Field of Invention:
The present invention relates to an improved process for the preparation of 1-Deoxy-l(methylamino)-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-l,2,4-triazol-l-yl]phosphonate (2:1), having the following structural formula-1.

l-Deoxy-l(methylamino)-D-glucitol[3-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoro methyl)phenyl]ethoxy]-3-(4-fluorophenyl)4-morpholinyl]methyl]-2,5-dihydro-5-oxo-lH-1,2,4-triazol-l-yl] phosphonate (2:1) is commonly known as Fosaprepitant dimeglumine. Fosaprepitant (Emend for Injection (US), Ivemend (EU)) is an antiemetic drug, administered intravenously. Fosaprepitant was developed by Merck & Co and was approved by the United States Food and Drug Administration (FDA) on January 25,2008 and by the European Medicines Agency (EMA) on January 11 of the same year. EMEND (Fosaprepitant dimeglumine) for Injection is a sterile, lyophilized prodrug of aprepitant, a substance P/neurokinin-1 (NK1) receptor antagonist.
Fosaprepitant in combination with other antiemetic agents intended for the treatment of chemotherapy-induced nausea and vomiting (CINV). Since aprepitant is the physiologically active moiety in fosaprepitant dimeglumine would not be classified as a new molecular entity, but as a type II molecule.
Background of Invention:
Fosaprepitant dimeglumine and its preparation was first disclosed in US 5691336. The disclosed process involves the condensation of tetrabenzylpyrophosphate with
aprepitant in presence of sodium hexamethyl disilazide in tetrahydrofuran provides
dibenzyl 3-(((2R,3S)-2-((R)-l-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluoro
phenyl)morpholino)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1 -ylphosphonate (herein after referred as fosaprepitant dibenzyl ester), which is in-situ treated with meglumine in the presence of Pd-C in aqueous methanol under hydrogen pressure provides fosaprepitant dimeglumine as a residue. The obtained residue was dissolved in methanol and precipitating the solid by adding isopropanol to it. The obtained solid was filtered, washed with isopropanol and methyl tertiary butyl ether and then air dried to provide pure fosaprepitant dimeglumine. The Fosaprepitant dimeglumine obtained from the said process was failing with respect to residual solvents/ organic volatile impurities (RS/OVI) of isopropanol. Hence there is a need for developing a new purification process which can reduce the isopropanol content in the fosaprepitant dimeglumine.
Moreover, the residual impurities formed in the reaction are remained in the solution containing fosaprepitant dibenzyl ester, hence further separation of said impurities is very difficult. Which in-turn results in fosaprepitant dimeglumine with low purity.
Hence there is a need in the art for developing an improved process which can easily separates the residual impurities and reduces the palladium and isopropanol contents in the final product of fosaprepitant dimeglumine.
j
Brief Description of the Invention: I
The first aspect of the present invention is to provide an improved process for the preparation of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dehydrating the dibenzyl phosphate compound of formula-2 in the presence of a suitable dehydrating agent in a suitable solvent to provide tetrabenzyl pyrophosphate compound of formula-3,
b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant compound of formula-4 in the presence of a base in a suitable solvent and quenching the reaction mixture with an aqueous base,
c) extracting the compound from the reaction mixture with a suitable solvent and distilling off the solvent from the reaction mixture to obtain fosaprepitant dibenzyl
ester compound of formula-5 as a residue,
d) slurring the obtained residue in a hydrocarbon solvent,
e) allowing the reaction mixture to settle down,
f) decanting the solvent from the reaction mixture under reduced pressure (by vacuum sucking),
g) adding a suitable solvent to the reaction mixture obtained in step-f) and distilling off the solvent from the reaction mixture to provide compound of formula-5 as a residue,
h) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen pressure, i) filtering the unwanted solid and washing with a suitable solvent, j) adding thiophenol resin to the filtrate and stirring the reaction mixture, k) filtering the resin, washing with a suitable solvent and then distilling off the solvent from the filtrate to provide fosaprepitant dimeglumine compound of formula-1 as a solid, 1) optionally, dissolving the obtained solid in a suitable solvent and pouring the obtained solution into a suitable anti-solvent, followed by slurring in a ketone solvent to provide pure fosaprepitant dimeglumine compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dehydrating the dibenzyl phosphate compound of formula-2 in the presence of a suitable dehydrating agent in a suitable solvent to provide tetrabenzyl pyrophosphate compound of formula-3,
b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant compound of formula-4 in the presence of a base in a suitable solvent and quenching the reaction mixture with an aqueous base,
c) extracting the compound from the reaction mixture with a suitable solvent and distilling off the solvent from the reaction mixture to obtain fosaprepitant dibenzyl ester compound of formula-5 as a residue,

