WO2004009591A1 - Procede de preparation de risperidone antipsychotique - Google Patents

Procede de preparation de risperidone antipsychotique Download PDF

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Publication number
WO2004009591A1
WO2004009591A1 PCT/IN2003/000207 IN0300207W WO2004009591A1 WO 2004009591 A1 WO2004009591 A1 WO 2004009591A1 IN 0300207 W IN0300207 W IN 0300207W WO 2004009591 A1 WO2004009591 A1 WO 2004009591A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
risperidone
methyl
oxime
pyrido
Prior art date
Application number
PCT/IN2003/000207
Other languages
English (en)
Inventor
Sivakumaran Meenakshisunderam
Shankar Rama
Pandit Chetan
Original Assignee
Aurobindo Pharma 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 Aurobindo Pharma Ltd. filed Critical Aurobindo Pharma Ltd.
Priority to AU2003237597A priority Critical patent/AU2003237597A1/en
Publication of WO2004009591A1 publication Critical patent/WO2004009591A1/fr

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Definitions

  • Risperidone (Compound I) is an antipsychotic agent belonging to 3-piperidinyl-l-,2- benzisoxazole derivative reported by Janssen Pharmaceutica in US Patent 4,804,663.
  • COMPOUND I The benzisoxazole intermediate (Compound V) required in this route of risperidone synthesis has been prepared in US Patent 4,804,663 and US Patent 5,134,147 by cyclization of 4-(2,4- difluorobenzoyl)piperidine oxime (Compound III) in aqueous sodium hydroxide solution.
  • This approach of preparing risperidone involves number of chemical steps and results in an overall yield of 40%.
  • the aim of the present invention is to provide a method to obtain highly pure risperidone in high yield.
  • the instant invention relates to an industrially advantageous, economic and efficient method for the preparation of highly pure risperidone.
  • the process comprises reacting 4-(2,4-difluorobenzoyl)piperidine oxime hydrochloride (Compound III) with 3-(2-chlbroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one monochloride (Compound II) in a solvent such as acetonitrile, methyl isobutyl ketone, NN-Dimethylformamide using potassium carbonate or sodium carbonate base in presence of catalytic amount of potassium iodide to obtain an intermediate oxime (Compound IV) that cyclizes in situ to produce risperidone.
  • the product thus produced is crystallized from ethyl acetate to obtain highly pure risperidone in 81% yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur un procédé de préparation de risperidone antipsychotique (Formule I); qui consiste à faire réagir 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one (Formule II); avec 4-(2,4-difluorobenzoyl)piperidine oxime (Formule III); afin de former de l'oxime (Formule IV); et comprend la cyclisation in situ d'oxime (Formule IV) afin de former du risperidone (Formule I) dans un solvant choisi dans le groupe acétonitrile,N, N dimetylformamide et méthyle isobutyle cétone.
PCT/IN2003/000207 2002-07-22 2003-06-02 Procede de preparation de risperidone antipsychotique WO2004009591A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003237597A AU2003237597A1 (en) 2002-07-22 2003-06-02 A process for the preparation of antipsychotic risperidone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN545/MAS/2002 2002-07-22
IN545CH2002 2002-07-22

Publications (1)

Publication Number Publication Date
WO2004009591A1 true WO2004009591A1 (fr) 2004-01-29

Family

ID=30471464

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000207 WO2004009591A1 (fr) 2002-07-22 2003-06-02 Procede de preparation de risperidone antipsychotique

Country Status (1)

Country Link
WO (1) WO2004009591A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030772A1 (fr) * 2003-09-26 2005-04-07 Jubilant Organosys Ltd. Procede de preparation de risperidone
WO2009077551A1 (fr) * 2007-12-18 2009-06-25 Janssen Pharmaceutica Nv Procédé de préparation de la rispéridone

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804663A (en) * 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
EP0453042A1 (fr) * 1990-04-19 1991-10-23 Janssen Pharmaceutica N.V. 4H-pyrido-(1,2-a)pyrimidin-4-ones substituées sur les positiones 2 et 9
US5134147A (en) * 1989-11-07 1992-07-28 Adir Et Compagnie 1,2-benzisoxazole compounds
ES2050069A1 (es) * 1992-07-10 1994-05-01 Vita Invest Sa Procedimiento para la obtencion de 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino)etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido(1,2-a) pirimidin-4-ona.
WO1995014691A1 (fr) * 1993-11-23 1995-06-01 Janssen Pharmaceutica N.V. NOUVEAUX DERIVES DU 9-HYDROXY-PYRIDO[1,2-a]PYRIMIDINE-4-ONE ETHER
WO2003042212A1 (fr) * 2001-11-13 2003-05-22 EGIS Gyógyszergyár Rt. Procede ameliore de preparation de 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4804663A (en) * 1985-03-27 1989-02-14 Janssen Pharmaceutica N.V. 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
US5134147A (en) * 1989-11-07 1992-07-28 Adir Et Compagnie 1,2-benzisoxazole compounds
EP0453042A1 (fr) * 1990-04-19 1991-10-23 Janssen Pharmaceutica N.V. 4H-pyrido-(1,2-a)pyrimidin-4-ones substituées sur les positiones 2 et 9
ES2050069A1 (es) * 1992-07-10 1994-05-01 Vita Invest Sa Procedimiento para la obtencion de 3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-il)piperidino)etil)-2-metil-6,7,8,9-tetrahidro-4h-pirido(1,2-a) pirimidin-4-ona.
WO1995014691A1 (fr) * 1993-11-23 1995-06-01 Janssen Pharmaceutica N.V. NOUVEAUX DERIVES DU 9-HYDROXY-PYRIDO[1,2-a]PYRIMIDINE-4-ONE ETHER
WO2003042212A1 (fr) * 2001-11-13 2003-05-22 EGIS Gyógyszergyár Rt. Procede ameliore de preparation de 3-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido[1,2-a]pyrimidin-4-one

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"RISPERIDONE", DRUGS OF THE FUTURE, BARCELONA, ES, vol. 13, no. 12, 1 December 1988 (1988-12-01), pages 1052 - 1055, XP002046839, ISSN: 0377-8282 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030772A1 (fr) * 2003-09-26 2005-04-07 Jubilant Organosys Ltd. Procede de preparation de risperidone
WO2009077551A1 (fr) * 2007-12-18 2009-06-25 Janssen Pharmaceutica Nv Procédé de préparation de la rispéridone

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