDC-0032, Formula I, and certain intermediates and reagents. Scheme 1:

Figure imgf000010_0001
Figure imgf000010_0002

Scheme 1 shows the synthesis of intermediate isopropylhydrazine hydrochloride 4 from Boc-hydrazine 1. Condensation of 1 with acetone and magnesium sulfate gave Boc-hydrazone, tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (Example 1). Palladium-catalyzed hydrogenation of 2 in acetic acid and methanol gave Boc-isopropyl-hydrazine 3 (Example 2) which was treated in situ with hydrogen chloride gas to give 4 (Example 3).

Alternatively, the double bond of 2 can be reduced with a hydride reagent such as sodium cyanoborohydride (Example 2).

Scheme 2:

Figure imgf000010_0003

Scheme 2 shows the synthesis of l-isopropyl-3-methyl-lH-l,2,4-triazole 7 from methyl acetimidate hydrochloride 5 and isopropylhydrazine hydrochloride 4. Reaction of 5 and 4 in triethylamine and methanol followed by cyclization of condensation product, N’- isopropylacetohydrazonamide 6 (Example 4) with triethyl orthoformate (triethoxymethane) gave 7 (Example 5). Alternatively, 4 and acetamidine can be reacted to give 6.

Or, 4 can be reacted with acetonitrile and an acid to form the corresponding salt of 6. Scheme 3:

Figure imgf000011_0001

0 K2C03, H20, MTBE w

Scheme 3 shows the synthesis of intermediate, 2-chloro-N-methoxy-N-methylacetamide 10. Reaction of 2-chloroacetyl chloride 8 and Ν,Ο-dimethylhydroxylamine hydrochloride 9 in aqueous potassium carbonate and methyl, tert-butyl ether (MTBE) gave 10 (Example 6).

Scheme 4:

Figure imgf000011_0002

Scheme 4 shows the synthesis of intermediate 4-bromo-2-fluorobenzimidamide hydrochloride 12 formed by reaction of 4-bromo-2-fluorobenzonitrile 11 with lithium hexamethyldisilazide (LiHMDS) in tetrahydrofuran (Example 7). Alternatively, 11 is treated with hydrogen chloride in an alcohol, such as ethanol, to form the imidate, ethyl 4-bromo-2- fluorobenzimidate hydrochloride, followed by ammonia in an alcohol, such as ethanol, to form 12 (Example 7).

Scheme 5:

Figure imgf000012_0001

Scheme 5 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole V from l-isopropyl-3-methyl-lH-l,2,4-triazole 7.

Deprotonation of 7 with n-butyllithium and acylation with 2-chloro-N-methoxy-N- methylacetamide 10 gave intermediate 2-chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)ethanone 13 (Example 8). Cyclization of 13 with 4-bromo-2-fluorobenzimidamide hydrochloride 12 and potassium hydrogen carbonate in water and THF (tetrahydrofuran) formed the imidazole V (Example 9).

Scheme 6:

Figure imgf000012_0002

Scheme 6 shows the synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from V. Alkylation of the imidazole nitrogen of V with a 2-hydroxyethylation reagent such as, l,3-dioxolan-2-one, gave 2-(2-(4- bromo-2-fluorophenyl)-4-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5 -yl)- 1 H-imidazol- 1 – yl)ethanol 14 (Example 10). Cyclization of 14 with an aqueous basic reagent, such as methyltributylammonium chloride in aqueous potassium hydroxide, gave III, which can be cystallized from ethanol and water (Example 11). Scheme 7:

Figure imgf000013_0001

IV

Scheme 7 shows the synthesis of ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate IV starting from 2-bromo-2-methylpropanoic acid 15. Alkylation of pyrazole with 15 gave 2- methyl-2-(lH-pyrazol-l-yl)propanoic acid 16 (Example 12). Esterification of 16 with sulfuric acid in ethanol gave ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 (Example 13).

Regiospecific bromination of 17 with N-bromosuccinimide (NBS) gave IV (Example 14). Alternatively, 16 was treated in situ with a brominating reagent such as l,3-dibromo-5,5- dimethylhydantoin (DBDMH) to give 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoic acid which was esterified to give IV, where R is ethyl. Other esters can also be prepared, such as methyl, iso-propyl, or any alkyl, benzyl or aryl ester.

Scheme 8:

Figure imgf000014_0001

Scheme 8 shows an alternative synthesis of ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2- methylpropanoate IV starting from ethyl 2-bromo-2-methylpropanoate 18. Alkylation of pyrazole with 18 in the presence of a base such as sodium tert-butyloxide or cesium carbonate gave a mixture of ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 and ethyl 2-methyl-3-(lH- pyrazol-l-yl)propanoate 19. Bromination of the mixture with l,3-dibromo-5,5- dimethylimidazolidine-2,4-dione (DBDMH) gave a mixture containing IV, ethyl 3-(4-bromo- lH-pyrazol-l-yl)-2-methylpropanoate 20, and 4-bromo-lH-pyrazole 21 which was treated with a strong base under anhydrous conditions, such as lithium hexamethyldisilazide in tetrahydrofuran. Acidification with hydrochloric acid gave IV.

Scheme 9:

Pd(O) catalyst

Figure imgf000015_0001

KOAc, EtOH

Figure imgf000015_0002

Scheme 9 shows the synthesis of 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)- 5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanamide, GDC-0032, 1 from ethyl 2-(4-bromo- 1 H-pyrazol- 1 -yl)-2-methylpropanoate IV (CAS Registry Number: 1040377-17-0, WO 2008/088881) and 9-bromo-2-(l-isopropyl-3-methyl-lH- 1,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III (CAS Registry Number: 1282514-63-9, US 2012/0245144, US 8242104). Other esters besides ethyl can also be used which can be hydrolyzed with aqueous base, such as methyl, iso-propyl, or any alkyl, benzyl or aryl ester. In a one-pot Miyaura Borylation /Suzuki, Buchwald system, ethyl 2-(4-bromo-lH- pyrazol-l-yl)-2-methylpropanoate IV is reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l,3,2- dioxaborolane), CAS Reg. No. 73183-34-3, also referred to as B2Pin2, and a palladium catalyst such as XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, CAS Reg. No. 564483- 18-7), with a salt such as potassium acetate, in a solvent such as ethanol, at about 75 °C to form the intermediate ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol- l-yl)propanoate 22 (Example 15, CAS Registry Number: 1201657-32-0, US 8242104, US 8263633, WO 2009/150240).

Figure imgf000016_0001

XPhos ligandIntermediate 22 can be isolated or reacted in situ (one pot) with III to form 23.

A variety of low valent, Pd(II) and Pd(0) palladium catalysts can be used during the Suzuki coupling step to form 23 (Example 16) from 22 and III, including PdCl2(PPh3)2, Pd(t- Bu)3, PdCl2 dppf CH2C12, Pd(PPh3)4, Pd(OAc)/PPh3, Cl2Pd[(Pet3)]2, Pd(DIPHOS)2, Cl2Pd(Bipy), [PdCl(Ph2PCH2PPh2)]2, Cl2Pd[P(o-tol)3]2, Pd2(dba)3/P(o-tol)3, Pd2(dba)/P(furyl)3,

Cl2Pd[P(furyl)3]2, Cl2Pd(PMePh2)2, Cl2Pd[P(4-F-Ph)3]2, Cl2Pd[P(C6F6)3]2, Cl2Pd[P(2-COOH- Ph)(Ph)2]2, Cl2Pd[P(4-COOH-Ph)(Ph)2]2, and encapsulated catalysts Pd EnCat™ 30, Pd EnCat™ TPP30, and Pd(II)EnCat™ BINAP30 (US 2004/0254066).

The ester group of 23 is saponified with an aqueous basic reagent such as lithium hydroxide, to give 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoic acid II (Example 17). Intermediate 23 can be isolated or further reacted in situ with the aqueous basic reagent to form II. The carboxylic acid group of II is activated with an acyl activating reagent such as di(lH-imidazol-l-yl)methanone (carbonyl diimidazole, CDI) or Ν,Ν,Ν’,Ν’-tetramethyl- 0-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (HATU), and then reacted with an alcoholic ammonia reagent, such as ammonia dissolved in methanol, ethanol, or isopropanol, aqueous ammonium hydroxide, aqueous ammonium chloride, or ammonia dissolved in THF, to give I (Example 18).

A variety of solid adsorbent palladium scavengers can be used to remove palladium after the Suzuki coupling step to form compound I. Exemplary embodiments of palladium scavengers include FLORISIL®, SILIABOND®Thiol, and SILIABOND® Thiourea. Other palladium scavengers include silica gel, controlled-pore glass (TosoHaas), and derivatized low crosslinked polystyrene QUADRAPURE™ AEA, QUADRAPURE™ IMDAZ, QUADRAPURE™ MPA, QUADRAPURE™ TU (Reaxa Ltd., Sigma-Aldrich Chemical Co.).

Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003

Scheme 10 shows the synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2- fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2- fluorophenyl)-lH-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2- fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3- dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4- bromo-2-fluorophenyl)-l-(2-hydroxyethyl)-lH-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(l-iminoethyl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2- carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepine III.

Alternatively, 28 can be reacted with N’-isopropylacetohydrazonamide 6 to give III (Scheme 12).

Scheme 11 :

Figure imgf000018_0001

Scheme 11 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l ,2,4-triazole V from 4-bromo-2-fluorobenzimidamide hydrochloride 12. 3-Chloro-2-oxopropanoic acid and 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)- lH-imidazole-4-carboxylic acid 30. Alternatively, 3-bromo-2-oxopropanoic acid can be reacted with 12 to give 30. Reaction of 30 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU (N,N,N’,N’-tetramethyl-0-(lH-benzotriazol-l-yl)uronium hexafluorophosphate, O- (Benzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, CAS Ref. No. 94790- 37-1) in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(l-(2- isopropylhydrazinyl)ethylidene)-lH-imidazole-4-carboxamide 31 which need not be isolated and cyclizes upon heating to give V.

Alternatively, 5-(2-(4-chloro-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl- lH-l,2,4-triazole 44, the chloro version of V, can be prepared from 4-chloro-2-fluorobenzonitrile 38 (Scheme 15) Scheme 12:

Figure imgf000019_0001

Scheme 12 shows an alternative synthesis of 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4- triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III from 4-bromo-2- fluorobenzonitrile 11. Alkylation of 11 with tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2-cyanophenoxy)ethylcarbamate 32. Cyclization of 32 under acidic conditions, such as hydrochloric acid in ethanol, gives 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33. It will be noted that 33 has an alternative tautomeric form where the double bond is inside the oxazepine ring. Formation of the imidazole ring occurs by reaction of 3-bromo-2- oxopropanoic acid (X = Br, R = OH), or other 3-halo-2-oxopropanoic acid or ester (R = alkyl), and 33 to give 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28. Coupling of 28 with N’-isopropylacetohydrazonamide 6 and a coupling reagent such as HBTU, HATU or CDI in DMF gives intermediate, 9-bromo-N-(l-(2-isopropylhydrazinyl)ethylidene)- 5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxamide 34, which need not be isolated and forms 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III upon heating.

Alternatively, N’-isopropylacetohydrazonamide 6 is used as monohydrochloride salt, which has to be set free under the reaction conditions with an appropriate base, such as K2CO3. Scheme 13:

Figure imgf000020_0001

Scheme 13 shows an alternative synthesis of 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin- 5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with sodium methoxide in methanol gives methyl 4-bromo-2-fluorobenzimidate 35. Alkylation of 35 with 2- aminoethanol gives 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33.

Scheme 14:

Figure imgf000020_0002

37

11

Scheme 14 shows another alternative synthesis of 8-bromo-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with 2-aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2- aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with

trimethylaluminum gave 33. Alternatively, other trialkylaluminum reagents can be used, or magnesium alkoxide reagents such as magnesium ethoxide (magnesium bisethoxide, CAS Reg. No. 2414-98-4) to cyclize 37 to 33.

Figure imgf000021_0001
Figure imgf000021_0002

Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39.

Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2- fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-lH- imidazole-4-carboxylic acid 42. Reaction of 42 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(l-(2- isopropylhydrazinyl)ethylidene)-lH-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.

EXAMPLES

Example 1 tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2

To a solution of tert-butyl hydrazinecarboxylate 1 (CAS Reg. No. 870-46-2) (25.1 g, 0.190 mol) in acetone (185 mL) was added the magnesium sulfate (6 g) and 12 drops acetic acid (Wu et al (2012) Jour. Med. Chem. 55(6):2724-2736; WO 2007/056170; Zawadzki et al (2003) Polish Jour. Chem. 77(3):315-319). The mixture was heated to reflux for 2.5 h and cooled to rt and filtered. The filtrate was concentrated to give tert-butyl 2-(propan-2- ylidene)hydrazinecarboxylate 2 (CAS Reg. No. 16689-34-2) as an off-white solid (32 g, 98%) (used in the next step without further purification). LC-MS [M+H]+ = 172.9, RT = 2.11 min. 1H NMR 300 MHz (CDC13) d 7.35 (br s, 1H, NH), 2.04 (s, 3H), 1.82 (s, 3H), 1.54 (s, 9H); 13C NMR 300 MHz (CDC13) d 152.9, 149.7, 80.7, 28.1, 25.3, 15.9. Example 2 tert-butyl 2-isopropylhydrazinecarboxylate 3

tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 was reduced with palladium catalyst on carbon with hydrogen gas in acetic acid and methanol to give tert-butyl 2- isopropylhydrazinecarboxylate 3 (CAS Reg. No. 16689-35-3).

Alternatively, tert-Butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (0.51 g, 3.0 mmol) was dissolved in 20 mL of THF, treated with NaB¾CN (0.19 g, 3.0 mmol) and a few mg of bromocresol green, followed by a solution of p-toluenesulfonic acid (0.57 g, 3.0 mmol) in 1.5 mL of THF which was added dropwise over approximately 1 h to maintain the reaction pH between 3.5-5.0. After stirring at room temperature for an additional hour, the solvent was removed by rotary evaporation, and the residue was partitioned between EtOAc (30 mL) and brine. The organic phase was extracted with sat. NaHCC>3, 20 mL and brine, evaporated to a residue and dissolved in 10 mL of ethanol. The ethanolic solution was treated with 3.6 mL of 1M NaOH solution (3.6 mmol) and left to stir at rt for 30 min. The solvent was removed by rotary evaporation and the residue was taken up into ethyl acetate and extracted with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography using 5 % MeOH in DCM as eluent to collect tert-butyl 2- isopropylhydrazinecarboxylate 3 (0.4 g, 77 % yield): mp = 47-49 °C; Rf = 0.44 (5 % MeOH in DCM); IH NMR 300 MHz (CDC13) d 6.03 (s, N-H, IH), 3.92 (s, N-H, IH), 3.14 (m, IH), 1.46 (s, 9H), 1.02 (d, 6H, J = 6 Hz); 13C NMR 300 MHz (CDC13) d 157.2, 80.8, 51.2, 28.7, 21.0.

Example 3 isopropylhydrazine hydrochloride 4

tert-butyl 2-isopropylhydrazinecarboxylate 3 was treated with hydrochloric acid to remove the Boc protecting group and give 4 (CAS Reg. No. 16726-41-3).

Example 4 N’-isopropylacetohydrazonamide 6

Methyl acetimidate hydrochloride 5 (CAS Reg. No. 14777-27-6), isopropylhydrazine hydrochloride 4, and triethylamine were reacted in methanol to give 6 (CAS Reg. No. 73479-06- 8).

Example 5 l-isopropyl-3 -methyl- lH-l,2,4-triazole 7

N’-isopropylacetohydrazonamide 6 was treated with triethylorthoformate in ethanol, followed by triethylamine and tetrahydrofuran to give 7 (CAS Reg. No. 1401305-30-3). Example 6 2-chloro-N-methoxy-N-methylacetamide 10

To a solution of 21.2 kg potassium carbonate K2CO3 (153.7 mol, 3.0 eq) in 30 L H20 was added, Ν,Ο-dimethylhydroxylamine 9 (CAS Reg. No. 1117-97-1) (5.0 kg, 51.3 mol, 1.0 eq) at 15-20 °C. The reaction was stirred at rt for 30min and 30 L methyl tert-butyl ether (TBME) was added. After stirred for 30min, the mixture was cooled to 5°C, and 11.6 kg of 2-Chloroacetyl chloride 8 (CAS Reg. No. 79-04-9 (102.7 mol, 2.0 eq) were added slowly. The reaction was stirred at rt overnight. Organics were separated from aqueous, and aqueous was extracted with TBME (30 L). The combined organics were washed with H20 (50 L), brine (50 L) and dried over Na2S04. Filtered and concentrated under vacuum afforded 5.1 kg of 2-chloro-N-methoxy- N-methylacetamide 10 (CAS Reg. No. 67442-07-3) as a white solid.

Example 7 4-bromo-2-fluorobenzimidamide hydrochloride 12

To 35.0 L of lithium hexamethyldisilazide LiHMDS (35.0 mol, 1.4 eq, 1.0 M in THF) under N2 was added a THF solution of 4-Bromo-2-fluorobenzonitrile 11 (CAS Reg. No. 105942- 08-3) (5.0 kg in 10 L THF) at 10 °C, the mixture was stirred at rt for 3h. Cooled to -20°C and 8.3 L of HCl-EtOH (6.6 M) were added. The mixture was stirred at -10 °C for additional lh, filtered. The wet cake was washed with EA (10 L) and H20 (6 L). Drying in vacuo yielded 5.8 kg 4- bromo-2-fluorobenzimidamide hydrochloride 12 (CAS Reg. No. 1187927-25-8) as an off-white solid.

Alternatively, to a 200-L vessel was charged 4-bromo-2-fluorobenzonitrile 11 (10 kg, 50.00 mol, 1.00 equiv) and ethanol (100 L) followed by purging 40 kg Hydrogen chloride (g) at – 10 °C with stirring (Scheme 4). The resulting solution was allowed to react for an additional 36 h at 10 °C. The reaction progress was monitored by TLC until 11 was consumed completely. The resulting mixture was concentrated under vacuum while maintaining the temperature below 60 °C. The volume was concentrated to 10-15 L before 60 L MTBE was added to precipitate the product. The precipitates were collected by filtration to afford in 12 k g of ethyl 4-bromo-2- fluorobenzimidate hydrochloride 12 as a white solid. (Yield: 85%). 1H NMR δ 7.88-7.67 (m), 4.89 (br s), 4.68 (q), 3.33 (m), 1.61 (t). MS M+l: 245.9, 248.0.

To a 200L vessel, was charged ethyl 4-bromo-2-fluorobenzimidate hydrochloride (12.5 k g, 44mol, 1.00 equiv, 99%) and ethanol (125 L) followed by purging NH3 (g) at -5 °C for 12 h. The resulting solution was stirred at 30 °C for an additional 24 h. The reaction progress was monitored by TLC until SM was consumed completely. The precipitates were filtered and the filtrate was concentrated under vacuum. The product was precipitated and collected by filtration to afford 6.1 kg (54.5%) of 4-bromo-2-fluorobenzamidine hydrochloride 12 as a white solid. 1H NMR δ 9.60 (br), 7.91-7.64 (m), 3.40 (s), 2.50 (m). MS M+l: 216.9, 219.9.

Example 8 2-chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)ethanone 13

To a 10L four necked flask was charged l-Isopropyl-3-methyl-lH-l,2,4-triazole 7 (400 g) in THF (2.5 L). The resulting solution was cooled to -40 °C and 2.5 M n-butyllithium BuLi in n- hexanes (1.41 L) was added while keeping the internal temp, below -20°C. The resulting yellow suspension was stirred at -40°C for 1 hour before being transferred. To a 20L flask was charged 2-chloro-N-methoxy-N-methylacetamide 10 (485 g) in THF (4 L). The resulting solution was cooled to -40 °C at which point a white suspension was obtained, and to this was added the solution of lithiated triazole 7 keeping the internal temp, below -20°C. At this point a yellow orange solution was obtained which was stirred at – 30°C for lhour. Propionic acid (520 mL) was added keeping the internal temp, below -20°C. The resulting off-white to yellowish suspension was warmed to -5 °C over 30 minutes. Citric acid (200 g) in water (0.8 L) was added and after stirring for 5 minutes a clear biphasic mixture was obtained. At this point stirring was stopped and the bottom aqueous layer was removed. The organic phase was washed with 20w% K3PO4 solution (1 L), 20w% K2HP04 solution (2 L), and 20w% NaCl solution (1 L). The organics was reduced to ca 4L via distillation under vacuum to afford 2-chloro-l-(l-isopropyl-3- methyl-lH-l,2,4-triazol-5-yl)ethanone 13 as a dark amber liquid which was used “as is” in the next step.

Example 9 5-(2-(4-bromo-2-fluorophenyl)- lH-imidazol-4-yl)-l -isopropyl-3-methyl- lH-l,2,4-triazole V

To a 10 L four- neck flask were charged with THF (5.6 L), 4-bromo-2- fluorobenzimidamide hydrochloride 12 (567 g), KHCO3 (567 g) and water (1.15 L). The resulting white suspension was heated to 60°C over 2 hours. At this point a hazy solution was obtained to which was added a solution of 2-Chloro-l-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5- yl)ethanone 13 in THF (2 L). This solution was stirred at 60-65 °C for 24 hours. Then the aqueous bottom layer was removed. The organic layer was concentrated under vacuum. The residue was slurried in a mixture of MIBK (1.25 L) and toluene (0.7 L), and the precipitated product was filtered giving 552 g of 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l- isopropyl-3 -methyl- lH-l,2,4-triazole V (98.0% purity, 254 nm) as a brown solid Example 10 2-(2-(4-bromo-2-fluorophenyl)-4-(l-isopropyl-3-methyl-lH-l,2,4-triazol- 5-yl)- 1 H-imidazol- 1 -yl)ethanol 14

5-(2-(4-Bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl-lH- 1,2,4- triazole V (2.75 kg, 7.55 mol) was added to a solution of 3-dioxolan-2-one (ethylene carbonate, 3.99 kg, 45.3 mol) inN-methylimidazole (12 L) at 50 °C. The suspension was heated at 80°C for 7 h until the reaction was judged complete by HPLC. The solution of 14 was cooled to 35 °C and used directly in the subsequent cyclization.

Example 11 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine III

To a solution of 2-(2-(4-Bromo-2-fluorophenyl)-4-(l-isopropyl-3-methyl-lH-l,2,4- triazol-5-yl)-l H-imidazol- l-yl)ethanol (7.55 mmol) 14 inN-methylimidazole(12 L) at 35 °C was added methyl tributylammonium chloride (115 g, 0.453 mol), toluene (27.5 L) and 35% potassium hydroxide solution (10.6 kg, 25 mol in 22 L of water). The biphasic solution was stirred vigorously at 65 °C for 18 h when it was judged complete by HPLC. Stirring was stopped but heating was continued and the bottom aqueous layer was removed. Added isopropyl acetate (13.8 L) and the organic phase was washed twice with water (13.8 L and 27.5 L). The solvent was removed via vacuum distillation and after 30 L had been removed, isopropanol (67.6 L) was added. Vacuum distillation was resumed until an additional 30 L of solvent had been removed. Added additional isopropanol (28.8 L) and continued vacuum distillation until the volume was reduced by 42 L. Added isopropanol (4L) and the temperature was increased to >50 °C. Added water (28 L) such that the internal temperature was maintained above 50 °C, then heated to 75 °C to obtain a clear solution. The mixture was allowed to cool slowly and the product crystallized out of solution. The resulting suspension was cooled to 0 °C, held for 1 h then filtered and the cake was washed with water (5.5 L). The cake was dried at 45 °C under a nitrogen sweep to give III as a tan solid (3.30 kg, 71.6 wt %, 80.6% yield).

Example 12 2-methyl-2-(lH-pyrazol-l-yl)propanoic acid 16

2-Bromo-2-methylpropanoic acid 15 and pyrazole were reacted in triethylamine and 2- methyltetrahydrofuran to give 16.

Example 13 ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17

2-Methyl-2-(lH-pyrazol-l-yl)propanoic acid 16 was treated with sulfuric acid in ethanol to give 17. Alternatively, pyrazole (10 g, 147 mmol, 1.0 eq.) was dissolved in DMF (500 ml) at room temperature (Scheme 8). 2-Bromoisobutyrate 18 (22 ml, 147 mmol, 1.0 eq.), cesium carbonate CS2CO3 (53 g, 162 mmol, 1.1 eq) and catalytic sodium iodide Nal (2.2 g, 15 mmol, 0.1, eq) were added to the mixture that was then heated to 60 °C for 24 hr. Reaction was followed by 1H NMR and pyrazole was not detected after 24 hr. The reaction mixture was quenched with a saturated solution of NaHCC>3 (200 ml) and ethyl acetate EtOAc (150 ml) was added and organics were separated from aqueous. Organics were dried over Na2S04, filtered and concentrated under vacuum to afford an oil which was purified by flash chromatography to give 17.

Example 14 Ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate IV

Method A: Ethyl 2-methyl-2-(lH-pyrazol-l-yl)propanoate 17 was reacted with N- bromosuccinimide (NBS) in 2-methyltetrahydrofuran to give IV (CAS Reg. No. 1040377-17-0).

Method B: Ethyl 2-bromo-2-methylpropanoate 18 and pyrazole were reacted with sodium tert-butoxide in dimethylformamide (DMF) to give a mixture of ethyl 2-methyl-2-(lH- pyrazol-l-yl)propanoate 17 and ethyl 2-methyl-3-(lH-pyrazol-l-yl)propanoate 19 which was treated with l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione to give a mixture of IV, ethyl 3- (4-bromo-lH-pyrazol-l-yl)-2-methylpropanoate 20, and 4-bromo-lH-pyrazole 21. The mixture was treated with a catalytic amount of lithium hexamethyldisilazide in tetrahydrofuran followed by acidification with hydrochloric acid to give IV.

Example 15 ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)propanoate 22

To a 50 L glass reactor was charged ethyl 2-(4-bromo-lH-pyrazol-l-yl)-2- methylpropanoate IV (1.00 kg, 3.85 mol, 1.00 equiv), potassium acetate, KOAc (0.47 kg, 4.79 mol 1.25 equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(l,3,2-dioxaborolane),

bis(pinacolato)diboron, B2Pin2 (1.22 kg, 4.79 mol, 1.25 equiv) and ethanol (10 L, 10 vol) and the mixture was stirred until a clear solution was obtained. The solution was vacuum/degassed 3x with nitrogen. To this mixture was charged XPhos ligand (0.023 kg, 0.048 mol, 1.0 mol ) and the Pd precatalyst (0.018 kg, 0.022 mol, 0.5 mol ) resulting in a homogeneous orange solution. The solution was vacuum/degassed once with nitrogen. The internal temperature of the reaction was set to 75 °C and the reaction was sampled every 30 min once the set temperature was reached and was monitored by LC (IPC method: XTerra MS Boronic). After 5 h, conversion to 22 (CAS Reg. No. 1201657-32-0) was almost complete, with 1.3% IV remaining. Example 16 ethyl 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoate 23

Ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)propanoate 22 and 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III were reacted under Suzuki conditions with palladium catalyst, in isopropanol and aqueous phosphate buffer to give 23.

