Title of Invention	PROCESS FOR PREPARATION OF CLOPIDOGREL HYDROGEN SULPHATE
Abstract	The present invention relates to an improved process for preparation of (+)-(S)-alpha-2-(chlorphenyl)-6, 7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester, commonly known as Clopidogrel . The invention is characterized by process improvements in resolution of racemic Clopidogrel and recycling of resolving agent.

Full Text

FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Process for preparation of clopidogrel hydrogen sulphate " 2. APPLICANT: (a) NAME: IPCA LABORATORIES LTD. (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400067, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention. Technical Field of Invention: The present invention relates to an improved process for preparation of (+)-(S)-alpha-2-(chlorphenyl)-6, 7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester of Formula I, commonly known as Clopidogrel . The invention is characterized by process improvements in resolution of racemic Clopidogrel and recycling of resolving agent. Background of the invention: (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno [3,2-C] pyridine-5 (4-H)-acetic acid methyl ester known as clopidogrel under the International Non-Proprietary Name is marketed as hydrogen sulphate salt. Clopidogrel is known for its platelet aggregating and anti-thrombotic properties and finds medicinal applications in this field. It can be represented by Formula-I, and was disclosed in Patent US 4529596 (hereinafter referred as '596' patent) in its racemic form for the first time. The pure enantiomeric forms of clopidogrel (dextro and levo-isomers) was disclosed in EP 281459 which teaches the isolation of the dextro rotatory isomer of Clopidogrel by reaction of racemic Clopidogrel base with an optically active acid such as 10-L-camphor sulfonic acid in solvents like acetone, followed by successive recrystallization of the diastereomer salt until a product with constant rotatory power was obtained. The pure dextrorotatory isomer of clopidogrel (herein after referred as clopidogrel free base) was released from the respective diastereomeric salt by reaction with sodium bicarbonate in an aqueous solvent followed by extractive work-up. The starting racemic clopidogrel free base was, in turn, obtained from hydrogen sulphate salt of racemic clopidogrel by following an aqueous treatment in presence of bicarbonate. The camphor sulphonic acid for resolution was obtained from ammonium camphor sulphonate by ion exchange column isolation. The pure Clopidogrel free base was then converted into its hydrogen sulfate salt, which is the marketed salt form of clopidogrel. Subsequently International patent publication, WO 99/65915 (herein after referred as '915 patent), disclosed two polymorph forms of Clopidogrel hydrogen sulfate referred to as Form-1 and Form-Il. The process to obtain clopidogrel free base from camphor sulphonate salt was carried out in aqueous reaction conditions in presence of potassium carbonate followed by an extractive work-up. US6800759, US6737411 and US 2006/0074242 patents discloses resolution of clopidogrel by treating clopidogrel free base using optically active camphor-10-sulphonic acid in a mixture of solvents, followed by successive crystallizations, and an aqueous extractive work-up for cleavage of the resultant diastereomeric salt. In parallel to the above reports on the preparation' of clopidogrel, the applicants own publication WO/2005/104663 disclosed the use of mixture of solvents for resolution of racemic clopidogrel base using camphor-10-sulphonic acid. According to our search, in all the preparative methods disclosed for clopidogrel, the resolution of clopidogrel by treatment of racemic clopidogrel base with optically active acid such as camphor sulphonic acid, followed by an aqueous extractive work-up is common. Clopidogrel being an oily substance, it is advantageous to convert to an acid addition salt for better handling, isolation/purification and storage and therefore, its conversion to a salt form is almost unavoidable for stable storage. Clopidogrel has a methyl ester group as evidenced from the structure of Formula I. The clopidogrel when hydrolyzed it forms an impurity named Clopidogrel free acid of Formula X, which needs to be monitored in the active substance as per pharmacopoeial specification. The main cause of this impurity is the hydrolysis of methyl ester under aqueous conditions. In order to control the hydrolysis of ester, very mild bases like bicarbonates and controlled reactions conditions were employed in the art. Due to the poor solubility of either clopidogrel acid addition salt or clopidogrel free base in water, the process of breaking the salt in aqueous conditions were not so effective leading to larger reaction time which is detrimental to product purity. Thus, carrying out reactions at higher temperatures or for longer period in aqueous conditions may lead to formation of acid impurity which