CLIAMS:1. A process for the purification of Aprepitant or its pharmaceutically acceptable salt, which comprises:

a) providing solution of crude Aprepitant in alcohol at above 60 °C;
b) cooling to a temperature less than 5 °C; and
c) isolating the solid from the suspension of stet b)

2. The process of claim 1, wherein the alcohol is methanol, ethanol, isopropyl alcohol and n-butanol.

3. The process of claim 1, wherein the alcohol is methanol.

4. The process of claim 1, wherein the temperature of above 60 °C is about 60 to about 70 °C.

5. The process of claim 1, wherein the temperature less than 5 °C is about -5 °C to 5 °C.

6. The process of claim 1, wherein the purified Aprepitant has purity greater than or equal to 99.5%.

7. A process for the purification of Aprepitant or its pharmaceutically acceptable salt, which comprises:

a) providing solution of crude Aprepitant in methanol at reflux;
b) cooling to a temperature to -5 °C to 5 °C; and
c) isolating the solid from the suspension of step b).

8. The process of claim 7, wherein the purified Aprepitant has purity greater than or equal to 99.8%.
,TagSPECI:Field of Invention

The present invention relates to a process for the purification of Aprepitant or its pharmaceutically acceptable salt. The present invention particularly relates to a process for the purification of Aprepitant or its pharmaceutically acceptable salt from recrystallization technique using alcoholic solvent.

Background of the invention

Aprepitant, chemically known as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, represent as Formula I:

Formula I

Aprepitant is a substance P (neurokinin-1) receptor antagonist useful in the treatment of chemotherapy-induced nausea and vomiting, and is commercially available in the market under the brand name EMEND™ as 40 mg, 80 mg or 125 mg capsules.

U.S. Pat. No. 5,719,147 discloses Aprepitant and its pharmaceutically acceptable salts, process, sa pharmaceutical composition, and methods of treatment. Further, it discloses purification of Aprepitant by flash chromatography using a 50:1:0.1 ratio of methylene chloride/methanol/ammonium hydroxide as the eluant, which is industrially not feasible.

U.S. Pat. No. 8,133,994 discloses purification of Aprepitant using solvent such as acetonitrile, toluene, isopropyl alcohol, methyl tert-butyl ether, dichloromethane, and chloroform. However, none of the processes of the US ‘994 patent is provided greater than or equal to 99% purity.

PCT publication No. 2009/001203 A2 discloses a process for the purification of Aprepitant, which involves dissolution of crude Aprepitant in methanol, treating with charcoal, cooling the methanol solution to 30 °C and then 30 °C to provide purity 99.6% of Aprepitant. Further, The WO ‘203 discloses purification of crude aprepitant by using MDC:methanol:heptane mixture to get 99.5%.

PCT publication No. 2009/11608 A2 discloses a process for the purification of Aprepitant, which involves isolation of solid having purity of 99.96% form the solution of crude Aprepitant in methanol by the addition of water slowly.

PCT publication No. 2008/026216 A2 discloses a process for the purification of Aprepitant, which involves purification from ethyl acetate and then purification from methanol and water to provide pure Aprepitant.

None of the prior art processes provides simple and well suited process to provide pure Aprepitant or its pharmaceutically acceptable salt, therefore, there is a need to develop simple, industrially feasible and cost effective process for providing pure Aprepitant or its pharmaceutically acceptable salt.

Summary of the invention

The present invention provides a process for the purification of Aprepitant or its pharmaceutically acceptable salt. Further, the present invention provides Aprepitant having purity of greater than or equal to 99.5% obtained from the simple purification using alcohol.

In an aspect, the present invention provides a process for the purification of Aprepitant or its pharmaceutically acceptable salt, which comprises:

a) providing solution of crude Aprepitant in alcohol at above 60 °C;
b) cooling to a temperature less than 5 °C; and
c) isolating the solid from the suspension of stet b).

In another aspect, the present invention provides a process for the purification of Aprepitant or its pharmaceutically acceptable salt, which comprises:

a) providing solution of crude Aprepitant in methanol at reflux;
b) cooling to a temperature to -5 °C to 5 °C; and
c) isolating the solid from the suspension of step b).

The resultant Aprepitant or its pharmaceutically acceptable salt of the present invention can be used for the preparation of pharmaceutical composition and for the treatment of chemotherapy-induced nausea and vomiting.

