FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
Title of the invention – An improved process for the purification of Clopidogrel bisulphate
2. Applicant(s)
(a) NAME : ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which is to be
preformed :

Field of the invention
The present invention relates to an improved process for the purification of (S)-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)-acetic acid methyl ester compound of formula I (Clopidogrel bisulphate)

Background of the invention
Clopidogrel, methyl (S)-(+)-α -(2-chlorophenyl)-6,7-dihydrothieno[3,2- a]pyridine-5(4H)-acetate of formula (II), is a platelet-aggregation inhibitor which is effective in treating peripheral arterial diseases such as stroke, thrombosis and embolism, as well as coronary arterial diseases such as myocardial infarction and angina pectoris :

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.

U. S. Pat. No. 4, 847, 265 (EP 291459, JP 63203684) discloses methods for separating one enantiomer of clopidogrel from another by selective crystallization of the camphor sulfonate of the (S) enantiomer. The'265 patent discloses crystallizing the (S) enantiomer from dimethylformamide ("DMF"), ketones, and alcohols, though crystallization with acetone is primarily disclosed. U. S. Pat. No. 5,132, 435 (EP 465358, JP 3055819), 6,215, 005 and 6, 258, 961, incorporated herein by reference, also disclose separating the (S) enantiomer of clopidogrel by crystallization of the camphor sulfonate from acetone.
Various methods of preparing clopidogrel are described in European Patent Nos. 0,281,459, 0,466,569, 0,971,915, 0,099,802, 1,021,449, 1,404,681 and 1,353,928, and International Publication Patent No. WO2004/094374. Among these methods, preferred in terms of commercial applicability are methods which involve resolving a racemate composed of clopidogrel of formula (I) or an intermediate thereof and its levorotatory isomer using an optical resolution agent.
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.
European Patent No. 0,281,459 discloses a method of preparing clopidogrel of formula (I) by way of reacting a racemate of clopidogrel with (lR)-(-)-10-camphorsulfonic acid to selectively form camphorsulfonate of clopidogrel, and removing the camphorsulfonate moiety therefrom (optical resolution process); and European Patent Nos. 0,099,802 and 1,353,928, by way of optically resolving an intermediate of clopidogrel racemate as described above using (lR)-(-)-10-camphorsulfonic acid, and then preparing the desired clopidogrel from the resolved intermediate.
However, these methods have the problem that the salt of clopidogrel or an intermediate thereof formed by the selective crystallization from the racemate of clopidogrel or its intermediate and (lR)-(-)-10-camphorsulfonic acid has an insufficient optical purity and must be subjected to further purification, the purification resulting in a yield reduction.

Accordingly, an inexpensive and commercially viable process to prepare clopidogrel and pharmaceutically acceptable salts thereof is required.
Object of the invention
The present object of the invention to provide an improved process for the purification of (S)-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)-acetic acid methyl ester compound of formula I (Clopidogrel bisulphate).
Another object of the present invention is to provide an improved process for the purification of clopidogrel bisulphate which is operationally simple, easy to handle and applicable at an industrial scale.
In another object of the present invention provides a process for the purification of clopidogrel bisulphate. The process comprises
a) treating clopidogrel bisulphate with sodium bicarbonate in cyclohexane to obtain clopidogrel free base
b) contacting clopidogrel free base with levorotatory camphor-10-sulfonic acid in acetone to obtain camphor-10-sulfonic salts of clopidogrel
c) converting camphor-10-sulfonic salts of clopidogrel into clopidogrel free base by reacting with sodium bicarbonate in cyclohexane
d) reacting clopidogrel base in 1-pentanol followed by adding concentrated sulphuric acid and water followed by seeding of clopidogrel bisulphate form 1 to obtain clear solution followed by precipitating clopidogrel bisulphate form 1 from clear solution by adding methyl tertiary butyl ether.

Summary of invention
The one aspect of the present invention relates to provide an improved process for the purification of (S)-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)-acetic acid methyl ester compound of formula I (Clopidogrel bisulphate).
In another aspect of the present invention provides a process for the purification of Clopidogrel bisulphate. The process comprises
a) treating clopidogrel bisulphate with sodium bicarbonate in cyclohexane to obtain clopidogrel free base
b) contacting clopidogrel free base with levorotatory camphor-10-sulfonic acid in acetone to obtain camphor-10-sulfonic salts of clopidogrel
c) converting camphor-10-sulfonic salts of clopidogrel into clopidogrel free base by reacting with sodium bicarbonate in cyclohexane
d) reacting clopidogrel base in 1-pentanol followed by adding concentrated sulphuric acid and water followed by seeding of clopidogrel bisulphate form 1 to obtain clear solution followed by precipitating clopidogrel bisulphate form 1 from clear solution by adding methyl tertiary butyl ether.
Detailed description of the invention
The first embodiment of the present invention related to provide an improved process for the purification of (S)-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H)-acetic acid methyl ester compound of formula I (Clopidogrel bisulphate).

In another embodiment of the present invention provides a process for the purification of Clopidogrel bisulphate. The process comprises
a) treating clopidogrel bisulphate with sodium bicarbonate in cyclohexane to obtain clopidogrel free base
b) contacting clopidogrel free base with levorotatory camphor-10-sulfonic acid in acetone to obtain camphor-10-sulfonic salts of clopidogrel
c) converting camphor-10-sulfonic salts of clopidogrel into clopidogrel free base by reacting with sodium bicarbonate in cyclohexane
d) reacting clopidogrel base in 1-pentanol followed by adding concentrated sulphuric acid and water followed by seeding of clopidogrel bisulphate form 1 to obtain clear solution followed by precipitating clopidogrel bisulphate form 1 from clear solution by adding methyl tertiary butyl ether.
In another embodiment, present invention provides a process for the purification of Clopidogrel bisulphate comprising a step of treating clopidogrel bisulphate with sodium bicarbonate in cyclohexane to obtain clopidogrel free base.
In another embodiment, present invention provides a process for the purification of Clopidogrel bisulphate comprising a step of contacting clopidogrel free base with levorotatory camphor-10-sulfonic acid in acetone obtain camphor-10-sulfonic salts of clopidogrel.
In another embodiment, present invention provides a process for the purification of
Clopidogrel bisulphate comprising a step of converting camphor-10-sulfonic salts of
clopidogrel into clopidogrel free base by reacting with sodium bicarbonate in
cyclohexane.
In another embodiment, present invention provides a process for the purification of Clopidogrel bisulphate comprising a step of reacting clopidogrel base in 1-pentanol followed by adding concentrated sulphuric acid and water followed by seeding of

clopidogrel bisulphate form 1 to obtain clear solution followed by precipitating clopidogrel bisulphate form 1 from clear solution by adding methyl tertiary butyl ether.
Examples:
Example:1 Preparation of Camphor -10-sulphonic acid salt of Methyl (2S)-(2-Chlorophenyl)[6, 7-dihydrothieno [3, 2-C] pyridine-5(4H)-yl] ethanoate. Methyl (2S)-(2-Chlorophenyl) [6, 7-dihydrothieno [3, 2-C] pyridine-5(4H)-yl] ethanoate sulphate (100gm) and cyclohexane (400ml) was charged at 25-35 °C and the reaction mixture was cooled to 15 °C. Sodium bicarbonate (48gm in 600ml water) was added to adjust pH to 6-7.Cyclohexane was distilled under vacuum at 40-45 °C. Acetone (200ml) and L (-) camphorsulphonic acid solution (55.32 gm in 300ml acetone) was added to reaction mixture at 20-25°C. The reaction mixture was seeded with Methyl (2S)-(2-Chlorophenyl) [6, 7-dihydrothieno [3, 2-C] pyridine-5(4H)-yl] ethanoate sulphate (0.25gm) and stirred. The product was filtered, washed with acetone (100ml) and dried under vacuum at 25-30 °C. Yield: 90%
Example:2 Preparation of Methyl (2S)-(2-Chlorophenyl)[6, 7-dihydrothieno [3, 2-C] pyridine-5(4H)-yl] ethanoate sulphate.
Camphor -10-sulphonic acid salt of Methyl (2S)-(2-Chlorophenyl)[6, 7-dihydrothieno [3, 2-C] pyridine-5(4H)-yl] ethanoate(100gm), DM water(500ml) and Cyclohexane(400ml) was charged at 25-35 °C. Sodium bicarbonate (56gm in 700ml water) was added to adjust pH to 6-7. Cyclohexane was distilled under vacuum at 40-45 °C.1-pentanol (290ml) was charged with stirring at 40-45 °C. The reaction mixture was cooled to 5-10°C and slowly

Con.H2SO4 (9.16ml) was added. DM water (1.5ml) was charged at 5-10°C with stirring.
The reaction was seeded with Methyl (2S)-(2-Chlorophenyl) [6, 7-dihydrothieno [3, 2-C]
pyridine-5(4H)-yl] ethanoate sulphate form 1(1.5gm) at 5-10 °C with stirring for 10-15
mins. Methyl tert butyl ether (580ml) was added to the clear solution at 25-30 °C and
form 1 of Methyl (2S)-(2-Chlorophenyl)[6, 7-dihydrothieno [3, 2-C] pyridine-5(4H)-yl]
ethanoate sulphate was precipitated. The product was washed with Methyl tert butyl ether
(300ml), dried under vacuum at 25-30 °C.
Yield: 85%
Example:3 Purification of Methyl (2S)-(2-Chlorophenyl)[6, 7-dihydrothieno [3, 2-C]
pyridine-5(4H)-yl] ethanoate sulphate.(Form 1)
Methyl tert butyl ether (500ml) and Methyl (2S)-(2-Chlorophenyl)[6, 7-dihydrothieno [3,
2-C] pyridine-5(4H)-yl] ethanoate sulphate.(Form 1) (100gm) was charged with stirring at
20-25 °C. The product was filtered, washed with Methyl tert butyl ether (50ml) and dried
under vacuum at 25-30 °C.
Yield: 95%

The synthetic reaction scheme of the present invention is shown in the scheme-I


Claims,
1. A process for the purification of clopidogrel bisulphate comprising: i. treating clopidogrel bisulphate with sodium bicarbonate in cyclohexane to
obtain clopidogrel free base ii. contacting clopidogrel free base with levorotatory camphor-10-sulfonic acid in
acetone to obtain camphor-10-sulfonic salts of clopidogrel iii. converting camphor-10-sulfonic salts of clopidogrel into clopidogrel free base
by reacting with sodium bicarbonate in cyclohexane iv. reacting clopidogrel base in 1-pentanol followed by adding concentrated
sulphuric acid and water followed by seeding of clopidogrel bisulphate form 1
to obtain clear solution followed by precipitating clopidogrel bisulphate form 1
from clear solution by adding methyl tertiary butyl ether.