CLIAMS:1. A N-Benzyl Fosaprepitant, compound of formula-II or its salts thereof

Formula-II
has purity more than 99 % when measured by HPLC.

2. A N-Benzyl Fosaprepitant Dimeglumine, compound of formula-IIA

Formula-IIA
has purity more than 99 % when measured by HPLC.

3. A process for the preparation of N-Benzyl Fosaprepitant Dimeglumine compound of formula IIA,

Formula IIA
the process comprises step of;
a) reacting dibenzyl Fosaprepitant compound of formula III

Formula III
with benzyl chloride in a aprotic solvent in presence of suitable base to obtain N-benzyl dibenzyl Fosaprepitant compound of formula IV,

Formula IV
b) reacting N-benzyl dibenzyl Fosaprepitant with N-methyl-D-glucamine compound of formula V,

Formula V
in presence of reducing agent in a solvent to obtain N-Benzyl Fosaprepitant dimeglumine,
c) optionally, lyophilization of N-Benzyl Fosaprepitant Dimeglumine to obtain white solid of N-Benzyl Fosaprepitant Dimeglumine.

4. The process of claim 3, wherein aprotic solvent is N,N-dimethylformamide.

5. The process of claim 3, wherein base is potassium carbonate.

6. The process of claim 5, wherein potassium carbonate particle size is less than 400 micron.

7. The process of claim 3, wherein the solvent is selected from the group comprising methanol, water and mixture thereof.

8. The process of claim 3 wherein suitable reducing agent is Pd/C.

9. The compound of claim 2, where in N-Benzyl Fosaprepitant Dimeglumine is converted to Fosaprepitant Dimeglumine.

10. A process for the preparation of Fosaprepitant Dimeglumine compound of formula I,

Formula I
which comprises step of
a) reacting dibenzyl Fosaprepitant of formula III

Formula III
with benzyl chloride in a aprotic solvent in presence of suitable base to obtain N-benzyl dibenzyl Fosaprepitant of formula IV,

Formula IV

b) contacting N-benzyl dibenzyl Fosaprepitant of formula IV with N-methyl-D-glucamine of formula V

Formula V
in presence of reducing agent in a solvent to obtain N-Benzyl Fosaprepitant Dimeglumine,
c) optionally, lyophilization of N-Benzyl Fosaprepitant Dimeglumine of formula IIA

Formula IIA
to obtain amorphous form of N-Benzyl Fosaprepitant Dimeglumine,
d) converting N-Benzyl Fosaprepitant Dimeglumine to Fosaprepitant Dimeglumine,

,TagSPECI:Field of Invention

The present invention provides a novel intermediate of Fosaprepitant Dimeglumine e.g. N-Benzyl Fosaprepitant Dimeglumine. In the particular aspect of the present invention provides the process for the preparation of N-Benzyl Fosaprepitant Dimeglumine and its conversion to Fosaprepitant Dimeglumine. In another aspect of present invention provides the use of an N-Benzyl Fosaprepitant Dimeglumine as reference markers and/or reference standards during the synthesis of Fosaprepitant Dimeglumine. In another aspect of present invention provides amorphous solid form of N-Benzyl Fosaprepitant Dimeglumine.

Background of the invention

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 under the trade name Emend®.

U.S. Patent No. 5,691,336 describes Fosaprepitant dimeglumine and process for the preparation thereof. The process for the preparation of Fosaprepitant Dimeglumine described in several patents, e.g. PCT application Nos. 2006/060110 A2; WO 2010/018595 A2; WO 2011/045817 A2 and WO 2012/164576 A2.

