Home » 2015 » July

Monthly Archives: July 2015

DACLATASVIR, 达拉他韦 , Даклатасвир , داكلاتاسفير ,

July 30, 2015 5:23 am / 1 Comment on DACLATASVIR, 达拉他韦 , Даклатасвир , داكلاتاسفير ,

Daclatasvir

BMS-790052,

EBP 883; BMS 790052

THERAPEUTIC CLAIM Treatment of hepatitis C

CHEMICAL NAMES

1. Carbamic acid, N,N’-[[1,1′-biphenyl]-4,4′-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-

pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C’-dimethyl ester

2. dimethyl N,N’-(biphenyl-4,4′-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-

diyl][(1S)-1-(1-methylethyl)-2-oxoethane-2,1-diyl]})dicarbamate

MF C40H50N8O6

MW 738.9

SPONSOR Bristol-Myers Squibb

CODE BMS-790052

CAS 1009119-64-5

SMILES:CC(C)C(C(=O)N1CCCC1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C=C4)C5=CN=C(N5)C6CCCN6C(=O)C(C(C)C)NC(=O)OC)NC(=O)OC

UNII-LI2427F9CI

Activity: Treatment of Hepatitis C; HCV Drug; Treatment of HCV; Inhibitor of NS5A
Status: Launched 2014 (EU, Japan)
Originator: Bristol-Myers Squibb

NMR

http://www.medchemexpress.com/product_pdf/HY-10466/Daclatasvir-NMR-HY-10466-03482-2011.pdf

FDA APPROVAL……..July 24th, 2015

Daklinza (daclatasvir) is an NS5A inhibitor indicated for use in combination with sofosbuvir for the treatment of chronic hepatitis C virus (HCV) genotype 3 infection.

Daclatasvir dihydrochloride

1. Carbamic acid, N,N’-[[1,1′-biphenyl]-4,4′-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-

pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C’-dimethyl ester,

hydrochloride (1:2)

2. dimethyl N,N’-(biphenyl-4,4′-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-

diyl][(1S)-1-(1-methylethyl)-2-oxoethane-2,1-diyl]})dicarbamate dihydrochloride

MF C40H50N8O6 . 2 HCl, MW 811.8

SPONSOR Bristol-Myers Squibb

CODE BMS-790052-05

CAS 1009119-65-6

Daclatasvir (USAN^[1]) (formerly BMS-790052, trade name Daklinza) is a drug for the treatment of hepatitis C (HCV). It is was developed by Bristol-Myers Squibb and was approved in Europe on 22 August 2014.

Daclatasvir inhibits the HCV nonstructural protein NS5A.^[2]^[3] Recent research suggests that it targets two steps of the viral replication process, enabling rapid decline of HCV RNA.^[4]

Daclatasvir has been tested in combination regimens with pegylated interferon and ribavirin,^[5] as well as with other direct-acting antiviral agents including asunaprevir^[6]^[7]^[8]^[9] and sofosbuvir.^[10]^[11]

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medications needed in a basic health system.^[12]

ChemSpider 2D Image | Daclatasvir | C40H50N8O6

Hepatitis C virus (HCV) is a major global health problem, with an estimated 150-200 million people infected worldwide, including at least 5 million in Europe (Pawlotsky, Trends Microbiol, 2004, 12: 96-102). According to the World Health Organization, 3 to 4 million new infections occur each year. The infection is often asymptomatic; however, the majority of HCV-infected individuals develop chronic infection (Hoof agle, Hepatology, 2002, 36: S21-S29; Lauer et al, N. Engl. J. Med., 2001, 345: 41-52; Seeff, Semin. Gastrointest., 1995, 6: 20-27). Chronic infection frequently results in serious liver disease, including fibrosis and steatosis (Chisari, Nature, 2005, 435: 930-932).

About 20% of patients with chronic HCV infection develop liver cirrhosis, which progresses to hepatocellular carcinoma in 5% of the cases (Hoofnagle, Hepatology, 2002, 36: S21-S29; Blonski et al, Clin. Liver Dis., 2008, 12: 661-674; Jacobson et al, Clin. Gastroenterol. Hepatol, 2010, 8: 924-933; Castello et al., Clin. Immunol, 2010, 134: 237-250; McGivern et al., Oncogene, 2011, 30: 1969-1983).

Chronic HCV infection is the leading indication for liver transplantations (Seeff et al., Hepatology, 2002, 36: 1-2). Unfortunately, liver transplantation is not a cure for hepatitis C; viral recurrence being an invariable problem and the leading cause of graft loss (Brown, Nature, 2005, 436: 973-978; Watt et al, Am. J. Transplant, 2009, 9: 1707-1713). No vaccine protecting against HCV is yet available. Current therapies include administration of ribavirin and/or interferon-alpha (IFN-Cc), two non-specific anti-viral agents.

Using a combination treatment of pegylated IFN-CC and ribavirin, persistent clearance is achieved in about 50% of patients with genotype 1 chronic hepatitis C. However, a large number of patients have contraindications to one of the components of the combination; cannot tolerate the treatment; do not respond to interferon therapy at all; or experience a relapse when administration is stopped. In addition to limited efficacy and substantial side effects such as neutropenia, haemo lytic anemia and severe depression, current antiviral therapies are also characterized by high cost.

To improve efficacy of standard of care (SOC), a large number of direct acting antivirals (DAAs) targeting viral polyprotein processing and replication have been developed (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol., 2011, 8: 257-264). These include small molecule compounds targeting HCV nonstructural proteins including the HCV protease, polymerase and NS5A protein.

Although a marked improvement of antiviral response was observed when protease inhibitors were combined with SOC (Hofmann et al, Nat. Rev; Gastroenterol. Hepatol, 2011, 8: 257-264; Bacon et al, New Engl. J. Med., 2011, 364: 1207-1217; McHutchison et al, New Engl. J. Med., 2010, 362: 1292-1303; Poordad et al, New Engl. J. Med., 201 1, 364: 1195-1206; Hezode et al, New Engl. J. Med., 2009, 360: 1839-1850; Kwo et al, Lancet, 2010, 376: 705-716), toxicity of the individual compounds and rapid development of viral resistance in a substantial fraction of patients remain major challenges (Pawlotsky, Hepatology, 2011, 53: 1742-1751; Pereira et al, Nat. Rev. Gastroenterol. Hepatol., 2009, 6: 403-411; Sarrazin et al, Gastroenterol., 2010, 138: 447-462).

New therapeutic approaches against HCV are therefore still needed. HCV entry into target cells is a promising target for antiviral preventive and therapeutic strategies since it is essential for initiation, spread, and maintenance of infection (Timpe et al, Gut, 2008, 57: 1728-1737; Zeisel et al, Hepatology, 2008, 48: 299-307). Indeed, HCV initiates infection by attaching to molecules or receptors on the surface of hepatocytes.

Current evidence suggests that HCV entry is a multistep process involving several host factors including heparan sulfate (Barth et al, J. Biol. Chem., 2003, 278: 41003-41012), the tetraspanin CD81 (Pileri et al, Science, 1998, 282: 938-941), the scavenger receptor class B type I (SR-BI) (Zeisel et al, Hepatology, 2007, 46: 1722-1731; Bartosch et al, J. Exp. Med., 2003, 197: 633-642; Grove et al, J. Virol, 2007, 81 : 3162-3169; Kapadia et al, J. Virol, 2007, 81 : 374- 383; Scarselli et al, EMBO J., 2002, 21 : 5017-5025), Occludin (Ploss et al, Nature, 2009, 457: 882-886) and Claudin-1 (CLDN1), an integral membrane protein and a component of tight-junction strands (Evans et al, Nature, 2007, 446: 801-805).

Furthermore, Niemann-Pick CI -like cholesterol absorption receptor has been identified as a new hepatitis C virus entry factor (Sainz et al, Nature Medicine, 2012, 18: 281-285).

Daclatasvir (BMS-790052; EBP 883) is a first-in-class, highly-selective oral HCV NS5A inhibitor. NS5A is an essential component for hepatitis C virus (HCV) replication complex.Daclatasvir (BMS-790052; EBP 883)has broad genotype coverage and exhibits picomolar in vitro potency against genotypes 1a (EC50 50pm) and 1b (EC50 9pm).Daclatasvir (BMS-790052; EBP 883) produces a robust decline in HCV RNA (-3.6 logs after 48 hours from a single 100 mg) dosefollowing a single dose in patients chronically infected with HCV genotype 1.

It may be many years before the symptoms of hepatitis C infection appear. However, once they do, the consequences are significant: patients may have developed fibrosis, cirrhosis or even liver cancer, with the end result being liver failure. Even if diagnosed early, there’s no guarantee of a cure.

Only around half of patients respond to the standard therapy of an interferon plus the antiviral drug ribavirin, and while two add-on antiviral therapies were approved in 2011, the treatment period is long with no guarantee of a cure, and for non-responders treatment options remain limited.

A new drug with a different mechanism is being developed by Bristol-Myers Squibb, in conjunction with Pharmasset. Daclatasvir targets non-structural protein 5A, which is an important component of the viral replication process, although its precise role in this remains unclear. The drug is active in single oral doses, and may have potential as part of a treatment regimen that avoids the use of interferon, and in patients who do not respond to standard therapy.

In an open label Phase IIa study, 10 patients with chronic hepatitis C genotype 1b infection who did not respond to standard therapy were given daclatasvir in once daily 60mg doses, plus another experimental drug, BMS-790052, which is an NSP 3 protease inhibitor, in initial twice-daily 600mg doses, later reduced to 200mg twice a day.2 Nine patients completed 24 weeks of treatment, with the 10th discontinuing after 10 weeks. In those who completed the course, HCV RNA was undetectable at week 8, and remained so until the end of the trial, with all achieving a sustained virologic response. It was also undetectable post-treatment in the patient who discontinued.

Daclatasvir has also been investigated as monotherapy in a double blind, placebo-controlled, sequential panel, multiple ascending dose study.3 Thirty patients with chronic geno-type 1 hepatitis C infection were randomised to receive a 14 day course of the drug, in once daily doses of 1, 10, 30, 60 or 100mg, 30mg twice a day, or placebo. There was no evidence of antiviral activity in the placebo group, but the mean maximum decline of 2.8 to 4.1 log IU/ml. Most experienced viral rebound on or before day 7 of treatment, which was associated with viral variants that had previously been implicated in resistance development. It was well tolerated in all dose groups.

M. Gao et al. Nature 2010, 465, 96

22/11/2013

EUROPEAN MEDICINES AGENCY ADVISES ON COMPASSIONATE USE OF DACLATASVIR

Opinion concerns use in combination with sofosbuvir in patients with chronic hepatitis C in urgent need of therapy to prevent progression of liver disease

The European Medicines Agency’s Committee for Medicinal Products for Human Use(CHMP) has given an opinion on the use of daclatasvir in combination with sofosbuvir in the treatment of chronic (long-term) hepatitis C virus (HCV) infection, in a compassionate-use programme.

Compassionate-use programmes are set up at the level of individual Member States. They are intended to give patients with a life-threatening, long-lasting or seriously disabling disease with no available treatment options access to treatments that are still under development and that have not yet received amarketing authorisation. In this specific case, Sweden has requested an opinion from the CHMP on the conditions under which early access through compassionate use could be given to daclatasvir, for the use in combination with sofosbuvir, with or without ribavirin, for a specific patient population.

The recommended compassionate use is intended for adult patients at a high risk of their liver being no longer able to function normally (decompensation) or death within 12 months if left untreated, and who have a genotype 1 infection. Further, it is recognised that the potential benefit of such combination therapy may extend to patients infected with other HCV genotypes.

Daclatasvir and sofosbuvir are both first-in-class anti-viral medicines against HCV. These medicines have been studied in combination, with or without ribavirin, in aclinical trial which included treatment-naive (previously untreated) HCV genotype-1, -2 and -3 infected patients, as well as patients with genotype 1 infection who have previously failed telaprevir or boceprevir treatment. Results from the trial indicate high efficacy, also in those who have failed treatment with these protease inhibitors. Many such patients have very advanced liver disease and are in urgent need of effective therapy in order to cease the progression of liver injury.

This is the second opinion provided by the CHMP on compassionate use of medicines in development for the treatment of hepatitis C. Overall, it isthe fourth time compassionate use has been assessed by the CHMP.

The aim of the CHMP assessment and opinion on a compassionate-use programme for new medicinal products is to ensure a common approach, whenever possible, regarding the criteria and conditions of use under Member States’ legislation. The opinion provides recommendations to the EU Member States that are considering setting up such a programme, and its implementation is not mandatory. In addition to describing which patients may benefit from the medicine, it explains how to use it and gives information on safety.

The assessment report and conditions of use of daclatasvir in combination with sofosbuvir with or without ribavirin in this setting will be published shortly on the Agency’s website.

Notes

The first compassionate-use opinion for a hepatitis C treatment was adopted by the CHMP in October 2013.
Sofosbuvir, which is part of this compassionate-use opinion, received a positive opinion from the CHMP recommending granting of a marketing authorisation at its November 2013 meeting.
Daclatasvir is developed by Bristol-Myers Squibb and sofosbuvir is developed by Gilead.

US2012004196	1-6-2012	Anti-Viral Compounds
US2009041716	2-13-2009	CRYSTALLINE FORM OF METHYL ((1S)-1-(((2S) -2-(5-(4′-(2-((2S)-1((2S)-2-((METHOXYCARBONYL)AMINO)-3-METHYLBUTANOYL)-2-PYRROLIDINYL) -1H-IMIDAZOL-5-YL)-4-BIPHENYLYL)-1H-IMIDAZOL-2-YL)-1-PYRROLIDINYL)CARBONYL) -2-METHYLPROPYL)CARBAMATE DIHYDROCHLORIDE SALT

Synthesis

Daclatasvir dihydrochloride (Daklinza)

Daclatasvir dihydrochloride is a hepatitis C virus nonstructural 5A (NS5A) replication complex inhibitor which was first approved in Japan for the treatment of genotype 1 HCV patients who fail to respond to interferon plus ribavirin. The drug has also been approved for patients with untreated, chronic HCV who are eligible for interferon. Additionally, in Europe, daclatasvir was approved for use in combination with other products across genotype 1–4 HCV. Daclatasvir was discovered and developed by Bristol–Myers Squibb and a fascinating account describing the initiation of the program from a phenotypic screen and the medicinal chemistry strategy leading to the discovery of the compound has been recently reported.80 Daclatasvir has been prepared via two different routes81,82 and the process route is outlined in Scheme 11.83 Bromination of commercial 4,40-diacetylbiphenyl (58) gave 4,40-bis(bromoacetyl)biphenyl 59 in 82% yield. Alkylation of NBoc- L-proline (60) with 59 gave diester 61 which was treated with ammonium acetate to effect cyclization of the bis-ketoester to provide bis-imidazole 62 in 63% yield for the two steps. Acidic removal of the Boc protecting groups followed by recrystallization provided bis-pyrrolidine 63 in high yield. Acylation of 63 with N-(methoxycarbonyl)- L-valine (64) using N-(3-dimethylaminopropyl)-N0-ethylcarbodiimide(EDC) and 1-hydroxybenxotriazole hydrate (HOBT) provided declatasvir. The dihydrochloride salt was prepared and treated with Cuno Zet Carbon followed by crystallization from acetone

to give daclatasvir dihydrochloride (IX) in 74% yield.

80 Belema, M.; Meanwell, N. A. J. Med. Chem. 2014, 57, 5057.

81. Bachand, C.; Belema, M.; Deon, D. H.; Good, A. C.; Goodrich, J.; James, C. A.;

Lavoie, R.; Lopez, O. D.; Martel, A.; Meanwell, N. A.; Nguyen, V. N.; Romine, J.

L.; Ruediger, E. H.; Snyder, L. B.; St. Laurent, D. R.; Yang, F.; Langley, D. R.;

Wang, G.; Hamann, L. G. WO Patent 2008021927A2, 2008.

82. Belema, M.; Nguyen, V. N.; Bachand, C.; Deon, D. H.; Goodrich, J. T.; James, C.

A.; Lavoie, R.; Lopez, O. D.; Martel, A.; Romine, J. L.; Ruediger, E. H.; Snyder, L.

B.; St Laurent, D. R.; Yang, F.; Zhu, J.; Wong, H. S.; Langley, D. R.; Adams, S. P.;

Cantor, G. H.; Chimalakonda, A.; Fura, A.; Johnson, B. M.; Knipe, J. O.; Parker, D.

D.; Santone, K. S.; Fridell, R. A.; Lemm, J. A.; O’Boyle, D. R., 2nd; Colonno, R. J.;

Gao, M.; Meanwell, N. A.; Hamann, L. G. J. Med. Chem. 2014, 57, 2013.

83. Pack, S. K.; Geng, P.; Smith, M. J.; Hamm, J. WO Patent 2009020825A1, 2009.

PATENT

US20090041716

https://www.google.co.in/patents/US20090041716?pg=PA1&dq=us+2009041716&hl=en&sa=X&ei=3ki4Uo-jEsTirAfzwoHQBQ&ved=0CD4Q6AEwAQ

EXAMPLES

A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL CH₂Cl₂and 8.7 mL (27.1 g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL CH₂Cl₂and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25° C. over 1 hour and allowed to stir at 20-25° C. for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH₂Cl₂. The product was dried under vacuum at 60° C. to yield 27.4 g (69.2 mmol, 82%) of the desired product : ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); ¹³C NMR (100 MHz, CDCl₃) 6 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm−1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C₁₆H₁₂Br₂O₂: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53 HRMS calcd for C₁₆H₁₃Br₂O₂(M+H; DCI⁺): 394.9282. Found: 394.9292. mp 224-226° C.

A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20° C. followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25° C. and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3×100 mL 13 wt % aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume=215 mL) by vacuum distillation until there was less than 0.5 vol % acetonitrile.

The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100° C. The mixture was allowed to stir at 95-100° C. for 15 hours. After reaction completion, the mixture was cooled to 70-80° C. and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol % aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature >50° C. The rich organic phase was charged with 80 mL of 5 vol % aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature >50° C. The resulting biphasic solution was split while maintaining a temperature >50° C. and the rich organic phase was washed with an additional 80 mL of 5 vol % aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature >60° C., 64 mL methanol was charged. The resulting slurry was heated to 70-75° C. and aged for 1 hour. The slurry was cooled to 20-25° C. over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70° C., resulting in 19.8 g (31.7 mmol, 63%) of the desired product: ¹H NMR (400 MHz, DMSO-d₆) δ 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); ¹³C NMR (100 MHz, DMSO-d₆) δ 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm−1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C₃₆H₄₅N₆O₄(M+H; ESI⁺): 625.3502. Found: 625.3502. mp 190-195° C. (decomposed).

To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50° C. and agitated at 50° C. for 5 hours. The resulting slurry was cooled to 20-25° C. and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanol/water (V/V) and 2×100 mL of methanol. The wet cake was dried in a vacuum oven at 50° C. overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.

Recrystallization of Compound 5

To a 250 mL reactor equipped with a nitrogen line and an overhead stirrer, 17.8 g of Compound 5 from above was charged followed by 72 mL methanol. The resulting slurry was agitated at 50° C. for 4 hours, cooled to 20-25° C. and held with agitation at 20-25° C. for 1 hour. Filtration of the slurry afforded a crystalline solid which was washed with 60 mL methanol. The resulting wet cake was dried in a vacuum oven at 50° C. for 4 days to yield 14.7 g (25.7 mmol, 82.6%) of the purified product: ¹H NMR (400 MHz, DMSO-d₆) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19 (s, 2H), 7.05 (d, J=8.4, 4H), 7.92 (d, J=8.5, 4H), 5.06 (m, 2H), 3.5-3.35 (m, 4H), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 156.6, 142.5, 139.3, 128.1, 127.5, 126.1, 116.9, 53.2, 45.8, 29.8, 24.3; IR (KBr, cm⁻¹) 3429, 2627, 1636, 1567, 1493, 1428, 1028. Anal calcd for C₂₆H₃₂N₆Cl₄: C, 54.75; H, 5.65; Cl, 24.86; Adjusted for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39. Found: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF=1.9. mp 240° C. (decomposed).

A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 16.46 g (85.9 mmol, 2.4 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20° C. for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 5. The slurry was cooled to about 0° C. and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10° C. The solution was slowly heated to 15° C. over 3 hours and held at 15° C. for 12 hours. The resulting solution was charged with 120 mL 13 wt % aqueous NaCl and heated to 50° C. for 1 hour. After cooling to 20° C., 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2×240 mL of a 0.5 N NaOH solution containing 13 wt % NaCl followed by 120 mL 13 wt % aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20° C. and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50° C., 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50° C. for 3 hours. The mixture was cooled to 20° C. over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 70° C. to give 22.15 g (27.3 mmol, 76.3%) of the desired product.

A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47 mm Cuno Zeta Carbon® 53SP filter at ˜5 psig at a flow rate of ˜58 mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50° C., 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50° C. for 2 hours, cooled to 20° C. over about 1 hour and held at 20° C. for about 20 hours. The solids were filtered, washed with 16 mL 2:1 acetone:methanol and dried in a vacuum oven at 60° C. to give 2.14 g (67.5%) of purified Compound (I):

¹H NMR (400 MHz, DMSO-d₆, 80° C.): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97-4.11 (m, 2 H), 3.74-3.90 (m, 2 H), 3.57 (s, 6 H), 2.32-2.46 (m, 2 H), 2.09-2.31 (m, 6 H), 1.91-2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);

¹³C NMR (75 MHz, DMSO-d₆): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;

IR (neat, cm⁻¹): 3385, 2971, 2873, 2669, 1731, 1650.

Anal. Calcd for C₄₀H₅₂N₈O₆Cl₂: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267° C. (decomposed).

Preparation of Seed Crystals of Compound (I)

A 250 mL round-bottom flask was charged with 6.0 g (10.5 mmol, 1 equiv) Compound 5, 3.87 g (22.1 mmol, 2.1 equiv) N-(methoxycarbonyl)-L-valine, 4.45 g (23.2 mmol, 2.2 equiv) 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.289 g (2.14 mmol, 0.2 equiv) 1-hydroxybenzotriazole, and 30 mL acetonitrile. The resulting slurry was then charged with 7.33 mL (42.03 mmol, 4 equiv) diisopropylethylamine and allowed to stir at 24-30° C. for about 18 hours. The mixture was charged with 6 mL of water and heated to 50° C. for about 5 hours. The mixture was cooled and charged with 32 mL ethyl acetate and 30 mL water. The layers were separated and the rich organic layer was washed with 30 mL of 10 wt % aqueous NaHCO₃, 30 mL water, and 20 mL of 10 wt % aqueous NaCl. The rich organic layer was then dried over MgSO₄, filtered, and concentrated down to a residue. The crude material was then purified via flash chromatography (silica gel, 0-10% methanol in dichloromethane) to provide the free base of Compound (I).

The free-base of Compound (I) (0.03 g) was dissolved in 1 mL isopropanol at 20° C. Anhydrous HCl (70 μL, dissolved in ethanol, approximately 1.25M concentration) was added and the reaction mixture was stirred. To the solution was added methyl tert-butyl ether (1 mL) and the resulting slurry was stirred vigorously at 40° C. to 50° C. for 12 hours. The crystal slurry was cooled to 20° C. and filtered. The wet cake was air-dried at 20° C. A white crystalline solid (Form N-2 of Compound (I)) was obtained.

