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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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GRANISETRON


GRANISETRON

1-methyl-N-((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-indazole-3-carboxamide

Nausea and Vomiting, Treatment of, Neurologic Drugs, 5-HT3 Antagonists

107007-99-8 hydrochloride
109889-09-0 (free base)

AB-1001
ALM-101
BRL-43694
Inno-P08002
SP-01
SyB D-0701
SyB L-0701
SyB-0701
TRG

Chugai (Proprietary), Roche (Proprietary), GlaxoSmithKline (Originator)

Granisetron is a serotonin 5-HT3 receptor antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much effect on vomiting due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Granisetron hydrochloride is an anti-emetic drug, used for treatment or prophylaxis of emesis and post operative nausea and vomiting. Granisetron hydrochloride is marketed under the trade name Kytril as solution for injection as well as tablets. The chemical name of granisetron is N-(endo-9-methyl-9- azabicyclo[3.3.2]non-3-yl)-l-methylindazole-3-carboxamide and it is represented by the following structural formula :

Figure imgf000002_0001

Granisetron is usually administered as the hydrochloride salt for relieving the symptoms of vomiting and nausea in cancer patients. Recently the U.S. Food and Drug Administration (FDA) has accepted an investigational New Drug (IND) application for transdermal granisetron patch, Sancuso™, for the prevention of chemotherapy-induced nausea and vomiting (CINV). The Sancuso™ Phase I I Istudy is now underway in Europe and in the U.S. Typically, a non-oral form such as transdermal patch uses granisetron base as the active ingredient.  The preparation of granisetron base is described in U.S. Patent No. 6,268,498 without referring to the solid state characteristics of granisetron. The preparation of granisetron base is further described in example 3 of U.S. Patent No. 7,071,209 (hereinafter the ‘209 patent), having a melting point of 121-1220C. The ‘209 patent is silent with regard to the solid state of granisetron base as well as to the solid state of the hydrochloride salt,

Granisetron was developed by chemists working at the British drug company Beecham around 1988 and is available as a generic. It is produced byRoche Laboratories under the trade name Kytril. The drug was approved in the United Kingdom in 1991 and in United States in 1994 by the FDA.

A granisetron transdermal patch with the trade name Sancuso was approved by the US FDA on September 12, 2008.[1] Sancuso is manufactured by ProStrakan, Inc., a pharmaceutical company headquartered in Bedminster, NJ, with global headquarters in Scotland.

Granisetron is metabolized slowly by the liver, giving it a longer than average half-life. One dose usually lasts 4 to 9 hours and is usually administered once or twice daily. This drug is removed from the body by the liver and kidneys.

Granisetron hydrochloride is a 5-HT3 antagonist that was launched in 1991 at Roche for the oral treatment of nausea. Preclinical studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In 2008, FDA approval of a transdermal patch was obtained by ProStrakan for the prophylaxis of chemotherapy-induced nausea/vomiting. Commercial launch took place the same year. This formulation has been filed for approval in the E.U. for the prevention of chemotherapy-induced nausea and vomiting. E.U. approval was obtained in 2012. In 2013, launch took place in United Kingdom. In 2011, Chugai Pharmaceutical received approval in Japan for the prevention of nausea and vomiting associated with antineoplastic agent administration and radiotherapy. Translational Research has developed an intranasal formulation that is in the preclinical phase of development. Acrux has also studied a proprietary metered-dose transdermal system, but progress reports on this formulation are not presently available. Currently marketed formulations include an oral solution, film-coated tablets, injections and sachets. BioDelivery Sciences is developing a formulation of granisetron hydrochloride using its film technology (BioErodable MucoAdhesive) BEMA technology. Almac is developing the compound in phase I clinical studies for the prevention of chemotherapy-induced nausea/vomiting.

It may be used for chemotherapy-induced nausea and vomiting and appears to work about the same as ondansetron.[2]

A number of medications including granisetron appear to be effective in controlling post-operative nausea and vomiting (PONV).[3] It is unclear if it is better than or worse than other agents like droperidolmetoclopramideondansetron or cyclizine.[3]

Its efficacy has also been questioned with a research Dr. Yoshitaka Fujii having 12 published papers on this topic in Canadian Journal of Anesthesia retracted. A further five papers in the same journal on the same drug by Dr Fujii are considered indeterminate.

  • Is a possible therapy for nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis
  • Treatment of cyclic vomiting syndrome although there are no formal trials to confirm efficacy.

Granisetron is a well-tolerated drug with few side effects. Headache, dizziness, and constipation are the most commonly reported side effects associated with its use. There have been no significant drug interactions reported with this drug’s use. It is broken down by the liver‘s cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system.

APF530

A New Drug Application (NDA) for APF530, a sustained-delivery form of Granisetron, was accepted in October 2012.[4] APF530 will be targeted as anantiemetic, towards patients undergoing radiation therapy and chemotherapy. APF530 contains the 5-HT3 antagonist, granisetron, formulated in the Company’s proprietary Biochronomer™ drug delivery system, which allows therapeutic drug levels to be maintained for five days with a single subcutaneous injection.

Originally developed at GlaxoSmithKline, granisetron hydrochloride was divested in September 2000 giving Roche global rights to the drug. Currently, granisetron is being distributed by Roche in France, Italy, South Africa, the U.K. and the U.S. and in Japan by Roche’s subsidiary Chugai. In 2007, a license agreement was signed between LG Life Sciences and ProStrakan in Korea. In 2008, the product was licensed to JapanBridge by ProStrakan for development and marketing in Asia for the prophylaxis of chemotherapy-induced nausea and vomiting. An additional license agreement was made in 2008 granting Paladin rights to granisetron transdermal patches for the treatment of nausea. In 2010, granisetron hydrochloride extended-release transdermal patches were licensed to Kyowa Hakko Kirin by Solasia Pharma in Taiwan, Hong Kong, Singapore and Malaysia for the prevention of chemotherapy-induced nausea and vomiting. Solasia retains full rights in Japan and China.

  • Kytril Web site
  • Sancuso Web siteKYTRIL Tablets and KYTRIL Oral Solution contain granisetron hydrochloride, an antinauseant and antiemetic agent. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical formula is C18H24N4O•HCl, while its chemical structure is:
    KYTRIL® (granisetron hydrochloride) Structural Formula Illustration

    granisetron hydrochloride

    Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C.

  1.  PRNewswire. FDA Approves Sancuso, the First and Only Patch for Preventing Nausea and Vomiting in Cancer Patients Undergoing Chemotherapy. September 12, 2008.
  2.  Billio, A; Morello, E; Clarke, MJ (2010 Jan 20). “Serotonin receptor antagonists for highly emetogenic chemotherapy in adults.”. The Cochrane database of systematic reviews (1): CD006272.PMID 20091591.
  3.  Carlisle, JB; Stevenson, CA (2006 Jul 19). “Drugs for preventing postoperative nausea and vomiting.”. The Cochrane database of systematic reviews (3): CD004125. PMID 16856030.
  4.  Drugs.com A.P. Pharma Announces PDUFA Action Date for APF530 New Drug Application Resubmission. October 16, 2012.
EP0200444A2 * Apr 21, 1986 Nov 5, 1986 Beecham Group Plc Azabicyclononyl-indazole-carboxamide having 5-HT antagonist activity
EP1484321A1 * May 27, 2004 Dec 8, 2004 Chemagis Ltd. Process for preparing 1-methylindazole-3-carboxylic acid
WO1995023799A1 * Feb 28, 1995 Sep 8, 1995 Victor Witold Jacewicz Process for the preparation of an indazole-3-carboxamide derivative
WO1997030049A1 * Feb 11, 1997 Aug 21, 1997 Victor Witold Jacewicz Process for the preparation of granisetron
EP0200444A2 * Apr 21, 1986 Nov 5, 1986 Beecham Group Plc Azabicyclononyl-indazole-carboxamide having 5-HT antagonist activity
ES2129349A * Title not available
1 * BERMUDEZ J. ET AL.: ‘5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives‘ J. MED. CHEM. vol. 33, no. 7, 1990, pages 1924 – 1929
Patent Filing date Publication date Applicant Title
WO2008117282A1 * Mar 24, 2008 Oct 2, 2008 Itai Adin Polymorph of granisetron base and production process therefor
EP2323654A1 * Aug 18, 2009 May 25, 2011 ScinoPharm Taiwan, Ltd. Polymorphic form of granisetron hydrochloride and methods of making the same
WO2003080606A1 * Mar 21, 2003 Oct 2, 2003 Barjoan Pere Dalmases Process for preparing a pharmaceutically active compound (granisetron)
WO2007054784A1 * Nov 8, 2006 May 18, 2007 Shanmuga Sundaram Bharan Kumar An improved process for the preparation of granisetron hydrochloride
WO2007088557A1 * Jan 18, 2007 Aug 9, 2007 Prasad Ramanadham Jyothi Process for highly pure crystalline granisetron base
ES2124162A1 * Title not available
WO2007007886A1 * Jul 10, 2006 Jan 18, 2007 Tanabe Seiyaku Co An oxime derivative and preparations thereof
WO2007088557A1 * Jan 18, 2007 Aug 9, 2007 Prasad Ramanadham Jyothi Process for highly pure crystalline granisetron base
WO2008117282A1 * Mar 24, 2008 Oct 2, 2008 Itai Adin Polymorph of granisetron base and production process therefor
WO2008151677A1 Dec 20, 2007 Dec 18, 2008 Inke Sa Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2164848A1 * Dec 20, 2007 Mar 24, 2010 Inke, S.A. Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2323654A1 * Aug 18, 2009 May 25, 2011 ScinoPharm Taiwan, Ltd. Polymorphic form of granisetron hydrochloride and methods of making the same
US8193217 * Aug 18, 2009 Jun 5, 2012 Scinopharm Taiwan Ltd. Polymorphic form of granisetron hydrochloride and methods of making the same
US20100048613 * Aug 18, 2009 Feb 25, 2010 Scinopharm Taiwan Ltd. Polymorphic form of granisetron hydrochloride and methods of making the same
WO2007088557A1 * Jan 18, 2007 Aug 9, 2007 Prasad Ramanadham Jyothi Process for highly pure crystalline granisetron base
WO2008117282A1 * Mar 24, 2008 Oct 2, 2008 Itai Adin Polymorph of granisetron base and production process therefor
WO2008151677A1 Dec 20, 2007 Dec 18, 2008 Inke Sa Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2164848A1 * Dec 20, 2007 Mar 24, 2010 Inke, S.A. Polymorphic form of granisetron base, methods for obtaining it and formulation containing it
EP2323654A1 * Aug 18, 2009 May 25, 2011 ScinoPharm Taiwan, Ltd. Polymorphic form of granisetron hydrochloride and methods of making the same

Drugs Fut 1989, 14(9): 875

5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives
J Med Chem 1990, 33(7): 1924

WO 2007054784

US 4886808
US 5034398

IN 200901669

……………………………………………………………………………………………………………………………………

Granisetron hydrochloride of formula (I). More particularly this invention relates to the preparation of Granisetron hydrochloride using methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic base such as triethylamine.

Figure imgf000002_0001

(I)

Granisetron hydrochloride which is chemically known as endo-l-methyl-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)-lH-indazole-3-carboxamide monohydrochloride is a 5-HT (5 -hydroxy triptamine) antagonist, and has the following structural formula:

Figure imgf000002_0002

(I)

Granisetron hydrochloride is useful as an anti-emetic and marketed as Kytril by Roche.

EP-A-0200444 provides certain 5-HT (5-hydroxytryptamine) antagonists, which are described as possessing a number of therapeutic utilities, inter alia, the prevention of vomiting following the administration of cytotoxic agents. The compound described in Example 6 is endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)- l-methylindazole-3-carboxamide, and this compound has been assigned the INN Granisetron. EP-A-0200444 also discloses that Granisetron can be prepared by reacting l-methylindazole-3-carboxylic acid chloride with endo-3-amino-9-methyl-9-azabicyclo [3.3.1] nonane.

EP 748321 claims a process for preparing Granisetron or a pharmaceutical acceptable salt thereof. The process comprises the condensation of compound of formula (3) and (4) followed by de-protecting the intermediate compound of structure (2) to get the granisetron or optionally forming a pharmaceutically accepted salt of Granisetron. The scheme is presented below in which Q is a leaving group displaceable by a secondary amine wherein R may be represented as benzyl, benzyl substituted with one or more chloro, alkyl or alkoxy group, t-butyl, allyl or a t-butyldimethylsilylgroup.

Figure imgf000003_0001

GRANISETRON

US Pat. No. 6,268,498 discloses an alternative process for preparing

Granisetron, by cyclisation of a previously methylated compound of formula (C), which is shown below. It should be noted that the methylation prior to cyclisation is carried out with sodium hydride and methyl iodide as disclosed in example 1 (b) of said patent. However, the cyclisation conditions applied to that compound of formula (C) may facilitate demethylation of the indazole of the Granisetron so obtained. Thus, for example, in examples 2 and 3 of said patent described the cyclisation reaction, but although in example 2 the reaction leads to Granisetron, in example 3, when the reaction time is increased under the same conditions, quantitatively demethylated Granisetron is provided. The reaction time therefore has a consideration influence on the yield values in the second step of the process that is in the cyclisation, since the Granisetron provided by this process contains as an impurity significant amounts of demethylated Granisetron, which will have to be re-methylated in an additional step.

Figure imgf000004_0001

(C) ES 2,124,162 patent discloses a procedure for the preparation of Granisetron or its pharmaceutically acceptable salts consisting of reaction of l-methylindazole-3- carboxamide of formula (A) with 9-methyl-9-azabicyclononane of formula (B) (L = halogen, OMs, OTs; halogen = esp. Cl, Br; Ms = SO2Me; Ts = SO2C6H4Me4). Thus, l-methylindazole-3-carboxamide in tetrahydrofuran (THF) containing tetramethylethylenediamine is treated with BuLi in hexane followed by addition of endo-3-(mesyloxy)-9-methyl-9-azabicyclo [3.3.1] nonane hydrochloride (L = OMs) to give the title compound i.e. Granisetron The scheme is represented below:

Figure imgf000004_0002

(A) (B) GRANISETRON

As discussed above none of the prior art references disclosed or claimed the use of methyl isobutyl ketone (MIBK) as a single solvent in presence of an organic Λ

4

base such as triethylamine for the preparation of compound of formula (I), hence we focused our research to develop an improved and efficient process for the preparation of the compound of formula (I) in substantial good yield and high purity.

,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

 

 

The synthesis of granisetron has been reported: The reaction of 1-methylindazole-3-carboxylic acid (I) with oxalyl chloride and DMF in dichloromethane gives 1-methylindazole-3-carbonyl chloride (II), which is then condensed with endo-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (III) by means of triethylamine in dichloromethane.

AU 8656579; EP 0200444; EP 0223385; EP 0498466; ES 8707948; JP 1986275276; JP 1993194508; US 4886808; US 5034398

 

…………………………………………………………………………………………………….

WO2007054784A1

Figure imgf000006_0001

Example (1) Preparation of Granisetron hydrochloride

10OmL of methyl isobutyl ketone (MIBK), 8.6g of triethylamine and 1Og of 1- methyl indazole-3-carboxylic acid were placed in a 25OmL RBF. The reaction mass was stirred and treated with 7.4g of ethyl chloro formate at O0C to (-) 50C to get a mixed anhydride and then condensed with 8.75g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 100 mL of water was added, organic layer separated and distilled to 8 volumes of MIBK, cooled the reaction mass and treated with 10.3g of IPA/HC1 (~ 20%) to get 1Og of Granisetron hydrochloride. Example (2) Preparation of Granisetron base

75OmL of methyl isobutyl ketone, 4Og of triethylamine and 5Og of 1-methyl indazole-3-carboxylic acid were placed in a 2L RBF. The reaction mass was stirred and treated with 34g of ethyl chloro formate at 20°C to 25°C to get a mixed anhydride and then condensed with 48g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 500 mL of water was added and the organic layer separated, washed with 5% sodium carbonate

(50OmL) solution and distilled the organic layer to obtain Granisetron freebase with HPLC purity 99.91%.

