WO2011154860A1 - Procédé amélioré pour la préparation de l'ilopéridone - Google Patents

Procédé amélioré pour la préparation de l'ilopéridone Download PDF

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Publication number
WO2011154860A1
WO2011154860A1 PCT/IB2011/052103 IB2011052103W WO2011154860A1 WO 2011154860 A1 WO2011154860 A1 WO 2011154860A1 IB 2011052103 W IB2011052103 W IB 2011052103W WO 2011154860 A1 WO2011154860 A1 WO 2011154860A1
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WO
WIPO (PCT)
Prior art keywords
solvent
ethanone
methoxyphenyl
iloperidone
tetra
Prior art date
Application number
PCT/IB2011/052103
Other languages
English (en)
Inventor
Jayaraman Venkat Raman
Dnyandev Rane
Jitendra Kevat
Dattatray Patil
Original Assignee
Alembic Pharmaceuticals 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 Alembic Pharmaceuticals Limited filed Critical Alembic Pharmaceuticals Limited
Publication of WO2011154860A1 publication Critical patent/WO2011154860A1/fr

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Classifications

    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to an improved process for preparing Iloperidone of formula (I).
  • Iloperidone is 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone.
  • the current pharmaceutical product containing this drug is being sold by Novartis using the tradename Zomaril, in the form of tablets.
  • Iloperidone is used as Antipsychotic. It is combined dopamine (D 2) and serotonin (5HT 2) receptor antagonist. It is used in the treatment of Schizophrenia.
  • the first process involves reacting 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazol hydrochloride with 1-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone in the presence of potassuim carbonate and N,N' dimethyl formamide to give Iloperidone whereas in the second process the reaction is carried out with free base 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazol in the presence of acetonitrile.
  • This process affords crude iloperidone which is purified by flash chromatography and then recrystallized from ethanol.
  • the process involves alkylating hydroxyl group of 1-(4-hydroxy-3-methoxyphenyl) ethanone with 1-bromo-3-chloropropane in the presence of potassuim carbonate and acetone at reflux temperature for 20h to give 1-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone.
  • the product obtained as residual oil is purified by high vacuum distillation at 141-143°C.
  • the above process involves long reaction time which results in formation of dimer impurity.
  • the crude product needs to be purified by high vacuum distillation.
  • the high vacuum distillation is always a cumbersome process at industrial scale and requires special apparatus and skill. It requires high temperature which further contributes to degradation or charring of some portion of product and result in loss of yield.
  • the unwanted dimer impurity is having structural formula as shown below.
  • This dimer impurity is difficult to remove by conventional purification methods.
  • the present inventors have directed their research work towards developing a process for the preparation of Iloperiodne which is devoid of the above disadvantages.
  • the present inventors used methylethyl ketone (MEK) as solvent as well as Phase transfer catalyst (PTC) in the reaction for preparation of 1-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone.
  • MEK methylethyl ketone
  • PTC Phase transfer catalyst
  • This change in reagents reduced the reaction time and thereby formation of dimer impurity which in turn increase the yield and purity of Iloperidone.
  • the present inventors isolated the compound by trituration method and avoided high vacuum distillation.
  • Another object of the present invention is to provide a process which gives Iloperidone with high purity.
  • Yet another object of the present invention is to provide a process which gives 1-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone with minimum formation of unwanted dimer impurity.
  • Another object of the present invention is to provide a process which is operationally simple and cost effective.
  • present invention provides an improved process for preparation of Iloperidone (I)
  • present invention provides an improved process for preparation of Iloperidone (I)
  • present invention provides Iloperidone having dimer impurity content less than 4.0%.
  • the present invention provides an improved process for preparation of Iloperidone (I)
  • a mixture of 4-hydroxy-3-methoxy acetophenone, 1-bromo-3-chloropropane, base, solvent and phase transfer catalyst (PTC) is heated at about 75 to 80°C for time sufficient to complete the reaction.
  • Base is selected from the group comprising alkali or alkaline earth metal hydroxide, carbonate, bicarbonate.
  • the base is selected from NaOH, KOH, LiOH, NaHCO 3 , KHCO 3 , LiHCO 3 , Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , Mg(OH) 2 , Ca(OH) 2 , CaCO 3 , MgCO 3 , Ba(OH) 2 , Be(OH) 2 , BaCO 3 , SrCO 3 and the like or mixtures thereof.
  • the preferred base is K 2 CO 3.
  • solvent are selected from a group comprising ketones, nitriles, acetates, aromatic hydrocarbons and the like or mixtures thereof.
  • Ketones used herein above are selected from methyl ethyl ketone, acetone, metyl isobutyl ketone, 3-heptanone.
  • Acetates used herein above are selected from isopropyl acetate, ethyl acetate, methyl acetate, n-butyl acetate, t-butyl acetate.
  • Nitriles used herein above are selected from acetonitrile, benzonitrile.
  • Aromatic hydrocarbons used herein above are selected from toluene, xylene.
  • the preferred solvent is methyl ethyl ketone or isopropyl acetate.
  • the example of the PTC as mentioned hereinabove includes but not limited to benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, Tetra Propyl Ammonium Bromide, Tri butyl Benzyl Ammonium Chloride, Tetra Ethyl Ammonium Bromide, Tetra Octyl Ammonium Bromide, Tetra Butyl Ammonium Hydrogen Sulphate, Benzyl Trimethyl Ammonium Chloride, Benzyl Triethyl Ammonium Chloride, Tetra Butyl Ammonium Acetate, Tetra Butyl Ammonium Iodide, Ethyl Triphenyl Phosphonium Bromide, tetrahexylammonium chloride, Tetra-n-butylammonium fluoride, phenyltrimethylammonium chloride and the like or the mixture thereof.
  • TBAB tetra
  • reaction completes within 1.5 to 2 hours.
  • the progress of the reaction is monitored on thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the reaction mixture is cooled at ambient temperature and DM Water is added to the reaction and extracted.
  • the organic phase is separated and washed with 5% sodium chloride solution.
  • the organic phase is distilled out under vacuum at 50°C.
  • Non-polar aliphatic hydrocarbon solvent such as Cyclohexane is added to the oily residue and stirred to give solid.
  • the other non-polar aliphatic hydrocarbon solvents are selected from a group comprising cyclopentane, cyclooctane, pentane, heptane, hexane, iso-octane, petroleum ether or mixtures thereof.
  • the solid is filtered, washed with cyclohexane and suck dried.
  • the solid is dried in oven at 45°C to give 1-[4-(3-chloropropoxy)
  • Alkali metal salt is selected from the group comprising sodium Bromide, potassium bromide, sodium chloride, potassium chloride and the like or mixtures thereof.
  • Base is selected from the group comprising alkali or alkaline earth metal hydroxide, carbonate, bicarbonate.
  • the base is selected from NaOH, KOH, LiOH, NaHCO 3 , KHCO 3 , LiHCO 3 , Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , Mg(OH) 2 , Ca(OH) 2 , CaCO 3 , MgCO 3 , Ba(OH) 2 , Be(OH) 2 , BaCO 3 , SrCO 3 and the like or mixtures thereof.
  • the preferred base is K 2 CO 3.
  • Solvents are selected from the group comprising dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl acetamide, N,N'-dimethyl formamide (DMF), propylene carbonate, acetonitrile, acetone, 1,4-dioxane, 2-butanone, methyl ethyl ketone, methyl n-propyl ketone, ethyl acetate, toluene, xylene, water and the like or mixtures thereof.
  • the solvent and water is generally taken in the ratio of about 2-10:1-3.
  • the suitable solvent mixtures are DMF: Water (2:1), Acetonitrile: Water (2:1), Toluene: Water (10:3).
  • DM Water is added slowly to the reaction mixture.
  • the reaction mixture is cooled to 30°C and stirred for 1 hour.
  • the resulting precipitates are filtered and suck dried.
  • the solid is added to DM Water and heated at 50°C for 30mins.
  • the reaction mixture is filtered and washed first with DM Water and then with Ethyl acetate.
  • the solid is suck dried and then dried in oven at 50°C to give Iloperidone as a crude product.
  • the crude product is optionally purified by methods known in the art. For example, methods such as charcoalization, crystallization or leaching process are used to remove impurities.
  • the crude product can be purified by crystallization or leaching from alcohol solvents such as methanol, ethanol, isopropanol, butanol.
  • alcohol solvents such as methanol, ethanol, isopropanol, butanol.
  • the Iloperidone crude was dissolved in methanol at about 60 to about 65°C. Activated carbon is added and heated at the same temperature for 30 mins. The mixture is filtered through hyflo bed. The bed is washed with hot methanol. The filtrate is distilled approximately to half volume of the original at elevated temperature. The precipitation occurs while removing solvent.
  • the slurry is cooled to 30°C and stirred for 1h.
  • the precipitated solid is filtered and washed with methanol.
  • the solid is dried in oven at 45 to 50°C to give pure
  • the major advantage of this process is that the dimer impurity formation is very less in the first step compare to prior art process. Using prior art process, unwanted isomer is formed in more than 10%, whereas in present invention dimer impurity is formed only 3-4% in 1-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone.
  • the advantage of the present invention can be understand from the following data depicted in Table-1
  • the process of the present invention has following advantages:
  • the solid was added to DM Water (300 ml) and heated at 50°C for 30mins.
  • the reaction mixture was filtered and washed first with DM Water (100 ml) and then with Ethyl acetate (140 ml).
  • the solid was suck dried and then dried in oven at 50°C to give the title product (150.0 g).
  • Iloperidone crude (100 g) was dissolved in methanol (800 ml) at 64°C.
  • activated carbon (5 g) was added and heated at the same temperature for 30 mins.
  • the mixture was filtered through hyflo.
  • the bed was washed with hot methanol (100 ml).
  • the filtrate was distilled out ( ⁇ 550 ml methanol) at 64°C.
  • the slurry was cooled to 30°C and stirred for 1h.
  • the solid was filtered and washed with methanol (50ml). The solid was dried in oven at 45°C to give the title product (88.0 g).

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation de l'ilopéridone de formule (I).
PCT/IB2011/052103 2010-06-08 2011-05-13 Procédé amélioré pour la préparation de l'ilopéridone WO2011154860A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1752MU2010 2010-06-08
IN1752/MUM/2010 2010-06-08

Publications (1)

Publication Number Publication Date
WO2011154860A1 true WO2011154860A1 (fr) 2011-12-15

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012090138A1 (fr) * 2010-12-27 2012-07-05 Ranbaxy Laboratories Limited Procédés de synthèse de l'ilopéridone
WO2012164516A1 (fr) * 2011-06-03 2012-12-06 Lupin Limited Procédé pour la préparation d'ilopéridone
CN104170267A (zh) * 2012-09-25 2014-11-26 Dsp集团有限公司 基于cmos的tx/rx开关
US9312820B2 (en) 2012-09-23 2016-04-12 Dsp Group Ltd. CMOS based TX/RX switch
CN110903178A (zh) * 2019-12-20 2020-03-24 盐城锦明药业有限公司 一种制备香草乙酮的方法及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4366162A (en) 1977-11-09 1982-12-28 Ab Ferrosan Aryl ethers of N-alkyl-piperidines and acid addition salts thereof
EP0402644A1 (fr) * 1989-05-19 1990-12-19 Hoechst-Roussel Pharmaceuticals Incorporated N-(aryloxyalkyl)hétéroarylpipéridines et -hétéroarylpipérazines, leur procédé de préparation et leur application comme médicaments
EP0542136A1 (fr) * 1991-11-05 1993-05-19 Hoechst-Roussel Pharmaceuticals Incorporated Hétéroarylpiperidines, pyrrolidines et piperazines et leur utilisation comme antipsychotiques et analgésiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4366162A (en) 1977-11-09 1982-12-28 Ab Ferrosan Aryl ethers of N-alkyl-piperidines and acid addition salts thereof
EP0402644A1 (fr) * 1989-05-19 1990-12-19 Hoechst-Roussel Pharmaceuticals Incorporated N-(aryloxyalkyl)hétéroarylpipéridines et -hétéroarylpipérazines, leur procédé de préparation et leur application comme médicaments
USRE39198E1 (en) 1989-05-19 2006-07-18 Aventis Pharmaceuticals Inc. Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgesics
EP0542136A1 (fr) * 1991-11-05 1993-05-19 Hoechst-Roussel Pharmaceuticals Incorporated Hétéroarylpiperidines, pyrrolidines et piperazines et leur utilisation comme antipsychotiques et analgésiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WALSH D A ET AL: "Synthesis and antiallergy activity of 4-(diarylhydroxymethyl)-1-[3-(a ryloxy)propyl]piperidines and structurally related compounds", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 32, no. 1, 1 January 1989 (1989-01-01), pages 105 - 118, XP002582701, ISSN: 0022-2623, DOI: 10.1021/JM00121A022 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012090138A1 (fr) * 2010-12-27 2012-07-05 Ranbaxy Laboratories Limited Procédés de synthèse de l'ilopéridone
WO2012164516A1 (fr) * 2011-06-03 2012-12-06 Lupin Limited Procédé pour la préparation d'ilopéridone
US9312820B2 (en) 2012-09-23 2016-04-12 Dsp Group Ltd. CMOS based TX/RX switch
CN104170267A (zh) * 2012-09-25 2014-11-26 Dsp集团有限公司 基于cmos的tx/rx开关
CN104170267B (zh) * 2012-09-25 2017-02-22 Dsp集团有限公司 基于cmos的tx/rx开关
CN104170267B9 (zh) * 2012-09-25 2017-04-05 Dsp集团有限公司 基于cmos的tx/rx开关
CN110903178A (zh) * 2019-12-20 2020-03-24 盐城锦明药业有限公司 一种制备香草乙酮的方法及其应用

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