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

The present invention also relates to novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine and its crystalline forms.
Prasugrel is a member of the thienopyridine class of antiplatelet agents. Currently available thienopyridines include clopidogrel and ticlopidine. Prasugrel is an orally bioavailable prodrug 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. Prasugrel is recently approved in US and Europe and available under the brand name of Effient.
Background of the Invention:
Prasugrel and its pharmaceutically acceptable salts have been disclosed in US 5,288,726. The said patent also disclosed a process for the preparation of prasugrel and its pharmaceutically acceptable salts, which involves the condensation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one hydrochloride with a-cyclopropylcarbonyl-2-fluorobenzyl bromide in presence of potassium carbonate in dimethyl formamide to provide 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine, which on acetylation in the presence of a strong base like sodium hydride provides prasugrel. The yield and purity of the intermediates and final compounds are not satisfactory, also it involves the usage of column purification for isolation of intermediates as well as final compound. It involves the use of strong base like sodium hydride. Hence this process is difficult to perform in commercial scale.

us 5288726 also disclosed the hydrochloride salt of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine with the melting point of 104-109°C, which is obtained by passing hydrogen chloride gas to a solution containing 5-(a-cycIopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno [3,2-c] pyridine in diethylether with a yield of 46%, which is very low.
WO 2009/006859 disclosed a process for the preparation of prasugrel, which comprises of condensing the 3-cyclopropyl-l-(2-flurophenyl)-3-oxopropyl methane sulfonate with 2-oxo-thineotetrahydropyridine to provide 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7-hexahydro thieno pyridine, which on acetylation with acetic anhydride provides prasugrel. This process involves the usage of column chromatography to get the pure product from the crude. Hence this process is not suitable for commercial scale.
Our International publication WO 2009/066326 disclosed a process for the preparation of prasugrel by acetylation of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine with acetic anhydride in presence of triethyl amine using acetonitrile as a solvent. We surprisingly found that the usage of hydrocarbon solvent like toluene in place of acetonitrile provided excellent yield and purity. It is also having cost advantage over the usage of acetonitrile in the acetylation reaction. The said patent disclosed a powder X-ray diffractogram of prasugrel, the said crystalline form is similar to the prasugrel obtained as per the process disclosed in US 5288726. The said crystalline form herein is designated as Form-I.
Polymorphism is the formation of a variety of crystalline forms of the same compound having distinct crystal stnictures and physical properties like melting points. X-ray diffraction pattern, infrared absorption pattern in fingerprint region, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The difference in the physical properties of different crystalline forms results in some forms having distinct advantageous physical properties compared to other crystalline forms of the same compound. The discovery of new polymorphic forms of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Those skilled in the art

understand that crystallization of an active pharmaceutical ingredient offers the best method for controlling important qualities like chemical quality, particle size, and polymorphic content. There is a need in the art for the preparation of new polymorphic forms of pharmaceutically acceptable salts of prasugrel as well as its intermediates and its salts.
Hence there is a need to develop a process which can be performed at an industrial scale. The present invention overcomes the problems associated with the prior art, and provides a process for the preparation of prasugrel and its pharmaceutically acceptable salts, with better yields and purity.
Brief Description of Invention:
The present invention relates to an improved process for the preparation of prasugrel and its pharmaceutically acceptable salts. Also relates to novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine and its crystalline forms.
The first aspect of the present invention is to provide the novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine with the proviso that the salt is not a hydrochloride.
The second aspect of the present invention is to provide a process for the preparation of novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine.
The third aspect of the present invention is to provide a crystalline form of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine hydrobromide as well as a process for its preparation. The novel crystalline form of the present invention is characterized by its PXRD, IR spectrum and DSC thermogram, substantially as shown in figure-1,2 &, 3 respectively.
The fourth aspect of the present invention is to provide the use of novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine of the present invention and crystalline form of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine hydrobromide in the

