FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"Process for preparation of Fosaprepitant and salt thereof
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered
office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099
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 fosaprepitant and salt thereof. More specifically the present invention relates to an improved process for preparing fosaprepitant dibenzylester from aprepitant.
BACKGROUND OF THE INVENTION
Fosaprepitant represented by compound of Formula I is a prodrug of aprepitant.

The meglumine salt of fosaprepitant, Fosaprepitant dimeglumine is approved for the treatment of emesis, nausea, cancer therapy toxicity and is available in the market by brand name EMEND® in the US and IVEMEND® in Europe, with the dosage strength 115 mg equivalent base.
Fosaprepitant dimeglumine is chemically known as l-deoxy-l-(methyl amino)-D-glucitol[3-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]-ethoxy]-3-(4-fluorophenyl)4-morpholinyl] methyl]-2,5-dihydro-5-oxo-lH-1,2,4-triazol-1 -yl]phosphonate (2:1) (salt).
United States Pat. No. 5,691,336 (U.S.Pat..336) describes morpholine compounds including fosaprepitant and its pharmaceutically acceptable salts thereof. U.S.Pat.'336 patent exemplifies the process for the preparation of fosaprepitant by reacting aprepitant compound of Formula II with tetrabenzyl pyrophosphate in presence of a sodium hexamethyldisilazane (NaHMDS) base in dry tetrahydrofuran (THF) followed by workup in ethyl ether to obtain fosaprepitant dibenzylester, a compound of Formula III.


The fosaprepitant dibenzylester, compound of Formula III is then converted to fosaprepitant compound of Formula I by debenzylation with palladium catalyst. Disadvantageously, the reaction of aprepitant, compound of Formula II with tetrabenzyl pyrophosphate to obtain fosaprepitant dibenzylester, compound of Formula III leads to varied yields of fosaprepitant dibenzylester, compound of Formula III. Further in said process, the starting material aprepitant, compound of Formula II, thereto is present to the extent of 0.8-20%, which subsequently results to batch variations; thus the process in itself, is inconsistent and commercially unviable on an industrial scale.
Herein, the present invention provides the formation of fosaprepitant dibenzylester, compound of Formula III, from aprepitant, compound of Formula II and tetrabenzyl pyrophosphate in high yields, high purity, with lower content of aprepitant, consistently on an industrial scale, where the selection of the base and the reaction solvent and the work up solventare critical.
The present invention provides a process for obtaining the fosaprepitant dibenzylester, compound of Formula III, as a white solid in purity greater than 95%, in yields greater than 80% and wherein the starting material aprepitant, compound of Formula II is present to an extent of less than 2%. The process of the present invention is reproducible on an industrial scale as the yields obtained are consistent and the aprepitant content is lower and does not show batch to batch variation when reaction is carried out on a large scale. Thus the process of the present invention is commercially feasible for large sale preparation of fosaprepitant dibenzylester, compound of Formula III.

SUMMARY OF THE INVENTION
a) reacting aprepitant, compound of Formula II,
The present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, content less than 2% w/w of fosaprepitant dibenzyl ester, the compound of Formula III, comprising:


with tetrabenzyl pyrophosphate in presence of a hydride base to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from a hydrocarbon solvent or
halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzyl ester, compound of Formula III in the form of a solid.
DETAILED DESCRIPTION OF THE INVENTION


a) reacting aprepitant, compound of Formula II,

The present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
with tetrabenzyl pyrophosphate in presence of a hydride base to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.


a) reacting aprepitant, compound of Formula II,

The present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
Formula II with tetrabenzyl pyrophosphate in presence of a hydride base to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid
wherein said process yields fosaprepitant dibenzylester, compound of Formula III in more than 80% yields based on aprepitant compound of Formula II.

