CLIAMS:We Claim:

1. An improved process for the preparation of Fosaprepitant dimeglumine having purity greater than 99.5%, which comprises:

a) reaction of dibenzyl ester of Fosaprepitant with N-methyl D-glucamine using catalyst such as Pd/C in presence of aqueous medium to provide Fosaprepitant dimeglumine; and

b) purification of Fosaprepitant dimeglumine by using methanol and isopropyl alcohol to provide purity greater than 99.5%.

2. The process of claim 1, wherein the Pd/C is 5% w/w Pd/C and used as catalytic amount of 0.25% w/w.

3. The process of claim 1, wherein the step a) is carried out in presence of hydrogen pursing.

4. The process of claim 1, wherein the aqueous medium comprises water and water miscible organic solvent.

5. The process of claim 4, wherein the organic solvent is alcohol such as methanol.

6. The process of claim 1, wherein Fosaprepitant dimeglumine of step a) has purity greater than 98% determined by HPLC.

7. The process of claim 1, wherein the step b) comprises dissolution of Fosaprepitant dimeglumine in methanol and then isolation of solid with isopropyl alcohol.

8. The process of claim 1, wherein the purity of Fosaprepitant dimeglumine is 99.7% determined by HPLC.

9. An improved process for the preparation of Fosaprepitant dimeglumine comprising reaction of dibenzyl ester of Fosaprepitant with N-methyl D-glucamine using 5% Pd/C in presence of water and methanol.
,TagSPECI:FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rule13)
1. TITLE OF THE INVENTION: An Improved Process For Preparing Fosaprepitant Dimeglumine
2. APPLICANT (S) (a) NAME: WOCKHARDT RESEARCH CENTRE (b) NATIONALITY: INDIAN (c) ADDRESS: D-4, M.I.D.C INDUSTRIAL AREA, CHIKALTHANA, AURANGABAD- 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTIONThe present invention provides an improved process for preparing Fosaprepitant dimeglumine from dibenzyl ester of Fosaprepitant in presence of water.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION

The present invention provides an improved process for preparing Fosaprepitant dimeglumine by the reaction of dibenzyl ester of Fosaprepitant with N-methyl D-glucamine using catalyst such as Pd/C in presence of aqueous medium.

Fosaprepitant dimeglumine is chemically known as 1-deoxy-1(methylamino)-D-glucitol[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate (2:1) (salt) and is structurally represented by formula (I):

Formula I

Fosaprepitant dimeglumine is approved for the treatment of emesis, nausea, cancer therapy toxicity and is available in the market as EMEND® in the US and IVEMEND® in Europe, with the dosage strength 115 mg equivalent base.

U.S. Patent No. 5,691,336 describes Fosaprepitant dimeglumine and process for the preparation thereof.

PCT application No. 2006/060110 A2 discloses a process for the preparation of Fosaprepitant dimeglumine which involves dissolution of monobenzyl ester of Fosaprepitant and N-methyl-D-glucamine in water and methanol followed by reaction with Pd/C and hydrogen pressure for a period of over night. Further, this patent application involves tedious work up procedure for the isolation of solid after the reaction.

PCT applications 2010/018595 A2 and 2011/045817 A2 disclose a process for the preparation of intermediates of Fosaprepitant dimeglumine and their conversions to Fosaprepitant using methanol as solvent.

Inventors of the present invention surprisingly found that the presence of aqueous medium and elimination of hydrogen pressure for hydrogenation reaction minimizes the use of catalyst and enhances the quality of the product with regard to purity.

In an aspect of the present invention is to provide an improved process for the preparation of Fosaprepitant dimeglumine comprising reaction of dibenzyl ester of Fosaprepitant with N-methyl D-glucamine using catalyst such as Pd/C in presence of aqueous medium.

In another aspect of the present invention is to provide an improved process for the preparation of Fosaprepitant dimeglumine having purity greater than 99.5%, which comprises:

a) reaction of dibenzyl ester of Fosaprepitant with N-methyl D-glucamine using catalyst such as Pd/C in presence of aqueous medium to provide Fosaprepitant dimeglumine having purity greater than 98%; and

b) purification of Fosaprepitant dimeglumine by using methanol and isopropyl alcohol to provide purity greater than 99.5%.

The step a) of the present invention involves reaction of dibenzyl ester of Fosaprepitant with N-methyl D-glucamine using catalyst such as Pd/C in presence of aqueous medium to provide Fosaprepitant dimeglumine having purity greater than 98%.