Clip
Daclatasvir synthesis: WO2009020828A1

Procedure:

Step a: A 1 L, 3 -neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple, was charged with 20 g (83.9 mmol, 1 equiv) 1,1′-(biphenyl-4,4′-diyl)diethanone, 200 mL Dichloromethane and 8.7 mL (27.1g, 169.3 mmol, 2.02 equiv) bromine. The mixture was allowed to stir under nitrogen for about 20 hours under ambient conditions. The resulting slurry was charged with 200 mL Dichloromethane and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 20-25 ⁰C over 1 hour and allowed to stir at 20-25 ⁰C for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL Dichloromethane. The product was dried under vacuum at 60 0C to yield 27.4 g (69.2 mmol, 82%) of the desired product: 1H NMR (400 MHz, CDCl3) d 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); 13C NMR 100 MHz, CDCl3) d 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, 1691, 1599, 1199; Anal calcd for C16H12Br2O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H12Br2O2 (M + H; DCI+): 394.9282. Found: 394.9292. mp 224-226 0C.

Step b: A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Compound 2, 22.8 g (105.9 moles, 2.10 equiv) 1-(tert-butoxycarbonyl)-L-proline and 200 mL acetonitrile. The slurry was cooled to 20 ⁰C followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25 ⁰C and allowed to stir for 3 hours. The resulting clear, organic solution was washed with 3 x 100 mL 13 wt% aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume = 215 mL) by vacuum distillation until there was less than 0.5 vol% acetonitrile.

Step c: The toluene solution of Compound 3 was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100 ⁰C. The mixture was allowed to stir at 95-100 ⁰C for 15 hours. After reaction completion, the mixture was cooled to 70- 80 ⁰C and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol% aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature > 50 ⁰C. The rich organic phase was charged with 80 mL of 5 vol% aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature > 50 ⁰C. The resulting biphasic solution was split while maintaining a temperature > 50 ⁰C and the rich organic phase was washed with an additional 80 mL of 5 vol% aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature > 60 ⁰C, 64 mL methanol was charged. The resulting slurry was heated to 70-75 0C and aged for 1 hour. The slurry was cooled to 20-25 ⁰C over 1 hour and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:methanol. The product was dried under vacuum at 70 ⁰C, resulting in 19.8 g (31.7 mmol, 63%) of the desired product: 1H NMR (400 MHz, DMSO-^) d 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); 13C NMR (100 MHz, DMSO-?fe) d 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0, 46.7, 33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm-1) 2975, 2876, 1663, 1407, 1156, 1125; HRMS calcd for C36H45N6O4 (M + H; ESI+): 625.3502. Found: 625.3502. mp 190-195 0C (decomposed).

Step d: To a 250 mL reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Compound 4 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous HCl. The temperature was increased to 50 ⁰C and agitated at 50 ⁰C for 5 hours. The resulting slurry was cooled to 20-25 ⁰C and held with agitation for about 18 hours. Filtration of the slurry afforded a solid which was washed successively with 100 mL 90% methanoI/water (WV) and 2 x 100 mL of methanol. The wet cake was dried in a vacuum oven at 50 ⁰C overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.

CUT PASTE…….WO2009020825

Preparation of Compound (I)

A 1 L jacketed flask equipped with a nitrogen line and an overhead stirrer was sequentially charged with 100 mL acetonitrile, 13.69 g (89.4 mmol, 2.5 equiv) hydroxybenzotriazole hydrate, 15.07 g (86 mmol, 2.4 equiv) N-(methoxycarbonyl)- L-valine, 16.46 g (85.9 mmol, 2.4 equiv) l-(3-dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride and an additional 100 mL acetonitrile. The resulting solution was agitated at 20 ⁰C for 1 hour and charged with 20.4 g (35.8 mmol, 1 equiv) of purified Compound 7. The slurry was cooled to about 0 ⁰C and 18.47 g (142.9 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 ⁰C. The solution was slowly heated to 15 ⁰C over 3 hours and held at 15 ⁰C for 12 hours. The resulting solution was charged with 120 mL 13 wt% aqueous NaCl and heated to 50 ⁰C for 1 hour. After cooling to 20 ⁰C, 100 mL of isopropyl acetate was added. The biphasic solution was filtered through a 0.45 μm filter and the mixture split. The rich organic phase was washed with 2 x 240 mL of a 0.5 Ν NaOH solution containing 13 wt% NaCl followed by 120 mL 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation with a target volume of 400 mL. The resulting hazy solution was cooled to 20 ⁰C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 140 mL. While maintaining a temperature of 50 ⁰C, 66.4 mL (82.3 mmol, 2.3 equiv) of 1.24M HCl in ethanol was added. The mixture was then charged with 33 mg (0.04 mmol, 0.001 equiv) of seed crystals of Compound (I) (see preparation below) and the resulting slurry was stirred at 50 ⁰C for 3 hours. The mixture was cooled to 20 ⁰C over 1 hour and aged at that temperature for an additional 22 hours. The slurry was filtered and the wet cake was washed with 100 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 70 ⁰C to give 22.15 g (27.3 mmol, 76.3%) of the desired product.

Alternative Preparation of Compound (I)

A jacketed reactor equipped with a mechanical agitator, a thermocouple and a nitrogen inlet was sequentially charged with 10 L acetonitrile, 0.671 kg (4.38 moles, 2.50 equiv) 1-hydroxybenzotriazole, 0.737 kg (4.21 moles, 2.40 equiv) N- (methoxycarbonyl)-L-valine and 0.790 kg (4.12 moles, 2.35 equiv) l-(3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was agitated at 20⁰C for 1 hour, cooled to 5 ⁰C and charged with 1 kg (1.75 moles, 1.00 equiv) Compound 7. While maintaining a temperature < 10 ⁰C, 0.906 kg (7.01 moles, 4 equiv) diisopropylethylamine was added. The mixture was heated to 15-20 ⁰C over 2 hours and agitated for an additional 15 hours. After the reaction was complete, the mixture was washed once with 6.0 L 13 wt% aqueous NaCl, twice with 6.1 L (6.12 moles, 3.5 equiv) 1.0 M aqueous NaOH containing 13 wt% NaCl and once with 6.0 L 13 wt% aqueous NaCl. Water was then removed from the rich organic solution via azeotropic distillation. The mixture was cooled to 20 ⁰C, agitated for 1 hour and filtered. The rich organic solution was then solvent exchanged into EtOH via vacuum distillation to a target volume of 5 L. While maintaining a temperature of 50 ⁰C, 3.2 L (4.0 moles, 2.3 equiv) 1.25M HCl in EtOH was charged. The mixture was seeded with 1.6 g Compound (I) (see preparation below) and agitated at 50 ⁰C for 3 hours. The resulting slurry was cooled to 20 ⁰C and agitated for at least 3 hours. The product was collected by filtration and washed with 5 L 2: 1 acetone:

EtOH to give 1.29 kg (ca. 90 wt% product) of wet crude product. A reactor equipped with an overhead agitator, nitrogen inlet and thermocouple was charged with 1.11 kg of the above crude product and 7 L methanol. The resulting solution was treated with Cuno Zeta Carbon (TM) 55SP. The carbon was washed with 15 L MeOH and the combined filtrate and wash was concentrated down to 4 L via vacuum distillation. The concentrated solution was charged with 5 L acetone and seeded with 1.6 g Compound (I) (see preparation below) while maintaining a temperature of 50 ⁰C. An additional 10 L acetone was charged and the resulting slurry was stirred at 50 ⁰C for 3 hours. The slurry was cooled to 20 ⁰C and allowed to agitate at 20⁰C for 3 hours. The product was collected by filtration, washed with 5 L 2: 1 acetone: EtOH and dried under vacuum at 50-60 ⁰C to give 0.900 kg (1.11 moles, 74% adjusted) of Compound (I)-

Carbon Treatment and Recrystallization of Compound (I) A solution of Compound (I) was prepared by dissolving 3.17 g of Compound (I) from above in 22 mL methanol. The solution was passed through a 47mm Cuno Zeta Carbon 53SP filter at ~5 psig at a flow rate of~58mL/min. The carbon filter was rinsed with 32 mL of methanol. The solution was concentrated down to 16 mL by vacuum distillation. While maintaining a temperature of 40-50 ⁰C, 15.9 mL acetone and 5 mg of seed crystals of Compound (I) (see procedure below) were added. The resulting slurry was then charged with 32 mL acetone over 30 minutes. The slurry was held at 50 ⁰C for 2 hours, cooled to 20 ⁰C over about 1 hour and held at 20 ⁰C for about 20 hours. The solids were filtered, washed with 16 mL 2: 1 acetone:methanol and dried in a vacuum oven at 60 ⁰C to give 2.14 g (67.5%) of purified Compound (I):

¹H NMR (400 MHz, DMSO-έfc, 80 ⁰C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 – 4.11 (m, 2 H), 3.74 – 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 – 2.46 (m, 2 H), 2.09 – 2.31 (m, 6 H), 1.91 – 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H);

¹³C NMR (75 MHz, DMSO-έfc): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7;

IR (neat, cm^“1): 3385, 2971, 2873, 2669, 1731, 1650.

Anal. Calcd for C₄₀H₅₂N₈O₆Cl₂: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 ⁰C (decomposed).

Characteristic diffraction peak positions (degrees 2Θ + 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7

Daclatasvir faces problems in USA

The US-FDA in 2014 issued a complete response letter for NS5A inhibitor daclatasvir saying it was unable to approve the drug because the marketing application was for its use in tandem with asunaprevir, an NS3/NS4A protease inhibitor discontinued in the US by BMS for commercial reasons. Daclatasvir is already on the market in Europe-where it is sold as Daklinza-and also in Japan where it was approved alongside asunaprevir in July as the country’s first all-oral HCV therapy. However, a delay in the large US market is clearly a major setback for BMS’ ambitions in hepatitis therapy.

To make the matter worse, US FDA has rescinded breakthrough therapy designation status from Bristol-Myers Squibb for Daclatasvir for the treatment of hepatitis C virus infection in Feb 2015.

PAPER

Makonen, B.; et. al. Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir. J Med Chem 2014, 57(5), 2013–2032.

http://pubs.acs.org/doi/abs/10.1021/jm401836p

PATENT

http://www.google.com/patents/WO2008021927A2?cl=en

Example 24-23

methyl ((lS)-l-(((2S)-2-(5-(4′-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-

1 -pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate

A 50 mL flask equipped with a stir bar was sequentially charged with 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazole hydrate, 0.374 g (2.13 mmol, 2.4 equiv) N-(methoxycarbonyl)-L-valine, 0.400 g (2.09 mmol, 2.4 equiv) 1 -(3 -dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 2.5 mL acetonitrile. The resulting solution was agitated at 20 ⁰C for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) Example A-le-4. The slurry was cooled to about 0 ⁰C and 0.45 g (3.48 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 ⁰C. The solution was slowly heated to 15 ⁰C over 3 hours and held at 15 ⁰C for 16 hours. The temperature was increased to 20 ⁰C and stirred for 3.25 hours. The resulting solution was charged with 3.3 g of 13 wt% aqueous NaCl and heated to 50 ⁰C for 1 hour. After cooling to 20 ⁰C, 2.5 mL of isopropyl acetate was added. The rich organic phase was washed with 2 x 6.9 g of a 0.5 N NaOH solution containing 13 wt% NaCl followed by 3.3 g of 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting hazy solution was cooled to 20 ⁰C and filtered through a 0.45 μm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 M HCl in ethanol was added. The mixture was then stirred at 25 ⁰C for 15 hours. The resulting slurry was filtered and the wet cake was washed with 2.5 mL of 2: 1 acetone:ethanol. The solids were dried in a vacuum oven at 50 ⁰C to give 0.550 g (0.68 mmol, 77 %) of the desired product.

RecrystalHzation of Example 24-23

A solution of Example 24-23 prepared above was prepared by dissolving 0.520 g of the above product in 3.65 mL methanol. The solution was then charged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 ml of methanol. The product rich solution was concentrated down to 2.6 mL by vacuum distillation. 7.8 mL acetone was added and allowed to stir at 25 ⁰C for 15 h. The solids were filtered, washed with 2.5 mL 2: 1 acetone:ethanol and dried in a vacuum oven at 70 ⁰C to give 0.406 g (57.0%) of the desired product as white crystals: ¹H NMR (400 MHz, OMSO-d_6, 80 ⁰C): 8.02 (d, J=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, J=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, J=6.44 Hz, 2 H), 4.17 (t, J=6.95 Hz, 2 H), 3.97 – 4.11 (m, 2 H), 3.74 – 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 – 2.46 (m, 2 H), 2.09 – 2.31 (m, 6 H), 1.91 – 2.07 (m, 2 H), 0.88 (d, J=6.57 Hz, 6 H), 0.79 (d, J=6.32 Hz, 6 H); ¹³C NMR (75 MHz, DMSO- d₆): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2, 31.1, 28.9, 24.9, 19.6, 17.7; IR (neat, cm^“1): 3385, 2971, 2873, 2669, 1731, 1650. Anal. Calcd for C₄₀H₅₂N₈O₆Cl₂: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 ⁰C (decomposed). Characteristic diffraction peak positions (degrees 2Θ ± 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3, 12.4, 12.8, 13.3, 13.6, 15.5, 20.3, 21.2, 22.4, 22.7, 23.7

PAPER

Bioorganic & Medicinal Chemistry Letters (2015), 25(16), 3147-3150

http://www.sciencedirect.com/science/article/pii/S0960894X15005995

Scheme 1.

Synthetic route for the preparation of the target compounds 8a–8y. Reagents and conditions: (a) Br₂, CH₂Cl₂, rt, overnight, 86%; (b) N-Boc-l-proline, MeCN, Et₃N, rt, 2 h, 98%; (c) NH₄OAc, toulene, 130 °C, 15 h, 85%; (d) 6 N HCl, MeOH, 50 °C, 4 h, 87%; (e) HATU, N-(methoxycarbonyl)-l-valine, DIPEA, rt, 14 h, 83%; (f) RCOCl, TEA, CH₂Cl₂, rt, 3 h, 64–87%.

Dimethyl((2S,2’S)-((2S,2’S)-2,2′-(5,5′-([1,1′-biphenyl]-4,4′-diyl)bis(1H-imidazole-

5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-

diyl))dicarbamate 7……………FREE BASE

To a solution of 5 (90 mg, 0.181 mmol), N-me-thoxycarbonyl-l-valine 6 (92 mg,0.525 mmol) and DIPEA (0.18 mL, 1.03 mmol) in DMF (5 mL) was added HATU(165.5 mg, 0.434 mmol). The resulting reaction was allowed to stir at room temperature for 15 h, the reaction mixture was filtered and the residue was partitioned between EtOAc and H2O, The aqueous phase was extracted with EtOAc, and the combined organic phase was dried (MgSO4), ﬁltered, and concentrated in vacuo. The residue was puriﬁed by ﬂash chromatography (silica gel; 5% Methanol /CH2Cl2) to

afford 7 (0.11 g, 83 %)as white solid.

1H NMR (DMSO-d6, 500 MHz) δ: 11.56 (s, 2H), 7.69-7.48 (m, 8H), 7.26-7.03 (m, 4H), 5.24-5.05 (m, 2H), 4.09-4.04 (m, 2H), 3.85-3.75 (m, 4H), 3.58 (s, 6H), 2.24-1.98 (m, 10H), 0.87 (d, J = 3.6 Hz, 12H).

Anal. calcd. (%) for C40H50N8O6: C 65.02, H 6.82, N 15.17; found: C 65.20, H 6.79, N 15.31.

ESI-MS m/z: 739.5 (M+H)+.

NMR PREDICT

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

Patents

http://www.who.int/phi/implementation/ip_trade/daclatasvir_report_2014_09-02.pdf

Click on images to view

d70 Click on images to view

Click on images to view

http://www.who.int/phi/implementation/ip_trade/daclatasvir_report_2014_09-02.pdf

Click on images to view

Daclatasvir
Names

IUPAC name Methyl [(2S)-1-{(2S)-2-[4-(4’-{2-[(2S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}-3-methyl-1-oxo-2-butanyl]carbamate
Other names BMS-790052
Identifiers
CAS Registry Number	1009119-64-5
ATC code	J05AX14
ChEBI	CHEBI:82977
ChEMBL	ChEMBL2023898 ChEMBL2303621
ChemSpider	24609522
InChI [show]
Jmol-3D images	Image
SMILES [show]
Properties
Chemical formula	C₄₀H₅₀N₈O₆
Molar mass	738.89 g·mol⁻¹

CLIP 1

Australian Government, National Measurement Institute

REFERENCE MATERIAL ANALYSIS REPORT

HPLC: Instrument: Shimadzu Binary pump LC-20AB, SIL-20 A HT autosampler
Column: X-Bridge C-18, 5.0 m (4.6 mm x 150 mm)
Column oven: 40 °C
Mobile Phase: A = Milli-Q water buffered at pH 10 with NH4
+ -OAc; B = MeCN
Gradient 0 min 35% B; 0-15 min 35% B; 15-18 min 35-75% B; 18-23 min 75% B.
Flow rate: 1.0 mL/min
Detector: Shimadzu SPD-M20A PDA operating at 310 nm
Relative peak area response of main component:
Initial analysis: Mean = 99.2%, s = 0.01%

Thermogravimetric analysis: Non volatile residue < 0.2% mass fraction . The volatile
content (e.g. organic solvents and/or water) could not be determined by
thermogravimetric analysis.

Karl Fischer analysis: Moisture content 0.6% mass fraction

QNMR: Instrument: Bruker Avance-III-500
Field strength: 500 MHz Solvent: DMSO-d6 (2.50 ppm)
Internal standard: Potassium hydrogen maleate (98.8% mass fraction)
Initial analysis: Mean (0.86 ppm) = 98.2%, s = 0.2%

LC-MS: Instrument: Thermo Scientific Dionex UltiMate 3000 Degasser,
Column: ZORBAX RRHD SB-C8, 2.1 x 50 mm, 1.8 μm (Agilent, 857700-906)
Column temp: 30.0 °C
Solvent system: Mobile phase A: 10 mM ammonium formate, 0.01% (v/v) formic acid in Milli-Q® water.
Mobile phase B: 0.01% (v/v) formic acid in acetonitrile.
Gradient from 90% A to 100% B
Flow rate: 0.25 mL/min
Sample prep: 2 mg/mL in MeOH with trace of formic acid
Injection volume: 10 L
Ionisation mode: Electrospray positive ion
Capillary voltage: 4.5 kV
Capillary temp: 360ºC Desolvation gas temperature: 300 ºC
Cone gas flow rate: 10 (arbitrary unit) Desolvation gas flow rate: 70 (arbitrary unit)
The retention time of daclatasvir is reported along with the major peak in the mass spectrum. The latter is reported as a mass/charge ratio.
9.98 min: 739.39545 (M+H+) m/z

HS-GC-MS: Instrument: Agilent 6890/5973/G1888
Column: DB-624, 30 m x 0.25 mm I.D. x 1.4 μm
Program: 50 C (5 min), 7 C/min to 120 C, 15 °C/min to 220 °C (8.3 min)
Injector: 150 C Transfer line temp: 280 C
Carrier: Helium, 1.2 mL/min Split ratio: 50/1
Solvents detected: Ethyl acetate

TLC: Conditions: Kieselgel 60F254. Ethyl acetate : methanol (95/5)
Single spot observed, Rf = 0.18. Visualisation with UV at 254 nm
The TLC was performed on the liberated free base.

IR: Instrument: Bruker Alpha FT-IR
Range: 4000-400 cm-1, neat
Peaks: 1723, 1697, 1643, 1523, 1439, 1235, 1099, 1024 cm-1

1H NMR: Instrument: Bruker Avance III 500
Field strength: 500 MHz Solvent: DMSO-d6 (2.50 ppm)
Spectral data:  0.77 (6H, d, J = 6.7 Hz), 0.83 (6H, d, J = 6.7 Hz), 2.01 (2H, m), 2.07 (2H, m), 2.12-2.27 (4H, m), 2.38 (2H, m), 3.54 (6H, s), 3.84 (2H, m), 3.97 (2H, m), 4.12 (2H, t, J = 7.7 Hz), 5.18 (2H, t, J = 7.0 Hz), 7.31 (2 N-H, d, J = 8.5 Hz), 7.94 (4H, d, J = 8.4 Hz), 7.99 (4H, d, J = 8.4 Hz), 8.16 (2H, s) ppm
Ethyl acetate estimated at 0.6% mass fraction was observed in the 1H NMR

13C NMR: Instrument: Bruker Avance III 500
Field strength: 126 MHz Solvent: DMSO-d6 (39.5 ppm)
Spectral data:  17.8, 19.6, 25.0, 29.0, 31.2, 47.3, 51.6, 52.9, 58.0, 115.1, 125.9, 126.6, 127.3, 131.8, 139.2, 149.4, 157.0, 171.1 ppm

Melting point: > 250 oC

Microanalysis: Found: C = 59.0%; H = 6.5%; N = 13.7% (August 2015)
Calc: C = 59.2%; H = 6.5%; N = 13.8% (Calculated for C40H50N8O6.2HCl)

REFERENCE

Australian NMI NATA Certification Daclatasvir – FixHepC

https://fixhepc.com/images/coa/NMI-NATA-Daclatasvir-Certification.pdf

Oct 7, 2015 – Compound Name: Daclatasvir dihydrochloride … Note: The assigned stereochemistry of this sample of daclatasvir has not …. Melting point:.

CLIP 2

Full Text Article – European Journal of Pharmaceutical and Medical …

http://www.ejpmr.com/admin/download/article/MTQ4MzE3Mjk1Ny5wZGY=

Nov 28, 2016 – Daclatasvir dihydrochloride (DCLD) is a new drug …. DSC thermogram of daclatasvirdihydrochloriderealed drug melting point at 273.600C as …

CLIP 3

DCV dihydrochloride (anhydrous) is a white to yellow, non hygroscopic powder which is highly soluble in water (>700mg/mL). Solubility is higher at low pH. In aqueous buffers over the physiological pH range (pH 1.2-6.8) solubility is very low (4mg/mL to 0.004 mg/mL) due to the slow formation of the less soluble hydrated form. Water content in the drug substance is adequately controlled by in process tests. The desired anhydrous crystalline form of DCV dihydrochloride (N-2) is consistently produced and has been shown to not change on storage.

[DOC]AusPAR Daclatasvir dihydrochloride – Therapeutic Goods Administration

https://www.tga.gov.au/sites/default/…/auspar-daclatasvir–dihydrochloride-151214.do…

Dec 14, 2015 – Australian Public Assessment Report for daclatasvir dihydrochloride …. Figure 1:Chemical structure of daclatasvir dihydrochloride. …… 24 weeks is based on a selected literaturereview mostly of studies in patients with GT-1.

CLIP 4

The structure of the active substance has been confirmed by UV, IR, Raman and 1 H and 13C NMR spectroscopy, MS spectrometry, and crystal X-Ray diffraction.

Daclatasvir is a white to yellow crystalline non-hygroscopic powder. It is freely soluble in water, dimethyl sulfoxide, methanol; soluble in ethanol (95%); practically insoluble in dichloromethane, tetrahydrofuran, acetonitrile, acetone and ethyl acetate.

Daclatasvir is a chiral molecule with four stereocenters (1,1’, 2, 2;) in the S configuration. The synthetic strategy and process design such as starting material and reagent selection, process parameters, and in-process controls ensure the desired configuration at each of the four chiral centers. In addition, the established control strategy minimizes epimerization and eliminates other diastereomeric impurity formation in each step.

Polymorphism has been observed for daclatasvir hydrochloride. Although two neat crystalline dihydrochloride salts, N1 and N-2 have been identified in screening studies, it has been confirmed that the form N-2 is the thermodynamically most stable polymorph and only this form produced by the proposed synthetic process.

Manufacture, characterisation and process controls

Daclatasvir dihydrochloride is synthesised in three main steps using three commercially available well defined starting materials with acceptable specifications. The synthesis involves an alkylation and formation of the imidazole ring, a coupling reaction and the formation of the hydrochloride salt.

