FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-( a CYCLOPRPYLCARBONYL-2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality : Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the invention :

PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-( a -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 2-Acetoxy-5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine & pharmaceutically acceptable salt thereof comprising the use of 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (III) & (II) or salt thereof. The present invention also relates to the process for the preparation of 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (III) & (II) or salt thereof.
BACKGROUND OF THE INVENTION
Prasugrel is a next generation thienopyridine currently undergoing clinical development for the treatment of thrombosis and/or related diseases including as an adjunct to percutaneous coronary intervention procedures.
Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine and clopidogrel (Plavix®). These agents are believed to reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors.
Prasugrel is chemically known as 2-Acetoxy-5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine having chemical structure of formula (I).



US Patent 5,288,726 is the basic product patent of prasugrel, which discloses and claims tetrahydrothienopyridine derivatives including 2-Acetoxy-5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
There are several approaches known in the art for preparing prasugrel, which can be described below.
US 5,288,726 disclose the process for the preparation of prasugrel comprising the following steps:
(a) reaction of the Grignard reagent prepared from 2-flurobenzyl bromide and Mg in ether with cyclopropanecarbonitrile in ether gives l-cyclopropyl-2-(2-fluorophenyl) ethanone,
(b) bromination of l-cyclopropyl-2-(2-fluorophenyl) ethanone with Br2 in CCU yield the a-bromo ketone,
(c) condensation of a- bromo ketone with 2,3,4,5,6,7-hexahydrothieno [3,2-C]pyridine-2-one hydrochloride in the presence of base and DMF affords the adduct,
(d) acetylation of adduct obtained in step (c) with acetic anhydride in the presence of sodium hydride in DMF provides prasugrel (I).
The schematic representation of above process for the preparation of prasugrel as disclosed in US 5,288,726 is given as below.


Scheme-1:

Br,
KS

CN

(a)

^^

^^


(c)



^^

As per scheme-I crude prasugrel was obtained as an oily residue that was purified by silica gel column chromatography using a mixture of solvents, which was further recrystallized from diisopropyl ether to obtain crystals of prasugrel. Furthermore, the acetylation of adduct obtained in step (c) required almost ~ 7 mole acetic anhydride per mole of adduct obtained in step (c), which is quite higher amount. As concern to step (b) & (c), US 5,288,726 discloses the analogues process for the preparation of compound as obtained in step (b) & (c) and hence exact yield was not reported. US 5,288,726 suggested that haloimide such as N-bromosuccinimide, N-chlorosuccinimide in the presence of radical initiator or halogen such as chlorine, bromine or iodine in inert solvent such as halogenated hydrocarbon can be used for the halogenation of compound as obtained in step (a).
Although NBS (N-bromosuccinimide) is easier and safer to handle than bromine, however, precautions should be taken to avoid inhalation.


Furthermore, the purification of oily adduct as obtained in step (c) and a- bromo ketone as obtained in step (b) also required silica gel column chromatography as disclosed in US 6,693,115.
According to US 5,874,581, the process for the preparation of prasugrel as disclosed in US 5,288,726 is not an industrially satisfactory process because the 5-alkyl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one derivative i.e. adduct as obtained in step (c) is unstable under reaction condition such that yield is low.
Another patent US 5,874,581 discloses the alternative process for the preparation of Prasugrel comprises the use of novel 2-silyoxy-tetrahydrothienopyridine intermediate. The said process can be schematically represented as below in scheme-2.
Scheme-2:


x^OTBDMS

(e) reaction of 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridine-2one PTSA with TBDMS-C1 and TEA in suitable solvent gives the silylated enol ether,
(f) condensation of silylated enol ether obtained in step (a) with l-cyclopropyl-2-chloro-2-(2-fluorophenyl)ethanone in the presence of TEA in suitable solvent,


(g) the compound obtained in step (f) is treated with TEA and DMAP and acetylated with acetic anhydride or the compound of step (f) is first hydrolyzed by using organic carboxylic acid and then acetylated with acetic anhydride.
The process as disclosed in above patent i.e. US 5,874,581 is lengthy process because it involves TBDMS protection before condensation and de-protection step before acetylation, which makes it somewhat expensive and industrially unfavorable.
US patent 6,693,115 B2 discloses and claims the hydrochloric acid and maleic acid salts of 2-Acetoxy-5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
Drugs of Future 2001, 26(9): 385 disclose the process for the preparation of prasugrel as disclosed in US 5,288,726 and US 5,874,581.
WO 2007/114526 discloses the process for the preparation of highly pure prasugrel and its pharmaceutically acceptable salt by recrystallizing it from the specific solvent system. The same application also discloses that pure hydrochloride salt of prasugrel can be prepared by slow addition of hydrochloric acid to the prasugrel.
Thus, the known processes for the preparation of prasugrel and its pharmaceutically acceptable salts are not satisfactory, in particular for plant scale production, as they are lengthy and economically not viable.
In accordance with the foregoing an object of the present invention is to provide a new and improved process for the preparation of prasugrel and its pharmaceutically acceptable salts which overcomes the aforementioned drawbacks, in particular for plant scale.
It has now been found that a process for the preparation of prasugrel and its pharmaceutically acceptable salts, which employs the compound of formula (III) doesn't show the aforementioned drawbacks.


It was found that process for the preparation of prasugrel and its pharmaceutical^ acceptable salts is improved when compound of formula (III) having acetoxy group in second position are used.
It has also found that when bromination of compound of formula (VI) is carried out with DBDMH in cyclic hydrocarbon, the compound of formula (IV) is obtained with higher yield than other known brominating agent and rate of reaction will be fast.
Furthermore, we have also observed when bromination of compound of formula (VI) is carried out with NBS particularly in cyclohexane to prepare the compound of formula (IV), the rate of reaction will be fast than the bromination carried out in halogenated solvent like carbon tetrachloride and yield is also improved.
SUMMARY OF THE INVENTION
The first embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I)

(I) comprising the following steps;
a) condensing the compound of formula (III) or a salt thereof with the compound of formula (IV) in the presence of base and suitable solvent,

isolating the compound of formula (I),
c) optionally purifying the compound of formula (I) with the suitable solvent.
Another embodiment of the present invention is to provide a process for the preparation of compound of formula (III) or salt thereof

comprising the following steps;
i) acetylating the compound of formula (V) in the presence of base and suitable solvent
Ph -Ph
S'


to obtain the compound of formula (II),

(V)
(II)



ii) hydrolyzing the compound of formula (II) in the presence of acid in suitable solvent to obtain the compound of formula (III) or salt thereof.
Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (IV)

(IV)
comprising the bromination of the compound of formula (VI)

(VI)
with l,3-Dibromo-5,5-dimethylhydantoin (DBDMH) optionally in the presence of radical initiator in suitable solvent.
Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (IV)


(IV) comprising the bromination of the compound of formula (VI)

(VI)
with NBS optionally in the presence of radical initiator in cyclohexane.
Yet another embodiment of the present invention is to provide the compound of formula (III) or salt thereof in an isolated form.
Yet another embodiment of the present invention is to provide the use of compound of formula (III) or salt thereof for the preparation of prasugrel and its pharmaceutically acceptable salts.
Yet another embodiment of the present invention is to provide the compound of formula (II) in isolated form.
Yet another embodiment of the present invention is to provide the use of compound of formula (II) for the preparation of prasugrel and its pharmaceutically acceptable salts.


Yet another embodiment of the present invention is to provide the pharmaceutical composition of Prasugrel (I) and its pharmaceutically acceptable salts obtained according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The term "Prasugrel" refers to 2-Acetoxy-5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahy drothieno[3,2-c] pyridine.
The term "DBDMH" refers to l,3-Dibromo-5,5-dimethylhydantoin.
The term "NBS" refers to N-bromo succinimide.
The first embodiment of the present invention is to provide a novel process for the preparation of prasugrel (I)
O


comprising the following steps;



a) condensing the compound of formula (III) or a salt thereof with the compound of formula (IV) in the presence of base and suitable solvent,



(III)

b) isolating the compound of formula (I),
c) optionally purifying the compound of formula (I) with the suitable solvent.
In Step a) of the above reaction the compound of formula (III) or salt thereof is condensed with the compound (IV), to give the compound of formula (I). This reaction is carried out in presence of suitable solvent and base.
There is no limitation on the nature of the base employed, and any base known for use in reactions of this type may equally be used here. Examples of suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali bicarbonates are preferred. The amount of base employed is not critical, but generally it can be from an equimolar amount to 4 times the equimolar amount with respect to the starting material of formula (III).
The above reaction is normally carried out in presence of a suitable solvent. There is no particular restriction on the nature of the suitable solvent to be employed, provided that it has no adverse effect on the reaction, at least to some extent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as


acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. Among the given suitable solvents, the amides are preferred, preferably N,N-dimethylformamide.
The condensation reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature from 0°C to 45°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 the preferred time required for condensation can be of a period from 1 to 5 hours, which will usually suffice. Optionally, the reaction mixture can be added with some little amount of acetic anhydride after some time, which will convert the deacetylated intermediate (if formed) to prasugrel (I) as precautionary measure.
After completion of the condensation reaction, the desired compound of formula (I) can be obtained from the reaction mixture by conventional means. For example, if the compound is produced immediately in the form of crystals, these can be separated simply by filtration. Alternatively, a suitable recovery procedure comprises: adding water with any water-immiscible organic solvent such as ether like tert-butyl methyl ether; separating the layers and drying the organic layer; and distilling the solvent off. Optionally, the product thus obtained can be further purified by conventional means, such as recrystallization from the organic solvent such as alcohol, preferably ethanol. The obtained compound of formula (I) can be further dried at 40°C-60°C for sufficient time.
Another embodiment of the present invention is to provide a process for the preparation of compound of formula (III) or salt thereof
/O
O—f"
s-
(III) comprising the following steps;
i) acetylating the compound of formula (V) in the presence of base and suitable solvent





(V)
to obtain the compound of formula (II),
(II)
ii) hydrolyzing the compound of formula (II) in the presence of acid in suitable solvent to obtain the compound (III) or salt thereof.
The compound of formula (V) i.e. 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one can be prepared according the process described in US 4740150.
In Step i) of the above reaction the acetylation of the compound of formula (V) can be done by using acetylating agent such as acetyl halide (like as acetyl chloride) or acetic anhydride. The amount of acetylating agent is not critical, but generally it can be from 3 to 5 times the equimolar amount with respect to the starting material of formula (V). This reaction can be carried out in presence of suitable solvent and base.
There is no limitation on the nature of the base employed in step i), and any base known for use in reactions of this type may equally be used here. Examples of suitable bases include: organic amines, such as triethylamine or tributylamine; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali bicarbonate such as sodium bicarbonate or potassium bicarbonate. Among them, the alkali bicarbonates are preferred.


The above reaction is normally carried out in presence of a suitable solvent. Examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide. Among the given suitable solvents, the amides are preferred, preferably N,N-dimethylformamide.
The acetylation can take place at temperature from 0°C to 50°C. In general, it is convenient to carry out the reaction at a room temperature. 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, the preferred period for acetylation is from 1 to 5 hours.
After completion of the acetylation, the compound of formula (II) can be obtained from the reaction mixture by conventional means. For example, a suitable recovery procedure comprises: adding water with any water-immiscible organic solvent such as ether like tert-butyl methyl ether; separating the layers and drying the organic layer; and distilling the solvent off. Optionally, the product thus obtained can be further purified by conventional means, such as recrystallization from the organic solvent or it can be taken as it is for hydrolysis.
The hydrolysis reaction of step ii) can be carried out in presence of, for example, an organic
carboxylic acid such as acetic acid, etc., an organic sulfonic acid such as p-toluenesulfonic acid, etc.,
an inorganic acid such as hydrochloric acid. The preferred acid is p-toluenesulfonic acid. The
hydrolysis is easily finished for reaction time of 2 hour to 5 hour. The hydrolysis proceeds
sufficiently at a reaction temperature of about room temperature (25 °C), and heating is not
particularly required. The suitable organic solvent to be used for the hydrolysis is not particularly
limited, examples of suitable solvents include: ethers, such as diethyl ether, tetrahydrofuran or
dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such
as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as
N,N-dimethylforrnamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or


hexamethylphosphoric triamide; and sulphoxides, such as dimethyl sulphoxide, an ether type solvent such as tetrahydrofuran is preferred.
Furthermore, the compound of formula (III), obtainable after hydrolysis is obtained generally as a salt of the acid used. After the hydrolysis, the compound of formula (III) can be obtained from the reaction mixture by conventional means; generally it is obtained as solid, which can be separated simply by filtration. The obtained compound of formula (III) can be further dried at 40°C-60°C for sufficient time.
(IV) comprising the bromination of the compound of formula (VI)
Another embodiment of the present invention is to provide a process for the preparation of compound of formula (IV)


