WO2009080469A1 - Procédé de préparation de bisulfate de clopidogrel de forme i - Google Patents

Procédé de préparation de bisulfate de clopidogrel de forme i Download PDF

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Publication number
WO2009080469A1
WO2009080469A1 PCT/EP2008/066866 EP2008066866W WO2009080469A1 WO 2009080469 A1 WO2009080469 A1 WO 2009080469A1 EP 2008066866 W EP2008066866 W EP 2008066866W WO 2009080469 A1 WO2009080469 A1 WO 2009080469A1
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WO
WIPO (PCT)
Prior art keywords
formula
clopidogrel
compound
acetone
yield
Prior art date
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PCT/EP2008/066866
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English (en)
Inventor
Sanjukumar Salunke
Aniruddha Paul
Raji Nair
Ramana Venkata Kintali
Original Assignee
Sandoz Ag
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 Sandoz Ag filed Critical Sandoz Ag
Publication of WO2009080469A1 publication Critical patent/WO2009080469A1/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 relates to a process for the preparation of (+)-(S)-alpha-(2- chlorophenyl)-6, 7-dihydrothieno [3, 2-C] pyridine-5(4H)-acetic acid methyl ester and its salt of formula I, commonly known as clopidogrel bisulphate.
  • the present invention further provides a process for the isolation of S-(+)-clopidogrel camphor sulphonic acid salt.
  • the present invention further provides a process for the preparation of crystalline form-I of S -(+) -clopidogrel bisulphate with high chiral purity.
  • (+)-(S)-alpha-(2-chlorophenyl)-6, 7-dihydrothieno [3, 2-C] pyridine-5(4 H)-acetic acid methyl ester is marketed as hydrogen sulphate salt and is known as Clopidogrel bisulphate and has the following structure.
  • Clopidogrel bisulphate is an antiplatelet agent. Cloidogrel's platelet inhibiting activity makes it an effective drug for reducing the incidences of ischemic stroke, heart attacks or claudation due to vascular disease such as atherosclerosis. By inhibiting platelet aggregation the chances of arterial blockages is reduced, thus preventing strokes and heart attacks.
  • Clopidogrel is more effective in blocking platelet aggregation than aspirin and does not have any gastrointestinal side effects.
  • Clopidogrel is administered as the bisulphate salt. Both the racemic form and the S-isomer are known in the art.
  • the S-enantiomer of clopidogrel is particularly preferred since it is the pharmaceutically active compound.
  • U.S. Patent No. 6,429,210 (the '210 patent) describes, however, that clopidogrel bisulphate can exist in different polymorphic crystalline forms which differ from each other in terms of stability, physical properties, spectral characteristics and the process by which the different polymorphic crystalline forms are prepared.
  • a method of preparing the novel polymorph sulfate is disclosed in the '210 patent.
  • the powder of crystalline form II is more compact and much less electrostatic than crystalline form I and may, hence, have better formulation processibility.
  • clopidogrel bisulfate in its polymorphic crystalline form II is thermodynamically more stable than crystalline form I.
  • Plavix® which is commercially available clopidogrel bisulfate, contains crystalline form II, according to the '210 patent, as the active ingredient.
  • EP 281459 (the '459 patent) teaches the isolation of the two isomers of clopidogrel base using optically active acid such as camphor sulphonic acid in solvents like acetone, followed by successive recrystallization of the salt until a product with constant rotatory power was obtained.
  • optically active acid such as camphor sulphonic acid
  • PCT patent publication WO2004/020443 discloses a process to produce clopidogrel bisulphate form I from a solvent selected form the series of C 1 -C 5 alcohols or their esters , optionally mixtures of alcohols and esters.
  • the process involves dissolving clopidogrel freebase in solvents like isopropyl alcohol and/or butyl acetate, cooling the mixture, adding sulphuric acid and inoculating the mixture with form I of clopidogrel bisulphate.
  • PCT patent publication WO2005/012300 discloses a process to produce clopidogrel bisulphate form I by using a single solvent preferably ethyl acetate.
  • PCT patent publication WO2007/017886 describes a process for the preparation of (S)-(+) clopidogrel bisulphate form I from form II without affecting the chiral purity using Ci to C 4 alcohol as solvent.
  • PCT patent publication WO2005/104663 describes a one pot process for the manufacture of Clopidogrel.
  • PCT patent publication WO 2002/059128 describes a novel process for the synthesis of (S)-(+) clopidogrel bisulphate form I.
  • 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.
