DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“IMPROVED PROCESS FOR PREPARATION OF FOSAPREPITANT OR SALT THEREOF”

Glenmark Pharmaceuticals 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 nature of the invention and the manner in which it is to be performed.

PRIORITY
This application claims the benefit to Indian Provisional Application No. 201721017210, filed on 17 May, 2017, the contents of which are incorporated by reference herein.

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.

BACKGROUND OF THE INVENTION
Fosaprepitant represented by compound of Formula I is a prodrug of aprepitant.

Formula I
Fosaprepitant dimeglumine is approved in United States by brand name EMEND®
EMEND® for injection is a substance P/neurokinin-1 (NK1) receptor antagonist, indicated in adults, in combination with other antiemetic agents, for the prevention of (1): acute and delayed nausea and vomiting associated with initial and repeat courses of high emetogenic cancer chemotherapy (HEC) including high-dose cisplatin; and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).
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).
United States Pat. No. 5,691,336 describes process for the preparation of fosaprepitant by reacting aprepitant, a compound of Formula III with tetrabenzyl pyrophosphate in presence of a sodium hexamethyldisilazane (NaHMDS) base to obtain fosaprepitant dibenzylester, a compound of Formula II.

Formula III Formula II
The fosaprepitant dibenzylester, compound of Formula II is then converted to fosaprepitant compound of Formula I by debenzylation.
There are evolving and more rigorous requirements demanded of drug manufacturers and with the prevailing disadvantages present with the prior art, there is a need for an improved process for the preparation of fosaprepitant or salt thereof and its intermediates, which circumvents the formation of process related impurities, while ensuring a target fosaprepitant product with high yield and high purity.
Surprisingly, it has been found that when aprepitant, a compound of Formula III was reacted with tetrabenzyl pyrophosphate in presence of catalytic amount of water in ether solvent, the reaction proceeded to completion fast and provided fosaprepitant dibenzylester, a compound of Formula II in a purity of more than 99% which leads to fosaprepitant or salt in a high purity and wherein level of impurity F is less than 0.25% as determined by HPLC.
Thus the process of the present invention is commercially feasible for large scale preparation of fosaprepitant dibenzylester, compound of Formula II and fosaprepitant, compound of Formula I or salt thereof.

SUMMARY OF THE INVENTION
The present invention relates to process for the preparation of fosaprepitant a compound of Formula I or salt thereof,

Formula I
comprising: a) reacting aprepitant, a compound of Formula III,

Formula III
with tetrabenzyl pyrophosphate in presence of catalytic amount of water in ether solvent, in the presence of a hydride base to obtain a reaction mass containing fosaprepitant dibenzylester, compound of Formula II;
b) optionally stirring the reaction mass;
c) isolating the fosaprepitant dibenzylester, compound of Formula II from the reaction mass; and

Formula II
d) debenzylating the fosaprepitant dibenzylester, compound of Formula II to fosaprepitant, compound of Formula I or salt thereof, wherein level of impurity F is less than 0.25% w/w of fosaprepitant as determined by HPLC.

Impurity F

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of fosaprepitant, compound of formula I or salt thereof.
In one embodiment, the present invention provides a process for the preparation of fosaprepitant, compound of formula I or salt thereof, comprising:

Formula I
a) reacting aprepitant, a compound of Formula III,

Formula III
with tetrabenzyl pyrophosphate in presence of catalytic amount of water in ether solvent, in the presence of a hydride base to obtain a reaction mass containing fosaprepitant dibenzylester, compound of Formula II;
b) optionally stirring the reaction mass;
c) isolating the fosaprepitant dibenzylester, compound of Formula II from the reaction mass; and

Formula II
d) debenzylating the fosaprepitant dibenzylester, compound of Formula II to fosaprepitant, compound of Formula I or salt thereof, wherein level of impurity F is less than 0.25% w/w of fosaprepitant as determined by HPLC.

Impurity F
In step a) catalytic amount of water means water used in less than 1% w/v of ether solvent.
In one embodiment, in step a) water is used in an amount of less than 0.5% w/v of ether solvent.
In one embodiment, in step a) less than 0.5% w/v means less than 0.001% to 0.0045% w/v of ether solvent.

