WO2011012961A1 - Procédé amélioré pour la préparation de bisulfate de clopidogrel - Google Patents

Procédé amélioré pour la préparation de bisulfate de clopidogrel Download PDF

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Publication number
WO2011012961A1
WO2011012961A1 PCT/IB2010/001800 IB2010001800W WO2011012961A1 WO 2011012961 A1 WO2011012961 A1 WO 2011012961A1 IB 2010001800 W IB2010001800 W IB 2010001800W WO 2011012961 A1 WO2011012961 A1 WO 2011012961A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
acetate
methyl
process according
Prior art date
Application number
PCT/IB2010/001800
Other languages
English (en)
Inventor
Jagadeeshwar Rao
Harikrishna Nandam
Anjireddy Redamalla
Buchi Reddy Reguri
Original Assignee
Orchid Chemicals And Pharmaceuticals 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.)
Filing date
Publication date
Application filed by Orchid Chemicals And Pharmaceuticals Ltd filed Critical Orchid Chemicals And Pharmaceuticals Ltd
Publication of WO2011012961A1 publication Critical patent/WO2011012961A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
  • Clopidogrel is used to prevent heart attacks and strokes in persons with heart disease (recent heart attack, unstable angina), recent stroke, or blood circulation disease (peripheral vascular disease). It works by blocking certain blood cells called platelets and prevents them from forming harmful blood clots. This "anti-platelet" effect helps to keep blood flowing smoothly in your body.
  • Clopidogrel is a pro-drug whose action may be related to adenosine diphosphate (ADP) receptor on platelet cell membranes.
  • ADP adenosine diphosphate
  • Clopidogrel is an oral antiplatelet agent (thienopyridine class); chemically known as (+)-(S)-methyl 2-(2-chloro ⁇ henyl)-2-(6, 7-dihydrothieno [3,2- c]pyridin-5(4H)-yl)acetate. This drug is dextrorotatory isomer and is marketed as i
  • COWFIRMATION COPY its bisulfate salt (Clopidogrel bisulfate of formula (V)) under the brand name Plavix.
  • US 4,529,596 patent claims the racemic mixture of methyl ⁇ -(4,5,6,7- tetrahydro-thieno[3,2-c]-5-pyridyl)-O-chlorophenyl-acetate and discloses a process for the preparation of the same.
  • US 4,847,265 patent specifically claims the bisulfate salt of dextrorotatory isomer of methyl ⁇ -(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2- chlorophenyl)-acetate substantially separated from the levo-rotatory isomer.
  • This patent discloses a process for the preparation of the same by forming the salt of the racemic compound with an optically active acid in a solvent
  • US 5,204,469 patent discloses dextrorotatory methyl- ⁇ -(2- thienylethylamino) (2-chlorophenyl) acetate hydrochloride.
  • the patent discloses a process for the preparation of methyl-(+)- ⁇ -(2-thienylethylamino)(2- chlorophenyl)acetate by the reaction of methyl-(+)- ⁇ -amino(2- chlorophenyl)acetate with (2-thienyl)ethyl-para-toluenesulphonate in presence of a base and a solvent.
  • the reaction time for the completion of the reaction is nearly 50 hours and hence is found to be time consuming.
  • the main objective of the present invention is to provide a process for the preparation of compound of formula (II) or its pharmaceutically acceptable salt in higher yield and greater chemical purity.
  • Another objective of the present invention is to provide an improved process for the preparation of clopidogrel bisulfate of formula (V), which is easy to implement on commercial scale.
  • the present invention provides an improved process for the preparation of Clopidogrel or its pharmaceutically acceptable salt comprising the steps of:
  • the compound of formula (III) is used either as free base or its inorganic acid addition salt selected from hydrochloride, hydrobromide and the like.
  • the leaving group represnted by LG in compound of formula (IV) is selected from to ' syl (-OTs), mesyl (-OMs) and the like.
  • the base used in step (i) is selected from inorganic base comprising Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , K 2 HPO 4 and the like and organic bases selected from triethylamine, diethylamine, N,N- diethyl methylamine, N,N-diethyl aniline, N,N-diethylethylenediamine, or N,N- diisopropylethylamine, dimethylaminopyridine, diisopropylethylamine, ⁇ - methylmorpholine, ⁇ -methylpyrrolidine, 2,6-di-tertbutyl-4-methylpyridine, pyridine and the like.
  • the catalyst used in step (i) is selected from quaternary ammonium salts comprising tetrabutylammonium acetate; tetrabutylammonium hydrogensulphate; tetraethylammonium bromide; methyltributylammonium chloride (MTBAC); tetrabutylammonium bromide (TBAB); tetrabutylammonium hydroxide (TBAH); benzyltrimethylammonium hydroxide (BTMAH); tetramethylammonium hydroxide (TMAH); tributylbenzylammonium chloride and the like. Crown ethers are also used as catalyst in the present invention.
  • the step (i) is conducted in presence of a solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate, methanol, ethanol, isopropanol, n- propanol, n-butanol, iso-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl tert-butyl ketone, toluene, acetonitrile, methylene dichloride, n-hexane and cyclohexane, tetrahydrofurane; dimethylether, diethyl ether, butyl ether and methyl tert.-butyl ether and the like or mixtures there of.
  • a solvent selected from ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, is
  • the compound of formula (II) is preferably isolated in the form of pharmacetucally acceptable salt selected from its hydrochloride, hydrobromide and the like. Accordingly the compound of formula (II) is taken in an ester, halocarbon solvent, lower alcohol or mixture there of followed by addition of con HCl or HCl gas or HCl in solvent.
  • the cyclization step (ii) is performed by any of the conventional process known in the prior art.
  • the compound of formula (II) is cyclized in presence of aqueous formaldehyde.
  • the pharmaceutically acceptable salts of clopidogrel are prepared by the conventional methods.
  • the starting materials used in the preparation of clopidogrel or its pharmaceutically acceptable salts are prepared as per the process known in the prior art.
  • the methyl ester of 2-amino- 2-(2-chlorophenyl)acetate was resolved using tartaric acid to obtain methyl (+)- ⁇ -amino(2-chlorophenyl)acetate having optical purity greater than 99.5%, which was then neutralized with aqueous ammonia and converted to its hydrochloride in presence of methylene dichloride.
  • the thick mass thus obtained was dissolved in methylisobutyl ketone (MIBK) (900 mL), cooled to 5 to 12°C.
  • MIBK methylisobutyl ketone
  • the reaction mass was optionally seeded with Clopidogrel bisulfate Form -I; followed by the addition of Cone. H 2 SO 4 in methylisobutyl ketone (MIBK) at -5 to 0 0 C.
  • the temperature of the reaction mass was raised slowly to 25 to 30 0 C, stirred and the solid was filtered.
  • the solid was washed with methylisobutyl ketone (MIBK) and dried under vacuum to yield Clopidogrel bisulfate Form -I.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé amélioré pour la préparation de clopidogrel de formule (I) ou de ses sels pharmaceutiquement acceptables et ses intermédiaires de formule (II). Formule (I) formule (II).
PCT/IB2010/001800 2009-07-29 2010-07-23 Procédé amélioré pour la préparation de bisulfate de clopidogrel WO2011012961A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1793CHE2009 2009-07-29
IN1793CH2009 2009-07-29

