Field of the Invention:
The present invention relates to a novel process for the preparation of ADP receptor inhibitors such as prasugrel and its pharmaceutically acceptable salts. Prasugrel is chemically known as 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahyclrothieno[3,2-c]pyridin-2-yl acetate compound of formula-1.

Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticloidine (TICLID®) and clopidogrel (PLAVIX®). These agents are believed to reduce the aggregation (i.e., clumping) of platelets by irreversibly binding to P2Y12 receptors. Prasugrel is a novel platelet inhibitor that is expected to be administered as a solid oral dosage form. Prasugrel is undergoing the approval process for acute coronary syndromes planned for percutaneous coronary intervention (PCI).
Background of the Invention:
Prasugrel and its pharmaceutically acceptable salts have been disclosed in US patent 5,288,726. The disclosed process for the preparation of prasugrel is schematically represented in following shceme-1


The disclosed process involves the preparation of Grignard reagent from 2-fluorobenzylbromide(i) then reaction with cyclopropylcyanide (ii) in ether to provide the compound (iii). The compound (iii) is brominated with N-bromosuccinamide (NBS) in the presence of dibenzoylperoxide provides a-cyclopropylcarbonyl-2-fluorobenzyl bromide (iv). Condensation of compound (iv) with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one (v) in presence of potassium carbonate in dimethylformamide provides 5-(a-cyclopropylcarbonyl-2-fluorobenzy)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine (vi). Acetylation of 5-(a-cyclopropylcarbonyl-2-flu6robenzy)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c]pyridine(vi) using acetic anhydride in presence of sodium hydride provides prasugrel. As per the above process the compound (vi) obtained by the condensation of compound (iv) and (v) is very low in yield (32% only) which leads to increase in cost of the product. Moreover the process involves the usage of strong base like sodium hydride for acetylation which is not advisable at an industrial scale.
The process for the preparation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one(v) intermediate used in the above process is disclosed in US 4740510. The disclosed process schematically represented by the following scheme-2

The disclosed process comprises of protecting the amino functional group of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine (vii) compound by using triphenylmethylchloride provides trityl protected 4,5,6,7-tetrahydrothieno[3,2-c] pyridine (viii) and converting it into 2-0X0 derivative (ix) by treating with tri-n-butyl borate in presence of n-butyl lithium in tetrahydrofuran followed by treatment with hydrogen peroxide and finally deprotecting the trityl group using formic acid to provide 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one (v). The said process involves unwanted protection and

deprotection of amino group in order to introduce oxo group at second position of compound (vii), which leads to increase the number of steps, increased timeliness and cost of production.
Till the date, 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine was prepared from the condensation of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one or its salt with a-cyclopropylcarbonyl-2-fluorobenzyl bromide in presence of base and solvent with very low yields. Moreover the 5,6,7,7a-tetrahydro-4H-thleno[3,2-c] pyridine-2-one is less stable and hence its usage decrease the over all yield makes the process commercially not suitable. So there is a need in the art for novel process which avoids the use of less stable 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one and which reduces the number of steps.
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 novel process for the preparation of prasugrel and its pharmaceutically acceptable salts, with better yields and purity.
Brief description of the Invention:
The present invention relates to a novel process for the preparation of Prasugrel, chemically known as 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate compoimd of formula-1 and pharmaceutically acceptable salts thereof.

The first aspect of the present invention is to provide a novel process for the
preparation of 5-(a.-cyclopropylcarbonyl-2-f[uorobenzyl)-2-oxo-2,4,5,6,7,7a-
hexahydrothieno[3,2-c]pyridine compound of Formula-7, Which comprises of,

a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of fonnula-2 or its salts, with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-3, in presence of a suitable base in a suitable solvent to provide 5-(a,-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine compound of formula-4,
b) converting the 5-(a.-cyclopropylcarbonyl-2-fluoroben2yl)-4,5,6,7,-tetrahydrothieno [3,2-c]pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7, by in-situ protecting the keto functionality of compound of formula-4 as an enolate by treating with a lithium reagent and by introducing a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton by treating it with second lithium reagent in a suitable solvent and a suitable boronating agent, in presence or absence of co-solvent and subsequent oxidation by treating it with suitable oxidizing agent to provide the compound of formula-7.
The second aspect of the present invention provides a novel process for the preparation of 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c] pyridin-2-yl acetate compound of formula-l and pharmaceutically acceptable salts thereof, Which comprises of,
a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of fonnula-2 or its salts, with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-3, in presence of a suitable base in a suitable solvent to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of fonnula-4,
b) converting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno [3,2-c]pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7, by in-situ protecting the keto fimctionality of compound of formula-4 as an enolate by treating with a lithium reagent and by introducing a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton by treating it with second lithium reagent in a suitable solvent and a suitable boronating agent, in