(VI)
with l,3-Dibromo-5,5-dimethylhydantoin (DBDMH) optionally in the presence of radical initiator in suitable solvent.
In the above bromination reaction, a compound of formula (IV) is prepared by reacting a compound of formula (VI) with a l,3-Dibromo-5,5-dimethylhydantoin (DBDMH) in presence of a radical


initiator, such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN), in cyclic hydrocarbon such as benzene, cyclohexane, toluene, more preferred is cyclohexane. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a reflux temperature. The time required for the reaction may also vary widely, however it is generally completed within 2 to 3 hours.
After the halogenation, the compound of formula (IV) can be obtained from the reaction mixture by any conventional means; alternatively, a suitable recovery procedure comprises: cooling the reaction mass, filtering the unwanted solid mass, washing the organic layer with sodium metabisulphite; and distilling the solvent off. Optionally, the product thus obtained can be further purified by any conventional means.
(IV) comprising the bromination of the compound of formula (VI)
Yet another embodiment of the present invention is to provide a process for the preparation of compound of formula (IV)


(VI) with NBS optionally in the presence of radical initiator in cyclohexane.


In the above bromination reaction, a compound of formula (IV) is prepared by reacting a compound of formula (VI) with NBS in presence of a radical initiator, such as benzoyl peroxide or azo-bis-isobutyronitrile (AIBN), in cyclohexane. The overall reaction parameters, reaction methodology and work-up process remain same as described for halogenation of compound of formula (IV) by using DBDMH.
The prasugrel (I) and its pharmaceutically acceptable salts obtained according to the present invention can be administered alone or as a mixture with pharmaceutically acceptable excipients, diluents and the like, in various dosage forms such as tablets, capsules, granules, powders, syrups or the like for oral administration; and injections, suppositories or the like for parenteral administration.
The above described formulations can be prepared by well-known methods using additives for the formulation such as diluents, lubricants, binders, disintegrants, emulsifiers, stabilizers, organoleptic agent.
Examples of diluents include lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, cellulose derivatives such as crystalline cellulose; calcium hydrogenphosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, and the like.
Examples of lubricants include stearic acid; metal stearate derivatives such as calcium stearate or magnesium stearate; talc; DL-Leucine; lauryl sulfate derivatives such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid derivatives such as silicic anhydride or silicic acid hydrate; and starch derivatives, sodium stearyl fumarate.
Examples of binders include cellulose derivative such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and gums.
Examples of disintegrants include cellulose derivatives such as lower-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally cross-linked sodium carboxymethylcellulose; chemically modified starch or cellulose derivatives


such as carboxymethylstarch or sodium carboxymethylstarch; cross-linked polyvinylpyrrolidine; and starch derivatives as described above.
Examples of emulsifiers include colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; non-ionic surfactants such as polyoxyethylene alkyl ether, polyoxyethyene sorbitan esters of fatty acids or sucrose esters of fatty acids.
Examples of stabilizers include para-hydroxybenzoic acid ester derivatives such as methylparaben or propylparaben; alcohol derivatives such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzalkonium chloride; phenol derivatives such as phenol or cresol; thimerosal; dehydroacetic acid or sorbic acid.
Examples of organoleptic agent include sweeteners, souring agents, flavorings or the like which are conventionally used.
The processes described in the present invention were 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.
Example-1:
Preparation of l-cyclopropyl-2-(2-fluorophenyl) ethanone (VI)
To a suspension of magnesium powder (1.39 gm) in diethyl ether (50 ml) with catalytic amount of methyl iodide was added a solution of 2-fluorobenzylbromide (10 gm) in diethyl ether (30 ml) over period of 45 minutes, then the mixture was stirred at room temperature for 1 hour. The reaction mixture was added drop wise to a solution of cyclopropanecarbonitrile (3.2 gm) in diethyl ether (15 ml) over 15 minutes. After stirring for 90 minutes at room temperature the stirred mixture was


