WO2004048385A2 - Procede de preparation de la forme cristalline 1 du clopidogrel hydrogene sulfate - Google Patents

Procede de preparation de la forme cristalline 1 du clopidogrel hydrogene sulfate Download PDF

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Publication number
WO2004048385A2
WO2004048385A2 PCT/PL2003/000130 PL0300130W WO2004048385A2 WO 2004048385 A2 WO2004048385 A2 WO 2004048385A2 PL 0300130 W PL0300130 W PL 0300130W WO 2004048385 A2 WO2004048385 A2 WO 2004048385A2
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WO
WIPO (PCT)
Prior art keywords
methyl
hydrogen sulfate
chlorophenyl
tetrahydrothieno
pyridine
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Application number
PCT/PL2003/000130
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English (en)
Other versions
WO2004048385A3 (fr
Inventor
Janina Piechaczek
Jadwiga Serafin
Wioleta Maruszak
Roman Balicki
Wieslaw Szelejewski
Marcin Cybulski
Grzegorz Maciejewski
Maria Wysoczynska
Magdalena Glice
Katarzyna Korczak
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Instytut Farmaceutyczny
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Publication date
Application filed by Instytut Farmaceutyczny filed Critical Instytut Farmaceutyczny
Priority to AU2003285841A priority Critical patent/AU2003285841A1/en
Publication of WO2004048385A2 publication Critical patent/WO2004048385A2/fr
Publication of WO2004048385A3 publication Critical patent/WO2004048385A3/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 crystalline Form 1 of clopidogrel hydrogen sulfate or methyl (S) -(+) - ⁇ - (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate hydrogen sulfate.
  • Clopidogrel hydrogen sulfate is an antithrombotic agent, known from the disclosure of EP 0281459 Bl .
  • EP 0281459 Bl the method of preparation of the pharmacologically preferred dextrorotatory isomer of this compound was also disclosed.
  • the method consisted in reacting methyl ⁇ - (2-chlorophenyl) -4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine-5-acetate with an optically active acid, such as 10-L-camphorsulfonic acid and successively crystallizing the salt thus formed, until a product showing a constant value of optical rotatory power was obtained, followed by base-mediated liberation from its salt of the dextrorotatory free base isomer, methyl (S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate, which was then converted to its hydrogen sulfate salt by reacting with concentrated sulfuric acid.
  • Acetone was the solvent used for both the crystallization of the 10-camphorsulfonic acid salt and the conversion of the free base to the hydrogen sulfate salt.
  • the experimental examples of this patent application include the procedure for the preparation of amorphous ( S) -clopidogrel hydrogen sulfate at about 0-5°C, at a high dilution (about 3% of free base/ 1 L of solvent) , and after 1-5 hours after the dropwise addition of sulfuric acid has been completed.
  • the amorphous (S) -clopidogrel hydrogen sulfate was thermodynamically stable in the solid state.
  • a crystalline form of (S) -clopidogrel hydrogen sulfate is defined as essentially pure, when the crystalline form is free from other forms detectable by the spectral methods typically used, which corresponds to the content of less than 5%, and preferably less than 2% of other forms.
  • the crystalline (S) -clopidogrel hydrogen sulfate obtained according to the process of the present invention is characterized based on an analysis of the infrared spectrum, X-ray powder diffractogram and of differential scanning calorimetry results.
  • the Fourier-transform infrared (FT-IR) spectrum of Form 1 was obtained using the compressed KBr disk technique, on a Perkin Elmer 1725X spectrometer, in the range 4000cm “1 - 400cm “1 , and with a resolution of 4cm “1 .
  • the spectrum is substantially different from the spectrum of Form 2 disclosed in the patent US 6429210 Bl, and from the spectrum of amorphous form known from PL 355814 in the entire spectral range 4000 - 400 cm "1 , as is illustrated in Figures .
  • FT-IR spectra (KBr disk) : a comparison of characteristic bands, differentiating Form 1 from Form 2 and from amorphic (S) -clopidogrel hydrogen sulfate.
  • Fig.2 presents X-ray powder diffractograms of crystalline Forms 1 and 2, and of amorphous (S) -clopidogrel hydrogen sulfate.
  • the diffraction profiles are presented in the form of relative CuK ⁇ diffraction line intensity as a function of the deflection angle ⁇ and the interlattice distance d, and were obtained on a Rigaku MINI FLEX diffractometer, within the 2 ⁇ angle range 3 - 40°, at scanning speed of 0.5 deg/min and with counting interval of 0.03 deg.
  • a comparison of peak position and intensity of main diffraction lines for crystalline Forms 1 and 2 is presented in Table 2. Table 2
  • Fig.3 illustrates a comparison of DSC curves of crystalline Forms 1 and 2 and of amorphous (S) -clopidogrel hydrogen sulfate.
  • the curves were obtained by the differential scanning calorimetry method, using a Mettler Toledo DSC 822 apparatus, in an aluminum cup, in the temperature range 40-200°C, in the dynamic segment at the rate of heating 10°C/min.
  • the dynamic measurement segment was preceded with an isothermal segment (40°C for 3 minutes) .
  • the curves for crystalline Forms 1 and 2 show characteristic endothermic peaks corresponding to the melting of crystalline substances, while the curve for the amorphous substance shows a broad, diluted endothermic signal corresponding to a small enthalpic effect, changing into a curve characteristic of substance decomposition.