The hydride base may be selected from the group consisting of sodium hydride, potassium hydride, lithium hydride and the like.
The reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may be carried out in a solvent selected from ether or halogenated hydrocarbon.
Ethers may be acyclic and cyclic ethers selected from the group the group consisting of isopropyl ether, diethyl ether, tetrahydrofuran, tetrahydropyran and the like.
Halogenated hydrocarbons may be selected from the group consisting of methylene chloride, chloroform, dichloroethane and the like.
The reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may be carried out at lower temperature, preferably in the temperature range of about 5°C-20°C.
The reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may be carried out for a period of about 30 minutes to about 2 hours.
In one embodiment, the reaction of aprepitant with tetrabenzyl pyrophosphate may be carried out in presence of sodium hydride base in presence of ether solvent, preferably the ether solvent is tetrahydrofuran.
In b) of the process described directly above, the reaction mass obtained from a) is extracted with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof.
The hydrocarbon solvent may be an aliphatic hydrocarbon selected from the group consisting of hexane, heptane and the like or aromatic hydrocarbon like toluene, benzene, xylene and the like.
Halogenated hydrocarbons may be selected from the group consisting of methylene chloride, chloroform, dichloroethane and the like.
In one embodiment the reaction mass obtained from a) is extracted with halogenated hydrocarbon preferably methylene chloride.
In c) of the process described directly above, the fosaprepitant dibenzylester, compound of Formula 111 is obtained as a solid.

In one embodiment, the reaction mass obtained after b) is distilled off and degassed. The compound of formula III may then be obtained as a solid by dissolving the degassed mass in a solvent or mixture thereof and precipitating by addition of an antisolvent.
The solvent(s) that can be used for dissolution may be selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixtures thereof, preferably ethyl acetate.
The anti-solvent(s) that can be used to precipitate the solid is selected from hydrocarbon solvents like n-pentane, n-hexane, n-heptane, cyclohexane or mixtures thereof, preferably cyclohexane.
In one embodiment in c) the fosaprepitant dibenzylester, compound of Formula III may be obtained as a solid by dissolving the degassed mass in ethyl acetate and precipitating by addition of cyclohexane.

a) reacting aprepitant, compound of Formula II,
In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising


with tetrabenzyl pyrophosphate in presence of a hydride base in an ether solvent to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.
In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
a) reacting aprepitant, compound of Formula II with tetrabenzyl pyrophosphate in presence of a
hydride base in an ether solvent to obtain a reaction mass;
b) extracting the reaction mass with a halogenated hydrocarbon solvent; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.
In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
a) reacting aprepitant, compound of Formula II, with tetrabenzyl pyrophosphate in presence of a hydride base in tetrahydofuran to obtain a reaction mass;
b) extracting the reaction mass with methylene chloride; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of solid.

In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III having aprepitant, compound of Formula II content less than 1% w/w of fosaprepitant dibenzylester, compound of Formula III, as determined by high performance liquid chromatography (HPLC).
In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III having content of aprepitant, a compound of Formula II less than 0.5% w/w of fosaprepitant dibenzylester, compound of Formula III as determined by HPLC, preferably having aprepitant, compound of Formula II content less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III as determined by HPLC.
In one embodiment, the present invention provides solid fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II content less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III and in purity greater than 95% as determined by HPLC.
The process of the present invention is reproducible and consistently provides fosaprepitant dibenzylester, compound of Formula III as a white solid in purity greater than 95% as determined by HPLC, in yields greater than 80% and wherein the starting material aprepitant, compound of Formula II is present to an extent of less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III as determined by HPLC.
The fosaprepitant dibenzylester, compound of Formula III, obtained by the process of the present invention may be converted to the neutral form of fosaprepitant, or may optionally be converted into a pharmaceutically acceptable salt of fosaprepitant by any method known to one of ordinary skill in the art. A preferred pharmaceutically acceptable salt is the fosaprepitant dimeglumine.
The dimeglumine salt may be prepared by a method including, but not limited to, reacting the neutral form of fosaprepitant with N-methyl-D-glucamine. Typically, the fosaprepitant is dissolved in an organic solvent and combined with a solution of acid or base used to obtain the desired salt of fosaprepitant.
The dimeglumine salt may be prepared by hydrogenating the fosaprepitant dibenzylester, compound of Formula III in the presence of palladium-carbon and N-methyl -D- glucamine.