Example (2 – a ) Preparation of Granisetron hydrochloride

1Og of Granisetron freebase, 10OmL of methanol were placed in 250 mL RBF and heated the reaction mass to 400C to 550C to get a clear solution. The clear solution was filtered and treated with 3.5g of concentrated hydrochloric acid (36%) and diluted the reaction mass with 20OmL of MIBK, heated the reaction mass to 600C to 65°C and distilled the reaction mass up to 10 to 12 Volumes. The reaction mass was cooled and isolated 1Og of Granisetron hydrochloride with HPLC purity 99.91%.

………………………………………………………………………………………………………………………….

http://www.google.com/patents/WO1997030049A1?cl=en

Example 3 Preparation of endo-N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3- carboxamide.

A solution of 2-(N-methylbenzylidenehydrazino)-α-oxophenyl-[endo-N-(9- methyl-9-azabicyclo[3.3.1]non-3-yl)] carboxamide(0.536 g) in methanol (8 ml) was treated with 2N hydrochloric acid (0.4 ml) at room temperature. A rapid colour change from orange to green was observed. The solution was stirred for 24 hours then evaporated to the give the crude endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)-indazole-3-carboxamide (0.630g).

Example 4 Preparation of endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l-methylindazole- 3-cjχboxamide (granisetron).

Sodium hydride (72 mg, 60% dispersion in oil) was added to a solution of endo- N-(9-methyl-9-azabicyclo[3.3. l]non-3-yl)-indazole-3-carboxamide (0.130g) in dry tetrahydrofuran (3.0 ml) under nitrogen at -50°C. The resultant solution was warmed to room temperature over 20 minutes then cooled to -40°C and treated with methyl iodide (0.015 ml). After 3 hours at room temperature HPLC analysis showed complete conversion to endo-N-(9-methyl-9-azabicyclo[3.3.1] non-3-yl)- l-methy-indazole-3-carboxamide. Water (10 ml) was added and the mixture extracted with ethyl acetate (2x 20 ml). The extracts were dried (MgSO4) ^ evaporated to give endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-l- methylindazole-3-carboxamide 50 mg (41%). MS 313 (M+H)+.

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MAROPITANT


 

MAROPITANT

http://www.allfordrugs.com/2013/12/31/maropitant/

Duchenne Muscular Dystrophy: EspeRare Foundation And Drug Repositioning


Orphan Druganaut Blog

This is the fifth Blog Post in a series examining Duchenne Muscular Dystrophy (DMD) in the rare disease and orphan drug space. This Blog Post discusses the EspeRare Foundation and how the organization is using repositioning or repurposing of an old drug to benefit DMD.

Drug repositioning or drug repurposing (DR) is applying existing drugs to new indications or diseases. DR is increasing in importance to many drug development and pharmaceutical companies. Using DR provides several advantages to companies:

•   Repositioned drug has already passed toxicity and other tests

•   Repositioned drug’s safety profile is already known

•   Repositioned drug decreases the development time and cost of developing a drug.

Merck Serono, a division of Merck, announces in April 2013, the launch of the EspeRare Foundation. The EspeRare Foundation is presented to the public and international rare disease community at the IRDiRC (International Rare Diseases Research Consortium) Conference, in April…

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Fedratinib » All About Drugs


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Linsitinib » All About Drugs


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MARIZOMIB, Salinosporamide A


MARIZOMIB
http://www.ama-assn.org/resources/doc/usan/marizomib.pdf
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. 6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-
cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-
2. (1R,4R,5S)-4-(2-chloroethyl)-1-{(S)-[(1S)-cyclohex-2-en-1-yl]hydroxymethyl}-5-methyl-
6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione

MOLECULAR FORMULA C15H20ClNO4
MOLECULAR WEIGHT 313.8

MANUFACTURER Nereus Pharmaceuticals, Inc.

NOTE….Nereus Pharmaceuticals was acquired by Triphase Research and Development in 2012.
CODE DESIGNATION NPI-0052
CAS REGISTRY NUMBER 437742-34-2

Scripps Institution of Oceanography (Originator)

US7183417

mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C.

[α]23 −73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357);

FTIR (film) νmax: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm−1;

1H NMR (CDCl3, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);

13C NMR (CDCl3, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00;

HRMS (ESI) calcd. for (M−H) C15H19ClNO312.1003, found 312.1003.

Marizomib, a highly potent proteasome inhibitor, is in early clinical development at Triphase Research and Development I Corp for the treatment of relapsed or relapsed/refractory multiple myeloma. Phase I clinical trials have also been carried out for the treatment of solid tumors and lymphoma; however, no recent developments have been reported for these studies.

HDAC inhibitors halt tumor cell differentiation and growth, and when combined with marizomib in preclinical in vitro and in vivo studies, show additive and synergistic antitumor activities.

The compound was discovered from a new marine-obligate gram-positive actinomycete (Salinispora tropica). Preclinical studies suggest that this next-generation compound may be superior to other proteasome inhibitors, with broader target inhibition, faster onset and longer duration of action, higher potency, and oral and intravenous availability. By inhibiting proteasomes, marizomib prevents the breakdown of proteins involved in signal transduction, which blocks growth and induces apoptosis in cancer cells.

In 2013, orphan drug designation was assigned in the U.S. for the treatment of multiple myeloma.

The compound was originally developed by Nereus Pharmaceuticals, which was acquired by Triphase Research and Development in 2012.

marizomib is a naturally-occurring salinosporamide, isolated from the marine actinomycete Salinospora tropica, with potential antineoplastic activity. Marizomib irreversibly binds to and inhibits the 20S catalytic core subunit of the proteasome by covalently modifying its active site threonine residues; inhibition of ubiquitin-proteasome mediated proteolysis results in an accumulation of poly-ubiquitinated proteins, which may result in the disruption of cellular processes, cell cycle arrest, the induction of apoptosis, and the inhibition of tumor growth and angiogenesis. This agent more may more potent and selective than the proteasome inhibitor bortezomib

Marizomib (NPI-0052) is an oral, irreversible ββ-lactone derivative that binds selectively to the active proteasomal sites. In vivo studies with marizomib demonstrate reduced tumor growth without significant toxicity in myeloma xenograft models. A phase I trial in refractory and relapsed MM is under way.

Salinosporamide A is a potent proteasome inhibitor used as an anticancer agent that recently entered phase I human clinical trials for the treatment of multiple myeloma only three years after its discovery.[1][2] This novel marine natural product is produced by the recently described obligate marine bacteria Salinispora tropica and Salinispora arenicola, which are found in ocean sediment. Salinosporamide A belongs to a family of compounds, known collectively as salinosporamides, which possess a densely functionalized γ-lactam-β-lactone bicyclic core.

Salinosporamide A was discovered by William Fenical and Paul Jensen from Scripps Institution of Oceanography in La Jolla, CA. In preliminary screening, a high percentage of the organic extracts of cultured Salinospora strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery.Salinospora strain CNB-392 was isolated from a heat-treated marine sediment sample and cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A. Although salinosporamide A shares an identical bicyclic ring structure with omuralide, it is uniquely functionalized. Salinosporamide A displayed potent in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 value of 11 ng mL-1. This compound also displayed potent and highly selective activity in the NCI’s 60-cell-line panel with a mean GI50 value (the concentration required to achieve 50% growth inhibition) of less than 10 nM and a greater than 4 log LC50 differential between resistant and susceptible cell lines. The greatest potency was observed against NCI-H226 non-small cell lung cancer, SF-539 CNS cancer, SK-MEL-28 melanoma, and MDA-MB-435 breast cancer (all with LC50 values less than 10 nM). Salinosporamide A was tested for its effects on proteasome function because of its structural relationship to omuralide. When tested against purified 20S proteasome, salinosporamide A inhibited proteasomal chymotrypsin-like proteolytic activity with an IC50 value of 1.3 nM.[3] This compound is approximately 35 times more potent than omuralide which was tested as a positive control in the same assay. Thus, the unique functionalization of the core bicyclic ring structure of salinosporamide A appears to have resulted in a molecule that is a significantly more potent proteasome inhibitor than omuralide.[1]

Salinosporamide A inhibits proteasome activity by covalently modifying the active site threonine residues of the 20S proteasome.

Biosynthesis

Salinosporamide A and B building blocks

Proposed biosynthesis of the nonproteinogenic amino-acid beta-hydroxycyclohex-2′-enylanine (3) (R = H or S~PCP) via a shunt in the phenylalanine biosynthetic pathway

Biosynthesis

It was originally hypothesized that salinosporamide B was a biosynthetic precursor to salinosporamide A due to their structural similarities.

It was thought that the halogenation of the unactivated methyl group was catalyzed by a non-heme iron halogenase.[4][5]Recent work using 13C-labeled feeding experiments reveal distinct biosynthetic origins of salinosporamide A and B.[4][6]

While they share the biosynthetic precursors acetate and presumed β-hydroxycyclohex-2′-enylalanine (3), they differ in the origin of the four-carbon building block that gives rise to their structural differences involving the halogen atom. A hybrid polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) pathway is most likely the biosynthetic mechanism in which acetyl-CoA and butyrate-derived ethylmalonyl-CoA condense to yield the β-ketothioester (4), which then reacts with (3) to generate the linear precursor (5).

The first stereoselective synthesis was reported by Rajender Reddy Leleti and E. J.Corey.[7] Later several routes to the total synthesis of salinosporamide A have been reported.[7][8][9][10]

In vitro studies using purified 20S proteasomes showed that salinosporamide A has lower EC50 for trypsin-like (T-L) activity than does Bortezomib. In vivo animal model studies show marked inhibition of T-L activity in response to salinosporamide A, whereas bortezomib enhances T-L proteasome activity.

Initial results from early-stage clinical trials of salinosporamide A in relapsed/refractory multiple myeloma patients were presented at the 2011 American Society of Hematology annual meeting.[11] Further early-stage trials of the drug in a number of different cancers are ongoing.[12]

  1.  Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003). “Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora”. Angew. Chem. Int. Ed. Engl. 42 (3): 355–7.doi:10.1002/anie.200390115PMID 12548698.
  2.  Chauhan D, Catley L, Li G et al. (2005). “A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib”. Cancer Cell 8 (5): 407–19.doi:10.1016/j.ccr.2005.10.013PMID 16286248.
  3.  K. Lloyd, S. Glaser, B. Miller, Nereus Pharmaceuticals Inc.
  4.  Beer LL, Moore BS (2007). “Biosynthetic convergence of salinosporamides A and B in the marine actinomycete Salinispora tropica”. Org. Lett. 9 (5): 845–8.doi:10.1021/ol063102oPMID 17274624.
  5.  Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT (2006). “Nature’s inventory of halogenation catalysts: oxidative strategies predominate”. Chem. Rev.106 (8): 3364–78. doi:10.1021/cr050313i.PMID 16895332.
  6.  Tsueng G, McArthur KA, Potts BC, Lam KS (2007). “Unique butyric acid incorporation patterns for salinosporamides A and B reveal distinct biosynthetic origins”. Applied Microbiology and Biotechnology 75 (5): 999–1005. doi:10.1007/s00253-007-0899-7.PMID 17340108.
  7.  Reddy LR, Saravanan P, Corey EJ (2004). “A simple stereocontrolled synthesis of salinosporamide A”. J. Am. Chem. Soc. 126 (20): 6230–1. doi:10.1021/ja048613p.PMID 15149210.
  8.  Ling T, Macherla VR, Manam RR, McArthur KA, Potts BC (2007). “Enantioselective Total Synthesis of (-)-Salinosporamide A (NPI-0052)”.Org. Lett. 9 (12): 2289–92. doi:10.1021/ol0706051PMID 17497868.
  9.  Ma G, Nguyen H, Romo D (2007). “Concise Total Synthesis of (±)-Salinosporamide A, (±)-Cinnabaramide A, and Derivatives via a Bis-Cyclization Process: Implications for a Biosynthetic Pathway?”Org. Lett. 9 (11): 2143–6. doi:10.1021/ol070616uPMC 2518687.PMID 17477539.
  10.  Endo A, Danishefsky SJ (2005). “Total synthesis of salinosporamide A”. J. Am. Chem. Soc. 127 (23): 8298–9.doi:10.1021/ja0522783PMID 15941259.
  11.  “Marizomib May Be Effective In Relapsed/Refractory Multiple Myeloma (ASH 2011)”. The Myeloma Beacon. 2012-01-23. Retrieved 2012-06-10.
  12.  ClinicalTrials.gov: Marizomib

……………………………………………………

IMPORTANT PAPERS

Total synthesis of salinosporamide A
Org Lett 2008, 10(19): 4239

Entry to heterocycles based on indium-catalyzed conia-ene reactions: Asymmetric synthesis of (-)-salinosporamide A
Angew Chem Int Ed 2008, 47(33): 6244

A concise and straightforward total synthesis of (+/-)-salinosporamide A, based on a biosynthesis model
Org Biomol Chem 2008, 6(15): 2782

Formal synthesis of salinosporamide A starting from D-glucose
Synthesis (Stuttgart) 2009, 2009(17): 2983

Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A
Tetrahedron 2012, 68(32): 6504

………………

Salinosporamide A(1) was recently discovered by Fenical et al. as a bioactive product of a marine microorganism that is widely distributed in ocean sediments. Feeling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.; Jensen, P. R.; Fenical, W., Angew. Chem. Int. Ed., 2003, 42, 355–357.

Figure US07183417-20070227-C00002

Structurally Salinosporamide A closely resembles the terrestrial microbial product omuralide (2a) that was synthesized by Corey et al. several years ago and demonstrated to be a potent inhibitor of proteasome function. See, (a) Corey, E. J.; Li, W. D., Z. Chem. Pharm. Bull., 1999, 47, 1–10; (b) Corey, E. J., Reichard, G. A.; Kania, R., Tetrahedron Lett., 1993, 34, 6977–6980; (c) Corey, E. J.; Reichard, G. A., J. Am. Chem. Soc., 1992, 114, 10677–10678; (d) Fenteany, G.; Standaert, R. F.; Reichard, G. A.; Corey, E. J.; Schreiber, S. L., Proc. Natl. Acad. Sci. USA, 1994, 91, 3358–3362.

Omuralide is generated by β-lactonization of the N-acetylcysteine thiolester lactacystin (2b) that was first isolated by the Omura group as a result of microbial screening for nerve growth factor-like activity. See, Omura, S., Fujimoto, T., Otoguro, K., Matsuzaki, K., Moriguchi, R., Tanaka, H., Sasaki, Y., Antibiot., 1991, 44, 113–116; Omura, S., Matsuzaki, K., Fujimoto, T., Kosuge, K., Furuya, T., Fujita, S., Nakagawa, A., J. Antibiot., 1991, 44, 117–118.

Salinosporamide A, the first compound Fenical’s group isolated from Salinospora, not only had a never-before-seen chemical structure 1, but is also a highly selective and potent inhibitor of cancer-cell growth. The compound is an even more effective proteasome inhibitor than omuralide and, in addition, it displays surprisingly high in vitro cytotoxic activity against many tumor cell lines (IC50values of 10 nM or less). Fenical et al. first found the microbe, which they’ve dubbed Salinospora, off the coasts of the Bahamas and in the Red Sea. See,Appl. Environ. Microbiol., 68, 5005 (2002).