A 1M solution of K3PO4 (1.60 kg in 7.6 L of water, 7.54 mol, 2.00 equiv) was charged to the above reaction mixture from Example 15, followed by the addition of a solution of III in THF (1.33 kg in 5.0 L, 3.43 mol, 0.90 equiv) over 2 min. The reaction mixture was warmed to 75 °C (internal temperature) over 45 min and stirred for 13 h at 75 °C, then analyzed by HPLC (III not detected) showing the formation of 23.

Example 17 2-(4-(2-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- IH-pyrazol- 1 -yl)-2-methylpropanoic acid II

Ethyl 2-(4-(2-(l -isopropyl-3 -methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanoate 23 was treated with aqueous lithium hydroxide to give II.

The ester saponification reaction was initiated with the addition of 3.5 M aqueous LiOH (0.74 kg in 5.0 L, 17.64 mol, 5 equiv) to the reaction mixture from Example 16 and allowed to warm to 75 °C. The mixture was sampled every 30 min (IPC method: XTerra MS Boronic) and the saponification was complete after 4.5 h (with less than 0.3% 23 remaining). The reaction mixture was concentrated via distillation to approximately half volume (starting vol = 37 L; final vol = 19 L) to remove EtOH and THF, resulting in tan-brown slurry. Water (5 L, 5 vol) was charged to the mixture and then distilled (starting vol = 25 L; final vol = 21 L). The temperature was set at 60 °C (jacket control) and then charged with isopropyl acetate, IP Ac (4 L, 4 vol). The biphasic mixture was stirred a minimum of 5 min and then the layers allowed to separate for a minimum of 5 min. The bottom aqueous layer was removed into a clean carboy and the organics were collected into a second carboy. The extraction process was repeated a total of four times, until the organic layer was visibly clear. The aqueous mixture was transferred back to the reactor and then cooled to 15 °C. A 6 M solution of HC1 (6.4 L, 38.40 mol, 10 equiv) was charged slowly until a final pH = 1 was obtained. The heterogeneous mixture was then filtered. The resulting solids were washed twice with 5 L (2 x 5 vol) of water. The filter was then heated to 80 °C and the vacuum set to -10 Psi (with nitrogen bleed) and the solids were dried for 24 h (KF = 2.0 % H20) to give 1.54 kg (95% corrected yield) of II as a white solid; 98% wt, 97.3 % pure.

Example 18 2-(4-(2-( 1 -isopropyl-3-methyl- 1 H- 1 ,2,4-triazol-5-yl)-5 ,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- lH-pyrazol- 1 -yl)-2-methylpropanamide I (GDC-0032)

2-(4-(2-(l-Isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[l,2- d][l,4]oxazepin-9-yl)-lH-pyrazol-l-yl)-2-methylpropanoic acid II was treated with di(lH- imidazol-l-yl)methanone (carbonyldiimidazole, CDI) in tetrahydrofuran followed by methanolic ammonia to give crude I.

Solid II (1.44 kg, 3.12 mol, 1.00 equiv) was transferred into a 20 L bottle and then THF

(10 L, 7 vol) was charged. The slurry was transferred under reduced pressure into a second 50 L reactor and additional THF (5 L, 3 vol) was added for the rinse. The internal temperature of the slurry was set to 22 °C and Γ1 -carbonyldiimidazole, CDI (0.76 Kg, 5.12 mol, 1.50 equiv) was charged to the mixture and a clear solution was observed after 5 min. The reaction mixture was sampled every 30 min and analyzed by HPLC (IPC: XTerra MS Boronic method) which showed almost complete conversion to the acyl-imidazole intermediate and 1.2% remaining II after 30 min. An additional portion of CDI (0.07 kg, 0.15 mol, 0.14 equiv) was added, and the reaction mixture was stirred for 1 h and then analyzed by HPLC (IPC: XTerra MS Boronic method) which showed 0.8% remaining II.

Into a second 50-L reactor, was added NH3/MeOH (1.5 L, 10.5 mol, 3.37 equiv) and THF

(5 L, 3 vol). The acyl-imidazole intermediate was transferred to a second reactor under reduced pressure (transfer time -10 min). The internal temperature was then set to 45 °C and the volume of solvent was distilled down from 35 L to 12 L. Water (6 L, 4 vol) was then added to the mixture that was further distilled from 18 L to 11 L. Finally, another portion of water (6 L, 4 vol) was added and the solvents were distilled one last time from 17 L to 14 L, until no more THF was coming out. The reaction was then cooled down to 10 °C (internal temperature). The white slurry was filtered and the filter cake was washed with water (2 x 6 L, 2 x 4 vol). The solids were then dried at 80 °C (jacket temp) in the Aurora filter for 24 h (KF = 1.5 % H20) under vacuum to give 1.25 kg crude I, GDC-0032 (84% corrected yield, 96% wt, 97.3 % pure by HPLC) as a white solid.

A slurry of crude I (1.15 kg, 2.50 moles) in MeOH (6 L, 5 vol) was prepared and then charged to a 50 L glass reactor. Additional MeOH (24 L, 21 vol) was added to the mixture, which was then heated to 65 °C. A homogenous mixture was obtained. Si-thiol (Silicycle, Inc., 0.23 kg, 20% wt) was added to the solution via the addition port and the mixture was stirred for 3 hours. It was then filtered warm via the Aurora filter (jacket temperature = 60 °C, polish filtered and transferred directly into a second 50 L reactor with reduced pressure. The solution was then heated back to 65 °C internal temperature (IT). The homogeneous solution was cooled down to 54 °C and I seeds (12 g, 1 % wt) in MeOH (50 mL) were added with reduced pressure applied to the reactor. The mixture was then cooled down to 20 °C over 16 hours. The solids were then filtered via the Aurora filter and dried at 80 °C for 72 hours to give 921 g, 80% yield of I as a methanoate solvate (form A by XRPD,) and transferred to a pre-weighed charge-point bag.

In an isolator, the solids were slurred in IP Ac (8 L, 7 vol) and transferred to a clean 10 L reactor. The mixture was stirred for 1 h at 60 °C (IT). The solids were then filtered via the Aurora system and dried at 80 °C (jacket) for 96 h. A sample of I was removed and analyzed by GC (IP Ac = 1 %). To attempt more efficient drying, the API was transferred to two glass trays in an isolator and sealed with a drying bag before being dried in a vacuum oven set at 100 °C for 16 h. GC (IPC: Q12690V2) showed 1 % solvent was still present. The process afforded 760 g (68% corrected yield, 68% wt, 99.9 % purity by LC) of a white solid (form B by XRPD).

Crude I (340.7 g) was charged to a 2-1 . 1 1 DPI · bottle and slurried with 0.81 ,

isoamylalcohol (I A A). The slurry was transferred to a 20 L reactor and diluted with 6.7 L round- bottom flask (22 vol total). The white slurry was heated until a solution was observed (internal temperature rose to 118 °C and then cooled to 109 °C). The solution was polish filtered (0.2 μ .Μ filter). A flask was equipped with overhead stirring and the filtrate was slurried in isoamyl alcohol (344 ml ., 21 vol). The mixture was warmed to 95 °C (internal) until the solids dissolved. A slurry of charcoal (10 wt%, 0.16g) and silicycle thiol (10 wt%, 0.16g) in isoamyl alcohol (1 vol, 1 6 ml . ) was charged and the mixture was stirred at 90-95 °C for 1 h and then filtered (over Celite® pad). The clear amber colored solution was cooled to 73 °C (seeding temp range = 70 ±5 °C) and a GDC-0032 I seed (10 wt%, 0.16g) was added. The temperature of the heating mantle was turned off and the mixture was allowed to cool to room temperature overnight with stirrin (200 rpni). After 17 hr, the white solids were filtered starting with slow gravity filtration and then vacuum was applied. The solids were suction dried for 20 min with mixing until a free flowing powder was obtained. ( rude weight prior to oven drying = 16 g. The solids were oven- dried at 100 °C for 24 h and then sampled for testing. Drying continued at 100 °C for another 24 hr. I l l NMR (DMSO d6) δ 8.38 (t), 8.01 (s), 7.87 (s), 7.44, 7.46 (d), 7.36 (s), 7.18 (br s), 6.81

(br s), 5.82 (m), 3.99 (s), 2.50 (s), 2.26 (s), 1.75 (s), 1.48, 1.46 (d).

Purified 2-(4-(2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)- lH-pyrazol- 1 -yl)-2-methylpropanamide I (GDC-0032) was dry granulation formulated in tablet form by the roller compaction method (He et al (2007) Jour, of Pharm. Sci., 96(5):1342-1355) with excipients including lactose, microcrystalline cellulose (AVICEL® PH 01, FMC BioPolymer, 50 μΜ particle),

croscarmellose sodium (Ac-Di-Sol®, FMC BioPolymer), and magnesium stearate.

Example 19 4-bromo-2-fluoro-N-hydroxybenzimidamide 24

To a solution of 4-Bromo-2-fluorobenzonitrile 11 (800 g, 4 mol, 1 eq), hydroxylamine hydrochloride (695 g, 10 mol, 2.5 eq) in MeOH (2 L, 2.5 vol) was added Et3N (485 g, 4.8 mol, 1.2 eq), then the mixture was stirred at 60 °C for 40 min and checked by HPLC (no nitrile remaining). Reaction was then quenched by H20 (30 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L x 2) and 1350 g wet 4-bromo-2-fluoro-N-hydroxybenzimidamide 24 was obtained with 96% purity.

Example 20 ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25

To a solution of 4-Bromo-2-fluoro-N-hydroxybenzimidamide 24 (800 g, 3.43 mol, 1 eq) and Amberlyst® A21 (20 wt%, 160 g) in PhMe (12 L, 15 vol) was added ethyl propiolate (471 g, 4.8 mol, 1.4 eq) at 10 °C. The reaction was stirred at 50 °C overnight and checked by LC-MS (ca 14A% of starting material 24 was left). Reaction was then filtered and the filtrate was concentrated under vacuum, and 1015 g ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 was obtained as a yellow oil with 84.9% LC purity (yield: 89%).

Example 21 ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26

A solution of ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25 (300 g, 0.91 mol, 1 eq) in diphenyl oxide (900 mL, 3 vol) was stirred at 190 °C under N2 for 1 h and checked by LC-MS (no 25 remaining). Cooled the mixture to rt and TBME (600 mL, 2 vol of 25) was added, and then PE (1.8 L, 6 vol of 25) was dropwise added to separate out solids. The mixture was stirred at rt for 20 min, and filtered to give 160 g wet cake. The wet cake was washed with PE (1 L) and dried to afford 120 g ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26 with 92% LC purity as brown solids. Example 22 ethyl 2-(4-bromo-2-fluorophenyl)- 1 -(2-hydroxyethyl)- 1 H-imidazole-4- carboxylate 27

Ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylate 26 and l,3-dioxolan-2- one and N-methylimidazole were reacted to give 27.

Example 23 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28

Ethyl 2-(4-bromo-2-fluorophenyl)-l -(2-hydroxyethyl)- lH-imidazole-4-carboxylate 27, potassium hydroxide and methyl tributylammonium hydrochloride were reacted at 65 °C, cooled, and concentrated. The mixture was dissolved in ethanol and water to crystallize 28.

Example 24 9-bromo-N-(l-iminoethyl)-5,6-dihydrobenzo[f]imidazo[l,2- d] [ 1 ,4]oxazepine-2-carboxamide 29

9-Bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28, triphenylphosphine, and acetamidine were reacted to give 29.

Example 25 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine III

9-Bromo-N-( 1 -iminoethyl)-5 ,6-dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine-2- carboxamide 29 was reacted with isopropylhydrazine hydrochloride 4 in acetic acid to give III.

Example 26 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 30

3-Chloro-2-oxopropanoic acid and 4-bromo-2-fluorobenzimidamide hydrochloride 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 30.

Alternatively, to a solution of ethyl 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4- carboxylate 26 (1350 g, 4.3 mol) in THF (8.1 L, 6 vol) and H20 (4 L, 3 vol) was added NaOH (520 g, 13 mol, 3 eq), and the reaction was stirred at 65 °C for 48 h till it completed (checked by LC-MS). Adjust the mixture with 2 M HC1 to pH = 5, and product was separated out as a yellow solid, filtered to give 2.2 kg wet cake, the wet cake was washed with H20 (1.5 L), DCM (1.5 L x 3), PE (1 L), and dried to afford 970 g pure 2-(4-bromo-2-fluorophenyl)-lH-imidazole-4- carboxylic acid 30 (Scheme 10). Example 27 5-(2-(4-bromo-2-fluorophenyl)-lH-imidazol-4-yl)-l-isopropyl-3-methyl- lH-l,2,4-triazole V

Reaction of 30 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(l-(2-isopropylhydrazinyl)ethylidene)- lH-imidazole-4-carboxamide 31 which cyclizes upon heating to give V.

Example 28 tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2- cyanophenoxy)ethylcarbamate 32

Alkylation of 4-bromo-2-fluorobenzonitrile 11 with tert-butyl 2-hydroxyethylcarbamate gives 32.

Example 29 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33

Cyclization of tert-butyl 2-hydroxyethylcarbamate gives tert-butyl 2-(5-bromo-2- cyanophenoxy)ethylcarbamate 32 under acidic conditions, such as hydrochloric acid in ethanol, gives 33.

Example 30 9-bromo-5,6-dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxylic acid 28

Reaction of 3-bromo-2-oxopropanoic acid and 8-bromo-3,4- dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 gives 28 (CAS Reg. No. 1282516-74-8).

Example 31 9-bromo-2-(l-isopropyl-3-methyl-lH-l,2,4-triazol-5-yl)-5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepine III

Coupling of 28 with N’-isopropylacetohydrazonamide 6 and coupling reagent HBTU in

DMF gives intermediate, 9-bromo-N-(l-(2-isopropylhydrazinyl)ethylidene)-5,6- dihydrobenzo[f]imidazo[l,2-d][l,4]oxazepine-2-carboxamide 34, which forms III upon heating.

Example 32 methyl 4-bromo-2-fluorobenzimidate 35

Reaction of 4-bromo-2-fluorobenzonitrile 11 with sodium methoxide in methanol gives 35.

Example 33 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33

Alkylation of methyl 4-bromo-2-fluorobenzimidate 35 with 2-aminoethanol gives 4- bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33 (Scheme 13). Alternatively, reaction of 11 with 2- aminoethanol and potassium tert-butoxide displaces fluorine to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37. Ring closure of 37 with trimethylaluminum gave 33 (Scheme 14). A solution of 11 (10 g, 50 mmol) and 2- aminoethanol (3.1 mL, 50.8 mmol) in 2-methyltetrahydrofuran (80 mL) was cooled to 0 °C and a solution of 1M potassium tert-butoxide in tetrahydrofuran (55 mL, 55 mmol) was slowly added while maintaining the solution temperature below 5 °C. The reaction was stirred at 0 °C for 30 min until judged complete by HPLC at which point it was warmed to 25 °C. A solution of 0.5M HC1 in isopropanol (100 mL, 50 mmol) was added and the desired HC1 salt 3 crystallized directly from the solution. The solid was collected by filtration and dried under vacuum with a nitrogen bleed to give 2-(2-aminoethoxy)-4-bromobenzonitrile hydrochloride 37 as a white solid. (12.1 g, 87 % yield).

To a flask was charged 37 (9.00 g, 32.4 mmol) and toluene (90.0 ml). The suspension was cooled to 0 °C and was added trimethylaluminum (1.8 equiv., 58.4 mmol, 2M in toluene) drop-wise over 30 minutes. The suspension was then stirred at room temperature for 1 h and then warmed to 100 °C. After 5 h, the solution was cooled to 0 °C and quenched with aqueous NaOH (2N, 90.0 ml). The suspension was extracted with EtOAc (4 x 90 ml) and the combined extracts were dried over then filtered through Celite®. The solution was concentrated and the residue triturated with EtOAc to afford 8-bromo-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-imine 33 (6.26 g, 26.0 mmol, 80% yield) as white crystalline solid.

Example 34 4-chloro-2-fluoro-N-hydroxybenzimidamide 39

To a solution of 4-chloro-2-fluorobenzonitrile 38 (400 g, 2.58 mol, 1.0 eq),

hydroxylamine hydrochloride (448 g, 6.45 mol, 2.5 eq) in MeOH (1 L, 2.5 vol) was added Et3N (313 g, 3.1 mol, 1.2 eq), then the mixture was stirred at 60 °C for 40 min and checked by HPLC (no nitrile remaining). Reaction was then quenched by H20 (10 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L x 2) and 378 g 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 was obtained with 93% purity (Scheme 15).

Example 35 ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40

To a solution of 4-chloro-2-fluoro-N-hydroxybenzimidamide 39 (378 g, 2 mol, 1.0 eq) and Amberlyst® A21 (20 wt%, 75.6 g) in toluene PhMe (5.6 L, 15 vol) was added ethyl propiolate (275 g, 2.8 mol, 1.4 eq) at 30 °C. The reaction was stirred at 30 °C overnight and checked by LC-MS. Reaction was then filtered and the filtrate was concentrated under vacuum, and 550 g ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40 was obtained as a yellow oil with 83% LC purity (Scheme 15).

Example 36 ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41

A solution of ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40 (550 g, 1.9 mol, 1.0 eq, 83% LC purity) in diphenyl oxide (1.65 L, 3 vol) was stirred at 190 °C under N2 for 1 h and checked by LC-MS (no 40 remaining). Cooled the mixture to rt and PE (10 L) was added dropwise. The mixture was stirred at rt for 20 min, and filtered to give 400 g wet cake, after purified by chromatography on silica gel (PE / EA=1 / 5) to get 175 g pure ethyl 2-(4-chloro-2- fluorophenyl)-lH-imidazole-4-carboxylate 41 with 98% LC purity (Scheme 15).

Example 37 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 42

To a solution of ethyl 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylate 41 (175 g, 4.3 mol) in THF (1 L, 6 vol) and H20 (500 mL, 3 vol) was added NaOH (78 g, 1.95 mol, 3.0 eq), and the reaction was stirred at 65 °C for 48 h till it completed (checked by LC-MS). Adjust the mixture with 2 N HC1 to pH = 5, and product was separated out as a yellow solid, filtered to give 210 g wet cake, the wet cake was washed with H20 (300 mL), DCM (3 x 300 mL), PE (500 mL), and dried to afford 110 g pure 2-(4-chloro-2-fluorophenyl)-lH-imidazole-4-carboxylic acid 42 (CAS Reg. No. 1260649-87-3) (Scheme 15 ). I l l NMR (DMSO d6) δ: 12.8 (br s), 8.0, 7.9 (br s), 7.46, 7.4 (m).

PATENT

US 2014275523

SYNTHESIS

Taselisib_药物数据_原料药API_CCIS-CHEM化学平台科研物资一站式采购平台 …

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商品规格

Taselisib

Taselisib是罗氏集团及其下属公司Genentech和Chugai研发,目前治疗绝经后妇女雌激素受体阳性(ER +)乳腺癌和非小细胞肺癌(NSCLC)的三期临床研究均在进行中。

基本信息更新时间:2016-02-01

药品名称:
Taselisib
研发代码:
GDC-0032; RG-7604
商品名称:
作用机制:
PI3K inhibitor; Cytochrome P450 CYP3A4 Inhibitors
适应症:
乳腺癌,非小细胞肺癌
研发阶段:
临床三期 (进行中)
研发公司:
罗氏 (原研)

化学信息更新时间:2015-08-27

分子量 460.53
分子式 C24H28N8O2
CAS号 1282512-48-4 (Taselisib);
化学名称 1H-Pyrazole-1-acetamide, 4-[5,6-dihydro-2-[3-methyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-d][1,4]benzoxazepin-9-yl]-a,a-dimethyl-
Fudosteine药品(游离态)参数:
MW HD HA FRB* PSA* cLogP*
460.53 2 10 5 119 2.548±1.034

化学合成路线及相关杂质更新时间:2015-12-15

参考文献:J. Med. Chem. 2013, 56, 4597−4610

参考文献:WO2014140073A1

PAPER

J Med Chem 2013, 56(11): 4597

Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

Departments of Discovery Chemistry, Drug Metabolism and Pharmacokinetics, §Translational Oncology, and Biochemical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
 Argenta Discovery, 8-9 Spire Green Centre, Flex Meadow, Harlow, Essex, CM19 5TR, United Kingdom
J. Med. Chem.201356 (11), pp 4597–4610
DOI: 10.1021/jm4003632
*Phone: 650-225-2923 (C.O.N.); +1-(650)-467-3214 (T.P.H.). E-mail: chudin@gene.com (C.O.N.); theffron@gene.com (T.P.H.).
Abstract Image

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.

2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (11l)

1H NMR (500 MHz, DMSO) δ 8.42 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.46 (dd, J = 8.3, 1.8 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.22 (s, 1H), 6.87 (s, 1H), 5.90–5.73 (m, 1H), 4.62–4.42 (m, 4H), 2.50 (dt, J = 3.6, 1.7 Hz, 5H), 2.26 (s, 3H), 1.74 (s, 6H), 1.47 (d, J = 6.5 Hz, 6H). 13C NMR (126 MHz, DMSO) δ 173.78, 158.24, 155.88, 147.31, 143.94, 136.64, 134.60, 130.26, 129.88, 126.42, 123.62, 120.32, 119.31, 116.17, 115.26, 68.31, 64.48, 49.89, 49.70, 40.06, 39.97, 39.89, 39.80, 39.72, 39.63, 39.56, 39.47, 39.30, 39.13, 38.96, 25.47, 22.34, 13.82. HRMS (ESI+): m/z (M + H+) calcd: 461.2413, found: 461.2427. Melting point: 259 °C.
POLYMORPHS almost A to Z
GDC-0032, also known as taselisib, RG7604, or the IUPAC name: 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide, has potent PI3K activity (Ndubaku et al (2013) J. Med. Chem. 56(11):4597-4610; WO 2013/182668; WO 2011/036280; U.S. Pat. No. 8,242,104; U.S. Pat. No. 8,343,955) and is being studied in patients with locally advanced or metastatic solid tumors (Juric et al “GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study”, 2013 (Apr. 7) Abs LB-64 American Association for Cancer Research Annual Meeting).

the invention relates to polymorph forms of the PI3K inhibitor I (taselisib, GDC-0032, RG7604, CAS Reg. No. 1282512-48-4, Genentech, Inc.), named as 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide, having the structure:

Figure US09266903-20160223-C00001

and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.

Publication numberPriority datePublication dateAssigneeTitle
WO2011036280A12009-09-282011-03-31F. Hoffmann-La Roche AgBenzoxazepin pi3k inhibitor compounds and methods of use
WO2014140073A12013-03-132014-09-18F. Hoffmann-La Roche AgProcess for making benzoxazepin compounds

References

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Patent Title

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US2016375033 METHODS OF TREATMENT WITH TASELISIB
2016-06-28
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2014-12-15
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2016-09-29
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Patent ID

Patent Title

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Granted Date

US2016220537 COMPOSITIONS TO IMPROVE THE THERAPEUTIC BENEFIT OF BISANTRENE AND ANALOGS AND DERIVATIVES THEREOF
2014-07-25
2016-08-04
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2013-09-16
2014-04-24
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2013-09-16
2014-04-24
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2013-09-16
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Patent Title

Submitted Date

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2015-04-03
2015-10-15
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2015-04-03
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2015-04-03
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2015-03-12
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2016-05-26
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2016-03-10
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2015-04-15
2015-11-12
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2015-04-15
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2016-10-25
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2016-07-01
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2015-04-03
2015-10-15
Taselisib
Taselisib skeletal.svg
Clinical data
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C24H28N8O2
Molar mass 460.54 g·mol−1
3D model (JSmol)

Taselisib

(GDC-0032, RG7604)

BREAST
  • PHASE II,
  • III

This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

Taselisib, a PI3K inhibitor

Taselisib, an investigational PI3K inhibitor, is currently in clinical development based on its potential selectivity for the PI3Kα isoform.1,2 Preclinical data have shown that taselisib induced growth inhibition in PI3Kα-mutant cell lines.Taselisib continues to be investigated in ongoing clinical studies.

1Taselisib is an investigational PI3K inhibitor currently being studied for its potential to selectively inhibit the PI3Kα isoform.1,2

2Taselisib is designed to bind to the ATP-binding pocket of PI3Kα to potentially prevent subsequent downstream signaling.1

3In preclinical studies, taselisib induced growth inhibition in PI3Kα-mutant xenograft mouse models.1 Taselisib continues to be investigated in ongoing clinical studies.

References

  1. Lopez S, Schwab CL, Cocco E, et al. Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol Oncol.2014;135:312-317. PMID: 25172762
  2. Ndubaku CO, Heffron TP, Staben ST, et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem. 2013;56:4597-4610. PMID: 23662903

//////////////////RG7604, Taselisib, PHASE 3,  metastatic breast cancer,  non-small cell lung cancer, RO5537381, Roche

CC1=NN(C(=N1)C2=CN3CCOC4=C(C3=N2)C=CC(=C4)C5=CN(N=C5)C(C)(C)C(=O)N)C(C)C

Alatrofloxacin Mesylate


 

Alatrofloxacin.svg

Alatrofloxacin mesylate.png

Alatrofloxacin Mesylate

Chemical Names: Alatrofloxacin mesylate; UNII-2IXX802851; 146961-77-5; Alatrofloxacin mesylate [USAN]; 157605-25-9; 2IXX802851
Molecular Formula: C27H29F3N6O8S
Molecular Weight: 654.618 g/mol
CAS No. 146961-76-4 (Alatrofloxacin );
157605-25-9 (Alatrofloxacin Mesylate);
Chemical Name (1α, 5α, 6α)-L-alanyl-N-[3-[6-carboxy-8-(2,4-difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridine-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-L-alaninamide, monomethanesulfonate

Research Code:CP-116517-27; CP-116517,    Trade Name:Trovan I.V.®          MOA:Quinolone antibiotic            Indication:Life- or limb-threatening infections caused by susceptible strains          Status:Withdrawn    Company:Pfizer (Originator)

Alatrofloxacin (Trovan IV) is a fluoroquinolone antibiotic developed by Pfizer, delivered as a mesylate salt.[1]

Trovafloxacin and alatrofloxacin were both withdrawn from the U.S. market in 2001

Alatrofloxacin mesylate was first approved by the U.S. Food and Drug Administration (FDA) on Dec 18, 1997. It was developed and marketed as Trovan I.V. ® by Pfizer in the US.

Alatrofloxacin mesylate is a fluoronaphthyridone related to the fluoroquinolones with in vitro activity against a wide range of gram-negative and gram-positive aerobic and anaerobic microorganisms. The bactericidal action of alatrofloxacin results from inhibition of DNA gyrase and topoisomerase IV. Trovan I.V.® is indicated for the treatment of patients initiating therapy in in-patient health care facilities (i.e., hospitals and long term nursing care facilities) with serious, life- or limb-threatening infections caused by susceptible strains of the designated microorganisms in the conditions listed below.

Trovan I.V.® is available as injection solution for intravenous use, containing 7.86 mg/ml of Alatrofloxacin mesylate. The recommended starting dose is 200 mg or 300 mg administered intravenously.

Alatrofloxacin mesylate was withdrawn from the U.S. market in 2001.

Image result for Alatrofloxacin mesylate

Alatrofloxacin mesilate

    • Synonyms:CP 116517, CP 116517-27
    • ATC:J01MA
  • Use:antibiotic, prodrug of trovafloxacin
  • Chemical name:l-Alanyl-N-[(1α,5α,6α)-3-[6-carboxy-8-(2,4-difluorophenyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-l-alaninamide monomethanesulfonate
  • Formula:C26H25F3N6O5 • CH4O3S
  • MW:654.62 g/mol
  • CAS-RN:146961-77-5

Derivatives

base

  • Formula:C26H25F3N6O5
  • MW:558.52 g/mol
  • CAS-RN:146961-76-4

Substance Classes

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN Formula Chemical Name CAS Index Name
27317-69-7 C11H20N2O5 Ntert-butoxycarbonyl-l-alanyl-l-alanine L-Alanine, N-[(1,1-dimethylethoxy)carbonyl]-L-alanyl-
186772-86-1 C33H37F3N6O7 N-[(1,1-dimethylethoxy)carbonyl]-l-alanyl-N-[(1α,5α,6α)-3-[8-(2,4-difluorophenyl)-6-(ethoxycarbonyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-l-alaninamide L-Alaninamide, N-[(1,1-dimethylethoxy)carbonyl]-L-alanyl-N-[(1α,5α,6α)-3-[8-(2,4-difluorophenyl)-6-(ethoxycarbonyl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthyridin-2-yl]-3-azabicyclo[3.1.0]hex-6-yl]-
171176-56-0 C22H19F3N4O3 ethyl (1α,5α,6α)-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 1,8-Naphthyridine-3-carboxylic acid, 7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-, ethyl ester, (1α,5α,6α)-
134575-66-9 C27H27F3N4O5 ethyl (1α,5α,6α)-1-(2,4-difluorophenyl)-7-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 1,8-Naphthyridine-3-carboxylic acid, 1-(2,4-difluorophenyl)-7-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1,4-dihydro-4-oxo-, ethyl ester, (1α,5α,6α)-
75-75-2 CH4O3S methanesulfonic acid Methanesulfonic acid

Trade Names

Country Trade Name Vendor Annotation
D TROVAN Pfizer wfm
F Turvel Pfizer wfm
GB Turvel Pfizer wfm
I Turvel Pfizer wfm
USA Trovan Pfizer wfm

(wfm = withdrawn from market)

Formulations

  • vial 200 mg/40 ml, 300 mg/60 ml (5 mg/ml) (as mesilate)

References

    • US 5 164 402 (Pfizer; 17.11.1992; appl. 4.2.1991; WO-prior. 16.8.1989).
    • US 5 229 396 (Pfizer; 20.7.1993; appl. 24.7.1992).
    • WO 9 700 268 (Pfizer; appl. 27.3.1996; USA-prior. 15.6.1995).
    • US 5 763 454 (Pfizer; 9.6.1998; appl. 21.5.1997; WO-prior. 6.6.1995).
  • polymorphs:

    • US 6 080 756 (Pfizer; 27.6.2000; appl. 30.1.1998; WO-prior. 5.7.1996).

References
“Center for Drug Evaluation and Research – Application Number: 020759/020760 – Chemistry Review(s)” (PDF). Food and Drug Administration. Retrieved 29 August 2014.

Alatrofloxacin
Alatrofloxacin.svg
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a605016
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Intravenous
ATC code
  • none
Legal status
Legal status
  • Withdrawn
Pharmacokinetic data
Bioavailability N/A
Protein binding 76% (trovafloxacin)
Metabolism Quickly hydrolyzed to trovafloxacin
Elimination half-life 9 to 12 hours (trovafloxacin)
Excretion Fecal and renal(trovafloxacin)
Identifiers
CAS Number
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C26H25F3N6O5
Molar mass 558.509 g/mol
3D model (JSmol)

/////////////////

THELIATINIB


img str1

THELIATINIB

CAS: 1353644-70-8
Chemical Formula: C25H26N6O2

Molecular Weight: 442.523

HMPL-309; HMPL 309; HMPL309; Theliatinib.

  • Originator Hutchison MediPharma
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Epidermal growth factor receptor antagonists

Highest Development Phases

  • Phase I Oesophageal cancer; Solid tumours

Most Recent Events

  • 29 Sep 2017 Efficacy and adverse events data from a phase I trial in Oesophageal cancer released by Hutchison Pharma
  • 13 Mar 2017 Phase-I clinical trials in Oesophageal cancer (First-line therapy) in China (PO) before March 2017 (Hutchison MediPharma pipeline, July 2017)
  • 02 Aug 2016 Hutchison MediPharma plans a phase Ib proof-of-concept trial for Oesophageal cancer, and Head and Neck cancer in China

Theliatinib, also known as HMPL-309, is a novel small molecule, epidermal growth factor receptor tyrosine kinase inhibitor with potential antineoplastic and anti-angiogenesis activities. In vitro studies suggest that Theliatinib is a potent EGFR kinase inhibitor with good kinase selectivity and in vivo data demonstrated broad spectrum anti-tumor activity via oral dosing in multiple xerographs such as A-431, Bcap-37 and Fadu.

PRODUCT PATENT

  • By Zhang, Weihan; Su, Wei-Guo; Yang, Haibin; Cui, Yumin; Ren, Yongxin; Yan, Xiaoqiang

WO2012000356 , covering quinazoline compounds as EGFR inhibitors

https://encrypted.google.com/patents/WO2012000356A1?cl=pt-PT&hl=en&output=html_text

Example 3:

(3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-l-methyl-hexahydropyrrolo [3,4-b]pyrrole-5(lH)-carboxamide

[060] To a solution of Compound 3-a (40 g, 0.138 mol, prepared according to procedures disclosed in WO2010002845), pyridine (40 mL, 0.495 mol) and DMF (anhydrous, 22 mL) in anhydrous THF (500 mL), was added phenyl carbonochloridate 3-b (22 mL, 0.175 mol) dropwise at -10°C. The mixture was stirred at room temperature for 12 hours. The precipitates were filtered and then suspended in saturated NaHC03 solution (500 mL). The solid was filtered, washed with H20 and EtOAc, and dried in vacuum to give compound 3-c (46 g).

A mixture of compound 3-c (1 g, 2.44 mmol) and compound 3-d (369 mg, 2.92 mmol) in dioxane (30mL) was stirred at 70°C for 5 hours, and then cooled to the ambient temperature. The precipitates were filtered, washed with EtOAc, and dried in vacuum to give compound 3 (0.8 g). MS (m/e): 443.4 (M+l)+.

PATENT

https://patents.google.com/patent/WO2010002845A2/en

PATENT

US 9168253

https://patents.google.com/patent/US9168253

Example 3 (3aR,6aR)—N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide

Figure US09168253-20151027-C00004

To a solution of Compound 3-a (40 g, 0.138 mol, prepared according to procedures disclosed in WO2010002845), pyridine (40 mL, 0.495 mol) and DMF (anhydrous, 22 mL) in anhydrous THF (500 mL), was added phenyl carbonochloridate 3-b (22 mL, 0.175 mol) dropwise at −10° C. The mixture was stirred at room temperature for 12 hours. The precipitates were filtered and then suspended in saturated NaHCO3solution (500 mL). The solid was filtered, washed with H2O and EtOAc, and dried in vacuum to give compound 3-c (46 g). A mixture of compound 3-c (1 g, 2.44 mmol) and compound 3-d (369 mg, 2.92 mmol) in dioxane (30 mL) was stirred at 70° C. for 5 hours, and then cooled to the ambient temperature. The precipitates were filtered, washed with EtOAc, and dried in vacuum to give compound 3 (0.8 g). MS (m/e): 443.4 (M+1)+.

PATENT

THELIATINIB BY HUTCHISON

WO-2018099451

The present invention belongs to the field of pharmacy and provides a crystal form of a compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, a pharmaceutical composition thereof, and a preparation method therefor and the use thereof.
(FR)La présente invention concerne le domaine de la pharmacie et fournit une forme cristalline d’un composé (3aR,6aR)-N-(4-(3-éthynylphénylamino)-7-méthoxyquinazolin-6-yl)-1-méthyl-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, une composition pharmaceutique de celui-ci, et son procédé de préparation et son utilisation.

Novel crystalline forms of the compound presumed to be theliatinib , processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating lung cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, stomach cancer, kidney cancer, liver cancer, brain cancer, esophageal cancer, bone cancer and leukemia.

Hutchison Medipharma is developing theliatinib, a small molecule EGFR tyrosine kinase and AKT cell proliferation pathway inhibitor, for treating cancer, including brain tumor, esophageal tumor and NSCLC; in September 2017, positive preliminary data were presented. Hutchison is also developing epitinib succinate , for treating cancer including glioblastoma.

Binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR) activates tyrosine kinase activity and triggers a response that leads to cell proliferation. Overexpression and/or overactivation of EGFR can lead to uncontrolled cell division, and uncontrolled cell division can be a cause of cancer. Therefore, compounds that inhibit the over-expression and/or over-activation of EGFR are candidates for treating tumors.
Relevant compounds of the present invention (3aR, 6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo [3, 4-b]pyrrole-5(1H)-carboxamide, whose chemical structure is shown in Formula A, has the effect of effectively inhibiting overexpression and/or overactivation of EGFR. Therefore, it can be used for the treatment of diseases associated with overexpression and/or overactivation of EGFR, such as the treatment of cancer.
Before discovering the crystal form of a compound, it is difficult to predict (1) whether a particular compound exists in crystalline form; (2) how an unknown crystal form is made; (3) what the properties of the crystal form would be, such as stability , bioavailability and so on.
Since the properties of the solid depend on the structure and the nature of the compound itself, different solid forms of the compound often exhibit different physical and chemical properties. Differences in chemical properties can be measured, analyzed, and compared using a variety of analytical techniques that ultimately can be used to distinguish these different solid forms. Differences in physical properties, such as solubility and bioavailability, are also important in describing the solid form of the drug compound. Likewise, in the development of pharmaceutical compounds, such as compounds of Formula A, the new crystalline and amorphous forms of the pharmaceutical compounds are also important.

Patent CN102906086A discloses compound (3aR,6aR)-N-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl)-1-methyl-hexahydropyrrolo[3 4-b]pyrrole-5(1H)-carboxamide and its preparation method.

Experimental part
 
The starting material of the compound of formula A used in the examples was prepared according to CN102906086A
PATENT

Example 3: (3aR, 6aR) -N- (4- (3- ethynyl-phenylamino) -7-methoxy-quinazolin-6-yl) -1-methyl-hexahydro-pyrrolo [3,4-b] pyrrol -5 (IH) – carboxamide

[0102]

Figure CN102906086AD00131

[0103] at -10 ° C, to (40g, 0. 138mol, was prepared in accordance with the operation disclosed in W02010002845) Compound 3-a, pyridine (40mL, O. 495mol) and DMF (anhydrous, 22mL) in dry solution (500 mL) in THF dropwise phenyl chloroformate 3-b (22mL, O. 175mol). The mixture was stirred at room temperature for 12h. The precipitate was filtered off, and then it was suspended in saturated NaHCO3 solution (500mL). The solid was filtered off, washed with H2O and EtOAc, and dried in vacuo to give compound 3_c (46g). Compound 3-c (lg, 2. 44mmol) and the compound 3_d (369mg, 2. 92mmol) in a mixture of two anger dioxane (30mL) was stirred at 70 ° C 5 h, then cooled to ambient temperature. The precipitate was filtered off, washed with EtOAc, and dried in vacuo to give compound 3 (O. 8g). MS (m / e): 443. 4 (M + 1) +.

Theliatinib (HMPL-309)

Theliatinib (HMPL-309) is a novel small molecule, epidermal growth factor receptor tyrosine kinase inhibitor with potential antineoplastic and anti-angiogenesis activities. Theliatinib is being developed as an oral formulation for the treatment of solid tumors like non-small cell lung cancer.

Theliatinib pre-clinical studies were conducted in China. In vitro studies suggest that Theliatinib is a potent EGFR kinase inhibitor with good kinase selectivity and in vivo data demonstrated broad spectrum anti-tumor activity via oral dosing in multiple xerographs such as A-431, Bcap-37 and Fadu. Non-clinical safety studies have indicated that Theliatinib is generally well tolerated in animals.

In November 2012, HMP initiated the first-in-human clinical trials of theliatinib.

Patent Citations (4)

Publication number Priority date Publication date  AssigneeTitle
CN101094840A *2004-12-292007-12-26韩美药品株式会社Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof
CN101619043A *2008-06-302010-01-06和记黄埔医药(上海)有限公司Quinazoline derivant and medical application thereof
WO2010002845A2 *2008-06-302010-01-07Hutchison Medipharma Enterprises LimitedQuinazoline derivatives
CN102311438A *2010-06-302012-01-11和记黄埔医药(上海)有限公司Quinazoline compound
CN106117182A *2016-06-202016-11-16中国药科大学Quinazoline-N-phenethyl tetrahydroisoquinoline compound and preparation method and application thereof

REFERENCES

1: Ren Y, Zheng J, Fan S, Wang L, Cheng M, Shi D, Zhang W, Tang R, Yu Y, Jiao L,
Ni J, Yang H, Cai H, Yin F, Chen Y, Zhou F, Zhang W, Qing W, Su W. Anti-tumor
efficacy of theliatinib in esophageal cancer patient-derived xenografts models
with epidermal growth factor receptor (EGFR) overexpression and gene
amplification. Oncotarget. 2017 Apr 19. doi: 10.18632/oncotarget.17243. [Epub
ahead of print] PubMed PMID: 28472779.

//////THELIATINIB, HMPL-309, HMPL 309, HMPL309, Phase I,  Oesophageal cancer,  Solid tumours

 O=C(N1C[C@]2([H])N(C)CC[C@]2([H])C1)NC3=CC4=C(NC5=CC=CC(C#C)=C5)N=CN=C4C=C3OC

Gadobenate Dimeglumine


Gadobenate dimeglumine.png

2D chemical structure of 127000-20-8

ChemSpider 2D Image | UNII:3Q6PPC19PO | C36H62GdN5O21

Gadobenate Dimeglumine

Gadobenate Dimeglumine

Molecular Formula: C36H62GdN5O21
Molecular Weight: 1058.156 g/mol

cas 113662-23-0 FREEFORM

INGREDIENT UNII CAS
Gadobenate dimeglumine 3Q6PPC19PO 127000-20-8

Used in MR imaging of liver.

UNII-15G12L5X8K

  1. 3,6,9-triaza-12-oxa-3,6,9-tricarboxymethylene-10-carboxy-13-phenyltridecanoic acid, gadolinium
  2. B 19036
  3. B-19036
  4. gadobenate dimeglumine
  5. gadobenic acid
  6. gadobenic acid, dimeglumine salt
  7. gadolinium-benzyloxypropionyl tetraacetate
  8. gadolinium-BOPTA-Dimeg
  9. Gd(BOPTA)2
  10. Gd-BOPTA
  11. Multihance (TN)
  12. E-7155

2-[2-[carboxylatomethyl-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl]amino]ethyl-(carboxymethyl)amino]-3-phenylmethoxypropanoate;gadolinium(3+);(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol

gadolinium(3+) ion bis((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol) 8-(carboxylatomethyl)-5,11-bis(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-4,13-dioate

Gadolinium hydrogen 4-carboxylato-5,8,11-tris(carboxylatomethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oate – 1-deoxy-1-(methylamino)-D-glucitol (1:2:1:2)

4-Carboxylato-5,8,11-tris(carboxylatométhyl)-1-phényl-2-oxa-5,8,11-triazatridécan-13-oate de gadolinium et de hydrogène – 1-désoxy-1-(méthylamino)-D-glucitol (1:1:2:2)

Gadolinate(2-), (4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)-N5,N8,N11,O4,O5,O8,O11,O13)-, dihydrogen, comp. with 1-deoxy-1-(methylamino)-D-glucitol (1:2)
gadolinium(3+) bis(meglumine) 8-(carboxylatomethyl)-5,11-bis(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-4,13-dioate
gadolinium(3+) ion bis((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol) 8-(carboxylatomethyl)-5,11-bis(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-4,13-dioate
gadolinium(3+) ion bis(N-methyl-D(-)-glucamine) 8-(carboxylatomethyl)-5,11-bis(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecane-4,13-dioate
GADOLINIUM(3+) ION DIHYDROGEN BIS(N-METHYL-D(-)-GLUCAMINE) 5,8,11-TRIS(CARBOXYLATOMETHYL)-1-PHENYL-2-OXA-5,8,11-TRIAZATRIDECANE-4,13-DIOATE
  • D-Glucitol, 1-deoxy-1-(methylamino)-, [4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)-N5,N8,N11,O4,O5,O8,O11,O13]gadolinate(2-) (2:1)
  • 2-Oxa-5,8,11-triazatridecan-13-oic acid, 4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-, gadolinium complex
  • Gadolinate(2-), [4-(carboxy-κO)-5,8,11-tris[(carboxy-κO)methyl]-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)-κN5,κN8,κN11,κO13]-, dihydrogen, compd. with 1-deoxy-1-(methylamino)-D-glucitol (1:2) (9CI)
  • Gadolinate(2-), [4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)-N5,N8,N11,O4,O5,O8,O11,O13]-, dihydrogen, compd. with 1-deoxy-1-(methylamino)-D-glucitol (1:2)
  • B 19036/7

Hygroscopic powder

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 794

Melting Point

124 deg C

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 794

Spectral Properties

Specific optical rotation: -26.9 deg at 20 deg C/365 deg C (c = 1.45 in water)

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 794

Absorption maximum: 257.8 nm (epsilon 203)

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 794
Title: Gadobenate Dimeglumine
CAS Registry Number: 127000-20-8
CAS Name: 1-Deoxy-1-(methylamino)-D-glucitol [4-(carboxy-kO)-5,8,11-tris[(carboxy-kO)methyl]-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)-kN5,kN8,kN11,kO13]gadolinate(2-) (2:1)
Additional Names: gadolinium benzyloxypropionictetraacetate dimeglumine; Gd-BOPTA/Dimeg
Manufacturers’ Codes: B-19036/7
Trademarks: MultiHance (Bracco)
Molecular Formula: C36H62GdN5O21
Molecular Weight: 1058.15
Percent Composition: C 40.86%, H 5.91%, Gd 14.86%, N 6.62%, O 31.75%
Literature References: Intravascular paramagnetic MRI contrast agent.
Prepn: E. Felder et al.,EP230893eidem,US4916246(1987, 1990 both to Bracco); F. Ungerri et al.,Inorg. Chem.34, 633 (1995). HPLC determn in biological samples: T. Arbughi et al.,J. Chromatogr. B713, 415 (1998). Physicochemical properties: C. de Haen et al.,J. Comput. Assist. Tomogr.23, Suppl. 1, S161 (1999). Pharmacology: P. Tirone et al.,ibid. S195. Pharmacokinetics: V. Lorusso et al.,ibid. S181. Toxicology: A. Morisetti et al.,ibid. S207. Clinical study in MRI of liver lesions: J. Petersein et al.Radiology215, 727 (2000). Review of clinical studies: B. Hamm et al.,J. Comput. Assist. Tomogr.23, Suppl. 1, S53-S60 (1999).
Properties: Hygroscopic powder. mp 124°. Freely sol in water, sol in methanol. Practically insol in n-butanol, n-octanol, chloroform. Abs max 257.8 nm (e 203). [a]36520 -26.9° (c = 1.45 in water). Prepd as 0.5M soln, osmolality (37°) 1.97 mol/kg. d20 1.22. Viscosity (mPa.s): 9.2 (20°), 5.3 (37°). LD50 i.v. in mice (mmol/kg): 5.7 (at 1 mL/min), 7.9 (at 0.2 mL/min); LD50 i.v. in rats (mmol/kg): 6.6 (at 6 mL/min), 9.2 (at 1 mL/min) (Morisetti).
Melting point: mp 124°
Optical Rotation: [a]36520 -26.9° (c = 1.45 in water)
Absorption maximum: Abs max 257.8 nm (e 203)
Density: d20 1.22
Toxicity data: LD50 i.v. in mice (mmol/kg): 5.7 (at 1 mL/min), 7.9 (at 0.2 mL/min); LD50 i.v. in rats (mmol/kg): 6.6 (at 6 mL/min), 9.2 (at 1 mL/min) (Morisetti)
Therap-Cat: Diagnostic aid (MRI contrast agent).
Keywords: Diagnostic Aid (MRI Contrast Agent).

Launched – 1998 Bracco,

Imaging, magnetic resonance

MultiHance injection is supplied as a sterile, nonpyrogenic, clear, colorless to slightly yellow aqueous solution intended for intravenous use only. Each mL of MultiHance contains 529 mg gadobenate dimeglumine and water for injection. MultiHance contains no preservatives.

Gadobenate dimeglumine is a gadolinium-based, paramagnetic contrast agent that was launched by Bracco in 1998 for use in magnetic resonance imaging (MRI). The drug is administered as an injection, and is approved in the U.S. for use in imaging of the central nervous system in adults and for visualization of lesions, abnormalities in the blood brain barrier, or abnormal vascularity of the brain, spine and associated tissues. Commercialization took place in 2010. In 2012, the product was approved and launched in the U.S. as a contrast agent for magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease

Gadobenate dimeglumine is chemically designated as (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)-1phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)] gadolinate(2-) dihydrogen compound with 1-deoxy-1(methylamino)-D-glucitol (1:2) with a molecular weight of 1058.2 and an empirical formula of C22H28GdN3O11 • 2C7H17NO5. The structural formula is as follows:

Image result for Gadobenate Dimeglumine SYNTHESIS

Prescription Drug Products

Prescription Drug Products: 1 of 2 (RX Drug Ingredient)
Drug Ingredient GADOBENATE DIMEGLUMINE
Proprietary Name MULTIHANCE MULTIPACK
Applicant BRACCO (Application Number: N021358)
Prescription Drug Products: 2 of 2 (RX Drug Ingredient)
Drug Ingredient GADOBENATE DIMEGLUMINE
Proprietary Name MULTIHANCE
Applicant BRACCO (Application Number: N021357)

PATENT

US4916246 Paramagnetic chelates useful for NMR imaging
1990-04-10

Gadolinium-Based, paramagnetic contrast agent launched by Bracco in 1998 for use in magnetic resonance imaging (MRI).

Gadobenate Dimeglumine is a gadolinium-based paramagnetic contrast agent. When placed in a magnetic field, gadobenate dimeglumine produces a large magnetic moment and so a large local magnetic field, which can enhance the relaxation rate of nearby protons; as a result, the signal intensity of tissue images observed with magnetic resonance imaging (MRI) may be enhanced. Because this agent is preferentially taken up by normal functioning hepatocytes, normal hepatic tissue is enhanced with MRI while tumor tissue is unenhanced. In addition, because gadobenate dimeglumine is excreted in the bile, it may be used to visualize the biliary system using MRI.

Image result for Gadobenate Dimeglumine SYNTHESIS

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021357s000_Multihance_Chemr.pdf

Gadobenate Dimeglumine is an MRI contrast agent used primarily for MR imaging of the liver. It can also be used for MRI of the heart, as well as and central nervous system in adults to visualize lesions with abnormal brain vascularity or abnormalities in the blood brain barrier, the brain, spine, or other associated tissues.

Gadobenate Dimeglumine is an MRI contrast agent used primarily for MR imaging of the liver. It can also be used for visualizing the CNS and heart. In contrast to conventional extracellular fluid contrast agents, gadobenate dimeglumine is characterized by a weak and transient binding capacity to serum proteins. This binding leads to an increased relaxivity of gadobenate dimeglumine and, consequently, to a considerably increased signal intensity over that of other agents.

The drug is administered as an injection, and is approved in the U.S. for use in imaging of the central nervous system in adults and for visualization of lesions, abnormalities in the blood brain barrier, or abnormal vascularity of the brain, spine and associated tissues

Gadobenic acid (INN, trade name MultiHance) is a complex of gadolinium with the ligand BOPTA. In the form of the methylglucaminesalt meglumine gadobenate (INNm) or gadobenate dimeglumine (USAN), it is used as a gadolinium-based MRI contrast medium.[1]

BOPTA is a derivative of DTPA in which one terminal carboxyl group, –C(O)OH is replaced by -C–O–CH2C6H5. Thus gadobenic acid is closely related to gadopentetic acid. BOPTA itself was first synthesized in 1995. [2] In the “gadobenate” ion gadolinium ion is 9-coordinate with BOPTA acting as an 8-coordinating ligand. The ninth position is occupied by a water molecule, which exchanges rapidly with water molecules in the immediate vicinity of the strongly paramagnetic complex, providing a mechanism for MRI contrast enhancement139La NMR studies on the diamagnetic La-BOPTA2− complex suggest that the Gd complex maintains in solution the same kind of coordination as found, by X-ray crystallography, in the solid state for Gd-BOPTA disodium salt.[2]

2D chemical structure of 113662-23-0

ChemSpider 2D Image | 6688 | C22H28GdN3O11

MW: 670.7469

Gadobenic Acid [INN:BAN]
113662-23-0

PATENT

https://encrypted.google.com/patents/US20090155181

  • Gadolinium-based contrast agents are commonly used to improve visibility of internal structures when a patient undergoes magnetic resonance imaging (MRI). These agents are typically administered intravenously immediately prior to imaging. Many contrast agents used in MRI cause toxicity in various areas of the body if they are not excreted rapidly by the kidney. These include for example, chelated organic gadolinium compounds which are not nephrotoxic in themselves, but which if retained in the body for extended periods of time release gadolinium ions which are toxic to various organs and cells of the body including skin, nerves, etc. The problems particularly occur in patients who are at risk for reduced kidney function. Serious diseases including nephrogenic systemic fibrosis (NSF) are among the consequences of this problem. (see, for example, Briguori et al., Catheter Cardiovasc. Intery (2006) 67(2): 175-80; Grobner et al., Kidney Int. (2007) 72(3): 260-4; Nortier et al., Nephrol. Dial. Transplant (2007) 22(11): 3097-101).
  • [0003]
    The FDA requested a boxed warning for contrast agents used to improve MRI images on May 23, 2007 stating that patients with severe kidney insufficiency who receive gadolinium-based agents are at risk for developing NSF, a debilitating and potentially fatal disease. In addition, patients just before or just after liver transplantation, or those with chronic liver disease, are also at risk for developing NSF if they are experiencing kidney insufficiency of any severity. The boxed warning is now included in each of the five gadolinium-based contrast agents currently approved for use in the United States. Thus, a need exists to reduce the toxicity that is caused by contrast agents in patients with risk factors for compromised renal function.

PATENT

https://patents.google.com/patent/CN104606686A/en

gadobenate dimeglumine according to the present invention is a pharmaceutical composition, a chemical reaction equation I and the preparation was prepared as follows:

Figure CN104606686AD00051

Example 1 were added to the vessel IOOmL 7. 7gBOPTA and 4. 2g thirty-two gadolinia weighed, followed by addition of 47mL water for injection, stirring and heated to 60 ° C. After incubation the reaction at this temperature for 1.5h, added the same amount in ten batches 5.77g meglumine. After each addition was complete meglumine, taking a small sample using a pH meter to monitor the reaction solution pH. If the sample pH <6. 9, the reaction was continued until the reaction solution was added next batch PH interposed between Meglumine 6.9 ~ 7.3. After the addition of meglumine, the reaction was continued heating and stirring 1.5 hours. Followed by addition of decolorizing charcoal 〇.16g pharmaceutically acceptable, holding the temperature, stirred for 1.5 hours. Finally hot filtration, the filtrate was collected, concentrated in vacuo to give a white solid 14. 2g.

[0022] Example 2 were added to the vessel IOOmL 7. 7gBOPTA weighed and 5. Ig trioxide followed by addition of 68mL of water for injection, stirring and heated to 65 ° C. After incubation the reaction I. 5h at that temperature, was added an equal amount of sub-batches twelve 6. 24g meglumine. After each addition was complete meglumine, taking a small sample using a pH meter to monitor the reaction solution pH. If the sample pH <6. 9, the reaction was continued until the reaction solution was added at a pH between batch Meglumine between 6.9 ~ 7.3.After the addition of meglumine, the reaction solution and heating was continued for 2 hours. Followed by addition of decolorizing charcoal 〇.23g pharmaceutically acceptable, holding the temperature, stirring for 2 hours. Finally hot filtration, the filtrate was collected, concentrated in vacuo to give a white solid 14. 8g.

[0023] Example 3 were added to the vessel IOOOmL 77gBOPTA weighed 42g and gadolinium oxide, followed by addition of 470mL injection water and heated with stirring to 60 ° C. After incubation the reaction at this temperature for 2h, the same amount was added in ten 58g batches meglumine. After each addition was complete meglumine, small sample, monitoring the reaction solution with a PH meter pH. If the sample pH <6. 9, the reaction was continued until the reaction solution was added next batch PH interposed between Meglumine 6.9 ~ 7.3. After the addition of meglumine, the reaction solution and heating was continued for 2 hours. Followed by addition of 2. 5g medicinal charcoal decolorization, holding the temperature, stirring for 2 hours. Finally hot filtration, the filtrate was collected, and concentrated to give a white solid 131g.

PATENT

https://patents.google.com/patent/CN104606686A/en

Magnetic resonance imaging (MRI) is a tomographic image, which is obtained using a magnetic resonance phenomenon of electromagnetic signals from the body, the body information and reconstructed. Currently in clinical use development speed is very fast, widely used in nerve, spinal cord, heart and great vessels, joint bone, soft tissue and pelvic enhanced prosecution, has a three-dimensional object to be measured non-destructive and can perform high-resolution imaging and so on.

[0003] paramagnetic contrast agent is a contrast agent suitable for diagnostic magnetic resonance imaging (MRI), and into the body tissue can shorten the imaging time of protons, thereby enhancing the image sharpness and contrast. The paramagnetic contrast agents include Gd-DTPA and gadobenate dimeglumine.

[0004] Patent No. US5733528 discloses a metal chelate Gd-DTPA is applied to a magnetic resonance imaging (MRI) imaging study based on human organs; CN100325733C Patent discloses a gadolinia and diethylene triamine pentaacetic acid (DTPA) complex , to give after separation of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), Gd-DTPA method of re-chelated meglumine obtained.

[0005] gadobenate dimeglumine gadolinium DTPA derivatives, widely used as paramagnetic contrast agents for magnetic resonance imaging. Clinical research shows that traitor, compared to Gd-DTPA, Gd Tony dimeglumine showed obvious advantages in terms of allergy, side effects and efficacy and so on. Moreover, Gd-DTPA was prepared using the purified and then after intermediate isolation, reacted not only with the stepwise synthesis of certain other compounds prepared by reacting the starting material many steps, long reaction period, and intermediate separation and purification operation complicated and likely to cause loss of product increased production costs. Therefore, the development of a simple method of synthesis Gadobenate dimeglumine is of great significance.

Patent

WO 2007031390

WO 2011073236

WO 2000002847

CN 102603550

PATENT

IN 201203216

IN 2012MU03216

The last step is Coordination of a Metal 12064-62-9, Gadolinium(III) oxide, to Carbon and Heteroatom

FIRST REPORT

  • By Vittadini, Giorgio; Felder, Ernst; Musu, Carlo; Tirone, Piero
  • From Investigative Radiology (1990), 25(Suppl. 1), S59-S60.

PRODUCT PATENT

  • By Cavagna, Friedrich; Dapra, Massimo; De Haen, Christoph; Maggioni, Fabio; Vicinanza, Eleonora
  • From Ital. Appl. (1992), IT 91MI1422 A1

AND WO 2011073236

References

  1. Jump up^ Sweetman, Sean C., ed. (2009). “Contrast Media”. Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 1478. ISBN 978-0-85369-840-1.
  2. Jump up to:a b Uggeri, F.; Aime, S., Anelli, P.L., Botta, M., Brocchetta, M., De Haën, C., Ermondi, G., Grandi, M., Paoli, P. (1995). “Novel contrast agents for magnetic resonance imaging. Synthesis and characterization of the ligand BOPTA and its Ln(III) complexes (Ln = Gd, La, Lu). X-ray structure of disodium (TPS-9-145337286-C-S)-[4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8, 11-triazatridecan-13-oato(5-)]gadolinate(2-) in a mixture with its enantiomer”. Inorg. Chem34 (3): 633–642. doi:10.1021/ic00107a017.
Gadobenic acid
Structure of Gadobenic acid.png
Clinical data
AHFS/Drugs.com International Drug Names
ATC code
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
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Chemical and physical data
Formula C22H28GdN3O11
Molar mass 667.72 g/mol
3D model (JSmol)

////////////////Gadobenate Dimeglumine, 113662-23-0, x ray contrast agent, b 1906, Gd(BOPTA)2, Gd-BOPTA, MultihanceE-7155

CNCC(C(C(C(CO)O)O)O)O.CNCC(C(C(C(CO)O)O)O)O.C1=CC=C(C=C1)COCC(C(=O)[O-])N(CCN(CCN(CC(=O)O)CC(=O)[O-])CC(=O)[O-])CC(=O)O.[Gd+3]

Chenodeoxycholic acid, ケノデオキシコール酸


Skeletal formula of chenodeoxycholic acid

ChemSpider 2D Image | chenodeoxycholic acid | C24H40O4Chenodeoxycholic acid.png

Chenodeoxycholic acid

Chenodiol

  • Molecular FormulaC24H40O4
  • Average mass392.572
UNII-0GEI24LG0J
ケノデオキシコール酸
474-25-9 [RN]
chenodeoxycholic acid [JP15] [Wiki]
(+)-chenodeoxycholic acid
(3a,5b,7a)-3,7-dihydroxy-cholan-24-oic acid
(3α,5β,7α,8ξ,20R)-3,7-Dihydroxycholan-24-säure[German] [ACD/IUPAC Name]
(4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-Dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
0GEI24LG0J
17b-(1-Methyl-3-carboxypropyl)etiocholane-3a,7a-diol
207-481-8[EINECS]
3a,7a-dihydroxy-5b-cholan-24-oic acid
3a,7a-dihydroxy-5b-cholanic acid; anthropodesoxycholic acid; gallodesoxycholic acid; 17b-(1-methyl-3-carboxypropyl)etiocholane-3a,7a-diol; chenic acid; chenodeoxycholic acid; CDC
Chenodeoxycholate;
Chenodeoxycholic acid;
3alpha,7alpha-Dihydroxy-5beta-cholanic acid;
Chenodiol

Synthesis ReferenceHenry Francis Frost, Fritz Fabian, Christopher James Sharpe, William Arthur Jones, “Process for preparing chenodeoxycholic acid.” U.S. Patent US4022806, issued October, 1974. US4022806

First ref 

  • By Windaus, A.; Bohne, A.; Schwarzkopf, E.
  • From Z. physiol. Chem. (1924), 140, 177-85
  • By Wieland, Heinrich; Reverey, Gustav
  • From Z. physiol. Chem. (1924), 140, 186-202.  

Title: Chenodiol
CAS Registry Number: 474-25-9
CAS Name: (3a,5b,7a)-3,7-Dihydroxycholan-24-oic acid
Additional Names: 3a,7a-dihydroxy-5b-cholanic acid; anthropodesoxycholic acid; gallodesoxycholic acid; 17b-(1-methyl-3-carboxypropyl)etiocholane-3a,7a-diol; chenic acid; chenodeoxycholic acid; CDC
Trademarks: Chendol (CP Pharm.); Chenocol (Astellas); Chenofalk (Falk); Chenossil (Sanofi-Aventis); Cholanorm (Grñenthal); Fluibil (Zambon)
Molecular Formula: C24H40O4
Molecular Weight: 392.57
Percent Composition: C 73.43%, H 10.27%, O 16.30%
Literature References: A major bile acid in many vertebrates, occurring as the N-glycine and/or N-taurine conjugate. With other bile acids, forms mixed micelles with lecithin in bile which solubilize cholesterol and thus facilitates its excretion. Facilitates fat absorption in the small intestine by micellar solubilization of fatty acids and monoglycerides. Has cathartic properties since it induces fluid secretion from large intestine. Main constituent of the bile of hens, geese and other fowl; occurs in appreciable amounts in the bile of hamster, hog, guinea pig, bear and man. Epimeric with ursodiol, q.v. Isoln: Windhaus et al.,Z. Physiol. Chem.140, 177 (1924); Wieland, Reveney, ibid. 186. Configuration: Lettré, Ber.68, 766 (1935). Prepn from cholic acid: Fieser, Rajagopalan, J. Am. Chem. Soc.72, 5530 (1950); Hauser et al.,Helv. Chim. Acta43, 1595 (1960); Hofmann, Acta Chem. Scand.17, 173 (1963). Alternate prepns: Sato, Ikekawa, J. Org. Chem.24, 1367 (1959); T. Iida, F. C. Chang, ibid.46, 2786 (1981). Stereoselective total synthesis: T. Kametani et al.,J. Am. Chem. Soc.103, 2890 (1981). Asymmetric total synthesis of (+)-form:eidem,J. Org. Chem.47, 2331 (1982). Dissolution of cholesterol gallstones: Danzinger et al.,N. Engl. J. Med.286, 1 (1972); Bell et al.,LancetII, 1213 (1972). Use in long-term treatment of cerebrotendinous xanthomatosis: V. M. Berginer et al.,N. Engl. J. Med.311, 1649 (1984). Monograph on bile acids: The Bile Acids, 2 vols., P. P. Nair, D. Kritchevsky, Eds. (Plenum Press, New York, 1971, 1973). Review of pharmacology and therapeutic use of chenodeoxycholic acid: J. H. Iser, A. Sali, Drugs21, 90-119 (1981). Effect on cholesterol and bile acid metabolism: G. S. Tint et al.,Gastroenterology91, 1007 (1986).
Properties: Needles from ethyl acetate + heptane, mp 119°. [a]D20 +11.5° (dioxane). Freely sol in methanol, alc, acetone, acetic acid; more sol in ether and ethyl acetate than deoxycholic acid. Practically insol in water, petr ether, benzene. High solvent power for alkali soaps, but does not form “choleic” acid addition compds as does deoxycholic acid. Forms beautiful cryst salts of Na, K and Ba. While the acid is tasteless, the Na salt tastes slightly sweet at first, then bitter.
Melting point: mp 119°
Optical Rotation: [a]D20 +11.5° (dioxane)
Derivative Type: Diformate
Molecular Formula: C25H40O6
Molecular Weight: 436.58
Percent Composition: C 68.78%, H 9.23%, O 21.99%
Properties: Clusters of needles from alc; mp with slight effervescence at 137°, upon further heating solidifies again, and finally melts around 172°.
Melting point: mp with slight effervescence at 137°
Derivative Type: Methyl ester
Molecular Formula: C25H42O4
Molecular Weight: 406.60
Percent Composition: C 73.85%, H 10.41%, O 15.74%
Properties: Fine needles from benzene + heptane, mp 90-91°. [a]D25 +20°.
Melting point: mp 90-91°
Optical Rotation: [a]D25 +20°
Therap-Cat: Anticholelithogenic.
Keywords: Cholelitholytic Agent.
SPECIFIC ROTATION
+13.23 °   ethanol ,  589.3 nm;  21 °C, Yonemura, Sadatomo; Journal of Biochemistry 1926, Vol6, Pg287-96
+12.5 °  chloroform, 589.3 nm; 17 °C  Plattner, Pl. A.; Helvetica Chimica Acta 1944, Vol27, Pg748-57
MP
Chenodeoxycholic acid (or Chenodiol) is an epimer of ursodeoxycholic acid (DB01586). Chenodeoxycholic acid is a bile acid naturally found in the body. It works by dissolving the cholesterol that makes gallstones and inhibiting production of cholesterol in the liver and absorption in the intestines, which helps to decrease the formation of gallstones. It can also reduce the amount of other bile acids that can be harmful to liver cells when levels are elevated.

Chenodeoxycholic acid (also known as chenodesoxycholic acidchenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165–167 °C. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the main bile acids produced by the liver.[1]

It was first isolated from the bile of the domestic goose, which gives it the “cheno” portion of its name (Greek: χήν = goose).[2]

Chenodeoxycholic acid and cholic acid are the two primary bile acids in humans. Some other mammals have muricholic acid or deoxycholic acid rather than chenodeoxycholic acid.[1]

Chenodeoxycholic acid is synthesized in the liver from cholesterol by a process which involves several enzymatic steps.[1] Like other bile acids, it can be conjugated in the liver with taurine or glycine, forming taurochenodeoxycholate or glycochenodeoxycholate. Conjugation results in a lower pKa. This means the conjugated bile acids are ionized at the usual pH in the intestine and will stay in the gastrointestinal tract until reaching the ileum where most will be reabsorbed. Bile acids form micelles which facilitate lipid digestion. After absorption, they are taken up by the liver and resecreted, so undergoing an enterohepatic circulation. Unabsorbed chenodeoxycholic acid can be metabolised by bacteria in the colon to form the secondary bile acid known as lithocholic acid.

Chenodeoxycholic acid is the most potent natural bile acid at stimulating the nuclear bile acid receptor, farnesoid X receptor (FXR).[3]The transcription of many genes is activated by FXR.

Indication

Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

Associated Conditions

Pharmacodynamics

It acts by reducing levels of cholesterol in the bile, helping gallstones that are made predominantly of cholesterol to dissolve. Chenodeoxycholic acid is ineffective with stones of a high calcium or bile acid content.

Mechanism of action

Chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Bile acids may also bind the the bile acid receptor (FXR) which regulates the synthesis and transport of bile acids.

EMA

On 16 December 2014, orphan designation (EU/3/14/1406) was granted by the European Commission to Sigma-Tau Pharma Ltd, United Kingdom, for chenodeoxycholic acid for the treatment of inborn errors in primary bile acid synthesis.

The sponsorship was transferred to sigma-tau Arzneimittel GmbH, Germany, in May 2015.

Chenodeoxycholic acid has been authorised in the EU as Chenodeoxycholic acid sigma-tau since 10 April 2017.

The name of the product changed to Chenodeoxycholic acid Leadiant in May 2017.

The sponsorship was transferred to Leadiant GmbH, Germany, in June 2017.

On 16 February 2017, the Committee for Orphan Medicinal Products (COMP) concluded its review of the designation EU/3/14/1406 for Chenodeoxycholic acid sigma-tau (chenodeoxycholic acid) as an orphan medicinal product for the treatment of inborn errors in primary bile acid synthesis. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with inborn errors in primary bile acid synthesis. The COMP recommended that the orphan designation of the medicine be maintained1.


1 The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with the same therapeutic indication cannot be placed on the market.

http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2015/02/WC500183233.pdf

Therapeutic applications

Chenodeoxycholic acid has been used as medical therapy to dissolve gallstones.[4]

Chenodeoxycholic acid can be used in the treatment of cerebrotendineous xanthomatosis.[5]

The Australian biotechnology company Giaconda has tested a treatment for Hepatitis C infection that combines chenodeoxycholic acid with bezafibrate.[6]

As diarrhea is a complication of chenodeoxycholic acid therapy, it has also been used to treat constipation.[7][8]

In supramolecular chemistrymolecular tweezers based on a chenodeoxycholic acid scaffold is a urea receptor that can contain anionsin its binding pocket in order of affinity: H2PO4 (dihydrogen phosphate) > Cl > Br > I reflecting their basicities (tetrabutylammonium counter ion).[9]

Molecular tweezer based on chenodeoxycholic acid
PAPER
1H and 13C NMR characterization and stereochemical assignments of bile acids in aqueous media
Lipids (2005), 40, (10), 1031-1041.
https://onlinelibrary.wiley.com/doi/abs/10.1007/s11745-005-1466-1

PAPER

Improved Chemical Synthesis, X-Ray Crystallographic Analysis, and NMR Characterization of (22R)-/(22S)-Hydroxy Epimers of Bile Acids
Lipids (2014), 49, (11), 1169-1180.

Improved Chemical Synthesis, X‐Ray Crystallographic Analysis, and NMR Characterization of (22R)‐/(22S)‐Hydroxy Epimers of Bile Acids

PAPER

A Practical and Eco-friendly Synthesis of Oxo-bile Acids

By Han, Young Taek and Yun, HwayoungFrom Organic Preparations and Procedures International, 48(1), 55-61; 2016

DOI:10.1080/00304948.2016.1127101

General Procedure

An aqueous solution of 0.2 M NaBrO3 (1.5 equiv. per hydroxy group) was added dropwise to a slurry of bile acid (1 equiv.) and ceric ammonium nitrate (0.05 equiv.) in 20% aqueous acetonitrile (0.2 M) at 80°C over 20 min. The bile acid slowly dissolved in a few minutes, and then the color of the reaction mixture changed to orange. The reaction mixture was stirred at the same temperature and the progress of the reaction was monitored by TLC on silica gel (1:20 MeOH-CH2Cl2) until disappearance of the starting material and partially oxidized intermediates. It was then cooled in an ice bath and quenched with aqueous Na2S2O3 solution. Water was added slowly to the resulting white suspension until no more oxo-bile acid precipitated. The white solid was collected, washed with water until the filtrate was colorless, and then dried in vacuo at 50°C. Methyl 3,7α-Diacetoxy-12-oxo-5β-cholanoate(3),21 was obtained in 92% yield (275 mg) as a white solid from 300 mg (0.590 mmol) of 2 via the general procedure. mp. 176-178°C, lit.22 mp. 178-179°C, IR (thin film, neat): 2947 (m), 2873 (s), 1736 (w), 1706 (w), 1436 (s), 1365 (m) cm-1; 1H-NMR (400 MHz, CDCl3): δ 4.96 (m, 1H, 7-CH), 4.55 (m, 1H, 3-CH), 3.64 (s, 3H), 2.49 (t, 1H, J = 12.6 Hz), 2.41-0.80 (m, 23H), 2.01 (s, 3H), 2.00 (s, 3H), 1.01 (s, 3H, 18-CH3), 1.00 (s, 3H, 19-CH3), 0.83 (d, 3H, J = 6.6 Hz, 21-CH3); 13C-NMR (CDCl3, 100 MHz): δ 214.0 (12-C), 174.6 (24-C), 170.7 (C = O), 170.2 (C = O), 73.5 (3-C), 70.5 (7-C), 57.1 (13-C), 53.1 (14-C), 51.5 (CH3O), 46.3 (17-C), 40.5 (5-C), 37.9 (11-C), 37.8 (4-C), 37.6 (8-C), 35.54 (9-C), 35.52 (20-C), 34.9 (1-C), 34.5 (10-C), 31.3 (6-C), 31.2 (22-C), 30.4 (23-C), 27.4 (16-C), 26.5 (2-C), 23.8 (15-C), 22.1 (19-C), 21.51 (CH3CO2), 21.46 (CH3CO2), 18.6 (21-C), 11.5 (18-C); LR-MS (FABC) m/z 505 (M+H +). HR-MS (FABC): Calcd for C29H45O7 (M+H +): 505.3165. Found 505.3161.

next step

R:KOH, R:N2H4

NOTE STARTING  IS BILE ACID AS BELOW

Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

  • 5β-Cholan-24-oic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (8CI)
  • 5β-Cholanic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (6CI,7CI)
  • 3α,7α-Diacetoxy-12-oxo-5β-cholan-24-oic acid methyl ester
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholanate
CAS 28535-81-1
C29 H44 O7  504.66
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo01091a623

Journal of Organic Chemistry
Volume24
Pages1367-8
Journal
1959

DOI:10.1021/jo01091a623

Chenodeoxycholic acid (V). Five hundred mg. of the above ester IV was hydrolyzed with 80 ml. of ethanolic 5% potassium hydroxide for 4 hr. After partial concentration of the volume and addition of water, the reaction product was acidified with hydrochloric acid. The resulting precipitate was collected, dried, and crystallized from ethyl acetate. A quantitative crop (400 mg.) of prisms melting at 143- 145° were obtained. Recrystallization from the same solvent yielded a product of m.p. 145-146°, [ ]2 +10.7° (dioxane). Anal. Caled, for C24H40O4: C, 73.43; H, 10.27. Found: C, 73.49; H, 10.31.

NOTE I IS BILE ACID

Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

  • 5β-Cholan-24-oic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (8CI)
  • 5β-Cholanic acid, 3α,7α-dihydroxy-12-oxo-, methyl ester, diacetate (6CI,7CI)
  • 3α,7α-Diacetoxy-12-oxo-5β-cholan-24-oic acid methyl ester
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate
  • Methyl 3α,7α-diacetoxy-12-oxo-5β-cholanate
CAS 28535-81-1
C29 H44 O7  504.66
Cholan-24-oic acid, 3,7-bis(acetyloxy)-12-oxo-, methyl ester, (3α,5β,7α)-

PATENT

https://patents.google.com/patent/CN102060902A/en

chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.

[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.

[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.

 Figure CN102060902AD00041

n particular by the following steps:

(1) Preparation of cholate: bile acid in alcohol, concentrated hydrochloric acid as catalyst, at reflux, cooling and crystallization, filtration, and washed with methanol.

[0008] (2) Preparation of 3α, 7α- diacetyl hydroxy -12α- cholate: bile acid ester was dissolved in dichloromethane and triethylamine was added with stirring acetic anhydride and the catalyst N, N- dimethyl pyridine, methylene chloride was distilled off, poured into water, filtered to give 3α, 7α- diacetyl -12 α – hydroxy cholate.

[0009] (3) 3α, 7α- diacetyl -12– Preparation oxo chenodeoxycholic acid ester: Take 3 α, 7 α – diacetyl -12 α – hydroxy cholate dissolved in ethyl acetate and methanol, bromide and tetrabutylammonium bromide as catalyst, and acetic acid was added dropwise under stirring hypochlorite, the organic solvent was distilled off and filtered, to give 12-oxo-3,7-diacetyl Chenodeoxy cholate.

[0010] (4) i2 – Preparation oxo chenodeoxycholic acid: 3,7-diacetyl-12-oxo-chenodeoxycholic acid ester added ethanol – sodium hydroxide solution, at reflux.PH adjusted with hydrochloric acid value of the reaction system acidic, ethanol was distilled off, and filtered to give 12- oxo crude chenodeoxycholic acid, fine recrystallization.

[0011] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid, ethylene glycol and solid sodium hydroxide, hydrated corpus, refluxed for 2 hours, gradually warming evaporated partially hydrated corpus, continue to heat up to 150 ° C, continued to reflux, cooled to room temperature, poured into water, adjusting the PH with hydrochloric acid, the white precipitate was filtered, washed with water to give crude chenodeoxycholic acid, recrystallization

Azusa mouth

M ο not mesh

[0012] Step (1): cholic acid to alcohol weight to volume ratio of 1: 2 ~ 5, the volume ratio of concentrated hydrochloric acid to alcohol is 10 wide: 100, 5-5 hours reflux time was 0.5.

[0013] Step (2): cholate: acetic anhydride molar ratio = 1: 2 ~ 5, the reaction temperature, time; Tl2O hours; cholate was added per mole of N, N- dimethylpyridine wide 5g.

[0014] Step (; 3): The hypochlorite is sodium hypochlorite or calcium hypochlorite; bromide is sodium bromide, potassium bromide and the like.

[0015] Step (4): recrystallization from a solvent with an alcohol such: as methanol or ethanol.

[0016] Step (5): recrystallization solvent is a water-miscible organic solvents, such as: methanol, ethanol, acetonitrile, acetone and the like.

[0017] Step (cholate was used ¾ of methyl cholate, ethyl cholate, cholic acid or cholic acid propyl ester; Step (3) used as 3 [alpha], 7 α – diacetyl -12 α – hydroxy cholate as 3 α, 7 α – diacetyl -12 α – hydroxy methyl cholate, 3 α, 7α- diacetyl -12 α – hydroxy bile acid ethyl ester, 3 α, 7α- diacetyl yl -12 α – hydroxy acid or ester 3α, 7α- diacetyl -12 α – hydroxy acid ester.

