| Title of Invention | IMPROVED PROCESSES FOR THE PREPARATION OF (S)-(+)-CLOPIDOGREL BASE AND ITS DIFFERENT SALTS |
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| Abstract | The present invention relates to an improved processes for the preparation of Methyl(+)-(S)-(2-chlorophenyl)-(6,7dihydro-4H-theino[3,2-c]pyridine-5-yl)acetate [Clopidogrel base (I)] and their various pharmaceutically acceptable salts. |
| Full Text | FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENT RULES, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "IMPROVED PROCESSES FOR THE PREPARATION OF (S)-(+)-CLOPIDOGREL BASE AND ITS DIFFERENT SALTS" We, CADILA HEALTHCARE LIMITED, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Sarkhej- Gandhinagar Highway, Ahmedabad - 380015, Gujarat, India. The following specification describes the invention: ZRC-PD-028 Field of invention: The present invention relates to an improved process for the preparation of Methyl (+)-(S)-(2-chlorophenyl)-(6,7dihydro-4H-thieno[3,2-c] pyridin-5-yl) acetate [Clopidogrel base, (I)] and their various pharmaceutically acceptable salts. Background to the invention: Clopidogrel has the following structure (1) It is available in the market as its bisulfate salt and is marketed by Sanofi-Synthelabo as "Plavix". Clopidogrel is an inhibitor of platelet aggregation and is marketed as an antianginal agent, antiplatelet agent and is found to decrease morbid events in people with established atherosclerotic cardiovascular disease and cerebrovascular diseases. The therapeutic application of Clopidogrel as blood-platelet aggregation inhibiting agents and antithrombotic agent and its preparation is disclosed in U.S. Patent No. 4,529,596. US Patent No 4,847,265 describes the process for the preparation of the hydrogen sulfate salt of Clopidogrel wherein first the racemic base is obtained which is then resolved using (-) Camphor sulfonic acid [(-) CSA] to obtain the chirally pure base which is then converted to the corresponding salts such as sulfate, hydrochloride etc. salts. Various other strategies to prepare Clopidogrel are disclosed in WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, US 5,036,156, US 5,132, 435, US 5,139,170, US 5,204,469 and US 6,080,875 etc. all of which are incorporated herein as reference. We have earlier disclosed improved processes for the manufacture of (5)-(+)-Clopidogrel base, its intermediates and its bisulfate salt [Indian Patent Applications 84/MUM/2001 (WO 02059128/US6635763), & 335/MUM/2001] which are cited herein in their entirety as reference. The process described therein may be represented as: 2 ZRC-PD-028 (+>-S-Clopidogrel (chemically & chirally pure) EP 1480985 (Helm AG) describes a process for purifying impure Clopidogrel base by treating the impure base with benzenesulfonic acid and subsequently hydrolyzing the salt to obtain the pure base. In all prior art process, the Clopidogrel base needs to be resolved/chirally enriched using (-)-Camphor sulfonic acid salt. Such a process is expensive and hence industrially less suitable. The present inventors have surprisingly found that chemically and chirally pure Clopidogrel base can be prepared without the need for further treatment with camphor sulfonic acid, which is costly and less viable. The base so prepared could be used for preparing different salts. We herein describe a novel process for preparing optically pure Clopidogrel base which does not require subsequent purification step, and is easy to scale up and operationally simple. Summary of the invention The present invention provides an improved process to prepare Clopidogrel base and its corresponding salts, of general formula (I). The present invention especially provides a process to prepare chemically and optically pure Clopidogrel base and its pharmaceutically acceptable salts. AH prior art process requires that the Clopidogrel base (I) is either resolved or chirally enriched using (-) Camphor sulfonic acid [(-) CSAJ. The process involved treatment of the base with (-) CSA, to obtain the corresponding