Fenical et al. have shown that Salinospora species requires a salt environment to live. Salinospora thrives in hostile ocean-bottom conditions: no light, low temperature, and high pressure. The Fenical group has now identified Salinosporain five oceans, and with 10,000 organisms per cmof sediment and several distinct strains in each sample; and according to press reports, they’ve been able to isolate 5,000 strains. See, Chemical Engineering News, 81, 37 (2003).

A great percentage of the cultures Fenical et al. have tested are said to have shown both anticancer and antibiotic activity. Like omuralide 2a, salinosporamide A inhibits the proteasome, an intracellular enzyme complex that destroys proteins the cell no longer needs. Without the proteasome, proteins would build up and clog cellular machinery. Fast-growing cancer cells make especially heavy use of the proteasome, so thwarting its action is a compelling drug strategy. See, Fenical et al., U.S. Patent Publication No. 2003-0157695A1

PATENTS

WO 2005113558

http://www.google.com/patents/US7183417

Part I. Synthesis of the Salinosporamide A(1)

EXAMPLE 1

Figure US07183417-20070227-C00016

(4S, 5R) Methyl 4,5-dihydro-2 (4-methoxyphenyl)-5-methyloxazole-4-carboxylate (4)

A mixture of (2S, 3R)-methyl 2-(4-methoxybenzamido)-3-hydroxybutanoate (3) (35.0 g, 131 mmol) and p-TsOH.H2O (2.5 g, 13.1 mmol) in toluene (400 mL) was heated at reflux for 12 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give crude oxazoline as yellow oil. Flash column chromatography on silica gel (eluent 15% EtOAc-Hexanes) afforded the pure oxazoline (26.1 g, 80%) as solid.

Rf=0.51 (50% ethyl acetate in hexanes), mp, 86–87° C.; [α]23 D+69.4 (c 2.0, CHCl3); FTIR (film) νmax: 2955, 1750, 1545, 1355, 1187, 1011, 810 cm−11HNMR(CDCl3, 400 MHz): δ 7.87 (2H, d, J=9.2 Hz), 6.84 (2H, d, J=8.8 Hz), 4.90 (1H, m), 4.40 (1H, d, J=7.6 Hz), 3.79 (3H,s), 3.71 (3H, s), 1.49 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 171.93, 165.54, 162.64, 130.52, 119.80, 113.85, 78.91, 75.16, 55.51, 52.73, 21.14; HRMS (ESI) calcd for C13H16NO(M+H)+.250.1079, found 250.1084.

EXAMPLE 2

Figure US07183417-20070227-C00017

(4R, 5R)-Methyl 4-{(benzyloxy) methyl)}-4,5-dihydro-2-(4-methoxyphenyl)-5-methyloxazole-4-carboxylate (5)

To a solution of LDA (50 mmol, 1.0 M stock solution in THF) was added HMPA (24 mL, 215 mmol) at −78° C. and then oxazoline 4 (12.45 g, 50 mmol, in 20 mL THF) was added dropwise with stirring at −78° C. for 1 h to allow complete enolate formation. Benzyloxy chloromethyl ether (8.35 mL, 60 mmol) was added at this temperature and after stirring the mixture at −78° C. for 4 h, it was quenched with water (50 mL) and warmed to 23° C. for 30 min. Then the mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:4 then 1:3) to give the benzyl ether 5 (12.7 g, 69%).

Rf=0.59 (50% ethyl acetate in hexanes). [α]23 D−6.3 (c 1.0, CHCl3); FTIR (film) (νmax; 3050, 2975, 1724, 1642, 1607, 1252, 1027, 745, 697 cm−11H NMR (CDCl3, 400 MHz): δ 7.96 (2H, d, J=9.2 Hz), 7.26 (5H, m), 6.90 (2H, J=8.8 Hz), 4.80 (1H, m), 4.61 (2H, s), 3.87 (3H, m), 3.81 (3H, s), 3.73 (3H, s), 1.34 (3H, d, J=6.8 Hz); 13C NMR (CDCl3, 100 MHZ): 6171.23, 165.47, 162.63, 138.25, 130.64, 128.52, 127.87, 127.77, 120.15, 113.87, 81.40, 79.92, 73.91, 73.43, 55.58, 52.45, 16.92; HRMS (ESI) calcd for C21H24O(M+H)+370.1654, found 370.1644.

EXAMPLE 3

Figure US07183417-20070227-C00018

(2R,3R)-Methyl 2-(4-methoxybenzylamino)-2-((benzyloxy)methyl)-3hydroxybutanoate (6)

To a solution of oxazoline 5 (18.45 g, 50 mmol) in AcOH (25 mL) at 23° C. was added in portions NaCNBH(9.3 g, 150 mmol). The reaction mixture was then stirred at 40° C. for 12 h to allow complete consumption of the starting material. The reaction mixture was diluted with water (100 mL), neutralized with solid Na2COand the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over NaSOand concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give the N-PMB amino alcohol 6 (16.78 g, 90%).

Rf=0.50 (50% ethyl acetate in hexanes). [α]23 D−9.1(c 1.0, CHCl3); FTIR (film) νmax; 3354, 2949, 1731, 1511, 1242, 1070, 1030, 820, 736, 697 cm−11H NMR (CDCl3, 400 MHz): δ 7.32 (7H, m), 6.87 (2H, d, J=8.8 Hz), 4.55 (2H, m), 4.10 (1H, q, J=6.4 Hz), 3.85 (2H, dd, J=17.2, 10.0 Hz), 3.81 (3H, s,), 3.77 (3H, s), 3. 69 (2H, dd, J=22.8, 11.6 Hz), 3.22 (2H, bs), 1.16 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 173.34, 159.03, 137.92, 132.51, 129.78, 128.67, 128.07, 127.98, 114.07, 73.80, 70.55, 69.82, 69.65, 55.51, 55.29, 47.68, 18.15; HRMS (ESI) calcd. for C21H28NO(M+H)374.1967, found 374.1974.

EXAMPLE 4

Figure US07183417-20070227-C00019

(2R,3R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-hydroxybutanoate (7)

A solution of amino alcohol 6 (26.2 g, 68.5 mmol) in Et2O (200 mL) was treated with Et3N (14.2 mL, 102.8 mmol) and trimethylchlorosilane (10.4 mL, 82.2 mmol) at 23° C. and stirred for 12 h. After completion, the reaction mixture was diluted with ether (200 mL) and then resulting suspension was filtered through celite. The solvent was removed to furnish the crude product (31.2 g, 99%) in quantitative yield as viscous oil. A solution of this crude trimethylsilyl ether (31.1 g) in CH2Cl(200 mL) was charged with diisopropylethylamine (14.2 mL, 81.6 mmol) and then cooled to 0° C. Acryloyl chloride (6.64 mL, 82.2 mmol) was added dropwise with vigorous stirring and the reaction temperature was maintained at 0° C. until completion (1 h). The reaction mixture was then diluted with CH2Cl(100 mL) and the organic layer was washed with water and brine. The organic layer was separated and dried over Na2SO4. The solvent was removed to afford the crude acrylamide 7 as a viscous oil. The crude product was then dissolved in Et2O (200 mL) and stirred with 6N HCl (40 mL) at 23° C. for 1 h. The reaction mixture was diluted with water (100 mL) and concentrated to provide crude product. The residue was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:1) to give pure amide 7 (28.3 g, 96%) as colorless solid, mp 88–89° C.

Rf=0.40 (50% ethyl acetate in hexanes), [α]23 D−31.1 (c 0.45, CHCl3), FTIR (film) νmax; 3435, 2990, 1725, 1649, 1610, 1512, 1415, 1287, 1242, 1175, 1087, 1029, 732, 698 cm−11H NMR (CDCl3, 500 MHz): δ 7.25 (5H, m), 7.15 (2H, d, J=6.0 Hz), 6.85 (2H, d, J=7.5 Hz), 6.38 (2H, d, J=6.0 Hz), 5.55 (1H, t, J=6.0 Hz), 4.81 (2H, s), 4.71 (1H, q, J=6.5 Hz), 4.35 (2H, s), 4.00 (1H, d, J=10.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.76 (3H, s), 3.75 (3H, s), 3.28 (1H, bs), 1.22 (3H, d, J=6.0 Hz); 13C NMR (CDCl3, 125 MHz): δ 171.87, 168.74, 158.81, 137.73, 131.04, 129.68, 128.58, 128.51, 127.94, 127.72, 127.20, 127.14, 114.21, 73.71, 70.42, 69.76, 67.65, 55.45, 52.52, 49.09, 18.88; HRMS (ESI) calcd. for C24H30NO(M+H)+428.2073, found 428.2073.

EXAMPLE 5

Figure US07183417-20070227-C00020

(R)-Methyl-2-(N-(4-methoxybenzyl)acrylamido)-2-(benzyloxy)methyl)-3-oxybutanoate (8)

To a solution of amide 7 (10.67 g, 25.0 mmol) in CH2Cl(100 mL) was added Dess-Martin periodinane reagent (12.75 g, 30.0 mmol, Aldrich Co.) at 23° C. After stirring for 1 h, the reaction mixture was quenched with aq NaHCO3—Na2S2O(1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude ketone. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes) to give pure keto amide 8 (10.2 g, 96%).

Rf=0.80 (50% ethyl acetate in hexanes), mp 85 to 86° C.; [α]23 D−12.8 (c 1.45, CHCl3); FTIR (film) νmax: 3030, 2995, 1733, 1717, 1510, 1256, 1178, 1088, 1027, 733, 697 cm−11H NMR (CDCl3, 500 MHz): δ 7.30 (2H, d, J=8.0), 7.25 (3H, m), 7.11 (2H, m), 6.88 (2H, d, J=9.0 Hz), 6.38 (2H, m), 5.63 (1H, dd, J=8.5, 3.5 Hz), 4.93 (1H, d, J=18.5 Hz), 4.78 (1H, d, J=18.5, Hz), 4.27 (2H, m), 3.78 (3H, s), 3.76 (3H, s), 2.42 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 198.12, 169.23, 168.62, 158.01, 136.95, 130.64, 130.38, 128.63, 128.13, 127.77, 127.32, 114.33, 77.49, 73.97, 70.66, 55.49, 53.09, 49.03, 28.24; HRMS (ESI) calcd. for C24H28NO(M+H)+ 426.1916, found 426.1909.

EXAMPLE 6

Figure US07183417-20070227-C00021

(2R,3S)-Methyl-1-(4-methoxybenzyl)-2-((benzyloxy)methyl)-3-hydroxy-3-methyl-4-methylene-5-oxopyrrolidine-2-carboxylate (9+10)

A mixture of keto amide 8 (8.5 g, 20.0 mmol) and quinuclidine (2.22 g, 20.0 mmol) in DME (10 mL) was stirred for 5 h at 23° C. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) washed with 2N HCl, followed by water and dried over Na2SO4. The solvent was removed in vacuo to give the crude adduct (8.03 g, 94.5%, 3:1 ratio of 9 to 10 dr) as a viscous oil. The diastereomeric mixture was separated at the next step, although small amounts of 9 and 10 were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2) for analytical purposes.

Major Diastereomer (9).

[α]23 D−37.8 (c 0.51, CHCl3); FTIR (film) vmax: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808,734 cm−11H NMR (CDCl3, 500 MHz): δ 7.29 (5H, m), 7.15 (2H, d, J=7.5 Hz), 6.74 (2H, d, J=8.5 Hz), 6.13 (1H, s), 5.57 (1H, s), 4.81 (1H, d, J=14.5 Hz), 4.45(1H, d, J=15.0 Hz), 4.20 (1H, d, J=12.0 Hz), 4.10 (1H, d, J=12.0 Hz) 3.75 (3H, s), 3.70 (1H, d, J=10.5 Hz), 3.64 (3H, s), 3.54 (1H, d, J=10.5 Hz), 2.55 (1H, bs, OH), 1.50 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 169.67, 168.42, 158.97, 145.96, 137.57, 130.19, 130.12, 128.53, 127.83, 127.44, 116.79, 113.71, 76.32, 76.00, 73.16, 68.29, 55.45, 52.63, 45.36, 22.64; HRMS (ESI) calcd. for C24H28NO(M+H)+ 426.1916, found 426.1915.
Minor Diastereomer (10).
[α]23 D−.50.1 (c 0.40, CHCl3); FTIR (film) νmax: 3450, 3055, 2990, 1733, 1683, 1507, 1107, 1028, 808, 734 cm−11H NMR (CDCl3, 500 MHz): δ 7.29 (5H, m), 7.12 (2H, d, J=7.5 Hz), 6.73 (2H, d, J=8.5 Hz), 6.12 (1H, s), 5.57 (1H, s), 4.88 (1H, d, J=15.5 Hz), 4.31 (1H, d, J=15.0 Hz), 4.08 (3H, m), 3.99 (1H, d, J=12.0 Hz) 3.73 (3H, s), 3.62 (3H, s), 3.47 (1H, bs, OH), 3.43 (1H, d, J=10.0 Hz), 1.31 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 169.65, 167.89, 159.13, 147.19, 136.95, 130.29, 129.76, 128.74, 128.19, 127.55, 116.80, 113.82, 76.21, 75.66, 73.27, 68.02, 55.45, 52.52, 45.24, 25.25; HRMS (ESI) calcd. for (M+H)+ C24H28NO426.1916, found 426.1915.

EXAMPLE 7

Silylation of 9 and 10 and Purification of 11.

To a solution of lactams 9 and 10 (7.67 g, 18 mmol) in CH2Cl(25 ml) was added Et3N (7.54 ml, 54 mmol), and DMAP (2.2 g, 18 mmol) at 0° C., and then bromomethyl-dimethylchlorosilane (5.05 g, 27 mmol) (added dropwise). After stirring the mixture for 30 min at 0° C., it was quenched with aq NaHCOand the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed in vacuo to give a mixture of the silated derivatives of 9 and 10 (9.83 g, 95%). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5 to 1:4) to give pure diastereomer 11 (7.4 g, 72%) and its diastereomer (2.4 g, 22%).

Silyl Ether (11).

Rf=0.80 (30% ethyl acetate in hexanes). [α]23 D−58.9 (c 0.55, CHCl3); FTIR (film) νmax; 3050, 2995, 1738, 1697, 1512, 1405, 1243, 1108, 1003, 809, 732 cm−11H NMR (CDCl3, 500 MHz): δ 7.27 (5H, m), 7.05 (2H, d, J=7.0 Hz), 6.71 (2H, d, J=8.5 Hz), 6.18 (1H, s), 5.53 (1H, s), 4.95 (1H, d, J=15.5 Hz), 4.45 (1H, d, J=15.0 Hz), 4.02 (1H, J=12.0 Hz), 3.86 (1H, d, J=11.5 Hz) 3.72 (3H, s), 3.68 (3H, s), 3.65 (1H, d, J=10.5 Hz), 3.30 (1H, d, J=10.0 Hz), 2.34 (2H, d, J=2.0 Hz), 1.58 (3H, s), 0.19 (3H, s), 0.18 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 168.62, 168.12, 158.93, 145.24, 137.53, 130.32, 130.30, 128.49, 127.76,127.22, 117.26, 113.60, 78.55, 78.03, 72.89, 68.45, 55.43, 52.37, 45.74, 21.87, 17.32, −0.72, −0.80; HRMS (ESI) Calcd. for C27H35BrNO6Si (M+H)576.1417, found 576.1407.

EXAMPLE 8

Figure US07183417-20070227-C00022

Conversion of (11) to (12).