In one embodiment, in step a) water is used in catalytic amount in the range of 0.1% to 0.4% w/v of ether solvent.
In one embodiment, in step a) water is used in catalytic amount in the range of 0.1% to 0.2% w/v of ether solvent.
It has been found that when aprepitant, a compound of Formula III was reacted with tetrabenzyl pyrophosphate in more than 1 % of water w/v of ether solvent then formation of impurity F increased.
In step a) ether may be selected from the group consisting of isopropyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether tetrahydrofuran, tetrahydropyran and the like.
In step a) the hydride base may be selected from the group consisting of sodium, hydride potassium hydride, lithium hydride and the like.
In one embodiment, reaction of step a) is carried out below about 20 0C.
In one embodiment, reaction of step a) is carried out for a period of about 5 minutes to about 30 minutes.
In one embodiment, the reaction of aprepitant a compound of formula III with tetrabenzyl pyrophosphate may be carried out in presence of catalytic amount of water in tetrahydrofuran.
In step b) stirring can be carried out for a period of about about 5 minutes to about 20 minutes.
In one embodiment, in step c) the fosaprepitant dibenzylester, compound of Formula II may be obtained as a solid by dissolving the degasses mass in ethyl acetate and precipitated by addition of cyclohexane.
In one embodiment, the fosaprepitant dibenzylester, compound of Formula II may be purified by ethyl acetate and cyclohexane.

In one embodiment, the present invention provides fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 1% w/w relative to the amount of compound of Formula as determined by HPLC.

Impurity F
In one embodiment, the present invention provides fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.5% w/w relative to the amount of compound of Formula II as determined by HPLC.
In one embodiment, the present invention provides fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.15% w/w relative to the amount of compound of Formula II as determined by HPLC.
In step d) debenzylation of fosaprepitant dibenzylester, compound of Formula II can be carried out by hydrogenating in the presence of palladium-carbon.

In one embodiment, debenzylation of fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.15% leads to fosaprepitant, compound of Formula I or salt thereof, wherein level of impurity F less than 0.15%.
In one embodiment, debenzylation of fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.15% leads to fosaprepitant, compound of Formula I or salt thereof, wherein level of impurity F is not detected or absent.

In one embodiment, fosaprepitant dimeglumine may be prepared by reacting foasprepitant, compound of Formula I with N-methyl-D-glucamine.
In one embodiment, the fosaprepitant dimeglumine may be prepared by hydrogenating the fosaprepitant dibenzylester, compound of Formula II in the presence of Pd/C and N-methyl-D-glucamine.
In one embodiment, the fosaprepitant dimeglumine obtained by the processes herein described may be purified by methanol and acetone.
In one embodiment, the present invention provides fosaprepitant dimeglumine obtained by the processes herein described, having purity at least about 99.8% as determined by High Performance Liquid Chromatography (HPLC).
In one embodiment, the present invention provides fosaprepitant dimeglumine, wherein level of impurity F is less than 1% w/w relative to the amount of fosaprepitant dimeglumin as determined by HPLC.
In one embodiment, the present invention provides fosaprepitant dimeglumine, wherein level of impurity F is less than 0.5% w/w relative to the amount of fosaprepitant dimeglumin as determined by HPLC.
In one embodiment, the present invention provides fosaprepitant dimeglumine, wherein level of impurity F is less than 0.15% w/w relative to the amount of fosaprepitant dimeglumin as determined by HPLC.
In one embodiment, the present invention provides fosaprepitant dimeglumine obtained by the processes herein described, having purity at least about 99.8% as determined by High Performance Liquid Chromatography (HPLC), wherein aprepitant, a compound of formula III less than 0.15% and impurity F less than 0.15% as determined by HPLC.
In one embodiment, the present invention provides fosaprepitant dimeglumine obtained by the processes herein described, having purity at least about 99.8% as determined by High Performance Liquid Chromatography (HPLC), wherein aprepitant, a compound of formula III and impurity F are not detected.
HPLC Methodology
Reagents and Solvents:
Water (Milli Q or equivalent); Acetonitrile (HPLC Grade); Methanol (HPLC Grade); Di-potassium hydrogen phosphate anhydrous (GR Grade; Merck);
O-Phosphoric acid (GR Grade)
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 Agilent Eclips XDB, 250 x 4.6mm, 5µ
Column temperature: 30°C
Mobile Phase: Mobile Phase A = Buffer: Acetonitrile (80:20, v/v)
Buffer: 0.01M of Di-potassium hydrogen phosphate anhydrous in water. Adjust pH to 3.5 with diluted o-phosphoric acid (10% in water).
Mobile Phase B = Acetonitrile: Methanol (80: 20, v/v)
Time (min.) % Mobile Phase A % Mobile Phase B
0.0 90 10
45 55 45
60 25 75
70 25 75
74 90 10
80 90 10

Diluent: Acetonitrile: Water (70: 30, v/v)
Flow Rate: 1.0 mL/min
Detection: UV 220nm
Injection Volume: 10µL
The retention time of fosaprepitant dimeglumine is about 28.0 minutes under these conditions.
Relative retention time for compound III is about 1.82 and impurity F is about 1.65 with respect to fosaprepitant dimeglumine.