d) adding sodium chloride to the obtained residue and stirring the reaction mixture,
e) adding a mixture of ether and hydrocarbon solvents to the reaction mixture and stirring the reaction mixture to provide co-crystals of compound of formula-5 and sodium chloride,
f) filtering the obtained co-crystals and washing with a mixture of ether and hydrocarbon solvents,
g) adding water and followed by an ether solvent to the co-crystals obtained in step-f) and separating the ether and aqueous layers,
h) distilling off the solvent from the ether layer to provide fosaprepitant dibenzyl ester
compound of formula-5 as a residue, i) treating the residue compound of formula-5 in-situ with meglumine compound of
formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen
pressure, j) filtering the unwanted solid and washing with a suitable solvent, k) adding thiophenol resin to the filtrate and stirring the reaction mixture, 1) filtering the resin, washing with a suitable solvent and then distilling off the solvent
from the filtrate to get fosparepitant dimeglumine compound of formula-1 as a
solid, m) optionally, dissolving the obtained solid in a suitable solvent and pouring the
obtained solution into a suitable anti-solvent, followed by slurring in a ketone
solvent to provide pure fosaprepitant dimeglumine compound of formula-1.
The third aspect of the present invention is to provide an improved process for the preparation of pure fosaprepitant dimeglumine compound of formula-1.
The fourth aspect of the present invention relates to a process for the preparation of pure fosaprepitant dimeglumine compound of formula-1, through co-crystallization process of fosaprepitant dibenzyl ester compound of formula-5.
The fifth aspect of the present invention is to provide a process for purification of fosaprepitant dimeglumine compound of formula-1 in a ketone solvent.
The sixth aspect of the present invention is to provide a process for purification of

fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dissolving the fosaprepitant dimeglumine compound of formula-1 in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) pouring the filtrate into a suitable anti-solvent to precipitate the solid,
e) filtering the solid and washing with a suitable solvent,
f) slurring the obtained solid in a ketone solvent,
g) heating the reaction mixture to reflux temperature,
h) stirring the reaction mixture,
i) filtering the solid and washing with a ketone solvent, j) drying the solid to get pure compound of formula-1.
The seventh aspect of the present invention is to provide a process for scavenging metal catalyst in the synthesis of fosaprepitant dimeglumine compound of formula-1.
Advantages of the Invention:
• Provides fosaprepitant dibenzyl ester compound of formula-5 as a residue, which is a useful intermediate used in the synthesis of pure fosaprepitant dimeglumine compound of formula-1 without isolating the compound of formula-5.
• Provides fosaprepitant dimeglumine compound of formula-1 with palladium content less than 1 ppm.
• Provides fosaprepitant dimeglumine, having a residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia.
Detailed Description of the Invention:
As used herein the present invention, the term "suitable solvents" wherever necessary, is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate; "ether solvents" like tetrahydrofuran, diethylether, methyl tertiary butyl ether, diisopropyl ether and methyl isopropyl ether; "hydrocarbon solvents" like n-hexane, n-

heptane, toluene and cyclohexane; "ketone solvents" like acetone, methyethyl ketone, methyl isobutyl ketone and the like; "alcohol solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, diglycol and isobutanol; and "polar solvents" like water; and also mixtures thereof.
The term "co-crystal" as used herein the present invention refers to a crystalline structure made up of two or more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule. Co-crystallization occurs in general by slow evaporation of a solution that contains stoichiometric amounts of the co-crystal components or by adding a molar excess of one co-crystal former, which decreases the solubility of other component or by crystallization in a slurry. Changing the solvent will also change the intermolecular interactions and possibly lead to co-crystal formation. Co-crystallization may also induced by simply melting two co-crystal components together and cooling, if a co-crystal is not formed from a melt, a seed from a melt may be used in a crystallization solution in order to afford a co-crystal.
The term "suitable dehydrating agent" as used here in the present invention is selected from carbodiimides such as dicyclohexyl carbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC); carbonyl diimidazole; alkyl chloro formate such as phenyl chloro formate, ethyl chloro formate and methyl chloro formate; alumina, sodium dioxide, phosphorus oxy chloride, sulfuric acid and phosphorous pentoxide.
The term "base" as used here in the present invention is selected from organic bases such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, piperidine, dimethyl amino pyridine, pyridine, sodium hexamethyl disilazide (NaHMDS), lithium hexamethyl disilazide (LiHMDS), n-butyl lithium and lithium diisopropyl amide (LDA); inorganic bases like inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate.
The object of the present invention is to provide an improved process for the

preparation of fosaprepitant dimeglumine compound of formula-1, which can easily separates the residual impurities and reduces the isopropanol and palladium contents in fosaprepitant dimeglumine compound of formula-1 to meet the ICH limits.
Accordingly, the first aspect of the present invention is to provide an improved process for the preparation of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dehydrating the dibenzyl phosphate compound of formula-2

with a suitable dehydrating agent in a suitable solvent to provide tetrabenzyl pyrophosphate compound of formula-3,

b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant
compound of formula-4,

in the presence of a base in a suitable solvent and quenching the reaction mixture with an aqueous base,
c) extracting the compound from the reaction mixture with a suitable solvent and
distilling off the solvent from the reaction mixture to obtain fosaprepitant dibenzyl

ester compound of formula-5 as a residue,

d) slurring the obtained residue in a hydrocarbon solvent,
e) allowing the reaction mixture to settle down,
f) decanting the solvent from the reaction mixture under reduced pressure (by vacuum sucking),
g) adding a suitable solvent to the reaction mixture obtained in step-f) and distilling off the solvent from the reaction mixture to provide compound of formula-5 as a residue,
h) treating the residue compound of formula-5 in-situ with meglumine compound of
formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen
pressure, i) filtering the unwanted solid and washing with a suitable solvent, j) adding thiophenol resin to the filtrate and stirring the reaction mixture, k) filtering the resin, washing with a suitable solvent and then distilling off the solvent
from the filtrate to get fosaprepitant dimeglumine compound of formula-1 as a
solid, 1) optionally, dissolving the solid in a suitable solvent and pouring the solution into a
suitable anti-solvent, followed by slurring in a ketone solvent to provide pure
fosaprepitant dimeglumine compound of formula-1.
wherein, the suitable solvent used in, step a) is selected from ester solvent such as methyl acetate, ethyl acetate, isopropyl
acetate and the like, step b) & step c) is selected from ether solvent such as tetrahydrofuran, methyl

