FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
RACEMIZATION PROCESS FOR R(-)CLOPIDOGREL
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY; INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a process for the preparation of clopidogrel and salts thereof. Further it relates to process for recycling the (R) enantiomer left in the mother liquor, via racemization and resolving the desired enantiomers from the reaction mass.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides a process for the preparation of clopidogrel and salts thereof. Further it relates to process for recycling the (R) enantiomer left in the mother liquor, via racemization and resolving the desired enantiomers from the reaction mass.
Clopidogrel is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/llla complex. Clopidogrel bisulfate of formula I, is chemically known as, methyl (+)-(S)-α(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).

ci Formula I
Clopidogrel hydrochloride of formula II is chemically known as, methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrochloride. Clopidogrel and its salts are used in the treatment of platelet aggregation inhibitory and anti- thrombotic effect.

. HCI
Formula II
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U.S. Patent. 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. Patent. No. 4,847,265 discloses process for preparation of the dextrorotatory enantiomer of the clopidogrel bisulfate. Racemic clopidogrel is resolved using camphor sulfonic acid to obtain optically pure dextrorotatory isomer. The patent describes the crystallization of the (S) enantiomer using dimethylformamide, ketones and alcohols.
U.S. Patent. No. 5,036,156, discloses a method for preparation of an intermediate in the synthesis of clopidogrel, 2-chloro-a-bromopheny! acetic acid and a process for condensing methyl ester with tetrahydrothienopyridine.
U.S. Patent. No. 6,080,875 discloses a process for preparation of methyl (+)-(S)-α- (2-thienyl-2-ethylarnino)-a- (2-chlorophenyl) acetate hydrochloride by reaction of sodium-2-thienylglycidate with (S) 2:chloro phenyl glycine in presence of cyanoborohydride.
U.S. Patent. No. 6,180,793 discloses a process for preparation of (S) clopidogrel by reaction of 2-thiophene ethanol with (S)-2-chlorophenyl glycineamide, (S)-2-chlorophenyl-a-amino acetonirile or (S)-2-chlorophenyl glycine methyl ester. The resulting compound is cyclised, hydrolysed and esterified.
U.S. Patent. 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. Patent. No. 6,800,759 discloses a process for resolution of racemic clopidogrel, along with the conversion of (R) enantiomer of the clopidogrel to (S).
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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. Patent. No. 6,429,210 discloses a process for preparation of the dextrorotatory (S) enantiomer of Clopidogrel bisulfate in the crystalline Form II.
Several racemization process using a sodium/potassium t- butoxide or methoxide as bases have been reported for the preparation of Clopidogrel for example, in U.S. Patent. No. 6,737,411, PCT Application WO04013147 & PCT Application WO06087729.
A problem with the preparation of clopidogrel is the presence of a therapeutically inactive enantiomer, the (R) enantiomer. The presence of the (R) enantiomer results in contamination of the final product, and lowers the yield. The skilled artisan knows few racemization processes utilizing a base. But there exists the need of an industrial process for recycling the (R) enantiomer via racemization and resolving the desired enantiomers from the reaction mass.
The present invention while working on the racemization process has come up with a simple improvement of using the anhydrous base in powdered form, which allow complete racemization of the (R) enantiomer and thus contributes to better yield and purity at industrial scale.
In one aspect of the present invention, there is provided a process for racemizing (R) clopidogrel comprising reacting (R) clopidogrel with a catalytic amount of an anhydrous base in powdered form using a solvent.
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The repetition of recycling step can be minimized by use of anhydrous base in powdered form instead of being granular. This makes the process industrially suitable as complete racemization of the (R) enantiomer takes place.
In yet another aspect of the present invention, base is selected from the group consisting of sodium carbonate, potassium carbonate, Lithium Hydroxide, trimethyl amine and the like.
Non-limiting examples of base may include one or more of bases to include sodium t-butoxide, potassium t-butoxide, diisopropylamide, sodium hydride, potassium hydride, sodium methoxide and potassium methoxide and the like.
The racemizing is carried out in polar solvent. Non-limiting examples of the solvent for racemization include any polar solvent, for eg. Acetic acid, n-Butanol, Isopropanol, n-Propano(, EthanoZ, methanol and the like.
The temperature conditions of racemization reaction include the range of 0°C -45°C. Preferably the racemizing is carried out at a temperature of less than about 20° C, more preferably at a temperature of about 15-20 ° C.
The specific optical rotation of racemic clopidogrel is usually within the range of
(-)1 °to(+)1°.
Embodiments of racemic clopidogrel may include one or more of the following
features. For example, the specific optical rotation of racemic clopidogrel is (+)
0.42°.
The racemic clopidogrel so obtained is used as an intermediate in synthesis of Clopidogrel and its enantiomers and salt thereof.
The (R) enantiomer left in the mother liquor, can be obtained by any know method in the art. After racemization using an anhydrous base in powdered form the racemic clopidogrel so obtained is resolved using L-camphor sulfonic acid to
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obtain optically pure dextrorotatory isomer of clopidogrel, which can be converted to its desired salts form.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
Example 1: Racemization of R (-) Clopidogrel base
Mother liquor of S (+) Clopidogrel camphor sulphonate (150 gm) was treated with 10% sodium bicarbonate solution in chloroform to get R (-) Clopidogrel base (102 gm). This R (-) Clopidogrel base (102 gm) was treated with potassium carbonate (Anhydrous, powdered 43.84 gm) in methanol at 15-20 ° C for 24 hrs. After completion of reaction, reaction mixture was filtered and filtrate subjected for distillation from methanol to get racemic clopidogrel base.
Analysis-Clopidogrel racemic base- SOR- (+) 0.42°
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WE CLAIM:
1. A process for racemizing (R) clopidogrel comprising the steps of reacting (R) clopidogrel with a catalytic amount of an anhydrous base in powdered form using a solvent.
2. A process as claimed in claim 1, wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, Lithium Hydroxide and the like.
3. A process as claimed in claim 2, base is potassium carbonate.
4. A process as claimed in claim 1, wherein the racemizing is carried out in polar solvent.
5. A process as claimed in claim 1, wherein the racemizing is carried out in Acetic acid, n-Butanol, Isopropanol, n-Propanol, Ethanol, methanol and the like.
6. A process as claimed in claim 5, wherein the racemizing is carried out in methanol.
7. A process as claimed in claim 1, wherein the racemizing is carried out at a
temperature of about 0°C - 45 °C.
8. A process as claimed in claim 8, wherein the racemizing is carried out at a temperature of about 15°C -20°C.
9. A process as claimed in claim 1, wherein the specific optical rotation of racemic clopidogrel is (+) 0.42.
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10. A process as claimed in claim 1, wherein the racemic clopidogrel so obtained is used as an intermediate in synthesis of Clopidogrel and its enantiomers and salt thereof.
Dated this 26TH day of May, 2007 For Wockhardt Limited

(Mandar Kodgule) Authorized Signatory