WO2017093899A1 - A process for preparation of fosaprepitant dimeglumine and an intermediate thereof - Google Patents

A process for preparation of fosaprepitant dimeglumine and an intermediate thereof Download PDF

Info

Publication number
WO2017093899A1
WO2017093899A1 PCT/IB2016/057194 IB2016057194W WO2017093899A1 WO 2017093899 A1 WO2017093899 A1 WO 2017093899A1 IB 2016057194 W IB2016057194 W IB 2016057194W WO 2017093899 A1 WO2017093899 A1 WO 2017093899A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
reaction mass
fosaprepitant
mixture
residue
Prior art date
Application number
PCT/IB2016/057194
Other languages
French (fr)
Inventor
Milind Gharpure
Prashant LADKAT
Navnath SHINDE
Ashutosh JAGTAP
Original Assignee
Piramal Enterprises Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Piramal Enterprises Limited filed Critical Piramal Enterprises Limited
Priority to EP16870086.2A priority Critical patent/EP3383829B1/en
Priority to US15/779,910 priority patent/US10428097B2/en
Publication of WO2017093899A1 publication Critical patent/WO2017093899A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to a novel process for the preparation of an intermediate of fosaprepitant dimeglumine. More particularly, the present invention relates to a process for the preparation of fosaprepitant dibenzyl ester (represented herein by formula II), an intermediate of fosaprepitant dimeglumine. The present invention also relates to a process for the in-situ preparation of fosaprepitant dimeglumine, an antiemetic drug.
  • Fosaprepitant, a prodrug of aprepitant is chemically known as [3-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo holinyl]methyl]-2,5-dihydro-5- oxo-lH-l,2,4-triazol-l-yl] phosphonic acid.
  • the N-methyl-D- glucamine salt of fosaprepitant is approved for the treatment of emesis, nausea, cancer therapy toxicity and is available in the market as EMEND ® in the US and as IVEMEND ® in Europe.
  • Fosaprepitant dimeglumine is structurally represented by following formula I,
  • Emend ® is used together with other medications to prevent nausea and vomiting that may be caused by surgery or cancer chemotherapy.
  • Fosaprepitant and its salts are disclosed in US Patent No. 5,691,336, which further discloses a process for manufacturing these compounds. The process for preparation of fosaprepitant dimeglumine disclosed in said patent involves two steps, which are schematically presented herein:
  • the process for preparation of fosaprepitant dimeglumine involves reaction of aprepitant with tetrabenzyl pyrophosphate using sodium bis(trimethylsilyl)amide (NaHMDS) as a base in the presence of THF as a solvent to obtain crude fosaprepitant dibenzyl ester.
  • NaHMDS sodium bis(trimethylsilyl)amide
  • This crude fosaprepitant dibenzyl ester obtained is then treated with N-methyl-D-glucamine and Pd/C in the presence of methanol as a solvent to obtain fosaprepitant dimeglumine.
  • 8,623,844 describes a process for preparation of isolated solid crystalline fosaprepitant dibenzyl ester from crude fosaprepitant dibenzyl ester.
  • the process involves obtaining a solution of fosaprepitant dibenzyl ester in a solvent such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixture of solvents; followed by addition of an anti-solvent such as n-pentane, n-hexane, n-heptane, cyclohexane to recover fosaprepitant dibenzyl ester as a crystalline solid.
  • a solvent such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate,
  • the isolated solid crystalline fosaprepitant dibenzyl ester is of 93.74 % purity and contains unknown impurities to an extent of 3.83 %.
  • the fosaprepitant dimeglumine prepared from said isolated solid crystalline fosaprepitant dibenzyl ester is of 94.5 % purity and the purity of fosaprepitant dimeglumine after additional step of purification is enhanced to 99.76 %.
  • Indian Patent Application No. 2188/CHE/2011 describes an improved process for preparation of fosaprepitant dimeglumine and its intermediate fosaprepitant dibenzyl ester.
  • the process also teaches preparation of co-crystal of fosaprepitant dibenzyl ester with sodium chloride.
  • the purity of fosaprepitant dibenzyl ester prepared using said process is not reported in the IN'2188 application.
  • the fosaprepitant dimeglumine prepared using said improved process has purity of at least about 97.1 , which is not a pharmaceutically acceptable grade purity of fosaprepitant dimeglumine.
  • fosaprepitant dimeglumine is a highly sensitive moiety and multiple purifications to achieve pharmaceutically acceptable grade purity leads to degradation of fosaprepitant dimeglumine to aprepitant. Therefore, there is a need to prepare highly pure fosaprepitant dibenzyl ester and then convert it to fosaprepitant dimeglumine in order to achieve pharmaceutically acceptable grade purity.
  • An object of the present invention is to provide a process for the in-situ preparation of fosaprepitant dimeglumine of formula I from aprepitant of formula III.
  • Yet another object of the present invention is to provide a process for the preparation of fosaprepitant dimeglumine from said pure fosaprepitant dibenzyl ester, wherein the purity of fosaprepitant dimeglumine is > 99 , without any additional step of purification.
  • a process for the preparation of intermediate of fosaprepitant dimeglumine particularly provides a process for the preparation of [3-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo holinyl]methyl]-2,5-dihydro-5- oxo-lH-l,2,4-triazol-l-yl]-phosphonic acid bis(phenylmethyl) ester (fosaprepitant dibenzyl ester) of formula II,
  • step (b) adding an inorganic acid to the solution obtained in step (a),
  • step (c) concentrating the reaction mass obtained in step (b), (d) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (c),
  • step (e) filtering the reaction mass obtained in step (d) to obtain a residue, Residue-A,
  • step (f) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (e),
  • step (g) filtering the reaction mass obtained in step (f) to obtain a residue, Residue-B,
  • step (h) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (g),
  • step (j) concentrating the filtrate obtained in step (i) to yield fosaprepitant dibenzyl ester of purity > 96 %.
  • step (iv) concentrating the reaction mass obtained in step (iii), (v) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (iv),
  • step (vi) filtering the reaction mass obtained in step (v) to obtain a residue, Residue-A,
  • step (vii) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (vi),
  • step (viii) filtering the reaction mass obtained in step (vii) to obtain a residue, Residue-B,
  • step (ix) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (viii),
  • step (x) filtering the reaction mass obtained in step (ix) and concentrating the filtrate to yield fosaprepitant dibenzyl ester of purity > 96 % as an oil
  • step (xi) dissolving the oil obtained in step (x) in at least one solvent or a mixture of solvents thereof
  • step (xii) adding N-methyl-D-glucamine and Pd/C to the reaction mass obtained in step (xi) and hydrogenating the reaction mass for 8 h to 14 h at 2 kg to 8 kg pressure,
  • step (xiv) adding metal scavenger to the reaction mass obtained in step (xiii) and stirring for 8 h to 14 h,
  • step (xv) obtaining fosaprepitant dimeglumine of purity > 99 % from the resulting reaction mass of step (xiv) on further work-up.
  • the process of the present invention overcomes the disadvantages associated with the processes described in the prior art, which involves use of multiple column chromatography for purification of fosaprepitant dibenzyl ester or involves the isolation of unstable crystalline fosaprepitant dibenzyl ester.
  • the inventors of the present invention surprisingly found that use of an inorganic acid in the process results in highly pure fosaprepitant dibenzyl ester.
  • the inorganic acid used in the process is simple, easy to handle on commercial scale and cost-effective; thereby making the process for preparation of fosaprepitant dibenzyl ester and its conversion to fosaprepitant dimeglumine simple, efficient and industrially applicable.
  • the present invention relates to a process for the preparation of [3-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo holinyl]methyl]-2,5-dihydro-5- oxo-lH-l,2,4-triazol-l-yl]-phosphonic acid bis(phenylmethyl) ester (fosaprepitant dibenzyl ester) of formula II,
  • step (b) adding an inorganic acid to the solution obtained in step (a),
  • step (d) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (c),
  • step (e) filtering the reaction mass obtained in step (d) to obtain a residue, Residue-A,
  • step (f) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (e),
  • step (g) filtering the reaction mass obtained in step (f) to obtain a residue, Residue-B,
  • step (h) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (g),
  • step (j) concentrating the filtrate obtained in step (i) to yield fosaprepitant dibenzyl ester of purity
  • the term, 'pharmaceutically acceptable grade' used herein refers to the Fosaprepitant Dimeglumine of formula I of purity > 99 , fosaprepitant dimeglumine is not listed in any pharmacopeia.
  • a solution of fosaprepitant dibenzyl ester is prepared by dissolving fosaprepitant dibenzyl ester in at least one solvent or a mixture of solvents.
  • the fosaprepitant dibenzyl ester used at this step can be obtained from reaction of aprepitant with tetrabenzyl pyrophosphate in the presence of a base and a solvent, as described in the US Patent No. 5,691,336. Also, the fosaprepitant dibenzyl ester prepared by any process can be used in-situ at this step of the process.
  • step (a) of the process obtained according to the process described in US Patent No. 5,691,336 or prepared by any other process known in the prior art is of purity ⁇ 78 %.
  • the solvent(s) used for preparing the fosaprepitant dibenzyl ester solution in step (a) of the process is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
  • the solvent(s) used in the step (a) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • the solution of fosaprepitant dibenzyl ester of step (a) can be prepared by addition of one solvent or by addition of more than one solvents, that is two, three or more solvents sequentially, or as a mixture of solvents.
  • an inorganic acid is added to the solution of fosaprepitant dibenzyl ester obtained in step (a).
  • the said inorganic acid is selected from, but not limited to boric acid.
  • the inorganic acid charged is about 0.5 to 5 equivalents based on the quantity of fosaprepitant dibenzyl ester of formula II.
  • the reaction mass obtained after treatment with inorganic acid in the step (b) is concentrated or evaporated to dryness.
  • the concentration of reaction mass is carried out at a temperature lower than 40 °C.
  • the reaction mass obtained after concentration is light yellow to brown thick sticky mass.
