WO2007017886A1 - Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i - Google Patents

Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i Download PDF

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Publication number
WO2007017886A1
WO2007017886A1 PCT/IN2005/000287 IN2005000287W WO2007017886A1 WO 2007017886 A1 WO2007017886 A1 WO 2007017886A1 IN 2005000287 W IN2005000287 W IN 2005000287W WO 2007017886 A1 WO2007017886 A1 WO 2007017886A1
Authority
WO
WIPO (PCT)
Prior art keywords
clopidogrel
clopidogrel bisulphate
organic solvent
bisulphate
room temperature
Prior art date
Application number
PCT/IN2005/000287
Other languages
English (en)
Inventor
Ajit Kamath
Subhash Mali
Kamlesh Ranbhan
Jotiba Patil
Yuvraj Zunjarrao
Original Assignee
Arch Pharmalabs Limited
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 Arch Pharmalabs Limited filed Critical Arch Pharmalabs Limited
Priority to PCT/IN2005/000287 priority Critical patent/WO2007017886A1/fr
Publication of WO2007017886A1 publication Critical patent/WO2007017886A1/fr

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Classifications

    • 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

  • This invention relates to the field of organic chemistry comprising a novel and cost effective process for preparation of stable polymorphic form I of Clopidogrel bisulphate.
  • Clopidogrel is a generic name given to (S)-(+)-Methyl (2-chlorophenyl)-(6,7-dihydro- 4H-thieno[3,2-c]pyrid-5-yl) acetate which is having the following structure.
  • Clopidogrel' s platelet inhibiting activity makes it an effective drug for reducing the incidence ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis.
  • Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks.
  • Clopidogrel is more effective in blocking platelet aggregation than asprin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than asprin even at much lower dosage. Clopidogrel is administered as its bisulphate salt. The enantiomer (S)-(+) Clopidogrel is particularly preferred since it is the pharmaceutically active compound. Clopidogrel was first disclosed in European patent 99802 filed by Sanofi, and was claimed as racemic product.
  • European patent 281459 (herein after referred 459'patent) also filed by Sanofi, disclosed the enantiomers of tetrahydro thieno pyridine derivatives and its pharmaceutically acceptable salts and claims specifically for Clopidogrel bisulphate and its enantiomers.
  • This patent claims dextro rotatory isomer which posses excellent platelet aggregation inhibiting activity rather than its counter part i.e. levoisomer.
  • Clopidogrel bisulphate is thus isolated in a pure crystalline form melting at 184 0 C and having optical rotatory power in methanol of +55.10°. This patent does not mention about its polymorphic forms.
  • WO2003/051362 discloses a process to prepare polymorphic Form I of Clopidogrel bisulphate which comprises dissolving Form II in methanol or ethanol and precipitating with anti solvent ether.
  • WO2005012300 report that Form I was prepared from ester solvent; more preferably from ethyl acetate. The reported yields and HPLC purity are 88% and 99% respectively.
  • the process comprises dissolving Clopidogrel base in ethyl acetate followed by seeding with Clopidogrel bisulphate Form-I; followed by adding cone. Sulphuric acid at room temperature and then refluxing for 1 hr; stirring for 1 hr at room temperature and filtering the product by suction to obtain Form L. The formation of the form-1 crystals preferred at little higher temperature.
  • This patent does not mentioned about the chiral purity of Clopidogrel bisulphate Form I.
  • a process for preparing Clopidogrel bisulphate Form I comprising contacting amorphous Clopidogrel bisulphate with ether, and separating the Clopidogrel bisulphate Form I. was disclosed in WO03051362.
  • the problem with this process is that ethers are highly expensive and inflammable solvents and it is not easy to recover and recycle the solvent this makes the process industrially non- viable.
  • the present invention is aimed to ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative.
  • the present invention describes a simple and efficient process for preparation of polymorphic Form I of Clopidogrel bisulphate easily adopted over industrial scale.
  • the main objective of the present invention is to provide an efficient and cost effective process to prepare (S)-(+) Clopidogrel bisulphate form I which is easy to carry out on industrial scale.
  • Another objective of the present invention is to provide (S)-(+) Clopidogrel bisulphate form I in high purity and yield without affecting the chiral purity.
  • Another objective of the present invention is to provide a stable polymorphic form I of
  • the present invention discloses a cost effective process for preparation of (S)-(+)- Clopidogrel bisulphate form I without affecting the chiral purity.
  • (S)-(+) Clopidogrel bisulphate Form II is dissolved/suspended in first organic solvent at room temperature under stirring and the solvent is distilled to get the residue.
  • This residue is inoculated with 2-2.5% of (S)-(+) Clopidogrel bisulphate Form I and allowed to stir for 1 hr. This is charged with second organic solvent at ambient temperature and stirred for 3-4 hrs at same temperature. The solid is filtered and washed with second solvent and dried at room temperature to get (S)-(+) Clopidogrel bisulphate Form I.
  • the present process can be carried out conveniently at relatively low temperature.
  • the preferred temperature is 30-40 0 C. Since the precipitation of (S)-(+) Clopidogrel bisulphate Form I is carried out at relatively low temperature, preferably at room temperature, the product is obtained without affecting the chiral purity.
  • the first organic solvent is selected from alcoholic solvents; can be methanol, ethanol, n-propanol, isopropanol, (C 1 -C 3 alcohols) etc.
  • the second organic solvent is selected from acetate esters of C 1 to C 4 alcohols such as methyl acetate, ethylacetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tert-.butyl acetate.
  • the solvents used in the present invention are easy to recover and recycle from the reaction mixture thus, making the process economically feasible.
  • the volume of anti solvent used in the present invention is also less as compared to prior art.
  • the preferred embodiment of the process includes the steps of; dissolving/suspending (S)-(+) Clopidogrel bisulphate Form II in first organic solvent at room temperature under stirring; distilling the said solvent to obtain the residue; inoculating with 2-2.5 % of (S)- (+) Clopidogrel bisulphate Form I; stirring for 1 hr; charging this with second organic solvent at ambient temperature and maintained stirring for 3-4 hrs at same temperature, filtering the solid and washing with second solvent and drying at room temperature to get (S)-(+) Clopidogrel bisulphate Form I.
  • the present invention is further illustrated with the following examples.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un procédé efficace et rentable de fabrication de (S)-(+) Clopidogrel polymorphique de forme 1 stable sans affecter la pureté chirale, en dissolvant/mettant en suspension le (S)-(+) Clopidogrel bisulphate de forme II dans un premier solvant organique, et en le précipitant au moyen d'un second solvant organique. Ledit procédé est réalisé à température ambiante, et permet d'obtenir de bons rendements et une grande pureté.
PCT/IN2005/000287 2005-08-11 2005-08-11 Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i WO2007017886A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000287 WO2007017886A1 (fr) 2005-08-11 2005-08-11 Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000287 WO2007017886A1 (fr) 2005-08-11 2005-08-11 Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i