In one embodiment, the present invention provides a fosaprepitant dimeglumine wherein the bacterial endotoxin limit is less than 1.0 EU/mg as determined by Limulus Amebocyte Lysate (LAL) according to USP 35.
In one embodiment, the present invention provides a process for preparation of fosaprepitant dimeglumine wherein the bacterial endotoxin limit is less than 1.0 EU/mg as determined by Limulus Amebocyte Lysate (LAL) according to USP 35 comprising
(a) dissolving the fosaprepitant dimeglumine in a solvent System;
(b) optionally heating to obtain solution of fosaprepitant dimeglumine;
(c) treating the solution of fosaprepitant dimeglumine with an activated carbon;

(d) filtering off the activated carbon to obtain a filtrate; and
(e) adding an antisolvent to the filtrate to precipitate the fosaprepitant dimeglumine.
The solvent for dissolving the fosaprepitant dimeglumine may be selected from methanol and dimethylformamide.
The antisolvent may be selected from isopropanol, acetone and methyl ethyl ketone.
In one embodiment, the present invention provides a process for preparation of fosaprepitant dimeglumine wherein the bacterial endotoxin limit is less than 1.0 EU/mg as determined by Limulus Amebocyte Lysate (LAL) according to USP 35 comprising
(a) dissolving the fosaprepitant dimeglumine in a solvent system to obtain a solution;
(b) filtering the solution of fosaprepitant dimeglumine over a sterile filter having pore size of 0.22 u or less; and
(c) adding an antisolvent to the filtrate to precipitate the fosaprepitant dimeglumine,
The solvent for dissolving the fosaprepitant dimeglumine may be selected from methanol and dimethylformamide.
The antisolvent may be selected from isopropanol, acetone and methyl ethyl ketone. Preferably the antisolvent is passed through a sterile filter having pore size of 0.22 μ or less.

The fosaprepitant dimeglumine thus obtained is dried in vacuum to obtain aseptic crystalline fosaprepitant dimeglumine.
The aseptic fosaprepitant dimeglumine obtained by the process of the present invention may be used for formulating an injectable of fosaprepitant dimeglumine.
In one embodiment the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II characterized by X-ray powder diffraction having peaks expressed as 2 θ values at about 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8±0.2
In one embodiment, the present invention provides a process for preparing aprepitant compound of formula 11 in crystalline Farm 11 comprising
(a)dissolving aprepitant in alkanol;
(b) optional filtering the solution;
(c) adding a hydrocarbon solvent to the alkanoic solution of aprepitant obtained in (b); and
(d) distilling of the solvent to obtain Form II of aprepitant.
The alkanol may be selected from methanol, ethanol and the like.
The hydrocarbon solvent may be aliphatic selected from the group consisting of hexane, heptane and the like or aromatic hydrocarbon like toluene, benzene, xylene and the like.
The amount of hydrocarbon solvent used is 3 to 5 times the amount of alkanolic solvent used.
The distillation is carried out to the extent that alkanol is almost removed from the solvent; while allowing crystalline Form II of aprepitant, compound of formula II, to precipitate out from the hydrocarbon.
In one embodiment, the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II, comprising:
(a) dissolving aprepitant in methanol;

(b) optional filtering the solution;
(c) adding toluene to the methanolic solution of aprepitant obtained in step b; and
(d) distilling of the solvent to obtain crystalline Form II of aprepitant.
HPLC Methodology
Reagents, Solvents and Standards:
Water (Milli Q or equivalent); Acetonitrile (Merck, HPLC grade);Disodium hydrogen phosphate anhydrous (GR Grade);Methanol (HPLC Grade); Ortho phosphoric acid (GR Grade)
01.2. Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient
pumps, variable wavelength UV detector attached with data recorder and integrator software,
Column : C18 Thermo BDS Hypersil, 250 x 4.6, 5u
Column temperature: 30 °C
Mobile Phase : Mobile Phase A = Buffer;Buffer : 2.42gm of Disodium hydrogen phosphate
anhydrous in 1000ml of water. Adjust pH to 6.5 with o-Phosphoric acid
Mobile Phase B = Acetonitrile : Methanol (60 : 40, v/v)
Time (min.) % Mobile Phase A % Mobile Phase B
0.01 60 40
30 30 70
55 20 80
60 60 40
65 60 40
Diluent: Water : Acetonitrile (50 : 50,v/v)
Flow Rate : 1 .OmL/minute; Detection : UV 210nm;Injection Volume : lOμL
01.3. Preparation of reference solution (a):
Transfer about lO.Omg each of Tetrabenzyl pyrophosphate standard and aprepitant standard accurately weighed, into a 10 mL volumetric flask. Add 5 mL of acetonitrile and sonicate to dissolve. Make up to the mark with water & mix.

