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
"Synthesis of Prasugrel"
2. Applicant(s)
Name Nationality Address
USV Limited Indian company incorporated Arvind vithal Gandhi Chowk. B.S.D. Marg. Govandi.
under Companies Act 1956 Mumbai-400 088, 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 substantially pure Prasugrel or pharmaceutically acceptable salt thereof. The present invention further relates to a process for obtaining 2-Fluorobenzyl alcohol. 2-Fluorotoluene or 2-Fluorobenzyl cyanide substantially free from impurities, including isomeric impurities.

Prasugrel is chemically known as 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. Prasugrel is marketed as Prasugrel hydrochloride by Daiichi Sankyo Inc. and Eli Lilly and Company, under the brand name Effient®. Prasugrel acts as an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. Prasugrel hydrochloride is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI). Effient® has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (MI) or nonfatal stroke compared to Clopidogrel.
Effient® is available for oral administration as 5mg or l0 mg elongated hexagonal, film-coated, non-scored tablets, debossed on each sides. The treatment with Effient® is initiated with a single 60mg oral loading dose and then continued at l0 mg orally once daily. Patients taking Effient® have to take aspirin (75mg and 325mg) daily. Effient® may be administered with or without food.
Background of the invention:
US6452056 describes the process for preparation of Fluorobenzyl derivatives. This document also teaches that Fluorobenzyl alcohols produced by hydrolysis of the corresponding Fluorobenzyl amines may be purified. A purification method is mentioned wherein the crude reaction solution after the completion of hydrolysis is extracted with the

organic layer, followed by distillation under reduced pressure of a level from 200 mmHg to 0.01 mmHg. However, this document does not mention regarding the closely boiling compounds such as 3-Fluorobenzyl alcohol. 4-Fluorobenzyl alcohol or des-Fluorobenzyl alcohol (benzyl alcohol) which may be present in 2-Fluorobenzyl alcohol and methods of removing the same.
Olah et al, Journal of Organic Chemistry vol. 22 (1957), p. 879-881 discloses the separation of isomers of Fluorobenzyl cyanide by fractional distillation. However, the temperature and pressure conditions used for fractional distillation are not disclosed. In the process disclosed in this document, the distillation appears to be carried out at atmospheric pressure, where there is a high likelihood of 2-Fluorobenzyl cyanide getting exposed to air resulting in the formation of acid impurities.
US5288726 discloses Prasugrel and pharmaceutically acceptable salts thereof. The process disclosed in this document involves reaction of 2-Fluorobenzyl bromide with Cyclopropy) cyanide in the presence of magnesium and ether to provide cyclopropyl-2-fluorobenzyl ketone. The same is used as an intermediate in the preparation of Prasugrel. The disadvantage of this process is that the yield and purity of the intermediates and final compound are not satisfactory. It also involves the use of column chromatography for isolation of intermediates as well as final compound. Besides it involves the use of strong base like sodium hydride. This document does not discuss regarding the purification of starting materials such as 2-Fluorotoluene, 2-Fluorobenzyl alcohol or 2-Fluorobenzyl cvanide.
US5874581 describes a process for preparation of Prasugrel using alkyl-silyl protected tetrahydrothienopyridine intermediate. This process involves reaction of 2-Fluorophenyl acetic acid with ethyl cyclopropane carboxylate in presence of isopropyl magnesium bromide to provide CycIopropyl-2-fluorobenzyi ketone, which is reacted with sulfuryl chloride to yield 2-FIuoro-a-(cyclopropylcarbonyl) benzyl chloride. The obtained compound is condensed with alkyl-silyl protected tetrahydrothienopyridine compound in presence of triethylamine to yield 2-(tert-butyldimethylsilyloxy)-5-[a-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, which is finally reacted with acetic anhydride in presence of triethyl amine and dimethyl amino pyridine (DMAP)

to yield Prasugrel. However, this document does not discuss regarding the purification of starting materials such as 2-Fluorotoluene, 2-Fluorobenzyl alcohol or 2-Fluorobenzyl cyanide.
WO2012018791 describes a process for preparing Prasugrel or a pharmaceutically acceptable salt thereof having less than about 0,1% of des-Fluoro impurity, 3-Fluoro impurity or 4-Fluoro impurity comprising purifying 2-Fluorophenyl acetic acid so the concentration of 3-Fluorophenyl acetic acid. 4-Fluorophenyl acetic acid or2-Phenyl acetic acid is less than about 0.1%. This document teaches that 2-Fluorophenyl acetic acid may be purified by any method such as recrystallization, reprecipitation, slurring in a solvent or chromatography. This document teaches that 2-Fluorophenyl acetic acid can also be purified by converting to its salt followed by neutralization with an acid to produce the free base of 2-Fluorophenyl acetic acid.
WO2009066326 discloses an improved process for preparation of l-Cyclopropyl-2-(2-fluorophenyl)ethanone, key intermediate in the synthesis of Prasugrel. This document discloses that when experiments were conducted as per the reference example in US6693115. the product obtained is 50 % pure by Gas chromatography. It further teaches that when Grignard reaction was carried out using higher dilution of diethyl ether solvent 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. It was observed that the concentration of the dimer impurity had decreased substantially. The major impurity discussed in this document is 2-Fluorobenzyl dimer impurity. However, it does not disclose regarding the purification of starting materials such as 2-Fluorotoluene, 2-Fluorobenzyl alcohol or 2-Fluorobenzyl cyanide.
WO2009062044 discloses processes for the preparation of Prasugrel and pharmaceutically acceptable salt thereof. It further discloses that Cyclopropyl-2-fluorobenzyl ketone may be purified using suitable purification technique such as crystallization, making a slurry, extractions into a suitable solvent, fractional distillation techniques, or a combination thereof, to provide purity greater than 80% by weight as determined by HPLC. However, it does not disclose regarding the purification of starting materials such as 2-Fluorotoluene, 2-Fluorobenzyl alcohol or 2-Fluorobenzyl cyanide.

WO2012001486 discloses an improved process for the preparation of Prasugrel hydrochloride and its intermediates. This document teaches that Cyclopropyl-2-fluorobenzyl ketone is purified by High Vacuum Distillation. However, it does not disclose regarding the purification of starting materials such as 2-Fluorotoluene, 2-Fluorobenzyl alcohol or 2-Fluorobenzyl cyanide.
Even though many of the prior art documents discussed above discloses the process for obtaining pure Prasugrel, there still exists a need to develop a process for preparation of Prasugrel or pharmaceutically acceptable salts thereof substantially free of impurities, including isomeric impurities. The process of the present invention aims at controlling the impurities at the early stages of the process thereby ensuring the desired yield and purity of the final product. The present invention provides a cost-effective, simple and industrially viable process for preparation of substantially pure Prasugrel or pharmaceutic ally acceptable salt thereof.
Object of the present invention:
An object of the present invention is to provide a cost effective, simple and industrially viable process for preparation of substantially pure Prasugrel or pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a process for obtaining 2-Fluorobenzyl alcohol, 2-Fluorotoluene or 2-Fluorobenzyl cyanide substantially free from impurities, including isomeric impurities.
Another object of the present invention is to provide Prasugrel or pharmaceutically
acceptable salt thereof substantially free of impurity selected from the group consisting of
3-Fluoro-isomer, 4-Fluoro-isomer, 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-
2.4,5,6.7,7a-hexahydrothieno[3,2 -cjpyridine, 2-Acetoxy-5-[α-(cyclopropylcarbonyI)
benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (des-Fluoro impurity). 6-[(lRS)-2-cyclo propyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2.3-c]pyridin-2-yl acetate (Positional isomer). 2-Acetoxy-5-[α-(5-chloro-l-oxopentyl)-2-fluorobenzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 2-[α-Cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4.5,6,7 tetrahydrothienopyridine (N-acetyl impurity).

Summary of the invention:
According to one aspect of the present invention, there is provided a process for preparation of Prasugrel or pharmaceutically acceptable salt thereof comprising the steps
of.
a) subjecting 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene to purification to obtain 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene substantially free of closely boiling impurities; and
b) converting said 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene to Prasugrel or pharmaceutically acceptable salt thereof.
Preferably, said closely boiling impurities are selected from 3-Fluoro impurity, 4-Fluoro impurity or des-Fluoro impurity. Preferably, said purification is carried out by High Vacuum Fractional Distillation.
Another aspect of the present invention provides High Vacuum Fractional Distillation of said 2-Fluorobenzyl cyanide using a fractionating column at a temperature of about 110 to 120°C and pressure of about 0 mmHg to 10 mmHg; High Vacuum Fractional Distillation of said 2-Fluorobenzyl alcohol using a fractionating column at a temperature of about 90 to 100°C and pressure of about 0 mmHg to 10 mmHg; and High Vacuum Fractional Distillation of said 2-Fluorotoluene using a fractionating column at a temperature of about 65 to 75°C and pressure of about 20 mmHg to 22 mmHg.
Another aspect of the present invention provides conversion of 2-Fluorobenzyl alcohol to Prasugrel comprises the steps of,
a) treating said 2-Fluorobenzyl alcohol with a halogenating agent to obtain 2-Fluorobenzyl halide;
b) reacting said 2-Fluorobenzyl halide with cyanating agent to obtain 2-Fluorobenzyl cyanide; and
c) converting said 2-Fluorobenzyl cyanide to Prasugrel.
Another aspect of the present invention provides conversion of 2-Fluorobenzyl cyanide to Prasugrel comprises the steps of,

a) hydrolyzing 2-Fluorobenzyl cyanide to obtain 2-Fluoropheny] acetic acid;
b) coupling said 2-Fluorophenyl acetic acid with ethyl cyclopropane carboxylate under Grignard reaction conditions to obtain Cyclopropyl 2-fluorobenzyl ketone;
c) optionally purifying Cyclopropyl 2-fluorobenzyl ketone;
d) halogenating said Cyclopropyl 2-fluorobenzyl ketone to obtain 2-Fluoro-a-(cyclopropylcarbonyl) benzyl halide;
e) condensing said 2-Fluoro-a-(cyc!opropylcarbonyl) benzyl halide with 5,6.7.7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate in presence of tert-butyldimethylchlorosilane to obtain 2-(tert-butyl dimethyl siIyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c] pyridine:
f) optionally purifying said 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropyl carbonyl-2-fluorobenzyI)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
g) acetylating said 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine with suitable acetylating agent to obtain Prasugrel. which is optionally purified; and
h) optionally converting said Prasugrel to its pharmaceutically acceptable salt.
Another aspect of the present invention provides the conversion of 2-Fluorotoluene to Prasugel comprises the steps of.
a) treating 2-Fluorotoluene with a halogenating agent to obtain 2-Fluorobenzyl halide:
b) reacting 2-Fluorobenzyl halide with cyclopropyl cyanide under Grignard reaction conditions to obtain Cyclopropyl 2-fluorobenzyl ketone;
c) optionally purifying Cyclopropyl 2-fluorobenzyl ketone; and
d) converting Cyclopropyl 2-fluorobenzyl ketone to Prasugrel or pharmaceutically acceptable salt thereof.
Preferably, said Cyclopropyl 2-fluorobenzyl ketone is purified by High Vacuum Fractional Distillation. Preferably, said Prasugrel is treated with activated charcoal and/or neutral alumina to obtain pure Prasugrel.
Another aspect of the present invention provides Prasugrel or pharmaceutically acceptable salts thereof is substantially free of impurity selected from the group consisting of 3-

Fluoro-isomer, 4-Fluoro-isomer, 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-
2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine, 2-Acetoxy-5-[a-(cyclopropyIcarbonyl)
benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (des-Fluoro impurity), 6-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6.7-tetrahydro thieno[2,3-c]pyridin-2-yl acetate (Positional isomer for Prasugrel), 2-Acetoxy-5-[a-(5-chioro-l-oxopentyI)-2-fluorobenzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 2-[a-Cyclopropyl carbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4,5,6,7 tetrahydro thienopyridine (N-acetyl impurity).
Detailed description of the invention:
The present invention provides a simple, cost effective and industrially viable process for preparation of substantially pure Prasugrel or pharmaceutically acceptable salt thereof.
According to one embodiment of the present invention, there is provided a process for preparation of Prasugrel or pharmaceutically acceptable salt thereof comprising the steps
of,
a) subjecting 2-Fluorobenzy] cyanide or 2-Fluorobenzyl alcohol or 2-Fluoro toluene to purification to obtain 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene substantially free of closely boiling impurities; and
b) converting said 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene to Prasugrel or pharmaceutically acceptable salt thereof.
Preferably, said closely boiling impurities are selected from 3-Fluoro impurity, 4-Fluoro impurity or des-Fluoro impurity. Purification can be carried out by various techniques known in the art.
According to a preferred embodiment of the present invention, 2-Fluorobenzyl cyanide is purified by High Vacuum Fractional Distillation. The distillation is carried out at a reduced pressure of about 50mmHg to 0.0lmmHg. preferably at 0mmHg to l0mmHg and at a temperature of about 100 to 130°C, preferably at 110 to 120°C. 2-Fluorobenzyl cyanide is collected at a vapour temperature of about 70 to 95°C, preferably 75 to 90°C. 2-Fluorobenzyl cyanide thus obtained is substantially free of closely boiling impurities. The content of impurities such as 3-Fluorobenzyl cyanide, 4-Fluorobenzyl cyanide or des-Fluorobenzyl cyanide (Benzyl cyanide) get reduced to less than about 0.15%, preferably in

the range of 0.02 to 0.15%, more preferably less than about 0.05%. 2-Fluorobenzyl cyanide is converted to Prasugrel by techniques known in the art or by the process of the present invention.
Fractional Distillation is a process in which a mixture of two or more miscible liquids is separated into its components. Typically the boiling point of the component liquids differ by 25°C or less at standard atmospheric pressure.
Fractionating columns used for High Vacuum Distillation is about 1 to 100 meters long, preferably about one meter long. Condenser used is about 1 to 100 meters long, preferably about one meter long. Glass beads and Reflux divider are used for efficient removal of closely boiling impurities. The length of the fractionating column and the quantity of glass beads can be adjusted so as to efficiently separate out closely boiling impurities such as 3-Fluorobenzyl cyanide, 4-Fluorobenzyl cyanide or des-Fluoro benzyl cyanide. The presence of glass beads increase the surface area for condensation. As the lower boiling liquid boils, some of the higher boiling liquid also boils and starts to climb the fractionating column. As the higher boiling liquid moves away from the heat source, it is more likely to condense and the glass beads provide the surface area to accomplish this. The higher boiling liquid then falls down the column and transfers its heat to lower boiling liquid, which continues to climb the column in vapour form and later condenses in the condenser tube. This process helps provide for a greater separation of compounds with narrow difference in boiling point.



Prior art teaches the separation of 2-Fluorobenzyl cyanide from its closely boiling isomers by fractionation. However it has been found that when distillation is carried out at atmospheric pressure, there is a high likelihood of benzyl cyanide derivatives getting exposed to air resulting in the formation of acid impurities. So the inventors of the present invention have purified 2-Fluorobenzyl cyanide by High Vacuum Fractional Distillation.
According to an embodiment of the present invention, the conversion of 2-Fluorobenzyl cyanide to Prasugrel comprises the steps of,
a) hydrolyzing said 2-Fluorobenzyl cyanide to obtain 2-Fluorophenyl acetic acid;
b) coupling said 2-Fluorophenyl acetic acid with ethyl cyclopropane carboxylate in presence of Grignard reagent to obtain Cyclopropyl 2-fluorobenzyl ketone;
c) optionally purifying said Cyclopropyl 2-fluorobenzyl ketone;
d) halogenating said Cyclopropyl 2-fluorobenzyl ketone to obtain 2-Fluoro-a-(cyclopropylcarbonyl) benzyl halide;
e) condensing said 2-Fluoro-α-(cyclopropylcarbonyl) benzyl halidewith 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate in presence of tert-butyldimethylchlorosilane to obtain 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine;
f) optionally purifying said 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropyIcarbonyl -2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
g) reacting said 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine with an acetylating agent in presence of a base and an acylating catalyst to obtain Prasugrel, which is optionally purified; and
h) optionally converting said Prasugrel to its pharamceutically acceptable salt.
In a preferred embodiment,
Step I involves the hydrolysis of 2-Fluorobenzyl cyanide in presence of acid selected from
hydrochloric acid or sulphuric acid preferably hydrochloric acid at a temperature of about

20 to 40°C, preferably 25 to 35°C to obtain a reaction mass. The obtained reaction mass is further refluxed for 2 to 5 hours, preferably for 3 to 4 hours. The completion of reaction is monitored by TLC. After the completion of reaction, the reaction mass is cooled to 20 to 40°C, preferably 25 to 35°C and is further chilled to about 0 to 5°C. The obtained solid is filtered, washed and dried to obtain 2-Fluorophenyl acetic acid. 2-Fluorophenyl acetic acid thus obtained has purity of more than 99.5%. 2-Fluorophenyl acetic acid thus obtained can be used for further reaction without purification.
Step II involves treatment of 2-Fluorophenyl acetic acid with isopropyl magnesium bromide in presence of solvent selected from tetrahydrofuran (THF), methyl tert butyl ether (MTBE), diethyl ether, 1,4-dioxane, dimethoxyethane (DME). diethoxyethane or mixture thereof, preferably tetrahydrofuran at a temperature of about 5 to 25°C, preferably 10 to 20°C for 30 to 90 minutes, preferably for 60 minutes to obtain a reaction mixture. The temperature of reaction mixture is slowly raised to 50 to 70°C. preferably to 60 to 65°C and maintained at the same temperature under stirring for 2 to 4 hours, preferably for 3 hours. The reaction mixture is further cooled to 0 to 5°C. Ethyl cyclopropyl carboxylate is added to the cold reaction mixture at the same temperature over a period of 10 to 30 minutes, preferably 15 to 20 minutes. The temperature of the reaction mixture is slowly raised to 50 to 70°C, preferably 60 to 65°C and maintained under stirring for 4 to 8 hours, preferably for 5 to 6 hours. The completion of the reaction is monitored by TLC. The reaction mixture is cooled to about 0 to 5°C and quenched by adding water followed by adjusting the pH of the reaction mixture to 2. The reaction mixture is extracted with a solvent selected from dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably dichloromethane followed by layer separation. The aqueous layer is extracted with dichloromethane. The combined organic layers are washed with saturated NaHCOs solution followed by washing with water, dried over anhydrous sodium sulfate and concentrated to obtain Cyclopropyl 2-fluorobenzyl ketone.
Step III involves the purification of Cyclopropyl-2-fluorobenzyl ketone by subjecting Cyclopropyl-2-fluorobenzyl ketone to High Vacuum Fractional distillation. Fractionating columns used for High Vacuum Distillation is about 1 to 100 meters long, preferably about one meter long. Condenser used is about 1 to 100 meters long, preferably about one

meter long. The distillation is carried out at a reduced pressure of about 0 to 10 mm Hg and a temperature of about 70 to 90°C. Cyclopropyl-2-fluorobenzyl ketone is collected at a vapour temperature of about 68 to 75°C. Cyclopropyl-2-fluorobenzyl ketone thus obtained is substantially free of polar impurities. It has been found that Cyclopropyl-2-fluorobenzyl ketone obtained using 2-Fluorobenzyl cyanide, purified by the process of the present invention, is substantially free of isomeric impurities.

Step IV involves treating Cyclopropyl-2-fluorobenzyl ketone with N-bromosuccinimide (NBS) in presence of azobisisobutyronitrile (AIBN) and chlorinated solvent such as ethylene dichloride at reflux temperature. The addition of NBS is carried out in a lot-wise manner over a period of 1 to 5 hours, preferably 3 hours. The obtained mixture is stirred for a period of about 16 hours at the same temperature. After the completion of reaction, the reaction mixture is cooled to 10 to 30°C, preferably 15 to 20°C followed by stirring for about 30 min and then filtered. The obtained filtrate is washed with 5% sodium metabisulfite solution and water followed by separation of layers. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 2-ffuoro-α-(cyclopropylcarbonyl) benzyl bromide.
Step V involves treating 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate with tert-butyldimethylchlorosilane in presence of triethylamine and dichloromethane at temperature of 0 to 20°C, preferably at 10 to 15°C to obtain, a mixture.

The obtained mixture is stirred for 1 to 4 hours, preferably for 2 hours at the same temperature. To this mixture, are added 2-fluoro-α-(cyclopropylcarbonyl)-benzyl bromide, triethylamine and sodium iodide at the same temperature followed by stirring for 10 to 20 minutes, preferably for 15 minutes. The temperature of the obtained reaction mixture is slowly raised to 40 to 60°C, preferably 50 to 55°C. The reaction mixture is allowed to react under stirring for 6 to 10 hours, preferably for 8 hours. After the completion of the reaction, the reaction mixture is treated with aqueous solution of potassium dihydrogen phosphate and stirred for 10-20 min, preferably for 15 min. This reaction mixture is then subjected to extraction with a solvent, such as dichloromethane, dichloroethane or chloroform. The combined organic layers are concentrated under vacuum to obtain a residue. Acetonitrile is added to the obtained residue and the mixture is stirred at 20 to 40°C, preferably 25 to 35°C for 20 to 40 min, preferably for 30 min followed by addition of water. The mixture is cooled to 0 to 5°C and maintained at the same temperature for 1 to 4 hours, preferably for 3 hours to precipitate out the product. The obtained product is filtered, washed and dried under vacuum to obtain 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in purity of more than 98%.
Step VI involves the process for purification of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, comprising dissolving the obtained 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropyl carbonyl-2-fluorobenzyI)-4,5,6,7-tetra hydrothieno[3,2-c]pyridine in a suitable solvent selected from acetonitrile, propionitrile, methyl ethyl ketone, acetone or DMF, preferably acetonitrile at 40 to 60°C, preferably at 50 to 55°C to obtain a clear solution. The obtained clear solution is stirred for 10 to 20 min, preferably for 15 min and cooled to 20 to 40°C, preferably 25 to 35°C and maintained under stirring for about 30 min. Water is added to the obtained mixture and the obtained mixture is cooled to about 0 to 5°C. The mixture is maintained at the same temperature for about 1 hour. The obtained solid is filtered, washed with cold acetonitrile and dried under vacuum to obtain 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-Fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine in purity of more than 99%.

Step VII: The obtained 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno[3,2-c] pyridine is taken in acetonitrile to obtain a mixture and the mixture is cooled to about 10 to 20°C. 4-Dim ethyl amino pyridine and triethylamine are added to the mixture at the same temperature and stirred for 1 to 4 hours, preferably for 2 hours. The reaction mixture is further cooled to about 0 to 10°C followed by drop-wise addition of acetic anhydride at the same temperature over a period of 10 to 20 min, preferably 15 min. The obtained reaction mixture is stirred at -20 to 0°C, preferably at -15°C to -10°C for 1 to 3 hours, preferably for 2 hours followed by addition of aqueous potassium dihydrogen phosphate. The mixture is stirred at -10 to 0°C for 30 to 90 min, preferably for 60 min to obtain solid. The obtained solid is washed with acetonitrile, water or mixture thereof and dried under vacuum.
Other acylating catalyst which can be used in place of 4-dimethylaminopyridine is 4-diethylaminopyridine or 4-dipropylaminopyridine.
Step VIII involves purification of Prasugrel which comprises,
a) dissolving Prasugrel in suitable solvent selected from acetonitrile, acetone, methyl ethyl ketone or DMF to get a solution;
b) optionally treating the obtained solution with neutral alumina and/or charcoal;
c) optionally treating the obtained solution with an antisolvent;and
d) isolating pure Prasugrel.
Preferably, Prasugrel base is dissolved in acetonitrile at 35°C-40°C to get a clear solution. The obtained clear solution is treated with neutral alumina and/or activated charcoal at 35 to 40°C. The mixture is filtered and the obtained filtrate is cooled to -10°C. Water is added to the cooled filtrate to increase the polarity of the mixture. The separated product is filtered to obtain Prasugrel which is washed with aqueous acetonitrile. Prasugrel is obtained in purity of more than 99%.
Step IX involves the preparation of Prasugrel salt which comprises the steps of,
a) dissolving Prasugrel in suitable solvent selected from acetone, methyl ethyl ketone, DMF, acetonitrile or the like to obtain a solution;
b) adding suitable salt forming agent such as HCl, SOCl2, NH4C1, HBr, acetic acid or

formic acid to the obtained solution;
c) optionally adding seed crystal of desired form to obtain a reaction mixture;and
d) isolating the Prasugrel salt.
Preferably, said Prasugrel salt is Prasugrel hydrochloride, which is prepared by treating a solution of Prasugrel base in acetone with conc. HC1 at 35°C to 40°C to obtain a reaction mixture. Conc. HC1 is added in a drop-wise manner. The reaction mixture is seeded with crystal Blor B2 of Prasugrel hydrochloride and stirred at 35°C to 40°C for about 1 to 2 hours. To the resulting mixture is further added conc. HC1 in a drop-wise manner over a period of 1 hour. The obtained reaction mixture is stirred at 35°C to 40°C for about 2 to 4 hours. The resulting crystals are separated by filtration, washed with acetone and dried to obtain Prasugrel hydrochloride in purity of more than 99.5%.
According to another embodiment of the present invention, there is provided a process for preparation of Prasugrel or pharmaceutically acceptable salt thereof comprising the steps of,
a) subjecting 2-Fluorobenzyl alcohol to High Vacuum Fractional Distillation to obtain 2-Fluorobenzyl alcohol substantially free of closely boiling impurities; and
b) converting said 2-Fluorobenzyl alcohol to Prasugrel or pharmaceutically acceptable salt thereof.
According to a preferred embodiment of the present invention, 2-Fluorobenzyl alcohol is subjected to High Vacuum Fractional Distillation. The distillation is carried out at a reduced pressure of about 50mmHg to O.OlmmHg, preferably at OmmHg to lOmmHg and at a temperature of about 80 to 120°C. preferably at 90 to 100°C. 2-Fluorobenzyl alcohol is collected at a vapour temperature of about 40 to 60°C, preferably 45 to 50°C. 2-Fluorobenzyl alcohol thus obtained is substantially free of closely boiling impurities. The content of impurities such as 3-Fluorobenzyl alcohol, 4-Fluorobenzyl alcohol or des-Fluorobenzyl alcohol (Benzyl alcohol) get reduced to less than about 0.15%, preferably in the range of 0.02 to 0.15%, more preferably less than about 0.05%. 2-Fluorobenzyl alcohol is converted to Prasugrel by techniques known in the art or by the process of the present invention.

Fractionating columns used for High Vacuum Distillation is about 1 to 100 meters long, preferably about one meter long. Condenser used is about 1 to 100 meters long, preferably about one meter long. Glass beads and Reflux divider are used for efficient removal of closely boiling impurities. The length of the fractionating column and the quantity of glass beads can be adjusted so as to efficiently separate out closely boiling impurities such as 3-Fluorobenzyl alcohol, 4-Fluorobenzyl alcohol or des-fluoro benzyl alcohol.
Another embodiment of the present invention provides the conversion of 2-Fluorobenzyl alcohol to Prasugrel comprising the steps of,
a) treating 2-FIuorobenzyl alcohol with halogenating agent to obtain 2-FIuorobenzyI halide;
b) reacting 2-Fluorobenzyl halide with cyanating agent to obtain 2-Fluorobenzyl cyanide; and
c) converting 2-Fluorobenzyl cyanide to Prasugrel.
In a preferred embodiment. 2-Fluorobenzyl alcohol purified by fractional distillation is treating with brominating agent such as 33% HBr/acetic acid at 25-35°C for 2-3 hours. After the completion of reaction, the product is extracted with dichloromethane, washed with 5% sodium metabisulfite solution followed by water washings. The separated organic layer is dried on anhydrous sodium sulfate and concentrated under vacuum followed by degassing the residue at 50 to 55°C to obtain 2-Fluorobenzyl bromide as a reddish brown liquid. Degassing removes the traces of dichloromethane.
2-Fluorobenzyl bromide is further reacted with aqueous solution of sodium cyanide in presence of catalyst selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium hydrogen sulphate, sodium iodide or potassium iodide, preferably tetrabutyl ammonium bromide in presence of solvent selected from dichloromethane, N,N-dirnethyIformamide, acetonitrile, ethyl acetate, acetone, tetrahydrofuran or dimethylsulfoxide preferably, dichloromethane at a temperature of 20 to 40°C. preferably at 25 to 30°C to obtain a reaction mass. The obtained reaction mass is stirred at the same temperature for about 12 to 16 hours. The organic layer is separated, washed with water and concentrated to obtain an oily residue of 2-Fluorobenzyl cyanide having purity of more than 99% .2-Fluorobenzyl cyanide is converted to Prasugrel by

techniques known in the art or by the process of the present invention.
Commercially available 2-Fluorobenzyl alcohol contains impurities such as 3-Fluoro benzyl alcohol. 4-Fluorobenzyl alcohol and des-Fluorobenzyl alcohol. However, 2-Fluorobenzyl alcohol purified by Fractional Distiilation is substantially free of impurities selected from 3-Fluorobenzyl alcohol. 4-Fluorobenzyl alcohol and des-Fluorobenzyl alcohol. The content of these impurities is controlled well below 0.05%. When such purified 2-Fluorobenzyl alcohol is used for the preparation of 2-FIuorobenzyI cyanide, the product thus obtained is substantially pure i.e., substantially free of impurities selected from 3-Fluorobenzyl cyanide, 4-Fluorobenzyl cyanide and des-Fluorobenzyl cyanide.

Yet another embodiment of the present invention provides a process for preparation of Prasugrel comprising the steps of,
a) subjecting 2-Fluorotoluene to Fractional Distillation to obtain 2-Fluorotoluene substantially free of closely boiling impurities; and
b) converting said 2-Fluorotoluene to Prasugrel or pharmaceutically acceptable salt thereof.
According to a preferred embodiment of the present invention, 2-Fluorotoluene is subjected to High Vacuum Fractional Distillation. The distillation is carried out at a reduced pressure of about 50mmHg to lOmmHg, preferably at 25mmHg to 22mmHg and at a temperature of about 60 to 80°C, preferably at 65 to 75°C. 2-Fluorotoluene is collected at a vapour temperature of about 15 to 25°C, preferably 20 to 22°C. 2-Fluorotoluene thus obtained is substantially free of closely boiling impurities. The content of impurities such

as 3-Fluorotoluene or 4-Fluorotoluene get reduced to less than about 0.15%, preferably in the range of 0.02 to 0.15%, more preferably less than about 0.05%. 2-Fluorobenzyl toluene is converted to Prasugrel by techniques known in the art or by the process of the present invention.
Fractionating columns used for High Vacuum Distillation is about 1 to 100 meters long, preferably about one meter long. Condenser used is about 1 to 100 meters long, preferably about one meter long. Glass beads and Reflux divider are used for efficient removal of closely boiling impurities. The length of the fractionating column and the quantity of glass beads can be adjusted so as to efficiently separate out closely boiling impurities such as 3-Fluorotoluene or 4-Fluorotoluene.
In an alternate embodiment, 2-Fluorotoluene is subjected to Fractional Distillation at atmospheric pressure at a temperature of 113 to 114°C.

In a preferred embodiment, 2-Fluorotoluene is taken in cyclohexane and AIBN is added to the mixture. N-Bromosuccinimide is added lot wise to the obtained mixture by maintaining temperature at 78 to 80°C over a period of 3 hours and mixture is stirred at the same temperature for 8 to 16 hours. After completion of reaction, the reaction mixture is cooled to 15°C to 20°C followed by stirring for 30 min and filtered. The obtained solid is washed with cyclohexane. The solid mass is discarded and the obtained filtrate is washed with 5% sodium metabisulfite solution followed by washing with water. The separated organic layer is dried over anhydrous sodium sulfate and concentrated under vacuum followed by degassing the residue at 50 to 55°C to remove the traces of cyclohexane to obtain 2-Fluorobenzyl bromide. 2-Fluorobenzyl bromide thus obtained is reacted with cyclopropyl cyanide under Grignard reaction conditions to obtain 2-Fluorobenzyl cyclopropyl ketone. 2-Fluorobenzyl cyclopropyl ketone is converted to Prasugrel by techniques known in the art or by the process of the present invention.

It has been observed that OXTP .i.e., 5-(a-cyclo-propylcarbonyl-2-fluorobenzyl-2-oxo-2,4,5,6,7,7a-hezahydrothieno[3,2-c]pyridine gets generated in the process for preparation of Prasugrel. Prior art discloses that OXTP impuirty can be removed by techniques such as recrystallization or acid treatment of Prasugrel. The inventors of the present invention have found that using neutral alumina and/or charcoal can reduce the content of the OXTP in the Prasugrel base. OXTP, being a polar compound, gets removed when Prasugrel is treated with neutral alumina in presence of a polar solvent. The content of the OXTP in the obtained Prasugrel base is NMT 0.08%, preferably NMT 0.02%, more preferably NMT 0.01%.
Another embodiment of the present invention provides a process for the preparation of Prasugrel or pharmaceutically acceptable salt thereof comprising the steps of,
a) subjecting said 2-Fluorobenzyl alcohol to High Vacuum Fractional Distillation to obtain substantially pure 2-Fluorobenzyl alcohol;
b) treating said 2-Fluorobenzyl alcohol with sodium cyanide to obtain 2-Fluorobenzyl cyanide;
c) optionally purifying said 2-Fluorobenzyl cyanide to obtain substantially pure 2-Fluorobenzyl cyanide;
d) subjecting said 2-Fluorobenzyl cyanide to hydrolysis to obtain 2-Fluorophenyl acetic acid;
e) coupling said 2-Fluorophenyl acetic acid with ethyl cyclopropane carboxylate to obtain Cyclopropyl 2-fluorobenzyl ketone;
i) optionally purifying said Cyclopropyl 2-fluorobenzyl ketone;
g) halogenating said Cyclopropyl 2-fluorobenzyl ketone with a halogenating agent to obtain 2-fluoro-a-(cyclopropylcarbonyl)-benzyl halide;
h) coupling said 2-fluoro-a-(cyclopropylcarbonyl)-benzyl halide with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate in presence of tert-butyldimethylchlorosilane to obtain 2-(tert-butyldimethylsilyloxy)-5-(a-cyclo propylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine;
i) optionally purifying said 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl -2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
j) acetylating said 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluoro

benzyI)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine with suitable acetylating agent to obtain Prasugrel, which is optionally purified; and k) optionally converting said Prasugrel to its pharamceutically acceptable salt.
When commercially available 2-Fluorobenzyl alcohol containing 3-Fluorobenzyl alcohol in an amount of 1% was subjected to High Vacuum Fractional Distillation, the content of 3-Fluorobenzyl alcohol impurity gets reduced to about 0.05%.
The process for preparation of Prasugrel salts according to the present invention is illustrated by the following reaction scheme,


Alternate embodiment of the present invention provides a process for preparation of Prasugrel or pharmaceutically acceptable salt thereof comprising the steps of,
a) subjecting 2-Fluorotoluene to High Vacuum Fractional Distillation to obtain substantially pure 2-Fluorotoluene;
b) treating 2-Fluorotoluene with a halogenating agent to obtain 2-Fluorobenzyl halide;
c) reacting 2-Fluorobenzyl halide with cyclopropyl cyanide under Grignard reaction conditions to obtain Cyclopropyl 2-fluorobenzyl ketone;
d) optionally purifying Cyclopropyl 2-fluorobenzyl ketone;
e) halogenating Cyclopropyl 2-fluorobenzyl ketone with a halogenating agent to obtain 2-fluoro-α-(cyclopropylcarbonyl)-benzyl halide;
f) coupling 2-fluoro-α-(cyclopropylcarbonyl)-benzyl halide with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate in presence of tert-butyldimethylchlorosilane to obtain 2-(tert-butyldimethylsilyloxy)-5-(a-cyclo propylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine;
g) optionally purifying said 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl -2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
h) acetylating said 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine with suitable acetylating agent to obtain Prasugrel, which is optionally purified; and
i) optionally converting Prasugrel to its pharamceutically acceptable salt.
It has been observed by the inventors of the present invention that by following the process disclosed in the prior art, the impurity profile of the obtained Prasugrel and Prasugrel hydrochloride is as shown in Table No. 1
Table No. 1

Product % OXTP
0.02 % des-Fluoro % 3-Fluoro Purity
Prasugrel base
0.05 0.09
0.06 99.5
Prasugrel hydrochloride j 0.01 0.04
99.8
The process of the present invention avoids the use of column chromatography thereby

making the process simple, cost effective and industrially feasible.The impurity profile of the obtained Prasugrel and its pharmaceutically acceptable salt as per the present invention is as shown in Table No. 2
Table No. 2

Name of the Product % OXTP % Des-Fluoro % 3-Fluoro Purity
Prasugrel Base 0.08 0.04 0.02 0.11 0.05 99.45
(Crude)
0.11 0.05 0.06 0.07 0.04 99.67
Prasugrel Base

0.03 99.78
(Pure) 0.01
0.04 99.81
Prasugrel hydrochloride Not Detected
0.05 99.87

Not Detected 0.05 0.05 99.90
Table No. 3 shows the impurity profile of the various starting material and intermediates used in the preparation of Prasugrel.
Table No. 3

Name of the intermediate % des-Fluoro % 3-fluoro % 4-fluoro % Purity
2-Fluoro benzyl alcohol ND 0.15 0.03 99.63 99.64
(commercially available) ND ND 0.18 0.05 0,04 ND

2-Fluoro benzyl alcohol obtained

0.02 99.86
by process of present invention ND
ND 99.83
2-Fluoro benzyl cyanide 0.1 0.19 0.04 99.42
(commercially available) 0.09 0.21 0.06 99.34
2-Fluoro benzyl cyanide obtained 0.01 0.03 0.02 99.82
by process of present invention 0.01 Not Detected 0.04 0.01
Not Detected 99.6
2-Fluoro phenyl acetic acid obtained by process of present
0.05
99.88
* invention Not Detected 0.01 0.03 0.05 0.02 99.9
Cyclopropyl 2-fluorobenzyl ketone obtained by process of

Not Detected 86.5
present invention 0.01 0.03 Not Detected 92

Cyclopropyl 2-fluorobenzyl ketone obtained after purification Not Detected 0.05 Not Detected 99
Not Detected 0.03 Not Detected 99.4
Prasugrel hydrochloride obtained according to present invention is characterized by X-ray powder diffraction pattern having peaks at about 9.21, 9.56, 14.85, 15.53, 15.23, 20.62, 21.59, 23.19, 23.85 and 25.52. XRPD pattern of the obtained Prasugrel hydrochloride matches with Prasugrel hydrochloride obtained according to process disclosed in US 6693115 (crystal B2).
Another embodiment of the present invention provides Prasugrel or pharmaceutically
acceptable salts thereof substantially free of impurity selected from the group consisting of
3-Fluoro-isomer, 4-Fluoro-isomer, 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-
2.4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine, 2-Acetoxy-5-[a-(cyclopropylcarbonyl)
benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (des-Fluoro impurity), 6-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydro thieno[2,3-c]pyridin-2-yl acetate (Positional isomer for Prasugrel), 2-Acetoxy-5-[a-(5-chloro-l-oxopentyl)-2-fluorobenzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 2-[a-Cyclopropylcarbonyl-(2-fluoro)benzyioxy]-5-acetoxy-4,5,6,7 tetrahydro thienopyridine (N-acetyl impurity). 3 -Fluoro-isomer is 5-[(1 RS)-2-cyclopropyl-1 -(3-fluorophenyl)-2-oxoethyl] -4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. 4-Fluoro-isomer is 5-[(lRS)-2-cyclopropyl-l-(4-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate.
It has been observed by the inventors of the present invention that if 2-Fluorobenzyl alcohol or 2-Fluorobenzyl cyanide, the starting material of the Prasugrel is purified, the possible impurities can be controlled at the initial stage of the process thereby providing substantially pure Prasugrel.
Another embodiment of the present invention provides pharmaceutical composition comprising Prasugrel or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions may be prepared by any conventional techniques known in the art.

Halogenating agent may be a chlorinating agent or a brominating agent or iodinating agent and may be selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, HBr/acetic acid, NBS or the like. Cyanating agent may be selected from sodium cyanide, potassium cyanide or the like.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term "substantially pure" means a compound having less than about 0.5%, preferably less than about 0.15%, more preferably in the range of 0.02 to 0.15%, most preferably less than about 0.05% of impurities including isomeric impurity.
The term "substantially free" means a compound having less than about 0.5%, preferably less than about 0.15%, more preferably in the range of 0.02 to 0.15%, most preferably less than about 0.05% of impurities including isomeric impurity.
The term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
The term "closely related" refers to compounds having narrow differences in boiling points.
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any manner.
Examples:
Example-1: Purification of 2-Fluorobenzyl alcohol
In a 1 liter 4-necked flask equipped with a thermometer and mechanical stirrer, commercially available 2-fluorobenzyl alcohol (200 gm) was subjected to High Vacuum Fractional Distillation using 1 meter long fractionating column having glass beads, reflux divider and a 1 meter long condenser. The distillation was carried out at 90 to 100°C and at a reduced pressure of 0 to 10 mm Hg. The main fraction .i.e., 2-Fluorobenzyl alcohol was collected at a vapour temperature of 45 to 50°C. Yield: 85-90% w/w; Purity: more than 99.5%.

Content of impurities prior to distillation: 3-Fluorobenzyl alcohol 0.15%; 4-Fluorobenzyl alcohol 0.03%. Content of impurities after distillation: 3-Fluorobenzyl alcohol 0.05%; 4-Fluorobenzy] alcohol 0.02%.
Example 2: Purification of 2-Fluorotoluene
In a 1 liter 4-necked flask equipped with a thermometer and mechanical stirrer, commercially available 2-Fluorotoluene (200 gm) is subjected to High Vacuum Fractional Distillation using 1 meter long fractionating column having glass beads, reflux divider and a 1 meter long condenser. The distillation is carried out at 65 to 75°C and at a reduced pressure of 22 to 25 mmHg. The main fraction .i.e., 2-Fluorotoluene is collected at a vapour temperature of 20 to 25°C. Yield: 80-85 % w/w; Purity: more than 99.5%.
Isomeric impurities: less than 0.05%.
The above purification can be carried out at atmospheric pressure.
Example 3: 2-Fluorobcnzyl bromide
a) using 2-Fluorobenzyl alcohol
In a 250 ml 4-necked flask equipped with a thermometer and mechanical stirrer were taken 2-Fluorobenzyl alcohol obtained from example 1 (50 gm, 0.3964 moles), acetic acid 100 ml and 33% HBr/acetic acid (100 ml, 0.4074 moles) to obtain a reaction mixture. This reaction mixture was stirred at 25-35°C for 2-3 hours. After the completion of reaction, the product was extracted with dichloromethane (250 ml). This dichloromethane extract was separated, washed with 5% sodium metabisulfite solution (100 ml) followed by water washings (3 x 100ml). The separated organic layer was dried on anhydrous sodium sulfate and concentrated under vacuum to obtain a reddish brown coloured liquid. Yield: 65 gm. Purity: more than 90%
b) using 2-Fluorotoluene
2-Fluorotoluene (50gm, 0.4540 moles) is taken in 500ml of cyclohexane and (lgm, 0.0060 moles) of AIBN is added to the mixture. N-Bromosuccinimide (96.96gm, 0.5448 moles) is added lot wise to the obtained mixture by maintaining temperature at 78 to 80°C over a period of 3 hours and mixture is stirred at the same temperature for 8 to 16 hours. After

completion of reaction, the reaction mixture is cooled to 15°C to 20°C followed by stirring for 30 min and filtered. The obtained solid is washed with cyclohexane. The solid mass is discarded and the obtained filtrate is washed with 5% sodium metabisulfite solution (400 ml) followed by washing with water (3 x 175 ml). The separated organic layer is dried over anhydrous sodium sulfate and concentrated under vacuum followed by degassing the residue at 50 to 55°C to remove the traces of cyclohexane to obtain the titled product. Yield: 95%; Purity: 85 to 90%.
Example 4: 2-Fluorobenzyl cyanide
a) In a 1 liter 4-necked flask equipped with a thermometer and mechanical stirrer, 2-fluorobenzyl bromide (lOOg, 0.5290 moles), tetrabutyl ammonium bromide (4.5 g, 0.0139 moles) and dichloromethane (280 ml) were added to a clear solution of sodium cyanide (32.4g, 0.6610 moles) in water (280ml) at 25 to 30°C. The reaction mass was stirred for 12-16 h at the same temperature. After the completion of reaction, the organic layer was separated, washed with water and concentrated under vacuum to obtain 2-Fluorobenzyl cyanide. Yield: 68 gm; Purity: more than 99%.
b) Purification of 2-fluoro benzyl cyanide
2-Fluorobenzyl cyanide was subjected to high vacuum fractional distillation using 1 meter long fractionating column with glass beads, reflux divider and 1 meter long condenser. The distillation was carried out at a 110 to 120°C and at a reduced pressure of 0 to 10 mmHg. The main fraction was collected at a vapour temperature of 75 to 90°C to obtain 2-Fluorobenzyl cyanide. Yield: 75-85% w/w; Purity: more than 99.5%.
This purification process can be utilized for the purification of commercially available 2-Fluorobenzyl cyanide.
Content of impurities prior to distillation: 3-Fluorobenzyl cyanide 0.21%; 4-Fluorobenzyl cyanide 0.06%; des-Fluorobenzyl cyanide 0.09%. Content of impurities after distillation: 3-Fluorobenzyl cyanide 0.04%; 4-Fluorobenzyl cyanide 0.01%; des-Fluorobenzyl cyanide 0.01%

Example 5:Cyclopropyl 2-fluorobenzyl ketone (Prasu cyclopropyl ketone) A) First approach
a) In a 0.5 liter 4-necked flask equipped with a thermometer and mechanical stirrer, 30 -35% aqueous hydrochloric acid (540 ml, 5.185 moles) was added to 2-Fluorobenzyl cyanide (250 gm, 1.8499 moles) at 25-35°C. The reaction mass was refluxed for 3 to 4 h. The presence of the starting material was checked by TLC. After the completion of the reaction, the reaction mass was cooled to 25-35°C. The reaction mass was further cooled to 0-5°C and stirred at the same temperature for 30 min to obtain a solid. The obtained solid was filtered, washed with cold water (2 x 25ml) and dried. The obtained wet product (280 gm) was dried under reduced pressure at 35 to 40°C to obtain 2-Fluorophenyl acetic acid. Yield: 260 gm (90-95%); Purity: more than 99%.
b) In a 5 litre, 4-necked flask equipped with a thermometer and mechanical stirrer, isopropyl bromide (301gm, 2.447 moles) was added slowly to a suspension of magnesium (60gm, 2.468 moles) in tetrahydrofuran (2.5 lit). The reaction mixture was refluxed for 1 hr and cooled to 10 to 20°C. 2-Fluorophenyl acetic acid (150gm, 0.9731moles) was slowly dissolved in tetrahydrofuran (270 ml) at the same temperature over a period of 1 hour. The temperature of the reaction mass was slowly raised to 60-65°C and maintained for 3 firs followed by cooling at 0-5°C. Ethylcyclopropyl carboxylate (106.61gm, 0.9339 moles) was slowly added to the reaction mass by maintaining the temperature at 0-5°C over a period of 15-20 minutes. The temperature was slowly raised to 60-65°C and maintained for 5-6 hrs. The progress of the reaction was monitored by TLC. After the completion of the reaction; the mass was cooled to 0-5°C and was quenched by adding purified water
(150 ml). The pH of the reaction mass was adjusted to 2 by adding aqueous (2 N) hydrochloric acid (approx. 1550 lit). Dichloromethane (300 ml) was charged to the reaction mass and stirred for 15 min and the layers were separated. The aqueous layer was extracted with 300 ml of dichloromethane. The combined layers were washed with saturated sodium bicarbonate solution (750 ml), purified water, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the desired product. Yield: 113 gm (60-65%), Purity: more than 98%

B) Second approach
In a 5 litre, 4-necked flask equipped with a thermometer and mechanical stirrer, 2-Fluorobenzyl bromide (200 grr.., 1.057 moles) in tetrahydrofuran (0,660 lit) is added slowly to a suspension of magnesium (30.4 gm. 1.251 moles) in tetrahydrofuran (0.660 lit). The reaction mixture is refluxed for 1 hr and cooled to 10 to 20°C. The temperature of the reaction mass is slowly raised to 60-65°C and maintained for 3 hrs followed by cooling at 0-5°C. Cyclopropyl cyanide (92gm, 1.3731 moles) in tetrahydrofuran (0.660 lit) is added to the cooled solution over a period of 30 minutes. The temperature is slowly raised to 60-65°C and maintained for 5-6 hrs. The progress of the reaction is monitored by TLC. After the completion of the reaction, the mass is cooled to 0-5°C and quenched by adding purified water (1 lit). The pH of the reaction mass is adjusted to 2 by adding 2 N hydrochloric acid (approx. 2050 lit). Dichloromethane (0.660 lit) is charged to the reaction mass and stirred for 15 min and the layers are separated. The aqueous layer is extracted with 0.660 lit of dichloromethane. The combined organic layers are washed with saturated sodium bicarbonate solution (1.5 lit), water and dried over anhydrous sodium sulfate. The organic layer is concentrated under vacuum to obtain the desired product. Yield: 165 gm (85-90%), Purity: more than 85% .
Example 6: Preparation of Prasugrel
a-1) Purification of Cyclopropyl 2-fluorobenzyl ketone
Cyclopropyl 2-fluorobenzyl ketone obtained from Example 4 (145gm) was subjected to High Vacuum Fractional Distillation using 1 meter long fractionating column with glass beads, reflux divider and a ore meter long condenser. The distillation was carried out under reduced pressure of 0 to 10 mmHg and temperature of 70 to 90°C. The main fraction was collected at a vapour temperature of 68 to 75°C to obtain the desired product. Yield: 75-85%; Purity: 99.5%
a-2) Purification of Cyclopropyl 2-fluorobenzyJ ketone
Commercially available Cyclopropyl 2-fluorobenzyl ketone contains impurities selected from Cyclopropyl-3-fluorober.zyl ketone, Cyclopropyl-4-fluorobenzyl ketone or des-Fluoro cyclopropyl benzyl ketone. Commercially available Cyclopropyl 2-fluorobenzyl ketone was purified as per Example 5 a-1) to obtain substantially pure Cyclopropyl 2-

fluorobenzyl ketone.
b) 2-Fluoro -a-(cyclopropyl cat bonyl) benzyl bromide
Cyclopropyl-2-fluorobenzyl ketone (l00gm. 0.56Imoles) was taken in 1000ml of ethylene dichloride and 4 gm of AIBN (0.042 moles) was added to the mixture. N-Bromo succinimide (119.81 gm, 0.6730 moles) was added lot wise to the obtained mixture by maintaining temperature at 85 to 90°C over a period of 3 hours and mixture was stirred at the same temperature for 8 to 16 hours. After completion of reaction, the reaction mixture was cooled to 15°C to 20°C followed by stirring for 30 min and filtered. The obtained solid was washed with 100ml of ethylene dichloride. The solid mass was discarded and the obtained filtrate was washed with 5% sodium metabisulfite solution (800 ml) followed by washing with water (3 x 335 m!). The separated organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum followed by degassing the residue at 50 to 55°C to remove the traces of ethylene dichloride to obtain the titled product as a yellow coloured oil. Yield: more than 90%; Purity: more than 80%.
c) 5,6,7,7a-tetrahydro-4H-thieno [3,2-c] -pyridine- 2-one- p-toluene sulfonate
A mixture of 500 gm (1.257moles) of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one, 238.61 gm (1.254moles) of p-toluene sulfonic acid monohydrate and 8.8 L of tetrahydrofuran was stirred at 50°C for 3 hrs to obtain a precipitate. The obtained precipitate was filtered, washed with tetrahydrofuran (2 x 500 ml) and dried at 50°C -55°C to obtain 408 gm of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridine-2-one-p-toluenesulfonate.Yield : 99.81%.
d) 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-
tetrahydrothieno [3,2-c]pyridine
To a mixture of 5,6.7,7a-tetrahydro-4H-thieno[3.2-c]-pyridine-2-one-p-toluene sulfonate (286gm, 0.880 mole) in 200 ml of methylene dichloride, tertbutyldimethylchlorosilane (151gm, 1.0017 moles) and 318 ml of methylene chloride was added triethyl amine (101.31gm, 1.0011 moles) by maintaining temperature at 0°C to 15°C over a period of 30 min and the mixture was stirred for 2 to 4 hrs at 0°C to 15°C. A solution of 2-fluoro-a-(cyclopropylcarbonyl) benzyl bromide (226.24 gm, 0.8799 moles) was added at same

temperature to the mixture followed by dropwise addition of triethyl amine (175.61 gm, 1.7354 moles) and sodium iodide (6.41 gm. 0.0427 moles) at the same temperature. The reaction mixture was stirred at the same temperature for 15 min. The temperature of the reaction mixture was slowly raised to 50 to 55°C and the mixture was allowed to react under stirring at same temperature for 8 hrs. After completion of reaction, 23.57gm of potassium orthophosphate and 2.34 gm of disodium hydrogen phosphate in 890 ml of purified water as buffer solution was added and resulting solution was stirred for 15 min and layers were separated. The aqueous layer was extracted with 220 ml of methylene dichloride. The combined organic layers were concentrated under vacuum and methylene dichloride was distilled out followed by addition of 607 ml of acetonitrile followed by distillation to remove traces of methylene chloride to obtain a residue. 1639 ml of acetonitrile was added to the residue and stirred at 25 to 35°C for 30 min to obtain a mixture. This mixture was treated with 302 ml of water followed by chilling at 0-5°C and maintained for 3 hrs to obtain a precipitate. The obtained precipitate was filtered, washed with chilled 50% aqueous acetonitrile (521 ml) and dried under vacuum at 50 to 55°C to obtain 274 gm of 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluoro benzyl)-4,5.6,7-tetrahydrothieno-[3,2-c]pyridine.Yield :70%; Purity: more than 98%.
e) Purification of crude 2-(tert-butyldimethyIsiIyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzy I)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Prasu silylated product)
Crude 2-(tert-butyldimethyls:.lyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7 tetrahydrothieno-[3,2-c]pyridine (303 gm, 0.6808 moles) was taken in 2.424 lit of acetonitrile and the mixture was heated at 50 to 55°C to get a clear solution. The solution was stirred for 15 min and was cooled to 25 to 35°C and maintained under stirring for 30 min. 303 ml of water was charged to the obtained mixture and cooled to 0 to 5°C. The reaction mixture was maintained at the same temperature for 1 hr. The reaction mixture was filtered and the product obtained was washed with 273 ml of cold acetonitrile followed by drying under vacuum at 55 to 60°C for 8 hrs to obtain 282 gm of 2-(tert-butyldimethylsilyloxy)-5-(α-cyc;opropylcarbonyl-2-fluorobenzyl)-4.5,6.7-tetrahydro thieno-[3,2-c]pyridine. Yield: 90- 93%; Purity: more than 99%.

f) 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno
[3,2-c]pyridine (Prasugrel)
2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6.7-tetra hydrothieno[3.2-c]pyridine (200,3m, 0.4494 moles) was taken in 600 ml of acetonitrile and cooled to 10 to 20°C to obtain a mixture. 2.8 gm of 4-dimethyl amino pyridine and triethylamine (92 gm, 0.9091 moles) were added to the obtained mixture at 10 to 20°C over a period of 20-30 min. The mixture was stirred for 2 hrs. The mixture was cooled to 0 to 5°C followed by dropwise addition of acetic anhydride (92gm, 0.9011 moles) dissolved in 400ml of acetonitrile at 0 to .0°C over a period of 15min to obtain a reaction mixture. The obtained reaction mixture was stirred at -15 to -10°C for 2 h. After completion of reaction, 0.898 gm of potassium dihydrogen phosphate (0.0051 moles) in 660ml of water was added to the reaction mixture and stirred for 60 min at -10 to 0°C. The reaction mixture was filtered, washed with 50% aqueous acetonitrile (360 ml) and dried under vacuum at 55 to 60°C for 8 h to obtain 149 gm of titled product. Yield: 85 to 90%; Purity: more than 99%.
b) The process of example 6(f) was repeated by carrying the acetylation reaction at temperature of-10 to -15°C to obtain 140 gm of 2-Acetoxy-5-(a-cyclopropyl carbonyI-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine having 80 to 85% yield and purity of more than 90%.
Example 7: Purification of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine (Pure Prasugrel)
146 gm of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyI)-4,5,6,7- tetrahydrothieno [3,2-c]pyridine (Prasugrel) was dissolved in 1.028 lit of acetonitrile at 45 to 50°C to obtain a solution. Activated charcoal (14.6 gm) and neutral alumina (14.6 gm) were added to the obtained solution and the mixture was stirred at 40 to 45°C for 15 min. The reaction mixture was then filtered through hyflobed and washed with hot acetonitrile (196 ml). The combined filtrate was cooled at -15 to 0°C and 614 ml of water was added to it over a period of 15 min at temperature of-10 to 0°C followed by stirring the mixture for 1 hr at -10 to 0°C .The obtained solid was filtered and washed with 50% aqueous acetonitrile (2 x 73 ml) to obtain 135 gm of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-

tetrahydrothieno[3,2-c]pyridine. Yield: 85 to 90%; Purity: more than 99%.
b)The process of example 6 (a) was repeated without addition of activated charcoal to
obtain 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno
[3,2-c]pyridine with 80 to 85% }yield and more than 99% purity.
c)The process of example 6 (a) was repeated without addition of neutral alumina to obtain 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine with 80 to 85% yield and more than 99% purity.
Example 8: 2-Acetoxy-5-(a-eyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridine hydrochloride (Prasugrel hydrochloride)
2-Acetoxy-5-(α-cyclopropylcartionyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine (50 gm. 0.1340 moles) was dissolved in 730 ml of acetone and 7.14 gm (0.4SS0 moles) of concentrated hydrochloric acid (36%) was added dropwise to the obtained solution at temperature of 35 to 40°C within 5 min. 1% of Crystal B2 of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride was added to the reaction mixture as seed crystals and the resulting mixture was stirred at the same temperature for 60 min. The resulting mixture was treated with another lot of 5.85 gm (0.0577 moles) concentrated hydrochloric acid (36.0%) drop wise over a period of 60 min and the mixture was stirred at temperature of 35 to 40°C for 120 min. The obtained solid crystals were filtered, washed with 2 vol of acetone and dried at 65 to 70°C under vacuum for 3 hrs to obtain 61.50 gm of Crystal B2 of Prasugrel hydrochloride. Yield: 85 to 90% ; Purity: more than 99.80% ; Melting point: 165-178°C.
b)The process of example 8 (a) was repeated without addition of Crystal B2 of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5;6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride to obtain 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (Prasugrel hydrochloride).

We claim:
1. A process for preparation of Prasugrel or pharmaceutically acceptable salt thereof
comprising the steps of.
a) subjecting 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene to purification to obtain 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene substantially free of closely boiling impurities; and
b) converting said 2-Fluorobenzyl cyanide or 2-Fluorobenzyl alcohol or 2-Fluorotoluene to Prasugrel or pharmaceutically acceptable salt thereof.

2. The process as claimed in claim 1 wherein said closely boiling impurities are selected from 3-Fluoro impurity, 4-Fluoro impurity or des-Fluoro impurity.
3. The process as claimed in claim 1 wherein said purification is carried out by High Vacuum Fractional Distillation.
4. The process as claimed in claim 3. wherein said 2-Fluorobenzyl cyanide is subjected to High Vacuum Fractional Distillation using a fractionating column at a temperature of about 110 to 120°C and pressure of about 0 mmHg to 10 mmHg; wherein said 2-Fluorobenzyl alcohol is subjected to High Vacuum Fractional Distillation using a fractionating column at a temperature of about 90 to 100°C and pressure of about 0 mmHg to 10 mmHg; and wherein said 2-Fluorotoluene is subjected to High Vacuum Fractional Distillation using a fractionating column at a temperature of about 65 to 75°C and pressure of about 20 mmHg to 22 mmHg.
5. The process as claimed in claim 4 wherein said conversion of 2-Fluorobenzyl alcohol to Prasugrel comprises the steps of,

a) treating said 2-Fluorobenzyl alcohol with a halogenating agent to obtain 2-Fluorobenzyl halide;
b) reacting said 2-Fluorobenzyl halide with a cyanating agent to obtain 2-Fluorobenzyl cyanide; and
c) converting said 2-Fluorobenzyl cyanide to Prasugrel.

6. The process as claimed in claim 4 or claim 5 wherein said conversion of 2-
Fluorobenzyl cyanide to Prasugrel comprises the steps of,
a) hydrolyzing said 2-Fluorobenzyl cyanide to obtain 2-Fluorophenyl acetic acid;
b) coupling said 2-Fluorophenyl acetic acid with ethyl cyclopropane carboxylate under Grignard reaction conditions to obtain Cyclopropyl 2-fluorobenzyl ketone;
c) optionally purifying sa.d Cyclopropyl 2-fluorobenzyl ketone;
d) halogenating said Cyclopropyl 2-fluorobenzyl ketone to obtain 2-Fluoro-ct-(cyclopropylcarbonyl) benzyl halide;
e) condensing said 2-Fluoro-a-(cyclopropylcarbonyl) benzyl halide with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate in presence of tert-butyldimethylchlorosilane to obtain 2-(tert-butyl dimethyl silyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c] pyridine;
f) optionally purifying said 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropyl carbonyl-2-fluorobenzyI)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
g) reacting said 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine with an acetylating agent in the presence of a base and an acylating catalyst to obtain Prasugrel, which is optionally purified; and
h) optionally converting said Prasugrel to its pharmaceutically acceptable salt.
7. The process as claimed in claim 4 wherein said conversion of 2-Fluorotoluene to
Prasugrel comprises the steps of,
a) treating said 2-Fluorotoluene with a halogenating agent to obtain 2-Fluorobenzyl halide;
b) reacting said 2-Fluorobenzyl halide with Cyclopropyl cyanide under Grignard reaction conditions to obtain Cyclopropyl 2-fluorobenzyl ketone;
c) optionally purifying said Cyclopropyl 2-fluorobenzyl ketone; and
d) converting said Cyclopropyl 2-fluorobenzyl ketone to Prasugrel or pharmaceutically acceptable salt thereof.
8. The process as claimed in claim 6 or claim 7 wherein said Cyclopropyl 2-

fluorobenzyl ketone is purified by High Vacuum Fractional Distillation.
9. The process as claimed in any of the preceding claims wherein said Prasugrel is treated with activated charcoal and/or neutral alumina to obtain pure Prasugrel.
10. The process as claimed in any of the preceding claims wherein said Prasugrel or pharmaceutically acceptable salt thereof is substantially free of impurity selected from the group consisting of 3-Fluoro-isomer, 4-Fluoro-isomer, 5-(α-cyclopropylcarbonyl-2-flu.oroben2yl)-2-oxo-2,4,5,6.7,7a-hexahydrothieno[3,2-c] pyridine, 2-Acetoxy-5-[α-(cycIopropylcarbonyl)benzyl]-4,5,6,7-tetrahydro thieno [3,2-c]pyridine (des-Fluoro impurity), 6-[(lRS)-2-cyclopropyl-l-(2-fruorophenyl)-2-oxoethyl]-4.5,6,7-tetrahydro thieno[2,3-c]pyridin-2-yl acetate (Positional isomer for Prasugrel), 2-Acetoxy-5-[α-(5-chloro-l-oxopentyl)-2-fluorobenzyl]-4,5,6,7-tetrahydrothieno[3.2-c]pyndine and 2-[α-Cyclopropylcarbonyl-(2-fluoro)benzyl oxy]-5-acetoxy-4,5,6,7-te1rahydrothienopyridine (N-acetyl impurity).