In one embodiment, the present invention provides fosaprepitant dimeglumine, obtained by the processes herein described, having a D90 particle size of less than about 50 microns, D50 particle size of less than about 20 microns and D10 particle size of less than about 10 microns.
In one embodiment, the present invention provides fosaprepitant dimeglumine, obtained by the processes herein described, having a D90 particle size of less than about 35 microns, D50 particle size of less than about 15 microns and D10 particle size of less than about 5 microns.
In one embodiment, the present invention provides a process for the preparation of fosaprepitant, compound of formula I or salt thereof, comprising:

Formula I
a) reacting aprepitant, a compound of Formula III,

Formula III
with tetrabenzyl pyrophosphate in water and water miscible organic solvent, in the presence of a hydride base to obtain a reaction mass containing fosaprepitant dibenzylester, compound of Formula II;
b) stirring the reaction mass;
c) isolating the fosaprepitant dibenzylester, compound of Formula II from the reaction mass; and
d) debenzylating the fosaprepitant dibenzylester, compound of Formula II to fosaprepitant, compound of Formula I or salt thereof.
Water miscible organic solvent in step a) may be selected from ether, hydrocarbon, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like or mixture thereof.
Ether solvent may be selected from the group consisting of isopropyl ether, diisopropyl ether, diethyl ether, dimethoxyethane (DME), methyl tert-butyl ether, tetrahydropyran, tetrahfydrofuran and the like.
Halogenated hydrocarbon may be selected from the group consisting of methylene chloride, chloroform, dichloromethane and the like.
Hydride base used in step a) as described supra.
The examples that follow 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 II
37.50 gm of sodium hydride (60% disperse in oil) was added in 4-5 equal lots to a solution of 150gm of aprepitant and 218gm of tetrabenzyl pyrophosphate in mixture of 3000ml tetrahydrofuran and 3ml water (0.10% w/v) under nitrogen atmosphere at about 8°C-15°C. The reaction mass was stirred for about 5-15 minutes, then ethyl acetate and methylene dichloride was added to reaction mass at about 0°C to 5°C. The reaction mass was stirred for about 5 minutes and organic layer was washed with 10% aqueous sodium bicarbonate solution followed by aqueous sodium chloride solution. The organic layer was dried over sodium sulphate, distilled out solvent and degassed. Cyclohexane was added in solution of degassed mass in ethyl acetate at 25 to 30°C to obtain a white solid. The slurry mass was stirred, filtered and dried at about 30°C. Crude product obtained further purified by ethyl acetate and cyclohexane to yield pure titled compound. Dry wt: 190gm. Purity: 99.80%; Aprepitant (Formula III): Not detected; Impurity F: Not detected.
Example 2: Preparation of Fosaprepitant dibenzylester, compound II
6.25gm of sodium hydride (60% disperse in oil) was added in 4-5 equal lots to a solution of 25gm of aprepitant and 36.50gm of tetrabenzyl pyrophosphate in mixture of 500ml tetrahydrofuran and 1ml water (0.20% w/v) under nitrogen atmosphere at about 8°C-15°C. The reaction mass was stirred for about 5-15 minutes, then ethyl acetate and methylene dichloride was added to reaction mass at about 0°C to 5°C. The reaction mass was stirred for about 5 minutes and organic layer was washed with 10% aqueous sodium bicarbonate solution followed by aqueous sodium chloride solution. The organic layer was dried over sodium sulphate, distilled out solvent and degassed. Cyclohexane was added in solution of degassed mass in ethyl acetate at 25 to 30°C to obtain a white solid. The slurry mass was stirred, filtered and dried to yield titled compound. Crude product obtained further purified by ethyl acetate and cyclohexane to yield pure titled compound. Dry wt: 34gm. Purity: 99.30%; Aprepitant (Formula III): 0.09%; Impurity F: 0.09%
Example 3: Preparation of Fosaprepitant dibenzylester, compound II
2.50gm of sodium hydride (60% disperse in oil) was added in 4-5 equal lots to a solution of 10gm of aprepitant and 14.60gm of tetrabenzyl pyrophosphate in mixture of 200ml tetrahydrofuran and 0.8ml water (0.40% w/v) under nitrogen atmosphere at about 8°C-15°C. The reaction mass was stirred for about 5-15 minutes, then ethyl acetate and methylene dichloride was added to reaction mass at about 0°C to 5°C. The reaction mass was stirred for about 5 minutes and organic layer was washed with 10% aqueous sodium bicarbonate solution followed by aqueous sodium chloride solution. The organic layer was dried over sodium sulphate, distilled out solvent and degassed. Cyclohexane was added in solution of degassed mass in ethyl acetate at 25 to 30°C to obtain a white solid. The slurry mass was stirred, filtered and dried to yield titled compound. Crude product obtained further purified by ethyl acetate and cyclohexane to yield pure titled compound. Dry wt: 10.80gm. Purity: 99.08%; Aprepitant (Formula III): 0.15%; Impurity F: 0.18%
