WO2008081473A2

WO2008081473A2 - Process for preparing clopidogrel

Info

Publication number: WO2008081473A2
Application number: PCT/IN2007/000612
Authority: WO
Inventors: Niraj Shyamlal Shah; Shriprakash Dhar Dwivedi
Original assignee: Cadila Healthcare Limited
Priority date: 2006-12-29
Filing date: 2007-12-27
Publication date: 2008-07-10
Also published as: WO2008081473A3

Abstract

A process for the preparation of clopidogrel of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof is disclosed. The process comprises treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide of formula (II) with acid to provide novel acid salt of (+)-(S)- 2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide of formula (III) wherein in S represent acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, nephthalene sulfonic acid and converting acid salt of (+)-(S)-2-Chlorophenyl- (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide to Clopidogrel (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof.

Description

PROCESS FOR PREPARING CLOPIDOGREL FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Clopidogrel of formula (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof. More particularly, present invention relates to the process for the preparation of (S) isomer of amide of formula (II), which is a key intermediate for the presentation. The present invention further relates the acid addition salt of (S) isomer of amide of formula (II). Clopidogrel is chemically known as (S)- (+)- (2-chlorophenyl)- (6, 7-dihydro-4H- thieno [3,2-c] pyridin-5-yl) acetic acid methyl ester and represented by formula (I). It is useful for the treatment of platelet aggregation.

BACKGROUND OF THE INVENTION Thieno [3,2-c] pyridine derivatives disclosed in FR 2,215,948, FR 2,530,247 and FR 2,612,929, are pharmacologically active and have significant anti-aggregating and anti- thrombotic properties. One such example is 'Clopidogrel', (S)- (+)- (2- chlorophenyl)- (6, 7- dihydro-4H-thieno [3,2-c] pyridin-5-yl) acetic acid methyl ester and its pharmaceutically acceptable salts. Later, it was found that the biological activity resides only with (S)- (+)- stereoisomer (US 4,847,265). DESCRIPTION OF THE PRIOR ART:

The reported methods to synthesize the compounds of general formula (I) (US 4529596, GB 0420706 and GB 0466569), use α-halophenylacetic acid derivatives, which are lacrimatory and irritant in nature. The processes to synthesize such compounds involve multiple steps, and have other drawbacks due to the chemicals/reagents used, which usually are difficult to handle, scale-up and unfavorable from human health as well as environmental point of view. Moreover, overall yields of these processes range from poor to average. Various other synthetic approaches found in literature, involve expensive or hazardous chemicals, which do not significantly improve the yield of the desired product.

Various process for the preparation of Clopidogrel are disclosed in: WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, US 4,876,362, US 5,036,156, US 5,132,435, US 5,139,170, US 5,204,469 and US 6,080,875.

Recently, a new polymorph of Clopidogrel bisulfate (named as form II) has been disclosed in patent application (WO 99/65915), which has a melting point of 176 3 ⁰C. It also mentions that the compound disclosed in the earlier US patent (US 4,847,265), had a different melting point of about 184 A 3 °C (now referred as, form I). It has been shown that both the polymorphs have distinct and characteristic XRD and IR spectrum.

Consequently, the present invention aims to provide an inexpensive and commercially viable process to prepare compounds of formula (I) in good yields. OBJECTS OF THE INVENTION

The object of the present invention is to provide a process for the preparation of Clopidogrel of formula (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof. Another object of the present invention is to provide a process for the preparation of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide of formula (II).

Yet another object of the present invention is to provide a process for the preparation of substantially pure Clopidogrel of formula (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof.

Yet another object of the present invention is to provide a process for the preparation of Clopidogrel bisulfate. DESCRIPTION OF THE INVENTION

According to the present invention, there is provided a process for the preparation of clopidogrel of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof

which comprises treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide of formula (II) with acid to provide novel acid salt of (+)-(S)- 2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide of formula (III)

jvherein in S represent acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, nephthalene sulfonic acid and converting acid salt of (+)-(S)-2-Chlorophenyl- (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide to Clopidogrel (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof.