preparation of highly pure 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine as well as the usage in the preparation of highly pure prasugrel and its pharmaceutically acceptable salts..
The fifth aspect of the present invention is to provide a novel crystalline form of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine as well as process for its preparation.
The sixth aspect of the present invention is to provide a novel crystalline form-N of prasugrel free base as well as a process for its preparation. The novel crystalline form-N of prasugrel is characterized by its Powder X-ray diffractogram and is shown in figure-4.
The seventh aspect of the present invention is to provide an improved process for the preparation of prasugrel compound of formula-1 and its pharmaceutically acceptable salts, which comprises of acetylating the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine with a suitable acetylating agent in presence of a suitable organic base in a suitable hydrocarbon solvent, followed by crystallization from a suitable solvent to provide prasugrel compound of formula-1.
The eighth aspect of the present invention provides an improved and one-pot process for the preparation of prasugrel and its pharmaceutically acceptable salts.
Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray diffractogram of crystalline form-M of
5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c]
pyridine hydrobromide.
Figure-2: Illustrates the IR spectrum of crystalline form-M of
5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]
pyridine hydrobromide.
Figure-3: Illustrates the DSC thermogram of crystalline form-M of
5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]
pyridine hydrobromide

Figure-4: Illustrates the powder X-ray diffractogram of crystalline form-S of
5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]
pyridine
Figure-5: Illustrates the powder X-ray diffractogram of crystalline form-N of Prasugrel
Detailed description of the invention
The present invention relates to an improved process for the preparation of prasugrel and its pharmaceutically acceptable sahs. Prasugrel is chemically known as 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine represented by the following structural formula.
A

and its pharmaceutically acceptable salts.
As used here in the term "alcoholic solvent" is selected from methanol, ethanol, isopropanol, n-propanol, butanol and the like; the term "ester solvents" refers to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; the term "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like; the term "chloro solvents" refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; polar aprortic solvents refers to dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and the like; the term "nitrile solvents" refers to acetonitrile and the like; the term "polar solvent" refers to water and the like.
As used herein the term "inorganic base" refers to alkali metal carbonates like
sodium carbonate, potassium carbonate; alkali metal hydroxide like sodium hydroxide,
potassium hydroxide; alkali metal bicarbonates like sodium bicarbonate, potassium
bicarbonate and the like; the term "organic base" refers to triethylamine, tributyl
amine, pyridine, 4-dlmethylaminopyridine, N-methylmorpholine and diisopropylethyl amine and the like;

As used here in the term "crude" refers to the compound obtained directly after the reaction may be in the form of solid, residue or oily residue or the compound before purification.
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.
Accordingly, the first aspect of the present invention provides the novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine and is represented by the following general formula-8,
A

wherein "Acid" is an acid which is capable of forming acid addition salt with 5-(a-cyclopropyIcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine and is selected from group comprising of oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, d-tartaric acid, 1-tartaric acid, dl-tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid or hydrobromic acid, with a proviso that the acid is not hydrochloric acid.
The second aspect of the present invention provides a process for the preparation of novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine, which comprises of treating the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine with a suitable acid selected from the acids which are defined above, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof for the sufficient period of time, to provide the corresponding salt of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine.

il The third aspect of the present invention provides a crystalline form of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine hydrobromide compound of formula-8a.

The crystalline form of the present invention is herein designated as crystalline form M. The novel crystalline form-M of the present invention is characterized by its Powder X-ray diffractogram having characteristic 20 peaks at 7.07, 10.18, 14.81, 19.41, 20.44, 21.03, 22.37, 26.39, 26.86 and 27.32 ± 0.2 degrees 29 as illustrated in figure-1; and by its Infra-Red spectrum having peaks at 3410.8, 3045.9, 2919.4, 2629.0, 2545.7, 1713.4, 1686.0, 1494.8, 1377.8, 1174.2, 1091.5, 1013.6, 1091.5 and 798.0 cm"' as illustrated in figure-3 and Differential Scanning Calorimetry showing exothermic peak at 202.98°C as illustrated in figure-3.
The present invention also provides a process for the preparation of crystalline form-M of compound of formula-8a, which comprises of treating the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine in a suitable ketone solvent, preferably acetone with aqueous hydrobromic acid or hydrobromic acid in a suitable ester or alcohol solvent, at a suitable temperature ranges from 0 to 20°C, preferably 0-5°C to provide the crystalline form M of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine hydrobromide.
The fourth aspect of the present invention provides the use of novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine of the present invention and crystalline form-M of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine hydrobromide in the preparation of highly pure 5-(a-cyclopropyIcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c]| pyridine as well as in the preparation of highly pure prasugrel and its pharmaceutically acceptable salts.