presence or absence of co-solvent and subsequent oxidation by treating it witli suitable oxidizing agent to provide the compound of formula-7,
c) acetylating the compound of Formula-7 with a suitable acetylating agent like acetic
anhydride in a suitable solvent in presence of a suitable organic base selected to
provide the compound of formula-1,
d) optionally converting the prasugrel into its acid addition salts by treating it with a
suitable acid in a suitable solvent to provide an acid addition sah of prasugrel.
The third aspect of the present invention relates to acid addition salts of 5-(a.-cyclopropylcarbonyl-2-fluoroben2yl)-4,5,6,7,-tetrahydrothieno [3,2-c] pyridine compounds of general Formula-8 and process for their preparation as well as their use.
Detailed description of the invention:
As used herein, the term "pharmaceutically acceptable salts" refers to the salt compound formed with a suitable acid selected from an inorganic acid addition salts such as hydrobromic acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-toluenesulfonic acid and malic acid.
The first aspect of the present invention provides a process for the preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of Formula-7,

Which comprises of;
a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,

with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compoimd of formula-3.


in presence of a suitable base in a suitable solvent to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of formula-4,

b) converting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno [3,2-c]pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7, by in-situ protecting the keto functionality of compound of formula-4 as an enolate by treating with a lithium reagent and by introducing a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton by treating it with second lithium reagent in a suitable solvent and a suitable boronating agent, in presence or absence of co-solvent and subsequent oxidation by treating it with suitable oxidizing agent to provide compound of Formula-7,

Wherein in step a) the suitable base is selected from a group consisting of alkali metal carbonates like sodium carbonate, potassium carbonate; or an alkali metal hydroxide like sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal alkoxides like sodium tertiary butoxide, potassium tertiary butoxide or an organic base like triethylamine, tributylamine, diisopropylethlyamine preferably potassium carbonate, in a suitable solvent selected from

aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles like acetonitrile and propionitrile; dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof preferably acetonitrile;
In step b) the suitable lithium reagent for protecting the keto functionality as enolate is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium lithium hexamethyldisilazide and lithium diisopropylamide preferably lithium diisopropylamide; the suitable boronating agent is selected from boron oxides such as B2O3, boron acids such as H3BO3, lower alkyl esters of boron acids such as trimethylborate, triethylborate, tri n-butylborate, boron halides like BF3, BCI3, salts of boron acids like sodium borate, ammonium borate preferably tri n-butylborate; the suitable second lithiating agent for the generation of lithium salt at 2 position of thieno[3,2-c] pyridine skeleton is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium hexamethyldisilazide and lithium diisopropylamide; preferably n-butyl lithium; and the suitable oxidising agent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, selenium dioxide, sodiirai hypochlorite, sodiimi metaperiodate and the like, preferably hydrogen peroxide; the suitable co solvent is selected from tetramethyl urea(TMU), l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), N-Methyl-2-pyrrolidone (NMP), hexamethylphosphoramide (HMPA) and the like; and the suitable solvent is selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydroftiran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles like acetonitrile and

propionitrile; dimethyl fonnamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof preferably tetrahydrofuran. Optionally in place of second lithium reagent dialkyl zinc compounds like diethyl zinc, dimethyl zinc ethyl methyl zinc and the like also can be used.
In the above aspect of the present invention the conversion of the 5-(a.-cyclo propylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno [3,2-c]pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c]pyridine compound of Formula-7 can be carried out using a single lithium reagent for both enolation as well as formation of lithium salt during the introduction of a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton.
The second aspect of the present invention provides a novel process for the preparation of 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydro thieno[3,2-c]pyridin-2-yl acetate compound of formula-1

and pharmaceutically acceptable salts thereof, which comprises of; a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or its salts,

with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of fonnula-3,


in presence of a suitable base in a suitable solvent to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of fonnula-4,

b) converting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno
[3,2-c]pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-
fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of
Formula-7, by in-situ protecting the keto functionality of compound of formula-4
as an enolate by treating with a lithium reagent and by introducing a boronic group
-B(0R')2 at second position of thieno [3,2-c] pyridine skeleton by treating it with
second lithium reagent in a suitable solvent and a suitable boronating agent, in
presence or absence of co-solvent and subsequent oxidation by treating it with
suitable oxidizing agent to provide compound of Formula-7,

c) acetylating the compound of Formula-7 with a suitable acetylating agent in a suitable solvent in presence of a suitable organic base to provide the compound of formula-1,
d) optionally converting the prasugrel into its acid addition salts by treating it vwth a suitable acid in a suitable solvent to provide an acid addition salt of prasugrel.
Wherein in step a) the suitable base is selected from a group consisting of alkali metal carbonates like sodium carbonate, potassium carbonate; or an alkali metal hydroxide like sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal alkoxides like sodium tertiary butoxide, potassium tertiary butoxide or an organic base like triethylamine, tributylamine, diisopropylethlyamine preferably potassium carbonate, in a suitable solvent selected from

aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles like acetonitrile and propionitrile; dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof preferably acetonitrile;
In step b) the suitable lithium derivative for protecting the keto functionality as enolate is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium lithium hexamethyldisilazide and lithium diisopropylamide preferably lithium diisopropylamide; the suitable boronating agent is selected from boron oxides such as B2O3, boron acids such as H3BO3, lower alkyl esters of boron acids such as trimethylborate, triethylborate, tri n-butylborate, boron halides like BF3, BCI3, salts of boron acids like sodium borate, ammonium borate preferably tri n-butylborate; the suitable lithiating agent for the generation of lithium salt at 2"** position of thieno[3,2-c] pyridine skeleton is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium lithium hexamethyldisilazide and lithium diisopropylamide; preferably n-butyl lithium; the suitable oxidising agent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, seleniimi dioxide, sodium hypochlorite, sodium metaperiodate and the like, preferably hydrogen peroxide; the suitable co-solvent is selected from tetramethyl la-eaCTMU), l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), N-Methyl-2-pyrrolidone (NMP), hexamethylphosphoramide (HMPA) and the like; and the suitable solvent is selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofiiran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles like acetonitrile and

propionitrile; dimethyl fomiamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof preferably tetrahydrofuran. Optionally in place of second lithium reagent dialkyl zinc compounds like diethyl zinc, dimethyl zinc ethyl methyl zinc and the like also can be used.
in step c) the suitable acetylating agent is like acetic anhydride in a suitable solvent selected from diethylether, tetrahydrofuran, dioxane, acetone, methylethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide preferably acetonitrile, in presence of a suitable organic base selected from triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine preferably triethylamine,
in step d) the suitable acid selected from an inorganic acids such as hydrochloric acid, hydrobromic acid; or an organic acids such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-tolunesulfonic acid and malic acid, in a suitable solvent selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohol like isopropyl alcohol; or nitriles like acetonitrile and propionitrile or mixtures thereof. The present invention was schematically represented as follows.


The third aspect of the present invention provides novel acid addition salts of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno[3,2-c]pyridine compound represented by the following structural formula-8.

Wherein the acid is a acid group which is capable of forming addition salts with the compound of formula-4 and such acid is selected from inorganic acids such as hydrobromic acid, sulfuric acid, nitric acid or organic acids such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-tolunesulfonic acid and malic acid, provided that the acid is not hydrochloric acid.
The process for the preparation of acid addition salts of 5-(a.-cyclopropylcarbonyl-2-fluoroben2yl)-4,5,6,7,-tetrahydrothieno[3,2-c]pyridine compounds of general Formula-8, comprises of treating the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of formula-4 with a suitable acid in a suitable solvent, to provide the corresponding salts compounds of general Formula-8.
The suitable acid used is selected from an inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid; or an organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-tolunesulfonic acid and malic acid; and the suitable solvent is selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles like acetonitrile and propionitrile; dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof; the suitable temperature is -20''C to reflux temperature of the solvent used.

The acid addition salts compound of Formula-S of the present invention is used to prepare highly pure compound of Formula-7 and prasugrel or its pharmaceutically acceptable salt.
As used herein the present invention the term "highly pure" refers to the compound with purity greater than 99.00% by HPLC, preferably > 99.50 % by HPLC and more preferably > 99.90% by HPLC.
The 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one [V] compoimd can also be prepared by treating N-trityl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine compound with dialkyl zinc compoimds like diethyl zinc, dimethyl zinc ethyl methyl zinc etc. followed by treating Mdth suitable boronic agent and subsequent treatment with a suitable oxidizing agent to provide N- trityl 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one [ix] which is treated with formic acid to provide compound [V]. The suitable boronating agent and suitable oxidizing agents are same as described above.


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:
Example-l:Preparatioii of 5-(a.-cycIopropyIcarbonyl-2-fluorobeii2yl)- 4,5,6,7,-
tetrahydrothieno[3,2-c] pyridine compound of formula-4.
2-fluoro-a-cyclopropyl carbonyl benzyl bromide (6.1 grams) was added to a mixture of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride (5.0 grams) and potassium carbonate (6.0 grams) in acetonitrile (50 ml) at temperature 25 to 35''C and stirred for 5 hours. The reaction mixture was filtered and the filtrate was distilled off completely. The obtained residue was purified using cyclohexane and ethyl acetate to provide the title compound. Yield: 8,0 grams
Examp!e-2:Preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of formuIa-4.
2-fluoro-a-cyclopropyl carbonyl benzyl bromide (6.1 grams) was added to a mixture of 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride (5.0 grams) and sodium carbonate (5.0 grams) in acetonitrile (50 ml) at temperature 25 to 35°C and stirred for 5 hours. The reaction mixture was filtered and the filtrate was distilled off completely. The obtained residue was purified using cyclohexane and ethyl acetate to provide the title compound. Yield: 7.9 grams.
Example-3: Preparation of 5-(o.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine hydro bromide.
To 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno[3,2-c] pyridine (25 grams) added acetone (50 ml) and stirred for 15 minutes. Cool the reaction mixture to 0 - 5°C. Added aqueous hydrobromide (13 ml) slowly to the reaction mixture. Raised tiie temperature to 25 - 30°C and stirred for 3 hours. Cooled the reaction mass to 0-5° C and stirred for 2 hours at same temperature, Filtered the reaction mixture and

washed with acetone. Dried the material to get the title compound. Yield: 29 grams
Example-4: Preparation of S-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3-c]pyridine compound of formula-7.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine(5.0 g) in tetrahydrofuran(100 ml) added a solution of lithium diisopropylamide (1.86 g) in tetrahydrofuran dropwise at -78°C. Stirred the reaction mixture for 1 hr at -78°C and added tetramethylurea and n-butyl lithium (22 ml) at same temperature. Stirred the reaction mixture for 1 hr and tri methyl borate (4 ml) was added to it at -60°C. Slowly warmed the reaction mixture to 0°C and added (2.1 ml) of hydrogen peroxide to it. Stirred the reaction mixture for further 1 hr at 0°C. 25 ml of water was added to the reaction mixture and extracted with 60 ml of methyl tertiary butyl ether. Separated the both aqueous and organic layers. Neutralized the P" using aqueous hydrochloric acid and organic layer was washed with brine solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 2.7 grams.
ExampIe-5: Preparation of 5-(a.-cycIopropyIcarbonyI-2-fluorobenzyl)-2-oxo-2,4,6, 7,7a-hexaIiydrothieno[3-c]pyridine compound of formula-7.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine(5.0 g) in tetrahydrofuran(100 ml) added a solution of lithium diisopropylamide (1.86 g) in tetrahydrofuran dropwise at -78°C. Stirred the reaction mixture for 1 hr at -78°C and added tetramethylurea and n-butyl lithium (22 ml) at same temperature. Stured the reaction mixture for 1 hr and tri n-butylborate (9.5 ml) was added to it at -60°C. Slowly wanned the reaction mixture to 0°C and added (2.1 ml) of hydrogen peroxide to it. Stirred the reaction mixture for further 1 hr at 0°C. 25 ml of water was added to the reaction mixture and extracted with 60 ml of methyl tertiary butyl ether. Separated the both aqueous and organic layers. Neutralized the P" using aqueous hydrochloric acid and organic layer was washed with brine solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 3.0 grams

Example-6: Preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobeiizyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridme compound of formuIa-7.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine(5.0 g) in tetrahydrofuran(100 ml) added a solution of lithium diisopropylamide (1.86 g) in tetrahydrofuran dropwise at -78°C. Stirred the reaction mixture for 1 hr at -78°C and added l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone(4,2 ml) and n-butyl lithixmi (22 ml) at same temperature. Stirred the reaction mixture for 1 hr and tri n-butylborate (9.5 ml) was added to it at -60°C. Slowly warmed the reaction mixture to 0°C and added (2.1 ml) of hydrogen peroxide to it. Stirred the reaction mixture for further 1 hr at 0°e. 25 ml of water was added to the reaction mixture and extracted with 60 ml of ethyl acetate. Separated the both aqueous and organic layers. Neutralized the P" using aqueous hydrochloric acid and organic layer was washed with brine solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 2.9 grams.
Example-7: Preparation of 5-(a.-cyclopropylcarbonyI-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3-c]pyridine compound of formula-7.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine(5.0 g) in tetrahydrofuran(100 ml) added a solution of lithium diisopropylamide (1.86 g) in tetrahydrofuran dropwise at -78°C. Stirred the reaction mixture for 1 hr at -78°C and added n-butyl lithium (40 ml) at same temperature. Stirred the reaction mixture for 1 hr and tri n-butylborate (9.5 ml) was added to it at -60°C. Slowly warmed the reaction mixture to 0°C and added (2.1 ml) of hydrogen peroxide to it. Stirred the reaction mixture for further 1 hr at 0°C. 25 ml of water was added to the reaction mixture and extracted with 60 ml of methyl tertiary butyl ether. Separated the both aqueous and organic layers. Neutralized the P" using aqueous hydrochloric acid and organic layer was washed with brine solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 3.2 grams.

Example-8: Preparation of 5-(a.-cycIopropyIcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3-c]pyridine compound of formula-?.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine(5.0 g) in tetrahydrofuran(100 ml) added a solution of lithium diisopropylamide (1.86 g) in tetrahydrofuran dropwise at -78°C. Stirred the reaction mixture for 1 hr at -78°C and added lithium hexamethyldisilazide (80 ml) at same temperature. Stirred the reaction mixture for 1 hr and tri n-butylborate (9.5 ml) was added to it at -60°C. Slowly warmed the reaction mixture to OC and added (2.1 ml) of hydrogen peroxide to it. Stirred the reaction mixture for further 1 hr at O'C. 25 ml of water was added to the reaction mixture and extracted with 60 ml of methyl tertiary butyl ether. Separated the both aqueous and organic layers. Neutralized the P" using aqueous hydrochloric acid and organic layer was washed with brine solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 2.6 grams.
Example-9: Preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine compound of formula-?.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydro thieno[3,2-c] pyridine(5.0 g) in tetrahydrofuran(100 ml) added a solution of lithium diisopropylamide (2.54 g) in tetrahydrofuran dropwise at -78°C. Stirred the reaction mixture for 1 hr at -78°C and added tetramethylurea (4.5 ml),and n-butyl lithium (40 ml) at same temperature. Stirred the reaction mixture for 1 hr and tri n-butylborate (9.5 ml) was added to it at -60°C. Slowly warmed the reaction mixture to 0°C and added (2.1 ml) of hydrogen peroxide to it. Stirred the reaction mixture for further 1 hr at 0°C. 25 ml of water was added to the reaction mixture and extracted with 60 ml of methyl tertiary butyl ether. Separated the both aqueous and organic layers. Neutralized the P" using aqueous hydrochloric acid and organic layer was washed with brine solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 3.4 grams.

ExampIe-10: Preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of formula-?.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine(5.0 g) in tetrahydrofuran(100 ml) added a solution of n-butyl lithium (30 ml) dropwise at -78°C. Stirred the reaction mixture for 1 hr at -78°C and added tetramethylurea (4.5 ml), n-butyl lithium (30 ml) at same temperature. Stirred the reaction mixture for 1 hr and tri n-butylborate (9.5 ml) was added to it at -60°C. Slowly warmed the reaction mixture to 0°C and added (2.1 ml) of hydrogen peroxide to it. Stirred the reaction mixture for further 1 hr at 0°C. 25 ml of water was added to the reaction mixture and extracted with 60 ml of methyl tertiary butyl ether. Separated the both aqueous and organic layers. Neutralized the P" using aqueous hydrochloric acid and organic layer was washed with brine solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 1.9grams.
Example-11: Preparation of 2-Acetoxy-5-(o-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno[3,2-c] pyridine.
To a solution of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine (0.5 grams) dissolved in a mixture of acetonitrile (10 ml) and acetic anhydride(3 ml), added diisopropylethyl amine (3ml). The mixture was then stirred for 20 minutes at 10-15°C temperature, after which it was stirred for further 3 hours at 25-30°C temperature. Ethyl acetate (20 ml) was added to the mixture, vch was then washed four times, each time with 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to give yellow oil. This oil was crystallized from diisopropyl ether to get the title compound as white crystals. Yield: 0.31 grams Melting point: 120-123° C.

We Claim:
1. A novel process for the preparation of Prasugrel and its pharmaceutically acceptable salts; which comprises of
a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine compound of formula-2 or
its salts,

with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compoimd of formula-3,

in presence of a suitable base in a suitable solvent to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of formula-4,

b) converting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydro
thieno[3,2-c] pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-
fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of
Formula-7


by in-situ protecting the keto functionality of compound of formula-4 as an enolate by treating with a lithium reagent and by introducing a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton by treating it with second lithium reagent in a suitable solvent and a suitable boronating agent, in presence or absence of co-solvent and subsequent oxidation by treating it with suitable oxidizing agent to provide compound of Formula-7,
c) acetylating the compound of Formula-7 with a suitable acetylating agent in a
suitable solvent in presence of a suitable organic base selected to provide the
compound of formula-1,

d) optionally converting the prasugrel into its acid addition salts by treating it with a
suitable acid in a suitable solvent to provide an acid addition salt of prasugrel.
2. The process according to claim 1, wherein;
in step a) the suitable base is selected from a group consisting of alkali metal carbonates like sodium carbonate, potassium carbonate; or an alkali metal hydroxide like sodium hydroxide, potassium hydroxide; or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal alkoxides like sodium tertiary butoxide, potassium tertiary butoxide or an organic base like triethylamine, tributylamine, diisopropylethlyamine preferably potassium carbonate, in a suitable solvent selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles

like acetonitrile and propionitrile; dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof preferably acetonitrile, in step b) the suitable lithium derivative for protecting the keto functionality as enolate is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium lithium hexamethyldisilazide and lithium diisopropylamide preferably lithium diisopropylamide; the suitable boronating agent is selected from boron oxides such as B2O3, boron acids such as H3BO3 , lower alkyl esters of boron acids such as trimethylborate, triethylborate, tri n-butylborate, boron halides like BF3, BCI3, sahs of boron acids like sodium borate, ammonium borate preferably tri n-butylborate;the suitable lithiating agent is selected from n-butyl lithium, sec-butyl lithium, tert-butyl lithium lithium hexamethyldisilazide and lithium diisopropylamide preferably n-butyl lithium; the suitable oxidising agent is selected from nitric acid, hydrogen peroxide, per acids such as peracetic acid, trifluoro peracetic acid, perbenzoic acid, m-chloro perbenzoic acid and the like; ozone, manganese dioxide, potassium permanganate, chromic acid, chromium trioxide, selenium dioxide, sodium hypochlorite, sodium metapericdate and the like, preferably hydrogen peroxide; the suitable co solvent is selected from tetramethyl urea(TMU), l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), N-Methyl-2-pyrrolidone (NMP), hexamethylphosphoramide (HMPA) and the like; the suitable solvent is selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofiiran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohols like methanol, ethanol, propanol, butanol, isopropanol; or nitriles like acetonitrile and propionitrile; dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide or mixtures thereof preferably tetrahydrofiiran.
in step c) the suitable acetylating agent is like acetic anhydride in a suitable solvent selected from diethylether, tetrahydrofiiran, dioxane, acetone, methylethyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide preferably acetonitrile, in presence of a suitable organic base selected from

triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and diisopropylethyl amine preferably triethylamine, in step d) the suitable acid selected from an inorganic acids such as hydrochloric acid, hydrobromic acid; or an organic acids such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic acid, p-tolunesulfonic acid and malic acid, in a suitable solvent selected from aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofiiran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohol like isopropyl alcohol; or nitriles like acetonitrile and propionitrile or mixtures thereof.
3. A novel process for the preparation of prasugrel hydrochloride,

which comprises of
a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride compound of formula-2a

with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-3,


in presence of sodium carbonate in acetonitrile provides 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of formula-4,

b) converting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydro
thieno[3,2-c] pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyI-2-
fluorobenzyI)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine compound of
Formula-7,

by in-situ protecting the keto functionality of compound of formula-4 as an enolate by treating with a lithium reagent and by introducing a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton by treating it with second lithium reagent in a suitable solvent and a suitable boronating agent, in presence or absence of co-solvent and subsequent oxidation by treating it with suitable oxidizing agent to provide compound of Formula-7,
c) acetylating the compound of formula-7 with acetic anhydride in presence of
triethyl amine in acetonitrile to provide prasugrel compound of formula-1,

d) treating the prasugrel with hydrochloric acid in a suitable solvent to provide
prasugrel hydrochloride compound of formula-1 a.

4. Acid addition salts of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydro
thieno[3,2-c] pyridine compounds of general Formula-S, with the proviso that the
acid addition salt is not hydrochloride.

5. According to claim 4, wherein the acid is selected from an inorganic acids such as hydrobromic acid, sulfuric acid, nitric acid or an organic acids such as benzene sulfonic acid, maleic acid, oxalic acid, fVunaric acid, succinic acid, p-tolunesulfonic acid and malic acid.
6. A process for the preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7,

which comprises of reacting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno [3,2-c]pyridine compound of formula-4,

with lithium reagent for in-situ protection the keto functionality as enolate, followed by introduction of a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton by treating it with second lithium reagent in a suitable solvent and a

suitable boronating agent, in presence or absence of co-solvent and subsequent oxidation by treating it with suitable oxidizing agent to provide compound of Formula-7.
7. A process for the preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-
2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7,

comprising of reacting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetra hydrothieno[3,2-c]pyridine compound of formula-4,

with lithium diisopropylamide for in-situ protection of keto functionality as enolate, followed by mtroduction a boronic group at second position of thieno[3,2-c] pyridine skeleton, by treating it with n-butyl lithium and then with tri n-butyl borate in tetrahydrofuran solvent, followed by treatment with hydrogen peroxide to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine compound of Formula-7.
8. A process for the preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyI)-2-oxo-
2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7 comprises of,
a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride compound of
formula-2a,


with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-3,

in presence of a suitable base in a suitable solvent to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of formula-4,

b) converting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydro thieno[3,2-c] pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-fluoroben2yl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7

by in-situ protecting the keto functionality of compound of formula-4 as an enolate by treating with a lithium reagent and by introducing a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton by treating it with second lithium reagent in a suitable solvent and a suitable boronating agent, in presence or absence of co-solvent and subsequent oxidation by treating it with suitable oxidizing agent to provide compound of Formula-7,

9. A process for the preparation of 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-? comprises of,
a) Reacting the 4,5,6,7-tetrahydrothieno[3,2-c] pyridine hydrochloride compound of
formula-2a,

with a-cyclopropylcarbonyl-2-fluorobenzyl bromide compound of formula-3,

in presence of sodium carbonate in acetonitrile to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7,-tetrahydrothieno[3,2-c] pyridine compound of formula-4,

b) converting the 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7,-tetrahydro
thieno[3,2-c] pyridine compound of formula-4 into 5-(a.-cyclopropylcarbonyl-2-
fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine compound of
Formula-7


by in-situ protecting the keto functionality as enolate using lithium diisopropylamide and followed by introducing a boronic group -B(0R')2 at second position of thieno[3,2-c] pyridine skeleton, by treating it with n-butyl lithium and tri n-butyl borate in tetrahydrofuran, followed by treatment with hydrogen peroxide to provide 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydro thieno[3,2-c] pyridine compound of Formula-?.
10. Use of acid addition salts of compounds of general Formula-8 as claimed in claim-4 in the preparation of highly pure 5-(a.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine compound of Formula-7 and prasugrel or its pharmaceutically acceptable salts.