[0018] The invention has the advantages: in cholic acid as raw materials, and the choice of bromide tetrabutylammonium bromide as catalyst, in a non-polluting oxidizing agent is hypochlorite, Intermediate 3 α, 7 α – Diacetyl _12_ oxo chenodeoxycholic acid ester yield of 90% or more, thereby improving the yield of the final product of chenodeoxycholic acid, 99% yield, low cost and no pollution, very convenient for industrial production. detailed description

[0019] The present invention will be better described, for example is as follows:

(1) Preparation of methyl cholate: bile acid 5. lg, 15ml of anhydrous methanol, heating the whole solution. Refluxed for 3 hours, was added 0. 4ml concentrated hydrochloric acid, the reaction was stopped after 30min, after slow cooling, and filtered to give methyl cholate 5. 05g, 95% yield. 1HNMR (CDCl3):. Δ 0. 70 (s, 3H, 18- CH3), 0.90 (s, 3H, 19- CH3), 0.98 (d, 3H, 21-CH3), 3 50 (m, 1H, 3 β -H), 3. 67 (s, 3H, OCH3), 3. 87 (s, 1H, 7 β -H), 3. 99 (s, 1H, 12 β -H).

[0020] (2) Preparation of 3α, 7α- methyl cholate diacetyl-hydroxy -12α-: bile acid methyl ester 4. 71g (Ilmmol) IOOml was placed in a flask, was added methylene chloride 30ml, triethylamine 3 . Chiu 1, stirred at room temperature, was added dropwise acetic anhydride 2. 7ml (28. 6mmo 1), followed by addition of 20mg N, N- dimethylpyridine catalyst, the reaction time of 7 hours, methylene chloride was distilled off, into the water, filtered to give a white solid. The crude product was recrystallized from methanol to give white crystals 4. 05g, yield 67.2%. 1H NMR (CDCl3) δ: 4.90 (m, 1H, 7 β -H), 4. 59 (s, 1H, 3 β -H), 4 01 (s, 1H, 12 β -H), 3 67.. (s, 3Η, OCH3), 2. 08 (s, 3Η, CH3CO), 2. 02 (s, 3Η, CH3CO), 0. 98 (s, 3Η, 21-CH3), 0. 93 (s, 3Η , 19-CH3), 0.69 (s, 3Η, 18_CH3).

[0021] (3) 3α, 7α – 12-oxo-diacetyl chenodeoxycholic acid methyl ester prepared: Take 3 α, 7 α – diacetyl -12 α- hydroxy methyl cholate 1.917 g ( 3. 79mmol) was placed in a 50ml round bottom flask, 12ml of ethyl acetate was added, 5ml methanol, stirring at room temperature, was added 0. 25g 0. Ig of potassium bromide and tetrabutylammonium bromide. Was added dropwise a solution of acetic acid and 6g of sodium hypochlorite (7%) (5.62mmol), for 10 hours. Methanol was distilled off under reduced pressure and ethyl acetate, filtered, washed with water, and dried to give crude 1.915g, 1.75g as a white solid after recrystallization from methanol, yield 91.2%. 1H bandit R (CDCl3) δ:.. 4. 99 (d, 1H, 7 β-H), 4 60 (m, 1H, 3 β-H), 3 67 (s, 3H, OCH3), 2. 07 (s, 6H, CH3CO), 1. 03 (s, 6H, I8-CH3 and 19-CH3), 0. 82 (d, 3H, 21-CH3) ο

[0022] (4) 12- oxo chenodeoxycholic acid Preparation: Take 3 α, 7 α – diacetyl _12_ oxo chenodeoxycholic acid methyl ester 1. 56g, was dissolved in 30ml 95% ethanol was added 3. 2g of sodium hydroxide, heated at reflux for 5 hours. PH adjusted with hydrochloric acid value of the reaction system, most of the ethanol was distilled off, filtered, washed with water, and dried to give a white solid 12- oxo-1 crude chenodeoxycholic acid, recrystallized from methanol ^ g 1. 25g, yield rate of 96%. Tun bandit R (CDCl3) δ:. 3.96 (d, 1H, 7 β-H), 3 47 (m, 1H, 3 β-H), 1.03 (s, 3H, 19_CH3), 0.89 (s, 3H, 18_CH3 ), 0 · 70 (d, 3 H, 21_CH3).

[0023] Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid 0. 9g, 15ml ethylene glycol was added solid sodium hydroxide and 1. 5g, 15ml hydrated corpus (80%) , 120 ° C reflux for 2 hours, change return device is a distillation apparatus, was gradually warmed evaporated amount hydrated corpus, continue to heat up to 150 ° C, continuing reflux for 4h, cooled to room temperature, poured into water, adjusted with HCl of PH3, white precipitated, was filtered cake was washed with water, and dried to give crude chenodeoxycholic acid 0. 92g, recrystallized from methanol to give 0. 86g, 99 (s, 1H, C00H).

Paper

https://pubs.acs.org/doi/abs/10.1021/ja01168a045

Reactions of 2-Arylcyclohexanones. IV. Michael Addition of Malonic Ester to 2-Phenyl-Δ2-cyclohexenone

J. Am. Chem. Soc.195072 (12), pp 5529–5530
DOI: 10.1021/ja01168a045
Publication Date: December 1950
PAPER
Hauser et al., Helv. Chim. Acta 43, 1595 (1960);
Paper

The Preparation of Chenodeoxycholic Acid and Its Glycine and Taurine Conjugates.Hofmann, Alan F.

Pages: 173-186.
DOI number: 10.3891/acta.chem.scand.17-0173
Download as: PDF DjVu
PAPER
Sato, Ikekawa, J. Org. Chem. 24, 1367 (1959)

Preparation of Chenodeoxycholic Acid

J. Org. Chem.195924 (9), pp 1367–1368
DOI: 10.1021/jo01091a623
Publication Date: September 1959
PAPER
J. Org. Chem. 47, 2331 (1982)

Further studies on the synthesis of thienamycin: a facile and stereoselective synthesis of a bicyclic .beta.-keto ester by 1,3-dipolar cycloaddition

J. Org. Chem.198247 (12), pp 2328–2331
DOI: 10.1021/jo00133a019
PAPER
PATENT

Chenodeoxycholic acid (3α, 7α- -5β- dihydroxy-cholestane acid) Chenodeoxycholic Acid (referred to as CDCA), a medicine for treating gallstones. 1848 first discovered in goose bile, 1924, known as the CDCA. By reducing cholesterol absorption, synthesis, the bile cholesterol decreased, thereby suppressing cholesterol gallstone formation and promote dissolution, and can reduce cholesterol saturation.

Chenodeoxycholic acid addition pharmaceutically itself, but also as the preparation of ursodeoxycholic acid (3α, 7β- -5β- dihydroxy bile acid, abbreviated UDCA) starting material. Ursodeoxycholic acid is the main active ingredient contained bile valuable medicine, in clinical treatment of various gastrointestinal diseases and bladder diseases. But the limited sources of bear bile medicine, and contrary to the principles of animal protection. So, dwindling source of natural bear bile, can not meet the medical requirements. Therefore, the preparation of chenodeoxycholic acid is also of great significance for further preparation of ursodeoxycholic acid.

CDCA bile extracted mainly from poultry or animal bile extraction methods in the past as it involves toxic chemicals (animal biological pharmacy, 1981, People’s Medical Publishing House, P259; pharmaceutical industry, 1987,18 (2): 75-76; ) or unsafe to use a large amount of organic solvent (Chinese Journal of biochemical Pharmaceutics, 1996,17 (1): 17; application technology, 1998,4: 9-10; US Patent, 3,965,131; US Patent, 4,331,607; USPatent, 4,163,017), can not be meet the requirements of modern industry, CDCA and low purity prepared costly.

PATENT

https://patents.google.com/patent/WO2007069814A1/en

Chenodeoxycholic acid is generally contained in bile of cow, swine, bear, or poultry such as chicken or goose, as well as in bile of human. Chenodeoxycholic acid is used as starting material for the preparation of ursodeoxycholic acid which is effective to alleviate biliary system diseases, hyperlipidemia, cholelithiasis, and chronic liver diseases, and a typical process for preparing ursodeoxycholic acid known in the art is as follows.

A typical process for preparing chenodeoxycholic acid comprises the steps of: esterifying cholic acid (3α,7α,12θ!-trihydroxy cholic acid) with methyl; protecting the hydroxyl group of 3α and Ia position by acetylating them with anhydrous acetic acid; oxidizing the hydroxyl group of 12α position to carbonyl group by using chromic acid, and then removing the carbonyl group by Wolff-kichner reduction reaction; hydrolyzing and deprotecting the obtained product to yield chenodeoxycholic acid. The above process requires the reaction to be maintained at a high temperature of more than 200 °C , and the supply of raw material may be interrupted by bovine spongiform encephalopathy, etc. Bile ,of poultry contains chenodeoxycholic acid, lithocholic acid, and a small amount of cholic acid. Thus, the process for separating chenodeoxycholic acid from poultry is well known in the art, but is not economically reasonable due to the supply decrease of raw material and low yield [see, Windhaus et al, I Physiol. Chem., 140, 177-185 (1924)].

US Patent No. 4,186,143 disclosed a process for purely separating and purifying chenodeoxycholic acid from chenodeoxycholic acid mixture derived from natural swine bile. This process comprises the major steps of: pre-treatment to remove 3ohydroxy-6- oxo-5/3-cholic acid by saponification of bile; esterification of bile acid; acetylation of bile acid ester; removal of intermediate product by using non-polar organic solvent; crystallization of acetylated ester of formula I; deprotection; and production of the compound of formula I by using crystallization in organic solvent. However, this patent does not describe HPLC content for acetylated ester of formula I, and the purity of the final product is very low since the specific rotatory power is [ofo25 +13.8° (c=l, CHCl3), and the melting point is 119-121 °C [STD: [α]D 25 +15.2°(c=l, CHCl3), melting point 127- 129 “C]. Also, the crystallization for purifying the final product requires a very long time (i.e., 16-48 hours), and the entire process is complex as eight (8) steps. Thus, when purifying the compound of formula I by using the above process, the yield of the final product becomes low, and the reaction time is as long as 12 days. Therefore, the process is not economically reasonable.

Step 6: Deprotection and crystallization of chenodeoxycholic acid

To 220ml of water were added 24.5g of chenodeoxycholic acid-diacetate-ester and 29.5g of sodium hydroxide, and then the solution was stirred with reflux for 4 hours. To the solution was added 370ml of water. The solution’s pH is adjusted to 2.0-3.0 by using 59ml of hydrochloric acid. Then, the solution was stirred at 35-45 °C for 1 hour, and then filtered. The filtered material was washed with 24.5ml of water and dried in vacuum at 70 °C to obtain 19.5g of pure chenodeoxycholic acid, m.p.: 160-161 °C, [α]o25 +13.0°(c=l, CHCl3).

Step 8: Production of the compound of formula I

The reaction solution was extracted by using ethyl acetate, and aqueous layer was discarded therefrom. Ethyl acetate layer in the solution was washed with 6% saline, and the solution was distilled to about 90ml. This solution was cooled, kept cool for one day after adding 90ml of hexane, and filtered. Thus filtered material was washed with 20ml of hexane, and dried in vacuum at 60 °C to produce 12.7g of chenodeoxycholic acid. m.p. 142-1450C; [α]D 25 +13.0°(c=l, CHCl3). INDUSTRIAL APPLICABILITY The present invention can purify chenodeoxycholic acid of formula I from swine bile solid in high yield and purity. Also, the present invention is suitable for industrial purification by reducing the purification time.

PATENT

https://patents.google.com/patent/CN102060902A/en

chenodeoxycholic acid (3 α, 7 α – dihydroxy _5 β – cholestane-24-oic acid) Chenodeoxycholic Ac id (referred to as CDCA), clinically used to correct dissolving cholesterol calculi and bile saturation drugs, the main function is to reduce the cholesterol in the bile saturation, large doses can inhibit the synthesis of cholesterol CDCA and increasing bile gallstone patients cholesterol level in a non-saturated, thereby preventing the formation of cholesterol gallstones of cholesterol and promote stone dissolve and fall off. It also has significant anti-asthmatic, anti-inflammatory, antitussive and expectorant effects.

[0003] Synthesis of chenodeoxycholic acid or ursodeoxycholic acid (3 α, 7β_ -5β_ dihydroxy-cholestane-24-oic acid, ursodeoxycholic Acid, referred UDCA), a key intermediate. Ursodeoxycholic acid is the main active ingredient of precious Chinese medicine bear bile, used in a variety of clinical hepatobiliary disease and dyspepsia. Currently we bear bile resources are scarce, mainly used synthetic chemical ursodeoxycholic acid as a clinical treatment. Therefore, the preparation of chenodeoxycholic acid is also important for the preparation of ursodeoxycholic acid.

[0004] CDCA mainly come from poultry or livestock bile extraction. Traditional extraction process complicated operation, low yield, (pharmaceutical industry, 1987,18 (9), 416; Chinese Journal of Biochemical Pharmaceutics, 1996,17 (1), 17; Applied Technology, 1998, (4), 9; CN1850846A ) can not meet the needs of modern industry. Chemical synthesis of chenodeoxycholic acid have also been reported (Japanese Journal of Chemistry 1955,76 (3), 297 -J Org Chem 1982,47 (2): 2331; Journal of Biochemical Pharmaceutics 1987,1,6 -, Tap Chi Duoc ^ oc2004 , 44 (1), 11; CN1869043A), but lower yield widespread pollution major problem, especially in the oxidation reaction is often used to expensive, and polluting agents.Therefore, to reduce pollution, reduce environmental hazards, streamline operations, improve yield, reduce costs, important for the synthesis of chenodeoxycholic acid.

 Preparation of chenodeoxycholic acid.

[0007]

Figure CN102060902AD00041
Preparation of chenodeoxycholic acid (5): 12- oxo take chenodeoxycholic acid 0. 9g, 15ml ethylene glycol was added solid sodium hydroxide and 1. 5g, 15ml hydrated corpus (80%) , 120 ° C reflux for 2 hours, change return device is a distillation apparatus, was gradually warmed evaporated amount hydrated corpus, continue to heat up to 150 ° C, continuing reflux for 4h, cooled to room temperature, poured into water, adjusted with HCl of PH3, white precipitated, was filtered cake was washed with water, and dried to give crude chenodeoxycholic acid 0. 92g, recrystallized from methanol to give 0. 86g, 99% yield. .. 1HnMR (CD3SOCD3) S: 0.60 (s, 3H, 18- CH3), 0 90 (s, 3H, 19_CH3), 0.95 (d, 3H, 21-CH3), 3 47 (s, IH, 3 β – H), 3. 96 (s, 1H, 7 β -H), 11. 94 (s, 1H, C00H).
PATENT

Cholic acid esters prepared by (1) Weigh 50 g of cholic acid, dissolved in 150 ml of anhydrous methanol was added 5 ml of concentrated hydrochloric acid was refluxed for 30 minutes, cooled slowly into the freezer, the available capacity methyl cholate It was 95%.

(2) hydroxy -12α- diacetyl – Preparation of methyl cholate methyl cholate weighed 50 g, was dissolved in 100 ml of pyridine was purified, dissolved completely, 100 ml of acetic anhydride was stirred at room temperature for 3 to 4 hours, poured into 500 ml of water, a white precipitate in the refrigerator, filtered the next day, diacetyl -12α- available hydroxy – methyl cholate, yield 40%.

(3) 3α, 7α–diacetoxy-12-oxo – Preparation of methyl cholanic acid prepared above was weighed 25 g of crude product, dissolved in 250 ml of acetone, filtered to remove insolubles, the stirring conditions , the Jones reagent was slowly added, at room temperature for 30 minutes, filtered, water was added to the filtrate precipitated white precipitate was filtered available 3α, 7α–diacetoxy-12-oxo – methyl-cholanic acid. The yield was 100%.

(4) 12- oxo – Preparation of chenodeoxycholic acid in ethanol 10% – sodium hydroxide solution and saponified for 1 hour at room temperature, the solution was acidified, poured into water to give 12- oxo – chenodeoxycholic acid , 100% yield.Recrystallized in absolute ethanol.

Preparation of chenodeoxycholic acid (5) was weighed 12- oxo – chenodeoxycholic acid, 20 grams, was added 300 ml of ethylene glycol and 30 g of solid sodium hydroxide and 300 ml of hydrazine hydrate (85%), 100 ℃ refluxed for 2 hours, warming gradually raised to 130. ℃, generated by hydrazine hydrate was distilled off, continue to heat up to 185 ~ 190 ℃, continued reflux for 4 hours, cooled to a lower temperature, poured into water and heat, PH adjusted with hydrochloric acid (20%) 3, a white precipitate was filtered cake was washed with water to give chenodeoxycholic acid.

(6) Purification of chenodeoxycholic acid obtained weighed amount of chenodeoxycholic acid, dissolved with a small amount of ethanol, was impregnated on a silica gel column petroleum ether, liquid flow linear velocity by column chromatography 1 ~ 5cm / control points, with petroleum ether: acetone = 2, begins to elute, detected by TLC chromatography therebetween, Junichi appearance of spots to be chenodeoxycholic acid appears to start collecting the eluate until no Chenodeoxy acid spots, distillation under reduced pressure and dried to give pure higher chenodeoxycholic acid.

PATENTS

Publication numberPriority datePublication dateAssigneeTitle
WO2007069814A1 *2005-12-122007-06-21Daewoong Pharmaceutical Co., Ltd.Purification process for chenodeoxycholic acid
WO2007078039A1 *2005-12-302007-07-12Daewoong Pharmaceutical Co., Ltd.Purification process for chenodeoxycholic acid
CN100484952C2005-12-132009-05-06山东博尔德生物科技有限公司Method for producing high-purity chenodeoxy cholic acid from poultry and livestock bile
CN102060902A *2011-01-212011-05-18郑州大学Chenodeoxycholic acid synthesis method
CN102286051A *2011-08-152011-12-21上海华震科技有限公司A method for separating chenodeoxycholic acid and ursodeoxycholic acid
CN102690856A *2012-05-302012-09-26绵阳劲柏生物科技有限责任公司Process using microbial solution to prepare free bile acid
CN102703556A *2012-05-302012-10-03绵阳劲柏生物科技有限责任公司Method for separating chenodeoxycholic acid from duck bile by using macroporous resin
CN101830956B2008-11-192012-11-21毕小升Preparation method for separating and purifying chenodeoxycholic acid in porcine bile paste or leftovers
CN102827234A *2012-08-302012-12-19苏州天绿生物制药有限公司Method for separating and purifying chenodeoxycholic acid from duck gall
CN103360454A *2013-05-062013-10-23广西大学Method for separating and purifying chenodeoxycholic acid from goose bile
US3919266A1972-09-211975-11-11Intellectual Property Dev CorpProduction of bile acids
FR2429224A1 *1978-06-191980-01-18Canada Packers LtdChenodeoxycholic acid recovery from porcine bile – useful for dissolving gall stones in vivo
JPS60181096A *1984-02-281985-09-14Tokyo Tanabe Co LtdPurification of bile acid
EP0386538A21989-03-061990-09-12ERREGIERRE INDUSTRIA CHIMICA SpaProcess for preparing high purity 3-alpha-7-beta-dihydroxycholanic acid
JPH03227998A *1990-02-021991-10-08Showa Denko KkMethod for purifying chenodeoxycholic acid
CN1528779A *2003-09-292004-09-15华东理工大学Method for preparing cheodexycholic acid
Family To Family Citations
GB1450939A *1973-12-191976-09-29Intellectual Property
US4186143A *1977-06-201980-01-29Canada Packers LimitedChenodeoxycholic acid recovery process
KR100658512B1 *2005-12-302006-12-11주식회사 대웅제약Purification process for chenodeoxycholic acid

References

  1. Jump up to:a b c Russell DW (2003). “The enzymes, regulation, and genetics of bile acid synthesis”Annu. Rev. Biochem72: 137–74. doi:10.1146/annurev.biochem.72.121801.161712PMID 12543708.
  2. Jump up^ Carey MC (December 1975). “Editorial: Cheno and urso: what the goose and the bear have in common”. N. Engl. J. Med293 (24): 1255–7. doi:10.1056/NEJM197512112932412PMID 1186807.
  3. Jump up^ Parks DJ, Blanchard SG, Bledsoe RK, et al. (May 1999). “Bile acids: natural ligands for an orphan nuclear receptor”Science284 (5418): 1365–8. doi:10.1126/science.284.5418.1365PMID 10334993.
  4. Jump up^ Thistle JL, Hofmann AF (September 1973). “Efficacy and specificity of chenodeoxycholic acid therapy for dissolving gallstones”N. Engl. J. Med289 (13): 655–9. doi:10.1056/NEJM197309272891303PMID 4580472.
  5. Jump up^ Berginer VM, Salen G, Shefer S (December 1984). “Long-term treatment of cerebrotendinous xanthomatosis with chenodeoxycholic acid”N. Engl. J. Med311 (26): 1649–52. doi:10.1056/NEJM198412273112601PMID 6504105.
  6. Jump up^ Giaconda. “Press release”. Retrieved 5 April 2014.
  7. Jump up^ Bazzoli F, Malavolti M, Petronelli A, Barbara L, Roda E (1983). “Treatment of constipation with chenodeoxycholic acid”. J. Int. Med. Res11 (2): 120–3. PMID 6852359.
  8. Jump up^ Rao AS, Wong BS, Camilleri M, et al. (November 2010). “Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis”Gastroenterology139 (5): 1549–58, 1558.e1. doi:10.1053/j.gastro.2010.07.052PMC 3189402Freely accessiblePMID 20691689.
  9. Jump up^ Ki Soo Kim, Hong-Seok Kim Molecular Tweezer Based on Chenodeoxycholic Acid:Synthesis, Anion Binding Properties. Bulletin of the Korean Society 1411-1413 2004 Article ArchivedSeptember 27, 2007, at the Wayback Machine.
Chenodeoxycholic acid
Skeletal formula of chenodeoxycholic acid
Ball-and-stick model of the chenodeoxycholic acid molecule
Names
IUPAC names

chenodiol
OR
3α,7α-dihydroxy-5β-cholanic acid
OR
5β-cholanic acid-3α,7α-diol
OR
(R)-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.006.803
EC Number 207-481-8
KEGG
PubChem CID
UNII
Properties
C24H40O4
Molar mass 392.57 g/mol
Melting point 165 to 167 °C (329 to 333 °F; 438 to 440 K)
Pharmacology
A05AA01 (WHO)
License data
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
No verify (what is YesNo ?)
Infobox references

////////////////////Chenodeoxycholic acid,  ケノデオキシコール酸 , orphan designation

[H][C@@]1(CC[C@@]2([H])[C@]3([H])[C@H](O)C[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)[C@H](C)CCC(O)=O

VORAPAXAR SULPHATE


ChemSpider 2D Image | Vorapaxar | C29H33FN2O4

Vorapaxar.png

VORAPAXAR

Thrombosis, Antiplatelet Therapy, PAR1 Antagonists , MERCK ..ORIGINATOR

Ethyl N-[(3R,3aS,4S,4aR,7R,8aR,9aR)-4-[(E)-2-[5-(3-fluorophenyl)-2-pyridyl]vinyl]-3-methyl-1-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3H-benzo[f]isobenzofuran-7-yl]carbamate

Carbamic acid, [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2- pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-, ethyl ester
Carbamic acid, N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)-2-pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-, ethyl ester
Ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(E)-2-[5-(3-fluorophenyl)-2-pyridinyl]vinyl}-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate

Ethyl ((1R,3aR,4aR,6R,8aR,9S,9aS)-9-((1E)-2-(5-(3-fluorophenyl)pyridin-2-yl)ethenyl)- 1-methyl-3-oxododecahydronaphtho(2,3-c)furan-6-yl)carbamate

Carbamic acid, ((1R,3aR,4aR,6R,8aR,9S,9aS)-9-((1E)-2-(5-(3-fluorophenyl)-2- pyridinyl)ethenyl)dodecahydro-1-methyl-3-oxonaphtho(2,3-c)furan-6-yl)-, ethyl ester

618385-01-6 CAS NO FREE FORM

CAS Number: 705260-08-8 SULPHATE

Has antiplatelet activity.

Also known as: SCH-530348, MK-5348
Molecular Formula: C29H33FN2O4
 Molecular Weight: 492.581723
ZCE93644N2
  • UNII-ZCE93644N2
  • Zontivity

Registered – 2015 MERCK Thrombosis

Vorapaxar (formerly SCH 530348) is a thrombin receptor (protease-activated receptor, PAR-1) antagonist based on the natural product himbacine. Discovered by Schering-Plough and currently being developed by Merck & Co., it is an experimental pharmaceutical treatment for acute coronary syndrome chest pain caused by coronary artery disease.[1]

In January 2011, clinical trials being conducted by Merck were halted for patients with stroke and mild heart conditions.[2] In a randomized double-blinded trial comparing vorapaxar with placebo in addition to standard therapy in 12,944 patients who had acute coronary syndromes, there was no significant reduction in a composite end point of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. However, there was increased risk of major bleeding.[3]

A trial published in February 2012, found no change in all cause mortality while decreasing the risk of cardiac death and increasing the risk of major bleeding.[4]

SCH-530348 is a protease-activated thrombin receptor (PAR-1) antagonist developed by Schering-Plough and waiting for approval in U.S. for the oral secondary prevention of cardiovascular events in patients with a history of heart attack and no history of stroke or transient ischemic attack. The drug candidate is being investigated to determine its potential to provide clinical benefit without the liability of increased bleeding; a tendency associated with drugs that block thromboxane or ADP pathways. In April 2006, SCH-530348 was granted fast track designation in the U.S. for the secondary prevention of cardiovascular morbidity and mortality outcomes in at-risk patients.

Vorapaxar was recommended for FDA approval on January 15, 2014.[5]

Vorapaxar is a protease-activated thrombin receptor (PAR-1) antagonist developed by Schering-Plough (now, Merck & Co.) and approved in the U.S. in 2014 for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. However, in 2018 Aralez discontinued U.S. commercial operations. In 2015, the product was approved in the E.U. for the reduction of atherothrombotic events in adult patients with a history of myocardial infarction. In April 2006, vorapaxar was granted fast track designation in the U.S. for the secondary prevention of cardiovascular morbidity and mortality outcomes in at-risk patients. In 2016, Aralez Pharmaceuticals acquired the U.S. and Canadian rights to the product pursuant to an asset purchase agreement entered into between this company and Merck & Co.

