FIELD OF THE INVENTION

The present invention relates to a process for racemization of enriched R-(-)-Clopidogrel of Formula I.

BACKGROUND OF THE INVENTION

Clopidogrel bisulfate is chemically known as methyl (+)-(S)-cc-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5-(4H)acetate hydrogen sulfate (1:1) of Formula II.

Clopidogrel is an inhibitor of platelet aggregation. Clopidogre'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.

Clopidogrel is marketed under the name Plavix® in the US. It has been approved for the treatment of atherothrombotic events such as Recent Stroke or Established Peripheral Arterial Disease and Acute Coronary Syndrome.

US 4,529,596 discloses Clopidogrel as a racemic compound. This patent discloses a process to prepare Clopidogrel, which comprises condensation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine of Formula III with methyl a-chloro-o-chlorophenyl acetate of

Formula IV.
US 4,847,265 discloses a method for separating (R)-(-)-Clopidogrel (I) from the desired (S)-(+)-Clopidogrel (IIa) using levo-rotatory camphor-10-sulfonic acid. Resolution is carried out using dimethylformamide, ketones and alcohols. The crystallization with acetone is specifically exemplified.

During resolution of a racemic compound if undesired (R)-(-)-Clopidogrel (I) is not recycled, the synthetic route becomes uneconomical. The yield of the desired isomer can be increased by racemising the undesired isomer to the racemic product, which can be further resolved to produce the desired (S)-(+)-Clopidogrel (Ha).

The recovery process of (S)-(+)-Clopidogrel bisulfate (II) from its unwanted stereo isomers (R)-(-)-Clopidogrel (I) or variable mixture of (S) and (R)-Clopidogrel was not mentioned in the above said patents. Later in WO 02/059128 A2, the process of recycling of unwanted stereo isomer of Clopidogrel and its intermediates by racemization using an equimolar amount of a base was mentioned in detailed description of invention, but in the experimental section the racemization process was given for amide intermediate of Formula VI using a base.

The racemized amide of Formula VII is converted to Clopidogrel as shown below:
WO 98/39286 discloses a racemization process for phenyl glycine esters. A mixture of enantiomers of phenyl glycine ester is treated with a carbonyl compound in the presence of a carboxylic acid and a single enantiomer of an N-protected-a-amino acid as resolving agent. The formation of an imino intermediate causes the racemization of the starting product leading to the precipitation of a single diastereomeric salt. After hydrolysis of the salt, an enantiomer of phenyl glycine ester is obtained.

US 6,737,411 discloses a process for racemization of enriched (R)-(-)-Clopidogrel (I), which is left in the mother liquor, after removal of (S)-(+)-Clopidogrel (IIa). The process comprises reacting (R)-(-)-Clopidogrel (I) with a catalytic amount of a base in a solvent to convert a portion of the (R)-(-)-Clopidogrel (I) to (S)-(+)-Clopidogrel (IIa). Preferred bases are sodium t-butoxide, potassium t-butoxide, diisopropylamide, sodium hydride, potassium hydride, sodium methoxide and potassium methoxide. Preferably, the solvent is a hydrocarbon.

WO 2004/074215 discloses a process, which comprises treating R-(-)-Clopidogrel with an acid in a solvent at a temperature in the range of 60-100°C to produce (R,S)-Clopidogrel (V). This salt is neutralized with a base to give racemic Clopidogrel.
WO 2009/121946 A2 disclose the racemization of (R)-Clopidogrel by treating with acetic acid without solvent.

US 2008/0182869 Al disclose the racemization process of (R)-Clopidogrel by treating with a base selected from alkyl-, aryl- or cycloalkyl-ammonium hydroxides in a solvent selected from alcohol, ester, ketone or ethers.

The reported procedures are time consuming and industrially difficult to practice. Hence, there is a need for simple, easy to handle and cost effective racemization process, which converts undesired R-isomer into racemic form.

The present invention is specifically directed towards the process, which provides racemization of (R)-Clopidogrel bisulfate (la) using a base. By this recovery process, the overall production cost of (S)-Clopidogrel bisulfate will reduce and as well as environmental point of view it reduces the effluent load.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide an improved racemization process to convert enriched (R)-Clopidogrel to racemic Clopidogrel.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for racemization of enriched R-(-)-Clopidogrel of Formula I,
which comprises,

(i) treating mother liquor obtained after isolation of (S)-(+)-Clopidogrel camphorsulfonate containing variable mixture of (R)-(-)-Clopidogrel camphorsulfonate and (S)-(+)-Clopidogrel camphorsulfonate;

with base in a solvent to produce Clopidogrel base containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel;

(ii) treating the variable mixture of (R)-Clopidogrel (I) and (S)-Clopidogrel (IIa) with sulfuric acid in a solvent to produce Clopidogrel bisulfate containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel;

(iii) treating Clopidogrel bisulfate containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel with a base to produce racemic Clopidogrel free base;

Another embodiment of the present invention provides a process for the preparation of (+)-(S)-cc-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5-(4H)acetate hydrogen sulfate (1:1) ((+)-Clopidogrel bisulfate) of Formula II using (R,S)-Clopidogrel free base prepared by the racemization of enriched R-(-)-Clopidogrel of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the racemization of enriched R-(-)-Clopidogrel of Formula I.

The process comprises, treating mother liquor obtained after isolation of (S)-(+)-Clopidogrel camphorsulfonate contains variable mixture of (R)-(-)-Clopidogrel camphorsulfonate and (S)-(+)-Clopidogrel camphorsulfonate with aqueous base selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate; in a solvent selected from dichloromethane, chloroform, toluene, and ethylacetate under stirring at the temperature range 0°C to 50°C to produce Clopidogrel base containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel.

The mother liquor obtained after isolation of (S)-(+)-Clopidogrel camphorsulfonate contains variable mixture of 75 to 100% of (R)-(-)-Clopidogrel camphorsulfonate and 0 to 25 % of (S)-(+)-Clopidogrel camphorsulfonate.

Treating the variable mixture of (R)-Clopidogrel and (S)-Clopidogrel with sulfuric acid in a solvent selected from ketone, alcohol, alkyl ester, dichloromethane, acetonitrile, methyl acetate; to produce Clopidogrel bisulfate containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel. The reaction is carried out at a temperature ranges from 0°C to reflux temperature of the solvent used.

The variable mixture contains 75 to 100% of (R)-Clopidogrel and 0 to 25 % of (S)-Clopidogrel.

Treating Clopidogrel bisulfate containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel with a base selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, potassium tert-butoxide, sodium hydride, potassium hydride, tri ethyl amine, trimethyl amine and the like, in suitable solvent, like ketone, alcohol, alkyl ester, dichloromethane, chloroform, acetonitrile, methyl acetate, DMF, toluene, or mixture of water and DCM to produce racemic Clopidogrel free base. The racemization reaction is carried out in suitable temperature range for the racemization includes temperature from 0°C to reflux temperature of the solvent used.

The variable mixture contains 75 to 100% of (R)-Clopidogrel bisulfate and 0 to 25 % of (S)-Clopidogrel bisulfate.

The racemic Clopidogrel free base prepared by the above process is converted to (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5-(4H)acetate hydrogen sulfate (1:1) of Formula II by resolution using chiral reagent, followed by salt formation with sulfuric acid. The process of resolution comprises of dissolving the racemic mixture in suitable solvent and addition of a suitable chiral reagent. Suitable solvent is selected on the basis whether the diastereomeric salt precipitates out differently. The separation may result simply by stirring at a suitable temperature in a solvent until one of the salts preferentially precipitate out. Purification of diastereomeric salt is possible by refluxing in a suitable solvent. Preferably in aqueous acetone, the free base is liberated from its salt using a suitable base reagent. The diastereomeric salt is dissolved or suspended in a mixture of water and organic solvent and is neutralized with a base under stirring, the free base is obtained after separation of aqueous layer and evaporation of the organic solvent.

Suitable base reagent for the neutralization of diastereomeric salt includes sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide and potassium hydroxide in aqueous medium at temperature varying between 5°C to 25°C.

The solvents used during the resolution can include solvents or mixture there of such as C1-C4 alcohol, C1-C4 ketone, ethyl acetate, methyl acetate, methyl ethyl ketone, DMF, acetonitrile, propionitrile, THF, dioxane and the like. The solvent used optionally may contain water up to 2%, but presence of water or its amount is not critical. Suitable temperature range for the resolution includes temperature from 0°C to reflux temperature of the solvent used, the acid chiral reagents used for the resolution include tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, and the like.
The optically pure (+) compound of formula (II) is converted into its bisulfate salt using sulfuric acid in an appropriate solvent at suitable temperature to afford (+)-Clopidogrel bisulfate (II). The obtained (+)-Clopidogrel bisulfate by the above process shows crystalline Form-I.

Mother liquor contains variable mixture of (R)-(-)-Clopidogrel camphorsulfonate and (S)-(+)-Clopidogrel camphorsulfonate used in the present invention is prepared by treating the (R,S)-Clopidogrel base with (lR)-(-)-10-camphorsulfonic acid in acetone, followed by filtering the (S)-(+)-Clopidogrel camphorsulfonate and leaving the mother liquor containing variable mixture of (R)-(-)-Clopidogrel camphorsulfonate and (S)-(+)-Clopidogrel camphorsulfonate.

(R,S)-Clopidogrel base used in the present invention is prepared as per the process disclosed in US 4,529,596.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLE
Step I:
Recovery of (R)-Isomer enriched Clopidogrel as it's hydrogen sulfate salt.

Acetone mother liquor was obtained after isolation of (S)-(+)-Clopidogrel camphorsulfonate contains -75% of (R)-(-)-Clopidogrel camphorsulfonate and ~ 25% of (S)-(+)-Clopidogrel camphorsulfonate. This mother liquor was concentrated and the concentrated mass was dissolved in toluene (400 ml). The toluene solution was washed with 5% aqueous sodium bicarbonate solution (1000 ml) to remove Camphorsulfonic acid. The toluene solution containing (R)-Isomer enriched Clopidogrel base was concentrated and the concentrated mass was dissolved in acetone (500 ml). To the acetone solution, concentrated sulfuric acid (39.6 g) were added to the reaction mass to precipitate (i?)-Isomer enriched Clopidogrel bisulfate (containing -75% (R)-(-)-Clopidogrel and ~ 25% of (S)-(+)-Clopidogrel). The precipitated product was collected by filtration and dried to get (i?)-Isomer enriched Clopidogrel bisulfate (containing -75% (R)-(-)-Clopidogrel and - 25% of (S)-(+)-Clopidogrel).

Step II:
Racemization of (R)-Isomer enriched Clopidogrel Bisulfate.

100 g of (R)-Isomer enriched Clopidogrel bisulfate was dissolved in methanol (800 ml). Anhydrous potassium carbonate (39.53 g, 1.2 m.eq) was added to the above solution and heated to 65-70°C. Reaction mass was continued refluxing at 65-70°C for -4 hr for completion of racemization reaction (racemization monitored by SOR). After completion of racemization, reaction mass was cooled to 25-30°C and removed the potassium carbonate by filtration. Methanolic filtrate was concentrated at 45-50°C under reduced pressure and concentrated mass was dissolved in toluene (400 ml). This toluene solution was washed with DM water (300 ml) and concentrated under vacuum to obtain ~ 75 g of (R, S)-Clopidogrel base as an oily mass.

Step III:
Preparation of (S)-(+)-Clopidogrel Camphorsulfonate.
(R, S)-Clopidogrel base obtained in step II was dissolved in acetone (900 ml) and added (1R)-(-)-10-camphorsulfonic acid (137.2 g, 0.59 mol) at 25-30°C. Reaction mass was stirred for -24 hr at 25-30°C to complete the precipitation of (S)-(+)-Clopidogrel camphorsulfonate. The product was collected by filtration, washed with acetone and dried at 55-60°C to get -100 g of (S)-(+)-Clopidogrel camphorsulfonate.
Step IV:
Preparation of (S)-(+)-Clopidogrel Bisulfate:
S-(+)-Clopidogrel camphorsulfonate (80 g) was dissolved in methylene chloride (400 ml) and pH was adjusted to -7.5 with 5% w/w aqueous sodium bicarbonate (-320 ml) at 20-30°C. After 30 min of stirring, the organic layer was separated and concentrated at < 40°C to get S-(+)-Clopidogrel base (-50 g) as an oily residue.
S-(+)-Clopidogrel base (50 g) was dissolved in methyl tert-butyl ether (400 ml) and slowly butanolic sulfuric acid solution (13.5 g of concentrated sulfuric acid dissolved in 100 ml of n-butanol) was added at 0-5°C to obtain slurry. Thereafter, the reaction mass was stirred for 24 h at 22-28°C and filtered the product. The wet product was washed with acetone and dried at 40-45°C under reduced pressure to get 50 g of S-(+)-Clopidogrel bisulfate Form I.

WE CLAIM:

1. A process for racemization of enriched R-(-)-Clopidogrel of Formula I, which comprises,

i) treating mother liquor obtained after isolation of (S)-(+)-Clopidogrel camphorsulfonate containing variable mixture of (R)-(-)-Clopidogrel camphorsulfonate and (S)-(+)-Clopidogrel camphorsulfonate;

with a base in a solvent to produce Clopidogrel base containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel;

ii) treating the variable mixture of (R)-Clopidogrel (I) and (S)-Clopidogrel (Ha) with sulfuric acid in a solvent to produce Clopidogrel bisulfate containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel;

iii) treating Clopidogrel bisulfate containing variable mixture of (R)-Clopidogrel and (S)-Clopidogrel with a base to produce racemic Clopidogrel free base;

2. The process according to claim 1, wherein the base used in step (i) is selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium hydroxide, potassium carbonate and mixture thereof and the solvent used in step (i) is selected from dichloromethane, chloroform, toluene, and ethylacetate or mixture thereof.

3. The process according to claim 1, wherein the solvent used in step (ii) is selected from ketone, alcohol, alkyl ester, dichloromethane, acetonitrile, methyl acetate or mixture thereof.

4. The process according to claim 1, wherein the base used in step (iii) is selected from sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium hydroxide, potassium carbonate, potassium tert-butoxide, sodium hydride, potassium hydride, tri ethyl amine, trimethyl amine and mixture thereof.

5. A process for the preparation of (+)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5-(4H)acetate hydrogen sulfate (1:1) ((+)-Clopidogrel bisulfate) of Formula II using (R,S)-Clopidogrel free base prepared by the racemization of enriched R-(-)-Clopidogrel of Formula I.

Formula I