New Drug Approvals
Follow New Drug Approvals on WordPress.com
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

Categories

FLAGS AND HITS

Flag Counter
Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Researchgate

Anthony Melvin Crasto Dr.

  Join me on Facebook FACEBOOK   ...................................................................Join me on twitter Follow amcrasto on Twitter     ..................................................................Join me on google plus Googleplus

MYSELF

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,114 other followers

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 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

Personal Links

Verified Services

View Full Profile →

Recent Posts

NASTORAZEPIDE


imgNastorazepide.png

Nastorazepide (Z-360)
CAS: 209219-38-5
Chemical Formula: C29H36N4O5
Molecular Weight: 520.61994

UNII-R22TMY97SG; 209219-38-5;

Phase II, treatment of pancreatic cancer.

(R)-3-(3-(5-cyclohexyl-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)ureido)benzoic acid

Image result

Nastorazepide, also known as Z-360, is a selective, orally available, 1,5-benzodiazepine-derivative gastrin/cholecystokinin 2 (CCK-2) receptor antagonist with potential antineoplastic activity. Z-360 binds to the gastrin/CCK-2 receptor, thereby preventing receptor activation by gastrin, a peptide hormone frequently associated with the proliferation of gastrointestinal and pancreatic tumor cells.

In January 2018, Zeria is developing nastorazepide calcium (phase II clinical trial), a CCK2 receptor antagonist, for the treatment of pancreatic cancer.

Zeria is developing nastorazepide calcium (Z-360), an oral CCK2 receptor (gastrin receptor) antagonist, for the potential treatment of pancreatic cancer. In September 2005, a phase Ib/IIa trial began in the UK for pancreatic cancer ,  in February 2008, the trial was completed ; in June 2008, data were presented . In March 2010, the drug was listed as being in phase II preparation in Europe ; in August 2011, this was still the case . In April 2014, a phase II trial began in patients with metastatic pancreatic adenocarcinoma in Japan, Korea and Taiwan. In November 2015, the drug was listed as being in phase II development

343326-69-2

Nastorazepide (calcium salt)

CAS No. : 343326-69-2

M.Wt:540.62Formula:C29H36N4O5Ca0.5

Cholecystokinin (CK) is a digestive hormone produced and released in the duodenum, jejunal membrane and is known to have actions such as secretion of secretion, constriction of the gallbladder, stimulation of insulin secretion and the like. C CK is also known to exist in high concentrations in the cerebral cortex, hypothalamus and hippocampus, and it is also known that it has actions such as suppression of food intake, memory enhancement, anxiety action and the like. On the other hand, gastrin is a gastrointestinal hormone produced and released in G cells distributed in the pyloric region of the stomach, and it is known that it has gastric acid secretion action, contraction action of the gastric pyloric part and gallbladder, and the like. These C CK and gastrin have the same 5 amino acids at the C-terminus, and all express the action through the receptor. C CK receptors are classified into peripheral type C CK – A distributed in the ile, gall bladder and intestinal tract and central type C CK – B distributed in the brain. The gastrin receptor and the CKK – B receptor show similar properties in receptor binding experiments and sometimes called C CK 1 B / gastrin receptor due to high homology. These receptors, such as gastrin or a CCK-B receptor antagonist compound, are useful in the treatment of gastric ulcers, duodenal ulcers, gastritis, reflux esophagitis, splenitis, Zollinger-EUison syndrome, cavitary G cell hyperplasia, basal hyperplasia, Choleditis, gallstone stroke, gastrointestinal motility disorder, sensitive bowel syndrome, certain tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson’s disease, late onset dyskinesia, It is expected to be useful for treatment and prevention of La Tourette’s syndrome, addiction due to drug ingestion, and withdrawal symptoms. It is also expected that the induction of analgesia or the enhancement of induction of analgesia by opioid drugs is expected (Journal of Pharmacology, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18, 919-931 (1993), American Journal of Physiology, Vol.

As a gastrin receptor antagonist already, prolumide is known as a therapeutic agent for gastric ulcer and gastritis. However, proglumide has considerably low affinity for gastrin or CKK-B receptor and its therapeutic effect is weak. In addition, L – 3 6 4, 7 1 8 (Dibazepide, Japanese Unexamined Patent Publication No. 616366), L -3 6 5, 2 6 0 (Japanese Patent Laid-Open No. 6 3- 9), and the like, have been reported to exhibit either CKK-A receptor antagonism or CKK-B receptor antagonism. Furthermore, it is disclosed that a compound having a strong C 4 C – – B receptor antagonistic effect suppresses gastric acid secretion by pentagastrin stimulation (International Patent Publication WO 94/438, International Patent Publication WO 95/18110) , It is not always satisfactory and clinically applicable gastrin or CKK-B receptor antagonist has not yet been provided.

Compounds capable of strongly binding to gastrin or cholecystokinin receptors are expected for the prevention and treatment of diseases involving their respective receptors in the digestive tract and the central nervous system.

PRODUCT PATENT WO1998025911

Inventors Katsuo ShinozakiTomoyuki YonetaMasakazu MurataNaoyoshi MiuraKiyoto MaedaLess «
Applicant Zeria Pharmaceutical Co., Ltd.

SYNTHESIS WO 2017030859

PATENT

WO 9825911

https://www.google.co.in/patents/WO1998025911A1?cl=und

PATENT

WO2017175854

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017175854&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Compound A ((R) – (-) – 3- [3- (1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl- 1,3,4,5-tetrahydro- 2H- 1,5-benzodiazepine -3-yl) ureido] benzoate) has the following structural formula and can be produced by the method described in Patent Document 1.
[Chemical formula 1]
Example 1
Compound A 20.0 g of amorphous substance was suspended in 253 mL of methanol. After dissolving by heating, it was cooled and the precipitated crystals were collected by filtration and washed with methanol. The obtained wet crystals were dried under reduced pressure.
1 H-NMR (DMSO-d 6 ) δ: 1.18 (18H, s), 1.10-2.03 (20H, m), 3.17 (12H, d), 3.19-3.29 (4H, m), 3.37-3.44 (2H, (2H, m), 7.07-7.12 (2H, m), 4.07-4.16 (4H, br)
IR (KBr) cm -1 : 2935 (2H, m), 7.15 (2H, t), 7.22-7.29 (4H, m), 7.50-7.56 (4H, m), 7.88 , 2361, 1648, 1553, 1497, 1388, 1219, 776
 The powder X-ray diffraction spectrum of the obtained crystal is shown in FIG. 2. From NMR, IR and FIG. 2, the obtained crystals were Compound AI type crystals.
Example 5
Compound A 50.0 g of amorphous material was suspended in 380 mL of isopropanol (IPA). After dissolving by heating, it was cooled and precipitated. Precipitated crystals were collected by filtration and washed with IPA to obtain wet crystals. This was dried under reduced pressure. The powder X-ray diffraction spectrum of the obtained crystal is shown in FIG.
1 H-NMR (DMSO-d 6 ) [delta]: 1.04 (24H, d), 1.18 (18H, s), 1.10-2.03 (20H, m), 3.16-3.28 (4H, m), 3.37-3.45 (2H, (2H, m), 7.07-7.12 (2H, m), 3.72-3.83 (4H, m), 4.33-4.43 (8H, m), 5.13 (2H, d), 6.71
IR (KBr) cm -1 : 2933 (2H, m), 7.15 (2H, t), 7.21-7.30 (4H, m), 7.48-7.54 (4H, m), 7.84 , 2361, 1653, 1553, 1498, 1394, 1219, 769
 From NMR, IR and FIG. 4, the obtained crystals were Compound AIII type crystals.

PATENT

WO-2018008569

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018008569&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Process for producing a calcium salt of a 1,5-benzodiazepine compound – nastorazepide calcium – a cholecystokinin CCK2 receptor antagonist. Useful for the treatment of gastritis, reflux esophagitis, Zollinger-Ellison syndrome.

Example 1
(1) (R) – (-) – 2-Oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (compound 2)), 139.3 g of 1-chloropinacolone and 8.3 g of tetrabutylammonium bromide in 1432 ml of toluene was added dropwise 461 g of 30% sodium hydroxide aqueous solution at 10 ° C. or lower. After stirring for 1 hour, the aqueous layer was removed. To the toluene layer, 620 ml of water was added and the liquid was separated, and the toluene layer was used for the next step.
(2) 628.9 g of hydrochloric acid was added dropwise to the toluene layer obtained in the previous step at 30 ° C. or lower. After stirring for 30 minutes, liquid separation was carried out, and the aqueous layer was separated. It was neutralized with 908.5 g of 30% sodium hydroxide aqueous solution and extracted with 1432 ml of toluene. The toluene layer was separated with 620 g of a 20% sodium chloride aqueous solution, and toluene was distilled off under reduced pressure. (R) – (-) – 1 -tert-butylcarbonylmethyl-2-oxo-3-amino-5- cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (Compound (6) ) Was obtained.
(3) The (R) – (-) – 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1 , 5-benzodiazepine (Compound (6)), 221.8 g of 3-phenyloxycarbonylaminobenzoic acid, 174.5 g of triethylamine and 77.7 g of water were added and the mixture was stirred at 45 to 50 ° C. for 2 hours. To the reaction solution were added 1375 ml of ethanol and 930 ml of water, and 62.9 g of hydrochloric acid was added dropwise at 30 ° C. or lower. The precipitated crystals were centrifuged.
The obtained crystals were heated to dissolve in 4714 ml of ethanol at 60 ° C., and 2790 ml of water was added dropwise to precipitate crystals. The precipitated crystals were separated by centrifugation and dried under reduced pressure to give (R) – (-) – 3- [3- (1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl- 5-tetrahydro-2H-1,5-benzodiazepin-3-yl) ureido] benzoic acid (Compound (5)) 0.5 ethanolate monohydrate 430.2 g.
(4) (R) – (-) – 3- [3- (1-tert-Butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H- 1,5-benzodiazepine -3-yl) ureido] benzoic acid (Compound (5)) 0.5 Ethanol solvate monohydrate 430.3 g was suspended in 1645 ml of isopropyl alcohol (IPA), sodium hydroxide 31.6 g / A solution of 934 ml of water was added dropwise to dissolve (a).
112.7 g of calcium chloride dihydrate was dissolved in 3012 ml of water. Here, the solution of (a) was added dropwise at 10 ° C. or lower. After dropping, the temperature was raised to 50 ° C., after stirring for 2 hours, it was cooled to 10 ° C. or lower. The precipitated powder was centrifuged and washed with a mixed solution of IPA 658 ml / water 2065 ml, followed by 4303 ml of water and dried under reduced pressure to give (R) – (-) – 3- [3- (1-tert- Oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl) ureido] benzoate (compound (1)). The powder X-ray diffraction spectrum was measured (as 7% water content), and the obtained compound (1) was amorphous.
Example 2 In
step (4) of Example 1, investigation was carried out by changing the amount of the solvent and sodium hydroxide.
First, when the IPA / water ratio is 1 / 2.5 to 1/10, preferably 1 / 2.75 to 1/8, more preferably 1 / 2.75 to 1/5, the compound (1 ) Amorphous can be stably obtained.
Next, when the amount of sodium hydroxide is 1.0 to 1.10 mol with respect to the compound (1) and the amount of calcium chloride is 0.5 to 1.5 mol with respect to the compound (1), the amount of the compound 1) can be obtained in high yield.
Further, it was found that impurities are not produced when the reaction temperature of the compound (1) and sodium hydroxide in the step (4) is 20 ° C. or less, more preferably 10 ° C. or less, further preferably 0 to 10 ° C.
Patent ID

Patent Title

Submitted Date

Granted Date

US2008161293 Antitumor Agent
2008-07-03
Patent ID

Patent Title

Submitted Date

Granted Date

US2015038495 THERAPEUTIC AGENT FOR PAIN
2014-09-24
2015-02-05
US2011059956 THERAPEUTIC AGENT FOR PAIN
2011-03-10
US2017151256 ANTITUMOR AGENT
2017-02-10
US2010143366 ANTITUMOR AGENT
2010-06-10
US2010086553 ANTITUMOR AGENT
2010-04-08
Patent ID

Patent Title

Submitted Date

Granted Date

US6747022 Calcium salts of 1, 5-benzodiazepine derivatives, process for producing the salts and drugs containing the same
2003-05-22
2004-06-08
US6239131 1, 5 Benzodiazepine derivatives
2001-05-29
EP0945445 1, 5-BENZODIAZEPINE DERIVATIVES 1, 5-BENZODIAZEPINE DERIVATIVES
1999-09-29
2005-12-28
US2015050212 CHOLECYSTOKININ B RECEPTOR TARGETING FOR IMAGING AND THERAPY
2013-02-22
2015-02-19
US2012010401 METHOD FOR MANUFACTURING 1, 5-BENZODIAZEPINE DERIVATIVE
2012-01-12

1: Kato H, Seto K, Kobayashi N, Yoshinaga K, Meyer T, Takei M. CCK-2/gastrin receptor signaling pathway is significant for gemcitabine-induced gene expression of VEGF in pancreatic carcinoma cells. Life Sci. 2011 Oct 24;89(17-18):603-8. doi: 10.1016/j.lfs.2011.07.019. Epub 2011 Aug 3. PubMed PMID: 21839751.

////////////NASTORAZEPIDE, phase II, treatment of pancreatic cancer,

O=C(O)C1=CC=CC(NC(N[C@@H]2CN(C3CCCCC3)C4=CC=CC=C4N(CC(C(C)(C)C)=O)C2=O)=O)=C1

Advertisements

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids


Green Chem., 2018, 20,108-112
DOI: 10.1039/C7GC02913F, Communication
Open Access Open Access
Creative Commons Licence  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Manuel Kockinger, Tanja Ciaglia, Michael Bersier, Paul Hanselmann, Bernhard Gutmann, C. Oliver Kappe
Difluoromethylated esters, malonates and amino acids (including the drug eflornithine) are obtained by a gas-liquid continuous flow protocol employing the abundant waste product fluoroform as an atom-efficient reagent.

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids

Author affiliations

Abstract

Fluoroform (CHF3) can be considered as an ideal reagent for difluoromethylation reactions. However, due to the low reactivity of fluoroform, only very few applications have been reported so far. Herein we report a continuous flow difluoromethylation protocol on sp3 carbons employing fluoroform as a reagent. The protocol is applicable for the direct Cα-difluoromethylation of protected α-amino acids, and enables a highly atom efficient synthesis of the active pharmaceutical ingredient eflornithine.

Methyl 3,3-(difluoro)-2,2-diphenylpropanoate (2a) The product mixtures were collected and the solvent removed in vacuo. The products were isolated by thin layer chromatography (dichloromethane/hexane = 3/2 (v/v)). Yield: 173 mg (0.62 mmol, 62%); 93% by 19F NMR ;light yellow viscous liquid. 1 H NMR (300 MHz, D2O): δ = 7.45 – 7.19 (m, 10H), 6.90 (t, 2 JHF = 55.0 Hz, 1H), 3.79 (s, 3H). 13C NMR (75 MHz, D2O): δ = 171.1, 136.3, 129.8, 128.3, 128.2, 115.6 (t, 1 JCF = 246.2 Hz), 64.7, 53.1.19F NMR (282 MHz, D2O):δ = -123.0 (d, 2 JHF = 55.0 Hz).

STR1 STR2 STR3

Conclusions

A gas–liquid continuous flow difluoromethylation protocol employing fluoroform as a reagent was reported. Fluoroform, a by-product of Teflon manufacture with little current synthetic value, is the most attractive reagent for difluoromethylation reactions. The continuous flow process allows this reaction to be performed within reaction times of 20 min with 2 equiv. of base and 3 equiv. of fluoroform. Importantly, the protocol allows the direct Cα-difluoromethylation of protected α-amino acids. These compounds are highly selective and potent inhibitors of pyridoxal phosphate-dependent decarboxylases. The starting materials are conveniently derived from the commercially available α-amino acid methyl esters, and the final products are obtained in excellent purities and yields after simple hydrolysis and precipitation. The developed process appears to be especially appealing for industrial applications, where atom economy, sustainability, reagent cost and reagent availability are important factors.

//////////

OLINCIGUAT


img2D chemical structure of 1628732-62-6

OLINCIGUAT

cas 1628732-62-6
Chemical Formula: C21H16F5N7O3
UNII-PD5F4ZXD21
Molecular Weight: 509.4

Olinciguat is a guanylate cyclase activator drug candidate.

(2R)-3,3,3-trifluoro-2-{[(5-fluoro-2-{1-[(2-fluorophenyl)methyl]- 5-(1,2-oxazol-3-yl)-1H-pyrazol- 3-yl}pyrimidin-4-yl)amino]methyl}-2-hydroxypropanamide

  • Originator Ironwood Pharmaceuticals
  • Class Antifibrotics; Cardiovascular therapies
  • Mechanism of Action Soluble guanylyl cyclase agonists
  • Orphan Drug StatusNo
  • New Molecular EntityYes

Highest Development Phases

  • Phase II Gastrointestinal disorders; Sickle cell anaemia
  • Phase I Cardiovascular disorders; Fibrosis

Most Recent Events

  • 03 Jan 2018 Pharmacodynamics data from a preclinical trial in Cardiovascular disorders presented at the 59th Annual Meeting and Exposition of the American Society of Hematology (ASH-2017)
  • 21 Dec 2017 Phase-II clinical trials in Sickle cell anaemia in USA (PO)
  • 09 Dec 2017 Adverse events, pharmacokinetic and pharmacodynamics data from a phase Ib trial in healthy volunteers presented at the 59th Annual Meeting and Exposition of the American Society of Hematology

IW-1701

Currently in Phase II Clinical Development

Area of focus:

Achalasia and Sickle Cell Disease
Dysregulation of the nitric oxide-soluble guanylate cyclase-cyclical guanosine monophosphate (NO-sGC-cGMP) signaling pathway is believed to be linked to multiple vascular and fibrotic diseases, such as achalasia and sickle cell disease.

Our candidate:

IW-1701 is an investigational soluble guanylate cyclase (sGC) stimulator from Ironwood’s diverse library of sGC stimulators, which are being investigated for their potential effects on vascular and fibrotic diseases. The compound has been shown in nonclinical studies to modulate the NO-sGC-cGMP signaling pathway and is currently being evaluated in a Phase II study in achalasia. IW-1701 is wholly-owned by Ironwood Pharmaceuticals.

sGC is the primary receptor for NO in vivo. sGC can be activated via both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts Guanosine-5′-triphosphate (GTP) into the secondary messenger cGMP. The increased level of cGMP, in turn, modulates the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs) and ion channels.

In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by sequential reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long term potentiation; and constitutive endothelial NOS (eNOS or NOS III) which regulates smooth muscle relaxation and blood pressure. Experimental and clinical evidence indicates that reduced concentrations orbioavailability of NO and/or diminished responsiveness to endogenously produced NO contributes to the development of disease.

NO-independent, heme -dependent sGC stimulators, have shown several important differentiating characteristics, when compared to sGC activators, including crucial dependency on the presence of the reduced prosthetic heme moiety for their activity, strong synergistic enzyme activation when combined with NO and stimulation of the synthesis of cGMP by direct stimulation of sGC, independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Additional sGC stimulators with improved potency and specificity for sGC have since been developed.

Compounds that stimulate sGC in an NO-independent manner offer considerable advantages over other current alternative therapies that target the aberrant NO pathway. There is a need to develop novel, well-characterized stimulators of sGC. Compound I is an sGC stimulator that has demonstrated efficacy for the treatment of a number of NO related disorders in preclinical models. Compound I was previously described in WO2014144100, Example 1, as a light orange solid. Compound I may be present in various crystalline forms and may also form several pharmaceutically acceptable salts.

Compounds which enhance eNOS transcription: for example those described in WO

02/064146, WO 02/064545, WO 02/064546 and WO 02/064565, and corresponding patent documents such as US2003/0008915, US2003/0022935, US2003/0022939 and US2003/0055093. Other eNOS transcriptional enhancers including those described in US20050101599 (e.g. 2,2-difluorobenzo[l,3]dioxol-5-carboxylic acid indan-2-ylamide, and 4-fluoro-N-(indan-2-yl)-benzamide), and Sanofi-Aventis compounds AVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schafer et al., Journal of Thrombosis and Homeostasis 2005; Volume 3, Supplement 1 : abstract number P 1487);

NO independent heme-independent sGC activators, including, but not limited to: -2667 (see patent publication DE19943635)

HMR-1766 (ataciguat sodi

S 3448 (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomoφholine-4-sulfonyl)-phenyl)-benzamide (see patent publi

HMR-1069 (Sanofi-Aventis).

(7) Heme-dependent sGC stimulators including, but not limited to:

YC-1 (see patent publications EP667345 and DE19744026)

Riociguat (BAY 63-2521, Adempas, commercial product, described in DE19834044)

Neliciguat (BAY 60-4552, described in WO 2003095451)

Vericiguat (BAY 1021189, clinical backup to Riociguat),

BAY 41-2272 (described in DE19834047 and DE19942809)

BAY 41-8543 (described in DE I 9834044)

Etriciguat (described in WO 2003086407)

CFM-1571 (see patent publicatio

A-344905, its acrylamide analo analogue A-778935.

A-344905;

Compounds disclosed in one of publications: US20090209556, US8455638, US20110118282 (WO2009032249), US20100292192, US20110201621, US7947664, US8053455 (WO2009094242), US20100216764, US8507512, (WO2010099054) US20110218202 (WO2010065275),

US20130012511 (WO2011119518), US20130072492 (WO2011149921), US20130210798

(WO2012058132) and other compounds disclosed in Tetrahedron Letters (2003), 44(48): 8661-8663.

Pictorial synthesis

FROM PATENTS

CONSTRUCT YOUR OWN

SIDE CHAIN SHOWN ABOVE

                     FINAL STEP SHOWN ABOVE  OLINCIGUAT

PATENT

WO2014144100, Example 1

Inventors Takashi NakaiJoel MooreNicholas Robert PerlRajesh R. IyengarAra MermerianG-Yoon Jamie ImThomas Wai-Ho LeeColleen HudsonGlen Robert RENNIEJames JiaPaul Allen RENHOWETimothy Claude BardenXiang Y YuJames Edward SHEPPECKKarthik IyerJoon JungLess «
Applicant Takashi NakaiJoel MooreNicholas Robert PerlIyengar Rajesh RAra MermerianG-Yoon Jamie ImThomas Wai-Ho LeeColleen HudsonRennie Glen RobertJames JiaRenhowe Paul AllenTimothy Claude BardenXiang Y YuSheppeck James EdwardKarthik IyerJoon JungLess «

PATENT

WO 2016044447

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016044447

Inventors Timothy Claude BardenJames Edward SHEPPECKGlen Robert RENNIEPaul Allan RenhoweNicholas PerlTakashi NakaiAra MermerianThomas Wai-Ho LeeJoon JungJames JiaKarthik IyerRajesh R. IyengarG-Yoon Jamie Im
Applicant Ironwood Pharmaceuticals, Inc.