necessitates extra purification resulting into yield losses and increase in number of operations that are not desirable for a practical process. Owing to the economy of the process, the expensive resolving agent 'camphor sulphonic acid' should be recovered and recycled after resolution, which is almost impractical in reported aqueous processes because of its high solubility in aqueous solutions. Being freely soluble in water, the recovery from aqueous reaction solution is very difficult and in most cases requires ion exchange column purification, which is not economically viable. Thus, the search for a manufacturing process for the preparation of Clopidogrel resulting in a satisfactory yield / purity of final product remains undoubtedly of interest. It is also an objective of the present invention to discover an efficient process to recover and recycle the optically active resolving agent, apart from simplifying the process for clopidogrel. The present invention ameliorates above problems in the prior art and also the reduced a number of unit operations. Summary of the invention: The present invention thus provides a process for resolution of clopidogrel directly from its racemic acid addition salt. The present process comprises diastereomeric crystallization of optically active clopidogrel from a mixture of racemic clopidogrel acid salt and optically active camphor-10-sulphonate salt in a suitable solvent. The camphor-10-sulphonate salt is an alkali salt including alkali metal, amine and/or ammonia. In one aspect, the process according to the invention comprises treating clopidogrel acid salt, for example, bisulphate, hydrochloride, hydrobromide, or similar salts with a base addition salt of optically active camphor sulphonic acid (Alkali camphor sulphonate salt) in an organic solvent. Alkali metal, organic amine or ammonium salt of camphor sulphonic acid can be used as base addition salt of camphor sulphonic acid, especially preferred salt is ammonium camphor sulphonate, After resolution, the clopidogrel optical isomer, for example dextroclopidogrel base can be recovered from the (S)-clopidorgel camphor sulphonate diastereomer by treating with a base. In a second aspect of the invention, a process for recycling of optically active resolving agent for resolution of racemic clopidogrel acid salt is provided which process comprises treating the diastereomeric clopidogrel camphor sulphonate salt with an organic base or ammonia or metal alkoxide to liberate free optically active isomer of clopidogrel and generate the base salt of camphor sulphonic acid for recycling in the resolution process. In a preferred embodiment of the process according to the second aspect of the present invention, the process comprises treating clopidogrel camphor sulphonate salt with an alkali, for example metal alkoxide, organic base or ammonia, in non-aqueous organic solvent. On completion of reaction, alkali camphor sulphonate salt crystallized out can be isolated in pure form from the solution. The clopidogrel free base can be recovered after filtering out the alkali camphor sulphonate salt from the organic solvent, followed by elimination of solvent and further processing clopidogrel isomer to obtain the marketed bisulphate salt. The alkali camphor sulphonate salt may be recycled in the resolution step directly without any further processing. The present invention eliminates the need for making camphor sulphonic acid from the recovered alkali camphor sulphonate salt in conventional resolution processes, and makes it possible to maintain non-aqueous conditions, if desired. Detailed description of the invention: Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows. Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. The term "treating" means adding or combining or mixing the stated reagent or materials to the thing being treated. The term "non-aqueous medium" means a solvent medium that does not contain water in significant amounts. The term does not exclude solvents containing insignificant amounts of water, which may be less than 5%, more preferably less than 2%. The term "alkali salt" or alkali means any basic ionic salt of alkali/alkaline earth metals or amines, or ammonia. The term "alkali" is not limited to alkali metal ions, but includes any group of basic character that can form salt with an acid. The present improvement in the process for preparation clopidogrel, leading to optical isomers of clopidogrel and pharmaceutically valuable salts are described in detail with the specific embodiments/conditions here after. It has now been found that new process makes it possible to resolve racemic acid salt of Clopidogrel with alkali salt of camphor sulphonic acid and thereby, eliminating the need for obtaining either clopidogrel free base or free camphor sulphonic acid by separate hydrolysis. In addition, the invention process can now be practiced in non-aqueous conditions also, and thereby occurrence of hydrolysis of ester leading to