The fifth aspect of the present invention provides a crystalline form of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine having the following structural formula

The novel crystalline form of the present invention herein designated as form-S. The crystalline form-S of the present invention is characterized by its Powder X-ray diffractogram having characteristic 29 peaks at 7.63, 9.07, 12.73, 14.78, 15.30, 17.43, 18.20, 18.53, 19.47, 19.89, 21.70, 22.58, 24.00, 30.92 ± 0.2 degrees 20 and the same has been illustrated in figure-4.
The present invention also provides a process for the purification and crystallization of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine, which comprises of treating the crude 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of formula-7 with a suitable acid as defined above in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof to provide the corresponding salt of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine compound of formula-8.

Wherein "acid" is as defined above;
Treating the thus obtained salt compound of formula-8 with a suitable inorganic or organic base, preferably inorganic base like sodium bicarbonate in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof to provide pure

crystalline 5-(a-cyclopropylcarbonyl-2-fIuorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine. The PXRD of the obtained crystalline form is shown in figure-4.
In the preferred embodiment of the present invention, the crystallization/purification of 5-(a-cyclopropylcarbonyl-2-f[uorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine process comprises of the following steps;
a) Reacting the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine with hydrobromic acid in acetone to provide the hydrobromide salt of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine,.
b) treating the above obtained hydrobromide salt compound with aqueous sodium bicarbonate at 10-15°C,
c) stirring the reaction mixture for 30 minutes at 10-15°C,
d) extracting the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine in to suitable solvent like methylene chloride,
e) distilling off the solvent under reduced pressure at below 55-60°C,
f) adding a suitable hydrocarbon solvent, preferably cyclohexane to the obtained residue,
g) stirring the reaction mixture for an hour at 25-30°C,
h) filtering and washing the solid then drying the solid to provide highly pure crystalline 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine.
The sixth aspect of the present invention provides a novel crystalline form of prasugrel free base compound of fonnula-l.

The novel crystalline form of the present invention herein is designated as form-N. The crystalline form-N of the present invention is characterized by its Powder X-ray diffractogram having characteristic 20 peaks at 7.80, 9.35, 11.79, 15.38, 15.64, 15.98, 16.28, 17.14, 18.78, 20.10, 20.36, 20.91, 21.35, 22.35, 22.63, 23.59, 24.39,

25.51, 29.43, 31.08, 31.99 ± 0.2 degrees 20 and the same has been illustrated in figure-5.
The seventh aspect of the present invention provides an improved process for the preparation of prasugrel compound of formula-1

and its pharmaceutically acceptable salts, which comprises of acetylating the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine with a suitable acetylating agent like acetic anhydride, in presence of a suitable organic base selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine and the like, preferably triethylamine in a suitable hydrocarbon solvent, preferably toluene, followed by crystallization from a suitable alcoholic solvent to provide prasugrel compound of formula-1. Optionally converting the obtained prasugrel into its pharmaceutically acceptable salts by the process known in the art.
In a preferred embodiment of the present aspect of the invention, the process for the preparation of prasugrel compound of formula-1 comprises of reacting the 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of formula-7 with acetic anhydride in presence of triethyl amine at a temperature ranges from 0-30°C, preferably 25-30°C followed isolating the prasugrel compound of formula-1 from methanol.
The eighth aspect of the invention provides an improved process for the preparation of prasugrel and its phannaceutically acceptable salts, which comprises of; a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 hydrochloride.