Compound 195

lntermediate-36 Compound 195

[00463] lntermediate-36 (35 mg, 0.09 mmol),

(R)-2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (60 mg, 0.35 mmol) and

N-ethyl-N-isopropylpropan-2-amine (0.10 mL, 0.56 mmol) were mixed in dimethylsulfoxide (1.5 mL) and heated at 95°C for 8 hr. The solution was cooled to room temperature, diluted with water (2 mL) and the pH taken to 2-3 with 1 N (aq) HC1. The solution was mixed with ethyl acetate (50 mL) and the organic phase was washed with water (2 x 5 mL), brine, then dried over Na2S04, filtered and concentrated by rotary evaporation. The residue was subjected to preparative reverse phase HPLC

. . . t . + + . using a giauiciu ui water acetonitri e . tni uoroacetic aci as e uant to give me iouu i s a wnite solid (11 mg, 23% yield). ¾-NMR (400 MHz, CD3OD) δ 8.83 (br s, 1H), 8.27 (br s, 1H), 7.49 (br s,

1H), 6.9-7.0 (m, 2H), 6.5-6.6 (m, 2H), 5.86 (s, 2H), 4.35 (d, 1H), 4.16 (d, 1H) ppm. Note: exchangable protons all appeared under the residual HOD peak at 4.91 ppm.

PATENT

WO-2018009609

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018009609&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel crystalline solid forms of olinciguat (presumed to be IW-1701), an SGC stimulator and their salts, such as hydrochloride acid (designated as Forms A, B, D, E, F, H and G), processes for their preparation and compositions comprising them are claimed. Also claimed are processes for preparing the crystalline forms. Further claimed are their use for treating cancer, sickle cell disease, osteoporosis, dyspepsia, Duchenne muscular dystrophy, amyotrophic lateral sclerosis and spinal muscle atrophy

In one aspect, the invention relates to crystalline solid forms of Compound I, depicted below:

Compound I

[0009] For purposes of this disclosure, “Compound I,” unless otherwise specifically indicated, refers to the free base or to the hydrochloric acid salt of the structure denoted above. Compound I, as its crystalline free base, is highly polymorphic and known to have seven crystalline forms (Forms A, B, D, E, F, G and H) as well as multiple solvates. Compound I was previously described in

WO2014144100, Example 1, as a light orange solid.

[0010] In one embodiment, the crystalline solid forms of Compound I here disclosed are polymorphs of the free base. In another embodiment, a crystalline solid form of Compound I is the hydrochloric acid salt. In one embodiment, the polymorphs of Compound I are crystalline free base forms. In another embodiment, they are solvates.

[001 1] In another aspect, also provided herein are methods for the preparation of the above described crystalline free forms and salts of Compound I.

[0012J In another aspect, the invention relates to pharmaceutical compositions comprising one or more of the polymorphs of Compound I herein disclosed, or the hydrochloric acid salt of Compound I, and at least one pharmaceutically acceptable excipient or carrier. In another embodiment, the invention relates to pharmaceutical dosage forms comprising said pharmaceutical compositions.

[0013] In another embodiment, the invention relates to a method of treating a disease, health condition or disorder in a subject in need thereof, comprising administering, alone or in combination therapy, a therapeutically effective amount of a polymorph of Compound I herein disclosed, or a mixture of polymorphs thereof, or its hydrochloric acid salt , to the subject; wherein the disease or disorder is one that may benefit from sGC stimulation or from an increase in the concentration of NO and/or cGMP.

EXAMPLES

Example 1: Preparation of crude Compound I

i): Coupling of Compound (1′) and 7V,0-Dimethylhydroxylamine to provide N-methoxy-N-methylisoxazole-3-carboxamide (2′)

[00238] Isooxazole-3-carboxylic acid ((l’)> 241.6 g, 2137 mmoles, 1.0 equiv.), toluene (1450 mL) and DMF (7.8 g, 107 mmoles, 0.05 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The resulting slurry was heated to 45-50 °C. Oxalyl chloride (325 g, 2559 mmoles, 1.2 equiv.) was then charged via an addition funnel over the course of 2 h while maintaining the reaction temperature between 45 to 50 °C and a vigorous gas evolution was observed. A brown mixture was obtained after addition. The brown mixture was heated to 87 to 92 °C over 1 h and stirred at 87 to 92 °C for 1 h. The reaction was completed as shown by HPLC. During heating, the brown mixture turned into a dark solution. The reaction was monitored by quenching a portion of the reaction mixture into piperidine and monitoring the piperidine amide by HPLC. The dark mixture was cooled to 20-25 °C and then filtered through a sintered glass funnel to remove any insolubles. The dark filtrate was concentrated under reduced pressure to a volume of 400 mL dark oil.

[00239] Potassium carbonate (413 g, 2988 mmoles, 1.4 equiv.) and water (1000 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction solution was cooled to -10 to -5 °C. N,0-dimethylhydroxyamine hydrochloride (229 g, 2348 mmoles, 1.1 equiv.) was charged to a suitable reaction vessel and dissolved in water (1000 mL). The N,0-dimethylhydroxyamine solution and dichloromethane (2500 mL) were then charged to the potassium carbonate solution.

[00240] The above dark oil (400 mL) was then charged slowly via an addition funnel while maintaining the reaction temperature -10 to 0 °C. The addition was slightly exothermic and a brown mixture was obtained after addition. The mixture was stirred at 0 to 5 °C over 20 min. and then warmed to 20 to 25 °C. The bottom organic layer was collected and the top aq. layer was extracted with dichloromethane (400 mL). The combined organic layers were washed with 15% sodium chloride solution (1200 mL). The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give intermediate (2′) as a dark oil (261.9 g, 97 wt%, 76% yield, 3 wt% toluene by Ή-ΝΜΡν, 0.04 wt % water content by KF). Ή-ΝΜΡν (500 MHz, CDC13) δ ppm 8.48 (s, 1 H); 6.71(s, 1 H); 3.78 (s, 3 H); 3.38 (s, 3 H).

ii): alkylation of Compound (2′) and ethyl propiolate to provide (E)-ethyl 4-(isoxazol-3-yl)-2-(methox methyl)amino)-4-oxobut-2-enoate (3′)

(2′) (3′)

[00241] Intermediate (2′) (72.2 g, 96 wt%, 444 mmoles, 1.0 equiv.), ethyl propiolate (65.7 g, 670 mmoles, 1.5 equiv.) and anhydrous THF (650 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to -65 to -55 °C. Sodium bis(trimethylsilyl)amide in THF (1 M, 650 mL, 650 mmoles, 1.46 equiv.) was then charged slowly via an addition funnel while maintaining the reaction temperature -65 to -55 °C. The mixture was stirred below -55 °C over 10 min. after addition was complete. Then 1 N HC1 (650 mL, 650 mmoles, 1.46 equiv.) was charged to quench the reaction while maintaining the reaction temperature below -20 °C followed immediately with the addition of ethyl acetate (1500 mL) and water (650 mL). The top ethyl acetate layer was collected and the bottom aqueous layer was extracted with ethyl acetate (800 mL). The combined organic layers were washed with 10% citric acid (1000 mL) and saturated sodium chloride solution (650 mL). The organic layer was concentrated under reduced pressure to give a dark oil.

[00242] The dark oil was dissolved in a solution of dichloromethane/ethyl acetate/heptane

(150mL/100mL/100mL). The solution was loaded on a silica pad (410 g) and the silica pad was eluted with ethyl acetate/heptane (1/1 v/v). The filtrate (~ 3000 mL) was collected and then concentrated under reduced pressure to a volume of 150 mL to give a slurry upon standing. Heptane (200 mL) was then added to the slurry and the slurry was concentrated under reduced pressure to a volume of 150 mL. The resulting slurry was filtered, and the filter cake was washed with heptane (150 mL). The filter cake was then air dried overnight to furnish intermediate (3′) as a brown solid (63.4 g, 56% yield, >99% pure by HPLC). i-NMR (500 MHz, CDC13) δ ppm 8.42 (d, J=1.53 Hz, 1 H); 6.76 (d, J=1.53 Hz, 1 H); 6.18 (s, 1 H); 4.47 (q, J=7.07 Hz, 2H); 3.75 (s, 3 H); 3.21 (s, 3 H); 1.41 (t, J=7.17 Hz, 3 H). iii): cyclization of Compound 3′ and 2-fluorobenzylhydrazine to provide ethyl l-(2-fluorobenz l)-5-(isoxazol-3-yl)-lH-pyrazole-3-carboxylate (4′)

[00243] Intermediate (3′) (72.9 g, 287 mmoles, 1.0 equiv.) and absolute ethanol (730 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was cooled to 0 to 5 °C. 2-Fluorobenzylhydrazine (48.2 g, 344 mmoles, 1.2 equiv.) was then charged to the mixture. The mixture was stirred at 0 to 10 °C over 1 h and then warmed to 20 to 25 °C and stirred at 20 to 25 °C over 16 h. The reaction was completed by HPLC. Concentrated HCl (33.9 g, 37 wt%, 344 mmoles, 1.2 equiv.) was charged to the reaction mixture over 1 min and the batch temperature exothermed from 20 °C to 38 °C. A slurry was obtained. The mixture was cooled to 0 to 10 °C over 1 h and stirred at 0-10 °C for 1 h. The resulting slurry was filtered, and the filter cake was washed with ethanol (200 mL). The filter cake was dried under vacuum at 30 to 40 °C over 16 h to furnish intermediate (4′) as an off-white solid (81.3 g, 90% yield, >99% pure by HPLC). ¾-NMR (500 MHz, CDC13) δ ppm 8.47 (d, J=1.68 Hz, 1 H); 7.15 – 7.26 (m, 2 H); 6.94 – 7.08 (m, 2H); 6.77 – 6.87 (m, 1 H); 6.55 (d, J=1.68 Hz, 1 H); 5.95 (s, 2 H); 4.43 (q, J=7.02 Hz, 2 H); 1.41 (t, J=7.17 Hz, 3 H).

iv): amination of Compound (4′) to provide l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazole-3-carboximidamide hydrochloride (5’B)

[00244] Anhydrous ammonium chloride (267 g, 4991 mmoles, 5.0 equiv.) and toluene (5400 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Trimethylaluminum in toluene (2 M, 2400 mL, 4800 mmoles, 4.8 equiv.) was charged

slowly via an addition funnel while maintaining the reaction temperature at 20 to 40 °C (Note:

Methane gas evolution was observed during addition). Then the mixture was heated to 75 to 80 °C over 30 min. and a clear white solution was obtained. Intermediate (4′) (315 g, 999 mmoles, 1.0 equiv.) was charged to reaction mixture in four equal portions over 1 h at 75 to 90 °C. The reaction was stirred at 80 to 90 °C over 30 min. and then heated to 100 to 110 °C and stirred at 100 to 110 °C over 3 h. The reaction was completed by HPLC. The reaction mixture was cooled to 10 to 20 °C and methanol (461 g, 14.4 moles, 14.4 equiv.) was charged slowly via an addition funnel while

maintaining the reaction temperature 10-40 °C. Note the quenching was very exothermic and a lot gas evolution was observed. A thick slurry was obtained. A 3N HQ (6400 mL, 3 N, 19.2 moles, 19.2 equiv.) was then charged slowly via an addition funnel while maintaining the reaction temperature at 20 to 45 °C. The mixture was heated to 80 to 85 °C and stirred at 80 to 85 °C over 10 min. to obtain a clear biphasic mixture. The mixture was cooled to 0 to 5 °C over 3 h and stirred at 0 to 5 °C over 1 h. The resulting slurry was filtered, and the filter cake was washed with water (3000 mL). The filter cake was dried under vacuum at 40 to 50 °C over 24 h to furnish intermediate (5’B) as an off-white solid (292 g, 91% yield, >99% pure by HPLC). ¾-ΝΜΡν (500 MHz, DMSO- 6) δ ppm 9.52 (s, 2 H); 9.33 (s, 2 H); 9.18 (d, J=1.53 Hz, 1 H); 7.88 (s, 1 H); 7.29 – 7.38 (m, 1 H); 7.19 – 7.25 (m, 1 H); 7.10 – 7.16 (m, 1 H); 7.03 (d, J=1.53 Hz, 1 H); 6.92 – 6.98 (m, 1 H); 5.91 (s, 2 H). M.P. 180-185 °C.

v): cyclization of Compound (5’B) and diethyl fluoromalonate to provide 5-fluoro-2-(l-(2-fluorobenz l)-5-(isoxazol-3-yl)-lH-pyrazol-3-yl)pyrimidine-4,6-diol (6′)

(5’B) (6·)

[00245] Intermediate (5’B) (224.6 g, 698 mmoles, 1.0 equiv.), methanol (2250 mL) and diethyl fluoromalonate (187 g, 1050 mmoles, 1.5 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Then sodium methoxide in methanol solution (567 g, 30 wt %, 3149 mmoles, 4.5 equiv.) was charged via an addition funnel while maintaining the reaction temperature 20 to 35 °C. The mixture was stirred at 20 to 35 °C over 30 min. and a light suspension was obtained. The reaction was completed by HPLC. A solution of 1.5 N HQ (2300 mL, 3450 mmoles, 4.9 equiv.) was charged via an addition funnel over 1 h while maintaining the reaction temperature 20 to 30 °C. A white suspension was obtained. The pH of the reaction mixture was to be ~1 by pH paper. The slurry was stirred at 20 to 30 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of methanol and water (500 mL/500 mL), and then with water (1000 mL). The filter cake was dried under vacuum at 50 to 60 °C over 16 h to furnish intermediate (6′) as an off-white solid (264 g, 97% yield, >99% pure by HPLC). ¾-NMR (500 MHz,

DMSO- s) δ ppm 12.82 (br. s., 1 H); 12.31 (br. s., 1 H); 9.14 (d, J=1.53 Hz, 1 H); 7.55 (s, 1 H); 7.31 -7.37 (m, 1 H); 7.18 – 7.25 (m, 1 H); 7.10 – 7.15 (m, 2 H); 6.97 – 7.02 (t, J=7.55 Hz, 1 H); 5.88 (s, 2 H).

vi): chlorination of Compound (6′) to provide 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-l-(2-fluorobenz l)-lH-pyrazol-5-yl)isoxazole (7′)

(6«) (7«)

[00246] Intermediate (6′) (264 g, 71 1 mmoles, 1.0 equiv.), acetonitrile (4000 mL) and N,N-dimethylaniline (138 g, 1 137 mmoles, 1.6 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The slurry mixture was heated to 70-80 °C. Then phosphorous oxychloride (655 g, 4270 mmoles, 6.0 equiv.) was charged via an addition funnel over 1 h while maintaining the reaction temperature 70 to 80 °C. The mixture was stirred at 75 to 80 °C over 22 h and a brown solution was obtained. The reaction was completed by HPLC. Then the mixture was cooled to between 0 and 5 °C and cotton like solids precipitated out at 25 °C. Water (3000 mL) was charged slowly via an addition funnel while maintaining the reaction temperature at 0 to 10 °C. The slurry was stirred at 0 to 10 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of acetonitrile and water (500 mL/500 mL). The filter cake was dried under vacuum at 35 to 45 °C over 16 h to furnish intermediate (7′) as an off-white solid (283 g, 98% yield, >99% pure by HPLC). ‘H-NMR (500 MHz, CDC13) δ ppm 8.48 (d, J=1.68 Hz, 1 H); 7.44 (s, 1 H); 7.19 – 7.25 (m, 1 H); 6.96 – 7.08 (m, 2 H); 6.81 – 6.88 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 6.03 (s, 2 H).

vii): substitution of Compound (7′) with meth oxide to provide 3-(3-(4-chloro-5-fluoro-6-m

(7′) (8′)

[00247] Methanol (3400 mL) and sodium methoxide in methanol (154 mL, 5.4 M, 832 mmoles,

1.2 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 23 to 27 °C. Intermediate (7′) (283 g, 693 mmoles, 1.0 equiv.) was charged to the mixture in small portions (5-10 g each portion) over 40 min while maintaining the reaction temperature 23 to 27 °C. The slurry was stirred at 23 to 27 °C over 30 min. The reaction was completed by HPLC. The resulting slurry was filtered, and the filter cake was washed with methanol (850 mL) and then water (850 mL). The filter cake was dried under vacuum at 35 to 45 °C over 16 h to furnish intermediate (8′) as an off-white solid (277 g, 99% yield, 97% pure by HPLC). i-NMR (500 MHz, CDCl3) 5 ppm 8.47 (d, J=1.83 Hz, 1 H); 7.38 (s, 1 H); 7.18 – 7.25 (m, 1 H); 7.01 – 7.08 (m, 1 H); 6.94 – 7.00 (m, 1 H); 6.81 – 6.88 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 6.00 (s, 2 H); 4.21 (s, 3 H).

viii): hydrogenation of Compound (8′) to provide 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-l-(2-fluorobenz l)-lH-pyrazol-5-yl)isoxazole (9′)

[00248] Intermediate (8′) (226 g, 560 mmoles, 1.0 equiv.), palladium (10% on activated carbon, nominally 50% water wet, 22.6 g, 0.01 moles, 0.018 equiv), tetrahydrofuran (3400 mL) and triethylamine (91 g, 897 mmoles, 1.6 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Nitrogen was bubbled into the reaction mixture via teflon tubing over 10 min. at 20 to 30 °C. Then the mixture was heated to 40 to 50 °C and hydrogen gas was bubbled into the reaction mixture via teflon tubing over 6 h while maintaining the reaction temperature 40 to 50 °C. The reaction was completed by HPLC. Nitrogen was then bubbled into the reaction mixture via teflon tubing over 10 min. at 40 to 50 °C The reaction mixture was hot filtered through Hypo Supercel™ and the filter cake was washed with tetrahydrofuran (2000 mL). The filtrate was concentrated under reduced pressure to a volume of -1300 mL to give a slurry. Tetrahydrofuran was then solvent exchanged to methanol under reduced pressure via continuously feeding methanol (3000 mL). The final volume after solvent exchange was 1300 mL. The resulting slurry was filtered, and the filter cake was washed with methanol (500 mL). The filter cake was dried under vacuum at 20 to 25 °C over 16 h to furnish intermediate (9′) as a white solid (192 g, 93% yield, 98% pure by HPLC). ¾-NMR (500 MHz, CDC13) δ ppm 8.47 (d, J=1.68 Hz, 1 H); 8.41 (d, J=2.59 Hz, 1 H); 7.36 (s, 1 H); 7.17 – 7.24 (m, 1 H); 6.95 – 7.07 (m, 2 H); 6.83 – 6.90 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 5.99 (s, 2 H); 4.19 (s, 3 H).

ix: demethylation of Compound (9′) to provide 5-fluoro-2-(l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazol-3-yl)pyrimidin-4-ol (10′)

[00249] Intermediate (9′) (230 g, 623 mmoles, 1.0 equiv.), Me OH (3450 mL) and cone. HC1

(307 g, 37 wt%, 3117 mmoles, 5.0 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was heated to 60 to 65 °C and a solution was obtained. The mixture was then stirred at 60 to 65 °C over 17 h and a slurry was obtained. The reaction was completed by HPLC. The slurry was cooled to 20 to 25 °C over 2 h and stirred at 20 to 25 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with methanol (1000 mL). The filter cake was dried under vacuum at 35 to 45 °C over 16 h to furnish intermediate (10′) as a white solid (214 g, 97% yield, >99% pure by HPLC). ¾-NMR (500 MHz, DMSO-t/6) δ ppm 12.90 – 13.61 (br. s., 1 H); 9.11 (d, J=1.68 Hz, 1 H); 8.16 (s, 1 H); 7.64 (s, 1 H); 7.29 – 7.42 (m, 1 H); 7.17 – 7.28 (m, 2 H); 7.08 – 7.15 (m, 1 H); 6.97 (s, 1 H); 5.91 (s, 3 H).

x): chlorination of Compound (10′) to provide 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-l-(2-fluorobenzyl)-lH-pyrazol-5-yi)isoxazole (Formula IV)


Formula IV

[00250] Intermediate (10′) (214 g, 602 mmoles, 1.0 equiv.), acetonitrile (3000 mL) and NN-dimethylaniline (109 g, 899 mmoles, 1.5 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The slurry mixture was heated to 70 to 80 °C. Then phosphorous oxychloride (276 g, 1802 mmoles, 3.0 equiv.) was charged via an addition funnel over 30 min. while maintaining the reaction temperature 70-80 °C. The mixture was stirred at 75 to 80 °C over 2 h and a green solution was obtained. The reaction was completed by HPLC. Then the mixture was cooled to 0 to 5 °C. Water (1500 mL) was charged slowly via an addition funnel while maintaining the reaction temperature at 0 to 10 °C. The slurry was stirred at 0 to 10 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of

acetonitrile and water (500 mL/500 mL) and water (500 mL). The filter cake was dried under vacuum at 30 to 40 °C over 16 h to furnish intermediate of Formula IV as an off-white to pink solid (214 g, 95% yield, >99% pure by HPLC). 1H NMR (500 MHz, CDC13) 5 ppm 8.65 (s, 1 H); 8.48 (d, J=1.68 Hz, 1 H); 7.44 (s, 1 H); 7.21 – 7.25 (m, 1 H); 6.97 – 7.06 (m, 2 H); 6.83 – 6.87 (m, 1 H); 6.61 (d, J=1.68 Hz, 1 H); 6.03 (s, 2 H).

a): Cyanation of intermediate (15) to provide 2-(bromomethyl)-3,3,3-trifluoro-2-((trimethylsilyl)oxy)propanenitrile (16)

(15) (16)

[00251 ] Trimethylsilanecarbonitrile ( 153 g, 1.54 moles, 0.97 equiv) and triethylamine (4.44 mL,

3.22 g, 0.032 mole, 0.02 equiv) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was cooled to 5 °C. 3-Bromo-l, l, l-trifluoropropan-2-one ((15), 304 g, 1.59 moles, 1.0 equiv) was charged via an addition funnel over 35 min, while maintaining the reaction temperature between 10 to 20 °C. The mixture was stirred at 20 to 30 °C over 3 h after the addition to furnish intermediate (16) as a dense oil which was used directly in the next step. 1H-NMR (500 MHz, CDC13) δ ppm 3.68 (d, J=1 1.14 Hz, 1 H); 3.57 (d, J=11.14 Hz, 1 H), 0.34 – 0.37 (m, 9 H).

b): Conversion of nitrile Compound (16) to amide to provide 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (17)

2

(16) (17)

[00252] Concentrated sulfuric acid (339 mL, 6.37 moles, 4.0 equiv) was stirred in a suitable reaction vessel equipped with a mechanical stirrer, digital thermometer and an addition funnel. The sulfuric acid was heated to 45 °C. The above intermediate (16) was added via an addition funnel over 50 min, while keeping the temperature below 75 °C. The reaction mixture was stirred at 75 °C for 2 h and then allowed to cool to room temperature. ¾-NMR indicated reaction complete. The reaction mixture was cooled to -15 °C and diluted with ethyl acetate (1824 mL) via an addition funnel over 45 min (very exothermic), while keeping the temperature between -15 to 5 °C. Water ( 1520 mL) was added slowly via an addition funnel for 1 h 20 min. (very exothermic) between -10 to 0 °C. The layers were separated and the organic layer was washed with 15% aqueous sodium chloride solution ( 1520

mL), 25% aqueous sodium carbonate solution (911 mL) followed by 15% aqueous sodium chloride solution (911 mL). The organic layer was filtered and concentrated under reduced pressure to get 348 g of intermediate (17) as light yellow oil. This oil was dissolved in methanol (1200 mL) and concentrated to furnish 380 g of intermediate (17). (296 g adjusted weight, 79% yield). i-NMR (500 MHz, CDC13) 5 6.61 – 6.94 (m, 1 H); 5.92 – 6.26 (m, 1 H); 3.93 – 4.00 (m, 1 H); 3.68 (d, J=l 1.14 Hz, 1 H).

c): N-Alkylation of compound (17) to provide of 2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (14)

(17) (14)

[00253] A 7 N solution of ammonia in methanol (600 mL, 4.28 moles, 10 equiv) was charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to 0 to 5 °C. Then the intermediate (17) (102 g, 0.432 moles, 1 equiv) was added via an addition funnel over 30 min at 0 to 5 °C. The reaction mixture was warmed to 20 to 25 °C over 1 h and held for 72 h. The reaction was completed by HPLC. The reaction mixture was cooled to 0 to 5 °C and sodium methoxide (78 mL, 5.4 M, 0.421 moles, 0.97 equiv) was added over 2 min. The reaction mixture was then concentrated under reduced pressure to a volume of 300 mL. 2 L of ethyl acetate was added and concentration was continued under reduced pressure to a volume to 700 mL to get a slurry. 700 mL of ethyl acetate was added to the slurry to make the final volume to 1400 mL. 102 mL of water was added and stirred for 2 min to get a biphasic solution. The layers were separated. The ethyl acetate layer was concentrated under reduced pressure to a volume of 600 mL. Then the ethyl acetate layer was heated to > 60 °C and heptane (600 mL) was added slowly between 55 to 60 °C. The mixture was cooled to 15 to 20 °C to give a slurry. The slurry was stirred at 15 to 20 °C for 2 h and filtered. The solids were dried under vacuum at 25 °C for 16 h to furnish amine (14) as white solid (48 g, 64% yield). ‘H-NMR (500 MHz, MeOH-d4) δ ppm 2.94 (d, J= 13.73 Hz, 1H); 3.24 (d, J= 13.58 Hz, 1H).

d): chiral resolution of amine (14) as the 1:1 salt of (R)-2,2-dimethyl-5- (trifluoromethyl)oxazolidine-5-carboxamide (R)-2-hydroxysuccinate (18A) and (D)-malic acid.