tertiary butyl ether, diethyl ether, diisopropyl ether, methyl isopropyl ether
and the like, step d) is selected from hydrocarbon solvent such as n-hexane, n-heptane,
cyclohexane, toluene and the like, step h) is selected from alcohol solvents such as methanol, ethanol, isopropanol,
tertiary butanol and the like; polar solvents such as water and also mixtures
thereof, step g), step i) & step k) is selected from alcohol solvent such as methanol, ethanol,
isopropanol, tertiary butanol and the like, step 1) the suitable solvent is methanol; anti-solvent is isopropanol.
The metal catalyst used herein the present invention is selected from palladium hydroxide, palladium on carbon, platinum, platinum dioxide, Raney-nickel and Pearl man's catalyst.
In a preferred embodiment of the present invention is to provide an improved process for the preparation of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dehydrating the dibenzyl phosphate compound of formula-2 in the presence of DCC in ethyl acetate to provide tetrabenzyl pyrophosphate compound of formula-3,
b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant compound of formula-4 in the presence of NaHMDS in tetrahydrofuran and quenching the reaction mixture with an aqueous sodium bicarbonate,
c) extracting the compound from the reaction mixture with methyl tertiary butyl ether and distilling off the solvent from the reaction mixture to obtain fosaprepitant dibenzyl ester compound of formula-5 as a residue,
d) slurring the obtained residue in cyclohexane,
e) allowing the reaction mixture to settle down,
f) decanting the solvent from the reaction mixture under reduced pressure (by vacuum sucking),
g) adding methanol to the reaction mixture obtained in step-f) and distilling off the solvent from the reaction mixture to provide compound of formula-5 as a residue,

h) treating the residue compound of formula-5 in-situ with meglumine compound of
formula-6 in the presence of Pd-C in aqueous methanol under hydrogen pressure, i) filtering the unwanted solid and washing with methanol, j) adding thiophenol resin to the filtrate and stirring the reaction mixture, k) filtering the resin, washing with methanol and then distilling off the solvent from the
filtrate to provide fosaprepitant dimeglumine compound of formula-1 as a solid, 1) dissolving the solid in methanol and pouring the solution into isopropanol, followed by slurring in acetone to provide pure fosaprepitant dimeglumine compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dehydrating the dibenzyl phosphate compound of formula-2 in the presence of a suitable dehydrating agent in a suitable solvent to provide tetrabenzyl pyrophosphate compound of formula-3,
b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant compound of formula-4 in the presence of a base in a suitable solvent and quenching the reaction mixture with an aqueous base,
c) extracting the compound from the reaction mixture with a suitable solvent and distilling off the solvent from the reaction mixture to obtain fosaprepitant dibenzyl ester compound of formula-5 as a residue,
d) adding sodium chloride to the obtained residue and stirring the reaction mixture,
e) adding a mixture of ether and hydrocarbon solvents to the reaction mixture and stirring the reaction mixture to provide co-crystals of compound of formula-5 and sodium chloride,
f) filtering the obtained co-crystals and washing with a mixture of ether and hydrocarbon solvents,
g) adding water followed by an ether solvent to the co-crystals obtained in step-f) and separating the ether and aqueous layers,
h) distilling off the solvent from ether layer to provide fosaprepitant dibenzyl ester compound of formula-5 as a residue,

i) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen pressure, j) filtering the unwanted solid and washing with a suitable solvent, k) adding thiophenol resin to the filtrate and stirring the reaction mixture, 1) filtering the resin, washing with a suitable solvent and then distilling off the solvent from the filtrate to provide fosaprepitant dimeglumine compound of formula-1 as a solid, m) optionally, dissolving the solid in a suitable solvent and pouring the solution into a suitable anti-solvent, followed by slurrying in a ketone solvent to provide pure fosaprepitant dimeglumine compound of formula-1. wherein, the suitable solvent used in, step a) is selected from ester solvent such as methyl acetate, ethyl acetate, isopropyl
acetate and the like, step b) & step c) is selected from ether solvent such as tetrahydrofuran, methyl tertiary butyl ether, diethyl ether, diisopropyl ether, methyl isopropyl ether and the like, step i) is selected from alcohol solvents such as methanol, ethanol, isopropanol, tertiary butanol and the like; polar solvents such as water and also mixtures thereof, step j) & 1) is selected from alcohol solvents such as methanol, ethanol, isopropanol,
tertiary butanol and the like, step m) the suitable solvent is methanol; anti-solvent is isopropanol.
A mixture of ether and hydrocarbon solvents used herein the present invention is in a specific ratio of about 0.5:99.5.
The metal catalyst used herein the present invention is selected from palladium hydroxide, palladium on carbon, platinum, platinum dioxide, Raney-nickel and pearl man's catalyst.
In a preferred embodiment of the present invention is to provide an improved process for the preparation of fosaprepitant dimeglumine compound of formula-1,

