WO2012007019A1 - Procédé de synthèse du clopidogrel et de ses sels - Google Patents

Procédé de synthèse du clopidogrel et de ses sels Download PDF

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Publication number
WO2012007019A1
WO2012007019A1 PCT/EP2010/004240 EP2010004240W WO2012007019A1 WO 2012007019 A1 WO2012007019 A1 WO 2012007019A1 EP 2010004240 W EP2010004240 W EP 2010004240W WO 2012007019 A1 WO2012007019 A1 WO 2012007019A1
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WO
WIPO (PCT)
Prior art keywords
formula
chlorophenyl
acetic acid
clopidogrel
process according
Prior art date
Application number
PCT/EP2010/004240
Other languages
English (en)
Inventor
Theoharis V. Koftis
Eustratios Neokosmidis
Rohit Ravikant Soni
Ioanna Georgopoulou
Original Assignee
Pharmathen S.A.
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 Pharmathen S.A. filed Critical Pharmathen S.A.
Priority to PCT/EP2010/004240 priority Critical patent/WO2012007019A1/fr
Publication of WO2012007019A1 publication Critical patent/WO2012007019A1/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 thieno[3, 2-c]pyridine derivatives, such as Clopidogrel and pharmaceutically acceptable salts thereof and in particular to a cost-effective process for large scale production of thieno[3, 2-c]pyridine derivatives, such as optically pure Clopidogrel besylate and pharmaceutical preparations containing said compounds.
  • Thieno[3, 2-c]pyridines are a class of adenosine diphosphate (ADP) receptor inhibitors used as anti-coagulants in the pharmaceutical industry, such as Clopidogrel.
  • ADP adenosine diphosphate
  • Clopidogrel is chemically designated as methyl (S)-2-(2-chlorophenyl)-2-(6, 7-dihydrothieno [3, 2-c] pyridin-5(4H)-yl) acetate and is presented by the chemical structure of Formula I.
  • Clopidogrel is a known anti-thrombotic agent with therapeutical activity of preventing platelet aggregation and is useful in reducing the frequency of thrombotic events, such as strokes or ischaemic attacks, in patients with established vascular disease.
  • Clopidogrel is a more effective and well-tolerated platelet aggregation inhibiting agent as compared to other antiplatelet agents, such as Aspirin and Ticlopidine.
  • the molecule of Formula I has one optically active center.
  • Clopidogrel is used in the form of its dextro-rotary enantiomer, also known as the (S)-enantiomer.
  • the levo-rotary enantiomer also known as the (R)-enantiomer, is not only inactive but also less tolerated and therefore, a cost- effective process for the manufacture of Clopidogrel in the form of the single dextro-rotary enantiomer is needed.
  • Clopidogrel and its salts and methods for the preparation thereof were first disclosed in EP-B-0 099 802, wherein Clopidogrel is obtained in racemic form by reacting methyl 2-halo-o- chlorophenyl acetate with 4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine.
  • EP-B-0 281 459 discloses a process for the preparation of the desired dextro-rotary enantiomer by fractional crystallization using levo-rotary camphor- 10-sulfonic acid.
  • this method utilizes DMF as reaction media, which is expensive and highly toxic, and the yield of the product is low.
  • WO-A-2006/137628 discloses a process for the preparation of clopidogrel, which comprises preparation of ( ⁇ )-2-(2-chlorophenyl)-6, 7-dihydro-4H-thieno[3, 2-c]pyridine-5-acetic acid by the reaction of 4,5,6,7-tetrahydrothieno[3, 2-c]pyridine hydrochloride and 2-bromo-(2- chlorophenyl)acetic acid and optical resolution of the resulted carboxylic acid intermediate using optically active amines. According to this process, the formation of the (+)-2-(2-chlorophenyl)-6, 7-dihydro-4H-thieno[3, 2-c]pyridine-5-acetic acid ammonium salt requires long period of reaction time to be completed.
  • WO-A-2008/018779 discloses a process for the preparation Clopidogrel comprising optically resolving 2-(2-chlorophenyl)-6, 7-dihydro-4H-thieno[3, 2-c]pyridine-5-acetic acid intermediate using (+)-cinchonine and recycling the unwanted levo-rotary enantiomer by racemization.
  • solvent extraction is carried out several times using a large amount of organic solvents.
