FORM 2 THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
TITLE OF THE INVENTION:
"NOVEL AND COST EFFECTIVE PROCESS FOR PREPARATION OF FORM-1 OF ANTITHROMBOTIC AGENT"

2. APPLICANT:
(a) NAME: AARTI DRUGS LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: Mahendra Industrial Estate, Ground Floor, Plot No. 109-D,
Road No. 29, Sion (East), Mumbai ~ 400 022, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it has to be performed.

Technical field of Invention:
The present invention relates to a novel, convenient and cost effective process for preparation of crystalline Form-1 of antithrombotic agent Methyl (S)-(+)-oc-(2-chIorophenyl)-4,5,6,7-tetrahydrothieno [2,3-c] pyridine-5-acetate hydrogen sulfate, commonly known as "clopidogrel bisulfate" (illustrated below as Formula I) from condensation, cyclisation and isolation of Tartarate salt of methyl ester of 2-chlorophenyl glycine

Formula-I Background and Prior Art
Clopidogrel is administered as its hydrogen sulfate (syn. Bisulfate) salt. Its anti-platelet activity makes it an effective drug for reducing ischemic strokes, heart attack and atherosclerosis, a vascular disease causing claudication, is a buildup of plaque in the wall of arteries, which leads to thickening of the arterial wall and reduction in elasticity of arteries. High cholesterol, high blood pressure, smoking and infection also may cause injuries to the inner wall of arteries, which leads to atherosclerosis. The blood platelet aggregation inhibiting property exhibited by Clopidogrel, binds adenosine diphosphate to its receptor, thereby inducing platelet reduction, which is desirable in fighting against atherosclerosis.
US Pat. No. 6,180,793 disclose processes for synthesizing (S) clopidogrel by reaction of an activated form of 2-thiophene ethanol with (S)-2-chlorophenyI glycineamide, (S)-2-chlorophenyl-[alpha]-amino acetonitrile or (S) 2-chlorophenyl glycine methyl ester. After condensation, the resulting compound is cyclicized, hydrolyzed and esterified.
US Pat, No, 5,204,469 (EP 466569, JP 4230387) discloses a process for preparation of racemic methyl a!pha-(4, 5, 6, 7-tetra hydro- 5- thieno [3,2c] pyridyl) (2-chlorophenyl)
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acetate and of its two enantiomers. The synthesis of dextrorotatory enantvomer of clopidogrel comprises reaction of (+)-2-chloro phenylglycine and an activated form of 2-thiophene ethanol followed by cyclization with formaldehyde. The hemisulfate is then obtained by dissolution in acetone and addition of concentrated sulfuric acid.
EP0281459 describes the formation of dextrorotatory isomer of clopidogrel by dissolving clopidogrel camphor sulfate in acetone, followed by successive recrystallization until a product with constant optical rotatory power was obtained, followed by the release of the dextro rotatory isomer from its salt by a base. The pure Clopidogrel free base was further converted into its hydrogen sulfate salt by dissolving in acetone, followed by addition of concentrated sulfuric acid to precipitation. But EP'459 patent do not characterize any polymorphic crystals of Clopidogrel hydrogen sulfate. However, W099/65915 has identified that the precipitation method described in EP'459 patent had led to crystalline Form-I.
International patent application WO2004G48385 describes a process for the preparation of crystalline Form-I of S-Clopidogrel hydrogen sulfate by reacting the optically active base, (S)-(+) clopidogrel with concentrated sulfuric acid, wherein the salt formed by the said reaction in the reaction medium is precipitated with the precipitating solvent such as aliphatic or cyclic ethers and/ or their mixtures or isobutyl methyl ketone,
Form-II of clopidogrel Bisulfate is thermodynamically more stable. Hence a small change in reaction conditions during the preparation of Form-I, can result in the formation of Form-II instead.
W099/65915 discloses two polymorphic forms of Clopidogrel hydrogen sulfate referred to as Form-I and Form-II. According to the said publication both the polymorphs, namely Form II and I, were prepared from the same solvent viz: acetone.
US6429210 describes process for preparation of crystalline polymorph of (+)-(S) clopidogrel hydrogen sulfate Form II.
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18 APR 2009

US2003114479 describes the novel crystalline forms, FormlU, IV and V along with the process for preparation of Form I. In the US'479 patent application, polymorphic Form I is prepared by suspending amorphous clopidogrel hydrogen sulfate in ether.
International patent application WO2004020443 describes process for preparation of Clopidogrel hydrogen sulfate in the crystalline Form-I, which comprises separating out crystalline Form-I from solution of clopidogrel in the form of free base or salt in a solvent selected from series of primary, secondary or tertiary C1-C5 alcohols or their esters with C1-C4 carboxylic acids or optionally of mixtures thereof.
.In another process variant, clopidogrel hydrogen sulfate was directly dissolved at reflux temperature in the above mentioned solvents and crystallized under cooling.
US2003225129 describes the process for preparation of Form-II from solvents selected from dichloromethane, 1, 4-dioxane, toluene, chloroform, ethyl acetate, methyl ethyl ketone and t-butyl methyl ether. The '129' patent, for first time, claimed to produce Form-II from ethyl acetate which was the main subject of'443' patent application.
International patent publication WO2004048385 describes a process for the preparation of crystalline Form-1 of S-CIopidogrel hydrogen sulfate by reacting the optically active base, (S)-(+) clopidogrel with concentrated sulfuric acid, wherein the salt formed by the said reaction in the reaction medium is precipitated with the precipitating solvent such as aliphatic or cyclic ethers and/ or their mixtures or isobutyl methyl ketone.
It is clear from above discussion that same solvent can give two different crystalline forms of clopidogrel hydrogen sulfate.
Also, it is evident from prior art that the methods to produce Form-I of clopidogrel hydrogen sulfate from known solvents are poorly reproducible, necessitating the optimization of experimental conditions other than of the selection of solvent. Since From-I is kinetically controlled and Form-II is thermodynamically controlled form, they require very specific temperature range and specific condition for getting reproducible result. Also a minor variation in condition appears to give Form-II instead of expected
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Form-I or a mixture of Form-I, and Form-II. Since, Form-I of clopidogrel hydrogen sulfate is often used for pharmaceutical formulation, it becomes important to provide a method that will give Form-I consistently.
Apart from the inconsistency of the process in solvent like ethyl acetate, the process given in WO2004020443 also suffers from operational problems from an industrial scale-up point of view as follows;
\) During the salt formation in solvent like ethyl acetate at lower temperature, the product forms a sticky and lumpy mass that sticks to the stirrer and difficult to disperse due to the lowered solubility at this condition, 2) The crystal form obtained by performing the salt formation between 5° to 15°C in ethyl acetate is Form-II clopidogrel hydrogen sulfate. This may be due to the non-dispersability of the sticky mass obtained under these conditions and the fast-prolonged stirring performed for dispersion, allows the crystals to grow and rearrange to the most stable form.
Moreover, carrying out reaction at higher temp, that too for longer period, leads to formation of various impurities due to lack of selectivity of reaction or decomposition of the reactants or products, which necessitates extra purification resulting into yield loss and increase in number of operation unit desirable for practical process.
Thus there is a need to get industrially reliable process for the preparation of Form-I crystals of clopidogrel bisulfate without contamination of Form II or other polymorphs. Also it was of interest to find a suitable solvent where the crystallization can be performed at a temperature near to ambient temperature, for solving the inconsistency/operational problems in the prior art, to effect a fast and easily dispersible crystallization condition, an important factor for operation.
Objective of present invention:
It is, therefore, an objective of the present invention to provide an industrially useful and cost effective process for the manufacture of Clopidogrel Form 1 from starting materials that are readily and commercially available, relatively inexpensive, and easily maneuvered at large scale operations,
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Formula-II Formula-Ill
Other objectives of this invention are;
1) To provide a one pot conversion process for unstable intermediate like Methyl (S)-(+)-<*-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (Formula-II) and Clopidogrel base (Formula-Ill) formed in the reaction to convert into a stable clopidogrel Form-I.
2) To design a process for preparation of Clopidogrel Form-1 under ambient conditions with accelerated rate of reaction.
3) A further objective of the present invention was to find solvent system where the Form-I crystals of Clopidogrel hydrogen sulfate can be efficiently and reproducibly formed on industrial scale. These objectives become the subject of the present invention.
Summary of invention:
Accordingly, in a first aspect, there is provided an improved process for manufacture of Clopidogrel bisulfate starting from (+)-Tartarate salt of methyl ester of 2-chlorophenyl glycine, which eliminate, the isolation of unstable intermediate Methyl (S)-(+)-«>(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (Formula-II) and clopidogrel base(Formula III) by subjecting to condensation with benzene sulfonic acid salt of thiophene-2-ethanol followed by cyclisation with paraformadehyde.
In one embodiment of the present invention, Methyl (S)-(+)-cc-(2-chIorophenyl)-{[2-(thiOphen-2-yl) ethyl] amino} ethanoate (Formula-II) is prepared by condensation of (+)-Tartarate salt of methyl ester of 2-chloro phenyl glycine with benzene sulfonic acid salt of thiophene-2-ethanol at 80-100°C in water in presence of organic or inorganic base like dipotassium hydrogen orthophosphate or disodium hydrogen orthophosphate.
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In another embodiment of the present invention, Methyl (S)-(+)-oc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (Formula-II) is reacted with paraformadehyde at 50-70°C in solvent like n-butyl acetate and water in presence of organic or inorganic acid as catalyst like sulfuric acid or acetic acid or mixture thereof to obtain clopidogrel acid addition salt.
In yet another preferred embodiment of the present invention the process for 'Form-I' comprises of isolating clopidogrel base (Formula-Ill) in n-butyl acetate at 10-35 °Cand then crystallizing Clopidogrel bisulfate Form-1 at ambient temperature by adding sulfuric acid in n-butyl acetate or as such..
Detailed description of drawings:
Figure 1 shows XRD of Clopidogrel Bisulfate form I Figure 2 shows IR of Clopidogrel Bisulfate form I Figure 3 shows DSC of Clopidogrel Bisulfate form I
Detailed 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.
According to the present invention, the improved process for preparation of Clopidogrel bisulfate Form-I comprising conversion of (+)-Tartarate salt of methyl ester of 2-chlorophenyl glycine to Methyl (S)-(+)-cc-(2-chIorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (Formula-II) and then to Clopidogrel base and further to clopidogrel bisulphate Form-I by eliminating the isolation of unstable intermediate, Clopdogrel base(Formula III), making the process industrially more feasible and economical. The detailed process is depicted below;
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In one embodiment of the present invention acid catalyzed cyclization of Methyl (S)-(+)-cc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (FormuIa-II) with paraformaldehyde is carried out at temperature range 25-8Q°C, for period of 6-8 hr in presence of acid catalyst in solvent n-butyl acetate to obtain clopidogrel base. Further, solvents like, methanol, DMF and water or mixtures thereof may be added the reaction mass to increase the rate of cyclization.The acid catalyst used for cyclization is organic or inorganic acid like sulfuric acid or acetic acid. The Clopidogrel base thus obtained is extracted in n-butyl acetate and sulfuric acid is then added slowly by stirring the reaction
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mass for 24 hr at room temperature, followed by filtering and drying the crystals to obtain Form-1 of Clopidogrel Bisulfate.
The purity of Clopidogrel Form-1 without detectable contamination by Form-II, obtained in accordance with this invention, is documented by X-ray powder diffraction (XRD), Differential scanning calorimeter (DSC) and IR spectra.
The following examples are provided to illustrate the invention and not intended to limit the scope of the appended claims.
Examples
Example 1
Preparation of (+) Tartarate salt of methyl ester of 2-chlorophenyl gylcine.
To the mixture of 800 ml methanol and 100 gm 2-Chlorophenyl glycine was added 150 gm thionyl chloride at 15-20°C.After complete addition the temperature was raised to 55-60°C and maintained for 3 hr. The excess methanol and thionyl chloride was distilled off completely under vacuum below 50°C.The residual solvent are removed by adding 340 ml toluene and distilling it under vacuum below 50°C-To the residue 500 ml purified water and 220 ml toluene was added. The pH of the solution was adjusted to neutral by adding ammonia. The aqueous layer was separated and again extracted with 150 ml toluene. The combined organic layer was distilled out completely under vacuum below 50°C.
The residue was dissolved in a mixture of 40 ml acetone and 500 ml methanol. To the solution 80 gm L (+)-Tartaric acid was added under stirring at 25-30°C,The reaction mixture was allowed to stir at 25-30°C for 24 hr. The solid filtered and washed with methanol and dried at 50-60°C for 4 hr to yield 125 gm of (+)Tartarate salt of methyl ester of 2-chlorophenyl glycine.
Example 2
Preparation of Methyl (SH+)-<*-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino}
ethanoate (Formula-II) base
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To the chilled solution of methylene chloride (330 ml), water (330 ml) and 125 gm of tartarate salt obtained in example-I was added ammonia solution till neutral pH was reached. Aqueous layer was separated and again extracted with 65 ml methylene chloride. The organic layer was dried over sodium sulfate and distilled and degassed to get 110-115 gm residue.
The residue was mixed with 113 gm of benzene sulfonic acid salt of Thiophene -2-ethanol, 85 ml water and dipotassium hydrogen phosphate (133 gm). The reaction mixture was heated to 90-95°C for 5 hr. Reaction mixture was cooled to 20-25°C and extracted with 335 ml ethyl acetate. The aqueous layer was separated and again extracted with 65 ml ethyl acetate. The combined ethyl acetate was then distilled out completely under vacuum to get oil of Methyl (S)-(+)-ac-(2-chlorophenyI)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (Formula-II).
Example 3
Preparation of Methyl (S)-(+)-oc-(2-chlorophenylHI2-(thiopheii«2-yl) ethyl] amino}
ethanoate (Formula-II) Hydrochloride
To the chilled solution of methylene chloride (330 ml), water (330 ml) and 125 gm of tartarate salt obtained in example-I was added ammonia solution till neutral pH was reached. Aqueous layer was separated and again extracted with 65 ml methylene chloride. The organic layer was dried over sodium sulfate and distilled and degassed to get 110-115 gm residue.
The residue was mixed with 113 gm of benzene sulfonic acid salt of Thiophene -2-ethanol, 85 ml water and dipotassium hydrogen phosphate (133 gm). The reaction mixture was heated to 90-95°C for 5 hr. Reaction mixture was cooled to 20-25°C and extracted with ethyl acetate. The aqueous layer was separated and again extracted with 65 ml ethyl acetate. The combined ethyl acetate was then acidified with hydrochloric acid (35 ml) at 10-15°C. Solid obtained was filtered and washed with ethyl acetate. The solid after drying (dry wt 60 gm) have SOR (+) 105-115°.
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28 APR 2009,

Example 4
Preparation of Methyl (S)-(+)-cc-(2-chlorophenyI)-{[2-(tliiophen-2-yl) ethyl] amino} ethanoatc (Formula-ll) from its hydrochloride
100 gm of Methyl (S)-(+)-oc-(2-chlorophenyI)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate HC1 was suspended in 400 ml methylene chloride, the pH of above solution was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 200 ml methylene chloride. The organic layer was dried over sodium sulfate and distilled and degassed to get 70-75 gm oil of Methyl (S)~ (+)-cc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (Formula-II) HPLC purity; >99.0 %
Example 5
Preparation of Clopidogrel Bisulfate Form-1
20 gm of Methyl (S)-(+)-cc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate from Example-2, 10 gm paraformaldehyde was suspended in 200 ml n-butyl acetate and 50 ml water. To the reaction mixture 0.25 ml sulfuric acid was charged at 20-30°C and the reaction mixture was heated to 60-65°C for 10-12 hr for complete conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture was stirred overnight for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hrto yield 15-18 gm Clopidogrel bisulfate Form-1. Yield: >96% HPLC purity: >99.0 %, Melting Point: 198-204°C.
Example 6
Preparation of Clopidogrel Bisulfate Form-1
20 gm of Methyl (S)-(+)-cc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate from Example-2, 10 gm paraformaldehyde was suspended in 200 ml n-butyl acetate. To
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the reaction mixture 0.25 ml sulfuric acid was charged at 20-30°C and the reaction mixture was heated to 60-65°C for 10-12 hr for complete conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture was stirred over night for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hr to yield 15-18 gm Clopidogrel bisulfate Form-1. Yield: >96 % HPLC purity: >99.0 %, Melting Point: 198-204°C.
Example 7
Preparation of Clopidogrel Bisulfate Form-1
20 gm of Methyl (S)-(+)-oc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate from Example-2» 10 gm paraformaldehyde was suspended in 200 ml n-butyl acetate and 50 ml water. To the reaction mixture 25 ml acetic acid was charged at 20-30°C and the reaction mixture was heated to 60-65°C for 4-5 hr for complete conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture was stirred overnight for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hr to yield 16-19 gm Clopidogrel bisulfate Form-1. Yield: >96% HPLC purity: >99.0 %, Melting Point: 198-204°C.
Example 8
Preparation of Clopidogrel Bisulfate Form-1
20 gm of Methyl (S)-(+)-oc-(2-chIorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate from Example-2, 10 gm paraformaldehyde was suspended in 200 ml n-butyl acetate and
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10 ml thionyl chloride reaction mixture was heated to 60-65°C for 4-5 hr for complete
conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding
10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-
butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml
sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture
was stirred over night for 12-15 hr. Solid material was filtered and washed with n-butyl
acetate. Wet material was dried at 60-70° for 8 hr to yield 16-19 gm Clopidogrel bisulfate
Form-1. Yield; >96 %
HPLC purity: >99.0 %, Melting Point: 198-204°C.
Example 9
Preparation of Clopidogrel Bisulfate Form-1
20 gm of Methyl (S)-(+)-oc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate from Example-2, 10 gm paraformaldehyde was suspended in 200 ml n-butyl acetate and 5 ml dimethyl formamide. The reaction mixture was heated to 60-65°C for 8-10 hr for complete conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture was stirred over night for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hr to yield 15-18 gm Clopidogrel bisulfate Form-1. Yield: >96 % HPLC purity: >99.0 %, Melting Point: 198^204°C.
Example 10
Preparation of Clopidogrel Bisulfate Form-1
20 gm of Methyl (S)-(+)-oc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate from Example-2, 10 gm paraformaldehyde was suspended in 200 ml n-butyl acetate and
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50 ml methanol. The reaction mixture was heated to 60-65°C for 12-15 hr for complete conversion of starting material
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture was stirred overnight for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hr to yield 16-19 gm Clopidogrel bisulfate Form-1. Yield: >96 % HPLC purity; >99.0 %, Melting Point: 198-204°C.
Example 11
Preparation of Clopidogrel Bisulfate Form-1
25 gm of Methyl (S)-(+)-oc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate HCI Example-3, 10 gm paraformaldehyde was suspended in 200 ml n-butyl acetate and 90 ml water. To the reaction mixture 0.25 ml Sulfuric acid was charged at 20-3Q°C and the reaction mixture was heated to 60-65°C for 4-5 hr for complete conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture was stirred overnight for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hr to yield 16-19 gm Clopidogrel bisulfate Form-1. Yield: >96 % HPLC purity: >99.0 % Melting Point: 198-204°C.
Example 12
Preparation of Clopidogrel Bisulfate Form-1
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25 gm of Methyl (S)-(+)-oc-(2-chlorophenyl)-{[2-(thiophen«2-yl) ethyl] amino} ethanoate HO ExampIe-3, 10 gm Paraformaldehyde was suspended in 200 ml n-butyl acetate and 90 ml water. To the reaction mixture 25 ml acetic acid was charged at 20-30°C and the reaction mixture was heated to 60-65°C for 4-5 hr for complete conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 100 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml sulfuric acid in 33 ml n- butyl acetate was slowly added at 2Q-25°C.The reaction mixture was stirred overnight for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hr to yield 16-19 gm Clopidogrel bisulfate Form- K Yield: >96 % HPLC purity; >99.0 %, Melting Point: 198-204°C.
Example 13
Preparation of Clopidogrel Bisulfate Form-1
20 gm of Methyl (S)-(+)-cc-(2-chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate from ExampIe-2, 200 ml formaldehyde solution and the reaction mixture was heated to 20-25°C for 16 hr for complete conversion of starting material.
Reaction mixture was cooled to 10-15°C and the pH was adjusted to 8-9 by slowly adding 10% sodium hydroxide. Aqueous layer was separated and again extracted with 3*200 ml n-butyl acetate. The organic layer was dried over sodium sulfate and solution of 3 ml Sulfuric acid in 33 ml n- butyl acetate was slowly added at 20-25°C.The reaction mixture was stir overnight for 12-15 hr. Solid material was filtered and washed with n-butyl acetate. Wet material was dried at 60-70° for 8 hr to yield 15-18 gm Clopidogrel bisulfate Form-1. Yield: >96% HPLC purity: >99-0 %, Melting Point: 198-204°C.
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We claim,
1. A process for the preparation of polymorphic form I of (S)-Clopidogrel bisulfate( Formula I) comprising the following steps:
a) rating (+)-Tartarate salt of methyl ester of 2-chloro phenyl glycine with benzene sulfonic acid salt of thiophene-2-ethanol at a temperature of 80-100°C;
b) cyclizing Methyl (S)-(+)-oc-(2*chlorophenyl)-{[2-(thiophen-2-yl) ethyl] amino} ethanoate (Formula-II) or its hydrochloride salt using cyclizing agent in n-butyl acetate in presence of acid catalyst at a temperature ranging 50-70° Cand
c) precipitating the clopidogrel base as acid addition salt in Form I. from n-buty! acetate.
Formula-I

2. The process as claimed in claim-1, wherein said cyclizing agent is paraformaldehyde or formaldehyde solution.
3. The process as claimed in claim-1, wherein the reaction mass further comprises a solvent selected from water, methanol or dimethylformamide to increase the rate
ofcyclization.
4. The process as claimed in claim-1, wherein said acid catalyst is selected from organic or inorganic acid.
5. The process as claimed in claim-4, wherein the organic or inorganic acid used is sulfuric acid or acetic acid.
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6. The process as claimed in ciaim-1, wherein the precipitation is performed at a temperature between 10 to 35°C.
7. The process according to any of the preceding claims, wherein Clopidogrel bisuifate of formula-I having the content of 98% of crystalline Form-1.