According to the present invention, (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin- 5-yl)acetamide of formula (II) is treated with acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic aicd, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic aicd, p-toluene sulfonic acid, nephthalene sulfonic acid in suitable solvent to provide a acid addition salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide (III), which is enationmerically substantially pure. Thus, acid addition salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- cjpyridin- 5-yl)acetamide (III) is treated with methanol in presence of acid, preferably in presence of sulfuric acid to provide Clopidogrel of formula (I), which may be subsequently converted to its pharmaceutically acceptable salts, hydrates, solvates thereof. Alternatively, acid addition salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide (III) is treated with base to provide enantiomerically pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (II), which is converted to Clopidogrel or its pharmaceutically acceptable salts, solvates, hydrates thereof, in presence of methanol and acid, in suitable solvent.

Base is selected from inorganic base or organic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, monomethyl amine, triethyl amine, isopropyl amine and the like. Preferably sodium hydroxide

Suitable acids which can be used include acetic acid, polyphosphoric acid, p- toluenesulfonic acid, trifluoroacetic acid, chloroacetic acid, or mineral acids, which includes, sulfuric acid, HCl, HBr and the like, which could be in different forms like acid dissolved in alcohol, anhydrous acids dissolved or saturated in alcohol and alcohol used may be methanol.

The preferable acid is concentrated sulfuric acid in the 1 to 50 equivalent ratio. Suitable solvents for the above transformation may be polar or protic solvent such as hydrophilic solvents including methanol, acetone, acetic acid, THF, DMSO, dioxane,

DME and the like or mixtures thereof. The preferable solvent consists of methanol at least in one equivalent and may be in large excess such that it acts as a solvent.

Sometimes inert cosolvent, such as toluene, xylene etc. can also be used. The temperature ranges from 20 ⁰C to 250 ⁰C, preferably from 50 ⁰C to 150 ⁰C.

The reaction may be carried out in the absence or presence of an inert atmosphere such as N2, He or Ar. The duration of reaction may range from 3 hrs to 5 days, preferably from 4 hrs to 2 days.

According to the present invention, there is further provided a process for preparation of substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide (II), which comprises treating (+)-(S)-2-Chlorophenyl-(6,7- dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) with acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, nephthalene sulfonic acid to provide acid salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin- 5- yl)acetamide of formula (III)

wherein in S is same as describe herein above, and treating with base in suitable solvent to provide substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide (II).

According to the preferred embodiment, (+)-(S)-2-Chlorophenyl-(6,7-dihydro- 4H-thieno[3,2-c]pyridin-5-yl)acetamide (II), is treated with acid in suitable solvent to provide acid salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide, which is isolated and optionally purified with suitable solvent. Further, acid salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin- 5- yl)acetamide (III) is treated with base in suitable solvent provides substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-y])acetamide (II).

The present invention further provides novel acid salt of (+)-(S)-2- ChlorophenyI-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (III)

wherein in S represent acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic aicd, p-toluene sulfonic acid, nephthalene sulfonic acid.

According to another embodiment of the present invention, there is provided a process for the preparation of acid salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin- 5-yl)acetamide (III) comprises treating acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic aicd, p-toluene sulfonic acid, nephthalene sulfonic acid with (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) in suitable solvent to provide acid salt of the present invention.

Preferably, reaction of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide (II) with acid is carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting acid salt of formula (III). Advantageously, both (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) and the acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of (+)-(S)-2-Chlorophenyl-(6,7-dihydro- 4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) and a solvent may be contacted with a acid, or conversely, a mixture, slurry, or solution of acid and a solvent may be contacted with (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II). In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for acid may be identical with or different from the solvent system used for the (+)-(S)-2-Chlorophenyl-(6,7- dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II). The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two-phase reaction scheme may be used wherein the (+)-(S)-2-Chlorophenyl- (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) and acid are primarily reacted in one phase and the resulting (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-y])acetamide acid salt (III) compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include a lower alcohol (Cl- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso- butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso- butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isopropyl ether, dioxane and the like.

The reaction is can be carried out at room temperature to reflux temperature of the solvent.

Thus obtained acid salt is isolated by convention technique such as crystallization by cooling the reaction mixture, distillation of solvent, addition of anti solvent. Preferably, acid salt can be isolated by cooling the reaction mixture to provide crystalline or amorphous form of acid salt.

According to the preferred embodiment of the present invention, there is provided a process for the preparation of Clopidogrel of formula (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof, which comprises (i) treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide acid salt (II) with benzene sulfonic acid in suitable solvent to provide (+)- (S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (Ilia)

(ii) treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide besylate with methanol in presence of sulfuric acid to provide Clopidogrel of formula (I), which may be subsequently converted to its pharmaceutically acceptable salt such as bisulfate, besylate, napsylate, tosylate, oxalate, hydrochloride, hydrobromide, methane sulfonate and the like.

Preferably, reaction of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide (II) with benzene sulfonic acid is carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting besylate salt of formula (Ilia). Advantageously, both (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (II) and the benzene sulfonic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (II) and a solvent may be contacted with a benzene sulfonic acid, or conversely, a mixture, slurry, or solution of benzene sulfonic acid and a solvent may be contacted with (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (II). In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for acid may be identical with or different from the solvent system used for the (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II). The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two-phase reaction scheme may be used wherein the (+)-(S)- 2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) and benzene sulfonic acid are primarily reacted in one phase and the resulting (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate salt (Ilia) compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include a lower alcohol (Cl- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane and the like.

In the preferred embodiment, (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide (II) is dissolved in acetone to provide solution. The said solution is treated with benezene sulfonic acid at reflux temperature to form (+)-

(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (Ilia). The reaction mixture is cooled to provide crystalline besylate salt.

The present invention provides crystalline form of (+)-(S)-2-Chlorophenyl-(6,7- dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (Ilia). The crystalline form of present invention, (+)-(S)-2-Chlorophenyl-(6,7-dihydro-

4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate is herein after designated as "(S)- amide Form I". The (S)-amide Form I is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.2, 14.2, 19.0, 20.9, 21.8, 23.0, 25.0 degrees. The (S)-amide Form I is further characterized by its powder X-ray diffraction pattern as shown in Figure- 1.

The present invention also provides a process for preparing crystalline "(S)- amide Form I, which comprises treating (+)-(S)-2-ChIorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide with benzene sulfonic acid. The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting (S)-amide Form I. Advantageously, both (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide and benzene sulfonic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of (+)-(S)-2-Chlorophenyl- (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide and a solvent may be contacted with a benzene sulfonic acid, or conversely, a mixture, slurry, or solution of benzene sulfonic acid and a solvent may be contacted with (+)-(S)-2-Chlorophenyl-(6,7- dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide. The solvent system can be comprised of a single solvent or a mixture of solvents. Suitable solvents include water, a lower alcohol (Cl- C6) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso- butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso- butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisoproipyl ether, dioxane and the like.

The temperature of contact of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide and benzene succinic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two-phase solution are also possible, though a single solution is generally preferred.

The crystalline (S)-amide Form I can be isolated or recovered from the salt forming reaction by any convenient means. For example, it can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent. Seed crystals of (S)-amide Form I may also be added to help induce precipitation. The precipitated (S)-amide Form I compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

The said besylate salt is further treated with one molar equivalent of methanol in presence of acid preferably sulfuric acid to provide Clopidogrel, which is substaintally pure. Thus obtained Clopidogrel is converted to its salt such as bisulfate, besylate, napsylate, tosylate, oxalate, hydrochloride, hydrobromide, methane sulfonate and the like by method known perse.

According to preferred embodiment of the present invention, there is provided a process for the preparation of substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro- 4H-thieno[3,2-c]pyridin-5-yl)acetamide (II), which comprises (i) treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide acid salt (II) with benzene sulfonic acid in suitable solvent to provide (+)- (S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (Ilia)

(ii) treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide besylate with base in suitable solvent to provide substantially pure (+)- (S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II).

Preferably, reaction of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide (II) with benzene sulfonic acid is carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting besylate salt of formula (IHa). Advantageously, both (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (II) and the benzene sulfonic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (II) and a solvent may be contacted with a benzene sulfonic acid, or conversely, a mixture, slurry, or solution of benzene sulfonic acid and a solvent may be contacted with (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (II). In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for acid may be identical with or different from the solvent system used for the (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II). The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two-phase reaction scheme may be used wherein the (+)-(S)- 2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) and acid are primarily reacted in one phase and the resulting (+)-(S)-2-Chlorophenyl-(6,7-dihydro- 4H-thieno[3,2-c]pyridin-5-yl)acetamide acid salt (III) compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include a lower alcohol (Cl- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane and the like.

In the preferred embodiment, (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide (II) is dissolved in acetone to provide solution. The said solution is treated with benezene sulfonic acid at reflux temperature to form (+)- (S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (Ilia). The reaction mixture is cooled to provide crystalline besylate salt.

Thus obtained (+)-(S)-2-Chloropheny l-(6,7-dihydro-4H-thieno [3 ,2-c]pyridin-5 - yl)acetamide besylate of formula (Ilia) is further treated with base in suitable solvent to provide substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide (II).

Preferably, reaction of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide besylate (IHa) with base is carried out in suitable solvent. Base is selected from inorganic base or organic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, monomethyl amine, triethyl amine, isopropyl amine and the like. The solvent system is preferably selected so as to facilitate the reaction and to allow subsequent separation of the resulting substantially pure compound (II). Advantageously, both (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate (Ha) and base are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of (+)-(S)-2-Chlorophenyl- (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylatte (Ilia) and a solvent may be contacted with base or conversely, a mixture, slurry, or solution of base and a solvent may be contacted with (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide besylate (Ilia). Suitable solvents include water, a lower alcohol (Cl- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso- butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso- butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isopropyl ether, dioxane and or the like or mixture thereof.

The reaction is can be carried out at room temperature to reflux temperature of the solvent. Thus obtained substantially pure compound (II) is isolated by convention technique such as crystallization by cooling the reaction mixture, distillation of solvent, addition of anti solvent.

In the preferred embodiment, (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide besylate (II) is dissolved in acetone to provide solution. The said solution is treated with the solution of sodium hydroxide solution at room temperature and stirred for sufficient time to form substantially pure (+)-(S)-2-

Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II).

As referred here in substantially pure, (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide means it contains any impurity less than 0.1%. preferably less than 0.05%. Overall, it is having purity more than 99.8%, more preferably 99.9%. Further, the enationmeric purity of substantially pure, (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide refers to greater than 99.5%, preferably greater than 99.8%, more preferably 99.9% or higher. BRIEF DESCRIPTION OF DRAWINGS Fig 1. illustrate the XRPD pattern of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide besylate salt.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Examples: Example 1:

Preparation of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c|pyridin-5- yl)acetamide besylate (Ilia): In four neck round bottom flask, 130 gm of (+)-(S)-2-Chlorophenyl-(6,7- dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide and 1300 ml of acetone was added and the mixture was stirred for 30 minutes to obtain clear solution. 54 gm of benzene sulfonic acid was dissolved in 100ml of acetone was added to above solution and heated to reflux under stirring for 30 minutes. The reaction mixture was cooled to 20- 30o C and stirred for 2 hours to obtain (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide besylate (Ilia) in crystalline form. Example 2:

Preparation of substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide (II): In four neck round bottom flask, 10 gm of (+)-(S)-2-Chlorophenyl-(6,7- dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide and 90 ml of acetone was added and the mixture was stirred for 20 minutes at 40 to 50o C to obtain clear solution. Further, solution of sodium hydroxide was added to the solution and stirred at same temperature for 60 minutes. The reaction mixture was cooled to 5-19o C and stirred for 2 hours to obtain substantially (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide (HPLC purity 99.875) Example 3: Preparation of Clopidogrel

In four neck round bottom flask, Methanol (583 mL) and Besylate salt of (+)- (S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (100.Og) was added and heated to 50-55oC. Con. Sulfuric acid (41.0 mL) into RB flask at 50°C -

60⁰C within 10-15 min. Con. Sulfuric acid (41.0 mL) was slowly added to the reaction mixture Further Methanol (41.0 mL) was added to the reaction mixture and was heated 65o 7Oo C for 10 to 12 hours. Further, water (1 104 mL) and potassium carbonate (278 g) were added and stirred for 10-15 min. at 30⁰C - 35°C. Clopidogrel base was isolated by extraction with hexane and conventional technique. HPLC was performed by USP method. R - (-) Isomer (Imp C) = 0.61 % , other impurity Imp-A : 0.038%, Imp_B : 0.090 %, Imp D : 0.067 %)

Claims

We claim:

1. A process for the preparation of clopidogrel of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof

C⁾ which comprises treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide of formula (II) with acid to provide novel acid salt of (+)-(S)- 2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide of formula (III)

wherein in S represent acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, nephthalene sulfonic acid and converting acid salt of (+)-(S)-2-Chlorophenyl- (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide to Clopidogrel (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof.

2. A process as claimed in calaim 1, wherein said acid addition salt of (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin- 5-yl)acetamide (III) is treated with methanol in presence of acid, preferably in presence of sulfuric acid to provide to Clopidogrel of formula (I) and optionally converted to its pharmaceutically acceptable salts, hydrates, solvates thereof.

3. A process as claimed in claim 1, wherein acid addition salt ot (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (III) is treated with base to provide enantiomerically pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide (II), which is converted to Clopidogrel or its pharmaceutically acceptable salts, solvates, hydrates thereof, in presence of methanol and acid, in suitable solvent.

4. A process as claimed in claim 3, wherein said enantiomerically pure (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) is treated with methanol in presence of acid, preferably in presence of sulfuric acid to provide to Clopidogrel of formula (I) and optionally converted to its pharmaceutically acceptable salts, hydrates, solvates thereof.

5. A process for preparing substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-yl)acetamide (II), which comprises treating (+)-(S)-2- Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (II) with acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, nephthalene sulfonic acid to provide acid salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin- 5-yl)acetamide of formula (III)

6. A process as claimed in claim 5, wherein said solvent include a lower alcohol (Cl- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert- butanol, ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isopropyl ether, dioxane and the like.

7. A process as claimed in claim 3 or 5, where in said base is inorganic base or organic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert- butoxide, monomethyl amine, triethyl amine, isopropyl amine, preferably sodium hydroxide.

8. A process for the preparation of Clopidogrel of formula (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof, which comprises (i) treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide acid salt (II) with benzene sulfonic acid in suitable solvent to provide (+)- (S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (Ilia)

9. A process as claimed in claim 8, wherein said suitable solvent is selected from a lower alcohol (Cl- C4) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, di isoproipyl ether, dioxane and the like.

10. A process as claimed in claim 9, wherein said solvent is acetone.

1 1. A process as claimed in claim 8, wherein said (+)-(S)-2-Chlorophenyl-(6,7-dihydro- 4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (Ilia) is crystalline besylate salt.

12. (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate Form I is characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.2, 14.2, 19.0, 20.9, 21.8, 23.0, 25.0 degrees.

13. A process for preparing (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide besylate Form I characterized by its powder X-ray diffraction pattern having peaks expressed as 2Θ at about 7.2, 14.2, 19.0, 20.9, 21.8, 23.0, 25.0 degrees, which comprises reacting (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide with benzene sulfonic acid in acetone to provide solution and isolating Form I from said solution

14. A process as claimed in claim 13, wherein said Form I is isolated by cooling the solution.

15. A process for preparing substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro- 4H-thieno[3,2-c]pyridin-5-yI)acetamide (II), which comprises

(i) treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide acid salt (II) with benzene sulfonic acid in suitable solvent to provide (+)- (S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide besylate of formula (HIa)

16. A process as claimed in claim 15, wherein said base is selected from inorganic base or organic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert- butoxide, monomethyl amine, triethyl amine, isopropyl amine, preferably sodium hydroxide

17. Substantially pure (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5- yl)acetamide of formula (II),

having purity of 99.9%, impurity content less than 0.05% and enantiomeric purity of 99.9% or higher.

18. Novel acid addition salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide of formula (III) in crystalline, amorphous, hydrates or solvate forms thereof,

wherein S represents hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, nephthalene sulfonic acid.

19. Novel acid addition salt of (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide as claimed in claim 18, wherein in preferred acid is benzenesulfonic acid.

20. A process for preparation of Clopidogrel as claimed in any preceding claims lto 1 1 and 13 to 16 wherein said clopidogrel has a purity more than 99.5% and total impurity content not more than 0.5%.

20