with triphenyl methyl chloride in presence of a suitable base like triethyl amine in a suitable solvent like methylene chloride, followed by crystallization from a suitable alcoholic solvents selected from methanol, ethanol, propanol, isopropyl alcohol and butanol or mixtures thereof, preferably isopropyl alcohol to provide a compound of formula-3,

b) reacting the compound of fonnula-3 with n-butyl lithium in tetrahydrofuran at
0-5°C under nitrogen atmosphere, followed by treating the reaction mixture with
tri-n-butyl borate and then treating with hydrogen peroxide, followed by
crystallization from a suitable alcoholic solvents like methanol, ethanol, propanol,
isopropyl alcohol and butanol or mixtures thereof, preferably isopropyl alcohol to
provide a compound of formula-4,

c) treating the compound of formula-4 with a suitable acid like hydrochloric acid or
p-toluene sulfonic acid in a suitable solvent like acetone, followed by crystallization
from acetone to provide the corresponding acid addition salt of 5,6,7,7a-tetrahydro-
4H-thieno[3,2-c]pyridine-2-one compound of general formula-5,
/=^r^NH .Acid
Formula -5 5a) ACID = PTSA and 5b) ACID = HCl
d) reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid addition salt
compound of formula-5 or its free base with a-cyclopropylcarbonyl-2-fluorobenzyl
bromide compound of formula-6,,


in the presence of potassium carbonate in acetonitrile, followed by crystallization from a mixture of ethyl acetate and cyclohexane to provide compound of formula-7,

e) acetylating the compound of fonnula-7 with a suitable acetylating agent like acetic
anhydride in a suitable solvent selected from hydrocarbon solvents like toluene,
xylene, heptane, cyclohexane and hexane, preferably toluene in presence of a
suitable organic base, preferably triethylamine, followed by crystallization/isolation
from a suitable alcoholic solvent, preferably methanol to provide the compound of
formula-1,

f) optionally converting the prasugrel into its hydrochloric acid salt by treating it with
HCl gas or HCl gas dissolved in organic solvent like ethyl acetate, isopropyl acetate
preferably ethyl acetate hydrochloride provides prasugrel hydrochloride salt
compound of formula-la.
A

The present invention also provides a one-pot process for the preparation of prasugrel compound of formula-1, which comprises of
a) reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid addition salt compound of formula-5

5a) ACID = PTSA and 5b) ACID = HCl

or its free base with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-6,

in presence of suitable organic or inorganic bases, preferably inorganic base in a suitable solvent selected from nitrile solvent, ketone solvent, ester solvent, polar aprotic solvent or mixtures thereof, preferably nitrile solvent like acetonitrile,
b) filtering the unwanted solid and washing with a suitable solvent,
c) treating the filtrate containing 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-
2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of formula-7 with acetic
anhydride in presence of a suitable organic base, preferably triethylamine,
d) extracting the reaction mixture into suitable hydrocarbon solvent preferably toluene,
e) distilling off the solvent completely under reduced pressure,
f) crystallizing the obtained residue from a suitable alcoholic solvent to provide the prasugrel compound of formula-1
A

Prasugrel and its pharmaceutically acceptable salts of the present invention can be micronized or milled to get the desired particle size.

The present invention is schematically represented as follows. Scheme-1:

PXRD analysis of prasugrel, its intermediates and their salts were carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FI-IR spectrum of prasugrel and its intermediate were recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of prasugrel and intermediates were carried out on Waters DSC Q-10 model differential scanning calorimeter.
The related substance of prasugrel, its pharmaceutical acceptable salts and intermediates were analyzed by HPLC using the following conditions: Column: Hypersil BDS, 250 X 4.6 mm or equivalent; Flow rate: 0.8 ml/min; wavelength: 240 nm; Temperature: 40°C; Load: 20 [d; and using acetonitrile as a mobile phase