  • the process of the present invention provides a method which is most suitable for application on an industrial scale due to the more direct, high yield, main reaction and use of chemicals which are more environmentally friendly than prior art processes.
  • Another objective of the present invention is to prepare and isolate S-(+)- clopidogrel camphor sulphonic acid salt.
  • Another objective of the present invention is to provide (S)-(+) clopidogrel bisulphate form I in high purity and yield without affecting the chiral purity.
  • the present invention provides a process for the isolation of S-(+)-clopidogrel camphor sulphonic acid salt, a compound of formula [F] comprising, a) reacting alpha -bromo -O-chloro phenyl acetic acid methyl ester, a compound of formula [A] with 4,5,6,7-tetrahydrothieno[3,2,c] pyridine, a compound of formula [D] in the presence of toluene and triethylamine to form racemic alpha (2- chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4 H)-acetic acid methyl acetate [ clopidogrel base], a compound of formula [E], b) resolving racemic clopidogrel base, a compound of formula [E] using levo camphor sulphonic acid monohydrate to obtain S-(+)-clopidogrel camphor sulphonic acid salt, a
  • the present invention further provides a process for the preparation of crystalline form-I of S -(+) -clopidogrel bisulphate, a compound of formula I comprises,
  • the present invention also provides a process for the preparation of crystalline form-I of S-(+)-clopidogrel bisulphate, a compound of formula I by the displacement reaction of S-(+)-clopidogrel camphor sulphonic acid salt (F) comprises,
  • Figure 1 represents powder X- ray diffraction pattern of S-(+) - clopidogrel bisulphate form I
  • Figure 2 represents Differential scanning calorimeter thermograph of S-(+) - clopidogrel bisulphate form I
  • a process for the isolation of S-(+)-clopidogrel camphor sulphonic acid salt there is provided a process for the preparation of crystalline form-I of S-(+)-clopidogrel bisulphate with high chiral purity.
  • alpha bromo ortho-chloro phenyl acetic acid methyl ester (A) was prepared from alpha bromo ortho-chloro phenyl acetic acid (B). The reaction was carried out in methanol and extracted in toluene. The final product alpha bromo o-chloro phenyl acetic acid methyl ester (A) was obtained in Toluene.
  • 4,5,6,7-tetrahydrothieno [3,2,c] pyridine was obtained from 4,5,6,7-tetrahydrothieno[3,2,c]pyridine hydrochloride (C). This reaction is carried out in toluene and the final product is obtained as a solution in Toluene which is taken for further reaction.
  • racemic clopidogrel base reaction is carried out in a single solvent namely toluene and thus avoids the transfer and handling of oily and lachrymatory intermediates. Further, the racemic clopidogrel base (E) is reacted with levo- rotatory camphorsulfonic acid in acetone to form S-(+) clopidogrel camphorsulfonic acid salt (F)
  • S - (+) clopidogrel camphorsulfonic acid salt obtained via above mentioned process was then converted to the S - (+) clopidogrel free base (G) using sodium bicarbonate solution and ethyl acetate.
  • S - (+) clopidogrel free base (G) was obtained by distilling the ethyl acetate layer.
  • S - (+) clopidogrel free base (G) was then dissolved in acetone followed by the addition of concentrated sulfuric acid to form the bisulphate salt.
  • the acetone was distilled off partly followed by the addition of n-butyl acetate and seed of Form I of S- (+) clopidogrel bisulphate.
  • S-(+)-clopidogrel bisulphate form I (I) from the enantiomerically pure clopidogrel is a simple procedure which involves basification of S-(+) - clopidogrel camphorsulfonic acid salt (F) with aqueous sodium bicarbonate and ethyl acetate as solvent.
  • the isolated base (G) is further treated with concentrated sulphuric acid using acetone as solvent followed by partial removal of acetone. Addition of n-butyl acetate and seeding with form I results in the precipitation of the desired form I of clopidogrel bisulphate.
  • a suitable organic solvent for this step includes, for example, n-butyl acetate and methoxy propyl acetate or a mixture thereof.
  • the process of the present invention produces clopidogrel bisulphate form-I (I) in crystalline form.
  • This crystalline form of clopidogrel bisulphate form-I (I) was characterized by an X-ray powder diffraction pattern. An example of one X-ray diffraction analysis is shown in Figure 1, and the characteristic 2- theta values (in degrees) in the X-ray diffractogram are shown in Table 1.
  • Table 1 (Clopidogrel bisulphate form-I)
  • the differential scanning calorimetry (DSC) thermogram was recorded on TAQlOOO instrument with 107min heating rate in a nitrogen atmosphere, having empty pan as a reference with closed system.
  • the differential scanning calorimetry (DSC) thermogram of crystalline form of clopidogrel bisulphate form - I (I) is shown in Figure