01.4. Preparation of reference solution (b):
Transfer about 1OO.Omg of test sample accurately weighed, into a 100 mL volumetric flask. Add 0.5 mL of reference solution (a). Add about 50-60ml of diluent and sonicate to dissolve. Make up to the mark with diluent & mix, Note: Reference solution (b) should be prepared freshly for every analysis.
01.5. Preparation of Test Solution:
Transfer about 50.0 mg of sample, accurately weighed into a 50mL volumetric flask. Add about 25-30ml of diluent and sonicate to dissolve. Make up to the mark with diluent & mix. Note: Test solution should be prepared freshly for every analysis.
01.6. Procedure:
Separately inject the equal volumes of blank (diluent), reference solution (b) and then inject test solution in duplicate into the liquid chromatograph. Record the responses eliminating the peaks due to blank. Calculate the chromatographic purity by area normalization method. Confirm the retention time of aprepitant and Tetrabenzyl pyrophosphate from reference solution (b) chromatogram. The retention time of main peak i.e. fosaprepitant dibenzyl ester is about 45.4 minutes, retention time of aprepitant is about 31.1 minutes, retention time of Ethyl acetate is about 4.9 minutes and retention time of Tetrabenzyl pyrophosphate is about 36.1 minutes under these conditions.
01.7. System suitability test
Theoretical plates of the main peak from test solution should not be less than 5000.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
Example 1 Preparation of Fosaprepitant dibenzylester, compound of Formula HI
To the mixture of 20 gm of aprepitant (0.0375 moles) and 29 gm of tetrabenzyl pyrophosphate (0.054 moles) in 400 ml dry tetrahydrofuran under nitrogen atmosphere and cooling to about 5°C, 4.8 gm of sodium hydride (60% disperse in oil) (0.08 moles) was charged. The reaction mass was stirred for about 60 minutes at about 5°C to about 10°C. The reaction mass was cooled to about 0°C and 20 ml of ethyl acetate and 400ml of methylene dichloride were charged. The reaction mass was stirred for about 5 minutes. The organic layer was washed with 10% aqueous sodium bicarbonate solution followed by washing with sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 60 ml of ethyl acetate and 240 ml of cyclohexane was charged, to obtain a white solid. The mass was stirred for about 60 minutes, filtered & dried at about 30°C to give 25.4 gm product with purity of more than 97%; aprepitant content: 0.51%.
The conversion of lOOg of aprepitant compound of Formula II to fosaprepitant dibenzyl ester was carried out as described above and the results obtained are tabulated below:

Conversion of aprepitant to fosaprepitant dibenzyl
ester HPLC analysis
Sr.
N RXN
Solvent Base Workup solvent Input in Gm output inGm Purity of fosaprepitant dibenzyl ester Aprepitant content % Yield
1 THF NaH MDC 100 124 98.57 0.06 83.45

2 THF NaH MDC 100 128 98.88 0.07 86.14

3 THF NaH MDC 100 120 98.02 0.12 80.75
These results indicate that the process of the present invention provides fosaprepitant dibenzyl ester in high yield with purity greater than 95% as determined by High performance liquid chromatography with aprepitant content lower than 0.15% w/w of the fosaprepitant dibenzylester.

