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WO2013168176A2 - Process for preparation of fosaprepitant and salt thereof - Google Patents

Process for preparation of fosaprepitant and salt thereof Download PDF

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Publication number
WO2013168176A2
WO2013168176A2 PCT/IN2013/000182 IN2013000182W WO2013168176A2 WO 2013168176 A2 WO2013168176 A2 WO 2013168176A2 IN 2013000182 W IN2013000182 W IN 2013000182W WO 2013168176 A2 WO2013168176 A2 WO 2013168176A2
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Prior art keywords
fosaprepitant
compound
formula
dibenzylester
formula iii
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PCT/IN2013/000182
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French (fr)
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WO2013168176A3 (en
Inventor
Shekhar Bhaskar Bhirud
Bhargav Krishnaji Upadhye
Navin Ganesh BHATT
Mahendra Joma CHORAGHE
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Glenmark Generics Limited
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Publication of WO2013168176A2 publication Critical patent/WO2013168176A2/en
Publication of WO2013168176A3 publication Critical patent/WO2013168176A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to an improved process for the preparation of fosaprepitant and salt thereof. More specifically the present invention relates to an improved process for preparing fosaprepitant dibenzylester from aprepitant.
  • Fosaprepitant represented by compound of Formula I is a prodrug of aprepitant.
  • the meglumine salt of fosaprepitant, Fosaprepitant dimeglumine is approved for the treatment 20 of emesis, nausea, cancer therapy toxicity and is available in the market as EMEND ® in the US and as IVEMEND ® in Europe, with the dosage strength 115 mg equivalent base.
  • Fosaprepitant dimeglumine is chemically known as 1-deoxy-l -(methyl amino)-D-glucitol[3- [[(2R,3S)-2-[(lR)-l-[3,5-bis(triIluoromethyl)phenyl]-ethoxy]-3-(4-fluorophenyl)4-mo holinyl] methyl]-2,5-dihydro-5-oxo- 1 H- 1 ,2,4-triazoI- 1 -yl]phosphonate (2: 1) (salt).
  • United States Pat. No. 5,691,336 (U.S. Pat/336) describes morpholine compounds including fosaprepitant and its pharmaceutically acceptable salts thereof.
  • U.S.Pat.'336 exemplifies the process for the preparation of fosaprepitant by reacting aprepitant compound of Formula II with tetrabenzyl pyrophosphate in presence of a sodium hexamethyldisilazane (NaHMDS) base in
  • the present invention provides the formation of fosaprepitant dibenzylester, compound of Formula III, from aprepitant, compound of Formula II and tetrabenzyl pyrophosphate in high yields, high purity, with lower content of aprepitant, consistently on an industrial scale, where the selection of the base and the reaction solvent and the work up solvent are critical.
  • the present invention provides a process for obtaining the fosaprepitant dibenzylester, compound of Formula III, as a white solid in purity greater than 95%, in yields greater than 80% and wherein the starting material aprepitant, compound of Formula II is present to an extent of less than 2%.
  • the process of the present invention is reproducible on an industrial
  • the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, content less than 2% w/w of fosaprepitant dibenzylester, the compound of Formula III, comprising:
  • the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
  • the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
  • the hydride base may be selected from the group consisting of sodium hydride, potassium 10 hydride, lithium hydride and the like.
  • reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may be carried out in a solvent selected from ether or halogenated hydrocarbon.
  • Ethers may be acyclic and cyclic ethers selected from the group the group consisting of isopropyl ether, diethyl ether, tetrahydrofuran, tetrahydropyran and the like.
  • Halogenated hydrocarbons may be selected from the group consisting of methylene chloride, 20 chloroform, dichloroethane and the like.
  • the reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may be carried out at lower temperature, preferably in the temperature range of about 5°C-20°C.
  • reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may 5 be carried out for a period of about 30 minutes to about 2 hours.
  • reaction of aprepitant with tetrabenzyl pyrophosphate may be carried out in presence of sodium hydride base in presence of ether solvent, preferably the ether 10 solvent is tetrahydrofuran.
  • reaction mass obtained from a) is extracted with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof.
  • the hydrocarbon solvent may be an aliphatic hydrocarbon selected from the group consisting of hexane, heptane and the like or aromatic hydrocarbon like toluene, benzene, xylene and the like.
  • Halogenated hydrocarbons may be selected from the group consisting of methylene chloride, chloroform, dichloroethane and the like.
  • reaction mass obtained from a) is extracted with halogenated 25 hydrocarbon preferably methylene chloride.
  • Formula III is obtained as a solid.
  • reaction mass obtained after b) is distilled off and degassed.
  • the compound of formula III may then be obtained as a solid by dissolving the degassed mass in a solvent or mixture thereof and precipitating by addition of an antisolvent.
  • the solvent(s) that can be used for dissolution may be selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixtures thereof, preferably ethyl acetate.
  • the anti-solvent(s) that can be used to precipitate the solid is selected from hydrocarbon 10 solvents like n-pentane, n-hexane, n-heptane, cyclohexane or mixtures thereof, preferably cyclohexane.
  • the fosaprepitant dibenzylester, compound of Formula III may be obtained as a solid by dissolving the degassed mass in ethyl acetate and precipitating by 15 addition of cyclohexane.
