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WO2013093928A1 - Procédé amélioré de préparation de 2-oxindoles de formule i, une matière première clé pour la fabrication de médicaments et de leurs intermédiaires - Google Patents

Procédé amélioré de préparation de 2-oxindoles de formule i, une matière première clé pour la fabrication de médicaments et de leurs intermédiaires Download PDF

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Publication number
WO2013093928A1
WO2013093928A1 PCT/IN2012/000137 IN2012000137W WO2013093928A1 WO 2013093928 A1 WO2013093928 A1 WO 2013093928A1 IN 2012000137 W IN2012000137 W IN 2012000137W WO 2013093928 A1 WO2013093928 A1 WO 2013093928A1
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formula
slurry
metal
compound
acid
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Anant Audi Ajay
C Ramachandran
Gurpur Pai Ganesh
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Arch Pharmalabs Ltd
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Arch Pharmalabs Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • 2-oxindoles of formula I which is a key raw material for making pharmaceutical drugs like Ziprasidone and intermediates thereof.
  • 2-oxindoles is also known as 2-oxindolines or indole-2(3H)-ones.
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • This invention relates to a process for the preparation of insitu generated 2-oxindole of formula I free from the impurities generated during the metallic reduction of nitro group of compound of formula II thereby enhancing the purity and yield of compound of formula I and drug molecules formed therefrom.
  • the process for making 2-oxindole of formula I comprises azeotropic drying of alkali metal carbonates and using the said alkali metal carbonate insitu for the preparation of 2-nitro arylmalonate of formula II which is converted into 2-oxindoles of formula I with high purity using metal-acid combination as a reducing agent.
  • R' and R" are same or different and is selected from linear,branched and cyclic alkyl (C r C 4 groups)preferably methyl
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen, preferably R is chloro
  • the said cyclised oxindole product remains trapped or contaminated with metallic impurities as basic salt represented by the formula M(OH)X, wherein M is any metal cation which reacts with an acid to produce hydrogen gas, OH represent basic nature.
  • metal ion is selected from Sn, Fe, Zn and the like.
  • X is an anion representing an acid which reacts with a metal ion to produce hydrogen.
  • acid ion is selected from CI, Br, I, SO4' -COOCH 3 and the like.
  • 2-oxindoles are valuable pharmaceutical agents and/or intermediates for the production of pharmaceutical agents, including analgesic and antiinflammatory agents.
  • 6-chloro-2-oxindole represented by formula I of the present invention is a key raw material for the preparation of Ziprasidone which is used in the treatment of schizophrenia.
  • US4721712 discloses reduction of isatins by Wolf-Kishner reduction using first hydrazine hydrate, then sodium alcoholate in alcohol. This method has the drawback of using hydrazine hydrate.
  • US6469181 discloses reduction of 2-nitrophenylacetic acids or esters to 2-oxindoles via catalytically hydrogenation of 2-nitro arylmalonate diester to produce a 2-(N-hydroxyamino)arylmalonate diester, a 2- aminoarylmalonate diester, or mixtures thereof as a first reaction intermediate; cyclizing, by intramolecular aminolysis of one ester group, the first reaction intermediate to produce a N-hydroxy-2-oxindole-3- carboxylate ester, 2-oxindole-3-carboxylate ester, or mixtures thereof as a second reaction intermediate; and hydrolyzing and decarboxylating the remaining ester group of the second reaction intermediate to produce the N-hydroxy-2-oxindole > the 2-oxindole, or mixtures thereof, wherein the cyclization reaction and the hydrolysis and decarboxylation reaction are conducted in situ with the catalytic hydrogenation reaction without isolation of said reaction intermediates.
  • US4160032 discloses the preparation of 6-chloro-oxindole, by reaction of 4-chloro-2-nitrotoluene 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 platinum dioxide. It discloses a route starting with 4-chloro-2-nitrctoluene and not 2,5- dichloronitrobenzene.