Description of the Invention

The term “pure” as used herein, unless otherwise defined, refers to Aprepitant or its pharmaceutically acceptable salt that has purity of about 99.5 % or above.

The term “crude” as used herein, unless otherwise defined, refers to Aprepitant or its pharmaceutically acceptable salt that has purity less than about 99.5 % or less than 99% or less then 98% or less than 95%.

The salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.

In an aspect, the present invention provides a process for the purification of Aprepitant or its pharmaceutically acceptable salt, which comprises:

a) providing solution of crude Aprepitant in alcohol at above 60 °C;
b) cooling to a temperature less than 5 °C; and
c) isolating the solid from the suspension of stet b).

The individual steps of the process are detailed herein below.

Step a) involves providing a solution of crude Aprepitant in alcohol. The crude Aprepitant used in the process of the present disclosure may be obtained from processes disclosed in the art or as per the process described in the present application. The solution of crude Aprepitant may be provided by combining crude Aprepitant with alcohol and heating to a temperature of about 60 to about 80 °C or to reflux. The alcohol is selected from methanol, ethanol, isopropyl alcohol, n-butanol and the like.

In an embodiment, a solution of Aprepitant in methanol is provided by combining Aprepitant with methanol and heating to a temperature of about 60 to about 70 °C.

The solution obtained may be optionally treated with charcoal and filtered to provide clear solution.

The solution of Aprepitant obtained in step a) is maintained at a temperature of about 30°C to about 80°C for a period of about 1 to 4 hours or more. In one embodiment, the solution is maintained at a temperature of about of 60°C to about 70°C.

Step b) involves cooling to a temperature less than 5 °C. The reaction solution of step a) may be optionally cooled to a temperature less than 5 °C to affect the precipitation of Aprepitant.

The reaction mass of the step b) is maintained at a temperature of about -5 °C to 5 °C for a period of about 30 minutes to about 2 hours to increase the precipitation of solid.

Step c) involves isolating solid from the suspension of step b).

Isolation of the solid may be done by techniques known in art which include, but are not limited to, filtration by gravity or by suction, distillation, centrifugation, or slow evaporation, or the like.

The product obtained may be dried at a temperature of about 45°C to about 80°C to provide Aprepitant having a purity of greater than or equal to 99.5% by HPLC.

In another aspect, the present invention provides a process for the purification of Aprepitant or its pharmaceutically acceptable salt, which comprises:
a) providing solution of crude Aprepitant in methanol at reflux;
b) cooling to a temperature to -5 °C to 5 °C; and
c) isolating the solid from the suspension of step b).

The crude Aprepitant is combined with methanol, heated to reflux with stirring and then maintained at reflux for a period of 2 to 4 hours to provide solution of Aprepitant. The obtained solution is cooled to -5 °C to 5 °C and maintained at the same temperature for a period of about 2 hours to increase the precipitation of solid. The obtained suspension is filtered using known technique to afford pure Aprepitant having purity greater than or equal to 99.9%.

In another aspect, the present invention relates to pharmaceutical composition comprising Aprepitant or its pharmaceutically acceptable salt obtained from the present invention and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the treatment of major depressive disorder.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example 1: A process for the preparation of crude Aprepitant

Morpholine hydrochloride (10 g) and water (10 ml) were charged into dimethylformamide (30 ml). Potassium carbonate (0.73 g; milled) was charged and then cooled the reaction mixture to 14-20 °C. 3-chloromethyl-1,2,4-triazolin-5-one (3.3 g) was charged and stirred the resultant reaction mixture at 14-20 °C. After completion of the reaction, water (75 ml) was charged, stirred for 1 hour at room temperature and then filtered the reaction mixture. The resultant solid was dried under vacuum to afford 10 g of crude Aprepitant.

Purity: 98% by HPLC

Example 2: A process for the Purification of Aprepitant

Crude Aprepitant (10 g) and methanol (30 ml) were charged into a clean and dry round bottom flask and then heated to 60-70 °C. The reaction was maintained for 4 hours and cooled to -5 °C to 5 °C. The reaction mass was stirred for 2 hours and then filtered the suspension. The resultant solid was washed with chilled methanol (5 ml) and dried under vacuum at NMT 75 °C for about 8-12 hours.

Yield: 8.5 g.
Purity : 99.9%.