  • the present invention provides a process for the preparation of fosaprepitant diberizylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III,
  • the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
  • reaction mass a) reacting aprepitant, compound of Formula II with tetrabenzyl pyrophosphate in presence of a hydride base in an ether solvent to obtain a reaction mass;
  • the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
  • the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III having aprepitant, compound of 5 Formula II content less than 1% w/w of fosaprepitant dibenzylester, compound of Formula
  • the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III having content of aprepitant, a
  • Formula III as determined by HPLC preferably having aprepitant, compound of Formula II content less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III as determined by HPLC.
  • the present invention provides solid fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II content less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III and in purity greater than 95% as determined by HPLC.
  • the process of the present invention is reproducible and consistently provides fosaprepitant dibenzylester, compound of Formula III as a white solid in purity greater than 95% as determined by HPLC, in yields greater than 80% and wherein the starting material aprepitant, compound of Formula II is present to an extent of less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III as determined by HPLC.
  • the fosaprepitant dibenzylester, compound of Formula III, obtained by the process of the present invention may be converted to the neutral form of fosaprepitant, or may optionally be converted into a pharmaceutically acceptable salt of fosaprepitant by any method known to
  • a preferred pharmaceutically acceptable salt is the fosaprepitant dimeglumine.
  • the dimeglumine salt may be prepared by a method including, but not limited to, reacting the neutral form of fosaprepitant with N-methyl-D-glucamine. Typically, the fosaprepitant is dissolved in an organic solvent and combined with a solution of acid or base used to obtain the desired salt of fosaprepitant.
  • the dimeglumine salt may be prepared by hydrogenating the fosaprepitant dibenzylester, compound of Formula III in the presence of palladium-carbon and N-methyl -D- glucamine.
  • the present invention provides a fosaprepitant dimeglumine wherein the 10 bacterial endotoxin limit is less than 1.0 EU/mg as determined by Limulus Amebocyte
  • Lysate (LAL) according to USP 35.
  • the present invention provides a process for preparation of fosaprepitant dimeglumine wherein the bacterial endotoxin limit is less than 1.0 EU/mg as determined by 15 Limulus Amebocyte Lysate (LAL) according to USP 35 comprising
  • the solvent for dissolving the fosaprepitant dimeglumine may be selected from methanol and dimethylformamide.
  • the antisolvent may be selected from isopropanol, acetone and methyl ethyl ketone.
  • the present invention provides a process for preparation of fosaprepitant dimeglumine wherein the bacterial endotoxin limit is less than 1.0 EU/mg as determined by
  • LAL Limulus Amebocyte Lysate
  • the solvent for dissolving the fosaprepitant dimeglumine may be selected from methanol and dimethylformamide .
  • the antisolvent may be selected from isopropanol, acetone and methyl ethyl ketone.
  • the antisolvent is passed through a sterile filter having pore size of 0.22 ⁇ or less.
  • the fosaprepitant dimeglumine thus obtained is dried in vacuum to obtain aseptic crystalline 10 fosaprepitant dimeglumine.
  • the aseptic fosaprepitant dimeglumine obtained by the process of the present invention may be used for formulating an injectable of fosaprepitant dimeglumine.
  • the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II characterized by X-ray powder diffraction having peaks expressed as 2 ⁇ values at about 12.6, 16.7, 17.1 , 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8 ⁇ 0.2
  • the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II comprising
  • the alkanol may be selected from methanol, ethanol and the like.
  • the hydrocarbon solvent may be aliphatic selected from the group consisting of hexane, heptane and the like or aromatic hydrocarbon like toluene, benzene, xylene and the like.
  • the amount of hydrocarbon solvent used is 3 to 5 times the amount of alkanolic solvent used.
  • the distillation is carried out to the extent that alkanol is almost removed from the solvent; while allowing crystalline Form II of aprepitant, compound of formula II, to precipitate out from the hydrocarbon.
  • the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II, comprising:
  • Apparatus A High Performance Liquid Chromatograph equipped with quaternary gradient 20 pumps, variable wavelength UV detector attached with data recorder and integrator software.
  • Mobile Phase A Buffer;Buffer : 2.42gm of Disodium hydrogen phosphate anhydrous in 1000ml of water. Adjust pH to 6.5 with o-Phosphoric acid
  • Test solution should be prepared freshly for every analysis.
  • Theoretical plates of the main peak from test solution should not be less than 5000.
  • Example 4 Preparation of Fosaprepitant dibenzylester, compound of Formula III using NaHMDS and ether solvent in workup.
  • aprepitant aprepitant and 62 gm of tetrabenzyl pyrophosphate in 1000 ml dry THF under nitrogen atmosphere which was cooled to about -10°C
  • 190 ml of 1 M sodium HMDS solution in THF were added in about 2 to 3 hours.
  • the reaction mass was stirred for about about 15 min at about -10°C to about 0°C.
  • 1000ml of isopropyl ether was charged and reaction mixture was stirred for about 5 min.
  • the organic layer was washed with 1000ml of 10% aqueous sodium bicarbonate solution.
  • the layers were separated and washed with 1000 ml of 0.5 M aqueous potassium hydrogen sulphate solution.
  • the layers were separated and washed with 1000 ml of 10% aqueous sodium bicarbonate solution.
  • the layers were separated and organic layer was washed with 1000 ml of 20% sodium chloride solution.
  • the organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 120 ml of ethyl acetate and 500 ml of cyclohexane was charged to obtain 35 g of compound.
  • the degassed mass was dissolved in about 50ml of methanol and 0.3 ml of tributylphosphine (TBP) was added and stirred for about 24 hours and then about 125 ml of isopropyl alcohol was added to give a white precipitate, which was filtered and dried under vacuum at about 25-30°C to give 5.75gm of crude fosaprepitant dimeglumine, which was, then purified using methanol and acetone to give 4.0 gm of the fosaprepitant dimeglumine, having purity of more than 99.5%, as determined by high performance liquid chromatography.
  • TBP tributylphosphine
  • Example 7 Preparation of Fosaprepitant dimeglumine with bacterial endotoxin limit less than 1.0 EU/mg.

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Abstract

The present invention relates to an improved process for the preparation of fosaprepitant and salt thereof.

Description

PROCESS FOR PREPARATION OF FOSAPREPITANT AND SALT THEREOF
PRIORITY
[0001] This application claims the benefit under 35 U.S.C.§1 19 to Indian Provisional Application No.
5 1030/MUM/2012, filed on March 30, 2012, United States Provisional Application No.
61702852, filed on September 19, 2012; and entitled "PROCESS FOR THE PREPARATION OF FOSAPREPITANT AND SALT THEREOF"; the contents of which are incorporated by reference herein.
10 FIELD OF THE INVENTION
[0002] The present invention relates to an improved process for the preparation of fosaprepitant and salt thereof. More specifically the present invention relates to an improved process for preparing fosaprepitant dibenzylester from aprepitant.
15 BACKGROUND OF THE INVENTION
[0003] Fosaprepitant represented by compound of Formula I is a prodrug of aprepitant.
Figure imgf000002_0001
Formula I
[0004] The meglumine salt of fosaprepitant, Fosaprepitant dimeglumine is approved for the treatment 20 of emesis, nausea, cancer therapy toxicity and is available in the market as EMEND® in the US and as IVEMEND® in Europe, with the dosage strength 115 mg equivalent base. [0005] Fosaprepitant dimeglumine is chemically known as 1-deoxy-l -(methyl amino)-D-glucitol[3- [[(2R,3S)-2-[(lR)-l-[3,5-bis(triIluoromethyl)phenyl]-ethoxy]-3-(4-fluorophenyl)4-mo holinyl] methyl]-2,5-dihydro-5-oxo- 1 H- 1 ,2,4-triazoI- 1 -yl]phosphonate (2: 1) (salt).
5
[0006] United States Pat. No. 5,691,336 (U.S. Pat/336) describes morpholine compounds including fosaprepitant and its pharmaceutically acceptable salts thereof. U.S.Pat.'336 exemplifies the process for the preparation of fosaprepitant by reacting aprepitant compound of Formula II with tetrabenzyl pyrophosphate in presence of a sodium hexamethyldisilazane (NaHMDS) base in
10 dry tetrahydrofuran (THF) followed by workup in ethyl ether to obtain fosaprepitant dibenzylester, a compound of Formula III.
Figure imgf000003_0001
Formula II Formula III
15
[0007] The fosaprepitant dibenzylester, compound of Formula III is then converted to fosaprepitant compound of Formula I by debenzylation with palladium catalyst. Disadvantageous^, the reaction of aprepitant, compound of Formula II with tetrabenzyl pyrophosphate to obtain fosaprepitant dibenzylester, compound of Formula III leads to varied yields of fosaprepitant
20 dibenzylester, compound of Formula III. Further in said process, the starting material aprepitant, compound of Formula II, thereto is present to the extent of 0.8-20%, which subsequently results to batch variations; thus the process is inconsistent and commercially unviable on an industrial scale. [0008] Herein, the present invention provides the formation of fosaprepitant dibenzylester, compound of Formula III, from aprepitant, compound of Formula II and tetrabenzyl pyrophosphate in high yields, high purity, with lower content of aprepitant, consistently on an industrial scale, where the selection of the base and the reaction solvent and the work up solvent are critical.
5
[0009] The present invention provides a process for obtaining the fosaprepitant dibenzylester, compound of Formula III, as a white solid in purity greater than 95%, in yields greater than 80% and wherein the starting material aprepitant, compound of Formula II is present to an extent of less than 2%. The process of the present invention is reproducible on an industrial
10 scale as the yields obtained are consistent and the aprepitant content is lower and does not show batch to batch variation when reaction is carried out on a large scale. Thus the process of the present invention is commercially feasible for large scale preparation of fosaprepitant dibenzylester, compound of Formula III.
15 SUMMARY OF THE INVENTION
[0010] The present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, content less than 2% w/w of fosaprepitant dibenzylester, the compound of Formula III, comprising:
Figure imgf000004_0001
20 Formula III
a) reacting aprepitant, compound of Formula II,
Figure imgf000005_0001
Formula II
with tetrabenzyl pyrophosphate in presence of a hydride base to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from a hydrocarbon solvent or
halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
Figure imgf000005_0002
Formula III a) reacting aprepitant, compound of Formula II,
Figure imgf000006_0001
H
Formula II
with tetrabenzyl pyrophosphate in presence of a hydride base to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.
The present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
Figure imgf000006_0002
Formula III
a) reacting aprepitant, compound of Formula II,
Figure imgf000007_0001
Formula II
with tetrabenzyl pyrophosphate in presence of a hydride base to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from hydrocarbon solvent or halogenated 5 hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid wherein said process yields fosaprepitant dibenzylester, compound of Formula III in more than 80% yields based on aprepitant compound of Formula II.