cooled to 0°C and quenched with ammonium chloride solution. After then the reaction mixture was extracted with ethyl acetate: diethyl ether and washed successively with water, saturated aqueous sodium bicarbonate solution, and diluted hydrochloric acid, then dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to afford the desired product 6.8 gm (Yield = 72.18%).
Example-2;
Preparation of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (IV)
To a solution of l-cyclopropyl-2-(2-fluorophenyl) ethanone (3.0 gm) in cyclohexane (60 ml) was added DBDMH (7.2 gm) and AIBN (0.27 g) and then the mixture was heated under reflux for 3 hours. After then reaction mass was cooled to 10°C and stirred for 2 hours and the reaction mass was filtered off to remove unwanted solid. The filtrate was washed with 5% sodium metabisulphite, water and sodium bicarbonate solution, and then concentrated under reduced pressure to afford 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (4.03 g Yield = 93.28%) as a oil.
Example-3:
Preparation of 2-bromo-l-cyclopropyl-2-(2-fIuorophenyl) ethanone (IV)
To a solution of l-cyclopropyl-2-(2-fluorophenyl) ethanone (3.0 gm) in cyclohexane (60 ml) was added N-bromo succinimide (9.2 gm) and AIBN (0.27 g) and then the mixture was heated under reflux for 3 hours. After then reaction mass was cooled to 10°C and stirred for 2 hours and the reaction mass was filtered off to remove unwanted solid. The filtrate was washed with 5% sodium metabisulphite, water and sodium bicarbonate solution, and then concentrated under reduced pressure to afford 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (3.42 g, Yield = 79.16%) as a oil.


Example-4:
Preparation of 2-acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (II).
To a solution of 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one (10 gm) in Dimethyl formamide (100 ml) was added with acetic anhydride (10 ml) at room temperature and then cooled to 0°C. The reaction mass was added with sodium bicarbonate (1.2 gm) and stirred for 3 hours at room temperature. After then reaction mass was cooled to 0°C and added with chilled water and tert-butyl methyl ether (100 ml). Obtained organic layer was washed with excess water and dried over sodium sulphate. Distilled off the solvent under vacuum to obtain 2-acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (12.0 gm) as a semi solid.
Example-5:
Preparation of 2-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate (III).
To a solution of 2-acetoxy-5-trityl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10 gm) in tetrahydrofuran (100 ml) was added with p-toluene sulfonic acid (5.18 gm) at room temperature and then stirred for 3 hrs. The obtained solid product was filtered and washed with little amount of tetrahydrofuran. The obtained solid was dried under vacuum at 50°C for 24 hrs to obtain 2-acetoxy--4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate (6.8 gm) as a solid (Yield = 80.95%).
Example-6:
Preparation of 2-Acetoxy-5-(a-cycloprpylcarbonyI-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno
[3,2-c] pyridine (I).
To a solution of 2-acetoxy- -4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate (7.0 gm) in dimethylformamide (35 ml) was cooled to 5 -10°C and was added with sodium bicarbonate (2.38 gm). The reaction mass was stirred for 15 minutes and added with 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (5.1 gm) in dimethylformamide (15 ml) and stirred for 5 hours at room temperature and added with little amount of acetic anhydride (3.8 ml) and stirred for 3 hrs. After then reaction mass was cooled to 5 -10°C and added with water (700 ml) and tert-butyl methyl ether (105 ml). Stirring the mixture at room temperature and filtered through celite bed and washed celite


bed with TBME. The obtained TBME layer was washed with water and brine solution, then dried the organic layer, and distilled solvent under reduced pressure to get the oily mass. The oily product was crystallized from ethanol to afford the good crystal of prasugrel free base, which was dried under vacuum at 50°C for 24 hours (2.3 g, yield = 32.85%).




ABSTRACT
The present invention relates to a process for the preparation of 2-Acetoxy-5-(a-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine & pharmaceutically acceptable salt thereof comprising the use of 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (III) & (II) or salt thereof. The present invention also relates to the process for the preparation of 2-acetoxy-tetrahydrothienopyridine derivatives i.e. compound of formula (III) & (II) or salt thereof.