  • platinum dioxide is used for the reduction of nitro group which not only increases the cost but also causes dehalogenation imparting the formation of impurities.
  • the said patent does not teach the concept of insitu reductive cyclisation.
  • WO 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 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.
  • WO03/099198 discloses a three step process to prepare oxindoles from 2-halonitrobenzenes involving the reaction of a substituted halo nitrobenzene with a malonate, usually dimethyl malonate, in the presence of potassium carbonate as mild base to obtain the diester of arylmalonate.
  • the diester of arylmalonate is subjected for the hydrolysis and decarboxylation to prepare nitro aryl acetic acid which is isolated and then subjected to reductive cyclisation using iron-acetic acid optionally using methanol as co-solvent to give 2- oxindole.
  • INI 85117 discloses a process for the preparation of 6-chloro-oxindole comprising treating 5-halo-2-nitrophenyl malonate diester with mineral acid in presence of organic acid to obtain the corresponding 5-halo-2- nitrophenyl acetic acid which is converted into corresponding phenyl acetic ester. Substituted nitro-phenylester is hydrogenated to obtain the corresponding oxindole.
  • the drawback associated with the said process is re-esterification of the free acid obtained after the hydrolysis of the diester before it is subjected for the reductive cyclisation.
  • WO02/14275 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.
  • 2270/MUM/2010 discloses a short process comprising contacting nitro arylmalonate of formula II with a metal or its compound and mineral acid to obtain 6-chloro-oxindole of formula I in a single step comprising mixing of all the reactants in the reaction vessel in presence of solvent.
  • the drawback associated with this process is the purity profile.
  • the basic reason is that the product remains trapped with un-reacted intermediates as impurities and metal associated water insoluble impurities that get generated during reduction of the nitro group.
  • the inventors of the present invention have found that the proper monitoring of this reaction and further modification in the work-up of the reaction mass minimizes these impurities.
  • Metal associated impurities in form of sludge are minimized by treating the reaction mass with additional quantity of mineral acid that converts water insoluble compounds which are part of the sludge and remains trapped with the product as impurities into water soluble compounds which get easily removed alongwith the aqueous other liquor during the improved work-up.
  • WO03/099198 discloses that preparation of nitro arylmalonate of formula II does not require the use of absolute anhydrous reaction conditions.
  • the inventors of the present invention have observed that optimized results for the said reaction are obtained only when moisture content of the reaction mass remains below 2%. It has been observed that the moisture level of the reaction media plays an important role in the reaction progression, yield and quality of the isolated product of formula II.
  • potassium carbonate being hygroscopic in nature is a major source of the moisture content for the reaction mass.
  • Drying of potassium carbonate under vacuum is difficult, therefore, it was thought to dry potassium carbonate by azeotropic method comprising mixing commercial grade potassium carbonate having moisture content more than 2% with an aromatic hydrocarbon as a solvent to obtain a slurry which herein above and herein below is referred as first slurry and the solvent is distilled of from the said first slurry by azeotropic distillation method to obtain dry potassium carbonate.
  • first slurry a slurry which herein above and herein below
  • the solvent is distilled of from the said first slurry by azeotropic distillation method to obtain dry potassium carbonate.
  • To the said dried potassium carbonate DMSO is added insitu to obtain a slurry which hereinabove and hereinbelow is referred as second slurry and in-situ proceeding with further reaction comprising contacting the said second slurry with compound of formula III with alkyl malonate of formula IIIA to obtain a compound of formula II.
