WO2011042804A2 - Procédé perfectionné pour la préparation de la forme i d'hydrogénosulfate de clopidogrel - Google Patents

Procédé perfectionné pour la préparation de la forme i d'hydrogénosulfate de clopidogrel Download PDF

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Publication number
WO2011042804A2
WO2011042804A2 PCT/IB2010/002553 IB2010002553W WO2011042804A2 WO 2011042804 A2 WO2011042804 A2 WO 2011042804A2 IB 2010002553 W IB2010002553 W IB 2010002553W WO 2011042804 A2 WO2011042804 A2 WO 2011042804A2
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WO
WIPO (PCT)
Prior art keywords
process according
ether
hydrogen sulfate
acetate
clopidogrel hydrogen
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PCT/IB2010/002553
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English (en)
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WO2011042804A3 (fr
Inventor
Hrishikesh Dilip Acharya
Jayant Srivastava
Satish Kumar
Arun Kumar Awasthi
Pramod Kumar
Dharam Vir
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Jubliant Life Sciences Limited
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Publication of WO2011042804A2 publication Critical patent/WO2011042804A2/fr
Publication of WO2011042804A3 publication Critical patent/WO2011042804A3/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 an improved process for the preparation of polymorphic Form I of clopidogrel hydrogen sulfate.
  • Clopidogrel hydrogen sulfate is a platelet aggregation inhibitor, which was described first time in EP281459.
  • the synthetic process claimed in this patent leads to the preparation of clopidogrel hydrogen sulfate, subsequently given the name Form I. It has now been discovered that clopidogrel hydrogen sulfate can exists in different crystalline forms, which differ from each other by their stability, their physical properties, their spectral characteristics and the process for their preparation.
  • W099/65915 discloses two polymorphs of clopidogrel hydrogen sulfate referred as Form I and Form II, although Form I is already disclosed in EP281459 patent. Both forms are crystallized from acetone under different conditions but according to the disclosure of W099/65915, Form II of clopidogrel hydrogen sulfate is thermodynamically more stable than Form I. This encourages the inventor to explore reliable solvent/solvent mixture for the preparation of clopidogrel hydrogen sulfate Form I, where the spontaneous transformation into Form II can be avoided.
  • US 6,767,913 discloses various polymorphs of clopidogrel hydrogen sulfate i.e. Form III, IV, V and amorphous forms and processes of preparation thereof.
  • US 2003/1 14479 discloses novel processes for the preparation of clopidogrel hydrogensulfate i.e. Form I, Form III, Form IV, Form V and the amorphous forms. US '479 further discloses a novel process for preparation of Form I, wherein the amorphous clopidogrel hydrogensulfate is converted to Form I using t-butyl methyl ether.
  • US 2006/0041 136 discloses process for the preparation of Form . I from clopidogrel base or clopidogrel hydrogen sulfate in alcohols or their esters.
  • US 2006/0047121 discloses process for the preparation of Form I by dissolving clopidogrel hydrogen sulfate Form II in C1-C5 carboxylic acid, followed by precipitation from aliphatic or cyclic ether.
  • WO2005/104663 discloses process for the preparation of clopidogrel hydrogen sulfate Form I, by dissolving clopidogrel base in methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or ethyl acetate and ketones mixture, cooling the resulting solution of about -10 to 20°C, adding concentrated sulphuric acid and maintaining the resultant solution at about 10 to 30°C to precipitate clopidogrel hydrogen sulfate Form I crystals.
  • WO2006/087729 discloses process for the preparation of clopidogrel hydrogen sulfate Form I by dissolving clopidogrel base in acetic acid followed by adding ether solution containing sulfuric acid to precipitate Form I.
  • US 2006/0183907 discloses process for the preparation of clopidogrel hydrogen sulfate Form I by reacting clopidogrel base with concentrated sulfuric acid in ethyl acetate followed by seeding with crystals of Form I.
  • US 2006/0205766 discloses another process for preparation of clopidogrel hydrogen sulfate Form I by reacting clopidogrel base with sulfuric acid in 2-propanol or 2-butanol, followed by seeding with crystals of Form I.
  • a process for the preparation of polymorphic Form I of clopidogrel hydrogen sulfate comprising the steps of dissolving clopidogrel base in an organic solvent selected from ether, ester or mixture thereof; mixing the resulting solution with sulfuric acid and alcoholic solvent and isolating clopidogrel hydrogen sulfate Form I.
  • a process for the preparation of polymorphic Form I of clopidogrel hydrogen sulfate comprising the steps of dissolving clopidogrel hydrogen sulphate in an alcoholic solvent, adding antisolvent selected from ether, ester or mixture thereof and isolating clopidogrel hydrogen sulfate Form I.
  • the present invention provides a commercially viable and cost effective process for preparing clopidogrel hydrogen sulfate Form I in high yield and high polymorphic purity.
  • An improved process for the preparation of polymorphic Form I of clopidogrel hydrogen sulfate comprising the steps of:
  • Clopidogrel base as used in step (a) can be prepared from any of the processes described in prior art.
