This application claims priority to this Indian patent application number 925/CHE/2013 filed on March 4, 2013.

FIELD OF THE INVENTION:

The present invention is process for the preparation of Clopidogrel bisulphate form 1 from different salts of clopidogrel.

BACKGROUND:

Clopidogrel, Methyl (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of formula (I), ooto

Formula I an inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation which is effective in treating peripheral arterial diseases such as stroke, thrombosis and embolism, as well as coronary arterial diseases such as stroke, thrombosis, embolism, and myocardial infarction. Clopidogrel is administered as its bisulphate salt. Clopidogrel bisulphate is currently being marketed as PLAVIX® tablets. PLAVIX® is a white to off-white powder that is practically insoluble in water at neutral pH but highly soluble at acidic pH. The enantiomer (S)-clopidogrel is particularly preferred since it is the pharmaceutically active compound.
US4529596 describes a process for the preparation of racemic clopidogrel by the reaction of methyl 2-chloro-o-chlorophenylacetate and 4, 5, 6, 7-tetrahydro thieno [3, 2-c] pyridine in dimethylformamide and potassium carbonate at elevated temperature.

US4847265 describes the preparation of (S)-clopidogrel from racemic clopidogrel by resolution with levorotatory camphorsulphonic acid. The clopidogrel camphorsulphonate salt is then neutralized to the free base using sodium bicarbonate followed by the conversion to (S)-clopidogrel bisulphate, which is isolated from acetone. The polymorphic form obtained is characterized as clopidogrel bisulphate polymorphic form 1.

US5204469 describes the process for the preparation of clopidogrel free base wherein a-bromo (2-chlorophenyl) acetic acid is converted to methyl(2-thienylethylamino) (2-chlorophenyl) acetate,

which is then cyclised using formaldehyde solution in the presence of an acid to produce clopidogrel.
US6429210 discloses the crystalline form 1 and 2 of Clopidogrel bisulphate, which form 1 is the prior-art form and form 2 is novel. US6504030 claims a process for the preparation of Clopidogrel bisulphate form 2, wherein the polymorph is isolated from acetone.
WO2009121946A1 discloses the preparation of clopidogrel free base from camphoursulfonic of clopidogrel using the methyl isobutyl ketone and subsequently converted to clopidogrel bisulfate form 1 in same solvent.
The present invention is an improved process for the preparation for clopidogrel bisulfate form 1 from different salts such as clopidogrel hydrobromide, clopidogrel camphoursulfonic and clopidogrel bisulfate. The present process is simple cost-effective and industrially feasible.
SUMMARY:
The main aspect, the present invention provides Clopidogrel bisulphate polymorphic form 1 from different salts of clopidogrel.
One aspect of the present invention is to provide a process for the preparation of clopidogrel bisulfate form 1, comprising the steps of;
a) reacting the clopidogrel bisulfate form 2 with aqueous base in a solvent to get clopidogrel free base,
b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1 as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and
f) isolating clopidogrel bisulfate form 1.
Another aspect of the present invention is to provide a process for the preparation of clopidogrel bisulfate form 1, comprising the steps of,
a) reacting the clopidogrel hydrobromide with aqueous base in a solvent to get clopidogrel free base,
b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1 as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and

f) isolating clopidogrel bisulfate form 1.
Yet another aspect of the present invention is to provide a process for preparation of clopidogrel bisulfate form 1, comprising the steps of,
a) reacting the clopidogrel camphorsulfonic acid with aqueous base in a solvent to get clopidogrel free base,
b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1 as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and
f) isolating clopidogrel bisulfate form 1.
DETAILED DESCRIPTION:
The present invention relates to Clopidogrel bisulphate polymorphic form 1 from different salts of clopidogrel.
One embodiment of the present invention is to provide a process for preparation of clopidogrel bisulfate form 1, comprising the steps of,
a) reacting the clopidogrel bisulfate form 2 with aqueous base in a solvent to get clopidogrel free base,
b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and
f) isolating clopidogrel bisulfate form 1.
Another embodiment of the present invention is to provide a process for preparation clopidogrel bisulfate form 1, comprising the steps of,
a) reacting the clopidogrel hydrobromide with aqueous base in a solvent to get clopidogrel free base,
b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1 as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and
f) isolating clopidogrel bisulfate form 1.

