FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR PREPARATION OF PRASUGREL
HYDROCHLORIDE"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of prasugrel hydrochloride. More specifically, the invention relates to a cost-effective process, which provides prasugrel hydrochloride having desired purity, free from its associated impurity.
BACKGROUND OF THE INVENTION
Prasugrel hydrochloride of formula (I), chemically known as 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)4,5,-tetrahydrothieno[3,2-c]pyridine hydrochloride is a platelet inhibitor indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome.

Various researchers have attempted to synthesize the active pharmaceutical ingredient prasugrel hydrochloride of formula (I).
US 5,288,726 discloses synthesis of tetrahydropyridine derivatives including prasugrel hydrochloride and their pharmaceutically acceptable salts, The patent describes a method for recrystallization of prasugrel hydrochloride utilizing diisopropyl ether. However, the present inventors have found while replicating the method an impurity of formula (II) was formed, which was difficult to remove and required several purifications.


US 6,693,115 describes methods for the preparation of various acid addition salts of prasugrel derived from inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, but preferably hydrochloric acid or maleic acid. The solvents employed for the preparation of the acid addition salt include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ether derivatives, ketone derivatives, carboxylic acid derivatives, ester derivatives and nitrile derivatives. The reaction temperature for the preparation of the salts varied from -20°C to 100°C, but for the hydrochloride salt, the reaction temperature was between 30°C and 60°C Various polymorphs such as crystal A, crystal Bl & crystal B2 were obtained depending upon the isolation condition and the type of crystal utilized for seeding.
However, it was found during replication of these methods that the impurity of formula (II) again appeared in the final product and the crystallization process also required seeding with the corresponding prasugrel acid addition salt. However, the specification is silent about the appearance of the said impurity during the preparation of the salt. Further, the product thus obtained required atleast one further step of purification to remove the said impurity.
WO 2009/062044 A2 discloses a method for the preparation of form C, form D, form E and amorphous form of prasugrel hydrochloride. However, these methods also resulted in varying amounts of the associated impurity ranging from 0.15 to 2% under the reported conditions.

WO 2010/070677 A2 application discloses preparation of polymorphic forms Gl and G2, which are respectively prepared by the addition of an anti solvent to prasugrel hydrochloride dissolved in dichloromethane or isopropyl alcohol respectively with the same drawback.
The present inventors have found that an impurity of formula (II) of upto 12% is generally found in the final product by utilizing the reported methods. Therefore, there was a need to develop a convenient and reproducible method for preparing prasugrel hydrochloride, which would not result in the formation of the associated impurity during preparation.
The present invention is directed towards the preparation of Prasugrel hydrochloride having the desired purity with the level of associated impurity conforming to regulatory guidelines. The inventors in their quest for obtaining prasugrel hydrochloride of the desired purity tried out several experiments and found that catalytic amounts of a reagent like potassium hydrogen sulfate, acetic acid or acetic anhydride when employed during the preparation of the hydrochloride salt prevented the formation of the impurity (II). Further, it was also found that the amount of hydrochloric acid employed also played an important role in controlling the undesired impurity.
OBJECT OF THE INVENTION
An object of the present invention is to provide a cost-effective and industrially viable method for the preparation of prasugrel hydrochloride having the desired purity.
Another object of the present invention is to provide a method for the control of the undesired impurity (II) within regulatory limits during the preparation of prasugrel hydrochloride.
SUMMARY OF THE INVENTION
An aspect of the present invention relates to a method for the preparation of prasugrel hydrochloride comprising addition of hydrogen chloride to a mixture of prasugrel free


base in dialkyl carbonate as solvent in the presence of a reagent, at a temperature between 15°C and 35°C and isolating compound of formula (I).
Another aspect of the invention relates to a method for the preparation of prasugrel hydrochloride by utilization of reagents selected from acetic acid, acetic anhydride and potassium hydrogen sulfate in catalytic amount for controlling the formation of impurity of formula (II).
DETAILED DESCRIPTION OF THE INVENTION
Prasugrel free base was prepared by conventional methods reported in prior art such as the method disclosed in example 23 of US 5,288,726.
The preparation of prasugrel hydrochloride of formula (I) comprises of the following steps:
• dissolving prasugrel free base in dialkyl carbonate,
• adding a reagent selected from the group comprising of acetic anhydride, acetic acid and potassium hydrogen sulfate to the mixture,
• adding a solution of gaseous hydrochloric acid dissolved in dialkyl carbonate solvent,
• stirring the reaction mixture at 15°C to 35°C,
• partially concentrating the reaction mixture under reduced pressure,
• cooling the solution to temperature of 10°C to 15°C and
• filtering and drying the pure prasugrel hydrochloride.

It is pertinent to mention that the reagents selected from the group comprising of acetic anhydride, acetic acid and potassium hydrogen sulfate were added in catalytic amounts ranging from 0.05 to 0.30 mole equivalent per mole of prasugrel free base.
Further the amount of hydrochloric acid gas utilized was between 0.7 to 0.9 mole equivalent per mole of prasugrel free base.
In an embodiment, prasugrel base was dissolved in a solvent such as dialkyl carbonates, which was selected from the group comprising of dimethyl carbonate or diethyl carbonate.
The prasugrel free base was dissolved in 8 to 15 volumes of dialkyl carbonate solvent, but preferably between 10 and 12 volumes of dialkyl carbonate per mole of prasugrel free base.
The mixture was stirred for 30 minutes between 15 to 35°C, but preferably at 25°C to 30°C. A reagent selected from the group comprising of acetic anhydride, acetic acid and potassium hydrogen sulfate was added to the mixture and stirred at same temperature.
When potassium hydrogen sulfate was employed, the mixture was heated between 45 and 55°C for 30 minutes and filtered.
Hydrochloric acid gas dissolved in 3 to 5 volumes of dialkyl carbonate solvent was added gradually to the clear solution of prasugrel base dissolved in dialkyl carbonate solvent.
The reaction mixture was stirred for 1 to 3 hours at 25°C to 30°C and partially concentrated under reduced pressure.

The mixture was cooled between 10°C and 15°C for 2 hours and the solid obtained was filtered and washed with dialkyl carbonate solvent. The pure prasugrel hydrochloride was dried under reduced pressure at 40°C and the yield obtained was between 85-95%.
It should be noted that the purity of the isolated prasugrel hydrochloride was > 99.5% with the undesired impurity of formula (II) being below 0.10%.
Thus the invention was able to provide prasugrel hydrochloride of formula (I) with high yield and purity.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of me invention.

EXAMPLES:
Example 1:
Preparation of prasugrel hydrochloride (I):
Prasugrel free base (l0gms; 0.026moles) was suspended in dimethyl carbonate (120
ml). Acetic acid (0.5ml; 0.0052 moles) was added to the mixture and stirred.
Hydrochloric acid gas (0.9mole equivalent) dissolved in dimethyl carbonate (30ml) was
added to the reaction mixture at 25°C to 30°C. The reaction mixture was stirred for 2
hours at 25°C to 30°C. The mixture was concentrated under reduced pressure and
dimethyl carbonate (70ml) was added to the residue. The reaction mass was cooled to
10 to 15°C and maintained for 2 hours. The mixture was filtered, washed with dimethyl
carbonate (50ml) and dried under reduced pressure.
Yield; llgms;
Purity: > 99.5%.
Formula (II) impurity level: < 0.1 %.
Example 2:
Preparation of prasugrel hydrochloride (I):
Prasugrel free base (lOgms; 0.026moles) was suspended in dimethyl carbonate (120 ml). Acetic anhydride (0.50 mole equivalent) was added to the mixture and stirred. Hydrochloric acid gas (0.9 mole equivalent) dissolved in dimethyl carbonate (30ml) was added to the reaction mixture at 25°C to 30°C. The reaction mixture was stirred for 2 hours at 25°C to 30°C. The mixture was concentrated under reduced pressure and dimethyl carbonate (70ml) was added to the residue. The reaction mass was cooled to 10 to 15°C and maintained for 2 hours. The mixture was filtered, washed with dimethyl carbonate (50ml) and dried under reduced pressure. Yield: 10.8gms; Purity: > 99.5%. Formula (II) impurity level: < 0.1%.

Example 3:
Preparation of prasugrel hydrochloride (I):
Prasugrel free base (20g; 0.026 moles) was dissolved in diethyl carbonate (240 ml) and potassium hydrogen sulfate (0.10 mole equivalent) was added to the mixture. The mixture was heated to 55±2°C, filtered and cooled. Hydrochloric acid gas (0.8 mole equivalent) dissolved in diethyl carbonate (60 ml) was added to the reaction mixture at 25°C to 30°C. The reaction mixture was stirred for 2 hours at 25°C to 30°C. Diethyl carbonate (140 ml) was distilled off under reduced pressure. The reaction mass was cooled to 10°C to 15°C and maintained for 2 hours. The mixture was filtered, washed with diethyl carbonate (100ml) and dried at reduced pressure. Yield: 22gms Purity: > 99.5%. Formula (II) impurity level: < 0.1 %.

We claim:
1. A process for preparation of prasugrel hydrochloride comprising addition of hydrogen chloride to a mixture of prasugrel free base of formula (III) dissolved in dialkyl carbonate as solvent and in the presence of a reagent, at a temperature between 15°C and 35°C and isolating compound of formula (I).
2. The process as claimed in claim 1, wherein the dialkyl carbonate solvent is selected from the group comprising of dimethyl carbonate or diethyl carbonate.
3. The process as claimed in claim 1, wherein the amount of hydrogen chloride gas employed is in the range between 0.70 and 0.90 mole equivalent per mole of the prasugrel free base of formula (III).
4. The process as claimed in claim 1, wherein the reagent is selected from the group comprising of acetic acid, acetic anhydride and potassium hydrogen sulfate.
5. The process as claimed in claim 1 and claim 4, wherein the amount of reagent employed is between 0.05 and 0.30 mole equivalent per mole of the prasugrel free base of formula (III).
6. The process as claimed in claim 1, wherein prasugrel hydrochloride of formula (I) is isolated by partially concentrating the mixture, cooling between 10°C and 15°C , filtering and drying.