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WO2009001203A2 - Procédé perfectionné pour la préparation d'aprépitant - Google Patents

Procédé perfectionné pour la préparation d'aprépitant Download PDF

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Publication number
WO2009001203A2
WO2009001203A2 PCT/IB2008/001674 IB2008001674W WO2009001203A2 WO 2009001203 A2 WO2009001203 A2 WO 2009001203A2 IB 2008001674 W IB2008001674 W IB 2008001674W WO 2009001203 A2 WO2009001203 A2 WO 2009001203A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
fluorophenyl
preparation
apt
benzyl
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/IB2008/001674
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English (en)
Other versions
WO2009001203A3 (fr
Inventor
Sampath Kumar Upparapalli
Sivadas Anand
Senthilnathan Palanivel
Lakshmi Sivalingam
Loganathan Veluppillai
Siripragada Mahender Rao
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.)
Orchid Pharma Ltd
Original Assignee
Orchid Chemicals and 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 Orchid Chemicals and Pharmaceuticals Ltd filed Critical Orchid Chemicals and Pharmaceuticals Ltd
Priority claimed from IN1376CH2007 external-priority patent/IN2007CH01376A/en
Publication of WO2009001203A2 publication Critical patent/WO2009001203A2/fr
Publication of WO2009001203A3 publication Critical patent/WO2009001203A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
  • the present invention relates to a method for the preparation of 3-(5)-(4-fluorophenyl)-4-benzyl-2- morpholinone of Formula (III) or its salts thereof by reacting N-benzyl- (5)-(4- fluorophenyl) glycine of formula (II) with 1,2-dibromoethane in presence of an organic base.
  • Aprepitant of formula (I) is a selective high-affinity antagonist of human substance P/neurokinin 1 (NKi) receptors, is chemically known as 5-[[(2R,3S)-2-[(lR)- l-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-mo ⁇ holinyl]methyl]- l,2-dihydro-3H-l,2,4-triazol-3-one.
  • NKi human substance P/neurokinin 1
  • Aprepitant is useful in the treatment of chemotherapy-induced nausea and vomiting, and is commercially available in the market under the brand name Emend TM as 80 mg or 125 mg capsules.
  • US Patent No. 5,719,147 discloses the process for the preparation of compound of formula (III) by reacting N-benzyl-(S)-(4-fluorophenyl) glycine of formula (II) with 1,2-dibromoethane in presence of an organic base such as N,N- diisopropylethylamine and using N, N-dimethylformamide as a solvent.
  • an organic base such as N,N- diisopropylethylamine
  • N, N-dimethylformamide as a solvent
  • US Patent No. 6,177,564 claims a process for the preparation of a compound of formula (III) which comprises: (a) treating 4-fluorobenzaldehyde with sodium metabisulfite in a first solvent followed by reaction with a cyanide source selected from sodium cyanide and potassium cyanide, and the reaction is conducted at a temperature range of about 10 to about 50 0 C, to give l-cyano-l-(4-fluorophenyl)methanol (b) followed by treating l-cyano-l-(4-fluorophenyl)methanol with N-benzylethanolamine which is reacted at a temperature range of about 10 to about 50 0 C to give its corresponding amino derivative (c) followed by treating the corresponding amino derivative with a strong acid in a second solvent to give N-benzyl-3-(S)-(4- fluorophenyl)-l,4-oxazin-2-one.
  • This process is not preferred in industrial scale because it involves more number of steps and uses
  • Chiral 3-(4-fluorophenyl)-l,4-oxazin-2-one derivatives are important intermediates and useful in making therapeutic agents such as Aprepitant. Therefore, there is a need for development of a process for the preparation of N-benzyl-3-(4- fluoro-phenyl)-l,4-oxazin-2-one, which is readily amenable to scale-up.
  • the main object of the present invention is to provide a process for the preparation of compound of formula (III), which is simple, economical and commercially viable.
  • Another object of the present invention is to provide a process for the preparation of compound of formula (III), which would be easy to implement on commercial scale and which can avoid the use of toxic solvent like N, N- dimethylformamide.
  • Still another object of the present invention is to provide a process for the preparation of compound of formula (III) in high yield and very high purity.
  • the present invention provides an improved process for the preparation of 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone of Formula (IN) or its salts which comprises reacting N-benzyl-(S)-(4-fluorophenyl) glycine of formula (II) with 1,2 dibromoethane in the presence of an organic base and in absence of any additional solvent to obtain 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone of formula (III) or its acid addition salt.
  • the above process is illustrated in the Scheme A.
  • 1,2-dibromoethane is used as a reactant as well as solvent in the preparation of 3-(iS)-(4-fIuorophenyl)-4-benzyl-2- morpholinone of Formula (III) or its salts.
  • solvent like N 1 N- dimethylformamide (DMF) as disclosed in prior art processes is avoided.
  • high boiling solvent N,N-dimethylformamide is not preferable in industrial scale since it requires high temperature for distillation and further this solvent is not environmental friendly.
  • the present invention avoids the use of such high boiling solvents and conducts the reaction only in 1,2-dibromoethane for the preparation of compound of formula (III).
  • the organic base used for the preparation of compound of formula (III) includes but not limited to triethylamine, diethylamine, dimethylamine, NN-diethylmethylamine, NN-diethyl aniline, N 1 N- diethylethylenediamine, or NN-diisopropylethylamine, diisopropylethylamine, dimethylaminopyridine, N-methylmorpholine, N-methylpyrrolidine, 2,6-di-tertbutyl-4- methylpyridine, pyridine; most preferably, N,N-diisopropylethylamine.
  • the compound of formula (III) is isolated as its acid addition salt by reacting the compound of formula (HI) with an acid. More preferably the compound of formula (III) is converted to hydrochloride salt by reacting with HCl gas or HCl gas dissolved in solvent like alcohol (isopropyl alcohol, ethanol and the like), ester, ketone, ether and the like, further the acid addition salt is converted into its free base in presence of a base preferably sodium bicarbonate and a solvent preferably toluene, ethyl acetate and dichloromethane.
  • a base preferably sodium bicarbonate
  • solvent preferably toluene, ethyl acetate and dichloromethane.
  • a) 3-(S)-(4-fluorophenyl)-4-benzyl-2-morpholinone of Formula (III) was reduced using a reducing agent, which is selected from the group consisting of diisobutyl aluminum hydride, lithium aluminum hydride, lithium tri(sec- butyl)-borohydride (L-Selectride.) in presence of an organic solvent selected from the group comprising of tetrahydrofuran, ether, isopropyl ether, dioxane, methyl tertiarybutyl ether, and the like to obtain Lactol;
  • a reducing agent which is selected from the group consisting of diisobutyl aluminum hydride, lithium aluminum hydride, lithium tri(sec- butyl)-borohydride (L-Selectride.) in presence of an organic solvent selected from the group comprising of tetrahydrofuran, ether, isopropyl ether, dioxane, methyl tertiary
  • APT-I was converted into 2R-cis(-2-[[l-[3,5-bis(trifluoromethyl)-phenyl]- ethenyl]oxy]-3-(4-fluoro-p'henyl)-4-(phenylmethyl)-morpholine (APT-2) by using dimethyl titanocene (DMT)) in presence of solvent selected from toluene, tetrahydrofuran or a mixture there of;
  • DMT dimethyl titanocene
  • APT-2 was reduced to [2R-[2a(R*),3a]]-2-[l-[3,5-bis(trifluoromethyl) phenyl]ethoxy]-3-(4-fluorophenyl)-morpholine (APT-3) using suitable reducing agents preferably Palladium/carbon, palladium oxide and the like;
  • APT-3 was optionally converted into acid addition salt preferably sulphonic acid salt where the sulphonic acid salt is selected from the group consisting of camphor sulphonic acid, benzene sulphonic acid, naphthalene-2-sulfonic acid, paratoluene sulphonic acid most preferably camphor sulphonic acid;
  • APT-4 was cyclised to obtain aprepitant where the cyclisation is carried out in the presence of xylene or mixture of xylene:DMF in presence of alkali carbonate preferably sodium carbonate.
  • alkali carbonate preferably sodium carbonate.
  • the starting materials are either commercially available or prepared according to the literature available in the prior art.
  • Example 1 The present invention is illustrated with the following examples, which should not be construed for limiting the scope of the invention.
  • Example 1
  • N-benzyl-4-fluorophenyl morpholinone hydrochloride (6Og) was made into freebase using 100ml of 5% sodium bicarbonate solution in presence of solvent ethyl acetate. N- benzyl-4-fluorophenyl morpholinone freebase in toluene was cooled to -8O 0 C to -6O 0 C and L-Selectride (252ml) was added slowly by maintaining the same temperature. After completion of reaction, 3,5-bis (trifluoromethyl) benzoyl chloride (57.8g) was added to the reaction mass and stirred the contents at the same temperature till the completion of reaction.
  • reaction mass was quenched into mixture of 500ml of sodium perborate solutipn and 100ml of toluene or IPE at 0 0 C and the reaction mass was stirred for lhr at 0-25 0 C.
  • Organic layer was separated and washed with waterl20ml, brinel20ml and dried over sodium sulphate and distilled out the solvent to get the crude APT-I base.
  • APT-I hydrochloride (5Og) was charged in to a mixture of toluene and sodium bicarbonate solution and stirred. ⁇ Organic layer was separated, washed with 5% sodium bicarbonate solution, water, brine and concentrated the organic layer to obtain APT-I freebase. APT-I freebase was dissolved in THF, DMT > in toluene (1600 mL) was added under nitrogen. The reaction mass was heated to 70°C-73°C for about 5 hours. After completion of the reaction, the reaction mass was brought down to room temperature 12.5g sodium bicarbonate, 200ml of methanol and 7.5ml of water were added to the reaction mass and the temperature was raised to 40°C-45°C and allowed to stir for 14 hours at the same temp.
  • APT-2 (1Og) was dissolved in 100 mL of ethanol /ethyl acetate (1 : 1) and hydrogenated using 2.5g of 5% Pd/C at room temperature. After the completion of reaction, the reaction mass was filtered through hyflow bed. The filtrate was distilled out completely and flushed with methyl tert-butyl ether (MTBE).
  • MTBE methyl tert-butyl ether
  • APT-3 camphor sulphonic acid salt (3g) was taken in a mixture of DMF (12 mL) and potassium carbonate (0.16 g), a solution of 1.05 g of N-methyl carboxy-2- chloroacetamidrazone in DMF (12mL) was added to the reaction mass and stirred till the completion of reaction. After completion of reaction, 30 mL of water and 6OmL of
  • APT-4 was dissolved in 3V of xylene:DMF (2.5:0.5) and 0.25g sodium carbonate was added to the reaction mass and heated to 120 to 130 0 C for 3 hours. After completion of reaction the reaction mass was cooled to 30 0 C and 20 mL of ethyl acetate was added. *
  • Titanocene dichloride 120 g
  • toluene 10V
  • Methyl magnesium chloride 406 mL was added drop wise into the reaction mass maintaining the temperature below 0 0 C.
  • the reaction mass was stirred for 2 hours at -10 0 C to 0 0 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention sur un procédé perfectionné pour la préparation d'Aprépitant de formule (I) et de ses intermédiaires. Plus particulièrement, la présente invention porte sur la préparation de la 3-(-S)-(4-fluorophényl)-4-benzyl-2-morpholinone de Formule (III) ou ses sels par réaction de la N-benzyl-(S)-(4-fluorophényl) glycine de formule (II) avec le 1,2-dibromoéthane en présence d'une base organique.
PCT/IB2008/001674 2007-06-27 2008-06-26 Procédé perfectionné pour la préparation d'aprépitant Ceased WO2009001203A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1376/CHE/2007 2007-06-27
IN1376CH2007 IN2007CH01376A (fr) 2005-02-24 2008-06-26

Publications (2)

Publication Number Publication Date
WO2009001203A2 true WO2009001203A2 (fr) 2008-12-31
WO2009001203A3 WO2009001203A3 (fr) 2009-02-26

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140132A1 (fr) 2009-06-02 2010-12-09 Ranbaxy Laboratories Limited Procédé pour la préparation d'aprépitant cristallin ayant une teneur en forme i
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
WO2011158053A1 (fr) 2010-06-18 2011-12-22 Nanoform Cardiovascular Therapeutics Ltd. Compositions nanostructurées d'aprépitant, leur procédé de préparation, et compositions pharmaceutiques les contenant
CN102352389A (zh) * 2011-09-29 2012-02-15 重庆邮电大学 一种制备l-对氟苯甘氨酸的化学-酶法
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)
CN103694146A (zh) * 2013-12-04 2014-04-02 深圳万乐药业有限公司 2-(2-氯-1-亚乙基)酰肼甲酸甲酯的制备方法
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

Family Cites Families (4)

* 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
GB9819890D0 (en) * 1998-09-11 1998-11-04 Merck Sharp & Dohme Chemical synthesis
EP2266980A1 (fr) * 2005-10-05 2010-12-29 Ranbaxy Laboratories Limited Forme polymorphe d'un produit intermédiaire de l'aprepitant
WO2007044829A2 (fr) * 2005-10-06 2007-04-19 Dr. Reddy's Laboratories Ltd. Preparation de l'aprepitant

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010140132A1 (fr) 2009-06-02 2010-12-09 Ranbaxy Laboratories Limited Procédé pour la préparation d'aprépitant cristallin ayant une teneur en forme i
US8816072B2 (en) 2009-06-02 2014-08-26 Ranbaxy Laboratories Limited Process for the preparation of crystalline aprepitant having form I content
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
CN102295611A (zh) * 2010-05-24 2011-12-28 成都地奥制药集团有限公司 一种神经激肽1受体拮抗剂类药物的合成方法
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
WO2011158053A1 (fr) 2010-06-18 2011-12-22 Nanoform Cardiovascular Therapeutics Ltd. Compositions nanostructurées d'aprépitant, leur procédé de préparation, et compositions pharmaceutiques les contenant
CN102352389A (zh) * 2011-09-29 2012-02-15 重庆邮电大学 一种制备l-对氟苯甘氨酸的化学-酶法
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)
CN103694146A (zh) * 2013-12-04 2014-04-02 深圳万乐药业有限公司 2-(2-氯-1-亚乙基)酰肼甲酸甲酯的制备方法
CN103694146B (zh) * 2013-12-04 2015-10-28 深圳万乐药业有限公司 2-(2-氯-1-亚乙基)酰肼甲酸甲酯的制备方法
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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