Field of the invention:

The present invention relates to a process for the preparation of highly pure 5-[(1RS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c] pyridin-2-yl acetate compound of formula-1 and its salts.

The present invention also relates to a novel process for the preparation and purification of 1-cyclopropyl-2-(2-fluorophenyl)Ethan one compound of formula-5.

5-[( 1 RS)-2-cyclopropyl-1 -(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydro then [3,2-c] pyridin-2-yl acetate is commonly known as Pressure. Pressure is a member of the thienopyridine class of ant platelet agents. Currently available thienopyridines include clopidogrel and ticlopidine. Pressure is an orally bioavailability prod rug metabolized to an active adenosine diphosphate (ADP) receptor antagonist, which is a potent inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Pressure is recently approved in US and Europe and available under the brand name of Efferent.

Background of the Invention:

l-cyclopropyl-2-(2-fluorophenyl)Ethan one and its use in the preparation of prasugrel as well as process for its preparation was disclosed in US 5,288,726. The disclosed process involves the reaction of 2-fluorobenzyl bromide with magnesium metal in diethyl ether followed by treatment with cyclopropyl cyanide to provide l-cyclopropyl-2-(2-fluorophenyl)Ethan one. Similar process is also disclosed in US 6693115. The purity of the obtained compound is very low such as 50-55% by Gas chromatography. When the same has been used to proceed further without any purification in the preparation of pressure leads to the formation of corresponding impurities (i.e., impurities carried over from the impure material) which makes the process not suitable at commercial level.

International publication WO 2009/066326 disclosed an improved process for the preparation of l-cyclopropyl-2-(2-flourophenyl)Ethan one, which comprises of treating 2-fluorobenzyl bromide with magnesium metal in higher volumes of diethyl ether to provide 2-fIuorobenzyl magnesium bromide, which on in-situ condensation with cyclopropyl cyanide in higher volumes of diethyl ether to get the l-cyclopropyl-2- (2-fluorophenyl)Ethan one. As per the said publication, higher volumes of diethyl ether is used to control the formation of 2-fluorobenzyl dimmer impurity. The said patent does not describe any other impurity formation at this stage. Moreover the process involves excess volumes of ether solvent, which increase the cost of production. Hence the process may not be suitable at commercial level.

2-acetoxy-5-(α-methyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine (herein designated as "methyl Kato impurity") having the following structural formula has been observed in pressure and its salts prepared by the processes known in the art
The said impurity has not been washed out by the conventional purification methods at final stages. Hence it is necessary to have a method to control the formation of the said impurity at origin.

We the present inventors working on prasugrel to find out the origin of the said impurity, after various experimentation we found that the origin of the impurity is at the formation of l-methyl-2-(2-fluorophenyl)ethanone in the preparation of 1-cyclopropyl- 2-(2-flourophenyl)ethanone i.e., during the reaction between 2-fluorobenzyl bromide with cyclopropyl cyanide under grignard condition. The said impurity is formed upto the maximum level of 4%. The said impurity carried further along with the keto compound in prior art process results in the formation of corresponding derivatives (i.e., 2-acetoxy-5-(a-methylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine) at prasugrel. It is important for any pharmaceutical compound to be free of impurities or impurities to the level as per ICH guidelines. Hence it is necessary to develop a process which controls the formation of impurity at initial stages.

The formation of methyl keto impurity schematically represented by the following scheme l-cyclopropyl-2-(2-flourophenyl)ethanone is a key intermediate in the preparation of pharmaceutically important compound such as prasugrel. It is more advantages to have a novel process which provides a compound with high purity and yield and avoids the problems associated with the prior art.

Brief Description of Invention:

The first aspect of the present invention is to provide a novel process for the preparation of highly pure l-cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5, which comprises of the following steps;

a) Reacting the 2-(2-fluorophenyl)acetic acid compound of formula-2 with N,0-dialkylhydroxylamine or its salts compound of general formula-3 in presence of a base in a suitable solvent provides 2-(2-fluorophenyl)-N-alkoxy-N- alkylacetamide compound of general formula-4,

b) reacting the compound of general formula-4 with cyclopropyl bromide in presence of Grignard reagent and in presence or absence of a catalyst in a suitable solvent provides pure l-cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5.
Further the present invention also provides novel 2-(2-fluorophenyl)-N-alkoxy- N-alkylacetamide compound of general formula-4 and its use.