To a solution of compound 11 (5.67 g 10 mmol) in benzene (250 mL) at 80° C. under nitrogen was added a mixture of tributyltin hydride (4.03 ml, 15 mmol) and AIBN (164 mg, 1 mmol) in 50 ml benzene by syringe pump over 4 h. After the addition was complete, the reaction mixture was stirred for an additional 4 h at 80° C. and the solvent was removed in vacuo. The residue was dissolved in hexanes (20 mL) and washed with saturated NaHCO(3×25 mL), water and dried over Na2SO4. The solvent was removed in vacuo to give crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to afford the pure 12 (4.42 g, 89%).

Rf=0.80 (30% ethyl acetate in hexanes). [α]23 D−38.8 (c 0.25, CHCl3); FTIR (film) νmax; 3025, 2985, 1756, 1692, 1513, 1247, 1177, 1059, 667 cm−11H NMR (CDCl3, 500 MHz): δ 7.28 (5H, m), 7.09 (2H, d, J=7.0 Hz), 6.73 (2H, d, J=9.0 Hz), 4.96(1H, d, J=15.0 Hz), 4.35 (1H, d, J=15.5 Hz), 3.97 (1H, d, J=12.5 Hz), 3.86 (1H, d, J=12.0 Hz), 3.80 (1H, d, J=10.0 Hz), 3.72 (3H, s), 3.65 (3H, s), 3.27 (1H, d, J=10.5 Hz), 2.67 (1H, t, J=4.0 Hz), 2.41 (1H, m), 1.79 (1H, m), 1.46 (3H, s), 0.77 (1H, m), 0.46 (1H, m), 0.10 (3H, s), 0.19 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 175.48, 169.46, 158.76, 137.59, 131.04, 129.90, 128.58, 127.88, 127.52, 113.59, 113.60, 81.05, 78.88, 73.12, 69.03, 55.45, 51.94, 48.81, 45.50, 22.79, 17.06, 7.76, 0.54; HRMS (ESI) calcd. for (M+H)+ C27H36NO6Si 498.2312, found 498.2309.

EXAMPLE 9

Figure US07183417-20070227-C00023

Debenzylation of (12).

A solution of 12 (3.98 g, 8 mmol) in EtOH (50 ml) at 23° C. was treated with 10% Pd—C (˜1 g) under an argon atmosphere. The reaction mixture was evacuated and flushed with Hgas (four times) and then stirred vigorously under an atmosphere of H(1 atm, Hballoon) at 23° C. After 12 h, the reaction mixture was filtered through Celite and concentrated in vacuo to give the crude debenzylation product (3.08 g, 95%) which was used for the next step. A small amount crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:3) for analytical purposes. Rf=0.41 (50% ethyl acetate in hexanes).

mp, 45–47° C.; [α]23 D−30.9 (c 0.55, CHCl3); FTIR (film) νmax: 3432, 3020, 2926, 1735, 1692, 1512, 1244, 1174, 1094, 1024, 870, 795 cm−11H NMR (CDCl3, 400 MHz): δ 7.36 (2H, d, J=8.5 Hz), 6.83 (2H, d, J=8.5 Hz), 5.16 (1H, d, J=15.0 Hz), 4.29 (1H, d, J=15.0 Hz), 3.92 (1H, m), 3.78 (3H, s), 3.68 (3H, s), 3.45 (1H, m), 2.53 (1H, t, J=4.0 Hz), 2.42 (1H, m), 1.82 (1H, m), 1.50 (3H, s), 1.28 (1H, m), 0.75 (1H, m), 0.47 (1H, m), 0.11 (3H, s), 0.02 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 175.82, 169.51, 159.32, 131.00, 129.72, 114.52, 80.79, 80.13, 61.85, 55.48, 51.99, 49.29, 45.06, 23.11, 17.03, 7.44, 0.54; HRMS (ESI) calcd. for C20H30NO6Si (M+H)+ 408.1842, found 408.1846.

EXAMPLE 10

Oxidation to Form Aldehyde (13).

To a solution of the above alcohol from debenzylation of 12 (2.84 g, 7 mmol) in CH2Cl(30 mL) was added Dess-Martin reagent (3.57 g, 8.4 mmol) at 23° C. After stirring for 1 h at 23° C., the reaction mixture was quenched with aq NaHCO3—Na2S2O(1:1, 50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated in vacuo to afford the crude aldehyde. The crude product was purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:5) to give pure aldehyde 13 (2.68 g, 95%). Rf=0.56 (50% ethyl acetate in hexanes).

mp, 54–56° C.; [α]23 D−16.5 (c 0.60, CHCl3); FTIR (film) νmax: 3015, 2925, 1702 1297, 1247, 1170, 1096, 987, 794 cm−11H NMR (CDCl3, 500 MHz): δ 9.62 (1H, s), 7.07 (2H, d, J=8.0 Hz), 6.73 (2H, d, J=8.5 Hz), 4.49 (1H, quart, J=8.5 Hz), 3.70 (3H, s), 3.67 (3H, s), 2.36 (2H, m), 1.75 (1H, m), 1.37 (3H, s), 0.73 (1H, m), 0.48 (1H, m), 0.07 (3H, s), 0.004 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 197.26, 174.70, 167.36, 158.07, 130.49, 128.96, 113.81, 83.97, 82.36, 55.34, 52.43, 47.74, 46.32, 23.83, 16.90, 7.52, 0.56, 0.45; HRMS (ESD calcd. for C20H28NO6Si (M+H)+ 406.1686, found 406.1692.

EXAMPLE 11

Figure US07183417-20070227-C00024

Conversion of (13) to (14).

To a solution of freshly prepared cyclohexenyl zinc chloride (10 mL, 0.5 M solution in THF, 5 mmol) (see Example 15 below) at −78° C. under nitrogen was added a −78° C. solution of aldehyde 13 (1.01 g, in 3 ml of THF, 2.5 mmol). After stirring for 5 h at −78° C. reaction mixture was quenched with water (10 mL) then extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over Na2SOand solvent was removed in vacuo to give crude product (20:1 dr). The diastereomers were purified by column chromatography (silica gel, ethyl acetate/hexanes, 1:10 to 1:2 affords the pure major diastereomer 14 (1.0 g, 83%) and a minor diastereomer (50 mg 5%). For 14: Rf=0.56 (50% ethyl acetate in hexanes).

mp, 79–81° C.; [a]23 D−28.5 (c 1.45, CHCl3); FTIR (film) νmax: 3267, 2927, 2894, 2829, 1742, 1667, 1509, 1248, 1164, 1024, 795 cm−11H NMR (CDCl3, 500 MHz): δ 7.34 (2H, d, J=8.5 Hz), 6.81 (2H, d, J=9.0 Hz), 5.84 (1H, m), 5.73 (1H, m), 4.88 (1H, d, J=15.5 Hz), 4.39 (1H, d, J=14.5 Hz), 4.11 (1H, t, J=6.5 Hz), 3.77 (3H, s), 3.58 (3H, s), 3.00 (1H, m), 2.95 (1H, d, J=9.0 Hz), 2.83 (1H, t, J=3.5 Hz), 3.36 (1H, m), 2.27 (1H, m), 1.98 (2H, m), 1.74 (3H, m), 1.62 (3H, s), 1.14 (2H, m), 0.59 (1H, m), 0.39 (11H, m), 0.13 (3H, s), 0.03 (3H, s); 13C NMR (CDCl3, 125 MHz): δ 176.80, 170.03, 158.27, 131.86, 131.34, 128.50, 126.15, 113.40, 83.96, 82.45, 77.17, 55.45, 51.46, 48.34, 48.29, 39.08, 28.34, 25.29, 22.45, 21.09, 17.30, 7.75, 0.39, 0.28; HRMS (ESI) calcd. for C26H38NO6Si (M+H)+ 488.2468, found 488.2477.

EXAMPLE 12

Figure US07183417-20070227-C00025

Tamao-Fleming Oxidation of (14) to (15).

To a solution of 14 (0.974 g, 2 mmol) in THF (5 mL) and MeOH (5 mL) at 23° C. was added KHCO(0.8 g, 8 mmol) and KF (0.348 g, 6 mmol). Hydrogen peroxide (30% in water, 5 mL) was then introduced to this mixture. The reaction mixture was vigorously stirred at 23° C. and additional hydrogen peroxide (2 ml) was added after 12 h. After 18 h, the reaction mixture was quenched carefully with NaHSOsolution (15 mL). The mixture was extracted with ethyl acetate (3×25 mL) and the combined organic layers were washed with water and dried over Na2SO4. The solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography (silica gel, ethyl acetate) to give the pure triol 15 (0.82 g, 92%).

Rf=0.15 (in ethyl acetate). mp, 83–84° C.; [α]23 D: +5.2 (c 0.60, CHCl3); FTIR (film) νmax; 3317, 2920, 2827, 1741, 1654, 1502, 1246, 1170, 1018, 802 cm−11HNMR(CDCl3, 500 MHz): δ 7.77 (2H, d, J=8.0 Hz), 6.28 (2H, d, J=8.0 Hz), 5. 76 (1H, m), 5.63 (1H, d, J=10.0 Hz), 4.74 (1H, d, J=15.5 Hz), 4.54 (1H, d, J=15.0 Hz), 4.12 (1H, d, J=2.5 Hz), 3.80 (1H, m), 3.76 (3H, s), 3.72 (1H, m), 3.68 (3H, s), 3.00 (1H, m), 2.60 (1H, br), 2.20 (1H, m), 1.98 (2H, s), 1.87 (1H, m), 1.80 (1H, m), 1.71 (2H, m), 1.61 (3H, s), 1.14 (2H, m); 13C NMR (CDCl3, 125 MHz): δ 178.99, 170.12, 158.27, 131.30, 130.55, 128.13, 126.39, 113.74, 81.93, 80.75, 76.87, 61.61, 55.45, 51.97, 51.32, 48.07, 39.17, 27.71, 27.13, 25.22, 21.35, 21.22; HRMS (ESI) calcd. for C24H34NO(M+H)+ 448.2335, found 448.2334.

EXAMPLE 13

Figure US07183417-20070227-C00026

Deprotection of (15) to (16).

To a solution of 15 (0.670 g, 1.5 mmol) in acetonitrile (8 mL) at 0° C. was added a pre-cooled solution of ceric ammonium nitrate (CAN) (2.46 g 4.5 mmol in 2 mL H2O). After stirring for 1 h at 0° C. the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaCl solution (5 mL) and organic layers was dried over Na2SO4. The solvent was removed in vacuo to give the crude product which was purified by column chromatography (silica gel, ethyl acetate) to give the pure 16 (0.4 g, 83%).

Rf=0.10 (5% MeOH in ethyl acetate). mp, 138 to 140° C.; [α]23 D+14.5 (c 1.05, CHCl3); FTIR (film) νmax 3301, 2949, 2911, 2850, 1723, 1673, 1437, 1371, 1239, 1156, 1008, 689 cm−11H NMR (CDCl3, 600 MHz): δ 8.48 (1H, br), 6.08 (1H, m), 5. 75 (1H, d, J=9.6 Hz), 5.29 (1H, br), 4.13 (1H, d, J=6.6 Hz), 3.83 (3H, m), 3.79 (1H, m), 3.72 (1H, m), 2.84 (1H, d, J=10.2 Hz), 2.20 (1H, m), 2.16 (1H, br), 1.98 (3H, m), 1.77 (3H, m), 1.59 (1H, m), 1.54 (3H, s), 1.25 (1H, m). 13C NMR (CDCl3, 125 MHz): δ 180.84, 172.95, 135.27, 123.75, 82.00, 80.11, 75.56, 62.39, 53.14, 51.78, 38.95, 28.79, 26.48, 25.04, 20.66, 19.99; HRMS (ESI) calcd. (M+H)+ for C16H26NO328.1760, found 328.1752.

EXAMPLE 14

Figure US07183417-20070227-C00027

Conversion of (16) to Salinosporamide A(1).

A solution of triol ester 16 (0.164 g, 0.5 mmol) in 3 N aq LiOH (3 mL) and THF (1 mL) was stirred at 5° C. for 4 days until hydrolysis was complete. The acid reaction mixture was acidified with phosphoric acid (to pH 3.5). The solvent was removed in vacuo and the residue was extracted with EtOAc, separated, and concentrated in vacuo to give the crude trihydroxy carboxylic acid 16a (not shown). The crude acid was suspended in dry CH2Cl(2 mL), treated with pyridine (0.5 mL) and stirred vigorously at 23° C. for 5 min. To this solution was added BOPCl (152 mg, 0.6 mmol) at 23° C. under argon, and stirring was continued for 1 h. The solvent was removed under high vacuum and the residue was suspended in dry CH3CN (1 mL) and treated with pyridine (1 mL). To this solution was added PPh3Cl(333 mg, 1.0 mmol) at 23° C. under argon with stirring. After 1 h the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate-CH2Cl2, 1:5) to give the pure β-lactone 1 (100 mg, 64%) as a colorless solid.

Rf=0.55 (50% ethyl acetate in hexane). mp, 168–170° C. (authentic sample: 168–170° C., 169–171° C. in Angew. Chem. Int. Ed., 2003, 42, 355–357); mixture mp, 168–170C. [α]23 −73.2 (c 0.49, MeOH), −72.9 (c 0.55, MeOH, in Angew. Chem. Int. Ed., 2003, 42, 355–357); FTIR (film) νmax: 3406, 2955, 2920, 2844, 1823, 1701, 1257, 1076, 1012, 785, 691 cm−11H NMR (CDCl3, 500 MHz): δ 10.62 (1H, br), 6.42 (1H, d, J=10.5 Hz), 5.88 (1H, m), 4.25 (1H, d, J=9.0 Hz), 4.14 (1H, m), 4.01 (1H, m), 3.17 (1H, t, J=7.0 Hz), 2.85 (1H, m), 2.48 (1H, m), 2.32 (2H, m), 2.07 (3H, s), 1.91 (2H, m), 1.66 (2H, m), 1.38 (1H, m);13C NMR (CDCl3, 125 MHz): δ 176.92, 169.43, 129.08, 128.69, 86.32, 80.35, 70.98, 46.18, 43.28, 39.31, 29.01, 26.47, 25.35, 21.73, 20.00; HRMS (ESI) calcd. for (M−H) C15H19ClNO312.1003, found 312.1003.