(14) (ISA)

[00254] Amine (14) (105 g, 0.608 moles, 1.0 equiv.), (D)-Malic acid (82 g, 0.608 moles, 1.0 equiv.) and acetone (1571 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was stirred at 20 to 25 °C for 16 h. The resulting slurry was filtered, and the wet cake was washed with acetone (300 mL). The wet cake was charged back to the reaction vessel, and acetone (625 mL) was charged. The slurry was heated to 53 °C and held for 6 h. The slurry was cooled to 20 to 25 °C and held at this temperature for 16 h. The slurry was filtered, and the wet cake was washed with acetone (200 mL). The wet cake was dried under vacuum at 40 °C for 4 h to furnish 82.4 g of the 1 : 1 salt of (18A) and (D)-malic acid as a white solid (82.4 g, 39% yield, 97% ee). i-NMR (500 MHz, D20) δ ppm 4.33 (br, s, 1H); 3.61 (br, d, J= 13.58 Hz, 1H); 3.40 – 3.47 (m, 1H); 2.76 (br, d, J= 15.87 Hz, 1H); 2.53 – 2.63 (m, 1H); 2.16 (br, s, 4H).

e): Coupling of the 1:1 (D)-malic acid salt of intermediate (18A) and Formula IV to provide (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (Compound I)

Formula IV Compound I

[00255] The 1: 1 salt of intermediate (18A) and (D)-malic acid (74.1 g, 0.214 moles, 2.5 equiv) and water (44.8 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 70 °C and stirred for 20 min. Acetone generated during the reaction was removed by blowing with nitrogen. The reaction mixture was cooled to 30 to 40 °C and Formula IV (32 g, 0.086 moles, 1.0 equiv), DMSO (448 mL) and Hunig’s base (44.7 mL, 0.257 moles, 3.0 equiv) were charged. The reaction mixture was heated to 90 °C and stirred at 90 °C over 17 h. The reaction was complete by HPLC. Then the mixture was cooled to 60 °C. Another portion of Hunig’s base (104 mL, 0.599 moles, 7.0 equiv) was charged followed by water (224 mL) at 55 to 62 °C. The reaction mixture was stirred for 15 min at 55 to 60 °C to form the seed bed. Water (320 mL) was added via addition funnel at 55 to 62 °C over the course of 30 min, and the resultant slurry was stirred for 1 h at 55 to 60 °C. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of methanol and water (320 mL/320 mL) followed by water (640 mL). The filter cake was then dried under vacuum at 40 °C over 16 h to furnish Compound I as an off-white solid (40 g, 92% yield, 99% pure by HPLC, 98% ee). ¾-NMR (500 MHz, DMSO-t/6) δ ppm 9.10 (s, 1 H); 8.33 (d, J=2.90 Hz, 1 H); 7.93 (s, br, 1 H); 7.90 (s, 1 H); 7.78 (s, br, 1 H); 7.69 (s, br, 1 H); 7.52 (s, 1 H); 7.33 (q, J=7.02 Hz, 1 H); 7.17 – 7.25 (m, 1 H); 7.17 – 7.25

(m, 1 H); 7.10 (t, J=7.48 Hz, l H); 6.98 (t, J=7.55 Hz, 1 H); 5.90 (s, 2 H); 3.92-4.05 (m, 2 H).

////////////OLINCIGUAT, IW-1701, phase 2, ironwood

NC(=O)[C@](O)(CNc1nc(ncc1F)c2cc(c3ccon3)n(Cc4ccccc4F)n2)C(F)(F)F

OXCARBAZEPINE


Oxcarbazepine

Image result for oxcarbazepine

Oxcarbazepine

  • Molecular FormulaC15H12N2O2
  • Average mass252.268 Da
  • 10-Oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid amide
    28721-07-5 [RN]
    5H-Dibenz[b,f]azepine-5-carboxamide, 10,11-dihydro-10-oxo-

Image result for oxcarbazepine synthesis shodhganga

UV Spectroscopy The UV absorption spectrum of carbamazepine in methanol shown in Fig. 1 was recorded using Shimadzu UV–vis Spectrometer 1601 PC. The compound exhibited maxima at 288 and 259 nm. Clarke reported the following: methanol—237 and 285 nm (A 1%, 1 cm¼490) [1].

1 A.C. Moffat (Ed.), Clarke’s Isolation and Identification of Drugs, second ed.,
The Pharmaceutical Press, London, 1986, p. 428.

Vibrational Spectroscopy The FT-infrared absorption spectrum of carbamazepine was obtained in a KBr pellet using a Perkin-Elmer FT-infrared spectrophotometer. FTinfrared spectrum is shown in Fig. 2, where the principal peaks are observed at 3465, 3157, 1675, 1604, 1594, 1488, 1381, 1307, 870, 800, 762, and 724 cm1 .

1 H NMR Spectra The proton nuclear resonance (1 H NMR) spectra of carbamazepine were obtained using a Bruker instrument operating at 500 MHz. Standard Bruker software was used to execute the recording of the 1D and 2D spectra. The sample was dissolved in DMSO-d6 and all resonance bands were referencedto tetramethylsilane (TMS) as internal standard. The entire proton spectra are shown in Figs. 3 and 4. A singlet resonates at δ 5.54 representing the two protons of the amino group. An additional singlet which resonates at δ 6.99 ppm is assigned to the olefinic protons at positions 10 and 11. The two multiplets which resonate at δ 7.30–7.34 and δ 7.41–7.43 ppm are assigned to the aromatic protons of the two phenyl rings.

13C NMR Spectra A noise-modulated, broadband decoupling 13C NMR spectrum (Fig. 5) showed 11 carbon absorptions in accordance with what is anticipated for the structure of carbamazepine. Carbon resonance bands at δ 127.1, 129.0, 129.2, 129.3, 129.8, 130.3, 131.0, and 134.8 ppm account for the CH functions. A carbon band at δ 140.6 ppm represents the ethylene carbons. The carbonyl carbon resonates at δ 156.3 ppm. A DEPT experiment (Fig. 6) permitted the identification and confirmation of the methyl and methine carbons. Another confirmation was obtained through the HSQC experiment (Fig. 7).

SYN 1

http://www.drugfuture.com/synth/syndata.aspx?ID=117845

DD 153835; EP 0028028; JP 1045366; JP 1045367; JP 1045368; US 4452738; US 4540514; US 4559174; US 4579683

The nitration of 5-cyano 5H-dibenz[f,b]azepine (IV) with NaNO2 in acetic anhydride – acetic acid gives 5-cyano 10-nitro-5H-dibenz[b, f]azepine (V), which is then treated with BrF3 and powdered Fe in hot acetic acid.

SYN2

DE 2011087

The reaction of 10-methoxy-5H-dibenz[b,f]azepine (I) with phosgene in hot toluene gives 10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride (II), which is treated with NH3 in refluxing ethanol to afford 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide (III). Finally, this compound is hydrolyzed with refluxing 2N HCl.

SYN 3

WO 9621649

This compound has been obtained by two related ways: 1. The hydrolysis of 10-methoxy-5H-dibenzo[b,f]azepine (I) with refluxing 2N HCl gives 10,11-dihydro-5H-dibenzo[b,f]azepin-5-one (II), which is then treated with chlorosulfonyl isocyanate in chloroform to yield the target carboxamide. 2. The reaction of 10-methoxy-5H-dibenzo[b,f]azepine (I) with potassium cyanate in hot sulfuric acid also gives the target carboxamide. In this reaction sodium cyanate can also be used instead of the potassium salt. Other strong acids such as trichloroacetic acid or anhydrous HCl in acetic acid can be used instead of sulfuric acid.

SYN 4

The reaction of 10-methoxy-5H-dibenz[b,f]azepine (I) with phosgene in hot toluene gives 10-methoxy-5H-dibenz[b,f]azepine-5-carbonyl chloride (II), which is treated with NH3 in refluxing ethanol to afford 10-methoxy-5H-dibenz[b,f]azepine-5-carboxamide (III). Finally, this compound is hydrolyzed with refluxing 2N HCl.

SYN 5

WO 0156992

A new process for the preparation of oxcarbamazepine has been reported: Reaction of 1-phenyl-2,3-dihydro-1H-indol-2-one (I) with NaOH in refluxing THF gives 2-[2-(phenylamino)phenyl]acetic acid (II), which is condensed with dimethyl carbonate (III) by means of butyl lithium in the same solvent to yield 2-[2-[N-(methoxycarbonyl)-N-phenylamino]phenyl]acetic acid (IV). Cyclization of compound (IV) by means of polyphosphoric acid (PPA) at 100 C, followed by treatment of the reaction mixture with hot methanol (65 C) affords 10-methoxy-5H-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (V), which is treated with NaOH in polyethyleneglycol at 100 C to provide 10-methoxy-5H-dibenzo[b,f]azepine (VI). Reaction of (VI) with sodium

SYN 6

Tetrahedron Lett 2001,42(3),385

Syntheses of intermediate (V), 5-benzyl-10,11-dihydro-5H-dibenz[b,f]azepin-10-one: Cyclization of either 2-[N-benzyl-N-(2-methylphenyl)amino]-N,N-dimethylbenzamide (I), 2-[N-benzyl-N-(2-methylphenyl)amino]-N,N-diethylbenzamide (II), 2-[N-benzyl-N-(2-methylphenyl)amino]-N,N-diisopropylbenzamide (III) or the morpholine derivative (IV) by means of LDA and TMEDA in THF

Syntheses of intermediate (VIII), 5-(4-methoxybenzyl)-10,11-dihydro-5H-dibenz[b,f]azepin-10-one: Cyclization of 2-[N-(4-methoxybenzyl)-N-(2-methylphenyl)amino]-N,N-dimethylbenzamide (VI) or 2-[N-(4-methoxybenzyl)-N-(2-methylphenyl)amino]-N,N-diethylbenzamide (VII)) by means of LDA and TMEDA in THF.

Syntheses of intermediate (XI), 5-allyl-10,11-dihydro-5H-dibenz[b,f]azepin-10-one: Cyclization of 2-[N-allyl-N-(2-methylphenyl)amino]-N,N-dimethylbenzamide (IX) or 2-[N-allyl-N-(2-methylphenyl)amino]-N,N-diethylbenzamide (X) by means of LDA and TMEDA in THF.

Finally, deprotection of either intermediate (V) with TMS-Cl and NaI, intermediate (VIII) with TiCl4 or intermediate (XI) with Rh(PPh3)3Cl give, in all cases, 10,11-dihydro-5H-dibenz[b,f]azepin-10-one (XII), which is finally treated with chlorosulfonyl isocyanate to afford oxcarbazepine.

PATENT

Image result for oxcarbazepine synthesis shodhganga

https://www.google.com/patents/US6670472

Oxcarbazepine is an anticonvulsant drug (as described in U.S. Pat. No. 3,642,775), and has been proposed for use as an anti-epileptical agent in the treatment of AIDS-related neural disorders (as described in PCT patent specification no. WO 94/20110); and for the treatment of Parkinson’s disease and/or Parkinsonian syndromes (as described in U.S. Pat. No. 5,658,900 and European patent specification no. 678 026).

Various processes for preparing oxcarbazepine have been described in the prior art. For example, U.S. Pat. No. 3,642,775 describes the preparation of oxcarbazepine from 10-methoxyiminostilbene (Scheme-1), which is first phosgenated in toluene, followed by amidation (ethanol and ammonia) and hydrolysis in an acidic medium to furnish the desired product. The main drawback of this process is the use of phosgene (COCl2), a toxic and hazardous substance.

Canadian patent specification no. 1 112 241 describes an alternative preparation of oxcarbazepine from the catalysed re-arrangement of 10,11-epoxycarbamazepine, which itself may be prepared from carbamazepine by reaction with m-chloroperbenzoic acid (CPBA) (Scheme-2). However, the drawbacks of this process are: use of carbamazepine, an expensive raw material; and converting this into its corresponding epoxide in poor yields and quality.

Figure US06670472-20031230-C00001
Figure US06670472-20031230-C00002

Another process, disclosed in European patent specification no. 028 028, starts from 5-cyanoiminostilbene through nitration, reduction and hydrolysis stages (Scheme-3). However, the drawback of the process is in the preparation of the 5-cyanoiminostilbene itself, which can be made from iminostilbene and cyanogen chloride. The latter is also toxic, hazardous and difficult to handle.

Figure US06670472-20031230-C00003

Another alternative is described in Swiss patent specification no. 642 950 and comprises hydrolysis, using concentrated sulphuric acid, of the corresponding chloride (10-chloro-5H-dibenz[b,f]azepin-5carboxamide) to form the oxcarbazepine.

More recently, a process has been described in PCT patent specification no. WO 96/21649 (Scheme-4), which starts with 10-methoxyiminostilbene and treats it with an alkali or alkaline earth metal cyanate and acid to produce 10-methoxycarbamazepine which, on acid hydrolysis, furnishes oxcarbazepine. Alternatively, 10-methoxyiminostilbene is first hydrolysed to produce 10-oxo-iminodibenzyl (10-keto-iminodibenzyl) which, upon condensation with chlorosulphonyl isocyanate followed by hydrolysis, furnishes oxcarbazepine. Chlorosulphonyl isocyanate is a very costly, highly moisture-sensitive and toxic reagents which is the main drawback of this latter process.

The biggest problem with the former process is that 10-methoxyiminostilbene undergoes two kinds of competitive reactions when an alkali metal cyanate and an acid are added. The enol-ether moiety of the compound undergoes hydrolysis to give the corresponding ketone (“oxo” compound), which does not undergo a carboxamidation reaction with HOCN, whereas the imino function of the intact 10-methoxyiminostilbene does undergo a carboxamidation reaction. Therefore, the end result is that a mixture of oxcarbazepine, oxo-iminodibenzyl and impurities are obtained, after hydrolysis, making the subsequent crystallization process highly tedious and uneconomical.

Figure US06670472-20031230-C00004

The acids that are used in this reaction (Scheme-4), according to the Examples of WO 96/21649, include acetic acid, mono-, di- and tri-chloroacetic acids, dry HCl and concentrated sulphuric acid etc. The general description teaches that concentrated mineral acids are to be used, optionally in solution in the organic acids. Nevertheless, all these acids produce substantial quantities of side products, ie oxo-iminodibenzyl and impurities formed therefrom. Due to this, although the conversion is high, the selectivity leading to the carboxamidation reaction is poor.

Furthermore, international patent specification no. WO 01/56992 describes the use of acetic acid in the absence of an additional solvent in this process, which is stated to result in an improved yield. Nothing about the purity of the end-product (oxcarbazepine) is mentioned, however, and the specific example given shows that the yield thereof is less than or equal to 78% after hydrolysis with water and sulphuric acid in the absence of a solvent such as toluene.

All the known methods therefore suffer from disadvantages, in particular, the requirement to use “environmentally unfriendly” reactants, and/or result in poor yields due to side reactions as mentioned above. In particular, the method described in WO 01/56992 precludes the use of a solvent, which imposes unfavourable limitations on the subsequent processing of the intermediate in the preparation of the end-product.

We have surprisingly found that reaction of 10-methoxyiminostilbene with cyanic acid (HOCN) in the presence of a mild acidic reagent, especially an aromatic acid, enables the disadvantages of the prior art preparation of 10-methoxycarbamazepine to be overcome. In particular, it allows for the use of a solvent in the subsequent reaction steps, which has advantages as will be further described hereinbelow

Accordingly, the present invention provides a process for the preparation of 10-methoxycarbamazepine, which process comprises reacting 10-methoxyiminostilbene with HOCN in a solvent therefor in the presence of a mild acidic reagent. It is important that the mild acidic reagent be chosen so that the enol-ether function is not rapidly hydrolysed. Accordingly, this reagent is preferably a weak acid, such as an aromatic acid. Preferred aromatic acids include weak, non-aliphatic organic acids, such as benzoic acid and substituted benzoic acids; suitable substituents being halo, especially chloro eg para-chlorobenzoic acid. Suitably, the acid has a pKa value in the range of from about 10−4 to 10−5.

Furthermore, the mild acidic reagent is preferably relatively insoluble in the solvent, especially at room temperature but also preferably at the temperature of the reaction, compared to other acids, such as acetic acid. Suitably, the mild acidic reagent has a solubility in the solvent of less than 75%, preferably less than 50% and more preferably less than 25% in the solvent. Especially preferred is when the mild acidic reagent has a solubility of less than about 10-12%, even at elevated temperatures, such as at the temperature of the reaction, and particularly preferred is when the mild acidic reagent has a solubility of less than about 1% at room/ambient Temperature. In this context, it is to be understood that ‘room temperature’ is less than 35° C. and more usually about 20-25° C., such as 21-22° C. Of all the aromatic acids, benzoic acid is the most suitable acid in terms of selectivity (by ‘selectivity’ in this context is meant preference for the carboxamidation reaction over the enol-ether hydrolysis).

Excess molar quantity of the weak acid is preferably used in comparison to the 10-methoxyiminostilbene starting material; for example, in the range of from 2 to 10 molar excess, more preferably about 5 to 8 times, eg 6-7 times, benzoic acid is most preferably employed in the reaction. Most of the acidic reagent can be easily recovered and re-used, such as up to 90-95% can be re-cycled. Such acids less readily hydrolyse the enol-ether moiety present in the 10-methoxyiminostilbene, while nevertheless being able readily to catalyse the reaction between the 10-methoxyiminostilbene and the HOCN.

In another aspect, the present invention provides a process for the preparation of 10-methoxycarbamazepine, which process comprises reacting 10-methoxyiminostilbene with HOCN in the absence of a strong acid. In particular, the present invention provides a process for the preparation of 10-methoxycarbamazepine, which process comprises reacting 10-methoxyiminostilbene with HOCN in the absence of an acid having a high solubility in the solvent. In this context, a strong acid is one that would rapidly hydrolyse the enol-ether function of the starting material, such as aliphatic organic acids (including acetic acid, which also has a high solubility in solvents such as toluene) and mineral acids. For example, when aliphatic acids, such as acetic acid, monochloro-acetic acid, ethylhexanoic acid and phenylacetic acid etc, were used in the reaction, the percentage formation of 10-methoxycarbamazepine was very poor, varying from 26% to 51%. Worse still, when mineral acids, such as hydrochloric acid and sulphuric acid, were tried, the percentage formation of 10-methoxycarbamazepine was even more poor (˜1%). In all the above reactions (ie when aliphatic acids or mineral acids were used), a significant percentage of 10-oxo-iminostilbene and impurities were formed. Table 1 below shows the results, using sodium cyanate in all reactions and 10 volumes of toluene per part of 10-methoxyiminostilbene.

TABLE 1
HPLC Analysis
% of 10- % of
Reflux Conversion methoxycarba- Oxo- Total % of Unreacted
Acid used (hours) (%) mazepine IDB Impurity 10-methoxy ISB
Hydrochloric acid 4 89.63 0.24 70.19 19.19 10.37
Sulphuric acid 4 99.48 1.12 93.67 4.69 0.52
Acetic acid 12 59.05 26.22 12.97 19.86 40.95
Monochloro-acetic acid 12 96.32 51.5 24.00 20.82 3.68
Ethylhexanoic acid 22 44.14 22.86 12.93 8.35 55.86
Benzoic acid 12 98.00 75.50 9.10 13.40 2.00
p-Chlorobenzoic acid 12 99.66 56.44 20.00 23.22 0.34
o-Chlorobenzoic acid 12 98.13 31.25 54.77 12.11 1.87
2,4-Dichlorobenzoic acid 6 98.48 55.45 30.04 12.99 1.52
Phenylacetic acid 6 72.88 34.38 18.36 20.14 27.12

On the contrary, when the aromatic acids such as mentioned above are used, the selectivity of the main reaction (ie the carboxamidation reaction as compared to hydrolysis of the enol-ether moiety) can increase to more than 75%. This results in improved efficiency and eventually in simpler methods of purification of the end product oxcarbazepine, resulting in easier commercialization of the process.