The object of present invention is to provide an improved process for the preparation of Fosaprepitant dimeglumine and its novel intermediate. The present invention provides novel intermediate, e.g. 3-(((2R,3S)-2-((R)-1-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(4-fluorophenyl)morpholino)methyl)-4-benzyl-4,5-dihydro-5-oxo-1,2,4-triazol -1-yl-1-phosphonic acid (referred herein after “N-Benzyl Fosaprepitant”). N-Benzyl Fosaprepitant or salts thereof, are useful for the preparation of Fosaprepitant or its pharmaceutically acceptable salts thereof. The process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale. The product obtained by using novel intermediate yield the Fosaprepitant of purity 99% or more, when measured by HPLC.

Summary of the invention

The present invention provides N-Benzyl Fosaprepitant or its salts thereof, compound of formula-II

Formula-II
has purity more than 99 % as measured by HPLC

The present invention provides a N-Benzyl Fosaprepitant Dimeglumine, compound of formula-IIA

Formula-IIA
has purity more than 99 % when measured by HPLC.

The present invention provides an amorphous form of N-Benzyl Fosaprepitant Dimeglumine, compound of formula-IIA

Formula-IIA
has purity more than 99 % when measured by HPLC.

In an aspect, the present invention provides a process for the preparation of N-Benzyl Fosaprepitant Dimeglumine compound of formula IIA,

Formula IIA
which includes step of
a) reacting dibenzyl Fosaprepitant with benzyl chloride in a aprotic solvent in presence of suitable base to obtain N-benzyl dibenzyl fosaprepitant,
b) contacting N-benzyl dibenzyl Fosaprepitant with N-methyl-D-glucamine in presence of reducing agent in a solvent to obtain N-Benzyl Fosaprepitant Dimeglumine
c) optionally, lyophilization of N-Benzyl Fosaprepitant Dimeglumine to obtain amorphous form of N-Benzyl Fosaprepitant Dimeglumine.

In one another aspect of the present invention provides use of N-Benzyl Fosaprepitant Dimeglumine as reference marker.

In one another aspect of the present invention provides use of N-Benzyl Fosaprepitant Dimeglumine as intermediate to provide pure Fosaprepitant Dimeglumine.

In an aspect, the present invention provides a process for the preparation of Fosaprepitant Dimeglumine compound of formula I,

Formula I
the process includes step of
a) reacting dibenzyl Fosaprepitant with benzyl chloride in a aprotic solvent in presence of suitable base to obtain N-benzyl dibenzyl fosaprepitant,
b) contacting N-benzyl dibenzyl Fosaprepitant with N-methyl-D-glucamine in presence of reducing agent in a solvent to obtain N-Benzyl Fosaprepitant Dimeglumine,
c) optionally, lyophilization of N-Benzyl Fosaprepitant Dimeglumine to obtain amorphous form of N-Benzyl Fosaprepitant Dimeglumine,
d) converting N-Benzyl Fosaprepitant Dimeglumine to Fosaprepitant Dimeglumine.

The present invention also provides a Fosaprepitant Dimeglumine, has purity more than 99 % when measured by HPLC.

Brief Description of the Drawings

Figure 1 shows an illustrative example of X-ray powder diffraction pattern of amorphous form of N-Benzyl Fosaprepitant Dimeglumine

Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of amorphous form of N-Benzyl Fosaprepitant Dimeglumine

Figure 3 shows an illustrative example of Thermogravimetric analysis curve of amorphous form of N-Benzyl Fosaprepitant Dimeglumine
Detailed description of the invention

For purposes of the present invention, the following terms are defined below.

The X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Kα radiation, having the wavelength 1.54 Å.

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

As used herein, the term “reference standard” refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. A reference marker” is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

In an aspect, the present invention provides N-Benzyl Fosaprepitant or its salts thereof, compound of formula-II

Formula-II
has purity more than 99 % when measured by HPLC.

In an aspect, the present invention provides N-Benzyl Fosaprepitant Dimeglumine, compound of formula-IIA

Formula-IIA
has purity more than 99 % when measured by HPLC.

The present invention provides a amorphous form of N-Benzyl Fosaprepitant Dimeglumine, compound of formula-IIA

Formula-IIA
has purity more than 99 % when measured by HPLC.