salt, resolving &/or chirally enrichment and subsequent basification to obtain the (+)-(S) isomer. However, this process is costly due to the high cost of camphor sulfonic acid. We herein describe a method which does not require the use of (-) CSA. The method may be described as below: Scheme: 3 ZRC-PD-028 a) Chirally enriched amide of formula (III) is treated with methanol and suitable acids in suitable solvents to obtain chirally enriched Clopidogrel base. Suitable acids may be inorganic acids such as sulfuric acid or organic acids such as methane sulfonic acid or benzene sulfonic acid. b) The chirally enriched base is treated with suitable inorganic acids such as hydrochloride acid or hydrobromic acid to obtain the corresponding salt which is subsequently broken using suitable inorganic bases to obtain Clopidogrel base (I). Suitable inorganic bases may be selected from ammonia, sodium hydroxide, potassium hydroxide, sodium or potassium carbonates, sodium bicarbonate and the like. The temperature of the reaction is suitably controlled. The amide of formula (III) may be prepared according to processes known in the art, preferably it is prepared according to the process described in US 6635763 and in our application 914/Mum/2006. The pure base may further be converted to corresponding salts such as bisulfate, hydrochloride, hydrobromide, mesylate, besylate, tosylate and the like by reacting the base with the corresponding acids in suitable solvents by techniques known. Advantages of the present process: The process of the present invention has following advantages: 1) The process does not require the use of camphor sulfonic acid, which is very expensive. 2) The reagents and chemicals used are readily available. 3) The reactions conditions employed during the various steps are mild. 4) Easy to scale up 5) No requirement of subsequent resolution or further purification H. SUBRAMANTAM Of Subramapam7Nataraj & Associates Attorneys fur the Applicants Dated this the 22nd day of November 2006 4 |
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1937-mum-2006-abstract(8-1-2007).pdf
1937-mum-2006-claims(8-1-2007).pdf
1937-MUM-2006-CLAIMS(AMENDED)-(19-4-2013).pdf
1937-MUM-2006-CLAIMS(MARKED COPY)-(19-4-2013).pdf
1937-mum-2006-correspondance-received.pdf
1937-MUM-2006-CORRESPONDENCE(1-8-2013).pdf
1937-MUM-2006-CORRESPONDENCE(10-6-2013).pdf
1937-MUM-2006-CORRESPONDENCE(14-10-2010).pdf
1937-MUM-2006-CORRESPONDENCE(2-9-2013).pdf
1937-MUM-2006-CORRESPONDENCE(21-4-2014).pdf
1937-MUM-2006-CORRESPONDENCE(4-9-2013).pdf
1937-mum-2006-correspondence(8-1-2007).pdf
1937-MUM-2006-CORRESPONDENCE(8-7-2013).pdf
1937-mum-2006-description (provisional).pdf
1937-mum-2006-description(complete)-(8-1-2007).pdf
1937-mum-2006-form 1(28-12-2006).pdf
1937-MUM-2006-FORM 18(14-10-2010).pdf
1937-mum-2006-form 2(8-1-2007).pdf
1937-mum-2006-form 2(title page)-(complete)-(8-1-2007).pdf
1937-mum-2006-form 2(title page)-(provisional)-(24-11-2006).pdf
1937-MUM-2006-FORM 3(28-9-2012).pdf
1937-mum-2006-form 5(8-1-2007).pdf
1937-MUM-2006-FORM PCT-IPEA-409(28-9-2012).pdf
1937-MUM-2006-GENERAL POWER OF ATTORNEY(28-9-2012).pdf
1937-MUM-2006-PETITION UNDER RULE-137(28-9-2012).pdf
1937-MUM-2006-REPLY TO EXAMINATION REPORT(19-4-2013).pdf
1937-MUM-2006-US DOCUMENT(28-9-2012).pdf
| Patent Number | 264095 | ||||||||||||
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| Indian Patent Application Number | 1937/MUM/2006 | ||||||||||||
| PG Journal Number | 50/2014 | ||||||||||||
| Publication Date | 12-Dec-2014 | ||||||||||||
| Grant Date | 05-Dec-2014 | ||||||||||||
| Date of Filing | 24-Nov-2006 | ||||||||||||
| Name of Patentee | CADILA HEALTHCARE LIMITED | ||||||||||||
| Applicant Address | ZYDUS RESEARCH CENTRE," ZYDUS TOWER", SATELLITE CROSS ROADS, SARKHEJ- GANDHINAGAR HIGHWAY, AHMEDABAD- 380015, | ||||||||||||
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| PCT International Classification Number | C07D495/04 | ||||||||||||
| PCT International Application Number | N/A | ||||||||||||
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