Improved Process for the Preparation of Prasugrel and its Pharmaceuticallv Acceptable Salts.

Priority Claim:

This application claims the priority of our earlier provisional application Number: 2689/CHE/2007, filed on 19thNovember 2007.

Field of the invention:

The present invention relates to an improved process for the preparation of prasugrel and its pharmaceutically acceptable salts. Prasugrel is chemically known as 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c] pyridine having structural formula-1,and its pharmaceutically acceptable salts.

According to patent literature EP542411, 2-acetoxy-5-(a-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and its derivatives thereof described as antagonists of receptors of adenosine diphosphate (ADP), exhibit excellent activity in inhibition of platelet aggregation and are useful as antithrombotic or antiembolic agents.. They are useful as medicaments (preferably useful as therapeutic or prophylactic agents) for thrombus formation-induced or embolization-induced diseases. They can be used to prevent thrombolytic cardiovascular complications in patients with recent ischemic stroke or with acute coronary syndromes. They may also be useful for reducing secondary complications, recurrent myocardial infraction, recurrent stroke and rehospitalization for severe angina. The acid addition salts of 2-acetoxy-5-(a-cyclopropylcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine i.e. prasugrel exhibit excellent oral absorption, metabolization into the active compound, low toxicity, and excellent storage and handling stability and hence useful in preparation of the medicaments which exhibit activity in inhibition of platelet aggregation.

Background of the Invention:

Analogues of prasugrel i.e., 2-acetyloxy-5-alkyl-4,5,6,7-tetrahydro thieno [3,2-c] pyridine derivatives have been initially disclosed in Japanese provisional patent publication No.I30289/1991 & 41139/1994. Prasugrel and its pharmaceutically acceptable salts have been disclosed in US patent 5,288,726. The disclosed process for the preparation of prasugrel and its pharmaceutically acceptable salts involves the acetylation of 5-(a-cyclopropyl carbonyl-2-fluorobenzy)2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine in the presence of a strong base like sodium hydride. But use of strong base like sodium hydride is not advisable when the reaction is performed at an industrial scale.
Hence there is a need to develop a process which can be performed at an industrial scale. The present invention overcomes the problems associated with the prior art, and provides a process for the preparation of prasugrel and its pharmaceutically acceptable salts, with better yields and purity.

Brief Description of Invention:

The present invention relates to an improved process for the preparation of prasugrel. The first aspect of the present invention is to provide a process for the preparation of prasugrel and its pharmaceutically acceptable salts comprises of;

a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,

with a suitable protecting group to give a compound of formula-3,

b) converting the compound of formula-3, by introducing a boronic group -B(0R')2 in position 2 to the thieno[3,2-c] pyridine skeleton through a lithium derivative, and treating it with an oxidizing agent to provide a 2-oxo-compound of general formula-4.

c) removing the protective group on nitrogen in formula-4 by treating with an acid to provide acid addition salt of the compound of general formula-5,

d) reacting the acid addition salt of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2- one of general formula-5 with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-6,

in presence of a suitable base to provide a compound of formula-7,

e) acetylating the compound of formula-7 with a suitable acetylating agent in presence of a suitable base to provide prasugrel compound of formula-1,

f) optionally converting the prasugrel into its acid addition salts by treating with a suitable acid in a suitable solvent.

The second aspect of the present invention is to provide a process for the purification of prasugrel compound of formula-1.

The third aspect of the present invention is to provide an improved process for the preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone.
Brief Description of Drawings:

Figure-1: Illustrates the powder X-ray diffraction pattern of Prasugrel Figure-2: Illustrates the powder X-ray diffraction pattern of Prasugrel fumatrate Figure-3: Illustrates the powder X-ray diffraction pattern of Prasugrel hydrochloride Figure-4: Illustrates the powder X-ray diffraction pattern of Prasugrel maleate
Detailed description of the invention
As used herein, the term "PG" refers to protective group which is selected from trityl, BOC (tert-butyloxy carbonyl) and Benzoyl.
As used herein, the term "pharmaceutically acceptable salts" refers to the salt compound formed with a suitable acid selected from an inorganic acid addition salts such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid and malic acid.

The present invention relates to an improved process for the preparation of prasugrel. Prasugrel is chemically known as 2-acetoxy-5-(a-cyclopropylcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.

In accordance with the present invention, the first aspect of the invention provides an improved process for the preparation of prasugrel compound of formula-1 and its pharmaceutically acceptable salts which comprises of; a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,
with suitable protecting agent selected from benzoyl chloride, BOC anhydride and triphenyl methyl chloride preferably triphenyl methyl chloride, in presence of a suitable base selected from a group of organic bases selected from triethylamine, tributylamine, pyridine, N-methyl morpholine or 4-dimethylamino pyridine preferably triethyl amine, in a suitable solvent is selected from dichloromethane, dichloroethane, carbon tetrachloride, dioxane, dimethyl acetamide and N-methyl pyrrolidine preferably methylene chloride, followed by crystallization from a suitable solvent selected from C5-C10 aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene.

xylene; and cyclohexane or mixtures thereof, to provide a compound of formula-3,wherein PG is a protecting group

b) converting the compound of formula-3 by introducing a boronic group -B(0R')2 using tri n-butylborate in second position of thieno[3,2-c] pyridine skeleton through a lithium derivative using n-butyl lithium in a suitable solvents like tetrahydrofuran, and then treating with oxidizing agent like hydrogen peroxide, followed by crystallization from a suitable solvent selected from C5-C10 aliphatic hydrocarbons like hexane, heptane; aromatic hydrocarbon solvents like toluene, xylene; and cyclohexane or mixtures thereof, to provide a compound of formula-4,

wherein PG is a protecting group;

c) removing the protecting group on nitrogen compound of formula-4 by treating it with a suitable acid selected from inorganic acids such as hydrobromic acid, phosphoric acid or an organic acid such as benzene sulfonic acid, p- toluenesulfonic acid, succinic acid, fumaric acid, maleic acid oxalic acid preferably p-toluene sulfonic acid, in a suitable solvent selected from dichloromethane,l,2-dichloroethane, toluene, isopropyl alcohol, ethanol, acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate, propyl acetate and acetonitile, to provide the acid addition salt compound of formula-5,

d) reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid addition salt compound of formula-5 with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-6.

in presence of suitable base selected from a group consisting of alkali metal carbonates like sodium carbonate, potassium carbonate; or an alkali metal hydroxide like sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; or an organic base like triethylamine, tributylamine, diisopropylethlyamine preferably sodium carbonate, in a suitable solvent selected from diisopropylether, tetrahydrofuran, dimethylformamide, dimethoxy ethane, diethyl ketone, propyl acetate, butyl acetate, and propionitrile preferably dimethylformamide, to provide compound of formula-7,

e) acetylating the compound of formula-7 in presence of a suitable acetylating agent like acetic anhydride in a suitable organic solvent selected from diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide preferably acetonifrile, in presence of a suitable organic base selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethylamine preferably triethylamine to provide the compound of formula-1,

f) optionally converting the prasugrel into its acid addition salt by treating it with a suitable acid selected from an inorganic acid such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid,oxalic acid, fumaric acid, succinic acid and malic acid, in a suitable solvent selected fi-om aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether, or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohol like isopropyl alcohol; or nitriles like acetonitrile and propionitrile or mixtures thereof to provide an acid addition sah of prasugrel.

The second aspect of the present invention provides a process for the preparation of prasugrel compound of formula-1, which comprises of the following steps;

a) dissolving prasugrel in a suitable ester solvent like ethyl acetate, methyl acetate, isopropyl acetate by heating to reflux temperature,

b) stirring the reaction mixture for 1 hour at reflux,

c) adding suitable anti-solvent selected from hydrocarbon solvent such as cyclohexane, heptate at 55-60°C,

d) stirring the reaction for an hour at reflux,

e) cooling the reaction mixture to 0-5°C,

f) filtering the solid and washing it with a suitable hydrocarbon solvent,

g) drying the solid to provide highly pure prasugrel.

Third aspect of the present invention is to provide an improved process for the preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone, which comprises of treating 1 gram equivalent of 2-fluorobenzyl bromide with magnesium metal in 15 volumes of diethyl ether to provide 2-fluorobenzyl magnesium bromide, which is condensed in-situ with cyclopropyl cyanide in diethylether to provide highly pure 1- cyclopropyl-2-(2-fluorophenyl)ethanone.
l-cyclopropyl-2-(2-fluorophenyl)ethanone, the key intermediate in the synthesis of prasugrel is prepared by the condensation of 2-fluorobenzyl bromide with cyclopropyl cyanide by Grignard reaction using magnesium metal in diethyl ether. This reaction has been disclosed as a reference example-1 in US patent 6693115. When experiments were conducted as per the above reference example, provided the product with 50% purity by Gas chromatography. Hence further research was carried out in order to improve the quality and yields of the said intermediate. It was found that, when the ratio of diethyl ether volume was increased with respect to the starting material i.e., 2-fluorobenzyl bromide, there was a substantial increase in the yields and quality of the product formed. When 15 times of diethyl ether was taken for 1 gram equivalent of 2-flourobenzyl bromide, the purity of the l-cyclopropyl-2-(2-fluorophenyl)ethanone was enhanced to 85 % by GC.

5-(a-Cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno [3, 2-c] pyridine(formula-7) is in equilibrium with its enolic form which is represented below.

The present invention is schematically represented as follows;

The impurities observed and controlled by the present invention are 2-(a- cyclopropylcarbonyl-2-fluorobenzyloxy)-5H-4,5,6,7-tetrahydrothieno[3,2-c]pyridine designated as IMP-1, 2-(a-cyclopropylcarbonyl-2-fluorobenzyloxy)-5-(a- cyclopropylcarbony-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine design¬ated as IMP-2, 2-(a-cyclopropylcarbonyl-2-fluorobenzyloxy)-5-acetoxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine designated as IMP-3, 5-(5-chloro-l-(2- fluorophenyl)-2-oxopentyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl-acetate desig -nated as IMP-4, 6-(2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-2-yl acetate designated as IMP-5, 5-(5-chloro-l-(2- fluorophenyl)-2-oxopentyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one designated as IMP-6, have the following structures:

The formation of these impurities during the preparation of prasugrel and its acid addition sahs have been depicted in Scheme-II and Scheme-III.

The invention controls and minimizes the formation of these impurities by using specific reagents and specific reaction conditions.
The process disclosed in US Patent No 5,288,726 involves the coupling of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one hydrochloride with 2-fluoro-a- cyclopropyl carbonylbenzyl bromide yielding 32% of 5-(a-cyclopropylcarbonyl-2- fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine. When the reaction was carried out it was observed that debromination of 2-fluoro-a-cyclopropyl carbonylbenzyl bromide took place which led to the poor yield of the coupling product.

Another process disclosed in US Patent No.5,874,581 involves converting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one to 'O' protected ,2-(trialkly silyloxy)-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridine salt and subsequently condensing with 2-fluoro-a-cyclopropyl carbonylbenzyl bromide. The condensed product has to be deprotected and then acetylated to obtain prasugrel, which involves multiple steps and decrease in the yields.
In our process of the present invention involves coupling of organic salt of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one (formula-5) with 2-fluoro-a- cyclopropyl carbonylbenzyl bromide. The reaction was carried out using sodium carbonate in tetrahydrofuran, prevented debromination of 2-fluoro-a-cyclopropyl carbonylbenzyl bromide which increases the yield of condensed product.

The reaction conditions also prevented 'O' alkylation which controlled the formation of impurities viz. IMP-1 and IMP-2 fi-om being formed. The decrease in formation of impurity IMP-1 is manifest in the decrease of N-acetylated impurity IMP-3 in the step involving acetylation of compound of formula-7 to yield prasugrel.

In prior art the step involving acetylation of compound of formula -7 to obtain prasugrel, strong base like sodium hydride was used along with acetic anhydride which may lead to the deacetylation of the prasugrel formed, to give back the starting material i.e. compound of formula-7 which may be the major reason for the decrease in the yields of prasugrel obtained. In the present invention an organic base is used in this step i.e., triethylamine or diisopropylamine which controlled the deacetylation, and hence there was an increase in the yield of prasugrel formed as well as decrease in the quantity of compound of formula-7 as an impurity.

The impurity designated as IMP-5 is formed due to the presence of isomer 4,5,6,7-tetrahydrothieno[2,3-c]pyridine in the starting material i.e. 4,5,6,7- tetrahydrothieno[3,2-c] pyridine(formula-2), which undergoes the same sequence of reactions to form IMP-5.
In the present invention the organic acid addition salts of prasugrel have been prepared which were found to be substantially free of the impurities mentioned above. Hence they can be used directly in the preparation of the medicament or can optionally be converted to its hydrochloride salt or maleate salt of high purity.

The impurities can be synthesized in pure form by methods as illustrated in Scheme-IV.
It is observed that the sahs of API's generally are hygroscopic and absorb moisture on storage for long periods. Hence to increase the stability and shelf life, special packing conditions were employed.

A process for packing and storage of prasugrel hydrochloride comprises of the following steps:

a) placing prasugrel salt in a clear polyethylene bag and tied with a thread,

b) placing the primary packing containing prasugrel salt, inside a black color polyethylene bag and sealing it,

c) placing the above double polyethylene bag inside a triple laminated bag,

d) placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container

The oxygen busters can be used inside the black color polyethylene bag and a triple laminated bag.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-l: Preparation of 5-triphenylmethyI-4,5,6,7-tetrahydrothieno[3^- c] pyridine:
To a solution of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine (100 grams) in dichloromethane (200 ml) added triethylamine (80 ml). A solution of triphenylmethyl chloride (95.2 grams) in dichloromethane (100 ml) was added drop wise, at 0-5 °C over a period of 1 hr. The reaction medium was maintained at 0-5°C for 16 hrs and then poured it into water (200 ml). The aqueous and the organic layers were separated; the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The compound was isolated using cyclohexane to obtain white crystalline solid.

Yield: 240 grams; Melting range: 163-165° C
Exaniple-2: Preparation of 5-benzoyl-4,5,6,7-tetrahydrothieno[3^-c] pyridine.

To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 grams) in dichloromethane (30 ml) added triethylamine (10 ml). A solution of benzoyl chloride (10 grams) in dichloromethane (20 ml) was added drop wise, at 0-5 °C over a period of 1 hr. The reaction medium was maintained at 0-5°C for 16 hrs and then is poured into ice cold water (50 ml). The aqueous and the organic layers were separated, the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The compound was isolated using cyclohexane to obtain white crystalline solid.

Yield: 14.0 grams

Example-3: Preparation of 5-t-butyioxycarbonyl-4,5,6,7-tetrahydrothieno[3^- c] pyridine.
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 grams) in dichloromethane (30 ml) added triethylamine (10 ml). A solution of BOC anhydride (16 grams) in dichloromethane (30 ml) was added drop wise at 0-5°C over a period of 1 hr. The reaction medium was maintained at 0-5°C for duration of 15 hrs and then is poured it into ice cold water (50 ml). The aqueous and the organic layers were separated; the organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. The compound was isolated using cyclohexane to obtain white crystalline solid. Yield: 14.5 grams

ExampIe-4: Preparation of 5-triphenyImethyl-5,6,7,7a-tetrahydro-4H- thieno [3.2-c]2-py ridone.

To a solution of 5-triphenylmethyl-4,5,6,7-tetrahydro thieno [3,2-c] pyridine (50 grams) in tetrahydrofuran (1000 ml), added a solution of butyl lithium (142.81 ml, 2.3 M solution in hexane) drop wise at 0° C. The mixture was maintained at 10-15° C for Ihr. The reaction mass was cooled to -20°C and charged with tri-n-butyl borate. The reaction mass was maintained at this temperature for 1.5 hrs, further cooled to -40 ° C and charged with aqueous hydrogen peroxide (45.0 ml, 30% (v/v)). The reaction mixture was stirred for 1 hour at room temperature and quenched with water. The reaction mixture was extracted with dichloromethane. The organic extraction phase was washed with water and dried over sodium sulfate. Evaporation of the solvent to dryness and isolation in cyclohexane provided the title compound. Yield: 36.0 grams

Example-5: Preparation of 5-benzoyl-5,6,7,7a-tetrahydro-4H-thieno[3.2-c]2- pyridone.
To a solution of 5- benzoyl-4, 5, 6, 7-tetrahydrothieno[3, 2-c] pyridine (5 grams) in tetrahydrofuran (60 ml), added a solution of butyl lithium (10ml, 2.3 M solution in hexane) drop by drop at 0° C. The mixture was maintained at 10-15° C for Ihr. The reaction mass was cooled to -20°C and charged with tri-n-butyl borate. The reaction mass was maintained at this temperature for 1.5 hrs, further cooled to -40 ° C and charged with aqueous hydrogen peroxide (45.0 ml, 30% (v/v)). The reaction mixture was stirred for 1 hour at room temperature and quenched with water. The reaction mixture was extracted with dichloromethane. The organic extraction phase was washed with water and dried over sodium sulfate. Evaporation of the solvent to dryness and isolation in cyclohexane provided the title compound. Yield: 3.0 grams
Example-6: Preparation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p-toluene sulfonate.
A mixture of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one (15.0 grams), p-toluenesulfonic acid monohydrate (7.4 grams) and tetrahydrofuran (200 ml) was stirred at 50° C for 2 hours. The precipitated solid was filtered, washed with 30 ml of tetrahydrofuran and then dried to obtain 5,6,7,7a-tetrahydro-4H-
thieno[3,2-c]-pyridin-2-onep-toluenesulfonate.
Yield: 10.0 grams

Example-7: Preparation of 5,6,7,7a-tetrahydro-4H-thieno[3;2-c]-pyridin-2-one benzene sulfonate.
A mixture of 5-benzoyl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one (5.0 grams) in isopropyl alcohol added aqueous sodium hydroxide (3 grams dissolved in 40 ml of water) and heated to 80°C for two hrs. Cooled the reaction mixture to 25° C and adjusted the pH to 6 using hydrochloric acid, extracted the reaction mixture with dichloromethane and concentrated. The residue obtained was dissolved in isopropyl alcohol (50 ml) and benzene sulfonic acid (3 grams) was added and stirred at 40-50° C for 2 hours. The precipitated solid was filtered, washed with isopropyl alcohol (10 ml) and then dried to obtain 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]-pyridin-2-one benzene sulfonate. Yield: 4.0 grams

Example-8: Preparation of 5-(a-CyclopropylcarbonyI-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine.
To a solution of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one benzene sulfonate (5.0 grams) in tetrahydrofuran (50 ml), added 2-fluoro-a-cyclopropyl carbonylbenzyl bromide (3.5 grams) and sodium carbonate (3.5 grams).The resuUing mixture was stirred at 0-5° C for 5 hours. The reaction mixture was quenched with water and ethyl acetate was added to the reaction mixture. Aqueous and organic layers were separated. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated to dryness. The title compound was obtained as brown oil. Yield: 1.4 grams
Exaniple-9: Preparation of 2-Acetoxy-5-(a-cyclopropyicarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.

To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (0.5 grams) dissolved in a mixture of acetonitrile (10 ml) and acetic anhydride(3 ml), added diisopropylethyl amine (3ml). The mixture was then stirred for 20 minutes at the 10- 15°C temperature, after which it was stirred for a further 3 hours at 25-30°C temperature. Ethyl acetate (20 ml) was added to the mixture, which was then washed four times, each time with 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to give yellow oil. This oil was crystallized from diisopropyl ether, to obtain the title compound as white crystals, melting at 120-123° C. ' H NMR (CDClj) 6ppm: 0.81-0.94 (2H, m), 1.03-1.08 (2H, m), 2.21-2.34 (4H, m), 2.79-2.94 (4H, m), 3.52-3.56 (2H, m), 4.88 (IH, s), 6.26 (IH, s), 7.10-7.49 (4H, m) Mass (CI, m/z): 374 (M^" +1), 331, 206, 177; Yield: 0.31 grams

Example-10: Preparation of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine fumarate.
To a solution of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydrothieno[3, 2-c] pyridine (5 grams) in isopropyl alcohol( 50ml) added drop wise a solution of fumaric acid (1.5 grams) in isopropyl alcohol (20ml) with constant stirring at 25° C the mixture was stirred for 2 hrs at 60-65° C. The reaction mixture was cooled to 20-25° C. The crystals obtained were filtered, washed with isopropyl alcohol (10 ml) and dried to obtain the title compound as crystalline solid. M. R: 218-220° C. Yield: 5.5 grams

Example-ll: Preparation of 2-Acetoxy-5-(a-cyclopropyicarbonyI-2- fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride.
To a solution of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydrothieno[3,2-c] pyridine fumarate (5 grams) in water (50 ml) added sodium carbonate (3.5 grams) and stirred the solution for one hour. At the end of this time, ethyl acetate was added to the mixture. Aqueous and organic layers were separated. To the organic layer added drop wise a solution of hydrochloric acid (36 %, 1.5 grams)in ethyl acetate, with constant stirring at 20° C over a period of one hour and after the addition completion of addition the mixture was further stirred for one hour at the same temperature. The crystals obtained were filtered, washed with ethyl acetate (20 ml) and dried to obtain the title compound as white crystalline solid. Yield: 6.5 grams
Example-12: Preparation of S-triphenylmethyl 4,5,6,7-tetrahydro thieno[3,2-c] pyridine:
Triethylamine (181 ml) was added to a mixture of 4,5,6,7-tetrahydrothieno [3,2-c]pyridine hydrochloride (100 grams) and dichloromethane (220 ml) at 0-5°C. A solution of triphenyl methylchloride (151 grams) in dichloromethane (250 ml) was added drop-wise at 0-5°C over a period of 1 hour and then stirred for 9 hours. The reaction mixture was filtered and the solid washed with methylene chloride. The filtrate washed with water and the aqueous and organic layers were separated. The organic layer was dried over sodium sulphate and then distilled off the solvent. Cyclohexane (75 ml) was added to the obtained residue and cooled to 0-5°C then stirred for 1 hour. The separated solid was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 172 grams; M.R: 162-164°C

Example-13: Preparation of 5-triphenylmethyl-5,6,7,7a-tetrahydro-4H- thieno [3.2-c]2-py ridone.

A solution of butyl lithium (139 ml, 1.6 M solution in hexane) was added to a solution of 5-triphenylmethyl-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine (50 grams) in tetrahydrofuran (1000 ml) was added drop-wise at 0-5°C under nitrogen atmosphere and stirred for an hour at 10-15° C. The reaction mixture was cooled to 0-5°C and trin-butylborate (90 grams) in tetrahydrofuran (75 ml) was added then stirred for 2 hours. Aqueous hydrogen peroxide (45.0 ml, 30% (v/v)) was added and then stirred for 2 hours at 25-30°C. The reaction mixture was quenched with water and then extracted with methylene chloride. The methylene chloride layer was distilled under reduced pressure. Cyclohexane (30 ml) was added to the obtained residue and stirred for 30 minutes. The separated solid was filtered, washed with cyclohexane and then dried at 50°C to get the title compound. Yield: 38 grams
£xample-14: Preparation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p-toluene sulfonate:

A mixture of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one (110 grams), p-toluenesulfonic acid (52.6 grams) and tetrahydrofuran (1100 ml) was heated to 60-65°C and stirred for 3 hours. Then the reaction mixture was cooled to 0-5°C and stirred for 30 minutes. The precipitated solid was filtered, washed with tetrahydrofuran and then dried to get the title compound. Yield: 86 grams M.R: 195-196°C

Example-15: Preparation of 5-(o-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine.
2-fluoro-a-cyclopropyl carbonyl benzyl bromide (3.5 grams) was added to a mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p-touenesulfonate (5.0 grams) and sodium carbonate (3.5 grams) in dimethylformamide (80 ml) at 0-5 °C and stirred for 3 hours. The reaction mixture was quenched with water and then extracted it with methylene chloride. The methylene chloride washed with water and organic and aqueous layers were separated. The methylene chloride from the organic layers was distilled off completely and the obtained residue purified using cyclohexane and ethyl acetate to provide the title compound. Yield: 1.4 grams

Example-16: Preparation of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine.
The title compound is prepared analogues manner to example-l5 using the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one hydrochloride in place of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one p-touenesulfonate. Yield: 1.25 grams

ExampIe-17: Preparation of Prasugrel:
Triethylamine (53.5 grams) was added to a mixture of 5-(a-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (50 grams) and acetonitrile (350 ml) at 0-5°C. Acetic anhydride (50 ml) was added drop-wise to the reaction mixture at 0-5°C and then stirred for 3 hours at 25-30°C. The reaction mixture was quenched with water and then extracted it with ethyl acetate. The ethyl acetate layer washed with sodium chloride followed by water. The ethyl acetate layer dried over sodium sulphate and then distilled off the solvent completely. Cyclohexane and ethylacetate was added to the obtained crude and cooled to 0-5°C. The reaction mixture was stirred for 90 minutes at 0-5°C. The solid was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 28.7 grams: Purity: 96.5% HPLC
ExampIe-18: Preparation of 5-(a-cycIopropylcarbonyl-2-fluorobenzyI)-2-oxo- 2,4,5,6,7,7a-hexabydrothieno[3,2-c] pyridine.
2-fluoro-a-cyclopropyl carbonyl benzyl bromide (3.5 grams) was added to a mixture of 5,6,7,7a-tetr^ydro-4H-thieno[3,2-c]-pyridin-2-one(5.0 grams) and sodium carbonate (2.0 grams) in dimethylformamide (80 ml) at 0-5°C and stirred for 3 hours. The reaction mixture was quenched with water and then extracted it with methylene chloride. The methylene chloride washed with water and organic and aqueous layers were separated. The methylene chloride from the organic layers was distilled off completely and the obtained residue purified using cyclohexane and ethyl acetate to provide the title compound. Yield: 3.5 grams

Reference Example: Preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone
To a suspension of magnesium powder (7.2 g) in anhydrous diethyl ether (60 ml) was added a solution of 2-fluorobenzylbromide (30 ml) in diethyl ether (30 ml), then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of cyclopropyl cyanide (18.2 ml) in diethylether (120 ml) over 100 minutes. After stirring for 30 minutes at room temperature the stirred mixture was heated under reflux for 1 hour. After the reaction, the reaction mixture was partitioned between ethylacetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed successively with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfite, and then evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene as the eluant to afford the desired product (23 g containing solvent) as a yellow liquid.

ExampIe-18: Preparation of l-cycIopropyI-2-(2-fluoropbenyl)ethanone l-(bromomethyl)-2-fluorobenzene (100 grams) in diethylether (500 ml) was added to a suspension of magnesium metal (14 grams) in diethyl ether (500 ml) under nitrogen atmosphere 25-30°C. The reaction mixture was stirred for 30 minutes at 25-30°C and cyclopropyl cyanide (42 grams) in diethyl ether (500 ml) was added. The reaction mixture was heated to reflux temperature and stirred for 4 hours. The reaction mixture was quenched with ammonium chloride. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water followed by 10% sodium carbonate and then with sodium chloride solution. The ethyl acetate layer was distilled off completely under reduced pressure. Yield: 80 grams; Purity: 85% by GC

The above obtained residue can be further purified by distillation under reduced pressure
Exaniple-19: Preparation of 2-fluoro- a-cyciopropyl carbonyl benzyl bromide

A mixture of l-cyclopropyl-2-(2-fluorophenyl)ethanone (40 grams), chloroform (400 ml), N-bromo succinamide (50 grams) and benzoylperoxide (0.6 gram) was heated to reflux temperature and stirred for 6 hours. The reaction mixture was cooled to 25-30°C and then filtered and the solid washed with chloroform. The filtrate washed with water and then distilled off the filtrate under reduced pressure. The residue was cooled to 25-30°C and extracted the product with cyclohexane. The extracted layer was distilled under reduced pressure to get the title compound. Yield: 45 grams;

Example-20: Purification of Prasugrel:
A mixture of prasugrel (52 grams) and ethyl acetate (75 ml) was heated to 60-65°C to get a clear solution. The reaction mixture was stirred for an hour at 60-65°C. cyclohexane (75 ml) was added to the reaction mixture at 60-65°C and stirred for an hour. The reaction mixture was cooled to 0-5 °C and stirred for an hour. The solid obtained is filtered, washed with cyclohexane and then dried to get high pure prasugrel.

Yield: 35 grams; Purity: 99.90% by HPLC
£xample-21: Purification of Prasugrel:
A mixture of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c] pyridine fumarate (5 grams) and ethyl acetate and aqueous sodium carbonate was stirred for 30 minutes. The aqueous and organic layers were separated. The combined organic layer was washed with water and distilled the organic layer completely under reduced pressure and isolated pure prasugrel as a solid prasugrel.
Yield: 2 grams; 99.89% by HPLC

Method of Analysis:

The related substance of prasugrel was analyzed by HPLC using the following conditions: Column: Hypersil BDS, 250 X 4.6 mm or equivalent; Flow rate: 0.8 ml/min; wavelength:240 nm ; Temperature: 40°C; Load: 20 jil; Run time: 3 times of the main peak; diluent: acetonitrile; mobile phase: 40:60 v/v of buffer and acetonitrile.

The related substance of l-cyclopropyl-2-(2-fluorophenyl)ethanone was analyzed by Gas chromatography using the following conditions: Column: DB-1 or equivalent; Length: 30mts. ID:0.53mm; Film thickness:l.O^im; carrier gas: Helium; Flow rate: 3.0Psi; Injector mode: Split ratio 1:50; Injector temperature: 220°C; Detector temp.: 260°C and Injection volume: 0.2

We claim:

I. An improved process for the preparation of prasugrel compound of formula-1,

and its pharmaceutically acceptable salts thereof;

Which comprises of:

a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts, Formula-2

with a suitable amino protecting agent to provide a compound of formula-3,

b) converting the compound of formula-3 into 2-oxo compound of formula-4, by introducing a boronic group -B(0R')2 with suitable borate compound in second position to the thieno[3,2-c] pyridine skeleton through a suitable lithium derivative, and then treating it with an oxidizing agent,

c) removing the protecting group on nitrogen in compound of formula-4 by treating with suitable acid to provide corresponding salt compound of general formula-5,

d) reacting the salt compound of general formula-5 with a-cyclopropylcarbonyl-2- fluorobenzyl bromide compound of formula-6 in presence of a suitable base in a suitable solvent to provide a condensed compound of formula-7,

e) acetylating the compound of formula-7 with a suitable acetylating agent in presence of a suitable base in a suitable solvent to provide prasugrel compound of formula-1,

f) treating the prasugrel with suitable acid in a suitable solvent to provide an acid addition salt of prasugrel.

2. A process of claim 1, comprise of any one of the following steps;

i) a step a) wherein the suitable protecting agent is selected from benzoylchloride, BOC anhydride and triphenyl methyl chloride; and the base is organic base selected from triethylamine, tributylamine, pyridine, N-methyl morpholine and 4-dimethylamino pyridine; and a suitable solvent is inert solvent selected from dichloromethane, dichloroethane, carbon tetrachloride, dioxane, dimethyl acetamide and N-methyl pyrrolidine;

ii) a step b) wherein the boronic group is tri,n-butylborate; and the lithium derivative is n-BuLi; and the suitable solvent is tetrahydrofuran; and a suitable oxidizing agent is hydrogen peroxide;

iii) a step c) wherein the suitable acid is selected from an inorganic acid like hydrobromic acid and phosphoric acid; an organic acid such as benzene sulfonic acid, p-toluenesulfonic acid, succinic acid, fumaric acid, maleic acid and oxalic acid; and the suitable solvent is selected from the group comprising of dichloromethane, 1,2-dichloroethane, toluene, isopropyl alcohol, ethanol, acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate, propyl acetate and acetonitile or mixtures thereof;

iv) a step d) wherein the suitable base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate; or a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; or an organic base such as triethylamine, tributylamine and diisopropylethlyamine; and the suitable solvent is selected from diisopropylether, tetrahydrofuran, dimethyl formamide, dimethoxy ethane, diethyl ketone, propyl acetate, butyl acetate, and propionitrile or mixtures thereof;

v) a step e) wherein the suitable acetylating agent is acetic anhydride; and the suitable base is an organic base selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropyl ethylamine; and the suitable solvent is selected from diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof;

vi) a step f) where in the suitable acid addition salt is selected from an inorganic acid such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, malic acid and succinic acid; and the suitable solvent is selected from diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof;

3. An improved process for the preparation prasugrel hydrochloride compound of formula-la, which comprises of;

a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride compound of formula-2a,

with triphenylmethyl chloride in presence of triethylamine in methylene chloride, followed by crystallization using cyclohexane to provide a compound of formula-3 a.


b) reacting the compound of formula-3 a with tri n-butylborate in presence of n-butyl lithium in tetrahydrofuran followed by treatment with hydrogen peroxide to provide the 2-oxo compound of formula-4a,

c) deprotecting the tritylprotecting group by treating it with p-toluene sulfonic acid to provide p-toluene sulfonic acid salt compound of formula-5a,

g) reacting the p-toluene sulfonic acid salt compound of formula-5a with a-cyclopropylcarbonyl-2-flurobenzyl bromide compound of formula-6 in presence of sodium carbonate in dimethylformamide to provide a condensed compound of formula-7,

h) acetylating the compound of formula-7 with acetic anhydride in presence of triethyl amine in acetonitrile to provide prasugrel compound of formula-1,

i) treating the prasugrel with hydrochloric acid in a suitable solvent to provide an acid addition salt of prasugrel.

4. A process for the preparation of prasugrel compound of formula-1, which comprises of acetylating the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of formula-7 with suitable acetylating agent in presence of an organic base and in a suitable solvent.

5. A process of claim 4, where in suitable acetylating agent is selected either acetic anhydride or acetyl chloride; and a suitable organic bases is selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine; and a suitable solvent is selected from diethyl ether, tefrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof.

6. A process for the preparation of high pure prasugrel compound of formula-1, which comprises of treating the acid addition salts of prasugrel with a suitable base in a suitable solvent.

7. A process according to claim 6, wherein acid addition salt is selected from an inorganic acid such as hydrochloric acid, hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid and succinic acid and malic acid; and a suitable base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate; or a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and a suitable solvent is selected from ester solvent like ethyl acetate, methyl acetate, isopropylacetate; chloro solvents like methylene chloride; hydrocarbon solvents like cyclohexane, hepatane or mixtures thereof.

8. A process for the preparation of compound of formula-7

Which comprises of reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2- one or its p-toluene sulfonate salt with a-cyclopropylcarbonyl-2-flurobenzyl bromide compound of formula-6 in presence of suitable base selected from alkali metal carbonates such as sodium carbonate, potassium carbonate; or a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; or an organic base such as triethylamine, tributylamine and diisopropylethlyaminesodium carbonate in dimethylformamide; and in a suitable solvent selected from diisopropylether, tetrahydrofuran, dimethyl formamide, dimethoxy ethane, diethyl ketone, propyl acetate, butyl acetate, and propionitrile or mixtures thereof.

9. A process for the preparation of l-cyclopropyl-2-(2-fluorophenyl)ethanone, which comprises of treating 1 gram equivalent of 2-fluorobenzyl bromide with magnesium metal in 15 volumes of diethyl ether to provide 2-fluorobenzyl magnesium bromide, which is condensed in-situ with cyclopropyl cyanide in diethyl ether to provide high pure l-cyclopropyl-2-(2-fluorophenyl)ethanone.

10. A process for the purification of prasugrel compound of formula-1, which comprises of the following steps;

a) dissolving prasugrel in a suitable ester solvent like ethyl acetate by heating to reflux temperature,

b) stirring the reaction mixture for 1 hour at reflux,

c) adding suitable anti-solvent like cyclohexane at 55-60°C,

d) stirring the reaction for an hour at reflux,

e) cooling the reaction mixture to 0-5°C,

f) filtering the solid and washing it with cyclohexane,

g) drying the solid to provide highly pure prasugrel.