PROCESS FOR PREPARING CLOPIDOGREL BISULFATE
TECHNICAL FIELD The present application encompasses an improved process for preparing ciopidogre! bisulfate, and intermediates useful in the synthesis there of.
INTRODUCTION Clopidogrel bisulfate is chemically known as (+)-(S)-a- (2-chlorophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5 (4H)- methyl acetate sulfate (1:1) It is represented by the Formula I:
Clopidogrel bisulfate is an antithrombotic agent for treatment of patients with vascular diseases, myocardial infraction and stroke. It is available in the market under the brand name "PLAVIX" in the form of tablets for oral administration.
Badore et al., in U.S. Patent No. 4,847,265 describes clopidogrel and its pharmaceutically acceptable salts, a pharmaceutical composition and the dosage strengths for effective platelet aggregation inhibition. It also describes a method for the preparation of clopidogrel employing classical resolution techniques. The process for the preparation of clopidogrel involves resolution of racemic mixture of clopidogrel of Formula II using levorotatory camphor-10-sulfonic acid in the presence of acetone followed by repeated crystallizations to give the clopidogrel L-(-)-camphor sulfonate, which is then converted to clopidogrel of Formula (lla). The process is summarized in scheme-1.


Scheme 2: Process for preparing racemic clopidogrel as per US 5,036,156
Although various processes for preparation of clopidogrel bisulfate are disclosed in the art, they suffer from one or more drawbacks. Hence, there is a continuing need for a commercially viable process for preparing clopidogrel bisulfate.
SUMMARY OF THE INVENTION
In one embodiment, there is provided an improved process for the preparation of clopidogrel bisulfate comprising the steps of:
a) reaction of compound 4,5,6,7-tetrahydro thieno[3,2-c] pyridine of Formula IV or an acid addition salt there of with the compound methyl-a-bromo-2-chloro phenyl acetate of Formula III:


b) with out isolating tlie compound of Formula II, resolution with L-(-)-camphor
sulfonic acid to form clopidogrel of Formula (lla);
c) reaction of the clopidogrel with sulfuric acid to form clopidogrel bisulfate.
DETAILED DESCRIPTION OF THE INVENTION There is provided an improved process for the preparation of clopidogrel bisulfate
comprising the steps of:
a) reaction of the compound 4,5,6,7-tetrahydro thieno[3,2-c] pyridine of Formula
IV or an acid addition salt there of with the compound methyl-a-bromo-2-chloro phenyl
acetate of Formula III:

in the presence of a base and a ketone solvent to form the compound of Formula (II);

r

b) with out isolating the compound of Formula II, resolution with L-(-)-camphor
sulfonic acid to form clopidogrel of Formula (lla);
c) reaction of the clopidogrel with sulfuric acid to form clopidogrel bisulfate.
As set forth above, reaction of the compound 4,5,6,7-tetrahydro thieno[3,2-c] pyridine Formula IV hydrochloride with the compound methyl-a-bromo-2-chloro phenyl acetate of Formula III is carried out at a temperature of about 0 °C to about 40 °C.
The starting compound of Formula III that is used can be prepared by using simple esterification procedures disclosed in U.S. Patent No. 5,036,156.
Suitable bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like preferable base is potassium carbonate for a commercially viable reaction.
Suitable ketone solvents for conducting the reaction Include acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; or mixtures thereof.
The molar equivalents of compound of Formula IV to be used can range from about 0.8 to about 1.5 equivalents, per equivalent of the compound Formula III. The compound of Formula III is added to the reaction mixture below about 15 °C.
The molar equivalents of base to be used are from about 1 to about 5 molar equivalents, per equivalent of compound of Formula IV.
After completion of the reaction, the reaction mixture is filtered on celite and the obtained filtrate is taken up directly to the further reaction or it is concentrated completely to form the residue.
The resolution of the intermediate of Formula II involves reacting with L-(-)-camphor sulfonic acid followed by reaction with a base to form clopidogrel of Formula (lla)
The process for the preparation of racemic clopidogrel of Formula II and conversion to clopidogrel bisulfate is summarized in the scheme-3.


0*SQ^°^^3
cX)" • 'to

K2CO3 in acetone
*-

OCH3

IV

(i) L(-)-camphor sulfonic acid in Acetone

(ii) Aqeous NaHCOj (III) H2SO4 in Acetone

o^c^°^"'


•H2SO4

Scheme-3: Process for preparing Clopidogrel bisulfate
The compound of Formula II can be further converted into clopidogrel bisulfate of Formula I by using the methods known, for example by using the process described in U.S. Patent No. 5,204,469.
The compound of Formula II prepared in accordance with the present invention contains total impurities less than or equal to 0.5% and individual impurity less than or equal to 0.1%, as characterized by a high performance liquid chromatography ("HPLC") chromatogram obtained from a mixture comprising the desired compound and one or more of the said impurities. The percentage here refers to weight percent obtained from the area-% of the peaks representing the impurities.
The processes of present invention are simple, easily reproducible, and eco-friendly, which produces the desired compounds with high yield and purity.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following example, which is provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLE
EXAMPLE-1: PREPARATION OFCLOPIDOGREL L-(-) CAMPHORSULFONATE
Acetone (800 ml), 4,5,6,7-tetrahydro thieno [3,2-c] pyridine hydrochloride (100 g) of Formula IV and potassium carbonate (100 g) were charged into a clean and dry 4 neck round bottom flask followed by stirring for about 10 minutes. The resultant reaction mixture was cooled to about 10 °C followed by addition of methyl-a-bromo-2-chloro phenyl acetate of Formula III (150 g) over about 2 hours. The reaction mixture was stirred at about 10 °C for about 1 hour followed by allowing the reaction mixture to attain the temperature of about 30 °C. The reaction mixture was stirred at about 30 "C for about 25 hours. After completion of the reaction, the reaction mixture was cooled to about 10 °C followed by filtration of the reaction mixture through a celite bed and the celite was washed with acetone (250 ml). The total filtrate was taken into a clean and dry 4 neck round bottom flask and the solvent was distilled completely at about 60 "C under vacuum to afford a residue (183 gm) of Formula II.
The residue was cooled to about 30 X followed by charging of acetone (850 ml). The resultant suspension was stirred for about 30 minutes followed by charging of L-(-)-camphor-10-sulfonic acid (136.5 g). The suspension was stirred for about 30 minutes followed by charging of clopidogrel-L(-)-camphorsulfonate (0.1 g) and the suspension was stirred for about 16 hours. The solid separated was filtered and the solid was washed with acetone (100 ml) followed by drying the solid obtained at about 45 °C for about 2 hours to afford 97.1 g of the title compound.
Purity by chiral HPLC 99%.
EXAMPLE-2: PREPARATION OF CLOPIDOGREL BISULFATE (FORMULA I)
350 liters of dichloromethane was taken into a reactor and 80 kg of clopidogrel camphor sulfonate obtained by the process similar to the above was added to it. The reaction mass was cooled to 2 °C. A solution of 8 kg of sodium carbonate in 80 liters of water was added to the above reaction mass slowly at a temperature of 2 °C. The

reaction mass was maintained at 3 °C for 30 minutes. Tlie organic layer was separated and the aqueous layer was extracted with 240 liters of dichloromethane in two equal lots. The combined dichloromethane layer was washed with 240 liters of demineralized water in two equal lots. The dichloromethane layer was distilled under vacuum at 47 °C. The residue was then cooled to 32 °C. To the residue 90 liters of 2-butanol was added. The solvent was distilled off at 53 °C under a vacuum of 620 mm Hg. Then traces of dichloromethane were removed using nitrogen purging for 30 minutes. The reaction mass was then cooled to 40 °C. Then 800 liters of 2-butanol was added to the reaction mass and stirred for 15 minutes. 4.0 kg of activated charcoal was added to the reaction mass and stirred for 10 minutes. The reaction mass was then filtered through a leaf filter, online and cartridge filters into another reactor. The filter bed was washed with 100 liters of 2-butanol. The reaction mass was then cooled to about 24 °C. 7.3 liters of 98% sulfuric acid was added to the reaction mass slowly at 24 °C. The reaction mass was seeded with 450 grams of pure clopidogrel bisulfate and maintained for about 12 hours. The reaction mass was then cooled to about 23 °C and maintained for about 2 hours. The reaction mass was centrifuged, and the wet cake was washed with 80 liters of 2-butanol. Then the wet cake was washed with 40 liters of cyclohexane. The wet cake was dried in an oven at a temperature of 100 °C and a vacuum of 680 mm/Hg for about 22 hours to yield 34.7 kg (56.9%) of the title compound. Purity by HPLC: 99.96. Specific Optical Rotation: +56.2° (C=1.89 wt. %, methanol).

We Claim:
1. A process for preparing clopidogrel bisulfate comprises of:
a) reaction of the compound 4,5,6,7-tetrahydro then[3,2-c] pyridine of Formula IV or an acid addition salt there of with the compound methyl-a-bromo-2-chloro phenyl acetate of Formula III in the presence of a base and a ketone solvent to form the racemic clopidogrel of Formula (II);
b) with out isolating the compound of Formula II resolution with L-(-)-camphor sulfonic acid to form clopidogrel of Formula (lla);

2. The process of claim 1 further comprising reaction of the clopidogrel with sulfuric acid to form clopidogrel bisulfate.
3. The process of claim 1, wherein said base in step (a) is potassium carbonate and ketone is acetone.
4. The process of claim 1, wherein the reacting step (a) is carried out at a temperature of about 10 °C to about 35 X.
5. The process of claim 1, wherein the compound methyl-a-bromo-2-chloro phenyl acetate of Formula III in reacting step (a) is added at a below temperature of about 15 °C.
6. The process of claim 1, wherein the amount of 4,5,6,7-tetrahydro thieno[3,2-c] pyridine hydrochloride ranges from about 0.8 to about 1.5 molar equivalents per molar equivalent of methyl-a-bromo-2-chloro phenyl acetate.
7. The process of claim 1, wherein the reacting step (b) is carried out at a temperature of about 20 °C to about 40 °C.
8. A process for preparing racemic clopidogrel of Formula II:

comprising reaction of 4,5,6,7-tetrahydro thieno[3,2-c] pyridine hydrochloride with methyl-a-bromo-2-chloro phenyl acetate in the presence of potassium carbonate and acetone.

9. The process of claim 8, wherein racemic clopidogrel of Formula II having total
impurities less than or equal to 0.5% and individual impurity less than or equal to 0.1%,
as characterized by a high performance liquid chromatography ("HPLC")
10. A process for preparing clopidogrel bisulfate comprises of:
a) reaction of the compound 4,5,6,7-tetrahydro thieno[3,2-c] pyridine of Formula
IV or an acid addition salt there of with the compound methyl-a-bromo-2-chloro phenyl
acetate of Formula III in the presence of potassium carbonate and acetone to form the
compound of Formula (II);
b) with out isolating the compound of Formula II, resolution with L-(-)-camphor
sulfonic acid to form clopidogrel;
c) reaction of the clopidogrel with sulfuric acid to form clopidogrel bisulfate.