The starting material, dibenzyl ester of Fosaprepitant, may be obtained from the known processes disclosed in the prior art, for example, WO 2006/060110 A2.

The percentage of Pd in Pd/C, ranges from about 5% w/w to about 10% w/w, preferably about 5% w/w. The quantity of Pd/c is about of 0.1% to about 0.35% w/w or about 0.25% w/w.

The reaction of step a) is conducted in presence of hydrogen pursing at a temperature of about 15 to about 35 °C.

The aqueous medium is comprised with water. The aqueous medium may be a combination of water and water miscible organic solvent. The organic solvent is selected from alcohol such as methanol, ethanol, isopropyl alcohol, butanol and the like. In an embodiment, the organic solvent can be methanol.

The quantity of the starting material, N-methyl-D-glucamine, is in the range of 2 to 3 molar equivalents or 2.5 molar equivalents per the molar equivalent of dibenzyl ester of Fosaprepitant.

The reaction may be conducted at a temperature of about 15 to about 35 °C. The reaction may be performed for a period of about 1 to about 2 hours.

The reaction conditions of the present invention such as addition of 5% Pd/c and water to the solution of dibenzyl ester and N-methyl-D-glucamine in methanol, pursing hydrogen to provide bubbling and conducting reaction at room temperature i.e. 15-35°C provide the improved quality of Fosaprepitant dimeglumine and easy isolation of solid, and also reduce required the time period for completion of the reaction. The present invention is also industrially feasible and uses eco-friendly reagents.

After completion of the reaction, the reaction mixture is filtered and the filtrate is subjected for isolation of solid using suitable recrystallization techniques. The solution may be concentrated or/and treated with anti-solvent such as isopropyl alcohol to provide suspension of Fosaprepitant dimeglumine.

The resultant Fosaprepitant dimeglumine has the purity greater than 98% determined by HPLC.

Process related Impurities, for example, dibenzyl ester of Fosaprepitant dimeglumine and mono benzyl ester of Fosaprepitant dimeglumine, in the Fosaprepitant dimeglumine obtained from the present invention are not present in the detectable range.

The step b) of the present invention involves purification of Fosaprepitant dimeglumine by using methanol and isopropyl alcohol to provide purity greater than 99.5%.

The Fosaprepitant dimeglumine is dissolved in methanol and then the solid is isolated by the addition of isopropyl alcohol at a room temperature and stirred for a period of about 30 minutes to about 1 hour to enhance the yield and purity of Fosaprepitant dimeglumine.

The obtained Fosaprepitant dimeglumine is filtered and then dried at a temperature from about 25 °C to about 35 °C or at 30 °C., under vacuum for a period of about 1 hour or more.

The present invention provides Fosaprepitant dimeglumine produced by the process of purification of the present invention is characterized by a purity greater than 99.5% as measured by HPLC, or greater than 99.7%, as measured by HPLC.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES:

Example-1:
Preparation of Fosaprepitant Dimeglumine

Dibenzyl ester Fosaprepitant (10.0 gm) and N-methyl-D-glucamine (6.1 gm) were charged in methanol (100.0 ml). 5% palladium –carbon (50% wet, 0.25 gm) and water (20 ml) was charged to the solution and then stirred under hydrogen bubbling for 1-2 hrs at room temperature. After completion of reaction, reaction suspension was filtered on celite and celite was washed with methanol (10 ml). The filtrate was distilled completely at about 50°C under vacuum and then methanol (100 ml) was charged. The resulting residual suspension was stirred for about 10-20 minutes to get clear solution. Isopropyl alcohol (200 ml) was charged to the suspension, stirred for about 30-45 minutes, filtered under nitrogen and then washed the solid with Isopropyl alcohol (50 ml). The resultant solid was dried under vacuum at 30°C for 1-2 hrs.

Yield: 9.8 gm
Purity: 98.57 %

Example-2:

Purification of Fosaprepitant Dimeglumine

Fosaprepitant dimeglumine (10.0 gm) obtained from the example 1 and methanol (100.0 ml) were charged into a clean and dry 4 necks round bottom flask followed by stirring at room temperature for about 10-20 minutes to get clear solution. Isopropyl alcohol (200 ml) was charged to the clear solution, stirred for about 1.0 hour. The resulting solid was filtered under nitrogen and solid washed with Isopropyl alcohol (20 ml). The solid was dried under vacuum at 30°C for about 1-2 hours.

Yield: 8.5 gm
Purity: 99.78 %