The carboxamidation of the 10-methoxyiminostilbene according to the present invention is preferably carried out in an organic medium, most preferably under reflux conditions. The organic medium is suitably an aromatic hydrocarbon solvent or an aliphatic chlorinated solvent, such as benzene, toluene, xylene, dichloromethane, chloroform and dichloroethane etc, including others described in relation to the Scheme-4 synthesis mentioned above and in WO 96/21649. The solvent(s) used in the carboxamidation reaction also play an important role in the selectivity and completion of reaction. We have found that toluene is the best solvent both in terms of selectivity and completion of reaction. It is important that the solvent is chosen such that the starting material and the HOCN are both soluble therein. Furthermore, as indicated above, it is important that the weak acid is relatively insoluble therein.

The HOCN reacts with the imino function to produce desired intermediate, 10-methoxycarbamazepine, which can afford the pharmacologically active end-product, ie oxcarbazepine, after hydrolysis.

The HOCN may be generated in situ by reaction of an alkali metal cyanate with the mild acidic reagent. Suitable cyanates include sodium and potassium, preferably sodium, cyanates. However, other methods of generating the HOCN, such as from cyanuric acid (as described in the Merck Index or by Linhard in Anorg Allgem Chem 236 200 (1938)) or other means may be used. Nevertheless, we have found that the method using sodium cyanate and an aromatic organic acid, especially benzoic acid, is commercially the most viable. In the preferred method of this invention, therefore, the mild acidic reagent is also capable of reacting with an alkali metal cyanate to produce cyanic acid (HOCN).

Accordingly, the present invention in a preferred aspect provides a process for the preparation of 10-methoxycarbamazepine, which process comprises reacting 10-methoxyiminostilbene with an alkali metal cyanate and a mild acidic reagent, as defined above.

Accordingly, the present invention further provides an improved method for preparing oxcarbazepine from 10-methoxystilbene, wherein the improvement comprises preparing the intermediate 10-methoxycarbamazepine according to the method described above.

The intermediate 10-methoxycarbamazepine is then preferably hydrolysed with an acid, more preferably a dilute mineral acid, such as hydrochloric and sulphuric acids, especially hydrochloric acid (HCI) to furnish oxcarbazepine. Finally, the oxcarbazepine thus obtained may be purified in a mixture of solvent systems selected from both a protic solvent with either an aromatic hydrocarbon solvent or a halogenated aliphatic solvent and an aromatic hydrocarbon solvent with a halogenated aliphatic solvent. Preferably, the mixed solvent system is one wherein the oxcarbazepine is soluble at elevated temperatures, suitably in the range of from 45 to 75° C., but crystallizes therefrom upon cooling. The oxcarbazepine may not be appreciably soluble in any of these solvents individually, but may be soluble in the mixture at elevated temperature. Examples of suitable mixtures include those such as methanol:toluene; dichloromethane:toluene; dichloroethane:toluene; dichloromethane:methanol; and dichloroethane:methanol.

Hydrolysis of the methoxycarbamazepine is preferably carried out in a biphasic system chosen such that the oxcarbazepine is substantially insoluble in both phases, whereas the by-products or impurities are soluble in at least one of the phases. The biphasic system comprises an organic phase and an aqueous phase in which the organic phase preferably comprises the solvent used in the carboxylation reaction eg toluene. Preferably, an excess of this solvent, compared with the amount of impurity or by-product to be produced, is used in the process of this invention. The preferred aqueous phase comprises an aqueous solution of the acid for the hydrolysis step and is therefore most preferably dilute hydrochloric acid. The advantage of this biphasic system is that oxcarbazepine formed in the reaction is thrown out from both the solvents, whereas the impurities remain soluble in the toluene.

Accordingly, the present invention further provides an improved method of hydrolyzing 10-methoxycarbazepine, which improvement comprises carrying out the hydrolysis in a biphasic system as described above.

Especially preferred is when both improved processes of the invention are used, consecutively. The improved processes of the invention enable the oxcarbazepine thereby produced to be purified in a single step.

An especially preferred method according to this invention comprises reaction of 10-methoxy-5H-dibenz[b,f]azepine with benzoic acid and sodium cyanate in toluene at reflux temperature to give 10-methoxy-5H-dibenz[b,f]azepine carboxamide as a major product (such as about 75%), along with 10-oxo-iminodibenzyl and other impurities. The reaction mixture is thereafter filtered and washed with water, and the toluene layer taken as such for hydrolysis in a biphasic system (aqueous hydrochloric acid/toluene) to furnish oxcarbazepine, which is purified just once (whereas twice at least is needed when the prior art process is carried out) in a mixture of methanol and dichloromethane (Scheme-5).

Figure US06670472-20031230-C00005

10-methoxyiminostilbene, the key starting material in the following Examples, maybe prepared according to the process disclosed in Belgian patent specification no. 597 793 and Swiss patent specification no. 392 515.

EXAMPLE A Using Monochloro-Acetic Acid and Sodium CyanateA mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 106 gms of monochloro-acetic acid and 73 gms of sodium cyanate were heated to 40° C. under stirring and maintained for 4 hours. After completion of the reaction (monitored by HPLC and/or TLC), the mixture was cooled to room temperature, filtered and washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid, and the mixture was heated to 75-80° C. and maintained for 2 hours under good agitation. It was then cooled to 0-5° C. and maintained for 2 hours, and the product oxcarbazepine was separated by filtration. This was then purified twice in toluene:methanol followed by methanol:dichloromethane solvent mixture to furnish 28 gms of pure oxcarbazepine.

EXAMPLE 1 Using benzoic acid and sodium cyanateA mixture of 100 gms of 10-methoxyiminostilbene in 2000 mL of toluene containing 274 gms of benzoic acid and 370 gms of sodium cyanate were heated to reflux temperature under stirring and maintained for 12 hours. The reaction mixture was then cooled to room temperature and filtered. The clear toluene filtrate was washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid and the mixture was heated at 75-90° C. for a period of 2 hours under good agitation. It was then cooled to 0-5° C., maintained for 2 hours and the product oxcarbazepine was separated by filtration. This was then purified once in a dichloromethane:methanol mixture to furnish 46 gms of pure oxcarbazepine. Purity was determined by HPLC to be 99.45%.

EXAMPLE 2 Using para-chlorobenzoic acid and sodium cyanateA mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 351 gms of para-chlorobenzoic acid and 370 gms of sodium cyanate were heated to reflux and refluxed for 12 hours. The reaction mixture was then cooled to room temperature and filtered. The clear toluene filtrate was then washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid and the mixture was heated at 75-80° C. for a period of 2 hours under good agitation. It was then cooled to 0-5° C., maintained for 2 hours and the product oxcarbazepine was separated by filtration. This was then purified once in a dichloromethane methanol mixture to furnish 44 gms of pure oxcarbazepine.

EXAMPLE 3 Alternative Use of benzoic acid and sodium cyanateThe method of Example 1 was repeated, but using 1000 ml toluene; 164 g benzoic acid and 44 g of sodium cyanate, which were heated to 85-90° C. for 14 hours with the 10-methoxyiminostilbene to result in 55 gms of pure oxcarbazepine, found to be 99.45% pure by HPLC.

EXAMPLE 4 Using 2,4-dichloro benzoic acid and sodium cyanateA mixture of 100 gms of 10-methoxyiminostilbene in 1000 mL of toluene containing 430 gms of 2,4-dichlorobenzoic acid and 370 gms of sodium cyanate were heated to reflux and refluxed for 6 hours. The reaction mixture was then cooled to room temperature and filtered. The clear toluene filtrate was then washed with 5% sodium carbonate solution followed by water. The toluene layer was then added to 1000 mL of 2N hydrochloric acid and the mixture was heated at 75-80° C. for a period of 2 hours under good agitation. It was then cooled to 0-5° C., maintained for 2 hours and the product oxcarbazepine was separated by filtration. This was then purified once in a dichloromethane:methanol mixture to furnish 40 gms of pure oxcarbazepine.

EXAMPLE 5 Using benzoic acid and potassium cyanateThe method was carried out according to that described in Example 1, but replacing sodium cyanate with potassium cyanate (461.5 gm) and reflux maintained for 24 hrs to complete consumption of starting material. Following the similar process for hydrolysis and purification produced 32.00 gm of pure oxcarbazepine. Purity was determined according to Example 1 and found 98.80%.

EXAMPLE 6The method was carried out according to that described in Example 1, but replacing 2N hydrochloric with 2N sulphuric acid (1000 mL). Following a similar process of carboxamidation and purification produced 25.00 gm of pure oxcarbazepine. Purity was determined according to Example 1 and found 98.50%.

EXAMPLE 7 Hydrolysis Step Using 2N monochloro-acetic acidThe method was carried out according to that described in Example 1, but replacing 2N hydrochloric acid with 2N monochloro-acetic acid (1000 mL). The reaction mixture was heated to 75° C. to 80° C. and maintained for 24 hrs (after which 20% of unreacted methoxy ISB was found to be present). Under similar conditions for the carboxamidation reaction and purification step, this comparative Example produced 20.00 gm of pure oxcarbazepine. Purity was determined according to Example 1 and found to be 98.00%.

EXAMPLE 8 Purification Using toluene:methanol solvent systemThe method was carried out according to that described in Example 1, but replacing dichloromethane with toluene. Following a similar process of carboxamidation and hydrolysis produced 47.0 gm of pure oxcarbazepine. Purity was determined according to Example 1 and found 98.50%.

EXAMPLE 9 Purification Using toluene:dichloromethane solvent systemThe method was carried out according to that described in Example 1, but replacing methanol with toluene. Following a similar process of carboxamidation and hydrolysis produced 45.00 gm of pure oxcarbazepine. Purity was determined according to Example 1 and found to be 98.00%.

Cited Patent Filing date Publication date Applicant Title
WO1996021649A1 Jan 3, 1996 Jul 18, 1996 Trifarma, S.R.L. A PROCESS FOR THE PREPARATION OF 10-OXO-10,11-DIHYDRO-5H-DIBENZ(b,f)AZEPIN-5-CARBOXAMIDE
WO2001056992A2 Feb 7, 2001 Aug 9, 2001 Novartis Ag Dibenzo (b,f) azepine intermediates
Citing Patent Filing date Publication date Applicant Title
US7091339 Jun 13, 2003 Aug 15, 2006 Taro Pharmaceuticals Usa, Inc. Method of preparing a 5H-dibenz(b,f)azepine-5-carboxamide
US7125987 Jun 16, 2005 Oct 24, 2006 Apotex Pharmachem Inc. Process for the preparation of oxcarbazepine and related intermediates
US7183272 Feb 12, 2002 Feb 27, 2007 Teva Pharmaceutical Industries Ltd. Crystal forms of oxcarbazepine and processes for their preparation
US7459553 Mar 11, 2005 Dec 2, 2008 Glenmark Generics Ltd. Process for the preparation of carboxamide compounds
US7722898 Apr 13, 2007 May 25, 2010 Supernus Pharmaceuticals, Inc. Modified-release preparations containing oxcarbazepine and derivatives thereof
US7723514 Jun 29, 2006 May 25, 2010 Taro Pharmaceuticals U.S.A., Inc. Method of preparing a 5H-dibenz(b,f)azepine-5-carboxamide
US8530647 May 6, 2009 Sep 10, 2013 Mylan Laboratories Limited Process for the preparation of oxcarbazepine
US20030004154 * Feb 12, 2002 Jan 2, 2003 Judith Aronhime New crystal forms of oxcarbazepine and processes for their preparation
US20040044200 * Jun 13, 2003 Mar 4, 2004 Daniella Gutman Method of preparing a 5H-dibenz(b,f)azepine-5-carboxamide
US20050203297 * Mar 11, 2005 Sep 15, 2005 Sivakumar Bobba V. Process for the preparation of carboxamide compounds
US20050282797 * Jun 16, 2005 Dec 22, 2005 Apotex Pharmachem Inc. Process for the preparation of oxcarbazepine and related intermediates
US20060241292 * Jun 29, 2006 Oct 26, 2006 Taro Pharmaceuticals Usa, Inc Method of preparing a 5H-dibenz(b,f)azepine-5-carboxamide
US20070254033 * Apr 13, 2007 Nov 1, 2007 Supernus Pharmaceuticals, Inc. Modified-release preparations containing oxcarbazepine and derivatives thereof
US20110065917 * May 6, 2009 Mar 17, 2011 Matrix Laboratories Ltd process for the preparation of oxcarbazepine
WO2009139001A2 * May 6, 2009 Nov 19, 2009 Matrix Laboratories Ltd An improved process for the preparation of oxcarbazepine
WO2009139001A3 * May 6, 2009 Jan 27, 2011 Matrix Laboratories Ltd An improved process for the preparation of oxcarbazepine
WO2014049550A1 Sep 26, 2013 Apr 3, 2014 Ranbaxy Laboratories Limited Process for the preparation of oxcarbazepine and its use as intermediate in the preparation of eslicarbazepine acetate
Title: Oxcarbazepine
CAS Registry Number: 28721-07-5
CAS Name: 10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide
Additional Names: oxacarbazepine
Manufacturers’ Codes: GP-47680
Trademarks: Trileptal (Novartis)
Molecular Formula: C15H12N2O2
Molecular Weight: 252.27
Percent Composition: C 71.42%, H 4.79%, N 11.10%, O 12.68%
Literature References:
Ketoderivative of carbamazepine, q.v. Prepn: W. Schindler, DE 2011087 (1970 to Geigy); idem, US3642775 (1972 to Ciba-Geigy).
Improved prepn: D. Kaufmann et al., Tetrahedron Lett. 45, 5275 (2004). Metabolism: H. Schütz et al., Xenobiotica 16, 769 (1986).
Hyponatremic effects: O. A. Nielsen et al., Epilepsy Res. 2, 269 (1988). Determn of oxcarbazepine and main metabolites by GC in plasma: G. E. Von Unruh, W. D. Paar, J. Chromatogr. 345, 67 (1985); by HPLC: A. A. Elyas, V. D. Goldberg, ibid. 528, 473 (1990). Clinical evaluation in treatment of epilepsy: M. Dam et al., Epilepsy Res. 3, 70 (1989); in management of trigeminal neuralgia: J. M. Zakrzewska, P. N. Patsalos, J. Neurol. Neurosurg. Psychiatry 52, 472 (1989). Review of pharmacology and therapeutic efficacy: A. Beydoun, E. Kutluay, Expert Opin. Pharmacother. 3, 59-71 (2001).
Properties: Crystals from ethanol, mp 215-216°.
Melting point: mp 215-216°
Therap-Cat: Anticonvulsant.
Keywords: Anticonvulsant.

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

BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA


Image result for CONCERT PHARMACEUTICALS, INC.

Image result for CONCERT PHARMACEUTICALS, INC.

BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA

WO2018005328) DEUTERATED BICTEGRAVIR 

CONCERT PHARMACEUTICALS, INC.

TUNG, Roger, D.; (US)

How A Kidney Drug Almost Torpedoed Concert Pharma’s IPO

Concert CEO Roger Tung

Novel deuterated forms of bictegravir is claimed.  Gilead Sciences is developing the integrase inhibitor bictegravir as an oral tablet for the treatment of HIV-1 infection.

This invention relates to deuterated forms of bictegravir, and pharmaceutically acceptable salts thereof. In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11b is independently hydrogen or deuterium; provided that if each Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, and Y11 is hydrogen, then Y11b is deuterium.

front page image

Image result for CONCERT PHARMACEUTICALS, INC.

Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Exemplary Synthesis

[72] Deuterium-modified analogs of bictegravir can be synthesized by means known in the art of organic chemistry. For instance, using methods described in US Patent No.9,216,996 (Haolun J. et al., assigned to Gilead Sciences, Inc. and incorporated herein by reference), using deuterium-containing reagents provides the desired deuterated analogs.

[73] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

[74] A convenient method for synthesizing compounds of Formula I is depicted in the Schemes below.

 [75] A generic scheme for the synthesis of compounds of Formula I is shown in Scheme 1 above. In a manner analogous to the procedure described in Wang, H. et al. Org. Lett.2015, 17, 564-567, aldol condensation of compound 1 with appropriately deuterated compound 2 affords enamine 3. Enamine 3 is then reacted with primary amine 4 to afford enamine 5, which then undergoes cyclization with dimethyl oxalate followed by ester hydrolysis to provide carboxylic acid 7.

[76] In a manner analogous to the procedure described in US 9,216,996, acetal deprotection of carboxylic acid 7 followed by cyclization with appropriately deuterated aminocyclopentanol 9 provides carboxylic acid intermediate 10. Amide coupling with appropriately deuterated benzylamine 11 followed by deprotection of the methyl ether ultimately affords a compound of Formula I in eight overall steps from compound 1.

[77] Use of appropriately deuterated reagents allows deuterium incorporation at the Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and Y11bpositions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y1, Y2, Y3, Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, Y8, Y9, Y10a, Y10b, Y11a, and/or Y11b.

[78] Appropriately deuterated intermediates 2a and 2b, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 2 below.

S h 2 S th i f C d 2 d 2b

[79] Synthesis of compound 2a (wherein Y3=H) by acetal formation of N,N-dimethylformamide (DMF) with dimethylsulfate has been described in Mesnard, D. et. al. J. Organomet. Chem.1989, 373, 1-10. Replacing DMF with N,N-dimethylformamide-d1 (98-99 atom % D; commercially available from Cambridge Isotope Laboratories) in this reaction would thereby provide compound 2b (wherein Y3=D).

[80] Use of appropriately deuterated reagents allows deuterium incorporation at the Y3 position of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at Y3.

[81] Appropriately deuterated intermediates 4a-4d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 3 below.

[82] As described in Malik, M. S. et. al. Org. Prep. Proc. Int.1991, 26, 764-766, acetaldehyde is converted to alkylhalide 14a via reaction with chlorine gas and subsequent acetal protection with CaCl2 in methanol. As described in CN 103739506, reaction of 14a with aqueous ammonia and then sodium hydroxide provides primary amine 4a (wherein Y9=Y10a=Y10b=H). Replacing acetaldehyde with acetaldehyde-d1, acetaldehyde-2,2,2-d3, or acetaldehyde-d4 (all commercially available from CDN Isotopes with 98-99 atom % D) in the sequence then provides access to compounds 4b (Y9=D, Y10a=Y10b=H), 4c (Y9=H,

Y10a=Y10b=D) and 4d (Y9=Y10a=Y10b=D) respectively (Schemes 3b-d).

[83] Use of appropriately deuterated reagents allows deuterium incorporation at the Y9, Y10a, and Y10b positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y9, Y10a, and/or Y10b.

[84] Appropriately deuterated intermediates 9a-9d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 4 below.

 [85] Following the procedures described by Gurjar, M. et. al. Heterocycles, 2009, 77, 909-925, meso-diacetate 16a is prepared in 2 steps from cyclopentadiene. Desymmetrization of 16a is then achieved enzymatically by treatment with Lipase as described in Specklin, S. et. al. Tet. Lett.201455, 6987-6991, providing 17a which is subsequently converted to aminocyclopentanol 9a (wherein Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b=Y8=H) via a 3 step sequence as reported in WO 2015195656.

[86] As depicted in Scheme 4b, aminocyclopentanol 9b (Y4a=Y4b=Y5a=Y5b=Y6=Y7a=Y7b= Y8=D) is obtained through an analogous synthetic sequence using cyclopentadiene-d6 and performing the penultimate hydrogenation with D2 in place of H2. Cyclopentadiene-d6 is prepared according to the procedure described in Cangoenuel, A. et. al. Inorg. Chem.2013, 52, 11859-11866.

[87] Alternatively, as shown in Scheme 4c, the meso-diol obtained in Scheme 4a is oxidized to the diketone following the procedure reported by Rasmusson, G.H. et. al. Org. Syn.1962, 42, 36-38. Subsequent mono-reduction with sodium borodeuteride and CeCl3 then affords the D1-alcohol in analogy to the method described in WO 2001044254 for the all-protio analog using sodium borohydride. Reduction of the remaining ketone using similar conditions provides the meso-D2-diol in analogy to the method reported in Specklin, S. et. al. Tet. Lett.2014, 55, 6987-6991 for the all protio analog using sodium borohydride. The meso-D2-diol is then converted to 9c (Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=H, Y6=Y8=D) following the same procedures outlined in Scheme 4a.

[88] Likewise, the meso-diol obtained in Scheme 4b may be converted to 9d

(Y4a=Y4b=Y5a=Y5b=Y7a=Y7b=D, Y6=Y8=H) in an analogous manner as depicted in Scheme 4d. The use of deuterated solvents such as D2O or MeOD may be considered to reduce the risk of D to H exchange for ketone containing intermediates.

[89] Use of appropriately deuterated reagents allows deuterium incorporation at the Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and Y8 positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y4a, Y4b, Y5a, Y5b, Y6, Y7a, Y7b, and/or Y8.

[90] Appropriately deuterated intermediates 11a-11d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5 below.

Scheme 5. Synthesis of Benzylamines 11a-11d

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

TRILACICLIB, G1T28


ChemSpider 2D Image | Trilaciclib | C24H30N8OTrilaciclib.png

Trilaciclib

  • Molecular FormulaC24H30N8O
  • Average mass446.548 Da
  • G1T 28
CAS 1374743-00-6
2′-{[5-(4-Methyl-1-piperazinyl)-2-pyridinyl]amino}-7′,8′-dihydro-6’H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one
G1T28, SHR 6390
Spiro[cyclohexane-1,9′(6’H)-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one, 7′,8′-dihydro-2′-[[5-(4-methyl-1-piperazinyl)-2-pyridinyl]amino]-
  • 7′,8′-Dihydro-2′-[[5-(4-methyl-1-piperazinyl)-2-pyridinyl]amino]spiro[cyclohexane-1,9′(6’H)-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one
  • 2′-[[5-(4-Methylpiperazin-1-yl)pyridin-2-yl]amino}-7′,8′-dihydro-6’H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one
UNII:U6072DO9XG

Reduction of Chemotherapy-Induced Myelosuppression

Trilaciclib dihydrochloride
1977495-97-8

2D chemical structure of 1977495-97-8

In phase II clinical development as a chemoprotectant at G1 Therapeutics for first- or second-line treatment in patients with metastatic triple negative breast cancer, in combination with gemcitabine and carboplatin

logo

PATENT, WO 2014144326Compound 89 (also referred to as Compound T)

WO2014144847A3
Inventors Norman E. SharplessJay Copeland StrumJohn Emerson BisiPatrick Joseph RobertsFrancis Xavier Tavares
Applicant G1 Therapeutics, Inc.
Norman Sharpless
Norman Sharpless official photo.jpg
Born Norman Edward Sharpless
September 20, 1966 (age 51)
Greensboro, North Carolina
Nationality American
Other names Ned Sharpless
Occupation Director, Lineberger Comprehensive Cancer Center Founder, G1 Therapeutics ($GTHX)
Notable work Wellcome Distinguished Professor, American Society of Clinical Investigation Member, Association of American Cancer Institute board of directors,

NCI Director Dr. Norman E. SharplessPinterest

NCI Director Dr. Norman E. Sharpless, Credit: National Institutes of Health

Norman E. “Ned” Sharpless, M.D., was officially sworn in as the 15th director of the National Cancer Institute (NCI) on October 17, 2017. Prior to his appointment, Dr. Sharpless served as the director of the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center, a position he held since January 2014.