As mentioned above, the synthetic process has been designed to ensure the correct configuration at each of the four chiral centres is achieved. In addition, it has been demonstrated that the stereogenic centres do not epimerize during normal or stressed processing conditions.

The manufacturing process has been developed using a combination of conventional univariate studies and elements of QbD such as risk assessment.

The characterisation of the active substance and its impurities are in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities were well discussed with regards to their origin and characterised. Adequate in-process controls are applied during the synthesis. The specifications and control methods for intermediate products, starting materials and reagents have been presented.

The active substance specification includes tests for: appearance, colour, identity (IR/Raman, HPLC), assay (HPLC), impurities (HPLC), residual solvents (GC), HCl content (titration), total inorganic impurities (ICP-MS), and particle size (laser light scattering). The absence of a test for chiral purity in the active substance specification has been adequately justified based on the stereochemical control during the synthetic process and demonstration that there is no epimerization during normal or stressed processing conditions. Similarly, since the N-2 form of daclatasvir hydrochloride is the thermodynamically most stable polymorph and, is consistently produced by the synthetic process and remained unchanged during storage under long-term or accelerated conditions, this parameter is not included in the specification

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003768/WC500172849.pdf

CLIP5

SEE

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206843Orig1s000ChemR.pdf

CLIP6

Daclatasvir dihydrochloride

COA

NMR

HPLC

LCMS

References

1 Statement on a Nonproprietary Name Adopted by the USAN Council
2 Gao, Min; Nettles, Richard E.; Belema, Makonen; Snyder, Lawrence B.; Nguyen, Van N.; Fridell, Robert A.; Serrano-Wu, Michael H.; Langley, David R.; Sun, Jin-Hua; O’Boyle, Donald R., II; Lemm, Julie A.; Wang, Chunfu; Knipe, Jay O.; Chien, Caly; Colonno, Richard J.; Grasela, Dennis M.; Meanwell, Nicholas A.; Hamann, Lawrence G. (2010). “Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect”. Nature 465 (7294): 96–100. doi:10.1038/nature08960. PMID 20410884.
3 Bell, Thomas W. (2010). “Drugs for hepatitis C: unlocking a new mechanism of action”. ChemMedChem 5 (10): 1663–1665. doi:10.1002/cmdc.201000334. PMID 20821796.
4 Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Guedj, J et al. Proceedings of the National Academy of Sciences. February 19, 2013.
5 AASLD: Daclatasvir with Pegylated Interferon/Ribavirin Produces High Rates of HCV Suppression. Highleyman, L. HIVandHepatitis.com. 6 December 2011.
6Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. Lok, A et al. New England Journal of Medicine. 366(3):216-224. January 19, 2012.
7“Bristol-Myers’ Daclatasvir, Asunaprevir Cured 77%: Study”. Bloomberg. Apr 19, 2012.
8AASLD: Daclatasvir plus Asunaprevir Rapidly Suppresses HCV in Prior Null Responders. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
9High rate of response to BMS HCV drugs in harder-to-treat patients – but interferon-free prospects differ by sub-genotype. Alcorn, K. Aidsmap.com. 12 November 2012.
10AASLD 2012: Sofosbuvir + Daclatasvir Dual Regimen Cures Most Patients with HCV Genotypes 1, 2, or 3. Highleyman, L. HIVandHepatitis.com. 15 November 2012.
11Mark Sulkowski et al. (January 16, 2014). “Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection”. New England Journal of Medicine. doi:10.1056/NEJMoa1306218.
12“www.who.int” (PDF).

WO2004005264A2 *	7 Jul 2003	15 Jan 2004	Axxima Pharmaceuticals Ag	Imidazole compounds for the treatment of hepatitis c virus infections
WO2008021927A2 *	9 Aug 2007	21 Feb 2008	Squibb Bristol Myers Co	Hepatitis c virus inhibitors
WO2008021928A2 *	9 Aug 2007	21 Feb 2008	Squibb Bristol Myers Co	Hepatitis c virus inhibitors
WO2008021936A2 *	9 Aug 2007	21 Feb 2008	Squibb Bristol Myers Co	Hepatitis c virus inhibitors

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus

Googleplus

amcrasto@gmail.com

LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

//////////

Ozanimod, RPC1063

July 29, 2015 10:38 am / 1 Comment on Ozanimod, RPC1063

ChemSpider 2D Image | 5-(3-{(1S)-1-[(2-Hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl}-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile | C23H24N4O3

cas 1306760-87-1

Ozanimod, RPC1063

Receptos, Inc. INNOVATOR

IUPAC/Chemical name: (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

Benzonitrile, 5-(3-((1S)-2,3-dihydro-1-((2-hydroxyethyl)amino)-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-(1-methylethoxy)-

SMILES: N#CC1=CC(C2=NC(C3=CC=CC4=C3CC[C@@H]4NCCO)=NO2)=CC=C1OC(C)C

C23H24N4O3
Molecular Weight: 404.46
Elemental Analysis: C, 68.30; H, 5.98; N, 13.85; O, 11.87

Ozanimod is a selective sphingosine 1 phosphate receptor modulators and methods which may be useful in the treatment of S1P1-associated diseases. ozanimod, a sphingosine-1-phosphate receptor 1 (S1P1) agonist in Phase III studies as a treatment for ulcerative colitis and multiple sclerosis (MS). Although Novartis’s S1P1 modulator Gilenya has been available to treat MS since 2010,

Relapsing multiple sclerosis (RMS) is a chronic autoimmune disorder of the central nervous system (CNS), characterized by recurrent acute exacerbations (relapses) of neurological dysfunction followed by variable degrees of recovery with clinical stability between relapses (remission). The CNS destruction caused by autoreactive lymphocytes can lead to the clinical symptoms, such as numbness, difficulty walking, visual loss, lack of coordination and muscle weakness, experienced by patients. The disease invariably results in progressive and permanent accumulation of disability and impairment, affecting adults during their most productive years. RMS disproportionately affects women, with its peak onset around age 30. In the past, the treatments for RMS were generally injectable agents with significant side effects. There is a substantial market opportunity for effective oral RMS therapies with improved safety and tolerability profiles.

RPC1063 is a novel, orally administered, once daily, specific and potent modulator of the sphingosine 1-phosphate 1 receptor (S1P1R) pathway. The S1P1R is expressed on white blood cells (lymphocytes), including those responsible for the development of disease. S1P1R modulation causes selective and reversible retention, or sequestration, of circulating lymphocytes in peripheral lymphoid tissue. This sequestration is achieved by modulating cell migration patterns (known as “lymphocyte trafficking”), specifically preventing migration of autoreactive lymphocytes to areas of disease inflammation, which is a major contributor to autoimmune disease. S1P1R modulation may also involve the reduction of lymphocyte migration into the central nervous system (CNS), where certain disease processes take place. This therapeutic approach diminishes the activity of autoreactive lymphocytes that are the underlying cause of many types of autoimmune disease.

WO 2015066515

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015066515&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Scheme 3:

Reagents: (i) (a) MsCl, pyridine; (b) TsCl, pyridine; (c) NsCl, pyridine; (d) SOCl₂, DCM; (e) SOCl₂, pyridine, DCM; (f) NaN₃, PPh₃, CBr₄; (ii) (a) DIEA, DMA, HNR’R”; (b) DIEA, NaBr or Nal, DMA, HNR’R”.

Enantiomerically enriched material can be prepared in the same manner outlined in Scheme 3 using the (R)- or (5)-indanols.

Scheme 4:

Reagents: (i) Zn(CN)₂, Pd(PPh₃)₄, NMP; (ii) (i?)-2-methylpropane-2-sulfmamide, Ti(OEt)₄, toluene; (iii) NaBH₄, THF; (iv) 4M HCl in dioxane, MeOH; (v) Boc₂0, TEA, DCM; (vi) NH₂OH HCl, TEA, EtOH; (vii) HOBt, EDC, substituted benzoic acid, DMF (viii) 4M HCl in dioxane; (ix) (a) R’-LG or R”-LG, where LG represents a leaving group, K₂C0₃, CH₃CN; (b) R -C0₂H or R²-C0₂H, HOBt, EDC, DMF or R -COCl or R²-COCl, TEA, DCM; (c) R -S0₂C1 or R³-S0₂C1, TEA, DCM (d) R²-CHO, HO Ac, NaBH₄ or NaCNBH₃ or Na(OAc)₃BH, MeOH; (e) R -OCOCl or R²-OCOCl, DIEA, DMF; (f) HN(R⁵R⁵), CDI, TEA, DCM; (g) H₂NS0₂NH₂, Δ, dioxane; (h)

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2 ,3-dihydro- lH-inden- 1-yl)carbamate INT-16)

Prepared using General Procedure 9. To a flame-dried flask under N₂ was added {R)-tert- vXy\ 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 (8.3 g, 32.1 mmol) in anhydrous DMF (240 mL). The reaction mixture was cooled to 0°C and sodium hydride (3.8 g, 60% in oil, 160.6 mmol) was added portionwise. After stirring at 0°C for 2.75 h, (2-bromoethoxy)(tert-butyl)dimethylsilane (16.9 mL, 70.7 mmol) was added. The ice bath was removed after 5 mins and the reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction mixture was quenched by the slow addition of sat. NaHC0₃ at 0°C. Once gas evolution was complete the reaction was extracted with EA. The organic layers were washed with water and brine, dried over MgS0₄ and concentrated. The product was purified by chromatography (EA / hexanes) to provide 10.76 g (80%) of {R)-tert-bvXy\ 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 as a colorless oil. LCMS-ESI (m/z) calculated for C₂₃H₃₆N₂0₃Si: 416.6; found 317.2 [M-Boc]⁺ and 439.0 [M+Na]⁺, t_R = 4.04 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 7.46 (d, J = 7.6, 1H), 7.38- 7.32 (m, 1H), 7.33 – 7.18 (m, 1H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 3.70 (ddd, J = 48.8, 26.6, 22.9, 1.5 H), 3.50 – 3.37 (m, 1H), 3.17 (ddd, J = 16.7, 9.4, 2.2, 2H), 2.93 (m, 1.5 H), 2.45 (s, 1H), 2.21 (dd, J = 24.5, 14.5, 1H), 1.56 – 1.37 (bs, 4.5H), 1.22 (bs, 4.5H), 0.87 – 0.74 (m, 9H), -0.04 (dd, J = 26.6, 8.2, 6H). ¹³C NMR (101 MHz, CDC1₃) δ 155.03, 146.55, 145.54, 131.16, 130.76, [128.11, 127.03], 117.58, 109.20, 79.88, [63.93, 61.88], [61.44, 60.34], [49.73, 46.76], 30.30, 29.70, 28.44, 28.12, [25.87, 25.62], -5.43. (5)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro- 1 H-inden- 1 -yl)carbamate INT- 17 is prepared in an analogous fashion using INT-9.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate (INT-18)

Prepared using General Procedure 3. To a solution of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 (12.0 g, 28.9 mmol) in EtOH (120 mL), under an atmosphere of N₂ was added hydroxylamine-HCl (6.0 g, 86.5 mmol) and triethylamine (13.4 mL, 9.7 g, 86.5 mmol). The reaction mixture was refluxed at 80°C for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness and then diluted with DCM (500 mL). The organic layer was washed with NaHC0₃, water, and brine. The combined organic layers were dried over MgSC^ and concentrated to produce 11.8 g of {R)-tert- vXy\ 2-(tert-butyldimethylsilyloxy) ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 as a white foamy solid, which was used without purification in the next experiment. LCMS-ESI (m/z) calculated for C₂₃H₃9N₃0₄Si: 449.7; found 350.2 [M-Boc]⁺ and 472.2 [M+Na]⁺, t_R = 1.79 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.32 (t, J= 7.3 Hz, 1H), 7.21 – 7.07 (m, 2H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 4.89 (s, 2H), 3.85 – 3.50 (m, 2H), 3.31 (ddd, J = 12.2, 9.2, 2.5 Hz, 2H), 3.28 – 3.03 (m, 2H), 3.03 – 2.70 (m, 1H), 2.29 (t, J= 23.6 Hz, 1H), 1.43 (bs, 4.5H), 1.28 (bs, 4.5H), 1.16 – 1.04 (m, 1H), 0.90 – 0.71 (m, 9H), 0.08 – -0.14 (m, 6H). ¹³C NMR (101 MHz, CDC1₃) δ 170.99, [156.20, 155.62], 152.38, [144.53, 143.57], [141.82, 141.21], 129.61, 126.78, [126.59, 126.25], [125.02, 124.77], [79.91, 79.68], 64.04, 61.88, [61.57, 61.23], [46.03, 45.76], 30.76, 30.21, [28.53, 28.28], 25.95, [25.66, 25.29], 25.13, [18.28, 17.94], 3.72, -5.34. (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate INT-19 is prepared in an analogous fashion using INT- 17.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl)carbamate and (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl) (2-hydroxethyl) carbamate

Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (4.5 g, 21.9 mmol) in anhydrous DMF (100 mL) was added HOBt (5.4 g, 40.0 mmol) and EDC (5.6 g, 29.6 mmol). After 1 h, (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT- 18 (11.8 g, 26.3 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. LCMS analysis showed complete conversion to the intermediate, (R)-tert-butyl 2-(tert-butyldimethylsilyloxy) ethyl (4-(N-(3-cyano-4-isopropoxybenzoyloxy) carbamimidoyl)-2,3-dihydro-7H-inden-l-yl)carbamate INT-20. The reaction mixture was then heated to 80°C for 12 h. The reaction mixture was cooled to room temperature and diluted with EA (250 mL). NaHC0₃ (250 mL) and water (350 mL) were added until all the solids dissolved. The mixture was extracted with EA and the organic layers washed successively with water and brine. The organic layers were dried over MgS0₄ and concentrated to produce 15.3 g of a mixture of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5 -(3 -cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)- 2,3-dihydro-iH-inden-l-yl) carbamate INT-21, and the corresponding material without the TBS protecting group, {R)-tert-bvXy\ 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxy ethyl) carbamate INT-22. The mixture was a brown oil, which could used directly without further purification or purified by chromatography (EA/hexane). INT-21: LCMS-ESI (m/z) calculated for C₃₄H₄₆N₄0₅Si: 618.8; found 519.2 [M-Boc]⁺ and 641.3 [M+Na]⁺, t_R = 7.30 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 8.43 (d, J =

2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.07 (d, J= 8.1, 1H), 7.46 – 7.26 (m, 2H), 7.12 (d, J = 9.0, 1H), 5.85 (s, 0.5H), 5.37 (s, 0.5H), 4.80 (dt, J = 12.2, 6.1, 1H), 3.92 – 3.32 (m, 3.5 H), 3.17 (s, 2H), 2.95 (s, 0.5 H), 2.62 – 2.39 (m, 1H), 2.38 – 2.05 (m, 1H), 1.53 (s, 4.5H), 1.48 (d, J = 6.1, 6H), 1.33 – 1.27 (m, 4.5H), 0.94 – 0.77 (m, 9H), 0.01 (d, J = 20.9, 6H). ¹³C NMR (101 MHz, DMSO) δ 173.02, 169.00, 162.75, [156.22, 155.52], [145.18, 144.12], [143.39, 142.76], 134.16, 133.89, 128.20, [128.01, 127.85], [127.04, 126.90], 126.43, 123.31, 116.93, 115.30, 113.55, 103.96, [79.95, 79.68], 72.73, 67.61, 63.42, [61.91, 61.77], 60.99, 46.11, 31.78, [30.47, 29.87], [28.55, 28.26], 25.93, 21.75, 18.30, 0.00, -5.37. INT-22: LCMS-ESI calculated for C₂8H32N₄0₅: 504.6; found 527.2 [M+Na]⁺, t_R = 2.65 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 8.36 (d, J = 2.1, 1H), 8.27 (dd, J = 8.9, 2.2, 1H), 8.03 (d, J = 7.2, 1H), 7.35 – 7.26 (m, 2H), 7.06 (d, J = 9.0, 1H), 5.44 (s, 1H), 4.73 (dt, J= 12.2, 6.1, 1H), 3.64 (s, 2H), 3.44 (ddd, J= 17.5, 9.5,

3.2, 2H), 3.11 (dt, J = 17.4, 8.6, 3H), 2.54 – 2.38 (m, 1H), 2.04 (td, J = 17.6, 8.8, 1H), 1.50 – 1.24 (m, 15H).

(S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-23 and {S)-tert- vXy\ 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT-24 were made in an analogous fashion.

(S) IS DESIRED CONFIGURATION

……………………………………

(S)-tert-Butanesulfinamide

(S)-(−)-2-Methyl-2-propanesulfinamide 97% CAS 343338-28-3

3-CYANO-4-ISOPROPOXYBENZOIC ACID;3-cyano-4-(propan-2-yloxy)benzoic acid;5-(1-hydroxyvinyl)-2-isopropoxybenzonitrile

cas 258273-31-3

(S)-1-Amino-2,3-dihydro-1H-indene-4-carbonitrile hydrochloride

cas 1306763-57-4 HCl, 1213099-69-4 FREE BASE

4-bromo-2,3-dihydro-1H-inden-1-one

cas 15115-60-3

S CONFIGURATION

Carbamic acid, N-[(1S)-4-cyano-2,3-dihydro-1H-inden-1-yl]-, 1,1-dimethylethyl ester, cas 1306763-31-4

(S) IS DESIRED CONFIGURATION

……………….

CAS 1306763-70-1, Carbamic acid, N-[(1S)-2,3-dihydro-4-[(hydroxyamino)iminomethyl]-1H-inden-1-yl]-, 1,1-dimethylethyl ester

…………………

CAS 1306763-71-2, Carbamic acid, N-[(1S)-4-[5-[3-cyano-4-(1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl]-, 1,1-dimethylethyl ester

1306760-73-5, Benzonitrile, 5-[3-[(1S)-1-amino-2,3-dihydro-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-(1-methylethoxy)-

………………………..

1306763-63-2,

………………….

86864-60-0, (2-Bromoethoxy)dimethyl-tert-butylsilane

Synthesis

……………………………………

WO 2011060392

http://www.google.com/patents/WO2011060392A1?cl=en

(R)-N-(4-cyano-2,3-dihydro-lH-indene-l-ylidene)-2-methylpropane-^

(INT-4

[0304] To l-oxo-2,3-dihydro-/H-indene-4-carbonitrile INT-1 (42.5 g, 0.27 mol) and (R)-2- methylpropane-2-sulfmamide (36.0 g, 0.30 mol) in toluene (530 mL) was added titanium tetraethoxide (84.1 mL, 92.5 g, 0.40 mol) and the reaction mixture was heated at 60°C for 12 h under N₂. The crude (R)-N-(4-cyano-2,3-dihydro-lH-indene-l-ylidene)-2-methylpropane- 2-sulfinamide INT-4 was used directly in the next experiment. LCMS-ESI (m/z) calculated for C₁₄Hi₆N₂OS: 260.3; found 261.1 [M+H]⁺, t_R= 3.19 min.

[0305] (R)-N'((R)-4-cyano-2,3-dihydro-lH nden-l-yl)-2-n thylprop ne-2-sulfirmmide

(INT-5)

[0306] To a flask containing the crude suspension of (R)-N-(4-cyano-2,3-dihydro-iH-indene- l-ylidene)-2-methylpropane-2-sulfrnaniide INT -4 under N₂ was added THF (1.0 L) and the reaction mixture cooled to -78°C. Sodium borohydride (40.9 g, 1.08 mol) was added portion- wise over 30 mins. (The internal temperature did not rise during the addition). The reaction mixture was stirred at -78°C for 30 mins, half out of the bath for 30 mins, then warmed to 0°C over 1 h. The 0°C reaction mixture was placed in an ice bath and quenched with brine (100 mL) followed by saturated sodium potassium tartrate (420 mL) and the Ti salts precipitated. The reaction mixture was diluted with EA (1.5 L) and stirred at room temperature overnight. The organic layers were decanted and washed successively with saturated NH4CI, water, and brine. The organic layers were dried over MgS0₄ and filtered through a pad of MgS0₄. The filtrate was concentrated to produce 52.9 g of crude (R)-N-((/?)-4-cyano-2,3-dihydro-lH- inden-l-yl)-2-methylpropane-2-sulfmamide INT-5 as a brown oil, which was used directly in the next step. LCMS-ESI (m/z) calculated for C14H18 2OS: 262.3; found 263.1 [M+H]⁺, t_R = 2.99 min. 1H NMR (400 MHz, CDC1₃) δ 7.89 (d, J = 7.7, 1H), 7.56 (t, J = 6.8, 1H), 7.36 (t, J = 7.7, 1H), 4.97 (q, J = 7.5, 1H), 3.50 (d, J = 7.6, 1H), 3.22 (ddd, J = 16.9, 8.8, 3.9, 1H), 3.01 (dt, J = 22.4, 6.9, 1H), 2.70 – 2.53 (m, 1H), 2.15 – 1.95 (m, 1H), 1.33 – 1.20 (m, 9H).

[0307] (R)-l-amino-2,3-dihydro-lH-indene-l-yl)-4-carbonitrile (T^T-6)

[0308] To crude (R)-N-((R)-4-cyano-2,3-dihydro-iH-inden-l-yl)-2-methylpropane-2- sulfinamide INT-5 (52.9 g, 0.20 mol) in MeOH (200 mL) was added 4N HC1 in dioxane (152.0 mL, 0.60 mol) and the resulting yellow suspension was stirred at room temperature for 1.5 h. The crude reaction mixture was diluted with MeOH (500 mL) and filtered to remove some Ti by-products. The filtrate was concentrated and the resulting solid refluxed in acetonitrile (500 mL). The resulting white solid was collected to produce 13.0 g (31% over 3 steps) of the HC1 salt of (R)-l-amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile INT-6. LCMS-ESI (m/z) calculated for Ci₀H₁₀N₂: 158.2; found 142.0 [M-NH₂]⁺, f_R = 0.84 min. Ή NMR (400 MHz, DMSO) δ 8.61 (s, 3H), 7.96 (d, J = 7.7, 1H), 7.83 (d, J = 7.5, 1H), 7.52 (t, J = 7.7, 1H), 4.80 (s, 1H), 3.23 (ddd, J = 16.6, 8.7, 5.2, 1H), 3.05 (ddd, J = 16.6, 8.6, 6.3, 1H), 2.62 – 2.51 (m, 1H), 2.15 – 2.01 (m, 1H). ¹³C NMR (101 MHz, DMSO) δ 148.09, 141.15, 132.48, 130.32, 127.89, 117.27, 108.05, 54.36, 39.08, 29.64. The free base can be prepared by extraction with IN NaHC0₃and DCM. LCMS-ESI (m/z) calculated for Ci₀H₁₀N₂: 158.2; found 142.0 [M-NH₂]⁺, t_R = 0.83 min. 1H NMR (400 MHz, CDC1₃) δ 7.52 – 7.38 (m, 2H), 7.23 (dd, 7 = 17.4, 9.8, 1H), 4.35 (t, J = 7.6, 1H), 3.11 (ddd, 7 = 16.8, 8.7, 3.2, 1H), 2.89 (dt, J = 16.9, 8.5, 1H), 2.53 (dddd, J = 12.8, 8.1, 7.3, 3.2, 1H), 1.70 (dtd, J = 12.8, 8.8, 8.0, 1H). ¹³C NMR (101 MHz, DMSO) δ 150.16, 146.67, 130.19, 128.74, 127.38, 117.77, 107.42, 56.86, 38.86, 29.14. Chiral HPLC: (R)-l-amino-2,3-dihydro-7H-indene-l-yl)-4-carbonitrile was eluted using 5% EtOH in hexanes, plus 0.05% TEA: 95% ee, ¾ = 23.02 min. The (S)- enantiomer INT-7 was prepared in an analogous fashion using (5)-2-methylpropane-2- sulfinamide. tR for (S)-enantiomer = 20.17 min.

