EP1848720A1 - Procede de resolution rapide destine a une base de clopidogrel et procede de preparation de la forme i polymorphique de l'hydrogenosulfate de clopidogrel - Google Patents

Procede de resolution rapide destine a une base de clopidogrel et procede de preparation de la forme i polymorphique de l'hydrogenosulfate de clopidogrel

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Publication number
EP1848720A1
EP1848720A1 EP05747156A EP05747156A EP1848720A1 EP 1848720 A1 EP1848720 A1 EP 1848720A1 EP 05747156 A EP05747156 A EP 05747156A EP 05747156 A EP05747156 A EP 05747156A EP 1848720 A1 EP1848720 A1 EP 1848720A1
Authority
EP
European Patent Office
Prior art keywords
clopidogrel
base
methyl
ether
solvent
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05747156A
Other languages
German (de)
English (en)
Inventor
Venkatasubramanian Radhakrishnan Tarur
Dhananjay Govind Sathe
Kamlesh Digambar Sawant
Harish Kashinath Mondkar
Manoj Madhukarrao Indrayani Niwas Deshpande
Tushar Anil Naik
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
USV Pvt Ltd
Original Assignee
USV Pvt 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 USV Pvt Ltd filed Critical USV Pvt Ltd
Publication of EP1848720A1 publication Critical patent/EP1848720A1/fr
Withdrawn legal-status Critical Current

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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

