WO2007094007A1 - Procede ameliore de preparation de l'entacapone - Google Patents

Procede ameliore de preparation de l'entacapone Download PDF

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Publication number
WO2007094007A1
WO2007094007A1 PCT/IN2006/000143 IN2006000143W WO2007094007A1 WO 2007094007 A1 WO2007094007 A1 WO 2007094007A1 IN 2006000143 W IN2006000143 W IN 2006000143W WO 2007094007 A1 WO2007094007 A1 WO 2007094007A1
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WO
WIPO (PCT)
Prior art keywords
formula
entacapone
impurity
crude
preparation
Prior art date
Application number
PCT/IN2006/000143
Other languages
English (en)
Inventor
Chinnapillai Chinnapillai Rajendiran
Kondakindi Kondakindi Indrasena Reddy
Arava Arava Veera Reddy
Jasti Jasti Venkateswaralu
Original Assignee
Suven Life Sciences 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 Suven Life Sciences Ltd., filed Critical Suven Life Sciences Ltd.,
Publication of WO2007094007A1 publication Critical patent/WO2007094007A1/fr

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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

Definitions

  • ENTACAPONE is (E)- N, N- Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide prepared by the process of the present invention has the formula 2 given below.
  • the present invention particularly relates to a process for the preparation of the (Z) isomer of N,N-Diethyl-2-cyano-3-(3,4-dihydroxy- 5-nitropenyl)-acrylamid.
  • the (Z)-N, N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-acrylamide prepared by the process of the present invention has the formula 1 which is geometrical isomer of (E)-N, N- Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide having the formula 2.
  • the invention also relates to an improved process for the preparation of (E)-N, N-Diethyl-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide having the formula 2 of polymorphic form A using the process of the present invention.
  • ENTACAPONE and its E & Z isomers prepared by the process of the present invention has COMT- inhibiting properties and are therefore useful for treating Parkinson's disease, sometime referred to as shaking palsy.
  • ENTACAPONE means (E)-N,N-Diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-acrylamide having the formula 2 is a potent and specific peripheral catechol-O-methyltransferase (CO ⁇ T) inhibitor. It is used in combination with levodopa/carbidopa to treat Parkinson's disease, sometime referred to as shaking palsy. Entacapone enhances the effect of levedopa/carbidopa by improving muscle control.
  • Entacapone of the formula 2 is known from the US Patent No. 4,963,590.
  • Entacapone is a novel drug used to improve the bioavailability of L- dopa in the treatment of parkinsonian diseases.
  • inhibitor 3-O- methylation by COMT become important consideration as 3-O- methyldopa is potentially harmful and amy compete with L-dopa for transport in to brain.
  • Entacapone is designed to inhibit COMT with high affinity and then reduce the formation of 3-O-methyldopa when coadministered under this treatment regime.
  • nitrogroup in position 5 and another strong electron withdrawing hydrophobic substituent in position 1 are essential for their pharmacological action as COMT inhibitor (lotta et al., J.Comput. Aided. MoI. Des 6,235-272 (1992))
  • US patent No 4,963,590 discloses a process for the preparation of crude N,N-Diethyl-2-cyano-3- (3,4-dihydroxy-5-nitrophenyl)-acryl amide (3).
  • Pat No WO 2005/063695 and WO 2005/063696 disclose a new crystalline (E)-Entacapone form C, D and E using different mixture of solvents for crystallization.
  • the main objective of the present invention is to provide a process for the preparation of high purity E-ENTACAPONE of the formula 2 given above.
  • Another objective of the present invention is to provide an improved process for the preparation of ENTACAPONE without the formation of any intermediate which forms as an impurity.
  • Still another objective of the present invention is to provide a process for the preparation of (Z)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenylj-acrylamide (Z-ENTACAPON E) of the formula I from the crude ENTACAPONE of the formula 3 useful for formulation and medicament, in place of E- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenyl)-acrylamide, as the activity and toxicology studies are same.
  • Yet another objective of the present invention is to provide a process for the preparation of (Z)- N,N-Diethyl-2-cyano-3-(3,4-dihydroxy-5- nitrophenylj-acrylamide of the formula 1 in >98 % Purity from the highly pure ENTACAPONE of the formula 2
  • Still another objective of the present invention is to provide a process for the preparation of Z-isomer of (Z)- N,N-Diethyl-2-yano-3-(3,4- dihydroxy-5-nitrophenyl)-acrylamide of the formula 1 in a stable form
  • Yet another objective of the present invention is to provide a process for the preparation of Z-isomer of (Z)- N,N-Diethyl-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-acrylamide of the formula 1 in pure form in98 % Purity , which is simple and economical as described in scheme-4 1 Toluene, acetic acid
  • Further objective of the invention is to provide ⁇ novel stable form of Z- entacapone.
  • the present invention provides an improved process for the preparation of highly pure ( >98% ) E-ENTACAPONE ( N,N-Diethyl- 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-acrylamide ) of the formula 2
  • R is methyl or ethyl without the formation of impurity of the formula (8)
  • R is methyl or ethyl without the formation of impurity of the formula (8)
  • the acid can be chosen from formic acid and acetic acid most preferably acetic acid.
  • the solvents can be used for the step involving the preparation Z- entacapone of the formula 1, from the crude ENTACAPONE of the formula 3 is hydrocarbon solvents like toluene, xylene, hexane, heptane and octane and protic solvents like methanol ethanol, isopropanol and n-butanol and acids like acetic acid and formic acid.
  • hydrocarbon solvents like toluene, xylene, hexane, heptane and octane and protic solvents like methanol ethanol, isopropanol and n-butanol and acids like acetic acid and formic acid.
  • toluene, xylene, acetic acid and methanol most preferably toluene, acetic acid and methanol and the mixture thereof to obtain a partially soluble slurry which on filtration gives clear solution. The same can be repeated two to three times to get
  • the polar solvents which may be used for the purification may be selected from methanol ethanol, isopropyl alcohol, tetrahydrofuran and ethyl acetate.
  • EXPERIMNTAL lnstrment SIEMEN DS5000 Range : 5-6.8° (2 ⁇ ) Power : 40KV/30mA
  • Fig.l Shows the IR Spectrum of Z-ENTACAPONE prepared by a process according to the present invention is shown .
  • Fig.2 Shows 1 HNMR Spectrum of Z-ENTACAPONE prepared by a process according to the present invention.
  • Fig.3 Shows 13 CNMR Spectrum of Z-ENTACAPONE prepared by a process according to the present invention
  • Fig.4 and TABLE-I shows X-RAY DIFFRACTOGRAMof Z-ENTACAPONE prepared by a process according to the present invention
  • a mixture containing 140.0 gm of the crude product obtained according to step-2 in 420.0 ml of acetic acid was heated to 85-90 0 C and 9.8 ml hydrogen bromide is added and cooled to 20-25 0 C.
  • the reaction mixture was stirred for 18-20 hrs at 20-25 0 C and for 5-6 hrs at 15-18 0 C.
  • the precipitated product was filtered and washed with a mixture of toluene and acetic acid (14.0 ml each) and finally with toluene (28.0 ml) .
  • the product was dried at 50-55 0 C.
  • the dried weight is 104.0 gm with HPLC purity of 99.88%.
  • the invention provides ⁇ novel highly pure Z isomer of N,N-Diethyl-2- cy ⁇ no-3-(3,4-dihydroxy-4-nitrophenyl)- ⁇ cryl ⁇ mide of the formula 1
  • the Z isomer is pharmacologically active as COMT-inhibitor and has an similar to E isomer 3
  • the process for the preparation of Z-isomer of Z- is simple economical 4.
  • the invention provides an improved process for the preparation of Highly pure (99.9%)Z-E ENTACAPONE
  • the invention provides an improved process for the preparation of Highly pur (99%) E isomer of Z-ENTACAPONE

Abstract

La présente invention concerne une nouvelle forme Z de l'ENTACAPONE-(Z)-N,N-diéthyl-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)acrylamide. Cette invention concerne également un procédé de préparation de la nouvelle forme Z de l'ENTACAPONE, ledit procédé consistant à : traiter l'Entacapone O-alkylée en position 3 par le chlorure d'aluminium et la pyridine, dans du dichlorométhane en tant que solvant, afin d'obtenir de l'Entacapone brute exempte d'impuretés ; dissoudre l'entacapone brute dans un ou plusieurs solvants choisis parmi des solvants solubles ou partiellement solubles ou leurs mélanges ; filtrer le mélange obtenu et le concentrer par distillation.
PCT/IN2006/000143 2006-02-13 2006-04-25 Procede ameliore de preparation de l'entacapone WO2007094007A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN226CH2006 2006-02-13
IN226CHE2006 2006-02-13

Publications (1)

Publication Number Publication Date
WO2007094007A1 true WO2007094007A1 (fr) 2007-08-23

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ID=37606934

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000143 WO2007094007A1 (fr) 2006-02-13 2006-04-25 Procede ameliore de preparation de l'entacapone

Country Status (1)

Country Link
WO (1) WO2007094007A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008007093A1 (fr) * 2006-07-12 2008-01-17 Pliva Hrvatska D.O.O. Procédé et produit
WO2009084031A2 (fr) * 2007-12-03 2009-07-09 Neuland Laboratories Ltd Procédé amélioré de préparation de la forme polymorphe a du (2e)-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-n,n-diéthyl-2-propènamide
EP2251323A1 (fr) * 2009-05-14 2010-11-17 F.I.S. Fabbrica Italiana Sintetici S.p.A. Procédé de purification d'entacapone
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB403862A (en) * 1932-05-04 1934-01-04 Ig Farbenindustrie Ag Manufacture of vat-dyestuffs
EP0426468A2 (fr) * 1989-11-03 1991-05-08 Orion-Yhtymä Oy Forme polymorphe stable de (E)-N,N-diéthyl-2-cyano-3-(3,4-dihydroxy-5-nitrophényl) acrylamide et procédé pour sa préparation
WO2005063696A2 (fr) * 2003-12-31 2005-07-14 Cilag Ag Nouvelles formes cristallines d'entacapone et fabrication
WO2005063693A1 (fr) * 2003-12-29 2005-07-14 Suven Life Sciences Ltd Procede ameliore de preparation de l'entacapone
WO2005070881A1 (fr) * 2003-12-24 2005-08-04 Wockhardt Limited Procede efficace de production de forme a polymorphe de (e)-entacapone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB403862A (en) * 1932-05-04 1934-01-04 Ig Farbenindustrie Ag Manufacture of vat-dyestuffs
EP0426468A2 (fr) * 1989-11-03 1991-05-08 Orion-Yhtymä Oy Forme polymorphe stable de (E)-N,N-diéthyl-2-cyano-3-(3,4-dihydroxy-5-nitrophényl) acrylamide et procédé pour sa préparation
WO2005070881A1 (fr) * 2003-12-24 2005-08-04 Wockhardt Limited Procede efficace de production de forme a polymorphe de (e)-entacapone
WO2005063693A1 (fr) * 2003-12-29 2005-07-14 Suven Life Sciences Ltd Procede ameliore de preparation de l'entacapone
WO2005063696A2 (fr) * 2003-12-31 2005-07-14 Cilag Ag Nouvelles formes cristallines d'entacapone et fabrication

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WIKBERG T ET AL: "Identification of Major Metabolites of the Catechol-O-Methyl Transferase Inhibitor Entacapone in Rats and Humans", DRUG METABOLISM AND DISPOSITION, WILLIAMS AND WILKINS., BALTIMORE, MD, US, vol. 21, no. 1, 1993, pages 81 - 92, XP009064899, ISSN: 0090-9556 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008007093A1 (fr) * 2006-07-12 2008-01-17 Pliva Hrvatska D.O.O. Procédé et produit
WO2009084031A2 (fr) * 2007-12-03 2009-07-09 Neuland Laboratories Ltd Procédé amélioré de préparation de la forme polymorphe a du (2e)-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-n,n-diéthyl-2-propènamide
WO2009084031A3 (fr) * 2007-12-03 2010-11-25 Neuland Laboratories Ltd Procédé amélioré de préparation de la forme polymorphe a du (2e)-2-cyano-3-(3,4-dihydroxy-5-nitrophényl)-n,n-diéthyl-2-propènamide
EP2251323A1 (fr) * 2009-05-14 2010-11-17 F.I.S. Fabbrica Italiana Sintetici S.p.A. Procédé de purification d'entacapone
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

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