Merck & Co (following its acquisition of Schering-Plough) has developed and launched vorapaxar (Zontivity; SCH-530348; MK-5348), an oral antagonist of the thrombin receptor (protease-activated receptor-1; PAR1); the product is marketed in the US by Aralez Pharmaceuticals

WO-03089428, published in October 2003, claims naphtho[2,3-c]furan-3-one derivatives as thrombin receptor antagonists. WO-03033501 and WO-0196330, published in April 2003 and December 2001, respectively, claim himbacine analogs as thrombin receptor antagonists. WO-9926943 published in June 1999 claims tricyclic compounds as thrombin receptor antagonists

VORAPAXAR

17 JAN 2014
FDA advisory panel votes to approve Merck & Co’s vorapaxar REF 6

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000ChemR.pdf

Zontivity (vorapaxar) tablets NDA 204886

VORAPAXAR SULPHATE

2D chemical structure of 705260-08-8

CAS Number: 705260-08-8 SULPHATE

Molecular Formula: C29H33FN2O4.H2O4S

Molecular Weight: 590.7

Chemical Name: Ethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)pyridin-2- yl]ethenyl]-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate sulfate

Synonyms: Carbamic acid, [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2- pyridinyl]ethenyl]dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-,ethyl ester,sulfate; SCH-530348

Vorapaxar Sulfate (SCH 530348) a thrombin receptor (PAR-1) antagonist for the prevention and treatment of atherothrombosis.

POLYMORPH

U.S.Pat. No. 7,304,078 discloses Vorapaxar base. U.S.Pat. No. 7,235,567 discloses Polymorph I and II of vorapaxar sulphate

CN 106478608 provides a crystalline polymorph A 

EMA

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002814/WC500183331.pdf

Atherosclerosis and ischemic cardiovascular (CV) diseases like coronary artery disease (CAD) are progressive systemic disorders in which clinical events are precipitated by episodes of vascular thrombosis. Patients with an established history of atherothrombotic or athero-ischemic disease are at particular risk of future cardiac or cerebral events, and vascular death. Anti-thrombotic therapy options in patients with stable atherosclerosis are not well-established. Long-term therapies to effectively modulate the key components responsible for atherothrombosis in secondary prevention of ischemic CV disease are therefore required. Vorapaxar is a first – in – class selective antagonist of the protease-activated receptor 1 (PAR-1), the primary thrombin receptor on human platelets, which mediates the downstream effects of this critical coagulation factor in hemostasis and thrombosis. Thrombin-induced platelet activation has been implicated in a variety of cardiovascular disorders including thrombosis, atherosclerosis, and restenosis following percutaneous coronary intervention (PCI). As an antagonist of PAR-1, vorapaxar blocks thrombin-mediated platelet aggregation and thereby has the potential to reduce the risk of atherothrombotic complications of coronary disease. The applicant has investigated whether a new class of antiplatelet agents, PAR-1 antagonists, can further decrease the risk of cardiovascular events in a population of established atherothrombosis when added to standard of care, in secondary prevention of ischemic diseases. The following therapeutic indication has been submitted for vorapaxar: Vorapaxar is indicated for the reduction of atherothrombotic events in patients with a history of MI. Vorapaxar has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization. Vorapaxar will be contraindicated in patients with a history of stroke or TIA. The indication sought in the current application is supported by the efficacy results of the TRA 2P-TIMI, which is considered the pivotal trial for this indication. During the procedure, the applicant requested the possibility of extending the indication initially sought for, to extend it to the population of PAD patients. This request was discussed at the CHMP and not accepted by the Committee.

Introduction The finished product is presented as immediate release film-coated tablets containing 2.5 mg of vorapaxar sulfate as active substance per tablet, corresponding to 2.08 mg vorapaxar. Other ingredients are: lactose monohydrate, microcrystalline cellulose (E460), croscarmellose sodium (E468), povidone (E1201) , magnesium stearate (E572), hypromellose (E464), titanium dioxide (E171), triacetin (glycerol triacetate) (E1518), iron oxide yellow (E172), as described in section 6.1 of the SmPC. The product is available in Aluminium–Aluminium blisters (Alu-Alu) as described in section 6.5 of the SmPC.

General information The chemical name of the active substance vorapaxar sulfate is ethyl[(1R,3aR,4aR,6R,8aR,9S,9aS)- -9-{(1E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethen-1-yl}-1-methyl-3-oxododecahydronaphtho[2,3-c] furan-6-yl]carbamate sulfate, corresponding to the molecular formula C29H33FN2O4 • H2SO4 and has a relative molecular mass 590.7. It has the following structure:

str1

The structure of the active substance has been confirmed by mass spectrometry, infrared spectroscopy, 1H- and 13C-NMR spectroscopy and X-ray crystallography, all of which support the chemical structure elemental analysis. It appears as a white to off-white, slightly hygroscopic, crystalline powder. It is freely soluble in methanol and slightly soluble in ethanol and acetone but insoluble to practically insoluble in aqueous solutions at pH above 3.0. The highest solubility in aqueous solution can be achieved at pH 1.0 or in simulated gastric fluids at pH 1.4. The dissociation constant of vorapaxar sulfate was determined to be pKa = 4.7 and its partition coefficient LogP was determined to be 5.1. Vorapaxar sulfate contains seven chiral centers and a trans double bond. The seven chiral centres are defined by the manufacturing process of one of the intermediates in the vorapaxar synthesis and potential enantiomers are controlled by appropriate specifications. The cis-isomer of the double bond is controlled by a highly stereo-specific process reaction resulting in non-detectable levels of cis-isomer impurity. The cis-isomer impurity is controlled in one of the intermediates as an unspecified impurity. A single crystalline stable anhydrous form has been observed.

GENERAL INTRODUCTION

SIMILAR NATURAL PRODUCT

+ HIMBACINE

(+)-Himbacine ~98% (GC), powder, muscarinic receptor antagonist

Himbacine is an alkaloid muscarinic receptor antagonist displaying more potent activity associated with M2 and M2 subtypes over M1 or M3. Observations show himbacine bound tightly to various chimeric receptors in COS-7 cells as well as possessed the ability to bind to cardiac muscarinic receptors allosterically. Recent studies have produced series of thrombin receptor (PAR1) antagonists derived from himbacine Himbacine is an inhibitor of mAChR M2 and mAChR M4.

Technical Information
Physical State: Solid
Derived from: Australian pine Galbulimima baccata
Solubility: Soluble in ethanol (50 mg/ml), methanol, and dichloromethane. Insoluble in water.
Storage: Store at -20° C
Melting Point: 132-134 °C
Boiling Point: 469.65 °C at 760 mmHg
Density: 1.08 g/cm3
Refractive Index: n20D 1.57
Optical Activity: α20/D +51.4º, c = 1.01 in chloroform
Application: An alkaloid muscarinic receptor antagonist
CAS Number: 6879-74-9
 
Molecular Weight: 345.5
Molecular Formula: C22H35NO2

General scheme:

Figure imgf000016_0001

PATENT

WO 2006076415

WO 2006076452

WO 2003089428

US 6063847

CN 107540564

WO 2008005344

CN 106749138

PATENT

CN 105348241 prepn

Example 1:

[0027] The steel shed amide (300mg, 7. 93mmol) and 15 blood THF was added to 100 blood Ξ jar. The starting material II (2.OOg, 5. 89mmol) was dissolved in 15mL of THF dropwise via pressure-equalizing dropping funnel to the reaction system, the process temperature will produce a large number of bubbles -2 ~ 0 ° C, in the process, Lan mix of about 0.1 until no bubbles generate. THF solution containing 13 Blood Ship (0.75 Yap, 2. 95mmol) is transferred to a pressure-equalizing dropping funnel. It was slowly added dropwise to the reaction system. After the completion of dropwise continue to embrace mix ratio. After the treatment, at 0 ° C under 0.8 blood, Imol / L 1 fat slowly dropped into the embrace mixed reaction system, after adding the right amount of water, acetic acid extraction. The combined organic phase with Imol / L of 0H (17mLX3) washing the organic phase coating. Tu brine, dried over anhydrous sulfate steel, 25 ° C under reduced pressure to spin dry to give 1. 75g light yellow oil, yield 91%.

[0028] After the content was determined using the external standard method, first prepared by a qualified reference determine its content, W this as a standard substance, measuring the external standard method to get the content of 99%.

[0029] Zan NMR: (400MHz, CD3CN):… 5 46 of r, 1H), 4 70 (td, 1H), 4 03 based 2H), 3 69-3 57 (m, 2 Η).. , 3. 45-3. 32 (based, IH), 2. 77 (br, IH), 2. 61-2. 51 (m, IH), 2. 49-2. 39 (m, 1 field, 2 30 of r IH), 2 .12-1. 92 (m, IH), 1. 87 (dt, IH), 1. 81-1. 72 (m, IH), 1. 61-1. 50 ( …. m, IH), 1 48 (d, 3H), 1 23-1 09 (m, 7H), 1. 05-0 90 (m, 2H);

[0030] MS (ES +) m / z: 326. 24 [M + + field.

[Cited 00] Example 2:

[003 cited the steel shed amide (312mg, 8. 25mmol) and 16 blood THF was added to the lOOmL Ξ jar. The starting material II (2.OOg, 5. 89mmol) was dissolved in 15mL of THF dropwise via pressure-equalizing dropping funnel to the reaction system, the process temperature will produce a large number of bubbles -2 ~ -5 ° C, in the process and takes about 45min mix until no bubbles generate. The 13 ships of blood containing 60g, 2. 36mmol) in THF solution was transferred to a pressure-equalizing dropping funnel. It was slowly added dropwise to the reaction system. After the completion of dropwise continue to embrace mix ratio. After the treatment, at 0 ° C under 0.8 blood, Imol / L 1 fat slowly dropped into the embrace mixed reaction system, after adding the right amount of water, acetic acid extraction. The combined organic phase with llmol / L of 0H (17mLX3) washing the organic phase coating. Tu brine, dried over anhydrous sulfate steel, 25 ° C under reduced pressure to spin dry to give 1. 65g light yellow oil.

[0033] Determination of Reference Example 1 in an amount of 98.7%.

[0034] MS (ES +) m / z: 326. 24 [M + + field.

[003 cited Example 3:

[0036] 50 single jar of blood, condenser. Intermediate inb (l.〇〇g, 3. 07mmol) was dissolved in 10ml of dichloromethane burn during and after the blood was added to a 50-port flask, make dioxide of 32g, 3.68mmol), the reaction of reflux. After completion of the reaction by TLC, cooled to 20 ~ 25 ° C after suction filtration, the filter cake rinsed with methylene burning (the X3 3 blood), at 30 ° CW and the filtrate was concentrated to dryness. To the residue was added 5 blood acetic acid, at 20 ~ 25 ° C after mixing 0. embrace of suction, the resulting cake was vacuum dried at 30 ° C 10 ~ 12h. Give 0. 87g of white solid.

[0037] Electric NMR: (400MHz, CD3CN):. 9 74 oriented 1H), 5 40 of r, 1H), 4 77-4.66 (m, 1H), 4 09-3 98 (m, 2H…. ), 3. 49-3. 37 (m, IH), 2. 75-2. 64 (m, 2H), 2. 55-2. 48 (m, IH), 1. 95-1. 87 (m , 2H), 1. 89-1 .77 (m, 2H), 1. 61-1. 49 (m, IH), 1. 32-1. 13 (m, 9H), 1. 08-0. 82 (m, 2H);

[0038] MS (ES +) m / z: 324. 33 [M + + field.

PATENT

CN 106478608 crystal

https://patents.google.com/patent/CN106478608A/en

The present invention provides a crystalline polymorph A one kind of the compound of formula I:

Figure CN106478608AD00051

In another embodiment, the present invention provides a method of preparing a crystalline polymorph of compound A I,

Figure CN106478608AD00052

Which comprising, a) the compound II is dissolved in acetonitrile and stirred to form a mixture; b) heating the mixture to 50 ° C ~ 70 ° C; c) adding sulfuric acid to the heated mixture; d) evaluating the temperature was lowered to 0 ° C ~ 20 ° C, seeded and stirred to precipitate crystals.

Preparation [0042] A crystalline polymorph of the compound of Example 1 I

Figure CN106478608AD00091

Compound II (1. 0g) was dissolved in 5. 0ml of acetonitrile, stirred and heated to 50 ° C ~ 70 ° C was added and this temperature was added 1.2ml 2N H2S04 / acetonitrile solution and then lowering the temperature of the system to 15 ° C ~ 20 ° C, the system was added to the appropriate amount of seed crystals and stirred for 2h, the precipitated solid was filtered and the cake washed twice with 2. 5ml of acetonitrile to give a white solid, the white solid was placed under 40 ° C desolventizing 2 hours and then dried at 80 ° C for vacuo to give a white solid 0. 83 g, 69. 3% yield, HPLC:. 99 94%. A powder X-ray diffraction spectrum shown in Figure 1, a DSC endothermic curve shown in Figure 2, which HPLC profile shown in Fig.

PATENT

CN 201510551080

https://patents.google.com/patent/CN106478608A/en

PATENT

WO 2009093972 synthesis

https://encrypted.google.com/patents/WO2009093972A1?cl=ko&hl=en&output=html_text

Clip

Vorapaxar sulfate (Zontivity)
Merck Sharp & Dohme successfully obtained approval in the EU in 2014 for vorapaxar sulfate, marketed as Zontivity. The drug is a first-in-class thrombin receptor (also referred to as a protease-activated or PAR-1) antagonist which, when used in conjunction with antiplatelet therapy, has been shown to reduce the chance of
myocardial infarction and stroke, particularly in patients with a history of cardiac events.277

Antagonism of PAR-1 allows for thrombin-mediated fibrin deposition while blocking thrombinmediated platelet activation.277 Although a variety of papers and patents describe the synthesis of vorapaxar sulfate (XXXVII),278–282 a combination of two patents describe the largest-scale synthesis reported in the literature, and this is depicted in Scheme 52.

Retrosynthetically, the drug can be divided into olefination partners 306 and 305.283,284 Lactone 305
is further derived from synthons 300 and 299, which are readily prepared from commercially available starting materials. Dienyl acid 300 was constructed in two steps starting from commercial vinyl bromide 307, which first undergoes a Heck reaction with methacrylate (308) followed by saponification of the ester to afford the desired acid 300 in 71% over two steps (Scheme 53).

The synthesis of alcohol 299 begins with tetrahydropyranyl (THP) protection of enantioenriched alcohol 295 to afford butyne 297 (Scheme 52). Lithiation of this system followed by trapping with (benzyloxy)chloroformate and Dowex work-up to remove the protective functionality provided acetyl ester 298. Hydrogenation of the alkyne with Lindlar’s catalyst delivered cis-allylic alcohol 299 in 93% yield. Acid 300 was then esterified with alcohol 299 by way of a 1,3-dicyclohexylcarbodiimide (DCC) coupling and, upon heating in refluxing xylenes, an intramolecular Diels–
Alder reaction occurred. Subsequent subjection to DBU secured the tricyclic system 301 in 38% over three steps as a single enantiomer.
Diastereoselective hydrogenation reduced the olefin with concomitant benzyl removal to give key fragment 302. Next, acidic revelation of the ketone followed by reductive amination with ammonium formate delivered primary amines 303a/303b as a mixture of diastereomers. These amines were then converted to the corresponding carbamates, and resolution by means of recrystallization yielded 50% of 304 as the desired diastereomer. Acid 304
was treated with oxalyl chloride and the resulting acid chloride was reduced to aldehyde 305 in 66% overall yield. Finally, deprotonation of phosphonate ester 306 (whose synthesis is described in Scheme 54) followed by careful addition of 305 and acidic quench delivered vorapaxar sulfate (XXXVII) in excellent yield over the
two-step protocol.

The preparation of vorapaxar phosponate ester 306 (Scheme 54)commenced from commercial sources of 5-(3-fluorophenyl)-2-methylpyridine (310). Removal of the methyl proton with LDA followed by quench with diethyl chlorophosphonate resulted in phosponate ester 306.

277. Frampton, J. E. Drugs 2015, 75, 797.
278. Chackalamannil, S.; Wang, Y.; Greenlee, W. J.; Hu, Z.; Xia, Y.; Ahn, H.; Boykow,G.; Hsieh, Y.; Palamanda, J.; Agans-Fantuzzi, J.; Kurowski, S.; Graziano, M.;Chintala, M. J. Med. Chem. 2008, 51, 3061.
279. Sudhakar, A.; Kwok, D.; Wu, G. G.; Green, M. D. WO Patent 2006076452A2,2006.

280. Wu, G. G.; Sudhakar, A.; Wang, T.; Ji, X.; Chen, F. X.; Poirier, M.; Huang, M.;Sabesan, V.; Kwok, D.; Cui, J.; Yang, X.; Thiruvengadam, T.; Liao, J.; Zavialov, I.;Nguyen, H. N.; Lim, N. K. WO Patent 2006076415A2, 2006.
281. Yong, K. H.; Zavialov, I. A.; Yin, J.; Fu, X.; Thiruvengadam, T. K. US Patent20080004449A1, 2008.
282. Chackalamannil, S.; Clasby, M.; Greenlee, W. J.; Wang, Y.; Xia, Y.; Veltri, E.;Chelliah, M. WO Patent 03089428A1, 2003.
283. Thiruven-Gadam, T. K.; Wang, T.; Liao, J.; Chiu, J. S.; Tsai, D. J. S.; Lee, H.; Wu,W.; Xiaoyong, F. WO Patent 2006076564A1, 2006.
284. Chackalamannil, S.; Asberon, T.;Xia, Y.; Doller, D.; Clasby, M. C.; Czarniecki,M. F. US Patent 6,063,847, 2000.

PRODUCT PATENT

SYNTHESIS

WO2003089428A1

Inventor Samuel ChackalamannilMartin C. ClasbyWilliam J. GreenleeYuguang WangYan XiaEnrico P. VeltriMariappan ChelliahWenxue Wu

Original Assignee Schering Corporation

Priority date 2002-04-16

THE EXACT BELOW COMPD IS 14

Example 2

Step 1 :

Figure imgf000019_0001

Phosphonate 7, described in US 6,063,847, (3.27 g, 8.1 mmol) was dissolved in THF (12 ml) and C(O)Oled to 0 °C, followed by addition of 2.5 M n- BuLi (3.2 ml, 8.1 mmol). The reaction mixture was stirred at 0 °C for 10 min and warmed up to rt. A solution of aldehyde 6, described in US 6,063,847, in THF (12 ml) was added to the reaction mixture. The reaction mixture was stirred for 30 min. Standard aqueous work-up, followed by column chromatography (30-50% EtOAc in hexane) afforded product 8. 1HNMR (CDCI3): δ 0.92-1.38 (m, 31 H), 1.41 (d, J= 6 Hz, 3H), 1.40-1.55 (m, 2H), 1.70-1.80 (m, 2H), 1.81-1.90 (m, 2H), 2.36 (m, 2H), 2.69 (m, 1 H), 3.89 (m, 4H), 4.75 (m, 1 H), 6.28-6.41 (m, 2H), 7.05-7.15 (m, 2H), 8.19 (br s, 1 H). Step 2:

Figure imgf000020_0001

Compound 8 (2.64 g, 4.8 mmol) was dissolved in THF (48 ml). The reaction mixture was C(O)Oled to 0 °C followed by addition of 1 M TBAF (4.8 ml). The reaction mixture was stirred for 5 min followed by standard aqueous work-up. Column chromatography (50% EtOAc/hexane) afforded product 9 (1.9 g, 100%). 1HNMR (CDCI3): δ 1.15-1.55 (m, 6H), 1.41 (d, J= 6 Hz, 3H), 1.70-1.82 (m, 3H), 1.85-1.90 (m, 1 H), 2.36 (m, 2H), 2.69 (m, 1 H), 3.91 (m, 4H), 4.75 (m, 1 H), 6.18- 6.45 (m, 2H), 7.19 (br s, 2H), 8.19 (br s, 1 H). Step 3:

Figure imgf000020_0002

To a solution of compound 9 (250 mg, 0.65 mmol) in pyridine (5 ml) C(O)Oled to 0 °C was added Tf2O (295 μL, 2.1 mmol). The reaction mixture was stirred overnight at rt. Standard aqueous work-up followed by column chromatography afforded product 10 (270 mg, 80%). 1HNMR (CDCI3): δ 1.15-1.55 (m, 6H), 1.41 (d, J= 6 Hz, 3H), 1.70-1.82 (m, 3H), 1.85-1.90 (m, 1 H), 2.36 (m, 2H), 2.69 (m, 1 H), 3.91 (m, 4H), 4.75 (m, 1 H), 6.42-6.68 (m, 2H), 7.25 (m, 1 H), 7.55 (m, 1 H), 8.49 (d, J= 2.8 Hz, 1 H).

Figure imgf000020_0003

Compound 10 (560 mg, 1.1 mmol), 3-fluorophenyl boronic acid (180 mg, 1.3 mmol) and K2CO3 (500 mg, 3.6 mmol) were mixed with toluene (4.4 ml), H2O (1.5 ml) and EtOH (0.7 ml) in a sealed tube. Under an atmosphere of N2, Pd(Ph3P)4 (110 mg, 0.13 mmol) was added. The reaction mixture was heated at 100 °C for 2 h under N2. The reaction mixture was C(O)Oled down to rt, poured to EtOAc (30 ml) and washed with water (2X20 ml). The EtOAc solution was dried with NaHCO3 and concentrated at reduced pressure to give a residue. Preparative TLC separation of the residue (50% EtOAc in hexane) afforded product 11 (445 mg, 89%). 1HNMR (CDCI3): δ 1.15-1.59 (m, 6H), 1.43 (d, J= 6 Hz, 3H), 1.70-1.79 (m, 2H), 1.82 (m, 1H), 1.91 (m, 2H), 2.41 (m, 2H), 2.69 (m, 1 H), 3.91 (m, 4H), 4.75 (m, 1 H), 6.52-6.68 (m, 2H), 7.15 (m, 1 H), 7.22 (m, 2H), 7.35 (m, 1 H), 7.44 (m, 1 H), 7.81 (m, 1 H), 8.77 (d, J= 1.2 Hz, 1 H). Step 5:

Compound 11 (445 mg, 0.96 mmol) was dissolved in a mixture of acetone (10 ml) and 1 N HCI (10 ml). The reaction mixture was heated at 50 °C for 1 h.

Standard aqueous work-up followed by preparative TLC separation (50% EtOAc in hexane) afforded product 12 (356 mg, 89%). 1HNMR (CDCI3): δ 1.21-1.45 (m, 2H), 1.47 (d, J= 5.6 Hz, 3H), 1.58-1.65 (m, 2H), 2.15 (m, 1 H), 2.18-2.28 (m, 2H), 2.35- 2.51 (m, 5H), 2.71 (m, 1 H), 4.79 (m, 1 H), 6.52-6.68 (m, 2H), 7.15 (m, 1 H), 7.22 (m, 2H), 7.35 (m, 1 H), 7.44 (m, 1 H), 7.81 (m, 1 H), 8.77 (d, J= 1.2 Hz, 1 H). Step 6:

Figure imgf000021_0002

Compound 12 (500 mg, 4.2 mmol) was dissolved in EtOH (40 ml) and CH2CI2 (15 ml) NH3 (g) was bubbled into the solution for 5 min. The reaction mixture was C(O)Oled to 0 °C followed by addition of Ti(O/Pr)4 (1.89 ml, 6.3 mmol). After stirring at 0 °C for 1 h, 1 M TiCI (6.3 ml, 6.3 mmol) was added. The reaction mixture was stirred at rt for 45 min and concentrated to dryness under reduced pressure. The residue was dissolved in CH3OH (10 ml) and NaBH3CN (510 mg, 8 mmol) was added. The reaction mixture was stirred overnight at rt. The reaction mixture was poured to 1 N NaOH (100 ml) and extracted with EtOAc (3x 100 ml). The organic layer was combined and dried with NaHC03. Removal of solvent and separation by PTLC (5% 2 M NH3 in CH3OH/ CH2CI2) afforded β-13 (spot 1 , 30 mg, 6%) and α-13 (spot 2, 98 mg, 20%). β-13: 1HNMR (CDCI3): δ 1.50-1.38 (m, 5H), 1.42 (d, J= 6 Hz, 3H), 1.51-1.75 (m, 5H), 1.84 (m, 2H), 2.38 (m, 1 H), 2.45 (m, 1 H), 3.38 (br s, 1 H), 4.78 (m, 1 H), 6.59 (m, 2H), 7.15 (m, 1 H), 7.26 (m, 2H), 7.36 (m, 1 H), 7.42 (m, 1 H), 7.82 (m, 1 H), 8.77 (d, J= 2 Hz, 1 H). α-13:1HNMR (CDCI3): δ 0.95 (m, 2H), 1.02-1.35 (m, 6H), 1.41 (d, J= 6 Hz, 3H), 1.82-1.95 (m, 4H), 2.37 (m; 2H), 2.69 (m, 2H), 4.71 (m, 1 H), 6.71 (m, 2H), 7.11 (m, 1 H), 7.25 (m, 2H), 7.38 (m, 1 H), 7.42 (m, 1 H), 7.80 (m, 1 H), 8.76 (d, J= 1.6 Hz, 1 H). Step 7:

Compound α-13 (300 mg, 0.71 mmol) was dissolved in CH2CI2 (10 ml) followed by addition of Et3N (0.9 ml). The reaction mixture was C(O)Oled to 0 °C and ethyl chloroformate (0.5 ml) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was directly separated by preparative TLC (EtOAc/ hexane, 1 :1) to give the title compound (14) VORAPAXAR   (300 mg, 86%). MS m/z 493 (M+1).

HRMS Calcd for C29H34N2O4F (M+1 ): 493.2503, found 493.2509.

PATENT

SYNTHESIS 1

http://www.google.com/patents/WO2006076564A1

VORAPAXAR= COMPD A

Example 6 – Preparation of Compound A

Figure imgf000035_0001

To a three-neck flask equipped with an agitator, thermometer and nitrogen inertion was added 7A (13.0 g), THF (30 mL). The mixture was cooled to below -200C after which lithium diisopropylamide (2M, 20 mL) was slowly added. The reaction mixture was agitated for an additional hour (Solution A). To another flask was added 6 (10.0 g) and THF (75 mL) . The mixture was stirred for about 30 minutes and then slowly transferred into the solution A while maintaining the temperature below 200C. The mixture was stirred at below -200C for an additional hour before quenching the reaction by adding 20 mL of water. The reaction mixture was warmed to 00C and the pH was adjusted to about 7 by addition of 25% HaSO4 (11 mL). The mixture was further warmed to 200C and then diluted with 100 mL of ethyl acetate and 70 mL of water. The two phases that had formed were separated and the aqueous layer was extracted with 50 mL of ethyl acetate. The solvents THF and ethyl acetate were then replaced with ethanol, and the Compound A was precipitated out as a crystalline solid from ethanol with seeding at 35 to 4O0C. After cooling to O0C, the suspension was stirred for an additional hour and then the product was filtered and washed with cold ethanol. The product was dried at 50 – 600C under vacuum to provide an off-white solid. VORAPAXAR

Yield: 12.7 g, (90%). m.p. 104.90C (DSC onset point).