  • the present invention relates to a rapid resolution process of racemic clopidogrel base followed by conversion of the resolved (S) isomer to crystalline Clopidogrel bisulfate Form I.
  • Clopidogrel bisulfate [Formula I] [Methyl (S)-(+)- ⁇ -(o-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate] is an Antithrombotic agent.
  • Clopidogrel is administrated as its hydrogensulfate (syn. Bisulfate) salt. Its antiplatelet activity makes it an effective drug for reducing ischemic strokes, heart attacks and in atherosclerosis (a vascular disease causing claudication).
  • Atherosclerosis is a buildup of plaque in the walls of arteries, which leads to thickening, and the reduction in the elasticity of the arteries.
  • High Cholesterol, high blood pressure, smoking and infection also causes an injury to the inner walls of the arteries, which leads to the atherosclerosis.
  • the plaque formation leads to blood clotting which is due to the platelet aggregation at the site of the injury.
  • Clopidogrel which binds adenosine diphosphate to its receptor and thereby induces platelet reduction, which is desirable in fighting against atherosclerosis.
  • Clopidogrel has found to be more effective in inhibiting platelet aggregation than aspirin and is also mild towards gastrointestinal tract.
  • (S) enantiomer of clopidogrel is pharmaceutically active and is administrated as bisulfate salt.
  • U.S.Pat.No. 4, 529,596 discloses a racemic mixture of clopidogrel bisulfate and process for preparation of such mixture, which involves condensation reaction between methyl-2-chloro-o-chlorophenylacetate and 4,5,6,7-tetrahydro thieno[3,2-c] pyridine. The reaction produces racemic clopidogrel.
  • U.S.Pat. No. 4,847,265 discloses process for preparation of the dextro-rotatory enantiomer of the clopidogrel bisulfate. Racemic clopidogrel is resolved using camphor sulfonic acid to obtain optically pure dextro rotatory isomer.
  • the patent describes the crystallization of the (S) enantiomer using dimethylformamide, ketones and alcohols. Amongst ketones, acetone is used for crystallization.
  • U.S.Pat. No. 5,036,156 discloses a method for preparation of an intermediate in the synthesis of clopidogrel, 2-chloro- ⁇ -bromophenyl acetic acid and a process for condensing methyl ester with tetrahydrothienopyridine.
  • the patent also describes process for preparation of pyridine derivative, which is one of the intermediate for preparation of clopidogrel.
  • U.S.Pat. No. 6,080,875 describes a process for preparation of methyl (+)-(S)- ⁇ -(2- thienyl-2-ethylamino)- ⁇ -(2-chlorophenyl)acetate hydrochloride by reaction of sodium-2-thienylglycidate with (S) 2-chloro phenyl glycine in presence of cyanoborohydride. This intermediate is further used to prepare (S) clopidogrel.
  • the patent also describes the process for recemization of phenyl glycine esters.
  • U.S.Pat. No. 6,180,793 describes a process for preparation of (S) clopidogrel by reaction of 2-thiophene ethanol with (S)-2-chlorophenyl glycineamide, (S)-2- chlorophenyl- ⁇ -amino acetonirile or (S)-2-chlorophenyl glycine methyl ester. The resulting compound is cyclised, hydrolysed and esterified.
  • U.S.Pat. No. 5, 204, 469 discloses enantioselective process for preparation of clopidogrel through the reaction of (+) -2-chlorophenyl glycine and an activated form of 2-thiophene ethanol followed by cyclization with formaldehyde.
  • U.S.Pat. No. 6800759 describes a process for resolution of racemic clopidogrel, along with the conversion of (R) enantiomer of the clopidogrel to (S).
  • the (S) enatiomer is separated by crystallizing it as camphor sulfonate salt from hydrocarbon, or a mixture of hydrocarbon and a co-solvent, preferably DMF:Toluene.
  • the (R) enantiomer is then racemized and recycled by reaction with catalytic amount of base.
  • the bases used are metal alkoxide, preferably potassium-t-butoxide.
  • U.S.Pat. No. 4,847,265 describes the formation of the dextrorotatory isomer of clopidogrel by salt formation using racemic compound and an optically active acid such as 10-L-camphorsulfonic acid in acetone, followed by successive recrystallisation until a product with constant rotatory power was obtained, followed by the release of the dextro rotatory isomer from its salt by a base.
  • the hydrogen sulfate salt is then obtained by dissolution of the base in acetone cooled in ice and addition of concentrated sulphuric acid to precipitation.
  • the precipitate thus obtained is crystalline Form I.
  • WO 98/39286 discloses racemization process for phenyl glycine ester in which a mixture of enantiomer of phenyl glycine ester is treated with a carbonyl compound in presence of carboxylic acid and single enantiomer of an N-protected-a-amino acid as a resolving agent.
  • the formation of the imino intermediate causes the racemisation of the starting product and the precipitation of the single diastereomeric salt.
  • an enantiomer of phenyl glycine ester is obtained.
  • WO/04/074215 discloses racemization process of (R) clopidogrel which involve conversion of (R) isomer to its racemic salt such as Hydrochloride, which is formed by dissolution of (R) Clopidogrel in Isopropyl alcohol and concentrated HCl. The salt thus formed is further converted to Racemic Clopidogrel base by treatment with base.
  • racemic salt such as Hydrochloride
  • WO2004013147 describes a process for racemization of (R) isomer of the clopidogrel by the reaction with catalytic amount of the base preferably with potassium t- butoxide.
  • US20031 14479 describes the novel crystalline forms, Form III, IV and V of clopidogrel hydrogen sulphate and amorphous form of clopidogrel hydrogen sulphate and processes for preparation of these forms and amorphous form as well as their pharmaceutical compositions.
  • polymorphic Form I is prepared by suspending amorphous clopidogrel hydrogen sulphate in ether.
  • Form II of Clopidogrel Bisulfate is thermodynamically more stable and hence small change in condition during the preparation of Form I can result in Form II.
  • the present invention relates to the novel process for resolution of racemic clopidogrel base followed by conversion of the resolved (S) isomer to crystalline Clopidogrel bisulfate Form I.
  • the present invention also relates to the racemization of unwanted (R) isomer.
  • the present invention also relates to a process for resolution of clopidogrel base which is simple and less time consuming.
  • the present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate from (S) clopidogrel base, which is reproducible.
  • the present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate, which is cost effective and economical.
  • the present invention also relates to the process for preparation of crystalline Form I of Clopidogrel Bisulfate, which is commercially viable.
