WO2009116081A2 - Procédé amélioré de préparation daprépitant - Google Patents

Procédé amélioré de préparation daprépitant Download PDF

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Publication number
WO2009116081A2
WO2009116081A2 PCT/IN2009/000134 IN2009000134W WO2009116081A2 WO 2009116081 A2 WO2009116081 A2 WO 2009116081A2 IN 2009000134 W IN2009000134 W IN 2009000134W WO 2009116081 A2 WO2009116081 A2 WO 2009116081A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
vii
aprepitant
methanol
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PCT/IN2009/000134
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English (en)
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WO2009116081A3 (fr
Inventor
Manne Satyanarayana Reddy
Sajja Eswaraiah
Mummadi Venkatesh
Mummadi Venkazesh
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Msn Laboratories Limited
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Application filed by Msn Laboratories Limited filed Critical Msn Laboratories Limited
Publication of WO2009116081A2 publication Critical patent/WO2009116081A2/fr
Publication of WO2009116081A3 publication Critical patent/WO2009116081A3/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to an improved process for the preparation of Aprepitant, which is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis (trifluoromethyl)phenyl]ethoxy] -3-(4-fluorophenyl)-4-morpholinyl]methyl]- 1 ,2-dihydro- 3H-l,2,4-triazol-3-one, having structural formula-I.
  • Aprepitant is a useful therapeutic agent, specifically as a P (neurokinin- 1) receptor antagonist useful in the treatment of chemotherapy-induced nausea and vomiting. It is commercially available in the market under the brand name EMENDTM as 80 mg or 125 mg capsules.
  • U.S. 6,395,898 discloses the preparation of optically pure intermediate compound 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl morpholine which features a highly stereo selective Lewis acid catalyzed transacetylization of (R)-3,5-bis(trifluoromethyl)phenylethanol with trichlroacetimidate followed by inversion of the adjacent chiral center on the morpholine ring.
  • the selective substitution reactions are governed by the thermodynamic stability of the intermediates 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)- phenyl morpholine prepared by reaction of 3,5-bis(trifluoromethyl)benzyl alcohol and 2,6-di-tert-butyl-4-methylpyridine in the presence of carbontetrachloride which is further treated with trifluoromethanesulfonic anhydride to afford 3,5-bis(trifiuoromethyl)benzyl alcohol, trifluromethanesulfonate ester.
  • N-benzyl-3-(S)-(4-fluoro)-phenylmorpholin-2-one was treated with lithium tri(sec-butyl)-borohydride (L-SelectrideTM) in THF at -75°C, then added to it, the above obtained 3,5-bis(trifluoromethyl) benzyl alcohol, trifluromethanesulfonate ester. After completion of reaction it was extracted with ethyl acetate and concentrated in vacuum to afford a residue, The residue was purified by flash chromatography to give pure 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-(4-fluoro)phenyl morpholine.
  • L-SelectrideTM lithium tri(sec-butyl)-borohydride
  • Aprepitant of formula-I which involves condensation of the hydrochloride salt of (2R, 2 ⁇ -R,3S)-2-[l-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-l,4-oxazine with amidrazone in presence of potassium carbonate in a mixture of toluene and dimethylsulfoxide to give an intermediate, which on cyclization at 140°C affords aprepitant.
  • the present invention provides a more efficient, practical, commercial and economical method for preparing the Aprepitant in relatively high yield and purity. Brief description of the Invention:
  • the present invention relates to an improved process for the preparation of aprepitant.
  • Aprepitant is chemically known as 5-[[(2R,3S)-2-[(lR)-l-[3,5-bis(trifluoro- methyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo ⁇ holinyl]methyl]- 1 ,2-dihydro-3H- 1 ,2,4- triazol-3-one, represented as a compound of formula-I.
  • the main feature of the present invention is to provide an improved process for the preparation of aprepitant compound of formula- 1, which comprises of the following steps; a) alkylation of (S)-2-(benzyl amino)-2-(4-fluorophenyl) acetic acid compound of formula-II with 1,2-dihaloethane, followed by treatment with an acid gives an acid addition salt of the compound of formula-Ill, b) reducing the free base of compound of formula-Ill or its salt thereof, with an active hydride reducing agent, and subsequently reacting this mixture with substituted benzoyl halide compound of formula-IV provides compound of formula-V, c) conversion of compound of formula-V using "Titanium ylide" to provide an enol ether compound of formula- VI, d) reduction and debenzylation of the compound of formula-VI with suitable reducing agent and treating the compound formed with oxalic acid to provide an oxalate salt of the compound of formula- VII, e) react
  • Figure-1 Illustrates the powder X-ray diffractogram of aprepitant.
  • Figure-2 Illustrates the photographs of aprepitant recorded on a microscope.
  • Figure-3 Illustrates the powder X-ray diffractogram of the compound of formula- VII
  • Figure-4 Illustrates the powder X-ray diffractogram of the compound of formula- VIII.
  • the present invention relates to a novel process for the preparation of aprepitant.
  • Aprepitant is chemically known as 5-[[(2R,3S)-2-[l(lR)-l-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-l,2-Dihydro-3H-l,2,4-triazol- 3 -one represented as a compound of formula-I
  • the main feature of the present invention provides a novel process for the preparation of aprepitant compound of formula- 1, which comprises of the following steps; a) The alkylation of (S)-2-(benzyl amino)-2-(4-fluorophenyl) acetic acid compound of formula II,
  • Formula-I g) purifying the Aprepitant formed in step f) to provide pure aprepitant.
  • step a) compound of formula-II is alkylated with 1 ,2-dibromoethane in the presence of diisopropylethylamine to provide the morpolin-2-one derivative compound of formula-Ill.
  • the reaction is carried out in toluene as a solvent, which improved the yield, purity and also facilitated the formation of crystalline acid addition salt of the morpholin- 2-one derivative by the addition of an acid.
  • Dimethylformamide can also be used in place of toluene.
  • the acid is selected from group consisting of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, hydrogen bromide, hydrogen iodide, trifluoromethane sulfonic acid, camphor sulfonic acid, sulfuric acid, phosphoric acid, benzene sulphonic acid, p-toluene sulfonic acid and p-chlorobenzene sulfonic acid.
  • step b) the compound of formula-Ill is treated with an active hydride reagent, lithium tri(sec-butyl)-borohydride (L-selectride®) at low temperature around -78 0 C in tetrahydrofuran or toluene solvent, and the resulting intermediate is reacted with 3,5-bis (trifluoromethyl)benzoyl chloride compound of formula-IV to provide 2,3-cis substituted compound of formula-V.
  • active hydride reagent lithium tri(sec-butyl)-borohydride (L-selectride®)
  • step c) the compound of formula-V is converted to its enol ether compound of formula- VI, using "titanium ylide” generated with dimethyl titanonocene (Petasis,N.A., Bzowej,E.L, Journal of the American Chemical Society, 112, 6392 (1990)).
  • the solvents used for the reaction are tetrahydrofuran and toluene.
  • the compound of formula- VI is treated with 5% Pd/C/H 2 in methanol, in conditions which assisted in simultaneous reduction of the double bond and to remove the N-benzyl group on the morpholine nitrogen as well, to provide the compound of formula- VII.
  • the processes in the prior art utilized two different reducing agents, first one to reduce the double bond and second one to remove the N-benzyl group on the morpholine nitrogen.
  • the present invention has been able to reduce the number of reagents used in this stage.
  • the use of 5% Pd/C for the reduction of the double bond provided greater yield of the required isomer.
  • Compound of formula-VII was converted into its oxalate salt by adding oxalic acid to yield the crystalline acid addition salt with high purity.
  • the obtained oxalate salt compound of formula-VII optionally recrystallized from suitable solvents selected from methanol, ethanol, isopropanol, butanol and ethyl acetate or mixtures thereof.
  • the p-toluene sulfonic acid salt of compound of formula-VII was also prepared. It has been observed that the inorganic acid salt of formula-VII were found to be hygroscopic in nature, hence were not suitable for getting high pure compound of formula-VII.
  • the oxalate salt was found to be manifest with more salient properties like purity, crystalline nature and non hygroscopic in nature etc. when compared with p-toluene sulfonic acid salt.
  • step e) the oxalate salt of formula- VII was treated with N-methylcarboxyl- 2-chloro acetamidrazone in presence of potassium carbonate or sodium carbonate and dimethyl sulfoxide solvent to obtain a compound of formula- VIII, which was isolated as a solid.
  • the solid obtained was slurried with water or in cyclohexane solvent to obtain pure compound of formula- VIII.
  • the compound of formula- VIII was reported as a foamy substance which was obtained as a residue on dry distillation. Isolation of the above compound by filtration from the solvent provided highly pure intermediate compound of formula- VIII.
  • step f) cyclisation of the compound of formula-VIII was carried out by heating it in xylene at 130°C in the presence of diisopropylethylamine followed by isolation using a mixture of methanol and water to provide aprepitant compound of formula-I.
  • the Aprepitant formed in step f) is crystallized using methanol, water or a mixture thereof to provide high pure Aprepitant compound of formula-I.
  • the present invention provides Aprepitant with particles having irregular flake morphology as illustrated in photographs of microscopic Aprepitant in figure-2, which could be further micronised or milled to provide highly crystalline aprepitant.
  • the present invention also provides a novel crystalline form of oxalic acid salt of 2(R)-[l-(R)-3,5-bis-(trifluoromethyl)phenyl)ethoxy]-3(S)-(4-fluorophenyl) morpholine compound of formula- VII.
  • the crystalline form of the present invention is characterized by its powder X-ray diffractogram having 2 ⁇ peaks at about 5.9, 11.5, 14.4, 14.7, 15.3, 20.8, 21.6, 23.4, 23.7, 29.2, 32.0, 35.6 ⁇ 0.2 degrees 2 ⁇ (as shown in figure-3).
  • the novel crystalline form of the present invention is used to prepare a high pure aprepitant compound of formula-I.
  • XRD analysis of aprepitant as well as its intermediate compounds was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.0457min.
  • the compound of formula-IIIa (23 grams) was converted in to its free base using water and sodium carbonate. Extracted the reaction mixture with toluene and distilled the toluene to get the crude free base of formula-Ill. Dissolved the free base in tetrahydofuran and added L-selectride at -70 to -75°C. Stirred the reaction mixture for 15-30 min at the same temperature and then added 3,5-bis(trifiuoromethyl)benzoyl chloride (25.19 grams). Maintained the reaction mixture for 15-30 min at -70 to -75°C, quenched the reaction mixture using mixture of acetic acid and tetrahydrofuran, then distilled the reaction mixture below 40°C.
  • Methyl magnesium chloride (119.3 ml) was added to the solution of titonocene dichloride in toluene (360 ml). The reaction mixture was stirred for 60-90 min at 0-5°C and the complete formation of Dimethyl titanocene was confirmed by HPLC analysis. Quenched the reaction mixture using 12% ammonium chloride solution at 0-5°C the layers then separated, added compound of formula-V (20 grams) and concentrated the organic layer volume to 70-80 ml below 35°C. Heated to 80-85°C and maintained for 5-6 hrs at 80-85°C and concentrated the reaction mixture to 30-40 ml below 40°C then slowly added n-Heptane (100 ml) during 10-15 min to the reaction mixture.
  • the compound of formula VII (15 grams) was converted in to its free base by treating it with 10% sodium hydroxide solution. The free base was extracted into dichloromethane (150 ml) then the solvent distilled off to get the free base of formula-VII. The free base was dissolved in DMSO (75 ml) and added potassium carbonate (9.6 grams). To the above mixture a solution of N-methylcarboxy-2- chloroacetamidrazone dissolved in DMSO (45 ml) was added. The reaction mixture was stirred for 30-60 min and then quenched with water (75 ml).
  • the reaction mixture was extracted with dichloromethane (75 ml and 45 ml) and the combined organic layer was washed using saturated sodium carbonate solution (25 ml), followed by saturated sodium chloride solution (25 ml). The organic layer was distilled off and the solid formed was slurried in cyclohexane (15 ml). The solid obtained was filtered and dried to get the title compound. Yield: 13.5 grams. Purity: 98.59 % by HPLC.
  • Example-7 Preparation of 2-(R)-[l-(R)-(3,5-bis(trifluoromethyl)pheny.)ethoxy]-3- (S)-(4-fluoro)phenyl-4-(2-(N-methylcarboxyacetamidrazono)morpholine compound of formula- VIII:
  • the compound of formula VII (20 grams) was converted in to its free base by treating it with 10% sodium hydroxide solution. The free base was extracted into dichloromethane (50 ml) then the solvent distilled off to get the free base of formula- VII. The free base was dissolved in dimethylsulfoxide (60 ml) and added sodium carbonate (10 grams). To the above mixture a solution of N-methylcarboxy-2-chloroacetamidrazone dissolved in DMSO (40 ml) was added. The reaction mixture was stirred for 30-60 min and then quenched with aqueous sodium carbonate solution and then stirred for 2 hours. The solid obtained was filtered and washed with water. The wet solid stirred in water (100 ml) for 60 min.
  • the amorphous compound of formula- VIII is characterized by its PXRD spectrum shown in figure-4: Yield: 21 grams. Purity: 98.65 % by HPLC.
  • the crude Aprepitant obtained in example-7 (65 grams) was dissolved in methanol (650 ml) by heating the reaction mixture to reflux temperature. Carbon was added and stirred for 5-10 min at reflux temperature. The reaction mixture was filtered through hyflow-bed and washed with methanol (65 ml). The reaction mixture was cooled and added water (585 ml) slowly in 45-60 min and stirred for 30-45 min at 25-30°C. Filtered the compound, washed with water (65 ml), and dried to get a pure compound of formula-I.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation d'un composé daprépitant de formule I ainsi que de nouveaux polymorphes de ses intermédiaires.
PCT/IN2009/000134 2008-03-03 2009-03-02 Procédé amélioré de préparation daprépitant WO2009116081A2 (fr)

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IN526/CHE/2008 2008-03-03
IN526CH2008 2008-03-03

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WO2009116081A3 WO2009116081A3 (fr) 2011-01-06

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011147279A1 (fr) * 2010-05-24 2011-12-01 成都地奥制药集团有限公司 Procédé de préparation de 5-[[2(r)-[1(r)-[3,5-bis(trifluorométhyl)phényl]éthoxy]-3(s)-4-fluorophényl-4-morpholinyl]méthyl]-1,2-dihydro-3h-1,2,4-triazole-3-one
WO2013135218A1 (fr) 2012-03-13 2013-09-19 Zentiva, K.S. Procédé de préparation de la forme polymorphe i ou ii de la 3-(((2r,3s)-2-((r)-l-(3,5-bis(trifluorométhyl)phényl)éthoxy)-3-(4- fluorophényl)morpholino)méthyl)-lh-l,2,4-triazol-5(4h)-one (aprépitant)
JP2015508095A (ja) * 2012-02-23 2015-03-16 ピラマル・エンタープライゼズ・リミテッドＰｉｒａｍａｌ Ｅｎｔｅｒｐｒｉｓｅｓ Ｌｉｍｉｔｅｄ アプレピタントの調製のための改良された製造方法
CN110746371A (zh) * 2019-11-20 2020-02-04 山东鲁抗医药股份有限公司 制备阿瑞匹坦的中间体及其制备方法与应用
CN111943904A (zh) * 2019-05-15 2020-11-17 南京正大天晴制药有限公司 一种神经激肽1受体拮抗剂关键中间体的精制方法
CN112939885A (zh) * 2021-02-05 2021-06-11 海南鑫开源医药科技有限公司 一种阿瑞吡坦关键中间体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096742A (en) * 1997-07-02 2000-08-01 Merck & Co., Inc. Polymorphic form of a tachykinin receptor antagonist
US6395898B1 (en) * 2000-06-09 2002-05-28 Merck & Co. Inc. Trans-glycosidation process for the synthesis of (2R, 2-alpha-R, 3a)-2-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-1,4-oxazine
US20040214746A1 (en) * 2001-12-10 2004-10-28 Bosch H. William Pharmaceutical composition of a tachykinin receptor antagonist
WO2007039883A2 (fr) * 2005-10-05 2007-04-12 Ranbaxy Laboratories Limited Procede permettant de preparer de l'aprepitant
WO2008026216A2 (fr) * 2006-08-28 2008-03-06 Hetero Drugs Limited Procédé de purification d'aprépitant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096742A (en) * 1997-07-02 2000-08-01 Merck & Co., Inc. Polymorphic form of a tachykinin receptor antagonist
US6395898B1 (en) * 2000-06-09 2002-05-28 Merck & Co. Inc. Trans-glycosidation process for the synthesis of (2R, 2-alpha-R, 3a)-2-[1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-1,4-oxazine
US20040214746A1 (en) * 2001-12-10 2004-10-28 Bosch H. William Pharmaceutical composition of a tachykinin receptor antagonist
WO2007039883A2 (fr) * 2005-10-05 2007-04-12 Ranbaxy Laboratories Limited Procede permettant de preparer de l'aprepitant
WO2008026216A2 (fr) * 2006-08-28 2008-03-06 Hetero Drugs Limited Procédé de purification d'aprépitant

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011147279A1 (fr) * 2010-05-24 2011-12-01 成都地奥制药集团有限公司 Procédé de préparation de 5-[[2(r)-[1(r)-[3,5-bis(trifluorométhyl)phényl]éthoxy]-3(s)-4-fluorophényl-4-morpholinyl]méthyl]-1,2-dihydro-3h-1,2,4-triazole-3-one
US8940890B2 (en) 2010-05-24 2015-01-27 Chengdu Di'ao Pharmaceutical Group Co., Ltd. Preparation method of 5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3(S)-4-fluorophenyl-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one
JP2015508095A (ja) * 2012-02-23 2015-03-16 ピラマル・エンタープライゼズ・リミテッドＰｉｒａｍａｌ Ｅｎｔｅｒｐｒｉｓｅｓ Ｌｉｍｉｔｅｄ アプレピタントの調製のための改良された製造方法
WO2013135218A1 (fr) 2012-03-13 2013-09-19 Zentiva, K.S. Procédé de préparation de la forme polymorphe i ou ii de la 3-(((2r,3s)-2-((r)-l-(3,5-bis(trifluorométhyl)phényl)éthoxy)-3-(4- fluorophényl)morpholino)méthyl)-lh-l,2,4-triazol-5(4h)-one (aprépitant)
CZ304770B6 (cs) * 2012-03-13 2014-10-08 Zentiva, K.S. Způsob výroby 3-(((2R,3S)-2-((R)-1-(3,5-bis(trifluormethyl)fenyl)ethoxy)-3-(4-fluorfenyl)morfolino)methyl)-1H-1,2,4-triazol-5(4H)-onu (Aprepitantu) v polymorfní formě II
CN111943904A (zh) * 2019-05-15 2020-11-17 南京正大天晴制药有限公司 一种神经激肽1受体拮抗剂关键中间体的精制方法
CN111943904B (zh) * 2019-05-15 2023-05-05 南京正大天晴制药有限公司 一种神经激肽1受体拮抗剂关键中间体的精制方法
CN110746371A (zh) * 2019-11-20 2020-02-04 山东鲁抗医药股份有限公司 制备阿瑞匹坦的中间体及其制备方法与应用
CN112939885A (zh) * 2021-02-05 2021-06-11 海南鑫开源医药科技有限公司 一种阿瑞吡坦关键中间体的制备方法

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