  • the reaction mass obtained after concentration in step (c) is charged with at least one solvent or a mixture of solvents.
  • the said solvent(s) is selected from the group consisting of a polar solvent and a non- polar solvent or a mixture thereof.
  • the solvent(s) used in the step (d) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • a single solvent is added to the reaction mass of step (c).
  • the addition of more than one solvent, that is two, three or more solvents to the reaction mass of step (c) can be made sequentially or can be added as a mixture of solvents.
  • the ratio of at least one solvent or mixture of solvents used in step (d) above to the solution in step (c) is about 2 volume to 20 volume.
  • the ratio of solvents when more than one solvent is used in step (d) is about 1 volume to 16 volume.
  • step (d) of the process reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
  • step (e) of the process in the step (e) of the process the reaction mass obtained in the step (d) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue.
  • the residue obtained in step (e) is referred to as 'Residue- A' .
  • the residue obtained in step (e) after filtration is charged with at least one solvent or a mixture of solvents.
  • the said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
  • the solvent(s) used in the step (f) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • a single solvent is added to the residue obtained in step (e).
  • the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (e) can be made sequentially or can be added as a mixture of solvents.
  • the ratio of at least one solvent or mixture of solvents used in step (f) above to the residue in step (e) is about 2 volume to 20 volume.
  • the ratio of solvents when more than one solvent is used in step (f) is about 1 volume to 16 volume.
  • step (f) the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
  • step (g) of the process in the step (g) of the process the reaction mass obtained in the step (f) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue.
  • the residue obtained in step (g) is referred to as 'Residue-B'.
  • the residue obtained in step (g) after filtration is charged with at least one solvent or a mixture of solvents.
  • the said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
  • the solvent(s) used in the step (h) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • a single solvent is added to the residue obtained in step (g).
  • the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (g) can be made sequentially or can be added as a mixture of solvents.
  • the ratio of at least one solvent or mixture of solvents used in step (h) above to the residue in step (g) is about 2 volume to 12 volume.
  • the ratio of solvents when more than one solvent is used in step (f) is about 1 volume to 16 volume.
  • step (h) the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 40 °C for 0.5 h to 5 h.
  • the reaction mass obtained in the step (h) after addition of at least one solvent or a mixture of solvents thereof is filtered and the filtrate is washed with solution of sodium chloride.
  • the resulting filtrate organic layer is dried using sodium sulphate and concentrated at a temperature lower than 40 °C to yield thick oily syrup of fosaprepitant dibenzyl ester of purity > 96 %.
  • the present invention also relates to a process for the in-situ 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- 1 H- 1 ,2,4-triazol- 1 -yl] phosphonate (2: 1) salt (fosaprep
  • step (ii) adding at least one solvent or a mixture of solvents to the reaction mass obtained in step (i),
  • step (iv) concentrating the reaction mass obtained in step (iii), (v) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (iv),
  • step (vi) filtering the reaction mass obtained in step (v) to obtain a residue, Residue-A,
  • step (vii) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (vi),
  • step (viii) filtering the reaction mass obtained in step (vii) to obtain a residue, Residue-B,
  • step (ix) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (viii),
  • step (x) filtering the reaction mass obtained in step (ix) and concentrating the filtrate to yield fosaprepitant dibenzyl ester of purity > 96 % as an oil
  • step (xi) dissolving the oil obtained in step (x) in at least one solvent or a mixture of solvents thereof
  • step (xii) adding N-methyl-D-glucamine and Pd/C to the reaction mass obtained in step (xi) and hydrogenating the reaction mass for 8 h to 14 h at 2 kg to 8 kg pressure,
  • step (xiv) adding metal scavenger to the reaction mass obtained in step (xiii) and stirring for 8 h to 14 h,
  • step (xv) obtaining fosaprepitant dimeglumine of purity > 99 % from the resulting reaction mass of step (xiv) on further work-up.
  • aprepitant is a known compound and can be prepared by a person skilled in the art by following the processes known in the art.
  • the US Patent No. 5,719,147 discloses aprepitant of formula II and its preparation method.
  • a solution of fosaprepitant dibenzyl ester is prepared by dissolving fosaprepitant dibenzyl ester in at least one solvent or a mixture of solvents.
  • the fosaprepitant dibenzyl ester used at this step can be obtained from reaction of aprepitant with tetrabenzyl pyrophosphate in the presence of a base and a solvent, as described in the US Patent No. 5,691,336.
  • the fosaprepitant dibenzyl ester prepared by any process can be used in-situ at this step of the process.
  • the fosaprepitant dibenzyl ester used in step (ii) of the process obtained according to the process described in US Patent No. 5,691,336 or prepared by any other process known in the prior art is of purity ⁇ 78 .
  • the solvent(s) used for preparing the fosaprepitant dibenzyl ester solution in step (ii) of the process is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
  • the solvent(s) used in the step (ii) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • the solution of fosaprepitant dibenzyl ester of step (ii) can be prepared by addition of one solvent or by addition of more than one solvent, that is two, three or more solvents sequentially, or as a mixture of solvents.
  • an inorganic acid is added to the solution of fosaprepitant dibenzyl ester obtained in step (ii).
  • the said inorganic acid is selected from, but not limited to boric acid.
  • the inorganic acid charged is about 0.5 to 5 equivalents based on the quantity of fosaprepitant dibenzyl ester of formula II.
  • the reaction mass obtained after treatment with inorganic acid in the step (iii) is concentrated or evaporated to dryness.
  • the concentration of reaction mass is carried out at a temperature lower than 40 °C.
  • the reaction mass obtained after concentration is light yellow to brown thick sticky mass.
  • the reaction mass obtained after concentration in step (iv) is charged with at least one solvent or a mixture of solvents.
  • the said solvent(s) is selected from the group consisting of a polar solvent and a non- polar solvent or a mixture thereof.
  • the solvent(s) used in the step (d) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • a single solvent is added to the reaction mass of step (iv).
  • the addition of more than one solvent, that is two, three or more solvents to the reaction mass of step (iv) can be made sequentially or can be added as a mixture of solvents.
  • the ratio of at least one solvent or mixture of solvents used in step (v) above to the solution in step (iv) is about 2 volume to 20 volume.
  • the ratio of solvents when more than one solvent is used in step (v) is about 1 volume to 16 volume.
  • step (v) of the process reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
  • step (vi) of the process in the step (vi) of the process the reaction mass obtained in the step (v) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue.
  • the residue obtained in step (vi) is referred to as 'Residue- A' .
  • the residue obtained in step (vi) after filtration is charged with at least one solvent or a mixture of solvents.
  • the said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
  • the solvent(s) used in the step (vii) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • a single solvent is added to the residue obtained in step (vi).
  • the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (vi) can be made sequentially or can be added as a mixture of solvents.
  • the ratio of at least one solvent or mixture of solvents used in step (vii) above to the residue in step (vi) is about 2 volume to 20 volume.
  • the ratio of solvents when more than one solvent is used in step (vii) is about 1 volume to 16 volume.
  • the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
  • step (viii) of the process in the step (viii) of the process the reaction mass obtained in the step (vii) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue.
  • the residue obtained in step (g) is referred to as 'Residue-B'.
  • the residue obtained in step (viii) after filtration is charged with at least one solvent or a mixture of solvents.
  • the said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
  • the solvent(s) used in the step (ix) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
  • a single solvent is added to the residue obtained in step (viii).
  • the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (viii) can be made sequentially or can be added as a mixture of solvents.
  • the ratio of at least one solvent or mixture of solvents used in step (ix) above to the residue in step (viii) is about 2 volume to 12 volume.
  • the ratio of solvents when more than one solvent is used in step (vii) is about 1 volume to 16 volume.
  • step (ix) the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 40 °C for 0.5 h to 5 h.
  • the metal scavenger of the process added to the reaction mass obtained in the step (xiii) can be selected from but not limited to triphenyl phosphine and tributyl phosphine.
  • Residue-A acetone (300 mL) was charged followed by cyclohexane (2000 mL) and the reaction mass was stirred at a temperature of 30 °C for 1 h to 2 h.
  • the resulting reaction mass was then filtered and washed with 13 % solution of acetone in cyclohexane to obtain Residue-B.
  • Residue-B was charged ethyl acetate (500 mL), and the reaction mass was stirred and filtered.
  • reaction mixture was stirred for 1 h, filtered and washed with mixture of methanol and isopropyl alcohol solution, acetone and methyl tert-butyl ether followed by drying at under vacuum below 25 °C for 3-4 h to yield fosaprepitant dimeglumine (50-64 ) having purity more than 99 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a novel process for the preparation of intermediate of fosaprepitant dimeglumine. The present invention particularly relates to a process for the preparation of fosaprepitant dibenzyl ester, an intermediate of fosaprepitant dimeglumine, which is simple, easy to handle on commercial scale and efficient.

