DESC:Field of the invention:
The present invention relates to a novel process for the preparation of (+)-(S)-alpha-2-(chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5-(4-H)-acetic acid methyl ester hydrogen sulphate of Formula I, commonly known as Clopidogrel bisulphate. Particularly, the invention relates to preparation of Clopidogrel bisulphate of formula-I using novel intermediates, aromatic/aliphatic sulfonic acid salts of methyl alpha-(2-thienylethylamino)-(2-chlorophenyl) acetate of formula-X prepared using non-chiral aromatic/aliphatic sulfonic acids.

Background of Invention:
Clopidogrel bisulphate, chemically known as (+)-(S)-alpha-2-(chlorphenyl)-6,7-dihydrothieno-[3,2-C]-pyridine-5-(4-H)-acetic acid methyl ester. Clopidogrel under the international non-proprietary name is marketed as hydrogen sulphate salt. Clopidogrel is known for its platelet aggregating and anti-thrombotic properties and finds medicinal applications in this field. It was disclosed in US4529596 patent (hereinafter referred as ‘596’ patent) in its racemic form for the first time.

The '596 patent provides a synthesis of Clopidogrel bisulphate by the reaction of a chloro compound of Formula II with thienopyridine derivative of Formula III in dimethyl formamide solvent and potassium carbonate to obtain Clopidogrel base which is further converted to Clopidogrel HCl. However, this process gave very poor yield (45%) of Clopidogrel.

Another patent US5204469 reported the preparation of Clopidogrel by reacting methyl alpha-amino(2-chlorophenyl)acetate of Formula-IV with 2-thienylethyl para-toluenesulphonate of Formula-V in acetonitrile solvent in presence of base to obtain methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate of Formula-VI. The product is extracted with ethyl acetate and then treated with HCl to obtain its HCl salt of Formula-VII. The hydrochloride salt of Formula-VII neutralized with aq. sodium bicarbonate and then extracted with methylene chloride. The organic phase is distilled to obtain residue which was dissolved in acetone and treated with (-)-10-camphorsulphonic acid to obtain (+)-camphorsulphonate of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate of Formula-VIII. The (+)-camphorsulphonate of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate are treated with aq.NaHCO3 and 1,2-dichloroethane and further reacted with paraformaldehyde to obtain Clopidogrel of Formula IX, which is further reacted with sulfuric acid to obtain Clopidogrel bisulphate of Formula I. The route is represented in following reaction scheme-I.
Scheme-I

Chinese patents - CN103450005 & CN103387497 - reported resolution of methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate of Formula-VI with D-camphorsulphonic acid to obtain (+)-camphorsulphonate of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate of Formula-VIII which is further converted to HCl salt of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate by reacting with Na2CO3 followed by addition of HCl. The HCl salt of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate is further converted to Clopidogrel by reaction with formaldehyde.

The process reported in these patents involves use of optically active camphor sulphonic acid enantiomer which is expensive and the process yields R-enantiomer of Clopidogrel bisulfate as impurity beyond acceptable levels. Because of these problems, the cost of manufacturing of Clopidogrel bisulphate is increased substantially.

Therefore, the object of the present invention is to overcome the above stated drawbacks of the prior art processes by providing an economical and industrially scalable process for preparing highly pure Clopidogrel bisulphate.

Summary of invention
The present inventors have, surprisingly, found a novel process to prepare highly pure Clopidogrel bisulfate having less than 0.2% of R-enantiomer of Clopidogrel bisulfate using non-chiral alkyl/aryl sulfonic acids for salt formation of methyl alpha-(2-thienylethylamino)-(2-chlorophenyl)acetate to purge out unwanted enantiomer at the penultimate stage of Clopidogrel manufacturing.

Accordingly, the invention provides a process for preparation of clopidogrel bisulphate comprising;
a) reacting methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate (CND base) with non-chiral aromatic/aliphatic sulfonic acids to obtain corresponding salts of methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate;
b) neutralizing the sulfonic acid salts of methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate with a base to liberate methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate free base followed by reaction with concentrated HCl to obtain (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate Hydrochloride (CND.HCl); and
c) reacting the (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate Hydrochloride (CND.HCl) with paraformaldehyde to obtain clopidogrel free base followed by treatment with sulfuric acid to obtain Clopidogrel Bisulfate.

Accordingly, one aspect of the present invention provides a novel aromatic/aliphatic sulfonic acid salts of methyl (2-thienylethylamino)(2-chlorophenyl)acetate including its enantiomers.

Preferably, the present invention provides aromatic/aliphatic sulfonic acid salts of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate (CND) with a provision that the sulfonic acids are non chiral alkyl/aryl sulfonic acids.
In a second aspect, the present invention provides a process for preparation of aromatic/aliphatic sulfonic acid salts of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate.

In a 3rd aspect, the present invention provides a process for preparation of aromatic/aliphatic sulfonic acid salts of methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate.

In a 4th aspect, the present invention provides a process for preparation of high purity Clopidogrel bisulfate with high efficiency.

Brief description of drawings
Figure 1: Represents Powder X-Ray diffraction pattern of CND. PTSA salt
Figure 2: Represents the 1H NMR of CND.PTSA salt
Figure 3: Represents the 13C NMR of CND.PTSA salt
Figure 4: Represents the differential scanning calorimeter thermogram of CND.PTSA salt
Figure 5: Represents the Infrared spectrum of CND.PTSA salt
Figure 6: Thermogravimetric analysis of CND.PTSA salt

Description of Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

Accordingly, one aspect of the present invention provides a novel aromatic/aliphatic sulfonic acid salts of methyl (2-thienylethylamino)(2-chlorophenyl)acetate of formula-X including its enantiomers with a provision that the sulfonic acid salts are prepared using non-chiral alkyl/aryl sulfonic acids.

The aromatic sulfonic acids include benzenesulfonic acid, alkyl substituted benzenesulfonic acids – such as ortho or para toluene sulfonic acid and the like. The aliphatic sulfonic acids include methanesulfonic acid, ethanesulfonic acid, propane sulfonic acid and the like.

However, in a preferred embodiment, the present invention provides aromatic/aliphatic sulfonic acid salts of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate of formula-Xa.

Most preferred salt is para toluene sulfonic acid salt of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate of formula-Xb.

According to a second aspect, the present invention provides a process for preparation of aromatic/aliphatic sulfonic acid salts of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl)acetate.

Accordingly, L-(+)-Tartaric acid salt of (S)-chlorophenylglycine Methyl ester is reacted with aqueous ammonia in a suitable solvent such as dichloromethane at less than 10°C to obtain (S)-chlorophenylglycine Methyl ester (S-CPGE Base). The base may be isolated from the reaction mass or it may be taken for directly for next reaction.

The S-CPGE base is further reacted with 2-Thienylethyl para toluene sulphonate in water in presence of tetrabutyl ammonium bromide (TBAB) catalyst and a base dipotassium hydrogen orthophosphate at temperature of about 95°C. After completion of reaction, the mass is extracted with suitable solvent to isolate the product, methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate (CND base). Optionally, the product present in the solution may, directly, be taken for formation of sulfonate salt preparation.
According to the present invention, methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate (CND base) is reacted with aromatic/aliphatic sulfonic acids with provision that the sulfonic acid are non chiral alkyl/aryl sulfonic acids. The aromatic sulfonic acids include benzenesulfonic acid, alkyl substituted benzenesulfonic acid such as ortho or para toluene sulfonic acid and the like. The aliphatic sulfonic acids include methanesulfonic acid, ethanesulfonic acid, propane sulfonic acid and the like. However, preferred sulfonic acid is para toluene sulfonic acid.

Salt formation reaction is conducted preferably in a suitable solvent such as esters, ethers and ketones. Esters include methyl acetate, ethyl acetate; isopropyl acetate and butyl acetate; Ethers include diethyl ether, methyl tert-butyl ether and tetrahydrofuran. Ketones include acetone, methyl ethyl ketone and methyl isobutyl ketone. However, the preferred solvent is ethyl acetate.

Salt formation may be conducted at ambient temperature for a period of 5 to 7 hours. After completion of salt formation, the reaction mass is filtered and cake is washed with same solvent to obtain corresponding (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate sulfonate salt.

The obtained wet salt is further dissolved in mixture of water and suitable solvent such as esters selected from methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate or chlorinated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane and neutralized with a suitable base such as ammonia to liberate base. After base is liberated, layers are separated and organic layer is reacted with concentrated HCl to obtain (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate Hydrochloride (CND.HCl).

In a 3rd aspect, the present invention provides a process for preparation of aromatic/aliphatic sulfonic acid salts of methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate. When the starting material is racemic chlorophenylglycine Methyl ester instead of its (S)-enantiomer, aromatic/aliphatic sulfonic acid salts of methyl alpha-(2-thienylethylamino)(2-chlorophenyl)acetate are obtained in similar way.

According to a fourth aspect, the present invention provides a process for preparation of Clopidogrel bisulphate. Accordingly, the obtained (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate Hydrochloride (CND.HCl) as per the present invention is further taken for preparation of Clopidogrel Bisulphate by the procedures well known in the literature. CND.HCl is reacted with parformaldehyde in water at about 50°C temperature. After completion of reaction, the mass is neutralized with ammonia and extracted Clopidogrel base with suitable solvent such as hexane followed by isolation of crude. Then the crude product is dissolved in acetone and reacted with sulfuric acid to obtain Clopidogrel Bisulfate in polymorphic form-II.

Alternatively, Clopidogrel Bisulphate can be prepared directly from sulfonic acid salts of methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate by reacting with formaldehyde in presence of HCl followed by reacting with sulfuric acid.

The following scheme-II illustrates the process of the present invention.
Scheme-II

The Clopidogrel Bisulfate thus obtained by the process of the present invention, may be formulated into a suitable dosage forms such as tablets, capsules, syrups etc., by combining with one or more pharmaceutically acceptable excipients using known techniques. The dosage form may include a suitable amount of the active ingredient and other pharmaceutical agents.

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

Reference example 1:
Preparation of DL-a-amino-(2-chlorophenyl) acetic acid methyl ester (CPG Ester)
To a suspension of DL-2-Chloro phenyl Glycine (100 gm) in methanol (500 ml) was charged thionyl chloride (128 gm) at 0-5°C followed by stirring at 50°C for 5 hrs. The progress of the reaction was monitored by HPLC. After completion of reaction, methanol and excess thionyl chloride were distilled out from the reaction mass. Methylene dichloride (300 ml) and water (500 ml) were charged to the residue at 15-25°C. The pH of the reaction mass was adjusted to ~9 using liquor ammonia solution. Methylene dichloride was distilled out from the organic layer to get 105 gm of DL-a-amino- (2-chlorophenyl)acetic acid methyl ester (CPG ester) as a pale yellow colored oil with 99% purity by HPLC.

Reference example 2:
Preparation of L-(+)-Tartaric Acid Salt of (S)-a-Amino-(2-Chlorophenyl) acetic acid methyl ester (S-CPGE Tartrate)
To a clear solution of L-(+)-Tartaric acid (83 gm) in acetone (1300 ml) was charged a solution of DL-a-amino-(2-chlorophenyl)acetic acid methyl ester (100 gm) in acetone (100 ml) at 25-35°C. The reaction mass was stirred at 50°C for 18 hrs followed by filtration at 25-35°C and the wet cake was washed with acetone. Acetone main mother liquor and washings (~1200 ml) were preserved in a clean container for recycling purpose (ML-1). The isolated wet cake (containing R-isomer ~5%) was purified in methanol (500 ml) followed by methanol washing (200 ml) and drying at 50°C to get 150 gm of L-(+)-Tartaric Acid Salt of (S)-a-Amino-(2-Chlorophenyl)acetic acid methyl ester with 98% purity by HPLC and chiral HPLC purity =99%. Methanol mother liquor and washings (~750 ml) were preserved in a clean container for recycling purpose (ML-2).

Reference example 3:
Preparation of 2-Thienylethyl para toluenesulphonate from 2-thiophene ethanol (Tosylate compound)
To a solution of 2-thiophene ethanol (100 gm) in toluene (400 ml) was charged p-Toluene sulfonyl chloride (179 gm) and Triethyl benzyl ammonium chloride (10 gm) at 25-35°C. The reaction mass was cooled to 0-5°C and sodium hydroxide solution (62.5 gm of NaOH in 84 ml water) was added at 0-10°C. After 4 hrs of stirring at 0-10°C, the temperature of the reaction mass was raised to 50°C and stirred for 1 hr to quench un-reacted p-Toluene sulfonyl chloride. Toluene layer was separated and repeatedly washed with water till neutral pH of aqueous layer. Toluene was distilled out from the organic layer under vacuum to get 215 gm of 2-Thienylethyl para toluenesulphonate with =99% HPLC purity.

Example 1:
Recovery and recycling process of L-(+)-Tartaric Acid Salt of (S)-a-Amino-(2-Chlorophenyl)acetic acid methyl ester (S-CPGE Tartrate) from ML-1 and ML-2 of Reference example 2.
Methanol mother liquor (ML-2 of reference example 2) was distilled under vacuum to get the residue (~26 g). To this residue total quantity of acetone mother liquor (ML-1) was charged to make up the volume of acetone mother liquor to total 16 times of input (fresh acetone can be added if ML-1 is not sufficient to make up the volume); followed by addition of L-(+)-tartaric acid (69 gm) at 25-35°C. A solution of DL-2-Chlorophenyl glycine methyl ester (100 gm) in acetone (100 ml) was added at 25-35°C. The reaction mass was stirred at 50°C for 18 hrs followed by filtration at 25-35°C and the wet cake washed with acetone (acetone main mother liquor and washings were preserved in a clean container for recycling purpose). The wet cake was slurried in methanol (500 ml) followed by washing with methanol (200 ml) and drying at 50°C to get 165 gm of L-(+)-Tartaric Acid Salt of (S)-a-Amino-(2-Chlorophenyl) acetic acid methyl ester (S-CPGE Tartrate) with 98% HPLC purity and chiral HPLC purity =99%. Methanol mother liquor and washings were preserved in a clean container for recycling purpose.
Note: As per the process given in example-1, acetone mother liquor and methanol mother liquor residue can be recycled up to 5 cycles to get the standard yield and quality of S-CPGE.Tartrate. After fifth recycle, acetone ML can be sent for recovery.

Advantage of recovery and recycling of acetone mother liquor and methanol mother liquor residue
? Recovery and recycling of ML-1 and ML-2 result in enhancement of yield by 8-10%.
? Recycling of acetone mother liquor of previous batch without subjecting to additional distillation makes the process more economically viable, energy efficient and environmental friendly.
? Less quantity of L-(+)-Tartaric acid (0.90 Eq) is required in recycling procedure because un-reacted L-(+)-Tartaric acid which is available in acetone mother liquor making over to the required quantity for resolution.
? Solvent consumption reduced significantly. Hence this process promotes the concept of green chemistry.

Example 2:
General procedure for the preparation of methyl (S)-2-(2-chlorophenyl) -2-((2-(thiophen-2-yl)ethyl)amino)acetate (CND base) by reaction of (S)-a-Amino-(2-Chlorophenyl)acetic acid methyl ester (S-CPGE base) with 2-Thienylethyl para toluenesulphonate.
A solution of L-(+)-Tartaric acid salt of (S)-a-Amino-(2-Chlorophenyl)acetic acid methyl ester (135 gm) in DCM (405 ml) and water (270 ml) was treated with ammonia solution (pH ~9) at 0-10°C, followed by DCM layer separation and distillation to get (S)-a-Amino-(2-Chlorophenyl)acetic acid methyl ester (S-CPGE Base).

To a dispersion of 2-Thienylethyl para toluene sulphonate (133.65 gm) (prepared in reference example 3) in DM water (75.6 ml) was charged Tetrabutyl ammonium bromide (2.27 gm) at 25-35°C. Dipotassium hydrogen orthophosphate (143 gm) was charged in six equal lots at 25-35°C over a period of 45 minutes. (S)-a-Amino-(2-Chlorophenyl) acetic acid methyl ester (S-CPGE base) was charged to this heterogeneous reaction mass and temperature of the reaction was raised slowly up to 95°C. The heterogeneous reaction mass was maintained under stirring at 95°C till the reaction proceeds to completion. After completion of reaction, the reaction mass was quenched with DM water (405 ml) and extracted with ethyl acetate (270 ml). The extracted ethyl acetate layer containing methyl (S)-2-(2-chlorophenyl)-2-((2- (thiophen-2-yl)ethyl)amino)acetate (CND base) was used as feed for salt formation.

Example 3: Process for the preparation of methyl (S)-2-(2-chlorophenyl)-2- ((2-(thiophen -2-yl) ethyl) amino) acetate para toluenesulfonate (CND.PTSA Salt)
Para toluene sulfonic acid (85 gm) was charged to the ethyl acetate layer containing methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate (CND Base) (Prepared in Example 2) and reaction mass stirred at 25-35°C for ~5 hrs followed by filtration and washed with ethyl acetate to get the wet cake of CND.PTSA. The wet cake was dried in a dryer at 50ºC under vacuum for 4-5 hrs to get 144 g of methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl) amino)acetate para toluenesulfonate (CND.PTSA) containing R-isomer less than 0.1%.The wet cake of this salt can also be carried forward for Clopidogrel Bisulfate formation. The isolated CND.PTSA salt was completely characterized by 1H-NMR(Figure 2), 13C-NMR(Figure 3), IR (Figure 5); Thermogravimetric analysis of CND.PTSA salt (Figure 6) and mass as given below.
1H NMR (300 MHz, DMSO-d6) d (ppm) 9.90 (bs, 2H), 7.67-7.64 (m, 1H), 7.62-7.51 (m, 3H), 7.50-7.46 (m, 2H), 7.42-7.40 (m, 1H), 7.13-7.10 (m, 2H), 7.00-6.97 (m, 1H), 6.95-6.94 (m, 1H), 5.68 (s, 1H), 3.76 (s, 3H), 3.23-3.12 (m, 4H), 2.29 (s, 3H);
13C NMR (300 MHz, DMSO-d6) d (ppm) 168.14, 145.97, 138.81, 138.20, 134.27, 132.65, 130.90, 130.63, 129.15, 128.91, 128.56, 127.76, 126.61, 125.94, 125.42, 59.51, 54.24, 47.73, 26.18, 21.15
IR Values: C=O stretching at 1757 cm-1; C-Cl stretching at 1221 cm-1; N-H stretching of amine salt at 3100 cm-1
Mass: ESI-MS m/z (+ve mode) = 311
Melting point by DSC: 160 °C
TGA: No loss observed
Powder X-Ray diffraction pattern of CND. PTSA salt is provided in figure 1 and differential scanning calorimeter thermogram of CND.PTSA salt is provided in figure 4.

Reference example 4: Process for the preparation of methyl (S)-2- (2-chlorophenyl) -2-((2-(thiophen-2-yl)ethyl)amino)acetate Hydrochloride (CND.HCl)
Conc. HCl (47 g) was slowly charged into the ethyl acetate layer containing methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate (CND Base) (Prepared in Example 2) at 10-15°C. Solid precipitates out from the reaction mass. The reaction mass was filtered to isolate the solid, followed by washing the wet cake with ethyl acetate at 10-15°C and slurried in isopropyl alcohol (540 ml) and filtered. The wet cake was dried at 50°C to get 108 g of methyl (S)-2-(2-Chlorophenyl) -2-((2-(thiophen-2-yl)ethyl) amino)acetate Hydrochloride (CND.HCl) with 99% purity by HPLC and 99.5% chiral Purity with R-isomer ~ 0.5 %.

Example 4: Preparation of Clopidogrel Bisulphate
Methyl(S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate para toluene -sulfonate (144 gm) (CND.PTSA) (Prepared in example 3) was dissolved in DM water (270 ml) and ethyl acetate (405 ml) and pH was adjusted to ~9 using liquor ammonia solution at 10-15°C. Layers were separated and to the ethyl acetate layer was charged Conc. HCl (47 ml) slowly at 10-15°C. Stirred and maintained the reaction mass at 20-30°C for 45 min and further at 10-15°C for 90 min. A portion of isolated solid (99 g) was taken for the next reaction.

Paraformaldehyde (26 gm) was dissolved in DM water (300 ml) at 90°C. To this solution was charged CND.HCl (50 gm) as prepared above and followed by addition of 0.5 ml Conc. HCl at 30-35°C. Reaction mass was stirred at 40±2°C for 20 hrs. Cooled the reaction mass to 20-25°C and n-Hexane (300 ml) was charged and pH was adjusted to ~2.25 using liquor ammonia at 20-25°C. Stirred the reaction mass at 20-25°C for 15 min and separated the layers. Aqueous layer was extracted with n-Hexane (500 ml). Hexane layer was washed with DM water (300 ml) and sodium bicarbonate (1.0 gm) solution followed by distillation under vacuum. The obtained Clopidogrel base (Oily mass) was dissolved in acetone (160 ml) and treated with activated carbon (1.0 gm) and filtered. The filtrate was cooled to -10 to 0°C and sulfuric acid (14 gm) was added. Seeded with Clopidogrel Bisulfate and stirred the reaction mass at 0-10°C for 5 hrs followed by filtration to get Clopidogrel Bisulfate wet cake. Wet cake was suspended in acetone (100 ml) at 25-35°C. Filtered the slurry and washed the wet cake with acetone. The wet cake was dried in a dryer under vacuum at 30-35°C for 5 hrs to get 51.75 gm of white Clopidogrel Bisulfate with R-isomer less than 0.15%.

Example 5: Process for preparation of Clopidogrel Bisulphate
To a suspension of CND.PTSA (25 gm) (Prepared in example 3) , DM water (75 ml) and Conc. HCl (6.0 gm) was charged a clear solution of paraformaldehyde (9.35 gm) in DM water (100 ml) at 25-35°C and heated the reaction mass to 40°C. Maintained the reaction mass at 40°C for 30 hrs and further at 55°C for 15 hrs. After completion of reaction, n-Hexane (150 ml) was charged to the reaction mass at 20-30°C and pH was adjusted to ~2.25 using liquor ammonia. Stirred the reaction mass and layers were separated. Aqueous layer was extracted with n-Hexane (250 ml). Hexane layer was washed with sodium bicarbonate solution. Organic layer was separated and hexane layer was distilled under vacuum to get Clopidogrel base as an oily mass. Clopidogrel base was dissolved in acetone (80 ml) and treated with activated carbon. Added sulfuric acid (4.3 gm) at -10 to 0°C. Seeded with Clopidogrel Bisulfate and stirred the slurry mass at 0-10°C for 5 hrs followed by filtration to get Clopidogrel Bisulfate wet cake. The wet cake was suspended in acetone (50 ml) and stirred at 25-35°C. Filtered the slurry and dried under vacuum at 30-35°C for 5 hrs to get 14.3 gm Clopidogrel Bisulfate containing 0.35 % of R-isomer.
,CLAIMS:
1) A process for preparation of Clopidogrel bisulphate comprising;

a) reacting methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate (CND base) with non-chiral aromatic/aliphatic sulfonic acids to obtain corresponding salts of methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate;
b) neutralizing the sulfonic acid salts of methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate with a base to liberate methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate free base (CND base) followed by reaction with concentrated HCl to obtain (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate Hydrochloride (CND.HCl); and
c) reacting the (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate Hydrochloride (CND.HCl) with paraformaldehyde to obtain clopidogrel free base followed by treatment with sulfuric acid to obtain Clopidogrel Bisulfate, or
d) Optionally, reacting the sulfonic acid salts of methyl (S)-2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate obtained in step a) directly with paraformaldehyde in presence of HCl to obtain clopidogrel free base followed by treatment with sulfuric acid to obtain Clopidogrel Bisulfate.

2) The process as claimed in claim 1, wherein, the sulfonic acids are aromatic sulfonic acids or aliphatic sulfonic acids selected from group consisting of benzenesulfonic acid, ortho or para toluene sulfonic acid, methanesulfonic acid, ethanesulfonic acid and propane sulfonic acid.

3) The process as claimed in claim 1, wherein, the reaction of step a) is conducted in a solvent selected from the group consisting of esters, ethers and/or ketone solvents.

4) The process as claimed in claim 3, wherein the solvents are selected from a group consisting of ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl ethyl ketone and methyl isobutyl ketone.

5) A process for preparation of sulfonic acid salts of methyl -2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate of formula-X, wherein R is non chiral alkyl or aryl group, comprising; reacting the methyl -2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate with non-chiral aromatic/aliphatic sulfonic acids to obtain corresponding sulfonic acid salts of methyl -2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate;

6) A compound of formula-X, wherein R is non-chiral alkyl or aryl group.

7) A compound of formula-Xa, wherein R is non-chiral alkyl or aryl group.

8) A compound of formula-Xb.

9) The compounds as claimed in claims 6, 7 and 9 wherein R is selected from a group consisting of benzenesulfonic acid, ortho or para toluene sulfonic acid, methanesulfonic acid, ethanesulfonic acid and propane sulfonic acid.