comprising of:
a) Dehydrating the dibenzyl phosphate compound of formula-2 in the presence of DCC in ethyl acetate to provide tetrabenzyl pyrophosphate compound of formula-3,
b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant compound of formula-4 in the presence of NaHMDS in tetrahydrofuran and quenching the reaction mixture with aqueous sodium bicarbonate,
c) extracting the compound from the reaction mixture with methyl tertiary butyl ether and distilling off the solvent from the reaction mixture to obtain fosaprepitant dibenzyl ester compound of formula-5 as a residue,
d) adding sodium chloride to the obtained residue and stirring the reaction mixture,
e) adding a mixture of methyl tertiary butyl ether and cyclohexane into the reaction mixture and stirring the reaction mixture to provide co-crystals of compound of formula-5 and sodium chloride,
f) filtering the obtained co-crystals and washing with a mixture of methyl tertiary butyl ether and cyclohexane,
g) adding water followed by methyl tertiary butylether to the co-crystals obtained in step f) and separating ether and aqueous layers,
h) distilling off the solvent from ether layer to provide fosaprepitant dibenzyl ester
compound of formula-5 as a residue, i) treating the residue compound of formula-5 in-situ with meglumine compound of
formula-6 in the presence of Pd-C in aqueous methanol under hydrogen pressure, j) filtering the reaction mixture and washing with methanol, k) adding thiophenol resin to the filtrate and stirring the reaction mixture, 1) filtering the resin, washing with methanol and then distilling off the solvent from the
filtrate to provide fosaprepitant dimeglumine compound of formula-1 as a solid, m) dissolving the solid in methanol and pouring the solution into isopropanol, followed
by slurrying in acetone to provide pure fosaprepitant dimeglumine compound of
formula-1.
Fosaprepitant dimeglumine obtained by the processes described above having purity greater than 99.84 % by HPLC.

In the present invention, the aprepitant compound of formula-4 can be prepared according to the process disclosed in US5719147 and WO2009116081, which is incorporated herein as a reference. The said compound of formula-4 may be in the form of crystalline form-1 or form-2 or mixture thereof.
The third aspect of the present invention is to provide an improved process for the preparation of pure fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Slurring the fosaprepitant dibenzyl ester compound of formula-5 in a hydrocarbon solvent,
b) allowing the reaction mixture to settle down,
c) decanting the solvent from the reaction mixture under reduced pressure (by vacuum sucking),
d) adding a suitable solvent to the reaction mixture obtained in step-c) and then distilling off the solvent from the reaction mixture to provide fosaprepitant dibenzyl ester compound of formula-5 as a residue,
e) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen pressure to provide pure fosaprepitant dimeglumine compound of formula-1.
Wherein, the metal catalyst is selected from palladium hydroxide, palladium on carbon, platinum, platinum dioxide, Raney nickel and pearl man's catalyst.
The same process from step-a to step-d has been repeated twice to get fosaprepitant dibenzyl ester compound of formula-5, which is utilized in the synthesis of highly pure fosaprepitant dimeglumine compound of formula-1 without isolation.
When the present inventors carried out the process for the fosaprepitant dimeglumine in the laboratory as described in US 5691336, the residual impurities formed in the reaction were remaining intact with the compound of formula-1, which is found to be difficult to separate. Whereas, the present invention provides fosaprepitant dibenzyl ester compound of formula-5 as a residue and the residual impurities were eliminated easily along with hydrocarbon solvent, further the resulting fosaprepitant dibenzyl ester compound of formula-5 can be utilized without isolating in the synthesis of

pure fosaprepitant dimeglumine compound of formula-1.
Fosaprepitant dimeglumine compound of formula-1 obtained by the above process is characterized by HPLC purity of at least about 99.6%. Therefore, the present invention is more advantageous over the prior art.
In a preferred embodiment of the present invention is to provide an improved process for the preparation of pure fosaprepitant dimeglumine compound of formula-1, which comprising of:
a) Slurring the fosaprepitant dibenzyl ester compound of formula-5 in cyclohexane,
b) allowing the reaction mixture to settle down,
c) decanting the cyclohexane from the reaction mixture under reduced pressure (by vacuum sucking),
d) adding methanol to the reaction mixture obtained in step-c) and then distilling off the solvent from the reaction mixture to provide fosaprepitant dibenzyl ester compound of formula-5 as a residue,
e) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of Pd-C in a suitable solvent under hydrogen pressure to provide pure fosaprepitant dimeglumine compound of formula-1.
The fourth aspect of the present invention relates to a process for the preparation of pure fosaprepitant dimeglumine compound of formula-1, through co-crystallization process of fosaprepitant dibenzyl ester compound of formula-5, comprising of:
a) Adding sodium chloride to fosaprepitant dibenzyl ester compound of formula-5,
b) stirring the reaction mixture,
c) adding a mixture of ether and hydrocarbon solvents to the reaction mixture,
d) stirring the reaction mixture to provide co-crystals of fosaprepitant dibenzyl ester compound of formula-5 and sodium chloride,
e) filtering the obtained co-crystals and washing with a mixture of ether and hydrocarbon solvents,
f) adding water followed by an ether solvent to the co-crystals obtained in step-e) and separating the ether and aqueous layers,
g) distilling off the solvent from ether layer to provide fosaprepitant dibenzyl ester