Example 2:Preparation of Fosaprepitant dibenzylester, compound of Formula III
To the mixture of 5 gm of aprepitant (0.0094 moles) & 7.25 gm of tetrabenzyl pyrophosphate (0.0135 moles) in 100 ml methylene chloride under nitrogen atmosphere and cooling to about 5°C, 1.2 gm of sodium hydride (60% disperse in oil) (0.02 moles) was charged. The reaction mass was stirred for about 60 minutes at about 5°C to about 10°C. The reaction mass was cooled to 0°C and 2.5 ml of ethyl acetate was charged. The reaction mass was stirred for about 5 minutes. The organic layer was washed with aqueous sodium bicarbonate solution followed by 100 ml of sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 15 ml of ethyl acetate and 60 ml of cyclohexane were charged to precipitate a white solid. The mass was stirred for about 60 minutes, filtered and dried at about 30°C to give fosaprepitant dibenzylester, compound of Formula III, with purity of more than 95%; aprepitant content 0.42%.
Example 3; Preparation of Fosaprepitant dibenzylester, compound of Formula III
To the mixture of 5 gm of aprepitant (0.0094 moles) and 7.25 gm of tetrabenzyl pyrophosphate (0.0135 moles) in 100 ml dry THF under nitrogen atmosphere which was cooled to about 5°C, 1.2 gm of sodium hydride (60% disperse in oil) (0.02 moles) was charged. The reaction mass was stirred for about 60 minutes at about 5°C to about 10°C. The reaction mass was cooled to about 0°C and 2.5 ml of ethyl acetate and 100ml of toluene was charged. The reaction mass was stirred for about 5 minutes. The reaction mass was stirred for about 5 minutes. The organic layer was washed with aqueous sodium bicarbonate solution followed by sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 15 ml of ethyl acetate and 60 ml of cyclohexane, was charged to precipitate a white solid. The mass was stirred for about 60 minutes, filtered and dried at about 30°C to give fosaprepitant dibenzyl ester, compound of Formula III, with purity of more than 95; aprepitant content: 1.5%.
Example 4: Preparation of Fosaprepitant dibenzyl ester, compound of Formula HI using NaHMDS and ether solvent in workup.
To the mixture of 40 gm of aprepitant and 62 gm of tetrabenzyl pyrophosphate in 1000 ml dry THF under nitrogen atmosphere which was cooled to about -10°C, 190 ml of 1 M sodium

HMDS solution in THF were added in about 2 to 3 hours. The reaction mass was stirred for about about 15 min at about -10°C to about 0°C. 1000ml of isopropyl ether was charged and reaction mixture was stirred for about 5 min. The organic layer was washed with 1000ml of 10% aqueous sodium bicarbonate solution. The layers were separated and washed with 1000 ml of 0.5 M aqueous potassium hydrogen sulphate solution. The layers were separated and washed with 1000 ml of 10% aqueous sodium bicarbonate solution. The layers were separated and organic layer was washed with 1000 ml of 20% sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 120 ml of ethyl acetate and 500 ml of cyclohexane was charged to obtain 35 g of compound.
The conversion of 40g of aprepitant compound of Formula II to fosaprepitant dibenzyl ester was carried out as described above and the results obtained are tabulated below

Conversion of aprepitant dibenzyl est to fosaprepitant er HPLC analysis Yield
Sr.
N RXN
Solvent Base Workup solvent Purity of fosaprepitant dibenzyl ester Aprepitant

1 THF NaHMDS IPE 80.1 15.66 62%
2 THF NaHMDS IPE 81.15 14.31 58,7%
Example 5 Preparation of Fosaprepitant dibenzvlester, compound of Formula III
The conversion of 5g of aprepitant, compound of Formula II to fosaprepitant dibenzyl ester, compound of Formula III was carried out by procedure as described in Example 4, where alkali metal HMDS was used and by Example 1, where alkali metal hydride was used and the results obtained are tabulated below:

Conversion of aprepitant to fosaprepitant dibenzyl ester
Sr.
N RXN
Solvent Base Workup solvent Input in Gm output in Gm % Yield
1 THF LiHMDS DIPE 5 3.6 48.45
2 THF NaH DIPE 5 2.5 33.65
3 THF NaHMDS MDC 5 1 13.46
4 THF LiHMDS MDC 5 2 26.92