 

 

544814 Oct 1, 2007 Jun 9, 2009 Nereus Pharmaceuticals, Inc. [3.2.0] Heterocyclic compounds and methods of using the same
US7579371 Jun 15, 2006 Aug 25, 2009 Nereus Pharmaceuticals, Inc. Methods of using [3.2.0] heterocyclic compounds and analogs thereof
US7824698 Feb 4, 2008 Nov 2, 2010 Nereus Pharmaceuticals, Inc. Lyophilized formulations of Salinosporamide A
US7842814 Apr 6, 2007 Nov 30, 2010 Nereus Pharmaceuticals, Inc. Total synthesis of salinosporamide A and analogs thereof
US7910616 May 12, 2009 Mar 22, 2011 Nereus Pharmaceuticals, Inc. Proteasome inhibitors
US8003802 Mar 6, 2009 Aug 23, 2011 Nereus Pharmaceuticals, Inc. Total synthesis of Salinosporamide A and analogs thereof
US8067616 Oct 27, 2010 Nov 29, 2011 Nereus Pharmaceuticals, Inc. Total synthesis of salinosporamide A and analogs thereof
US8168803 Jun 10, 2008 May 1, 2012 Nereus Pharmaceuticals, Inc. Methods of using [3.2.0] heterocyclic compounds and analogs thereof
US8217072 Jun 18, 2004 Jul 10, 2012 The Regents Of The University Of California Salinosporamides and methods for use thereof
US8222289 Dec 15, 2009 Jul 17, 2012 The Regents Of The University Of California Salinosporamides and methods for use thereof
US8227503 Mar 21, 2011 Jul 24, 2012 Nereus Pharmaceuticals, Inc. Proteasome inhibitors
US8314251 Jul 15, 2011 Nov 20, 2012 Nereus Pharmaceuticals, Inc. Total synthesis of salinosporamide A and analogs thereof
US8389564 May 14, 2012 Mar 5, 2013 Venkat Rami Reddy Macherla Proteasome inhibitors
US8394816 Dec 5, 2008 Mar 12, 2013 Irene Ghobrial Methods of using [3.2.0] heterocyclic compounds and analogs thereof in treating Waldenstrom’s Macroglobulinemia

 

Name: Marizomib
Synonyms: 6-Oxa-2-azabicyclo[3.2.0]heptane-3,7-dione, 4-(2-chloroethyl)-1-[(S)-(1S)-2-cyclohexen-1-ylhydroxymethyl]-5-methyl-, (1R,4R,5S)-;  Other Names: (-)-Salinosporamide A; ML 858; Marizomib; NPI 0052; Salinosporamide A
CAS Registry Number: 437742-34-2 
Molecular Formula: C15H20ClNO4
Molecular Weight: 313.1
Molecular Structure:  

RAMOSETRON


RAMOSETRON, Antiemetics

Ramosetron (INN),(1-methylindol-3-yl)-[(5R)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl]methanone,  132036-88-5 cas no

  C17H17N3O 
  279.33 g/mol

(1-methyl-1H-indol-3-yl)[(5R)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl]methanone

YM060

  • Nasea
  • Nor-YM 060
  • Ramosetron
  • UNII-7ZRO0SC54Y

…………………………………………………………………………………..

HYDROCHLORIDE SALT

2D image of a chemical structure

hyrochloride salt, cas no 132907-72-3

C17-H17-N3-O.Cl-H
315.8022
Yamanouchi (Originator)
GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, 5-HT3 Antagonists
Launched-1996 JAPAN

 (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 78.8%, 99.5% e.e.). FAB-MS (m/z): 280 [M+H+]

1H NMR (DMSO-d6, 30° C.): δ ppm (TMS internal standard): 1.82-1.95 (1H, m), 2.12-2.22 (1H, m), 2.66-2.94 (4H, m), 3.63-3.72 (1H, m), 3.88 (3H, s), 7.24 (1H, t, J=8.0 Hz), 7.30 (1H, t, J=8.0 Hz), 7.56 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=8.0 Hz), 8.53 (1H, s), 8.90 (1H, s), 14.42 (1H, br)

…………………………………………………………………………………….

Ramosetron (INN) is a serotonin 5-HT3 receptor antagonist for the treatment of nausea and vomiting.[1] Ramosetron is also indicated for a treatment of “diarrhea-predominant irritable bowel syndrome in males”.[2] In India it is marketed under the brand name of“IBset”.
It is only licensed for use in Japan and selected Southeast Asian countries. In Japan it is sold under the tradename Iribo (イリボー). [3] Elsewhere it is commonly sold under the tradename Nasea and in India as Nozia (300 mcg/ml Inj. & 100 mcg Tab.) [4]

  1.  Fujii Y, Saitoh Y, Tanaka H, Toyooka H (February 2000). “Ramosetron for preventing postoperative nausea and vomiting in women undergoing gynecological surgery”.Anesth. Analg. 90 (2): 472–5. doi:10.1097/00000539-200002000-00043.PMID 10648342.
  2. http://www.astellas.com/en/corporate/news/detail/astellas-launches-irribow-for.html
  3.  Summary in Japanese. Retrieved on September 4, 2012.
  4.  Abridged prescribing information – Nasea (MIMS Philippines). Retrieved on June 13, 2008.
  5. Synthesis and 5-HT3 antagonistic activities of 4,5,6, 7-tetrahydrobenzimidazole derivatives
    200th ACS Natl Meet (August 26-31, Washington DC) 1990, Abst MEDI 39
1-27-2010
Process for producing ramosetron or its salt
11-20-1996
Intrabuccally dissolving compressed moldings and production process thereof
3-6-1996
5-substituted tetrahydrobenzimidazole compounds
11-15-1995
Intrabuccally disintegrating preparation and production thereof
9-7-1994
Tetrahydrobenzimidazole derivatives and pharmaceutical compositions containing same
6-24-1994
NEW USE OF 5-HT3 RECEPTOR ANTAGONISTS

AU 9048890; EP 0381422; JP 1991223278; US 5344927

CN1696128A Nov 2, 2004 Nov 16, 2005 天津康鸿医药科技发展有限公司 New method for synthesizing Ramosetron Hydrochloride
CN1765896A Oct 28, 2004 May 3, 2006 北京博尔达生物技术开发有限公司 Novel preparation method of ramosetron hydrochloride
US5496942 * 14 Feb 1994 5 Mar 1996 Yamanouchi Pharmaceutical Co., Ltd. 5-substituted tetrahydrobenzimidazole compounds
US5677326 * 30 Sep 1994 14 Oct 1997 Tokyo Tanabe Company Limited Indoline compound and 5-HT.sub.3 receptor antagonist containing the same as active ingredient
US7358270 28 Jan 2005 15 Apr 2008 Astellas Pharma Inc. Treating agent for irritable bowel syndrome
US7683090 18 Oct 2006 23 Mar 2010 Astellas Pharma Inc. Treating agent for irritable bowel syndrome
US7794748 27 Aug 2004 14 Sep 2010 Yamanouchi Pharmaceutical Co., Ltd. Stable oral solid drug composition

WO 2010024306

WO 2013005760

WO 2013100701

WO 2011001954

The chemical name of ramosetron is (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole, and it has the structure represented by the formula (II).

Figure US07652052-20100126-C00002

It is known that ramosetron or a salt thereof has a potent 5-HTreceptor antagonism (Patent Reference 1, Non-patent references 1 and 2), and it is on the market as a preventive or therapeutic agent for digestive symptoms (nausea, emesis) caused by administration of an anti-malignant tumor agent (cisplatin or the like). In addition, a possibility has been reported that ramosetron or a salt thereof may be useful as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome (Patent Reference 1), and its clinical trials are now in progress as an agent for treating diarrheal-type irritable bowel syndrome or an agent for improving diarrheal symptoms of irritable bowel syndrome.

As a process for producing ramosetron or a salt thereof, the following production methods are known.

Patent Reference 1 describes a production method shown by the following Production method A, namely a method for producing a tetrahydrobenzimidazole derivative (V) by allowing a heterocyclic compound (III) to react with a carboxylic acid represented by a formula (IV) or its reactive derivative.

(Production Method A)

Figure US07652052-20100126-C00003

(In the formula, Xis a single bond and binds to a carbon atom on the heterocyclic ring represented by Het.)

As an illustrative production method of ramosetron, Patent Reference 1 describes a production method (Production method A-1) in which racemic ramosetron are obtained by using 1-methyl-1H-indole as the compound (III), and N,N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide or N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine, which are acid amides, as the reactive derivative of compound (IV), and allowing them to undergo treatment with phosphorus oxychloride (Vilsmeyer reaction), and then their optical resolution is carried out by fractional crystallization using (+)-dibenzoyltartaric acid.

In addition, the Patent Reference 1 exemplifies an acid halide as one of the reactive derivatives of the compound (IV), and also describes another production method of the compound (V) (Production method A-2) in which the heterocyclic compound (III) is condensed with an acid halide of the compound (IV) by the Friedel-Crafts acylation reaction using a Lewis acid as the catalyst. However, illustrative production example of ramosetron by the Friedel-Crafts acylation reaction is not described therein.

Also, a method similar to the Production example A-1 is described in Non-patent References 1 and 2 as a production method of ramosetron.

In addition, Non-patent Reference 3 describes a method for producing ramosetron labeled with 11C, represented by a Production method B. However, it discloses only the methylation step, and does not disclose a production method of nor-YM060 as the starting material.

(Production Method B)

Figure US07652052-20100126-C00004

(In the formula, nor-YM060 means (R)-5-[(1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole which was provided by the present applicant, DMF means dimethylformamide.)

  • Non-patent Reference 1: Chemical Pharmaceutical Bulletin, 1996, vol. 44, no. 9, p. 1707-1716
  • Non-patent Reference 2: Drugs of the Future, 1992, vol. 17, no. 1, p. 28-29
  • Non-patent Reference 3: Applied Radiation and Isotopes, 1995, vol. 46, no. 9, p. 907-910
  • Patent Reference 1: JP-B-6-25153

LIU Qing-wen, XU Hao, TIAN Hua, ZHENG Liang-yu, ZHANG Suo-qin
Chemoenzymatic Synthesis of Ramosetron Hydrochloride

2012 Vol. 28 (1): 70-72 [Abstract] ( 1143 ) [HTML 1KB] [PDF 206KB] ( 1052 )
doi:http://www.cjcu.jlu.edu.cn/hxyj/EN/abstract/abstract13356.shtml

…………………………………………………………………………..

The Vilsmeier-type reaction of 1-methylindole (I) with 5 – (1-pyrrolidinocarbonyl) -4,5,6,7-1 H-tetrahydrobenzimidazole hydrochloride (II) and phosphorous oxychloride in 1,2-dichloroethane gives (-5? -. [(1-methyl-3-indolyl) carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazol e (III) Optical resolution of (III) with (+)-dibenzoyltartaric acid (DIBTA) in DMF -H2O, followed by exchange of the salt affords YM060.

………………………………………………….

Ondansetron: 1,2,3 ,9-Tetrahydro-9-methyl-3-[(2-methyl1-H-imidazole-1-yl)methyl]-4H-carbazol-4-one

Figure US06451808-20020917-C00005

Granisetron: Endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide

Figure US06451808-20020917-C00006

Tropisetron: Endo-1H-indole-3-carbocylic acid8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester

Figure US06451808-20020917-C00007

Dolasetron: 1H-Indole-3 -carboxylic acid (2a, 6a, 8a, 9up)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl Ester

Figure US06451808-20020917-C00008

Azasetron: (±)-N-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide

Figure US06451808-20020917-C00009

Alosetron: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one

Figure US06451808-20020917-C00010

Ramosetron

Figure US06451808-20020917-C00011
2D image of a chemical structure
Galdansetron hydrochloride [USAN]
156712-35-5

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PF-868554 is an anti-hepatitis C drug candidate which had been in phase II clinical trials at Pfizer; however this research has been discontinued.
Li, H.; Tatlock, J.; Linton, A.; et al
Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor
J Med Chem 2009, 52(5): 1255
Johnson, S.; Drowns, M.; Tatlock, J.; et al.
Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation
Synlett (Stuttgart) 2010, 2010(5): 796
WO 2012016995
WO 2013101550
WO 2011072370
WO 2007023381
WO 2006018725
WO2003095441A1 * 7 mei 2003 20 nov 2003 Melwyn A Abreo Inhibitors of hepatitis c virus rna-dependent rna polymerase, and compositions and treatments using the same
WO2006018725A1 * 5 aug 2005 23 feb 2006 Pfizer Inhibitors of hepatitis c virus rna-dependent rna polymerase, and compositions and treatments using the same
US20050176701 * 19 nov 2003 11 aug 2005 Agouron Pharmaceuticals, Inc. Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the sameWO2007023381A1
Example 1 : Preparation of the glycolate salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol
Figure imgf000055_0001
glycolate salt
Glycolic acid (1 L, 70% in water, 11.51 mol) was added to a 5 L flask. To the solution was slowly added aminoguanidine bicarbonate (783.33 g, 5.755 mol) in portions to control significant bubbling. As solids are added, the solution cools due to endothermic dissolution. The solution was gently heated to maintain an internal temp of 25 °C during addition. Ten minutes after complete addition of aminoguanidine bicarbonate, cone. Nitric acid (6.8 ml_) was carefully added. The solution was heated to an internal temperature of 104-108 0C (mild reflux) for 22 h. The heating was discontinued and the solution allowed to cool, with stirring. At an internal temp of aboutδi °C, solids began to crystallize. After the internal temperature was just below 80 0C, ethanol (absolute, 375 mL) was slowly added to the mixture. After the internal temp had cooled to aboutδδ 0C1the cooling was sped up by the use of an ice/water bath. After cooling below rt, the solution became very thick but remained stirrable at all times. The slurry was stirred for 2h at T<10 0C, then filtered and the solids rinsed with ethanol (900 mL cold, then 250 mL rt). The solids were dried overnight in a vacuum oven (about25 mmHg, 45-50 0C) to provide 815.80 g (75%) of (5-amino-1H-1 ,2,4-triazol-3-yl)methanol as the glycolate salt. 1H (300 MHz, de-DMSO): 3.90 (s, 2), 4.24 (s, 2).
Example 2: Preparation of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol
Figure imgf000056_0001
To a 2L, 3-neck flask was charged glycolate salt of (5-amino-1tf-1 ,2,4-triazol-3-yl)methanol (99.93 g, 0.526 mol), 2,4 pentanedione (0.578 mols, 60 mL), acetic acid (6.70 mL), and EtOH (550 mL). The mixture was heated to a slight reflux. One hour after adding the reagents, the resulting solution was cooled to ambient temperature, and CH2CI2 (500 mL) and Celite (25.03 g) were added. After stirring for 1 h, the mixture was filtered through a 4″ Buchner funnel packed with celite (20 g) and rinsed with EtOH (100 mL). The solution was distilled to 5 vols then cooled to 0 °C for 1-2 hours. The slurry was filtered and the cake was rinsed with cold EtOH (2×100 mL). The solids were dried to provide 76.67 g (81.7%) of the title compound.
1H NMR (300 MHz, d6-DMSO): 2.57 (s, 3), 2.71 (d, 3, J=0.8), 4.63 (uneven d, 2, J=5.7), 5.49
(t, 1 , J=6.2), 7.13 (d, 1 , J=0.8).
Example 3: Preparation of 5,7-dimethyl[1 ,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde
Figure imgf000056_0002
To a 10 L reactor was sequentially charged CH2CI2 (5.1 L)1 (5,7- dimethyl[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methanol (680 g, 3.816 mol), and iodobenzene diacetate (1352 g, 4.197 mol). As the iodobenzene diacetate dissolves, there is a significant endotherm (typically down to 15-16 0C). The jacket was set to 23 0C. The mixture was warmed to ambient temperature and Tempo (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical, 43.75 g, 0.28 mol) added in a single charge. The reaction was stirred until 5% of the starting alcohol remained by HPLC. Once the starting material is adjudged to be less than about about5%, the over-oxidized product begins to be observed. Allowing the reaction to run to further completion leads to an overall diminished yield of the desired product. For this reaction, the desired reaction completion was reached in 2.75 h. MTBE (5.1 L) was then slowly charged to the reactor, causing the product to precipitate, and the slurry stirred for an additional 30 mins. The mixture was filtered, washed twice with 1 :1 DCM/MTBE (2 x 1 L), and dried in a vacuum oven overnight at 50 0C to provide 500.3 g (74%) of 5,7- dimethyl[1,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde as an off-white solid. 1H NMR (300 MHz, ds-DMSO): 2.64 (s, 3), 2.78 (d, 3, J=0.8), 7.36 (d, 1 , J=0.9), 10.13 (s, 1). Example 4: Preparation of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one
Figure imgf000057_0001
DMAC
L-DBTA NEt3-HOTs + LiBr + NEt3-HBr THF/MTBE
Figure imgf000057_0002
A nitrogen-purged, 5-L, 3-neck flask containing 4-bromo-2,6-diethylpyridine (250.0 g, 0.6472 mol) was sequentially charged with LiBr (112.42 g, 1.2944 mol), 1-cyclopentyl-prop-2- en-1-ol ( 89.84 g, 0.7119 mol), DMAc (625 mL), and H2O (55.0 mL). The mixture was cooled to 5-10 0C and was then purged (subsurface) with N2 for 30 minutes. The flask was charged with Et3N (198.5 mL, 1.4242 mol) and Pd(OaC)2 (3.63 g, 0.0162 mol), followed by a careful purge of the headspace. The reaction was heated until the internal temperature reached 95 0C. After stirring at 95 °C for three hours, an aliquot was removed and analyzed by HPLC, showing >99% conversion to 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one. The reaction was then cooled to 30 0C over 20 min. The flask was charged with H2O (1500 mL), and MTBE (1500 mL). The solution was stirred well for 5 minutes before the mixture was allowed to settle and the aqueous layer was removed. To the organic layer was charged Celite (62.5Og), and Darco G-60 (6.25g). The slurry was stirred for 20 minutes at 20-25 0C. The slurry was then filtered using a Buchner funnel dressed with Celite. The filter cake was rinsed with MTBE (250 mL). The organic layer was extracted with 5% sodium bicarbonate solution (500 mL) and the phases separated. The organic layer was transferred to a 5 L, three-neck flask, and MTBE added to achieve a total reaction volume of 1750 mL. Additional MTBE (1500 mL) was added and atmospherically distilled until an internal volume of 1750 mL was reached. After cooling below 40 0C, a sample was removed for analysis of water content. After cooling to 20-25 0C, MTBE (250 mL) was added to bring the total volume to 2000 mL and the solution was seeded with crystals of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one (130 mg), which were prepared according to this procedure. A solution of dibenzoyl-L-tartaric acid (231.89 g, 0.6472 mol) in THF (900 mL) was added over 25 minutes. The slurry was granulated for 1 hour, the mixture was filtered, and the cake rinsed with MTBE (450 mL). The solids were dried in a vacuum oven at 50 0C for 12 h to provide 366.70 g (92% yield) of the title compound. 1H NMR (300 MHz, d6-DMSO): 1.19 (t, 6, J=7.6), 1.47-1.81 (m, 8), 2.73 (q, 4, J=7.6), 2.73-2.98 (m, 5), 5.86 (s, 2), 7.00 (S1 2), 7.55-7.63 (m, 4), 7.68-7.75 (m, 2), 7.98-8.04 (m, 4).
Example 5: Preparation of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid
Figure imgf000058_0001
A 3-L, 3-neck flask was charged with the dibenzoyl-L-tartaric acid salt of 1- cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one (174.95 g, 0.2832 mol), MTBE (875 mL), water (875 mL), and triethanolamine (113.0 mL, 0.8513 mol). After stirring for 2 h at rt, an aliquot of the aqueous phase was removed and analyzed by HPLC, showing no detectable starting material. The solution was transferred to a separatory funnel and the layers separated. The lower aqueous phase was discarded and the upper org. phase was washed with water (150 mL). The organic layer was added to a flask set up for distillation. The solution was distilled down to approx. 183 mL and an aliquot was removed and analyzed for water content. The dry solution of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one (th. Wt = 73.47 g) in MTBE was used directly in the next step.
A clean 2-L, 3-neck flask was charged with LiHMDS (1.0 M in THF, 355 mL, 0.355 mol) and purged with nitrogen. The flask was cooled to -34 0C. An addition funnel was then charged with EtOAc (35 mL, 0.3583 mol) and this reagent was slowly added to the reaction vessel at such a rate that the low temperature of the vessel could be maintained. After complete EtOAc addition another addition funnel was charged with the 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one solution (crude MTBE soln from prior reaction, theor. 73.47 g, 0.2832 mol) and rinsed over with THF (anhydrous, 5 ml_). The 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one solution was slowly added to the reaction flask at such a rate that the low internal temperature could be maintained. Five minutes after complete addition, a reaction aliquot was removed and analyzed by HPLC, showing less than 1% 1-cyclopentyl-3- (2,6-diethylpyridin-4-yl)propan-1-one. Ten minutes after complete ketone addition, the bath was switched to O 0C. Once the internal temperature had warmed to -10 0C, 1 M NaOH (510 mL) was added. After complete NaOH soln addition, the reaction was heated to 50 0C. After 21 hours the reaction solution was cooled below 30 0C and an aliquot of both layers was removed and analyzed for completion. The mixture was added to a separatory funnel with MTBE (350 mL) and the phases were mixed well and separated. An aliquot of the organic phase was analyzed by HPLC, verifying no significant product, and this layer was discarded. The aqueous phase was added to a flask with CH2CI2(350 mL). Concentrated aqueous HCI (about 100 mL) was slowly added to the aqueous phase until the pH = 5. The mixture was added back to a separatory funnel and mixed well. The phases were separated and the aqueous layer was extracted a second time with CH2CI2 (150 mL). The organic layers were combined and charged to a clean flask set up for distillation. The solution was distilled down to 370 mL then displaced with THF by addition of solvent portions followed by continued distillation down to 370 mL after each addition. When the distillation head temp, held steady at 65 °C for 30 min an aliquot was removed and analyzed by 1H NMR, showing a 12.5:1 ratio of THF:CH2CI2. The solution of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF was used directly in the next step.
Example 6a: Preparation of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanedioI salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid
Figure imgf000059_0001
A 2-L, 3-neck flask was sequentially charged with a solution of 3-cyclopentyl-5-(2,6- diethylpyridin-4-yl)-3-hydroxypentanoic acid (crude from last step, theoretical 95.28 g, 0.1792 mol, in about300 mL), (1 R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3-propanediol (38.03 g, 0.1792 moles) and THF (415 mL). A seed crystal of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid, prepared according to this procedure, was added and the mixture was stirred and heated to 65 0C, then held at this temperature for 16 h. The slurry was cooled slowly to rt and stirred for at least 1 h. The slurry was filtered and the cake rinsed with THF (100 mL). The filtrate (solution of (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF) was used directly in the next procedure. The solids were dried to provide 67.09 g (42 %) of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3-propanediol salt of ®-3-cyclopentyl-5-(2,6- diethylpyridin-4-yl)-3-hydroxypentanoic acid as an off-white crystalline solid. Chiral HPLC analysis of the product showed a 92.1:7.9 ratio of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)- 1 ,3-propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid to (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid. HPLC conditions: The solid was dissolved in methanol. HPLC conditions: Chirobiotic TAG column, 4.6 x 250 mm, 40 0C column chamber, flow rate = 0.5 mL/min, mobile phase = 100% MeOH (0.05% TEA, 0.05% HOAc). Gradient: Initial flow rate = 0.5 mL/min; 10 min flow rate = 0.5 mL/min; 10.10 min flow rate = 2.00 mL/min; 35 min flow rate = 2.00 mL/min; 36 min flow rate = 0.5 mLΛnin. Percentages reported are at 265 nm. Retention times: (1 R,2R)-(-)-2- amino-1-(4-nitrophenyl)-1 ,3-propanediol = >30 min; (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4- yl)-3-hydroxypentanoic acid = 5.8 min; ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3- hydroxypentanoic acid = 7.2 min. 1H NMR (300 MHz, d6-DMSO): 1.19 (t, 6, J=7.6), 1.38-1.62 (m, 8), 1.65-1.75 (m, 2), 1.93-2.07 (m, 1), 2.23 (d, 1 , J=14.4), 2.31 (d, 1 , J=14.4), 2.56 (m, 2), 2.64 (q, 4, J=7.6), 2.91-2.99 (m, 1), 3.22 (dd, 1 , J=5.8, 11.1), 3.42 (dd, 1 , J=4.8, 11.1), 4.77 (d, 1 , J=6.2), 6.0 (br s, 6), 6.84 (s, 2), 7.62 (d, 2, J=8.7), 8.20 (d, 2, J=8.8). Example 6b: Recrystallization of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid
A 2-L, 3-neck flask was charged with the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (66.20 g, 0.1245 moles) and 2B EtOH (970 mL absolute EtOH + 5 mL toluene). The slurry was stirred and heated to reflux. After holding at reflux for 40 min, all the solids had dissolved and the solution was cooled to an internal temp of about 65 0C over 30 min, and the solution was then seeded with crystals of the title compound. The solution was allowed to cool to 50 0C and held for an additional 2h. The solution was then cooled slowly to room temperature over about 2 hours. The cooled solution was stirred at rt for an additional 10 h. The mixture was then filtered and the solids rinsed with 2B EtOH (75 mL). The solids were dried to provide 52.72 g (80%) of product as an off-white crystalline solid that was then dried under vacuum (30 mm Hg) with a nitrogen bleed at 50 0C for 12 h. Chiral HPLC analysis showed product with 96% ee. For determination of e.e., the solid was dissolved in MeOH. HPLC conditions: Chirobiotic TAG column, 4.6 x 250 mm, 40 0C column chamber, flow rate = 0.5 ml_/min, 100% MeOH (0.05% TEA, 0.05% HOAc). Gradient: Initial flow rate = 0.5 mL/min; 10 min flow rate = 0.5 mL/min; 10.10 min flow rate = 2.00 mL/min; 35 min flow rate = 2.00 mL/min; 36 min flow rate = 0.5 mL/min. Percentages reported are at 265 nm. Retention times: (1 R,2R)-(-)-2- amino-1-(4-nitrophenyl)-1 ,3-propanediol = >30 min, (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4- yl)-3-hydroxypentanoic acid = 5.8 min, ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3- hydroxypentanoic acid = 7.2 min.
Example 7: Preparation of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one from (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid
Figure imgf000061_0001
A flask was charged with a solution of (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3- hydroxypentanoic acid (crude from last step, theoretical 15 g, 0.0470 mol, in about 200 mL THF) and ethanol (100 ml_, 1.7126 mol). To the solution, H2SO4 (5.0 ml_, 0.0938 mol) was added slowly. The solution was heated at reflux for 18 h. When the reaction was judged to be complete by HPLC, the solution was cooled and added to a separatory funnel with 0.5M NaOH (400 mL) and then extracted with MTBE (200 mL). The phases were separated and the organic layer was washed with aqueous acetic acid H2O (100 mL H2O + 3.0 mL HOAc). The phases were separated and the organic layer was washed with 0.5 M NaOH (100 mL). The phases were separated and the organic layer was washed with saturated aqueous NaCI solution (25 mL). The organic layer was distilled at atmospheric pressure down to an internal volume of 150 mL. The solvent was displaced by toluene via atmospheric distillation by adding toluene (100 mL), distilling down to 200 mL internal volume, and repeating this procedure two more times. The final solution was distilled down to an internal volume of 130 mL. An aliquot was removed and analyzed by KF titration. The solution was cooled to rt and a solution of KotBu (1.0M in THF, 4.7 mL, 0.0047 mol) was added in one portion. After 5 min, an aliquot was removed and analyzed by HPLC. The solution was added to a separatory funnel with 1M HCI (60 mL). The phases were mixed well and separated, transferring the product to the aqueous phase. The organic phase was extracted once with water (10 mL) and the aqueous phases combined. The organic phase was discarded. To the aqueous phase was added MTBE (60 mL) and 1 M NaOH (70 mL) and the phases mixed well. The phases were separated and the organic phase extracted with saturated aqueous NaCI solution (25 mL). MTBE was added to bring the volume up to 125 mL. The solution was cooled to rt and seeded with crystals of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3-(2,6-diethylpyridin- 4-yl)propan-1-one (prepared according to Example 4). In a separate vessel, L-DBTA (16.89 g, 0.0471 mol) was dissolved in THF (65 ml_). The solution of L-DBTA was added to the 1- cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution over 45 min, and the slurry granulated for 1 h. The slurry was filtered and the cake washed with MTBE (50 mL). The solids were dried to provide 19.54 g of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3- (2,6-diethylpyridin-4-yl)propan-1-one (67 %) as an off-white solid. Example 8a: Preparation of the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one
Figure imgf000062_0001
i. CDI, DWIAP O O
Ii. KO-^^OEt MgCI2
Figure imgf000062_0002
A nitrogen-purged flask containing the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (20.00 g, 0.0376 mol) was charged with CH2CI2 (200 mL) and H2O (100 mL). The pH of the mixture was adjusted to pH 4.75 with 40% aqueous citric acid (10 mL) and was stirred for 60 minutes. The layers were allowed to settle for 30 minutes and separated. The upper (aqueous) layer was charged CH2CI2 (50 mL), stirred 15 minutes, and was then allowed to settle. The organic layer was combined with the first organic layer and dried with sodium sulfate. The dried organic was concentrated under reduced pressure. The ®-3-cyclopentyl-5-(2,6-diethylpyridin- 4-yl)-3-hydroxypentanoic acid residue was dissolved in THF (47 mL) and this solution added to a slurry of carbonyl diimidazole (9.00 g, 0.0555 mol) and 4-N,N-dimethylaminopyridine (DMAP, 0.45 g, 0.0037 mol) in THF (106 mL) over 5 minutes. Upon complete acyl-imidazole formation, the solution was added to a slurry of potassium ethyl malonate (12.57 g, 0.0738 mol) and magnesium chloride (7.38 g, 0.0775 mol) in 106 mL THF over 5 minutes. The slurry was allowed to stir at 20-25 0C for 30 hours. An aliquot was removed and analyzed by HPLC, showing 96% conversion to ©-ethyl 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3- oxoheptanoate. The flask was charged with H2O (64 mL), and MTBE (118 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was removed. To the organic layer was charged brine (52 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was removed. The organic layer was then displaced via atmospheric distillation with methanol (2 x 210 mL) until a total volume of 140 mL was achieved. MTBE (105 mL) was added followed by powdered potassium carbonate (7.65 g, 0.0554 mol), and the slurry heated to reflux for 12 hours. After cooling to 40 °C, MTBE (140 mL) and water (140 mL) were added. The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was isolated. The organic layer was extracted with water (30 mL) and the aqueous layers were combined. CH2CI2 (140 mL) was added to the aqueous layer and the pH adjusted to 6.4 with 40% aqueous citric acid (29 mL). The aqueous layer was extracted a second time with CH2CI2 (25 mL). The combined organic layers were then displaced fully into MTBE (140 mL final volume) via atmospheric distillation, cooled, and added slowly to a solution of dibenzoyl-D-tartaric acid (9.92 g, 0.0277 mol) in MTBE (100 mL). The slurry was heated to reflux for 1 hour, then allowed to cool to 20-25 0C. The mixture was filtered, and the cake rinsed with MTBE (50 mL). The solids were dried in a vacuum oven at 50 0C for 12 h to provide 16.40 g (62%) of the title compound.
Example 8b: Preparation of the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one
A nitrogen-purged flask containing the (1 R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3-propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (50.00 g, 0.0940 mol) was charged with CH2CI2 (500 mL) and H2O (250 mL). The pH of the resulting suspension was adjusted to pH 4.6 to 4.8 (a measured pH of 4.75 is preferred) with 40% aqueous citric acid (21 mL) and was stirred for 30 minutes. The layers were allowed to settle for 30 minutes and separated. The upper (aqueous) layer was charged with CH2CI2 (100 mL), stirred 15 minutes, and allowed to settle. The organic layer was combined with the first organic layer. The upper (aqueous) layer was again charged with CH2CI2 (100 mL), stirred 15 minutes, and allowed to settle. This organic layer was also combined with the first organic layer. A sample of each of the combined organic layers and the aqueous layer was taken for HPLC analysis. The combined organic layers were atmospherically distilled until a total volume of 120 mL was reached. THF (100 mL) was charged and atmospheric distillation continued until a total volume of 120 mL was reached. The THF charge and displacement was repeated 3 times. A sample was removed and analyzed by NMR and KF. The resulting solution was added to a slurry of CDI (22.86 g, 0.1410 mol) and DMAP (1.15 g, 0.0094 mol) in THF (250 mL) over 15 minutes. The addition funnel was then rinsed with 10 mL THF which was then added to the CDI slurry. After stirring 15 minutes, a sample was removed and analyzed by HPLC. Upon complete acyl-imidazole formation, the solution was added to a slurry of potassium ethyl malonate (32.00 g, 0.1880 mol) and magnesium chloride (18.80 g, 0.1974 mol) in 250 mL THF at 20-25 0C over 25 minutes. The slurry was allowed to stir at 20-25 0C for 21 hours. An aliquot was removed and analyzed by HPLC, showing 96% conversion to ®- ethyl 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxoheptanoate. The flask was charged with H2O (162 mL), and MTBE (300 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the yellow aqueous (lower) layer was removed. To the organic layer was charged brine (100 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was removed. The organic layer was then atmospherically distilled down to 350 mL total volume. MTBE (250 mL) was charged and the solution distilled to 350 mL total volume. Additional MTBE (250 mL) was charged and the solution distilled at a temperature of at least 55 0C to 350 mL total volume. A sample was removed for KF titration. Methanol (250 mL) was charged and the solution was then atmospherically distilled until a total volume of 350 mL was achieved. Methanol (250 mL) was charged and then the solution was atmospherically distilled until a total volume of 350 mL was achieved and a temperature of ~66 0C was achieved. Powdered potassium carbonate (19.49 g, 0.1410 mol) was added and the slurry heated to reflux for 4 hours. A sample was removed for HPLC analysis showing >99% completion. After cooling to 22 0C, MTBE (350 mL) and water (350 mL) were added. The mixture was stirred well for 5 minutes before it was allowed to settle and the product rich aqueous (lower) layer was isolated. The organic layer was extracted with water (100 mL) and the aqueous layers were combined. To the combined aqueous layers was charged MTBE (100 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the product rich aqueous (lower) layer was isolated. CH2CI2 (350 mL) was added to the aqueous layer and the pH adjusted to 6.0-6.4 with 40% aqueous citric acid (75 mL). The aqueous layer was extracted a second time with CH2CI2 (100 mL). The combined organic layers were then atmospherically distilled to 250 mL total volume. MTBE (400 mL) was charged and the solution was atmospherically distilled at a temperature of at least 55 0C until 250 mL final volume was reached. After cooling the solution to 20-25 0C, a prepared solution of dibenzoyl-D-tartaric acid (23.58 g, 0.0658 mol) in MTBE (125 mL) was added over 10 minutes. The resulting slurry was heated to reflux for 4 hours, then allowed to cool to 20-25 0C and stirred an additional 4 hours. The slurry was filtered, and the cake rinsed with MTBE (125 mL). The solids were dried in a vacuum oven at 50 0C for 12 h to provide 38.19 g (58%) of the title compound. HPLC conditions: aliquots were withdrawn and dissolved in CH3CN/H2O (40:60). HPLC conditions: Kromasil C4 column, 5 μm, 4.6x150mm, 40 0C column chamber, flow rate= 1.0 mL/min, 40% CHsCN/60% aqueous (1.OmL 70% HcIO4 in 1 L H2O) isocratic. Percentages reported are at 254 nm. Approximate retention times: ®-3- cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid = 3.4 min; ©-ethyl 5- cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxoheptanoate = 7.3 min; ®-6-cyclopentyl- 3-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one = 3.9 min; D-DBTA = 5.5 min. Example 9a: Preparation of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- dimethyl-ri^.^triazoloII.S-alpyrimidini-Z-yOmethylH-hydroxy-S.e-clihyclropyran^-one
Figure imgf000065_0001
BHe-pyridine
Figure imgf000065_0002
A flask was charged with the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one (this material contained 1.5 eq DBTA counterion, 4.00 g, theor. 0.00454 mol), 2-MeTHF (40 ttiL), MTBE (40 mL), and water (20 mL). A solution of 5% aq NaHCO3 (about 20 mL) was added until the pH was 7.4. The solution pH was back-adjusted to pH = 7.2 with a small amount of 40% citric acid solution. The phases were separated and the aqueous layer was extracted with 2-MeTHF (25 mL). The combined organic layers were dried with Na2SO4 and concentrated to an oil. The oil was used directly in the subsequent condensation. To the crude ®-6-cyclopentyl-6-(2-(2,6- diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one was added methanol (32 mL) and the solution cooled to -40 0C. To the cold solution was added pyridine-borane complex (1.30 mL, 0.01287 mol) and 5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde (1.41 g, 0.00800 mol). The solution was warmed to 0 0C over 45 min then stirred for an additional 2 h. The reaction was quenched by the addition of water (10 mL) and the mixture stirred at rt overnight. To the mixture was added 1M HCI (10 mL), and the solution was stirred for 3 h. lsopropyl acetate (57 mL) was added and the pH adjusted to 7 by the addition of 1 M NaOH. The phases were separated and the organic layer extracted with water (25 mL x 2). The aqueous phases were extracted further with CH2CI2 (100 ml, 2 x 25 mL). The combined IPAc and CH2CI2 layers were dried (Na2SO4), filtered, and concentrated to yield 3.41 g of crude ®-6- cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2- yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one. To the residue was added isopropyl acetate (46 mL) and EtOH (2.5 mL) and the mixture heated to reflux until homogeneous. The solution was allowed to cool slowly to rt and stirred overnight. The slurry was filtered, the solids rinsed with IPAc (13 mL), and dried to provide 1.74 g (76 %) of ®-6-cyclopentyl-6-(2-(2,6- diethylpyridin-4-yl)ethyl)-3-((5J-dirnethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-
5,6-dihydropyran-2-one as an off-white solid.
Example 9b: Preparation of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- dimethyl-[1,2,4]triazolot1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one
A 500 mL flask was charged with the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-
6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one (15.00 g, 0.02137 moles), THF (75 mL), MeOH (75 mL), pyridine-borane (4.25 mL, 0.034 moles), and 5,7- dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde (5.65 g, 0.03207 moles) was added last. The resulting mixture was stirred at rt and an aliquot was removed after 1.25 h and analyzed by HPLC showing 13.5% ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4- hydroxy-5,6-dihydropyran-2-one. Stirring was continued for an additional 2 h, and HPLC analysis of an aliquot then showed 4.8% of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-
4-hydroxy-5,6-dihydropyran-2-one remaining. The reaction solution was charged with CH2CI2
(150 mL) and water (150 mL), and the phases were stirred overnight. The lower organic layer was removed and to the upper aqueous layer was charged CH2CI2 (25 mL), the phases were mixed well and separated and the aqueous layer was discarded. The organic layers were combined and charged to a flask containing water (150 mL) and triethanolamine (7.1 mL,
0.0535 mol), mixed well then separated. The lower organic layer was removed and to the upper aqueous layer was charged CH2CI2 (25 mL), the phases were mixed well, separated, and the aqueous layer was discarded. To the combined organic layers was charged water
(100 mL) and 1M NaOH (25 mL), the phases were mixed well, separated, and the lower organic layer was discarded. To the upper aqueous layer was charged CH2CI2 (75 mL) and
1N HCI was added until the pH=6.91 (~25 mL added), the phases were mixed well, separated, and the aqueous layer was discarded. The combined organic layers were extracted with water (3.2 volumes). The layers were separated and the organic layer was transferred to a
;lean flask marked with a 75 mL volume line. The organic layer was distilled atmospherically
0 75 mL. To the flask was charged isopropyl acetate (75 mL x 2) followed by distillation down
0 75 mL total volume after each addition. The flask was seeded and cooled to rt and stirred
)vemight. The reaction was filtered and the cake was washed with isopropyl acetate (25 ml).
he solids were dried to provide 7.20 g (67%) of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-
‘l)ethyl)-3-((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6- lihydropyran-2-one as an off-white powder, which was dried in a vacuum oven (~25 inHg at
0C) for 12 h. For HPLC monitoring, aliquots were withdrawn and dissolved in CH3CN/H2O
1-0:60). HPLC conditions: Kromasil C4 column, 5 μm, 4.6×150 mm, 40 0C column chamber, ow rate= 1.0 mL/min, 40% CH3CN/60% aqueous (1.0 mL 70% HcIO4 in 1L H2O) isocratic.
‘ercentages reported are at 254 nm. Retention times: ®-6-cyclopentyl-6-(2-(2,6- iethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one = 3.85 min; ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4- hydroxy-5,6-dihydropyran-2-one = 3.56 min; DBTA= 5.14 min; BH3 «pyr=3.36 min.
Example 10: Recrystallization of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-
((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2- one
A 200 mL flask was charged with ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3- ((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (10.05 g, 0.01995 mol) and THF (70 mL). The mixture was stirred and heated to 30 to 35 0C to provide a homogeneous solution. The solution was filtered through a 0.45 μm Teflon filter, and rinsed with THF (10 mL). The filtrate was added to a flask set up for atmospheric distillation and isopropyl acetate (IPAC, 50 mL) was added. The solution was concentrated by distillation to an internal volume of 100 mL. Isopropyl acetate (50 mL) was added and distillation continued at atmospheric pressure until the internal volume reached 100 mL. The solution was seeded with ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one and additional IPAC (30 mL) was added. The solution was again distilled to an internal volume of 100 mL and was cooled over about 1 h to 50 0C. The solution was held at 50 0C for an additional 1.5 h, cooled over about 2 h to rt, and stirred overnight. The resulting slurry was filtered and rinsed with IPAC (30 mL). The resulting solids were dried to provide 9.41 g (94%) of the title compound as an off-white powder that was vacuum dried (~25 in Hg, 50 0C) for 12 h.
CAS 877130-28-4
 FILIBUVIR
(R)-6-Cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one
Filibuvir;Pf-00868554;Unii-198J479Y2l;(6R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl(1,2,4)triazolo(1,5-A)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydro-2H-pyran-2-one;(R)-6-Cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;2H-Pyran-2-one, 6-cyclopentyl-6-(2-(2,6-diethyl-4-pyridinyl)ethyl)-3-((5,7-dimethyl(1,2,4)triazolo(1,5-A)pyrimidin-2-yl)methyl)-5,6-dihydro-4-hydroxy-, (6R)-
MF C29H37N5O3
MW 503.64

ANTHONY MELVIN CRASTO

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Medicinal Chemistry International: NARLAPREVIR


Medicinal Chemistry International: NARLAPREVIR

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NARLAPREVIR

NARLAPREVIR
An antiviral agent that inhibits hepatitis C virus NS3 protease.
M.Wt: 707.96
Formula: C36H61N5O7S
CAS No.: 865466-24-6
SCH 900518;SCH900518;SCH-900518
3-Azabicyclo[3.1.0]hexane-2-carboxamide, N-[(1S)-1-[2-(cyclopropylamino)-2-
oxoacetyl]pentyl]-3-[(2S)-2-[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]
amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-, (1R,2S,5S)-
2. (1R,2S,5S)-N-{(1S)-1-[2-(cyclopropylamino)-2-oxoacetyl]pentyl}-3-[(2S)-2-{[(1-{[(1,1-
dimethylethyl)sulfonyl]methyl}cyclohexyl)carbamoyl]amino}-3,3-dimethylbutanoyl]-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
3. (1R,2S,5S)-3-{N-[({1-[(tert-butylsulfonyl)methyl]cyclohexyl}amino)carbonyl]-3-methyl-L-
valyl}-N-{(1S)-1-[(cyclopropylamino)(oxo)acetyl]pentyl}-6,6-dimethyl-3-
azabicyco[3.1.0]hexane-2-carboxamide
Narlaprevir is a potent, Second Generation HCV NS3 Serine Protease Inhibitor.Narlaprevir is useful for Antiviral
Merck & Co. (Originator)
SCH-900518 had been in phase II clinical trials by Merck & Co. for the treatment of genotype 1 chronic hepatitis C; however, no recent development has been reported for this indication.
A potent oral inhibitor of HCV NS3 protease, SCH-900518 disrupts hepatitis C virus (HCV) polyprotein processing. When added to the current standard of care (SOC), peginterferon-alfa plus ribavirin, SCH-900518 is likely to increase the proportion of patients achieving undetectable HCV-RNA levels and sustained virologic response (SVR).
In 2012, the product was licensed by Merck & Co. to R-Pharm in Russia and the Commonwealth of Independent States (CIS) for the development and commercialization as treatment of hepatitis C (HCV)
PATENTS
WO 2011014494
WO 2010068714
(1 R,5S)-N-[1 (S)-[2-(cyclopropylamino)-1 ,2-dioxoethyl]pentyl]-3-[2(S)- [[[[1-[[1.1-dimethylethyl)sulfonyl]methyl]cyclohexyl]amino]carbonyl]amino]-3,3- dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxamide.
Figure imgf000003_0001
Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
The compound of Formula I is generically and specifically disclosed in
Published U.S. Patent No.2007/0042968, published February 22, 2007 (the ‘968 publication), incorporated herein by reference.
Processes suitable for making the compound of Formula I are generally described in the ‘968 publication. In particular, the ‘968 publication discusses preparing a sulfone carbamate compound, for example, the compound of Formula 837 comprising a cyclic sulfone substituent (paragraphs [0395] through [0403]). The following reaction scheme describes the procedure:
Figure imgf000004_0001
The process disclosed in the ‘968 publication produces the intermediate alcohol in step S7 as a mixture of diastereomers at the hydroxyl group; while this chiral center is lost in the final step of the disclosed process, the alcohol intermediate as a mixture of isomers cannot be crystallized and required a volumetrically inefficient precipitative isolation that did not remove any impurities
,………………………………………………………………………………………………………………………
Figure imgf000048_0001
……………………………………………………………………………………………………………………
Preparation of Compound VIJ
Figure US20120178942A1-20120712-C00062
LDA was made by slowly charging n-butyl lithium (2.5 M, 159 kg) to diisopropyl amine (60 kg) dissolved in THF (252 kg), keeping the temperature at about −20° C., followed by agitation at this temperature for about 30 min. To this solution was charged cyclohexane carboxylic acid, methyl ester (70 kg), keeping the temperature below −10° C. The mixture was agitated at this temperature for about 2 h. To the resulting enolate was charged TMSCI (64.4 kg). The mixture was agitated at −10 to −20° C. for about 30 min, and then heated to about 25° C. and held at this temperature to allow for conversion to the silylenol ether Compound VIH. The reaction mixture was solvent exchanged to n-heptane under vacuum, keeping the temperature below 50° C., resulting in the precipitation of solids. The solids were filtered and washed with n-heptane, and the wash was combined with the n-heptane reaction mixture. The n-heptane mixture of Compound VIH was concentrated under vacuum and diluted with CH2Cl2.
In a separate reactor was charged CH2Cl(461 kg) and anhydrous ZnBr(14.5 kg). The temperature of the zinc slurry was adjusted to about 20° C. To the zinc slurry was simultaneously charged the solution of Compound VIH and 2-chloromethylsulfanyl-2-methyl-propane (63.1 kg, ref: Bioorg. Med. Chem. Lett, 1996, 6, 2053-2058), keeping the temperature below 45° C. After complete addition, the mixture was agitated for about 1.5 h at 35 to 45° C., after which the reaction mixture was cooled to 10 to 15° C. A solution of dilute aqueous HCl was then charged, keeping the temperature between 0 and 15° C., followed by a separation of the aqueous and organic layers (desired compound in organic layer). The organic layer was washed with aqueous NaHCOand water. The organic layer was solvent exchanged to methanol by vacuum distillation, keeping the temperature below 35° C., and kept as a solution in methanol for further processing to Compound VIK. Active Yield of Compound VIJ=69.7 kg (molar yield=57.9%).
Preparation of Compound VIK
Figure US20120178942A1-20120712-C00063
To a fresh reactor was charged Compound VIJ (99.8 kg active in a methanol solution), water (270 kg), NaOH (70 kg), and methanol (603 kg). The mixture was heated to −70° C. and agitated at this temperature for about 16 h. Upon conversion to the sodium salt of Compound VIK, the reaction mixture was concentrated under vacuum, keeping the temperature below 55° C., and then cooled to about 25° C. Water and MTBE were then charged, agitiated, and the layers were separated (product in the aqueous layer). The product-containing aqueous layer was further washed with MTBE.
CH2Clwas charged to the aqueous layer and the temperature was adjusted to ˜10° C. The resultant mixture was acidified to a pH of about 1.5 with HCl, agitated, settled, and separated (the compound was in the organic layer). The aqueous layer was extracted with CH2Cl2, and the combined organic layers were stored as a CH2Clsolution for further processing to Compound VID. Active yield of Compound VIK=92.7 kg (molar yield=98.5 kg). MS Calculated: 230.13; MS Found (ES−, M−H): 229.11.
Preparation of Compound VID
Figure US20120178942A1-20120712-C00064
To a reactor was charged water (952 kg), Oxone® (92.7 kg), and Compound VIK (92.7 kg active as a solution in CH2Cl2). The reaction mixture was agitated for about 24 h at a temperature of about 15° C., during which time Compound VIK oxidized to sulfone Compound VID. The excess Oxone® was quenched with aqueous Na2S2O5, the reaction mixture was settled and the layers separated; the aqueous layer was back-extracted with CH2Cl2, and the combined product-containing organic layers were washed with water.
The resultant solution was then concentrated under vacuum. To precipitate Compound VID, n-heptane was charged, and the resulting slurry was agitated for about 60 min at a temperature of about 30° C. The reaction mixture was filtered, and the wet cake was washed with n-heptane. The wet cake was redissolved in CH2Cl2, followed by the addition of n-heptane. The resultant solution was then concentrated under vacuum, keeping the temperature below 35° C., to allow for product precipitation. The resultant solution was cooled to about 0° C. and agitated at this temperature for about 1 h. The solution was filtered, the wet cake was washed with n-heptane, and dried under vacuum at about 45° C. to yield 68.7 kg Compound VID (molar yield=65.7%). MS Calculated: 262.37; MS Found (ES−, M−H): 261.09
Preparation of Compound VI
Figure US20120178942A1-20120712-C00065
To a reactor was charged Compound VID (68.4 kg), toluene (531 kg), and Et3N (31 kg). The reaction mixture was atmospherically refluxed under Dean-Stark conditions to remove water (target KF <0.05%). The reaction temperature was adjusted to 80° C., DPPA (73.4 kg) was charged over 7 h, and the mixture was agitated for an additional 2 h. After conversion to isocyanate Compound VIE via the azide, the reaction mixture was cooled to about 0 to 5° C. and quenched with aqueous NaHCO3. The resultant mixture was agitated, settled and the layers were separated. The aqueous layer was extracted with toluene, and the combined isocyante Compound VIE organic layers were washed with water.
In a separate vessel was charged L-tert- Leucine (L-Tle, 30.8 kg), water (270 kg), and Et3N (60 kg). While keeping the temperature at about 5° C., the toluene solution of Compound VIE was transferred to the solution of L-Tle. The reaction mixture was stirred at 0 to 5° C. for about 5 h, at which time the mixture was heated to 15 to 20° C. and agitated at this temperature for 2 h to allow for conversion to urea Compound VI.
The reaction was quenched by the addition of aqueous NaOH, keeping the temperature between 0 and 25° C. The reaction mixture was separated, and the organic layer was extracted with water. The combined Compound VI-containing aqueous layers were washed with toluene, and acidified to pH 2 by the addition of HCl, at which time the product precipitated from solution. The reaction mixture was filtered, washed with water and dried under vacuum at 65 to 70° C. to yield 79.7 kg crude Compound VI (molar yield 52.7%). MS Calculated: 390.54; MS Found (ES−, M−H): 389.20.
Compound VI is further purified by slurrying in CH3CN at reflux (about 80° C.), followed by cooling to RT. Typical recovery is 94%, with an increase in purity from about 80% to 99%.
Preparation of Compound Va
Figure US20120178942A1-20120712-C00066
To a reactor was charged Compound VI (87.6 kg), Compound VII-1 (48.2 kg), HOBt (6 kg) and CH3CN (615 kg). The reaction mixture was cooled to about 5° C., and NMM (35 kg) and EDCi (53.4 kg) were charged. The reaction was heated to 20 to 25° C. for about 1 h, and then to 35 to 40° C., at which time water was charged to crystallize Compound Va. The reaction mixture was cooled to 5° C. and held at this temperature for about 4 h. Compound Va was filtered and washed with water. XRD data for the hydrated polymorph of Va is as follows:
The Compound Va wet cake was charged to a fresh vessel and was dissolved in ethyl acetate at 25 to 30° C. The solution was washed with an aqueous HCl solution, aqueous K2COsolution, and brine. The solution was then concentrated under vacuum, keeping the temperature between 35 to 50° C. Additional ethyl acetate was charged, and the solution was heated to 65 to 70° C. While keeping the temperature at 65 to 70° C., n-heptane was charged, followed by cooling the resultant solution to 0 to 5° C. Compound Va was filtered and washed with an ethyl acetate/n-heptane mix.
The wet cake was dried under vacuum between 55 to 60° C. to yield 96.6 kg crystalline Compound Va (molar yield 79.2%). MS Calculated: 541.32; MS Found (ES+, M+H): 542.35.
Preparation of Compound IUB
Figure US20120178942A1-20120712-C00067
Pyridine (92 L) was charged to the reactor and was cooled to 5° C. To the cooled pyridine was slowly charged malonic acid (48.5 kg) and valeraldehyde (59 L), keeping the temperature below 25° C. The reaction was stirred between 25 to 35° C. for at least 60 h. After this time, H2SOwas charged to acidify, keeping the temperature below 30° C. The reaction mixture was then extracted into MTBE. The organic layer was washed with water. In a separate reactor was charged water and NaOH. The MTBE solution was charged to the NaOH solution, keeping the temperature below 25° C., and the desired material was extracted into the basic layer. The basic layer was separated and the organic layer was discarded. MTBE was charged, the mixture was agitated, settled, and separated, and the organic layer was discarded. To the resultant solution (aqueous layer) was charged water and H2SOto acidify, keeping the temperature between 10 to 15° C. To the acidified mixture was charged MTBE, keeping the temperature below 25° C. The resultant solution was agitated, settled, and separated, and the aqueous layer was discarded. The product-containing organic layer was washed with water and was concentrated under vacuum, keeping the temperature below 70° C., to yield 45.4 kg Compound IIIB (molar yield=76.2%) as an oil. Compound Reference: Concellon, J. M.; Concellon, C J. Org. Chem., 2006, 71, 1728-1731
Preparation of Compound IIIC
Figure US20120178942A1-20120712-C00068
To a pressure vessel was charged Compound IIIB (9.1 kg), heptane (9 L), and H2SO(0.5 kg). The pressure vessel was sealed and isobutylene (13.7 kg) was charged, keeping the temperature between 19 to 25° C. The reaction mixture was agitated at this temperature for about 18 h. The pressure was released, and a solution of K2COwas charged to the reaction mixture, which was agitated and settled, and the bottom aqueous layer was then separated. The resultant organic solution was washed with water and distilled under vacuum (temp below 45° C.) to yield 13.5 kg Compound IIIC (molar yield=88.3%) as a yellow oil.
Preparation of Compound IIID
Figure US20120178942A1-20120712-C00069
To a reactor capable of maintaining a temperature of −60° C. was charged (S)-benzyl-1-phenyl ethylamine (18 kg) and THF (75 L). The reaction mixture was cooled to −60° C. To the mixture was charged n-hexyl lithium (42 L of 2.3 M in heptane) while maintaining a temperature of −65 to −55° C., followed by a 30 min agitation within this temperature range. To the in situ-formed lithium amide was charged Compound IIIC over 1 h, keeping the temperature between −65 to −55° C. . The reaction mixture was agitated at this temperature for 30 min to allow for conversion to the enolate intermediate. To the resultant reaction mixture was charged (+)-camphorsulfonyl oxaziridine (24 kg) as a solid, over a period of 2 h, keeping the temperature between −65 to −55° C. . The mixture was agitated at this temperature for 4 h.
The resultant reaction mixture was quenched by the addition of acetic acid (8 kg), keeping the temperature between −60 to −40° C. The mixture was warmed to 20 to 25° C., then charged into a separate reactor containing heptane. The resultant mixture was concentrated under vacuum, keeping the temperature below 35° C. Heptane and water were charged to the reaction mixture, and the precipitated solids were removed by filtration (the desired compound is in the supernatant). The cake was washed with heptane and this wash was combined with the supernatant. The heptane/water solution was agitated, settled, and separated to remove the aqueous layer. An aqueous solution of H2SOwas charged, and the mixture was agitated, settled, and separated. The heptane layer was washed with a solution of K2CO3.
The heptane layer was concentrated under reduced pressure, keeping the temperature below 45° C., and the resulting oil was diluted in toluene, yielding 27.1 kg (active) of Compound IIID (molar yield=81.0%). MS Calculated: 411.28; MS Found (ES+, M+H): 412.22.
A similar procedure for this step was reported in: Beevers, R, et al, Bioorg. Med. Chem. Lett. 2002, 12, 641-643.
Preparation of Compound IDE
Figure US20120178942A1-20120712-C00070
Toluene (324 L) and a toluene solution of Compound IIID (54.2 kg active) was charged to the reactor. TFA (86.8 kg) was charged over about 1.5 h, keeping the temperature below 50° C. The reaction mixture was agitated for 24 h at 50° C. The reaction mixture was cooled to 15° C. and water was charged. NaOH was slowly charged, keeping the temperature below 20° C., to adjust the batch to a pH between 5.0 and 6.0. The reaction mixture was agitated, settled, and separated; the aqueous layer was discarded. The organic layer was concentrated under vacuum, keeping the temperature below 40° C., and the resulting acid intermediate (an oil), was dissolved in 2-MeTHF.
In a separate reactor, 2-MeTHF (250 L), HOBt (35.2 kg), and EDCi-HCl (38.0 kg) were charged and the mixture was adjusted to a temperature between 0 to 10° C. DIPEA (27.2 kg) was charged, keeping the mixture within this temperature range. The mixture was agitated for 5 min, followed by the addition of cyclopropyl amine (11.4 kg), keeping the temperature between 0 to 10° C.
To this solution was charged the 2-MeTHF/ acid intermediate solution, keeping the resultant solution between 0 to 10° C. The resultant mixture was heated to 25 to 35° C., and was agitated at this temperature for about 4 h. The reaction mixture was cooled to about 20° C., and was washed with aqueous citric acid, aqueous K2CO3, and water. The solvent was exchanged to n-heptane, and the desired compound was crystallized from a mix of n-heptane and toluene by cooling to 0° C. The crystalline product was filtered, washed with n-heptane, and dried to yield 37.1 kg Compound IIIE (molar yield=70.7%). MS Calculated: 394.26; MS Found (ES+, M+H): 395.22.
Preparation of Compound III
Figure US20120178942A1-20120712-C00071
To a pressure reactor was charged acetic acid (1.1 kg), methanol (55 kg), and Compound IIIE (10.9 kg). In a separate vessel, Pd/C (50% water wet, 0.5 kg) was suspended in methanol (5 kg). The Pd/C suspension was transferred to the solution containing Compound IIIE. The resultant mixture was pressurized to 80 psi with hydrogen, and agitated at 60° C. for 7 h. The reaction mixture was then purged with nitrogen, and the Pd/C catalyst was filtered off. The resultant solution was concentrated under vacuum and adjusted to about 20° C. MTBE was charged, and the resultant solution was brought to reflux. Concentrated HCl (3 L) was charged and the product was crystallized by cooling the reaction mixture to about 3° C. The desired compound was filtered, washed with MTBE, and dried under vacuum, keeping the temperature below 40° C. to yield 5.5 kg Compound III (molar yield=83.0%). MS Calculated (free base): 200.15; MS Found (ES+, M+H): 201.12.
Preparation of Compound II
Figure US20120178942A1-20120712-C00072
Compound Va (119.3 kg) was dissolved in 2-MeTHF (720 kg) and water (180 kg). To this solution was charged 50% NaOH (21.4 kg) while maintaining a temperature between 20 and 30° C. The reaction mixture was then agitated for about 7 h at a temperature between 50 and 60° C. The reaction mixture was cooled to a temperature between 20 and 30° C.
The pH of the reaction mixture was adjusted to 1.5-3.0 with dilute phosphoric acid, maintaining a temperature between 20 and 30° C. The resultant mixture was agitated for 10 min, settled for 30 min, and the bottom aqueous layer was separated and removed. The top organic layer was washed with water, followed by concentration by atmospheric distillation.
The concentrated solution was solvent exchanged to CH3CN by continuous atmospheric distillation, and crystallized by cooling to 0° C. The crystalline product was filtered, washed with CH3CN, and dried under vacuum at a temperature between 45 and 55° C. to yield 97.9 kg Compound II (molar yield=83.7%). MS Calculated: 527.30; MS Found (ES+, M+H): 528.29.
Preparation of Compound IV
Figure US20120178942A1-20120712-C00073
Compound II (21.1 kg), Compound III (9.9 kg), HOBt (3.2 kg) and EDCi (11.2 kg) were charged to the vessel, followed by CH3CN (63 kg), ethyl acetate (20 kg) and water (1.5 kg). The reaction mixture was agitated and the heterogeneous mixture was cooled to −5 to +5° C. DIPEA (11.2 kg) was charged to the reaction mixture, maintaining a temperature between −5 to +5° C. and the mixture was agitated at a temperature of −5 to +5° C. for 1 h. The resultant reaction mixture was warmed to 20 to 30° C. and agitated for 2 to 3 h.
The resultant product was extracted with aqueous HCl, aqueous K2CO3, and water.
The desired product was crystallized from ethyl acetate by cooling from reflux (78° C.) to about 0° C. The crystalline product was filtered and dried at 30° C. under vacuum to yield 23.1 kg Compound IV (molar yield=81.3%). MS Calculated: 709.44; MS Found (ES+, M+H): 710.47.
Preparation of Compound I
Figure US20120178942A1-20120712-C00074
Compound IV (22.5 kg), TEMPO (5 kg), NaOAc (45 kg), methyl acetate (68 L), MTBE (158 L), water (23 L) and acetic acid (22.5 L) were charged to the reactor. The reaction mixture was stirred at 20-30° C. to allow for dissolution of the solids, and was then cooled to 5-15° C. NaOCl solution (1.4 molar equivalents) was charged to the reaction mixture, keeping the temperature at about 10° C. After complete addition of NaOCl, the reaction mixture was agitated at 10° C. for 2 h.
The reaction was quenched by washing with a buffered sodium ascorbate/HCl aqueous solution, followed by a water wash.
The reaction mixture was solvent exchanged to acetone under vacuum, keeping the temperature below 20° C.; the desired product was crystallized by the addition of water, and dried under vacuum, keeping the temperature below 40° C. to yield 18.6 kg Compound I (molar yield=82.7%). MS Calculated: 707.43: MS Found (ES+, M+H): 708.44.

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ANTHONY MELVIN CRASTO

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Medicinal Chemistry International: ROXADUSTAT


Medicinal Chemistry International: ROXADUSTAT

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