compound of formula-5 as a residue, h) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen pressure to provide fosaprepitant dimeglumine compound of formula-1.
Wherein, the mixture of ether and hydrocarbon solvents used in a specific ratio of about 0.5:99.5 and the metal catalyst is selected from palladium hydroxide, palladium on carbon, platinum, platinum dioxide, Raney nickel and pearl man's catalyst.
When the present inventor carried out the process as described in US 5691336, the residual impurities formed in the reaction were remaining intact with the fosaprepitant dimeglumine compound of formula-1, which is found to be difficult to separate. Whereas, the present inventor surprisingly found that, during the process of co-crystallization, the fosaprepitant dibenzyl ester and sodium chloride co-crystals were precipitated out using sodium choride, and further the residual impurities were remained in the hydrocarbon solution. Hence the separation becomes easier and provides compound of formula-5 as a residue, which is utilized in the synthesis of pure fosaprepitant dimeglumine compound of formula-1 without isolation. Hence the present invention is more advantageous over the prior art.
Fosaprepitant dimeglumine obtained by the process of the present invention is characterized by HPLC purity of at least about 97.1%.
In a preferred embodiment of the present invention relates to a process for the preparation of pure fosaprepitant dimeglumine compound of formula-1, through co-crystallization process of fosaprepitant dibenzyl ester compound of formula-5, comprising of:
a) Adding sodium chloride to fosaprepitant dibenzyl ester compound of formula-5,
b) stirring the reaction mixture,
c) adding a mixture of methyl tertiary butyl ether and cyclohexane to the reaction mixture,
d) stirring the reaction mixture to provide co-crystals of fosaprepitant dibenzyl ester compound of formula-5 and sodium chloride,
e) filtering the obtained co-crystals and washing with a mixture of methyl tertiary butyl

ether and cyclohexane,
f) adding water followed by methyl tertiary butyl ether to the co-crystals obtained in step-e) and separating the ether and aqueous layers,
g) distilling off the solvent from ether layer to provide fosaprepitant dibenzyl ester compound of formula-5 as a residue,
h) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of Pd-C in aqueous methanol under hydrogen pressure to provide fosaprepitant dimeglumine compound of formula-1.
The process for the preparation of fosaprepitant dibenzyl ester compound of formula-5 is disclosed in step-c of the first and second aspects of the present invention, which is used in corresponding 3 and 4 aspects of the present invention as a starting material.
The fifth aspect of the present invention is to provide a process for the purification of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Adding a ketone solvent to fosaprepitant dimeglumine compound of formula-1,
b) heating the reaction mixture,
c) stirring the reaction mixture,
d) filtering the solid and washing with a ketone solvent,
e) drying the solid to get the pure compound of formula-1.
In the present invention the reaction mixture is heated at a range 35-50°C and a temperature lower or higher than the above mentioned range can be varied based on the requirements.
In a preferred embodiment of the present invention is to provide a process for the purification of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Adding acetone to fosaprepitant dimeglumine compound of formula-1,
b) heating the reaction mixture,
c) stirring the reaction mixture,
d) filtering the solid and washing with acetone,
e) drying the solid to get the pure compound of formula-1.

The sixth aspect of the present invention is to provide a process for purification of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dissolving the fosaprepitant dimeglumine compound of formula-1 in a suitable solvent,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with a suitable solvent,
d) pouring the filtrate into a suitable anti-solvent to precipitate the solid,
e) filtering the solid and washing with a suitable solvent,
f) slurring the obtained solid in a ketone solvent,
g) heating the reaction mixture,
h) stirring the reaction mixture,
i) filtering the solid and washing with a ketone solvent, j) drying the solid to get pure compound of formula-1.
Wherein, the suitable solvent in step a) is methanol; and the suitable anti-solvent in step d) is isopropanol.
Fosaprepitant dimeglumine obtained as per the prior art process, for example US 5691336 having RS/OVI of isopropanol beyond the ICH limits after filtration from isopropanol. This is due to high viscosity and incomplete elimination of isopropanol traces from the crystal even after filtration.
Whereas, the present inventors when slurring the compound obtained after filtration from a mixture of methanol and isopropanol, in acetone surprisingly obtained the fosaprepitant dimeglumine having a residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia.
The following are the details of RS/OVI mentioned in terms of ppm, which are observed before and after acetone purification.


In a preferred embodiment of the present invention is to provide a process for purification of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Dissolving the fosaprepitant dimeglumine compound of formula-1 in methanol,
b) treating it with charcoal,
c) filtering the reaction mixture and washing with methanol,
d) pouring the solution into isopropanol to precipitate the solid,
e) filtering the solid and washing with isopropanol,
f) slurring the obtained solid in acetone,
g) heating the reaction mixture, h) stirring the reaction mixture,
i) filtering the solid and washing with acetone,
j) drying the solid to get pure compound of formula-1.
The seventh aspect of the present invention is to provide a process for scavenging metal catalyst in the synthesis of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Treating the fosaprepitant dibenzyl ester compound of formula-5 with meglumine compound of formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen pressure,
b) filtering the unwanted solid and washing with a suitable solvent,
c) adding thiophenol resin to the filtrate and stirring the reaction mixture,
d) filtering the resin and washing with a suitable solvent,
e) distilling off the solvent from the filtrate to provide fosaprepitant dimeglumine compound of formula-1.
Wherein, the metal catalyst is selected from palladium hydroxide, palladium on carbon, Raney nickel, platinum, platinum dioxide and pearl man's catalyst.
The Fosaprepitant dimeglumine obtained from the present invention after treating with thiophenol resin provides Fosaprepitant dimeglumine, having palladium content less than 1 ppm. Hence the fosaprepitant dimeglumine obtained as per the present invention is more suggestible for the preparation of dosage forms.