5 DMF NaHMDS DIPE 5 2.5 33.65
6 DMF LiHMDS DIPE 5 2.5 33.65
7 DMF NaH DIPE 5 2 26.92
8 DMF NaHMDS MDC 5 0.5 6.73
9 DMF LiHMDS MDC 5 3 40.38
10 MDC NaHMDS MDC 5 2.9 39.03
11 MDC LiHMDS MDC 5 3.3 44.41
These results indicate that the yields of fosaprepitant dibenzyl ester, compound of Formula III obtained are very low and the process is not commercially feasible.
Example 6: Preparation of Fosaprepitant dimeglumine:
In a par bottle, 5.0 gm of fosaprepitant dibenzyl ester, compound of Formula III, 3.0 gm of N-methyl glucamine and 1.0 gm of Pd/C in 100 ml of methanol were taken and hydrogen pressure of about 5 kg, was applied. The reaction mass was filtered through hyflo bed and the filtrate was distilled and degassed under racuarrr at about 30°C. The degassed mass was dissolved in about 50ml of methanol and 0.3 ml of tributylphosphine (TBP) was added and stirred for about 24 hours and then then about 125 ml of isopropyl alcohol was added to give a white precipitate, which was filtered and dried under vacuum at about 25-30°C to give 5.75gm of crude fosaprepitant dimeglumine, which was, then purified using methanol and acetone to give 4.0 gm of the fosaprepitant dimeglumine, having purity of more than 99.5%.
Example 7: Preparation of Fosaprepitant dimeglumine with bacterial endotoxin limit less than 1.0 EU/mg.
In a laminar flow environment, 100ml RBF was charged with 2.0 gm of fosaprepitant dimeglumine and 20 ml of methanol. The mixture was stirred to get a clear solution, 0.200gm of activated carbon (Acticarbone CPW) was charged and stirred for 30 min. The mixture was filtered to remove the carbon. The filtrate was charged to 250ml RBF and 80 ml of acetone was charged to precipitate the product. The mixture was stirred for 15 min filtered & washed with 10 ml acetone. The product was dried at 25-30°C for 24 hr, dry wt. 1.5 gm; Bacterial endotoxin limit is less than 1.0 EU/mg.
Example 8: Preparation of crystalline Form II of Aprepitant, compound of formula II

To 20 gm of Aprepitant, compound of formula II 400ml of methanol, was added and heated to about 50°C to about 55°C and stirred to get a clear solution. The solution was filtered. 1440 ml of toluene was charged and heated to about 5°C 0 to about 55°C. About 800ml of solvent was distilled out under low vacuum at about 50°C to about 55°C. The solid precipitated out. The reaction mass was cooled to about 25°C to about 30°C, and stirred for about 30 minutes and filtered. The solid was dried at about 30 to about 35°C for about 12 hours to obtain pure crystalline Form II of Aprepitant, compound of formula II characterized by X-ray powder diffraction having peaks expressed as 2 9 values at about 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8±0.2

We claim
a) reacting aprepitant, a compound of Formula II,

1] A process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, content less than 2% w/w of the fosaprepitant dibenzylester, compound of Formula III, comprising:

with tetrabenzyl pyrophosphate in the presence of a hydride base to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from a hydrocarbon solvent or
halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.
2] The process as claimed in claim 1, wherein hydride base is Selected from sodium hydride,
potassium hydride, lithium hydride.

3] The process as claimed in claim 1, wherein the reaction in step a) is carried out in a solvent
selected from an ether solvent or halogenated hydrocarbon solvent. 4] The process as claimed in claim 1, wherein the hydrocarbon solvent in step b) is toluene. 5] The process as claimed in claim 1, wherein the halogenated hydrocarbon solvent in step b)
is methylene chloride. 6] The process as claimed in claim 1, wherein the fosaprepitant dibenzylester compound of
Formula III has purity of more than 95% as determined by high performance liquid
chromatography. 7] The process as claimed in claim 1, further comprising converting fosaprepitant dibenzylester,
compound of Formula III obtained by process as claimed in claim 1, to fosaprepitant
compound of Formula I or salt thereof.