FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
Process for preparation of S (+) Clopidogrel and salts thereof
2. Applicant(s)
Name Nationality Address
USV LIMITED Indian company incorporated B.S.D.Marg, Station Road,Govandi, Mumbai- 400 088
under Companies Act, 1956 Maharashtra India
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention :
The present invention relates to a process for preparation of Clopidogrel or pharmaceutically acceptable salts thereof. More particularly, the present invention relates to process for preparation of Clopidogrel bisulfate of formula I.

Background and Prior Art:
Clopidogrel, Methyl (+)-(S)-a-(2-chlorophenyI)-6,7-dihydrothieno[3,2-cjpyridine-5(4H)-acetate is an antithrombotic agent. Clopidogrel is administered as its hydrogensulfate (syn. Bisulfate) salt, Formula I and its antiplatelet activity makes it an effective drug for reducing ischemic strokes, heart attacks and atherosclerosis, a vascular disease causing claudication. Clopidogrel has been found to be more effective in inhibiting platelet aggregation than aspirin and also mild towards gastrointestinal tract.
US4529596 discloses a racemic mixture of Clopidogrel and process for preparation thereof which involves condensation reaction between methyI-2-chIoro-o-chlorophenylacetate and 4,5,6,7-tetrahydrothieno [3,2-c]pyridine.
US4847265 discloses dextro-rotatory enantiomer, Methyl (+)-(S)-α-(2-chloro phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate (Clopidogrel) and process for preparation thereof. Racemic Methyl α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate is resolved using levo-camphorsulfonic acid to obtain optically pure dextrorotatory isomer. Also discloses that the dextrorotatory enantiomer (Clopidogrel) exhibits platelet aggregation inhibiting activity whereas the corresponding levorotatory enantiomer is less well tolerated and is inactive.

US6080875 describes a process for preparation of 2-thienylethylamine derivatives, in particular Methyl (+)-(S)-a-(2-thienyi-2-ethylamino)-a-(2-chlorophenyl)acetate hydrochloride, used as an intermediate in the synthesis of Clopidogrel, characterized in that a thienylglycidic derivative is reacted with a pheny]g]ycine ester, optionally in the form of a strong acid salt in the presence of an alkali metal borohydride optionally in the presence of a C1-C4 carboxylic acid to give the desired compound.
US6180793 discloses process to prepare Clopidogrel using racemic or optically active acetamide derivatives.
US5204469 discloses synthesis of Clopidogrel by reacting methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl) acetate with a formylating agent followed by cyclization of the obtained compound in presence of an acid. The formation of Clopidogrel is a two step process, first step involves reaction of methyl (+)-alpha-(2-thienylethylamino)(2-chlorophenyl) acetate in methylene dichloride with 30% w/w aqueous solution of formaldehyde. After 3 hrs, the organic phase is separated and washed with water, dried and concentrated to get residue. In the second step, a solution of obtained residue in methylene dichloride (MDC) is added to a solution of 6N HC1 in anhydrous DMF at 60°C followed by isolation of the desired dextrorotatory enantiomer (Clopidogrel). The shortcomings of this process are low yield, less chemical purity and less optical purity.
US6429210 describes process for preparation of Clopidogrel bisulfate Form II. This patent also discloses that the process disclosed in EP281459 leads to Form I of Clopidogrel bisulfate.
US6767913 discloses Clopidogrel hydrogen sulfate Form III, IV, V and amorphous form. It also provides process for preparation of Clopidogrel hydrogen sulfate Form I, Form III, Form IV, Form V and amorphous form.
WO2004020443 describes process for preparation of Clopidogrel bisulfate Form I

which comprises separating out Clopidogrel bisulfate from a solution of Clopidogrel in the form of free base or salt thereof in a solvent selected from the series of primary, secondary or tertiary C1-C5 alcohols, their esters with C1-C4 carboxylic acids, or optionally mixtures thereof.
WO2005026174 discloses Clopidogrel hydrogen bromide Form 1, 2, 3 and process for preparation thereof. WO' 174 discloses process for preparation of Clopidogrel hydrogen bromide form I which comprises adding aqueous HBr to a solution of Clopidogrel base in 2-propanol and diisopropyl ether with stirring at 20 to 28 deg C. It is observed that this process results in increased amounts of impurity A and impurity C.
WO2007144729 describes a process for preparation of Clopidogrel and its pharmaceutically acceptable salts thereof which comprises the steps of reacting methyl (2S)-amino-(2-chlorophenyl)acetate or its hydrochloride salt with 2-(2-thienyl)ethyl)-4-methylbenzenesulfonate using an organic base in the absence of an organic solvent to obtain an intermediate; cyclizing optionally the obtained intermediate compound in-situ with aqueous formaldehyde to obtain Clopidogrel; and converting Clopidogrel thus obtained to pharmaceutically acceptable salts thereof by conventional methods. It is observed that aqueous medium results in higher impurity content which in turn affects the yield and purity of the final product.
WO2007094006 discloses a process in which methyl (2S)-(2-chlorophenyl) [(2-thien-2-ylethyl)amino] acetate hydrochloride is subjected to cyclization using para formaldehyde as formylating agent, in aqueous medium with small quantity of HC1 as cycli2ation catalyst to obtain Clopidogrel, which is extracted in hexane and used as such for the preparation of Clopidogrel bisulfate Form I. It is observed that high water content in the reaction medium affects the yield and purity of the final product.

WO2008032995 discloses crystalline Clopidogrel (+)-camphorsulfonate salt, a method of preparing the same and a composition containing the same.
US20060223845 discloses Clopidogrel base having less than about 0.5% of total impurities. This patent application discloses a process for preparation of Clopidogrel base involving the use of a special equipment, Wiped Film Evaporator which is difficult to handle on a commercial scale, especially for a large volume API.
Prior art describes various processes for preparation of Clopidogrel or pharmaceutically acceptable salts thereof, in particular Clopidogrel bisulfate which either involves resolution of racemic Methyl a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or use of chiral intermediates. A control of therapeutically inactive R-isomer of Clopidogrel, an impurity, is very critical in the preparation of Clopidogrel bisulfate. Thus, there exists a need to provide a simple, cost-effective and industrially feasible process for preparation of Clopidogrel bisulfate, in particular Form I containing R-isomer not more than about 0.5%, preferably, not more than about 0.15%.
Object of the invention:
An object of the present invention is to provide an improved process for the preparation of Clopidogrel or pharmaceutically acceptable salt thereof, in particular Clopidogrel bisulfate.
Another object of the present invention is to provide Clopidogrel or pharmaceutically acceptable salt thereof, in particular Clopidogrel bisulfate, with R-isomer not more than about 0.5%, preferably not more than about 0.15%; unreacted Clopidogrel adduct and/or Impurity A not more than about 0.1%; and Methyl (S)-(+)-a-N-methyl (2-thienylethylamino)(2-chlorophenyl) acetate not more than about 0.15%; and process for preparation thereof.
Yet another object of the present invention is to provide a process for purification of Clopidogrel adduct and/or Clopidogrel.

Summary of the invention:
The present invention provides process for preparation of Clopidogrel which comprises :
a) treating methyl (S)-(+)-α-(2-thienylethylamino)(2-chlorophenyl)acetate or salt
thereof (Clopidogrel adduct) with paraformaldehyde in presence of catalytic amount
of water to obtain Clopidogrel;
b) optionally, purifying Clopidogrel.
Preferably, water is used in a catalytic amount of about 0.1 to 0.5% with respect to methyl (S)-(+)-α-(2-thienylethylamino)(2-chlorophenyl) acetate or salt thereof
Another aspect of the present invention provides a process for purification of Clopidogrel either by solvent treatment or by conversion to its acid addition salt.
Another aspect of the present invention provides conversion of Clopidogrel having unwanted (R)- isomer not more than about 0.5 % to Clopidogrel bisulfate.
Yet another aspect of the present invention provides methyl (S)-(+)-α-N-methyl-(2-thienylethylamino) (2-chlorophenyl) acetate and/or use thereof as a reference marker/reference standard in determining purity of Clopidogrel or pharmaceutically acceptable salts thereof.
Yet another aspect of the present invention provides process for purification of methyl (S)-(+)-α-(2-thienylethylamino)(2-chlorophenyl)acetate or salt thereof (Clopidogrel adduct) using alcohol selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof.
Brief description of the figures:
Fig. 1: X-ray Diffraction pattern of Clopidogrel bisulfate Form I obtained according to the present invention.
Fig. 2: X-ray Diffraction pattern of Clopidogrel hydrogen bromide obtained according to the present invention.

Detailed description of the invention:
The present invention provides an improved process for the preparation of Clopidogrel or pharmaceutically acceptable salt thereof, in particular Clopidogrel bisulfate, having R-isoraer less than about 1%, preferably less than about 0.5%, more preferably less than about 0.15%.
The process for preparation of pure Clopidogrel base is a key step in the preparation of Clopidogrel bisulfate. Being a large volume API required in pharmaceutical industry, there exists a need to develop a simple process for preparation of Clopidogrel base and its conversion to bisulfate salt. The main problem associated with prior art processes is that impurities get generated during the synthetic process which affects the yield and purity of the final product. The present inventors thus developed a simple, cost effective and industrially scalable process for the preparation of Clopidogrel and pharmaceutically acceptable salt thereof, in particular Clopidogrel bisulfate.
According to one embodiment of the present invention there is provided methyl (S)-(+)-α-(2-thienylethylamino)(2-chlorophenyl) acetate or salt thereof (Clopidogrel adduct), Clopidogrel and pharmaceutically acceptable salt thereof, in particular Clopidogrel bisulfate, having R-isomer not more than about 1 %, preferably not more than about 0.5%, more preferably less than about 0.15%.
Another embodiment of the present invention provides process for preparation of Clopidogrel comprising the steps of,
a) treating methyl (S) (+)-α-(2-thienylethylamino)(2-chlorophenyl)acetate or salt thereof with paraformaldehyde in presence of catalytic amount of water to obtain Clopidogrel;
b) optionally, purifying Clopidogrel.
In a preferred embodiment, the process for the preparation of Clopidogrel comprises
treating methyl (S)-(+)-α-(2-thienylethylamino)-(2-chlorophenyl)acetate

hydrochloride (Clopidogrel adduct) with paraformaldehyde in suitable solvent in presence of catalytic amount of water at 20 to 55°C preferably 30-40°C for 48 hours. The reaction mixture is cooled to 0-5°C and treated with base to neutralize hydrochloride salt followed by separation of the phases. The separated organic phase is washed with water and concentrated under reduced pressure at 50-55°C to get Clopidogrel. Water is used in a catalytic amount of about 0.1 to about 0.5% with respect to methyl (S)-(+)-α-(2-thienylethylamino)-(2-chlorophenyl)acetate or salt thereof, in particular hydrochloride salt (Clopidogrel adduct). Solvent is selected from methylene dichloride (MDC), chloroform, carbon tetrachloride and the like, preferably MDC. Paraformaldehyde is used in a molar ratio of 1 to 1.5, preferably 1.25 with respect to methyl (S)-(+)-α-(2-thienylethylamino)-(2-chlorophenyl)acetate hydrochloride (Clopidogrel adduct). An advantage of the process of the present invention is use of solid paraformaldehyde and catalytic amount of water to get Clopidogrel having R-isomer not more than about 1 %, preferably not more than about 0.5%, more preferably less than about 0.15%. Impurity A is also controlled well below 0.15%, preferably below 0.1%. Yield is quantitative.
According to another embodiment of the present invention there is provided a process for purification of Clopidogrel which comprises the steps of:
a) dissolving Clopidogrel in suitable solvent; and
b) isolating pure Clopidogrel.
In a preferred embodiment, Clopidogrel is dissolved in suitable solvent preferably hydrocarbon at 40-45°C. The obtained solution is treated with an inorganic metal oxide such as neutral alumina or silica, preferably neutral alumina and/or charcoal followed by heating at 60-65°C. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure at 50-55°C to get pure Clopidogrel having purity more than 97.5% with R-isomer content not more than about 1%, preferably not more than about 0.5%; unreacted Clopidogrel adduct not more than about 0.5%; Impurity A not more than about 0.1%; and Impurity 4 [.i.e., Methyl (S)-(+)-a-N-methyl (2-thienylethylamino) (2-chlorophenyl) acetate] not more than about 1% .

According to another embodiment of the present invention there is provided a process for purification of Clopidogrel which comprises the steps of;
a) dissolving Clopidogrel in suitable solvent to obtain a solution;
b) treating the obtained solution with an acid to get corresponding acid addition salt of Clopidogrel; and
c) converting the obtained acid addition salt of Clopidogrel to pure Clopidogrel.
Suitable acid is selected from HCl, HBr, methane sulfonic acid, camphor sulfonic
acid, preferably HBr or camphor sulfonic acid.
In one preferred embodiment, Clopidogrel is dissolved in ether and/or C1-C4 alcohol, preferably isopropyl alcohol at 35-40°C to obtain a solution. The solution is cooled to a temperature of-5° to 0°C and aqueous hydrobromic acid is added to the obtained solution with stirring at the same temperature. The temperature of the reaction mixture is raised from 0 to 10°C and maintained at the same temperature for 4 hours to get Clopidogrel hydrobromide Form A. Low temperature is maintained in order to avoid the formation of impurities, especially impurity A and impurity C. The obtained Clopidogrel hydrobromide is dissolved in suitable solvent preferably methylene dichloride and the obtained solution is cooled to 0 to 5°C. The cooled solution is treated with saturated sodium bicarbonate solution followed by separation of aqueous and organic phases. The separated organic phase is concentrated under reduced pressure at 50-55°C to get pure Clopidogrel with purity more than about 97% with R-isomer content not more than about 0.5%; unreacted Clopidogrel adduct not more than about 1.5%; Impurity A not more than about 0.1%; and Impurity 4 [Methyl (S)-(+)-ct-N -methyl (2-thienyl ethyl amino) (2-chlorophenyl) acetate] not more than about 0.5%
Clopidogrel hydrobromide obtained according to the present invention is characterized by XRPD as shown in Fig. 2. XRPD of Clopidogrel hydrobromide obtained according to the present invention matches with that of Clopidogrel hydrobromide Form A disclosed in WO2005103058 (Sanofi).

In another preferred embodiment, Clopidogrel is dissolved in acetone and/or methyl tert-butyl ether at 35-40°C. levo rotatory Camphor-10-sulfonic acid is added to the obtained solution. The reaction mixture is heated to reflux and maintained at the same temperature for 2 hrs. The reaction mixture is cooled to 0 to 10°C under stirring and maintained for 30 min at the same temperature to get free solid. The obtained solid is filtered and washed with acetone to get wet cake. The wet cake is dried at 50 to 55°C for 8 hours to get Clopidogrel camphor sulfonate salt with purity more than 97% with unwanted R- isomer less than about 0.5%. Clopidogrel camphor sulfonate salt is then converted to Clopidogrel by basification. Conversion of Clopidogrel to its camphor sulfonate salt can also be achieved by the processes known in the art.
Another embodiment of the present invention provides a process for purification of, camphor sulfonate salt of Clopidogrel comprising the steps of refluxing a solution of Clopidogrel camphor sulfonate in suitable solvent and isolating pure camphor sulfonate salt of Clopidogrel.
In a preferred embodiment, camphor sulfonate salt of Clopidogrel is dissolved in suitable solvent at 50°C-90°C under reflux conditions. The solution is maintained at reflux temperature for 30 minutes. The clear solution is concentrated (approximately 18 volumes are removed) and the resultant concentrated solution is cooled to 30°C under stirring to get pure camphor sulfonate salt of Clopidogrel.
In another preferred embodiment, camphor sulfonate salt of Clopidogrel is dissolved in suitable solvent under reflux conditions. The solution is maintained at reflux temperature for 30 minutes. The obtained clear solution is allowed to cool to get pure camphor sulfonate salt of Clopidogrel.
Alternatively, crude camphor sulfonate salt of Clopidogrel is dissolved in suitable solvent and pure camphor sulfonate salt of Clopidogrel is isolated using a suitable antisolvent.

Suitable solvent for purification is selected from hydrocarbon, halogenated hydrocarbon, ketone, nitrile, alcohol or ester. Hydrocarbon is selected from n-hexane, n-pentane, n-heptane or petroleum ether preferably n-hexane; halogenated hydrocarbon is selected from methylene dichloride or chloroform; ketone is selected from acetone, ethyl methyl ketone or methyl isobutyl ketone; nitrile is selected from acetonitrile or propionitrile; alcohol is selected from methanol, ethanol, n-propanol or isopropanol; and ester is selected from methyl acetate or ethyl acetate. Suitable antisolvent is selected from diethyl ether, diisopropyl ether or methyl tert-butyl ether.
Another embodiment of the present invention provides conversion of Clopidogrel having unwanted (R)-isomer not more than about 1 %, preferably not more than about 0.5%, to Clopidogrel bisulfate, in particular Form I. In practice, the process for preparation of Clopidogrel bisulfate Form I comprises the steps of,
a) obtaining a solution of Clopidogrel in suitable solvent, preferably ether and/or C1-C5 carboxylic acid;
b) adding sulfuric acid to the solution obtained in step a) to obtain a reaction mixture;
c) stirring the reaction mixture of step b) in a suitable antisolvent, preferably ether for about 30 minutes at a temperature of 0-30°C to obtain a suspension.
d) optionally, seeding the suspension with 1% of pure Clopidogrel bisulfate Form I with respect to Clopidogrel base to get pure Clopidogrel bisulfate Form I.
Ether is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane or mixture thereof, preferably, diisopropyl ether or methyl tert-butyl ether. C1-C5 carboxylic acid is selected from formic acid, acetic acid, propionic acid and the like, preferably acetic acid. Solvent is used in an amount of 1 to 5 parts per part of Clopidogrel base, preferably 1 part. Sulfuric acid used may be of >98% strength or in a diluted form. The solvent for dilution of sulfuric acid may be selected from

one of the solvents used for dissolving Clopidogrel base. The diluting solvent is preferably an ether, preferably DIPE.
In a preferred embodiment, the process for preparation of Clopidogrel bisulfate Form I comprises the steps of,
a) obtaining a solution of Clopidogrel in diisopropyl ether and acetic acid;
b) adding a solution of conc, sulfuric acid in diisopropyl ether to the solution of step a) to obtain a reaction mixture;
c) stirring the reaction mixture of step b) in methyl tert-butyl ether for about 30 minutes at a temperature of 0-30°C to obtain a suspension;
d) optionally, seeding the suspension with 1% of pure Clopidogrel bisulfate Form I with respect to Clopidogrel base to get pure Clopidogrel bisulfate Form J.
Solvents such as ether and C1-C5 carboxylic acid are used in a definite ratio. Preferred organic solvent is a mixture of acetic acid and DIPE. The ratio of acid to ether in the mixture may be 1:5 to 5:1, preferably 3:1. The low temperatures for dissolution or mixing are in the range of 0-15°C, preferably 5°C. Antisolvent added for complete precipitation of Clopidogrel bisulfate in the form of highly viscous gel is selected from the group consisting of diethyl ether (DEE), diisopropyl ether (DIPE), methyl tert-butyl ether (MTBE), THF, dioxane or mixture thereof, preferably MTBE. The total amount of antisolvent used for complete precipitation of Clopidogrel bisulfate gel is 5 to 30 volumes with respect to Clopidogrel, preferably 20 volumes. The supernatant solvent is decanted from the gel. The gel is again mixed with antisolvent and again decanted. To the resultant pure Clopidogrel bisulfate, fresh antisolvent is added. Total 10-20 volumes of the fresh antisolvent preferably 20 vol w.r.t. base is added. The suspension is stirred for several hours to transform highly viscous gel into chemically and polymorphically pure Clopidogrel bisulfate Form I.
US7446200 discloses process for preparation of Clopidogrel bisulfate Form I. Indian

patent application no. 1608/MUMNP/2007 also discloses process for preparation of Clopidogrel bisulfate Form I in a specially designed reactor assembly. The process disclosed uses DIPE as an antisolvent to obtain pure polymorphic Form I. The present inventors found that when the antisolvent, DIPE was replaced with MTBE, solid was obtained very rapidly. Further to induce rapid crystallization, the gel is seeded with crystals of pure Clopidogrel bisulfate Form I. Often a seeding process provides a reliable way to obtain the desired form because seeding provides nuclei and induces crystallization. The process of the present invention thus provides Clopidogrel bisulfate Form I on commercial scale, without altering the purity of polymorphic Form I of Clopidogrel bisulfate. The change in the solvent system along with seeding gave a breakthrough to isolate the product within 24 hrs.
Clopidogrel bisulfate Form I obtained according to present invention is characterized by X-ray powder diffraction having peaks at about 9.21, 9.56, 14.85, 15.23, 15.53, 20.62, 21.59, 23.19, 23.85, 25.52 ± 0.2 degrees 2 theta. It is further characterized by X-ray powder diffraction pattern as shown in Fig. 1.
According to one embodiment of the present invention there is provided a process for the preparation of Clopidogrel adduct, Methyl (S)-(+) α-(2-thienylethylamino)-(2-chlorophenyl)acetate or salt thereof, in particular hydrochloride salt, by reacting methyl (+)-α-amino (2-chlorophenyl) acetate with (2-thienyl)ethyl para-toluenesulphonate optionally in presence of base and suitable solvent selected from nitrile such as acetonitrile, ester such as ethyl acetate or butyl acetate, ketone such as acetone, ethyl methyl ketone, 2-butanone or methyl isobutyl ketone, hydrocarbon such as toluene and ether such as tetrahydrofuran (THF) or 1,4-dioxane to get the product having purity more than about 99.5% and R-isomer less than about 0.5%, preferably less than about 0.15%, more preferably less than about 0.1% The reaction is carried out at a temperature of 60-95°C, preferably 80-85°C. Preferably, reaction of methyl (+)-α-amino (2-chlorophenyl) acetate with (2-thienyl)ethyl para-toluenesulphonate is carried out in presence of base selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate

preferably potassium bicarbonate.
In another embodiment of the present invention, Clopidogrel adduct is purified using alcohol, ketone, ester, hydrocarbon, water or mixture thereof. Preferably Clopidogrel adduct is purified using alcohol selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof, preferably, isopropanol and/or methanol.
The process for preparation of Clopidogrel bisulfate according to the present invention is represented in scheme below,

The process for preparation of Clopidogrel base and its bisulfate salt as disclosed in US5204469 results in the following impurity profile as given in Table 1. Table 1:

Yield Imp A Imp B Imp C Imp.l Imp. 2 Imp.3 I nip.4 Purity
Clopi-Base 93% 0.44 0.14 0.68 0.22 1.12 5.12 0.17 91.58
Clopi-Bisulfate 86% 0.22 0.15 0.60 0.12 0.01 1.75 0.04 96.96

The purity of Clopidogrel obtained by US5204469 is 91.58% with major impurity of 5.12% (Impurity 3), which is identified and found to be unreacted compound [methyl (S)-(+)-α-(2-thienylethylamino) (2-chlorophenyl)acetate], Clopidogrel adduct. Impurity A, B and C are listed in US Pharmacopoeia whereas impurity 1 and 2 are unknown.
The structure of impurities as discussed above are given below,
Impurity A: (+)-(S)-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic
acid

Impurity B: Methyl(±)-(o-chlorophenyl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-acetate

Impurity 3: Methyl (S)-(+)-α-(2-thienylethylamino)(2-chlorophenyl)acetate
Impurity C : Methyl(-)-(R)-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5 (4H)-acetate


[Clopidogrel adduct]

Impurity 4: Methyl (S)-(+)-α-N -methyl (2-thienylethylamino) (2-chlorophenyl)acetate

As shown in Table 1, Clopidogrel obtained by process disclosed in US5204469, when converted to its bisulfate salt reduces the content of Impurity 3 from 5.12% to 1.75%. Clopidogrel bisulfate thus obtained does not meet ICH requirements. In regulated market, the drug substance produced should be of ICH quality. There is also no substantial change in the concentration of Impurity B and C. There is a change to some extent in impurity A while converting Clopidogrel base to its bisulfate salt Clopidogrel being an oii is difficult to crystallize. The purification of Clopidogrel bisulfate may result in yield loss as well as change in desired Polymorph, Form I. It is very important to prepare Clopidogrel in high purity and high yield. The process of the present invention provides a simple process for purification of Clopidogrel base and its conversion into Clopidogrel bisulfate minimizing the impurities viz., A, B, C, 1, 2, 3 and 4, in particular, impurity 3 and 4 as compared to the prior art processes.
Purification of Clopidogrel base, according to the process of the present invention, using suitable aliphatic hydrocarbon preferably with alumina treatment, successfully

reduces 50% of impurity 3, without increase in the Impurity C. Purification by conversion of Clopidogrel to its acid addition salt successfully reduces 50% of Impurity 3, without increase in the Impurity C, with unwanted R- isomer less than about 0.5%.
The purity of S (+) Clopidogrel and its bisulfate salt obtained according to the present invention is as shown in Table 2. The purification of Clopidogrel base by crystallization method (first approach) and purification via its hydrobromide salt (second approach) gives the following impurity profile, Table 2

Yield Imp A Imp B Imp C Imp. 1 Imp.
2 Imp.
3 Imp. 4 Purity
1st Approach;
Cl- Base crude 100% 0.04 0.10 0.51 0.06 0.10 0.83 0.89 97%
Cl- Base pure 89.5% 0.01 0.10 0.54 0.06 0.11 0.33 0.93 97.81%
Cl-Bisulfate pure 86.9% 0.02 0.09 0.39 ND ND 0.02 0.05 99.40%
2nd Approach:
Cl- Base crude 100% ND 1.62 0.25 0.15 0.21 1.9 0.11 95.78
Cl-Base pure via HBr salt 96% ND 0.1 0.25 0.04 0.19 1.20 0.4 97.58
Cl-Bisulfate pure 75% 0.02 0.1 0.24 0.04 0.14 0.31 0.13 98.98
From the above comparison it is observed that the major impurity in the present process is Impurity 3. To get ICH passing material of Clopidogrel bisulfate, Impurity 3 and 4 has to be maintained below 0.5% in Clopidogrel base. The first approach to reduce impurity 3 and 4 is found better than the second approach in controlling impurity 3 and 4.
Purification of Clopidogrel base by conversion to its camphor sulfonic acid salt

gives the following impurity profile

Yield Imp
A Imp B Imp C Imp 1 Imp
2 Imp 3 Imp 4 Purity
CI- Base
crude 98.5 ND 0.11 0.2 0.54 0.45 ND 1.21 97.16
Cl-Base pure via CSA salt 100 ND 0.09 0.05 0.18 0.03 ND ND 99.65
Cl-Bisulfate pure 85 0.02 0.03 0.13 ND ND ND ND 99.72
According to one embodiment of the present invention, there is provided Clopidogrel and Clopidogrel bisulfate substantially free of Clopidogrel adduct and/ or Methyl (S)- (+)-α-N-methyl (2-thienylethylamino) (2-chlorophenyl) acetate (Impurity 4)
Clopidogrel bisulfate, in particular Form I obtained according to the present invention has particle size such that about 90% of the particles have particle size less than about 800 microns, preferably less than about 600 microns, more preferably less than about 500 microns. In a preferred embodiment, about 90% particles have particle size in the range of about 100-500 microns. Clopidogrel bisulfate, in particular Form I thus obtained may be micronized by conventional techniques to get micronized particles such that about 90% of the particles have particle size less than about 100 microns, preferably less than about 50 microns, more preferably less than about 25 microns, most preferably less than about 10 microns.
As used herein, a solvent is any liquid substance, which has capacity to dissolve the organic compound, either at room temperature or higher temperature. Antisolvent is an organic solvent in which organic compound has poor solubility.
As used herein, the term "room temperature" means a temperature from about 10°C to 45°C, preferably 25°C to 30°C.

As used herein, the term "substantially free" means Clopidogrel and Clopidogrel bisulfate having not more than about 1% of Clopidogrel adduct and/or Methyl (S)-(+)-α-N-methyl (2-thienylethylamino) (2-chlorophenyl) acetate (Impurity 4), preferably not more than about 0.5%, more preferably not more than about 0.15%
The quality of Clopidogrel bisulfate Form I without detectable contamination of Form II, obtained in accordance with this invention, is characterized by X-ray powder diffraction pattern obtained on Panalytical X'pert Pro diffractometer equipped with accelerator detector using Copper Kα (λ= 1.5406 A) radiation with scanning range between 2-50 9 at scanning speed of 2°/min.
The following examples are provided to illustrate the invention and should not be construed to limit the scope of the present invention in any manner.
Examples
Example 1: Clopidogrel Adduct
Synthesis of Methyl (S)-(+)-α -(2-thienylethylamino)(2-chlorophenyl) acetate
hydrochloride
0.572 Kg of methyl (+)-alpha-amino(2- chlorophenyl) acetate was dissolved in 7.608L of acetonitrile. 0.8 Kg of KHC03 and 1.266Kg of (2-thienyl)ethyl para-toluenesulphonate were added to the obtained solution. The mixture was heated to 80-85°C and maintained at the same temperature for 48 hours. The solvent was removed under reduced pressure and the residue obtained was dissolved in 6.023 L of ethyl acetate. The inorganic salt precipitated was removed by filtration and washed with 1.2 L of ethyl acetate. Ethyl acetate layer was washed with 1.2 L of purified water and aqueous layer with 1.2L of ethyl acetate. The organic layers were combined and cooled to 0-10°C. The pH of the reaction mixture was made acidic using 0.577L of 35% conc. HC1 (d=1.18w/v) at 0-10°C. The mixture was maintained for 2 hour at 0-10 °C. The solid obtained was filtered, washed with 0.577L of chilled ethyl acetate followed by washing with chilled 0.50L acetone and

dried at 55-60°C for 6-8 hours to get 0.80 Kg Methyl (S)-(+)-a-(2-thienylethylamino)(2-chlorophenyl) acetate hydrochloride [α]20D +108.40° (c= CH3OH). HPLC purity more than 98 % with R-isomer less than 0.5%. The obtained solid was purified using 8L isopropyl alcohol and 2.8L volume of methanol to get 0.720 kg Methyl (S)-(+)-a-(2-thienylethylamino)(2-chlorophenyl) acetate hydrochloride with purity more than 99.5% and R-isomer less than 0.10%. [α ]D20: +110.0° to+112.0°.
Example 2; Synthesis of Clopidogrel
50 gm (0.1445M) of Methyl (S)-(+)-α -(2-thienylethylamino)(2-chlorophenyl) acetate hydrochloride was taken in 500 ml methylene dichloride. 5.43 gm (0.1810 M) of paraformaldehyde and 7.5 ml of purified water were added to the obtained solution. The mixture was heated at 35-40°C for 48 hours. After 48 hours, the reaction mixture was cooled to 0-5°C followed by addition of saturated sodium bicarbonate solution. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 50-55°C to get 46.5 gm yellow coloured oily residue. Purity: more than 97%
Example 3: Purification of Clopidogrel
The yellow coloured oily residue of crude Clopidogrel base obtained in example 2 was dissolved in 500 ml hexane at 40-45°C. 30 gm of neutral alumina and 5 gm charcoal were added to the obtained solution. The reaction mixture was heated to 60-65°C and maintained for 1 hour. The reaction mixture was filtered at 60-65°C on hyflo bed. The obtained filtrate was concentrated under reduced pressure at 50-55°C to get 41.96 gm of colourless oily residue. The yield was quantitative. Purity: more than 97.5% (HPLC), R- isomer content: less than 0.5%.
Example 4: Purification of Clopidogrel
46.5gm (0.1444M) of yellow coloured oily Clopidogrel base was dissolved in 465 ml diisopropylether at 35-40°C. 93 ml isopropyl alcohol was added to the obtained clear solution. The obtained solution was cooled to -5 to 0°C. 23.46 gm (0.1448 M)

of 50% w/w aqueous hydrobromic acid was added dropwise to the cooled solution at -5 to 0°C over a period of 30 min followed by stirring the reaction mixture at -5 to 0°C for 15 min. The temperature of mixture was raised from 0 to 10°C and maintained at the same temperature for 4 hours to get free solid. The obtained solid was filtered and washed with 47 ml diisopropylether to get the wet cake. The wet cake was charged in 141 ml diisopropylether and stirred for 30 min to get the solid which was washed with 47 ml diisopropylether and dried at 50 to 55°C for 8 hours to get 53.064 gm of Clopidogrel hydrobromide Form A having purity more than 97% and unwanted R-isomer less than about 0.5%. 53.064g of Clopidogrel hydrobromide was charged in 215 ml of methylene dichloride and cooled to 0 to 5°C. 300 ml of aqueous saturated sodium bicarbonate solution was added to the obtained solution. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure at 50-55°C to get 40.09gm (0.1245M) of yellow coloured oily residue. Purity: more than 97%; R-isomer: less than 0.5%.
Example 5 : Preparation of CS Salt of Clopidogrel
46.5gm (0.1444M) of yellow coloured oily Clopidogrel base was dissolved in 95 ml acetone and 95 ml of MTBE at 35-40°C. 33.50 gm (0.1444 M) of levo (-) camphor-10-sulfonic acid was added to the obtained solution. The solution was heated to reflux and maintained for 2 hrs. The solution was cooled to 0 to 10°C under stirring and maintained at the same temperature for 30 min to get free solid. The obtained solid was filtered and washed with 47 ml acetone to get a wet cake. The wet cake was dried at 50 to 55°C for 8 hours to get 70.76 gm (88%) of Clopidogrel camphor sulfonate salt. Purity: more than 97% , R- isomer: less than 0.5%.
Purification of CS Salt of Clopidogrel. Example 6:
25g of crude CS Salt of Clopidogrel was dissolved in 575 ml of acetone under reflux

and maintained at the same temperature for 30 minutes. The clear solution was concentrated till 5 volumes remain in the flask. The resultant concentrated solution was slowly cooled to 30°C and maintained for 30 min under stirring. The solution was further cooled to 0-5°C and stirred at the same temperature for.30 min. The precipitated solid was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 90%; Purity: 99.71%; R-content: 0.054%
Example 7
25g of crude CS Salt of Clopidogrel was dissolved in 100 ml of acetonitrile under reflux and maintained at the same temperature for 30 minutes. The resultant clear solution was allowed to cool to 30°C and maintained for 30 min under stirring. The separated solid was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 63%; Purity: 99.82%; R-content: 0.074%
Example 8
25g of crude CS Salt of Clopidogrel was dissolved in 50 ml of acetonitrile under reflux condition. The solution was maintained at reflux temperature for 30 minutes. The resultant clear solution was allowed to cool to 30°C and maintained for 2 hrs at the same temperature under stirring. The separated solid was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 77%; Purity: 99.72%; R-content: 0.076%
Example 9
25g of crude CS Salt of Clopidogrel was dissolved in 25 ml of acetonitrile under reflux condition. The solution was maintained at reflux temperature for 30 minutes. The resultant clear solution was allowed to cool to 30°C and maintained for 2 hrs at the same temperature under stirring. The separated solid was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 78%; Purity: 99.80%; R-content: 0.049%
Example 10
25g of crude CS Salt of Clopidogrel was dissolved in 250 ml of methanol under reflux condition. The solution was maintained at reflux temperature for 30 minutes.

To this clear solution, 1750 ml DIPE was added at reflux temperature. The resultant mixture was allowed to cool to 25-30°C and maintained at the same temperature for 2 hrs under stirring. The separated solid was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 89%; Purity: 99.75%; R-content: 0.048%
Example 11
25g of crude CS Salt of Clopidogrel was suspended in 750 ml of ethyl acetate under reflux condition. The solution was maintained at reflux temperature for 30 minutes. The resultant suspension was allowed to cool to 25-30°C and maintained at the same temperature for 2 hrs under stirring. The separated solid was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 87%; Purity: 99.46%; R-content: 0.231%
Example 12
25g of crude CS Salt of Clopidogrel was dissolved in 250ml of MDC under reflux condition. The solution was maintained at reflux temperature for 30 minutes. To this clear solution 1750 ml DIPE was added at reflux temperature. The resultant solution was allowed to cool to 25-30°C and maintained for 2 hrs at the same temperature under stirring. The separated solid was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 64%; Purity: 99.72%; R-content: 0.020%
Example 13
25g of crude CS Salt of Clopidogrel was dissolved in 250ml of isopropanol under reflux condition. The solution was maintained at reflux temperature for 30 minutes. The resultant clear solution was allowed to cool to 0-5°C and maintained for 2 hrs at the same temperature under stirring. The solid separated was isolated by filtration and dried at 55°C for 3-4 hrs. Yield: 60%; Purity: 99.72%; R-content: 0.065%
Example 14: Preparation of Clopidogrel bisulfate form I from Clopidogrel base
41g of pure Clopidogrel was dissolved in 41 ml of DIPE and the solution was cooled to 15°C. 123 ml of glacial acetic acid was added to the obtained solution by maintaining the temperature below 15°C. The reaction mixture was further cooled to

0-10°C. 41 ml of diisopropyl ether (DIPE) containing 12.51g of conc. H2S04 was added dropwise to the resultant clear solution by maintaining the same temperature and the mixture was further stirred for 15-30 minutes. 738 ml of MTBE was added to the reaction mixture by maintaining temperature of 0-30°C. The obtained gel was washed with MTBE twice (2x41ml). The gel was suspended in 820ml of MTBE and 1% seed of pure Clopidogrel Form I with respect to initial base was added to the suspension. The suspension was maintained at 30-40°C for 24 hrs to obtain solid material. This solid mass obtained was isolated and washed with 94ml of MTBE. This solid product in form of wet cake was again charged in 282ml of MTBE and stirred for 15-30 min. The solid obtained was filtered and washed further with 94ml MTBE. The wet cake was washed with 129ml of acetone. Acetone wash could be repeated, if required. The solid material was isolated and dried under vacuum at 50-55°C over 8-12 hrs to get Clopidogrel bisulfate Form I. m.p.: 184-186°C; [α]D20: 55.6; Yield: 85-95%; R-isomer below 0.5%.

We claim,
1. A process for preparation of Clopidogrel comprising the steps of:
a) treating methyl (S)-(+)-α -(2-thienylethyIamino)(2-chlorophenyl) acetate or salt thereof (Clopidogrel adduct) with paraformaldehyde in presence of catalytic amount of water to obtain Clopidogrel;
b) optionally, purifying said Clopidogrel.

2. The process as claimed in claim 1 wherein said catalytic amount ranges from about 0.1 to about 0.5% with respect to methyl (S)-(+)-α-(2-thienylethylamino) (2-chlorophenyl) acetate or salt thereof.
3. The process as claimed in claim 1 wherein said treatment is carried out at temperature of 20°C to 55°C.
4. The process as claimed in claim 1 wherein said Clopidogrel is purified either by solvent treatment or by conversion to its acid addition salt.
5. The process as claimed in claim 4 wherein the process for purification of Clopidogrel comprises :

a) dissolving said Clopidogrel in suitable solvent to obtain a solution;
b) treating obtained solution with inorganic metal oxide and/or activated charcoal to obtain a reaction mixture;
c) optionally, heating the reaction mixture of step b);
d) isolating pure Clopidogrel.

6. The process as claimed in claim 5 wherein said suitable solvent is selected from pentane, hexane, heptane or petroleum ether and said inorganic metal oxide is selected from neutral alumina or silica.
7. The process as claimed in claim 4 wherein the process for purification of Clopidogrel comprises :

a) dissolving said Clopidogrel in suitable solvent to obtain a solution;
b) treating the obtained solution with an acid to get corresponding acid

addition salt of Clopidogrel; c) converting the obtained acid addition salt of Clopidogrel to Clopidogrel.
8. The process as claimed in claim 7 wherein said acid is selected from HC1, HBr, methane sulfonic acid or camphor sulfonic acid and wherein said treatment is carried out at a temperature of -5 to 60 °C.
9. The process as claimed in any of the preceding claims wherein the Clopidogrel is further converted to its pharmaceutically acceptable salt
10. A process for preparation of Clopidogrel Bisulfate comprising the steps of:

a) obtaining a solution of Clopidogrel in ether and/or C1-C5 carboxylic acid;
b) adding conc, sulphuric acid to the solution of step a) to obtain a reaction mixture;
c) stirring the reaction mixture of step b) in an antisolvent to obtain a suspension;
d) optionally, seeding the suspension with 1% of desired polymorphic form of Clopidogrel bisulfate;
e) isolating Clopidogrel bisulfate.

11. The process as claimed in claim 10 wherein said ether is selected from diethyl ether, diisopropyl ether or methyl tert-butyl ether; said C1-C5 carboxylic acid is selected from formic acid, acetic acid or propionic acid; and said antisolvent is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane; and said desired polymorphic form is Clopidogrel bisulfate Form I.
12. The process as claimed in any of the preceding claims wherein said Clopidogrel and said Clopidogrel bisulfate has R-isomer content not more than about 0.5%; unreacted Clopidogrel adduct and/or Impurity A not more than about 0.1%; and Methyl (S)- (+)-α -N-methyl (2-thienylethylamino) (2-chlorophenyl) acetate (Impurity 4) not more than about 0.15%.

13. Clopidogrel and Clopidogrel bisulfate substantially free of Clopidogrel adduct and/or Methyl (S)~(+)-a-N-methyl (2-thienylethylamino) (2-chlorophenyl) acetate (Impurity 4).
14. A compound, Methyl (S)-(+)-α-N-methyl (2-thienylethylamino) (2-chlorophenyl) acetate and/or use thereof as a reference marker or reference standard in determining purity of Clopidogrel or pharmaceutically acceptable salt thereof.
15. The process as claimed in claim 1 wherein said methyl (S)-(+)-a-(2-thienylethylamino)(2-chlorophenyl) acetate or salt thereof (Clopidogrel adduct) is purified using alcohol selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof.
16. A process for purification of methyl (S)-(+)-α-(2-thienylethylamino)(2-chlorophenyl) acetate or salt thereof (Clopidogrel adduct) wherein methyl (S)-(+)-α-(2-thienylethylamino)(2-chlorophenyl) acetate or salt thereof (Clopidogrel adduct) is purified using isopropanol and/or methanol.