Description

A PROCESS FOR PREPARATION OF FOSAPREPITANT DIMEGLUMINE AND AN
INTERMEDIATE THEREOF
Field of the invention
The present invention relates to a novel process for the preparation of an intermediate of fosaprepitant dimeglumine. More particularly, the present invention relates to a process for the preparation of fosaprepitant dibenzyl ester (represented herein by formula II), an intermediate of fosaprepitant dimeglumine. The present invention also relates to a process for the in-situ preparation of fosaprepitant dimeglumine, an antiemetic drug.
Background of the invention
Fosaprepitant, a prodrug of aprepitant is chemically known as [3-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo holinyl]methyl]-2,5-dihydro-5- oxo-lH-l,2,4-triazol-l-yl] phosphonic acid. The N-methyl-D- glucamine salt of fosaprepitant is approved for the treatment of emesis, nausea, cancer therapy toxicity and is available in the market as EMEND® in the US and as IVEMEND® in Europe. Fosaprepitant dimeglumine is structurally represented by following formula I,
Figure imgf000002_0001
Formula I
Fosaprepitant, a phosphorylated aprepitant, when administered intravenously is rapidly converted to aprepitant, which is a substance P/neurokinin 1 (NK1) receptor antagonist. Emend® is used together with other medications to prevent nausea and vomiting that may be caused by surgery or cancer chemotherapy. Fosaprepitant and its salts are disclosed in US Patent No. 5,691,336, which further discloses a process for manufacturing these compounds. The process for preparation of fosaprepitant dimeglumine disclosed in said patent involves two steps, which are schematically presented herein:
Figure imgf000003_0001
Fosaprepitant dibenzyl ester of Formula II
Figure imgf000003_0002
ormu a
According to the US'336 Patent the process for preparation of fosaprepitant dimeglumine involves reaction of aprepitant with tetrabenzyl pyrophosphate using sodium bis(trimethylsilyl)amide (NaHMDS) as a base in the presence of THF as a solvent to obtain crude fosaprepitant dibenzyl ester. This crude fosaprepitant dibenzyl ester obtained is then treated with N-methyl-D-glucamine and Pd/C in the presence of methanol as a solvent to obtain fosaprepitant dimeglumine. The article, Journal of Medicinal Chemistry, 2000, vol. 43, page no. 1234-1241 by Merck Research Laboratories describes in the preparation example of compound 4 that, the compound 4 is isolated as an oil after three chromatographic runs. However, the article does not disclose the purity of compound 4 achieved after three chromatographic runs. US Patent No. 7,807,829 discloses monobenzyl fosaprepitant and its preparation method from aprepitant. The patent teaches that dibenzyl phosphoramidate compound (fosaprepitant dibenzyl ester) is very unstable and is present as an amorphous material, therefore the inventors of said patent converted unstable fosaprepitant dibenzyl ester to stable monobenzyl fosaprepitant. US Patent No. 8,623,844 describes a process for preparation of isolated solid crystalline fosaprepitant dibenzyl ester from crude fosaprepitant dibenzyl ester. The process involves obtaining a solution of fosaprepitant dibenzyl ester in a solvent such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tertiary butyl acetate or mixture of solvents; followed by addition of an anti-solvent such as n-pentane, n-hexane, n-heptane, cyclohexane to recover fosaprepitant dibenzyl ester as a crystalline solid. The isolated solid crystalline fosaprepitant dibenzyl ester is of 93.74 % purity and contains unknown impurities to an extent of 3.83 %. The fosaprepitant dimeglumine prepared from said isolated solid crystalline fosaprepitant dibenzyl ester is of 94.5 % purity and the purity of fosaprepitant dimeglumine after additional step of purification is enhanced to 99.76 %.
Indian Patent Application No. 2188/CHE/2011 describes an improved process for preparation of fosaprepitant dimeglumine and its intermediate fosaprepitant dibenzyl ester. The process also teaches preparation of co-crystal of fosaprepitant dibenzyl ester with sodium chloride. However, the purity of fosaprepitant dibenzyl ester prepared using said process is not reported in the IN'2188 application. Further, the fosaprepitant dimeglumine prepared using said improved process has purity of at least about 97.1 , which is not a pharmaceutically acceptable grade purity of fosaprepitant dimeglumine. Moreover, the improved process disclosed in IN'2188 application is very lengthy, tedious and involves use of thiophenol resin in the preparation process, which may result in the presence of sulfur content in the fosaprepitant dimeglumine. The API, fosaprepitant dimeglumine is a highly sensitive moiety and multiple purifications to achieve pharmaceutically acceptable grade purity leads to degradation of fosaprepitant dimeglumine to aprepitant. Therefore, there is a need to prepare highly pure fosaprepitant dibenzyl ester and then convert it to fosaprepitant dimeglumine in order to achieve pharmaceutically acceptable grade purity.
The afore discussed prior art references provide processes for the preparation of fosaprepitant dibenzyl ester and its conversion to fosaprepitant dimeglumine involves either chromatographic purification of fosaprepitant dibenzyl ester oil or isolation of solid crystalline fosaprepitant dibenzyl ester. However in case of column chromatographic purification of fosaprepitant dibenzyl ester oil, the purification involves three chromatographic runs, which is tedious, lengthy and commercially non-feasible process. Further, the non-disclosure of purity of fosaprepitant dibenzyl ester after three chromatographic runs leads to an uncertainty.
Although, US Patent No. 8,623,844 teaches isolation of solid crystalline fosaprepitant dibenzyl ester, the isolated fosaprepitant dibenzyl ester is unstable and highly hygroscopic in nature and even slight exposure to air will degrade fosaprepitant dibenzyl ester to fosaprepitant monobenzyl ester and/or aprepitant, therefore the fosaprepitant dibenzyl ester obtained according to US' 844 patent cannot be stored. Thus, the said process is commercially non-viable. Further, the purity of fosaprepitant dibenzyl ester and its converted fosaprepitant dimeglumine, without additional step of purification is 94.5 , which is not of pharmaceutically acceptable grade.
Thus, there is a need to develop a robust process for preparation of highly unstable fosaprepitant dibenzyl ester and its conversion to fosaprepitant dimeglumine, which is industrially acceptable, commercially viable and provides purity of pharmaceutically acceptable grade, without any additional step of purification.
Ob jects of the invention
An object of the present invention is to provide a process for preparation of pure fosaprepitant dibenzyl ester of formula II. Another object of the present invention is to provide a process for the preparation of fosaprepitant dibenzyl ester, wherein the purity of fosaprepitant dibenzyl ester is > 96 %.
An object of the present invention is to provide a process for the in-situ preparation of fosaprepitant dimeglumine of formula I from aprepitant of formula III.
Yet another object of the present invention is to provide a process for the preparation of fosaprepitant dimeglumine from said pure fosaprepitant dibenzyl ester, wherein the purity of fosaprepitant dimeglumine is > 99 , without any additional step of purification.
Summary of the invention
In accordance with an aspect of the present invention, there is provided a process for the preparation of intermediate of fosaprepitant dimeglumine. The present invention particularly provides a process for the preparation of [3-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo holinyl]methyl]-2,5-dihydro-5- oxo-lH-l,2,4-triazol-l-yl]-phosphonic acid bis(phenylmethyl) ester (fosaprepitant dibenzyl ester) of formula II,
Figure imgf000006_0001
Formula II
comprising the steps of,
(a) obtaining a solution of fosaprepitant dibenzyl ester of formula II in at least one solvent or a mixture of solvents thereof,
(b) adding an inorganic acid to the solution obtained in step (a),
(c) concentrating the reaction mass obtained in step (b), (d) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (c),
(e) filtering the reaction mass obtained in step (d) to obtain a residue, Residue-A,
(f) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (e),
(g) filtering the reaction mass obtained in step (f) to obtain a residue, Residue-B,
(h) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (g),
(i) filtering the reaction mass obtained in step (h),
(j) concentrating the filtrate obtained in step (i) to yield fosaprepitant dibenzyl ester of purity > 96 %.
In accordance with another aspect of the present invention, there is provided a process for the in situ preparation of l-deoxy-l-(methylamino)-D-Glucitol[3-[[(2R,3S)-2-[(lR)-l-[3,5 bis(trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl)-4-mo holinyl]methyl]-2,5-dihydro-5 oxo-lH-l,2,4-triazol-l-yl] phosphonate (2:1) salt (fosaprepitant dimeglumine) of formula I,
Figure imgf000007_0001
Formula I
comprising the steps of,
(i) treating aprepitant of formula III with tetrabenzyl pyrophosphate using a base in the presence of a solvent at a temperature of -35 °C to 0 °C for 1 h to 4 h to obtain fosaprepitant dibenzyl ester,
(ii) adding at least one solvent or a mixture of solvents to the reaction mass obtained in step
(i),
(iii) adding an inorganic acid to the reaction mass obtained in step (ii),
(iv) concentrating the reaction mass obtained in step (iii), (v) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (iv),
(vi) filtering the reaction mass obtained in step (v) to obtain a residue, Residue-A,
(vii) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (vi),
(viii) filtering the reaction mass obtained in step (vii) to obtain a residue, Residue-B,
(ix) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (viii),
(x) filtering the reaction mass obtained in step (ix) and concentrating the filtrate to yield fosaprepitant dibenzyl ester of purity > 96 % as an oil,
(xi) dissolving the oil obtained in step (x) in at least one solvent or a mixture of solvents thereof,
(xii) adding N-methyl-D-glucamine and Pd/C to the reaction mass obtained in step (xi) and hydrogenating the reaction mass for 8 h to 14 h at 2 kg to 8 kg pressure,
(xiii) filtering the reaction mass obtained in step (xii),
(xiv) adding metal scavenger to the reaction mass obtained in step (xiii) and stirring for 8 h to 14 h,
(xv) obtaining fosaprepitant dimeglumine of purity > 99 % from the resulting reaction mass of step (xiv) on further work-up.
In accordance with another aspect of the present invention, the process of the present invention overcomes the disadvantages associated with the processes described in the prior art, which involves use of multiple column chromatography for purification of fosaprepitant dibenzyl ester or involves the isolation of unstable crystalline fosaprepitant dibenzyl ester.
The inventors of the present invention surprisingly found that use of an inorganic acid in the process results in highly pure fosaprepitant dibenzyl ester. The inorganic acid used in the process is simple, easy to handle on commercial scale and cost-effective; thereby making the process for preparation of fosaprepitant dibenzyl ester and its conversion to fosaprepitant dimeglumine simple, efficient and industrially applicable. Detailed description of the invention
The present invention relates to a process for the preparation of [3-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo holinyl]methyl]-2,5-dihydro-5- oxo-lH-l,2,4-triazol-l-yl]-phosphonic acid bis(phenylmethyl) ester (fosaprepitant dibenzyl ester) of formula II,
Figure imgf000009_0001
Formula II
comprising the steps of,
(a) obtaining a solution of fosaprepitant dibenzyl ester of formula II in at least one solvent or a mixture of solvents thereof,
(b) adding an inorganic acid to the solution obtained in step (a),
(c) concentrating the reaction mass obtained in step (b),
(d) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (c),
(e) filtering the reaction mass obtained in step (d) to obtain a residue, Residue-A,
(f) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (e),
(g) filtering the reaction mass obtained in step (f) to obtain a residue, Residue-B,
(h) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (g),
(i) filtering the reaction mass obtained in step (h),
(j) concentrating the filtrate obtained in step (i) to yield fosaprepitant dibenzyl ester of purity The term, 'pharmaceutically acceptable grade' used herein refers to the Fosaprepitant Dimeglumine of formula I of purity > 99 , fosaprepitant dimeglumine is not listed in any pharmacopeia. In an embodiment of the present invention, in the step (a) of the process a solution of fosaprepitant dibenzyl ester is prepared by dissolving fosaprepitant dibenzyl ester in at least one solvent or a mixture of solvents. The fosaprepitant dibenzyl ester used at this step can be obtained from reaction of aprepitant with tetrabenzyl pyrophosphate in the presence of a base and a solvent, as described in the US Patent No. 5,691,336. Also, the fosaprepitant dibenzyl ester prepared by any process can be used in-situ at this step of the process.
The fosaprepitant dibenzyl ester used in step (a) of the process obtained according to the process described in US Patent No. 5,691,336 or prepared by any other process known in the prior art is of purity < 78 %.
The solvent(s) used for preparing the fosaprepitant dibenzyl ester solution in step (a) of the process is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof. The solvent(s) used in the step (a) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
The solution of fosaprepitant dibenzyl ester of step (a) can be prepared by addition of one solvent or by addition of more than one solvents, that is two, three or more solvents sequentially, or as a mixture of solvents.
In an embodiment of the present invention, in the step (b) of the process an inorganic acid is added to the solution of fosaprepitant dibenzyl ester obtained in step (a). The said inorganic acid is selected from, but not limited to boric acid.
In accordance with embodiment of said process step (b), the inorganic acid charged is about 0.5 to 5 equivalents based on the quantity of fosaprepitant dibenzyl ester of formula II. In an embodiment of the present invention, in the step (c) of the process the reaction mass obtained after treatment with inorganic acid in the step (b) is concentrated or evaporated to dryness. The concentration of reaction mass is carried out at a temperature lower than 40 °C. The reaction mass obtained after concentration is light yellow to brown thick sticky mass.
In an embodiment of the present invention, in the step (d) of the process the reaction mass obtained after concentration in step (c) is charged with at least one solvent or a mixture of solvents. The said solvent(s) is selected from the group consisting of a polar solvent and a non- polar solvent or a mixture thereof.
The solvent(s) used in the step (d) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof. In an embodiment, a single solvent is added to the reaction mass of step (c). In another embodiment, the addition of more than one solvent, that is two, three or more solvents to the reaction mass of step (c) can be made sequentially or can be added as a mixture of solvents.
The ratio of at least one solvent or mixture of solvents used in step (d) above to the solution in step (c) is about 2 volume to 20 volume. The ratio of solvents when more than one solvent is used in step (d) is about 1 volume to 16 volume.
In the step (d) of the process reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
In an embodiment of the present invention, in the step (e) of the process the reaction mass obtained in the step (d) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue. For the purpose of clarity the residue obtained in step (e) is referred to as 'Residue- A' .
In an embodiment of the present invention, in the step (f) of the process the residue obtained in step (e) after filtration is charged with at least one solvent or a mixture of solvents. The said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof. The solvent(s) used in the step (f) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
In an embodiment, a single solvent is added to the residue obtained in step (e). In another embodiment, the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (e) can be made sequentially or can be added as a mixture of solvents. The ratio of at least one solvent or mixture of solvents used in step (f) above to the residue in step (e) is about 2 volume to 20 volume. The ratio of solvents when more than one solvent is used in step (f) is about 1 volume to 16 volume.
In the step (f) the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
In an embodiment of the present invention, in the step (g) of the process the reaction mass obtained in the step (f) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue. For the purpose of clarity the residue obtained in step (g) is referred to as 'Residue-B'.
In an embodiment of the present invention, in the step (h) of the process, the residue obtained in step (g) after filtration is charged with at least one solvent or a mixture of solvents. The said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
The solvent(s) used in the step (h) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
In an embodiment, a single solvent is added to the residue obtained in step (g). In another embodiment, the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (g) can be made sequentially or can be added as a mixture of solvents. The ratio of at least one solvent or mixture of solvents used in step (h) above to the residue in step (g) is about 2 volume to 12 volume. The ratio of solvents when more than one solvent is used in step (f) is about 1 volume to 16 volume.
In the step (h), the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 40 °C for 0.5 h to 5 h.
In an embodiment of the present invention, in the step (i) of the process the reaction mass obtained in the step (h) after addition of at least one solvent or a mixture of solvents thereof is filtered and the filtrate is washed with solution of sodium chloride. The resulting filtrate organic layer is dried using sodium sulphate and concentrated at a temperature lower than 40 °C to yield thick oily syrup of fosaprepitant dibenzyl ester of purity > 96 %.
The present invention also relates to a process for the in-situ 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- 1 H- 1 ,2,4-triazol- 1 -yl] phosphonate (2: 1) salt (fosaprep
Figure imgf000013_0001
Formula I
comprising the steps of,
(i) treating aprepitant of formula III with tetrabenzyl pyrophosphate using a base in the presence of a solvent at a temperature of -35 °C to 0 °C for 1 h to 4 h to obtain fosaprepitant dibenzyl ester,
(ii) adding at least one solvent or a mixture of solvents to the reaction mass obtained in step (i),
(iii) adding an inorganic acid to the reaction mass obtained in step (ii),
(iv) concentrating the reaction mass obtained in step (iii), (v) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (iv),
(vi) filtering the reaction mass obtained in step (v) to obtain a residue, Residue-A,
(vii) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (vi),
(viii) filtering the reaction mass obtained in step (vii) to obtain a residue, Residue-B,
(ix) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (viii),
(x) filtering the reaction mass obtained in step (ix) and concentrating the filtrate to yield fosaprepitant dibenzyl ester of purity > 96 % as an oil,
(xi) dissolving the oil obtained in step (x) in at least one solvent or a mixture of solvents thereof,
(xii) adding N-methyl-D-glucamine and Pd/C to the reaction mass obtained in step (xi) and hydrogenating the reaction mass for 8 h to 14 h at 2 kg to 8 kg pressure,
(xiii) filtering the reaction mass obtained in step (xii),
(xiv) adding metal scavenger to the reaction mass obtained in step (xiii) and stirring for 8 h to 14 h,
(xv) obtaining fosaprepitant dimeglumine of purity > 99 % from the resulting reaction mass of step (xiv) on further work-up.
The compound of formula III, aprepitant is a known compound and can be prepared by a person skilled in the art by following the processes known in the art. For example the US Patent No. 5,719,147 discloses aprepitant of formula II and its preparation method. In an embodiment of the present invention, in the step (ii) of the process a solution of fosaprepitant dibenzyl ester is prepared by dissolving fosaprepitant dibenzyl ester in at least one solvent or a mixture of solvents. The fosaprepitant dibenzyl ester used at this step can be obtained from reaction of aprepitant with tetrabenzyl pyrophosphate in the presence of a base and a solvent, as described in the US Patent No. 5,691,336. Also, the fosaprepitant dibenzyl ester prepared by any process can be used in-situ at this step of the process.
The fosaprepitant dibenzyl ester used in step (ii) of the process obtained according to the process described in US Patent No. 5,691,336 or prepared by any other process known in the prior art is of purity < 78 . The solvent(s) used for preparing the fosaprepitant dibenzyl ester solution in step (ii) of the process is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
The solvent(s) used in the step (ii) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof. The solution of fosaprepitant dibenzyl ester of step (ii) can be prepared by addition of one solvent or by addition of more than one solvent, that is two, three or more solvents sequentially, or as a mixture of solvents.
In an embodiment of the present invention, in the step (iii) of the process an inorganic acid is added to the solution of fosaprepitant dibenzyl ester obtained in step (ii). The said inorganic acid is selected from, but not limited to boric acid.
In accordance with embodiment of said process step (iii), the inorganic acid charged is about 0.5 to 5 equivalents based on the quantity of fosaprepitant dibenzyl ester of formula II.
In an embodiment of the present invention, in the step (iv) of the process the reaction mass obtained after treatment with inorganic acid in the step (iii) is concentrated or evaporated to dryness. The concentration of reaction mass is carried out at a temperature lower than 40 °C. The reaction mass obtained after concentration is light yellow to brown thick sticky mass.
In an embodiment of the present invention, in the step (v) of the process the reaction mass obtained after concentration in step (iv) is charged with at least one solvent or a mixture of solvents. The said solvent(s) is selected from the group consisting of a polar solvent and a non- polar solvent or a mixture thereof.
The solvent(s) used in the step (d) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof. In an embodiment, a single solvent is added to the reaction mass of step (iv). In another embodiment, the addition of more than one solvent, that is two, three or more solvents to the reaction mass of step (iv) can be made sequentially or can be added as a mixture of solvents. The ratio of at least one solvent or mixture of solvents used in step (v) above to the solution in step (iv) is about 2 volume to 20 volume. The ratio of solvents when more than one solvent is used in step (v) is about 1 volume to 16 volume.
In the step (v) of the process reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
In an embodiment of the present invention, in the step (vi) of the process the reaction mass obtained in the step (v) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue. For the purpose of clarity the residue obtained in step (vi) is referred to as 'Residue- A' .
In an embodiment of the present invention, in the step (vii) of the process the residue obtained in step (vi) after filtration is charged with at least one solvent or a mixture of solvents. The said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
The solvent(s) used in the step (vii) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
In an embodiment, a single solvent is added to the residue obtained in step (vi). In another embodiment, the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (vi) can be made sequentially or can be added as a mixture of solvents. The ratio of at least one solvent or mixture of solvents used in step (vii) above to the residue in step (vi) is about 2 volume to 20 volume. The ratio of solvents when more than one solvent is used in step (vii) is about 1 volume to 16 volume. In the step (vii) the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 50 °C for 0.5 h to 5 h.
In an embodiment of the present invention, in the step (viii) of the process the reaction mass obtained in the step (vii) after addition of at least one solvent or a mixture of solvents thereof is filtered to obtain a residue. For the purpose of clarity the residue obtained in step (g) is referred to as 'Residue-B'.
In an embodiment of the present invention, in the step (ix) of the process, the residue obtained in step (viii) after filtration is charged with at least one solvent or a mixture of solvents. The said solvent(s) is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
The solvent(s) used in the step (ix) of the process is selected from, but not limited to methyl tert- butyl ether, tetrahydrofuran, toluene, acetone, isobutyl methyl ketone, ethyl acetate, dichloromethane and cyclohexane or a mixture thereof.
In an embodiment, a single solvent is added to the residue obtained in step (viii). In another embodiment, the addition of more than one solvent, that is two, three or more solvents to the residue obtained in step (viii) can be made sequentially or can be added as a mixture of solvents.
The ratio of at least one solvent or mixture of solvents used in step (ix) above to the residue in step (viii) is about 2 volume to 12 volume. The ratio of solvents when more than one solvent is used in step (vii) is about 1 volume to 16 volume.
In the step (ix), the reaction mass obtained after the addition of at least one solvent or a mixture of solvents is stirred at a temperature lower than 40 °C for 0.5 h to 5 h.
In an embodiment of the present invention, in the step (x) of the process of the reaction mass obtained in the step (ix) after addition of at least one solvent or a mixture of solvents thereof is filtered. The resulting filtrate organic layer is dried using sodium sulphate and concentrated at a temperature lower 40 °C to yield thick oily syrup of fosaprepitant dibenzyl ester of purity > 96 %. In an embodiment of the present invention, in the step (xiv), the metal scavenger of the process added to the reaction mass obtained in the step (xiii) can be selected from but not limited to triphenyl phosphine and tributyl phosphine. The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in anyway to limit the scope of the present invention.
Examples
Example-1: Preparation of fosaprepitant dibenzyl ester
To a reaction flask was charged fosaprepitant dibenzyl ester of formula II (170 g) and methyl tert-butyl ether (1000 mL) to obtain a solution. Then boric acid (100 g) was added to the resulting solution and the obtained reaction mass was concentrated at a temperature of 30 °C to obtain a light yellow to brown thick sticky mass. To this sticky mass, toluene (300 mL) was charged followed by cyclohexane (2000 mL) and the reaction mass was stirred at a temperature of 30 °C for 1 h to 2 h. The resulting reaction mass was then filtered, washed with 13 % solution of toluene in cyclohexane to obtain Residue-A. To the obtained Residue-A acetone (300 mL) was charged followed by cyclohexane (2000 mL) and the reaction mass was stirred at a temperature of 30 °C for 1 h to 2 h. The resulting reaction mass was then filtered and washed with 13 % solution of acetone in cyclohexane to obtain Residue-B. To the Residue-B obtained, was charged ethyl acetate (500 mL), and the reaction mass was stirred and filtered. The filtrate was then washed twice with 10 % solution of sodium chloride (500 mL). The resulting organic layer of ethyl acetate was dried over anhydrous sodium sulphate. The ethyl acetate layer was then concentrated under vacuum at a temperature of 30 °C to yield fosaprepitant dibenzyl ester of formula II as an oil of 99.18 % purity and a yield of 74 %.
Example-2: Preparation of fosaprepitant dimeglumine
To fosaprepitant dibenzyl ester (110 g) of formula II as an oil obtained in example-1, methanol (800 mL) added and stirred for a while followed by addition of 5 % Pd/C and methanol (110 mL). Hydrogen pressure 2.5kg /cm2 to 3.0 kg /cm2 was applied and stirred at 20-30 °C for 4 h. N- methyl D-glutamine (55 g) and methanol (200 mL) was added into the reaction mixture and hydrogen pressure 2.5kg /cm 2 to 3.0 kg /cm 2 was applied. The reaction mixture was stirred at 20- 30°C for 20 h. Pd/C was filtered from the reaction mixture and fresh methanol (220 mL) was added into it followed by addition of tributyl phosphine (6.6 mL), methanol (220 mL) and stirred for about 20-23 h under nitrogen at 20-30 °C. To the reaction mixture activated carbon (11 g) was added and stirred for about 1 h. The reaction mixture was filtered and concentrated under vacuum up to -2.0-3.5 volume at 20-30 °C. Then after 11 % orthophosphoric acid solution was added to adjust the pH reaction mass to 7.5-8.5 followed by addition of methanol (300 mL) and isopropyl alcohol (2750 mL) to the reaction mixture. The reaction mixture was stirred for 1 h, filtered and washed with mixture of methanol and isopropyl alcohol solution, acetone and methyl tert-butyl ether followed by drying at under vacuum below 25 °C for 3-4 h to yield fosaprepitant dimeglumine (50-64 ) having purity more than 99 .

Claims

We Claim:
1. A process for the preparation of [3-[[(2R,3S)-2-[(lR)-l-[3,5- bis(trifluoromemyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5- oxo-lH-l,2,4-triazol-l-yl]-phosphonic acid bis(phenylmethyl) ester (fosaprepitant dibenzyl ester) of formula II,
Figure imgf000020_0001
Formula II
comprising the steps of,
(a) obtaining a solution of fosaprepitant dibenzyl ester of formula II in at least one solvent or a mixture of solvents thereof,
(b) adding an inorganic acid to the solution obtained in step (a),
(c) concentrating the reaction mass obtained in step (b),
(d) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (c),
(e) filtering the reaction mass obtained in step (d) to obtain a residue, Residue-A,
(f) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (e),
(g) filtering the reaction mass obtained in step (f) to obtain a residue, Residue-B,
(h) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (g),
(i) filtering the reaction mass obtained in step (h),
(j) concentrating the filtrate obtained in step (i) to yield fosaprepitant dibenzyl ester of purity > 96 %.
2. The process according to claim 1, wherein solvent used for preparing the fosaprepitant dibenzyl ester solution in step (a), step (d), step (f) and step (h) of the process is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
3. The process according to claim 1, wherein inorganic acid used in step (b) is boric acid.
4. A process for the in-situ preparation of l-deoxy-l-(methylamino)-D-Glucitol[3-[[(2R,3S)-2- [( 1 R)- 1 - [3 ,5-bis(trifluoromethyl) phenyl] ethoxy] -3-(4-fluorophenyl)-4-mo holinyl]methyl] - 2,5-dihydro-5-oxo-lH-l,2,4-triazol-l-yl] phosphonate (2: 1) salt (fosaprepitant dimeglumine) of formula I,
Figure imgf000021_0001
Formula I
comprising the steps of,
(i) treating aprepitant of formula III with tetrabenzyl pyrophosphate using a base in the presence of a solvent at a temperature of -35 °C to 0 °C for 1 h to 4 h to obtain fosaprepitant dibenzyl ester,
(ii) adding at least one solvent or a mixture of solvents to the reaction mass obtained in step (i),
(iii) adding an inorganic acid to the reaction mass obtained in step (ii),
(iv) concentrating the reaction mass obtained in step (iii),
(v) adding at least one solvent or a mixture of solvents thereof to the reaction mass obtained in step (iv),
(vi) filtering the reaction mass obtained in step (v) to obtain a residue, Residue-A,
(vii) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (vi),
(viii) filtering the reaction mass obtained in step (vii) to obtain a residue, Residue-B, (ix) adding at least one solvent or a mixture of solvents thereof to the residue obtained in step (viii),
(x) filtering the reaction mass obtained in step (ix) and concentrating the filtrate to yield fosaprepitant dibenzyl ester of purity > 96 % as an oil,
(xi) dissolving the oil obtained in step (x) in at least one solvent or a mixture of solvents thereof,
(xii) adding N-methyl-D-glucamine and Pd/C to the reaction mass obtained in step (xi) and hydrogenating the reaction mass for 8 h to 14 h at 2 kg to 8 kg pressure,
(xiii) filtering the reaction mass obtained in step (xii),
(xiv) adding metal scavenger to the reaction mass obtained in step (xiii) and stirring for 8 h to 14 h,
(xv) obtaining fosaprepitant dimeglumine of purity > 99 % from the resulting reaction mass of step (xiv) on further work-up.
5. The process according to claim 4, wherein solvent used for preparing the fosaprepitant dimeglumine in step (ii), step (v), step (vii), step (ix) and step (xi) of the process is selected from the group consisting of a polar solvent and a non-polar solvent or a mixture thereof.
6. The process according to claim 4, wherein inorganic acid used in step (iii) is boric acid.
7. The process according to claim 4, wherein metal scavenger is selected from triphenyl phosphine and tributyl phosphine.
PCT/IB2016/057194 2015-12-01 2016-11-30 A process for preparation of fosaprepitant dimeglumine and an intermediate thereof WO2017093899A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP16870086.2A EP3383829B1 (en) 2015-12-01 2016-11-30 A process for preparation of fosaprepitant dimeglumine and an intermediate thereof
US15/779,910 US10428097B2 (en) 2015-12-01 2016-11-30 Process for preparation of fosaprepitant dimeglumine and an intermediate thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4518MU2015 2015-12-01
IN4518/MUM/2015 2015-12-01

Publications (1)

Publication Number Publication Date
WO2017093899A1 true WO2017093899A1 (en) 2017-06-08

Family

ID=58796406

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/057194 WO2017093899A1 (en) 2015-12-01 2016-11-30 A process for preparation of fosaprepitant dimeglumine and an intermediate thereof

Country Status (3)

Country Link
US (1) US10428097B2 (en)
EP (1) EP3383829B1 (en)
WO (1) WO2017093899A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045605A (en) * 2021-03-30 2021-06-29 浙江亚瑟医药有限公司 Preparation method and purification method of fosaprepitant dimeglumine

Citations (9)

* 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
US5719147A (en) 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
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
US7807829B2 (en) 2004-11-05 2010-10-05 Merck & Co., Inc. Process for {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
WO2012164576A2 (en) 2011-06-03 2012-12-06 Hetero Research Foundation Process for fosaprepitant
CN103183708A (en) 2011-12-31 2013-07-03 扬子江药业集团上海海尼药业有限公司 Preparation method for fosaprepitant dimeglumine
CZ2012294A3 (en) 2012-04-30 2013-11-13 Zentiva, K.S. Process for preparing and cleaning novel polymorphs of phosphaprepitant intermediate
WO2013168176A2 (en) * 2012-03-30 2013-11-14 Glenmark Generics Limited Process for preparation of fosaprepitant and salt thereof
IN2013MU01180A (en) * 2013-03-28 2015-04-17 Piramal Entpr Ltd

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5719147A (en) 1992-06-29 1998-02-17 Merck & Co., Inc. Morpholine and thiomorpholine tachykinin receptor antagonists
US5691336A (en) 1994-03-04 1997-11-25 Merck & Co., Inc. Morpholine compounds are prodrugs useful as tachykinin receptor antagonists
US7807829B2 (en) 2004-11-05 2010-10-05 Merck & Co., Inc. Process for {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
US8623844B2 (en) 2008-07-17 2014-01-07 Navin Ganesh Bhatt Fosaprepitant dimeglumine intermediate, neutral fosaprepitant, and amorphous fosaprepitant dimeglumine and processes for their preparations
WO2012164576A2 (en) 2011-06-03 2012-12-06 Hetero Research Foundation Process for fosaprepitant
CN103183708A (en) 2011-12-31 2013-07-03 扬子江药业集团上海海尼药业有限公司 Preparation method for fosaprepitant dimeglumine
WO2013168176A2 (en) * 2012-03-30 2013-11-14 Glenmark Generics Limited Process for preparation of fosaprepitant and salt thereof
CZ2012294A3 (en) 2012-04-30 2013-11-13 Zentiva, K.S. Process for preparing and cleaning novel polymorphs of phosphaprepitant intermediate
IN2013MU01180A (en) * 2013-03-28 2015-04-17 Piramal Entpr Ltd

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Journal of Medicinal Chemistry", vol. 43, 2000, MERCK RESEARCH LABORATORIES, pages: 1234 - 1241
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 2013:450723, ANONYMOUS XP 055554485 *
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 2015:703203, ANONYMOUS XP055554491 *
HALE, J. J. ET AL.: "Phosphorylated morpholine acetal human Neurokinin-1 receptor antagonists as water-soluble prodrugs", J. MED. CHEM., vol. 43, 2000, pages 1234 - 1241, XP 009066442 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045605A (en) * 2021-03-30 2021-06-29 浙江亚瑟医药有限公司 Preparation method and purification method of fosaprepitant dimeglumine
CN113045605B (en) * 2021-03-30 2022-06-07 浙江亚瑟医药有限公司 Preparation method and purification method of fosaprepitant dimeglumine

Also Published As

Publication number Publication date
EP3383829A4 (en) 2019-05-01
US20180354977A1 (en) 2018-12-13
EP3383829A1 (en) 2018-10-10
EP3383829B1 (en) 2020-10-21
US10428097B2 (en) 2019-10-01

Similar Documents

Publication Publication Date Title
EP3077404B1 (en) Purification of tenofovir alafenamide and its intermediates
JP6431155B2 (en) Phenol derivative, its production method and medicinal application
US8623844B2 (en) Fosaprepitant dimeglumine intermediate, neutral fosaprepitant, and amorphous fosaprepitant dimeglumine and processes for their preparations
RU2266909C2 (en) Water-soluble azole compounds and method for their preparing
EP2714701B1 (en) Process for fosaprepitant
CN102725300B (en) Proteasome inhibitors and processes for their preparation, purification and use
CN102143967B (en) Purification method for adefovir dipivoxil
WO2010095145A1 (en) Process for the preparation of voriconazole
EP3100735B1 (en) Crystalline fosaprepitant dicyclohexylamine salt and its preparation
CN101228109A (en) Separation of stereoisomeric n,n-dialkylamino-2-alkyl-3-phenyl alkanes
EP3383829B1 (en) A process for preparation of fosaprepitant dimeglumine and an intermediate thereof
JPH0395195A (en) Substituted aminoalkylphosphinic acid
WO2013168176A2 (en) Process for preparation of fosaprepitant and salt thereof
JP4579496B2 (en) Improved method for water-soluble azole compounds
WO2017118928A9 (en) Process for the separation of diastereomers of tenofovir alafenamide
EP2432788A1 (en) Amorphous fosamprenavir calcium
Antczak et al. AIBN-initiated radical reactions of ethyl phosphinate
Piotrowska Stereochemistry of substituted isoxazolidines derived from N-methyl C-diethoxyphosphorylated nitrone
WO2015083033A1 (en) An improved process for the preparation of fosaprepitant having improved purity
JP2007204384A (en) Optically active phosphoric acid derivative and method for producing optically active sphingosine 1-phosphate derivative using the same
AU2001284307A1 (en) Tetrahydrofuran derivatives and their use as NK-1 antagonists
WO2002024673A1 (en) Tetrahydrofuran derivatives and their use as nk-1 antagonists
JPH0390091A (en) Substituted amino acid or imino acid derivative and antihypertensive agent containing same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16870086

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016870086

Country of ref document: EP