In a preferred embodiment of the present invention is to provide a process for scavenging palladium catalyst in the synthesis of fosaprepitant dimeglumine compound of formula-1, comprising of:
a) Treating the fosaprepitant dibenzyl ester compound of formula-5 with meglumine compound of formula-6 in the presence of Pd-C in aqueous methanol under hydrogen pressure,
b) filtering the reaction mixture and washing with methanol,
c) adding thiophenol resin to the filtrate and stirring the reaction mixture,
d) filtering the resin and washing with a suitable solvent,
e) distilling off the solvent from the filtrate to provide fosaprepitant dimeglumine compound of formula-1.
In the present invention, the fosaprepitant dibenzyl ester compound of formula-5 prepared as disclosed in step-i) and step-j) of corresponding first and second aspects is taken as the starting material in the 7 aspect of the present invention.
Fosaprepitant dimeglumine obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
Related substances of the fosaprepitant dimeglumine was analyzed by HPLC using the following conditions: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: Symmetry C18, 150 x 4.6 mm, 3.5 μm; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Temperature: 30°C; Injection volume: 15 μL; Run time: 60 min; Diluent: chilled (Acetonitrile: water (1:1 v/v)); Elution: Gradient; Mobile phase-A: a degassed Buffer (100%) v/v; Mobile phase-B: Acetonitrile: water (90:10) v/v; Buffer: 2.72 grams of potassium dihydrogen phosphate and 1-octane sulfonic acid sodium salt anhydrous into 1000 ml of water, adjust pH to 3.0 with phosphoric acid. Filtered this solution through 0.22 μm Nylon membrane filter paper and sonicate to degas it.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention: Examples:
Example-1: Preparation of tetrabenzylpyrophosphate (Formula-3)
Ethyl acetate (400 ml) was added to dibenzylphosphate (4) (100 g) at 25-30°C and cooled to 0-5°C. N,N'-Dicyclohexylcarbidimide (118.65 g) was added lot wise to the above solution for about 30 min at 0-5 °C and stirred the reaction mixture for about 2 hours at 0-5°C. After completion of the reaction, filtered the reaction mixture, washed with ethylacetate and then distilled off the solvent from the filtrate under reduced pressure to get a residue. Cyclohexane (300 ml) was added slowly to the obtained residue for about 45 minutes at 25-30°C and stirred for an hour at 25-30°C. Filtered the solid, washed with cyclohexane and then dried to get the title compound. Yield: 90 grams Exainple-2: Preparation of Fosaprepitant dimeglumine (Formula-1)
A mixture of terabenzyl pyrophosphate (75 g), aprepitant (50 g) and tetrahydrofuran (500 ml) was cooled to -10 to 0°C. Sodium hexamethyldisilazide (116 ml) was added to the reaction mixture over a period of 45 minutes at -10 to 0°C and the reaction mixture was stirred for 1 hour at -10 to 0°C. After completion of the reaction, the reaction mixture was quenched with 10% sodium bicarbonate and extracted the compound from the reaction mixture with methyl tertiary butyl ether. Both the ether and aqueous layers were separated, washed the ether layer with 20% ammonium chloride solution and followed by washed with water. Both the ether and aqueous layers were separated and distilled off the solvent completely from the ether layer under reduced pressure and co-distilled with cyclohexane to get fosaprepitant dibenzyl ester as a residue. Slurrying the obtained residue in cyclohexane (1000 ml) and allowed to settle the reaction mixture for about 3 hours at 25-30°C. The cyclohexane was decanted under reduced pressure (by vacuum sucking) and the purification process was further repeated twice to get fosaprepotant dibenzyl ester compound of formula-5. Methanol was added to the obtained compound of formula-5 and stirred for 15 minutes at 25-30°C. Both the cyclohexane and methanol layers were separated and distilled off the solvent completely from the methanol layer to obtain fosaprepitant dibenzyl ester compound of formula-5 as

a residue. Dissolved the obtained residue in methanol (500 ml) and then transferred it to dry autoclave. Meglumine (36.5 g) followed by water (250 ml) and 5% Pd-C (10 g) were added to the reaction mixture at 25-30°C. 2.5-3 Kg/Cm2 of hydrogen gas was purged into the reaction mixture and stirred for 5 hours under hydrogen pressure of 2.5-3 Kg/Cm2 at 25-35°C. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed the bed with methanol. Thiophenol resin (5 g) was added to the filtrate at 25-30°C and stirred for 24 hours at 25-30°C. Filtered the resin through hyflow bed and washed the bed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol to get crude fosaprepitant dimeglumine. The crude compound was dissolved in methanol (125 ml) and the methanol solution was slowly added to isopropanol (500 ml) over a period of 30 minutes under nitrogen atmosphere at 25-30°C. The reaction mixture was stirred for 30 minutes at 25-30°C. Filtered the solid and washed with isopropanol to get the title compound as a wet solid. Example-3: Preparation of Fosaprepitant dimeglumine (Formula-1) A mixture of terabenzylpyrophosphate (75 g), aprepitant (50 g) and tetrahydrofuran (500 ml) was cooled to -10 to 0°C. Sodiumhexamethyldisilazide (116 ml) was added to the reaction mixture over a period of 45 minutes at -10 to 0°C and the reaction mixture was stirred for 1 hour at -10 to 0°C. After completion of the reaction, the reaction mixture was quenched with 10% sodiumbicarbonate and methyl tertiary butyl ether was added to the reaction mixture. Both the organic and aqueous layers were separated, washed the organic layer with 20% ammonium chloride solution and finally washed with water. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get fosaprepitant dibenzyl ester as a residue. Sodium chloride (250 g) was added to the reaction mixture and stirred for 10 minutes at 25-30°C. A mixture of tertiary butyl methyl ether and cyclohexane in a ratio of 0.5: 99.5 was added to the reaction mixture at 25-30°C and stirred for 1 hour at 25-30°C. Filtered the solid, washed with a mixture of methyltertiary butyl ether and cyclohexane in a ratio 0.5:99.5 to obtain sodium chloride co-crystals of fosaprepitant dibenzyl ester. Water was added to the sodium chloride co-crystals of fosaprepitant dibenzyl ester followed by methyl tertiary butyl ether at 25-30°C and stirred for 30 minutes at 25-30°C. Filtered the reaction mixture and organic and aqueous layers were separated from the

filtrate. Distilled off the solvent completely from the filtrate and co-distilled with methanol. Methanol (500 ml) was added to the reaction mixture and then transferred it to autoclave at 25-30°C. Meglumine (36.5 g) followed by 5% Pd-C (5 g) and water (18 ml) were added to the reaction mixture at 25-35°C. 2.5-3 Kg/Cm of hydrogen gas was purged into the reaction mixture and stirred for 5 hours under hydrogen pressure of 2.5-3 Kg/Cm at 25-35°C. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed the bed with methanol. Thiophenol resin (5 g) was added to the filtrate at 25-30°C and stirred for 24 hours at 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol to get crude fosaprepitant dimeglumine. The crude compound was dissolved in methanol (125 ml) and the methanol solution was slowly added to isopropanol (500 ml) over a period of 30 minutes under nitrogen atmosphere at 25-30°C. The reaction mixture was stirred for 30 minutes at 25-30°C. Filtered the solid and washed with isopropanol to get the title compound as a wet solid.
Example-4: Purification process for the preparation of pure Fosaprepitant Dimeglumine (Formula-l)
Dissolved the wet solid fosaprepitant dimeglumine compound of formula-l obtained in example-2 and/or example-3 in methanol (100 ml) under nitrogen atmosphere at 25-30°C. Carbon (5 g) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with methanol. Filtrate was slowly added to isopropanol (500 ml) over a period of 30 minutes under nitrogen atmosphere at 25-30°C. Filtered the solid and washed the solid with isopropanol. Acetone (500 ml) was added to the obtained solid and heated to 35-40°C. The reaction mixture was stirred for 45 minutes at 35-40°C. Filtered the solid under nitrogen atmosphere, washed with acetone and then dried to get pure title compound. Yield: 45 grams

We Claim:

1. A process for the preparation of fosaprepitant dimeglumine compound of formula-1,
comprising of:

a) Dehydrating the dibenzyl phosphate compound of formula-2 in the presence of DCC in ethyl acetate to provide tetrabenzyl pyrophosphate compound of formula-

b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant compound of formula-4 in the presence of NaHMDS in tetrahydrofuran and quenching the reaction mixture with an aqueous base,

c) extracting the compound from the reaction mixture with methyl tertiary butyl ether and distilling off the solvent to obtain fosaprepitant dibenzyl ester compound of formula-5 as a residue,

d) slurring the obtained residue in cyclohexane,

e) allowing the reaction mixture to settle down,

f) decanting the solvent from the reaction mixture by vacuum sucking,

g) adding methanol to the reaction mixture obtained in step-f) and then distilling off the solvent from the reaction mixture to provide fosaprepitant dibenzyl ester compound of formula-5 as a residue,

h) treating the residue compound of formula-5 in-situ with meglumine compound of
formula-6 in the presence of Pd-C in aqueous methanol under hydrogen pressure, i) filtering the unwanted solid and washing with methanol, j) adding thiophenol resin to the filtrate and stirring the reaction mixture, k) filtering the resin, washing with methanol and then distilling off the solvent from the filtrate to get fosaprepitant dimeglumine compound of formula-1 as a solid, 1) dissolving the solid in methanol and pouring the solution into isopropanol, followed by slurring in acetone to provide pure fosaprepitant dimeglumine compound of formula-1.