In another aspect, the present invention provides a amorphous form of N-Benzyl Fosaprepitant Dimeglumine is characterized by its X-ray powder diffraction pattern substantially as shown in Figure 1, differential scanning calorimetry thermogram as shown in Figure 2 and thermogravimetric analysis curve as shown in Figure 3.

In one another aspect, the present invention provides a process for the preparation of N-Benzyl Fosaprepitant Dimeglumine of formula IIA,

Formula IIA
which includes step of;
a) reacting dibenzyl Fosaprepitant compound of formula III

Formula III
with benzyl chloride in a aprotic solvent in presence of suitable base to obtain N-benzyl dibenzyl Fosaprepitant compound of formula IV,

Formula IV
b) reacting N-benzyl dibenzyl Fosaprepitant with N-methyl-D-glucamine compound of formula V

Formula V
in presence of reducing agent in a solvent to obtain N-Benzyl Fosaprepitant Dimeglumine,
c) optionally, lyophilization of N-Benzyl Fosaprepitant Dimeglumine to obtain amorphous form of N-Benzyl Fosaprepitant Dimeglumine.

The step a) of the present invention involves dissolving of dibenzyl Fosaprepitant of in a aprotic solvent to get a clear solution, followed by addition of powdered suitable base to the reaction mixture, wherein aprotic solvent is selected from the group comprising one or more of N,N-dimethylformamide, N,N-diethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide, tetrahydrofuran and mixture thereof.

The reaction mixture was stirred for the period of 0.5 hour to 1 hour followed by slow addition of benzyl chloride to the reaction mixture and continued stirring for 24 hours. After completion of the reaction dichloromethane is added and extracted the reaction mass. The organic layer is washed with brine, wherein brine solution is saturated solution of sodium chloride. The organic layer is concentrated under vacuum to get N-benzyl dibenzyl Fosaprepitant as thick oily mass,

The suitable base is selected from the group comprising one or more of organic base comprising dimethylamine, diethylamine or triethylamine and ammonia. Inorganic base include of one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide and potassium t-butoxide. The bases are powdered in mill to reduce the particle size less than 400 micron before use.

The step b) of the present invention involves the dissolving the N-benzyl dibenzyl fosaprepitant in a solvent followed by addition of N-methyl-D-glucamine and suitable reducing agent to the reaction mixture in a solvent. After the completion of the reaction, the reaction mass is passed through hyflowbed to obtain a clear filterate which is distilled out under reduced pressure at temperature below 50oC to get a semi solid mass. The semi solid mass is suspended in toluene and distilled out thrice followed by solid mass is dissolved in methanol and again distilled out. Finally solid residue is dissolved in methanol to get a clear solution and then isopropyl alcohol is added. The reaction mixture is stirred for 2 hours at room temperature, filtered and dried to get N-Benzyl Fosaprepitant Dimeglumine, wherein suitable reducing agent is selected from the group comprising Pd/C, Pt/C, PtO2, Pd(OH)2, Nickel, Zinc-metal, Raney nickel, Rhodium and sodium amalgam.

The step c) of the present invention involves the lyophilization of N-Benzyl Fosaprepitant Dimeglumine. The N-Benzyl Fosaprepitant Dimeglumine is dissolved in a solvent and sonicated to obtain clear solution, followed by freeze drying for the period 25 hour to 40 hours to obtain white solid powder of N-Benzyl Fosaprepitant Dimeglumine.

The solvent is selected from the group comprising one or more of as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol, water and mixture thereof.