Dr. Sharpless was a Morehead Scholar at UNC–Chapel Hill and received his undergraduate degree in mathematics. He went on to pursue his medical degree from the UNC School of Medicine, graduating with honors and distinction in 1993. He then completed his internal medicine residency at the Massachusetts General Hospital and a hematology/oncology fellowship at Dana-Farber/Partners Cancer Care, both of Harvard Medical School in Boston.

After 2 years on the faculty at Harvard Medical School, he joined the faculty of the UNC School of Medicine in the Departments of Medicine and Genetics in 2002. He became the Wellcome Professor of Cancer Research at UNC in 2012.

Dr. Sharpless is a member of the Association of American Physicians as well as the American Society for Clinical Investigation (ASCI), the nation’s oldest honor society for physician–scientists, and served on the ASCI council from 2011 to 2014. Dr. Sharpless was an associate editor of Aging Cell and deputy editor of the Journal of Clinical Investigation. He has authored more than 150 original scientific papers, reviews, and book chapters, and is an inventor on 10 patents. He cofounded two clinical-stage biotechnology companies: G1 Therapeutics and HealthSpan Diagnostics.

In addition to serving as director of NCI, Dr. Sharpless continues his research in understanding the biology of the aging process that promotes the conversion of normal self-renewing cells into dysfunctional cancer cells. Dr. Sharpless has made seminal contributions to the understanding of the relationship between aging and cancer, and in the preclinical development of novel therapeutics for melanoma, lung cancer, and breast cancer.

Record ID Title Status Phase
NCT03041311 CarboplatinEtoposide, and Atezolizumab With or Without Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Extensive Stage Small Cell Lung Cancer (SCLC) Recruiting 2
NCT02978716 Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Gemcitabineand Carboplatin in Metastatic Triple Negative Breast Cancer (mTNBC) Recruiting 2
NCT02514447 Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Patients With Previously Treated Extensive Stage SCLC Receiving Topotecan Chemotherapy Recruiting 2
NCT02499770 Trilaciclib (G1T28), a CDK 4/6 Inhibitor, in Combination With Etoposide and Carboplatin in Extensive Stage Small Cell Lung Cancer (SCLC) Active, not recruiting 2

Synthesis

WO  2016040858

Trilaciclib (G1T28)

Trilaciclib is a potential first-in-class short-acting CDK4/6 inhibitor in development to preserve hematopoietic stem cells and enhance immune system function during chemotherapy. Trilaciclib is administered intravenously prior to chemotherapy and has the potential to significantly improve treatment outcomes.

G1 is currently evaluating trilaciclib in four Phase 2 clinical trials: three studies in patients with small-cell lung cancer (SCLC), and one study in patients with triple-negative breast cancer (TNBC). Preliminary data from the SCLC trials were presented at the American Society of Clinical Oncology 2017 Annual Meeting and at the 2016 World Conference on Lung Cancer.

Data from a Phase 1 trial in healthy volunteers were presented at the American Society of Clinical Oncology 2015 Annual Meeting and published in Science Translational Medicine. Trilacicilib has been extensively studied in animals; these preclinical data have been presented at several scientific meetings and published in Molecular Cancer Therapeutics, Science Translational Medicine, and Cancer Discovery.

Trilaciclib is a small molecule, competitive inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), with potential antineoplastic and chemoprotective activities. Upon intravenous administration, trilaciclib binds to and inhibits the activity of CDK4/6, thereby blocking the phosphorylation of the retinoblastoma protein (Rb) in early G1. This prevents G1/S phase transition, causes cell cycle arrest in the G1 phase, induces apoptosis, and inhibits the proliferation of CDK4/6-overexpressing tumor cells. In patients with CDK4/6-independent tumor cells, G1T28 may protect against multi-lineage chemotherapy-induced myelosuppression (CIM) by transiently and reversibly inducing G1 cell cycle arrest in hematopoietic stem and progenitor cells (HSPCs) and preventing transition to the S phase. This protects all hematopoietic lineages, including red blood cells, platelets, neutrophils and lymphocytes, from the DNA-damaging effects of certain chemotherapeutics and preserves the function of the bone marrow and the immune system. CDKs are serine/threonine kinases involved in the regulation of the cell cycle and may be overexpressed in certain cancer cell types. HSPCs are dependent upon CDK4/6 for proliferation.

Trilaciclib (G1T28) is a CDK4/6 inhibitor in phase II clinical development as a chemoprotectant at G1 Therapeutics for first- or second-line treatment in patients with metastatic triple negative breast cancer, in combination with gemcitabine and carboplatin. Also, phase II trials are ongoing in newly diagnosed, treatment-naive small-cell lung cancer patients, in combination with carboplatin, etoposide, and atezolizumab and phase I trials in previously treated small-cell lung cancer patients, in combination with topotecan.

U.S. Patent Nos. 8,822,683; 8,598,197; 8,598,186, 8,691,830, 8,829,102, 8,822,683, 9, 102,682, 9,499,564, 9,481,591, and 9,260,442, filed by Tavares and Strum and assigned to Gl Therapeutics describe a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin dependent kinase inhibitors including those of the formula with variables as defined therein):

U.S. Patent Nos. 9,464,092, 9,487,530, and 9,527,857 which are also assigned to Gl Therapeutics describe the use of the above pyrimidine-based agents in the treatment of cancer.

These patents provide a general synthesis of the compounds that is based on a coupling reaction of a fused chloropyrimidine with a heteroaryl amine to form the central disubstituted amine. Such coupling reactions are sometimes referred to as Buchwald coupling (see WO Ί56 paragraph 127; reference WO 2010/020675). The lactam of the fused chloropyrimidine, for example, a 2-chloro-spirocyclo-pyrrolo[2,3-d]pyrimidine-one such as Intermediate K as shown below can be prepared by dehydration of the corresponding carboxylic acid. The reported process to prepare intermediate IK requires seven steps.


(Intermediate IK; page 60, paragraph 215 of WO Ί56)

WO 2013/148748 (U.S. S.N. 61/617,657) entitled “Lactam Kinase Inhibitors” filed by Tavares, and also assigned to Gl Therapeutics likewise describes the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines via the coupling reaction of a fused chloropyrimidine with a heteroaryl amine to form the central disubstituted amine.

WO 2013/163239 (U.S. S.N. 61/638,491) “Synthesis of Lactams” describes a method for the synthesis of this class of compounds with the variation that in the lactam preparation step, a carboxylic acid can be cyclized with a protected amine in the presence of a strong acid and a dehydrating agent, which can be together in one moiety as a strong acid anhydride. The purported improvement is that cyclization can occur without losing the protecting group on the amine before cyclization. The typical leaving group is “tBOC” (t-butoxycarbonyl). The application teaches (page 2 of WO 2013/163239) that the strong acid is, for example, trifluoroacetic acid anhydride, tribromoacetic acid anhydride, trichloroacetic acid anhydride or mixed anhydrides. An additional step may be necessary to take off the N-protecting group. The dehydrating agent can be a carbodiimide-based compound such as DCC (Ν,Ν-dicyclohexylcarbodiimide), EDC (l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or DIC (Ν,Ν-diisopropylcarbodiimide). DCC and DIC are in the same class of reagents-carbodiimides. DIC is sometimes considered better because it is a liquid at room temperature, which facilitates reactions.

WO 2015/061407 filed by Tavares and licensed to Gl Therapeutics also describes the synthesis of these compounds via the coupling of a fused chloropyrimidine with a heteroaryl amine to form the central disubstituted amine. WO ‘407 focuses on the lactam production step and in particular describes that the fused lactams of these compounds can be prepared by treating the carboxylic acid with an acid and a dehydrating agent in a manner that a leaving group on the amine is not removed during the amide-forming ring closing step.

Other publications that describe compounds of this general class include the following. WO 2014/144326 filed by Strum et al. and assigned to Gl Therapeutics describes compounds and methods for protection of normal cells during chemotherapy using pyrimidine based CDK4/6 inhibitors. WO 2014/144596 filed by Strum et al. and assigned to Gl Therapeutics describes compounds and methods for protection of hematopoietic stem and progenitor cells against ionizing radiation using pyrimidine based CDK4/6 inhibitors. WO 2014/144847 filed by Strum et al. and assigned to Gl Therapeutics describes HSPC-sparing treatments of abnormal cellular proliferation using pyrimidine based CDK4/6 inhibitors. WO2014/144740 filed by Strum et al. and assigned to Gl Therapeutics describes highly active anti -neoplastic and anti-proliferative pyrimidine based CDK 4/6 inhibitors. WO 2015/161285 filed by Strum et al. and assigned to Gl Therapeutics describes tricyclic pyrimidine based CDK inhibitors for use in radioprotection. WO 2015/161287 filed by Strum et al. and assigned to Gl Therapeutics describes analogous tricyclic pyrimidine based CDK inhibitors for the protection of cells during chemotherapy. WO 2015/161283 filed by Strum et al. and assigned to Gl Therapeutics describes analogous tricyclic pyrimidine based CDK inhibitors for use in HSPC-sparing treatments of RB-positive abnormal cellular proliferation. WO 2015/161288 filed by Strum et al. and assigned to Gl Therapeutics describes analogous tricyclic pyrimidine based CDK inhibitors for use as anti -neoplastic and anti-proliferative agents. WO 2016/040858 filed by Strum et al. and assigned to Gl Therapeutics describes the use of combinations of pyrimidine based CDK4/6 inhibitors with other anti-neoplastic agents. WO 2016/040848 filed by Strum et al. and assigned to Gl Therapeutics describes compounds and methods for treating certain Rb-negative cancers with CDK4/6 inhibitors and topoisomerase inhibitors.

Other biologically active fused spirolactams and their syntheses are described, for example, in the following publications. Griffith, D. A., et al. (2013). “Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure.” Journal of Medicinal Chemistry 56(17): 7110-7119, describes metabolically stable spirolactams wherein the lactam resides on the fused ring for the inhibition of acetyl-CoA carboxylase. WO 2013/169574 filed by Bell et al. describes aliphatic spirolactams as CGRP receptor antagonists wherein the lactam resides on the spiro ring. WO 2007/061677 filed by Bell et al. describes aryl spirolactams as CGRP receptor antagonists wherein the lactam resides on the spiro ring. WO 2008/073251 filed by Bell et al. describes constrained spirolactam compounds wherein the lactam resides on the spiro ring as CGRP receptor antagonists. WO 2006/031606 filed by Bell et al. describes carboxamide spirolactam compounds wherein the spirolactam resides on the spiro ring as CGRP receptor antagonists. WO 2006/031610, WO 2006/031491, and WO 2006/029153 filed by Bell et al. describe anilide spirolactam compounds wherein the spirolactam resides on the spiro ring; WO 2008/109464 filed by Bhunai et al. describes spirolactam compounds wherein the lactam resides on the spiro ring which is optionally further fused.

Given the therapeutic activity of selected N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines, it would be useful to have additional methods for their preparation. It would also be useful to have new intermediates that can be used to prepare this class of compounds.

PATENT

WO 2014144596

PATENT

WO 2014144326

Compound 89 (also referred to as Compound T)

WO2014144847A3
Inventors Norman E. SharplessJay Copeland StrumJohn Emerson BisiPatrick Joseph RobertsFrancis Xavier Tavares
Applicant G1 Therapeutics, Inc.

EXAMPLES

Intermediates B, E, K, L, 1A, IF and 1CA were synthesized according to US 8,598,186 entitled CDK Inhibitors to Tavares, F.X. and Strum, J.C..

The patents WO 2013/148748 entitled Lactam Kinase Inhibitors to Tavares, F.X., WO 2013/163239 entitled Synthesis of Lactams to Tavares, F.X., and US 8,598,186 entitled CDK Inhibitors to Tavares, F.X. and Strum, J.C. are incorporated by reference herein in their entirety. Example 1

Synthesis of tert-butyl N- [2- [(5-bromo-2-chloro-pyrimidin-4yl)amino] ethyl] carbamate, Compound 1

Figure imgf000106_0001

To a solution of 5-bromo-2,4-dichloropyrimidine (3.2 g, 0.0135 mol) in ethanol (80 mL) was added Hunig’s base (3.0 mL) followed by the addition of a solution of N-(tert- butoxycarbonyl)-l,2-diaminoethane (2.5 g, 0.0156 mole) in ethanol (20 mL). The contents were stirred overnight for 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and water (100 mL) were added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Column chromatography on silica gel using hexane/ethyl acetate (0- 60%) afforded tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4- yl)amino]ethyl]carbamate. 1HNMR (d6-DMSO) δ ppm 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M + H).

Example 2

Synthesis of tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-l-ynyl)pyrimidin-4- yl] amino] ethyl] carbamate, Compound 2

Figure imgf000106_0002

To tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (1.265 g, 6 mmol) in THF (10 mL) was added the acetal (0.778 mL, 5.43 mmol), Pd(dppf)CH2Cl2 (148 g), and triethylamine (0.757 mL, 5.43 mmol). The contents were degassed and then purged with nitrogen. To this was then added Cul (29 mg). The reaction mixture was heated at reflux for 48 hrs. After cooling, the contents were filtered over CELITE™ and concentrated. Column chromatography of the resulting residue using hexane/ethyl acetate (0- 30%) afforded tert-butyl N- [2- [ [2-chloro-5 -(3 ,3 -diethoxyprop- 1 -ynyl)pyrimidin-4-yl]amino] ethyl] carbamate. 1HNMR (d6-DMSO) δ ppm 8.18 (s, 1H), 7.63 (brs, 1H), 7.40 (brs, 1H), 5.55 (s, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 3.15 (m, 2H), 1.19 – 1.16 (m, 15H). LCMS (ESI) 399 (M + H).

Example 3

Synthesis of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7- yl] ethyl] carbamate, Compound 3

Figure imgf000107_0001

To a solution of the coupled product (2.1 g, 0.00526 mole) in THF (30 mL) was added TBAF solid (7.0 g). The contents were heated to and maintained at 65 degrees for 2 hrs. Concentration followed by column chromatography using ethyl acetate/hexane (0-50%) afforded tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate as a pale brown liquid (1.1 g). 1FiNMR (d6-DMSO) δ ppm 8.88 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34 (m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M + H).

Example 4

Synthesis of tert-buty\ N-[2-(2-chloro-6-formyl-pyrrolo [2,3-d] pyrimidin-7- yl)ethyl] carbamate, Compound 4

Figure imgf000108_0001

To the acetal (900 mg) from the preceeding step was added AcOH (8.0 mL) and water

(1.0 mL). The reaction was stirred at room temperature for 16 hrs. Cone, and column chromatography over silica gel using ethyl acetate/hexanes (0- 60%) afforded tert-butyl N-[2-(2- chloro-6-formyl-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate as a foam (0.510 g). 1HNMR (d6-DMSO) δ ppm 9.98 (s, 1H), 9.18 (s, 1H), 7.66 (s, 1H), 6.80 (brs, 1H), 4.52 (m, 2H), 4.36 (m, 2H), 1.14 (s, 9H). LCMS (ESI) 325 (M + H).

Example 5

Synthesis of 7- [2-(teri-butoxycarbonylamino)ethyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6- carboxylic acid, Compound 5

Figure imgf000108_0002

To the aldehyde (0.940 g) from the preceeding step in DMF (4 mL) was added oxone (1.95 g, 1.1 eq). The contents were stirred at room temp for 7 hrs. Silica gel column chromatography using hexane/ethyl acetate (0- 100%) afforded l-\2-(tert- butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (0.545 g). 1HNMR (d6-DMSO) δ ppm 9.11 (s, 1H), 7.39 (s, 1H), 4.38 (m, 2H), 4.15 (m, 2H), 1.48 (m, 9H). LCMS (ESI) 341(M + H).

Example 6

Synthesis of methyl 7-[2-(teri-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3- d]pyrimidine-6-carboxylate, Compound 6

Figure imgf000109_0001

To a solution of 2-chloro-7-propyl-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (0.545 g, 0.00156 mole) from the preceeding step in toluene (3.5 mL) and MeOH (1 mL) was added TMS- diazomethane (1.2 mL). After stirring overnight at room temperature, the excess of TMS- diazomethane was quenched with acetic acid (3 mL) and the reaction was concentrated under vacuum. The residue was purified by silica gel column chromatography with hexane/ethyl acetate (0- 70%) to afford methyl 7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3- d]pyrimidine-6-carboxylate as an off white solid (0.52 g). 1HNMR (d6-DMSO) δ ppm 9.10 (s, 1H), 7.45 (s, 1H), 6.81 (brs, 1H) 4.60 (m, 2H), 3.91 (s, 3H), 3.29 (m, 2H), 1.18 (m, 9H) LCMS (ESI) 355 (M + H).

Example 7

Synthesis of Chloro tricyclic amide, Compound 7

Figure imgf000109_0002

To methyl 7- [2-(tert-butoxycarbonylamino)ethyl] -2-chloro-pyrrolo [2,3 -d]pyrimidine-6- carboxylate (0.50 g, 0.0014 mole) from the preceeding step in dichloromethane (2.0 mL) was added TFA (0.830 mL). The contents were stirred at room temperature for 1 hr. Concentration under vacuum afforded the crude amino ester which was suspended in toluene (5 mL) and Hunig’s base (0.5 mL). The contents were heated at reflux for 2 hrs. Concentration followed by silica gel column chromatography using hexane/ethyl acetate (0- 50%) afforded the desired chloro tricyclic amide (0.260 g). 1HNMR (d6-DMSO) δ ppm 9.08 (s, 1H), 8.48 (brs, 1H), 7.21 (s, 1H) 4.33 (m, 2H), 3.64 (m, 2H). LCMS (ESI) 223 (M + H).

Example 8

Synthesis of chloro-N-methyltricyclic amide, Compound 8

Figure imgf000110_0001

To a solution of the chloro tricycliclactam, Compound 7, (185 mg, 0.00083 mole) in DMF (2.0 mL) was added sodium hydride (55% dispersion in oil, 52 mg). After stirring for 15 mins, methyl iodide (62 μί, 1.2 eq). The contents were stirred at room temperature for 30 mins. After the addition of methanol (5 mL), sat NaHCOs was added followed by the addition of ethyl acetate. Separation of the organic layer followed by drying with magnesium sulfate and concentration under vacuum afforded the N-methylated amide in quantitative yield. 1FiNMR (d6-DMSO) δ ppm 9.05 (s, 1H), 7.17 (s, 1H) 4.38 (m, 2H), 3.80 (m, 2H), 3.05 (s, 3H). LCMS (ESI) 237 (M + H). Example 9

Synthesis of l-methyl-4-(6-nitro-3-pyridyl)piperazine, Compound 9

Figure imgf000110_0002

To 5-bromo-2-nitropyridine (4.93 g, 24.3 mmole) in DMF (20 mL) was added N- methylpiperazine (2.96 g, 1.1 eq) followed by the addition of DIPEA (4.65 mL, 26.7 mmole). The contents were heated at 90 degrees for 24 hrs. After addition of ethyl acetate (200 mL), water (100 mL) was added and the layers separated. Drying followed by concentration afforded the crude product which was purified by silica gel column chromatography using (0-10%) DCM/Methanol. 1HNMR (d6-DMSO) δ ppm 8.26 (s, 1H), 8.15 (1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H).

Example 10

Synthesis of 5-(4-methylpiperazin-l-yl)pyridin-2-amine, Compound 10

Figure imgf000111_0001

To l-methyl-4-(6-nitro-3-pyridyl)piperazine (3.4 g) in ethyl acetate (100 mL) and ethanol (100 mL) was added 10%> Pd/C (400 mg) and then the reaction was stirred under hydrogen (10 psi) overnight. After filtration through CELITE™, the solvents were evaporated and the crude product was purified by silica gel column chromatography using DCM/ 7N ammonia in MeOH (0- 5%) to afford 5-(4-methylpiperazin-l-yl)pyridin-2-amine (2.2 g). 1HNMR (d6-DMSO) δ ppm 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).

Example 11

Synthesis of tert-butyl 4-(6-amino-3-pyridyl)piperazine-l-carboxylate, Compound 11

Figure imgf000111_0002

This compound was prepared as described in WO 2010/020675 Al .

Synthesis of Compound 89 (also referred to as Compound T)

Figure imgf000169_0002

Compound 89 was synthesized in a similar manner to that described for compound 78 and was converted to an HCl salt. 1HNMR (600 MHz, DMSO-d6) δ ppm 1.47 (br. s., 6 H) 1.72 (br. s., 2 H) 1.92 (br. s., 2 H) 2.77 (br. s., 3 H) 3.18 (br. s., 2 H) 3.46 (br. s., 2 H) 3.63 (br. s., 2 H) 3.66 (d, J=6.15 Hz, 2 H) 3.80 (br. s., 2 H) 7.25 (s, 1 H) 7.63 (br. s., 2 H) 7.94 (br. s., 1 H) 8.10 (br. s., 1 H) 8.39 (br. s., 1 H) 9.08 (br. s., 1 H) 11.59 (br. s., 1 H). LCMS (ESI) 447 (M + H)

PATENT

WO 2014144740

PATENT

WO 2016040858

Preparation of Active Compounds

Syntheses

The disclosed compounds can be made by the following general schemes:

Scheme 1

In Scheme 1, Ref-1 is WO 2010/020675 Al; Ref-2 is White, J. D.; et al. J. Org. Chem. 1995, 60, 3600; and Ref-3 Presser, A. and Hufher, A. Monatshefte fir Chemie 2004, 135, 1015.

Scheme 2

In Scheme 2, Ref-1 is WO 2010/020675 Al; Ref-4 is WO 2005/040166 Al; and Ref-5 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.