Abstract

La présente invention concerne un procédé de préparation de la forme cristalline I du bisulfate de S-(+)-clopidogrel.
PCT/EP2008/066866 2007-12-24 2008-12-05 Procédé de préparation de bisulfate de clopidogrel de forme i WO2009080469A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2535/MUM/2007 2007-12-24
IN2535MU2007 2007-12-24

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WO2009080469A1 true WO2009080469A1 (fr) 2009-07-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432625A (zh) * 2011-11-05 2012-05-02 江南大学 一种制备高纯度i型氯吡格雷硫酸氢盐的结晶方法
CN103044444A (zh) * 2013-01-21 2013-04-17 上海现代哈森（商丘）药业有限公司 一种高纯度ⅰ型(+)-(s)-硫酸氢氯吡格雷的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4529596A (en) * 1982-07-13 1985-07-16 Sanofi, S.A. Thieno [3,2-c] pyridine derivatives and their therapeutic application
US4847265A (en) * 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
US6429210B1 (en) * 1998-06-15 2002-08-06 Sanofi-Synthelabo Polymorphic clopidogrel hydrogenesulphate form
WO2006130852A1 (fr) * 2005-06-02 2006-12-07 Dr. Reddy's Laboratories Ltd. Extraction de clopidogrel bisulfate
WO2007017886A1 (fr) * 2005-08-11 2007-02-15 Arch Pharmalabs Limited Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4529596A (en) * 1982-07-13 1985-07-16 Sanofi, S.A. Thieno [3,2-c] pyridine derivatives and their therapeutic application
US4847265A (en) * 1987-02-17 1989-07-11 Sanofi Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it
US6429210B1 (en) * 1998-06-15 2002-08-06 Sanofi-Synthelabo Polymorphic clopidogrel hydrogenesulphate form
WO2006130852A1 (fr) * 2005-06-02 2006-12-07 Dr. Reddy's Laboratories Ltd. Extraction de clopidogrel bisulfate
WO2007017886A1 (fr) * 2005-08-11 2007-02-15 Arch Pharmalabs Limited Nouveau procede de preparation de clopidogrel bisulphate polymorphique de forme i

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432625A (zh) * 2011-11-05 2012-05-02 江南大学 一种制备高纯度i型氯吡格雷硫酸氢盐的结晶方法
CN103044444A (zh) * 2013-01-21 2013-04-17 上海现代哈森（商丘）药业有限公司 一种高纯度ⅰ型(+)-(s)-硫酸氢氯吡格雷的合成方法
CN103044444B (zh) * 2013-01-21 2015-04-15 上海现代哈森（商丘）药业有限公司 一种高纯度ⅰ型(+)-(s)-硫酸氢氯吡格雷的合成方法

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