  • Ether solvent used in step (a) is selected from C3-C8 ethers like di-ethyl ether, di-isopropyl ether, methyl t-butyl ether, di n-butyl ether and the like.
  • Ester solvent used in step (a) is selected from esters of C1-C4 carboxylic acid like methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like.
  • the more preferred organic solvent is methyl t-butyl ether or n-butyl acetate.
  • Reaction of step (a) is carried out at temperature range of -5 to 10°C, preferably at 0 to 5°C.
  • Alcoholic solvent used in step (b) is selected from the group comprising of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol and the like.
  • the preferred alcoholic solvent is n-butanol.
  • Reaction of step (b) is carried out at temperature range of -10 to 10°C, preferably at -5 to 5°C.
  • Isolation of clopidogrel hydrogen sulfate Form I in step (c) is performed by any conventional method like filtration.
  • Clopidogrel hydrogen sulphate as used in step (a) can be prepared from any of the processes described in prior art.
  • Alcoholic solvent used in step (a) is selected from the group comprising of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol and the like.
  • the preferred alcoholic solvent is n-butanol.
  • Ether solvent used in step (b) is selected from C 3 -Cs ethers like di-ethyl ether, di-isopropyl ether, methyl t-butyl ether, di n-butyl ether and the like.
  • Ester solvent used in step (b) is selected from esters of C1-C4 carboxylic acid like methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like.
  • the more preferred anti-solvent is methyl t-butyl ether or n-butyl acetate.
  • Reaction of step (b) is carried out at temperature range of -10 to 10°C, preferably at -5 to 5°C.
  • Isolation of clopidogrel hydrogen sulfate Form I in step (c) is performed by any conventional method like filtration.
  • Clopidogrel camphor sulfonate salt 50g was taken in toluene at 20-30°C.
  • the aqueous solution of sodium bicarbonate was added and stirred.
  • the pH of the reaction mass was adjusted to 7.0-8.5.
  • the layers were separated and aqueous layer was extracted with toluene (100 ml).
  • the organic solvent was evaporated under vacuum to obtain oily mass.
  • the oily mass was dissolved in methyl t-butyl ether (1100 ml) at 20- 30°C.
  • concentrated sulfuric acid 8.0 g
  • «-butanol (lOOml) was mixed by stirring at temperature between -5 to 5°C.
  • methyl t-butyl ether solution containing clopidogrel base was added within 2-3 h.
  • the resulting mass was stirred for 4-5 h at temperature between -5 to 5°C.
  • the temperature was then raised to 20-30°C and stirred for 32 h.
  • the precipitated solid was filtered, washed with methyl t-butyl ether and dried under vacuum at 50-60°C to obtain polymorphic Form I of clopidogrel hydrogen sulfate.
  • Clopidogrel hydrogen sulfate salt (20g) was taken in dichloromethane (100 ml) at 20-30°C. The aqueous solution of sodium bicarbonate (120 ml) was added and stirred. The pH of the reaction mass was adjusted to 7.0 - 8.5. The layers were separated and organic solvent was evaporated under vacuum to obtain clopidogrel base as oily mass. The oily mass was dissolved in methyl t-butyl ether (200 ml). The reaction mass was cooled to 0-5°C and methanol (2 ml) and concentrated sulfuric acid (2.5ml) and methyl t-butyl ether (100 ml) was mixed.
  • methyl t-butyl ether solution containing clopidogrel base was added at temperature between 0°C - 5°C within 1-2 h. The temperature of the mass was then raised to 20- 30°C and stirred for 10-12h at same temperature. The precipitated solid was filtered, washed with methyl t-butyl ether and dried under vacuum to obtain polymorphic Form I of clopidogrel hydrogen sulfate.
  • Clopidogrel base (23 g) was dissolved in di-isopropyl ether (540 ml). The reaction mass was cooled to -5 to 5°C. To it n-butanol ' (60 ml) and concentrated sulfuric acid (5.14 g) and di-isopropyl ether (100 ml) were mixed. The temperature of the mass was then raised to 20-30°C and stirred for 32 h at same temperature. The precipitated solid was filtered, washed with di-isopropyl ether and dried under vacuum to obtain polymorphic Form I of clopidogrel hydrogen sulfate.
  • Clopidogrel base 38 g was dissolved in n-butyl acetate (800 ml). Methanol (4 ml) and sulfuric acid (2.5ml) was added to reaction mass and cooled to 10-15°C. The temperature of the mass was then raised to 20-30°C and stirred for 18h. The precipitated solid was filtered, washed with n-butyl acetate and dried under vacuum to obtain polymorphic Form I of clopidogrel hydrogen sulfate.
  • Clopidogrel hydrogen sulfate 50 g was stirred with methanol (100 ml) to get clear solution. Then methanol was evaporated at 40-45°C till 5-10% methanol content remained and allowed it to come at 20-30°C. Then n-butyl acetate (900 ml) was added, seeded with crystals of Form-I of clopidogrel hydrogen sulfate and stirred for 18 h. The precipitated solid was filtered, washed with n-butyl acetate and dried under vacuum to obtain polymorphic Form I of clopidogrel hydrogen sulfate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur un procédé de préparation perfectionné pour la préparation de la forme polymorphe I d'hydrogénosulfate de clopidogrel.
PCT/IB2010/002553 2009-10-08 2010-10-08 Procédé perfectionné pour la préparation de la forme i d'hydrogénosulfate de clopidogrel WO2011042804A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2090/DEL/2009 2009-10-08
IN2090DE2009 2009-10-08

Publications (2)

Publication Number Publication Date
WO2011042804A2 true WO2011042804A2 (fr) 2011-04-14
WO2011042804A3 WO2011042804A3 (fr) 2011-07-21

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118802A1 (fr) 2013-01-31 2014-08-07 Pharmazell Gmbh Procédé amélioré pour la préparation de bisulfate de clopidogrel de forme i
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법
WO2020013305A1 (fr) * 2018-07-12 2020-01-16 有機合成薬品工業株式会社 Procédé de production de cristaux de forme i de sulfate de clopidogrel

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281459A1 (fr) 1987-02-17 1988-09-07 Sanofi Enantiomère dextrogyre de l'alpha-(tétrahydro-4,5,6,7 thiéno (3,2-c)pyridyl-5) (chloro-2 phényl)-acétate de méthyle, son procédé de préparation et les compositions pharmaceutiques le renfermant
WO1999065915A1 (fr) 1998-06-15 1999-12-23 Sanofi-Synthelabo Forme polymorphe de l'hydrogenosulfate de clopidogrel
US20030114479A1 (en) 2001-12-18 2003-06-19 Revital Lifshitz-Liron Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms
WO2004048385A2 (fr) 2002-11-28 2004-06-10 Instytut Farmaceutyczny Procede de preparation de la forme cristalline 1 du clopidogrel hydrogene sulfate
WO2005016931A2 (fr) 2003-08-13 2005-02-24 Krka, Torvarna Zdravil, D.D., Novo Mesto Cristallisation de formes solides de sels d'addition du clopidogrel
WO2005100364A1 (fr) 2004-04-19 2005-10-27 Krka, Tovarna Zdravil, D.D. Novo Mesto Procedes pour la preparation de clopidogrel hydrogenosulfate de forme polymorphe i
WO2005104663A2 (fr) 2004-03-05 2005-11-10 Ipca Laboratories Limited Procede industriel de fabrication de sulfate d'hydrogene de clopidrogrel
US20060041136A1 (en) 2002-08-27 2006-02-23 Zentiva, A.S. Method for manufacturing crystalline form I of clopidogrel hydrogen sulphate
US20060047121A1 (en) 2004-09-01 2006-03-02 Sawant Kamlesh D Novel process for preparation of clopidogrel bisulfate polymorph - Form I
US20060183907A1 (en) 2003-08-04 2006-08-17 Mukarram Mohammed Siddiqui J Novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-1
WO2006087729A1 (fr) 2005-02-15 2006-08-24 Usv Limited Procede de resolution rapide destine a une base de clopidogrel et procede de preparation de la forme i polymorphique de l'hydrogenosulfate de clopidogrel
US20060205766A1 (en) 2005-03-11 2006-09-14 Eswaraiah Sajja Process for making crystalline form I of clopidogrel hydrogen sulphate

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093635A1 (en) * 2006-03-09 2009-04-09 Sandor Garadnay PROCESS FOR MAKING POLYMORPH FROM I OF (S) - (+) -METHYL-ALPHA- (2-CHLOROPHENYL) -6, 7-DYHIDRO-THIENO- [3, 2-c] PYRIDINE-5 (4H) -ACETATE HYDROGEN SULFATE
WO2008004249A2 (fr) * 2006-07-04 2008-01-10 Msn Laboratories Limited Procédé amélioré de préparation de clopidogrel et de ses sels pharmaceutiquement acceptables
WO2008019053A2 (fr) * 2006-08-03 2008-02-14 Teva Pharmaceutical Industries Ltd. Procédé de préparation du bisulfate de clopidogrel
PL382055A1 (pl) * 2007-03-23 2008-09-29 Koźluk Tomasz Nobilus Ent Sposób wytwarzania formy krystalicznej 1 wodorosiarczanu klopidogrelu

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0281459A1 (fr) 1987-02-17 1988-09-07 Sanofi Enantiomère dextrogyre de l'alpha-(tétrahydro-4,5,6,7 thiéno (3,2-c)pyridyl-5) (chloro-2 phényl)-acétate de méthyle, son procédé de préparation et les compositions pharmaceutiques le renfermant
WO1999065915A1 (fr) 1998-06-15 1999-12-23 Sanofi-Synthelabo Forme polymorphe de l'hydrogenosulfate de clopidogrel
US20030114479A1 (en) 2001-12-18 2003-06-19 Revital Lifshitz-Liron Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms
US6767913B2 (en) 2001-12-18 2004-07-27 Teva Pharmaceutical Industries Ltd. Crystal forms iii, iv, v, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form i, compositions containing the new forms and methods of administering the new forms
US20060041136A1 (en) 2002-08-27 2006-02-23 Zentiva, A.S. Method for manufacturing crystalline form I of clopidogrel hydrogen sulphate
WO2004048385A2 (fr) 2002-11-28 2004-06-10 Instytut Farmaceutyczny Procede de preparation de la forme cristalline 1 du clopidogrel hydrogene sulfate
US20060183907A1 (en) 2003-08-04 2006-08-17 Mukarram Mohammed Siddiqui J Novel process for the manufacture of (+)-(s)-clopidogrel bisulfate form-1
WO2005016931A2 (fr) 2003-08-13 2005-02-24 Krka, Torvarna Zdravil, D.D., Novo Mesto Cristallisation de formes solides de sels d'addition du clopidogrel
WO2005104663A2 (fr) 2004-03-05 2005-11-10 Ipca Laboratories Limited Procede industriel de fabrication de sulfate d'hydrogene de clopidrogrel
WO2005100364A1 (fr) 2004-04-19 2005-10-27 Krka, Tovarna Zdravil, D.D. Novo Mesto Procedes pour la preparation de clopidogrel hydrogenosulfate de forme polymorphe i
US20060047121A1 (en) 2004-09-01 2006-03-02 Sawant Kamlesh D Novel process for preparation of clopidogrel bisulfate polymorph - Form I
WO2006087729A1 (fr) 2005-02-15 2006-08-24 Usv Limited Procede de resolution rapide destine a une base de clopidogrel et procede de preparation de la forme i polymorphique de l'hydrogenosulfate de clopidogrel
US20060205766A1 (en) 2005-03-11 2006-09-14 Eswaraiah Sajja Process for making crystalline form I of clopidogrel hydrogen sulphate

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118802A1 (fr) 2013-01-31 2014-08-07 Pharmazell Gmbh Procédé amélioré pour la préparation de bisulfate de clopidogrel de forme i
KR20160142578A (ko) 2015-06-03 2016-12-13 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법
WO2020013305A1 (fr) * 2018-07-12 2020-01-16 有機合成薬品工業株式会社 Procédé de production de cristaux de forme i de sulfate de clopidogrel
CN112399969A (zh) * 2018-07-12 2021-02-23 有机合成药品工业株式会社 硫酸氢氯吡格雷的ⅰ型晶体的制备方法
JPWO2020013305A1 (ja) * 2018-07-12 2021-07-15 有機合成薬品工業株式会社 クロピドグレル硫酸塩のｉ型結晶の製造方法
CN112399969B (zh) * 2018-07-12 2023-10-27 有机合成药品工业株式会社 硫酸氢氯吡格雷的ⅰ型晶体的制备方法

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