[0013] The hydride base may be selected from the group consisting of sodium hydride, potassium 10 hydride, lithium hydride and the like.
[0014] The reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may be carried out in a solvent selected from ether or halogenated hydrocarbon.
15
[0015] Ethers may be acyclic and cyclic ethers selected from the group the group consisting of isopropyl ether, diethyl ether, tetrahydrofuran, tetrahydropyran and the like.
[0016] Halogenated hydrocarbons may be selected from the group consisting of methylene chloride, 20 chloroform, dichloroethane and the like. [0017] The reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may be carried out at lower temperature, preferably in the temperature range of about 5°C-20°C.
[0018] The reaction of aprepitant with tetrabenzyl pyrophosphate in presence of a hydride base may 5 be carried out for a period of about 30 minutes to about 2 hours.
[0019] In one embodiment, the reaction of aprepitant with tetrabenzyl pyrophosphate may be carried out in presence of sodium hydride base in presence of ether solvent, preferably the ether 10 solvent is tetrahydrofuran.
[0020] In b) of the process described directly above, the reaction mass obtained from a) is extracted with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof.
15
[0021] The hydrocarbon solvent may be an aliphatic hydrocarbon selected from the group consisting of hexane, heptane and the like or aromatic hydrocarbon like toluene, benzene, xylene and the like.
20
[0022] Halogenated hydrocarbons may be selected from the group consisting of methylene chloride, chloroform, dichloroethane and the like.
[0023] In one embodiment the reaction mass obtained from a) is extracted with halogenated 25 hydrocarbon preferably methylene chloride.
[0024] In c) of the process described directly above, the fosaprepitant dibenzylester, compound of
Formula III is obtained as a solid.
30 [0025] In one embodiment, the reaction mass obtained after b) is distilled off and degassed. The compound of formula III may then be obtained as a solid by dissolving the degassed mass in a solvent or mixture thereof and precipitating by addition of an antisolvent.
[0S26] The solvent(s) that can be used for dissolution may be selected from the group consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixtures thereof, preferably ethyl acetate.
[0027] The anti-solvent(s) that can be used to precipitate the solid is selected from hydrocarbon 10 solvents like n-pentane, n-hexane, n-heptane, cyclohexane or mixtures thereof, preferably cyclohexane.
[0028] In one embodiment in c) the fosaprepitant dibenzylester, compound of Formula III may be obtained as a solid by dissolving the degassed mass in ethyl acetate and precipitating by 15 addition of cyclohexane.
[0029] In one embodiment, the present invention provides a process for the preparation of fosaprepitant diberizylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III,
20 comprising
Figure imgf000009_0001
Formula III
a) reacting aprepitant, compound of Formula II,
Figure imgf000010_0001
Formula II
with tetrabenzyl pyrophosphate in presence of a hydride base in an ether solvent to obtain a reaction mass;
b) extracting the reaction mass with a solvent selected from hydrocarbon solvent or halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.
In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
a) reacting aprepitant, compound of Formula II with tetrabenzyl pyrophosphate in presence of a hydride base in an ether solvent to obtain a reaction mass;
b) extracting the reaction mass with a halogenated hydrocarbon solvent; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid.
In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II, less than 2% w/w of fosaprepitant dibenzylester, compound of Formula III, comprising
a) reacting aprepitant, compound of Formula II, with tetrabenzyl pyrophosphate in presence of a hydride base in tetrahydrofuran to obtain a reaction mass; b) extracting the reaction mass with methylene chloride; and c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of solid.
[0032] In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III having aprepitant, compound of 5 Formula II content less than 1% w/w of fosaprepitant dibenzylester, compound of Formula
III, as determined by high performance liquid chromatography (HPLC).
[0033] In one embodiment, the present invention provides a process for the preparation of fosaprepitant dibenzylester, a compound of Formula III having content of aprepitant, a
10 compound of Formula II less than 0.5% w/w of fosaprepitant dibenzylester, compound of
Formula III as determined by HPLC, preferably having aprepitant, compound of Formula II content less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III as determined by HPLC.
[0.934] In one embodiment, the present invention provides solid fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, compound of Formula II content less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III and in purity greater than 95% as determined by HPLC.
[M35] The process of the present invention is reproducible and consistently provides fosaprepitant dibenzylester, compound of Formula III as a white solid in purity greater than 95% as determined by HPLC, in yields greater than 80% and wherein the starting material aprepitant, compound of Formula II is present to an extent of less than 0.15% w/w of fosaprepitant dibenzylester, compound of Formula III as determined by HPLC.
25
[0036] The fosaprepitant dibenzylester, compound of Formula III, obtained by the process of the present invention may be converted to the neutral form of fosaprepitant, or may optionally be converted into a pharmaceutically acceptable salt of fosaprepitant by any method known to
30 one of ordinary skill in the art. A preferred pharmaceutically acceptable salt is the fosaprepitant dimeglumine. [0037] The dimeglumine salt may be prepared by a method including, but not limited to, reacting the neutral form of fosaprepitant with N-methyl-D-glucamine. Typically, the fosaprepitant is dissolved in an organic solvent and combined with a solution of acid or base used to obtain the desired salt of fosaprepitant.
5
[0038] The dimeglumine salt may be prepared by hydrogenating the fosaprepitant dibenzylester, compound of Formula III in the presence of palladium-carbon and N-methyl -D- glucamine.
[0039] In one embodiment, the present invention provides a fosaprepitant dimeglumine wherein the 10 bacterial endotoxin limit is less than 1.0 EU/mg as determined by Limulus Amebocyte
Lysate (LAL) according to USP 35.
[0040] . In one embodiment, the present invention provides a process for preparation of fosaprepitant dimeglumine wherein the bacterial endotoxin limit is less than 1.0 EU/mg as determined by 15 Limulus Amebocyte Lysate (LAL) according to USP 35 comprising
(a) dissolving the fosaprepitant dimeglumine in a solvent system;
(b) optionally heating to obtain solution of fosaprepitant dimeglumine;
(c) treating the solution of fosaprepitant dimeglumine with an activated carbon;
(d) filtering off the activated carbon to obtain a filtrate; and
20 (e) adding an antisolvent to the filtrate to precipitate the fosaprepitant dimeglumine.
[0041] The solvent for dissolving the fosaprepitant dimeglumine may be selected from methanol and dimethylformamide.
[fl©42] The antisolvent may be selected from isopropanol, acetone and methyl ethyl ketone.
[0043] In one embodiment, the present invention provides a process for preparation of fosaprepitant dimeglumine wherein the bacterial endotoxin limit is less than 1.0 EU/mg as determined by
Limulus Amebocyte Lysate (LAL) according to USP 35 comprising
30 (a)dissolving the fosaprepitant dimeglumine in a solvent system to obtain a solution;
(b)filtering the solution of fosaprepitant dimeglumine over a sterile filter having pore size of
0.22 μ or less; and (c) adding an antisolvent to the filtrate to precipitate the fosaprepitant dimeglumine.
[0044] The solvent for dissolving the fosaprepitant dimeglumine may be selected from methanol and dimethylformamide .
5
[0045] The antisolvent may be selected from isopropanol, acetone and methyl ethyl ketone.
Preferably the antisolvent is passed through a sterile filter having pore size of 0.22 μ or less.
[0046] The fosaprepitant dimeglumine thus obtained is dried in vacuum to obtain aseptic crystalline 10 fosaprepitant dimeglumine.
[0047] The aseptic fosaprepitant dimeglumine obtained by the process of the present invention may be used for formulating an injectable of fosaprepitant dimeglumine.
15
[0048] In one embodiment the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II characterized by X-ray powder diffraction having peaks expressed as 2 Θ values at about 12.6, 16.7, 17.1 , 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8±0.2
20
[0049] In one embodiment, the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II comprising
(a) dissolving aprepitant in alkanol;
(b) optional filtering the solution;
25 (c) adding a hydrocarbon solvent to the alkanoic solution of aprepitant obtained in (b); and
(d) distilling of the solvent to obtain Form II of aprepitant.
[0050] The alkanol may be selected from methanol, ethanol and the like.
[8(851] The hydrocarbon solvent may be aliphatic selected from the group consisting of hexane, heptane and the like or aromatic hydrocarbon like toluene, benzene, xylene and the like.
[0052] The amount of hydrocarbon solvent used is 3 to 5 times the amount of alkanolic solvent used. [0053] The distillation is carried out to the extent that alkanol is almost removed from the solvent; while allowing crystalline Form II of aprepitant, compound of formula II, to precipitate out from the hydrocarbon.
5
[0054] In one embodiment, the present invention provides a process for preparing aprepitant compound of formula II in crystalline Form II, comprising:
(a) dissolving aprepitant in methanol;
(b) optional filtering the solution;
10 (c) adding toluene to the methanolic solution of aprepitant obtained in step b; and
(d) distilling of the solvent to obtain crystalline Form II of aprepitant.
[0055] HPLC Methodology
Reagents, Solvents and Standards:
15 Water (Milli Q or equivalent); Acetonitrile (Merck, HPLC grade); Disodium hydrogen phosphate anhydrous (GR Grade);Methanol (HPLC Grade); Ortho phosphoric acid (GR Grade)
01.2. Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient 20 pumps, variable wavelength UV detector attached with data recorder and integrator software.
Column : C18 Thermo BDS Hypersil, 250 x 4.6, 5μ
Column temperature : 30°C
Mobile Phase : Mobile Phase A = Buffer;Buffer : 2.42gm of Disodium hydrogen phosphate anhydrous in 1000ml of water. Adjust pH to 6.5 with o-Phosphoric acid
25 Mobile Phase B = Acetonitrile : Methanol (60 : 40, v/v)
Time (min.) % Mobile Phase A % Mobile Phase B
0.01 60 40
30 30 70
55 20 80
30 60 60 40
65 60 40
Diluent : Water : Acetonitrile (50 : 50,v/v) Flow Rate : 1.OmL/minute; Detection : UV 210nm;Injection Volume : ΙΟμί
01.3. Preparation of reference solution (a):
Transfer about lO.Omg each of Tetrabenzyl pyrophosphate standard and aprepitant standard accurately weighed, into a 10 mL volumetric flask. Add 5 mL of acetonitrile and sonicate to dissolve. Make up to the mark with water & mix.
01.4. Preparation of reference solution (b):
Transfer about lOO.Omg of test sample accurately weighed, into a 100 mL volumetric flask. Add 0.5 mL of reference solution (a). Add about 50-60ml of diluent and sonicate to dissolve. Make up to the mark with diluent & mix.
Note: Reference solution (b) should be prepared freshly for every analysis.
01.5. Preparation of Test Solution :
Transfer about 50.0 mg of sample, accurately weighed into a 50mL volumetric flask. Add about 25-30ml of diluent and sonicate to dissolve. Make up to the mark with diluent & mix. Note: Test solution should be prepared freshly for every analysis.
01.6. Procedure:
Separately inject the equal volumes of blank (diluent), reference solution (b) and then inject test solution in duplicate into the liquid chromatograph. Record the responses eliminating the peaks due to blank. Calculate the chromatographic purity by area normalization method. Confirm the retention time of aprepitant and Tetrabenzyl pyrophosphate from reference solution (b) chromatogram. The retention time of main peak i.e. fosaprepitant dibenzyl ester is about 45.4 minutes, retention time of aprepitant is about 31.1 minutes, retention time of Ethyl acetate is about 4.9 minutes and retention time of Tetrabenzyl pyrophosphate is about 36.1 minutes under these conditions.
01.7. System suitability test
Theoretical plates of the main peak from test solution should not be less than 5000.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages. EXAMPLES
Example 1 Preparation of Fosaprepitant dibenzylester, compound of Formula III
To the mixture of 20 gm of aprepitant (0.0375moles) and 29 gm of tetrabenzyl pyrophosphate (0.054moles) in 400 ml dry tetrahydrofuran under nitrogen atmosphere and cooling to about 5°C, 4.8 gm of sodium hydride (60% disperse in oil) (0.08moles) was charged. The reaction mass was stirred for about 60 minutes at about 5°C to about 10°C. The reaction mass was cooled to about 0°C and 20 ml of ethyl acetate and 400ml of methylene dichloride were charged. The reaction mass was stirred for about 5 minutes. The organic layer was washed with 10% aqueous sodium bicarbonate solution followed by washing with sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 60 ml of ethyl acetate and 240 ml of cyclohexane was charged, to obtain a white solid. The mass was stirred for about 60 minutes, filtered & dried at about 30°C to give 25.4 gm product with purity of more than 97%; aprepitant content: 0.51%. The conversion of lOOg of aprepitant compound of Formula II to fosaprepitant dibenzyl ester was carried out as described above and the results obtained are tabulated below:
Figure imgf000016_0001
These results indicate that the process of the present invention provides fosaprepitant dibenzyl ester in high yield with purity greater than 95% as determined by high performance liquid chromatography with aprepitant content lower than 0.15% w/w of the fosaprepitant dibenzylester. Example 2:Preparation of Fosaprepitant dibenzylester, compound of Formula III
To the mixture of 5 gm of aprepitant (0.0094moles) and 7.25 gm of etrabenzyl pyrophosphate (0.0135moles) in 100 ml methylene chloride under nitrogen atmosphere and cooling to about 5°C, 1.2 gm of sodium hydride (60% disperse in oil) (0.02moles) was charged. The reaction mass was stirred for about 60 minutes at about 5°C to about 10°C. The reaction mass was cooled to 0°C and 2.5 ml of ethyl acetate was charged. The reaction mass was stirred for about 5 minutes. The organic layer was washed with aqueous sodium bicarbonate solution followed by 100 ml of sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 15 ml of ethyl acetate and 60 ml of cyclohexane were charged to precipitate a white solid. The mass was stirred for about 60 minutes, filtered and dried at about 30°C to give fosaprepitant dibenzylester, compound of Formula III, with purity of more than 95%%; aprepitant content 0.42% as determined by high performance liquid chromatography. Example 3: Preparation of Fosaprepitant dibenzylester, compound of Formula III
To the mixture of 5 gm of aprepitant (0.0094moles) and 7.25 gm of tetrabenzyl pyrophosphate (0.0135moles) in 100 ml dry THF under nitrogen atmosphere which was cooled to about 5°C, 1.2 gm of sodium hydride (60% disperse in oil) (0.02moles) was charged. The reaction mass was stirred for about 60 minutes at about 5°C to about 10°C. The reaction mass was cooled to about 0°C and 2.5 ml of ethyl acetate and 100ml of toluene was charged. The reaction mass was stirred for about 5 minutes. The reaction mass was stirred for about 5 minutes. The organic layer was washed with aqueous sodium bicarbonate solution followed by sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 15 ml of ethyl acetate and 60 ml of cyclohexane was charged to precipitate a white solid. The mass was stirred for about 60 minutes, filtered and dried at about 30°C to give fosaprepitant dibenzylester, compound of Formula III, with purity of more than 95%; aprepitant content: 1.5% as determined by high performance liquid chromatography.
Example 4: Preparation of Fosaprepitant dibenzylester, compound of Formula III using NaHMDS and ether solvent in workup. To the mixture of 40 gm of aprepitant and 62 gm of tetrabenzyl pyrophosphate in 1000 ml dry THF under nitrogen atmosphere which was cooled to about -10°C, 190 ml of 1 M sodium HMDS solution in THF were added in about 2 to 3 hours. The reaction mass was stirred for about about 15 min at about -10°C to about 0°C. 1000ml of isopropyl ether was charged and reaction mixture was stirred for about 5 min. The organic layer was washed with 1000ml of 10% aqueous sodium bicarbonate solution. The layers were separated and washed with 1000 ml of 0.5 M aqueous potassium hydrogen sulphate solution. The layers were separated and washed with 1000 ml of 10% aqueous sodium bicarbonate solution. The layers were separated and organic layer was washed with 1000 ml of 20% sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed. To the degassed mass, 120 ml of ethyl acetate and 500 ml of cyclohexane was charged to obtain 35 g of compound.
The conversion of 40g of aprepitant compound of Formula II to fosaprepitant dibenzyl ester was carried out as described above and the results obtained, as determined by high performance liquid chromatography, are tabulated below.
Figure imgf000018_0001
Example 5 Preparation of Fosaprepitant dibenzylester, compound of Formula III
The conversion of 5g of aprepitant, compound of Formula II to fosaprepitant dibenzyl ester, compound of Formula III was carried out by the procedure as described in Example 4, where alkali metal HMDS was used and by Example 1 , where alkali metal hydride was used and the results obtained, as determined by high performance liquid chromatography, are tabulated below:
Figure imgf000018_0002
1 THF LiHMDS DIPE 5 3.6 48.45
2 THF NaH DIPE 5 2.5 33.65
3 THF NaHMDS MDC 5 1 13.46
4 THF LiHMDS MDC 5 2 26.92
5 DMF NaHMDS DIPE 5 2.5 33.65
6 DMF LiHMDS DIPE 5 2.5 33.65
7 DMF NaH DIPE 5 2 26.92
8 DMF NaHMDS MDC 5 0.5 6.73
9 DMF LiHMDS MDC 5 3 40.38
10 MDC NaHMDS MDC 5 2.9 39.03
1 1 MDC LiHMDS MDC 5 3.3 44.41
These results indicate that the yields of fosaprepitant dibenzyl ester, compound of Formula III obtained are very low and the process is not commercially feasible.
Example 6: Preparation of Fosaprepitant dimeglumine:
In a par bottle, 5.0 gm of fosaprepitant dibenzyl ester, compound of Formula III, 3.0 gm of N- methyl glucamine and 1.0 gm of Pd/C in 100 ml of methanol were taken and hydrogen pressure of about 5 kg. was applied. The reaction mass was filtered through hyflo bed and the filtrate was distilled and degassed under vacuum at about 30°C. The degassed mass was dissolved in about 50ml of methanol and 0.3 ml of tributylphosphine (TBP) was added and stirred for about 24 hours and then about 125 ml of isopropyl alcohol was added to give a white precipitate, which was filtered and dried under vacuum at about 25-30°C to give 5.75gm of crude fosaprepitant dimeglumine, which was, then purified using methanol and acetone to give 4.0 gm of the fosaprepitant dimeglumine, having purity of more than 99.5%, as determined by high performance liquid chromatography.
Example 7; Preparation of Fosaprepitant dimeglumine with bacterial endotoxin limit less than 1.0 EU/mg.
In a laminar flow environment, 100ml round bottomed flask (RBF) was charged with 2.0 gm of fosaprepitant dimeglumine and 20 ml of methanol. The mixture was stirred to get a clear solution, 0.200gm of activated carbon (Acticarbone® CPW) was charged and stirred for about 30 min. The mixture was filtered to remove the carbon. The filtrate was charged into a 250ml RBF and 80 ml of acetone was charged to precipitate the product. The mixture was stirred for 15 min filtered and washed with 10 ml acetone. The product was dried at 25-30°C for 24 hr, dry wt. 1.5 gm; Bacterial endotoxin limit is less than 1.0 EU/mg.
Example 8: Preparation of crystalline Form II of Aprepitant, compound of formula II
To 20 gm of Aprepitant, compound of formula II, 400ml of methanol was added and heated to about 50°C to 55°C and stirred to get a clear solution. The solution was filtered. 1440 ml of toluene was charged and heated to about 50°C to 55°C. About 800ml of solvent was distilled out under low vacuum at about 50°C to 55°C. The solid precipitated out. The reaction mass was cooled to about 25°C to 30°C, and stirred for about 30 minutes and filtered. The solid was dried at about 30°C to 35°C for about 12 hours to obtain pure crystalline Form II of aprepitant, compound of formula II characterized by X-ray powder diffraction having peaks expressed as 2 Θ values at about 12.6, 16.7, 17.1, 17.2, 18.0, 20.1 , 20.6, 21.1, 22.8, 23.9 and 24.8±0.2

Claims

1] A process for the preparation of fosaprepitant dibenzylester, a compound of Formula III, having aprepitant, a compound of Formula II, content less than 2% w/w of the fosaprepitant dibenzylester, compound of Formula III, comprising:
Figure imgf000021_0001
Formula III
a) reacting aprepitant, a compound of Formula II,
Figure imgf000021_0002
H
Formula II
with tetrabenzyl pyrophosphate in the presence of a hydride base to obtain a reaction mass; b) extracting the reaction mass with a solvent selected from a hydrocarbon solvent or
halogenated hydrocarbon solvent or mixture thereof; and
c) isolating the fosaprepitant dibenzylester, compound of Formula III in the form of a solid. 2] The process as claimed in claim 1 , wherein hydride base is selected from sodium hydride, potassium hydride, lithium hydride. ] The process as claimed in claim 1 , wherein the reaction in step a) is carried out in a solvent selected from an ether solvent or halogenated hydrocarbon solvent.
] The process as claimed in claim 1, wherein the hydrocarbon solvent in step b) is toluene.] The process as claimed in claim 1, wherein the halogenated hydrocarbon solvent in step b) is methylene chloride.
] The process as claimed in claim 1 , wherein the fosaprepitant dibenzylester compound of Formula III has purity of more than 95% as determined by high performance liquid chromatography.
] The process as claimed in claim 1 , further comprising converting fosaprepitant dibenzylester, compound of Formula III obtained by process as claimed in claim 1, to fosaprepitant compound of Formula I or salt thereof.
Figure imgf000022_0001
Formula I
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104650143A (en) * 2013-11-25 2015-05-27 山东新时代药业有限公司 Method for preparing fosaprepitant dimeglumine intermediates
WO2015083033A1 (en) * 2013-12-02 2015-06-11 Piramal Enterprises Limited An improved process for the preparation of fosaprepitant having improved purity
CN106432337A (en) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 Fosaprepitant derivative, synthesis thereof, and use thereof in long acting preparation
WO2017093899A1 (en) * 2015-12-01 2017-06-08 Piramal Enterprises Limited A process for preparation of fosaprepitant dimeglumine and an intermediate thereof
CN107353303A (en) * 2016-05-09 2017-11-17 上海奥博生物医药技术有限公司 A kind of preparation method of Fosaprepitant phosphate intermediate
WO2018211410A1 (en) * 2017-05-17 2018-11-22 Glenmark Pharmaceuticals Limited Improved process for preparation of fosaprepitant or salt thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5691336A (en) * 1994-03-04 1997-11-25 Merck & Co., Inc. Morpholine compounds are prodrugs useful as tachykinin receptor antagonists
US20030158173A1 (en) * 2001-12-18 2003-08-21 Schering Corporation NK 1 antagonists
WO2006060110A2 (en) * 2004-11-05 2006-06-08 Merck & Co., Inc. Process for preparing {3-[2(r)-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(s)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid
WO2010018595A2 (en) * 2008-07-17 2010-02-18 Glenmark Generics Limited Fosaprepitant dimeglumine intermediate, neutral fosaprepitant, and amorphous fosaprepitant dimeglumine and processes for their preparations
WO2011045817A2 (en) * 2009-10-15 2011-04-21 Sandoz Private Limited Process for the preparation of fosaprepitant, intermediate and pharmaceutical acceptable salt thereof
CN102558232A (en) * 2011-12-31 2012-07-11 江苏奥赛康药业股份有限公司 Preparation method of fosaprepitant dimeglumine
CN102850398A (en) * 2011-06-27 2013-01-02 上海医药工业研究院 Fosaprepitant preparation method

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5691336A (en) * 1994-03-04 1997-11-25 Merck & Co., Inc. Morpholine compounds are prodrugs useful as tachykinin receptor antagonists
US20030158173A1 (en) * 2001-12-18 2003-08-21 Schering Corporation NK 1 antagonists
WO2006060110A2 (en) * 2004-11-05 2006-06-08 Merck & Co., Inc. Process for preparing {3-[2(r)-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(s)-(4-fluorophenyl)morpholin-4-yl]methyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonic acid
WO2010018595A2 (en) * 2008-07-17 2010-02-18 Glenmark Generics Limited Fosaprepitant dimeglumine intermediate, neutral fosaprepitant, and amorphous fosaprepitant dimeglumine and processes for their preparations
WO2011045817A2 (en) * 2009-10-15 2011-04-21 Sandoz Private Limited Process for the preparation of fosaprepitant, intermediate and pharmaceutical acceptable salt thereof
CN102850398A (en) * 2011-06-27 2013-01-02 上海医药工业研究院 Fosaprepitant preparation method
CN102558232A (en) * 2011-12-31 2012-07-11 江苏奥赛康药业股份有限公司 Preparation method of fosaprepitant dimeglumine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JEFFREY J.: 'Hale Phosphorylated Morpholine Acetal Human Neurokinin-1 Receptor Antagonists as Water-Soluble Prodrugs.' J.MED.CHEM. vol. 43, no. 6, 25 February 2000, pages 1234 - 1241 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104650143A (en) * 2013-11-25 2015-05-27 山东新时代药业有限公司 Method for preparing fosaprepitant dimeglumine intermediates
CN104650143B (en) * 2013-11-25 2018-10-02 山东新时代药业有限公司 The method for preparing fosaprepitant dimeglumine intermediate
WO2015083033A1 (en) * 2013-12-02 2015-06-11 Piramal Enterprises Limited An improved process for the preparation of fosaprepitant having improved purity
CN106432337A (en) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 Fosaprepitant derivative, synthesis thereof, and use thereof in long acting preparation
WO2017093899A1 (en) * 2015-12-01 2017-06-08 Piramal Enterprises Limited A process for preparation of fosaprepitant dimeglumine and an intermediate thereof
US10428097B2 (en) 2015-12-01 2019-10-01 Piramal Enterprises Limited Process for preparation of fosaprepitant dimeglumine and an intermediate thereof
CN107353303A (en) * 2016-05-09 2017-11-17 上海奥博生物医药技术有限公司 A kind of preparation method of Fosaprepitant phosphate intermediate
CN109496215A (en) * 2016-05-09 2019-03-19 浙江华海药业股份有限公司 A kind of Fosaprepitant phosphate intermediate and preparation method thereof
WO2018211410A1 (en) * 2017-05-17 2018-11-22 Glenmark Pharmaceuticals Limited Improved process for preparation of fosaprepitant or salt thereof

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