[0309] (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate (INT-8)

[0310] To ( ?)-l-amino-2,3-dihydro-/H-indene-l-yl)-4-carbonitrile HC1 INT-6 (11.6 g, 59.6 mmol) in DCM (100 mL) at 0°C was added TEA (12.0 mL, 131.0 mmol). To the resulting solution was added a solution of Boc anhydride (14.3 g, 65.6 mmol) in DCM (30 mL) and the reaction mixture stirred at room temperature for 1.5 h. The reaction mixture was washed with brine, and the organic layers were dried over MgS0₄ and filtered. Additional DCM was added to a total volume of 250 mL and Norit (4.5 g) was added. The product was refluxed for 15 mins and the hot mixture filtered through a pad of celite / silica. The filtrate was concentrated and recrystallized from EA (50 mL) and hexane (150 mL) to produce 12.93 g (84%) of (/?)-tert-butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 as an off-white solid. LCMS-ESI (m/z) calculated for C₁₅H₁₈N₂0₂: 258.3; found 281.1 [M+Na]⁺, t_R = 3.45 min. Elemental Analysis determined for C^H^^O^ C calculated = 69.74%; found = 69.98%. H calculated = 7.02%; found = 7.14%. N calculated = 10.84%; found = 10.89%. 1H NMR (400 MHz, CDC1₃) δ 7.64 – 7.49 (m, 2H), 7.34 (dt, / = 7.7, 3.8, 1H), 5.36 – 5.20 (m, 1H), 4.78 (d, J = 6.8, 1H), 3.20 (ddd, J = 16.9, 8.9, 3.3, 1H), 3.02 (dt, J = 25.4, 8.4, 1H), 2.82 – 2.53 (m, 1H), 1.88 (dq, J = 13.2, 8.6, 1H), 1.55 – 1.44 (m, 9H). ¹³C NMR (101 MHz, DMSO) δ 155.52, 146.68, 146.32, 130.89, 128.70, 127.63, 117.51, 107.76, 77.98, 55.09, 31.88, 29.11, 28.19. Chiral HPLC: (R)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l- ylcarbamate was eluted using 2.5% EtOH in hexanes: >99.9% ee, tR = 19.36 min. The (5)- enantiomer INT-9 was prepared in an analogous fashion using (S)-l-amino-2,3-dihydro-7H- indene-l-yl)-4-carbonitrile HC1. tR for (5)-enantiomer = 28.98 min.

General Procedure 3. Preparation oflndane Amide Oximes

[0311] To (R)- or (5)-tert-butyl 4-cyano-2,3-dihydro-7H-inden-l-ylcarbamate (1 eq) in EtOH

(0.56 M) was added hydroxylamine hydrochloride (3 eq) and TEA (3 eq) and the reaction mixture heated at 85°C for 1-2 h. The organic soluble amide oximes were isolated by removal of the solvent and partitioning between water and DCM. The water soluble amide oximes were chromatographed or used directly in the cyclization. Pure amide oximes can be obtained by recrystallization from alcoholic solvents.

[0312] (R)-tert-butyl 4-(N -hydroxy carbamimidoyl )-2, 3-dihydro-lH-inden-l -ylcarbamate

(INT-10)

[0313] Prepared using General Procedure 3. To (R)-tert-butyl 4-cyano-2,3-dihydro-iH- inden-1 -ylcarbamate INT-8 (15.0 g, 58.2 mmol) in EtOH (100 niL) was added hydroxylamine hydrochloride (12.1 g, 174.2 mmol) and TEA (17.6 mL, 174.2 mmol) and the reaction mixture heated at 85°C for 2 h. The solvents were removed and the resulting white solid was partitioned between water and DCM. The organic layers were dried over Na₂S0_4, concentrated, and recrystallized from isopropanol (50 mL) to afford 14.4 g (85%) of (R)-tert- butyl 4-(N-hydroxycarbaniimidoyl)-2,3-dihydro-iH-inden-l-ylcarbamate INT-10 as white crystalline solid. LCMS-ESI (m/z) calculated for C₁₅H₂₁N₃0₃: 291.4; found 292.1 [M+H]⁺, ¾ = 2.04 min. 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 7.38 – 7.32 (m, 1H), 7.32 – 7.12 (m, 3H), 5.68 (s, 2H), 4.97 (q, J = 8.5, 1H), 3.07 (ddd, J = 16.6, 8.7, 2.6, 1H), 2.86 (dt, J = 16.8, 8.4, 1H), 2.30 (ddd, J = 12.6, 7.6, 3.6, 1H), 1.75 (dq, J = 12.3, 9.0, 1H), 1.44 (s, 9H). General Procedure 4. Cyclization to Indane Oxadiazole Amines

[0314] A solution of the appropriate acid (1 eq), HOBt (1.3 eq), and EDC (1.3 eq) in DMF

(0.08 M in acid) was stirred at room temperature under an atmosphere of N₂. After the complete formation of the HOBt- acid complex (1-3 h), the (R)- or (5)-amide oxime (1.1 eq) was added to the mixture. After complete formation of the coupled intermediate (ca. 0.5- 2 h), the mixture was heated to 75-95°C until the cyclization was complete (8-12 h). The reaction mixture was diluted with saturated NaHC0₃ and extracted with EA. The combined organic extracts were dried, concentrated, and either purified by chromatography (EA/hexanes) or taken on directly. The oxadiazole was treated with HC1 (5N in dioxane, 5 eq) at 50-60°C for 0.5-6 h. The reaction mixture could be extracted (DCM /NaHC0₃), or the resulting HC1 salt concentrated, suspended in Et₂0, and collected. Pure indane amines can be obtained by recrystallization from alcoholic solvents or by chromatography.

( R)-tert-butyl 4-(5-( 3-cyano-4-isopropoxyphenyl)-l,2, 4-oxadiazol-3-yl )-2,3-dihydro-lH- inden-l-ylcarbamate (INT- 12)

[0315] Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (7.74 g, 37.7 mmol) in DMF (50 mL) was added HOBt (6.02 g, 44.6 mmol) and EDC (8.53 g, 44.6 mmol) at room temperature. The reaction was stirred for 2 h until complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3- dihydro-iH-inden-l-ylcarbamate INT-10 (10.0 g, 34.3 mmol) was added and the reaction mixture stirred at room temperature for 2 h until the formation of INT-11, (R)-tert-butyl 4- (N-(3-cyano-4-isopropoxybenzolyloxy) carbamimidoyl)-2,3-dihydro-iH-inden-l- ylcarbamate. The mixture was partitioned between EA and NaHC0₃ and the organic layer was collected and dried over MgS0₄. INT-11 (16.3 g, 34.0 mmol) was re-dissolved in DMF (50 mL) and the mixture was heated to 95°C for 12 hrs. The reaction was diluted with NaHC0₃ (200 mL) and extracted with EA (3 X 50 mL). The organic layer was dried over Na₂S0₄and concentrated under reduced pressure to produce 12.8 g (81%) of (R)-tert-butyl 4- (5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden- 1-ylcarbamate INT-12 as a light brown solid and used without further purification in the next step. LCMS- ESI (m/z) calculated for C₂₆H₂₈N₄0₄: 460.5; found 483.2 [M+Na]⁺, t_R = 4.25 min. Ή NMR (400 MHz, CDCI3) δ 8.43 (d, J = 2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.09 (d, J = 7.6, 1H), 7.51 (d, / = 7.5, 1H), 7.39 (t, J = 7.6, 1H), 7.12 (d, J = 9.0, 1H), 5.28 (d, J = 8.2, 1H), 4.80 (hept, J = 6.0, 1H), 3.47 (ddd, J = 17.4, 8.9, 3.5, 1H), 3.27 – 3.03 (m, 1H), 2.68 (d, J = 8.7, 1H), 1.87 (td, J = 16.7, 8.5, 1H), 1.53 – 1.43 (m, 15H). ¹³C NMR (101 MHz, CDC13) δ 173.00, 168.82, 162.70, 155.68, 145.31, 142.96, 134.05, 133.83, 128.25, 127.21, 126.79, 123.09, 116.78, 115.24, 113.52, 103.87, 79.52, 72.70, 55.72, 33.86, 31.47, 28.39, 21.70. Chiral HPLC: (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-lH-inden-l-ylcarbamate was eluted using 20% /-PrOH in hexanes: >99.9% ee, ?R = 13.33 min. The (5)-enantiomer INT-13 was prepared in an analogous fashion using (S)-tert- butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate using General Procedures 3 and 4 (tR for (Syenantiomer = 16.31 min).

( R )-5-( 3-(l -amino-2,3-dihydro-lH-inden-4-yl)-l,2, 4-oxadiazol-5-yl)-2-isopropoxy- benzonitrile h drochloride (Compound 49)

[0317] To (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-iH-inden-l-ylcarbamate(12.8 g, 27.8 mmol) in dioxane (200 mL) was added 4N HCl in dioxane (69 mL). The solution was heated to 55°C for 1 h, and product precipitated. Dioxane was removed and the resulting solid suspended in ether and collected. The material was recrystallized from MeOH (200 mL) to produce 8.11 g (81%) of (R)-5-(3-(l-amino-2,3- dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 as the HCl salt. LCMS-ESI (m/z): calcd for: C₂₁H₂₀N₄O₂: 360.4; found 383.2 [M+Na]⁺, t_R = 2.49 min. Elemental Analysis and NMR spectra determined for C₂₁H₂₁N₄0₂C1 * 0.5 H₂0; C calculated = 62.14%; found = 62.25%. H calculated = 5.46%; found = 5.30%. N calculated = 13.80%; found = 13.84%. CI calculated = 8.73%; found = 8.34%. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 3H), 8.49 (d, J = 2.3, 1H), 8.39 (dd, J = 9.0, 2.3, 1H), 8.11 (d, J = 7.6, 1H), 7.91 (d, J = 7.6, 1H), 7.55 (t, J = 8.5, 2H), 4.97 (hept, J = 6.1, 1H), 4.80 (s, 1H), 3.47 (ddd, J = 17.4, 8.7, 5.3, 1H), 3.23 (ddd, 7 = 17.4, 8.6, 6.4, 1H), 2.55 (ddd, 7 = 13.7, 8.3, 3.2, 1H), 2.22 – 1.97 (m, 1H), 1.38 (d, J = 6.0, 6H). ¹³C NMR (101 MHz, CDC1₃) δ 173.28, 167.98, 162.53, 143.69, 141.29, 134.59, 133.80, 128.93, 128.11, 127.55, 122.72, 115.87, 115.24, 114.91, 102.46, 72.54, 54.38, 31.51, 29.91, 21.47. Chiral HPLC of the free base: (R)-5-(3-(l-amino-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy benzonitrile was eluted using 15% i^‘-PrOH in hexanes plus 0.3% DEA: > 99.9% ee, t_R = 30.80 min.

(S)- 5-(3-(l-amino-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy-benzonitrile 50 was prepared in an analogous fashion from (S)-tert-b tyl 4-cyano-2,3-dihydro-lH-inden-l-ylcarbamate: >99.9% ee, t_R for (5)-enantiomer = 28.58 min.

(R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-lH-inden-l- yl)carbamate ( -16)

[0366] Prepared using General Procedure 9. To a flame-dried flask under N₂ was added (R)- tert-butyl 4-cyano-2,3-dihydro-iH-inden-l-ylcarbamate INT-8 (8.3 g, 32.1 mmol) in anhydrous DMF (240 mL). The reaction mixture was cooled to 0°C and sodium hydride (3.8 g, 60% in oil, 160.6 mmol) was added portionwise. After stirring at 0°C for 2.75 h, (2- bromoethoxy)(½rt-butyl)dimethylsilane (16.9 mL, 70.7 mmol) was added. The ice bath was removed after 5 mins and the reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction mixture was quenched by the slow addition of sat. NaHC0₃at 0°C. Once gas evolution was complete the reaction was extracted with EA. The organic layers were washed with water and brine, dried over MgS0₄ and concentrated. The product was purified by chromatography (EA / hexanes) to provide 10.76 g (80%) of (R)-teri-butyl 2-(tert- butyldimemylsilyloxy)emyl(4-cyano-2,3-dihydro-iH-inden-l-yl)carbamate INT-16 as a colorless oil. LCMS-ESI (m/z) calculated for C₂₃H₃₆N₂0₃Si: 416.6; found 317.2 [M-Boc]⁺ and 439.0 [M+Na]⁺, t_R = 4.04 min (Method 1). 1H NMR (400 MHz, CDC1₃) δ 7.46 (d, J = 7.6, 1H), 7.38- 7.32 (m, 1H), 7.33 – 7.18 (m, 1H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 3.70 (ddd, J = 48.8, 26.6, 22.9, 1.5 H), 3.50 – 3.37 (m, 1H), 3.17 (ddd, J = 16.7, 9.4, 2.2, 2H), 2.93 (m, 1.5 H), 2.45 (s, 1H), 2.21 (dd, J = 24.5, 14.5, 1H), 1.56 – 1.37 (bs, 4.5H), 1.22 (bs, 4.5H), 0.87 – 0.74 (m, 9H), -0.04 (dd, J = 26.6, 8.2, 6H).¹³C NMR (101 MHz, CDC1₃) δ 155.03, 146.55, 145.54, 131.16, 130.76, [128.11, 127.03], 117.58, 109.20, 79.88, [63.93, 61.88], [61.44, 60.34], [49.73, 46.76], 30.30, 29.70, 28.44, 28.12, [25.87, 25.62], -5.43. (5)-tert-butyl 2-(tert- butyldimemylsilyloxy)emyl(4-cyano-2,3-dihydro-lH-inden-l-yl)carbamate INT-17 is prepared in an analogous fashion using INT -9. [0367] (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N-hydroxycarbamimidoyl)-2,3- dihydro-1 H-inden-1 -yl)carbamate (INT-18)

[0368] Prepared using General Procedure 3. To a solution of (R)-iert-butyl 2-(tert- butyldimemylsilyloxy)ethyl(4-cyano-2,3-dmydro-/H-inden-l-yl)carbamate INT-16 (12.0 g, 28.9 mmol) in EtOH (120 mL), under an atmosphere of N₂ was added hydroxylamine-HCl (6.0 g, 86.5 mmol) and triemylamine (13.4 mL, 9.7 g, 86.5 mmol). The reaction mixture was refluxed at 80°C for 4 h. The reaction mixture was cooled to room temperature and concentrated to dryness and then diluted with DCM (500 mL). The organic layer was washed with NaHC0₃, water, and brine. The combined organic layers were dried over MgS0₄ and concentrated to produce 11.8 g of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy) ethyl (4-(N- hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 as a white foamy solid, which was used without purification in the next experiment. LCMS-ESI (m/z) calculated for C₂₃H₃₉N₃0₄Si: 449.7; found 350.2 [M-Boc]⁺ and 472.2 [M+Na]⁺, ¾ = 1.79 min (Method 1). 1H NMR (400 MHz, CDC13) δ 7.32 (t, / = 7.3 Hz, 1H), 7.21 – 7.07 (m, 2H), 5.69 (s, 0.5 H), 5.19 (s, 0.5 H), 4.89 (s, 2H), 3.85 – 3.50 (m, 2H), 3.31 (ddd, / = 12.2, 9.2, 2.5 Hz, 2H), 3.28 – 3.03 (m, 2H), 3.03 – 2.70 (m, 1H), 2.29 (t, J = 23.6 Hz, 1H), 1.43 (bs, 4.5H), 1.28 (bs, 4.5H), 1.16 – 1.04 (m, 1H), 0.90 – 0.71 (m, 9H), 0.08 – -0.14 (m, 6H). ¹³C NMR (101 MHz, CDC1₃) 6 170.99, [156.20, 155.62], 152.38, [144.53, 143.57], [141.82, 141.21], 129.61, 126.78, [126.59, 126.25], [125.02, 124.77], [79.91, 79.68], 64.04, 61.88, [61.57, 61.23], [46.03, 45.76], 30.76, 30.21, [28.53, 28.28], 25.95, [25.66, 25.29], 25.13, [18.28, 17.94], 3.72, -5.34. ^-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl (4-(N- hydroxycarbamimidoyl)-2,3-dihydro-lH-inden-l-yl)carbamate INT-19 is prepared in an analogous fashion using INT-17. [0369] (R)-tert-butyl 2-( tert-butyldimethylsilyloxy)ethyl( 4-( 5-( 3-cyano-4-isopropoxyphenyl)- l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl)carbamate and (R)-tert-butyl 4-(5-(3-cyano- 4-isopropoxyphenyl )-l,2, 4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-yl) (2-hydroxethyl) carbamate

[0370] Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (4.5 g, 21.9 mmol) in anhydrous DMF (100 mL) was added HOBt (5.4 g, 40.0 mmol) and EDC (5.6 g, 29.6 mmol). After 1 h, {R)-tert-buiy\ 2-(tert-butyldimethylsilyloxy)ethyl (4- (N-hydroxycarbamimidoyl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-18 (11.8 g, 26.3 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. LCMS analysis showed complete conversion to the intermediate, (R)-tert-b\xty\ 2-(tert- butyldimethylsilyloxy) ethyl (4-(N-(3-cyano-4-isopropoxybenzoyloxy) carbamimidoyl)-2,3- dihydro-7H-inden-l-yl)carbamate INT-20. The reaction mixture was then heated to 80°C for 12 h. The reaction mixture was cooled to room temperature and diluted with EA (250 mL). NaHC0₃ (250 mL) and water (350 mL) were added until all the solids dissolved. The mixture was extracted with EA and the organic layers washed successively with water and brine. The organic layers were dried over MgS0₄ and concentrated to produce 15.3 g of a mixture of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4- oxadiazol-3-yl)- 2,3-dihydro-iH-inden-l-yl) carbamate INT-21, and the corresponding material without the TBS protecting group, (R)-tert-butyl 4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT -22. The mixture was a brown oil, which could used directly without further purification or purified by chromatography (EA hexane). INT-21: LCMS-ESI (m/z) calculated for C34H46N4O5S1: 618.8; found 519.2 [M-Boc]⁺ and 641.3 [M+Na]⁺, t_R = 7.30 min (Method 1). Ή NMR (400 MHz, CDC1₃) δ 8.43 (d, J = 2.1, 1H), 8.34 (dd, J = 8.9, 2.2, 1H), 8.07 (d, J = 8.1, 1H), 7.46 – 7.26 (m, 2H), 7.12 (d, / = 9.0, 1H), 5.85 (s, 0.5H), 5.37 (s, 0.5H), 4.80 (dt, J = 12.2, 6.1, 1H), 3.92 – 3.32 (m, 3.5 H), 3.17 (s, 2H), 2.95 (s, 0.5 H), 2.62 – 2.39 (m, 1H), 2.38 – 2.05 (m, 1H), 1.53 (s, 4.5H), 1.48 (d, J = 6.1, 6H), 1.33 – 1.27 (m, 4.5H), 0.94 – 0.77 (m, 9H), 0.01 (d, J = 20.9, 6H). ¹C NMR (101 MHz, DMSO) δ 173.02, 169.00, 162.75, [156.22, 155.52], [145.18, 144.12], [143.39, 142.76], 134.16, 133.89, 128.20, [128.01, 127.85], [127.04, 126.90], 126.43, 123.31, 116.93, 115.30, 113.55, 103.96, [79.95, 79.68], 72.73, 67.61, 63.42, [61.91, 61.77], 60.99, 46.11, 31.78, [30.47, 29.87], [28.55, 28.26], 25.93, 21.75, 18.30, 0.00, -5.37. INT-22: LCMS-ESI calculated for C₂₈H₃₂N₄O_s: 504.6; found 527.2 [M+Na]⁺, t_R = 2.65 min (Method 1). Ή NMR (400 MHz, CDC1₃) δ 8.36 (d, J = 2.1, 1H), 8.27 (dd, / = 8.9, 2.2, 1H), 8.03 (d, / = 7.2, 1H), 7.35 – 7.26 (m, 2H), 7.06 (d, / = 9.0, 1H), 5.44 (s, 1H), 4.73 (dt, J = 12.2, 6.1, 1H), 3.64 (s, 2H), 3.44 (ddd, / = 17.5, 9.5, 3.2, 2H), 3.11 (dt, J = 17.4, 8.6, 3H), 2.54 – 2.38 (m, 1H), 2.04 (td, J = 17.6, 8.8, 1H), 1.50 – 1.24 (m, 15H). (5 -teri-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH-inden-l-yl)carbamate INT-23 and (S)-terf-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-iH- inden-l-yl) (2-hydroxyethyl) carbamate INT -24 were made in an analogous fashion.

[0371] (R)-5-(3-(l-(2-hydroxyethylamino)-2,3-dihydro-lH-inden-4-yl)-l,2,4-oxadi zol-^ 2-isopropoxybenzonitrile (Compound 85)

[0372] To a solution of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4- isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-7H-inden-l-yl)carbamate INT-21 and (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydro-iH- inden-l-yl) (2-hydroxethyl) carbamate INT-22 (13.9 g, 27.5 mmol) in dioxane (70 mL) at 0°C was added 4N HCl in dioxane (68.8 g, 275.4 mmol). The reaction mixture was warmed to room temperature and then heated to 50°C for 1 h. The resulting suspension was cooled to room temperature and Et₂0 (75 mL) was added. The precipitate was collected by filtration, washed with Et₂0 and dried to produce 10.5 g of an off-white solid. The HCl salt was recrystallized from MeOH (165 mL) to produce 5.98 g (56% overall yield from (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-cyano-2,3-dihydro-iH-inden-l-yl) carbamate) of (R)-5- (3-(l-(2-hydroxyethylamino)-2,3-dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2- isopropoxybenzonitrile 85 as a white solid. LCMS-ESI (m/z) calculated for C₂₃H₂₄N₄0₃: 404.5; found 405.4 [M+H]⁺, t_R = 2.44 min. Ή NMR (400 MHz, DMSO) 5 9.25 (s, 2H), 8.53 (d, J = 2.3, 1H), 8.42 (dd, J = 9.0, 2.3, 1H), 8.17 (d, J = 7.7, 1H), 7.97 (d, J = 7.6, 1H), 7.63 – 7.50 (m, 2H), 5.28 (t, J = 5.0, 1H), 4.99 (hept, J = 6.1, 1H), 4.92 (s, 1H), 3.72 (q, J = 5.2, 2H), 3.57 – 3.43 (m, 1H), 3.27 (ddd, J = 17.6, 9.1, 5.0, 1H), 3.15-2.85 (m, J = 24.2, 2H), 2.53 (dtd, J = 9.0, 5.5, 5.3, 3.6, 1H), 2.30 (ddd, J = 13.4, 8.9, 4.6, 1H), 1.39 (d, J = 6.0, 6H). ¹³C NMR (101 MHz, DMSO) 6 173.25, 167.86, 162.47, 144.56, 139.13, 134.53, 133.77, 129.30, 128.93, 127.45, 122.83, 115.79, 115.15, 114.84, 102.40, 72.46, 61.04, 56.51, 46.38, 31.53, 27.74, 21.37. Elemental analysis for C₂₃H₂₅N₄0₃C1: C calc. = 62.65%; found = 62.73%; H calc. = 5.71%; found = 5.60%; N calc. = 12.71%; found = 12.64%; CI calc. = 8.04%; found = 8.16%. Chiral HRLC of the free base: (R)-5-(3-(l-(2-hydroxyemylamino)-2,3-dihydro-iH- inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxy – benzo-nitrile was eluted using 10% i^‘-PrOH in hexanes plus 0.3% DEA: >99.9% ee, t_R = 37.72 min.

(S)-5-(3-(l-(2-hydroxyethylamino)- 2,3-dihydro-iH-inden-4-yl)-l,2,4-oxadiazol-5-yl) -2-isopropoxy benzonitrile 86 was obtained in analogous fashion from (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3- cyano-4-isopropoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)-2, 3-dihydro-iH-inden- 1 -yl)carbamate INT-23 and (S)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydro-iH-inden-l-yl) (2-hydroxyethyl) carbamate INT-24: >99.9% ee, t_R for (5)- enantiomer = 35.86 min.

(S) IS DESIRED CONFIGURATION

THE SYNTHESIS IS SUMMARISED BELOW

COSY PREDICT

1H NMR PREDICT

13C NMR PREDICT

note——-(CH3 )2CH-O-AR appears at 72 ppm

////////

New Drug Approvals blog fast approaching 8 lakh views ( 27/7/2015)

July 27, 2015 5:53 am / 1 Comment on New Drug Approvals blog fast approaching 8 lakh views ( 27/7/2015)

Flag Counter New Drug Approvals blog fast approaching 8 lakh views ( 27/7/2015)

799174 VIEWS IN 208 COUNTRIES

RIVAROXABAN 利伐沙班 ريفاروكسابان Ривароксабан SPECTRAL VISIT

July 27, 2015 4:17 am / Leave a comment

RIVAROXABAN

5-Chloro-N-{[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinophenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide

5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide

Molecular formula: C₁₉H₁₈ClN₃O₅S, MW435.9

CAS 366789-02-8

BAY 59-7939, XARELTO

Patent Expiration Date:

Feb 8, 2021(US7157456),

Dec 11, 2020(US7585860 and US7592339)
Originator and Manufacturer:Bayer
Marketer in the US: Johnson & Johnson
Sales: $1.3 billion (2013)

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer;^[3]^[4] in a number of countries it is marketed as Xarelto.^[1] In the United States, it is marketed by Janssen Pharmaceutica.^[5] It is the first available orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

In September 2008, Health Canada granted marketing authorization for rivaroxaban for the prevention of venous thromboembolism(VTE) in people who have undergone elective total hip replacement or total knee replacement surgery.^[8]

In September 2008, the European Commission granted marketing authorization of rivaroxaban for the prevention of venous thromboembolism in adults undergoing elective hip and knee replacement surgery.^[9]

On July 1, 2011, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.^[5]

On November 4, 2011, the U.S. FDA approved rivaroxaban for stroke prophylaxis in patients with non-valvular atrial fibrillation.

The drug compound having the adopted name “Rivaroxaban” has chemical name, 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5- yljmethyl)-2-thiophenecarboxamide; and has the structural formula I,

Formula I
The commercial pharmaceutical product XARELTO® tablets, contains rivaroxaban as active ingredient. Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke,

transitory ischemic attacks, and peripheral arterial occlusive diseases.

U.S. Patent No. 7, 157,456 describes Rivaroxaban and process for the preparation thereof. The process of US ‘456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)-2-hydroxy-3- { [4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1 ,3(2H)-dione, which on cyclization using Ν,Ν-carbonyl diimidazole to afford 2-({5S)-2-Oxo-3-[4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione, which on reacted with methylamine followed by reaction with 5-chlorothiophene-2-carbonyl chloride to provide Rivaroxaban.

Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. 7,585,860; 7,351,823, 7,816,355, and 8,101,609; patent application Nos. WO 2011/012321, WO 2012/156983, WO 2012/153155, WO 2013/053739, WO 2013/098833, WO 2013/156936, WO 2013/152168, WO 2013/120464, WO 2013/164833, US 2012/0283434 and US 2013/184457; and J. Med. Chem. 2005, 48, 5900-5908.

PAPER CONTAING SPECTRAL DATA

JOURNAL OF CHEMICAL RESEARCH v 35, issue 7, pg 400-4-1, 2011

An approach to the anticoagulant agent rivaroxaban via an isocyanate-oxirane cycloaddition promoted by MgI2.etherate

Chao Lia, Yingshuai Liua, Yongjun Zhangb and Xingxian Zhanga*
a College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310032, P. R. China
b Zhejiang Apeloa Medical Technology Co., Ltd, Dongyang 322118, P. R. China

A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of commercially
available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI2 etherate as the
key step, in 22% overall yield.
Keywords: (R)-epichlorohydrin, isocyanate, MgI2.etherate, rivaroxaban

* Correspondent. E-mail: mhmosslemin@yahoo.com

(Rivaroxaban) (1):1

rivaroxaban 1 (689 mg) in 88% yield, Rf = 0.30 (ethyl acetate), as a white solid,

m.p. 229.3–230.7 °C(lit.1, 230 °C).

[α]D20 = −37° (c = 0.5, DMSO) [lit.1, [α]D21 = –38°(c = 0.2985, DMSO)].

IR (KBr) (νmax /cm−1): 3343, 1724 (C=O), 1649(C=O), 1523, 1430, 808, 756

δH 3.60–3.62 (m, 2H), 3.71–3.73 (m,2H), 3.84–3.87 (dd, J = 6.5, 9.5 Hz, 1H), 3.96–3.98 (m, 2H), 4.20 (s,2H), 4.18–4.21 (m, 1H), 4.83–4.86 (m, 1H), 7.20 (d, J = 4.0 Hz, 1H),7.41 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 4.0 Hz,1H), 8.99 (t, J = 5.5 Hz, 1H).

δC 42.19, 47.43, 49.00, 63.46, 67.71,71.30, 118.35, 125.92, 128.11, 128.43, 133.24, 136.48, 137.08,138.43, 154.08, 160.79, 165.95.

LIT REF 1=S. Roehrig, A. Straub, J. Pohlmann, T. Lampe, J. Pernerstorfer, K.Schlemmer, P. Reinemer and E. Perzborn, J. Med. Chem., 2005, 48, 5900.

STRUCTURE

SIMILARITY

Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies found the risk to be low

IH NMR PREDICT

13 C NMR PREDICT

COSY NMR.

13 C NMR…..http://www.nmrdb.org/13c/index.shtml?v=v2.14.1

CLICK TO PREDICT..ALLOW SOME TIME TO LOAD ON NMRDB SITE…..CHECK JAVA AND FLASH SETTINGS

ABOVE PICTURES ARE THE ONES YOU WILL GET

· 1H NMR prediction……http://www.nmrdb.org/new_predictor/index.shtml?v=v2.12.1

· 13C NMR prediction

· COSY prediction

· HSQC/HMBC prediction

· All predictions

New patent WO-2015104605

Process for preparing rivaroxaban – comprising the reaction of a thioester compound and its salts with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one.

Wockhardt Ltd

The synthesis of (II) via intermediate (I) is described (example 7, page 15)

4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (formula III) is (I) and rivaroxaban is (II) (claim 1, page 16).

The present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof. The present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC. The present invention especially relates to a process for the preparation of Rivaroxaban from thioester of formula II, or a pharmaceutically acceptable salt thereof, wherein R is leaving group.

process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof

Formula IIA

with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,

Formula III

Formula I

EXAMPLE 7: One pot process for Rivaroxaban

The triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr. The 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture. The reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one (lOg) and triethylamine (3.8g) were added. The resulting reaction mixture further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. aqueous layer was separated and washed with methylene chloride. The organic layer was acidified to pH 6-7 with 2N hydrochloric acid and finally the organic layer was concentrated to get desired product. The product was purified and dried to yield Rivaroxaban.

Yield: 10.0 gm

Purity: 99.3 %

EXAMPLE 8: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent ethyl acetate and base potassium hydroxide were used to get the rivaroxaban.

EXAMPLE 9: One pot process for Rivaroxaban

Exemplified procedure in example 7 with the replacement of solvent acetonitile and base potassium carbonate were used, methylene chloride was added in the reaction mixture to extract the Rivaroxaban.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015104605&recNum=7&maxRec=57790&office=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription

…………..

WO 01/47919 discloses ー species from 4_ (4_ aminophenyl) -3_ morpholinone (I) Preparation of rivaroxaban approach:

…………..

US 07/149522 discloses ー kind to 5_ chlorothiophenes _2_ carbonyl chloride (IV) is a method for preparing raw rivaroxaban in:

………….

http://www.google.com/patents/CN102786516A?cl=en

Preparation 6 rivaroxaban implementation

The 12.5 g (76.9 mmol) 5- chloro-thiophene-2-carboxylic acid was suspended in 35 g of toluene was heated to 80 で, at this temperature, a solution of 11.0 g (92.5 mmol) of thionyl chloride, reaction was continued for 30 min; then warmed to the boiling point of toluene was 120 ° C, and stirring was continued under reflux until cessation of gas; cooled to room temperature, the reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride and toluene to give 5-chloro-thiophene-2-carbonyl chloride;

The 11.6 g (37.0 mmol) 4- {4 – [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3 -one hydrochloride was added 40ml of water, was added 4. 64 g (43 8 mmol.) Na2CO3 stirred and dissolved; then added 50 ml of toluene, was added dropwise at 10 ° C under the mixture, the mixture is 8. 0 g ( 44. 4 mmol) 5- chloro-thiophene-2-carbonyl chloride was dissolved in 15 ml of toluene, 20 min the addition was complete, then stirring was continued at room temperature, TLC monitoring progress of the reaction, 2 h after completion of the reaction; and the filter cake washed with water and washed with acetone to give a pale yellow solid 19. 6 g, used directly ko acid recrystallization, as a white solid 15. 2 g,

mp 227. 2 – 228. 1 ° C, [a] D21 = -38 2 ° (. c = 0. 30, DMS0), rivaroxaban yield of 94%, the total yield of 87.5% 0

1H-NMR (DMSO) 8: 3. 61 (. 2 H, t, / = 5 4 Hz), 3. 71 (2 H, t, / = 5 4 Hz.), 3.85 (IH, m ), 3.97 (2 H, t, J = 4. 5 Hz), 4. 19 (3 H, t, / = 7. 5 Hz), 4.84 (IH, m), 7. 19 (IH, d, / = 4. 2Hz), 7.40 (2 H, d, /=9.0 Hz), 7. 57 (2 H, t, /=9.0 Hz), 7. 69 (IH, d, J = 4. 19 Hz), 8. 96 (IH, t, / = 5. 7 Hz).

…………………

WO2013120465

EXAMPLE 28 (preparation of rivaroxaban)

10 g of the salt prepared according to Example 18 were suspended in 75 ml of N- methylpyrolidone, the suspension was heated at 50°C, then 14 ml of triethylamine was added and the mixture was heated at 60°C. This was followed by addition of 15.7 ml of a solution of 5-chlorothiophene-2-carboxylic acid chloride in toluene (2.46 M) and the reaction mixture was stirred and heated at 55°C for 15 minutes, then slowly cooled below 30°C, 75 ml were added and the turbid solution was filtered. The clear filtrate was stirred at 50°C, which was followed by addition of 15 ml of water and 75 ml of ethanol and stirring for 1 hour under slow cooling. The separated product was filtered off, washed with water (15 ml, 60°C), ethanol (2 x 25 ml) and dried in vacuo. 9.1 g (yield 81%) of rivaroxaban in the form of an off-white powder with the melt, point of 229.5-231°C was obtained, HPLC 99.95%, content of the ( )-isomer below 0.03%.

1H NMR (250 MHz, DMSO-D₆), δ (ppm): 3.61 (t, 2H, CH₂); 3.71 (m, 2H, CH₂); 3.85 and 4.19 (m, 2×1 H, CH₂); 3.97 (m, 2H, CH₂); 4.19 (s, 2H, CH₂); 4.84 (pent, 1H, CH); 7.18 (d, 1H); 7.40 (m, 2H); 7.56 (m, 2H); 7.68 (d, 1H); 8.95 (bt, 1H, NH).

¹³C NMR (250 MHz, DMSO-D₆), δ (ppm): 42.2; 47.4; 49.0; 63.4; 67.7; 71.3; 1 18.3; 125.9; 128.1 ; 128.4; 133.2; 136.4; 137.0; 138.4; 154.0; 160.8; 165.9.

MS (m/z): 436.0729 (M+H)⁺. ation)

The optical isomer of rivaroxaban with the (R)- configuration was obtained by a process analogous to Example 28 starting from the salt prepared according to Example 19. The yield was 76%, HPLC 99.90%, content of the (5)-isomer below 0.03%. The NMR and MS spectra were in accordance with Example 28.

……………………..

……………………

5- chloro-thiophene-2-chloride by condensation, bromide, with 4- (4-amino-phenyl) -3-morpholinone cyclization reaction rivaroxaban, the following reaction scheme 😦 References : W02005068456, US20070149522, DE10300111)

………………………

5- chloro-thiophene-2-chloride by condensation, oxidation, and 4- (4-amino-phenyl) -3-morpholinone cyclization reaction racemic rivaroxaban, since the epoxidation step is not give any stereoselectivity, the final chiral separation need to get rivaroxaban, the reaction scheme is as follows 😦 References: W0-0147919)

…………

4- (4- amino-phenyl) -3-morpholinone by condensation, cyclization, and potassium phthalimide after reaction with methyl chloroformate to give (S) -2 – hydroxy -3- (I, 3- dioxo – isoindoline-2-yl) propyl-4- (3-oxo –morpholino) phenyl carbamate, by condensation, methylamine and Ethanol action under profit rivaroxaban, the following reaction scheme (Ref: US20110034465):

……….

4- (4- amino-phenyl) -3-morpholinone (R) and – epichlorohydrin, in the DMF solvent phthalimide potassium salt was reacted with ammonia solution and then prepared to succeed amino compound, and 5-chloro-thiophene-2-chloride in pyridine catalyzed system benefit rivaroxaban, the following reaction scheme (Ref: W02009023233):

………….

4- (4- amino-phenyl) -3-morpholinone after condensation with (R) – epichlorohydrin, then the 5-chloro-thiophene-2-amide lithium chloride and tert-butyl the reaction of an alcohol potassium enrichment rivaroxaban, the following reaction scheme (Ref: US7816355):

……………….

3-chloro-1,2-propanediol by cyclization, the reaction with phthalimide, then with 4- (4-aminophenyl) -3-morpholinone reaction, CDI and hydrazine to give 4- {4- [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one under the influence, in pyridine and under the action of tetrahydrofuran and 5-chloro-thiophene-2-chloride benefit rivaroxaban, the following reaction scheme (Reference: Gutcait, A. et al Tetrahedron:.. Asymmetry 1996, 7 (6), 1641-1648 Roehrig, .. S. et al J. Med Chem 2005,48 (19), 5900-5908)..:

…………..

http://www.google.com/patents/CN102702186A?cl=zh

Compound rivaroxaban Synthesis Example 7 formula (X), [0071] Example

[0072] Method One:

[0074] The compound of formula (VIII) of (180mg, 0. 618mmol), Ni chloride (5mL) and tris ko amine (187mg,

I. 85mmol) added to the reaction flask, stirred at room temperature for 10 minutes, cooled to 0 ° C, a solution of 5-chloro-2-thiophene chloride (224mg, 1.24mm0l), stirred at room temperature overnight; after the completion of the reaction, spin dry, rinse with anhydrous alcohol ko, filtered, washed ko anhydrous alcohol three times to obtain a white solid product rivaroxaban (215mg, embodiments of the total yield of 7,8 80%).

[0075] 1H-Mffi (DMSC) JOOMHz, δ d m):…. 3 61 (t, 2H, J = 5 6Hz), 3. 71 (t, 2H, J = 5 2Hz), 3 89 ( m, 1H), 3. 97 (t, 2H, J = 4. 4Hz), 4. 20 (m, 3H), 4. 85 (m, 1H), 7. 18 (d, 1H, J = 4. 0Hz), 7. 40 (d, 2H, J = 8. 8Hz), 7. 56 (d, 2H, J = 8. 8Hz), 7. 73 (d, 1H, J = 4. 0Hz).

The method of writing is:

[0078] The compound 5_ gas – oh -I- thiophene carboxylic acid (500mg, 3. 08mmol), MsCl (702mg, 6. 1 Bmmol) and sodium bicarbonate (. 517mg, 6 16mmol) was suspended in THF (20ml) in , heated to 60 ° C with stirring 45min, a large white suspension washed out; the reaction mixture was cooled to room temperature, the compound of formula VIII was added portionwise (800mg, 2 75mmol.), stirred for 5 hours, after completion of the reaction distilled THF, was added after the residue was cooled to room temperature, water (IOOml), at room temperature embrace Cheung 30min, filtered, and the filter cake washed with cold water, dried and added to a ko-ol (5ml) was heated at reflux for I hour. After cooling, stirred for 5 hours at room temperature After filtration to give the product of formula (X) of the compound rivaroxaban (719mg, 60%)

References

“Xarelto: Summary of Product Characteristics”. Bayer Schering Pharma AG. 2008. Retrieved 2009-02-11.
Abdulsattar, Y; Bhambri, R; Nogid, A (May 2009). “Rivaroxaban (xarelto) for the prevention of thromboembolic disease: an inside look at the oral direct factor xa inhibitor.”.P & T : a peer-reviewed journal for formulary management 34 (5): 238–44.PMID 19561868.
Roehrig S, Straub A, Pohlmann J et al. (September 2005). “Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor”. Journal of Medicinal Chemistry 48 (19): 5900–8. doi:10.1021/jm050101d.PMID 16161994.
Perzborn, Elisabeth; Roehrig, Susanne; Straub, Alexander; Kubitza, Dagmar; Misselwitz, Frank (17 December 2010). “The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor”. Nature Reviews Drug Discovery 10 (1): 61–75. doi:10.1038/nrd3185.
“FDA Approves XARELTO® (rivaroxaban tablets) to Help Prevent Deep Vein Thrombosis in Patients Undergoing Knee or Hip Replacement Surgery” (Press release).Janssen Pharmaceutica. 2011-07-01. Retrieved 2011-07-01.
Gómez-Outes, A; Terleira-Fernández, AI; Calvo-Rojas, G; Suárez-Gea, ML; Vargas-Castrillón, E (2013). “Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups.”. Thrombosis 2013: 640723. doi:10.1155/2013/640723. PMC 3885278.PMID 24455237.
Brown DG, Wilkerson EC, Love WE (March 2015). “A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons”.Journal of the American Academy of Dermatology 72 (3): 524–34.doi:10.1016/j.jaad.2014.10.027. PMID 25486915.
“Bayer’s Xarelto Approved in Canada” (Press release). Bayer. 2008-09-16. Retrieved2010-01-31.
“Bayer’s Novel Anticoagulant Xarelto now also Approved in the EU” (Press release).Bayer. 2008-02-10. Retrieved 2010-01-31.
“Medication Guide–Xarelto” (PDF). http://www.fda.gov/. U.S. Food and Drug Administration. Retrieved 1 September 2014.
“Xarelto Side Effects”. http://www.webmd.com/. WebMD. Retrieved 1 September2014.
“Xarelto Side Effects Center”. http://www.rxlist.com/. RxList. Retrieved 1 September2014.
Eriksson BI, Borris LC, Dahl OE et al. (November 2006). “A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement”. Circulation 114 (22): 2374–81.doi:10.1161/CIRCULATIONAHA.106.642074. PMID 17116766.
Eriksson BI, Borris LC, Friedman RJ et al. (June 2008). “Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty”. The New England Journal of Medicine 358(26): 2765–75. doi:10.1056/NEJMoa0800374. PMID 18579811.
Kakkar AK, Brenner B, Dahl OE et al. (July 2008). “Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial”. Lancet 372 (9632): 31–9.doi:10.1016/S0140-6736(08)60880-6. PMID 18582928.
Lassen MR, Ageno W, Borris LC et al. (June 2008). “Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty”. The New England Journal of Medicine358 (26): 2776–86. doi:10.1056/NEJMoa076016. PMID 18579812.
Turpie A, Bauer K, Davidson B et al. “Comparison of rivaroxaban – an oral, direct factor Xa inhibitor – and subcutaneous enoxaparin for thromboprophylaxis after total knee replacement (RECORD4: a phase 3 study) / European Federation of National Associations of Orthopaedics and Traumatology Annual Meeting; May 29 – June 1, 2008; Nice, France, Abstract F85”. Journal of Bone & Joint Surgery, British Volume 92–B (SUPP II): 329.
Turpie AG, Lassen MR, Davidson BL et al. (May 2009). “Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial”.Lancet 373 (9676): 1673–80. doi:10.1016/S0140-6736(09)60734-0. PMID 19411100.
ClinicalTrials.gov. “Randomized, Double-Blind Study Comparing Once Daily Oral Rivaroxaban With Adjusted-Dose Oral Warfarin for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation”. Retrieved 2009-02-11.
ClinicalTrials.gov. “MAGELLAN – Multicenter, Randomized, Parallel Group Efficacy Superiority Study in Hospitalized Medically Ill Patients Comparing Rivaroxaban with Enoxaparin”. Retrieved 2009-02-11.
ClinicalTrials.gov. “Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism. The Einstein-Extension Study”. Retrieved 2009-02-11.
ClinicalTrials.gov. “Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Deep-Vein Thrombosis (DVT) Without Symptomatic Pulmonary Embolism: Einstein-DVT Evaluation”. Retrieved 2009-02-11.
ClinicalTrials.gov. “Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Pulmonary Embolism (PE) With Or Without Symptomatic Deep-Vein Thrombosis: Einstein-PE Evaluation”. Retrieved 2009-02-11.
ClinicalTrials.gov. “A Randomized, Double-Blind, Placebo-Controlled, Event-Driven Multicenter Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects With a Recent Acute Coronary Syndrome”. Retrieved 2009-02-11.
“Venous Thromboembolic Event (VTE) Prophylaxis in Medically Ill Patients (MAGELLAN)”. ClinicalTrials.gov. 11 March 2011. Retrieved 15 April 2011.
Hughes, Sue (5 April 2011). “MAGELLAN: Rivaroxaban prevents VTE in medical patients, but bleeding an issue”. theheart.org. Retrieved 15 April 2011.
“About the MAGELLAN Study”. Bayer HealthCare. Retrieved 15 April 2011.
Bauersachs, M.D., Rupert; The EINSTEIN Investigators (December 23, 2010). “Oral Rivaroxaban for Symptomatic Venous Thromboembolism”. The New England Journal of Medecine 363 (26): 2499–2510. doi:10.1056/NEJMoa1007903. PMID 21128814. Retrieved 4 April 2011.
“Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Deep-Vein Thrombosis Without Symptomatic Pulmonary Embolism: Einstein-DVT Evaluation”. clinicaltrials.gov. Retrieved 15 April 2011.
European Medicines Agency (2008). “CHP Assessment Report for Xarelto (EMEA/543519/2008)” (PDF). Retrieved 2009-06-11.
Turpie AG (January 2008). “New oral anticoagulants in atrial fibrillation”. European Heart Journal 29 (2): 155–65. doi:10.1093/eurheartj/ehm575. PMID 18096568.

WO2013120465A1 *	Feb 18, 2013	Aug 22, 2013	Zentiva, K.S.	A process for the preparation of rivaroxaban based on the use of (s)-epichlorohydrin

WO2001047919A1	Dec 11, 2000	Jul 5, 2001	Bayer Ag	Substituted oxazolidinones and their use in the field of blood coagulation
WO2004060887A1	Dec 24, 2003	Jul 22, 2004	Bayer Healthcare Ag	Method for producing 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide
WO2007116284A1	Mar 26, 2007	Oct 18, 2007	Pfizer Prod Inc	Process for preparing linezolid
WO2009023233A1	Aug 14, 2008	Feb 19, 2009	Concert Pharmaceuticals Inc	Substituted oxazolidinone derivatives
WO2010043110A1	Oct 9, 2009	Apr 22, 2010	Changzhou Multiple Dimension Institute Of Industry Technology Co., Ltd.	A preparation method of high-purity l-carnitine
WO2010082627A1	Jan 15, 2010	Jul 22, 2010	Daiso Co., Ltd.	Process for producing 2-hydroxymethylmorpholine salt
WO2010124835A1	Apr 27, 2010	Nov 4, 2010	Belte Ag	Aluminium-silicon diecasting alloy for thin-walled structural components
WO2011080341A1	Jan 3, 2011	Jul 7, 2011	Enantia, S.L.	Process for the preparation of rivaroxaban and intermediates thereof
WO2011098501A1	Feb 10, 2011	Aug 18, 2011	Sandoz Ag	Method for the preparation of rivaroxaban
WO2011102640A2	Feb 16, 2011	Aug 25, 2011	Hanmi Holdings Co., Ltd.	Method for preparing sitagliptin and amine salt intermediates used therein
WO2012159992A1 *	May 18, 2012	Nov 29, 2012	Interquim, S.A.	Process for obtaining rivaroxaban and intermediate thereof
CN102786516A *	Aug 21, 2012	Nov 21, 2012	湖南师范大学	Method for synthesizing rivaroxaban
US7157456	Dec 11, 2000	Jan 2, 2007	Bayer Healthcare Ag	Substituted oxazolidinones and their use in the field of blood coagulation
US7816355 *	Apr 28, 2009	Oct 19, 2010	Apotex Pharmachem Inc	Processes for the preparation of rivaroxaban and intermediates thereof
US20110034465		Feb 10, 2011	Apotex Pharmachem Inc.	Processes for the preparation of rivaroxaban and intermediates thereof

CN101560209A *	Apr 15, 2008	Oct 21, 2009	Shenyang, one hundred million Leo Pharmaceutical Co., Ltd.	Pyrimidine oxazolidinone compound and preparation method comprising
CN101619061A *	Aug 11, 2009	Jan 6, 2010	Shenyang Pharmaceutical University	Cyanopyridyl substituted oxazolidinone compounds
CN101821260A *	Aug 14, 2008	Sep 1, 2010	Consett Pharmaceuticals Ltd.	Substituted oxazolidinone derivatives
CN102250076A *	May 27, 2011	Nov 23, 2011	Hengdian Group homes Chemical Co., Ltd.	One kind of rivaroxaban Rivaroxaban intermediates and preparation methods
CN102250077A *	Jun 15, 2011	Nov 23, 2011	Zhejiang University	A method for intermediate and rivaroxaban Rivaroxaban for the synthesis of
CN102311400A *	Jun 29, 2010	Jan 11, 2012	Xiang really Biotechnology Co., Ltd.	Aminomethyl-3-aryl-2-oxazolidinone class method – Preparation of L-5-
CN102320988A *	Jun 3, 2011	Jan 18, 2012	Shanghai Institute of Organic Chemistry	4- (4-aminophenyl) -3-morpholinone intermediate amide, the synthesis method and uses
EP2354128A1 *	Feb 10, 2010	Aug 10, 2011	Sandoz Ag	Method for the preparation of rivaroxaban
WO2010124385A1 *	Apr 28, 2010	Nov 4, 2010	Apotex Pharmachem Inc.	Processes for the preparation of rivaroxaban and intermediates thereof

FROM THE NET

RIVAROXABAN 5-Chloro-N-{[(5S) 2-oxo-3 [4-(3-oxo-4 …

https://plus.google.com/…/posts/EeEveU8xvUd

ANTHONY MELVIN CRASTO

32 mins ago – RIVAROXABAN 5-Chloro-N-{[(5S) 2-oxo-3 [4-(3-oxo-4-morpholinophenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide (Rivaroxaban) (1):1 rivaroxaban 1 …

WO 2015104605.new patent on Rivaroxaban, Wockhardt …

https://plus.google.com/…/posts/g4TXSPBA4YV

ANTHONY MELVIN CRASTO

1 hour ago – WO 2015104605.new patent on Rivaroxaban, Wockhardt Ltd Process for preparing rivaroxaban – comprising the reaction of a thioester compound and its salts …

Rivaroxaban
Systematic (IUPAC) name


(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade names	Xarelto
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU:C US:C (Risk not ruled out)
Legal status	AU:Prescription Only (S4) CA: ℞-only UK:Prescription-only (POM) US:℞-only
Routes of administration	oral
Pharmacokinetic data
Bioavailability	80% to 100%; Cmax = 2 – 4 hours (10 mg oral)^[1]
Metabolism	CYP3A4 , CYP2J2 and CYP-independent mechanisms^[1]
Biological half-life	5 – 9 hours in healthy subjects aged 20 to 45^[1]^[2]
Excretion	2/3 metabolized in liver and 1/3 eliminated unchanged^[1]
Identifiers
CAS Registry Number	366789-02-8
ATC code	B01AX06
PubChem	CID: 6433119
IUPHAR/BPS	6388
DrugBank	DB06228
ChemSpider	8051086
UNII	9NDF7JZ4M3
ChEMBL	CHEMBL198362
Synonyms	Xarelto, BAY 59-7939
Chemical data
Formula	C₁₉H₁₈Cl N₃O₅S
Molecular mass	435.882 g/mol

Rivaroxaban, a FXa inhibitor, is the active ingredient in XARELTO Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C₁₉H₁₈ClN₃O₅S and the molecular weight is 435.89. The structural formula is:

XARELTO (rivaroxaban) Structural Formula Illustration

Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of XARELTO are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for XARELTO 10 mg tablets is Opadry® Pink and for XARELTO 15 mg tablets is Opadry® Red, both containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

////////SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html

VORICONAZOLE SPECTRAL VISIT

July 26, 2015 1:13 pm / Leave a comment

VORICONAZOLE

CAS 137234-62-9

(aR,bS)-a-(2,4-Difluorophenyl)-5-fluoro-b-methyl-a-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimideethanol

2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Manufacturers’ Codes: UK-109496

Trademarks: Vfend (Pfizer)

MF: C16H14F3N5O

MW: 349.31

Percent Composition: C 55.01%, H 4.04%, F 16.32%, N 20.05%, O 4.58%

Properties: mp 127°. [a]D25 -62° (c = 1 in methanol).

Melting point: mp 127°

Optical Rotation: [a]D25 -62° (c = 1 in methanol)

Therap-Cat: Antifungal (systemic)

1H NMR……… http://file.selleckchem.com/downloads/nmr/S144202-Voriconazole-HNMR-Selleck.pdf

1H NMR DMSO-d6, peak at 3.3 is HOD

NMR PIC FROM THE NET

m.p=134

¹H-NMR (300 MHz, DMSO-d₆) δ
(ppm): 9.04 (1H), 8.84 (1H), 8.23 (1H), 7.61 (1H), 7.28 (1H), 7.17 (1H), 6.91 (1H),

5.97 (1H),

4.80 (1H),

4.34 (1H),

3.93 (1H),

1.1 (3H)………….US8263769

13 C NMR

DMSO-d6

NMR PIC FROM THE NET

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

HMBC PREDICT

HPLC

………………….

PAPER

J. Org. Chem., 2013, 78 (22), pp 11396–11403

DOI: 10.1021/jo4019528

http://pubs.acs.org/doi/full/10.1021/jo4019528

……………………..

Org. Proc. Res. Dev., 2001, 5 (1), pp 28–36

DOI: 10.1021/op0000879

http://pubs.acs.org/doi/full/10.1021/op0000879

(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1). ……………to provide the title compound as a white solid (7.6 g, 40% mass yield or 80% of available enantiomer), mp 134 °C

¹H NMR (DMSO-d₆) δ 1.1 (d, 3H), 3.93 (q, 1H), 4.34 (d, 1H), 4.80 (d, 1H), 5.97 (bs, 1H), 6.91 (ddd, 1H), 7.17 (ddd, 1H), 7.28 (ddd, 1H), 7.61 (s, 1H), 8.23 (s, 1H), 8.84 (s, 1H), 9.04 (s, 1H) ppm.

Cited Patent	Filing date	Publication date	Applicant	Title
US6586594	26 Jul 1996	1 Jul 2003	Pfizer, Inc.	Preparation of triazoles by organometallic addition to ketones and intermediates therefor
CN1488630A	8 Oct 2002	14 Apr 2004	张文更	Method for preparing triazole antifungal agent
CN1814597A	9 Dec 2005	9 Aug 2006	北京丰德医药科技有限公司	New method for preparing voriconazole
EP0440372A1	24 Jan 1991	7 Aug 1991	Pfizer Limited	Triazole antifungal agents
GB2452049A	Title not available
WO1993007139A1	1 Oct 1992	15 Apr 1993	Pfizer Ltd	Triazole antifungal agents
WO1997006160A1	26 Jul 1996	20 Feb 1997	Michael Butters	Preparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A2	13 Dec 2005	22 Jun 2006	Reddys Lab Ltd Dr	Process for preparing voriconazole
WO2007013096A1	26 Jun 2006	1 Feb 2007	Msn Lab Ltd	Improved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole)
WO2007132354A2	29 Jan 2007	22 Nov 2007	Medichem Sa	Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof
WO2009024214A1 *	10 Jul 2008	26 Feb 2009	Axellia Pharmaceuticals Aps	Process for the production of voriconazole
WO2009084029A2	2 Dec 2008	9 Jul 2009	Venkatesh Bhingolikar	Improved process for the preparation of (2r,3s)-2-(2,4- difluqrophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol

US8575344 *	1 Feb 2011	5 Nov 2013	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates
US20130005973 *	1 Feb 2011	3 Jan 2013	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates

WO2011096697A2 *	1 Feb 2011	11 Aug 2011	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates
US8263769 *	4 Aug 2008	11 Sep 2012	Hanmi Science	Process for preparing voriconazole
US8575344	1 Feb 2011	5 Nov 2013	Dongkook Pharmaceutical Co., Ltd.	Process for preparing voriconazole by using new intermediates
US20100190983 *	4 Aug 2008	29 Jul 2010	Hanmi Pharm, Co., Ltd.	Process for preparing voriconazole

WO1997006160A1 *	26 Jul 1996	20 Feb 1997	Michael Butters	Preparation of triazoles by organometallic addition to ketones and intermediates therefor
WO2006065726A2 *	13 Dec 2005	22 Jun 2006	Reddys Lab Ltd Dr	Process for preparing voriconazole
EP0440372A1 *	24 Jan 1991	7 Aug 1991	Pfizer Limited	Triazole antifungal agents

Reference

Butters et al., “Process Development of Voriconazole: A Novel Broad-Spectrum Triazole Antifungal Agent,” Organic Process Research & Development, 2001, vol. 5, pp. 28-36.

References:

Ergosterol biosynthesis inhibitor. Prepn: S. J. Ray, K. Richardson, EP 440372; eidem, US 5278175 (1991, 1994 both to Pfizer); R. P. Dickinson et al., Bioorg. Med. Chem. Lett. 6, 2031 (1996).

Mechanism of action: H. Sanati et al.,Antimicrob. Agents Chemother. 41, 2492 (1997). In vitro antifungal spectrum: F. Marco et al., ibid. 42, 161 (1998).

HPLC determn in plasma: R. Gage, D. A. Stopher, J. Pharm. Biomed. Anal. 17, 1449 (1998).

Review of pharmacology and clinical development: P. E. Verweij et al., Curr. Opin. Anti-Infect. Invest. Drugs 1, 361-372 (1999); J. A. Sabo, S. M. Abdel-Rahman, Ann. Pharmacother. 34, 1032-1043 (2000).

Clinical pharmacokinetics: L. Purkins et al., Antimicrob. Agents Chemother. 46, 2546 (2002).

Clinical comparison with amphotericin B: T. J. Walsh et al., N. Engl. J. Med. 346, 225 (2002).

MOLFILE

COPY ONLY BLUE SECTION

START

64684.mol

ChemDraw07261512442D

26 28 0 0 0 0 0 0 0 0999 V2000

0.5118 1.1267 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.2030 0.7149 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.9179 0.3031 0.0000 H 0 0 0 0 0 0 0 0 0 0 0 0

-0.6206 1.4298 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.2030 2.1447 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

-0.6206 2.8595 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.4441 2.8595 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

-1.8559 2.1447 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.4441 1.4298 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-1.8559 0.7149 0.0000 F 0 0 0 0 0 0 0 0 0 0 0 0

0.2088 0.0000 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

-0.5062 -0.4117 0.0000 O 0 0 0 0 0 0 0 0 0 0 0 0

0.9236 0.4118 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.9236 1.2411 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

1.5928 1.7215 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.3354 2.5107 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

0.5118 2.5107 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.2545 1.7215 0.0000 N 0 0 0 0 0 0 0 0 0 0 0 0

0.6205 -0.7149 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.2088 -1.4297 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

0.6205 -2.1446 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.4440 -2.1446 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.8559 -2.8595 0.0000 F 0 0 0 0 0 0 0 0 0 0 0 0

1.8559 -1.4297 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.4440 -0.7149 0.0000 C 0 0 0 0 0 0 0 0 0 0 0 0

1.8559 0.0000 0.0000 F 0 0 0 0 0 0 0 0 0 0 0 0

1 2 1 0

2 3 1 1

2 4 1 0

2 11 1 0

4 5 1 0

4 9 2 0

5 6 2 0

6 7 1 0

7 8 2 0

8 9 1 0

9 10 1 0

11 12 1 1

11 13 1 0

11 19 1 0

13 14 1 0

14 15 1 0

14 18 1 0

15 16 2 0

16 17 1 0

17 18 2 0

19 20 1 0

19 25 2 0

20 21 2 0

21 22 1 0

22 23 1 0

22 24 2 0

24 25 1 0

25 26 1 0

M END

END

/////////

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus

Googleplus

amcrasto@gmail.com

LIONEL MY SON

POSACONAZOLE

July 25, 2015 1:34 pm / Leave a comment

……

Posaconazole 泊沙康唑 , بوساكونازول , Позаконазол
Sch–56592
4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one

Noxafil
SCH 56592

U.S. Patents 5,661,151; 5,703,079; and 6,958,337.

Therap-Cat: Antifungal.

CAS 171228-49-2

Molecular Formula: C37H42F2N8O4

Molecular Weight: 700.78

CAS Name: 2,5-Anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol

Additional Names: (3R–cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl]-2-[1(S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-1,2,4-triazol-3-one

Syn……….Dominic De Souza, “PREPARATION OF POSACONAZOLE INTERMEDIATES.” U.S. Patent US20130203994, issued August 08, 2013.

Percent Composition: C 63.41%, H 6.04%, F 5.42%, N 15.99%, O 9.13%

Melting Point

170-172 deg C

O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1365
Solubility

In water, 0.027 mg/L at 25 deg C (est)

US EPA; Estimation Program Interface (EPI) Suite. Ver.3.12. Nov 30, 2004. Available from, as of Dec 19, 2005:http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

US5661151 EXP Jul 19, 2019 PRODUCT PATENT

US 5703079 EXP Aug 26, 2014

US8410077 EXPMar 13, 2029

US9023790 EXPJul 4, 2031

US 6958337 EXP Oct 5, 2018

US 8263600 EXPApr 1, 2022

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

CN101824009A *	May 27, 2010	Sep 8, 2010	北京德众万全药物技术开发有限公司	Simple preparation method for posaconazole and piperazine intermediate thereof

Citing Patent	Filing date	Publication date	Applicant	Title
WO2015011224A1 *	Jul 24, 2014	Jan 29, 2015	Sandoz Ag	Improved process for the preparation of crystalline form iv of posaconazole

/////
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus

Googleplus

amcrasto@gmail.com

LIONEL MY SON

TOFACITINIB 的合成, トファシチニブ, Тофацитиниб, توفاسيتين يب SPECTRAL VISIT

July 24, 2015 4:36 am / Leave a comment

Tofacitinib Citrate, 的合成

托法替布, トファシチニブクエン酸塩, Тофацитиниба Цитрат

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt

CAS : 540737-29-9

ROTATION +

Tofacitinib; Tasocitinib;

477600-75-2 base ; CP-690550;

3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;

3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt

CP 690550 Tofacitinib; CP-690550; CP-690550-10; Xeljanz; Jakvinus; Tofacitinib citrate

Trademarks: Xeljanz; Jakvinus

MF: C16H20N6O

CAS : 477600-75-2 BASE ; 540737-29-9(citrate) 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile

Molecular Weight: 312.369

SMILES: C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N

Activity: Treatment of Rheumatoid Arthritis; RA Treatment, JAK Inhibitor; Protein Kinase Inhibitor; JAK3 Inhibitor; Janus Kinase 3 Inhibitor; JAK-STAT Signaling Pathway; JAK1 Kinase Inhibitor; Selective Immunosuppressants

Status: Launched 2012

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Originator: Pfizer

Pfizer Inc’s oral JAK inhibitor tofacitinib was approved on November 6, 2012 by US FDA for the treatment of rheumatoid arthritis.

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,^[1] CP-690550^[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States,Russia, Japan and many other countries, is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.

An Improved and Efficient Process for the Preparation of Tofacitinib Citrate

Yogesh S. Patil, Nilesh L. Bonde, Ankush S. Kekan, Dhananjay G. Sathe*1, and Arijit Das

Publication Date (Web): November 17, 2014 (Article)

DOI: 10.1021/op500274j

http://pubs.acs.org/doi/full/10.1021/op500274j

MS m/z 313 (M⁺ + 1);

mp 201–202 °C;

¹H NMR (CDCl₃) δ 8.34 (s, 1H), δ 7.38 (d, 1H, J = 2.4 Hz), δ 6.93 (d, 1H, J = 2.4 Hz), δ 4.97 (m, 1H), δ 3.93–4.03 (m, 4H), δ 3.66 (m, 1H), δ 3.50 (m, 4H), δ 2.91 (d, 2H, J = 15.6 Hz), δ 2.80 (t, 2H, J = 12.8 Hz), δ 2.55 (m, 1H), δ 1.99 (m, 1H), δ 1.77 (m, 1H), δ 1.13–1.18 (m, 3H).

TEAMWORK

Part of the Pfizer group responsible for Xeljanz: Front row, from left: Sally Gut Ruggeri, Chakrapani Subramanyam, Eileen Elliott Mueller, and Frank Busch. Second row, from left: Matthew Brown, Mark Flanagan, and Robert Dugger. Back row, from left: Elizabeth Kudlacz and Douglas Ball.

Credit: Pfizer

Mark Flanagan, who was on the team at Pfizer that discovered Xeljanz, (tofacitinib citrate), an oral treatment for rheumatoid arthritis, remembers testing the drug in a rat model and seeing the drug decrease the level of inflammation in the rats’ footpads. “What we look for is physical measurements of the size of the joint. In the control animals, there was quite a bit of inflammation in the joints, whereas animals treated with different doses of the drug showed a dose-dependent decrease in the size of the joint. “Tofacitinib showed robust efficacy in the first such study run. I can remember the excitement that this data generated on the team,” he says.

Tofacitinib, chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3- d]pyrimidin-4-ylamino)-B-oxo-l -piperidinepi panenitrile, is represented Formula I. Tofacitinib citrate, a janus kinase inhibitor, is approved as XELJANZ® tablets for treatment .of rheumatoid arthritis.

Various intermediates and processes for preparation of tofacitinib are disclosed in patents like US7301 023 and US8232394.

Formula I or isomers or a mixture of isomers thereof by following any method provided in the prior art, for example, by following Example 14 of U.S. Patent No. RE41,783 or by following Example 6 of U.S. Patent No. 7,301,023. Tofacitinib of Formula I or isomers of tofacitinib or a mixture of isomers thereof may be converted into a salt by following any method provided in the prior art, for example, by following Example 1 of U.S. Patent No. 6,965,027 or by following Example 1 or Example 8 of PCT Publication No. WO 2012/135338. The potential significance of JAK3 inhibition was first discovered in the laboratory of John O’Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).^[5] In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.^[5] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the “health and safety needs of the public.”^[5] The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer.^[6] In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments.^[6] A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.^[7] It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3) , which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.^[3] Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.^[4]

Preparation of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt (Tofacitinib citrate, Xeljanz, CP-690550-10)

To a round-bottomed flask fitted with a temperature probe, condenser, nitrogen source, and heating mantle, methyl-[(3R,4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (5.0 g, 20.4 mmol) was added followed by 1-butanol (15 mL), ethyl cyanoacetate (4.6 g, 40.8 mmol), and DBU (1.6 g, 10.2 mmol). The resulting amber solution was stirred at 40 °C for 20 h. Upon reaction completion, citric acid monohydrate (8.57 g, 40.8 mmol) was added followed by water (7.5 mL) and 1-butanol (39.5 mL). The mixture was heated to 81 °C and held at that temperature for 30 min. The mixture was then cooled slowly to 22 ºC and stirred for 2 h. The slurry was filtered and washed with 1-butanol (20 mL). The filter cake was dried in a vacuum oven at 80 °C to afford 9.6 g (93%) of tofacitinib citrate as an off-white solid.

1H NMR (500 MHz, d6-DMSO): δ 8.14 (s, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H), 4.96 (q, J=6.0 Hz, 1H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1H), 2.45-2.41 (m, 1H), 1.81 (m, 1H), 1.69-1.65 (m, 1H), 1.04 (d, J=6.9 Hz, 3H).

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

PAPER

3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (1) Monocitrate

http://pubs.acs.org/doi/full/10.1021/jm1004286

J. Med. Chem., 2010, 53 (24), pp 8468–8484

DOI: 10.1021/jm1004286

1monocitrate as a white crystalline solid (mp = 201 dec).

LRMS: m/z 313.2 (MH⁺).

¹H NMR (400 MHz) (D₂O) δ HOD: 0.92 (2 H, d, J = 7.2 Hz), 0.96 (1 H, d, J = 7.6 Hz), 1.66 (1 H, m), 1.80 (1 H, m), 2.37 (1 H, m), 2.58 (2 H, 1/2 ABq, J = 15.4 Hz), 2.70 (2 H, 1/2 ABq, J = 15.4 Hz), 3.23 (2 H, s), 3.25 (1 H, s), 3.33 (1 H, m), 3.46 (1 H, m), 3.81 (4 H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

Anal. Calcd for C₂₂H₂₈N₆O₈: C, 52.38; H, 5.59; N, 16.66. Found: C, 52.32; H, 5.83; N, 16.30. For additional characterization of the monocitrate salt of 1 see WO 03/048162.

NMR PREDICT

References:

Weiling Cai, James L. Colony,Heather Frost, James P. Hudspeth, Peter M. Kendall, Ashwin M. Krishnan,Teresa Makowski, Duane J. Mazur, James Phillips, David H. Brown Ripin, Sally Gut Ruggeri, Jay F. Stearns, and Timothy D. White; Investigation of Practical Routes for the Kilogram-Scale Production of cis-3-Methylamino-4-methylpiperidines; Organic Process Research & Development 2005, 9, 51−56

Ripin, D. H.B.; 3-amino-piperidine derivatives and methods of manufacture, US patent application publication, US 2004/0102627 A1

Ruggeri, Sally, Gut;Hawkins, Joel, Michael; Makowski, Teresa, Margaret; Rutherford, Jennifer, Lea; Urban,Frank,John;Pyrrolo[2,3-d]pyrimidine derivatives: their intermediates and synthesis, PCT pub. No. WO 2007/012953 A 2, US20120259115 A1, United States Patent US8232393. Patent Issue Date: July 31, 2012

Kristin E. Price, Claude Larrive´e-Aboussafy, Brett M. Lillie, Robert W. McLaughlin, Jason Mustakis, Kevin W. Hettenbach, Joel M. Hawkins, and Rajappa Vaidyanathan; Mild and Efﬁcient DBU-Catalyzed Amidation of Cyanoacetates, Organic Letters, 2009, vol.11, No.9, 2003-2006

MORE NMR PREDICT

Tofacitinib

13C NMR PREDICT

SEE…….https://newdrugapprovals.org/2015/07/24/tofacitinib-%E7%9A%84%E5%90%88%E6%88%90-spectral-visit/

COSY PREDICT सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

NMR PICTURE FROM THE NET

PAPER

Tetrahedron Letters

Volume 54, Issue 37, 11 September 2013, Pages 5096–5098

Asymmetric total synthesis of Tofacitinib

^a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
^b Laboratory of Natural Products, Department of Chemistry, University of Antofagasta, P.O. Box 170, Antofagasta, Chile

http://dx.doi.org/10.1016/j.tetlet.2013.07.042

Abstract

A novel stereoselective synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor, has been achieved starting from (5S)-5-hydroxypiperidin-2-one in 10 steps from 2 with a 9.5% overall yield. The potentiality of this synthetic route is the obtention of tert-butyl-(3S,4R)-3-hydroxy-4-methylpiperidine-1-carboxylate (6b) as a new chiral precursor involved in the synthesis of CP690,550, in a three-step reaction, without epimerizations, rather than the 5 or more steps used in described reactions to achieve this compound from analogues of 6b.

Graphical abstract

…………………. Tofacitinib synthesis: US2001053782A1

Tofacitinib synthesis: WO2002096909A1

Tofacitinib synthesis: Org Process Res Dev 2014, 18(12), 1714-1720 (also from a chinese publication, same procedure just slight changes in reagents/conditions)

References:

1. Blumenkopf, T. A.; et. al. Pyrrolo[2,3-d]pyrimidine compounds. US2001053782A1

2. Flanagan, M. E.; et. al. Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors. WO2002096909A1

3. Das, A.; et. al. An Improved and Efficient Process for the Preparation of Tofacitinib Citrate. Org Process Res Dev2014, 18(12), 1714-1720.

Synthesis of Tofacitinib Citrate

Author(s): ZHAO Fanglu, ,CHEN Guohua, ,YAO Shilun, ,ZHANG Zhenxia Journal: Chinese Journal of Pharmaceuticals, Year 2014 , Issue 3 , Page 201-204,253 Keyword: tofacitinib citrate%; anti-rheumatoid arthritis drug%; synthesis%;

http://caod.oriprobe.com/articles/41372497/Synthesis_of_Tofacitinib_Citrate.htm

PATENT https://www.google.co.in/patents/WO2003048162A1?cl=en The crystalline form of the compound of this invention 3-{4-methyl-3-[methyl- (7H-pyrrolot2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt is prepared as described below. Scheme 1

Scheme 2

Example 1 3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt Ethanol (13 liters), (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine (1.3 kg), cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 kg), and triethylamine (1.5 liters) were combined and stirred at ambient temperature. Upon reaction completion (determined by High Pressure Liquid Chromotography (HPLC) analysis, approximately 30 minutes), the solution was filtered, concentrated and azeotroped with 15 liters of methylene chloride. The reaction mixture was washed sequentially with 12 liters of 0.5 N sodium hydroxide solution, 12 liters of brine and 12 liters of water. The organic layer was concentrated and azeotroped with 3 liters of acetone (final pot temperature was 42°C). The resulting solution was cooled to 20°C to 25°C followed by addition of 10 liters of acetone. This solution was filtered and then aqueous citric acid (0.8 kg in 4 liters of water) added via in-line filter. The reaction mixture was allowed to granulate. The slurry was cooled before collecting the solids by filtration. The solids were dried to yield 1.9 kg (71 %) (3R, 4R)- 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile mono citrate. This material was then combined with 15 liters of a 1:1 ratio of ethanol/water and the slurry was agitated overnight. The solids were filtered and dried to afford 1.7 kg (63% from (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine) of the title compound as a white crystalline solid. ¹H NMR (400 MH2)(D₂0) δ HOD: 0.92 (2H, d, J = 7.2 Hz), 0.96 (1H, d, J = 7.6 Hz), 1.66 (1H, m), 1.80 (1H, m), 2.37 (1H, m), 2.58 (2H, ¹/₂ ABq, J = 15.4 Hz), 2.70 (2H, 3 ABq, J = 154 Hz), 3.23 (2H, s), 3.25 (1H, s), 3.33 (1H, m), 3.46 (1H, m), 3.81 (4H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

Patent

http://www.google.co.in/patents/EP1913000A2?cl=en Example 10 Preparation of methyl-[(3R, 4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine:

KEY INTERMEDIATE

To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt% Pd(OH)₂/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yI)-methyi- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55°C and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-30⁰C and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-90⁰C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30°C and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30°C and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50^DC for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated. Mp 158.6-159.8°C. ¹H NMR (400 MHz, CDCI₃): δ 11.38 (bs, 1H), 8.30 (s, 1H), 7.05 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 4.89-4.87 (m, 1H), 3.39 (s, 3H), 3.27 (dd, J=12.0, 9.3 Hz, 1 H), 3.04 (dd, J=12.0, 3.9 Hz, 1H), 2.94 (td, J=12.6, 3.1 Hz, 1H0, 2.84 (dt, J=12.6, 4.3 Hz, 1H), 2.51-2.48 (m, 1H), 2.12 (bs, 2H), 1.89 (ddt, J=13.7, 10.6, 4 Hz, 1 H), 1.62 (dq, J=13.7, 4Hz, 1 H), 1.07 (d, J=7.3 Hz, 3H). ¹³C NMR (400 MHz, CDCI₃): δ 157.9, 152.0, 151.0, 120.0, 103.0, 102.5, 56.3, 46.2, 42.4, 34.7, 33.4, 32.4, 14.3. KEY INT

Example 11 Preparation of 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile….TOFACITINIB BASE

To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yI)-(7H- pyrroIo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 100⁰C and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound. Example 13 Preparation of 3-{(3R, 4R)~4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile citrate salt:…………..TOFACITINIB CITRATE To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to -15.0— 5.0⁰C over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below O⁰C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below O⁰C. After stirring for 1 hour, the mixture was warmed to room temperature and 1 M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution.was displaced with acetone until a volume of 500 ml and a temperature of 55-65⁰C had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65°C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-85⁰C for a minimum of 4 hours. The mixture was cooled to 20-30⁰C and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 50⁰C with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated. ¹H NMR (500 MHz, CZ₆-DMSO): δ 8.14 (s, 1 H), 7.11 (d, J=3.6 Hz, 1 H), 6.57 (d, J=3.6 Hz, 1 H), 4.96 (q, J=6.0 Hz, 1 H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1 H), 3.32 (s, 3H), 2.80 (Ab_q, J=15.6 Hz, 2H), 2.71 (Ab_q, J=15.6 Hz, 2H), 2.52-2.50 (m, 1 H), 2.45-2.41 (m, 1 H), 1.81 (m, 1 H), 1.69-1.65 (m, 1 H), 1.04 (d, J=6.9 Hz, 3H)

PAPER

Org. Lett., 2009, 11 (9), pp 2003–2006

DOI: 10.1021/ol900435t

http://pubs.acs.org/doi/full/10.1021/ol900435t

PATENT

http://www.omicsonline.org/open-access/advances-in-the-inhibitors-of-janus-kinase-2161-0444.1000540.php?aid=29799 …………….. सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Clinical trials

Rheumatoid arthritis

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.^[8] The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) andneutropenia.^[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.^[9] In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.^[10] By April 2011, three phase III trials for RA had reported positive results.^[11] In November 2012, the U.S. FDA approved tofacitinib “to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate.”^[12]

Psoriasis

As of April 2011 a phase III trial for psoriasis is under way.^[11]

Alopecia

In June 2014, scientists at Yale successfully treated a male patient afflicted with alopecia universalis. The patient was able to grow a full head of hair, eyebrows, eyelashes, facial, armpit, genitalia and other hair. No side effects were reported in the study.^[13]

Ulcerative colitis

The OCTAVE study of Tofacitinib in Ulcerative Colitis started in 2012. It is currently enrolling patients, though the NIH trials page states that they expect the trial to close in June 2015.^[14]

Vitiligo

In a June 2015 study, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.^[15]

Development of Safe, Robust, Environmentally Responsible Processes for New Chemical Entities

– Dr. V. Rajappa, Director & Head-Process R&D, Bristol-Myers Squibb, India

A PRESENTATION

Image result for wait The presentation will load below

Image result for scroll up arrow

Scroll with mouse to view 76 pages

Herper, Matthew (2 March 2011). “Why Pfizer’s Biggest Experimental Drug Got A Name Change”. Forbes. Retrieved 3 March 2011.
Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (2009). “The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo”. Arthritis & Rheumatism 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475. edit
“Tasocitinib”. Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673. edit
Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O’Shea, J. J. (2011). “Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)”. J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241. edit
^ Jump up to:^a ^b ^c “Seeking Profit for Taxpayers in Potential of New Drug”, Jonathan Weisman, New York Times, March 18, 2013
Ken Garber (9 January 2013). “Pfizer’s first-in-class JAK inhibitor pricey for rheumatoid arthritis market”. Nature Biotechnology 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910.
Jump up^ Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. DOI 10.1038/ncb3075
“EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain”. MedPage Today. June 2009. Retrieved 9 February 2011.
Clinical trial number NCT00413699 for “Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis” at ClinicalTrials.gov
Matthew Herper. “Pfizer’s Key Drug Walks A Tightrope”. Forbes.
“Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA”. 28 Apr 2011.
“FDA approves Xeljanz for rheumatoid arthritis”. 6 Nov 2012.
“Hairless man grows full head of hair in yale arthritis drug trial”. 19 Jun 2014.
https://clinicaltrials.gov/ct2/show/NCT01465763?term=A3921094&rank=1
“This Drug Brought Pigment Back for Woman with Vitiligo”. TIME. June 27, 2015. Retrieved June 29, 2015.
Nordqvist, Christian (27 April 2013). “Pfizer’s Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe”. Medical News Today. Retrieved 2 August 2013.
“”XALEJANZ PRESCRIBING INFORMATION @ Labeling.Pfizer.com””.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Tofacitinib
Systematic (IUPAC) name

3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Clinical data
Trade names	Xeljanz, Jakvinus
AHFS/Drugs.com	entry
Licence data	US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	74%
Protein binding	40%
Metabolism	Hepatic (via CYP3A4 andCYP2C19)
Biological half-life	3 hours
Excretion	Urine
Identifiers
CAS Registry Number	477600-75-2
ATC code	L04AA29
PubChem	CID: 9926791
IUPHAR/BPS	5677
DrugBank	DB08183
ChemSpider	8102425
UNII	87LA6FU830
ChEBI	CHEBI:71200
ChEMBL	CHEMBL221959
Synonyms	CP-690550
Chemical data
Formula	C₁₆H₂₀N₆O
Molecular mass	312.369 g/mol

Special Olympics World Games 2015

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus

Googleplus

amcrasto@gmail.com

LIONEL MY SON

//////

How flow chemistry can make processes greener…………Supercritical fluids

July 23, 2015 10:49 am / 1 Comment on How flow chemistry can make processes greener…………Supercritical fluids

Safe, small scale access to supercritical fluids

The ability to safely access high temperatures and pressures in flow reactors has implications not only on the rate of chemical reactions, but also on the types of solvents one can use. Many greensolvents such as methanol and acetone have boiling points too low for certain batch applications, whereas performing reactions at high pressure in a flow reactor may allow for their safe use at elevated temperatures.

Supercritical fluids are particularly interesting, since these solvents are entirely inaccessible without high pressure conditions. The use of supercritical fluids in a flow system offers numerous advantages over batch reactors.

Reactions may be performed on a small scale, improving safety and reducing the amount of material required. Depending on the type of reactor, it may be possible to visualize the reaction to evaluate the phase behaviour. Moreover, the reaction can be analyzed and the temperature and pressure subsequently changed without stopping the reaction and cleaning the vessel, as is necessary in a simple autoclave.

Continuous methods for utilizing supercritical fluids for extraction,¹ chromatography,² and as a reaction medium³ have all been commercialized, particularly for supercritical carbon dioxide (scCO₂).⁴ Academic examples using scMeOH, scH₂O, and scCO₂ for continuous reactions such as hydrogenations, esterifications, oxidations, and Friedel–Crafts reactions have been reported.⁵

A recent example that illustrates many of the green advantages of performing supercritical fluid chemistry in flow is in the ring opening of phthalic anhydride with methanol by Verboom and co-workers (Scheme 1).⁶ They designed a microreactor with a volume of just 0.32 μL that can withstand very high pressures.

The exceptionally small channel causes a large build-up of pressure, and supercritical conditions with pressures of up to 110 bar and temperatures up to 100 °C can occur inside the reactor, giving an ‘on-chip’ phase transition. The channel size increases near the outlet, allowing the fluid to expand to atmospheric conditions.

Thus, the total volume of scCO₂ under high pressure is exceptionally small, alleviating the major hazards of operating under supercritical conditions. The reaction was thoroughly studied on this small scale, allowing the authors to determine rate constants at several different temperatures and pressures.


	Scheme 1 Small scale continuous use of supercritical fluids.

Near- and supercritical water (scH₂O) can be an interesting green solvent only obtainable at very high temperature (T_c = 374 °C) and pressure (P_c = 221 bar). It is commonly used for completeoxidation of organic waste materials to CO₂; however, it has also been shown to be an effective solvent for selective oxidations.⁷ Given the harshness of the reaction conditions, it is not surprising that side product formation is common and highly dependent on the reaction time. For fast reactions in a batch reactor, precise control of reaction time is challenging, as the vessel takes time to heat and cool. In contrast, rapid heating, cooling, and quenching can be accomplished in a continuous process, allowing for well defined reaction times.

Fine tuning of the temperature, pressure, and time is also easier in a continuous process, as these variables can be changed without stopping and starting the reaction between samples. Thus, more data points can be obtained with less material and fewer heating and cooling cycles.

The Poliakoff group used these advantageous to perform a detailed study on the oxidation of p-xylene to terephthalic acid in scH₂O, a reaction carried out on industrial scale in acetic acid (Scheme 2).⁸ By using a flow reactor, reaction times as low as 9 seconds could be used. The equivalents of oxygen could also be finely varied on a small scale through the controlled thermal decomposition of H₂O₂.

Studying this aerobic oxidation with such precision in a batch process would prove highly challenging. Under optimal conditions, excellent selectivity for the desired product could be obtained. Further research by the same group identified improved conditions for this transformation.⁹


	Scheme 2 Selective oxidation in supercritical water.

Schematic Diagram of sample Supercritical CO2 system

Table 1. Critical properties of various solvents (Reid et al., 1987)
Solvent	Molecular weight	Critical temperature	Critical pressure	Critical density
Solvent	g/mol	K	MPa (atm)	g/cm³
Carbon dioxide (CO₂)	44.01	304.1	7.38 (72.8)	0.469
Water (H₂O) (acc. IAPWS)	18.015	647.096	22.064 (217.755)	0.322
Methane (CH₄)	16.04	190.4	4.60 (45.4)	0.162
Ethane (C₂H₆)	30.07	305.3	4.87 (48.1)	0.203
Propane (C₃H₈)	44.09	369.8	4.25 (41.9)	0.217
Ethylene (C₂H₄)	28.05	282.4	5.04 (49.7)	0.215
Propylene (C₃H₆)	42.08	364.9	4.60 (45.4)	0.232
Methanol (CH₃OH)	32.04	512.6	8.09 (79.8)	0.272
Ethanol (C₂H₅OH)	46.07	513.9	6.14 (60.6)	0.276
Acetone (C₃H₆O)	58.08	508.1	4.70 (46.4)	0.278
Nitrous oxide (N₂O)	44.013	306.57	7.35 (72.5)	0.452

Table 2 shows density, diffusivity and viscosity for typical liquids, gases and supercritical fluids.

Comparison of Gases, Supercritical Fluids and Liquids
	Density (kg/m³)	Viscosity (µPa∙s)	Diffusivity (mm²/s)
Gases	1	10	1–10
Supercritical Fluids	100–1000	50–100	0.01–0.1
Liquids	1000	500–1000	0.001

F. Sahena, I. S. M. Zaidul, S. Jinap, A. A. Karim, K. A. Abbas, N. A. N. Norulaini and A. K. M. Omar, J. Food Eng., 2009, 95, 240–253
D. J. Dixon and K. P. Jhonston, in Encyclopedia of Separation Technology, ed. D. M. Ruthven, John Wiley, 1997, 1544–1569
P. Licence, J. Ke, M. Sokolova, S. K. Ross and M. Poliakoff, Green Chem., 2003, 5, 99–104
X. Han and M. Poliakoff, Chem. Soc. Rev., 2012, 41, 1428–1436
S. Marre, Y. Roig and C. Aymonier, J. Supercrit. Fluids, 2012, 66, 251–264
F. Benito-Lopez, R. M. Tiggelaar, K. Salbut, J. Huskens, R. J. M. Egberink, D. N. Reinhoudt, H. J. G. E. Gardeniers and W. Verboom, Lab Chip, 2007, 7, 1345–1351
R. Holliday, B. Y. M. Jong and J. W. Kolis, J. Supercrit. Fluids, 1998, 12, 255–260
P. A. Hamley, T. Ilkenhans, J. M. Webster, E. García-Verdugo, E. Vernardou, M. J. Clarke, R. Auerbach, W. B. Thomas, K. Whiston and M. Poliakoff, Green Chem., 2002, 4, 235–238
E. Pérez, J. Fraga-Dubreuil, E. García-Verdugo, P. A. Hamley, M. L. Thomas, C. Yan, W. B. Thomas, D. Housley, W. Partenheimer and M. Poliakoff, Green Chem., 2011, 13, 2397–2407

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus

Googleplus

amcrasto@gmail.com

LIONEL MY SON

Odalasvir

July 23, 2015 8:14 am / Leave a comment

ACH-3102 , Odalasvir

Odalasvir
ACH-0143102; ACH-3102
CAS : 1415119-52-6
Dimethyl N, N ‘- (tricyclo [8.2.2.24,7] hexadeca-1 (12), 4,6, 10,13,15-hexaene-5,11-diylbis {1H-benzimidazole-5,2-diyl [(2S, 3aS, 7aS) -octahydro-1H-indole-2,1-diyl] [(1S) -1 – (1-methylethyl) -2-oxoethylene]}) biscarbamate

Carbamic acid, N,N’-(tricyclo(8.2.2.24,7)hexadeca-4,6,10,12,13,15-hexaene-5,11-diylbis(1H-benzimidazole-6,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl)))bis-, C,C’-dimethyl ester

Dimethyl N,N’-(1,4(1,4)-dibenzenacyclohexaphane-12,42-diylbis(1hbenzimidazole-5,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((2S)-3-methyl-1-oxobutan-1,2-diyl)))biscarbamate

2D chemical structure of 1415119-52-6
Mechanism of Action: HCV NS5A Protein inhibitor
Indication: Hepatitis C
Developer: Achillion Pharmaceuticals, Inc.

Achillion Pharmaceuticals, Inc

C60-H72-N8-O6

1001.2788

Odalasvir^[1] is an investigational new drug in development for the treatment hepatitis C.

Achillion Pharmaceuticals Inc’s Odalasvir (ACH-3102) is an investigational new drug in development for the treatment hepatitis C. Achillion’s ongoing study tests its NS5A inhibitor, ACH-3102, with Sovaldi in previously untreated genotype 1 hepatitis C patients over six and eight weeks of therapy. The main goal is to achieve a cure, or sustained virological response, 12 weeks after the completion of therapy.

Odalasvir is a hepatitis C virus (HCV NS5A) inhibitor in phase II clinical studies at Achillion for the treatment of hepatitis C.

In 2012, fast track designation was assigned to the compound in the U.S. for the treatment of chronic hepatitis C.

WILL BE UPDATED………….

WO 2012166716

http://www.google.com/patents/US20120302538

Figure US20120302538A1-20121129-C00189

General Considerations

All nonaqueous reactions were performed under an atmosphere of dry argon gas using oven-dried glassware and anhydrous solvents. The progress of reactions and the purity of target compounds were determined using one of the following two HPLC methods: (1) Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with an isocratic elution of 0.24 min at 90:10 water:acetonitrile containing 0.05% formic acid followed by a 4.26-min linear gradient elution from 90:10 to 10:90 at a flow rate of 1.0 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 1); and (2) Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with an isocratic elution of 0.31 min at 95:5 water:acetonitrile containing 0.05% formic acid followed by a 17.47-min linear gradient elution from 95:5 to 5:95 at a flow rate of 0.4 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 2).

Target compounds were purified via preparative reverse-phase HPLC using a YMC Pack Pro C18 5 μm 150×20 mm column with an isocratic elution of 0.35 min at 95:5 water:acetonitrile containing 0.1% trifluoroacetic acid followed by a 23.3-min linear gradient elution from 95:5 to 5:95 at a flow rate of 18.9 mL/min with UV and mass-based fraction collection.

Example 1

Synthesis of Compound 10

Compound 10 was prepared via bromination of [2.2]paracyclophane as outlined previously (Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3527-3533; Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3534-3543). Compounds 1, 2, 6, 8, and 10 can be obtained from commercial sources. Compounds 3-7 and 9 were prepared using general synthetic methods known in the art.

Example 2Synthesis of Compound 11

A deoxygenated (argon) mixture of 9 (284.2 mg), 10 (52.3 mg), K₃PO₄(248.1 mg), and PdCl₂dppf.CH₂Cl₂(7.4 mg) in dioxane/water (5.5 mL/0.55 mL) was irradiated in a microwave for 2 h at 80° C. The resulting mixture was evaporated under reduced pressure and the remaining solid was extracted with DCM. This crude material was purified by PTLC (20 cm×20 cm×2000 μm glass plates; eluted with 45:50:5 v/v/v DCM:EtOAc:MeOH, R_f0.28) to give 75.3 mg of 11. The purity of 11 was determined via analytical reverse-phase HPLC using a 3.5-min gradient elution of increasing concentrations of ACN in water (10-90%) containing 0.05% formic acid with a flow rate of 1.0 mL/min on a Waters AQUITY HPLC BEH C18 1.7 μm 2.1×50 mm column with UV (PDA), ELS, and MS (SQ in APCI mode) detection. HPLC: t_R1.57 min (98% purity). MS m/z calculated for C₅₆H₆₄N₈O₆([M]+), 945. found, 946 ([M+1]+).

Odalasvir

Systematic (IUPAC) name
Dimethyl N,N′-(1,4(1,4)-Dibenzenacyclohexaphane-12,42-diylbis(1hbenzimidazole-5,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((2S)-3-methyl-1-oxobutan-1,2-diyl)))biscarbamate
Clinical data
Legal status	Investigational
Identifiers
CAS Registry Number	1415119-52-6
ATC code	None
Chemical data
Formula	C₆₀H₇₂N₈O₆
Molecular mass	1001.28 g/mol

amcrasto@gmail.com

LIONEL MY SON

//////////

Verubecestat (MK-8931)

July 22, 2015 6:20 am / Leave a comment

Verubecestat (MK-8931)

Merck Alzheimer’s drugs Verubecestat (MK-8931) is an oral β- amyloid precursor protein cleaving enzyme (BACE1 or β-secretase enzyme) inhibitor, is currently in Phase III clinical trials

Verubecestat
MK 8931, MK-8931, SCH 900931
2-Pyridinecarboxamide, N- (3 – ((5R) -3-amino-5,6-dihydro-2,5-dimethyl-1 , 1-dioxido-2H-1,2,4-thiadiazin-5-yl) -4-fluorophenyl) -5-fluoro-

N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide

CAS : 1286770-55-5

C₁₇ H₁₇ F₂ N₅ O₃ S, 409.41
Mechanism: Oral β- amyloid precursor protein cleavage enzyme (BACE) inhibitors
Indications: Alzheimer’s disease
Development progress: phase III clinical
Companies: Merck

Verubecestat (MK-8931) is a small-molecule inhibitor of beta-secretase cleaving enzyme (BACE) 1 and BACE2 in development by Merck for the treatment of Alzheimer’s Disease.

MK-8931 is a beta-secretase 1 (BACE1) inhibitor in phase III development for the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer’s disease at Merck & Co. The company is also conducting phase II/III trials for the treatment of Alzheimer’s type dementia.

Alzheimer’s disease (AD) is a devastating, progressive neurodegenerative disease that is associated with up to 80% of the estimated 47 million cases of dementia worldwide and is a leading cause of death in the United States.(1, 2) As the elderly population increases, the worldwide incidence of dementia is expected to nearly triple to approximately 132 million by 2050, creating an unsustainable socioeconomic burden.(1) Currently available therapies, which include acetylcholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist memantine, produce modest and transient improvement in cognitive function but do not alter the progression of AD.(3) Treatments that delay or halt disease progression by targeting the underlying causes of AD would have lasting impacts on patient function and quality of life and would address an urgent unmet medical need.

Two histopathological hallmarks are invariably observed in the brains of AD patients, namely, extracellular amyloid plaques composed primarily of β-amyloid (Aβ) peptides and intraneuronal neurofibrillary tangles composed primarily of aggregates of abnormally phosphorylated tau protein. Aβ peptides are formed by two sequential cleavages of the amyloid precursor protein (APP), first by β-site amyloid precursor protein cleaving enzyme 1 (BACE1) followed by cleavage of the resulting C-terminal fragment C99 by γ-secretase. This cleavage sequence results in production of a family of Aβ peptides, of which Aβ40 is the most abundant isoform and Aβ42 is more highly prone to aggregate into neurotoxic, oligomeric species.(4) According to the amyloid hypothesis, aberrant production and/or accumulation of Aβ peptides, principally Aβ42, over a period of decades is causative of the underlying disease pathogenesis that ultimately leads to neuronal cell death.(4, 5) In addition to the invariant presence of amyloid plaques in the brains of AD patients, the amyloid hypothesis is underpinned by several other lines of evidence. First, many distinct neurodegenerative diseases are associated with the invariant presence of abnormal protein aggregates analogous to amyloid plaques. Second, low levels of Aβ42 in the CSF are a reasonably good diagnostic/prognostic biomarker for AD. Finally, and most significantly, early onset autosomal dominant familial AD is associated with mutations in APP and the presenilin proteins (which are components of the γ-secretase enzyme), and all of these mutations share the common phenotype of increasing total Aβ levels or the relative proportion of Aβ42.(6) Given this multifaceted evidence supporting the role of Aβ peptides in AD progression, substantial efforts have been invested in the development of amyloid-lowering therapies as a disease-modifying approach to AD treatment.(7) Prominent among these has been inhibition of BACE1 to reduce or prevent production of the Aβ peptides. This approach has been further supported by the recent finding that a rare mutation (A673T) near the BACE1 cleavage site in APP reduces Aβ peptide production and is associated with reduced risk of developing AD and improved cognitive function in the elderly.(8)

BACE1 is a membrane-bound aspartyl protease expressed primarily in the central nervous system (CNS), is the sole enzymatic activity responsible for the initial β-site APP cleavage, and is required for Aβ peptide production in vivo.(9) In the brain, BACE1 is expressed mainly in neurons and cleaves APP predominantly in the endosomal compartments where the acidic pH is near the optimum for its enzymatic activity (pH 5).(10) Since the characterization of BACE1 more than 15 years ago,(11) there have been intensive efforts to overcome the challenges of identifying small molecule inhibitors that can penetrate the CNS and inhibit the formation of centrally derived Aβ peptides.(12) These efforts have been driven by evidence that BACE1 inhibition, in comparison with γ-secretase inhibition and antiamyloid immunotherapy, may be an inherently safer amyloid-lowering approach,(7) a notion that has been informed by an evolving understanding of BACE1 biology. In this regard, Bace1 knockout mice have been reported to have a number of subtle phenotypes, including reduction of central and peripheral nerve myelination, and several putative BACE1 substrates other than APP have recently been proposed.(10, 13, 14) However, many of these phenotypes and substrates remain to be independently confirmed, have little if any functional consequence, are not recapitulated by pharmacological inhibition of BACE, or may be mitigated through partial BACE1 inhibition.(8, 10, 13-15)

Smiles: C [C @] 1 (CS (= O) (= O) N (C (= N1) N) C) c2cc (ccc2F) NC (= O) c3ccc (cn3) F

COSY PREDICT

PATENT

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3a:

https://www.google.co.in/patents/CN102639135A?cl=en

Scheme 3b:

The amine A (Scheme 3a, step 4) (13.7 g) in n-butanol (150 mL) was added a slurry solution of cyanogen bromide (5M, in MeCN). The resulting mixture was heated to reflux for 4 hours. The mixture was concentrated to 1/3 of original volume. To this mixture was added Et20 (200 mL). The resulting solid was removed by filtration, and the solid was washed with Et20 (2x). The solid was partitioned between EtOAc and saturated Na2CO3 (aq). The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 10.6 g

Scheme 10:

The nitro compound (Scheme 3b) (2. 50 g, 6. 0 mmol) of Et0H (150 mL) was degassed (To this solution was bubbled with nitrogen time 3 min). To this solution was added Pd / C (10% w / w, 50% water, 698 mg). The mixture was placed in a nitrogen atmosphere. Exhaust, and backfilled with H2 (3x). The obtained mixture at room temperature, followed by stirring under H2 balloon for 2 hours. Bubbling nitrogen gas, and the mixture was purged, filtered through Celite, and concentrated.Small plug filtered through a silica gel column, eluting with EtOAc, and the product was purified to give the aniline (2. 2g, 97%).

SEE

PATENT

http://www.google.co.in/patents/WO2011044181A1?cl=en

SNAPSHOT

SYNTHESIS CONSTUCTION

AND

ON RXN WITH WITH BuLi GIVES

THIS GIVES

THIS ON TREATMENT WITH BrCN

ON BOC2O TREATMENT GIVES

GIVES ON HYDGN

REACTION WITH

GIVES

FINAL COMPD Verubecestat

1H NMR PREDICT

13C NMR PREDICT

Updated…….WATCH OUT FOR MORE

https://www.google.co.in/patents/US8729071?cl=en

Steps 1-4:

These steps were performed using similar procedures to those described in steps 1-4 of Scheme 1a.

Step 5:

To a solution of the amine from step 4 (10.5 g, 36 mmol) in CH₂Cl₂(200 mL) was added benzoylisothiocyanate (4.3 mL, 1.1 eq.). The resulting solution was stirred at RT for 2.5 days. Additional benzoylisothiocyanate (0.86 mL, 0.2 eq.) was added and the solution was stirred at RT for an additional 2 hours. The solution was then concentrated in vacuo.

A portion of this material (6.5 g, ˜14 mmol) was dissolved in MeOH (200 mL). To this solution was added Na₂CO_{3 (s)}(1.52 g, 14 mmol). The resultant mixture was stirred at RT for 45 min. After that time, a slight excess of HOAc was added to the solution. The mixture was then concentrated. The residue was partitioned between CH₂Cl₂and ½ sat. NaHCO_{3 (aq.)}. The aqueous layer was extracted with CH₂Cl₂(3×). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The thiourea (˜4.9 g) was carried onto the next reaction without further purification.

Step 6:

Example 15 was prepared using a method similar to that described in Scheme 1a step 6.

To a shiny of amine A (Scheme 3a step 4) (13.7 grams) in n-butanol (150 mL) was added a solution of cyanogen bromide (5M in MeCN). The resultant mixture was heated to reflux for 4 hours. The mixture was concentrated to ⅓ of the original volume. To the mixture was added Et₂O (200 mL). The resultant solid was removed via filtration and the solid was washed with Et₂O (2×). The solid was partitioned between EtOAc and sat. Na₂CO₃(aq.). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to afford 10.6 grams of Ex. 15. This material was converted to the t-butyl carbamate using a procedure similar to that described in Scheme 3.

Step 7:

A mixture of the bromide (3.00 g, 6.92 mmol), benzophenone imine (1.39 mL, 8.30 mmol), Pd₂(dba)₃(0.634 g, 0.692 mmol), John-Phos (0.413 g, 1.38 mmol), sodium tert-butoxide (2.13 g, 22.1 mmol), and toluene (51 mL) was degassed (vacuum/N₂). The mixture was then stirred at 65° C. under nitrogen for 3 h. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of Celite and rinsed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was then dissolved in methanol (76 mL) and the resulting solution was charged with hydroxyl amine hydrochloride (2.16 g, 31.1 mmol) and sodium acetate (2.55 g, 31.1 mmol). The reaction mixture was stirred at room temperature for 40 min. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), water (100 mL), and brine (100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/heptane) to afford the amino pyridine (0.880 g, 34%).

To a flame-dried flask was added a pyridyl bromide (Table IIb, Entry 15, 1.5 g, 3.3 mmol), Pd₂(dba)₃(305 mg, 0.3 mmol), (2-biphenyl)di-tert-butylphosphine (200 mg, 0.7 mmol), sodium tert-butoxide (1.02 g, 0.011 mmol), benzophenone imine (670 ul, 4 mmol), and toluene (21 mL). The mixture was evacuated under vacuum and back-filled with N₂(3×). The mixture was stirred at 60° C. for 1 h. After filtration through celite, the filtrate was concentrated. The crude residue was dissolved in 36 mL of methanol, and hydroxyl amine hydrochloride (458 mg, 6.6 mmol) and sodium acetate (541 mg, 6.6 mmol) were added. The reaction was stirred for 35 min and then quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the combined organic portions were dried over magnesium sulfate and concentrated. The crude residue was purified by a flash silica column (50% ethyl acetate/hexane) to get an aminopyridine product (730 mg, 68%).

A solution of the nitro compound (Scheme 3b) (2.50 g, 6.0 mmol) in EtOH (150 mL) was degassed by bubbling N₂through the solution for 3 min. To this solution was added Pd/C (10% w/w, 50% H₂O, 698 mg.). The mixture was placed under an atmosphere of N₂. The atmosphere was evacuated and back-filled with H₂(3×). The resulting mixture was stirred at RT under a H₂balloon for 2 h. The mixture was purged by bubbling N₂through it, filtered through Celite and concentrated. The product was purified by filtering through a small plug of silica gel column eluting with EtOAc to afford the aniline (2.2 g, 97%).

ENTRY 25

MH⁺: 410.0, HPLC1.79 min, LCMSMETHOD D

Method D:

Column: Agilent Zorbax SB-C18 (3.0×50 mm) 1.8 uM

Mobile phase: A: 0.05% Trifluoroacetic acid in water

- B: 0.05% Trifluoroacetic acid in acetonitrile

Gradient: 90:10 (A:B) for 0.3 min, 90:10 to 5:95 (A:B) over 1.2 min, 5:95 (A:B) for 1.2 min.

Flow rate: 1.0 mL/min

UV detection: 254 and 220 nm

Mass spectrometer: Agilent 6140 quadrupole

update…………..

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

Departments of ^†Discovery Chemistry, ^‡Neuroscience, ^§Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, ^ΔTranslational Medicine, ^#Structural Chemistry, ^⊥Molecular and Materials Characterization, ^∥Pharmaceutical Sciences and Clinical Supply, and ^¶Toxicological Sciences, MRL, Merck & Co. Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States

^∇ Albany Molecular Research Inc., 26 Corporate Circle, Albany, New York 12203, United States

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.6b00307

Publication Date (Web): November 18, 2016

*Phone: 908-740-4729. E-mail: jack.scott@merck.com., *Phone: 973-868-2088. E-mail: andy.stamford1@gmail.com.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer’s disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

N-[3-[(5R)-3-Amino-5,6-dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide (3)

3 (2.70 g, 89% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.22 (dd, J = 8.8, 4.8 Hz, 1H), 8.03–7.95 (m, 2H), 7.79 (m, 1H), 7.14 (dd, J = 11.6, 8.8 Hz, 1H), 6.03 (br s, 2H), 3.78 (s, 1H), 3.34 (s, 1H), 3.05 (s, 3H), 1.61 (s, 3H). ESI MS m/z 410.2 [M + H]⁺. [α]_D²⁰ 37.2° (c 0.367, CH₃OH).

To generate its hydrochloride salt, 3prepared above was added to CH₂Cl₂ (50 mL) followed by a solution of HCl (2 N in Et₂O, 3.6 mL, 7.2 mmol), and the mixture was concentrated in vacuo. The product was slurried in distilled water (50 mL) and lyophilized to afford the HCl monohydrate salt of 3 (2.58 g, 79% yield, 3 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (d, J = 2.8 Hz, 1H), 8.26 (dd, J = 8.8, 4.8 Hz, 1H), 8.02 (dd, J = 7.6, 2.8 Hz, 1H), 7.82–7.75 (m, 2H), 7.22 (dd, J = 12.0, 8.8 Hz, 1H), 4.49 (dd, J = 14.4, 0.8 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H), 3.30 (s, 3H), 1.96 (s, 3H). ESI MS m/z410.2 [M + H]⁺. Anal. Calcd (C₁₇H₂₀ClF₂N₅O₄S): C, 44.02; H, 4.35; N, 15.10; Cl, 7.64; S, 6.91. Found: C, 43.77; H, 4.32; N, 14.81; Cl, 7.84; S, 7.04.

References

1.

(a) Wortmann, M.Dementia: a global health priority – highlights from an ADI and World Health Organization report Alzheimer’s Res. Ther. 2012, 4, 40– 43, DOI: 10.1186/alzrt143

(b) Alzheimer’s Disease International. World Alzheimer Report 2015. http://www.alz.co.uk/research/WorldAlzheimerReport2015.pdf.
2.

Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015, 332– 384.
3.

Zemek, F.; Drtinova, L.; Nepovimova, E.; Sepsova, V.; Korabecny, J.; Klimes, J.; Kuca, K.Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine Expert Opin. Drug Saf.2014, 13, 759– 774, DOI: 10.1517/14740338.2014.914168
4.

Haass, C.; Selkoe, D. J.Soluble protein oligomers in neurodegeneration: Lesson from the Alzheimer’s amyloid β-peptide Nat. Rev. Mol. Cell Biol. 2007, 8, 101– 112, DOI: 10.1038/nrm2101
5.

(a) Hardy, J.; Selkoe, D. J.The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics Science 2002, 297, 353– 356, DOI: 10.1126/science.1072994

(b) Karran, E.; Mercken, M.; De Strooper, B.The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics Nat. Rev. Drug Discovery 2011, 10, 698– 712, DOI: 10.1038/nrd3505

6.

Tanzi, R. E.The genetics of Alzheimer disease Cold Spring Harbor Perspect. Med. 2012, 2, 1– 10, DOI: 10.1101/cshperspect.a006296
7.

Citron, M.Alzheimer’s disease: strategies for disease modification Nat. Rev. Drug Discovery 2010, 9, 387– 398, DOI: 10.1038/nrd2896
8.

Jonsson, T.; Atwal, J. K.; Steinberg, S.; Snaedal, J.; Jonsson, P. V.; Bjornsson, S.; Stefansson, H.; Sulem,P.; Gudbjartsson, D.; Maloney, J.; Hoyte, K.; Gustafson, A.; Liu, Y.; Lu, Y.; Bhangale, T.; Graham, R. R.; Huttenlocher, J.; Bjornsdottir, G.; Andreassen, O. A.; Jönsson, E. G.; Palotie, A.; Behrens, T. W.; Magnusson, O. T.; Kong, A.; Thorsteinsdottir, U.; Watts, R. J.; Stefansson, K.A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline Nature 2012, 488, 96– 99, DOI: 10.1038/nature11283
9.

Roberds, S. L.; Anderson, J.; Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen, K. S.; Freedman, S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-Wood, K.; Kappenman, K. E.; Kawabe, T. T.; Kola, I.; Kuehn,R.; Lee, M.; Liu, W.; Motter, R.; Nichols, N. F.; Power, M.; Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G. M.; Shuck, M. E.; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.; Wijsman, J.; Wright, S.; McConlogue, L.BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics Hum. Mol. Genet. 2001, 10, 1317– 1324
10.

Vassar, R.; Kuhn, P.-H.; Haass, C.; Kennedy, M. E.; Rajendran, L.; Wong, P. C.; Lichtenthaler, S. F.Function, therapeutic potential and cell biology of BACE proteases: current status and future prospectsJ. Neurochem. 2014, 130, 4– 28, DOI: 10.1111/jnc.12715

11.

(a) Vassar, R.; Bennett, B. D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E. A.; Denis, P.; Teplow, D. B.; Ross, S.; Amarante, P.; Loeloff, R.; Luo, Y.; Fisher, S.; Fuller, J.; Edenson, S.; Lile, J.; Jarosinski, M. A.; Biere, A. L.; Curran, E.; Burgess, T.; Louis, J.-C.; Collins, F.; Treanor, J.; Rogers, G.; Citron, M.β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE Science 1999,286, 735– 741

(b) Sinha, S.; Anderson, J. P.; Barbour, R.; Basi, G. S.; Caccavello, R.; Davis, D.; Doan, M.; Dovey, H. F.; Frigon, N.; Hong, J.; Jacobson-Croak, K.; Jewett, N.; Keim, P.; Knops, J.; Lieberburg, I.; Power, M.; Tan, H.; Tatsuno, G.; Tung, J.; Schenk, D.; Seubert, P.; Suomensaari, S. M.; Wang, S.; Walker, D.; Zhao, J.; McConlogue, L.; John, V.Purification and cloning of amyloid precursor protein β-secretase from human brain Nature 1999, 402, 537– 540, DOI: 10.1038/990114

(c) Hussain, I.; Powell, D.; Howlett, D. R.; Tew, D. G.; Meek,T. D.; Chapman, C.; Gloger, I. S.; Murphy, K. E.; Southan, C. D.; Ryan, D. M.; Smith, T. S.; Simmons, D. L.; Walsh, F. S.; Dingwall, C.; Christie, G.Identification of a novel aspartic protease (Asp 2) as β-SecretaseMol. Cell. Neurosci. 1999, 14, 419– 427, DOI: 10.1006/mcne.1999.0811

(d) Yan, R.; Bienkowski, M. J.; Shuck, M. E.; Miao, H.; Tory, M. C.; Pauley, A. M.; Brashler, J. R.; Stratman, N. C.; Mathews, W. R.; Buhl, A. E.; Carter, D. B.; Tomasselli, A. G.; Parodi, L. A.; Heinrikson, R. L.; Gurney,M. E.Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity Nature 1999,402, 533– 537, DOI: 10.1038/990107

(e) Lin, X.; Koelsch, G.; Wu, S.; Downs,D.; Dashti, A.; Tang, J.Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 1456– 1460, DOI: 10.1073/pnas.97.4.1456
12.

(a) Oehlrich, D.; Prokopcova, H.; Gijsen, H. J. M.The evolution of amidine-based brain penetrant BACE1 inhibitors Bioorg. Med. Chem. Lett. 2014, 24, 2033– 2045, DOI: 10.1016/j.bmcl.2014.03.025

(b) Yuan, J.; Venkatraman, S.; Zheng, Y.; McKeever, B. M.; Dillard, L. W.; Singh, S. B.Structure-based design of β-site APP cleaving enzyme 1 (BACE) inhibitors for the treatment of Alzheimer’s disease. disease J. Med. Chem. 2013, 56, 4156– 4180, DOI: 10.1021/jm301659n

(c) Probst, G.; Xu, Y. z.Small-molecule BACE1 inhibitors: a patent literature review (2006 – 2011) Expert Opin. Ther. Pat. 2012, 22, 511– 540, DOI: 10.1517/13543776.2012.681302
13.

(a) Willem, M.; Garratt, A. N.; Novak, B.; Citron, M.; Kaufmann, S.; Rittger, A.; DeStrooper, B.; Saftig, P.; Birchmeier, C.; Haass, C.Control of peripheral nerve myelination by the β-Secretase BACE1 Science2006, 314, 664– 666, DOI: 10.1126/science.1132341

(b) Hu, X.; Hicks, C. W.; He, W.; Wong, P.; Macklin, W. B.; Trapp, B. D.; Yan, R.Bace1 modulates myelination in the central and peripheral nervous system Nat. Neurosci. 2006, 9, 1520– 1525, DOI: 10.1038/nn1797
14.

Cheret, C.; Willem, M.; Fricker, F. R.; Wende, H.; Wulf-Goldenberg, A.; Tahirovic, S.; Nave, K.-A.; Saftig,P.; Haass, C.; Garratt, A. N.; Bennett, D. L.; Birchmeier, C.Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles EMBO J. 2013, 32, 2015– 2028, DOI: 10.1038/emboj.2013.146
15.

McConlogue, L.; Buttini, M.; Anderson, J. P.; Brigham, E. F.; Chen, K. S.; Freedman, S. B.; Games, D.; Johnson-Wood, K.; Lee, M.; Zeller, M.; Liu, W.; Motter, R.; Sinha, S.Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice J. Biol. Chem. 2007,282, 26326– 26334, DOI: 10.1074/jbc.M611687200

16.

Wang, Y.-S.; Strickland, C.; Voigt, J. H.; Kennedy, M. E.; Beyer, B. M.; Senior, M. M.; Smith, E. M.; Nechuta, T. L.; Madison, V. S.; Czarniecki, M.; McKittrick, B. A.; Stamford, A. W.; Parker, E. M.; Hunter, J. C.; Greenlee, W. J.; Wyss, D. F.Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel μM leads for the development of nM BACE-1 (β-site APP cleaving enzyme 1) inhibitors J. Med. Chem. 2010, 53, 942– 950, DOI: 10.1021/jm901472u
17.

The CAS name represents the 3-aminothiadiazine tautomer, and the structures depicted in the manuscript represent the 3-iminothiadiazinane tautomer.

Join me on Linkedin

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus

Googleplus

amcrasto@gmail.com

LIONEL MY SON

///////

	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel
	VÍDEOS – A Pfizer ac… on Temanogrel

Monthly Archives: July 2015

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Personal Links

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Daclatasvir

EUROPEAN MEDICINES AGENCY ADVISES ON COMPASSIONATE USE OF DACLATASVIR

[DOC]AusPAR Daclatasvir dihydrochloride – Therapeutic Goods Administration

Daclatasvir dihydrochloride

References

amcrasto@gmail.com

Share this:

Benzonitrile, 5-(3-((1S)-2,3-dihydro-1-((2-hydroxyethyl)amino)-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-(1-methylethoxy)-

(S) IS DESIRED CONFIGURATION

4-bromo-2,3-dihydro-1H-inden-1-one

(S) IS DESIRED CONFIGURATION

(S) IS DESIRED CONFIGURATION

Share this:

Share this:

PAPER CONTAING SPECTRAL DATA

STRUCTURE

IH NMR PREDICT

13 C NMR PREDICT

New patent WO-2015104605

…………..

…………..

………….

…………………

…………

……….

………….

……………….

…………..

References

amcrasto@gmail.com

Share this:

amcrasto@gmail.com

Share this:

Melting Point

Solubility

amcrasto@gmail.com

Share this:

Tofacitinib Citrate, 的合成

3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt

CAS : 540737-29-9

Asymmetric total synthesis of Tofacitinib

Abstract

Graphical abstract

Clinical trials

Rheumatoid arthritis

Psoriasis

Alopecia

Ulcerative colitis

Vitiligo

amcrasto@gmail.com

Share this:

Safe, small scale access to supercritical fluids

Google+

amcrasto@gmail.com

Share this:

Carbamic acid, N,N’-(tricyclo(8.2.2.24,7)hexadeca-4,6,10,12,13,15-hexaene-5,11-diylbis(1H-benzimidazole-6,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl)))bis-, C,C’-dimethyl ester

Dimethyl N,N’-(1,4(1,4)-dibenzenacyclohexaphane-12,42-diylbis(1hbenzimidazole-5,2-diyl((2S,3aS,7aS)-octahydro-1H-indole-2,1-diyl)((2S)-3-methyl-1-oxobutan-1,2-diyl)))biscarbamate

amcrasto@gmail.com

Share this:

Verubecestat (MK-8931)

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease