WO2003099198A2 - Procede de preparation de derives d'oxindole - Google Patents

Procede de preparation de derives d'oxindole Download PDF

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Publication number
WO2003099198A2
WO2003099198A2 PCT/IN2003/000198 IN0300198W WO03099198A2 WO 2003099198 A2 WO2003099198 A2 WO 2003099198A2 IN 0300198 W IN0300198 W IN 0300198W WO 03099198 A2 WO03099198 A2 WO 03099198A2
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WIPO (PCT)
Prior art keywords
formula
compound
chloro
preparation
acid
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PCT/IN2003/000198
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English (en)
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WO2003099198A3 (fr
Inventor
Nagarajan Periyandi
Srinivasu Kilaru
Rajamannar Thennati
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Sun Pharmaceutical Industries Limited
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Priority to AU2003260942A priority Critical patent/AU2003260942A1/en
Publication of WO2003099198A2 publication Critical patent/WO2003099198A2/fr
Publication of WO2003099198A3 publication Critical patent/WO2003099198A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a proem s l i the preparation of oxindole derivative of formula I.
  • R is selected from linear, branched or cyclic alkyl, aryl, substituted aryl, et ⁇ oaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen.
  • United States Patent No. 4831031 discloses the preparation of 5-[2-[4-(l,2-benzisot iazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l,3-di hydro-2H- indol-2-one, compound of formula I, by reacting 6-chloro-oxindole with chloroacetyl chloride followed by reducing the carbonyl group wiih trifluoroacetic acid/triethylsilane to yield 5-(2-chlorocthyl)-6-chlorooxindole.
  • 5-(2-chloroethyl)-6- chlorooxindole is then reacted with 3-(l-piperazinyl)-i,2-benzisothiazole to give compound of formula I, zipra ⁇ idone.
  • United States Patent No. 5338846 discloses preparation of compound of formui I, wherein R is chloro, by reacting 5-(2- chloroethyl)-6-chlorooxindole with 3-(l-piperazinyl)-l,2-benzisothiazole followed by preparation of mono hydrate of its hydrochloride salt.
  • the disadvantage of this method is the use of sodium hydride in the preparation of the diester of the arylmalonate.
  • Sodium hydride is a. highly moisture sensitive and pyrophoric compound, thereby making its use on an industrial scale highly hazardous. Further, the overall yield reported by this process is about 50%.
  • United States Patent No. 4,160,032 discloses the preparation of 6-chloro-oxindole, wherein 4-chloro-2-nitrotoluene is treated with sodium ethoxide and diethyl oxalate, followed by refluxing it with hydrogen peroxide and acidification, to obtain 4-chloro- 2-nitrophenylacetic acid.
  • the 4-chloro-2-nitrophenylacetic acid is then subjected to reductive cychsation using hydrogen gas under pressuic, in the presence ol i'lO, to obtain 6-chlor ⁇ -oxindole.
  • PCT pulication 02/14275 also discloses the synthesis of 6-halosubstituted oxindoles using 4-halo-2-nitrophenylacetic acid as the starting material.
  • the starting material is subjected to reductive cyclisation using 50% sulfuric acid and zinc du in the presence of ethanol as the solvent.
  • the entire process is carried oui at high temperature under a nitrogen blanket.
  • Such a process is not feasible at industrial scale because the working up of the reaction involves extraction in organic solvents, followed by chromatographic separation of the final product.
  • Japanese Patent Nos. 56068668 and 62028133 disclose the process for the preparation of unsubstituted oxindole using 2-chlorophenylacetic acid as the starting material.
  • the 2-chloro ⁇ henylacetic acid is cyclised to the oxindole, using aqueous ammonia in the presence of CuCl.
  • Such a procedure may not be feasible for dihalo compounds, wherein the dihalo compound could lead to the formation of a mixture of products, such as the undesired mono and/or diaminohalo compounds.
  • the process is undesirable for the synthesis of substituted oxindoles.
  • the object of the present invention is to provide a simple, cost-effective and non- hazardous process for the preparation of compound of formula I.
  • a more specific object is to prepare compound of formula I, wherein R is chloro, using a simple, cost-effective and non-hazardous process.
  • Another object of the present invention is to prepare compound of formula V which is an intermediate for the preparation of compound of formula I.
  • the present invention provides a process for the preparation of compound of formula I involving synthesis of the diester of arylmalonate from 2,5-dichloronitrobenzene, compound of formula ⁇ , wherein a mild, readily - ailable, cheap and non-hazardous base is used, as opposed to prior art use of reactive bases such as sodium hydride.
  • a mild base such as an alkali carbonate or an alkaline earth metal carbonate is that it does not necessitate the use of absolutely anhydrous reaction conditions.
  • the prior art also reports the use of two equivalents of dialkyl malonate in the synthesis of the diester of the arylmalonate, in order to suppress the formation of the dialkyl bisarylmalonate impurity.
  • formula II formula HI wherein R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen.; R 1 is selected from linear, branched and cyclic alkyl (Ci to C 4 groups); and X is selected from chloro, bromo, fluoro and iodo g r oups; Turther converting compound of formula HI to compound of formula I.
  • compound of formula in is converted to compound of formula I by process comprising
  • the process of the present invention provides a process for the preparation of oxihdole derivative of formula I, wherein a substituted or unsubstituted halonitrobenzene (H) is used as the starting material.
  • Compound of formula H is reacted with a dialkyl malonate in the presence of an alkali carbonate or an alkaline earth metal carbonate to obtain the corresponding diester of the arylmalonate (HI).
  • This diester of the arylmalonate (HI) is then converted to the corresponding arylacetic acid derivative (IV), followed by reduction and cyclization of the acid derivative formed to yield the substituted or unsubstituted oxindole, compound of formula V.
  • the process of the present invention prepares compound of formula I from compound of formula V by reacting with chloroacetyl chloride in an organic solvent selected from halo or nitro substituted alkanes and benzene, to give compound of formula VI, followed by reduction of compound of formula VI to yield compound of formula VH and reacting compound of formula VH with compound of formula VIH.
  • chloroacetyl chloride in an organic solvent selected from halo or nitro substituted alkanes and benzene
  • compound of formula I is prepared by reacting substituted or unsubstituted halonitrobenzene with a dialkyl malonate to form diester of the arylmalonate.
  • the substituted or unsubstituted halonitrobenzene is reacted with 0.5 to 1.5 moles of a dialkyl malonate, preferably 1 to 1.5 moles of a dialkyl malonate, more preferably with 1 to 1.2 moles of a dialkyl malonate.
  • the reaction is carried out in the presence of a mild base selected from the group comprising alkali carbonates, alkaline earth metal carbonates and oxides.
  • a mild base selected from the group comprising alkali carbonates, alkaline earth metal carbonates and oxides.
  • an alkali carbonate is used as the base, more preferably the alkali carbonate is potassium carbonate.
  • the reaction of the halonitrobenzene with the dialkyl malonate is carried out using a polar protic solvent, polar aprotic solvent, aromatic high boiling solvent or aliphatic high boiling solvent, having a boiling point above 70°C.
  • the solvent used is a polar aprotic solvent, more preferably the solvent used is dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the reaction is carried out at a temperature ranging from about 50°C to about 130°C, preferably from about 70°C to about 120°C, more preferably from about 80°C t ⁇ about 100°C.
  • step (a) involves conversion of the diester of arylmalonate to the corresponding aryi acetic acid derivative.
  • step (a) is cai ⁇ ied out in the presence of mineral acid.
  • the diester of the arylmalonate is treated with a mineral acid.
  • the mineral acid may be selected from hydrochloric acid, sulfuric acid and nitric acid, the most preferred being hydrochloric acid.
  • the volume of concentrated hydrochloric used in the reaction ranges from about 3 to 7 parts by weight of compound of formula HI.
  • the conversion may be carried ou f . in the presence or absence of an organic acid such as acetic acid.
  • the ratio cf mineral acid- to organic acid ranges from about 10:1 to about 1: 1, preferably from about 10:2 to about 10:6, more preferably from about iC:3 to about 10:5.
  • the reaction is canned out in the absence of lithium salt.
  • the reaction is carried out at a temperature ranging from about 40°C to about 120°C, preferably from about 60°C to about ! 10°C, more preferably from about 90°C to about i l0°C.
  • step (b) involves reduction and cyclization of the arylacetic acid derivative to form the substituted or unsubstituted oxindole.
  • the arylacetic acid derivative is reduced using iron-acetic acid, in the presence or absence of a co-solvent.
  • the co-solvent if used, may be selected from a group comprising linear, branched or cyclic alcohols having Ci-Cio atoms.
  • the co-solvent used is a to C alcohol, more preferably a d to C 3 alcohol.
  • the co-solvent is used in an amount ranging from about 1% to about 50% by volume of the reaction mixture, preferably from about 20% to about 50% by volume of the reaction mixture, more preferably from about 15% to about 30% by volume of the reaction mixture.
  • the oxindole derivative obtained by the process of the present invention is 6-chloro-oxindole, also known as 6-chloro-indol-2-one.
  • the process for preparation of the 6-chloro-oxindole involves conversion of 2,5-dichloronitrobenzene to the corresponding dimethyl ester of malonate using dimethyl malonate in the presence of potassium carbonate and dimethyl sulfoxide. The dimethyl ester of malonate is then reacted with ION hydrochloric acid in the presence of acetic acid to yield the corresponding arylacetic acid. This acid is then reduced and cyclized using standard reaction conditions such as iron and acetic acid, in the presence or absence of a co-solvent such as methanol to yield 6-chloro-oxindole.
  • step (c) comprises reaction of compound of formula V with chloroacetyl chloride in an organic solvent selected from halo or nitro substituted alkanes or benzene such as methylene dichloride, nitromethane, nitrobenzene, chloroform, carbon tetrachloride and the like, preferably methylene dichloride
  • organic solvent selected from halo or nitro substituted alkanes or benzene such as methylene dichloride, nitromethane, nitrobenzene, chloroform, carbon tetrachloride and the like, preferably methylene dichloride
  • the first step for the preparation of compound of formula I is carried out in the presence of a mild base to yield compound of formula HI followed by hydrolysis, decarboxylation, reduction and cyclization to yield compound of formula V, formula E formula V reacting compound of formula V with chloroacetyl chloride in an organic solvent selected from halo or nitro substituted alkanes or benzene such as methylene dichloride, nitromethane, nitrobenzene, chloroform, carbon tetrachloride and the like to yield compound of formula VI and converting compound of formula VI to compound of formula I by the steps
  • oxindole derivatives, compound of formula V and VI, synthesized by the process steps of the. present invention can be used as intermediates for the syntnesis of pharmaceutically active an-ipsychotic compounds and other therapeutically active compounds bearing the following general structure -
  • Ar is benzoisothiazolyl or an oxi ⁇ c or dioxide thereof each optionally substituted by one fluoro, chloro, trifluoromcthyl, methoxy, cyano, or nitro; n i . 1 to 5, and R is hydrogen or halogen, or as described earlier.
  • Plexune (500ml) is then added to this and stirred for an hour at 20-25°C.
  • the dirnethyl-(4-chloro-2-nitrophenyl)malonate fo ⁇ ned is filtered and washed with water till the mother liquor shows a pH of 6.5-7.
  • the product is finally washed with hexane and d rried at 40-45°C under vacuum.
  • step (l) Preparation of 5-(2-chloroethyl)-6-chlo ⁇ oox ⁇ ndole' Chaige 650 ml of t ⁇ fluoroacetic acid and 130 gm of step (l) product into a 3 litre three neck flask under nitrogen atmosphere at 25 to 30°C Stir the mixture for 15 mins and cool to 0 to 5°C under stirnng. Charge 142.46 gms of t ⁇ ethylsilane slowly keeping tempciature betweer 0 to 5°C over 30 mins. Stir the reaction mixture for 30 mins at 0 to 5°C and allow it to gradually reach 30 to 35°C. Stir tne reaction for 6 hrs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

Cette invention se rapporte à un procédé de préparation d'un dérivé d'oxindole de formule (I), consistant à faire réagir un composé de formule (II) avec un dialkyle-malonate, COOR1-COOR1, en présence d'une base moyenne, pour produire un composé de formule (III); et à convertir ensuite le composé de formule (III) en composé de formule (I). Dans ces formules, R est choisi parmi hydrogène, alkyle linéaire ramifié ou cyclique, aryle, aryle substitué, hétéroaryle, haloalkyle de type CF3, alcoxy, haloalcoxy, thioalkyle et halogène; R1 est choisi parmi les groupes alkyle (C1 à C4) linéaires, ramifiés et cycliques ; et X est choisi parmi des groupes chloro, bromo, fluoro et iodo.
PCT/IN2003/000198 2002-05-24 2003-05-26 Procede de preparation de derives d'oxindole WO2003099198A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003260942A AU2003260942A1 (en) 2002-05-24 2003-05-26 A process for the preparation of oxindole derivatives

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IN464/MUM/2002 2002-05-24
IN464MU2002 2002-05-24

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WO2003099198A3 WO2003099198A3 (fr) 2004-04-08

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2250001A1 (es) * 2004-09-29 2006-04-01 Medichem, S.A. Proceso para la purificacion de ziprasidona.
ES2250000A1 (es) * 2004-09-29 2006-04-01 Medichem, S.A. Procedimiento para la preparacion de ziprasidona.
WO2006080025A1 (fr) * 2005-01-27 2006-08-03 Hetero Drugs Limited Procédé de synthèse de la ziprasidone impliquant de nouveaux intermédiaires
WO2012020424A1 (fr) 2010-08-12 2012-02-16 Arch Pharmalabs Limited Procédé court pour la préparation de ziprasidone et de ses intermédiaires
WO2013093928A1 (fr) 2011-12-20 2013-06-27 Arch Pharmalabs Limited Procédé amélioré de préparation de 2-oxindoles de formule i, une matière première clé pour la fabrication de médicaments et de leurs intermédiaires

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000510A1 (fr) * 1993-06-28 1995-01-05 Pfizer Inc. Procedes et intermediaires pour la preparation de 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995000510A1 (fr) * 1993-06-28 1995-01-05 Pfizer Inc. Procedes et intermediaires pour la preparation de 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 118, no. 21, 24 May 1993, Columbus, Ohio, US; abstract no. 212810U, QUALLICH G.J., MORRISSEY P.M.: 'A general oxindole synthesis' page 890; & SYNTHESIS no. 1, 1993, pages 51 - 53 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2250001A1 (es) * 2004-09-29 2006-04-01 Medichem, S.A. Proceso para la purificacion de ziprasidona.
ES2250000A1 (es) * 2004-09-29 2006-04-01 Medichem, S.A. Procedimiento para la preparacion de ziprasidona.
WO2006080025A1 (fr) * 2005-01-27 2006-08-03 Hetero Drugs Limited Procédé de synthèse de la ziprasidone impliquant de nouveaux intermédiaires
WO2012020424A1 (fr) 2010-08-12 2012-02-16 Arch Pharmalabs Limited Procédé court pour la préparation de ziprasidone et de ses intermédiaires
WO2013093928A1 (fr) 2011-12-20 2013-06-27 Arch Pharmalabs Limited Procédé amélioré de préparation de 2-oxindoles de formule i, une matière première clé pour la fabrication de médicaments et de leurs intermédiaires

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AU2003260942A1 (en) 2003-12-12
AU2003260942A8 (en) 2003-12-12
WO2003099198A3 (fr) 2004-04-08

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