impurity of formula X can be controlled more effectively. The process is simplifying the resolution of racemic clopidogrel free base as well as isolation/recycling of resolving agent, making the process industrially more feasible. Thus, according to the present invention, an improved synthesis of Clopidogrel is provided by reacting racemic clopidogrel acid salt with an alkali salt of camphor sulphonic acid in a suitable solvent, followed by crystallizing the required isomer of clopidogrel as camphor sulphonate diastereomer salt. The optical isomer of clopidogrel can be recovered by treatment with a base and may be further converted to the pharmaceutically acceptable salts. The clopidogrel acid salts may be selected from known ones, for example bisulphate, hydrochloride, hydrobromide, or any other acid salt that is exchangeable with base addition salt of camphor sulphonic ,acid. The salt of camphor sulphonic acid may be selected from any known ones, preferably an amine.camphor sulphonate or ammonium camphor sulphonate. The preferred amines are alkyl amines, especially triethylamine. Alkali metal salts of camphor sulphonate such as sodium camphor sulphonate or potassium camphor sulphonate are also useful. Especially preferred camphor sulphonate salt is ammonium camphor sulphonate due to the ease of handling, recovery, recycling and economy. The organic solvent may be selected from any inert solvent, where a difference of solubility of diastereomer salts can be attained. Examples of solvents include, alcohols such as isopropanol, ethanol; dimethylformamide; ketones such as acetone, methyl ethylketone, Methylisobutyl ketone,( methylpropylketone, etc.; and their mixtures with hydrocarbons, such as toluene, dichloromethane, dichloroethane or ethers such as diisopropyl ether, diglyme, ter.butylmethyl ether, cyclopentylmethyl ether etc.. Suitably preferred solvents are acetone, and its mixtures with toluene or dichloromethane. The organic solvent may contain 1-10% water may also be useful for resolution. In the process, the desired diastereomeric salts of clopidogrel camphor sulphonate can be crystallized selectively from the resolving solvent to effect separation of isomers. If desired, optical purity of clopidogrel isomer can be increased by recrystallizing the diastereomer salt of clopidogrel.camphor sulphonate. The substantially optically pure isomer of clopidogrel can be liberated from the diastereomeric camphor sulphonate salt by treatment with a base and may be further converted to the pharmaceutically acceptable salts. In a second aspect, the present invention provides a process for recycling of optically active resolving agent during resolution of racemic clopidogrel acid salt comprises treating the diastereomeric clopidogrel camphor sulphonate salt with a base, especially an organic base or ammonia or alkali metal alkoxide, to liberate free optically active isomer of clopidogrel and generate the base addition salt (alkali) of camphor sulphonic acid for recycling in the resolution process. As for base, ammonia & amines, for example trialkyl amines are especially preferred for this application. In the above embodiment of the present invention, the clopidogrel camphor sulphonate diastereomer salt is reacted with base, for example ammonia, in a solvent. The process is accomplished by making a solution or suspension of clopidogrel camphor sulphonate in an organic solution and treating with a base, for example ammonia, to attain a constant pH in the range of about 8 to 9. Ammonia may be employed in gaseous form or as solution prepared in an organic solution (by passing ammonia into a neat solvent). Preferably the solvent is selected from non-aqueous solvents, exemplerary solvents include alcohols such as isopropanol, ethanol; ketones such as acetone, methyl ethylketone, Methylisobutyl ketone, methylpropylketone, etc.; hydrocarbons, such as toluene, dichloromethane, dichloroethane; ethers such as diisopropyl ether, diglyme, ter.butylmethyl ether, cyclopentylmethyl ether and their mixtures. The reaction may be conducted at room temperature, but preferably under cooling to control the exothermicity. While progressing the reaction, the .alkali metal/amine/ammonium camphor sulphonate separates out from the solution and clopidogrel free base remain in solution in the organic solvent in stable form. The alkali metal/amine/ammonium camphor sulphonate may be conveniently recovered from the solution by simple filtration. The clopidogrel free base from the mother liquor is recovered after filtering out the ammonium salt of the camphor sulphonic acid from the organic solvent, followed by elimination of solvent. The yield of either clopidogrel free base or ammonium camphor sulphonate is nearly quantitative, whereas in conventional method it is about 75-90%. The amine or ammonium camphor sulphonate salt can be directly recycled in the resolution. If desired, it can be purified by solvent crystallization. In a second embodiment of the present invention the other isomer, for example (R)-clopidogrel.