WO2009084031A2 - Procédé amélioré de préparation de la forme polymorphe a du (2e)-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-n,n-diéthyl-2-propènamide - Google Patents

Procédé amélioré de préparation de la forme polymorphe a du (2e)-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-n,n-diéthyl-2-propènamide Download PDF

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Publication number
WO2009084031A2
WO2009084031A2 PCT/IN2008/000806 IN2008000806W WO2009084031A2 WO 2009084031 A2 WO2009084031 A2 WO 2009084031A2 IN 2008000806 W IN2008000806 W IN 2008000806W WO 2009084031 A2 WO2009084031 A2 WO 2009084031A2
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WO
WIPO (PCT)
Prior art keywords
entacapone
polymorphic form
cyano
preparation
dihydroxy
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Ceased
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PCT/IN2008/000806
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English (en)
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WO2009084031A3 (fr
Inventor
Arul Ramakrishnan
Guruswamy Bathani
Srilatha Taduri
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Neuland Laboratories Ltd
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Neuland Laboratories Ltd
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Publication of WO2009084031A2 publication Critical patent/WO2009084031A2/fr
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Publication of WO2009084031A3 publication Critical patent/WO2009084031A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/32—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • the present invention relates to an improved, cost effective, eco-friendly and easy to handle process to manufacture substantially pure form of (2E)-2-Cyano-3-(3,4-dihydroxy-5- nitrophenyl)-N,N-diethyl-2-propenamide or (E)- N,N-diethyl-2-cyano-3-(3,4-dihyroxy-5- nitrophenyl)-acrylamide polymorphic form
  • (E)-Entacapone represented by Formula I using ammonium acetate as a base.
  • Entacapone is a potent and specific peripheral catechol-O-methyltransferase (COMT) inhibitor and is used in the treatment of Parkinson's disease. This compound exists in two isomeric forms E & Z out of which E isomer being more pharmaceutically active. The Entacapone E isomer exists in five different polymorphic forms A, B, C, D and E.
  • CCT catechol-O-methyltransferase
  • entacapone was first described by Orion pharmaceutical in US5963590 which involves conversion of 5-nitrovanillin to 3, 4-dihyroxy-5-nitrobenzaldehyde and condensation with N 5 N-diethyl-2-cyano acetamide in presence of piperdine acetate and dry ethanol to give racemic entacapone with 73% yield wherein the ration of E:Z isomer is 70%: 30%.
  • the '590 patent discloses racemic entacapone without describing the stereochemistry and polymorphic forms. Piperdine used as a base in this reaction, forms unwanted side products.
  • US5135950 discloses the process for preparation of E-isomer polymorphic form-A of entacapone by purification of the racemic form of entacapone obtained from '590 patent by treating with lower aliphatic carboxylic acid as acetic acid in presence of catalytic amount of hydrobromic acid to give the polymorphic form A of the E isomer of Entacapone with less than 0.1% of Z isomer.
  • WO2005063693 discloses the preparation of entacapone from 3-alkoxy-4-hydroxy-5- nitrobenzaldehyde described as alkoxy benzaldehyde with the acetamide derivative followed by dealkylation to give Entacapone.
  • R methyl or ethyl 3-alkoxy entacapone Entacapone
  • WO2005054950 discloses the preparation of Entacapone which process comprises condensing hydroxy nitrobenzaldehyde with acetamide derivative followed by extraction and purification with acid, different halogenated and alcoholic solvents like dichloromethane and methanol to give E-entacapone with less than 0.02 % of Z isomer.
  • the process is one pot synthesis of pure E isomer of entacapone, which involves lengthy work up and the product was isolated after evaporation of solvent which is not advisable on higher manufacturing scale. More over the compound is contaminated with Z isomer being at least 0.1%.
  • WO2007094007 discloses the preparation E-entacapone which comprises condensation of 3-alkoxy-4-hyroxy-5-nitro-benzaldehyde with N,N-diethyl-2-cyano acetamide in the presence of glycine acetate and a solvent to give alkoxy Entacapone which is further dealkylated with aluminium chloride and pyridine to get crude entacapone which is further treated with acetic acid and catalytic amount of hydrobromic acid to give E-entacapone.
  • the invention uses glycine acetate which is expensive and commercially not viable at manufacturing scale, the invention also involves the extra step of dealkylation which causes extra time consumption and the yield is low and so the purity.
  • WO2007090923 discloses the preparation E-entacapone which comprises condensing 3,4-dihyroxy-5-nitro-benzaldehyde with N,N-diethyl-2-cyano acetamide in presence of C 4-S alcohol and in presence of base selected from methylamine hydrochloride, piperdine, N-methyl morpholine, pyridine and piperazine at a reduced pressure and at 70 C, cooling and seeding the reaction with entacapone with 60% of E isomer further cooling and again seeding with Entacapone with 30% Z isomer further cooling to 5 0 C during which time the product crystallises as racemic entacapone which is converted to pure E entacapone by known prior art methods.
  • This method has significant drawback of cumbersome method of seeding the reaction mixture which is not possible for higher scale production, the base used in condensation forms unwanted impurities making the yields lower.
  • WO2007077572 discloses the preparation E-entacapone which comprises condensing 3,4-dihyroxy-5-nitro-benzaldehyde with N,N-diethyl-2-cyano acetamide in presence of piperdine, pyrolidine, diisopropyl amine and like and mixture of solvent selected from ether and hydrocarbon to give crude entacapone which is further purified in halogenated and further crystallised using suitable solvent.
  • This process requires consequent purification and crystallisation which is time consuming and yields are also low, the base used in condensation forms unwanted impurities making the yields lower.
  • WO2005066117 discloses the preparation of different polymorphic forms C and D of E- Entacapone by condensing 3, 4-dihyroxy-5-nitro-benzaldehyde with N, N-diethyl-2-cyano acetamide in presence of piperdine, N-methyl morpholine, pyridine and piperazine in an alcoholic solvent and further treating with proper acid or mixture of solvent to get the desired forms.
  • WO2005063696 by Cilag discloses the preparation of Entacapone by heating 3, 4- Dihyroxy-5-nitrobenzaldehyde with raw N,N-diethyl-2-cyano acetamide in presence of acetic acid and diethyl amine and toluene and by removing the water formed during reaction through azeotropic distillation.
  • a significant drawback is large amount of solvent has to be used which is not feasible for a large scale production.
  • the objective of the invention is to provide an improved process for the preparation of (2E)-2-Cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide or (E) Entacapone polymorphic form A of formula I which is substantially free from the (2E)-3-(3, 4- dihydroxyphenyl)-2-(piperidrn-l-ylcarbonyl-) ⁇ rop-2-enenitrile of formula II.
  • Another aspect of the present invention relates to the synthesis of E-entacapone which is simple, cost effective easy to handle and feasible at commercial or production scale with high purity and good yield.
  • Yet another object of the present invention relates to a process comprising a) Reacting 3,4-dihyroxy-5-nitro-benzaldehyde with N,N-diethyl-2-cyano acetamide in the presence of anhydrous ammonium acetate and a suitable solvent to form racemic entacapone b) Treating racemic entacapone with hydrogen bromide gas dissolved in suitable aliphatic carboxylic acid in to give crude (E)-entacapone polymorphic form A c) Treating (E)-entacapone polymorphic form A first with an alcoholic solvent isolation of the product and further purification with a suitable ester to give pure polymorphic form A of E entacapone which is substantially free from the compound of formula II.
  • In yet another embodiment of the present invention is to provide a process for preparation of E-entacapone free from the (2E)-3-(3,4-dihydroxvphenyl)-2-(piperidm-l-ylcarbonyl)prop-2- enenitrile impurity.
  • Figure I XRD for polymorphic form A of E entacapone
  • Figure II DSC for polymorphic form A of E entacapone
  • Figure III IR Spectrum for polymorphic form A of E entacapone
  • the present invention relates to an improved process for the preparation of (2E)-2-Cyano-3-(3, 4-dihydroxy-5-nitrophenyl)-N ; , N-diethyl-2-propenamide of formula I
  • Formula I which comprises a) reacting 3,4-dihyroxy-5-nitrobenzaldehyde with N,N-diethyl-2-cyano acetamide in the presence of ammonium acetate and a suitable solvent selected from methanol, ethanol and isopropanol, most preferably ethanol to form racemic entacapone b) treating racemic entacapone with hydrogen bromide gas dissolved in suitable aliphatic carboxylic acid in to give crude (E)-entacapone polymorphic form A c) treating (E)-entacapone polymorphic form A first with an alcoholic solvent isolation of the product and further purification with a suitable ester to give pure polymorphic form A of E entacapone which is substantially free (means less than 0.1%) from compound of formula II.
  • a suitable solvent selected from methanol, ethanol and isopropanol, most preferably ethanol
  • the alcoholic solvent used in step c are selected from isopropanol, ethanol or methanol most preferably isopropanol.
  • the ester solvent used for purification in the step c is selected from methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, propylacetate; most preferably ethyl acetate.
  • the amount of hydrogen bromide used for the isomerisation of E & Z isomer to E-isomer of entacapone is 0.15-0.22 mole equivalent to that of the compound. This is to avoid the coloration of the final API which is caused because of less than 0.15 mole equivalent of hydrogen bromide and also to avoid the formation of decomposition of the compound which is caused due to use of more than 0.22 mole equivalent of hydrogen bromide.
  • the layer if not cleared was filtered through hyflobed and washed with methylene chloride.
  • the organic layer was separated and the aqueous layer was washed with dichloromethane twice.
  • the organic layer were combined and treated with dilute hydrochloric acid 30OmL (1:1 ratio of HCl and water).
  • the organic layer was separated and treated with purified water to remove any undissolved impurities, the water treatment was repeated two to three times and further the organic layer was treated with activated carbon at 25-30 ° C and filtered.
  • the filtrate distilled off under vacuum at 60 0 C and the residue was taken in ethyl alcohol at 25-3O 0 C, stirred for 15- 20min. and distilled off under vacuum at 35 0 C.
  • the compound (50 g) obtained from the example 1 above was taken in acetic acid (500 mL) at 25-3O 0 C and heated to 70-75 0 C for complete dissolution.
  • the reaction mass was treated with activated carbon (2.5 g) at 70-75 0 C for 15-30min and filtered.
  • the filtrate was cooled to 25-30 0 C and to it was added hydrogen bromide dissolved in acetic acid (7.14 g).
  • reaction mass was heated to 70-75 0 C for complete dissolution and cooled to 20 0 C during which time the compound starts to crystallize, the reaction contents were further stirred for 20hrs for complete crystallization of the compound, filtered and dried at 55-60 0 C to get (2E)-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide polymorphic form A. (Dry weight : 40.5 g (81%), HPLC purity: 99.52% single individual impurity : 0.14%)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un procédé amélioré, rentable, soucieux de l'environnement et facile à mettre en œuvre de fabrication d'une forme essentiellement pure de la forme polymorphe A du (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-N,N-diéthyl-2-propènamide ou du (E)-N,N-diéthyl-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-acrylamide habituellement connu sous le nom de (E)-entacapone représenté par la formule I, utilisant l'acétate d'ammonium comme base.
PCT/IN2008/000806 2007-12-03 2008-12-02 Procédé amélioré de préparation de la forme polymorphe a du (2e)-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-n,n-diéthyl-2-propènamide Ceased WO2009084031A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2864CH2007 2007-12-03
IN2864/CHE/2007 2007-12-03

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WO2009084031A2 true WO2009084031A2 (fr) 2009-07-09
WO2009084031A3 WO2009084031A3 (fr) 2010-11-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105061259A (zh) * 2015-08-25 2015-11-18 重庆植恩药业有限公司 一种恩他卡朋a型晶的制备方法
CN105237437A (zh) * 2015-12-03 2016-01-13 重庆植恩药业有限公司 一种恩他卡朋杂质化合物及其制备方法
WO2022221689A1 (fr) * 2021-04-15 2022-10-20 Brown University Nitrophényl-acrylamides et leurs utilisations

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
YU213587A (en) * 1986-11-28 1989-06-30 Orion Yhtymae Oy Process for obtaining new pharmacologic active cateholic derivatives
GB2238047B (en) * 1989-11-03 1993-02-10 Orion Yhtymae Oy Stable polymorphic form of (e)-n,n-diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide and the process for its preparation
AU2003296838A1 (en) * 2003-12-24 2005-08-11 Siddiqui Mohammed Jaweed Mukarram An efficient process for the manufacture of (e)-entacapone polymorphic form a
ATE445591T1 (de) * 2005-11-09 2009-10-15 Usv Ltd Verfahren zur herstellung von hochreinem (e)-n,n- diethyl-2-cyano-3-(3,4-dihydro-5- nitrophenyl)acrylamid (entacapon)
WO2007094007A1 (fr) * 2006-02-13 2007-08-23 Suven Life Sciences Ltd., Procede ameliore de preparation de l'entacapone
TW200817315A (en) * 2006-06-16 2008-04-16 Sanol Arznei Schwarz Gmbh Entacapone-derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105061259A (zh) * 2015-08-25 2015-11-18 重庆植恩药业有限公司 一种恩他卡朋a型晶的制备方法
CN105237437A (zh) * 2015-12-03 2016-01-13 重庆植恩药业有限公司 一种恩他卡朋杂质化合物及其制备方法
WO2022221689A1 (fr) * 2021-04-15 2022-10-20 Brown University Nitrophényl-acrylamides et leurs utilisations
CN117940401A (zh) * 2021-04-15 2024-04-26 布朗大学 硝基苯基-丙烯酰胺及其用途

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