Publications (1)

Publication Number Publication Date
WO2007017886A1 true WO2007017886A1 (fr) 2007-02-15

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PCT/IN2005/000287 WO2007017886A1 (fr) 2005-08-11 2005-08-11 Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i

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WO (1) WO2007017886A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080469A1 (fr) * 2007-12-24 2009-07-02 Sandoz Ag Procédé de préparation de bisulfate de clopidogrel de forme i
WO2009156279A2 (fr) * 2008-06-24 2009-12-30 Zach System S.P.A. Procédé pour la préparation de forme cristalline i d’hydrogénosulfate de clopidogrel
CN104045653A (zh) * 2014-07-15 2014-09-17 苏州天马精细化学品股份有限公司 一种硫酸氢氯吡格雷的纯化方法
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004020443A1 (fr) * 2002-08-27 2004-03-11 Zentiva, A.S. Procede de fabrication de la forme cristalline i du clopidogrel hydrogene sulfate
WO2005012300A1 (fr) * 2003-08-04 2005-02-10 Wockhardt Limited Procede nouveau de preparation de bisulfate de (+)-(s)-clopidogrel de forme i

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004020443A1 (fr) * 2002-08-27 2004-03-11 Zentiva, A.S. Procede de fabrication de la forme cristalline i du clopidogrel hydrogene sulfate
WO2005012300A1 (fr) * 2003-08-04 2005-02-10 Wockhardt Limited Procede nouveau de preparation de bisulfate de (+)-(s)-clopidogrel de forme i

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080469A1 (fr) * 2007-12-24 2009-07-02 Sandoz Ag Procédé de préparation de bisulfate de clopidogrel de forme i
WO2009156279A2 (fr) * 2008-06-24 2009-12-30 Zach System S.P.A. Procédé pour la préparation de forme cristalline i d’hydrogénosulfate de clopidogrel
WO2009156279A3 (fr) * 2008-06-24 2011-01-13 Zach System S.P.A. Procédé pour la préparation de forme cristalline i d’hydrogénosulfate de clopidogrel
CN104045653A (zh) * 2014-07-15 2014-09-17 苏州天马精细化学品股份有限公司 一种硫酸氢氯吡格雷的纯化方法
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법

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