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 5-trityl- 4, 5, 6, 7-tetrahydrotieno [3, 2-c]pyridine
compound of formula-3:
Triethylamine (181 ml) and trityl chloride (151 grams) was added a mixture of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (100 grams) in dichloromethane (220 ml) at 0-5°C and stirred for 9 hours. The reaction mixture was quenched with water (300 ml), stirred at 25-30°C then the aqueous and organic layers was separated. The solvent from the organic layer was distilled off completely under reduced pressure and isopropyl alcohol (250 ml) was added to the obtained residue and stirred for 45 minutes at reflux temperature. The reaction mixture was cooled to 25-30°C and stirred for an hour. The solid was fdtered, washed with isopropyl alcohol and dried to get the title compound. Yield: 168 grams; M.R:160-165°C
ExampIe-2: Preparation of 5-trityI-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-(4H)-one compound of formula-4:
n-butyl lithium (129 ml, 1.6 M) was added to a solution of 5-triyl-4,5,6,7-tetrahydrothieno[3,2-c] pyridine (50 grams) in tetrahydrofuran (350 ml) at 0-5°C under nitrogen atmosphere and stirred for 1 hour at 10-15°C. The reaction mixture was cooled to 0-5°C and tri-n-butyl borate (75 grams) in tetrahydrofuran (50 ml) was added, stirred for 1 hour at 10-15°C. Aqueous hydrogen peroxide (45 ml, 30(v/v)) was added to the reaction mixture at 0-5°C and then stirred for 2 hours at 25-30°C. The reaction mixture was quenched with water and then extracted into toluene. The organic layer was washed with sodium sulphite solution and the solvent from it was distilled off under reduced pressure. Isopropyl alcohol (150 ml) was added to the obtained residue and stirred for 45 minutes at reflux temperature. The reaction mixture was cooled to 25-30°C and stirred for 1 hour. The solid obtained was filtered, washed with isopropyl alcohol and dried to get the title compound. Yield: 45 grams

£xainpIe-3: Preparation of 5, 6, 7, 7a-tetrahydro-4H-thieno [3,2-c]-pyridin-2-one-p-toluenesulfonate compound of formula-5:
A mixture of 5-trityl-5,6,7,7a-tetrahydrothieno [3,2-c]pyridin-2(4H)-one (100 grams), acetone (1000 ml) and p-toluenesulfonic acid (48 grams) was stirred for 25 minutes at 25-30°C. Tlie solid obtained was filtered and washed with acetone. Acetone (200 ml) was added to the wet solid and stirred for 30 min. at reflux temperature. The reaction mixture was cooled to 25-30°C and stirred for 1 hour. The solid formed was filtered, washed with acetone and dried to get the title compound. Yield: 78 grams; M.R:182-187°C
Example-4: Preparation of 2-bromo-l-cycIopropyl-2-(2-fluorophenyl) ethanone compound of formula-6:
A mixture of l-cyclopropyl-2-(2-fluorophenyl) ethanone (40 grams), chloroform (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-5: Preparation of 5-(a-cyclopropylcarbonyI-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine compound of formula-7:
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) 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 form 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

ExampIe-6: Preparation of prasugrel compound of formuIa-1:
Triethylamine (32 grams) was added to the solution of 5-(a-cyclo propylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine (60 grams) in toluene (360 ml) and stirred for 15 minutes at 25-30°C and then cooled to 0-5°C. Acetic anhydride (64.5 ml) was added to the reaction mixture and stirred for 30 minutes at 0-5°C. The reaction mixture was stirred for 6 hours at 25-30°C. The reaction mixture was quenched with water and separated both the aqueous and organic layers. Organic layer washed with aqueous sodium bicarbonate followed by water and then the solvent from the organic layer was distilled off under reduced pressure and methanol (75 ml) was added to the obtained residue and stirred for 45 min at reflux temperature. The reaction mixture was cooled to 0-5°C and stirred for 45 minutes. The obtained solid was filtered, washed with methanol and then dried to get the title compound. Yield: 36 grams; Purity by HPLC: 99.00%
Example-?: Preparation of crystalline form-M of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3^-c] pyridine hydrobromide:
Acetone (130 ml) was added to 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine obtained in example-5 (55 grams) at 25-30°C. The reaction mixture was cooled to 0-5°C and aqueous hydrobromide (16 grams) was added to it and stirred for an hour at 0-5°C. The obtained solid was filtered, washed with acetone and dried to get the title compound. Yield: 30 grams; Purity by HPLC: 98.42%
ExampIe-8: Preparation of crystalline form-S of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3^-c] pyridine:
A mixture of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine hydrobromide (50 grams), water (500 ml) and 10% sodium bicarbonate solution (500 ml) was stirred for 30 minutes at 10-15°C. Methylene chloride (500 ml) was added to the reaction mixture and stirred for 15 min at 25-30°C. The organic and aqueous layer was separated and the solvent from the organic layer was distilled off completely under reduced pressure. Cyclohexane (150 ml) was added to the residue and stirred the reaction mixture for 1 hour at 25-30°C. The obtained solid was filtered, washed with cyclohexane and dried to get the title compound as crystals. Yield: 40 grams; Purity by HPLC: 99.00%

Example-9: Preparation of Prasugrel hydrochloride:
A mixture of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine (100 grams), acetone (1000 ml) and hydrochloric acid (10.5 grams) was stirred for 3 hours at 25-30°C. The precipitated solid was filtered and washed with acetone. To the wet material added acetone (300 ml) and stirred for 1 hour at 25-30°C. Filtered the reaction mixture, washed with acetone and dried the compound to get the title compound. Yield: 47 grams; M.R: 197-202°C; Purity: 99.90 % by HPLC
Example-10: Preparation of Prasugrel hydrochloride:
A mixture of 5-(a-cyclopropylcarbonyl-2-f]uorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine (100 grams) and acetone (800 ml) was heated to 40-45°C and the obtained solution was subjected to carbon treatment and then filtered. Filtrate was cooled to 0-5°C and 2.5% ethyl acetate hydrochloric acid (250 ml) was added to it and stirred for 45 minutes. The solid obtained was filtered, washed with acetone and dried the compound to get the title compound. Yield: 90 grams; Purity: 99.91 % by HPLC
Example-11: One pot process for the preparation of Prasugrel:
A mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one hydrochloride (100 grams), potassium carbonate (215 grams) and acetonitrile (500 ml) was stirred for 30 minutes at 25-30°C. 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)ethanone (89.5 grams) in acetonitrile (50 ml) was added to the reaction mixture and stirred for 6 hours at 25-30°C. The reaction mixture was filtered and removed the precipitated solid. Triethylamine (98.2 grams) was added to the filtrate and then cooled to 0-5°C. Acetic anhydride (119 grams) was added to the reaction mixture and stirred for 30 minutes at 0-5°C. The reaction mixture was stirred for 6 hours at 25-30°C. Then the reaction mixture was quenched with water and extracted the reaction mixture into toluene. The solvent from the toluene layer was distilled off under reduced pressure and methanol (100 ml) was added to the obtained residue and stirred for 45 min at reflux temperature. The reaction mixture was cooled to 0-5°C and stirred for 45 minutes. The obtained solid was filtered, washed with methanol and then dried to get the title compound. Yield: 60 grams; Purity by HPLC: 98.97%

Claim:
1. Novel salts of 5-(a-cyclopropylcarbonyl-2-fIuorobenzyl)-2-oxo-2,4,5,6,7,7a-
hexahydro thieno[3,2-c] pyridine having the following structural formula
A

wherein "Acid" is an acid which is capable of forming acid addition salt with 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine and is selected from a group comprising of oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, d-tartaric acid, 1-tartaric acid, dl-tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid or hydrobromic acid, with a proviso that the acid is not hydrochloric acid.
2. A process for the preparation of novel salts of 5-(a-cyclopropylcarbonyl-2-
fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine as claimed in
claim 1, which comprises of treating the 5-(a-cyclopropylcarbonyl-2-fluoro
benzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine with a suitable acid
selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid,
maleic acid, d-tartaric acid, 1-tartaric acid, dl-tartaric acid, citric acid,
methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid,
phosphoric acid and hydrobromic acid, in a suitable solvent selected from alcohols,
ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro
solvents, nitriles or mixtures thereof for the sufficient period of time, to provide the
corresponding salt of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-
hexahydro thieno[3,2-c] pyridine.
3. Novel crystalline form-M of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-
2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine hydrobromide, which is
characterized by any one of the following;

a) Its Powder X-ray diffractogram having characteristic 29 peaks at 7.07, 10.18, 14.81, 19.41, 20.44, 21.03, 22.37, 26.39, 26.86 and 27.32 ± 0.2 degrees 20 as illustrated in figure-1;
b) its Infra-Red spectrum having peaks at 3410.8, 3045.9, 2919.4, 2629.0, 2545.7, 1713.4, 1686.0, 1494.8, 1377.8, 1174.2, 1091.5, 1013.6, 1091.5 and 798.0 cm-' as illustrated in figure-2; and
c) Differential Scanning Calorimetry showing exothermic peak at 202.98°C as illustrated in figure-3.

4. Use of novel salts of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine as claimed in claim 1 and crystalline 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-0X0-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine hydrobromide as claimed in claim 3, in the preparation of highly pure 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno [3,2-c] pyridine as well as in the preparation of highly pure prasugrel and its pharmaceutically acceptable salts.
5. Crystalline form-S of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine, characterized by its Powder X-ray diffractogram having characteristic 20 peaks at 7.63, 9.07, 12.73, 14.78, 15.30, 17.43, 18.20, 18.53, 19.47, 19.89, 21.70, 22.58, 24.00, 30.92 ± 0.2 degrees 20 as illustrated in figure-4.
6. A process for the purification/crystallization of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine which comprises of the following steps,

a) treating the crude 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine with a suitable acid as defined above, in a suitable solvent to provide the corresponding salt of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine compound of formula-8,
b) treating the thus obtained salt compound of formula-8 with a suitable organic or inorganic base, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitriles or

mixtures thereof to provide pure crystalline 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine.
7. Crystalline form-N of prasugrel free base characterized by its Powder X-ray
diffractogram having characteristic 29 peaks at 7.80, 9.35, 11.79, 15.38, 15.64,
15.98, 16.28, 17.14, 18.78, 20.10, 20.36, 20.91, 21.35, 22.35, 22.63, 23.59, 24.39,
25.51, 29.43, 31.08 and 31.99 ± 0.2 degrees 29 as illustrated in figure-5.
8. An improved process for the preparation of prasugrel and its pharmaceutically
acceptable salts, which comprises of acetylating the 5-(a-cyclopropylcarbonyl-2-
fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c] pyridine with a acetic
anhydride in presence of a suitable organic base selected from triethyl amine,
tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and
diisopropylethyl amine in a suitable hydrocarbon solvent, followed by
crystallization from a suitable alcoholic solvent to provide prasugrel compound of
formula-1.
9. An improved process for the preparation of prasugrel and its pharmaceutically
acceptable salts, especially hydrochloride salt, which comprises of
a) protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c]
pyridine compound of formula-2 hydrochloride,

b) reacting the compound of fo:miula-3 with n-butyl lithium in tetrahydrofuran at
0-5°C under nitrogen atmosphere, followed by treating the reaction mixture
with tri-n-butyl borate and then treating with hydrogen peroxide, followed by

crystallization from a suitable alcoholic solvents like methanol, ethanol, propanol, isopropyl alcohol and butanol or mixtures thereof, to provide a compound of formula-4,

e) acetylating the compound of formula-7 with a suitable acetylating agent like acetic anhydride in a suitable solvent selected from hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane in presence of a suitable organic base selected from triethyl amine, tributyl amine, pyridine.

4-dimethylatninopyridine, N-methylmorpholine and diisopropylethyl amine, followed by crystallization/isolation from a suitable alcoholic solvent, to provide the prausgrel compound of formula-1, f) optionally converting the prasugrel into its hydrochloric acid salt by treating it with HCl gas or HCl gas dissolved in organic solvent like ethyl acetate, isopropyl acetate provides prasugrel hydrochloride salt compound of formula-la.
10. One-pot process for the preparation of prasugrel compound of formula-1, which comprises of
a) Reacting the 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid addition
salt compound of formula-5 or its free base with a-cyclopropylcarbonyl-2-
fluorobenzyl bromide compound of formula-6 in presence of suitable organic
base or inorganic base in a suitable solvent selected from nitrile solvent, ester
solvent, polar aprotic solvent and ketone solvent or mixtures thereof,
b) filtering the unwanted solid and washing with suitable solvent,
c) treating the filtrate containing 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of formula-7 with acetic anhydride in presence of a suitable organic base,
d) extracting the reaction mixture into suitable hydrocarbon solvent,
e) distilling off the solvent completely under reduced pressure,
f) crystallizing the obtained residue from a suitable alcoholic solvent to provide the prasugrel compound of formula-1.