WO2012020424A1 - Procédé court pour la préparation de ziprasidone et de ses intermédiaires - Google Patents

Procédé court pour la préparation de ziprasidone et de ses intermédiaires Download PDF

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Publication number
WO2012020424A1
WO2012020424A1 PCT/IN2011/000331 IN2011000331W WO2012020424A1 WO 2012020424 A1 WO2012020424 A1 WO 2012020424A1 IN 2011000331 W IN2011000331 W IN 2011000331W WO 2012020424 A1 WO2012020424 A1 WO 2012020424A1
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Prior art keywords
formula
compound
preparation
chloro
oxindole
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PCT/IN2011/000331
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English (en)
Inventor
Bhausaheb Nana Ghogare
Uday K. Deshpande
Ganesh Gurpur Pai
Arun Kanti Mandal
Sehgal Charanjit
Dixit Akshaya Neha
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Arch Pharmalabs Limited
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Publication of WO2012020424A1 publication Critical patent/WO2012020424A1/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 an efficient short process for the preparation of 6-chlorooxindole of formula ⁇ , an intermediate for the preparation of 5-(2-chloroethyl)-6-chlorooxindole of formula IV which is a key intermediate for the preparatrion of Ziprasidone of the formula I.
  • Ziprasidone hydrochloride is a serotonin and dopamine antagonist and effective as an antipsychotic drug. Ziprasidone does not increase the weight of the patient, therefore, has a distinctive advantage.
  • US20090047354 discloses a process for the preparation 5-(2-chloroacety)-6-chloro oxindole which is a key intermediate for the preparation of compound of formula I comprising reacting 6-chloro-oxindole with chloro acetyl chloride in halogenated hydrocarbon solvent in presence of A1CL 3 . It does not disclose the process for the preparation of 6-chloro-oxindole.
  • US7608711 (hereinafter described as '711) discloses a process for the preparation of 5-(2-chloroethyl)-6-chloro oxindole comprising reducing a compound of formula V to give a compound of formula VI which is reduced further to the said compound.
  • US20060089502 discloses a process for the preparation 5-(2-chloroethyl)-6-chloro oxindole comprising reacting 6-chloro-oxindole with chloro acetyl chloride to form 5-(2-chloroacetyl)- 6-chloro-2-oxindole which is reduced with an excess of triethylsilane in the presence of a strong acid to form a mixture of 5-(2-chloroethyl)-6- chlorooxindole, 5-(2-chloroacetyl)-6-chloro-2-oxindole, and 5-(2- chlorohydroxylethyl)-6-chlorooxindole which is used as an intermediate to prepare ziprasidone.
  • WO2003099198 discloses a process for the preparation of 5-(2-chloroethyl)-6-chloro oxindole comprising hydrolysis and decarboxylation of compound of formula Ila to give a corresponding substituted phenylacetic acid derivative of formula VII which is reacted with Fe and acetic acid to reduce and cyclise resulting into the formation of compound of formula III which is further converted into compound of formula IV which is a key intermediate for the preparation of compound of formula I
  • the said references also discloses the process for the preparation of compound of formula D comprising hydrolysis of compound of formula A to obtain compound of formula B which is converted into compound of formula C which is then reduced and cyclised to give an oxindole of formula D.
  • the process disclosed therein in the said references also comprises 3 steps starting from malonic acid substituted molecule of formula A to obtain the corresponding oxindole of formula D.
  • INI 85117 discloses a process for the preparation of 6-chloro-oxindole comprising treating 5-halo-2-nitrophenyl malonyldiester with mineral acid in presence of organic acid to obtain the corresponding 5-halo-2- nitrophenyl acetic acid which is converted into corresponding phenylacetic ester. Substituted nitrophenyl ester is hydrogenated to obtain the corresponding oxindole.
  • the process comprises the following operational steps to convert aryl malonic ester into corresponding oxindole:
  • US4831031 (hereinafter described as '031) discloses the process for the preparation of Ziprasidone and its intermediate 5-(2-chloroethyl)-6-chloro oxindole. '031 do not disclose the process for the preparation of 6-chloro- oxindole of formula ⁇ .
  • US5206366 discloses a process for the preparation of Ziprasidone wherein process for the preparation of 6-chloro-oxindole of formula III comprises Wolf-Kishner reduction of 6-chloroisatin of formula H. The process is shown in scheme- ⁇ .
  • US4831031 (hereinafter described as'031) and 5338846 (hereinafter described as'846) disclose the preparation of 5- [2-[4-(l,2-benzisothiazol- 3-yl)-l-piperazinyl]ethyl]-6-chloro-l, 3-di hydro-2H-indol-2-one, compound of formula I, .Ziprasidone. '03 land '846 do not disclose the process for the preparation of 6-chloro-oxindole.
  • G. J. Quallich discloses a process (Synthesis, 51, January 1993) comprising the reaction of a substituted halo nitrobenzene with a malonate, usually dimethyl malonate, in the presence of sodium hydride, to obtain the diester of arylmalonate.
  • the second step involves Krapcho decarboxylation of the diester of the arylmalonate with lithium chloride in dimethyl sulfoxide to obtain the malonate monoester.