1H NMR (CDCl3) δ 8.88 (d, J = 2.4 Hz, IH), 8.10 (dd, J = 8.2, 2.4 Hz, IH), 7.64 (IH), 7.61 (d, J = 8.8 Hz, IH), 7.55 (m, J = 8.2, 6.2 Hz, IH), 7.51 (d, J = 8.0 Hz, IH), 7.25 (dt, J = 9.0, 2.3 Hz, IH), 7.08 (d, J = 8.0 Hz, IH), 6.68 (dd, J = 15.4, 9.4 Hz, IH), 6.58 (d, J = 9.6 Hz, IH), 4.85 (dd, J = 14.2, 7.2 Hz, IH), 3.95 (dd, J = 14.2, 7.1 Hz, 2H), 3.29 (m, IH), 2.66 (m, J = 12.0, 6.4 Hz, IH), 2.33 (m, 2H), 1.76 (m, 4H), 1.30 (d, J = 5.6 Hz, 3H), 1.19 (m, 4H), 1.14 (t, J = 7.2 Hz, 3H), 0.98 (m, IH), 0.84 (m, IH). MS (EI) m/z: calcd. 492, found 492.

BISULPHATE SALT

Example 7 – Preparation of an Acid Salt (bisulfate) of Compound A:

Compound IA (5 g) was dissolved in about 25 mL of acetonitrile.

The solution was agitated for about 10 minutes and then heated to about 50 0C. About 6 mL of 2M sulfuric acid in acetonitrile was added into the heated reaction mixture. The solid salt of Compound A precipitated out during the addition of sulfuric acid in acetonitrile. After addition of sulfuric acid solution, the reaction mixture was agitated for 1 hour before cooling to room temperature. The precipitated solid was filtered and washed with about 30 mL of acetonitrile. The wet solid was dried under vacuum at room temperature for 1 hour and at 80 0C for about 12 hours to provide about 5 g white solid (yield 85%). m.p. 217.0 0C. 1H NMR (DMSO) 9.04 (s, IH), 8.60 (d, J = 8.1 Hz, IH), 8.10 (d, J = 8.2 Hz, IH), 7.76 (d, J = 10.4, IH), 7.71 (d, J = 7.8 Hz, IH), 7.60 (dd, J = 8.4, 1.8 Hz, IH), 7.34 (dd, 8.4, 1.8 Hz, IH), 7.08 (d, J = 8.0 Hz, IH), 7.02 (m, IH), 6.69 (d, J = 15.8 Hz, IH), 4.82 (m, IH), 3.94 (dd, J = 14.0, 7.0 Hz, 2H), 3.35 (brs, IH), 2.68 (m, IH), 2.38 (m, 2H), 1.80-1.70 (m, 4H), 1.27 (d, J = 5.8 Hz, 3H), 1.21 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H), 0.95 (m, IH, 0.85 (m, IH). MS (EI) m/z calcd. 590, found 492.

INTERMEDIATE 6

Example 5- Preparation of Compound 6

Figure imgf000032_0001

To a three-neck flask equipped with an agitator, thermometer and nitrogen inert were added the crude product solution of Compound 5 (containing about 31 g. of Compound 5 in 300 mL solution) and anhydrous DMF (0.05 mL). After the mixture was agitated for 5 minutes, oxalyl chloride (12.2 mL) was added slowly while maintaining the batch temperature between 15 and 25°C. The reaction mixture was agitated for about an hour after the addition and checked by NMR for completion of reaction. After the reaction was judged complete, the mixture was concentrated under vacuum to 135 mL while maintaining the temperature of the reaction mixture below 300C. The excess oxalyl chloride was removed completely by two cycles of vacuum concentration at below 500C with replenishment of toluene (315 mL) each time, resulting in a final volume of 68 mL. The reaction mixture was then cooled to 15 to 25°C, after which THF (160 mL) and 2,6-lutidine (22 mL) were added. The mixture was agitated for 16 hours at 20 to 25°C under 100 psi hydrogen in the presence of dry 5% Pd/C (9.0 g). After the reaction was judged complete, the reaction mixture was filtered through celite to remove catalyst. More THF was added to rinse the hydrogenator and catalyst, and the reaction mixture was again filtered through celite. Combined filtrates were concentrated under vacuum at below 25°C to 315 mL. MTBE (158 mL) and 10% aqueous solution of phosphoric acid (158 mL) were added for a thorough extraction at 100C to remove 2,6- lutidine. Then phosphoric acid was removed by extracting the organic layer with very dilute aqueous sodium bicarbonate solution (about 2%), which was followed by a washing with dilute brine. The organic solution was concentrated atmospherically to a volume of 90 mL for solvent replacement. IPA (315 mL) was added to the concentrated crude product solution. The remaining residual solvent was purged to <_ 0.5% of THF (by GC) by repeated concentration under vacuum to 68 mL, with replenishment of IPA (315 mL) before each concentration. The concentrated (68 mL) IPA solution was heated to 50°C, to initiate crystallization. To this mixture n-heptane (68 mL) was added very slowly while maintaining the batch temperature at 50°C. The crystallizing mixture was cooled very slowly over 2.5 hours to 25°C. Additional n- heptane (34 mL) was added very slowly into the suspension mixture at 250C. The mixture was further cooled to 200C, and aged at that temperature for about 20 hours. The solid was filtered and washed with a solvent mixture of 25% IPA in n-heptane, and then dried to provide

19.5 g of a beige colored solid of Compound 6. (Yield: 66%) m.p. 169.30C. IH NMR (CD3CN) δ 9.74 (d, J = 3.03 Hz, IH), 5.42 (br, IH), 4.69 (m, IH), 4.03 (q, J = 7.02 Hz, 2H), 3.43 (qt, J = 3.80, 7.84 Hz, IH), 2.67 (m, 2H), 2.50 (dt, J = 3.00, 8.52 Hz, IH), 1.93 (d, J = 12.0 Hz, 2H), 1.82 (dt, J = 3.28, 9.75 Hz, 2H), 1.54 (qd, J = 3.00, 10.5 Hz, IH), 1.27 (d, J = 5.97 Hz, 3H), 1.20 (m, 6H), 1.03 – 0.92 (m, 2H). MS (ESI) m/z (M++1): calcd. 324, found 324.

INTERMEDIATE 7A

Example 4 – Preparation of Compound 7A

+ 1-Pr2NLi + (EtO)2POCI – + LiCI

8
Figure imgf000031_0001

7A

To a 10 L three-necked round bottomed flask equipped with an agitator, thermometer and a nitrogen inlet tube, was added 20Og of

Compound 8 (1.07 mol, from Synergetica, Philadelphia, Pennsylvania). THF (1000 mL) was added to dissolve Compound 8. After the solution was cooled to -80 0C to -50 0C, 2.0 M LDA in hexane/THF(1175 mL, 2.2 eq) was added while maintaining the batch temperature below -50 0C. After about 15 minutes of agitation at -800C to -50 0C, diethyl chlorophosphate (185 mL, 1.2 eq) was added while maintaining the batch temperature below -50 0C. The mixture was agitated at a temperature from -800C to – 50 0C for about 15 minutes and diluted with n-heptane (1000 mL). This mixture was warmed up to about -35 0C and quenched with aqueous ammonium chloride (400 g in 1400 mL water) at a temperature below -10 0C. This mixture was agitated at -150C to -10 0C for about 15 minutes followed by agitation at 150C to 25 0C for about 15 minutes. The aqueous layer was split and extracted with toluene (400 mL). The combined organic layers were extracted with 2N hydrochloric acid (700 mL) twice. The product-containing hydrochloric acid layers were combined and added slowly to a mixture of toluene (1200 mL) and aqueous potassium carbonate (300 g in 800 mL water) at a temperature below 30 0C. The aqueous layer was extracted with toluene (1200 mL). The organic layers were combined and concentrated under vacuum to about 600 ml and filtered to remove inorganic salts. To the filtrate was added n-heptane (1000 ml) at about 55 0C. The mixture was cooled slowly to 40 0C, seeded, and cooled further slowly to -10 0C. The resulting slurry was aged at about -10 0C for 1 h, filtered, washed with n- heptane, and dried under vacuum to give a light brown solid (294 g, 85% yield), m.p. 52 0C (DSC onset point).1H NMR (CDCl3) δ 8.73 (d, J = 1.5 Hz, IH), 7.85 (dd, Ji = 8.0 Hz, J2 = 1.5 Hz, IH), 7.49 (dd, Ji = 8.0 Hz, J2 = 1.3 Hz, IH), 7.42 (m, IH), 7.32 (d, J = 7.8 Hz, IH), 7.24 (m, IH), 7.08 (dt, Ji = 8.3 Hz, J2 = 2.3 Hz, IH), 4.09 (m, 4H), 3.48 (d, J = 22.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 6H). MS (ESI) for M+H calcd. 324, found 324.

Example 3 – Preparation of Compound 5:

4                                                                                                            5

To a three-necked round bottomed flask equipped with an agitator, thermometer and a nitrogen inlet tube was added a solution of Compound 4 in aqueous ethanol (100 g active in 2870 ml). The solution was concentrated to about 700 ml under reduced pressure at 350C to 40°C to remove ethyl alcohol. The resultant homogeneous mixture was cooled to 200C to 300C and its pH was adjusted to range from 12 to 13 with 250 ml of 25% sodium hydroxide solution while maintaining the temperature at 20-300C. Then 82 ml of ethyl chloroformate was slowly added to the batch over a period of 1 hour while maintaining the batch temperature from 200C to 300C and aged for an additional 30 minutes. After the reaction was judged complete, the batch was acidified to pH 7 to 8 with 10 ml of concentrated hydrochloric acid (37%) and 750 ml of ethyl acetate. The pH of the reaction mixture was further adjusted to pH 2 to 3 with 35% aqueous hydrochloric acid solution. The organic layer was separated and the aqueous layer was extracted again with 750 ml of ethyl acetate. The combined organic layers were washed twice with water (200 ml) . Compound 5 was isolated from the organic layer by crystallization from ethyl acetate and heptane mixture (1: 1 mixture, 1500 ml) at about 700C to 80 0C. The solid was filtered at 500C to 60 °C, washed with heptane and then dried to provide an off-white solid (yield 50%). m.p. 197.7°C. 1HNMR (CD3CN) δ 5.31 (brs, IH), 4.67 (dt, J = 16.1, 5.9 Hz, IH), 4.03 (q, J = 7.1 Hz, 2H), 3.41 (m, IH), 2.55 – 2.70 (m, 2H), 1.87 – 1.92 (m, IH), 1.32 – 1.42 (m, IH), 1.30 (d, J = 5.92 Hz, 3H), 1.30 – 1.25 (m, 6H), 0.98 (qt, J = 15.7, 3.18 Hz, 2H). MS (ESI) M+l m/z calculated 340, found 340.

Example 2 – Preparation of Compound 4;

3                                                                                                4

7.4 kg of ammonium formate was dissolved in 9L of water at 15- 250C, and then cooled to 0-100C. 8.9 kg of Compound 3 was charged at 0-150C followed by an addition of 89L of 2B ethyl alcohol. The batch was cooled to 0-50C 0.9 kg of 10% Palladium on carbon (50% wet) and 9 L of water were charged. The batch was then warmed to 18-280C and agitated for 5 hours, while maintaining the temperature between 18-28 0C. After the reaction was judged complete, 7 IL of water was charged. The batch was filtered and the wet catalyst cake was then washed with 8OL of water. The pH of the filtrate was adjusted to 1-2 with 4N aqueous hydrochloric acid solution. The solution was used in the next process step without further isolation. The yield is typically quantiative. m.p. 216.40C. IH NMR (D2O+1 drop HCl) δ 3.15 (m, IH), 2.76 (m, IH), 2.62 (m, IH), 2.48 (dd,J-5.75Hz, IH), 1.94 (m, 2H), 1.78 (m, 2H), 1.38 (m, 2H), 1.20 (m, 6H), 1.18 (m, IH), 0.98 (q,J=2.99Hz, IH).

Example 1 – Preparation of Compound 3

Figure imgf000028_0001

2B                                                                                                              3

To a reactor equipped with an agitator, thermometer and nitrogen, were added about 10.5 kg of 2B, 68 L of acetone and 68 L of IN aqueous hydrochloric acid solution. The mixture was heated to a temperature between 50 and 600C and agitated for about 1 hour before cooling to room temperature. After the reaction was judged complete, the solution was concentrated under reduced pressure to about 42 L and then cooled to a temperature between 0 and 50C. The cooled mixture was agitated for an additional hour. The product 3 was filtered, washed with cooled water and dried to provide an off-white solid (6.9 kg, yield 76%). m.p. 2510C. Η NMR (DMSO) δ 12.8 (s, IH), 4.72 (m, J = 5.90 Hz, IH), 2.58 (m, 2H), 2.40 (m, J = 6.03 Hz, 2H), 2.21 (dd, J = 19.0, 12.8 Hz, 3H), 2.05 (m, IH), 1.87 (q, J = 8.92 Hz, IH), 1.75 (m, IH), 1.55 (m, IH), 1.35 (q, J = 12.6 Hz, IH), 1.27 (d, J = 5.88 Hz, 3H). MS (ESI) M+l m/z calcd. 267, found 267.

NOTE

Compound 7A may be prepared from Compound 8 by treating Compound 8 with diethylchlorophosphate:

Figure imgf000027_0001

Compound 8 may be obtained by the process described by Kyoku, Kagehira et al in “Preparation of (haloaryl)pyridines,” (API Corporation, Japan). Jpn. Kokai Tokkyo Koho (2004). 13pp. CODEN: JKXXAF JP

2004182713 A2 20040702. Compound 8 is subsequently reacted with a phosphate ester, such as a dialkyl halophosphate, to yield Compound 7A. Diethylchlorophosphate is preferred. The reaction is preferably conducted in the presence of a base, such as a dialkylithium amide, for example diisopropyl lithium amide.

Paper

J Med Chem 2008, 51(11): 3061

http://pubs.acs.org/doi/abs/10.1021/jm800180eAbstract Image

The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.

Ethyl [(3aR,4aR,8aR,9aS)-9(S)-[(E)-2-[5-(3-fluorophenyl)-2-
pyridinyl]ethenyl]dodecahydro-1(R)-methyl-3-oxonaphtho[2,3-c]furan-6(R)-yl]carbamate (4).

4 (300 mg, 86%). MS m/z 493 (M+1).

HRMS Calcd for C29H34N2O4F
(M+1): 493.2503, found 493.2509; mp125 °C;

[]D20 6.6 (c 0.5, MeOH).

1HNMR (CDCl3):

http://pubs.acs.org/doi/suppl/10.1021/jm800180e/suppl_file/jm800180e-file002.pdf

0.88-1.18 (m, 5 H), 1.22-1.30 (m, 3 H), 1.43 (d, J = 5.85 Hz, 3 H), 1.88-2.10 (m, 4 H), 2.33-2.42 (m, 2 H),
2.75-2.67 (m, 1 H), 3.52-3.60 (m, 1 H), 4.06-4.14 (m, 2 H), 4.54-4.80 (m, 1 H), 4.71-4.77 (m, 1 H),
6.55-6.63 (m, 2 H), 7.07-7.12 (m, 1 H), 7.26-7.29 (m, 2 H), 7.34 (d, J = 8.05 Hz, 1 H), 7.41-7.46 (m, 1 H), 7.80-7.82 (m, 1 H), 8.76-8.71 (m, 1 H).

PATENT

IN 201621010411

An improved process for preparation of Vorapaxar intermediates and a novel polymorphic form of Vorapaxar

ALEMBIC PHARMACEUTICALS LIMITED

Vorapaxar Sulfate is indicated for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD). ZONTIVITY has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR).

According to present invention Vorapaxar sulfate is synthesized from compound of formula 1.

str1

wherein R1 and R2 are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups. Process for the preparation of compound of formula 1 is disclosed in U.S Pat. No. 7,605,275. It disclosed preparation of compound of formula 1 via cyclization of compound 2 in presence of solvent selected from xylene, N-methylpyrrolidinone, Dimethylsulfoxide, diphenyl ether, dimethylacetamide. This cyclization step takes approximately 6-8 hrs.

There is need to develop a process which takes less time for cyclization step to prepare compound of formula 1. Therefore, our scientist works tenaciously to develop process which takes approximately 1-2 hrs for cyclization of compound 1.

str1

5 According to present invention Vorapaxar sulfate is synthesized from intermediate compound of formula-II.

str2

Formula-II Compound of formula-II is critical intermediate in the preparation of Vorapaxar Sulfate.

10 Patent WO2006076415 discloses the process of preparation of above Formula-II in example 7, in which purification/crystallisation step involves treating the reaction mixture having compound of Formula-II with an ethanol/water mixture followed by azeotropic distillation of the mixture. This process yielded formula-II with low yields and with low purities. WO2009055416 (page 9, second paragraph) discloses that use of various solvent systems for

15 formula-II purification such as Methyl-tert-Butyl Ether (MTBE) and various solvent/antisolvent systems, for example, ethylacetate/heptane and toluene/heptane and by using these solvent systems, compound of formula-II are obtained as oil. These oils did not yield a reduced impurity profile in synthesis of the compound of Formula II, nor provide an improvement in the quality of the product compound of Formula II.

20 The inventors surprisingly found that using the process according to the invention provides formula-II with improved yield and high purity. Further, present invention provides a process for the preparation of novel crystalline form of Vorapaxar base. The present invention also relates to novel impurity and process for its preparation.

U.S.Pat. No. 7,304,078 discloses Vorapaxar base. U.S.Pat. No. 7,235,567 discloses Polymorph I and II of vorapaxar sulphate

Example 1- Preparation of compound 1a:

str1

Process A: 5.0 g of compound 2a was suspended in 10.0 ml silicone oil at room temperature. The reaction mixture was then heated to 125°C and stirred for 30 min. Then reaction mass was further heated up to 150°C and stirred for 30 min. After completion of reaction, the reaction mass was cooled to 50-60°C and 25 ml of cyclohexane was added to the reaction mass. The reaction mass was cooled slowly up to room temperature and stirred for 30 min.

15 The precipitated product was filtered off and washed with 5.0 ml Cyclohexane. Wet solid was suspended in mixture of 45.0 ml isopropyl alcohol and 20.0 ml denatured ethanol at 40-45°C and further epimerized with 0.17 ml DBU. The crystallized solid was filtered off with suction, washed with mixture of 1.5 ml Isopropyl alcohol and 0.67 ml denatured ethanol and dried.

20 Process B: 5.0 g of compound 2a was suspended in 10.0 ml paraffin oil at room temperature. The reaction mixture was then heated to 125°C and stirred for 30 min. Then reaction mass was further heated up to 150°C and stirred for 30 min. After completion of reaction, the reaction mass was cooled to 50-60°C and 25 ml of cyclohexane was added to the reaction mass. The reaction mass was cooled slowly up to room temperature and stirred for 30 min.

25 The precipitated product was filtered off and washed with 5.0 ml Cyclohexane. Wet solid was suspended in mixture of 45.0 ml isopropyl alcohol and 20.0 ml denatured ethanol at 40-45°C and further epimerized with 0.17 ml DBU. The crystallized solid was filtered off with suction, washed with mixture of 1.5 ml Isopropyl alcohol and 0.67 ml denatured ethanol and dried. Yield: 4.3 g

Process C: 5.0 g of compound 2a was charged in reaction vessel at room temperature. The solid was then heated to 125°C and stirred for 30 min. Then reaction mass was further heated up to 150°C and stirred for 30 min. After completion of reaction, the reaction mass was cooled to 50-60°C and was added mixture of 45.0 ml isopropyl alcohol and 20.0 ml

5 denatured ethanol at 50-60°C. This was cooled to 40-45°C and further epimerized with 0.17 ml DBU. The crystallized solid was filtered off with suction, washed with mixture of 1.5 ml Isopropyl alcohol and 0.67 ml denatured ethanol and dried. Yield: 4.5 g Example 2: Preparation of Intermediate (Formula-II) of vorapaxar

10 Example 2(a): 50.0g of 1,3,3a,4,4a,5,6,7,8,9a-Decahydro-3-methyl-7-nitro-1-oxo-N,Ndiphenylnaphtho[2,3-c]furan-4-carboxamide compound was suspended in 300.0 ml THF, 15 g 10% Pd/C (50% wet) and 200 ml Process water at room temperature. The reaction mixture was heated to 45°C and drop wise formic acid (35 ml) was added and then stirred for 15 hrs. After completion of reaction, the reaction mass was cooled to 25-30°C and 100 ml THF was

15

added and pH was made acidic with 2M sulfuric acid solution. The reaction mass was filtered and washed with 150 ml THF, 150 ml water. Organic and aqueous layer were separated and aqueous layer was extracted with THF. Organic layers were combined and washed with water. The organic layer was cooled up to 5-10°C, 20 ml of TEA and 13 ml of Ethyl chloro formate were added. The reaction mass was stirred for 30 min. After completion of reaction,

20

reaction mass was washed with 2M sulfuric acid solution and distilled out reaction mass completely under vacuum. Acetonitrile (50 ml) was added to residue and heated up to 40- 45°C. Cooled the reaction mass up to 25-30°C and filtered the solid. Purity: 94-96% Example 2(b): Crystallization with Acetonitrile Acetonitrile (50 ml) was added to above obtained solid and heated to 40-45°C. Cooled the

25 reaction mass slowly up to 25-30°C and then up to 5-10°C. The reaction mass was stirred and the solid was filtered. XRD: Fig-1 Purity: 98-99% Example 2(c): Crystallization with Ethyl acetate To the solid obtained in example-1(a) Ethyl acetate (30 ml) was added. The reaction mass was heated up to 70-75°C and stirred for 10-15 min. The reaction mass was cooled slowly up 30 to 25-30°C and then up to 5-10°C. The reaction mass was stirred for 30 min. The solid was filtered and washed with Ethyl acetate. XRD: Fig-2 Purity: 98-99%

Example 3: Preparation of Amorphous Form of Vorapaxar base Vorapaxar base (10.0 g) was dissolved in 500 ml of 40% Ethyl acetate in Cyclohexane. The solvent was then completely removed under vacuum at 45-50o C to give a solid. Yield: 9.8 g

Example 3 (a): Preparation of crystalline vorapaxar base 5 (2-{[Ethyl (ethylperoxy)phosphory]methyl}-5-(3-fluorophenyl)pyridine) (10 g) was dissolved in THF (30ml) at 25±5°C under Nitrogen. Cool the reaction mass up to -30 to – 50°C. Add drop wise LDA (2.0 M solution in THF). After 1 hr add drop wise (N- [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-formyl dodecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-6- yl]-ethyl ester Carbamic acid) solution (10 g dissolved in 70 ml THF). After completion of 10 reaction mass quench the reaction mass to sulphuric acid solution. Separate the layers and distilled out organic layer under vacuum get foamy residue. (purity 82%) Add MIBK (10 ml) in above residue and stir it at 40-50°C till clear solution. Add drop wise n-Heptane (10 ml) and stir the reaction mass for 30 min. Gradually cool the reaction mass up to 25-30°C. Stir the reaction mass for 24 hrs. Filter the solid and washed it with n-Heptane (5.0 ml). Dry the 15 solid. Yield: 7.0 g. XRD: Fig-3 purity 96%

Example 3(b): Preparation of crystalline vorapaxar base Vorapaxar advance intermediate (2-{[Ethyl (ethylperoxy)phosphory]methyl}-5-(3- fluorophenyl)pyridine) (10 g) was dissolved in THF (30ml) at 25±5°C under Nitrogen. Cool the reaction mass up to -30 to -50°C. Add drop wise LDA (2.0 M solution in THF). After a 1

20 hr add drop wise VORA-Aldehyde (N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-formyl dodecahydro1-methyl-3-oxonaphtho[2,3-c]furan-6-yl]-ethyl ester Carbamic acid) solution (10 g dissolved in 70 ml THF). After completion of reaction mass quench the reaction mass to sulphuric acid solution. Separate the layers and distilled out organic layer under vacuum get foamy residue (purity 82%). Add MTBE (10 ml) in above residue and stir it at 40-50°C till clear solution.