Publications (1)

Publication Number Publication Date
WO2011012961A1 true WO2011012961A1 (fr) 2011-02-03

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ID=43528823

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2010/001800 WO2011012961A1 (fr) 2009-07-29 2010-07-23 Procédé amélioré pour la préparation de bisulfate de clopidogrel

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WO (1) WO2011012961A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103483356A (zh) * 2013-09-30 2014-01-01 浙江美诺华药物化学有限公司 一种（s）-氯吡格雷的硫酸盐或盐酸盐的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007094006A1 (fr) * 2006-02-13 2007-08-23 Lee Pharma Limited Procédé de synthèse de la forme 1 du clopidogrel bisulfate
US20070225320A1 (en) * 2006-03-27 2007-09-27 Eswaraiah Sajja Process for preparing clopidogrel
WO2007144729A1 (fr) * 2006-06-13 2007-12-21 Orchid Chemicals & Pharmaceuticals Limited Procédé amélioré pour la préparation de clopidogrel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007094006A1 (fr) * 2006-02-13 2007-08-23 Lee Pharma Limited Procédé de synthèse de la forme 1 du clopidogrel bisulfate
US20070225320A1 (en) * 2006-03-27 2007-09-27 Eswaraiah Sajja Process for preparing clopidogrel
WO2007144729A1 (fr) * 2006-06-13 2007-12-21 Orchid Chemicals & Pharmaceuticals Limited Procédé amélioré pour la préparation de clopidogrel

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS February 2007 (2007-02-01), Database accession no. 2010:500602 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103483356A (zh) * 2013-09-30 2014-01-01 浙江美诺华药物化学有限公司 一种（s）-氯吡格雷的硫酸盐或盐酸盐的制备方法
CN103483356B (zh) * 2013-09-30 2016-01-13 浙江美诺华药物化学有限公司 一种（s）-氯吡格雷的硫酸盐或盐酸盐的制备方法

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