  • the present invention discloses novel process for resolution of racemic clopidogrel base followed by conversion of the resolved (S) isomer to crystalline Clopidogrel bisulfate Form I.
  • the present invention also discloses the racemization of unwanted (R) isomer and further resolution to pure (S) isomer.
  • the present invention further discloses the preparation of crystalline Form of Clopidogrel Bisulfate Form I, by dissolving (S) Clopidogrel base in a solvent such as acetic acid and adding antisolvent such as di-isopropyl ether containing sulfuric acid.
  • the resolution is carried out in a mixture of solvent which comprises aliphatic ketones preferably Acetone and acyclic simple ethers like Diisopropyl ether, methyl-ter/-butyl ether, diethyl ether, preferably methyl-tert-butyl ether (MTBE).
  • solvent which comprises aliphatic ketones preferably Acetone and acyclic simple ethers like Diisopropyl ether, methyl-ter/-butyl ether, diethyl ether, preferably methyl-tert-butyl ether (MTBE).
  • MTBE methyl-tert-butyl ether
  • the unwanted (R) isomer separated during the resolution is further converted to (S) isomer by dissolving the (R)-isomer in C 5 -C 7 aliphatic hydrocarbon/ Ci -Cs alcohols/or aliphatic ethers like di ethyl ether, methyl-t-butyl ether, di isopropyl ether, Tetrahydrofuran (THF), 1,4-Dioxane, as solvents containing base such as metal alkoxide.
  • the resolved (S) Clopidogrel base is dissolved in a solvent such as acetic acid and adding antisolvent such as di-isopropyl ether containing sulfuric acid to get the crystalline Form 1 of Clopidogrel bisulfate.
  • the present invention relates to the novel process for resolution of racemic clopidogrel base followed by conversion of the resolved (S) isomer to crystalline Clopidogrel bisulfate Form I.
  • the present invention also relates to the racemization of unwanted (R) isomer of Clopidogrel base. The process is shown as below,
  • the manufacturing process described in this invention involves preparation of racemic Clopidogrel by the process similar to described in U.S.Pat. No.4,529,596.
  • the said process comprises, condensation of the 4,5,6,7-tetrahydrothieno[3,2- cjpyridine hydrochloride (A) and ⁇ -bromo-2-chlorophenyl acetic acid methyl ester (B) in DMF in presence of potassium carbonate, which gives racemic clopidogrel free base (I R I S )-
  • A 4,5,6,7-tetrahydrothieno[3,2- cjpyridine hydrochloride
  • B ⁇ -bromo-2-chlorophenyl acetic acid methyl ester
  • I R I S racemic clopidogrel free base
  • the present invention relates to rapid and simple process for resolution of (S) clopidogrel base (Is) which, comprises the steps of reacting a mixture of (R) and (S) clopidogrel base (I R I S ) with laevo rotatory camphor sulfonic acid (II) in a mixture of solvents to precipitate (S) clopidogrel camphor sulfonate.
  • the Chiral, laevo rotatory camphor- 10-sulfonic acid of formula (II) is allowed to react with the racemic clopidogrel base of Formula (I R I S ) in the mixture of solvent comprises a ketone and/or an aliphatic ether according to following scheme.
  • the ketones are selected from group consisting of acetone, 2-butanone, methyl iso- butyl ketone and 3-pentanone, preferably acetone.
  • the ethers are selected from the group comprising of di ethyl ether, methyl-t-butyl ether, di isopropyl ether, THF and 1,4-Dioxane, preferably methyl-tert-butyl ether.
  • the mixture of solvent is about 10% v/v to about 50% v/v of ether in acetone preferably 50% v/v.
  • the (S) Clopidogrel camphor sulfonate salt (IsII) is further purified with ketonic solvents like acetone, 2-butanone, 3-pentanone, methyl-ter/-butyl ketone. Converting the (S) Clopidogrel camphor sulfonate salt (IsII) to (S) Clopidogrel free base of formula (Is) by the conventional technique. Dissolving the resolved (S) Clopidogrel base (Is) in glacial acetic acid at room temperature; followed by adding an antisolvent containing sulfuric acid to the solution at room temperature. Stirring the reaction mixture for 24 hours at room temperature, filtering and drying the crystals to obtain Form I of Clopidogrel Bisulfate.
  • the unwanted (R) isomer Clopidogrel base (IR) enriched in the mother liquor of resolution is diluted with ether, washed with sodium bicarbonate solution to remove camphor sulfonate.
  • the ether layer containing the enriched unwanted (R) Clopidogrel base (I R ) isomer is treated with a base such as metal alkoxide preferably potassium-t- butoxide to get back racemic clopidogrel base (IRI S ) which is then resolved again as earlier described. This process is shown in the following scheme.
  • a solvent is any liquid substance, which has capacity to dissolve the organic compound, Clopidogrel Bisulfate, either at room temperature or higher temperature.
  • Antisolvent is an organic solvent in which organic compound such as Clopidogrel Bisulfate has poor solubility.
  • room temperature means a temperature from about 10 0 C to 45°C, preferably 25 0 C to 30 0 C
  • the quality of clopidogrel bisulfate of Form I without detectable contamination by Form II, obtained in accordance with this invention, is characterized by X-Ray crystallographic data, Differential Scanning Calorimeter and Fourier-transform infrared (FT-IR) spectrum.
  • FT-IR Fourier-transform infrared
  • Fig. 1 Shows the X-ray Diffraction Diagram of Clopidogrel Bisulfate Form I
  • Fig. 2 Shows the DSC Thermogram of Clopidogrel Bisulfate Form I
  • Fig. 3 Shows the FT-IR Spectrum of Clopidogrel Bisulfate Form I
  • Form I shows an X-ray powder diffraction pattern which is characterized by having peaks at about 9.21, 9.56, 14.85, 15.53, 15.23, 20.62, 21.59, 23.19, 23.85, 25.52, + 0.2 degrees.
  • Fig 2 shows the DSC thermogram of Form I which is characterized by having sharp endotherm at 187 0 C followed by another sharp endotherm at 212 0 C.
  • the FT-IR spectrum of Form I shows absorption at 2987, 2952, 1751, 1477, 1436, 1220, 1 191, 867, 841, 766, 592 cm “1 which is shown in Fig 3.
  • the following examples are provided to illustrate the invention and are not limiting the scope of the complete disclosure.
  • Racemic clopidogrel base(I R I s ) a) Conversion of Racemic clopidogrel base (I R I S ) to (S) Clopidogrel camphor sulfonate salt (IsII).
  • Example 2(a) The mother liquor obtained from Example 2(a) was washed with the saturated sodium bicarbonate solution. The organic layer was separated and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum to obtain the oily liquid. The 1Og (0.031 mole) of oily liquid was then dissolved in 50 mL Di isopropyl ether and to this 2 g (0.017 mole) of potassium-/er/-butoxide was added at room temperature. After 12 Hrs, potassium ter/-butoxide was neutralized with acetic acid. The organic phase was extracted with 50 mL water thrice. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the oily liquid, yield 75%. The racemic clopidogrel thus obtained was resolved with the process described in example 3.