Example 4: Preparation of Fosaprepitant dibenzylester, compound II
3.75gm of sodium hydride (60% disperse in oil) was added in 4-5 equal lots to a solution of 15gm of aprepitant and 21.8gm of tetrabenzyl pyrophosphate in mixture of 300ml tetrahydrofuran and 3ml water (1.0% w/v) under nitrogen atmosphere at about 8°C to about 15°C. The reaction mass was stirred for about 5 to about 15 minutes at about 8°C to about 15°C then ethyl acetate and ethylene dichloride was added to reaction mass at about 0°C to 5°C. The reaction mass was stirred for about 5 minutes and organic layer was washed with 10% aqueous sodium bicarbonate solution followed by aqueous sodium chloride solution. The organic layer was dried over sodium sulphate, distilled out solvent and degassed. Cyclohexane was added in solution of degassed mass in ethyl acetate at 25 to 30°C to obtain a white solid. The slurry mass was stirred, filtered and dried to yield titled compound. Crude product further purified by ethyl acetate and cyclohexane to yield pure titled compound. Dry wt: 8gm. Purity: 94.85%; Aprepitant (Formula III): 0.36%; Impurity F: 0.37%
Example 5: Preparation of Fosaprepitant dimeglumine
A mixture of 150gm of fosaprepitant dibenzyl ester, compound of formula III (prepared by example 1) 90gm of N-methyl glucamine and 30gm of palladium on carbon catalyst in 3000ml of methanol stirred under hydrogen atmosphere (hydrogen pressure about 5.0 to 7.0 kg/cm2) for about 2 hours at 25-30°C. The progress of reaction monitored by HPLC. The reaction mass was filtered through hyflo bed and the filtrate was distilled and degassed under vacuum at about 30°C. The degassed mass was dissolved in about 1350ml of methanol and 0.3ml of tributylphosphine (TBP) was added into reaction mass and stirred for about 24 hours. 4500ml isopropyl alcohol was added into reaction mass after charcolisation to give a white precipitate under nitrogen atmosphere. The slurry mass stirred, filtered and dried under vacuum at about 25-30°C to yield 160gm crude fosaprepitant dimeglumine, which was then purified using methanol and acetone to yield pure titled compound.
Purity: 99.90%; Aprepitant (Formula III): 0.06%; Impurity F: Not detected
Comparative Example: Preparation of Fosaprepitant dibenzylester, compound of formula II
10gm of sodium hydride (60% disperse in oil) was added to mixture of 40gm of aprepitant and 58.43gm of tetrabenzyl pyrophosphate in 800ml dry tetrahydrofuran under nitrogen atmosphere at about 5°C. The reaction mass was stirred for about 2 hours at about 12°C. The reaction mass was cooled to about 0°C and 20ml of ethyl acetate and 800ml 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 sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. 640ml of cyclohexane was added in solution of degassed mass in 120ml ethyl acetate to obtain a white solid. The slurry mass was stirred for about 60 minutes, filtered and dried at about 30°C to yield crude product which was further purified by ethyl acetate and cyclohexane to yield pure product.
Purity of product: 98.47%; Aprepitant (Formula III): 0.07%; Impurity F: 1.08%
,CLAIMS:1. A process for the preparation of fosaprepitant a compound of Formula I or salt thereof,

Formula I
comprising: a) reacting aprepitant, a compound of Formula III,

Formula III
with tetrabenzyl pyrophosphate in presence of catalytic amount of water in ether solvent, in the presence of a hydride base to obtain a reaction mass containing fosaprepitant dibenzylester, compound of Formula II;
b) optionally stirring the reaction mass;
c) isolating the fosaprepitant dibenzylester, compound of Formula II from the reaction mass; and

Formula II
d) debenzylating the fosaprepitant dibenzylester, compound of Formula II to fosaprepitant, compound of Formula I or salt thereof, wherein level of impurity F is less than 0.25% w/w of fosaprepitant as determined by HPLC

Impurity F.
2. The process as claimed in 1, wherein the amount of water used is less than 0.5% w/v of ether solvent.
3. The process as claimed in 1, wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, diisopropyl ether and methyl tert-butyl ether.
4. The process as claimed in 1, wherein the hydride base is selected from the group consisting of sodium hydride, potassium hydride and lithium hydride.
5. The process as claimed in 1, wherein fosaprepitant compound of Formula I or salt thereof, wherein level of impurity F is less than 0.15% w/w of fosaprepitant as determined by HPLC.

Dated this 14th day of May, 2018

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED