WO2013168176A2 - Procédé pour la préparation de fosaprépitant et sel de celui-ci - Google Patents

Procédé pour la préparation de fosaprépitant et sel de celui-ci 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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WO
WIPO (PCT)
Prior art keywords
fosaprepitant
compound
formula
dibenzylester
formula iii
Prior art date
Application number
PCT/IN2013/000182
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English (en)
Other versions
WO2013168176A3 (fr
Inventor
Shekhar Bhaskar Bhirud
Bhargav Krishnaji Upadhye
Navin Ganesh BHATT
Mahendra Joma CHORAGHE
Original Assignee
Glenmark Generics 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.)
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Publication date
Application filed by Glenmark Generics Limited filed Critical Glenmark Generics Limited
Publication of WO2013168176A2 publication Critical patent/WO2013168176A2/fr
Publication of WO2013168176A3 publication Critical patent/WO2013168176A3/fr

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de fosaprépitant et un sel de celui-ci.
PCT/IN2013/000182 2012-03-30 2013-03-19 Procédé pour la préparation de fosaprépitant et sel de celui-ci WO2013168176A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1030MU2012 2012-03-30
IN1030/MUM/2012 2012-03-30
US201261702852P 2012-09-19 2012-09-19
US61/702,852 2012-09-19

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WO2013168176A2 true WO2013168176A2 (fr) 2013-11-14
WO2013168176A3 WO2013168176A3 (fr) 2014-01-09

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104650143A (zh) * 2013-11-25 2015-05-27 山东新时代药业有限公司 制备福沙匹坦二甲葡胺中间体的方法
WO2015083033A1 (fr) * 2013-12-02 2015-06-11 Piramal Enterprises Limited Procédé amélioré pour la préparation d'un fosaprépitant de pureté plus élevée
CN106432337A (zh) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 福沙匹坦衍生物、合成和在长效制剂中的用途
WO2017093899A1 (fr) * 2015-12-01 2017-06-08 Piramal Enterprises Limited Procédé de préparation de fosaprépitant diméglumine et d'un intermédiaire de celui-ci
CN107353303A (zh) * 2016-05-09 2017-11-17 上海奥博生物医药技术有限公司 一种福沙匹坦磷酸酯中间体的制备方法
WO2018211410A1 (fr) * 2017-05-17 2018-11-22 Glenmark Pharmaceuticals Limited Procédé amélioré de préparation de fosaprépitant ou d'un sel de celui-ci

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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 (fr) * 2004-11-05 2006-06-08 Merck & Co., Inc. Procédé de production d'acide {3-[2(r)-[(1r)-1-[3,5-bis(trifluorométhyl)phényl]éthoxy]-3(s)-(4-fluorophényl)morpholin-4-yl]méthyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonique
WO2010018595A2 (fr) * 2008-07-17 2010-02-18 Glenmark Generics Limited Intermédiaire de fosaprépitant diméglumine, fosaprépitant neutre et fosaprépitant diméglumine amorphe et ses procédés de préparation
WO2011045817A2 (fr) * 2009-10-15 2011-04-21 Sandoz Private Limited Procédé pour la préparation de fosaprepitant, d'intermédiaire et de sel acceptable sur le plan pharmaceutique de celui-ci
CN102558232A (zh) * 2011-12-31 2012-07-11 江苏奥赛康药业股份有限公司 一种福沙吡坦二甲葡胺的制备方法
CN102850398A (zh) * 2011-06-27 2013-01-02 上海医药工业研究院 制备福沙匹坦的方法

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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 (fr) * 2004-11-05 2006-06-08 Merck & Co., Inc. Procédé de production d'acide {3-[2(r)-[(1r)-1-[3,5-bis(trifluorométhyl)phényl]éthoxy]-3(s)-(4-fluorophényl)morpholin-4-yl]méthyl]-5-oxo-4,5-dihydro-[1,2,4]-triazol-1-yl}phosphonique
WO2010018595A2 (fr) * 2008-07-17 2010-02-18 Glenmark Generics Limited Intermédiaire de fosaprépitant diméglumine, fosaprépitant neutre et fosaprépitant diméglumine amorphe et ses procédés de préparation
WO2011045817A2 (fr) * 2009-10-15 2011-04-21 Sandoz Private Limited Procédé pour la préparation de fosaprepitant, d'intermédiaire et de sel acceptable sur le plan pharmaceutique de celui-ci
CN102850398A (zh) * 2011-06-27 2013-01-02 上海医药工业研究院 制备福沙匹坦的方法
CN102558232A (zh) * 2011-12-31 2012-07-11 江苏奥赛康药业股份有限公司 一种福沙吡坦二甲葡胺的制备方法

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104650143A (zh) * 2013-11-25 2015-05-27 山东新时代药业有限公司 制备福沙匹坦二甲葡胺中间体的方法
CN104650143B (zh) * 2013-11-25 2018-10-02 山东新时代药业有限公司 制备福沙匹坦二甲葡胺中间体的方法
WO2015083033A1 (fr) * 2013-12-02 2015-06-11 Piramal Enterprises Limited Procédé amélioré pour la préparation d'un fosaprépitant de pureté plus élevée
CN106432337A (zh) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 福沙匹坦衍生物、合成和在长效制剂中的用途
WO2017093899A1 (fr) * 2015-12-01 2017-06-08 Piramal Enterprises Limited Procédé de préparation de fosaprépitant diméglumine et d'un intermédiaire de celui-ci
US10428097B2 (en) 2015-12-01 2019-10-01 Piramal Enterprises Limited Process for preparation of fosaprepitant dimeglumine and an intermediate thereof
CN107353303A (zh) * 2016-05-09 2017-11-17 上海奥博生物医药技术有限公司 一种福沙匹坦磷酸酯中间体的制备方法
CN109496215A (zh) * 2016-05-09 2019-03-19 浙江华海药业股份有限公司 一种福沙匹坦磷酸酯中间体及其制备方法
WO2018211410A1 (fr) * 2017-05-17 2018-11-22 Glenmark Pharmaceuticals Limited Procédé amélioré de préparation de fosaprépitant ou d'un sel de celui-ci

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