DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

INTRODUCTION
Aspect of the present application relates to process for the preparation of prasugrel and its pharmaceutical compositions.
The drug compound having the adopted name “prasugrel hydrochloride” can be represented by structural formula (I), and it is a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 adenosine diphosphate (ADP) receptor.

(I)
Prasugrel hydrochloride is the hydrochloride salt of a racemate of prasugrel. A chemical name for prasugrel hydrochloride is 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno [3, 2-c] pyridin-2-yl acetate hydrochloride, and it is the active ingredient in Effient® tablets approved for the treatment of acute coronary syndrome.
U.S. Patent No. 5,288,726 discloses prasugrel, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, pharmaceutical composition thereof and a method for the treatment or prophylaxis of thrombosis or embolisms comprising administering a mammal an effective amount of the compound(s) thereof. U.S. Patent No. 5,874,581 discloses a process for the preparation of prasugrel involving the use of silyl group protected intermediates. U.S. Patent No. 6,693,115 specifically discloses prasugrel hydrochloride, medicament composition thereof, and a method for the prevention or treatment of thrombosis or embolisms comprising administering a mammal an effective amount of the said compound.
A number of methods for the synthesis of Prasugrel have been reported in WO 2009/062044 A1, WO 2009/066326 A1, WO 2009/122440 A1, WO 2010/060389 A1, WO 2010/070677 A2, WO 2011/023027 A1, WO 2011/042918 A2, WO 2011/057592 A2 WO 2011/077173 A1, WO 2011/110219 A1 etc.
There remains a need for a short, industrially scalable, cost-effective, and environmentally-friendly process for the preparation of prasugrel with high purity which can be easily formulated.

SUMMARY
In an aspect, the application provides a process for preparing prasugrel, comprising:
a) reacting 5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one of formula (II), or a salt thereof with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone of formula (III), in the presence of an inorganic base and in a ketone solvent to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c] pyridin-2(4H)-one of formula (IV);
b) acetylating in situ the obtained 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one of formula (IV) in step a), into prasugrel by treating with an acetylating agent in the presence of an organic base and a ketone solvent; and
c) optionally purifying the prasugrel obtained in step b) in a ketone solvent.
In another aspect, the application provides pharmaceutical compositions containing a therapeutically effective amount of prasugrel base together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts PXRD pattern of prasugrel obtained by the procedure of Example 2.

DETAILED DESCRIPTION
In an aspect, the application provides a process for preparing prasugrel, comprising:
a) reacting 5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one of formula (II), or a salt thereof with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone of formula (III), in the presence of an inorganic base and in a ketone solvent to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c] pyridin-2(4H)-one of formula (IV);
b) acetylating in situ the obtained 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one of formula (IV) in step a), into prasugrel by treating with an acetylating agent in the presence of an organic base and a ketone solvent; and
c) optionally purifying the prasugrel obtained in step b) in a ketone solvent.
In embodiments of step a), the reaction of starting material used i.e., 5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one of formula (II), or a salt thereof with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone of formula (III), can be carried out in presence of a base and in a ketone solvent to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one of formula (IV) or a salt thereof.
In embodiments of step a), 5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one of formula (II), or a salt thereof, which is one of the starting materials for the preparation of prasugrel, may be prepared according to any of the processes disclosed in the art. Optionally, the compound of formula (II) may be converted into its acid-addition salt by reacting it with an acid. Examples of such acids include but are not limited to: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, or the like. Preferably the acid is hydrochloric acid. In embodiments of step a), the another starting material used i.e., 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone of formula (III) for the preparation of prasugrel, may be prepared according to any of the processes disclosed in the art.
In embodiments of step a), compound of formula (II) or a salt thereof and compound of formula (III) can be reacted in the mole ratio of 1:0.8 to 1:1.20 respectively. In one embodiment, they are reacted in the mole ratio of 1:1 respectively.
In embodiments of step a), the compound of formula (II), or a salt thereof, and the compound of formula (III), can be reacted in the presence of an inorganic base to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one, compound of formula (IV). Inorganic bases that are useful in the reaction include, but are not limited to; bases, such as, for example, alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide; alkaline metal hydroxides, such as, for example, barium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like; or any other suitable base. However, the compound of formula (II), or a salt thereof, and the compound of formula (III), can also be reacted in the presence of an organic bases such as for example, amines, e.g., triethylamine, N,N-diethylethanolamine, 4-ethylmorpholine, N-methyl morpholine, diisopropylamine, diisopropylethylamine, pyridine, or the like.
In embodiments of step a), the compound of formula (II), or a salt thereof, and the compound of formula (III), can be reacted in the presence of a ketone solvent, to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno [3,2-c]pyridin-2(4H)-one, compound of formula (IV). Examples of ketone solvents include but are not limited to solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone; or their mixtures thereof.
In embodiments of step a), the reaction of compound of formula (II), or a salt thereof, and the compound of formula (III), can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of from about 1 hour to about 24 hours or longer is sufficient.
In embodiments of step a), the obtained 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one of formula (IV) in step a), can be used in the next step without isolation i. e., in situ. In embodiments of step a), the obtained 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydro thieno[3,2-c]pyridin-2(4H)-one of formula (IV) in step a), can be isolated according to the procedures known in the art.
Step b) involves the in situ acetylation of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one of formula (IV) as obtained in step a), to obtain prasugrel by treating with an acetylating agent in the presence of an organic base.
In embodiments of step b), the compound of formula (IV) i.e. 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one, is reacted with an acetylating agent in presence of a base and a ketone solvent to produce prasugrel. The acetylating agents, which can be used include, but are not limited to, acetic anhydride, acetyl chloride or any other acetylating agent which produces prasugrel. In embodiments of step b), the compound of formula (IV), is reacted with an acetylating agent in presence of an organic base. Organic bases which can be used include, but are not limited to: amines, e.g., triethylamine, N, N-diethylethanolamine, 4-ethylmorpholine, 1,4-diazabicyclo[2.2.2]-octane, N-methyl morpholine, diisopropylamine, diisopropylethylamine, pyridine, or the like. However, inorganic bases can also be used in the acetylation step. Inorganic bases which can be used, but are not limited to: alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, alkoxides, and hydrides e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide, sodium hydride, potassium hydride or the like.
In embodiments of step b), the compound of formula (IV), is reacted with an acetylating agent in presence of a base and a ketone solvent to produce prasugrel. Examples of ketone solvents include but are not limited to solvents such as, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone; or their mixtures thereof.
In embodiments of step b), the compound of formula (IV), is optionally reacted with an acetylating agent in presence of a catalyst. In embodiments, catalysts that can be used may include but are not limited to, for example, 4-dialkylaminopyridines such as 4-dimethylaminopyridine, 4-diethylaminopyridine, 4-dipropylaminopyridine, etc. In embodiments of step b), acetylation of the compound of formula (IV) can be carried out at a temperature of from about -10°C to about 60°C. In one embodiment, the temperature employed is from about -10°C to about 30°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 1 to about 24 hours or longer. In embodiments of step b), prasugrel can be isolated from the reaction by cooling the reaction mass to a temperature from about 20oC to -20oC or by adding anti solvents such as water to the reaction mass.
In embodiments of step b), prasugrel produced in the reaction can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, evaporation of solvent, or the like, and optionally washing the resulting solid with a solvent. In one embodiment, the washing is done with the solvent used in the reaction. In embodiments of step b), the prasugrel obtained may be optionally dried according to the procedures known in the art.
In embodiments of step b), prasugrel that is isolated can be dried at suitable temperatures, such as from about 40°C to about 80°C and suitable time from about 1 hour to about 15 hours or longer, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
In embodiments of step c), the prasugrel obtained in step b) can be optionally purified by any method known in the art such as recrystallization involving single solvent, mixture of solvents, or solvent-anti solvent technique; reprecipitation; slurring in a solvent; or chromatography to improve its chemical purity.
In embodiments of step c) prasugrel obtained in step b) can be optionally purified in a ketone solvent such as acetone or methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone; or their mixtures thereof. In embodiments, prasugrel can be purified by dissolving prasugrel in a ketone solvent to obtain a solution and cooling the solution to precipitate prasugrel. In embodiments, a solution of prasugrel can be prepared at any suitable temperatures, such as from about room temperature to about the reflux temperature of the solvent used. Mixing may be used to reduce the time required for the dissolution process. Prasugrel solution can also be obtained directly from reaction mixtures during the synthesis of prasugrel. In embodiments, a solution of prasugrel may be filtered to make it clear, free of undissolved particles. In embodiments, the obtained solution may be optionally treated with a decolorizing agent or an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, the precipitation of prasugrel can be obtained by cooling the solution. In embodiments, the solution can be cooled to 25°C to -15°C preferably about 15°C to 0°C. In embodiments, the slurry comprising precipitated prasugrel can be maintained at any suitable temperatures, such as from about 25°C to about 0°C. In embodiments, the slurry comprising precipitated prasugrel can be maintained for about 10 minutes to about 10 hours, or longer.
In embodiments of step c), prasugrel can be purified by slurring prasugrel in suitable solvents. Examples of the suitable solvent used in the slurry include but are not limited to alcohol, ketone, hydrocarbon solvents or their mixture thereof. Prasugrel used in the purification by slurry can be wet which is obtained directly from the reaction mass or after drying.
In specific embodiments, the purification by slurry is useful to reduce the content of the residual solvents used in the preparation of prasugrel. Generally the removal residual solvents used in the synthesis of prasugrel are difficult by simply drying on heating. In embodiments, when acetonitrile used in the synthesis of prasugrel, the removal of acetonitrile was difficult by simply drying prasugrel on heating to achieve the desired acetonitrile content as per the acceptable ICH limits. It was observed that, when prasugrel was slurried in the solvents as mentioned above, the acetonitrile was easily removed.
The methods known in the art or the methods described herein can be used for the isolation and drying of the prasugrel obtained after the purification.
Prasugrel obtained after the purification as described above can be again purified by recrystallization as per the methods described herein or by any method known in the art such as recrystallization involving single solvent, mixture of solvents, or solvent-anti solvent technique; reprecipitation; slurring in a solvent; or chromatography to improve its overall quality.
A process for the preparation of prasugrel by a method of present application can be illustrated as given below in Scheme 1.

Scheme-1
In embodiments, prepared prasugrel according to the process described in the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC).
Prasugrel produced by a method of present application can be chemically pure prasugrel having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC.
Prasugrel produced by a method of present application can be chemically pure prasugrel having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.
In embodiments, prasugrel obtained from the methods described herein can be in a crystalline, amorphous, mixture of crystalline and amorphous and hydrated or solvated form.
Prasugrel obtained according to the process of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce a desired particle size distribution. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.
Prasugrel obtained according to the process of the present application has a particle size distribution wherein: d(0.5) is less than about 200 µm, less than about 25 µm, or less than about 10 µm; and d(0.9) is less than about 300 µm, less than about 50 µm, or less than about 25 µm, or less than about 10 µm.
In embodiments, optionally the prasugrel obtained according to the method describes in the present application can be converted into its pharmaceutically acceptable salts. Preferably, the prasugrel obtained according to the method describes in the present application can be converted into prasugrel hydrochloride by the methods known in the art.
Another aspect of the present application provides pharmaceutical compositions containing a therapeutically effective amount of prasugrel together with one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions comprising prasugrel of the invention together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.
Pharmaceutically acceptable excipients that are useful in the present invention include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

DEFINITIONS
The following definitions are used in connection with the compounds of the present application unless the context indicates otherwise. The term "reacting" is intended to represent bringing the chemical reactants together under condition such to cause the chemical reaction indicated to take place. The term “prasugrel” is intended to represent the free base of prasugrel. The following abbreviations and acronyms are used herein and have the indicated definitions: HPLC is high-pressure liquid chromatography and RT is retention time. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel® is a registered trademark of the Manville Corp.
An “acetylating agent” is an activated form of acetic acid, which is capable of transferring an acetyl group (CH3C(O)-) to a substrate. Examples of an “acetylating agent” include, but are not limited to, acetic acid/mineral acid; acetic acid/coupling agent such as DEAD/CAT; acetyl halides such as acetyl fluoride, acetyl chloride, or acetyl bromide; acetic anhydride; mixed anhydrides of acetic acid such as acetic (isobutyl carbonic) anhydride; activated acetic acid esters like isopropenyl acetate, vinyl acetate, acetic acid N-hydroxysuccinimide ester, or pentafluorophenyl acetate; ketene; or acetyl azide.
A “ketone” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-6Ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application.
EXAMPLES

Example 1: Preparation of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate (Prasugrel):
2-Bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone (7.45 gm, assay 90%) and isobutyl methyl ketone (50 mL) were charged into a round bottom flask at 30°C. Sodium carbonate (6.10 g) was added to the reaction mass at 30°C. 5, 6, 7, 7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one hydrochloride (5.0 g) was added to the reaction mass at 30°C. The reaction mass is stirred for 30 minutes at 30°C. The reaction mass was heated to 54°C and maintained for 7 hours at the same temperature. The reaction mass was filtered and washed with isobutyl methyl ketone (5 mL) to obtain a clear solution. The filtrate was charged into a round bottom flask at 30°C and the solution was cooled to 2°C. N-methylmorpholine (5.3 g) and 4-dimethylaminopyridine (0.03 g) were added to the solution at 2°C. Acetic anhydride (4.0 g) was added drop wise to the reaction mass in about 1 hour at 2°C. The reaction mass was stirred for 8 hours at 2°C. Water (60 ml) was added drop wise to the reaction mass at 2°C in 30 minutes. The reaction mass was stirred at 2°C for 1 hour 30 minutes. The precipitated solid was collected by filtration and washed with a mixture of chilled isobutyl methyl ketone (5 mL) and water (5 ml). The solid compound was dried under vacuum at 55°C for 5 hours. Yield: 4.0 g; HPLC Purity: 99.36%;

Example 2: Purification of Prasugrel in isobutyl methyl ketone
Prasugrel (2 g) and isobutyl methyl ketone (10 mL) were charged into a round bottom flask at 29°C under stirring and the mixture was heated to 50°C to obtain a solution. Activated carbon was added to the solution and stirred for 20 minutes at 50°C and filtered on hyflo and washed with isobutyl methyl ketone (5 mL). The filtrate was charged into the flask and cooled to 0°C and maintained for 3 hours 30 minutes under stirring. The precipitated solid was collected by filtration and washed with chilled isobutyl methyl ketone (5 mL). The obtained solid product was dried under vacuum at 55°C for 6 hours. Yield: 1.3 g; HPLC purity: 99.93%

Example 3: Purification of Prasugrel by slurry in Isopropanol.
Prasugrel (having acetonitrile content 365 ppm) (10 g) and isopropanol (100 mL) were charged into a round bottom flask at 29°C under stirring to obtain slurry. The obtained slurry was heated to 68°C and maintained for 30 minutes at the same temperature. The slurry was further cooled to 30°C. The solid was collected by filtration and washed with isopropanol (10 mL). The obtained solid product was dried under vacuum at 54°C for 3 hours. Yield: 9.0 g; HPLC purity: 99.87%; Acetonitrile content: 67 ppm

Example 4: Purification of Prasugrel by slurry in cyclohexane.
Prasugrel (having acetonitrile content 365 ppm) (10 g) and cyclohexane (100 mL) were charged into a round bottom flask at 29°C under stirring to obtain slurry. The obtained slurry was heated to 68°C and maintained for 30 minutes at the same temperature. The slurry was further cooled to 28°C. The solid was collected by filtration and washed with cyclohexane (10 mL). The obtained solid product was dried under vacuum at 60°C for 3 hours. Yield: 8.9 g; HPLC purity: 99.78%; Acetonitrile content: 98 ppm
,CLAIMS:WE CLAIM:

1. A process for the preparation of Prasugrel comprising:
a) reacting 5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one, or a salt thereof with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone, in the presence of an inorganic base and in a ketone solvent to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c] pyridin-2(4H)-one;
b) acetylating in situ the obtained 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one in step a), into Prasugrel by treating with an acetylating agent in the presence of an organic base; and
c) optionally purifying the Prasugrel obtained in step b) in a ketone solvent.

2. The process of claim 1, wherein the ketone solvent of step a) is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone or mixtures thereof.

3. The process of claim 2, wherein the ketone solvent of step a) is methyl isobutyl ketone.

4. The process of claim 1, wherein the inorganic base of step a) is alkali metal carbonates.

5. The process of claim 4, wherein the inorganic base of step a) is sodium carbonate.

6. The process of claim 1, wherein step b) is carried out without isolating the 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one obtained in step a).
7. The process of claim 1, wherein the acetylating agent of step b) is acetic anhydride.

8. The process of claim 1, wherein the organic base of step b) is N-methyl morpholine.

9. The process of claim 1, wherein the ketone solvent of step c) is methyl isobutyl ketone.

10. A process for the preparation of Prasugrel comprising:
a) reacting 5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one, or a salt thereof with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone, in the presence of sodium carbonate in methyl isobutyl ketone to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c] pyridin-2(4H)-one;
b) acetylating in situ the obtained 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one in step a), into Prasugrel by treating with acetic anhydride in the presence of N-methyl morpholine; and
c) optionally purifying the Prasugrel obtained in step b) with methyl isobutyl ketone.