92

93 

3) Pd/C/H2 

Scheme 6

Scheme 7

NHfOH

Scheme 8

In Scheme 8, Ref-1 is WO 2010/020675 Al; Ref-2 is WO 2005/040166 Al; and Ref-3 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.

Alternatively, the lactam can be generated by reacting the carboxylic acid with a protected amine in the presence of a strong acid and a dehydrating agent, which can be together in one moiety as a strong acid anhydride. Examples of strong acid anhydrides include, but are not limited to, trifluoroacetic acid anhydride, tribromoacetic acid anhydride, trichloroacetic acid anhydride, or mixed anhydrides. The dehydrating agent can be a carbodiimide based compound such as but not limited to DCC (Ν,Ν-dicyclohexylcarbodiimide), EDC (l-ethyl-3-(3-

dimethylaminopropyl)carbodiimide or DIC (Ν,Ν-diisopropylcarbodiimide). An additional step may be necessary to take off the N-protecting group and the methodologies are known to those skilled in the art.

Alternatively, the halogen moiety bonded to the pyrimidine ring can be substituted with any leaving group that can be displaced by a primary amine, for example to create an intermediate for a final product such as Br, I, F, SMe, SO2Me, SOalkyl, SO2alkyl. See, for Exmaple PCT /US2013/037878 to Tavares.

Other amine intermediates and final amine compounds can be synthesized by those skilled in the art. It will be appreciated that the chemistry can employ reagents that comprise reactive functionalities that can be protected and de-protected and will be known to those skilled in the art at the time of the invention. See for example, Greene, T.W. and Wuts, P.G.M., Greene’s Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons.

Scheme 9

CDK4/6 Inhibitors of the present invention can be synthesized according to the generalized Scheme 9. Specific synthesis and characterization of the Substituted 2-aminopyrmidines can be found in, for instance, WO2012/061156.

Compounds T, Q, GG, and U were prepared as above and were characterized by mass spectrometry and NMR as shown below:

Compound T

1H NMR (600 MHz, DMSO- d6) ppm 1.47 (br. s., 6 H) 1.72 (br. s., 2 H) 1.92 (br. s., 2 H) 2.77 (br. s., 3 H) 3.18 (br. s., 2 H) 3.46 (br. s., 2 H) 3.63 (br. s., 2 H) 3.66 (d, J=6.15 Hz, 2 H) 3.80 (br. s., 2 H) 7.25 (s, 1 H) 7.63 (br. s., 2 H) 7.94 (br. s., 1 H) 8.10 (br. s., 1 H) 8.39 (br. s., 1 H) 9.08 (br. s., 1 H) 11.59 (br. s., 1 H). LCMS ESI (M + H) 447.

PATENT

WO-2018005865

Synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines. The application appears to be particularly focused on methods for the preparation of trilaciclib and an analog of it. Trilaciclib is the company’s lead CDK4/6 inhibitor presently in phase II trials against small-cell lung cancer and triple negative breast cancer. Interestingly, the company is working on a second CDK4/6 inhibitor, G1T38 , which is in a phase II trial against breast cancer.

GENERAL METHODS

The structure of starting materials, intermediates, and final products was confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry. Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra were obtained on a Bruker AVANCE 500 at 500 MHz in DMSO-dis. HPLC analyses were performed on a Waters HPLC using the below HPLC method.

HPLC Method

Column: Atlantis T3 (150 χ 4.6, 3 μιη)

Column Temperature: 40°C

Flow Rate: 1 mL/min

Detection: UV @ 275 nm

Analysis Time: 36 min

Mobile Phase A: Water (with 0.1% Trifluoroacetic Acid)

Mobile Phase B : Acetonitrile (with 0.1% Trifluoroacetic Acid)

Sample preparation: dissolve PC sample, wet or dry solid (~1 mg of active compound) in acetonitrile/water (1/1) to achieve complete dissolution.

HPLC Method Gradient

Example 1. General Routes of Synthesis

Scheme 1-1 : Starting from an appropriately substituted halo pyrimidine, compounds of the present invention can be prepared. In Step 1 the appropriately substituted halo pyrimidine is subjected to l,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a substituted spirolactam. In Step 2 the appropriately substituted spirolactam is protected with a group selected from R2. In Step 3 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam. The fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 3, Step 4, Step 5, or Step 6. Oxidation prior to Step 3 results in undesired byproducts. In Step 4 the hydroxyl group of the fused spirolactam is converted to a leaving group.

In Step 5 the leaving group is dehydrated to afford a compound of Formula IV. In Step 6 the compound of Formula IV is optionally deprotected.

Scheme 1-2: Starting from an appropriately substituted halo pyrimidine compounds of the present invention can be prepared. In Step 1 the appropriately substituted halo pyrimidine is subjected to l,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a substituted spirolactam. In Step 2 the appropriately substituted spirolactam is protected with a group selected from R2. In Step 3 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam of Formula IV. The fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 3 or Step 4. Oxidation prior to Step 3 results in undesired byproducts. In Step 4 the compound of Formula IV is optionally deprotected.

Scheme 1-3 : Starting from an appropriately substituted alkyl glycinate, compounds of the present invention can be prepared. In Step 1 the appropriately substituted alkyl glycinate is subjected to cyclohexanone and TMSCN in the presence of base to afford a cyano species. In Step 2 the appropriately substituted cyanospecies is reduced and subsequently cyclized to afford a compound of Formula I.

Scheme 1-4

Scheme 1-4: Starting from an appropriately substituted l-(aminomethyl)cyclohexan-l-amine, compounds of the present invention can be prepared. In Step 1 the appropriately substituted l-(aminomethyl)cyclohexan-l -amine is reductively aminated with an aldehyde. In Step 2 the appropriately substituted cyclohexane amine is optionally deprotected (i.e.: the group selected from R2 if not H is optionally replaced by H). In Step 3 the cyclohexane amine is cyclized to afford a compound of Formula I. In Step 4 the compound of Formula I is optionally protected.

1-5

Conversion

Scheme 1-5: Starting from an appropriately substituted halo pyrimidine, compounds of the present invention can be prepared. In Step 1 the appropriately substituted halo pyrimidine is subjected to l,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a

substituted spirolactam. In Step 2 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam. The fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 2, Step 3, Step 4, or Step 5. Oxidation prior to Step 2 results in undesired byproducts. In Step 3 the hydroxyl group of the fused spirolactam is converted to a leaving group. In Step 4 the leaving group is dehydrated to afford a compound of Formula IV. In Step 5 the compound of Formula IV is optionally deprotected.

S

Scheme 1-6: Starting from an appropriately substituted halo pyrimidine compounds of the present invention can be prepared. In Step 1 the appropriately substituted halo pyrimidine is subjected to l,4-diazaspiro[5.5]undecan-3-one in the presence of base and heat to afford a substituted spirolactam. In Step 2 the protected spirolactam is cyclized in the presence of base to afford a fused spirolactam of Formula IV. The fused spirolactam can be optionally oxidized to a sulfoxide or sulfone after Step 2 or Step 3. Oxidation prior to Step 2 results in undesired byproducts. In Step 3 the compound of Formula IV is optionally deprotected.

Scheme 1-7: Starting from compound of Formula IV a CDK4/6 inhibitor can be prepared. In Step 1 a heteroaryl amine is subjected to a base and a compound of Formula IV is added slowly under chilled conditions to afford a nucleophilic substitution reaction. The compound of Formula IV can previously be prepared as described in the schemes herein.

Example 2. Representative Routes of Synthesis

Scheme 2-1

quant, yield 2 steps

isolated

70% yield 2 steps 75% yield 95% yield

isolated isolated isolated

Scheme 2-1 : An ester route is one embodiment, of the present invention. Ideally, the best synthesis scheme would afford crystalline intermediates to provide material of consistent purity without column chromatography, and high yielding steps while using safe and cost effective reagents when possible.

The first step in the ester route is a SNAr nucleophilic substitution of CI group in commercially available ester 3 using spirolactam 4. Due to low reactivity of 4, a reaction temperature of 85-95 °C was required. Because of the temperature requirements, DIPEA and dimethylacetamide were selected as the base and solvent, respectively. The reaction follows second-order kinetics and usually stalls after -85% conversion. Therefore, the reaction was typically stopped after 60 hours by first cooling it to room temperature at which point solid formation was observed. The mixture was then partitioned between MTBE and water and product was filtered with excellent purity with -53% yield of the desired product 5. The obtained

compound 5 was protected with a Boc group using Boc anhydride and DMAP as the catalyst and dichloromethane as the solvent. The intermediate 6 was obtained in a quantitative yield. Due to the semi-solid nature of compound 6, the material was taken to the next step without further purification. The Dieckmann condensation was initially performed with strong bases such as LiHMDS and tBuOK. A similar result to the aldehyde route (Scheme 2-2) was obtained: a partial deprotection of Boc group was observed that required column chromatography. However, the best results were obtained when DBU was used as base and THF as solvent. The reaction outcome was complete, clean conversion of 6 to 7. Moreover, the product crystallized from the reaction mixture upon seeding, and a quantitative yield was obtained for the two steps.

The hydroxyl group of 7 was removed via a two-step procedure. First, compound 7 was converted completely into triflate 8 using triflic anhydride and triethylamine in dichloromethane. The reaction was found to proceed well at 0°C. Due to the potential instability of the triflate intermediate, it was not isolated. It was immediately taken to the next step and reduced with triethylsilane and palladium tetrakis to afford the product 9 after ethyl acetate crystallization in -70% yield. The Boc group of 9 was removed using trifluoroacetic acid in dichloromethane to afford 10. Intermediate 10 was converted into the final sulfone 11 using Oxone™ in acetonitrile/water solvent system.

The obtained sulfone 11 was use-tested in the coupling step and was found to perform well. In conclusion, the route to sulfone 11 was developed which eliminated the use of column chromatography with good to excellent yields on all steps.

Scheme 2-2


Molecular Weight: 421 

Scheme 2-2: The first step of Scheme 2-2 consistently afforded product 13 contaminated with one major impurity found in substantial amount. Thorough evaluation of the reaction impurity profile by LC-MS and 2D MR was performed, which showed the impurity was structurally the condensation of two aldehyde 12 molecules and one molecule of lactam 4. Therefore, column chromatography was required to purify compound 13, which consistently resulted in a modest 30% yield. A solvent screen revealed that sec-butanol, amyl alcohol, dioxane, and tert-butanol can all be used in the reaction but a similar conversion was observed in each case. However, tert-butanol provided the cleanest reaction profile, so it was selected as a solvent for the reaction. Assessing the impact of varying the stoichiometric ratio of 4 and 12 on the reaction outcome was also investigated. The reaction was performed with 4 equivalents of amine 4 in an attempt to disrupt the 2: 1 aldehyde/amine composition of the impurity. The result was only a marginal increase in product 13 formation. The temperature impact on the reaction outcome was evaluated next. The coupling of aldehyde 12 and 4 was investigated at two different temperatures: 50 °C and 40 °C with 1 : 1 ratio of aldehyde/amine. Reactions were checked at 2 and 4 hours and then every 12 hours. The reaction progress was slow at 50°C and was accompanied by growth of other impurities. The reaction at 40°C was much cleaner; however the conversion was lower in the same time period. The mode of addition of the reagents was investigated as well at 80°C with a slow addition (over 6 hours) of either aldehyde 12 or amine 4 to the reaction mixture. The product distribution did not change and an about 1 to 1 ratio was observed between product and impurity when amine 4 was added slowly to the reaction mixture containing aldehyde 12 and

DIPEA at reflux. The product distribution did change when aldehyde 12 was added slowly to the mixture of amine 4 and DIPEA. However, the major product of the reaction was the undesired impurity. Other organic bases were tried as well as different ratios of DIPEA. No product was observed when potassium carbonate was used as a base. The results of the experiments are presented in Table 1 below.

Table 1

Compound 13 was successfully formed in three cases: triethylamine, 2,6-lutidine and DIPEA, with the DIPEA result being the best. The use of Boc protected spirolactam 4 had no effect on the impurity formation as well. Its utilization was speculated to be beneficial in performing the coupling step together with the following step, preparation of compound 14.

The major impurity formed during Step 1 of Scheme 2-2 is:

Chemical Formula:€2)Η(¾ 62ί>2

Molecular Weight: 527.4903

The second step (Boc protection of the free lactam) proceeded well using DMAP as a catalyst in dichloromethane at room temperature. The product 14 is a thick oil, and, therefore, cannot be purified by crystallization. The Boc protected intermediate 14 was cyclized successfully into the desired pentacyclic structure 10 upon treatment with a strong base such as LiHMDS or tBuOK. Surprisingly, the Boc group was partially removed during the reaction. The level of deprotection was independent from the internal reaction temperature and was positively correlated with excess of base used. Therefore the mixture of the desired product 10 and 10-Boc compound was treated with acid to completely deprotect Boc group. The conversion of methyl sulfide into the final sulfone 11 was carried out with Oxone™. Initially a mixture of methanol and water was used for the reaction. As the result, a partial displacement of sulfone by methoxy group was detected. The methanol was replaced with acetonitrile and the sulfone displacement was eliminated.

In summary, the ester route (Scheme 2-1) is preferred because:

1. Formation of the impurity during the first step of Scheme 2-2 was unavoidable and resulted in yields of < 35%.

2. Column purification was required to isolate intermediate 14.

3. The aldehyde starting material was not commercially available and required two synthetic steps from the corresponding ester.

Scheme 2-3 : Starting with cyclohexanone, compounds of the present invention can be prepared. In Step 1 the methyl glycinate is subjected to cyclohexanone and TMSCN in the presence of tri ethyl amine in DCM to afford 15. In Step 2 15 hydrogenated with hydrogen gas in the presence of catalytic platinum oxide and subsequently undergoes an intramolecular cyclization to afford compound 16 which is used in the schemes above.

Scheme 2-4: Starting with compound 17, compounds of the present invention can be prepared. In Step 1 compound 17 is subjected to ethyl 2-oxoacetate in the presence platinum on carbon and hydrogen gas to afford compound 18. In Step 2 compound 18 is Boc-deprotected with hydrochloric acid. In Step 3 compound 18 is cyclized to afford compound 16 which is used in the schemes above.

Scheme 2-5

11 19

Scheme 2-5: Starting from compound 11 the CDK 4/6 inhibitor 19 can be prepared. In Step 1 5-(4-methylpiperazin-l-yl)pyridin-2-amine is subjected to LiHMDS and compound 11 is added slowly under chilled conditions to afford a nucleophilic substitution reaction and compound 19. Compound 11 can be prepared as described in the schemes herein.

Scheme 2-6: Starting from compound 11 the CDK 4/6 inhibitor 20 can be prepared. In Step 1 5-(4-isopropylpiperazin-l-yl)pyridin-2-amine is subjected to LiHMDS and compound 11 is added slowly under chilled conditions to afford a nucleophilic substitution reaction and compound 20. Compound 11 can be prepared as described in the schemes herein.

Preparation of Compound 5:

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet, and reflux condenser was charged with ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 3 (49.2 g, 0.21 mol, 1.00 equiv.), spirolactam 4 (39.2 g, 0.23 mol, 1.10 equiv.), DIPEA (54.7 g, 0.42 mol, 2.00 equiv.), and DMAc (147.6 mL, 3 vol). The batch was heated to 90-95 °C, and after 60 h, IPC confirmed -14% (AUC) of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate remained. The batch was cooled to RT, and precipitate formation was observed. The suspension was diluted with MTBE (100 mL, 2 vol) and water (442 mL, 9 vol) and stirred for 2 h at RT. The product was isolated by vacuum filtration and washed with MTBE (49 mL, 1 vol). The solid cake was conditioned for 1 h and dried under vacuum at 40 °C for 16 h to afford compound 5 [41.0 g, 53% yield] as an off-white solid with a purity of >99% AUC. ¾ MR (CDCh): δ 8.76 (d, J = 2.0 Hz, 1H), 6.51-6.29 (br, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 3.58 (s, 2H), 2.92 (s, 2H), 2.53 (s, 3H), 1.63-1.37 (m, 12H). LCMS (ESI, m/z = 365.3 [M+H]).

Preparation of Compound 6:

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet was charged with 5 [41.0 g, 0.11 mol, 1.00 equiv.], Boc-anhydride (36.8 g, 0.17 mol, 1.50 equiv.), DMAP (1.37 g, 0.01 mol, 0.10 equiv.), and dichloromethane (287 mL, 7 vol). The batch was stirred for 3 h at RT. IPC confirmed no starting material remained (AUC). The batch was concentrated into a residue under reduced pressure and taken to the next step (a quantitative yield is assumed for this step). An aliquot (200 mg) was purified by column chromatography (heptanes/ethyl acetate 0 to 100%) to afford compound 6. 1H MR (CDCh): δ 8.64 (s, 1H), 4.31 (q, J = 7.0 Hz, 2H), 4.07 (s, 2H), 3.83 (S, 2H), 3.15 (m, 2H), 2.56 (s, 3H), 172 (m, 3H), 1.59 (m, 15H), 1.42 (t, J= 7.0 Hz, 3H). LCMS (ESI, m/z = 465.2 [M+H]).

Preparation of Compound 7:

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet was charged with compound 6 [residue from a previous step, quantitative yield assumed, 52.2 g, 0.11 mol, 1.00 equiv.], and THF (261 mL, 5 vol). The batch was cooled to 0°C and 1,8-diazabicyclo[5.4.0]un-dec-7-ene (17.1 g, 0.11 mmol, 1.00 equiv.) was added keeping the internal temperature in 0-10°C range. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm up to RT and after 2 h, IPC confirmed no starting material remained. The batch was seeded with the product (1.0 g) and was cooled to 0°C. The slurry was stirred at 0°C for 2 h. The product was isolated by vacuum filtration and washed with cold (0°C) THF (50 mL, 1 vol). The solid cake was conditioned for 1 h and dried under vacuum at 40°C for 16 h to afford 7 [47 g, quantitative yield] as a light orange solid with a purity of >99% AUC. The color of the product changed into yellow once the batch was exposed to air for an extended period of time (~ 1 day). Material was isolated with substantial amount DBU, according to proton NMR. However, it did not interfere with the next step. 1H MR (CDCh): δ 8.71 (s, 1H), 4.03 (s, 2H), 2.57 (s, 3H), 1.85 (m, 10H), 1.51 (s, 9H). LCMS (ESI, m/z = 419.2 [M+H]).

Preparation of Compound 8:

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet was charged with 7 [40.8 g, 0.10 mol, 1.00 equiv.], triethylamine (31.5 g, 0.31 mol, 3.20 equiv.), and dichloromethane (408 mL, 10 vol). The batch was purged with N2 for 15 min and was cooled to 0°C. Triflic anhydride (44.0 g, 0.16 mol, 1.60 equiv.) was added keeping the

internal temperature in 0-10°C range. The batch was stirred at 0°C and after 3 h, IPC confirmed -7.0% (AUC) of 7 remained. [It was speculated that the product was hydrolyzing back into starting material during the analysis.] Once the reaction was deemed complete, the batch was transferred to a 1 L, separatory funnel and was washed with 50% saturated sodium bicarbonate (200 mL, 5 vol). [It was prepared by mixing saturated sodium bicarbonate (100 mL) with water (100 mL)).] The aqueous layer was separated and was extracted with DCM (2×40 mL, 1 vol). The organic layers were combined and concentrated into a residue under reduced pressure and taken to the next step. LCMS (ESI, m/z = 551.6 [M+H]).

Preparation of Compound 9:

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet was charged with compound 8 [residue from a previous step, quantitative yield assumed, 53.7 g, 0.10 mol, 1.00 equiv.], and THF (110 mL, 2 vol). The solvent was removed under vacuum distillation and the procedure was repeated two times. The flask was charged with triethylsilane (22.7 g, 0.20 mol, 2.00 equiv.), and DMF (268 mL, 5 vol). The batch was degassed by five cycles of evacuation, followed by backfilling with nitrogen. The flask was charged with tetrakis(triphenylphosphine)palladium(0) (11.3 g, 0.01 mol, 0.1 equiv.). The batch was heated to 45-50°C, and after 14 h, IPC confirmed no starting material remained. The batch was transferred to a 500 mL, separatory funnel while still warm. The reaction was partitioned between water (5 vol) and ethyl acetate (5 vol). The aqueous layer was extracted with ethyl acetate (3 x3 vol). The organic layers were combined and concentrated down to 2 volumes. The precipitate was filtered and washed with ethyl acetate (2x 1 vol). The solid cake was conditioned for 1 h and dried under vacuum at 40°C for 16 h to afford 9 [27.5 g, 70% yield] as a yellow solid with a purity of -98% AUC. Proton NMR showed some triphenylphosphine oxide present. ¾ NMR (DMSO-i¾):5 9.01 (s, 1H), 7.40 (s, 1H), 4.30 (s, 2H), 2.58 (m, 2H), 2.58 (s, 3H), 1.81 (m, 5H), 1.51 (s, 9H). LCMS (ESI, m/z = 403.4 [M+H]).

Preparation of Compound 10 from the Scheme 2-1 route:

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet was charged 9 (12.8 g, 31.8 mmol, 1.00 equiv.) and dichloromethane (64 mL, 5 vol). Trifluoroacetic acid (18.2 g, 159 mmol, 5.00 equiv.) was added over 20 min and the solution was stirred for 2 h at RT. IPC confirmed reaction was complete. The batch was transferred to a 500 mL, separatory funnel and washed with saturated sodium bicarbonate (200 mL). The aqueous layer was extracted with dichlorom ethane (3 x3 vol). The organic layers were combined and concentrated down to 1 volume. The precipitate was filtered and conditioned for 1 h and dried under vacuum at 40 °C for 16 h to afford 9 [6.72 g, 70% yield] as an off-white solid with a purity of 99.1% AUC. ¾ NMR (DMSO-dis): δ 8.95 (s, 1H), 8.32 (s, 1H), 7.15 (s, 1H), 3.68 (d, J = 1.0 Hz, 2H), 2.86 (m, 2H), 2.57 (s, 3H), 1.92 (m, 2H), 1.73 (m, 3H), 1.39 (m, 3H). LCMS, ESI, m/z = 303.2 [M+H]).

Preparation of Compound 10 from Scheme 2-2 route:

A 50 mL, three-neck flask equipped with a magnetic stirring bar, thermocouple, N2 inlet was charged 14 (680 mg, 1.62 mmol, 1.00 equiv.) and THF (6.8 mL, 10 vol). A I M solution of potassium tert-butoxide (3.2 mL, 3.24 mmol, 2.00 equiv.) in THF was added over 10 min and the solution was stirred for 2 h at RT. IPC confirmed reaction was complete. The batch was acidified with 4 N hydrogen chloride solution in dioxane (2.4 mL, 9.72 mmol, 6.00 equiv.) and stirred for additional 1 h. The batch was transferred to a 500 mL, separatory funnel and washed with saturated sodium bicarbonate (100 mL). The aqueous layer was extracted with ethyl acetate (3 x20 vol). The organic layers were combined and concentrated down to 3volumes and product precipitated. The precipitate was filtered and conditioned for 1 h and dried under vacuum at 40 °C for 16 h to afford 9 [489 mg, quantitative yield] as an off-white solid.

Preparation of Compound 11 :

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet was charged with 10 (9.00 g, 29.8 mmol, 1.00 equiv.), and acetonitrile (180 mL, 20 vol). A solution of Oxone™ (45.9 g, 0.15 mol, 5.00 equiv.) in water (180 mL, 20 vol) was added to the batch over 20 min. The batch was stirred for 2 h and IPC confirmed the reaction was complete. The batch was concentrated down to ½ of the original volume and was extracted with dichloromethane DCM (4x 10 vol). The organic layers were combined; polish filtered and concentrated down to -10 vol of DCM. The product was slowly crystallized out by addition of heptanes (-30 vol). The mixture was cooled to 0°C and the product was filtered and dried under vacuum at 40 °C for 16 h to afford 11 [9.45 g, 95% yield] as an off-white solid with a purity of >99% AUC. ¾ NMR (CDCb): 5 9.24 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 3.89 (d, J= 2.0 Hz, 2H), 3.43 (s, 3H), 2.98 (m, 2H), 2.10 (m, 2H), 1.86 (m, 3H), 1.50 (m, 3H). LCMS (ESI, m/z = 335.2 [M+H]).

Preparation of Compound 13:

A 250 mL, single-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet, and reflux condenser was charged with 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde (2.00 g, 10.6 mmol, 1.00 equiv.), spirolactam 4 (1.96 g, 11.7 mmol, 1.10 equiv.), DIPEA (2.74 g, 21.2 mmol, 2.00 equiv.), and fert-butanol (20 mL, 10 vol). The batch was heated to 80-85 °C, and after 24 h, IPC confirmed no aldehyde 12 remained. The batch was cool to RT and concentrated into a residue, which was loaded on silica gel column. The product was eluted with ethyl acetate/heptanes (0% to 100%). The product containing fractions were pulled out and concentrated to afford 13 [0.98 g, 29% yield] as an off-white solid.

Preparation of Compound 14:

A 500 mL, three-neck flask equipped with a mechanical overhead stirrer, thermocouple, N2 inlet was charged with 13 [0.98 g, 3.00 mmol, 1.00 equiv.], Boc-anhydride (4.90 g, 21.5 mmol, 7.00 equiv.), DMAP (36 mg, 0.30 mmol, 0.10 equiv.), and dichloromethane (7 mL, 7 vol). The batch was stirred for 3 h at RT. IPC confirmed no starting material remained. The batch was cool to RT and concentrated into a residue, which was loaded on silica gel column. The product was eluted with ethyl acetate/heptanes (0% to 100%). The product containing fractions were pulled out and concentrated to afford 14 [0.98 g, 29% yield] as an off-white solid.

Preparation of Compound 15:

To a suspension of methyl glycinate (500 g, 3.98 mol, 1 eq) in DCM (10 L) was added

TEA dropwise at rt under nitrogen atmosphere, followed by the addition of cyclohexanone (781 g, 7.96 mol, 2 eq) dropwise over 15 min. To the resulting mixture was added TMSCN (591 g, 5.97 mol, 1.5 eq) dropwise over 1 hour while maintaining the internal reaction temperature below 35

°C. After stirred at rt for 2 hrs, the suspension became a clear solution. The progress of the reaction was monitored by H- MR.

When the methyl glycinate was consumed completely as indicated by H-NMR analysis, the reaction was quenched by water (5 L). The layers were separated. The aqueous layer was extracted with DCM (1 L). The combined organic phase was washed with water (5 L X 2) and

dried over Na2S04 (1.5 Kg). After filtration and concentration, 1.24 Kg of crude 15 was obtained as oil.

The crude 15 was dissolved in IPA (4 L). The solution was treated with HC1/IPA solution (4.4 mol/L, 1.1L) at RT. A large amount of solid was precipitated during the addition. The resulting suspension was stirred for 2 hrs. The solid product was collected by vacuum filtration and rinsed with MTBE (800 mL). 819 g of pure 15 was obtained as a white solid. The yield was 88.4%. ¾- MR (300 MHz, CD3OD) 4.20 (s, 2H), 3.88 (s, 3H), 2.30-2.40 (d, J = 12 Hz, 2H), 1.95-2.02 (d, J = 12 Hz, 2H), 1.55-1.85 (m, 5H), 1.20-1.40 (m, 1H).

Preparation of Compound 16:

To a solution of 15 (10 g, 43 mmol) in MeOH (100 mL) was added methanolic hydrochloride solution (2 .44 mol/L, 35.3 mL, 2 eq) and Pt02 (0.5 g, 5 wt %). The reaction suspension was stirred with hydrogen bubble at 40 °C for 6 hours. H- MR analysis showed consumption of 15. To the reaction mixture was added K2CO3 (15 g, 108 mmol, 2.5 eq) and the mixture was stirred for 3 hrs. The suspension was filtered and the filtrate was concentrated to dryness. The residual oil was diluted with DCM (100 mL) and resulting suspension was stirred for 3 hrs. After filtration, the filtrate was concentrated to provide crude 16 (6.6 g) as an oil. The crude 16 was diluted with EtOAc/hexane (1 : 1, 18 mL) at rt for 2 hrs. After filtration, 16 (4 g) was isolated. The obtained 16 was dissolved in DCM (16.7 mL) and hexane (100 mL) was added dropwise to precipitate the product. After further stirred for 1 h, 2.8 g of the pure 16 was isolated as a white solid. The yield was 39%. HPLC purity was 98.3%; MS (ESI): 169.2 (MH+); 1 H-NMR (300 MHz, D2O) 3.23 (s, 3H), 3.07 (s, 3H), 1.37-1.49 (m, 10H).

Preparation of compound 19:

5-(4-methylpiperazin-l-yl)pyridin-2-amine (803.1 g; 3.0 equivalents based on sulfone 11) was charged to a 22 L flask. The flask was blanketed with N2 and anhydrous THF added (12.4 kg). The resulting black-purple solution was cooled in an ice bath to < 5°C. 1M LiHMDS (4.7 L; 1.2 equivalents based on sulfone 11) was added via an addition funnel in three equal additions to keep the temperature below 10°C. Upon the completion of the addition, the reaction mixture was warmed to 16°C. The sulfone 11 (455.1 g; 1.00 equivalents) was added in five additions. Reaction proceeded until HPLC analysis of an IPC sample indicated less than 3% of sulfone 11 remained.

To quench the reaction, the contents of the 22L flask were transferred to a 100 L flask containing water. After stirring for 30 minutes at <30°C, the crude product was collected by filtration, washed with water and dried to afford 19 (387 g, 99.1% purity, 63.7% yield).

Preparation of compound 20:

5-(4-isopropylpiperazin-l-yl)pyridin-2-amine (1976.2 g; 3.0 equivalents based on sulfone 11) was charged to a 50 L flask. The flask was blanketed with N2 and anhydrous THF added (10.7 kg). The resulting black-purple solution was cooled in an ice bath to < 5°C. 1M LiHMDS (9.6 kg; 3.6 equivalents based on sulfone) was added via an addition funnel at a rate to keep the temperature below 10°C. Upon the completion of the addition, the reaction mixture was warmed to 16°C over 120 minutes by removing the ice bath. The sulfone (1000 g; 1.00 mol) was added in five additions. The reaction proceeded until HPLC analysis of an IPC sample indicated less than 1% of sulfone 11 remained. After completion of the reaction, ammonium chloride was added to the reaction mixture. The mixture stirred at < 32°C for at least 30 minutes and the solids collected by filtration to afford 20 (900 g, 99.1% purity, 64.2% yield).

Alternate Route to Spirolactam via cyclohexanone:

Scheme 2-7

26

In one embodiment the spirolactam is made via the synthetic scheme above. By reducing the nitrile group before addition of the glycinate group the reaction sequence proceeds in higher yield. The chemistry used in Step 1 is described in the literature (J. Org. Chem. 2005, 70,8027-8034), and was performed on a kilogram scale. The chemistry to convert Compound 24 into the

spirolactam was also demonstrated on kilogram scale. The Boc protection of Compound 23, is carried out at -70°C in order to limit formation of the di-Boc protected product. Experimental details of a 200 g pilot run are described below.

Step 1

200 g of cyclohexanone 21 was converted to 22 using Ti(Oi-Pr)4 /TMSCN/NH3. After work-up, 213 g of 22 was obtained. The H- MR was clean. The yield was 84%. The titanium salts were removed by vacuum filtration. In one embodiment, the titanium salts are removed by centrifugation or Celite filtration.

Step 2

190 g of 22 was mixed with LAH (2 eq) in MTBE for 30 minutes at 45°C. After work-up, 148 g of crude 23 was obtained.

Step 3

136 g of the crude 23 from step 2 was converted to 24 with 0.9 eq of B0C2O at -70°C. The reaction was completed and worked up. After concentration, 188 g of 24 was obtained. The yield was 86%. The H-NMR and C-NMR spectra confirmed that the compound was pure.

Step 4

188 g of 24 was subjected to methyl 2-bromoacetate and K2CO3 in acetonitrile to afford 25. 247 g of crude 25 was obtained.

Step 5

247 g of 25 was subjected to TFA in DCE heated to reflux to afford 26. After work-up, 112 g of 6 as TFA salt was obtained. H- MR was clean.

Step 6

26 27

Compound 26 was stirred in EtOH in the presence at room temperature overnight to afford 27. In one embodiment DCM is used as the solvent instead of EtOH.

Example 3. Purge of residual palladium from Step 5 Scheme 2-1:

Since palladium was used in Step 5 of Scheme 2-1, the levels of residual Pd present in the subsequent synthetic steps was determined. Table 2 below and Figure 3 show the palladium levels in the isolated solids.

Table 2

The material after Step 5 was isolated containing 1.47% (14700 ppm) of residual palladium. This data represents the highest level of palladium in the worst case scenario. The workup conditions of the latter steps purged nearly all of the palladium and the final product, 19 bis HC1 salt, contained 14 ppm of Pd, which is below the standard 20 ppm guidline. The Pd levels will likely be even lower once the catal st loading is optimized in Step 5.

19

The process developed in this route was a significant improvement over the one used for the first generation synthesis. Overall, the scheme consists of seven steps with five isolations, all by crystallization. No silica column chromatography is employed in the synthesis, which makes the process highly scalable. The process workup conditions can successfully purge the 1.47% of residual palladium after step 5 of Scheme 2-1.

Patent ID

Patent Title

Submitted Date

Granted Date

US8829012 CDK inhibitors
2014-01-23
2014-09-09
US8598197 CDK inhibitors
2013-04-24
2013-12-03
US8598186 CDK inhibitors
2013-04-24
2013-12-03
US8691830 CDK inhibitors
2013-04-24
2014-04-08
US2014274896 Transient Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation
2014-03-14
2014-09-18
Patent ID

Patent Title

Submitted Date

Granted Date

US2015297607 Tricyclic Lactams for Use in the Protection of Normal Cells During Chemotherapy
2015-04-17
2015-10-22
US2015297608 Tricyclic Lactams for Use as Anti-Neoplastic and Anti-Proliferative Agents
2015-04-17
2015-10-22
US9487530 Transient Protection of Normal Cells During Chemotherapy
2014-03-14
2014-09-18
US2017057971 CDK Inhibitors
2016-11-10
US2017037051 TRANSIENT PROTECTION OF NORMAL CELLS DURING CHEMOTHERAPY
2016-10-07
Patent ID

Patent Title

Submitted Date

Granted Date

US2017100405 HSPC-Sparing Treatments for RB-Positive Abnormal Cellular Proliferation
2016-12-21
US2017065597 Transient Protection of Normal Cells During Chemotherapy
2016-11-03
US2016310499 Highly Active Anti-Neoplastic and Anti-Proliferative Agents
2016-07-01
US2016220569 CDK4/6 Inhibitor Dosage Formulations For The Protection Of Hematopoietic Stem And Progenitor Cells During Chemotherapy
2016-02-03
2016-08-04
US2015297606 Tricyclic Lactams for Use in the Protection of Hematopoietic Stem and Progenitor Cells Against Ionizing Radiation
2015-04-17
2015-10-22
Patent ID

Patent Title

Submitted Date

Granted Date

US9717735 Tricyclic Lactams for Use in HSPC-Sparing Treatments for RB-Positive Abnormal Cellular Proliferation
2015-04-17
2015-10-22
US9527857 HSPC-Sparing Treatments for RB-Positive Abnormal Cellular Proliferation
2014-03-14
2014-09-18
US2014271460 Highly Active Anti-Neoplastic and Anti-Proliferative Agents
2014-03-14
2014-09-18
US2017182043 Anti-Neoplastic Combinations and Dosing Regimens using CDK4/6 Inhibitor Compounds to Treat RB-Positive Tumors
2017-03-13
US2017246171 Treatment Of RB-Negative Tumors Using Topoisomerase Inhibitors In Combination With Cyclin Dependent Kinase 4/6 Inhibitors
2017-03-13

///////////////TRILACICLIB, G1T28, G1T 28, SHR 6390, PHASE 2, G1 Therapeutics, Inc.

CN1CCN(CC1)C2=CN=C(C=C2)NC3=NC=C4C=C5C(=O)NCC6(N5C4=N3)CCCCC6

WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD


Image result

Image result for ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

 (WO2018001353) METHOD FOR PREPARING APREMILAST

ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

DU, Xiaoqiu; (CN).
ZHOU, Lianchao; (CN).
LIU, Jiegen; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018001353&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

EN)Method one: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L-leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an aprotic solvent to produce the compound of formula I; method two: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L- leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an organic solvent in the presence of an organic alkaline or an alkali metal hydride to produce the compound of formula I. The method for preparing apremilast requires inexpensive raw materials and reagents , is suitable for industrialized production, and has great economic effects.

Apremilast is a PDE4 inhibitor developed by Celgene. Currently, there are clinical indications such as rheumatoid arthritis, psoriatic arthritis, Behcet’s disease and ulcerative colitis. March 21, 2014 FDA approves first indication – adult active psoriatic arthritis (PsA). Name of Product: (FDA, as a post-marketing requirement, will evaluate the effect of this drug on pregnant women through a pregnancy registry study.) Three clinical trials evaluated the safety and efficacy of Asprate in the treatment of PsA, The response rates to ACR20 in the prest and placebo groups were 32-41% and 18-19%, respectively.
Aspast’s oral anti-rheumatic drug, a new mechanism of action, distinguishes itself from currently available anti-TNF monoclonal antibodies. Thomson Pharma predicts rapid sales growth of 201.2 million U.S. dollars in 2015 with sales of US $ 516 million in 2015 . Upstall’s sales are expected to reach a maximum of 2 billion U.S. dollars. Compared with its counterparts, Actuate has the following advantages: It inhibits the production of various proinflammatory mediators (PDE-4, TNF-α, IL-2, interferon γ, leukotriene, NO synthase) Inflammation; selective inhibitor of phosphodiesterase 4 (PDE4), approved for use in psoriatic arthritis in September 2014 FDA approved mid-to-severe treatment of plaque psoriasis for phototherapy or systemic therapy Patient, the first and only PDE4 inhibitor approved for the treatment of plaque psoriasis; clinical trials have shown that OTEZLA reduces erythema, thickening and scaling in patients with moderate to severe plaque psoriasis; clinical trials have demonstrated Painstrept was well tolerated and had minimal adverse reactions. Patients in the Otezla-treated and placebo clinical trials showed signs and symptoms of PsA improvement including tenderness, joint swelling and physical function.
The original patent CN 101683334A reports the synthesis of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- ) And 3-acetylaminophthalic anhydride (3) Prepared with acetic acid as solvent (1), and the synthetic route is as follows:
The method has low yield, needs lower than 50 DEG C to distill the high-boiling acetic acid, and produces one deacetyl impurity (4) during the reflux reaction and the acetic acid distillation, which affects the product purity. Acetic acid will corrode the equipment at high temperatures. Distillation of high-boiling acetic acid will also increase plant production time. Acetic acid, which is not distilled away, consumes a large amount of lye to neutralize and increases the amount of wastes and production costs, which is not conducive to industrialized production.
Example one
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- 4.6g (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, then add 50mL of acetonitrile, heating 75 ~ 80 ℃, the reaction incubated for 18 hours and cooled to room temperature. After the reaction mixture was evaporated to dryness, 60 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 25 mL of water was added to the organic layer and stirred for 10-30 minutes. The layers were evaporated to dryness to give a light yellow solid, then add 30mL absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.4 g of a white powder in 91.2% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.
Example two
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- A solution of 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride in a 250 mL three-necked flask was charged with 80 mL of toluene and 10 mL of N, N-dimethylformamide. The mixture was heated to 100 ° C and the reaction was incubated for 12 hours and then cooled to room temperature. After the reaction solution was evaporated to dryness, 80 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 50 mL of water was added to the organic layer and stirred for 10 to 30 minutes. Evaporated to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. Cooled to 0 ~ 5 ℃ and stirred for 1 ~ 2 hours, filtered and drained, the filter cake was dried in vacuo to give 9.2g white powder, yield 89.2%, HPLC: 99.9%, wherein the deacetyl impurities (4 ) Has an HPLC area of 0.03%.
Example three:
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- To a 250 mL three-necked flask was added 4.6 g (0.0224 mol) of 3-acetamidophthalic anhydride followed by 50 mL of ethyl acetate and 1.81 g (0.8 eq) of triethylamine. The mixture was heated at 75-80 ° C and incubated for 18 hours. The reaction was stopped, 100 mL of ethyl acetate was further added and the mixture was cooled to 20-30 ° C. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was heated to 0-5 ° C for 1 to 2 hours, filtered and drained. The filter cake was vacuum dried to give 9.8 g of a white powder in 95.1% yield. HPLC: 99.9% ) Had an HPLC area of 0.04%.
Example 4:
10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, followed by the addition of 120mL of isopropyl acetate and 30mL of acetonitrile and 1.81g (0.8eq) of triethylamine, heating 75 ~ 80 ℃, incubated reaction 16 hours. Stop the reaction, cooled to 20 ~ 30 ℃. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.6 g of a white powder in 93.1% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.
Comparative Example:
According to the preparation example of Compound A in original patent CN 101683334A, 10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4- methoxyphenyl) -2- (methylsulfonyl) N-acetyl-L-leucinate and 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride were placed in a 250 mL three-necked flask and 50 mL of acetic acid was added thereto. The mixture was heated at 75 to 80 ° C and the reaction was incubated for 18 hours. The reaction mixture was cooled to 40-50 ° C and the temperature of the water bath was controlled to 40-50 ° C. The reaction mixture was vortexed to glacial acetic acid without any significant fraction. 150 mL of ethyl acetate was added and the mixture was stirred to dissolve. 100 mL of water was added and the mixture was stirred 10 ~ 30 minutes, standing stratification, the organic layer was added 100mL water, stirred for 10 to 30 minutes, allowed to stand for stratification, the organic layer was added 100g 8% sodium bicarbonate solution, stirred for 10 to 30 minutes, The organic layer was added with 100g of 8% sodium bicarbonate solution and stirred for 10-30 minutes. The layers were separated and the organic layer was added with 100 mL of water. The mixture was stirred for 10-30 minutes, and the layers were separated. The organic layer was further added with 100 mL of water and stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. 68mL of anhydrous ethanol and 34mL of acetone were added to the solid, heated to 60-65 ° C, stirred to make it fully dissolved, and then cooled to 0-5 ° C and stirred for 1 to 2 hours, filtered and drained, and the filter cake was dried under vacuum to give 8.6 Class g white powder, yield 83.4%, HPLC: 99.7% with an HPLC area of deacetylated impurity (4) of 0.22%.

////////////WO 2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

NEW DRUG APPROVALS FAST APPROACHING 20 LAKH VIEWS MARK…….https://newdrugapprovals.org/


NEW DRUG APPROVALS FAST APPROACHING 20 LAKH VIEWS MARK…….https://newdrugapprovals.org/

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ELAGOLIX


Elagolix.svgChemSpider 2D Image | Elagolix | C32H30F5N3O5Elagolix.png

ELAGOLIX

  • Molecular FormulaC32H30F5N3O5
  • Average mass631.590 Da
NBI56418, ABT 620
UNII:5B2546MB5Z
4-({(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phenylethyl}amino)butanoic acid
834153-87-6 FREE ACID
SODIUM SALT  832720-36-2
Acide 4-({(1R)-2-[5-(2-fluoro-3-méthoxyphényl)-3-[2-fluoro-6-(trifluorométhyl)benzyl]-4-méthyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phényléthyl}amino)butanoïque
Butanoic acid, 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-

GNRH antagonist, Endometriosis

Endometriosis PREREGISTERED

Phase III Uterine leiomyoma

WO2001055119A2,

Inventors Yun-Fei ZhuChen ChenFabio C. TucciZhiqiang GuoTimothy D. GrossMartin RowbottomR. Scott Struthers,
Applicant Neurocrine Biosciences, Inc.

WO 2005007165 PDT PATENT

Image result for Neurocrine Biosciences, Inc.

Inventors Zhiqiang GuoYongsheng ChenDongpei WuChen ChenWarren WadeWesley J. DwightCharles Q. HuangFabio C. Tucci
Applicant Neurocrine Biosciences, Inc.
  • Originator Icahn School of Medicine at Mount Sinai
  • Developer AbbVie; Neurocrine Biosciences
  • Class Antineoplastics; Fluorinated hydrocarbons; Pyrimidines; Small molecules
  • Mechanism of Action LHRH receptor antagonists
  • Highest Development Phases
  • Preregistration Endometriosis
  • Phase III Uterine leiomyoma
  • Discontinued Benign prostatic hyperplasia; Prostate cancer
  • Most Recent Events
  • 23 Nov 2017 AbbVie plans a phase III trial for Endometriosis (Monotherapy, Combination therapy) in USA in November 2017 (NCT03343067)
  • 01 Nov 2017 Updated efficacy and adverse events data from two phase III extension trials in Endometriosis released by AbbVie
  • 27 Oct 2017 Elagolix receives priority review status for Endometriosis in USA

 

SYN

Elagolix is a specific highly potent non-peptide, orally active antagonist of the GnRH receptor. This compound inhibits pituitary luteinizing hormone (LH) secretion directly, potentially preventing the several week delay and flare associated with peptide agonist therapy.

Image result for Neurocrine Biosciences, Inc.

In 2010, elagolix sodium was licensed to Abbott by Neurocrine Biosciences for worldwide development and commercialization for the treatment of endometriosis. In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie.

AbbVie , following its spin-out from Abbott in January 2013, under license from Neurocrine , is developing elagolix, the lead from a series of non-peptide gonadotropin-releasing hormone antagonists, for treating hormone-dependent diseases, primarily endometriosis and uterine fibroids.

Elagolix sodium is an oral gonadotropin releasing hormone (GnRH) antagonist in development at Neurocrine Biosciences and Abbvie (previously Abbott). In 2017, Abbvie submitted a New Drug Application (NDA) in the U.S. for the management of endometriosis with associated pain. The candidate is being evaluated in phase III trials for the treatment of uterine fibroids.

Elagolix (INNUSAN) (former developmental code names NBI-56418ABT-620) is a highly potent, selective, orally-active, short-duration, non-peptide antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (KD = 54 pM) which is under development for clinical use by Neurocrine Biosciences and AbbVie.[2][3] As of 2017, it is in pre-registration for the treatment of endometriosis and phase III clinical trials for the treatment of uterine leiomyoma.[1][4] The drug was also under investigation for the treatment of prostate cancer and benign prostatic hyperplasia, but development for these indications was ultimately not pursued.[4] Elagolix is the first of a new class of GnRH inhibitors that have been denoted as “second-generation”, due to their non-peptide nature and oral bioavailability.[1]

Because of the relatively short elimination half-life of elagolix, the actions of gonadotropin-releasing hormone (GnRH) are not fully blocked throughout the day.[1][5] For this reason, gonadotropin and sex hormone levels are only partially suppressed, and the degree of suppression can be dose-dependently adjusted as desired.[1][5] In addition, if elagolix is discontinued, its effects are rapidly reversible.[1][5] Due to the suppression of estrogen levels by elagolix being incomplete, effects on bone mineral density are minimal, which is in contrast to first-generation GnRH inhibitors.[6][7] Moreover, the incidence and severity of menopausal side effects such as hot flashes are also reduced relative to first-generation GnRH inhibitors.[1][5]

Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl] -4-methyl-2,6-dioxopyrimidin- 1 -yl] -1 -phenylethyl] amino] butanoate as below.

The US patent number 7056927 B2 discloses, elagolix sodium salt as a white solid and process for its preparation in Example-1; Step-IH.

The US patent number 8765948 B2 discloses a process for preparation of amorphous elagolix sodium by spray drying method and solid dispersion of amorphous elagolix sodium with a polymer.

The US patent number 7056927 B2 discloses a process for preparation of elagolix sodium salt in Example -1 as given in below scheme -I.

Scheme -I

The US patent number 8765948 B2 describes a process for preparation of elagolix sodium in example- 1 and 4 as given below scheme-II:

(1c) (1e) (4a)

Scheme-II

Further, the US patent number 8765948 B2 discloses an alternate process for the preparation of compound of formula (le) as mentioned below scheme-Ill.

Scheme -III

PATENT

WO2001055119A2 * Jan 25, 2001 Aug 2, 2001 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

PATENT

WO 2005007165

https://encrypted.google.com/patents/WO2005007165A1?cl=en

EXAMPLE 1

3-[2(R)-{HYD OXYCARBONYLPROPYL-AMINθ} -2-PHENYLETHYL]-5-(2-FLUORO-3- METHOXYPHENYL)-l-[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]-6-METHYL- PYRIMIDINE-2,4(lH,3H)-DIONE

Figure imgf000027_0001

Step IA: Preparation of 2-fluoro-6-(trifluoromethyl)benzylamine la To 2-fluoro-6-(trifluoromethyl)benzonitrile (45 g, 0.238 mmol) in 60 mL of TΗF was added 1 M BΗ3:TΗF slowly at 60 °C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (C\) m/z 194.0 (MH+).

Step IB: Preparation of N-|2-fluoro-6-(trifluoromethyl)benzyl|urea lb To 2-fluoro-6-(trifluoromethyl)benzylamine la (51.5 g, 0.267 mmol) in a flask, urea (64 g, 1.07 mmol), HC1 (cone, 30.9 mmol, 0.374 mmol) and water (111 mL) were added. The mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, further cooled with ice and filtered to give a yellow solid. Recrystallization with 400 mL of EtOAc gave lb as a white solid (46.2 g, 0J96 mmol). MS (CI) m/z 237.0 (MH+).

Step 1C: Preparation of l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methylpyrimidine-2.4(lH.3H)-dione lc Nal (43.9 g, 293 mmol) was added to N-[2-fluoro-6- (trifluoromethyl)benzyl]urea lb (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give lc as a white solid (48.5 g, 16 mmol). 1H ΝMR (CDC13) δ 2.15 (s, 3Η), 5.37 (s, 2H), 5.60 (s, 1H), 7.23-7.56 (m, 3H), 9.02 (s, 1H); MS (CI) m/z 303.0 (MH+).

Step ID: Preparation of 5-bromo-l -[2-fluoro-6-(trifluoromethyl)benzyl|-6- methylpyrimidine-2.4(lH.3H)-dione Id Bromine (16.5 mL, 0.32 mmol) was added to l-[2-fluoro-6-

(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(lHJH)-dione lc (48.5 g, 0J6 mol) in 145 mL of acetic acid. The resulting mixture became clear then formed precipitate within an hour. After 2 hours stirring, the yellow solid was filtered and washed with cold EtOAc to an almost white solid. The filtrate was washed with sat. ΝaΗCO3 and dried over Na2SO4. Evaporation gave a yellow solid which was washed with EtOAC to give a light yellow solid. The two solids were combined to give 59.4 g of Id (0J56 mol) total. Η NMR (CDC13) δ 2.4 (s, 3H), 5.48 (s, 2H), 7.25-7.58 (m, 3H), 8.61 (s, 1H); MS (CI) m/z 380.9 (MH+). 5-Bromo-l-[2, 6-difluorobenzyl]-6-methylpyrimidine-2,4(lHJH)-dione ld.l was made using the same procedure.

Step IE: Preparation of 5-bromo-l -r2-fluoro-6-(trifluoromethyl)benzyll-6- methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyll-pyrimidine-2.4(lHJH)-dione le To 5-bromo- 1 -[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- 2,4(lHJH)-dione Id (15 g, 39.4 mmol) in 225 mL of TΗF were added N-t-Boc-D- phenylglycinol (11.7 g, 49.2 mmol) and triphenylphosphine (15.5 g, 59J mmol), followed by addition of di-tert-butyl azodicarboxylate (13.6 g, 59J mmol). The resulting yellow solution was stirred overnight. The volatiles were evaporated and the residue was purified by silica gel with 3:7 EtOAc Ηexane to give le as a white solid (23.6 g, 39.4 mmol). MS (CI) m/z 500.0 (MΗ+-Boc).

Step IF: Preparation of 3-[2(R)-amino-2-phenylethyll-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyll-6-methyl-pyrimidine- 2.4(lH.3H)-dione If To 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2(R)- tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(lH,3H)-dione le (15 g, 25 mmol) in 30 mL/90 mL of Η2O/dioxane in a pressure tube were added 2-fluoro-3- methoxyphenylboronic acid (4.25 g, 25 mmol) and sodium carbonate (15.75 g, 150 mmol). N2 gas was bubbled through for 10 min.

Tetrakis(triphenylphosphine)palladium (2.9 g, 2.5 mmol) was added, the tube was sealed and the resulting mixture was heated with stirring at 90 °C overnight. After cooling to ambient temperature, the precipitate was removed by filtration. The volatiles were removed by evaporation and the residue was partitioned between EtOAc/sat. NaHCO3. The organic solvent was evaporated and the residue was chromatographed with 2:3 EtOAc/Hexane to give 13.4 g (20.8 mmol, 83 %) yellow solid. This yellow solid (6.9 g, 10.7 mmol) was dissolved in 20 mL/20 mL CH2C12/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave If as a yellow oil (4.3 g, 7.9 mmol, 74%). Η NMR (CDC13) δ 2.03 (s, 3H), 3.72-4.59 (m, 6H), 5.32-5.61 (m, 2H), 6.74-7.56 (m, 11H); MS (CI) m/z 546.0 (MH+). 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2,6- difluorobenzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione lf.l was made using the same procedure described in this example.

Step 1G: Preparation of 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyll-5-

(2-fluoro-3 -methoxyphenyl)- 1 -[2-fluoro-6-(trifluoromethyl)benzyl|-6-methyl- pyrimidine-2,4(lHJH)-dione lg To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione If (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4- bromobutyrate (4 mL, 28.2 mmol) and Ηunig’s base (1.6 mL, 9.4 mmol). After reflux at 95 °C overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10: 1 EtOAc/Ηexane/Et3N to give lg as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).

Step 1H: Preparation of 3-[2(R)- {hydroxycarbonylpropyl-amino} -2-phenylethyl]- 5-(2-fluoro-3-methoxyphenyl)-l- 2-fluoro-6-(trifluoromethyl)benzyl1-6-methyl- pyrimidine-2,4(lHJH)-dione 1-1 Compound 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione lg (2.6 g, 4.0 mmol) was dissolved in 30 mL/30 mL of TΗF/water. Solid NaOΗ (1.6 g, 40 mmol) was added and the resulting mixture was heated at 50 °C overnight. The mixture was cooled to ambient temperature and the volatiles were evaporated. Citric acid was added to the aqueous solution until pΗ = 3. Extraction with EtOAc followed by evaporation of solvent gave 1.96 g of a white gel. The gel was passed through a Dowex MSC-1 macroporous strong cation-exchange column to convert to sodium salt. Lyopholization gave white solid 1-1 as the sodium salt (1.58 g, 2.47 mmol). Η NMR (CD3OD) δ 1.69-1.77 (m, 2H), 2.09 (s, 3H), 2.09-2.19 (t, J = 7.35 Hz, 2H), 2.49-2.53 (t, J = 735 H, 2H), 3.88 (s, 3H), 4.15-4.32 (m, 3H), 5.36-5.52 (m, 2H), 6.60-7.63 (m, 1 IH); HPLC-MS (CI) m/z 632.2 (MH+), tR = 26.45, (method 5)

PATENT

WO 2017221144

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017221144&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for the preparation of elagolix sodium and its polymorph forms and intermediates is claimed. Represents first filing from Dr. Reddy’s Laboratories Limited and the inventors on this API.

n a seventh aspect, the present invention provides a process for preparation of compound of formula (VII)

(VII)

wherein R is alkyl such as methyl, ethyl, propyl, isopropyl and the like,

comprising;

a) reacting the compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV)

wherein t-BOC is tertiary butoxycarbonyl group; R is as described above

b) reacting the compound of formula (IV) with the compound of formula (V) to obtain the compound formula (VI), and

c) N-deprotection of the compound of formula (VI) to obtain the compound of formula

(VII)

(VI) (VII)

The reaction of compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV) is carried in the presence of triarylphosphine such as triphenyl phosphine and the like and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.

The seventh aspect of the present invention is depicted below scheme-IV.

Scheme-IV

The eighth aspect of the present invention is depicted below scheme-IV.

R=alkyl

Scheme-IV

Example 11: Preparation of ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (Ilia; R is ethyl)

R-(-)-2-phenylglycinol (10 g), DMAP (0.17 g) were added in THF (80 ml) at room temperature under nitrogen atmosphere. Triethylamine (30.48 ml) was added to the reaction mixture and stirred for five minutes. Ethyl-4-bromo butyrate (15.64 ml) was added and the reaction mixture heated to 80°C then stirred for 16 hours. Water (20 volumes) followed by ethyl acetate (200 ml) were added to separate the aqueous and organic layer. The organic layer was washed with IN HC1 (100 ml) followed by neutralize the resulting aqueous layer with saturated sodium carbonate solution then extract with ethyl acetate (100 ml) and the organic layer was dried over anhydrous sodium sulfate then evaporated below 50°C under reduced pressure to obtain the title compound. Yield: 14.50 g. Purity: 94.75% (by HPLC). ¾ NMR (400 MHz, DMSO-d6): δ 7.17-7.30 (m, 5H), 4.83 (m, 1H), 3.99 (q, 2H), 3.58 (dd, 1H, J = 8.8, 4.4 Hz), 3.88 (m, 1H ), 3.27 (m, 1H), 2.38 (m, 1H), 2.26 (m, 3H), 2.10 (s, 1H), 1.61 (m, 2H), 1.12 (t, 3H); m/z: 252 (MH )

Example 12: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l-phenylethyl) amino)butanoate (III; R is ethyl)

Ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (14 g) was added to THF (140 ml) at room temperature. The reaction mixture was cooled to 0-5 °C. Triethylamine (16.9 mL) was added to the reaction mixture followed by Di-tert-butyl dicarbonate (13.37 g) was added to reaction mixture at 0-5 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. Water (300 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with sodium chloride then died over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound as a pale yellow syrup. Yield: 9.5 g. Purity: 95.42% (by HPLC). ¾ NMR (400 MHz, CDC13): δ 7.24-7.34 (m, 5H), 5.08 (m, 1H), 4.09 (m, 4H), 3.10 (m, 2H), 3.00 (s, 1H), 2.21(m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.23 (t, 3H). m/z: 352.20 (MH )

Example 13: Preparation of ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl)

Ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l -phenyl ethyl) amino)butanoate (III; R is ethyl) (1.0 g), 5-bromo-l-(2-fluoro-6-trifluoromethyl)benzyl-6-methylpyrimidine-2,4 (1H, 3H)-dione (II) (1.08 g), Triphenyl phosphine (1.49 g) were added to THF (30 mL) at room temperature under nitrogen atmosphere. DIAD (1.11 mL) was added to the reaction mixture and stirred for 16 hours at room temperature. Water (60 volume) was added to the reaction mixture followed by ethylacetate (60 mL) was added then the layers were separated. The organic layer was dried over sodium sulfate and evaporated below 50°C under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound. Yield (1.3 g). Purity: 68.87% (by HPLC); l NMR (DMSO-d6) δ 1.15-2.0 (11H), 2.43-2.48 (4H), 3.9 (2H), 4.71-4.8 (5H), 5.3 -5.4 (3H), 7.28-7.3 (8H), 8.4 (2H); m/z: 616 (M-BOC)+

Example 14: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl)

Ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl) (0.9 g), 2-fluoro-3-methoxy phenyl boronic acid (V) (0.214 g) and sodium carbonate (0.797 g) were added to the mixture of 1,4-dioxane (9 mL) and water (3.06 mL) at room temperature under nitrogen atmosphere. Argon gas was bubbled through for 30 minutes. Tetrakis (triphenylphosphine)palladium (0.145 g) was added to the reaction mixture at room temperature then heated to 90-95 °C and stirred for 5 hours. The reaction mixture cooled to room temperature and filtered through celite bed then the filtrate washed with ethylacetate (9 mL) and water (36 mL) was added and stirred for 30 minutes at room temperature. Ethylacetate (36 mL) was added and the separated organic layer washed with brine and dried over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with 20-25% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 0.5 g; Purity: 75.1% (by HPLC); m/z: 660 (M-BOC)+.

Example 15: Preparation of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VII; R is ethyl)

Ethyl(R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoro methyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl) (0.4 g) was added to dichloromethane (4 mL) at room temperature. The reaction mixture was cooled to 0-5 °C then trifluoroacetic acid (2 mL) was added and stirred for five hours at 0-5 °C. Saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture followed by dichloromethane (40 mL) was added. The organic layer was washed with brine then dried over sodium sulfate and evaporated at 35°C to obtain the crude compound. The crude compound purified by silica gel (60/120 mesh) with 30-35% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 160 mg; Purity: 88.6% (by HPLC). ‘H NMR (400 MHz, DMSO-d6): δ 7.64 (m, 1H), 7.54 (m, 2H), 7.15-7.27 (m, 6H), 6.85 (m, 2H), 5.31 (s, 2H), 3.99 (m, 3H), 3.87 (m, 2H), 3.83 (s, 3H), 2.30-2.16 (m, 4H), 2.10 (s, 3H), 1.50 (m, 2H), 1.10 (t, 3H). m/z: 660 (MH )

PAPER

Discovery of sodium R-(+)-4-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl-)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-1-phenylethamino)butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2008, 51(23): 7478

Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

Department of Medicinal Chemistry, Department of Endocrinology, and Department of Preclinical Development, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130
J. Med. Chem.200851 (23), pp 7478–7485
DOI: 10.1021/jm8006454

* To whom correspondence should be addressed. Phone: 1-858-617-7600. Fax: 1-858-617-7925. E-mail: cchen@neurocrine.comsstruthers@neurocrine.com., †

Department of Medicinal Chemistry., ‡ Department of Endocrinology., § Department of Preclinical Development.

Abstract

Abstract Image

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

NA SALT

(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric Acid Sodium Salt

sodium salt as a white solid (1.58 g, 2.47 mmol, 62%). HPLC purity: 100% (220 and 254 nm). 1H NMR (CD3OD): 1.72 (m, 2H), 2.08 (s, 3H), 2.16 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 4.24 (m, 3H), 5.40 (d, J = 9.0 Hz, 1H), 5.46 (d, J = 9.0 Hz, 1H), 6.62 and 6.78 (m, 1H), 7.12 (m, 2H), 7.34 (m, 5H), 7.41 (m, 1H), 7.56 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H). MS: 632 (M − Na + 2H+). Anal. (C32H29F5N3O5Na·0.75H2O): C, H, N, Na.

PATENT

CN 105218389

PATENT

WO2014143669A1

“Elagolix” refers to 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2- fluoro-6 rifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l- phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof. Elagolix is an orally active, non-peptide GnRH antagonist and is unlike other GnRH agonists and injectable (peptide) GnRH antagonists. Elagolix produces a dose dependent suppression of pituitary and ovarian hormones in women. Methods of making Elagolix and a pharmaceutically acceptable salt thereof are described in WO 2005/007165, the contents of which are herein incorporated by reference.

References

  1. Jump up to:a b c d e f g Ezzati, Mohammad; Carr, Bruce R (2015). “Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain”. Women’s Health11(1): 19–28. doi:10.2217/whe.14.68ISSN 1745-5057.
  2. Jump up^ Chen C, Wu D, Guo Z, Xie Q, Reinhart GJ, Madan A, Wen J, Chen T, Huang CQ, Chen M, Chen Y, Tucci FC, Rowbottom M, Pontillo J, Zhu YF, Wade W, Saunders J, Bozigian H, Struthers RS (2008). “Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor”. J. Med. Chem51 (23): 7478–85. doi:10.1021/jm8006454PMID 19006286.
  3. Jump up^ Thomas L. Lemke; David A. Williams (24 January 2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1411–. ISBN 978-1-60913-345-0.
  4. Jump up to:a b AdisInsight: Elagolix.
  5. Jump up to:a b c d Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP (2009). “Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix”J. Clin. Endocrinol. Metab94 (2): 545–51. doi:10.1210/jc.2008-1695PMC 2646513Freely accessiblePMID 19033369.
  6. Jump up^ Diamond MP, Carr B, Dmowski WP, Koltun W, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study”. Reprod Sci21 (3): 363–71. doi:10.1177/1933719113497292PMID 23885105.
  7. Jump up^ Carr B, Dmowski WP, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density”Reprod Sci21 (11): 1341–51. doi:10.1177/1933719114549848PMC 4212335Freely accessiblePMID 25249568.

External links

Citing Patent Filing date Publication date Applicant Title
WO2014143669A1 Mar 14, 2014 Sep 18, 2014 AbbVie Inc . Compositions for use in treating heavy menstrual bleeding and uterine fibroids
EP2881391A1 Dec 5, 2013 Jun 10, 2015 Bayer Pharma Aktiengesellschaft Spiroindoline carbocycle derivatives and pharmaceutical compositions thereof
US8084614 Apr 4, 2008 Dec 27, 2011 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8263588 Apr 4, 2008 Sep 11, 2012 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8481738 Nov 10, 2011 Jul 9, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8507536 Aug 10, 2012 Aug 13, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8952161 Jun 5, 2013 Feb 10, 2015 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US9034850 Nov 19, 2010 May 19, 2015 Sk Chemicals Co., Ltd. Gonadotropin releasing hormone receptor antagonist, preparation method thereof and pharmaceutical composition comprising the same
US9422310 Jan 8, 2015 Aug 23, 2016 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
Patent ID

Patent Title

Submitted Date

Granted Date

US9382214 Processes for the preparation of uracil derivatives
2014-06-19
2016-07-05
US2014288031 METHODS OF TREATING HEAVY MENSTRUAL BLEEDING
2014-03-14
2014-09-25
Patent ID

Patent Title

Submitted Date

Granted Date

US2010190692 METHODS FOR REDUCING GNRH-POSITIVE TUMOR CELL PROLIFERATION
2010-02-05
2010-07-29
US8273716 USE OF LHRH ANTAGONISTS FOR INTERMITTENT TREATMENTS
2009-09-03
US8765948 PROCESSES FOR THE PREPARATION OF URACIL DERIVATIVES
2011-04-28
US2010092463 Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject
2009-11-20
2010-04-15
US2010061976 Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject
2009-07-27
2010-03-11
Patent ID

Patent Title

Submitted Date

Granted Date

US9701647 Tetrazolones as a carboxylic acid bioisosteres
2016-08-10
2017-07-11
US9439888 Tetrazolones as a carboxylic acid bioisosteres
2016-01-25
2016-09-13
US7419983 Gonadotropin-releasing hormone receptor antagonists and methods related thereto
2007-08-16
2008-09-02
US7176211 Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
2006-06-08
2007-02-13
US7056927 Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
2005-02-17
2006-06-06
Elagolix
Elagolix.svg
Clinical data
Synonyms NBI-56418; ABT-620
Routes of
administration
By mouth
Drug class GnRH analogueGnRH antagonistantigonadotropin
Pharmacokinetic data
Biological half-life 2.4–6.3 hours[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C32H30F5N3O5
Molar mass 631.590 g/mol
3D model (JSmol)

///////////////ELAGOLIX, NBI 56418, UNII:5B2546MB5Z, ABT 620, priority review status, PHASE 3, AbbVie, Neurocrine Biosciences, Endometriosis

CC1=C(C(=O)N(C(=O)N1CC2=C(C=CC=C2F)C(F)(F)F)CC(C3=CC=CC=C3)NCCCC(=O)O)C4=C(C(=CC=C4)OC)F

Drug Patents International


All about Patents and Intellectual property by DR ANTHONY MELVIN CRASTO, worlddrugtracker, Ph.D ( ICT, Mumbai) , INDIA 30 Yrs Exp. in the feld of Organic Chemistry, Serving chemists around the world.

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

https://drugpatentsint.blogspot.in/

 

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

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,114 other followers

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

twitter

DISCLAIMER

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP