This application claims priority to Indian patent applications numbered 628/CHE/2011 filed on Mar 03, 2011 the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION:

The present invention relates to process for the purification of Prasugrel and its further conversion into pharmaceutically acceptable salts. It also provides crystalline form of Prasugrel free base.

BACKGROUND OF THE INVENTION:

Prasugrel is an oral antiplatelet agent that belongs to the thienopyridine family. It is designed to prevent platelet activation by blocking adenosine diphosphate (ADP) P2Y12 receptors on the platelet surface.

Prasugrel HCl, chemically known as 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride and is structurally represented as Formula I. Prasugrel hydrochloride marketed under the brand name of EFFIENT.


Prasugrel and its pharmaceutically acceptable salts are claimed in US 5,288,726. The disclosed process for the preparation of Prasugrel involves the acetylation of 5-(a-cyclopropylcarbonyl-2-fluorophenyl)-2-oxo2,4,5,6,7,7a-tetrahydrothieno[3,2-c]pyridine in presence of sodium hydride.

Specifically Prasugrel hydrochloride and maleate salts were claimed in US 6,693,115.
Further, it discloses crystal A, Crystal Bl and crystal B2 of Prasugrel Hydrochloride.

US 5,874,581 dislcoses a process for preparing Prasugrel. The process involves reaction of 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridine-2one PTSA with TBDMS-Cl and TEA in suitable solvent gives the silylated enol ether. Condensation of silylated enol ether with 1-cyclopropyl-2-chloro- 2-(2-fluorophenyl)ethanone in the presence of TEA gives 2(tert-butyldimethylsilyloxy)-5[2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]5,6,7,7a-tetrahydrothieno[3,2-c]pyridine, which on treating with TEA and DMAP followed by acetylation with acetic anhydride gives Prasugrel.

US 20090203729 discloses a method of producing Prasugrel with a reduced content of OXTP, comprising dissolving free Prasugrel containing OXTP in inert solvent and adding hydrochloric acid optionally dropwise to the solution for reaction. It also discloses that, the recrystallization of prasugrel containing OXTP, can reduce the content of by product OXTP in the resultant Prasugrel to produce high purity free Prasugrel.

US 20100094013 claims a process to provide Prasugrel hydrochloride with a reduced content of CATP comprising chlorinating cyclopropyl-2-fluorobenzyl ketone characterized that the temperature during the addition of the chlorinating agent is -20 °C to 5 °C, and the reaction temperature after the addition, of the chlorinating agent is -20 °C to 5 °C. The resulting chlorinated compound is condensed with tetra-hydrothienopyridine derivative and acetylated to give Prasugrel, which is fiirther treated with hydrochloric acid to acquire Prasugrel hydrochloride with a reduced content of CATP.

WO 2010060389 discloses a process for producing Prasugrel. It also claims
crystallization of Prasugrel from polar aprotic solvents in a mixture with water, or with aqueous solutions, in the presence of an acetylation agent.

Still there exists a need in the art for the preparation of Prasugrel and its hydrochloride with enhanced purity and yield.

The present invention provides process for the purification of Prasugrel hydrochloride thereby reducing the content of 3-fluoro Prasugrel impurity. It also provides crystalline form of Prasugrel free base.

OBJECT OF THE INVENTION:

Principle object of the present invention is to provide Prasugrel and its pharmaceutically acceptable salts with enhanced purity and yield.

Another object of the present invention is to provide purification of Prasugrel free base.

Yet another object of the present invention is to provide crystalline Prasugrel free base.

SUMMARY OF THE INVENTION:

Main aspect of the present invention is to provide Prasugrel and its pharmaceutically acceptable salts with enhanced purity and yield

In one aspect, the present invention provides purification of Prasugrel free base comprising the steps of:

a) suspending crude Prasugrel in an organic solvent; and

b) isolating crystalline prasugrel free base.

In another aspect, the present invention provides conversion of pure Prasugrel free base into pharmaceutically acceptable salts, comprising the steps of:

a) dissolving pure Prasugrel in an organic solvent;

b) treating with an acid; and

c) isolating pharmaceutically acceptable salt of prasugrel.

In one more aspect, the present invention provides crystalline Prasugrel free base.

BRIEF DESCRIPTION OF THE FIGURES

FIGURE I shows the X-Ray diffractogram of crystalline Prasugrel free base.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to process for the preparation of Prasugrel and its pharmaceutically acceptable salts with enhanced purity and yield. The present invention specifically directed to purification of Prasugrel free base and its further conversion into pharmaceutically acceptable salts. It also provides crystalline Prasugrel free base.

The main aspect of the present invention is to provide purification of Prasugrel free base comprising the steps of:

a) suspending crude Prasugrel in an organic solvent; and

b) isolating crystalline prasugrel free base.