In an aspect, the present invention provides a process for the preparation of Fosaprepitant Dimeglumine, compound of formula I,

Formula I
the process includes the step of
a) reacting dibenzyl Fosaprepitant of formula III

Formula III

with benzyl chloride in a aprotic solvent in presence of suitable base to obtain N-benzyl dibenzyl fosaprepitant of formula IV

Formula IV
b) contacting N-benzyl dibenzyl Fosaprepitant of formula IV with N-methyl-D-glucamine of formula V

Formula V
in presence of reducing agent in a solvent to obtain N-Benzyl Fosaprepitant Dimeglumine,
c) optionally, lyophilization of N-Benzyl Fosaprepitant Dimeglumine of formula IIA

Formula IIA
to obtain amorphous form of N-Benzyl Fosaprepitant Dimeglumine,
d) converting N-Benzyl Fosaprepitant Dimeglumine to Fosaprepitant Dimeglumine,

The conversion of N-Benzyl Fosaprepitant Dimeglumine to Fosaprepitant Dimeglumine is carried out by N-debenzylation using conventional method known in the art such as hydrogenation at pH about 2 to 5.

Yet in one another aspect of the present invention provides the use of N-Benzyl Fosaprepitant Dimeglumine, as reference standards in a qualitative analysis of Fosaprepitant dimeglumine.

Yet in one another aspect of the present invention provides use of N-Benzyl Fosaprepitant Dimeglumine as intermediate to provide pure Fosaprepitant Dimeglumine.

Yet in one another aspect of the present invention provides N-Benzyl Fosaprepitant Dimeglumine has purity more than 99% determined by HPLC.

Yet in one another aspect of the present invention provides Fosaprepitant Dimeglumine has purity more than 99% determined by HPLC.

The process of the present invention is depicted in the following scheme 1:

Scheme 1

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: Process for Preparation of N-Benzyl Dibenzyl Fosaprepitant

Charged dibenzyl fosaprepitant (10 gm) in dimethyl formamide (100 mL), the reaction mixture was stirred for the period of 5 to 10 minutes, followed by addition of powdered potassium carbonate powder (5.2 gm, 350 micron). The reaction mixture was stirred for 30 minutes followed by benzyl chloride (1.6 gm) was slowly added into the reaction mixture at temperature 25C to 30C for the period of 24 hours. After completion of the reaction dichloromethane was added. Finally dichloromethane layer was separated washed with brine solution and concentrated under vacuum to get titled compound as thick oily mass.
Yield: 12 gm
Mass (ES+): 885.3

Example-2: Process for Preparation of N-Benzyl Fosaprepitant Dimeglumine

Charged N-Benzyl Dibenzyl fosaprepitant (12 gm) in methanol (150 mL), followed by addition of N-methyl-D-glucamine (4.7 gm), Pd/C (0.25 gm) and water (10 mL). Hydrogen gas was purged to the reaction mixture for the period of 2 hours at temperature 25C to 30C. After completion of the reaction, reaction mass was filtered through hyflow-bed to obtain clear filtrate, which was distilled out under reduced pressure at temperature below 50 °C to obtain a semi-solid mass. Semi-solid was dissolved in toluene. The toluene was removed and methanol was added which is also removed to get solid mass. In the solid mass methanol (100 mL) was added it was stirred for the period to get a clear solution. To the solution isopropyl alcohol (200 mL) was added. The reaction mixture was stirred for the period of 2 hour at temperature 25°C to 30°C. Finally the reaction mixture was filtered and dried to get the titled compound.
Yield: 8.5 gm
HPLC purity: 92.581
Mass (ES+): 705.3

Example-3: Process for Preparation of Amorphous N-Benzyl Fosaprepitant Dimeglumine

Charged N-Benzyl fosaprepitant dimeglumine (8.5 gm) dissolved in water (85 mL) in lyophilizer flask. The reaction mixture was sonicated. The lyophilizer flask containing clear solution of N-Benzyl fosaprepitant dimeglumine was subjected to freeze drying for the period of 36 hours to get white solid powder of titled compound.
Yield: 8.0 gm
Moisture Content M/C: 5.35% w/w
HPLC purity: 91.674
Mass (ES+): 705.3