The second aspect of the present invention is to provide a process for the preparation of highly pure prasugrel compound of formula-1 and its pharmaceutically acceptable salts, which comprises of preparing the compound of formula-5 as per the first aspect of the present invention and converting the same into prasugrel compound of formula-1 by the conventional methods known in the art.

The third aspect of the present invention is to provide a process for the purification of l-cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5 or process for the removing of l-methyl-2-(2-fluorophenyl)ethanone from compound of formula-5, which comprises of subjecting the crude compound of formula-5 to high vaccum distillation/fractional distillation. Collecting the required product by fractionation at their specific boiling point.

The fourth aspect of the present invention is to provide a highly pure

1- cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5 having 5.0% or less of l-methyl-2-(2-fluorophenyl)ethanone by GC.

The fifth aspect of the present invention is to provide highly pure 5-(2- cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate compound of formula-1 and its pharmaceutically acceptable salts having

2- acetoxy-5-(a-methylcarbony!-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine in the level of less than 4.0% by HPLC.

The sixth aspect of the present invention is to provide a process for the purification of the prasugrel using suitable solvent to get pure prasugrel compound of formula-].
Detailed description of the invention:

As used herein the present invention the term "suitable solvents" refers to solvents selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethyl ether, methyl tert-butyl ether; "hydrocarbon solvents" like toluene, hexane, heptane and cyclohexane; "polar aprotic solvents" like dimethyl acetamide, dimethyl sulfoxide, acetonitrile; "ketone solvents" like acetone, methyl ethyl ketone, methyl isobutyl ketone; and "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol; "chloro solvents" like methylene chloride, chloroform and ethylene dichloride; polar solvents like water; and mixtures thereof.

As used herein the present invention the term "suitable bases" refers to the bases selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate, alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate; and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and their mixtures there of.

As used herein the term "highly pure" refers to the purity of the compound, in which the compound has the purity of about 96.00 % or more by HPLC, preferably greater than 99.00 % and more preferably greater than 99.90% by HPLC.
As used herein the term "crude" refers to the compound having less purity or compound containing high levels of impurities or the residue obtained directly from the reaction mixture.

Accordingly, the first aspect of the present invention provides a novel process for the preparation of l-cyclopropyl-2-(2-fluorophenyl)Ethan one compound of formula-5,

which comprise the following steps;

a) Reacting the 2-(2-fluorophenyl)acetic acid compound of formula-2c
with N,0-dialkylhydroxylamine or its salts compound of general formula-3.

Wherein R and R' each independently represents Ci-e alkyl group, having a straight chain or branched chain,

In the presence of a base in a suitable solvent provides 2-(2-fluorophenyl)-N- alkoxy-N-alkylacetamide compound of general formula-4.

Wherein R and R' each independently represents Ci-e alkyl group, having a straight chain or branched chain;

b) reacting the 2-(2-fluorophenyl)-N-alkoxy-N-alkylacetamide compound of general formula-4 with cyclopropyl magnesium bromide in a suitable solvent to provide 1 -cyclopropyl-2-(2-fIuorophenyl)ethanone compound of formula-5.

Wherein in step a) the reaction between 2-(2-fluorophenyI)acetic acid compound of formula-2 with N,0-dialkylhydroxylamine or its salts compound of general formula-3 is carried out with suitable reagent selected from N,N'-Dicyclohexyl carbodiimide (DCC) in presence of hydroxybenzotriazole (HOBT), or N,N'- Dicyclohexyl carbodiimide (DCC) in presence of 4-Dimethylaminopyridine (DMAP) orthionyl chloride, phosphorous pentachloride; preferably DCC in presence of HOBT.; the suitable base is selected from alkali metal hydroxides, alkali metal carbonates.

alkali metal bicarbonates, alkali metal alkoxides or the organic bases like triethyl amine, diisopropyl ethylamine preferably tri ethyl amine; and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, ketone solvents, nitrile solvents, chloro solvents, polar aprotic solvents, polar solvents or mixtures thereof; preferably methylene chloride;

Wherein in step b) the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, ketone solvents, alcoholic solvents, chloro solvents, polar solvents and mixtures thereof

In a preferred embodiment, the process for the preparation of compound of formula-5 comprises of the following steps;

a) Reacting the 2-(2-fIuorophenyl)acetic acid compound of formula-2

with N,0-dimethylhydroxylamine or its salts compound of formula-3a,

in the presence of dicyclohexylcarbodiimide (DCC) & 1-hydroxybenzotriazole (HOBt) and in the presence of triethyl amine in methylene chloride provides 2-(2- fluorophenyl)-N-methoxy-N-methylacetamide compound of formula-4a,

b) reacting the 2-(2-fluorophenyl)-N-methoxy-N-methylacetamide compound of formula-4a with cyclopropyl magnesium bromide in tetrahydrofuran to provide l-cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5.
Further the present invention also provides a novel 2-(2-fluorophenyl)-N- alkoxy-N-alkylacetamide compound represented by the following general structural formula-4

Wherein R and R' each independently represents Cue alkyl group, having a straight chain or branched chain.

The novel compound of formula-4 of the present invention is used to prepare the compound of formula-5 and prasugrel or its pharmaceutically acceptable salts.

In a preferred embodiment, the present invention provides the 2-(2- fluorophenyl)-N-methoxy-N-methylacetamide compound of formula-4a.

The l-cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5 prepared as per the present invention is obtained in a good yield and purity and free of l-methyl-2-(2-fluorophenyl)ethanone impurity. Hence the usage of compound of formula-5 obtained in the present invention in the preparation of prasugrel avoids the formation of corresponding impurities (especially methyl keto impurity).

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

a) Reacting the 2-(2-fluorophenyl)acetic acid compound of formula-2
with N,0-dialkylhydroxylamine or its salts compound of general formula-3.

Wherein R and R' each independently represents Ci-6 alkyl group, having a straight chain or branched chain, in the presence of a base in a suitable solvent provides 2-(2-fluorophenyl)-N- alkoxy-N-alkylacetamide compound of general formula-4,
Wherein R and R' each independently represents C.6 alkyl group, having a straight chain or branched chain;

b) reacting the 2-(2-fluorophenyl)-N-alkoxy-N-alkylacetamide compound of general formula-4 with cyclopropyl magnesium bromide in a suitable solvent to provide 1- cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5,

c) reacting the compound of formula-5 with a suitable brominating agent in presence or absence of base in a suitable solvent to provide 2-bromo-1-cyclopropyl-2-(2- fluorophenyl)ethanone compound of formula-6,

d) reacting the compound of formula-6 with 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin- 2(4H)-one compound of formula-7, in the presence of suitable base and in a suitable solvent provides 5-(2-cyclopropyl- l-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one compound of formula-8.

e) acetylating the compound of formula-8 with a suitable acetylating agent in presence of suitable base in a suitable solvent provides 5-(2-cyclopropyl-l-(2-fluorophenyl)- 2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yI acetate compound of formula-1,

f) optionally purifying the compound of formula-1 using suitable solvents and converting it into its pharmaceutically acceptable salts.

The third aspect of the present invention provides a process for the purification of l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formula-5, which comprises subjecting the crude l-cyclopropyl-2-(2-fluorophenyl) ethanone to distillation under reduced pressure (high vaccum distillation (HVD) to obtain pure 1- cyclopropyl-2-(2-fluorophenyl) ethanone. The purification is carried out by fractional distillation and the pure compound fractions of formula-5 obtained at a vapour temperature of 80-90°C.

The compound of formula-5 prepared as per the prior art process containing l-methyl-2-(2-fluorophenyl)ethanone having the following structural formula-9 as an impurity at the level of 1 to 5%. The same has been come down when subjecting the compound of formula-5 into the high vacuum distillation and the pure fraction of compound of formula-5 collected at a vapor temperature of 80-90°C and the impurity fraction collected at different temperature. According to the present invention the impurity level brought down to 0.5 to 0.1% from the level of 5% by GC and even to not detectable levels. When using this compound of formula-5 having least amount of impurity in the preparation of prasugrel provides highly pure prasugrel containing the corresponding derivatives (i.e. 2-acetoxy-5-(a-methyl carbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydro thieno[3,2-c] pyridine) to the lowest level i.e., less than 0.15%, preferably less than 0.05% and more preferably less than 0.01% by HPLC.

The fourth aspect of the present invention provides l-cyclopropyl-2-(2- fluorophenyl)ethanone compound of formula-5 containing less than 4.0% of 1-methyl- 2-(2-fluorophenyl)ethanone by GC; preferably less than LO % by GC and more preferably 0.1% by GC.

Further, the fifth aspect of the present invention provides 5-(2-cyclopropyl- l-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-ylacetate compound of formula-1 and its pharmaceutically acceptable salts containing less than 3.0 % of 2-acetoxy-5-(a-methyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2- c] pyridine (methyl keto impurity) by HPLC, preferably less than 1.0 % by HPLC and more preferably less than 0.1% by HPLC.

The sixth aspect of the present invention provides a process for the purification of 5-(2-cyclopropyl-1 -(2-fluorophenyl)-2-oxoethyI)-4,5,6,7-tetrahydrothieno[3,2-c] pyridin-2-yl acetate compound of formula-I, which comprises of crystallizing the compound of formula-1 using nitrile/alcohol solvent alone or mixture of nitrile and alcohol solvents. Preferably using a mixture of acetonitrile and isopropyl alcohol solvents. The prasugrel prepared by this process having purity greater than 99.15% by HPLC and preferably greater than 99.50% by HPLC.

The present invention is schematically represented as follows

Related substances of the l-cyclopropyl-2-(2-fluorophenyl)ethanone is measured by Gas Chromatography using the following conditions. Apparatus: A gas chromatographic system is to be equipped with FID; Column: DB-1 column or equivalent; Length: 30 mts; ID: 0.53 mm; Film thickness: 3.0 μm; Injector temperature: 220°C; Split ratio: 1:50; Detector temperature: 260°C(FID); Carrier gas: Helium; Carrier gas pressure: 3.0 PSI; Injection volume: 0.11.

Related substances of the prasugrel and its pharmaceutically acceptable salts were measured by High Performance Liquid Chromatography (HPLC) using the following conditions.

Apparatus: A liquid chromatograph is equipped with variable wavelength UV-Detector; Column: ZORBAX SB-Phenyl, 250x4.6 mm ID, 5 nm or equivalent; Flow rate: 1.20ml/min, wave length: 235 nm, Temperature: 30°C; load: 30 ml; Run time: 60 minutes; Diluent: Mobile phase-B, Elution: Gradient

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

Examples:

ExampIe-1: Preparation of 2-(2-fluorophenyl)-N-methoxy-N-methylacetamide compound of general forniuIa-4:

A mixture of N,0-dimethyl hydroxyl amine hydrochloride (76 grams) and methylene chloride (1000 ml) was cooled to 0-5°C. Triethyl amine (132 grams) was added to the reaction mixture and stirred for 15 minutes. 1-hydroxybenzotriazole (HOBt) (8.75 grams) was added to the reaction mixture followed by 2-(2-fluorophenyl acetic acid) (100 grams) at 0-5°C. Stirred the reaction mixture for 5 minutes and then added the mixture of dicyclohexylcarbodiimide (DCC) (134 grams) in 150 ml of methylene chloride to the reaction mixture at 0-5°C and stirred for 6 hours. The obtained solid was filtered off and washed with methylene chloride. The filtrate was washed with water. The organic layer was washed with aq.hydrochloric acid followed by water then sodium bicarbonate solution followed by water. Distilled off the solvent from the organic layer under reduced pressure. Methylene chloride was added to the obtained residue at 25-30°C and stirred for up to dissolution. The reaction mixture was stirred at 0-5°C for 45 minutes and the obtained solid was removed by filtration. The filtrate was distilled off completely under reduced pressure. Ether was added to the obtained residue, heated to reflux and then stirred the reaction mixture for 20 minutes at the same temperature. The reaction mixture was cooled to 0-5°C and stirred for 60 minutes. The solid obtained was filtered, washed with ether and dried to get the title compound. Yield: 108 grams.

Example-2: Preparation of l-cyciopropyl-2-(2-fluorophenyl) ethanone compound of formuIa-5:

Cyclopropyl bromide (122.5 grams) was added to the suspension of magnesium (24.5 grams) in tetrahydrofuran (700 ml) and iodine (0.03 grams) at 25-30°C then the reaction mixture was heated to 40-50°C. The mixture of 2-(2-fluorophenyl)-N- methoxy-N-methylacetamide (100 grams) and tetrahydrofuran (300 ml) was added to the reaction mixture and stirred at 40-50°C. After completion of the reaction, the reaction mixture was cooled to 0-5°C and quenched it with aq. hydrochloric acid. Stirred the reaction mixture for 15 minutes at 25-30°C and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with aq. sodium chloride solution followed by water. The ethyl acetate layer was distilled off under reduced pressure to get the title compound. Yield: 97 grams