In one embodiment of the present invention, crude Prasugrel free base is suspended in an organic solvent, wherein the organic solvent is selected from hydrocarbons, alkyl halides, esters, aldehydes, ketones, amines, alcohols, amides or mixtures thereof; preferably hydrocarbons and alcohols, more preferably mixture of hydrocarbons and alcohols.

In another embodiment of the present invention, the hydrocarbon solvents used for suspending crude prasugrel is selected from toluene, benzene, xylene, chlorobenzene, hexane, cyclohexane, n-heptane; alcoholic solvents selected from methanol, ethanol, isopropyl alcohol, n-propanol, preferably mixture of toluene and methanol.

As per the present invention, crude Prasugrel free base is suspended in a mixture of hydrocarbon solvents and alcoholic solvents, preferably mixture of toluene and methanol and filtered to isolate crystalline pure Prasugrel freebase.

As per the present invention, the process produced for the purification of crude Prasugrel free base provides high purity Prasugrel free base or an acid addition salt thereof by reducing the content of impurities. The purification of the Prasugrel free base of the present invention reduces the content of 3-fluoro Prasugrel in the resulting product.

In one embodiment, the present invention provides crystalline Prasugrel free base.

In one embodiment of the present invention, crystalline prasugrel free base is characterized by X-ray diffraction having peaks at about 13.40, 14.66, 18.81, 19.36, 21.54, 23.55 ±0.2 9.

In another embodiment of the present invention, the crystalline Prasugrel free base is further characterized by X-ray diffraction having peaks at about 7.72, 11.20, 13.40, 14.66, 15.23, 18.81, 19.36, 21.54, 23, 23.55, 24.29, 31.38 ± 0.2 8.

In one more embodiment of the present invention, the crystalline Prasugrel free base is further characterized by PXRD as shown in FIGURE 1.

In another embodiment, the present invention provides further conversion of purified Prasugrel into pharmaceutically acceptable salts, comprising the steps of:

a) dissolving pure Prasugrel in an organic solvent;

b) treating with an acid; and

c) isolating pharmaceutically acceptable sah of prasugrel.

In one embodiment of the present invention, the purified Prasugrel free base is dissolved in a ketonic solvent selected from acetone, methylethylketone, diethylketone, preferably acetone.

In one more embodiment of the present invention, dissolved Prasugrel free base is treated with an acid selected from hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, citric acid, tartaric acid, nitric acid; preferably hydrochloric acid to isolate Prasugrel hydrochloride.

As per the present invention, Prasugrel free base is dissolved in a solvent selected from acetone, methylethylketone, diethylketone, preferably acetone and treated with hydrochloric acid followed by seeding with Form B to isolate Prasugrel hydrochloride Form B.

In another embodiment of the present invention, the Prasugrel free base can be prepared
by a process comprising the steps of:

a) condensing 5,6,7,7a -tetrahydro-4H-thieno[3,2-c] pyridine-2-one free base or salt with 2-Fluro-a-cyclopropyl carbonylbenzyl bromide;

b) acetylating 5-(a-cyclopropylcarbonyl-2-fluorophenyl)-2-oxo-4,5,6,7-tetra hydro thieno [3,2-c]pyridine; and

c) isolating Prasugrel.

In one embodiment of the present invention, 5,6,7,7a -tetrahydro-4H-thieno[3,2-c] pyridine-2-one free base or salt is condensed with 2-Fluro-a-cyclopropyl carbonylbenzyl bromide in presence of a base selected from organic and inorganic base preferably inorganic base, more preferably potassium carbonate.

In another embodiment of the present invention, the condensed product 5-(a-cyclopropylcarbonyl-2-fluorophenyl)-2-oxo-4,5,6,7-tetra hydro thieno [3,2-c]pyridine is acetylated with an acetylating agent in suitable solvent and in presence of a suitable base, wherein the acetylating agent is acetic anhydride or acetyl chloride in a suitable solvent selected from aprotic polar solvents such as dimethyl formamide, dimethyl sulfoxide, acetone, ethyl acetate, acetonitrile, 1,4-Dioxane, tetrahydrofiiran, dichloromethane; preferably dimethyl formamide. The suitable base for acetylation is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, sodium hydride, preferably potassium carbonate.

As per the present invention, 5,6,7,7a -tetrahydro-4H-thieno[3,2-c] pyridine-2-one hydrochloride is condensed with 2-Fluro-a-cyclopropyl carbonylbenzyl bromide in presence of anhydrous potassium carbonate to acquire 5-(a-cyclopropylcarbonyl-2-fluorophenyl)-2-oxo-4,5,6,7-tetra hydro thieno [3,2-c]pyridine. This on acetylation with acetylating agent such as acetic anhydride in polar aprotic solvent such as dimethyl formamide, and in presence of suitable base such as potassium carbonate gives crude Prasugrel free base.

Another embodiment of the present invention, the Prasugrel free base can be prepared by a method described in US 5874581.

Instrumentation

Powder X-rav Diffraction (PXRD)

The said formic acid solvate of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker AXS D8 Discover powder X-ray diffractometer equipped with a goniometer of 9/29 configuration, Variol monochromator and Lynx-Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 25 seconds step time.

The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in any way.

Examples:

Example 1: 5-(a-eyclopropylcarbonyl-2-fluorophenyI)-2-oxo-4,5,6,7-tetrahydro
thieno [3,2-c] pyridine

To a suspension of 100 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c] pyridine-2-one Hydrochloride in 800 ml Acetonitrile, 144.5 g of anhydrous potassium carbonate was added at 20-25°C and the reaction mixture cooled to 0-5 °C. To this a solution of 107.5 g of 2-Fluro-a-cyclopropyl carbonylbenzyl bromide in 200 ml of acetonitrile was slowly added over a period of 30-45 min at 0-5°C. The Resulting mixture was stirred at 0-5°C for 5 hours. The reaction mixture was filtered and washed with 100 ml of acetonitrile.
From the filtrate, acetonitrile was removed by evaporation under reduced pressure to dryness. The title compound was obtained as brown oil.

Example 2: Prasugrel

5-(a-cyclopropylcarbonyl-2-lluorobenzyl)-2-oxo-2,4,5,6,7,7a-'hexahydrothieno[3,2-cipyridine obtained from Example-1 was dissolved in 700 ml of dimethyl formamide at 25-35 °C , stirred and the reaction mixture cooled to 0-5°C. To this 93.7 g potassium carbonate was added followed by 61.6 g of acetic anhydride over a period of 15-30 minutes. The reaction mixture was stirred for 45-60 min at 0-5°C. To the reaction mixture, further 15.4 g of acetic anhydride was added at the same temperature and stirred for 15-30 minutes. After completion of acetylation, 600 ml of toluene was added followed by 1000 ml of water. Layers were separated; aqueous layer was extracted with toluene. Both the organic layers were combined and distilled out toluene, and 100 ml of methanol was added and distilled out methanol and traces of toluene under reduced pressure at 40-45°C completely. To this a mixture of 200 ml of methanol and 20 ml of toluene was added and stirred for 1 hour at 25- 30 °C filtered, and the solid was further treated 160 ml of methanol and 15 ml of toluene and stirred for 4 hours at 25-30 °C. Solid was filtered and washed with methanol and dried to give 70-80 g of Prasugrel fi-ee base.

Example 3: Prasugrel hydrochloride

To the 100 g of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2-Fluorobenzyl)-4,5,6,7-tetrahydro thieno[3,2-c] pyridine, 1400 ml of acetone was added at 25-35 °C and stirred for 10 mins. The reaction mixture was heated to 40-42 °c and was added 5 g of activated carbon, stirred for 30 mins, filtered the reaction mass on hyflo and washed with 100 ml of acetone. To this 13.55 g of concentrated hydrochloric acid was added and seeded with 0.2 g of Bl crystals of Prasugrel hydrochloride at 40-42 °C, stirred for 1 hr. To the reaction mixture 12.2 g of concentrated hydrochloric acid was further added at 40-42 °C and maintained the same for 2 hrs. The reaction mixture was cooled to 25-30 °C, filtered and the obtained product was washed with acetone and dried to get 85-95 g of Prasugrel hydrochloride.

We Claim:

1. A process for the purification of Prasugrel free base comprising the steps of:

a) suspending crude Prasugrel in a mixture of organic solvents; and

b) isolating crystalline prasugrel free base.

2. The process according to claim 1, wherein the organic solvent is selected from hydrocarbons, alkyl halides, esters, aldehydes, ketones, amines, alcohols, amides or mixtures thereof

3. The process according to claim 2, wherein the mixture of organic solvent is a mixture of hydrocarbon and alcohol.

4. The process according to claim 1, wherein pure Prasugrel free base is further converted into pharmaceutically acceptable salts of Prasugrel.

5. A process for the purification of Prasugrel free base comprising the steps of:

a) suspending crude Prasugrel in mixture of toluene and methanol; and

b) isolating crystalline prasugrel free base.

6. Crystalline Prasugrel free base obtained by any of the proceeding claims.

7. The crystalline Prasugrel free base according claim 6, wherein crystalline Prasugrel free base is characterized by X-ray diffraction peaks at about 13.40, 14.66, 18.81, 19.36, 21.54, 23.55 ± 0.2 9.

8. The crystalline Prasugrel free base according claim 6, wherein crystalline Prasugrel free base is characterized by XRD as depicted in FIGURE 1.

9. The process according to any of the proceeding claims, wherein, conversion of pure Prasugrel free base into pharmaceutically acceptable salt of prasugrel comprising the steps of:

a) dissolving pure Prasugrel in an organic solvent;

b) treating with an acid; and

c) isolating pharmaceutically acceptable salt of prasugrel.