FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
AN IMPROVED PROCESS FOR PRODUCING A SOLID FORM OF DIBENZYL FOSAPREPITANT
PIRAMAL ENTERPRISES LIMITED, a company incorporated under the Companies Act, 1956, of Piramal Tower, GanpatraoKadamMarg, Lower Parel, Mumbai - 400 013, State of Maharashtra, India

FIELD OF THE INVENTION
The present invention relates to a process for producing a key intermediate used
in the synthesis of [3-[[(2R,3S)-2-[(lR)-l-[3,5-
bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyI]methy{]-2,5-dihydro-5-oxo-lH-l,2,4-triazol-l-yl]-(9CI)phosphonic acid (fosaprepitant or the compound of formula II) and its pharmaceutically acceptable salt, particularly bis(N-methyl-D-gIucamine) salt. More particularly, the present invention provides an improved process for producing dibenzyl{3-[2=(R)-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-yl]-5-oxo-4,5-dihydro-[l,2,4]-triazol-l-yI]phosphonic acid (referred to herein as dibenzyl fosaprepitant or the compound of formula I) in its solid form, which is used as the key intermediate for the synthesis of the compound of formula II and its bis(N-methyl-D-glucamine) salt (fosaprepitant dimeglumine).
BACKGROUND OF THE INVENTION
Fosaprepitant, [3-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-lH-l,2,4-triazol-l-yl] (9CI)phosphonic acid is prodrug of Aprepitant (5-([(2R,35)-2-((R)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl)-lH-l,2,4-triazol-3(2H)-one) and represented by following formula II (alternatively referred as "the compound of formula II").


Fosaprepitant is an anti-emetic drug and administered intravenously. Fosaprepitant and its bis(N-methyl-D-glucamine) salt 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 the Europe.
Dibenzyl{3-[2(R)-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-yl]-5-oxo-4,5-dihydro-[l,2,4]-triazol-l-yl]phosphonic acid (hereinafter referred as "the compound of formula I") is the key intermediate used for the synthesis of the compound of formula II (fosaprepitant) and its bis(N-methyl-D-glucamine) salt.

There are several methods known in the art for the preparation of the compound of formula II (Fosaprepitant). One of the most preferred process is disclosed in US patent no. 5691336. This patent also describes the process for the preparation of the compound of formula I, the key intermediate for the compound of Formula II. US patent no. 5691336 describes a process for the synthesis of the compound of formula I and also discloses its further conversion to the compound of formula II and its bis(N-methyl-D-glucamine) salt. The process involves reaction of the compound, 2-(R)-(l-(R)-(3,5-

bis(trifluormethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(lH,4H-5-oxo-l,2,4-triazolo)methylmorpholine with tetrabenzylpyrophosphate in dry tetrahydrofuran at 0°C to obtain a reaction mixture. To the resulting reaction mixture, a solution of sodium bis(trimethylsilyl)-amide (NaHMDS) is added and the resulting reaction mixture is stirred at 0°C for 15 minutes. After completion of the reaction, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution. The quenched mixture is extracted with ethyl ether and the resulting ether extract is first washed with aqueous potassium bisulphate solution followed by saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution. The ether extract is further dried over magnesium sulphate and evaporated to dryness to obtain the compound of formula I in the form of an oily residue. To this oily residue, methanol is added to make a solution of the compound of formula I. To the solution of the compound of formula I, an aqueous solution of N-methyl-D-glucamine and 10% palladium on carbon catalyst are added and the resulting reaction mixture is hydrogenated at 40 psi for 2 hours. The reaction mixture is then filtered and the filtrate is concentrated under vacuum to obtain crude bis(N-methyl-D-glucamine) salt of the compound of the formula II. This crude product is recrystallised by using the mixture of methanol and iso-propanol to obtain pure bis(N-methyl-D-glucamine) salt of the compound of formula II. The process disclosed in said patent involves insitu conversion of the compound of formula I to the compound of formula II, wherein the compound of formula I is in an oily form. The compound of formula I in an oily form is unstable and highly impure. The percentage of total unknown impurities observed in the said oily form of the compound of formula I is 15-17%. When the compound of formula I in an oily form is used insitu for the process for preparation of the compound of formula II and its bis(N-methyl-D-glucamine) salt, the said unknown impurities invariably remains contaminated with the product, fosaprepitant dimeglumine and do not get removed by further purification, thereby giving the product (fosaprepitant dimeglumine) of lower

purity. In view of this, there would arise a need to develop a process for the purification of the compound of formula I. The use of isolated solid form of the compound of formula I would provide a way to achieve the final active pharmaceutical ingredient (API), fosaprepitant dimeglumine in pharmaceutically acceptable purity.
US patent application no. 2011130366 described the process for obtaining the compound of formula I in solid form. The process involves reaction of 5-([(2R,3S)-2-((R)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl (Aprepitant) with tetrabenzylpyrophosphate using tetrahydrofuran (THF) as a solvent. To the reaction mixture 1M solution of sodium bis-(trimethylsilyl)amide in THF is added at -20°C over a period of 3 hours. The resulting reaction mixture is stirred for 30 minutes. After completion of the reaction, the reaction mixture is quenched with saturated sodium bicarbonate solution. To the quenched reaction mixture isopropyl ether is charged and the reaction mixture is stirred for 15 minutes. Organic and aqueous layers are separated and the organic layer is washed with potassium hydrogen sulphate solution followed by saturated sodium bicarbonate solution and then purified water. The washed organic layer is dried over anhydrous sodium sulphate. The organic layer is then distilled completely under vacuum to obtain an oily residue. To the oily residue, organic solvent is charged and the suspension is stirred for 30 minutes to get a clear solution. To the resulting solution anti-solvent is charged to precipitate solid. The precipitated solid is filtered and washed with anti-solvent to obtain the compound of formula I in solid form. The process disclosed in said patent application is economically not viable because of relatively poor yield of 67% and purity of 93.74% of the solid form of the compound of formula I. Thus, the solid form of the compound of formula I obtained by the process disclosed in the said patent application contains unknown impurities. By using said process, the compound of formula I precipitates out rapidly by the addition of an anti-solvent to the solution of the compound of formula I and hence, the compound of formula I obtained by

using said process is of lower purity. Hence, there is a need to develop simple, commercially advantageous and industrially viable process for producing the compound of formula I in its solid form that would removes the unknown impurities. The availability of intermediates of the compound of formula II in the pure solid form and minimum level of unknown impurities would be added advantage in the preparation of the compound of formula II or its pharmaceutically acceptable salts, fosaprepitant dimeglumine useful in the preparation of pharmaceutical formulations.
The inventers of the present invention have now found that the compound of formula I in solid form and free of unknown impurities can be obtained in good yield and enhanced purity through an improved process of the present invention involving dissolving the compound of formula I in a solvent or a mixture of solvents to obtain a solution and crystallising out the compound of formula I in solid form by cooling the resulting solution.
OBJECTS OF THE INVENTION
An object of the present invention is to provide an improved process for producing the compound of formula I in solid form comprising dissolving the compound of formula I in an oily form in an organic solvent or a mixture thereof at a temperature of 35-50°C to obtain a solution and crystallising out the resulting compound of formula I in solid form by cooling the obtained solution at0-10°C.
Another object of the present invention is to provide an improved process for producing the compound of formula I in solid form with total unknown impurities less than 1.5%.
Yet another object of the present invention is to provide an improved process for producing the compound of formula I in solid form in a yield of 95% and purity of 98.5%.

SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention, there is to provided an improved process for producing the compound of formula I in solid form comprising the steps of,
a. dissolving the compound of formula I in an organic solvent or a
mixture thereof at a temperature ranging from 35-50°C to obtain
a solution, wherein the said compound of formula I is in an oily
form;
b. crystallising out the compound of formula I in solid form by
cooling the solution of the step (a) at 0-10°C.
Importantly, the process for producing the compound of formula I in solid form involving dissolving the compound of formula I in an oily form in an organic solvent or a mixture thereof at a temperature of 35-50°C to obtain a solution and crystallising out the corresponding compound of formula I in solid form by cooling the obtained solution at 0-10°C minimizes the percentage of total unknown impurities below 1.5%.
DETAIL DESCRIPTION OF THE INVENTION
In accordance with an aspect of the present invention, an improved process for producing the compound of formula I in solid form comprising the steps of,


a. dissolving the compound of formula I in an organic solvent or a
mixture thereof at a temperature of 35-50°C to obtain a solution,
wherein the said compound of formula I is in an oily form;
b. crystallising out the compound of formula I in solid form by
cooling the solution of the step (a) at 0-10°C.
In accordance with an embodiment of the present invention, the organic solvent used in the step (a) is selected from the group consisting of methyl tert-butyl ether (MTBE), cyclohexane, n-pentane, n-hexane, n-heptane or a mixture thereof.
In accordance with an embodiment of the present invention, the organic solvent or the mixture of organic solvents used in the step (a) is in an amount ranging from 3 to 6 volumes based on the compound of formula I in an oily form.
In accordance with an embodiment of the present invention, the solution as obtained in the step (a) is a clear solution.
In accordance with an embodiment of the present invention, the solution as obtained in the step (a) is a slightly turbid solution.
The turbidity of the solution is the cloudiness or haziness of a solution caused by individual particles (suspended solids) that are generally invisible to the naked eye.
In the context of the present invention, the turbid solution contains a suspended solid whereas the clear solutions do not contain suspended solids.
According to the present invention, the compound of formula I in its solid form crystallises out by cooling the solution of the step (a); however, optionally the compound of formula I may be crystallised out by seeding the solution of step (a) with seeds of crystals of the pure compound of formula I and further cooling it at 0-10°C to yield the compound of formula I in solid form.
The solid form of the compound of formula I obtained by using the process of the present invention is of pharmaceutically acceptable purity and with

unknown impurities less than 1.5%; however, optionally the compound of formula I obtained in solid form may be further purified to yield a purer solid form of the compound of formula I.
Starting material of the process, i.e. the compound of formula I in an oily form is a known compound and can be obtained as an intermediate during the synthesis of fosaprepitant (the compound of formula II) by following the methods described in the literature. For example, the process described in the US patent no. 5691336 can be used to obtain the compound of formula I in an oily form. The process involves the reaction of 2-(R)-(l-(R)-(3,5-bis(trifluormethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(lH,4H-5-oxo-l,2,4-triazolo)methylmorpholine with tetrabenzylpyrophosphate in dry tetrahydrofuran at 0°C to obtain the reaction mixture. To the resulting reaction mixture, a solution of sodium bis(trimethylsilyl)-amide (NaHMDS) was added and the reaction mixture was stirred at 0°C for 15 minutes. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution. The quenched reaction mixture was extracted with ethyl ether. The ether extract was then washed with aqueous potassium bisulphate solution followed by saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution and further dried over magnesium sulphate. The ether extract was further evaporated to dryness to obtain the compound of formula I in the form of an oily residue.
According to the present invention, the process for obtaining the compound of formula I in solid form from the corresponding oily form involves the charging the compound of formula I in an oily form in an organic solvent or mixtures thereof at a temperature of 35-50°C to obtain a solution. The obtained solution was optionally seeded with the crystals of the pure compound of formula I. The solution was further cooled to 0-10°C to crystallise out the solid. The resulting solid was filtered and washed with organic solvent. The solid was dried under vacuum at 25-35°C to produce the solid form of the compound of formula I. The obtained solid form of the compound of formula I was further crystallised

optionally using MTBE as a solvent to yield the purer solid form of the compound of formula I.
The inventors of the present invention have observed that the compound of formula I obtained in solid form by using process of the present invention, involving the charging of the compound of the formula I in an oily form in the solvent or a mixture thereof to obtain a solution and crystallising out the compound of formula I in solid form by cooling the resulting solution, is highly pure as the process involves slow crystallisation of the compound of the formula I.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in any way limiting the scope of the present invention.
Examples Example 1:
To the reaction flask, 5-([(2R,35)-2-((R)-1-[3,5-
bis(trifluoromethyl)phenyl]ethoxy)-3-(4-fluorophenyl)morpholino]methyl (50g) and tetrahydrofuran (250ml) were charged to obtain a solution. To the obtained solution tetrabenzylpyrophosphate (85.55g) in tetrahydrofuran (100ml) was charged to obtain the reaction mixture. To the obtained reaction mixture 35% solution of sodium bis(trimethylsilyl)-amide (NaHMDS) (142ml) in tetrahydrofuran was added at -10 to 3°C and the reaction mixture was stirred for 2-3 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (500ml). The quenched mixture was extracted with methyl tert-butyl ether. The ether extract was then washed with 0.5N potassium bisulphate solution (500ml) followed by saturated sodium bicarbonate solution (500ml) and then saturated sodium chloride solution (1000ml). The ether extract was further evaporated to dryness to obtain the compound of formula I in the form of an oily residue. To a reaction flask the compound of formula I (l00g) in an oily form and a mixture

of methyl tert-butyl ether (MTBE) and cyclohexane (500ml) were charged and the reaction mixture was heated at a temperature of 35-50°C to obtain a solution. To the obtained solution the pure compound of formula I (0.25g) was added at a temperature of 25-35°C and the resulting solution was then cooled to a temperature of 0-10°C to precipitate a solid. The precipitated solid was then filtered and washed with cyclohexane (50ml). The solid was then dried under vacuum at a temperature of 25-35°C to yield the compound of formula I in solid form. Yield 80%, purity>98%.
Example 2:
To the reaction flask, 5-([(2R,3S)-2-((R)-l-[3,5-
bis(trifluoromethyl)phenyl]ethoxy) -3 -(4-fluorophenyl)morp ho lino] methyl (lOOg) and tetrahydrofuran (500ml) were charged to obtain a solution. To the obtained solution tetrabenzylpyrophosphate (171.lg) in tetrahydrofuran (200ml) was charged to obtain the reaction mixture. To the obtained reaction mixture 35% solution of sodium bis(trimethylsilyl)-amide (NaHMDS) (284ml) in tetrahydrofuran was added at -10 to 3°C and the reaction mixture was stirred for 2-3 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (1000ml). The quenched mixture was extracted with methyl tert-butyl ether. The ether extract was then washed with 0.5N potassium bisulphate solution (1000ml) followed by saturated sodium bicarbonate solution (1000ml) and then saturated sodium chloride solution (2000ml). The ether extract was further evaporated to dryness to obtain the compound of formula I in the form of an oily residue. To a reaction flask the compound of formula I in an oily form (200g) and a mixture of methyl tert-butyl ether (MTBE) and cyclohexane (1000ml) were charged and the reaction mixture was heated at a temperature of 35-50°C to obtain a solution. The obtained solution was then cooled to a temperature of 0-10°C to precipitate a solid. The precipitated solid was then filtered and washed with cyclohexane (100ml). The solid was then dried under vacuum at a temperature

of 25-35°C to yield the compound of formula I in solid form. Yield 86.9%, purity 99.12%.
Comparative study involving process for the preparation of the compound of formula II from the compound of formula I reported in the prior art wherein the compound of formula I is in the oil form vis-a-vis the process of the present invention wherein the compound of formula I is in solid form Table: 1

Ex. % of total Purity of Purity of the
No. unknown the compound of formula
impurities compound II obtained from
observed of formula I corresponding compound of formula I
1 The compound of
formula I used in an oil form 15-17% 75-80% 95-97%
2 the compound of formula I obtained in solid form,
from corresponding oil form by using the process of US2011130366 3-4% 92-94% 94-95%
3 The compound of formula I obtained in
solid form, from the corresponding oily form by using the process of the present invention 0.6-1.5% 97-99% 99.0-99.8%
The results presented in the above Table-1 are discussed herein below:

As indicated in Ex. No. 1, when the compound of formula I in an oily form containing 15 to 17% of total unknown impurities was converted to the compound of formula II (fosaprepitant), gives the compound of formula II contaminated with said unknown impurities. Thus, the presence of unknown impurities with the product ultimately decreases the purity of the therapeutically effective product i.e. the compound of formula II.
As indicated in Ex. No. 2, when the compound of formula I in an oily form containing 15 to 17% of total unknown impurities was converted to the corresponding solid form by using the process of US patent application no. 2011130366 it was observed that the compound of formula I in solid form contains 3-4% of total unknown impurities. Thus, the compound of formula II (fosaprepitant) obtained from the corresponding the compound of formula I in solid form having less purity.
As indicated in Ex. No. 3, when the compound of formula I in an oily form containing 15 to 17% of total unknown impurities was converted to the corresponding solid form by using the process of the present invention, it was observed that the compound of formula I obtained in solid form containing total unknown impurities is less than 1.5%. As a result the purity of the compound of formula II (fosaprepitant) prepared from the solid form of the compound of formula I was also increased
Details for HPLC analysis Mobile phase:
Mobile phase A: 0.1% Orthophosphoric acid
Mobile phase B: Acetonitrile
Column: Zorbax RX C8, 250 X 4.6 mm, 5um
Wavelength: 215 run
Diluent: Buffer: ACN (50:50)
Flow: 1.5 mL/min
Sample preparation:

l000 ppm in diluent

Time Mobile phase A Mobile phase B
0.0 75.0 25.0
7.0 55.0 45.0
25.0 10.0 90.0
30.0 10.0 90.0
35.0 75.0 25.0
40.0 75.0 25.0
Retention Time:
DBP: 6.3 min
Tetrabenzylpyrophosphate (TBPP): 18.9 min Aprepitant: 13.9 min Fosaprepitant: 9.3 min Toluene: 12.8 min DBPFosaprepitant: 21.1 min MonobenzylFosaprepitant: 12.0 min

We claim,
1. A process for obtaining a compound of formula I in solid form,

comprising,
a. dissolving the compound of formula I in an organic solvent or a
mixture thereof at a temperature of 35-50°C to obtain a solution,
wherein the said compound of formula I is in an oily form;
b. crystallising out the compound of formula I in solid form by
cooling the solution of the step (a) at 0-10°C.
2. The process as claimed in claim 1, wherein the said organic solvent used in the step (a) is selected from the group consisting of methyl tert-butyl ether (MTBE), cyclohexane, n-pentane, n-hexane, n-heptane or a mixtures thereof.
3. The process as claimed in claim 1, wherein the said organic solvent or the mixture of the organic solvent used in the step (a) is in an amount ranging from 3 to 6 volumes based on the compound of formula I in an oily form.

4. The process as claimed in claim 1, wherein the solution as obtained in the step (a) is a clear solution.
5. The process as claimed in claim 1, wherein the solution as obtained in the step (a) is a turbid solution.
6. The process as claimed in claim 1, wherein the solution as obtained in the step (a) is further seeded with crystals of the pure compound of formula I.
7. The process as claimed in claim 1, wherein the solid form of the compound of formula I obtained in the step (b) is having purity of 97-99%.