  • the nitro group of the monoester is then reduced with iron and acetic acid to yield the substituted oxindole derivative.
  • the process disclosed therein in the said reference involves the following two steps of operations for converting substituted arylmalonate of formula II into corresponding oxindole of formula III
  • US4160032 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 cyclisation using hydrogen gas under pressure, in the presence of Pt0 2 , to obtain 6-chloro- oxindole.
  • nitro phenylacetic acids were further subjected to reduction using zinc and sulfuric acid to yield the oxindoles.
  • the disadvantage of this process is that, the nitrophenyiacetic acids were obtained in moderate yields, and in the case of 4-chloro- 2-nitrophenylacetic acid, a precursor of 6-chloro-oxindole, a yield as low as 4% was reported.
  • WO02/14275 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 dust in the presence of ethanol as the solvent.
  • the entire process is carried out 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.
  • CZ191777 also discloses the process for the preparation of halo substituted oxindoles wherein 3-halosubstituted aniline is reacted with chloroacetyl chloride, followed by refluxing the mixture with aluminum chloride in a suitable solvent to obtain the 6-halosubstituted oxindole.
  • the disadvantage of this process is that it could also lead to the formation of the regioisomer, viz. 4-chloro- oxindole that needs to be separated from the final product.
  • JP56068668 and JP62028133 disclose the process for the preparation of unsubstituted oxindole using 2-chlorophenylacetic acid as the starting material.
  • the 2-chlorophenylacetic 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.
  • 6-chloro-oxindole molecule of formula III comprising hydrolysis of substituted arylmalonate compound of formula II using a mineral acid to obtain a corresponding phenyl acetic acid molecule of formula VII which is isolated and then subjected to reductive cyclization using Fe and acetic acid in a separate operational step to obtain 6-chloro- oxindole molecule of formula ⁇
  • the present invention discloses an improved, short and an efficient process for the preparation of 6-chloro-oxindole molecule of formula ⁇ in a single step by treating substituted arylmalonate compound of formula II with metal or their compounds and mineral acid.
  • the metal or their compounds is not particularly limited as long as it reacts with the mineral acid to give compound of formula III. Examples thereof include Titanium, Cadmium, Zinc, Tin and the like.
  • metal is tin and mineral acid is hydrochloric acid with variable concentration depending upon the requirement to obtain 6-chloro-oxindole molecule of formula ⁇ as shown below in scheme-Ill.
  • 6-chloro-oxindole molecule of formula ⁇ is an intermediate for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula- 1, Ziprasidone.
  • contacting means dissolving, slurring, stirring, adding, reacting and the like or combination thereof.
  • the present invention discloses an efficient, short, simple, cost effective and non-hazardous process for the preparation of 6-chloro-oxindole of formula ⁇ which is an intermediate for the preparation of 5-(2- chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone.
  • First aspect of the invention is to disclose an efficient, short, simple, cost effective and non-hazardous process for the preparation of compound of formula Ilia which is an intermediate for the preparation of 5-(2- chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone
  • Second aspect of the invention is to disclose an efficient, short, simple, cost effective and non-hazardous process for the preparation of 6- chloro-oxindole of formula ⁇ which is an intermediate for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone.
  • Third aspect of the present invention is to provide an efficient, short, simple, cost effective and non-hazardous process for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key-intermediate for the preparation of compound of formula- 1, Ziprasidone.
  • Fourth aspect of the invention is to provide an efficient, short, simple, cost effective and non-hazardous process for the preparation of Ziprasidone hydrochloride of formula I which is a serotonin and dopamine antagonist and effective as an antipsychotic drug.
  • Ziprasidone does not increase the weight of the patient, therefore, has a distinctive advantage.
  • the invention discloses an efficient, short, simple, cost effective and non- hazardous process for the preparation of 6-chloro-oxindole of formula ⁇ which is an intermediate for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula- 1, Ziprasidone, comprising contacting arylmalonate of formula II with a metal or its compound and mineral acid to obtain 6-chloro-oxindole of formula III in a single step.
  • substituted aryl maolnate ester of formula Ila is used as a starting material.
  • R is CI-C4 alky] group
  • Compound of formula Ila is contacted with a metal or its compound and mineral acid in an organic solvent to obtain the corresponding substituted oxindole derivative of formula Ilia.
  • the metal or their compounds is not particularly limited as long as it reacts with the mineral acid to give compound of formula III. Examples thereof include Titanium (TiCl 3 ), Cadmium, Zinc, Tin and the like.
  • metal is tin.
  • mineral acid is hydrochloric acid.
  • the process disclosed herein in the present invention converts the starting material of formula Ila into corresponding substituted oxyindole derivatives of formula Ilia in a single step comprising a single unit operation using one set of reagents comprising metal or its compound/ mineral acid as compared to the process disclosed in WO200309918 wherein the same starting material of formula Ila is converted into the corresponding substituted oxyindole in 2 operational steps process comprising first converting the starting material of formula Ila into corresponding substituted phenylacetic acid of formula Vila by treating with HC1 in combination with acetic acid.;
  • the substituted phenyl acetic acid derivative of formula Vila is isolated and in a second separate step is used as a starting material and is treated with a second set of reagents comprising iron and acetic acid to obtain the corresponding substituted oxindole derivative of formula nia.
  • starting material of formula Ha is contacted with only one set of reagent comprising metal or metal compound and minereal acid that directly forms compound of formula nia devoid of isolation of any intermediate at any stage during the formation of compound of formula Ilia.
  • the substituted oxyindole derivative is 6-chloro- oxindole also known as 6-chloro-indol-2-one of formula ⁇ .
  • the said 6- chloro-oxindole derivative of formula III is prepared by contacting arylmalonate diester of formula II with metal or metal compound and mineral acid in a solvent.
  • the metal or their compounds is not particularly limited as long as it reacts with the mineral acid to give compound of formula III.
  • Examples thereof include Titanium, Cadmium, Zinc, Tin and the like.
  • metal is tin and mineral acid is HC1.
  • the solvent to be used for the said reaction may be any as long as it does not inhibit the reaction. Examples thereof include ethers,aliphatic alcohols and the like.
  • solvent is methanol.
  • the reaction temperature for the said reaction depends upon the reagent particularly solvent to be used and the like.
  • the said reaction generally proceeds at temperature between about 5°C to about 80°C.
  • lewis acid is AICI 3 .
  • the solvent to be used for the said reaction may be any as long as it does not inhibit the reaction.
  • examples thereof include halo or nitro substituted alkanes or benzene such as methylene dichloride, nitromethane, nitrobenzene, chloroform, carbon tetrachloride and the like.
  • solvent is dichloroefhane.
  • 5-(2-chloroacetyl)-6-chloroxyindole of formula V is subjected to reduction with trialkyl silane in the presence of an acid in a solvent to form 5-(2-chloroethyl)-6-chloroxyindole of formula IV.
  • trialkyl silane is triethyl silane.
  • acid is trifluoroacetic acid.
  • solvent is n-hexane.
  • the compound of 5- [2- [4- (1, 2- benzisothiazol-3-yl)-l-piperazinyl ethyl] -6-chloro-l, 3-di hydro-2H- indol-2-one, compound of formula I or ziprasidone is prepared from compound of formula IV by any method disclosed in the prior art such as United States Patent No. 4831031 or United States Patent No. 5338846
  • the free base may be converted to its salt or hydrate form by using processes as disclosed in United States Patent
  • oxindole derivatives of formula II and IV prepared by the process steps of the present invention can be used as an intermediate for the synthesis of pharmaceutically active antiopsychotic compounds and other pharmaceutically active compounds bearing the following general structure:
  • Dimethyl malonate (312.5g) is added to a mixture of anhydrous potassium carbonate (535.5g) and dimethyl sulfoxide (0.4 liters) under a nitrogen atmosphere at 25-30°C.
  • the reaction mixture is heated to 60- 65 °C and 2,5-dichloronitrobenzene (250gm,) diluted in 0.25 litre 2,5- dichloronitrobenzene is added to it in portions over a period of one hour and the contents are maintained first at 40-45 °C for 5 hrs .
  • the temperature of the reaction mixture is then raised to 60-65 °C and maintained so for another 5 hours.
  • the temperature of the reaction mixture is further raised to 80-85°C and maintained so for another 5 hours and cooled to 40-45 °C.
  • reaction mass is quenched with water at 2-5°C.
  • the dimethyl-(4- chloro-2-nitrophenyl) malonate formed is filtered and washed with water till the mother liquor shows a pH of 6.5-7.
  • the product is finally washed with methanol and dried at 40-45°C. Purify the solid with methanol if required.
  • Dimcthyl-(4-chloro-2-nitrophenyl)malonate (68gm) obtained in example 1 is charged with methanol(500 ml) at 20-25°C and tin metal (50gm), followed by slow addition of concentrated hydrochloric acid (216gm) at around 10°C.
  • the reaction mixture is maintained first at 18-20°C followed by heating slowly to reflux at 65-70°C, maintained at this temperature for 6 hours and Filter hot to remove insolubles if any.
  • Methanol is removed under vacuum till solid cake is obtained. Quench the solid with water, stir the solid at 0-5°C and filter off the solid and wash with water till it is free from acid. Purify the solid using ethyl acetate if required. Dry it under vacuum at 40-45°C.

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

Abstract

L'invention concerne un procédé pour la préparation d'un dérivé d'oxindole (chlorhydrate de ziprasidone) de formule (I) comprenant la réaction d'un composé de formule (II) avec un métal ou un acide minéral d'un composé métallique pour donner un composé de formule (III) en une seule étape. Le composé de formule (III) est converti en un composé de formule IV qui est un intermédiaire clé pour la préparation du composé de formule (I).
PCT/IN2011/000331 2010-08-12 2011-05-12 Procédé court pour la préparation de ziprasidone et de ses intermédiaires WO2012020424A1 (fr)

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IN2270/MUM/2010 2010-08-12
IN2270MU2010 2010-08-12

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN103450068A (zh) * 2012-05-27 2013-12-18 重庆常捷医药化工有限公司 一种齐拉西酮中间体的合成方法
CN104744338A (zh) * 2015-03-31 2015-07-01 天津维智精细化工有限公司 一种6-氯羟吲哚的合成方法

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4160032A (en) 1973-11-21 1979-07-03 Sandoz, Inc. Oxindoles as sleep-inducers
JPS5668668A (en) 1979-11-08 1981-06-09 Denki Kagaku Kogyo Kk Preparation of 2-indolinones
US4831031A (en) 1988-01-22 1989-05-16 Pfizer Inc. Aryl piperazinyl-(C2 or C4) alkylene heterocyclic compounds having neuroleptic activity
US5206366A (en) 1992-08-26 1993-04-27 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds
US5312925A (en) 1992-09-01 1994-05-17 Pfizer Inc. Monohydrate of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one-hydrochloride
US5338846A (en) 1992-08-26 1994-08-16 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds with a piperazine salt
WO2002014275A2 (fr) 2000-08-11 2002-02-21 Eli Lilly And Company Derives sulfonamides heterocycliques
WO2003009918A1 (fr) 2001-07-25 2003-02-06 Institut Francais Du Petrole Materiau pour l elimination des oxydes d azote avec structure en feuillets
WO2003099198A2 (fr) 2002-05-24 2003-12-04 Sun Pharmaceutical Industries Limited Procede de preparation de derives d'oxindole
US20050049295A1 (en) * 2003-06-12 2005-03-03 Dr. Reddy's Laboratories Limited Process for the preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1piperazinyl) ethyl)-6-chloro-1, 3-dihydro-2h-indol-2-one hydrochloride (ziprasidone hydrochloride) and its intermediate
US20060089502A1 (en) 2004-10-27 2006-04-27 Sundaram Venkataraman Ziprasidone process
US7608711B2 (en) 2005-11-18 2009-10-27 Dipharma Francis Srl Process for the preparation of ziprasidone

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4160032A (en) 1973-11-21 1979-07-03 Sandoz, Inc. Oxindoles as sleep-inducers
JPS5668668A (en) 1979-11-08 1981-06-09 Denki Kagaku Kogyo Kk Preparation of 2-indolinones
JPS6228133B2 (fr) 1979-11-08 1987-06-18 Denki Kagaku Kogyo Kk
US4831031A (en) 1988-01-22 1989-05-16 Pfizer Inc. Aryl piperazinyl-(C2 or C4) alkylene heterocyclic compounds having neuroleptic activity
US5338846A (en) 1992-08-26 1994-08-16 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds with a piperazine salt
US5206366A (en) 1992-08-26 1993-04-27 Pfizer Inc. Process for preparing aryl piperazinyl-heterocyclic compounds
US5312925A (en) 1992-09-01 1994-05-17 Pfizer Inc. Monohydrate of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one-hydrochloride
WO2002014275A2 (fr) 2000-08-11 2002-02-21 Eli Lilly And Company Derives sulfonamides heterocycliques
WO2003009918A1 (fr) 2001-07-25 2003-02-06 Institut Francais Du Petrole Materiau pour l elimination des oxydes d azote avec structure en feuillets
WO2003099198A2 (fr) 2002-05-24 2003-12-04 Sun Pharmaceutical Industries Limited Procede de preparation de derives d'oxindole
US20050049295A1 (en) * 2003-06-12 2005-03-03 Dr. Reddy's Laboratories Limited Process for the preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1piperazinyl) ethyl)-6-chloro-1, 3-dihydro-2h-indol-2-one hydrochloride (ziprasidone hydrochloride) and its intermediate
US20090047354A1 (en) 2003-06-12 2009-02-19 Dr. Reddy's Laboratories Limited process for the preparation of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl) ethyl)-6-chloro-1, 3-dihydro-2h-indol-2-one hydrochloride (ziprasidone hydrochloride) and its intermediate
US20060089502A1 (en) 2004-10-27 2006-04-27 Sundaram Venkataraman Ziprasidone process
US7608711B2 (en) 2005-11-18 2009-10-27 Dipharma Francis Srl Process for the preparation of ziprasidone

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
COLLINS ET AL., J. AM. CHEM. SOC., vol. 221, no. 78, 1956
G. J. QUALLICH, SYNTHESIS, vol. 51, January 1993 (1993-01-01)
KRAYNACK E A ET AL: "An Improved Procedure for the Regiospecific Synthesis of Electron Deficient 4- and 6-Substituted Isatins", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 39, no. 42, 15 October 1998 (1998-10-15), pages 7679 - 7682, XP004134280, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(98)01719-5 *
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 7, 2003, pages 309 - 312
QUALLICH G J ET AL: "a general oxindole synthesis", SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE, vol. 1, 1 January 1993 (1993-01-01), pages 51 - 53, XP002330294, ISSN: 0039-7881, DOI: 10.1055/S-1993-25790 *
WALSH D A ET AL: "Antiinflammatory agents. 3. Synthesis and pharmacological evaluation of 1-amino-3-benzoylphenylacetic acid and analogues", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 27, no. 11, 1 November 1984 (1984-11-01), pages 1379 - 1388, XP002545538, ISSN: 0022-2623, DOI: 10.1021/JM00377A001 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN103450068A (zh) * 2012-05-27 2013-12-18 重庆常捷医药化工有限公司 一种齐拉西酮中间体的合成方法
CN103450068B (zh) * 2012-05-27 2015-09-16 重庆常捷医药化工有限公司 一种齐拉西酮中间体的合成方法
CN104744338A (zh) * 2015-03-31 2015-07-01 天津维智精细化工有限公司 一种6-氯羟吲哚的合成方法

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