(L)-camphor sulphonate left out after crystallization of desired diastereomer, for example (+)-(S)-clopidogrel.(L)-camphor sulphonate, in the mother liquor is also treated with base/ammonia as described above to recover alkali camphor sulphonate, and thereafter the undesired clopidogrel isomer may be racemized and recycled by treatment with NaOH in alcoholic solvents like methanol at a temperature ranging from 30 to 50°C to obtain a 50:50 ratio of both isomers (referred as racemic mixture). The (+)-(S)-clopidogrel isomer obtained by the process of the present invention is further converted to crystalline forms or amorphous forms of clopidogrel hydrogen sulphate according to any known process, for example according to the process described in our parent application WO/2005/104663 or pending application numbers; 626/MUM/2004 and 861/MUM/2004. The optical isomer of clopidogrel or its pharmaceutically acceptable salt obtained by the process of the present invention, for example, clopidogrel bisulphate, may be formulated into any dosage form, e.g., tablet, capsule, injectables etc., by combining with one or more pharmaceutically acceptable excipients using known techniques. The resulting dosage form may include a suitable amount of the active ingredient. Further, the dosage form may be immediate release or extended release. Further details about the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description. Examples: Example 1. Resolution of racemic clopidogrel bisulphate. 100 gm of racemic Clopidogrel bisulphate [methyl-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetate bisulphate] and 69 gm ammonium (L)-camphor-10-sulphonate were taken in 400 ml of dichloromethane at room temperature. 200 ml water was added to this mixture, and stirred for 2 hours. Dichloromethane layer was separated, aqueous layer extracted with 50 ml dichloromethane, and the combined extracts were washed with water, and distilled out dichloromethane. To this 500 ml acetone was added and stirred for ,4-5 hours at room temperature. The mixture then cooled to 10 degrees, filtered, cake was washed with acetone and dried to obtain 44 gm of diastereomeric (S)-clopidogrel.)L)-camphor sulphonate salt. Chiral purity 98.98% Example 2. Resolution of racemic clopidogrel bisulphate. 100 gm of racemic Clopidogrel bisulphate [methyl-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetate bisulphate] and 69 gm sodium (L)-camphor-10-sulphonate were taken in 400 ml of dichloromethane at room temperature. 200 ml water was added to this mixture, and stirred for 2 hours. Dichloromethane layer was separated, aqueous layer extracted with 50 ml dichloromethane, and the combined extracts were washed with water, and distilled out dichloromethane. To this 500 ml acetone was added and stirred for 4-5 hours at room temperature. The mixture then cooled to 10 degrees, filtered, cake was washed with acetone and dried to obtain 40 gm of diastereomeric (S)-clopidogrel.)L)-camphor sulphonate salt. Chiral purity 99.4%. Example 3. S)-(+)-clopidogrel base (S)-clopidogrel-(L)-camphor sulphonate salt (60 gm) was suspended in dichloromethane at room temperature. The solution suspension was cooled to about 15-20 degrees and passed ammonia gas until a constant pH of 8.5 to 9.0 is reached. The solution was stirred for 3 hours and filtered to obtain ammonium camphor sulphonate which is collected for recycling. The clopidogrel free base is recovered from the mother liquor by concentrating under vacuum to obtain clopidogrel free base in syrup form. Example 4. Resolution of racemic clopidogrel bisulphate 61 gm camphor sulphonic acid was added to 100 ml water, and 27 ml liquor ammonia was added to adjust pH 10. To this 100 gm of racemic Clopidogrel bisulphate [methyl-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetate bisulphate] and 400 ml of dichloromethane were added and stirred for 1.5 hours. Dichloromethane layer was separated, aqueous layer extracted with 50 ml dichloromethane, and the combined extracts, washed with water, and distilled out dichloromethane. To this 500 ml acetone was added and stirred for 4-5 hours at room temperature. The mixture then cooled to 10 degrees, filtered, cake was washed with acetone and dried to obtain 45 gm of diastereomeric (S)-clopidogrel.)L)-camphor sulphonate salt. Chiral purity 99.08% Example 5. Recovery of camphor sulphonic acid from mother liquor after resolution. The acetone mother liquor comprising mixture of (R)-Clopidogrel (enriched) & (S)- clopidogrel camphor sulphonate salt obtained after separation of pure (S)-clopidogrel camphor sulphonate salt was evaporated to dryness. To this 500 ml dichloromethane was added and passed gaseous ammonia while maintaining temperature about 15-20 degrees C. to reach a pH of 9. The suspension was stirred for 2 hours, filtered and washed with dichloromethane to obtain ammonium camphor sulphonate.

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