WO2012001486A1 - Procédé perfectionné pour la préparation de chlorhydrate de prasugrel et de ses intermédiaires - Google Patents

Procédé perfectionné pour la préparation de chlorhydrate de prasugrel et de ses intermédiaires Download PDF

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Publication number
WO2012001486A1
WO2012001486A1 PCT/IB2011/001498 IB2011001498W WO2012001486A1 WO 2012001486 A1 WO2012001486 A1 WO 2012001486A1 IB 2011001498 W IB2011001498 W IB 2011001498W WO 2012001486 A1 WO2012001486 A1 WO 2012001486A1
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WO
WIPO (PCT)
Prior art keywords
formula
solvent
mixture
toluene
methanol
Prior art date
Application number
PCT/IB2011/001498
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English (en)
Inventor
Chandra Sekhar Nakka Krishnamurthy
Jagat Singh
Mohd Yunus Khan
Original Assignee
Mayuka Labs Pvt. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Mayuka Labs Pvt. Ltd. filed Critical Mayuka Labs Pvt. Ltd.
Publication of WO2012001486A1 publication Critical patent/WO2012001486A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention provides an improved process for the preparation of prasugrel and its pharmaceutical acceptable salt.
  • Prasugrel chemically known as 2-acetoxy-5-(a- cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine or 5-[2- cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2,-c]pyridine- 2yl acetate and having the structural formula.
  • the present invention also provides an improved process for the preparation of cyclopropyl 2-fluorobenzyl ketone, 2-Fluoro-a-cyclopropyl carbonylbenzyl bromide, 5,6,7,7a Tetrahydro-4H- theino-[3,2-c]- pyridone-2 p-toluenesulfonate or its hydrochloride salt and 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]-pyridin -2-one.
  • Prasugrel has a chemical name 2-acetoxy-5(a-cyclcopropylcarbonyl-2-flurobenzyl)- 4,5,6,7-tetrahydrotheino[3,2-c]pyridine, or a 5-[2-cyclopropyl-l-(2-fluorophenyl)-2- oxethl]-4,5,6,7-tetrahydrotheino[3,2,-c]pyridine-2-ylacetate, and having the structural formula
  • Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticloidine and clopidogrel. These agents are believed to reduce the aggregation of platelets by irreversibly binding to P2Y12 receptors.
  • Prasugrel is a novel platelet inhibitor that is expected to be administered as a solid oral dosage form. Prasugrel is undergoing the approval process for acute coronary syndromes planned for percutaneous coronary intervention (PCI)
  • US 5,288,726 discloses process for the preparation of prasugrel and its pharmaceutically acceptable salts involves the acetylation of 5-(a-cyclopropylcarbonyl- 2-fluoro benzyl)-2-oxo-2,4,5,6,7,7a-hexahydrotheieno[3,2-c]pyridine in the presence of a strong base like sodium hydride.
  • a strong base like sodium hydride
  • WO 2009/066326 discloses process for the preparation of prasugrel and its pharmaceutically acceptable salts as shown in the scheme below:
  • ketone derivative is prepared by using 2-Fluoro benzyl bromide and cyclopropyl cyanide, followed by bromination of ketone in chloroform. Further, 4,5,6,7,-tetrahydro thieno [3,2,-c]-pyridine hydrochloride directly reacted with trityl chloride in presence of triethylamine in dichloromethane. Product is isolated in cyclohexane.
  • starting materials are different and also involves use of class 3 solvent instead of class 2 solvents.
  • Selection of solvents plays a critical role in the process since they are not completely removed by practical manufacturing techniques.
  • class 2 solvent should be limited in order to protect patients from potential adverse effects.
  • present invention provides a process wherein class 3 solvents, less toxic solvents is employed.
  • acetonitrile is class 2 solvent, as used in the cited document WO2009/062044 having limit only 410 ppm while acetic acid is class 3 solvent having limit 5000ppm.
  • acetic acid is class 3 solvent having limit 5000ppm.
  • the present invention overcomes the problems associated with priori art, and provides a process for the preparation of prasugrel and its pharmaceutically acceptable salts, with better yield and purity.
  • the primary objective of the invention is to provide simple and cost effective process for the preparation of Prasugrel and its hydrochloride salt.
  • Another objective of the present invention is to provide process for preparing prasugrel intermediates
  • Yet another objective of the invention is to provide a process for the preparation of Prasugrel hydrochloride wherein the process excludes the use of chromatographic purification.
  • the prime aspect is to develop an improved process for the preparation of prasugrel of formula 14 and it hydrochloride addition salt of formula 15 by developing a process to obtain highly pure advanced prasugrel intermediates and prasugrel free base.
  • method embodied in this invention increases the yields, avoid the chromatographic techniques which is not commercial viable for bulk drug industries and reduces the time cycle for each batch run, reduces cost, efforts and thereby makes the process highly economical and eco-friendly.
  • the present invention provides an improved method for the preparation of pharmaceutically acceptable salt of prasugrel from a compound of formula (14).
  • the process comprising the following steps that are explained in scheme 1 :
  • Scheme- 1 depicts a schematic diagram for the preparation of Prasugrel hydrochloride according to the present invention. i) Cyanation -fluoro benzylchloride with sodium cyanide. ii) Hydrolysis of 2-fluoro benzyl cyanide in the presence of sodium hydroxide in a mixture of water.
  • the present invention relates to an improved process of preparing prasugrel of formula 14
  • Formula (12) c. acetylating the compound of formula (12) with a acetylating agent in the presence of an organic base and solvent to provide prasugrel compound of formula (14).
  • One embodiment of the present invention wherein the process of preparing 2-Fluoro- a-cyclopropylcarbonylbenzyl bromide of formula (5), comprises of:
  • Formula (4) b bromination of compound of formula (4) in the presence of N-bromo succinamide and benzoyl peroxide in a organic solvent to obtain 2- Fluoro-a-cyclopropylcarbonylbenzyl bromide of formula (5).
  • the process of preparing 2-(tert-Butyldimethylsilyloxy)-5(a-cyclopropylcarbonyl-2-fluoro- benzyl)-4,5,6,7-tetrahydrothieno-[3,2,-c]-pyridine of formula (11) comprises of: a. protecting amino functional group of 4,5,6, 7-tetrahydrotheno [3,2,-c]- pyridine or its salt of formula (7),
  • Formula (10) d. reacting compound of formula (10) with Tert-butyldimethylsilylchloride (TBDMSC1) in the presence of base to obtain compound of formula (11)
  • TBDMSC1 Tert-butyldimethylsilylchloride
  • the acetylating agent is selected from acetyl chloride and solvent is acetic acid, toluene or mixture thereof.
  • organic base is selected from trimethyl amine, triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N- methyl morpholine and diisopropylethyl amine, ammonia, ammonium bicarbonate and preferable base is triethyl amine.
  • solvent is selected from a group comprising of benzene, toluene or xylene, dichloromethane, chloroform, methylene chloride, ethylene chloride, methyl isobutyl ketone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, DMF, DMSO, methanol, ethanol, IPA or t- butanol or mixture thereof.
  • solvent in 2 step (a) is toluene, tetrahydrofuran or mixture thereof and preferable solvent is mixture of toluene and tetrahydrofuran.
  • solvent in 2 step (b) is ethyl acetate, dichloromethane, chloroform, carbon tetrahydrochloride or mixture thereof and preferable solvent is a mixture of ethyl acetate and dichloromethane and most preferable solvent is ethyl acetate.
  • base in 3 step (a) is selected from diisopropyl ethyl amine, triethyl amine or ammonia.
  • solvent in claim 3 step (a) is selected from hexane, diisopropyl ether, methanol or mixture thereof and preferable solvent is methanol.
  • solvent in claim 3 step (b) is toluene, tetrahydrofuran or mixture thereof and preferable solvent for reaction is mixture of toluene and tetrahydrofuran
  • solvent in claim 3 step(b) for crystallization is methanol, hexane, diisopropyl ether or mixture thereof and preferable solvent is methanol.
  • solvent in claim 3 step (c) solvent is acetone, tetrahydrofuran, methanol or mixture thereof and preferable solvent is acetone.
  • weak acid in claim 3 step (c) is selected from an inorganic acid like hydrochloric acid or organic acid like benzene sulfonic acid, p-toluene sulfonic acid.
  • step (d) is selected from diisopropyl ethyl amine, triethyl amine, ammonia or ammonium bicarbonate and preferable base is triethyl amine.
  • ADVANTAGES OF INVENTION i) Chromatographic purification of prasugrel or its intermediates is not required.

Abstract

La présente invention porte sur un procédé perfectionné pour la préparation de prasugrel et de ses sels pharmaceutiquement acceptables. L'invention porte sur un procédé perfectionné pour la préparation de prasugrel, chimiquement appelé 2-acétoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[3,2-c]-pyridine ou acétate de 5-[2-cyclopropyl-1-(2-fluorophényl)-2-oxoéthyl]-4,5,6,7-tétrahydrothiéno[3,2,-c]pyridin-2-yle et répondant à la formule de structure (I) et de ses sels pharmaceutiquement acceptables. La présente invention porte également sur un procédé perfectionné pour la préparation de cyclopropyl-2-fluorobenzylcétone, de bromure de 2-fluoro-α-cyclopropylcarbonylbenzyle, de p-toluènesulfonate de 5,6,7,7a-tétrahydro-4H-thiéno-[3,2-c]-pyrid-2-one et de son sel de type chlorhydrate.
PCT/IB2011/001498 2010-06-28 2011-06-28 Procédé perfectionné pour la préparation de chlorhydrate de prasugrel et de ses intermédiaires WO2012001486A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1509/DEL/2010 2010-06-28
IN1509DE2010 2010-06-28

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WO2012001486A1 true WO2012001486A1 (fr) 2012-01-05

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8937053B2 (en) 2011-06-22 2015-01-20 Sunshine Lake Pharma Co., Ltd. Process for the preparation of prasugrel and several novel crystalline forms of prasugrel hydrochloride
CN105272993A (zh) * 2014-07-03 2016-01-27 重庆安格龙翔医药科技有限公司 一种制备普拉格雷中间体的方法
CN105601643A (zh) * 2015-12-23 2016-05-25 山东鲁抗医药股份有限公司 高纯度盐酸普拉格雷的制备方法
WO2017221187A1 (fr) 2016-06-23 2017-12-28 Richter Gedeon Nyrt. Procédé de préparation de prasugrel de haute purete
CN110746287A (zh) * 2019-10-11 2020-02-04 深圳市第二人民医院 普拉格雷中间体邻氟苯乙酸的合成方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288726A (en) 1991-09-09 1994-02-22 Ube Industries Limited Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
JPH0931010A (ja) * 1995-07-20 1997-02-04 Ube Ind Ltd アリールシクロプロピルケトン類の製造方法
US5874581A (en) * 1994-10-07 1999-02-23 Ube Industries, Ltd. 2-silyloxy-tetrahydrothienopyridine, salt thereof and process for preparing the same
EP1298132A1 (fr) * 2000-07-06 2003-04-02 Sankyo Company, Limited Sels d'addition acides de d riv s hydropyridine
WO2009062044A2 (fr) 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de prasugrel et ses sels et polymorphes
WO2009066326A2 (fr) 2007-11-19 2009-05-28 Msn Laboratories Limited Procédé amélioré pour la préparation de prasugrel et de ses sels pharmaceutiquement acceptables
WO2009122440A1 (fr) * 2008-03-31 2009-10-08 Torrent Pharmaceuticals Ltd. Procédé de préparation de 2-acétoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[3,2-c]pyridine
EP2123656A1 (fr) * 2007-03-02 2009-11-25 Daiichi Sankyo Company, Limited Procédé de production de chlorhydrate de prasugrel de grande pureté
CN101735241A (zh) * 2009-12-24 2010-06-16 浙江普洛家园药业有限公司 普拉格雷中间体及其制备方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288726A (en) 1991-09-09 1994-02-22 Ube Industries Limited Tetrahydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation
US5874581A (en) * 1994-10-07 1999-02-23 Ube Industries, Ltd. 2-silyloxy-tetrahydrothienopyridine, salt thereof and process for preparing the same
JPH0931010A (ja) * 1995-07-20 1997-02-04 Ube Ind Ltd アリールシクロプロピルケトン類の製造方法
EP1298132A1 (fr) * 2000-07-06 2003-04-02 Sankyo Company, Limited Sels d'addition acides de d riv s hydropyridine
EP2123656A1 (fr) * 2007-03-02 2009-11-25 Daiichi Sankyo Company, Limited Procédé de production de chlorhydrate de prasugrel de grande pureté
WO2009062044A2 (fr) 2007-11-09 2009-05-14 Dr. Reddy's Laboratories Ltd. Procédés de préparation de prasugrel et ses sels et polymorphes
WO2009066326A2 (fr) 2007-11-19 2009-05-28 Msn Laboratories Limited Procédé amélioré pour la préparation de prasugrel et de ses sels pharmaceutiquement acceptables
WO2009122440A1 (fr) * 2008-03-31 2009-10-08 Torrent Pharmaceuticals Ltd. Procédé de préparation de 2-acétoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tétrahydrothiéno[3,2-c]pyridine
CN101735241A (zh) * 2009-12-24 2010-06-16 浙江普洛家园药业有限公司 普拉格雷中间体及其制备方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8937053B2 (en) 2011-06-22 2015-01-20 Sunshine Lake Pharma Co., Ltd. Process for the preparation of prasugrel and several novel crystalline forms of prasugrel hydrochloride
CN105272993A (zh) * 2014-07-03 2016-01-27 重庆安格龙翔医药科技有限公司 一种制备普拉格雷中间体的方法
CN105601643A (zh) * 2015-12-23 2016-05-25 山东鲁抗医药股份有限公司 高纯度盐酸普拉格雷的制备方法
WO2017221187A1 (fr) 2016-06-23 2017-12-28 Richter Gedeon Nyrt. Procédé de préparation de prasugrel de haute purete
CN109311907A (zh) * 2016-06-23 2019-02-05 吉瑞工厂 高纯度普拉格雷的制备方法
CN109311907B (zh) * 2016-06-23 2022-09-13 吉瑞工厂 高纯度普拉格雷的制备方法
CN110746287A (zh) * 2019-10-11 2020-02-04 深圳市第二人民医院 普拉格雷中间体邻氟苯乙酸的合成方法
CN110746287B (zh) * 2019-10-11 2022-07-08 深圳市第二人民医院 普拉格雷中间体邻氟苯乙酸的合成方法

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