  • an object of the present invention to provide an improved process for the preparation of Clopidogrel or pharmaceutically acceptable salts thereof, which overcomes the deficiencies of the prior art and results to a cost effective production without sacrificing the yield and quality of the product.
  • Another object of the present invention is to provide an improved method for the preparation of Clopidogrel or salts thereof or its derivatives by selecting the appropriate reactants, catalysts, solvent systems and conditions used during the organic reactions, so that the purity and yield of the reaction are increased and the presence of any contaminants and formed by-products is minimized.
  • Further object of the present invention is to provide an improved method for the preparation of Clopidogrel or salts thereof, or its derivatives, by reducing the reaction time and using milder and safer reaction conditions that helps protect the environment and the personnel.
  • Yet another object of the present invention is to provide an improved method for the preparation of Clopidogrel or salts thereof, or its derivatives by using novel intermediate which plays an important role in improving the chemical and optical purity of the product.
  • step (iv) de -salting the remaining material from the optical resolution process of step (ii) and racemization to obtain compound of Formula III with chiral purity less than 60%.
  • the use of compound of Formula IV is provided for the preparation of clopidogrel or pharmaceutically acceptable salts thereof.
  • the present invention relates to an improved process for the preparation of Clopidogrel and pharmaceutically acceptable salts thereof or its derivatives, which is characterized by substantially shorter reaction time, milder and safer reaction conditions, without sacrificing the yield and quality of the product and low cost of reactants and reagents.
  • the process for the preparation of Clopidogrel and pharmaceutically acceptable salts thereof, or its derivatives comprises the following stages:
  • Stage-I Preparation of 2-(2-chlorophenyl)-2-(6, 7-dihydrothieno[3, 2-c]pyridine-5(4H)-yl)acetic acid of Formula III using water as reaction media.
  • Stage I comprises a condensation reaction of 4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine hydrochloride (KSM-1 ) and 2-bromo-2-(2-chlorophenyl)acetic acid (KSM-2), wherein said reaction is carried out in water at room temperature and in absence of any organic solvent.
  • KSM-1 4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine hydrochloride
  • KSM-2 2-bromo-2-(2-chlorophenyl)acetic acid
  • Table 1 summarizes the content of impurities and the purity of the product obtained according to the process of Stage-I of the present invention.
  • imp. 1 is 2-(2-chlorophenyl)acetic acid
  • imp. 2 is 2-(2-chlorophenyl)-2-hydroxyacetic acid
  • imp. 3 is 2-(thiophen-2-yl)ethanamine
  • imp. 4 is 2-bromo-2-(2-chlorophenyl) acetic acid
  • imp. 5 is 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride
  • imp. 6 is 5-(2-chlorobenzyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride
  • imp. 8 is 5, 5-Dimethyl hydantoin
  • imp. 9 is 2-(2-chlorophenyl)-2-(2-(thiophen-2-yl)ethylamino) acetic acid.
  • HPLC high-performance liquid chromatography
  • Stage-II Optical resolution of 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3, 2-c]pyridine-5(4H)- yl)acetic acid of Formula III using di-O-benzyl-L-tartaric acid to obtain the dextro-rotary enantiomer represented by Formula IV.
  • an improved process for optical resolution of 2-(2- chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)acetic acid of Formula ⁇ using L- di-O-benzoyl tartaric acid monohydrate is provided.
  • the resolution is carried out in ethanol media.
  • the obtained product is isolated from the reaction mixture by precipitation. Yield of this process is in the range of 53.2% to 59.7%, and the chemical purity of the obtained product is not less than 99.5%.
  • process of the present invention provides product in higher yield with higher purity.
  • the process according to the present invention also comprises a step of recycling the unwanted enantiomer (compound of Formula V), to compound of Formula III by racemization, as depicted in Scheme below.
  • the mother liquid from the optical resolution step which comprises compound of Formula V, is recovered and de-salted.
  • the de-salting procedure is carried out by extraction using ethyl acetate and water under acidic conditions.
  • the organic layer containing mainly L-di-O-benzoyl tartaric acid is discarded.
  • the aqueous layer containing compound of Formula VI is racemized using a strong inorganic base, such as ⁇ .
