FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
1. Title of the invention
"Process for preparation of Prasugrel and salts thereof
2. Applicant(s)
Name Nationality Address
USV LIMITED Indian company incorporated B.S.D. Marg,, Govandi, Mumbai- 400088
under Companies Act, 1956 Maharashtra, India
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention:
The present invention relates to a process for preparation of Prasugrel or pharmaceutically acceptable salts thereof. The present invention further relates to impurities formed during the synthesis of Prasugrel, their process of preparation and use thereof as reference marker/ reference standard for determining the purity of Prasugrel.
Background of the invention:
Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. It 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 having chemical structure represented as,

Prasugrel is marketed by Daiichi Sankyo, Inc., and Eli Lilly and Company under the brand name Effient®. Effient® (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 l0mg 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 l0mg orally once daily. Patients taking Effient® have to take aspirin (75mg and 325mg) daily. Effient® may be administered with or without food.
US5288726 discloses Prasugrel and its pharmaceuticaliy acceptable salts.The process disclosed in US'726 involves reaction of 2-fluorobenzyl bromide with cyclopropyl

cyanide in the presence of magnesium and ether to provide cyclopropyl 2-fluorobenzyl ketone which is then reacted with bromine in presence of carbon tetrachloride to provide 2-fluoro-α-(cyclopropylcarbonyl) benzylbromide. The obtained 2-fluoro-α-(cyclopropylcarbonyl) benzylbromide is condensed with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one hydrochloride in the presence of anhydrous potassium carbonate in DMF to afford 5-[α-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7α-tetrahydro-4H-thieno[3,2-c]pyridin-2-one which is finally reacted with acetic anhydride and sodium hydride in DMF followed by purification using column chromatography to yield Prasugrel. The disadvantage of the prior art process is that the yield and purity of the intermediates and final compounds 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. Hence this process is not feasible on a commercial scale.
US6693115 discloses Prasugrel hydrochloride, Prasugrel maleate and process for preparation thereof. Further it discloses three crystal forms for Prasugrel hydrochloride, designated as crystal A, crystal Bl and crystal B2.
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 cyclopropyl-2-fluorobenzyl ketone, which is reacted with sulfuryl chloride to yield 2-fluoro-α-(cyclopropylcarbonyl) benzyl chloride. The obtained compound is condensed with alkyl-silyl protected tetrahydrothienopyridine compound (V) in presence of triethylamine to yield 2-(tert-butyldimethylsilyloxy)-5-[α-cyclopropylcarbonyl-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.


WO2007114526 discloses a method for producing Prasugrel hydrochloride with a reduced content of OXTP which comprising dissolving free Prasugrel containing OXTP in an inert solvent and adding hydrochloric acid to the obtained solution to get Prasugrel hydrochloride. WO'526 also discloses free Prasugrel with reduced OXTP content and Prasugrel hydrochloride with reduced OXTP content.
US4740510 discloses a process for preparation of an intermediate 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2 -one.
WO2009062044 describes process for preparation of Prasugrel and its pharmaceutically acceptable salts. WO'044 also discloses crystalline Form C, Form D, Form E and amorphous form of Prasugrel hydrochloride and process for their preparation.
WO2009066326 describes a process for preparation of Prasugrel and its pharmaceutically acceptable salts using p-toluene sulphonic acid (PTSA) salt of 5,6,7 7α-tetrahydro-4H-thieno[3,2-c] pyridin-2-one.

WO2009122440 discloses a process for the preparation of 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Prasugrel) and pharmaceutically acceptable salt thereof using 2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate and 2-acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or acid addition salt of 5-(a-cyclopropylcarbonyl-2-fluoro-benzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

WO2009129983 discloses acid addition salts of Prasugrel with an alkyl or aryl sulphonic acid and process for preparation thereof.
WO2009130289 discloses crystalline Form I of Prasugrel hydrogensulfate and process for preparation thereof.
WO2010060389 describes the preparation of Prasugrel, using 3-cyclopropyl-l-(2-fluorophenyl)-3-oxopropyl methanesulfonate for alkylation of 2-oxo-thienotetrahydropyridine followed by acetylation of the resulting compound preferably directly with acetanhydride, preferably in the reaction mixture without isolation, and the produced Prasugrel is crystallized directly from the reaction mixture.
WO2011004392 discloses crystalline form of Prasugrel hydrobromide and the process for preparation thereof.
WO2011057592 discloses a method for the production of Prasugrel or its salts, characterized in that 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one in the form of a salt with an arene sulfonic acid is reacted with l-cyclopropyl-2-halo-2-(2-fluorophenyl)ethanone in an organic solvent in the presence of an inorganic base or organic base to give, after addition of an acetylating agent and organic base to the reaction mixture, Prasugrel which, after addition of a co-solvent is y crystallized from the reaction mixture.
The following shortcomings observed in the prior art processes for preparation of Prasugrel or salts thereof are,
a) Use of environmentally hazardous solvent such as carbon tetrachloride for halogenation (bromination) reaction is not suitable on a commercial scale.
b) Use of high boiling solvent such as dimethyl formamide for alkylation reaction is not suitable since the desired product is heat sensitive. Besides, use of high boiling solvent make the isolation of the product very difficult.

c) Use of sodium hydride for acetylation reaction in dimethylformamide is not suitable on a commercial scale from safety point of view.
d) Use of column chromatography for the final product makes the process costly and time consuming thus not suitable on a commercial scale.
Thus, there exists a need to develop a process for preparation of Prasugrel or pharmaceutically acceptable salts thereof to ameliorate the problems associated with prior art. The present invention is aimed to provide a cost effective, simple and industrially feasible process for preparation of Prasugrel and salt thereof.
Object of the present invention:
An object of the present invention is to provide a cost effective, simple and industrially scaleable process for preparation of Prasugrel or its salt in high yield and high purity.
Another object of the present invention is to provide process for the preparation of substantially pure 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4J5,6,7,7a-hexahydrothieno[3,2-c]pyridine or salt thereof in high yield and purity.
Another object of the present invention provides Prasugrel or acid addition salt thereof substantially free from impurity selected from the group consisting of 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Des-fluoro impurity), 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7, 7a-hexahydrothieno[3,2-c]pyridine,6-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxo ethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2yl acetate (Positional isomer), 2-Acetoxy-5-[a-(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-tetrahydrothieno[3,2-c]pyridine(N-acetyl impurity).
Another object of the present invention is to provide process for preparation polymorphs of Prasugrel hydrobromide.

Summary of the invention:
According to one aspect of the present invention, there is provided a process for preparation of Prasugrel or pharmaceutically acceptable salts thereof comprising the steps of,
a) condensing 2-fluoro-a-(cyclopropylcarbonyl)-benzyl bromide with 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine or its acid addition salt in the presence of a suitable base and suitable solvent at low temperature to obtain a reaction mixture containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c]pyridine;
b) isolating 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine from said reaction mixture;
c) optionally converting said 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine to its acid addition salt;
d) treating said 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine or acid addition salt thereof with an acetylating agent to obtain Prasugrel, which is optionally purified;
e) optionally converting said Prasugrel to pharmaceutically acceptable salts thereof.
Preferably, condensation in step a) is carried out at a low temperature of -5 °C to 20 °C; said suitable base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or potassium hydride; said suitable solvent is selected from acetonitrile, propionitrile, dimethylformamide (DMF), dimethylsulfoxide, dimethylacetamide (DMA), N-methylacetamide, N-methylformamide, N-methylpyrrolidinone, N,N-dimethylpropionamide, sulfolane, methyl acetate, ethyl acetate, butyl acetate, acetone, diethyl ketone, methylethyl ketone or methyl isobutyl ketone.
Preferably, isolation in step b) is carried out by filtering the reaction mixture containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexa hydro thieno[3,2-c]pyridine followed by concentrating the filtrate under vacuum to obtain an

oily residue; treating the oily residue with solvent selected from methyl tert butyl ether, diethyl ether, 1,4-dioxane, toluene, xylene, n-hexane, cyclohexane or mixture thereof to obtain a residue containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyI)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine.
Preferably, acid addition salt in step c) is hydrochloride and said conversion to the corresponding hydrochloride salt is achieved by treating the residue containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine with HC1 in a lot wise manner at a temperature of about 20°C to 40°C followed by optionally seeding with 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride.
Preferably, acetylation in step d) is carried out using acetic anhydride or acetyl chloride at temperature of -10°C to 0°C in a solvent selected from acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, N-methylacetamide or N-methylformamide in the presence of base selected from triethylamine, trimethylamine, tributylamine, pyridine, N-methylmorpholine or diisopropylethylamine; and catalyst selected from 4-dimethylaminopyridine, 4-diethylaminopyridine or 4-dipropylaminopyridine.
Another aspect of the present invention provides 2-Acetoxy-5-[a-(cyclopropyl carbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Des-fluoro impurity) represented by the following formula

Another aspect of the present invention provides process for preparation of 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Des-fluoro impurity) or salts thereof comprising the steps of,

a) treating 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate with tert-butyldimethylchlorosilane in presence of base and solvent to obtain silylated product;
b) condensing a-(cyclopropylcarbonyl) benzyl bromide with said silylated product to obtain 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclo propylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
c) optionally purifying said 2-(tert-butyldimethylsilyloxy)-5-[a-(cyclo propyl carbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
d) acetylating 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl) benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in presence of base to obtain 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydro thieno[3,2-c]pyridine, which is optionally purified;
e) optionally converting 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5, 6,7-tetrahydrothieno[3,2-c]pyridine to salts thereof.
Preferably, treatment in step a) is carried out at temperature of 10°C to 30°C; said base is selected from triethylamine, tributylamine, pyridine, N-methylmorpholine or diisopropylethylamine; said solvent is selected from methylene dichloride, ethylene dichloride, acetonitrile, propionitrile, benzonitrile, diethyl ether, 1,4-dioxane, tetrahydrofuran, toluene or xylene.
Another aspect of the present invention provides process for preparation of 2-[a-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (N-acetyl impurity) comprising the steps of,
a) condensing 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin -2- one-p-toluene sulphonate with 2-fluoro-a-cyclopropylcarbonylbenzyl bromide to obtain 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-4,5,6,7-tetrahydrothieno [3,2-c] pyridine;
b) acetylating said 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-4,5,6,7-tetrahydrothieno [3,2-c] pyridine with acetic anhydride or acetyl chloride in

presence of base to obtain 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (N-acetyl impurity).
Another aspect of the present invention provides Prasugrel or pharmaceutically
acceptable salts thereof substantially free of impurity selected from the group
consisting of 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (Des-fluoro impurity), 5-(a-cyclopropylcarbonyl-2-
fluorobenzyl)-2-oxo-2,4,5,6,7, 7a-hexahydrothieno[3,2-c]pyridine, 6-[(lRS)-2-
cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2yl acetate (Positional isomer), 2-Acetoxy-5-[α-(5-chloro-l-oxopentyl)-2-fluorobenzyl]-4,5,6,7-tetra hydrothieno[3,2-c]pyridine and 2-[a-cyclopropylcarbonyl-(2-fluoro) benzyl oxy]-5-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(N-acetyl impurity).
Brief description of the drawings:
Fig. 1: X-ray powder diffraction pattern of Prasugrel.
Fig.2: 13C-NMR spectrum of Prasugrel.
Fig.3 : X-ray powder diffraction pattern of Prasugrel hydrochloride.
Fig.4: X-ray powder diffraction pattern of 5-(α-cyclopropyl carbonyl-2-fluoro
benzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride.
Fig.5: IR of 5-(a-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexa hydro
thieno[3,2-c]pyridine hydrochloride.
Fig.6 : X-ray powder diffraction pattern of Prasugrel hydrobromide Form I.
Fig.7 : X-ray powder diffraction pattern of Prasugrel hydrobromide Form II.
Fig. 8: 1H-NMR Spectrum of Desfluoroprasugrel.
Fig. 9: 13C-NMR spectrum of Desfluoroprasugrel.
Detailed description of the invention:
The present invention provides a simple, cost effective and industrially scalable process for preparation of Prasugrel or its pharmaceutically acceptable salt in high yield and purity.

According to one embodiment of the present invention the process for preparation of Prasugrel or pharmaceutically acceptable salts thereof comprises the steps of,
a) condensing 2-fluoro-α-(cyclopropylcarbonyl)-benzyl bromide with 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine or its acid addition salt in the presence of a suitable base and suitable solvent at low temperature to obtain a reaction mixture containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine;
b) isolating 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexa hydrothieno[3,2-c]pyridine from said reaction mixture;
c) optionally converting the 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine to its acid addition salt;
d) treating 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine or acid addition salt with an acetylating agent to obtain Prasugrel, which is optionally purified;
e) optionally converting the obtained Prasugrel to pharmaceutically acceptable salts thereof.
Suitable solvent is selected from polar aprotic solvents such as acetonitrile, propionitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl acetamide, N-methylformamide, N-methylpyrrolidinone, N,N-dimethyl propionamide, dimethylsulfoxide, sulfolane, methyl acetate, ethyl acetate, butyl acetate, acetone, diethyl ketone, methylethyl ketone, methyl isobutyl ketone, preferably acetonitrile.
Suitable base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride and the like, preferably potassium carbonate.
According to a preferred embodiment of the present invention, the process for preparation of Prasugrel comprises the steps of,
Step I involves the condensation of 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine or its hydrochloride salt with 2-fluoro-a-(cyclopropylcarbonyl) benzyl

bromide in acetonitrile in presence of potassium carbonate at a low temperature of about -5°C to 20°C, preferably 0°C to 15°C to obtain a reaction mixture containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine. The reaction mixture is stirred for 18 to 26 hours, preferably for 24 hours at a low temperature, of about -5°C to 20°C, preferably at 0°C to 15°C. After the completion of the reaction, the reaction mixture is filtered followed by concentrating the filtrate under vacuum to obtain an oily residue. The obtained oily residue is treated with a solvent selected from methyl tert butyl ether, diethyl ether, 1,4 -dioxane, toluene, xylene, n-hexane, cyclohexane or mixture thereof, preferably methyl tert butyl ether and the mixture is stirred for 20 to 40 min, preferably for 30 min. The solid mass which precipitates out is filtered off. The filtrate is concentrated to obtain a residue containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexa hydro thieno[3,2-c]pyridine.
Step II involves treating the residue containing 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine with a salt forming agent at a temperature of 20°C to 40°C to obtain the corresponding salt of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine. Salt forming agent is selected from HC1, SOCl2, NH4C1, HBr, acetic acid, formic acid or the like. Salt forming agent can be employed either as its solution in water or any other organic solvent. Preferably about 35% to 36% aqueous HC1 is employed for the preparation of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexa hydrothieno[3,2-c]pyridine hydrochloride in a purity of about 90%.
Step III involves acetylating 5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexa hydro thieno-[3,2-c]-pyridine or its acid addition salt with acetic anhydride at a temperature of -10 to 0°C in a suitable solvent selected from acetonitrile, propionitrile, dimethylformamide (DMF), dimethylacetamide, N-methylacetamide, N-methylformamide in presence of base selected from triethyl amine, tributyl amine, pyridine, N-methylmorpholine or diisopropylethyl amine and catalyst selected from 4-dimethylaminopyridine, 4-diethylaminopyridine or 4-

dipropylaminopyridine. After the completion of the reaction, the reaction mixture is treated with potassium dihydrogen phosphate followed by isolation of Prasugrel.
Step IV involves purification of Prasugrel by dissolving Prasugrel in a suitable solvent selected from acetonitrile, acetone, DMF or methyl ethyl ketone to obtain a solution. This solution is then treated with charcoal and/or neutral alumina followed by filtration. The product is obtained from the filtrate by cooling and/or antisolvent treatment. The product is isolated and dried.
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 charcoal at 35°C-40°C. The mixture is filtered and the obtained filtrate is cooled to -10°C. Water is added to the cooled filtrate and the separated product is filtered to obtain Prasugrel which is washed with aqueous acetonitrile. Prasugrel is obtained in purity of more than 99%.
Step V 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 HC1, SOCl2, NH4C1, HBr, acetic acid or formic acid to the obtained solution; and
c) isolating desired Prasugrel salt from the solution of step b).
Preferably, Prasugrel hydrochloride is prepared by treating a solution of Prasugrel base in acetone with concentrated HCl at 35°C to 40°C to obtain a reaction mixture. Concentrated 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 concentrated 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%.

The formation of Prasugrel salt can be accelerated by seeding the mixture with the desired salt, preferably 1% Prasugrel hydrochloride w.r.t. Prasugrel base is used.
Prior art discloses that the condensation reaction is carried out at room temperature. It was found by the inventors of the present invention that carrying the condensation reaction at room temperature results in low yield due to generation of impurities. It has been surprisingly found that carrying out the condensation reaction at low temperature provides consistent yield and improves the quality of the resultant product.
The use of ethyl acetate and toluene for the work-up procedure is reported in the prior art. The present invention uses methyl tert butyl ether, diethyl ether, 1,4 -dioxane, toluene, xylene, n-hexane or cyclohexane, preferably methyl tert-butyl ether as the solvent for the work-up procedure. Use of methyl tert-butyl ether enables easy isolation of the desired product due to its low boiling point. Besides, methyl tert-butyl ether helps in easy removal of impurities formed during the condensation reaction. Use of a single solvent also enables easy recycling.
According to a preferred embodiment, 5-(α-cyclopropylcarbonyl-2-fluorobenzy])-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine is converted to its hydrochloride salt by treating the residual mass containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine with about 35% to 36% aqueous HC1 in a suitable solvent selected from acetone, diethylketone, methylethylketone, methylisobutyl ketone, DMF, acetonitrile, methanol, ethanol, n-propanol or isopropanol, preferably acetone to obtain the hydrochloride salt of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine. The treatment with aqueous HC1 is carried out in a lot wise manner at temperature of about 20°C to 40°C, preferably at 25°C to 35°C to obtain mixture. The obtained mixture is seeded with 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride and the mixture stirred over a period of 10 to 20 min, preferably for 15 min at the same temperature. The mixture is further treated with another lot of about 35% to 36% aqueous HC1 at the

same temperature followed by stirring for 8 to 12 hours, preferably for 10 hours to obtain a solid. The obtained 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride is filtered, washed with solvent used for dissolution, preferably acetone and dried.
The lot wise addition of salt forming agent, preferably aqueous HC1 avoids the opening of the cyclopropyl ring and generation of unwanted impurities. Seeding helps in accelerating the process of product precipitation. Besides, it helps in preventing the opening of the cyclopropyl ring.
In a preferred embodiment of the present invention, 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride is characterized by X-ray powder diffraction pattern as shown in Fig. 4. It is further characterized by X-ray powder diffraction spectra having peaks expressed as 2-theta values of about 6.97, 10.15, 14.79, 19.40, 20.28, 21.07, 21.50, 22.19, 23.34, 24.04, 24.45, 26.31, 26.74 and 27.44 degrees. It is further characterized by an infrared spectrum (IR) as shown in Fig. 5 showing bands at 3045, 3014, 2958, 2920, 2870, 2794, 2627, 2600, 2544, 2519, 1944, 1801, 1714, 1685, 1643, 1614, 1587, 1494, 1452, 1438, 1406, 1377, 1361, 1356, 1338, 1278, 1253, 1238, 1159, 1091, 1078, 1116, 1060, 1043, 1014, 995, 952, 926, 910, 877, 868, 846, 815, 800, 786, 765, 738, 705, 684, 638, 613, 570, 555, 493, 470, 424 cm -1.
Another embodiment of the present invention provides a process for the preparation of Prasugrel or pharmaceutically acceptable salts thereof comprising treating 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine or salt thereof with acetic anhydride in the presence of triethylamine and/or 4-dimethylaminopyridine in a suitable solvent at a temperature of -10°C to 10°C to obtain Prasugrel.
In a preferred embodiment, the process comprises the basiflcation of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine hydrochloride to obtain 5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-

2,4,5,6,7,7a-hexahydrothieno[3,2-c]-pyrid}ne; treating 5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexa hydro thieno-[3,2-c]-pyridine with acetic anhydride in the presence of triethylamine, 4-dimethylaminopyridine and acetonitrile at a temperature of -10°C to 0°C to obtain a reaction mixture; After the completion of reaction, potassium dihydrogen phosphate and water are charged to the reaction mixture and stirred for 40 to 80 min, preferably for 60 min by maintaining temperature at -10°C to 0°C to get solid mass. The obtained solid mass is filtered, washed with 50% aqueous acetonitrile and dried under vacuum to obtain 2-acetoxy-5-(a-cyclo propylcarbonylfluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Prasugrel) in purity of more than 98%.
The process for preparation of Prasugrel salts according to the present invention is illustrated by the following reaction scheme:

An alternate embodiment of the present invention provides the process for the preparation of Prasugrel or pharmaceutically acceptable salts thereof comprising the steps of,

a) treating 5,6,7a4etrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate with tert-butyldimethylchlorosilane in presence of base and solvent to obtain silylated product;
b) condensing 2-fluoro-α-(cyclopropylcarbonyl)-benzyl bromide with the obtained silylated product to obtain 2-(tert-butyldimethylsilyloxy)-5-(α-cyclo propylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
c) optionally purifying the obtained 2-(tert-butyldimethylsilyloxy)-5-(α-cyclo propylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
d) acetylating 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,74etrahydrothieno[3,2-c]pyridine with suitable acetylating agent in presence of base and solvent to obtain Prasugrel, which is optionally purified;
e) optionally converting prasugrel to its pharmaceutically acceptable salts.
Other halogenated silanes are selected from trimethylchlorosilane, triethylchlorosilane, tripropylchlorosilane, triisopropylchlorosilane or tert-butyldiphenylchlorosilane. Base used is selected from as triethylamine, tributylamine, diisopropylethylamine, pyridine or N-methylmorpholine. Solvent is selected from methylene dichloride, ethylene dichloride, acetonitrile, propionitrile, benzonitrile, diethyl ether, 1,4-dioxane, tetrahydrofuran, toluene, xylene, preferably methylene dichloride.
In a preferred embodiment, the process for the preparation of Prasugrel or pharmaceutically acceptable salts thereof comprises the steps of, Step I :
5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one -p-toluene sulfonate is treated with tert-butyldimethylchlorosilane in presence of triethylamine and methylene dichloride at temperature of 10°C to 30°C, preferably at 15°C to 20°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°C to 55°C, preferably 45°C to 50°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 an halogenated solvent, such as methylene dichloride. 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 25°C to 35°C for 20 to 40 min, preferably for 30 min followed by addition of water. The mixture is cooled to 0°C 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-tetra hydrothieno[3,2-c]pyridine in purity of more than 97.5%.
Step II:
It involves the process for purification of 2-(tert-butyldimethylsilyloxy)-5-(a-
cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
comprising dissolving the obtained 2-(tert-butyldimethylsilyloxy)-5-(a-
cyclopropylcarbonyl-2-fluorobenzyl)-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°C to 60°C, preferably at 50°C to 55°C to obtain clear solution. The obtained clear solution is stirred for 5 to 15 min, preferably for 10 min and cooled to 20°C to 40°C, preferably 25°C to 35°C and stirred for 20 to 40 min, preferably for 30 min. Water is added to the obtained solution and the mixture is cooled to 0°C 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-tetrahydrothieno[3,2-c]pyridine in purity of more than 98%.

Step III:
The obtained 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropyl carbonyl-2-fluoro benzyl) -4,5,6,7- tetrahydrothieno[3,2-c] pyridine is taken in acetonitrile to obtain a mixture and the mixture is cooled to 10°C to 25°C, preferably 15°C to 20°C. 4-dimethyl 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 0°C to 5°C followed by drop-wise addition of acetic anhydride at 0°C to 10°C over a period of 10 to 20 min, preferably 15 min. The obtained reaction mixture is stirred at -20°C 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°C to 0°C for 30 to 90 min, preferably for 60 min to obtain solid. The obtained solid is washed with acetonitriie, 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 IV involves purification of Prasugrel which comprises,
a) dissolving Prasugrel in suitable solvent selected from acetonitriie, 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;
d) isolating pure Prasugrel.
Preferably, Prasugrel base is dissolved in acetonitriie at 35°C-40°C to get a clear solution. The obtained clear solution is treated with neutral alumina and/or charcoal at 35°C-40°C. The mixture is filtered and the obtained filtrate is cooled to -10°C. Water is added to the cooled filtrate and the separated product is filtered to obtain Prasugrel which is washed with aqueous acetonitriie. Prasugrel is obtained in purity of more than 99%.
Step V 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 HC1, SOCI2, NH4C1, HBr, acetic acid or formic acid to the obtained solution; and
c) isolating desired Prasugrel salt from the solution of step b).
Preferably, Prasugrel hydrochloride is prepared by treating a solution of Prasugrel base in acetone with concentrated HC1 at 35°C to 40°C to obtain a reaction mixture. Concentrated HC1 is added in a drop-wise manner. The reaction mixture is seeded with crystal Bl or 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 concentrated 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%.
Prasugrel obtained according to the present invention is characterized by X-ray powder diffraction pattern as represented in Fig.l. It is further characterized by l3C-NMR spectrum as shown in Fig. 2.
Prasugrel hydrochloride obtained according to present invention is characterized by X-ray powder diffraction pattern as shown in Fig. 3. It is further characterized by 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).
2-Fluoro-a-(cyclopropylcarbonyl)benzyl bromide used in the synthesis of Prasugrel can be synthesized by any process known in the art or by a process comprising the steps of,
a) treating 2-fluorobenzyl-cyclopropyl ketone with N-bromosuccinimide in presence of radical initiator such as AIBN or benzoyl peroxide and solvent selected from methylene dichloride, ethylene dichloride, cyclohexane or 1,1,1

trichloroethylene at reflux temperature to obtain 2-fluoro-α-cyclopropylcarbonyl)benzyl bromide; b) isolating 2-fluoro-a-(cyclopropylcarbonyl)benzyl bromide .
Preferably, the process for preparation of 2-fluoro-a-(cyclopropylcarbonyl)-benzyl bromide comprises treating 2-fluorobenzyl-cyclopropyl ketone with N-bromosuccinimide in presence of AIBN and ethylene dichloride at reflux temperature, preferably at 75°C to 80°C. The addition of initiator is carried out in lot-wise manner over a period of 1 to 5 hours, preferably for 3 hours. The obtained mixture is stirred for a period of 6 to 10 hours, preferably 8 hours at the same temperature. After the completion of reaction, the reaction mixture is cooled to room temperature, preferably 20°C to 25°C and stirred for 20 to 40 min, preferably for 30 min followed by filtration. The obtained filtrate is washed with 5% sodium metabisulfite solution and water followed by separation of the organic layer. The organic layer is separated, dried over sodium sulphate and concentrated under vacuum to obtain 2-fluoro-α-(cyclopropylcarbonyl)benzyl bromide.
5,6,7,7a-tetrahydro-4H-thieno-[3,2-c]pyridin-2-one-p-toluene sulphonate, used in the preparation of Prasugrel, can be prepared by treating 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one with p-toluenesulfonic acid monohydrate in presence of tetrahydrofuran at 40°C to 60°C, preferably 50°C for about 2 to 4 hours to obtain 5,6,7,7a-tetrahydro-4H-thieno-[3,2-c]pyridin-2-one-p-toluene sulphonate.
Another embodiment of the present invention provides process for preparation of Prasugrel hydrobromide which comprises the steps of,
a) dissolving Prasugrel or salt thereof in suitable solvent to obtain a solution;
b) treating the obtained solution with HBr followed by isolation of Prasugrel hydrobromide.
Solvent used for dissolution of Prasugrel includes ketone, alcohol, ester, ether or mixture thereof. Said ketone is selected from acetone, 2- butanone or diethylketone preferably acetone; Said alcohol is selected from methanol, ethanol, 2-propanol or

butanol; Said ester is selected from ethyl acetate or methyl acetate and said ether is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF or 1,4-dioxane. HBr is used as an aqueous solution, alcoholic solution or as a solution in any other organic solvent. Preferably 15% solution of HBr in isopropyl alcohol is employed. Preferably, the mixture containing Prasugrel and HBr is stirred for about 2 to 26 hours to get Prasugrel hydrobromide.
In a preferred embodiment of the present invention, the mixture of Prasugrel 15% HBr/isopropyl alcohol and acetone is stirred for 2 to 4 hours to obtain Prasugrel hydrobromide Form I characterized by an X-ray powder diffraction pattern as shown in Fig. 6. Prasugrel hydrobromide Form I obtained according to the present invention is further characterized by X-ray diffraction pattern having peaks at 20 values of about 7.94, 8.36, 11.82, 12.63, 12.91, 15.24, 17.34, 18.14, 19.43, 20.49, 22.66, 23.39, 24.59, 24.98, 25.98, 26.93, 27.72, 29.18, 30.76, 31.87, 33.35, 37.45 and 39.72 degrees.
In a preferred embodiment of the present invention, the mixture of Prasugrel 15% HBr/isopropyl alcohol and acetone is stirred for 24 hours to obtain Prasugrel hydrobromide Form II characterized by an X-ray powder diffraction pattern as shown in Fig. 7. Prasugrel hydrobromide Form II obtained according to the present invention is further characterized by X-ray diffraction pattern having peaks at 20 values of about 7.16, 8.43, 10.21, 12.32, 13.84, 15.92, 16.80, 17.09, 17.83, 18.50, 18.79, 21.80, 23.55, 23.83, 24.53, 25.28, 25.90, 26.42, 27.14, 28.23, 29.18, 30.00, 30.49, 31.82, 32.84, 34.42, 37.40, 40.28 and 42.70.
Prasugrel or salt thereof used for preparation of Form I and Form II of Prasugrel hydrobromide may be any crystalline form of Prasugrel or salts thereof.
The present inventors have invented a simple process for preparation, purification of Prasugrel base and its conversion to its acid addition salts, minimizing the impurities formed during the process as compared to the prior art process, without using column chromatography thereby making the process cost effective and commercially viable.

Prasugrel or Prasugrel hydrochloride obtained according to the present invention shows the following impurity profile:

Imp at RRT 0.29 Imp at RRT 0.88 Imp at RRT 1.06 Imp at
1.70 RRT Purity
Prasugrel Base Not detectable 0.09 0.09 0.05 99.5
Prasugrel
hydrochloride 0.01 0.06 0.09 0.04 99.8
According to another embodiment of the present invention, there is provided Prasugrel or salt thereof substantially free of impurity selected from group consisting of,
a) impurity at RRT 0.29, namely 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-
oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine, a key intermediate used for
preparing Prasugrel;

b) impurity at RRT 0.88, namely 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(Des-fluoro impurity;

c) impurity at RRT 1.06, namely 6-[(lRS)-2-cyclopropyl-l-(2- fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl acetate (Positional isomer for Prasugrel);


d) impurity at RRT 1.70, namely 2-Acetoxy-5-[a-(5-chloro-l-oxopentyl)-2-fluorobenzyl]4,5,6,7-tetrahydrothieno[3,2-c]pyridine;

e) 2-[a-Cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4,5,6,7tetrahydro thienopyridine (N-acetyl impurity).

In the practice of the present invention, impurity at RRT 0.29 is likely to be formed due to acid hydrolysis of ester; impurity at RRT 0.88 is likely to be formed, if any unreacted benzyl bromide remains in 2-fluoro benzyl bromide, a starting material of 2-fluorobenzylcyclopropyl ketone; impurity at RRT 1.06 is likely to be formed, if 2-oxo-4,5,6,7-tetrahydrothieno [2,3-c] pyridine hydrochloride remains in 2-oxo-4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride, key raw material; and impurity at RRT 1.7 is likely to be formed due to opening of the cyclopropyl ring.
According to another embodiment of the present invention, there is provided 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, desfluoro impurity.
Another embodiment of the present invention provides the process for the preparation
of 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]
pyridine(desfluoro impurity) or salts thereof comprising the steps of,

a) treating 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate with tert-butyldimethylchlorosilane in presence of base and solvent to obtain silylated product;
b) condensing a-(cyclopropylcarbonyl)benzyl bromide with the obtained silylated product to obtain 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl) benzyl]-4,5,6,7-tetrahydrothieno [3,2-c]pyridine;
c) optionally purifying the obtained 2-(tert-butyldimethylsilyloxy)-5-[a-(cyclopropylcarbonyl) benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
d) acetylating 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl) benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine with suitable acetylating agent in presence of base and solvent to obtain 2-Acetoxy-5-[α-(cyclopropyl carbonyl) benzyl]-4,5,6,7-tetrahydromieno[3,2-c]pyridine, which is optionally purified;
e) optionally converting 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to salts thereof.
Other halogenated silanes are selected from trimethylchlorosilane, triethylchlorosilane, tripropylchlorosilane, triisopropyl chlorosilane or tert-butyldiphenylchlorosilane. Base used is selected from triethylamine, tributylamine, pyridine, N-methylmorpholine or diisopropylethylamine; solvent is selected from methylene dichloride, ethylene dichloride, acetonitrile, propionitrile, benzonitrile, diethyl ether, 1,4-dioxane, tetrahydrofuran, toluene, xylene, preferably methylene dichloride.
In a preferred embodiment, the process for the preparation of 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine comprises the steps of, Step I:
5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin-2-one -p-toluene sulfonate is treated with tert-butyldimethylchlorosilane in presence of triethylamine and methylene dichloride at temperature of 10°C to 30°C, preferably at 15°C to 20°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 (x-(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°C to 55°C, preferably 45°C to 50°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 an halogenated solvent, such as methylene dichloride. 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 25°C to 35°C for 20 to 40 min, preferably for 30 min followed by addition of water. The mixture is cooled to 0°C 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)benzyl]-4,5,6,7-tetrahydrothieno [3,2-c]pyridine in purity of more than 90%.
Step II:
It involves the process for purification of 2-(tert-butyldimethylsilyloxy)-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetra hydrothieno[3,2-c]pyridine, comprising dissolving the obtained 2-(tert-butyldimethylsilyloxy)-5-[a-(cyclopropyl carbonyl) benzyl]-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°C to 60°C, preferably at 50°C to 55°C to obtain clear solution. The obtained clear solution is stirred for 5 to 15 min, preferably for 10 min and cooled to 20°C to 40°C, preferably 25°C to 35°C and stirred for 20 to 40 min, preferably for 30 min. Water is added to the obtained solution and the mixture is cooled to 0°C 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)benzyl]-4,5,6,7-tetrahydrothieno [3,2-c]pyridine in purity of more than 95%.

Step III:
The obtained 2-(tert-butyldimethylsilyloxy)-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6, 7-tetrahydrothieno[3,2-c]pyridine is taken in acetonitrile to obtain a mixture and the mixture is cooled to 10°C to 25°C, preferably 15°C to 20°C. 4-dimethyl 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 0°C to 5°C followed by drop-wise addition of acetic anhydride at 0°C to 10°C over a period of 10 to 20 min, preferably 15 min. The obtained reaction mixture is stirred at -20°C 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°C to 0°C for 30 to 90 min, preferably for 60 min to obtain 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, which is washed with acetonitrile, water or mixture thereof and dried.
Other acylating catalyst which can be used in place of 4-dimethylaminopyridine is 4-diethylaminopyridine or 4-dipropylaminopyridine.
Step IV involves conversion of 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine to its hydrochloride salt by treating a solution
of 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]
pyridine in acetone with cone. HC1 at about 25°C to 45°C for about 1 to 4 hours.
Another embodiment of the present invention provides 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine characterized by ]H- NMR spectrum as shown in Fig. 8 and 13C-NMR spectrum as shown in Fig. 9.
The process for the preparation of 2-Acetoxy-5-[α-(cyclopropylcarbonyI)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine according to the present invention is illustrated in Scheme 2 below,


According to another embodiment of the present invention, there is provided a process for preparation of 6-[(lRS)-2-cyclopropyl-l-(2- fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl acetate, a positional isomeric impurity comprising the steps of,
a) condensing 5,6,7,7a-tetra hydro-4H-thieno[2,3-c]pyridin-2-one-p-toluene sulphonate with 2-fluoro-α-cyclopropylcarbonylbenzyl bromide in the presence of tert-butyldimethylchlorosilane, triethylamine and methylene dichloride to obtain 2-(tert-butyldimethylsilyloxy)-6-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine;
b) acetylating 2-(tert-butyldimethylsilyloxy)-6-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in presence of a suitable base and solvent to obtain 6-[(lRS)-2-cyclopropyl-l-(2- fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl acetate.

The process for the preparation of 6-[(lRS)-2-cyclopropyl-l-(2- fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl acetate, positional isomer of Prasugrel according to the present invention is illustrated in Scheme 3 below,

According to another embodiment of the present invention, there is provided a process for preparation of 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy- 4,5,6,7-tetrahydrothieno pyridine (N-acetyl impurity) comprising the steps of,
a) condensing 5,6,7,7a-tetrahydro-4 H-thieno- [3,2-c] pyridin -2- one -p-toluene sulphonate with 2-fluoro-α-cyclopropylcarbonylbenzyl bromide to obtain 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy] - 4,5,6,7-tetrahydro thieno[3,2c] pyridine;
b) acetylating 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-4,5,6,7-tetrahydro thieno[3,2c] pyridine with a suitable acetylating agent in presence of a suitable base and solvent to obtain 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4,5,6,7-tetrahydrothienopyridine (N-acetyl impurity).

The process for the preparation of 2-[a-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy- 4,5,6,7-tetrahydrothieno pyridine (N-acetyl impurity) according to the present invention is illustrated in Scheme 4 below,

Another embodiment of the present invention provides acid addition salt of Prasugrel, substantially free 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7 tetrahydrothieno[3,2-c]pyridine (Prasugrel base).
All the above mentioned impurities are used as reference marker and/or reference standard for determining the purity of Prasugrel or salts thereof.
Apart from potential process related impurities, there are some genotoxic impurities. The control of these potent impurities is critical which are generally controlled at very low levels i.e., ppm and ppb range.This poses many challenges in the analytical meth-ods to detect and further separating these impurities during the synthetic process. As per Muller guidelines and based on daily dose of product, the limit assigned for these impurities is NMT 150 ppm. The presence or absence of these impurities have been studied by the inventors of the present invention. Surprisingly the inventors found that the process of the present invention provides substantially pure Prasugrel or pharma-

ceutically acceptable salt thereof where these impurities are controlled well below 150
ppm thus complying the ICH guidelines.
Various genotoxic impurities may be present in the final API which are as described
below,
a) 2-fluorobenzyl bromide:

2-fluorobenzyl bromide is starting raw material of 2-fluorobenzyl cyclopropyl ketone.
b) 2-Fluoro-α-(cyclopropylcarbonyl)benzyl bromide

2-Fluoro-α-(cyclopropylcarbonyl)benzyl bromide is the brominated product obtained after bromination of 2-fluorobenzyl cyclopropyl ketone.
c) Mesityl oxide (4-methylpent-3-en-2-one):

Acetone is used as solvent for preparation of Prasugrel hydrochloride and hence formation of mesityl oxide is quite possible.
d) Formaldehyde : HCHO
Formaldehyde is raw material used during the preparation 2-oxo -tetrahydrothieno pyridine.

e) Thiophene 2-ethyl tosylate :

Imophene 2-ethyl tosylate is raw material used during the preparation 2-oxo -tetrahydro thieno pyridine.
f) Trityl chloride (Triphenylmethyl chloride):

Trityl chloride (Triphenylmethyl chloride) is used during the preparation of 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine.
The present invention provides a consistent process for preparation of Prasugrel or salts thereof having all impurities NMT 0.15% preferably NMT 0.1%. The present invention can be used to prepare different salts of Prasugrel such as maleate, fumarate, oxalate, mesylate, esylate, besylate, tosylate, sulphate, acetate, phosphate, tartrate and the like.
Prasugrel or hydrochloride or hydrobromide salt obtained according to the present invention has particle size such that about 90% of the particles have particle size less than about 500 microns. Preferably, about 90% of the particles have particle size less than about 300 microns, Prasugrel hydrochloride thus obtained may be micronized by conventional techniques to get micronized particles to enhance the desired properties of the active in the pharmaceutical composition such that about 90% of the particles have a particle size less than about 100 microns, preferably less than about 50 microns, more preferably less than about 25 microns, most preferably less than about 10 microns.
The processes of the present invention have several advantages, which are as follows:

a) The present invention uses ethylene dichloride, cyclohexane or 1,1,1 trichloroethylene as a solvent for halogenation which are less hazardous to environment as compared to carbon tetrachloride used in the prior art.
b) The present invention carries the condensation reaction at low temperature to improve the quality and yield of the Prasugrel.
c) The present invention uses low boiling acetonitrile for alkylation reaction which gives much cleaner product as compared to DMF, which is high boiling. Thus recovery and recycling of solvent is much easier and less energy consuming.
d) Lot wise addition of salt forming agent, preferably aqueous HC1 avoids the opening of the cyclopropyl ring and generation of unwanted impurities.
e) Judicious choice of solvents such as methyl tert butyl ether for work-up helps in reducing the impurities.
f) The present invention provides pure Prasugrel base without using column chromatography.
Another embodiment of the present invention provides pharmaceutical composition comprising Prasugrel or Prasugrel hydrochloride or Prasugrel hydrobromide or any polymorph thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions may be prepared by any conventional techniques known in the art.
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 1%,
preferably less than about 0.5%, more preferably less than about 0.3%, most
preferably less than about 0.15% of impurities or other polymorphic forms.

General Experimental Conditions X-ray Powder Diffraction (XRPD)
The X-ray powder diffraction pattern was obtained on Xpert'PRO, PANalytical, diffractometer equipped with accelerator detector using Copper Kα (n = 1.5406 A) radiation with scanning range between 2-theta 4-50° at a scanning speed of 2°/min.
IR Spectral Analysis:
IR spectra was recorded on SHIMADZU FT-IR spectrometer in the energy range of 4000 to 400cm-1.
NMR Spectral Analysis:
NMR spectra was recorded using a Bruker 400 MHz FT-NMR spectrometer in DMSO-d6.
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention.
Examples:
Example 1:
a) 2-Fluoro-α-(cyclopropylcarbonyl) benzyl bromide
2-Fluorobenzyl-cyclopropyl ketone (100 gm, 0.561 mol) was taken in 1000 ml of ethylene dichloride and 4 gm of of AIBN (0.042 mol) was added to the mixture. N-bromo succinimide (119.81 gm, 0.67 mol) was added lot wise to the obtained mixture by maintaining temperature at 75°C - 80°C over a period of 3 hours and the mixture was stirred at the same temperature for 8 hours. After completion of reaction, the reaction mixture was cooled to 20°C-25°C followed by stirring for 30 min and filtered. The obtained solid was washed with 100 ml of ethylene dichloride. The solid mass was discarded and the obtained filtrate was washed with 800 ml of 5% sodium metabisulfite solution followed by washing with water (3 x335 ml). The separated organic layer was dried on anhydrous sodium sulfate and concentrated under vacuum followed by degassing the residue at 50°C - 55°C to remove the traces of ethylene dichloride to get the titled product as yellow oil.

Yield: more than 90%; Purity : more than 80%.
b) The process of example 1 (a) was repeated by adding N-bromo succinimide (NBS) in one lot instead of lot-wise addition of NBS to get 2-fluoro -α-(cyclopropyl carbonyl) benzyl bromide.
c) The process of example 1 (a) was repeated by adding 0.58 mol of N-bromo succinimide instead of 0.67 mol of N-bromo succinimide to get 2-fluoro-α-(cyclopropyl carbonyl) benzyl bromide.
Example 2
5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,67,7a-hexahydrothieno [3,2-c]pyridine and its hydrochloride
(a) 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride (75 gm, 0.391 mol) and 750 ml of acetonitrile were taken in a round bottom flask under nitrogen atmosphere. 118.94 gm of anhydrous potassium carbonate (0.86 mol) was charged to the mixture and the mixture was stirred at 25°C-35°C for 1 hr. The reaction mixture was then cooled to 0°C to 15°C and 2-fluoro-α-(cyclopropyl carbonyl) benzyl bromide (146.68 gm, 0.57 mol) in acetonitrile (375 ml) was added dropwise to the cooled mass within 3 hrs maintaining the temperature at 0°C-15°C through out the addition. The reaction mixture was stirred at 0°C - 15°C for 24 hr. After reaction completion, the mixture was filtered and the filtrate was distilled under vacuum at 45°C-50°C to get oily residue. 750ml of methyl tert butyl ether was charged to the obtained residue and the mixture was stirred for 30 min. The separated solid mass was filtered and washed with 150 ml of methyl tert.butyl ether followed by water. The collected solvent layer was concentrated under vacuum at 40°C- 45°C to get residual mass. 150 ml of acetone was charged to the obtained residue and 22.65 gm (0.226 mol) of 36 % aqueous hydrochloric acid was added to it at 25°C-35°C within 15min. The obtained mixture was seeded with the titled product and the mixture was stirred for 15 min at 25°C-35°C. The mixture was treated with another lot of aqueous hydrochloric acid (7.55 gm, 0.191m) at 25°C-35°C maintaining pH of the mixture

between 0 to 2 and stirred for 10 hrs. The obtained solid was washed with (2 x 20 ml) acetone and dried at 50°C-55°C for 6-8 hrs in air oven to get the titled product. Yield: 53% w/w; Purity : 90%.
(b) 2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride (75 gm, 0.3912
M) and 750 ml of acetonitrile were taken round bottom flask under nitrogen
atmosphere. 108.12 gm of anhydrous potassium carbonate (0.782 mol) was charged to
the mixture and the mixture was stirred at 25-35°C for 1 hr. The reaction mixture was
cooled to 0°C to 15°C and 2-fluoro-a-(cyclopropyl carbonyl) benzyl bromide (146.68
gm, 0.570M) in acetonitrile (375 ml) was added dropwise to the cooled mass within 3
hrs maintaining the temperature at 0°C-15°C and nitrogen atmosphere through out the
addition. The reaction mixture was then stirred at 0°C - 15°C for 24 hr. After reaction
completion, the mixture was filtered and the filtrate was distilled under vacuum at
45°C-50°C to get oily residue. 750ml of methyl tert butyl ether was charged to the
obtained residue and the mixture was stirred for 30 min. The separated solid mass was
filtered and washed with 150 ml of methyl tert.butyl ether followed by water. The
collected solvent layer was concentrated under vacuum at 40°C- 45°C to get residual
mass. 150 ml of acetone was charged to the obtained residue and 22.65 gm (0.226
mol) of 36 % aqueous hydrochloric acid was added to it at 25°C-35°C within 15min.
The obtained mixture was seeded with the titled product and stirred for 15 min at
25°C-35°C. The mixture was treated with another lot of aqueous hydrochloric acid
(7.55 gm, 0.19 mol) at 25-35°C maintaining pH of the mixture between 0 to 2 and
stirred for 10 hrs. The obtained solid was washed with (2 x 20 ml) acetone and dried at
50°C-55°C for 6-8 hrs in air oven to get the titled product.
Yield: 53% w/w; Purity : 90%.
(c) 2-0x0-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride (75 gm, 0.391
mol) and 750 ml of acetonitrile were taken round bottom flask under nitrogen
atmosphere. 118.94 gm of anhydrous potassium carbonate (0.86 mol) was charged to
the mixture and the mixture was stirred at 25-35°C for 1 hr. The reaction mixture was
then cooled at 0°C to 15°C and 2-fluoro-α-(cyclopropyl carbonyl) benzyl bromide

(121.39gm, 0.47 mol) in acetonitrile (375 ml) was added dropwise to the cooled mass within 3 hrs maintaining the temperature at 0-15°C and nitrogen atmosphere through out the addition. The reaction mixture was then stirred at 0 - 15°C for 24 hr. After reaction completion, the mixture was filtered and the filtrate was distilled under vacuum at 45°C-50°C to get oily residue. 750ml of methyl tert butyl ether was charged to the obtained residue and the mixture was stirred for 30 min. The separated solid mass was filtered and washed with 150 ml of methyl tert butyl ether followed by water. The collected solvent layer was concentrated under vacuum at 40°C- 45°C to get residual mass. 150 ml of acetone was charged to the obtained residue and 22.65 gm (0.226 mol) of 36 % aqueous hydrochloric acid was added to it at 25°C-35°C within 15min. The obtained mixture was seeded with the titled product and stirred for 15 min at 25°C-35°C. The mixture was treated with another lot of aqueous hydrochloric acid (7.55 gm, 0.19 mol) at 25-35°C maintaining pH of the mixture between 0 to 2 and stirred for 10 hrs. The obtained solid was washed with (2 x 20 ml) acetone and dried at 50°C-55°C for 6-8 hrs in air oven to get the titled product. Yield: 53% w/w; Purity: 90%.
Example 3
a) 2-acetoxy-5-(α-cyclopropyl carbonyl -2-fluorobenzyl)-4,5,6,7-
tetrahydrothieno[3,2-c] pyridine (Prasugrel)
5-(a-Cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride (74gm, 0.201 mol) and 518 ml methylenedichloride (MDC) were taken in round bottom flask and mixture was chilled to 0-5°C. 373ml of saturated sodium bicarbonate solution was added to the chilled mixture maintaining temperature at 0°C to 5°C over a period of 30min. The separated MDC layer was washed with water (3x183 ml), dried over 35 gm of anhydrous sodium sulfate and evaporated under reduced pressure at 50°C-55°C to get 65.45 gm of free base of titled product (95% yield). The obtained solid mass was dissolved in 196 ml of acetonitrile and the solution was chilled to -10 to 0°C. 4-dimethyl amino pyridine (0.593 gm, 0.0048 mol) and triethylamine (25.41 gm, 0.251 mol) were added to the chilled solution followed by addition of acetic anhydride (29.27 gm, 0.2867 mol) in 130 ml of acetonitrile

maintaining temperature at -15°C to -5°C and stirred for 2 hrs. After reaction completion, the mixture was charged with potassium dihydrogen phosphate (0.0293 gm, 0.0021 mol) and 216 ml of water was added maintaining temperature at -10°C to 0°C and stirred for 60 min at the same temperature. The obtained solid mass was filtered, washed with 50% aqueous acetonitrile (65.45 ml) and dried at 55°C to 60°C under vacuum to get 63.5 gm of 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine. Yield: 80 to 85%; Purity: more than 98%.
b) The process of example 3 (a) was repeated at temperature 20°C-25°C instead of 0°C-5°C to get 5-(α-cyclopropyl carbonyl-2-fruorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine which was converted to 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine using acetic anhydride at -15°C to -5°C.
c) The process of example 3 (b) for converting 5-(α-cyclopropyl carbonyl -2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine to 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine was repeated at 0°C-10°C instead of-15°C to -5°C.
d) The process of example 3 (a) was repeated using 0.39 mol of acetic anhydride instead of 0.28 mol of acetic anhydride to get 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine.
Example 4
Purification of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetra
hydro thieno[3,2-c] pyridine (Prasugrel)
2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine (63 gm, 0.168mol) was dissolved in acetonitrile (443 ml) at 35 to 40°C to ob-tain a solution. 6.66 gm of activated charcoal and 6.66 gm of neutral alumina were ad-ded to the obtained solution and the mixture was stirred at 35 to 40°C for 15 min. The reaction mixture was then filtered through hyflobed and washed with hot acetonitrile

(85 ml). The combined filtrate was cooled to -10°C to 0°C and 265 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 lhr at -10°C to 0°C. The obtained solid was filtered and washed with 50% aqueous acetonitrile (2 x 31.5ml) to get 54.32 gm of 2-acetoxy-5-(α-cyclopropyl-carbonyl-2-fluorobenzyl)-4,5,6,7-tetra hydrothieno[3,2-c] pyridine having ICH purity. Yield: 80 to 85%.
Example 5
(a) 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetra hydrothieno
[3,2-c]pyridine (Prasugrel hydrochloride)
2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine (50gm, 0.134mol) was dissolved in 730ml acetone and 7.14 gm of cone, hy-drochloric acid (36%) was added to the obtained solution at 35°C to 40°C within 5 min. The reaction mixture was seeded with 1 % Prasugrel hydrochloride and stirred at 35°C to 40°C for 1 hr. The mixture was treated with another lot of concentrated hydro-chloric acid (5.85 gm) drop wise over a period of 1 hr and stirred at 35°C to 40°C for 2 hrs. The obtained solid crystals were filtered, washed with acetone (2x50 ml) and dried at 65°C to 70°C under vacuum for 3 hrs to get Prasugrel hydrochloride (crys-tal-B2) having ICH purity. Yield: 85 to 95%; Melting point: 165-178°C.
(b) 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno
[3,2-c] pyridine
The process of Example 5 (a) was repeated without seeding the reaction mixture to get Prasugrel hydrochloride (crystal B2) having ICH purity. Yield: 85 to 90%; Melting point: 165-178°C.
Example 6
2-Fluoro -a-(cyclopropyl carbonyl) benzyl bromide
2-Fluorobenzyl cyclopropyl ketone (250gm, 0.561mol) was taken in 2.5L of ethylene dichloride and 12 gm of AIBN (0. 073mol) was added to the mixture. N-Bromo

succinimide (300 gm, 1.685mol) was added lot wise to the obtained mixture by maintaining temperature at 85°C to 90°C over a period of 3 hours and mixture was stirred at the same temperature for 8 hours. After completion of reaction, the reaction mixture was cooled to 10°C to 15°C followed by stirring for 30 min and filtered. The obtained solid was washed with 250ml of ethylene dichloride. The solid mass was discarded and the obtained filtrate was washed with 5% sodium metabisulfite solution followed by washing with water. The separated organic layer was dried on anhydrous sodium sulfate and concentrated under vacuum followed by degassing the residue at 50°C to 55 °C to remove the traces of ethylene dichloride to obtain the titled product as a yellow coloured oil of titled product. Yield: more than 90%; Purity: more than 80%.
Example 7 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridine-2-one-p-toluenesulfonate
A mixture of 500 gm (1.257mol) of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno [3,2-c] pyridin-2-one, 238.61 gm (1.254mol) of p-toluenesulfonic 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%.
Example 8
2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-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 (115gm, 0.353 mol), terbutyldimethylchlorosilane (60.65gm, 0.402 mol) and 208 ml of methylene chloride was added to triethyl amine (40.68 gm, 0.402 mol) by maintaining temperature at 15°C to 20°C over a period of 15 min and the mixture is stirred for 2 hrs at 15°C to 20°C. A solution of 2-Fluoro-a-(cyclopropyl carbonyl) benzyl bromide (91.63 gm, 0.356 mol) was added at same temperature to the mixture

followed by addition of triethyl amine (70.61 gm, 0.697 mol) and 2.58 gm of sodium iodide at the same temperature. The reaction mixture was stirred at the same temperature for 15min. The temperature of the reaction mixture was slowly raised to 45°C to 50°C and the mixture was allowed to react under stirring at same temperature for 8 hrs. After completion of reaction, 368 ml of disodium hydrogen phosphate as buffer solution was added and resulting solution was stirred for 15 min and layers were separated. The aqueous layer was extracted with 88ml of methylene chloride. The combined organic layers were concentrated under vacuum and methylene chloride was distilled out followed by addition of 245 ml of acetonitrile followed by distilling cut the same to remove traces of methylene chloride to obtain residue. 661 ml of acetonitrile was added to the residue and stirred at 25°C to 35°C for 30 min to obtain reaction mixture. The reaction mixture was treated with 121.90 ml of water followed by chilling at 0-5 °C and maintained for 3 hrs to obtain precipitate. The obtained precipitate was filtered and dried under vacuum at 50°C to 55°C to obtain 105 gm of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine. Yield : 91.30%; Purity : more than 97.5% .
Example 9
Purification of crude 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-
fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Prasu silylated product)
Crude 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-
4,5,6,7 tetrahydrothieno-[3,2-c]pyridine (105 gm, 0.235 mol) was taken in 704 ml of aceto nitrile and heated at 50°C to 550C to get a clear solution and the solution was stirred for 10 min to obtain a reaction mixture. The reaction mixture was slowly cooled at 25°C to 35°C and stirred for 30 min followed by charging with 105ml of water and chilled at 0°C to 5°C. The reaction mixture was maintained at the same temperature for 1 hr. The reaction mixture was filtered and washed with 100 ml of chilled acetonitrile followed by drying under vacuum at 50°C to 55°C for 8 hrs to obtain 100 gm of 2-(tert-butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine;.

Yield: 94.85%; Purity: more than 98%.
Example 10
2-Acetoxy-5-(a-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-tetrahydrothieno[3,2-c]pyridine (105gm, 0.235 mol) was taken in 315 ml of acetonitrile and chilled to 15°C to 20°C to obtain a mixture. 1.47gm of 4-dimethyl amino pyridine and triethylamine (48.30 gm, 0.477 mol) was added to the obtained mixture at 15°C to 20°C. The mixture was stirred for 2 hrs. The mixture was chilled to 0°C to 5°C followed by drop wise addition of acetic anhydride (48.30gm, 0.473 mol) dissolved in 210ml of acetonitrile at 0 to 10°C over a period of 15min to obtain a reaction mixture. The obtained reaction mixture was stirred at -15°C to -10°C for 2 hr. After completion of reaction, 346 ml of aqueous potassium dihydrogen phosphate was added to the reaction mixture and stirred for 60 min at -10°C to 0°C. The reaction mixture was filtered, washed with 50% aqueous acetonitrile (2 x 95 ml) and dried under vacuum at 50°C to 55°C for 8 hrs to obtain 75.86 gm of titled product. Yield: 86.20%; Purity: more than 98.0% .
Example 11
Purification of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-
tetrahydrothieno [3,2-c]pyridine (Pure Prasugrel)
75.86 gm of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine (Prasugrel) was dissolved in 534.0 ml of acetonitrile at 35°C to 40°C to obtain a solution. 10% activated charcoal and 10% neutral alumina were added to the obtained solution and the mixture was stirred at 35°C to 40°C for 15 min. The reaction mixture was then filtered through hyflobed and washed with hot acetonitrile (100 ml). The combined filtrate was cooled at -10°C to 0°C and 319ml of water was added to it over a period of 15 min at temperature of-10°C 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 31.5ml) to obtain 65.22 gm of 2-Acetoxy-

5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
(pure Prasugrel).
Yield: 85.98%; Purity: more than 99.0%.
Example 12
2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine hydrochloride(Prasugrel hydrochloride)
2-Acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c]pyridine(65.22 gm, 0.174 mol) was dissolved in 952 ml of acetone and 9.38gm of concentrated hydrochloric acid (36.0%) was added dropwise to the obtained solution at temperature of 35°C to 40°C within 5 min. Crystal B2 of 2-Acetoxy-5-(α-cyclo propylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (0.56gm) 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 concentrated hydrochloric acid (36.0%) drop wise over a period of 60 min and the mixture was stirred at temperature of 35°C to 40°C for 120 min. The obtained solid crystals were filtered, washed with 2 vol of acetone and dried at 65°C to 70°C under vacuum for 3 hrs to obtain 61.50 gm of Crystal B2 of Prasugrel hydrochloride. Yield: 85.91 % ; Purity: more than 99.50% ; Melting point: 165-178°C.
Example 13
Preparation of Prasugrel hydrobromide Form I:
lg Prasugrel was dissolved in 10 ml of acetone at 25°C. 4 ml of 15% of HBr in isop-ropyl alcohol (IPA) solution was added to the obtained solution. The mixture was stirred for 2-4 hrs at 25°C. The solid obtained was filtered and dried at 60°C to get Prasugrel hydrobromide Form I.

Example 14
Preparation of Prasugrel hydrobromide Form II:
lg Prasugrel was dissolved in 10 ml of acetone at 250C. 4 ml of 15% HBr in isopropyl alcohol (IPA) solution was added to the obtained solution. The mixture was stirred for 24 hrs at 25°C. The solid obtained was filtered and dried at 60°C to get Prasugrel hydrobromide Form II.
Example 15
Preparation of Des-fluoro impurity
a) 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one-p-toluenesulfonate
A mixture of 500 gm of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno [3,2-c]pyridin -2-one (1.257 mol), 238.61 gm of p-toluenesulfonic acid monohydrate (1.254 mol) and 8.8 L of tetrhydrofuran was stirred at 50°C for 3 hrs to obtain precipitate. The obtained precipitate was filtered, washed with tetrahydrofuran (2 x 500 ml) and dried at 50°C to 55°C to obtain 408 gm of 5;6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridine-2-one-p-toluene sulfonate. Yield: 99.81%.
b) 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetra
hydrothieno[3,2-c]pyridine
To a mixture of 25 gm of 5,6,7,7a-tetrahydro-4H-thieno [3,2-c]-pyridine-2-one-p-toluenesulfonate (0.0769mol), 13.18 gm of tert-butyl dimethyl chlorosilane (0.087 mol) and 45 ml of methylene chloride was added to 8.86gm of triethyl amine (0.087 mol) by maintaining temperature at 15°C to 20°C over a period of 15 min followed by stirring for 2 hrs at 15°C to 20°C to obtain a solution. The obtained solution was added to a mixture of bromo benzyl cyclopropyl ketone (18.39gm, 0.076 mol) and triethyl amine (15.40 gm) and 0.56 gm of sodium iodide was added to the mixture. The mixture was stirred at same temperature for 15 min. The temperature was slowly raised to 45°C to 50°C and mixture was allowed to react under stirring at 45°C to 50°C for 8 hrs. After completion of reaction, 80ml of phosphate buffer solution was added and resulting solution was stirred for 15 min and layers were separated. The

obtained aqueous layer was washed with 200ml of methylene dichloride. The combined organic layers and washings were concentrated under vacuum to obtain a residue. 53.26 ml of acetonitrile was added to the obtained residue and the same was distilled out to remove traces of methylene chloride. 144 ml of acetonitrile was added to the residue and the mixture was stirred at 25°C to 35 °C for 30 min followed by addition of 26.5 ml of water. The obtained mixture was chilled at 0°C to 5°C and maintained for 3 hrs to precipitate. The precipitate was filtered and dried under vacuum at 50°C to 55°C to obtained 18 gm of 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. Yield : 72%; Purity: more than 90%.
c) Pure 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-
tetra hydrothieno[3,2-c]pyridine
Crude 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetra hydrothieno[3,2-c]pyridine(18gm, 0.042 mol) was taken in 120ml of acetonitrile and heated at 50°C to 55°C to get a clear solution and stirred for 10 min to obtain a reaction mixture. The reaction mixture was slowly cooled at 25°C to 35°C and stirred for 30 min followed by charging with 18 ml of water and chilled to 0°C to 5°C . The mixture was maintained at the same temperature for 1 hr. The obtained solid was filtered and washed with 18 ml of chilled acetonitrile followed by drying under vacuum at 50°C to 55°C for 8 hrs to obtain 13.5gm of 2-(tert-butyldimethylsilyloxy)-5-[a-(cyclopropyIcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. Yield: 75.0 %; Purity : more than 95.0% .
d) Des-fluoro impurity
2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetra hydrothieno[3,2-c]pyridine(13 gm, 0.030 mol) was taken in 39 ml of acetonitrile and chilled to 15°C to 20°C to obtain a reaction mixture. The obtained reaction mixture was charged with 0.182gm of 4-dimethyl amino pyridine and 6.22gm (0.061 mol) of triethylamine at 15°C to 20°C and stirred at the same temperature for 2 hrs. The reaction mixture was chilled at 0°C to 5°C followed by drop wise addition of acetic

anhydride (6.216gm, 0.060 mol) dissolved in 26 ml of acetonitrile at 0°C to 10°C over a period of 15 min. The obtained reaction mixture was stirred at -15°C to -10°C for 2 hrs and 42.83 ml of phosphate buffer solution was added and stirred for 60 min at -10°C to 0°C to obtain a solid mass. The obtained solid mass was washed with 50% aqueous acetonitrile (2x11 ml) and dried under vacuum at 50°C to 55°C for 8 hrs to obtain 9.28 gm of 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydro thieno[3,2-c]pyridine (Des-fluoro impurity) Yield: 85%; Purity: more than 90.0% .
Example 16
Preparation of 2-[α-cyclopropylcarbonyl-(2-fluoro) benzyl oxy]-5-acetoxy-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (N-acetyl impurity)
Stage I:
A mixture of 25 gm of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one-p-toluene sulfonate (0.0769 mol) and 45 ml of methylene chloride was added to 8.84 gm of tri-ethyl amine (0.0873 mol) by maintaining temperature of 15°C to 20°C over a period of 15 min and the mixture was stirred for 2 hrs at the same temperature to obtain a reaction mixture. 19.91 gm of 2-Fluoro-α-cyclopropylcarbonyl benzyl bromide (0.077 mol) was added to the reaction mixture followed by addition of 15.35 gm of triethyl-amine (0.151 mol) by maintaining the same temperature and the reaction mixture was stirred for 15 min. The temperature was slowly raised to 45°C - 50°C and the mixture was allowed to react under stirring at same'temperature for 8 hrs. After completion of reaction, 368 ml of potassium dihydrogen phosphate was added and the resulting solution was stirred for 15 min and the layers were separated. The aqueous layer was separated and washed with 20ml of methylene chloride. The combined organic layer and washings were concentrated under vacuum to obtain a residue. 55 ml of acetonitrile was added to the obtained residue and distilled out to remove the traces of methylene chloride. 30 ml of acetonitrile was added and the reaction mixture was stirred at 25 -35 °C for 30 min followed by addition of 25ml of water. The obtained mixture was chilled at 0-5°C and maintained for 3hrs. The layers were separated and

distilled out under vacuum to obtain 15 gm of 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-4,5,6,7 tetrahydrothienopyridine.
Stage II:
15 gm of 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-4,5,6,7 tetra hydrothieno pyridine (0.045 mol) was dissolved in 45 ml of acetonitrile and chilled to -10 to 0°C to obtain a mixture. 0.1328 gm of 4-dimethyl amino pyridine(0.0010 mol) and 5.82 gm of triethylamine (0.0575 M) were added to the obtained reaction mixture at -10°C to 0°C. The mixture was chilled at -15°C to -10°C followed by drop wise addition of 6.7gm of acetic anhydride (0.065 mol) dissolved in 30 ml of acetonitrile at -15°C to -10°C over a period of 15 min to obtain a reaction mixture. The obtained reaction mixture was stirred at-15°C to -10°C for 2 hrs. After completion of reaction, 27 ml of aqueous potassium dihydrogen phosphate was added to the reaction mixture and stirred for 60 min at -10°C to 0°C and layer separation was carried out. The acetonitrile layer was distilled out under vacuum to obtain residue. The obtained residue was purified by silica gel chromatography (eluent; ethyl acetate: hexane = 80:20) to obtain 5.0 gm of 2-[α-cyclopropylcarbonyl-(2-fluoro) benzyl oxy]-5-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(N-acetyl impurity). Purity : 90%.
Example 17
Preparation of 6-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-
tetrahydrothieno[2,3-c]pyridin-2yl acetate (Positional isomer):
a) 4 5,6,7-tetrahydrothieno [2,3-c]pyridine
50 gm of 2-(3-Thienyl) ethyl amine hydrochloride (0.3937mol) was taken in 500 ml of methylene dichloride to obtain a solution. 14.17 gm of paraformaldehyde (0.4724 mol) and 7.5 ml of water was added to the obtained solution. The mixture was heated at 35°C to 40°C for 24 hours. After 24 hours, the mixture was cooled to 0°C to 5°C. 200ml of saturated sodium bicarbonate Solution was added to the reaction mixture and the separation was carried out to obtain an organic layer. The separated organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under

reduced pressure at 50°C to 55°C to obtain 46.5 gm of 4,5,6,7-terahydro thieno [2,3-c] pyridine as a yellow coloured oily residue.
b) 6-triphenylmethyl 4,5,6,7-tetrahydrothieno [2,3-c] pyridine
To a solution of 46.5 gm of 4,5,6,7-tetrahydrothieno [2,3-c] pyridine (0.3338mol) in 100ml of dichloromethane was added 37.12 gm of triethylamine (0.3669mol) to obtain a solution followed by drop wise addition of 93.09gm of triphenylmethylchloride (0.3342mol) at ambient temperature to obtain a reaction mixture. The obtained reaction mixture was left overnight at ambient temperature and poured in to 930 ml of water. The organic phase was decanted, dried over sodium sulfate and evaporated to dryness to obtain a residue. The obtained residue was purified by silica gel chromatography (eluent:dichloromethane) to obtain 100 gm of 6-triphenylmethyl 4,5,6,7-tetrahydro thieno [2,3-c] pyridine.
c) 6-triphenylmethyl 5,6,7,7a-tetrahydro-4H-thieno [2,3-c]-2-pyridone
A solution of 27 gm of 6-triphenylmethyl 4,5,6,7-tetrahydrothieno [2,3-c] pyridine (0.0707mol) in 300 ml of tetrahydrofuran is added drop wise at 0°C to 5.31ml of n-butyl lithium (1.6M solution in hexane) to obtain a mixture. The obtained mixture is stirred for 15 minutes at ambient temperature and cooled to -20°C followed by drop wise addition of 23 ml of tri-n-butyl borate (0.085mol) dissolved in 50ml of tetrahydrofuran. The mixture is stirred for 1.0 hour at 10°C. The mixture is cooled at -40 °C and 20.1 ml of 30%(v/v) aqueous hydrogen peroxide is added drop wise to the cold mixture. The temperature of the mixture is raised to room temperature and stirred at this temperature for 1 hour. Water is added to the reaction mixture and extracted with dichloromethane. The obtained organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to obtain a residue. The obtained residue is crystallized from diisopropyl ether to obtain 16.87 gm of 6-triphenylmethyl 5,6,7,7a-tetrahydro 4H-thieno [2,3-c]-2-pyridone.

d) 5,6,7,7a-tetrahydro-4H-thieno[2,3-c]-pyridine-2-one-p-toluenesulfonate
A mixture of 50gm 6-triphenylmethyl 5,6,7,7a-tetrahydro 4H-thieno [2,3-c] 2-pyridone(0.1257mol), 23.86 gm (0.1254mol) of p-toluenesulfonic acid monohydrate and 880 ml of tetrahydrofuran is stirred at 50°C for 3 hrs to obtain a precipitate. The obtained precipitate is filtered and washed with tetrahydrofuran (2 x 50ml) and dried at 50°C to 55°C to obtain 40.8 gm of 5,6,7,7a-tetrahydro-4H-thieno[2,3-c]-pyridine-2-one-p-toluenesulfonate .
e) 2-(tert-butyldimethylsilyoxy)-6-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine
To a mixture of 115.0 gm of of 5,6,7,7a-tetrahydro-4H-thieno[2,3-c]-pyridine-2-one-p-toluenesulfonate (0.3538mol), 60.65gm tertbutyldimethylchlorosilane (0.4023mol) and 208.0 ml methylene chloride is added 40.68 gm of triethyl amine(0.4020mol) by maintaining temperature 15°C to 20°C over a period of 15 min followed by stirring for 2 hrs at 15°C to 20°C to obtain a solution. The obtained solution is added to a mixture of 91.63 gm of 2-Fluoro-a-cyclopropyl carbonyl benzyl bromide (0.3563mol) and 70.61 gm of triethyl amine(0.6977mol) by maintaining temperature of 15-20°C and 2.58 gm of sodium iodide is added to the mixture. The mixture is stirred at the same temperature for 15 min. The temperature is slowly raised to 45 - 50°C and mixture is allowed to react under stirring at 45-50°C for 8hrs. After completion of reaction, 368 ml of buffer solution is added and resulting solution is stirred for 15 min and layer separation is carried out. The obtained aqueous layer is washed with 88 ml of methylene chloride. The combined organic layer and washings are concentrated under vacuum to obtain a residue. 245 ml of acetonitrile is added to the obtained residue and distilled out to remove traces of methylene chloride. 661ml of acetonitrile is added to the obtained residue and the reaction mixture is stirred at 25 -35 °C for 30 min followed by addition of 121.90 ml of water. The obtained mixture is chilled at 0-5°C and maintained for 3 hrs to precipitate. The precipitate is filtered and dried under vacuum at 50 - 55°C to obtain 105.0 gm of 2-(tert-butyldimethylsilyloxy)-6-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine.

f) 2-(tert-butyldimethylsilyloxy)-6-(a-cycIopropyIcarbonyl-2-fluorobenzyl)-4,5,6,
7-tetrahydrothieno-[2,3-c]pyridine:
105 gm of crude 2-(tert-butyldimethylsilyloxy)-6-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.2359mol) is taken in 704ml of acetonitrile and heated to 50 - 55°C to obtain clear solution and stirred for 10 min to obtain reaction mixture. The reaction mixture is slowly cooled at 25 to 35°C and stirred for 30 min followed by charging with 105 ml of water and chilled to 0°C-5°C by maintaining the same temperature for 1 hr. The obtained solid is filtered and washed with 100 ml chilled acetonitrile. The mixture is dried to isolate the product under vacuum at 50 - 55°C for 8 hrs to obtain l00gm of 2-(tert-butyldimethylsilyloxy)-6-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno-[2,3-c]pyridine.
g) 6-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydro
thieno [2,3-c]pyridin-2yl acetate
105 gm 2-(tert-butyldimethylsilyloxy)-6-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine(0.2359 mol) is taken in 315 ml of acetonitrile and chilled to 15-20°C to obtain a reaction mixture. The obtained reaction mixture is charged with 1.47gm of 4-dimethyl amino pyridine and 48.30 gm of triethylamine (0.477 mol) at 15-20°C and the reaction mixture is stirred at same temperature for 2 hrs . The reaction mixture is chilled at 0°C-5°C followed by drop-wise addition of 48.30gm of acetic anhydride (0.473 mol) dissolved in 210 ml of acetonitrile at 0 to 10°C over a period of 15min. The obtained reaction mixture is stirred at -15 to -10°C for 2 hrs. After completion of reaction, 346.0 ml of buffer solution is added and stirred for 60 min at -10 to 0°C to obtain a solid mass. The obtained solid mass is washed with of 50%aqueous acetonitrile (2 x 95 ml) and dried under vacuum at 50 -55°C for 8 hrs to obtain 75.86 gm of titled product.

h) Purification of 6-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2yl acetate
75.86 gm of 2-Acetoxy-6-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[2,3-c] pyridine is dissolved in 534.0 ml of acetonitrile at 35 to 40°C to obtain a solution. 10% activated charcoal and 10% neutral alumina are added to the obtained solution and the mixture is stirred for 15 min at 35 to 40°C. The reaction mixture is then filtered through hyflobed and washed with 100 ml of hot acetonitrile. The combined filtrate is cooled at -10°C to 0°C and 319 ml of water is added to it over a period of 15 min at temperature of -10°C to 0°C followed by stirring the mixture for I hr at -10 to 0°C. The obtained solid is filtered and washed with 50% aqueous acetonitrile (2x95ml) to obtain 65.22 gm of titled product.
i) 6-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydro
thieno[2,3-c]pyridin-2yl acetate hydrochloride
65.22 gm of 2-Acetoxy-6-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro thieno[2,3-c] pyridine (0.1748mol) is taken in 952 ml of acetone and 9.38 gm of concentrated hydrochloric acid (36.0%, 0.0926 mol) is added drop wise to the obtained solution at temperature of 35 to 4()°C for 60 min. 7.67 gm of concentrated hydrochloric acid (36.0%) is further added drop wise to the obtained reaction mixture over a period of 60 min and stirred at the 35 to 40°C for 120 min. The obtained crystals are separated by filtration and washed with 2 vol of acetone and dried at 65 to 70°C under vacuum for 3.hrs to obtain 61.5 gm of titled product.

We claim:
1. A process for preparation of Prasugrel or pharmaceutically acceptable salts
thereof comprising the steps of,
a) condensing 2-fluoro-α-(cyclopropylcarbonyl)-benzyl bromide with 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine or its acid addition salt in the presence of a suitable base and suitable solvent at low temperature to obtain a reaction mixture containing 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c]pyridine;
b) isolating 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine from said reaction mixture;
c) optionally converting said 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine to its acid addition salt;
d) treating said 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine or acid addition salt thereof with an acetylating agent to obtain Prasugrel, which is optionally purified;
e) optionally converting said Prasugrel to pharmaceutically acceptable salts thereof.

2. The process as claimed in claim 1, wherein said condensation in step a) is carried out at a low temperature of-5 °C to 20 °C; said suitable base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride or potassium hydride; said suitable solvent is selected from acetonitrile, propionitrile, dimethylformamide (DMF), dimethylsulfoxide, dimethylacetamide (DMA), N-methylacetamide, N-methylformamide, N-methylpyrrolidinone, N,N-dimethylpropionamide, sulfolane, methyl acetate, ethyl acetate, butyl acetate, acetone, diethyl ketone, methylethyl ketone or methyl isobutyl ketone.
3. The process as claimed in claim 1, wherein said isolation in step b) is carried out by filtering the reaction mixture containing 5-(a-cyclopropylcarbonyl-2-

fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine followed by concentrating the filtrate under vacuum to obtain an oily residue; treating the oily residue with solvent selected from methyl tert butyl ether, diethyl ether, 1,4-dioxane, toluene, xylene, n-hexane, cyclohexane or mixture thereof to obtain a residue containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine.
4. The process as claimed in claim 1 or claim 3, wherein said acid addition salt is hydrochloride and said conversion to the corresponding hydrochloride salt is achieved by treating the residue containing 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine with HC1 in a lot wise manner at a temperature of about 20°C to 40°C followed by optionally seeding with 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride.
5. The process as claimed in claim 1, wherein said acetylation in step d) is carried out using acetic anhydride or acetyl chloride at temperature of -10°C to 0°C in a solvent selected from acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, N-methylacetamide or N-methylformamide in the presence of base selected from triethylamine, trimethylamine, tributylamine, pyridine, N-methylmorpholine or diisopropylethylamine; and catalyst selected from 4-dimethylaminopyridine, 4-diethylaminopyridine or 4-dipropylaminopyridine.
6. 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Des-fluoro impurity) represented by the following formula


7. A process for preparation of 2-Acetoxy-5-[a-(cyclopropylcarbonyI)benzyI]-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Des-fluoro impurity) or salts thereof
comprising the steps of,
a) treating 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluene sulfonate with tert-butyldirnethylchlorosilane in presence of base and solvent to obtain silylated product;
b) condensing α-(cyclopropylcarbonyl) benzyl bromide with said silylated product to obtain 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclo propylcarbonyl)benzyl]-tetrahydrothieno[3,2-c]-pyridine;
carbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine;
d) acetylating 2-(tert-butyldimethylsilyloxy)-5-[α-(cyclopropylcarbonyl) benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in presence of base to obtain 2-Acetoxy-5-[a-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydro thieno[3,2-c]pyridine, which is optionally purified;
e) optionally converting 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5, 6,7-tetrahydrothieno[3,2-c]pyridine to salts thereof.

8. The process as claimed in claim 7, wherein said treatment in step a) is carried out at temperature of 10°C to 30°C; said base is selected from triethylamine, tributylamine, pyridine, N-methylmorpholine or diisopropylethylamine; said solvent is selected from methylene dichloride, ethylene dichloride, acetonitrile, propionitrile, benzonitrile, diethyl ether, 1,4-dioxane, tetrahydrofuran, toluene or xylene.
9. A process for preparation of 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (N-acetyl impurity) comprising the steps of,
a) condensing 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridin -2- one-p-toluene sulphonate with 2-fluoro-α-cyclopropylcarbonylbenzyl bromide to obtain

2-[a-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-4,5,6,7-tetrahydrothieno [3,2-c] pyridine; b) acetylating said 2-[α-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-4,5,6,7-tetrahydrothieno [3,2-c] pyridine with acetic anhydride or acetyl chloride in presence of base to obtain 2-[a-cyclopropylcarbonyl-(2-fluoro)benzyloxy]-5-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (N-acetyl impurity).
10. Prasugrel or pharmaceutically acceptable salts thereof substantially free of impurity selected from the group consisting of 2-Acetoxy-5-[α-(cyclopropylcarbonyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Des-fluoro impurity), 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7, 7a-hexahydrothieno[3,2-c]pyridine, 6-[(lRS)-2-cyclopropyl-l-(2-fluorophe nyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2yl acetate (Positional isomer), 2-Acetoxy-5-[a-(5-chloro-l-oxopentyl)-2-fluorobenzyl]-4,5,6,7-tetra hydrothieno[3,2-c]pyridine and 2-[a-cyclopropylcarbonyl-(2-fluoro) benzyl oxy]-5-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine(N-acetyl impurity).