2. A process for the preparation of fosaprepitant dimeglumine compound of formula-1,
comprising of:

a) Dehydrating the dibenzyl phosphate compound of formula-2 in the presence of DCC in ethyl acetate to provide tetrabenzyl pyrophosphate compound of formula-3,

b) reacting the tetrabenzyl pyrophosphate compound of formula-3 with aprepitant compound of formula-4 in the presence of NaHMDS in tetrahydrofuran and quenching the reaction mixture with an aqueous base,

c) extracting the compound from the reaction mixture with methyl tertiary butyl ether and then distilling off the solvent from the reaction mixture to obtain fosaprepitant dibenzyl ester compound of formula-5 as a residue,

d) adding sodium chloride to the obtained residue and stirring the reaction mixture,

e) adding a mixture of methyl tertiary butyl ether and cyclohexane to the reaction mixture and stirring the reaction mixture to provide co-crystals of compound of formula-5 and sodium chloride,

f) filtering the obtained co-crystals and washing with a mixture of methyl tertiary butyl ether and cyclohexane,

g) adding water followed by methyl tertiary butyl ether to the crystals obtained in step f) and separating the ether and aqueous layers,

h) distilling off solvent from ether layer to provide fosaprepitant dibenzyl ester
compound of formula-5 as a residue,

i) treating the residue compound of formula-5 in-situ with meglumine compound of
formula-6 in the presence of Pd-C in aqueous methanol under hydrogen pressure,

j) filtering the unwanted solid and washing with methanol, k) adding thiophenol resin to the filtrate and stirring the reaction mixture,

1) filtering the resin, washing with methanol and then distilling off the solvent from
the filtrate to get fosaprepitant dimeglumine compound of formula-1 as a solid, m) dissolving the solid in methanol and pouring the solution into isopropanol,

followed by slurring in acetone to provide pure fosaprepitant dimeglumine compound of formula-1.

3. An improved process for the preparation of pure fosaprepitant dimeglumine compound of formula-1, comprising of:

a) Slurring the fosaprepitant dibenzyl ester compound of formula-5 in a hydrocarbon solvent,

b) allowing the reaction mixture to settle down,

c) decanting the solvent from the reaction mixture by vacuum sucking,

d) adding alcohol solvent to the reaction mixture obtained in step-c) and then distilling off the solvent from the reaction mixture to provide fosaprepitant dibenzyl ester compound of formula-5 as a residue,

e) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen pressure to provide fosaprepitant dimeglumine compound of formula-1.

4. A novel process for the preparation of sodium chloride co-crystals of fosaprepitant
dibenzyl ester compound of formula-5, comprising of:

a) Adding sodium chloride to fosaprepitant dibenzyl ester compound of formula-5,

b) stirring the reaction mixture,

c) adding a mixture of ether and hydrocarbon solvents to the reaction mixture,

d) stirring the reaction mixture to provide co-crystals of fosaprepitant dibenzyl ester compound of formula-5 and sodium chloride,

e) filtering the obtained co-crystals and washing with a mixture of ether and hydrocarbon solvents to provide sodium chloride co-crystals of compound of formula-5.

5. A process for the preparation of pure fosaprepitant dimeglumine compound of
formula-1 by using sodium chloride co-crystals of fosaprepitant dibenzyl ester, comprising of,

a) Dissolving the sodium chloride co-crystals of fosaprepitant dibenzyl ester in a mixture of water and ether,

b) separating the ether layer and aqueous layer,

c) distilling off the solvent from ether layer to provide fosaprepitant dibenzyl ester compound of formula-5 as a residue,

d) treating the residue compound of formula-5 in-situ with meglumine compound of formula-6 in the presence of a metal catalyst in a suitable solvent under hydrogen pressure to provide fosaprepitant dimeglumine compound of formula-1.

6. A process for the purification of fosaprepitant dimeglumine compound of formula-1,
comprising of:

a) Adding a ketone solvent to fosaprepitant dimeglumine compound of formula-1,

b) heating the reaction mixture,

c) stirring the reaction mixture,

d) filtering the solid and washing with a ketone solvent,

e) drying the solid to get the pure compound of formula-1.

7. A process for the purification of fosaprepitant dimeglumine compound of formula-1,
comprising of:

a) Adding acetone to fosaprepitant dimeglumine compound of formula-1,

b) heating the reaction mixture,

c) stirring the reaction mixture,

d) filtering the solid and washing with acetone,

e) drying the solid to get the pure compound of formula-1.

8. A process for the purification of fosaprepitant dimeglumine compound of formula-1,
comprising of:

a) Dissolving the fosaprepitant dimeglumine compound of formula-1 in methanol,

b) treating it with charcoal,

c) filtering the reaction mixture through hyflow bed and washing with methanol,

d) pouring the filtrate into isopropanol to precipitate the solid,

e) filtering the solid and washed with isopropanol,

f) slurring the obtained solid in a ketone solvent,

g) heating the reaction mixture,

h) stirring the reaction mixture,

i) filtering the solid and washing with a ketone solvent, j) drying the solid to get pure compound of formula-1.

9. A process for scavenging palladium in the synthesis of fosaprepitant dimeglumine
compound of formula-1, comprising of:

a) Treating the fosaprepitant dibenzyl ester compound of formula-5 with meglumine compound of formula-6 in the presence of Pd-C in aqueous methanol under hydrogen pressure to provide fosaprepitant dimeglumine compound of formula-1,

b) filtering the unwanted solid and washing with methanol,

c) adding thiophenol resin to the filtrate,

d) stirring the reaction mixture,

e) filtering the resin and washing with methanol,

f) distilling off the solvent from filtrate to provide fosaprepitant dimeglumine compound of formula-1.

10. A process according to claim-9, the content of palladium in the pure fosaprepitant dimeglumine is less than 1 ppm.