  • the racemization is carried out in a high pressure reactor at a temperature above the boiling point of water, which is used as the reaction media. Chiral purity is the percentage area of the S-enantiomer peak in the HPLC chromatogram.
  • the reaction according to said process is completed in about 24 hours.
  • Stage-Ill Conversion of the (5)-(o-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)- yl)acetic acid L-di-O-benzoyl tartaric acid salt of Formula IV into clopidogrel or pharmaceutically acceptable salts thereof, such as Clopidogrel besylate of Formula II.
  • the (S)-(o-chlorophenyl)-2-(6,7- dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetic acid L-di-O-benzoyl tartaric acid salt of Formula IV is de -salted and esterified with methanol to obtain clopidogrel.
  • the de-salting process is carried out by participation between ethyl acetate and water under acidic conditions.
  • the aqueous layer containing (5)-(o-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetic acid is back extracted using ethyl acetate at pH between 3.5 and 4.0.
  • the (5)-(o-chlorophenyl)-2-(6,7- dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetic acid thus obtained is dissolved in methanol and treated with thionyl chloride under argon atmosphere and is subjected to further work-up to obtain the highly pure Clopidogrel.
  • Clopidogrel thus obtained is converted into the pharmaceutically acceptable salt thereof, such as Clopidogrel besylate of Formula II.
  • the salt is formed in a mixture of isopropanol and tert-buty ⁇ methyl ether. Recrystallization of Clopidogrel besylate in the same solvent pair provides final product with chemical purity >99.5% and chiral purity >99.7%
  • the wet cake is suck-dried for 45 to 60 minutes and transferred into a 2L round-bottom flask, 300ml de -mineralised water are added and the mixture is stirred for 60 to 120 minutes. The mass is filtered under reduced pressure. The solid is washed with 100 ml de-mineralised water and dried in the vacuum to provide 165 to 185g of 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl) acetic acid.
  • the clear solution is heated under stirring at temperature from about 65 to 75°C. Then it is gradually cooled to temperature from about 22 to 27 °C over a period of 120 to 180 minutes and stirring is continued for additional 120 to 180 minutes at this temperature while precipitation starts at about 38 to 45°C.
  • the precipitated solid is filtered in Buchner funnel under reduced pressure and sucked dry in the vacuum pump for 45 to 60 minutes. The wet cake is transferred into a 1L round-bottom flask and 300 ml ethanol (96%, v/v) is added.
  • the aqueous layer is back extracted with 690 ml ethyl acetate and repeat with 450 ml ethyl acetate.
  • the three organic layers are combined and dehydrated over 40 g sodium sulfate anhydrous.
  • the solid is filtered off under vacuum and the filtrate is evaporated to dryness.
  • the residue is dissolved in 170 ml methanol and the solvent is evaporated to dryness.
  • the residue is dissolved in 95 ml methanol and the solvent is evaporated again to dryness. This residue is dissolved in 500 ml methanol and Argon atmosphere is applied.
  • 45 ml thionyl chloride (SOCl 2 ) are added at temperature from about 20 to 25°C.
  • the mixture is heated at temperature from about 55 to 60°C for 8 hours under stirring.
  • the progress of the reaction is monitored by in process high- performance liquid chromatography (HPLC).
  • reaction mixture is evaporated to dryness.
  • the yellow oily residue is dissolved in 100 ml toluene and the solvent is evaporated to dryness.
  • 135 ml aqueous NaOH solution (10%, w/v) is added to the residue, followed by 330 ml de -mineralised water and 1000 ml toluene.
  • the pH of the aqueous layer is adjusted to pH 6.5 to 7.5.
  • the organic layer is collected and back washed with 165 ml de-mineralised water and then 165 ml brine.
  • the light brown oil is dissolved in 30 ml isopropanol and the solvent is evaporated to dryness. 180 ml isopropanol are added to the light brown oil.
  • the mixture is heated to a temperature of about 35 to 40°C and then 22.5 g benzenesulfonic acid are added and heated further to temperature from about 50 to 55°C. After benzenesulfonic acid is completely dissolved, 40 ml iert-butylmethyl ether are added and the mixture is stirred at temperature from about 50 to 55°C until a clear solution is formed. Then the mixture is cooled gradually to temperature about 25 to 30°C.
  • Clopidogrel besylate are charged into a 1L 3-neck round-bottom flask and 300 ml isopropanol are added. The mixture is heated to temperature about 55 to 60°C under stirring until a clear solution is formed. This solution is filtered while hot and reheated to temperature of about 55 to 60°C. Then 100 ml rerr-butyl methyl ether is added and the mixture is stirred until a clear solution is formed. The mixture is cooled gradually to temperature from about 25 to 30°C over 50 to 60 minutes, and stirred at this temperature for 3 hours. The mixture is filtered under vacuum and the wet cake is spray-washed with 100 ml rr-butyl methyl ether. The product is suck-dried to obtain 85 to 95g of the title compound as white powder.
  • the solvent of the mother liquid obtained according to the resolution process as described in Example 2 is evaporated under reduced pressure at temperature about 40°C till dry.
  • 540ml water and 540 ml ethyl acetate are charged under stirring.
  • About 4 to 6ml HC1 solution (37% w/v) are added slowly till pH value equals to about 1.
  • An additional quantity of 12 to 15 ml HC1 (37%, w/v) is added to dissolve the gummy solids in the biphasic mass.
  • the mixture is stirred for 15 to 30 minutes.
  • the layers are allowed to settle and separate.
  • the organic layers containing mainly L-Dibenzoyl tartaric acid are discarded.
  • the aqueous layer is concentrated (about 324 ml of water is removed).
  • About 32g potassium hydroxide (KOH) are added at temperature from about 20 to 30°C till the pH value is within 13 to 14.
  • KOH potassium hydroxide
  • the reaction mixture is heated in a 2-L-glass high pressure reactor at oil bath temperature 130°C for about 25 to 35 hours, till chiral purity becomes about 50 to 55%.
  • the reaction mixture is cooled to temperature from about 20 to 30°C. 25 ml isopropanol are charged under stirring.
  • the present invention describes a large-scale manufacturing process for the preparation of Clopidogrel, and pharmaceutically acceptable salts thereof, in particular Clopidogrel besylate with improved quality at relative low production cost compared to the known prior art processes, wherein the reactions are carried out in low-toxic media, such as water and ethanol, with the average yield of 47.2% without recycling and 60% with recycling.
  • low-toxic media such as water and ethanol

Abstract

La présente invention concerne un procédé amélioré de synthèse du Clopidogrel, ainsi que de ses sels de qualité pharmaceutique, et en particulier un procédé économique de production à grande échelle de bésylate de Clopidogrel de pureté élevée.
PCT/EP2010/004240 2010-07-13 2010-07-13 Procédé de synthèse du clopidogrel et de ses sels WO2012007019A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802B1 (fr) 1982-07-13 1987-02-04 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
EP0281459B1 (fr) 1987-02-17 1995-04-26 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
WO2006137628A1 (fr) 2005-06-23 2006-12-28 Hanmi Pharm. Co., Ltd. Procédé de préparation de clopidogrel et intermédiaires utilisés dans ce procédé
WO2008018779A1 (fr) 2006-08-11 2008-02-14 Sk Chemicals Co., Ltd. Procédé pour une production à haut rendement de clopidogrel par racémisation de liquide résiduel
WO2008034912A2 (fr) * 2006-09-22 2008-03-27 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de synthèse du clopidogrel et nouvelles formes de sels pharmaceutiquement acceptables de celui-ci
EP2107061A1 (fr) * 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0099802B1 (fr) 1982-07-13 1987-02-04 Elf Sanofi Nouveaux dérivés de la thiéno-(3,2-c) pyridine, leur procédé de préparation et leur application thérapeutique
EP0281459B1 (fr) 1987-02-17 1995-04-26 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
WO2006137628A1 (fr) 2005-06-23 2006-12-28 Hanmi Pharm. Co., Ltd. Procédé de préparation de clopidogrel et intermédiaires utilisés dans ce procédé
WO2008018779A1 (fr) 2006-08-11 2008-02-14 Sk Chemicals Co., Ltd. Procédé pour une production à haut rendement de clopidogrel par racémisation de liquide résiduel
WO2008034912A2 (fr) * 2006-09-22 2008-03-27 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de synthèse du clopidogrel et nouvelles formes de sels pharmaceutiquement acceptables de celui-ci
EP2107061A1 (fr) * 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de clopidogrel enrichi optiquement

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