FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:
A NOVEL PROCESS FOR THE MANUFACTURE OF (+)-(S)-CLOPIDOGREL
BISULFATE FORM-I

2. APPLICANT (S)
(a) NAME: Wockhardt Limited
(b) NATIONALITY: Indian
(c) ADDRESS:
Wockhardt Towers,
Bandra- Kurla Complex,
Bandra (East),
Mumbai-400051,
India
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to a novel process for the manufacture of blood-platelet
aggregation inhibiting agent. In particular, the present invention is directed to a process for
the manufacture of Methyl-(+)-(S)-a-(2-Chlorophenyl)-6,7-dihydrothieno[3)2-c]pyridine
5(4H)-acetate bisulfate Form-1

The following specification particularly describes the invention and the manner in which it
is to be performed.

4. FIELD OF THE INVENTION
The present invention relates to a novel process for the manufacture of blood-platelet
aggregation inhibiting agent. In particular, the present invention is directed to a process for the
manufacture of Methyl-(+)-(S)-a-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4//)-
acetate bisulfate Form -1 of Formula:

BACKGROUND OF THE INVENTION
ClopidogreJ is an inhibitor of platelet aggregation. Clopidogrel's platelet inhibiting
activity makes it an effective drug for reducing the induce of ischemic strokes or heart attacks.
By inhibiting platelet aggregation, Clopidogrel reduces the chance of arterial blockage, thus
preventing strokes and heart attacks. Recent studies have shown that Clopidogrel is more
effective in blocking platelet aggregation than Asprin. Clopidogrel is much effective than
Aspirin even at much lower dosage. In addition to being more effective, Clopidogrel produces
much less gastrointestinal bleeding than Asprin.
European patent 281459 describes the enantiomers of tetrahydrothieno pyridine
derivatives and their pharmaceutically acceptable salts. The patent specifically claims
Clopidogrel hydrogen sulfate, i.e., the dextrorotatory isomer which posses an excellent platelet
aggregation inhibiting activity whereas the levd-rotatory isomer is less active. EP 281459
makes no reference to existence of the specific polymorphic forms of clopidigrel hydrogen
sulfate.

Dextro-rotatory isomer of Clopidogrel is prepared by salt formation from the racemic
compound using an optically active acid such as 10-L-camphorsuIphonic acid in acetone, -
followed by successive re-crystallization of the salt until a product with constant rotatory
power is obtained, followed by release of dextro-rotatory, isomer from its salt by a base.
Clopidogrel hydrogen sulfate is then obtained in standard manner by the dissolution of said
base in acetone cooled in ice and addition of concentrated sulfuric acid to precipitation. The
precipitate thus obtained is then isolated by filtration, washed and dried to give Clopidogrel
hydrogen sulfate in the form of white crystals. US Patent Nos. 4,874,265; 5,132,435;
6,258,961, 6,215,005 and 6,180,793 describe methods that can be used to prepare Clopidogrel
hydrogen sulfate.
Clopidogrel bisulfate Form I and II was first time disclosed in International Publication
No. WO 99/65915, though Form-I is originally disclosed in EP 281459. US patent 6,429,210;
6,504,030 and US patent application 2002/019829 Al disclose the manufacturing.process of
Clopidogrel hydrogen sulfate Form -1 and II. These polymorphs are prepared by dissolving
Clopidogrel camphor sulfate in acetone followed by addition of cone, sulfuric acid at an
ambient temperature. Excess of acetone is distilled and residue is cooled down to 0-5 °C
followed by filtration to get Clopidogrel Form-I. The Form - II of Clopidogrel is obtained
from residual mother liquor after 3-6 months period. These US patents does not disclose a
process for the manufacture of Form-I only and hence, there is huge loss in the yield of
s
Clopidogrel hydrogen sulfate Form-I. US patent application 2003/0114479 discloses the
manufacturing processes for Clopidogrel hydrogen sulfate Form-I, II, III, IV, V and
amorphous forms. The application also claims the preparation of Clopidogrel hydrogen sulfate
Form-I from amorphous Clopidogrel hydrogen sulfate. Specification of the US patent
application 2003/0114479 discloses the preparation method of Clopidogrel hydrogen sulfate
Form-I using different combinations of alcohol and ether in 56 - 88 % yield.
PRESENT INVENTION
The present invention relates to a novel process for the preparation of Clopidogrel
bisulfate or the bisulfate of methyl-(-i-)-(S)-a-(2-clilorophenyl)-4,5,6,7-tetrahydrothieno[3,2,-


cjpyridine-5-acetate. More particularly, the invention relates to a novel process for the
preparation of CJopidogrel b:sulfate Form-1 having Formula:

Single solvent like isopropyl alcohol, isopropyl ether, 2-butanol etc. afforded mixture
of Form-I and Form-II as evidenced by IR and XRD values. Even using seeded crystals of
pure Form-I in acetone afforded only (-(-)-(S)-Clopidogrel bisulfate Form-II.
It is observed that ethyl-acetate is the solvent of choice for getting (-f)-(S)-Clopidogrel
bisulfate Form-Iin good yield and highly pure form. The Forrn-I of Clopidogrel bisulfate is
well characterized by IR and XRD. These values are identical with the reported values of
Form-I (reported in US patent 6,429,210 Bl). HPLC purity of Clopidogrel bisulfate Form-I
prepared using ethyl acetate solvent is found more than 99 %. An increase in melting point is
observed in our process, i.e., 198 to 200 °C in comparison to 181,2 °C disclosed in US patent
6,429,210 Bl. The increase in melting point indicates higher purity of Form-I from what is
reported in the "210"patent.
The present process for the manufacture of Clopidogrel bisulfate in an ester solvent,
more specifically in ethyl acetate consumes less time than other solvent combinations reported
in the prior art. It is also observed that, the yield and purity of Clopidogrel bisulfate Form-I is
88 % and 99 %, respectively. The obtained yield and purity of the Clopidogrel bisulfate
Form-I by this process is better than reported in prior art. The specific rotation [ajo20 of the
Clopidogrel bisulfate Form-I is observed at +55.16° at a concentration of 1.61 gm / 100 ml
methanol.

Identical product, namely, (+)-(S)-Clopidogrel bisulfate Form-I is obtained having
similar purity and yield using Isopropyl acetate and n-Butyl acetate solvents.
Clopidogrel bisulfate is characterized by JH NMR, 13C NMR, mass and CHN analyses.
The (+)-(S)-Clopidogrel bisulfate Form-I is confirmed on the basis of IR, XRD and melting
point analyses.
These values are tabulated as follows. For comparison purpose the. values of Form-II are
also given in the table. IR, XRD, HPLC purity, melting point and Specific Rotation of (+)-(S)-
Clopidogrel bisulfate Form-I and Form-II are tabulated as follows:

Form-I obtained1 by this process is found to be stable and does not convert to any other
forms.
TABLE: Comparative analytical data of (+)-(S)-Clopidogrel bisulfate Form-I and Form-II.

Apart from all these technical and economical advantages of the process according to the
invention, excellent yields and very good quality of the desired product, viz., Clopidogrel
bisulfate Form-I is obtained. The process is suitable for industrial scale.
The following example illustrates the invention more clearly, without limiting its scope.
Examples
The following examples illustrate the invention, but is not limiting thereof.
PREPARATION OF (+)-(S>CLOPIDOGREL BISULFATE FORM-I
(a) Resolution of (+)-(S)-Clopidogrel
Racemic Clopidogrel base 12 gm (0.037 mole) (prepared according to procedure
.described in US patent 4,529,596) is dissolved in acetone (100 ml) and to it at 20 °C a solution
of L-camphor-10-sulphonic acid, 5.196 gm (0.037 mole) in 20 ml acetone is added drop-wise.
The mixture is heated at reflux temperature for 7 to 8 hours and then cooled to room
temperature. The mixture is seeded with (+)-(S)-Clopidogrel-camphor-sulfonate salt (2.5 % of
the weight of base), stirred at room temperature for 10-12 hours. The product is filtered under
suction to get (+)-(S)-Clopidogrel-caniphor-sulfonate salt and washed with acetone which
yielded 5.20 gm of product. The (+)-(S)-Clopidogrel is characterized on the basis of specific
rotation based on literature and [O,]DW of (+)-(S)-Clopidogrel is found + 24.70° at a
concentration of 1,68 gm/100 ml methanol. The 5.20 gm of the above compound is treated
with minimum amount of water and made alkaline with sodium bicarbonate at 5 °C, the
obtained mixture is extracted in dichloromethane and subsequently removal of the solvent
provided oily (+)-(S)-Clopidogrel in 4.92 gm yield and 99.96 % pure form based on HPLC.
The structure of the (+)-(S)-CIopidogreI has been assigned on the basis of spectral
values like JH NMR, 13C NMR and specific rotation etc.

(b) (+)-(S)-Clopidogrel bisulfate Form-I
(+)-(S)-CIopidogrel, 4.V50 gm (0.0139 mole) is dissolved in ethyl acetate 50 ml and
seeded with (+)-(S)-CIopidogreI bisulfate Form-I (2.5 % of the weight of base). During
stirring Cone, sulfuric acid 1.50 gm (0015 mole) is added at room temperature. After
complete addition the reaction slurry is heated at reflux for 1 hour. Then it is stirred at room
temperature for 1 hour. The product is then filtered under suction and washed with ethyl
acetate followed by drying under vacuum at 60 to 70 °C for 6-8 hours. After complete drying,
4.0 gm (+)-(S)-Clopidogrel bisulfate Form-I is obtained in having 99.96 % purity and
[a]D20 = -i- 55.16 ° at a concentration of. 1.61 gm/100 ml methanol. Isopropyl acetate and n-
Butyl acetate yields similar product.
The (+)-(S)-Clopidogrel bisulfate Form-I is characterized by 1H NMR, I3C NMR,
mass and CHN analyses. The Form-I of (+)-(S)-ClopidogreI bisulfate has been confirmed on
the basis of IR, XRD and melting point etc.

We claim:
1. (+)-(S)-Clopidogrel bisulfate Fonn-I in 99.96 purity and [ccjo20 = + 55.16 ° at a
concentration of 1.61 gm/100 ml methanol and having particle size from about 62 to about
426 microns.
2. Pharmaceutical composition of claim 1.
3. A process for the preparation of (+)-(S)-ClopidogreI bisulfate Form-I, comprising:

A) contacting a compound having the formula

B) with sulfuric acid solution in an acetate solvent for a sufficient time to form (+)-(S)-
Clopidogrel bisulfate Fonn-I; and
C) isolating the (+)-(S)-Clopidogrel bisulfate Form-I.

4. The process of claim 3, wherein molar ratio of (+)-(S)-Clopidogrel and concentrated
sulfuric acid is about 1:1.
5. The process of claim 3, wherein the solvent is an acetate solvent.
6. The process of claim 5, wherein the solvent is ethyl acetate.
7. The process of claim 3, wherein (+)-(S)-Clopidogrel is seeded with (+)-(S)-Clopidogrel
bisulfate fonn-I.
8. The process of claim 7, wherein seeding is between about 1.5 and about 3.5 % by weight
of the (+)-(S)-Clopidogrel bisulfate form-I.
9. The process of claim 8, wherein (+)-(S)-CIopidogrel bisulfate form-I is 2.5 % by weight.
10. The process of claim 3, wherein sulfuric acid is concentrate.
11. The process of claim 3, wherein sulfuric acid is added at room temperature.
12. The process of claim 3, wherein contacting step is conducted at reflux temperature.

13. The process of claim3, wherein (+)-(S)-Clopidogrel is heated between about 30 minutes
and about 1.5 hours at reflux temperature.
14. The process of claim 13, wherein heating time is about 1 hour.
15. The process of claim 3, wherein the mixture is stirred at room temperature for about 45
minutes to about 1.5 hours, after the heating is over.
16. The process of claim 15, wherein stirring time is about 1 hour.
17. The process of claim 1, wherein the purity of (-f )-(S)-Clopidogrel bisulfate form-I is more
than 99%.
18. The process of claim 3, wherein the isolated yield is between about 85 to about 95 %.
19. The process of claim 3, wherein isolated yield is about 89 96.