25 Add drop wise n-Heptane (30 ml) and stir the reaction mass for 30 min. Gradually cool the reaction mass up to 25-30°C. Stir the reaction mass for 24 hrs. Filter the solid and washed it with n-Heptane (5.0 ml). Dry the solid. Yield: 8.5.0 g. XRD: Fig-4 purity 97%

References

  1.  Samuel Chackalamannil; Wang, Yuguang; Greenlee, William J.; Hu, Zhiyong; Xia, Yan; Ahn, Ho-Sam; Boykow, George; Hsieh, Yunsheng et al. (2008). “Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity”. Journal of Medicinal Chemistry 51 (11): 3061–4.doi:10.1021/jm800180ePMID 18447380.
  2.  Merck Blood Thinner Studies Halted in Select PatientsBloomberg News, January 13, 2011
  3.  Tricoci et al. (2012). “Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes”New England Journal of Medicine 366 (1): 20–33.doi:10.1056/NEJMoa1109719PMID 22077816.
  4.  Morrow, DA; Braunwald, E; Bonaca, MP; Ameriso, SF; Dalby, AJ; Fish, MP; Fox, KA; Lipka, LJ; Liu, X; Nicolau, JC; Ophuis, AJ; Paolasso, E; Scirica, BM; Spinar, J; Theroux, P; Wiviott, SD; Strony, J; Murphy, SA; TRA 2P–TIMI 50 Steering Committee and, Investigators (Apr 12, 2012). “Vorapaxar in the secondary prevention of atherothrombotic events.”. The New England Journal of Medicine 366 (15): 1404–13. doi:10.1056/NEJMoa1200933.PMID 22443427.
  5.  “Merck Statement on FDA Advisory Committee for Vorapaxar, Merck’s Investigational Antiplatelet Medicine”. Merck. Retrieved 16 January 2014.
  6. http://www.forbes.com/sites/larryhusten/2014/01/15/fda-advisory-panel-votes-in-favor-of-approval-for-mercks-vorapaxar/
  7. SCH-530348 (Vorapaxar) is an investigational candidate for the prevention of arterial thrombosis in patients with acute coronary syndrome and peripheral arterial disease. “Convergent Synthesis of Both Enantiomers of 4-Hydroxypent-2-ynoic Acid Diphenylamide for a Thrombin Receptor Antagonist Sch530348 and Himbacine Analogues.” Alex Zaks et al.:  Adv. Synth. Catal. 2009, 351: 2351-2357 Full text;
  8. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity
    J Med Chem 2008, 51(11): 3061

PATENTS

  1. WO 2003089428
  2. WO 2006076452
  3. US 6063847
  4. WO 2006076565
  5. WO 2008005344
  6. WO2010/141525
  7. WO2008/5353
  8. US2008/26050
  9. WO2006/76564   mp, nmr
3-21-2012
EXO-SELECTIVE SYNTHESIS OF HIMBACINE ANALOGS
10-14-2011
EXO- AND DIASTEREO- SELECTIVE SYNTHESIS OF HIMBACINE ANALOGS
8-3-2011
Exo- and diastereo-selective syntheses of himbacine analogs
3-18-2011
COMBINATION THERAPIES COMPRISING PAR1 ANTAGONISTS WITH NAR AGONISTS
8-11-2010
Exo-selective synthesis of himbacine analogs
6-4-2010
SYNTHESIS Of DIETHYLPHOSPHONATE
5-12-2010
THROMBIN RECEPTOR ANTAGONISTS
3-31-2010
Synthesis of diethyl{[5-(3-fluorophenyl)-pyridine-2yl]methyl}phosphonate
12-4-2009
Local Delivery of PAR-1 Antagonists to Treat Vascular Complications
12-2-2009
SYNTHESIS OF HIMBACINE ANALOGS
10-21-2009
Exo- and diastereo- selective syntheses of himbacine analogs
6-31-2009
Synthesis of 3-(5-nitrocyclohex-1-enyl) acrylic acid and esters thereof
6-3-2009
Synthesis of himbacine analogs
1-23-2009
METHODS AND COMPOSITIONS FOR TREATING CARDIAC DYSFUNCTIONS
9-26-2008
REDUCTION OF ADVERSE EVENTS AFTER PERCUTANEOUS INTERVENTION BY USE OF A THROMBIN RECEPTOR ANTAGONIST
2-8-2008
IMMEDIATE-RELEASE TABLET FORMULATIONS OF A THROMBIN RECEPTOR ANTAGONIST
1-32-2008
SOLID DOSE FORMULATIONS OF A THROMBIN RECEPTOR ANTAGONIST
12-5-2007
Thrombin receptor antagonists
11-23-2007
THROMBIN RECEPTOR ANTAGONISTS
8-31-2007
THROMBIN RECEPTOR ANTAGONISTS AS PROPHYLAXIS TO COMPLICATIONS FROM CARDIOPULMONARY SURGERY
8-31-2007
CRYSTALLINE POLYMORPH OF A BISULFATE SALT OF A THROMBIN RECEPTOR ANTAGONIST
6-27-2007
Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist
8-4-2006
Preparation of chiral propargylic alcohol and ester intermediates of himbacine analogs
9-31-2004
Methods of use of thrombin receptor antagonists
US6063847 * Nov 23, 1998 May 16, 2000 Schering Corporation Thrombin receptor antagonists
US6326380 * Apr 7, 2000 Dec 4, 2001 Schering Corporation Thrombin receptor antagonists
US20030216437 * Apr 14, 2003 Nov 20, 2003 Schering Corporation Thrombin receptor antagonists
US20040176418 * Jan 9, 2004 Sep 9, 2004 Schering Corporation Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist
WO2011128420A1 Apr 14, 2011 Oct 20, 2011 Sanofi Pyridyl-vinyl pyrazoloquinolines as par1 inhibitors

//////////////fast track designation , VORAPAXAR, FDA 2014, EU 2016, Zontivity,  NDA 204886, MERCK, VORAPAXAR SULPHATE

CCOC(=O)NC1CCC2C(C1)CC3C(C2C=CC4=NC=C(C=C4)C5=CC(=CC=C5)F)C(OC3=O)C

Isavuconazonium sulfate, Изавуконазониев сулфат


Image result for isavuconazonium
ChemSpider 2D Image | Isavuconazonium sulfate | C35H36F2N8O9S2
Isavuconazonium sulfate
Изавуконазониев сулфат
MOLECULAR FORMULA: C35H36F2N8O9S2
MOLECULAR WEIGHT: 814.837 g/mol
BAL-8557-002, BAL 8557
[2-[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]ethoxycarbonyl-methylamino]pyridin-3-yl]methyl 2-(methylamino)acetate;hydrogen sulfate
UNII:31Q44514JV
(2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl N-methylglycinate hydrogen sulfate
(2-{[(1-{1-[(2R,3R)-3-[4-(4-Cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}-3-pyridinyl)methyl N-methylglycinate hydrog en sulfate
FDA 2015, EU 2015, BAL8557-002, BCS CLASS I, RO-0098557 , AK-1820
fast track designation
QIDP
ORPHAN DRUG EU
Image result for Isavuconazonium sulfate
1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47.
Isavuconazonium is a second-generation triazole antifungal approved on March 6, 2015 by the FDA for the treatment of invasive aspergillosis and invasive mucormycosis, marketed by Astellas under the brand Cresemba. It is the prodrug form of isavuconazole, the active moiety, and it is available in oral and parenteral formulations. Due to low solubility in waterof isavuconazole on its own, the isovuconazonium formulation is favorable as it has high solubility in water and allows for intravenous administration. This formulation also avoids the use of a cyclodextrin vehicle for solubilization required for intravenous administration of other antifungals such as voriconazole and posaconazole, eliminating concerns of nephrotoxicity associated with cyclodextrin. Isovuconazonium has excellent oral bioavailability, predictable pharmacokinetics, and a good safety profile, making it a reasonable alternative to its few other competitors on the market.
Originally developed at Roche, the drug candidate was subsequently acquired by Basilea. In 2010, the product was licensed to Astellas Pharma by Basilea Pharmaceutica for codevelopment and copromotion worldwide, including an option for Japan, for the treatment of fungal infection.
03/06/2015 02:10 PM EST
The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.

Syn……https://newdrugapprovals.org/2013/10/02/isavuconazole-basilea-reports-positive-results-from-study/

PRODUCT PATENT

https://patents.google.com/patent/US6300353

InventorTadakatsu HayaseShigeyasu IchiharaYoshiaki IsshikiPingli LiuJun OhwadaToshiya SakaiNobuo ShimmaMasao TsukazakiIsao UmedaToshikazu Yamazaki

Current Assignee Basilea Pharmaceutica International Ltd Original

AssigneeBasilea Pharmaceutica AG Priority date 1998-03-06

https://patents.google.com/patent/WO1999045008A1/en

POLYMORPHS OF BASE

WO 2016055918

https://patents.google.com/patent/WO2016055918A1/en

PATENT

IN 2014MU03189

WOCKHARDT

Isavuconazole, isavuconazonium, Voriconazole, and Ravuconazole are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238. The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5- difluorophenyl)-butan-2-ol;

The Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate can be prepared according to known methods, e.g. pending Indian Patent Applications IN 2424/MUM/2014 and IN 2588/MUM/2014.

Example-1: Preparation of Amorphous Isavuconazole

str1

4-cyano Phenacyl bromide F F N N N OH N S CN Formula-I Formula-III In a round bottomed flask charged ethanol (250 ml), thioamide compound of formula-II (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) under stirring. The reaction mixture were heated to 70 0C. After completion of reaction the solvent was removed under vacuum distillation and water (250 ml) and Ethyl acetate (350 ml) were added to reaction mass. The reaction mixture was stirred and its pH was adjusted between 7 to 7.5 by 10 % solution of sodium bicarbonate. The layer aqueous layer was discarded and organic layer was washed with saturated sodium chloride solution (100 ml) and concentrated under vacuum to get residue. The residue was suspended in methyl tert-butyl ether (250 ml) and the reaction mixture was heated to at 40°C to make crystals uniform and finally reaction mass is cooled to room temperature filtered and washed with the methyl tert-butyl ether. The product was isolated dried to get pale yellowish solid product. Yield: 26.5 gm HPLC purity: 92.7%

CLIP

March 6, 2015

Release

The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.

Aspergillosis is a fungal infection caused by Aspergillus species, and mucormycosis is caused by the Mucorales fungi. These infections occur most often in people with weakened immune systems.

Cresemba belongs to a class of drugs called azole antifungal agents, which target the cell wall of a fungus. Cresemba is available in oral and intravenous formulations.

“Today’s approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Cresemba is the sixth approved antibacterial or antifungal drug product designated as a Qualified Infectious Disease Product (QIDP). This designation is given to antibacterial or antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act.

As part of its QIDP designation, Cresemba was given priority review, which provides an expedited review of the drug’s application. The QIDP designation also qualifies Cresemba for an additional five years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act. As these types of fungal infections are rare, the FDA also granted Cresemba orphan drug designations for invasive aspergillosis and invasive mucormycosis.

The approval of Cresemba to treat invasive aspergillosis was based on a clinical trial involving 516 participants randomly assigned to receive either Cresemba or voriconazole, another drug approved to treat invasive aspergillosis. Cresemba’s approval to treat invasive mucormycosis was based on a single-arm clinical trial involving 37 participants treated with Cresemba and compared with the natural disease progression associated with untreated mucormycosis. Both studies showed Cresemba was safe and effective in treating these serious fungal infections.

The most common side effects associated with Cresemba include nausea, vomiting, diarrhea, headache, abnormal liver blood tests, low potassium levels in the blood (hypokalemia), constipation, shortness of breath (dyspnea), coughing and tissue swelling (peripheral edema).  Cresemba may also cause serious side effects including liver problems, infusion reactions and severe allergic and skin reactions.

Cresemba is marketed by Astellas Pharma US, Inc., based in Northbrook, Illinois.

str0

The active substance is isavuconazonium sulfate, a highly water soluble pro-drug of the active triazole isavuconazole. The chemical name of the active substance isavuconazonium sulfate is 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47. The active substance has the following structure:

STR1.JPG

The structure of the active substance has been confirmed by elemental analysis, mass spectrometry, UV, IR, 1H-, 13C- and 19F-NMR spectrometry, and single crystal X-ray analysis, all of which support the chemical structure. It appears as a white, amorphous, hygroscopic powder. It is very soluble in water and over the pH range 1-7. It is also very soluble in methanol and sparingly soluble in ethanol. Two pKa values have been found and calculated to be 2.0 and 7.3. Its logPoct/wat calculated by software is 1.31.

Isavuconazonium sulfate has three chiral centres. The stereochemistry of the active substance is introduced by one of the starting materials which is controlled by appropriate specification. The two centres, C7 and C8 in the isavuconazole moiety and in an intermediate of the active substance, have R configuration. The third chiral centre, C29, is not located on isavuconazole moiety and has both the R and S configurations. The nondefined stereo centre at C29 has been found in all batches produced so far to be racemic. Erosion of stereochemical purity has not been observed in the current process. The active substance is a mixture of two epimers of C29.

An enantiomer of drug substance was identified as C7 (S), C8 (S) and C29 (R/S) structure. The control of the stereochemistry of isavuconazonium sulfate is performed by chiral HPLC on the active substance and its two precursors. Subsequent intermediates are also controlled by relevant specification in the corresponding steps. Two crystal forms have been observed by recrystallisation studies. However the manufacturing process as described yields amorphous form only.

Two different salt forms of isavuconazonuium (chloride and sulfate) were identified during development. The sulfate salt was selected for further development. A polymorph screening study was also performed. None of the investigated salts could be obtained in crystalline Form………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002734/WC500196130.pdf

Image result for isavuconazonium

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Isavuconazonium (Cresemba ) is a water-soluble prodrug of the triazole antifungal isavuconazole (BAL4815), a 14-a-demethylase inhibitor, under development byBasilea Pharmaceutica International Ltd and Astellas Pharma Inc. Isavuconazonium, in both its intravenous and oral formulations, was approved for the treatment of invasive aspergillosis and invasive mucormycosis (formerly termed zygomycosis) in the US in March 2015. Isavuconazonium is under regulatory review in the EU for invasive aspergillosis and mucormycosis. It is also under phase III development worldwide for the treatment of invasive candidiasis and candidaemia. This article summarizes the milestones in the development of isavuconazonium leading to the first approval for invasive spergillosis and mucormycosis.

Introduction

The availability of both an intravenous (IV) and an oral formulation of isavuconazonium (Cresemba ), as a result of its water solubility, rapid hydrolysis to the active entity isavuconazole and very high oral bioavailability, provides maximum flexibility to clinicians for treating seriously ill patients with invasive fungal infections [1]. Both the IV and oral formulations have been approved by the US Food and Drug Administration (FDA) to treat adults with invasive aspergillosis and invasive mucormycosis [2]. The recommended dosages of each formulation are identical, consisting of loading doses of 372 mg (equivalent to 200 mg of isavuconazole) every eight hours for six doses, followed by maintenance therapy with 372 mg administered once daily [3]. The Qualified Infectious Disease Product (QIDP) designation of the drug with priority review status by the FDA isavuconazonium in the US provided and a five year extension of market exclusivity from launch. Owing to the rarity of the approved infections,

isavuconazonium was also granted orphan drug designation by the FDA for these indications [2]. It has also been granted orphan drug and QIDP designation in the US for the treatment of invasive candidiasis [4]. In July 2014, Basilea Pharmaceutica International Ltd submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for isavuconazonium in the treatment of invasive aspergillosis and invasive mucormycosis, indications for which the EMA has granted isavuconazonium orphan designation [5, 6]. Isavuconazonium is under phase III development in many countries worldwide for the treatment of invasive candidiasis and candidaemia.

1.1 Company agreements

In 2010, Basilea Pharmaceutica International Ltd (a spinoff from Roche, founded in 2000) entered into a licence agreement with Astellas Pharma Inc in which the latter would co-develop and co-promote isavuconazonium worldwide, including an option for Japan. In return for milestone payments, Astellas Pharma was granted an exclusive right to commercialize isavuconazonium, while Basilea Pharmaceutica retained an option to co-promote the drug in the US, Canada, major European countries and China [7]. The companies amended their agreement in 2014, making Astellas Pharma responsible for all regulatory filings, commercialization and manufacturing of isavuconazonium in the US and Canada. Basilea Pharmaceutica waived its right to co-promote the product in the US and Canada, in order to assume all rights in the rest of the world [8]. However, Astellas Pharma remains as sponsor of the multinational, phase III ACTIVE trial in patients with invasive candidiasis.

2 Scientific Summary

Isavuconazonium (as the sulphate; BAL 8557) is a prodrug that is rapidly hydrolyzed by esterases (mainly butylcholinesterase) in plasma into the active moiety isavuconazole

(BAL 4815) and an inactive cleavage product (BAL 8728).

References

1. Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013;6:163–74.

2. US Food and Drug Administration. FDA approves new antifungal drug Cresemba. 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437106.htm. Accessed 12 Mar 2015.

3. US Food and Drug Administration. Cresemba (isavuconazonium sulfate): US prescribing information. 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf. Accessed 18 Mar 2015.

4. Astellas Pharma US Inc. FDA grants Astellas Qualified Infectious Disease Product designation for isavuconazole for the treatment of invasive candidiasis (media release). 2014. http://newsroom astellas.us/2014-07-16-FDA-Grants-Astellas-Qualified-Infectious-Disease-Product-Designation-for-Isavuconazole-for-the-Treatmentof-Invasive-Candidiasis.

5. European Medicines Agency. Public summary of opinion on orphan designation: isavuconazonium sulfate for the treatment of invasive aspergillosis. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2014/07/WC500169890.pdf. Accessed 18 Mar 2015.

European Medicines Agency. Public summary of opinion on orphan designation: isavuconazonium sulfate for the treatment of mucormycosis. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2014/07/WC500169714.pdf. Accessed 18 Mar 2015.

7. Basilea Pharmaceutica. Basilea announces global partnership with Astellas for its antifungal isavuconazole (media release).2010. http://www.basilea.com/News-and-Media/Basilea-announcesglobal-partnership-with-Astellas-for-its-antifungal-isavuconazole/343.

8. Basilea Pharmaceutica. Basilea swaps its isavuconazole North American co-promote rights for full isavuconazole rights outside of North America (media release). 2014. http://www.basilea.com/News-and-Media/Basilea-swaps-its-isavuconazole-North-Americanco-promote-rights-for-full-isavuconazole-rights-outside-

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http://www.jpharmsci.org/article/S0022-3549(15)00035-0/pdf

A CLIP

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000ChemR.pdf

EMA

On 4 July 2014 orphan designation (EU/3/14/1284) was granted by the European Commission to Basilea Medical Ltd, United Kingdom, for isavuconazonium sulfate for the treatment of invasive aspergillosis.

Update: isavuconazonium sulfate (Cresemba) has been authorised in the EU since 15 October 2015. Cresemba is indicated in adults for the treatment of invasive aspergillosis.

Consideration should be given to official guidance on the appropriate use of antifungal agents.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002734/WC500196130.pdf

The active substance is isavuconazonium sulfate, a highly water soluble pro-drug of the active triazole isavuconazole. The chemical name of the active substance isavuconazonium sulfate is 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47. The active substance has the following structure

str1

It appears as a white, amorphous, hygroscopic powder. It is very soluble in water and over the pH range 1-7. It is also very soluble in methanol and sparingly soluble in ethanol. Two pKa values have been found and calculated to be 2.0 and 7.3. Its logPoct/wat calculated by software is 1.31.

Isavuconazonium sulfate has three chiral centres. The stereochemistry of the active substance is introduced by one of the starting materials which is controlled by appropriate specification. The two centres, C7 and C8 in the isavuconazole moiety and in an intermediate of the active substance, have R configuration. The third chiral centre, C29, is not located on isavuconazole moiety and has both the R and S configurations. The nondefined stereo centre at C29 has been found in all batches produced so far to be racemic. Erosion of stereochemical purity has not been observed in the current process. The active substance is a mixture of two epimers of C29. An enantiomer of drug substance was identified as C7 (S), C8 (S) and C29 (R/S) structure. The control of the stereochemistry of isavuconazonium sulfate is performed by chiral HPLC on the active substance and its two precursors.

FDA Orange Book Patents

US 6812238

US 7459561

FDA ORANGE BOOK PATENTS: 1 OF 2
Patent 7459561
Expiration Oct 31, 2020
Applicant ASTELLAS
Drug Application N207500 (Prescription Drug: CRESEMBA. Ingredients: ISAVUCONAZONIUM SULFATE)
FDA ORANGE BOOK PATENTS: 2 OF 2
Patent 6812238
Expiration Oct 31, 2020
Applicant ASTELLAS
Drug Application N207500 (Prescription Drug: CRESEMBA. Ingredients: ISAVUCONAZONIUM SULFATE)

FREE FORM

Isavuconazonium.png

Isavuconazonium; Isavuconazonium ion; Cresemba;  BAL-8557; 742049-41-8;

[2-[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]ethoxycarbonyl-methylamino]pyridin-3-yl]methyl 2-(methylamino)acetate

MOLECULAR FORMULA: C35H35F2N8O5S+
MOLECULAR WEIGHT: 717.773 g/mol

Patent IDDatePatent Title

US20102494262010-09-30STABILIZED PHARMACEUTICAL COMPOSITION

US74595612008-12-02N-substituted carbamoyloxyalkyl-azolium derivativesUS71898582007-03-13N-phenyl substituted carbamoyloxyalkyl-azolium derivatives

US71511822006-12-19Intermediates for N-substituted carbamoyloxyalkyl-azolium derivatives

US68122382004-11-02N-substituted carbamoyloxyalkyl-azolium derivatives

REF

http://www.drugbank.ca/drugs/DB06636

////////// , QIDP designation, Cresemba , priority review, FDA 2015, EU 2015, BAL8557-002, BCS CLASS I, orphan designation,  invasive aspergillosis, invasive mucormycosis,  RO-0098557 , AK-1820, fast track designation, QIDP, 946075-13-4

CC(C1=NC(=CS1)C2=CC=C(C=C2)C#N)C(CN3C=[N+](C=N3)C(C)OC(=O)N(C)C4=C(C=CC=N4)COC(=O)CNC)(C5=C(C=CC(=C5)F)F)O

CC(C1=NC(=CS1)C2=CC=C(C=C2)C#N)C(CN3C=[N+](C=N3)C(C)OC(=O)N(C)C4=C(C=CC=N4)COC(=O)CNC)(C5=C(C=CC(=C5)F)F)O.OS(=O)(=O)[O-]

UPDATE NEW PATENT

WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT

(WO2016016766) A PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM OR ITS SALT THEREOF

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016016766&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)

KHUNT, Rupesh Chhaganbhai; (IN).
RAFEEQ, Mohammad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)

The present invention relates to a process for the preparation of stable Isavuconazonium or its salt thereof. In particular of the present invention relates to process for the preparing of isavuconazonium sulfate, Isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide has purity more than 90%. The process is directed to preparation of solid amorphous form of isavuconazonium sulfate, isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide. The present invention process of Isavuconazonium or its salt thereof is industrially feasible, simple and cost effective to manufacture of isavuconazonium sulfate with the higher purity and better yield.

Isavuconazonium sulfate is chemically known l-[[N-methyl-N-3-[(methylamino) acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-lH-[l,2,4]-triazo-4-ium Sulfate and is structurally represented by formula (I):

Formula I

Isavuconazonium sulfate (BAL8557) is indicated for the treatment of antifungal infection. Isavuconazonium sulfate is a prodrug of Isavuconazole (BAL4815), which is chemically known 4-{2-[(lR,2R)-(2,5-Difluorophenyl)-2-hydroxy-l-methyl-3-(lH-l ,2,4-triazol-l-yl)propyl]-l ,3-thiazol-4-yl}benzonitrile compound of Formula II

Formula II

US Ppatent No. 6,812,238 (referred to herein as ‘238); 7,189,858 (referred to herein as ‘858); 7,459,561 (referred to herein as ‘561) describe Isavuconazonium and its process for the preparation thereof.

The US Pat. ‘238 patent describes the process of preparation of Isavuconazonium chloride hydrochloride.

The US Pat. ‘238 described the process for the Isavuconazonium chloride hydrochloride, involves the condensation of Isavuconazole and [N-methyl-N-3((tert-butoxycarbonyl methylamino) acetoxymethyl) pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester. The prior art reported process require almost 15-16 hours, whereas the present invention process requires only 8-10 hours. Inter alia prior art reported process requires too many step to prepare isavuconazonium sulfate, whereas the present invention process requires fewer steps.

Moreover, the US Pat. ‘238 describes the process for the preparation Isavuconazonium hydrochloride, which may be used as the key intermediate for the synthesis of isavuconazonium sulfate, compound of formula I. There are several drawbacks in the said process, which includes the use of anionic resin to prepare Isavuconazonium chloride hydrochloride, consequently it requires multiple time lyophilization, which makes the said prior art process industrially, not feasible.

The inventors of the present invention surprisingly found that Isavuconazonium or a pharmaceutically acceptable salt thereof in yield and purity could be prepared by using substantially pure intermediates in suitable solvent.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for manufacture of isavuconazonium sulfate. Inventors of the present invention surprisingly found that isavuconazonium sulfate prepared from isavuconazonium iodide hydrochloride, provides enhanced yield as well as purity.

The process of the present invention is depicted in the following scheme:

Formula I

Formula-IA

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Synthesis of l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino) acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3 – [4-(4-cyanophenyl)thiazol-2-yl]butyl] – 1 H-[ 1 ,2,4] -triazo-4-ium iodide

Isavuconazole (20 g) and [N-methyl-N-3((tert-butoxycarbonylmethylamino)acetoxy methyl)pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester (24.7 g) were dissolved in acetonitrile (200ml). The reaction mixture was stirred to add potassium iodide (9.9 g). The reaction mixture was stirred at 47-50°C for 10-13 hour. The reaction mixture was cooled to room temperature. The reaction mass was filtered through celite bed and washed acetonitrile. Residue was concentrated under reduced pressure to give the crude solid product (47.7 g). The crude product was purified by column chromatography to get its pure iodide form (36.5 g).

Yield: 84.5 %

HPLC Purity: 87%

Mass: m/z 817.4 (M- 1)+

Example-2: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride

l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide (36.5 g) was dissolved in ethyl acetate (600 ml). The reaction mixture was cooled to -5 to 0 °C. The ethyl acetate hydrochloride (150 ml) solution was added to reaction mixture. The reaction mixture was stirred for 4-5 hours at room temperature. The reaction mixture was filtered and obtained solid residue washed with ethyl acetate. The solid dried under vacuum at room temperature for 20-24 hrs to give 32.0 gm solid.

Yield: 93 %

HPLC Purity: 86%

Mass: m/z 717.3 (M-HC1- 1)

Example-3: Preparation of Strong anion exchange resin (Sulfate).

Indion GS-300 was treated with aqueous sulfate anion solution and then washed with DM water. It is directly used for sulfate salt.

Example-4: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium Sulfate

Dissolved 10.0 g l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride in 200 ml deminerahzed water and 30 ml methanol. The solution was cooled to about 0 to 5°C. The strong anion exchange resin (sulfate) was added to the cooled solution. The reaction mixture was stirred to about 60-80 minutes. The reaction was filtered and washed with 50ml of demineralized water and methylene chloride. The aqueous layer was lyophilized to obtain

(8.0 g) white solid.

Yield: 93 %

HPLC Purity: > 90%

Mass: m/z 717.4 (M- HS04+

PATENT

CN 105288648

PATENT

CN 106883226

https://patents.google.com/patent/CN106883226A/en

PATENT

CN 107982221

PAPER

Title: Introduction of New Drugs Approved by the U.S. FDA in 2015
Author: Ma Shuai; Wenying Ling; Zhou Weicheng;
Source: China Pharmaceutical Industry
Publisher: Tongfangzhiwang Beijing Technology Co., Ltd.
Year of publication:
DOI code: 10.16522/j.cnki.cjph.2016.01.022
Registration Time: 2016-02-19 02:04:15

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FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers


DRUG REGULATORY AFFAIRS INTERNATIONAL

Image result for FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers
As part of the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s ongoing effort to make the oversight of food safety stronger and more efficient, the FDA and the USDA today announced the alignment of the USDA Harmonized Good Agricultural Practices Audit Program (USDA H-GAP) with the requirements of the FDA Food Safety Modernization Act’s (FSMA’s) Produce Safety Rule.
The new step is part of an ongoing effort to streamline produce safety requirements for farmers. The joint announcement was made by Agriculture Secretary Sonny Perdue and FDA Commissioner Scott Gottlieb, M.D., during a visit by the Secretary to the FDA’s White Oak campus in Silver Spring, Md.

june 5, 2018

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Release

As part of the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s ongoing effort…

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