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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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de résolution rapide de base clopidogrel racémique suivi par la conversion de l'isomère résolu (S) en la forme I cristalline de l'hydrogénosulfate de clopidogrel. L'invention concerne également un procédé de racémisation de l'isomère non souhaité (R) de la base de clopidogrel. L'invention concerne également un procédé amélioré de préparation de sels d'addition acides de clopidogrel.
EP05747156A 2005-02-15 2005-02-15 Procede de resolution rapide destine a une base de clopidogrel et procede de preparation de la forme i polymorphique de l'hydrogenosulfate de clopidogrel Withdrawn EP1848720A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000048 WO2006087729A1 (fr) 2005-02-15 2005-02-15 Procede de resolution rapide destine a une base de clopidogrel et procede de preparation de la forme i polymorphique de l'hydrogenosulfate de clopidogrel

Publications (1)

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EP1848720A1 true EP1848720A1 (fr) 2007-10-31

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EP (1) EP1848720A1 (fr)
AU (1) AU2005327776A1 (fr)
CA (1) CA2567806C (fr)
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Families Citing this family (6)

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Publication number Priority date Publication date Assignee Title
PL382055A1 (pl) * 2007-03-23 2008-09-29 Koźluk Tomasz Nobilus Ent Sposób wytwarzania formy krystalicznej 1 wodorosiarczanu klopidogrelu
WO2008146249A1 (fr) * 2007-05-30 2008-12-04 Wockhardt Research Centre Procédé d'élaboration 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
KR101710922B1 (ko) 2015-06-03 2017-02-28 경동제약 주식회사 클로피도그렐 황산염 결정형 i형의 제조방법
CN107383055A (zh) * 2017-08-03 2017-11-24 江苏汉斯通药业有限公司 硫酸氢氯吡格雷的合成方法

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Publication number Priority date Publication date Assignee Title
FR2623810B2 (fr) * 1987-02-17 1992-01-24 Sanofi Sa Sels de l'alpha-(tetrahydro-4,5,6,7 thieno(3,2-c) pyridyl-5) (chloro-2 phenyl) -acetate de methyle dextrogyre et compositions pharmaceutiques en contenant
FR2779726B1 (fr) * 1998-06-15 2001-05-18 Sanofi Sa Forme polymorphe de l'hydrogenosulfate de clopidogrel
IL166593A0 (en) * 2002-08-02 2006-01-15 Racemization and enantiomer separation of clopidogrel
US6800759B2 (en) * 2002-08-02 2004-10-05 Teva Pharmaceutical Industries Ltd. Racemization and enantiomer separation of clopidogrel
WO2004074215A1 (fr) * 2003-02-03 2004-09-02 Sunil Sadanand Nadkarni Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques

Non-Patent Citations (1)

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Title
See references of WO2006087729A1 *

Also Published As

Publication number Publication date
WO2006087729A1 (fr) 2006-08-24
CA2567806C (fr) 2011-04-26
AU2005327776A1 (en) 2006-08-24
CA2567806A1 (fr) 2006-08-24
WO2006087729B1 (fr) 2006-11-09

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