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WO2008053304A2 - Procédés de préparation d'une forme polymorphe stable d'entacapone - Google Patents

Procédés de préparation d'une forme polymorphe stable d'entacapone Download PDF

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Publication number
WO2008053304A2
WO2008053304A2 PCT/IB2007/003233 IB2007003233W WO2008053304A2 WO 2008053304 A2 WO2008053304 A2 WO 2008053304A2 IB 2007003233 W IB2007003233 W IB 2007003233W WO 2008053304 A2 WO2008053304 A2 WO 2008053304A2
Authority
WO
WIPO (PCT)
Prior art keywords
acid
entacapone
cyano
preparation
solvents
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/IB2007/003233
Other languages
English (en)
Other versions
WO2008053304A3 (fr
Inventor
Ram Prasad Yadav
Zakir Gafoor Shaikh
Siddiqui Mohammed Jaweed Mukarram
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.)
Wockhardt Research Centre
Original Assignee
Wockhardt Research Centre
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 Wockhardt Research Centre filed Critical Wockhardt Research Centre
Publication of WO2008053304A2 publication Critical patent/WO2008053304A2/fr
Publication of WO2008053304A3 publication Critical patent/WO2008053304A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to processes for the preparation of a stable polymorphic form of entacapone. More particularly, it relates to the preparation of stable polymorphic fo ⁇ n designated as Form D. The invention also relates to an improved process for the preparation of 2-cyano-N,N-diethylacetamide, and to the use of this compound as an intermediate for the preparation of entacapone.
  • Entacapone of Formula I is chemically known as (E)-N, N-Diethyl-2- cyano-3-(3,4- dihydroxy-5-nitrophenyl)acrylamide.
  • British Patent No. 8,727,854 discloses entacapone as a potent inhibitor of catechol-O- methyl- transferase (COMT) enzyme. The product is indicated for the treatment of Parkinson's disease.
  • COMP catechol-O- methyl- transferase
  • U.S. Patent No. 4,963,590 discloses a process for the preparation of entacapone of Formula I by condensing 3,4-Dihydroxy-5- nitrobenzaldehyde with N,N- diethylcyanoacetamide in anhydrous ethanol.
  • U.S. Patent No. 5,135,950 discloses crystallographically essentially pure and stable polymorphic Form A of entacapone.
  • Several processes have been reported for the preparation of entacapone and different polymorphic forms for example, in International (PCT) Publication Nos. WO 2005063693; 2005063695; 2005063696; 20050661 17 and 2005070881.
  • Ge ⁇ nan Patent DE 2538254 discloses a process for the preparation of 2-cyano-N, N- diethylacetamide by reacting halo-acetamide derivatives with alkali cyanide in the presence of water as a solvent.
  • the present inventors have developed a process for the preparation of a stable polymorphic Fo ⁇ n D of entacapone.
  • the Form D of entacapone can be directly isolated by reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N, N-diethyl acetamide in an alcoholic solvent in the presence of a base and contacting the resultant product with an aqueous acid.
  • the present invention have developed a single step process for the preparation of 2-cyano-N,N-diethylacetamide without the use of toxic and lachrymatory alkali cyanide, chloroacetyl chloride reagents and haloacetamide.
  • a process for the preparation of stable polymorphic Form D of entacapone includes: a) reacting 3,4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N, N-diethyl acetamide in one or more alcoholic solvents in the presence of a base; b) contacting the product of step a) with an aqueous acid; and c) isolating the stable polymorphic Form D of entacapone by the removal of the solvents.
  • the Form D of entacapone may have the X-ray diffraction pattern as depicted in Figure 1 and may have the infrared spectrum as depicted in Figure 2.
  • Removing the solvents may include, for example, one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.
  • the process may include further drying of the product obtained.
  • a process for the preparation of 2-cyano-N,N- diethylacetamide includes: a) reacting N,N-diethyI amine with cyanoacetic acid in the presence of dicyclohexylcarbodiimide; and b) isolating the 2-cyano-N, N-diethylacetamide from reaction mass thereof.
  • the 2-cyano-N, N-diethylacetamide prepared by the process of the present invention may be condensed with 3,4-dihydroxy-5-nitrobenzaldehyde according to any of the known processes to give entacapone, for example, process as disclosed in International (PCT) Publication No. WO 20050661 17.
  • Figure 1 is an X-ray powder diffraction pattern of Form D of entacapone.
  • Figure 2 is an infrared spectrum of Form D of entacapone.
  • the inventors have developed a process for the preparation of a stable polymorphic Form D of entacapone by reacting 3, 4-dihydroxy-5-nitrobenzaldehyde with 2-cyano- N,N-diethyl acetamide in one or more alcoholic solvents in the presence of acetic acid and a base; contacting with an aqueous acid; and isolating the stable polymorphic Form D of entacapone by the removal of the solvents.
  • bases examples include piperidine, pyridine, N-methyl morpholine, morpholine, piperazine, methylamine, diethylamine, triethylamine, and the like.
  • the reaction of 3, 4-dihydroxy-5-nitrobenzaldehyde with 2-cyano-N,N-diethyl acetamide may be carried out at a reflux temperature of the solvent used. In particular, the reaction may be carried out at a temperature from about 30° C to about 100° C.
  • the reaction mixture may be concentrated and the residue obtained may be treated with a mixture of alcohol and acid.
  • the precipitated product may be then re-suspended in a mixture of water and an acid and polymorphic Form D of entacapone may be isolated from the reaction mass thereof.
  • the product obtained may be further or additionally dried.
  • the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
  • the acids which may be used include organic and inorganic acids.
  • organic acids include acetic acid, formic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid.
  • inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid.
  • a suitable alcoholic solvent includes one or more of straight chain and branched chain Ci-C 6 alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, and the like.
  • the inventors also have developed a process for the preparation of 2-cyano-N,N- diethylacetamide, by reacting N,N-diethyl amine with cyanoacetic acid in one or more solvents in the presence of dicyclohexylcarbodiimide.
  • the reaction of N,N-diethyl amine with cyanoacetic acid may be carried out at a reflux temperature of the solvent used. In particular, the reaction may be carried out at a temperature from about 3O 0 C to about 100 0 C.
  • the reaction mixture may be concentrated and the residue so obtained may be treated with a mixture of water and acetic acid.
  • the mixture so obtained may be filtered to remove solid impurities such as dicyclohexyl urea and the filtrate containing the product may be extracted in an organic solvent.
  • the organic solvent may be concentrated and 2- cyano-N,N-diethylacetamide isolated from the reaction mass thereof. Examples of organic solvents include haloalkanes, ethers, and aromatic solvents.
  • haloalkanes examples include methylene chloride, chloroform, carbon tetrachloride, and the like.
  • ethers include diethyl ether, tetrahydrofuran, dioxane, and the like.
  • aromatic solvents include solvents such as toluene, xylene, and the like.
  • Dicyclohexylcarbodiimide 85 Kg was added to a mixture of N,N-diethylamine (34 Kg) and cyanoacetic acid (36 Kg) in tetrahydrofuran (235 L) and stirred. The reaction mixture refluxed for about 6-9 hours. After completion of the reaction, the reaction mixture was concentrated and the residue so obtained was treated with a mixture of water (275 L) and acetic acid (12 L). The undissolved dicylohexylurea was removed through filtration and the filtrate was extracted with dichloromethane. The dichloromethane layer was concentrated to get the 2-cyano-N, N-diethyl acetamide as an oil.

Landscapes

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

Abstract

L'invention concerne des procédés de préparation d'une forme polymorphe stable d'entacapone. Plus particulièrement, la présente invention concerne la préparation de la forme polymorphe stable désignée comme la forme D. L'invention concerne également un procédé amélioré de préparation du 2-cyano-N,N-diéthylacétamide et l'utilisation de ce composé en tant qu'intermédiaire pour la préparation de l'entacapone.
PCT/IB2007/003233 2006-10-30 2007-10-26 Procédés de préparation d'une forme polymorphe stable d'entacapone Ceased WO2008053304A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1790/MUM/2006 2006-10-30
IN1792MU2006 2006-10-30
IN1792/MUM/2006 2006-10-30
IN1790MU2006 2006-10-30

Publications (2)

Publication Number Publication Date
WO2008053304A2 true WO2008053304A2 (fr) 2008-05-08
WO2008053304A3 WO2008053304A3 (fr) 2009-04-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/003233 Ceased WO2008053304A2 (fr) 2006-10-30 2007-10-26 Procédés de préparation d'une forme polymorphe stable d'entacapone

Country Status (1)

Country Link
WO (1) WO2008053304A2 (fr)

Cited By (1)

* 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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1699753B1 (fr) * 2003-12-29 2014-11-26 Suven Life Sciences Limited Procede ameliore de preparation de l'entacapone

Cited By (1)

* 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

Also Published As

Publication number Publication date
WO2008053304A3 (fr) 2009-04-23

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