Exaraple-3: Preparation of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of forMula-6:

A mixture of l-cyclopropyl-2-(2-fluorophenyl) ethanone (40 grams), methylene chloride (400 ml), N-bromo succinamide (50 grams), azobisisobutyronitrile (2.4 grams) and p-toluenesulfonic acid (1.2 grams) was stirred for 4 hrs at reflux temperature. The reaction mixture was cooled to 0-5°C and stirred for 45 minutes and the precipitated solid was filtered. The filtrate was distilled off completely under reduced pressure. Cyclohexane (100 ml) was added to the obtained residue and distilled off the solvent under reduced pressure to get the title compound. Yield: 55 grams

Example-4: Purification of l-cycIopropyl-2-(2-fluorophenyl) ethanone compound of formula-S:

The crude l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formula-5 (100 grams) (having purity of 93.41% and containing 3.73% of l-methyl-2-(2-fluoro phenyl)ethanone) prepared as per the reported process was charged into a clean and dry vessel and was purified by fraction distillation. The main fraction was collected at a vapour temperature of 80-90°C under reduced pressure to get 82 grams of the pure title compound.

Purity by GC: 98.53%; 1 -methyl-2-(2-fluorophenyl)ethanone: 0.02%

Example-5: Preparation of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formuia-6:

The title compound was prepared in a similar manner to example-3 except that pure compound of formula-5 obtained as per example-4 is used as a input in place of 1- cyclopropyl-2-(2-fluorophenyl) ethanone. Yield: 56 grams

Example-6: Preparation of 5-(a-cyclopropylcarbonyI-2-fluorobenzyl)-2-oxo-
2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine compound of formula-8:

A mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one-p-toluene sulfonate
(100 grams), potassium carbonate (63.5 grams) and acetonitrile (1000 ml) was stirred for 30 minutes at 25-30°C. 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (66 grams) prepared as per example-5 in acetonitrile (30 ml) was added to the reaction mixture and stirred for 7 hours at 25-30°C. The reaction mixture was filtered and removed the precipitated solid. The filtrate was distilled off completely under reduced pressure, ethyl acetate followed by cyclohexane was added to it. The reaction mixture was stirred for 25 minutes at 40-45°C. The reaction mixture was cooled to 25- 30°C and stirred for an hour.

The reaction mixture was filtered and solvent form the filtrated was distilled off completely under reduced pressure to get the title compound. Yield: 70 grams

Example-7: Preparation of 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyI)-2-oxoethyl]- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate compound of formula-1:
Triethylamine (98 grams) was added to a solution of 5-(a.-cyclopropylcarbonyl- 2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (100 grams) prepared as per example-6 in methylene chloride (1000 ml) and stirred for 15 minutes at 25-30°C. The reaction mixture was cooled to 0-5°C and acetic anhydride (62 grams) was added to it and then stirred for 6 hrs at 0-5°C. Added water (300 ml) to the reaction mixture at 25-30°C and stirred for 15 minutes. Separated the both aqueous and organic layers and the organic layer was washed with aq.sodium bicarbonate solution followed by washed with water. Distilled of the solvent from organic layer completely under reduced pressure. Added 75 ml of cyclohexane to the reaction mixture and distilled off the solvent completely under reduced pressure. To the obtained solid added acetonitrile (50 ml) at 25-30°C and heated the reaction mixture to 40-50°C. Stirred the reaction mixture for 20 minutes at same temperature. Added isopropyl alcohol (75 ml) to the reaction mixture at 25-30°C and then heated to 40-50°C. Stirred the reaction mixture for 30 minutes at same temperature. Cooled the reaction mixture to 10-15°C and stirred for 1 hr at same temperature. Filtered the precipitated solid and washed with isopropyl alcohol. Dried the compound to get the highly pure title compound. Yield: 75 grams; Melting point: 120-125° C. Purity by HPLC: 99.55%; Methyl keto impurity: Not detected

Example-8: Preparation of 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyI]- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride compound of formula-la:

A mixture of 5-[(lRS)-2-cyciopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate(100 grams) prepared as per example-7 and acetone(900 ml) was heated to 30-40°C. Added 5 grams of activated carbon to the above reaction mixture at same temperature and stirred for 15 minutes. Filtered the reaction mixture and the filtrate was heated to 50-55°C under nitrogen atmosphere. Added slowly 500 ml of ethyl acetate hydrochloride solution to the reaction mixture at 50-55°C. Stirred the reaction mixture for 45 minutes at 25-30°C under nitrogen atmosphere. Filtered the precipitated solid and washed with acetone. Acetone(1000 ml) was added to the obtained compound and stirred for 45 minutes at 25-30°C under nitrogen atmosphere. Filtered the precipitated solid and washed with acetone. Dried the compound to get the highly pure title compound. Yield: 83 grams. Purity by HPLC: 99.78%

Example-9: Purification of 5-[(1RS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate compound of formula-1:
To the crude 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate (50 grams), acetonitrile (25 ml) was added and heated to 40-50°C. The reaction mixture was stirred for 20 min at 40-50°C. Isopropyl alcohol (40 ml) was added to the reaction mixture at 25-30°C and heated to 40-50°C then stirred for 30 minutes. The reaction mixture was cooled to 10-15°C and stirred for 1 hr. The precipitated solid was filtered and washed with isopropyl alcohol and then dried to get the highly pure title compound. Yield: 42 grams Purity by HPLC: 99.61%

We Claim:

1. A novel process for the preparation of l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formula-5,

which comprises of the following steps;

a) Reacting the 2-(2-fluorophenyl)acetic acid compound of formula-2

with N,O-dialkylhydroxylamine or its salts compound of general formula-3.

Wherein R and R' each independently represents C1-6alkyl group, having a straight chain or branched chain,

in the presence of a base in a suitable solvent provides 2-(2-fluorophenyl)-N- alkoxy-N-alkylacetamide compound of general formula-4,

Wherein R and R' each as defined above,

b) reacting the 2-(2-fluorophenyl)-N-alkoxy-N-alkylacetamide compound of general formula-4 with cyclopropyl magnesium bromide in a suitable solvent to provide l-cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5.

2. A novel process for the preparation of 1-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formula-5, which comprise of the following steps;

a) Reacting the 2-(2-fluorophenyl)acetic acid compound of formula-2 with N,O-dimethylhydroxylamine or its salts compound of formula-3a, in the presence of dicyclohexylcarbodiimide (DCC) & I-hydroxybenzotriazole (HOBt) and in presence of triethyl amine in methylene chloride provides 2-(2-fluorophenyl)-N-methoxy-N-methylacetamide compound of formula-4a,

b) reacting the 2-(2-fluorophenyl)-N-methoxy-N-methylacetamide compound of formula-4a with cyclopropyl magnesium bromide in tetrahydrofuran to provide l-cyclopropyl-2-(2-fluorophenyl)ethanone compound of formula-5.

3. A process for the purification of l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formula-5, which comprises subjecting the crude l-cyclopropyl-2-(2- fluorophenyl) ethanone to distillation under reduced pressure (high vaccum distillation (HVD)/fractional distillation to obtain pure 1-cyclopropyl-2-(2- fluorophenyl) ethanone.

4. The process according to calim 3, wherein purification carried out by fractional distillation and the pure compound fractions obtained at a vapour temperature of 80-90°C.

5. A process for the preparation of prasugrel or its pharmaceutically acceptable salt thereof containing less than 3% contaminant of methyl keto impurity comprises of

a) Preparing the l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formula-5 either by the process of claim 1 or by the process of claim 3, and

b) converting the compound of formula-5 into prasugrel or its pharmaceutically acceptable salts by the conventional methods.

6. l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of formula-5 containing less than 4.0% of l-methyl-2-(2-fluorophenyl)ethanone by GC, preferably less than 1.0% and more preferably less than 0.1% by GC.

7. Prasugrel or its pharmaceutically acceptable salts containing less than 3% of methyl keto impurity by HPLC, preferably less than 1.0% by HPLC and more preferably less than 0.1% by HPLC.

8. A process for the purification of prasugrel comprises of recrystallizing the crude prasugrel from acetonitrile/isopropyl alcohol or a mixture of acetonitrile and isopropylalcohol.

9. 2-(2-fluorophenyl)-N-alkoxy-N-alkylacetamide compound represented by the following general formula-4

Wherein R and R' each independently represents C 1-6 alkyl group, having a straight chain or branched chain.

10. Use of compound of formula-4 as claimed in claim-9 in the preparation of highly pure l-cyclopropyl-2-(2-fluorophenyl) ethanone and prasugrel or its pharmaceutically acceptable salts.