  • Form 1 is characterized by a higher melting point than Form 2, however, the enthalpy of fusion determined for Form 1 is smaller than the corresponding value obtained for Form 2. Melting points and enthalpies of fusion for both crystalline forms are presented in Table 3.
  • the corresponding melting point value was determined using two methods: as an "extrapolated peak” temperature, which is the projection on the extrapolated baseline of the intersection of the tangents to the melting peak curve, and as an "onset” value, which corresponds to the intersection between the extrapolated baseline and the tangent to the ascending slope of the melting peak curve.
  • Table 3 A comparison of melting points and heats of fusion for crystalline Forms 1 and 2.
  • an essentially pure crystalline form of (S) -clopidogrel hydrogen sulfate is obtained by precipitating the salt formed from the optically active free base methyl ( S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3 , 2-c] yridine- 5-acetate and concentrated sulfuric acid, with a precipitating solvent.
  • Suitable precipitating solvents according to the process of the present invention are aliphatic and cyclic ethers, preferably 1, 2-dimethoxyethane, 1, 2-diethoxyethane, t-butyl methyl ether, bis (2-ethoxyethyl) ether, and dioxane, and also isobutyl methyl ketone.
  • variable A the reaction of the optically active free base methyl (S) - (+) - - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate with concentrated sulfuric acid is carried out directly in the precipitating solvent, such that the (S) -clopidogrel hydrogen sulfate formed precipitates during the dropwise addition of sulfuric acid.
  • the preparation of Form 1 is a process comprising the following steps: a) dissolution of methyl ( S) - (+) - - (2-chlorophenyl) - 4, 5, 6, 7-tetrahydrothieno [3 , 2-c] pyridine-5-acetate in the precipitating solvent, b) bringing the solution thus obtained to the temperature of 0-30 °C, preferably to 0-5 °C, c) dropwise addition of sulfuric acid to this solution, d) stirring the suspension thus formed at 0-30 °C, during over 10 hours, e) isolation of the precipitate from the reaction mixture ,, and f) drying the precipitate.
  • the optically active free base methyl ( S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3 , 2-c] pyridine-5-acetate is dissolved in a solvent chosen from among C ⁇ _ 3 aliphatic alcohols, followed by a slow addition of concentrated sulfuric acid to the solution thus obtained, and only after the dropwise addition of the acid has been completed, the precipitating solvent is added, which causes the (S) -clopidogrel hydrogen sulfate to precipitate out of the solution.
  • the preparation of Form 1 is a process comprising the following steps: a) dissolution of methyl (£>) - (+) - - (2-chlorophenyl) - 4 , 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine-5-acetate in a solvent capable of dissolving the free base, b) bringing the solution thus obtained to the temperature of 0-30°C, preferably to 0-5°C, c) dropwise addition of sulfuric acid to this solution, d) dropwise addition of the precipitating solvent to the solution, to which sulfuric acid has already been added, e) stirring the suspension of the precipitate thus formed at 0-30°C, during over 10 hours, f) isolation of the precipitate from the reaction mixture, and g) drying the precipitate.
  • Suitable solvents capable of dissolving the free base, are aliphatic alcohols such as ethanol, isopropanol and methoxyethanol .
  • the clopidogrel free base methyl (S) - (+) - ⁇ - (2-chlorophenyl) -4,5,6, 7-tetrahydrothieno [3,2- c]pyridine-5-acetate
  • a weak base such as sodium bicarbonate, ammonium carbonate or potassium carbonate
  • the organic phase is washed with water and concentrated under reduced pressure, which affords the dextroratatory clopidogrel free base.
  • the free base is dissolved in an organic solvent or directly in the selected precipitating solvent.
  • it is essential to select a suitable initial concentration of the clopidogrel free base in a solvent.
  • Beneficial results are obtained when using at least 1 weight part of (S) - clopidogrel free base per 3 volume parts of the solvent.
  • the upper level of free base concentration is limited only by technical capabilities to obtain a homogenous precipitate of the product, by the ease of isolation of the precipitate and the ease of excessive acid removal by washing the precipitate.
  • the suspension of (S) -clopidogrel hydrogen sulfate precipitate in a solvent is stirred for at least 10 more hours, at the temperature in the range from 0 to 30°C, after which (S) -clopidogrel hydrogen sulfate precipitate is isolated on a typical way, for example by filtration or decantation, washed with the precipitating solvent and the wet product is subjected to drying, first in air, at room temperature, and then under vacuum at temperatures below 50°C.
  • the process of the present invention provides essentially pure Form 1 of (S) -clopidogrel hydrogen sulfate, containing less than 5%, preferably less than 2% of crystalline Form 2.
  • the (S) -clopidogrel hydrogen sulfate prepared in crystalline Form 1 according to the process of the present invention is characterized by high enentiomeric purity - the content of the S isomer is in excess of 99%.
  • the crystalline Form 1 of (S) -clopidogrel hydrogen sulfate prepared according to the process of the present invention may be used as the active pharmaceutical ingredient for manufacturing of pharmaceuticals which find application in the treatment and prevention of thrombosis, by acting as a platelet aggregation inhibitor and an anticoagulant .

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

Abstract

L'invention concerne un procédé de préparation de la forme cristalline 1 du méthyl (S)-clopidogrel hydrogène sulfate par la précipitation du sel formé au cours de la réaction entre le méthyl (S)- (+) -α- (2-chlorophényl) -4, 5, 6, 7-tétrahydrothiéno[3,2-c]pyridine-5-acétate à base optiquement active et de l'acide sulfurique concentré, au moyen d'un solvant précipitant sélectionné dans le groupe constitué par des éthers aliphatiques et cycliques ainsi que le méthyl isobutyl cétone. Le méthyl (S) - (+) -α- (2-chlorophényl) -4,5,6,7- tétrahydrothiéno[3,2-c]pyridine-5-acétate hydrogène sulfate est utile dans le traitement et la prévention de la thrombose par son effet anticoagulant et inhibiteur d'agrégation plaquettaire.
PCT/PL2003/000130 2002-11-28 2003-11-26 Procede de preparation de la forme cristalline 1 du clopidogrel hydrogene sulfate WO2004048385A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003285841A AU2003285841A1 (en) 2002-11-28 2003-11-26 A process for the preparation of crystalline form 1 or clopidogrel hydrogen sulfate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL25442702 2002-11-28
PLP-357427 2002-11-28

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WO2004048385A3 WO2004048385A3 (fr) 2004-08-05

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016931A3 (fr) * 2003-08-13 2005-04-28 Krka Torvarna Zdravil D D Novo 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
WO2008019053A2 (fr) * 2006-08-03 2008-02-14 Teva Pharmaceutical Industries Ltd. Procédé de préparation du bisulfate de clopidogrel
WO2008118030A1 (fr) * 2007-03-23 2008-10-02 Tomasz Kozluk Procédé de préparation de la forme 1 polymorphe pure d'hydrogénosulfate de clopidogrel
EP2107061A1 (fr) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement
EP2114957A2 (fr) * 2007-01-29 2009-11-11 IPCA Laboratories Limited Procédé de préparation d'une forme 1 cristalline d'un sulfate d'hydrogène de clopidogrel
WO2011042804A2 (fr) 2009-10-08 2011-04-14 Jubliant Life Sciences Limited Procédé perfectionné pour la préparation de la forme i d'hydrogénosulfate de clopidogrel
WO2011051976A2 (fr) 2009-10-30 2011-05-05 Matrix Laboratories Ltd Procédé amélioré de préparation de la forme i du bisulfate de clopidogrel
CN102875568A (zh) * 2012-09-06 2013-01-16 苏州晶云药物科技有限公司 制备(+)-(s)-氯吡格雷硫酸氢盐纯晶型i的方法
WO2007125544A3 (fr) * 2006-04-27 2016-06-09 Ind-Swift Laboratories Limited Procédé de préparation de formes polymorphiques d'hydrogénosulfate de clopidogrel
KR20200099012A (ko) 2019-02-13 2020-08-21 한국바이오켐제약 주식회사 클로피도그렐황산염의 제조방법 및 이를 포함하는 약학제제

Citations (3)

* 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
WO2003051362A2 (fr) * 2001-12-18 2003-06-26 Teva Pharmaceutical Industries Ltd. Polymorphes d'hydrogenosulfate de clopidogrel

Patent Citations (3)

* 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
WO2003051362A2 (fr) * 2001-12-18 2003-06-26 Teva Pharmaceutical Industries Ltd. Polymorphes d'hydrogenosulfate de clopidogrel

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016931A3 (fr) * 2003-08-13 2005-04-28 Krka Torvarna Zdravil D D Novo 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
EA010198B1 (ru) * 2004-04-19 2008-06-30 Крка, Товарна Здравил, Д.Д., Ново Место Способы получения полиморфной формы i гидросульфата клопидогрела
US7999106B2 (en) 2004-04-19 2011-08-16 Krka, Tovarna Zdravil, D.D., Novo Mesto Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form I
WO2007125544A3 (fr) * 2006-04-27 2016-06-09 Ind-Swift Laboratories Limited Procédé de préparation de formes polymorphiques d'hydrogénosulfate de clopidogrel
WO2008019053A2 (fr) * 2006-08-03 2008-02-14 Teva Pharmaceutical Industries Ltd. Procédé de préparation du bisulfate de clopidogrel
WO2008019053A3 (fr) * 2006-08-03 2008-07-03 Teva Pharma Procédé de préparation du bisulfate de clopidogrel
EP2114957A4 (fr) * 2007-01-29 2011-06-08 Ipca Lab Ltd Procédé de préparation d'une forme 1 cristalline d'un sulfate d'hydrogène de clopidogrel
EP2114957A2 (fr) * 2007-01-29 2009-11-11 IPCA Laboratories Limited Procédé de préparation d'une forme 1 cristalline d'un sulfate d'hydrogène de clopidogrel
US20100216999A1 (en) * 2007-03-23 2010-08-26 Tomasz Kozluk Process for preparation of pure polymorphic form 1 of clopidogrel hydrogensulfate
WO2008118030A1 (fr) * 2007-03-23 2008-10-02 Tomasz Kozluk Procédé de préparation de la forme 1 polymorphe pure d'hydrogénosulfate de clopidogrel
EP2107061A1 (fr) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement
WO2011042804A2 (fr) 2009-10-08 2011-04-14 Jubliant Life Sciences Limited Procédé perfectionné pour la préparation de la forme i d'hydrogénosulfate de clopidogrel
WO2011042804A3 (fr) * 2009-10-08 2011-07-21 Jubliant Life Sciences Limited Procédé perfectionné pour la préparation de la forme i d'hydrogénosulfate de clopidogrel
WO2011051976A2 (fr) 2009-10-30 2011-05-05 Matrix Laboratories Ltd Procédé amélioré de préparation de la forme i du bisulfate de clopidogrel
CN102875568A (zh) * 2012-09-06 2013-01-16 苏州晶云药物科技有限公司 制备(+)-(s)-氯吡格雷硫酸氢盐纯晶型i的方法
KR20200099012A (ko) 2019-02-13 2020-08-21 한국바이오켐제약 주식회사 클로피도그렐황산염의 제조방법 및 이를 포함하는 약학제제

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WO2004048385A3 (fr) 2004-08-05
AU2003285841A8 (en) 2004-06-18

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