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WO2018211410A1 - Procédé amélioré de préparation de fosaprépitant ou d'un sel de celui-ci - Google Patents

Procédé amélioré de préparation de fosaprépitant ou d'un sel de celui-ci Download PDF

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Publication number
WO2018211410A1
WO2018211410A1 PCT/IB2018/053367 IB2018053367W WO2018211410A1 WO 2018211410 A1 WO2018211410 A1 WO 2018211410A1 IB 2018053367 W IB2018053367 W IB 2018053367W WO 2018211410 A1 WO2018211410 A1 WO 2018211410A1
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WO
WIPO (PCT)
Prior art keywords
fosaprepitant
formula
compound
dibenzylester
impurity
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2018/053367
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English (en)
Inventor
Shekhar Bhaskar Bhirud
Samir Naik
Amit Tewari
Yogesh Baburao Kajale
Mahendra Joma CHORAGHE
Shivaji Eknath JAGADALE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glenmark Pharmaceuticals Ltd
Original Assignee
Glenmark Pharmaceuticals Ltd
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 Glenmark Pharmaceuticals Ltd filed Critical Glenmark Pharmaceuticals Ltd
Publication of WO2018211410A1 publication Critical patent/WO2018211410A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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

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.
  • Fosaprepitant represented by compound of Formula I is a prodrug of aprepitant.
  • Fosaprepitant dimeglumine is approved in United States by brand name EMEND ®
  • EMEND ® for injection is a substance P/neurokinin-1 (NK1) receptor antagonist, indicated in adults, in combination with other antiemetic agents, for the prevention of (1): acute and delayed nausea and vomiting associated with initial and repeat courses of high emetogenic cancer chemotherapy (HEC) including high-dose cisplatin; and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC).
  • HEC high emetogenic cancer chemotherapy
  • MEC moderately emetogenic cancer chemotherapy
  • Fosaprepitant dimeglumine is chemically known as 1-Deoxy- l- (methylamino) -D-glucitol[3 - [ [(2R,3 S )-2- [( 1 R)- 1 - [3 ,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-lH- 1,2,4- triazol-l-yl] phosphonate (2: 1) (salt).
  • United States Pat. No. 5,691,336 describes process for the preparation of fosaprepitant by reacting aprepitant, a compound of Formula III with tetrabenzyl pyrophosphate in presence of a sodium hexamethyldisilazane (NaHMDS) base to obtain fosaprepitant dibenzylester, a compound of Formula II.
  • NaHMDS sodium hexamethyldisilazane
  • fosaprepitant dibenzylester, compound of Formula II is then converted to fosaprepitant compound of Formula I by debenzylation.
  • the present invention relates to process for the preparation of fosaprepitant a compound of Formula I or salt thereof,
  • Formula I comprising: a) reacting aprepitant, a compound of Formula III,
  • the present invention relates to an improved process for the preparation of fosaprepitant, compound of formula I or salt thereof.
  • the present invention provides a process for the preparation of fosaprepitant, compound of formula I or salt thereof, comprising:
  • reaction mass containing fosaprepitant dibenzylester, compound of Formula II; b) optionally stirring the reaction mass; c) isolating the fosaprepitant dibenzylester, compound of Formula II from the reaction mass; and
  • catalytic amount of water means water used in less than 1% w/v of ether solvent.
  • step a) water is used in an amount of less than 0.5% w/v of ether solvent.
  • step a) less than 0.5% w/v means less than 0.001% to 0.0045% w/v of ether solvent. In one embodiment, in step a) water is used in catalytic amount in the range of 0.1% to 0.4% w/v of ether solvent.
  • step a) water is used in catalytic amount in the range of 0.1% to 0.2% w/v of ether solvent.
  • ether may be selected from the group consisting of isopropyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether tetrahydrofuran, tetrahydropyran and the like.
  • the hydride base may be selected from the group consisting of sodium, hydride potassium hydride, lithium hydride and the like.
  • reaction of step a) is carried out below about 20 °C.
  • reaction of step a) is carried out for a period of about 5 minutes to about 30 minutes.
  • reaction of aprepitant a compound of formula III with tetrabenzyl pyrophosphate may be carried out in presence of catalytic amount of water in tetrahydrofuran.
  • step b) stirring can be carried out for a period of about about 5 minutes to about 20 minutes.
  • step c) the fosaprepitant dibenzylester, compound of Formula II may be obtained as a solid by dissolving the degasses mass in ethyl acetate and precipitated by addition of cyclohexane.
  • the fosaprepitant dibenzylester, compound of Formula II may be purified by ethyl acetate and cyclohexane.
  • the present invention provides fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 1% w/w relative to the amount of compound of Formula as determined by HPLC.
  • the present invention provides fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.5% w/w relative to the amount of compound of Formula II as determined by HPLC.
  • the present invention provides fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.15% w/w relative to the amount of compound of Formula II as determined by HPLC.
  • step d) debenzylation of fosaprepitant dibenzylester compound of Formula II can be carried out by hydrogenating in the presence of palladium- carbon.
  • debenzylation of fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.15% leads to fosaprepitant, compound of Formula I or salt thereof, wherein level of impurity F less than 0.15%.
  • debenzylation of fosaprepitant dibenzylester, compound of Formula II, wherein level of impurity F less than 0.15% leads to fosaprepitant, compound of Formula I or salt thereof, wherein level of impurity F is not detected or absent.
  • fosaprepitant dimeglumine may be prepared by reacting foasprepitant, compound of Formula I with N-methyl-D-glucamine.
  • the fosaprepitant dimeglumine may be prepared by hydrogenating the fosaprepitant dibenzylester, compound of Formula II in the presence of Pd/C and N-methyl-D-glucamine.
  • the fosaprepitant dimeglumine obtained by the processes herein described may be purified by methanol and acetone.
  • the present invention provides fosaprepitant dimeglumine obtained by the processes herein described, having purity at least about 99.8% as determined by High Performance Liquid Chromatography (HPLC).
  • HPLC High Performance Liquid Chromatography
  • the present invention provides fosaprepitant dimeglumine, wherein level of impurity F is less than 1 % w/w relative to the amount of fosaprepitant dimeglumin as determined by HPLC.
  • the present invention provides fosaprepitant dimeglumine, wherein level of impurity F is less than 0.5% w/w relative to the amount of fosaprepitant dimeglumin as determined by HPLC. In one embodiment, the present invention provides fosaprepitant dimeglumine, wherein level of impurity F is less than 0.15% w/w relative to the amount of fosaprepitant dimeglumin as determined by HPLC.
  • the present invention provides fosaprepitant dimeglumine obtained by the processes herein described, having purity at least about 99.8% as determined by High Performance Liquid Chromatography (HPLC), wherein aprepitant, a compound of formula III less than 0.15% and impurity F less than 0.15% as determined by HPLC.
  • HPLC High Performance Liquid Chromatography
  • the present invention provides fosaprepitant dimeglumine obtained by the processes herein described, having purity at least about 99.8% as determined by High Performance Liquid Chromatography (HPLC), wherein aprepitant, a compound of formula III and impurity F are not detected.
  • HPLC High Performance Liquid Chromatography
  • Apparatus A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
  • Mobile Phase A Buffer: Acetonitrile (80:20, v/v)
  • Buffer 0.01M of Di-potassium hydrogen phosphate anhydrous in water. Adjust pH to 3.5 with diluted o-phosphoric acid (10% in water).
  • the retention time of fosaprepitant dimeglumine is about 28.0 minutes under these conditions.
  • Relative retention time for compound III is about 1.82 and impurity F is about 1.65 with respect to fosaprepitant dimeglumine.
  • the present invention provides fosaprepitant dimeglumine, obtained by the processes herein described, having a D90 particle size of less than about 50 microns, D50 particle size of less than about 20 microns and D10 particle size of less than about 10 microns.
  • the present invention provides fosaprepitant dimeglumine, obtained by the processes herein described, having a D90 particle size of less than about 35 microns, D50 particle size of less than about 15 microns and D10 particle size of less than about 5 microns.
  • the present invention provides a process for the preparation of fosaprepitant, compound of formula I or salt thereof, comprising:
  • Water miscible organic solvent in step a) may be selected from ether, hydrocarbon, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like or mixture thereof.
  • Ether solvent may be selected from the group consisting of isopropyl ether, diisopropyl ether, diethyl ether, dimethoxyethane (DME), methyl tert-butyl ether, tetrahydropyran, tetrahfydrofuran and the like.
  • Halogenated hydrocarbon may be selected from the group consisting of methylene chloride, chloroform, dichloromethane and the like.
  • a mixture of 150gm of fosaprepitant dibenzyl ester, compound of formula III (prepared by example 1) 90gm of N-methyl glucamine and 30gm of palladium on carbon catalyst in 3000ml of methanol stirred under hydrogen atmosphere (hydrogen pressure about 5.0 to 7.0 kg/cm 2 ) for about 2 hours at 25-30°C.
  • the progress of reaction monitored by HPLC.
  • the reaction mass was filtered through hyflo bed and the filtrate was distilled and degassed under vacuum at about 30°C.
  • the degassed mass was dissolved in about 1350ml of methanol and 0.3ml of tributylphosphine (TBP) was added into reaction mass and stirred for about 24 hours.
  • TBP tributylphosphine

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  • 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

L'invention concerne un procédé amélioré de préparation de fosaprépitant ou d'un sel de celui-ci. L'invention concerne plus particulièrement un procédé efficace de préparation de dibenzylester de fosaprépitant, un composé de formule II, qui est un intermédiaire utile dans la préparation de fosaprépitant ou de fosaprépitant diméglumine.
PCT/IB2018/053367 2017-05-17 2018-05-15 Procédé amélioré de préparation de fosaprépitant ou d'un sel de celui-ci Ceased WO2018211410A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201721017210 2017-05-17
IN201721017210 2017-05-17

Publications (1)

Publication Number Publication Date
WO2018211410A1 true WO2018211410A1 (fr) 2018-11-22

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111662329A (zh) * 2020-06-22 2020-09-15 连云港贵科药业有限公司 一种福沙匹坦双葡甲胺的合成方法
CN113045605A (zh) * 2021-03-30 2021-06-29 浙江亚瑟医药有限公司 一种福沙匹坦二甲葡胺的制备方法和纯化方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013168176A2 (fr) * 2012-03-30 2013-11-14 Glenmark Generics Limited Procédé pour la préparation de fosaprépitant et sel de celui-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013168176A2 (fr) * 2012-03-30 2013-11-14 Glenmark Generics Limited Procédé pour la préparation de fosaprépitant et sel de celui-ci

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111662329A (zh) * 2020-06-22 2020-09-15 连云港贵科药业有限公司 一种福沙匹坦双葡甲胺的合成方法
CN111662329B (zh) * 2020-06-22 2021-03-30 连云港贵科药业有限公司 一种福沙匹坦双葡甲胺的合成方法
CN113045605A (zh) * 2021-03-30 2021-06-29 浙江亚瑟医药有限公司 一种福沙匹坦二甲葡胺的制备方法和纯化方法
CN113045605B (zh) * 2021-03-30 2022-06-07 浙江亚瑟医药有限公司 一种福沙匹坦二甲葡胺的制备方法和纯化方法

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