Yet another embodiment of the present invention is to provide a process for preparation clopidogrel bisulfate form 1, comprising the steps of,
a) reacting the clopidogrei camphorsulfonic acid with aqueous base in a solvent to get clopidogrel free base,
b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and
f) isolating clopidogrel bisulfate form 1.
According to the present invention, the clopidogrel free base is extracted from in a solvent using aqueous base, the base is added to the solution to adjust pH to 7.4 and separate the layers. The organic layer is washed with water and distilled off the organic layer to obtain the clopidogrel free base as a residue.
The residue is dissolved in methyl isobutyl ketone and cooled to 0 to -10 °C, added clopidogrel bisulfate seeding of form 1, followed by addition of sulphuric acid diluted in methyl isobutyl ketone solvent at 0 to -10°C and maintained for about 4-5 hrs. The temperature of the solution is raised to 10 to 20°C, preferably 15 to 20°C and maintains the reaction mass 10 to 20 hrs; obtained solid is filtered and washed with methyl isobutyl ketone to get wet cake of Clopidogrel bisulphate. The wet cake is dried under vacuum at 65±5 °C to obtain pure clopidogrel bisulphate salt form 1.
The solvent used for the dissolution of compound of clopidogrel salt is selected from dichloromethane, dichloroethane, chloroform, ethyl acetate, toluene, ether solvent such as isopropyl ether, diethyl ether; the pH is adjusted using sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXAMPLES:
EXAMPLE 1: Process for the preparation of Clopidogrel bisulphate form 1 from clopidogrel bisulphate form 2:
Clopidogrel bisulphate salt (Form-2) (100gm) was taken in dichloromethane (400 mL) and aqueous solution of sodium bicarbonate (60gm) was added. After adjusting the pH to 7.1 using sodium bicarbonate the layers were separated and extracted with dichloromethane (200 mL) combined the organic layers and washed with water (100 mL). Final organic layer was distilled off to obtain clopidogrel base (76gm) as residue. The obtained residue was dissolved in methyl isobutyl ketone (1000 mL) and the solution was cooled to -8±2 °C. To this added seed of clopidogrel form I (0.5gm). To the reaction mass, a cooled solution of sulfuric acid (21.5gm) in methyl isobutyl ketone (500 mL) was added drop wise under nitrogen atmosphere at -8±2 °C. Stir the reaction mixture for 3-4 hours at same temperature. Raised the temperature to 16±1 °C and maintained for 10-15 hours. Obtained product was filtered and washed with chilled methyl isobutyl ketone (100 mL) dried under vacuum at 65±5 °C to obtain pure clopidogrel bisulphate salt form 1.

EXAMPLE 2: Process for the preparation of Clopidogrel bisulphate form 1 from clopidogrel Hydrobromide salt:

Clopidogrel hydrobromide salt (25gm) was taken in dichloromethane (100 mL) and aqueous solution of sodium bicarbonate (12gm) was added. After adjusting the pH to 7.4 using sodium bicarbonate the layers were separated and extracted with dichloromethane (50 mL) combined the organic layers and washed with water (25 mL). Final organic layer was distilled off to obtain clopidogrel base (18gm) as residue. The obtained residue was dissolved in methyl isobutyl ketone (225 mL) and the solution was cooled to -8±2 °C. To this added seed of clopidogrel form I (0.1 gm). To the reaction mass, a cooled solution of sulfuric acid (5.0gm) in methyl isobutyl ketone (112.5 mL) was added drop wise under nitrogen atmosphere at -8±2 °C. Stir the reaction mixture for 3-4 hours at same temperature. Raised the temperature to 16±1 °C and maintained for 10-15 hours. Obtained product was filtered and washed with chilled methyl isobutyl ketone (100 mL) dried under vacuum at 65±5 °C to obtain pure clopidogrel bisulphate salt form 1.
EXAMPLE 3: Process for the preparation of Clopidogrel bisulphate form 1 from clopidogrel Camphor sulphonoate salt:

Clopidogrel camphor sulphonoate salt (50gm) was taken in dichloromethane (200 mL) and aqueous solution of sodium bicarbonate (15gm) was added. After adjusting the pH to 7.2 using sodium bicarbonate the layers were separated and extracted with dichloromethane (200 mL) combined the organic layers and washed with water (100 mL). Final organic layer was distilled off to obtain clopidogrel base (31 gm) as residue. The obtained residue was dissolved in methyl isobutyl ketone (388 mL) and the solution was cooled to -8±2 °C. To this added seed of clopidogrel form I (0.25gm). To the reaction mass, a cooled solution of sulfuric acid (8.7gm) in methyl isobutyl ketone (194 mL) was added drop wise under nitrogen atmosphere at -8±2 °C. Stir the reaction mixture for 3-4 hours at same temperature. Raised the temperature to 16±1 °C and maintained for 10-15 hours. Obtained product was filtered and washed with chilled methyl isobutyl ketone (100 mL) dried under vacuum at 65±5 °C to obtain pure clopidogrel bisulphate salt form 1.

We claim:

1. process for preparation of clopidogrel bisulfate form 1, comprising the steps of,

a) reacting the clopidogrel bisulfate form 2 with aqueous base in a solvent to get clopidogrel free base,

b) removing the solvent to get clopidogrel free base as a residue,

c) dissolving the above clopidogrel free base in methyl isobutyl ketone,

d) adding clopidogrel bisulfate form 1 as a seed,

e) adding sulfuric acid in methyl isobutyl ketone, and

f) isolating clopidogrel bisulfate form 1.

2. process for preparation clopidogrel bisulfate form 1, comprising the steps of,

a) reacting the clopidogrel hydrobromide with aqueous base in a solvent to get clopidogrel free base,

b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1 as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and
f) isolating clopidogrel bisulfate form 1.

3. process for preparation clopidogrel bisulfate form 1, comprising the steps of,
a) reacting the clopidogrel camphorsulfonic acid with aqueous base in a solvent to get clopidogrel free base,
b) removing the solvent to get clopidogrel free base as a residue,
c) dissolving the above clopidogrel free base in methyl isobutyl ketone,
d) adding clopidogrel bisulfate form 1 as a seed,
e) adding sulfuric acid in methyl isobutyl ketone, and
f) isolating clopidogrel bisulfate form 1.

4. The process according to claim 1, the solvent used for the dissolution of compound of
clopidogrel salt is selected from dichloromethane, dichloroethane, chloroform, ethyl acetate, toluene, ether solvent such as isopropyl ether, diethyl ether