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF3, alkoxy, haloalkoxy, thioalkyl and halogen, preferably R is chloro
  • X is selected from chloro, bromo, fluoro and iodo preferably chloro
  • R' and R" are same or different is selected from linear
  • R, R' , R" and X are same as described hereinabove
  • DCNB (2,5-dichloronitrobenzene) of formula III wherein R and X are chloro groups (Raw material):
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • X is selected from chloro, bromo, fluoro and iodo preferably chloro
  • R is selected from linear
  • CNPM Dimcthyl-(4-chloro-2-nitrophenyl) malonate
  • R' and R" are same or different and is selected from linear,branched and cyclic alkyl (C ] -C 4 groups)preferably methyl
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • the said basic tin chloride trapped into required oxindole of formula I contributes towards more sulphated ash and thereby less assay of the material that further affects the purity of the other intermediates and final API obtained therefrom. Therefore, there remains a scope for the improvisation.
  • Inventors of the present invention have used solubility profile of Tin(II) chloride and thus have applied classic chemistry as per which equilibrium between Tin(II) chloride and tin hydroxy chloride can be maintained by the addition of hydrochloric acid (using Le Chatelier's principle favoring the formation of SnCl 2 ).
  • iron when used as a reducing metal in combination with mineral acid or organic acid like acetic acid, it also form corresponding compounds like Fe(OH)Cl or Fe(OH)S0 4 or Fe(OH)(OOCH 3 ) or Fe 3 0(CH 3 COO) 6 (H 2 0) 3 which gets trapped in the required 2-oxindole thereby affecting the assay, sulphated ash and overall purity and yield.
  • ferrous (II) acetate in its anhydrous form is water insoluble.
  • Ferrous (II) salts even in acidic solution are oxidized in the air to ferric, in alkaline solution change takes place easily. Therefore, ferrous acetate thus formed gets converted into water insoluble basic ferric (III) acetate represented as [Fe 3 0(CH 3 COO) 6 (H 2 0) 3 ] + COOCH 3 " .
  • solution of ferric acetate is heated to boiling all of the iron is precipitated as basic ferric(III) acetate.
  • the said water insoluble impurities do not get removed during processing and instead gets trapped in the reaction product of formula I and gets carried forward to the finished drug molecule as impurities which adversely impact the yield and purity.
  • addition of mineral acid as per Le Chatelier's principle converts the said water insoluble impurities into corresponding water soluble iron salts that gets removed in the aq. mother liquor during filtration of product obtained after quenching over water.
  • the mineral acid is selected from HC1 and H 2 S0 4 .
  • Prior art neither teaches nor motivates a person of ordinary skill using the concept disclosed herein comprising treating metal associated water insoluble impurities with additional quantity of mineral acid to achieve assay and purity profile as per the required specification.
  • the desired constant boiling mixture can be achieved by using toluene or xylene or mixture thereof as a co-solvent.
  • xylene is an ideal co-solvent as it provides a higher temperature to the reaction mass thereby driving the reaction to completion in a shorter time. Therefore, it is preferable to use xylene as a co- solvent from the series of aromatic hydrocarbon.
  • Prior art neither teaches nor motivates a person of ordinary skill on the role and selectivity of co-solvent selected from the series of aromatic hydrocarbons.
  • the key feature of the invention is to monitor the reaction for the disappearance of diester, which generally occurs in about two hours.
  • the compounds of the formulae IV and V are mainly left as impurities if left unconverted in to oxindole. This mainly happens due to water present in hydrochloric acid that causes partial hydrolysis of both the ester group of diester resulting into the diacid out of which one carboxylic acid undergoes decarboxylation followed by cyclisation of this mono amino acid which is a slow process when compared with the cyclisation of mono amino ester.
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • X is selected from chloro, bromo, fluoro
  • reaction proceeds as per the following sequence comprising preference to reduction.
  • Prior reduction of nitro group immediately follows easy cyclisation of amino ester leaving behind cyclised mono ester of formula VII as only intermediate.
  • This mono ester thus formed gets hydrolyzed and undergoes decarboxylation yielding oxindole of formula I.
  • color development in the oxindole of formula I is time and temperature dependent; which is controlled by reducing the digestion period of the reaction mass after iron addition and with rise in temperature.
  • sulphated ash is widely used to control the extent of contamination by nonvolatile inorganic impurities in organic substances. Sulphated ash content of any product plays a vital role in deciding the HPLC assay in spite of high HPLC purity. Although HPLC purity and HPLC assay are determining factors in ascertaining analysis of any material, they differ from each other.
  • HPLC purity It explains how pure a material is in the given mixture. It is not related to the how much that material is in the given mixture i.e.% of a material without known or unknown impurities in HPLC.
  • HPLC assay It explains how much a material is in the given mixture (The content of the said component in the given mixture). It is not related to material's purity.
  • First aspect of the invention is to provide a simple, cost effective and non hazardous process for the preparation of oxindole of formula I free from metal generated impurities of formula M(OH)X wherein M and x are as described herein before..
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, tfaioalkyl and halogen
  • a specific aspect of the invention is to provide a simple, cost effective and non hazardous process for the preparation of 6-chloro -2-oxindole of formula I wherein R is chloro at position 6, free from metal generated impurities thereby improving sulphated ash and assay.
  • Another specific aspect of the invention is to provide 6-chloro-2- oxindole of formula I having sulphated ash less than 0.1%, HPLC assay not less than 97.5%, comprising reductive cyclisation using tin/HCl as reduction medium and contacting the reaction mass with mineral acid after quenching with water.
  • One more specific aspect of the invention is to provide 6-chloro-2- oxindole of formula I having sulphated ash less than 0.1%, HPLC assay not less than 99 %, and impurity of cyclised monoester of formula VII less than 0.1% comprising reductive cyclisation using iron/acetic acid combination alongwith aromatic hydrocarbon as a co-solvent as reduction medium and treating the reaction mass after quenching with water with mineral acid.
  • Second aspect of the invention is to provide an effective and efficient process for the preparation of substituted 2-nitro-aryl malonate diester of formula II comprising contacting substituted nitrobenzenes of formula III; with alky malonate of formula IIIA in the presence of alkali metal carbonate as a base which is dried by azeotropic distillation and using the said base insitu for the said reaction in the presence of a solvent.
  • R' and R" are same or different and is selected from linear,branched and cyclic alkyl (C ! -C 4 groups)preferably methyl
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen
  • X is selected from chloro, bromo, fluoro and iodo
  • R' and R" are same or different is selected from linear, branched and cyclic alkyl (C ] -C 4 groups)
  • a specific aspect of the invention is to provide an effective and efficient process for the preparation of substituted 5-chloro-2-nitro-phenyl malonate diester from 2,5-dichloronitrobenzenes and dimethylmalonate comprising azeotropic drying of potassium carbonate used as a base and insitu using the said base for the above said reaction in the presence of a solvent.
  • Third aspect of the invention is to use compound of formula II of the second aspect for the preparation of the compound of formula I of the first aspect.
  • R is selected from hydrogen, linear, branched or
  • alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl,
  • X is selected from chloro, bromo, fluoro and iodo
  • R' and R" are same or different is selected from linear
  • R' and R" are same or different and is selected from linear,branched and cyclic alkyl (C ! -C4groups)preferably methyl
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, ha!oalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • the invention is examplified with following processes.
  • the process for the preparation of oxindole of formula I comprising:
  • Sn/HCl as reduction source comprising forming a first slurry; the first slurry comprising potassium carbonate base and an aromatic hydrocarbon like xylene as a solvent and drying the said base azeotropically comprising simultaneous removal of water ;
  • potassium carbonate as dried above is contacted insitu with DMSO to form second slurry and said second slurry is contacted with 2,5- dichloronitrobenzene and dimethylmalonate;
  • step f optionally purifying the product obtained from step e;
  • Fe/Acetic acid a) comprising forming a first slurry;the first slurry comprising potassium carbonate base and an aromatic hydrocarbon like xylene as a solvent and drying the said base azeotropically comprising simultaneous removal of water ; b) potassium carbonate as dried above is contacted insitu with DMSO to form second slurry and said second slurry is contacted with 2,5- dichloronitrobenzene and dimethylmalonate;
  • step f optionally purifying the product obtained from step e';
  • step h contacted the reaction mass of step h with additional sulphuric acid or with hydrochloric acid during the work-up of the reaction in case of iron at the appropriate stages as mentioned in specification;
  • Contacting hereinabove and hereinbelow comprises adding, mixing, heating, stirring, refluxing or combination thereof.
  • azeotrope or constant boiling mixture used herein above and herein below is a mixture of two or more liquids in such a ratio that its composition cannot be changed by simple distillation. This occurs because, when an azeotrope is boiled, the resulting vapor has the same ratio of constituents as the original mixture. Because their composition is unchanged by distillation, azeotropes are also called (especially in older texts) constant boiling mixtures.
  • Azeotropic drying of alkali metal carbonates preferably potassium carbonate and maintaining perfect anhydrous reaction condition for the preparation of diester of nitro aryl malonate of the formula II not only increases the yield at least by about 10% over the prior art methods but also provides a very clean reaction (TABLE I) avoiding the formation of other impurities described in Table- 1 herein above thereby producing high purity product in high yield.
  • Sulphated ash and HPLC assay profile of oxindole are considerably improved by using the additional quantity of mineral acid during work up of the reaction mass.
  • WO03/099198 discloses use of a weak base selected from the series of alkali metal carbonates and alkaline earth metal carbonates with preference to potassium carbonate.
  • preparation of diester of aryl nitro malonate of the formula II does not necessitates the use of absolute anhydrous reaction conditions.
  • said reaction gets affected by the moisture content of reaction mass. This was confirmed by conducting a reaction comprising external addition of water into the reaction mass that will correspond to same water content as that of commercial potassium carbonate.
  • the said reaction produced same kind of results as observed when commercial grade potassium carbonate. Therefore it was thought to use absolute anhydrous reaction conditions and use of perfectly anhydrous alkali metal carbonate or . alkaline earth metal carbonate exemplified by potassium carbonate. This is achieved by azeotropic drying of potassium carbonate comprising forming first slurry by contacting potassium carbonate with an aromatic hydrocarbon and azeotropically distillation of solvent from the said first slurry to obtain anhydrous potassium carbonate..
  • Various results indicating the progress of the reaction affected by the moisture contents of the reaction mass/ medium is supported by the following HPLC chromatographs. The best result as seems from the following chromatographs is obtained with azeotropic drying and insitu reaction for DCNB.
  • Figure II Figure HI represents hplc progress of the reaction using commercial potassium carbonate (2-3% LOD) corresponding to about 1% moisture content of reaction mass indicating cleaner over 4%.
  • Results tabulated in table-2 clearly indicate that mineral acid treatment as described in specification improves sulphated ash at least by about 5% and hence HPLC assay at least by about 10%.
  • Figure IV represents HPLC purity (area basis) for 6-chloro-2-oxindole comprising the use of Tin/HCl as reducing medium and treated with mineral acid, #6CI/1101/ 076. ARCH PHARMALABS LIMITED
  • Figure V represents HPLC assay for 6-chloro-2-oxindole comprising the use of Tin/HCl acid as reducing medium and treated with mineral acid, #6CI/1101/ 076.
  • Figure VI represents HPLC purity (area basis) for 6-chloro-2-oxindole comprising the use of Iron/Acetic acid_ as reducing medium and treated with mineral acid #6CI/11 11/134.
  • Figure VII represents HPLC assay for 6-chloro-2-oxindole comprising the use of Iron/Acetic acid as reducing medium and treated with mineral acid #6CI/1111/134.
  • Figure VIII represents HPLC purity (area basis) for 6-chloro-2-oxindole comprising the use of Tin/HCl as reducing medium with no treatment of mineral acid #BDIND2090001.
  • Figure IX represents HPLC purity (area basis) for 6-chloro-2-oxindole comprising the use of Tin/HCl as reducing medium with no treatment of mineral acid #BDIND2090001.
  • Aromatic hydrocarbon solvent to be used for the preparation of constant boiling mixture can be selected from the group comprising benzene, toluene, xylene isomers or mixture thereof. Benzene being a carcinogenic solvent is not preferred for the said purpose.
  • the said reaction comprising toluene as a co-solvent has been carried out and has been observed that compound of formula II(wherein R is CI and R' is methyl) disappears in 2 hrs and the reaction mass contains 62% of corresponding cyclised monoester of formula VII and 34% of desired oxyindole of formula I. It takes about 30-35 hrs for the completion of reaction when compound of formula VII undergoes hydrolysis and decarboxylation to form compound of formula I.
  • reaction mass is not to be allowed for the accumulation of cyclised mono ester (the only intermediate) of formula VII in the reaction mass but it is to be allowed to undergo the accelerated hydrolysis and decarboxylation which does not occur at the natural exotherm of iron addition but requires external heating.
  • reaction mass is heated to reflux the said process get accelerated resulting into formation of 6-chloro-2- oxindole with improved color.
  • a weak base is taken in an aromatic hydrocarbon to form a first slurry and the said first slurry heated to reflux to remove the water azeotropically using Dean Stark apparatus.
  • the contents are cooled and an organic solvent is added to the said dried base to form second slurry and to the said second slurry are added compound of formula III wherein X is halogen and compound of formula (malonate IIIA, wherein R' and R" are methyl group).
  • Reaction mass is heated at about 90-95 °C, till the reaction gets completed.
  • Reaction mass is cooled and water is added and precipitated dialkyl aryl nitromalonate of formula II is collected by filtration.
  • the compound of formula II is then contacted with acid and a solvent, which is then further contacted with a metal under heating resulting into the formation of third slurry;the said third slurry comprising compound of formula I and water insoluble metal generated impurity of formula M(OH)X.
  • M and X are same as described hereinabove.
  • Product of the formula I is filtered off and washed with water to get the compound of the formula I free from the metal generated impurities..
  • potassium carbonate is contacted with toluene/xylene preferably with xylene to form first slurry and water is removed azeotropically from the said first slurry using the Dean Stark apparatus till it is free from the moisture.
  • the contents are cooled to about 60-65 °C followed by the addition of DMSO to form second slurry and to the second sluury 2,5-dichloronitrobenzene and dimethyl malonate are added. Contents are heated at about 90-95 °C till hplc shows dichloronitrobenzene to be less than about 2%.
  • the reaction mass is then cooled to about 10-15°C and chilled water is added keeping the temperature below 15°C under stirring. The contents are further chilled and finally dimethylnitrobenzene malonate separates and is filtered off.
  • Methanol is charged with dimethylnitrobenzene malonate optionally under stirring at about 25-30°C. Hydrochloric acid is added keeping the temperature in the range of about 30-40°C followed by heating the contents to get a clear solution. Preferably said contents are heated at about at about 75-80°C. Methanol is distilled off and compensating the reaction mass volume with water. Preferably methanol is distilled off at about 90-95°C. Heating is continued till HPLC shows dimethylnitrobenzene malonate to be less than about 2%. Contents are cooled and methanol is added. Preferably content are cooled to about 40- 45 °C. Tin metal is then added in lots keeping the temperature in the range of about 45-50°C.
  • a weak base is taken in an aromatic hydrocarbon to form a first slurry and the said first slurry is heated to reflux to remove the water azeotropically using Dean Stark apparatus.
  • the contents are cooled and an organic solvent is added to the said dried base to obtain second slurry and to the said slurry are added compounds of formula III and dialkyl malonate of formula IIIA.
  • Reaction mass is heated, till the reaction gets completed.
  • Preferably said reaction mass is heated at about 90-95 °C.
  • Reaction mass is cooled and water is added and precipitated dialkyl aryl nitromalonate of formula II is collected by filtration.
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen
  • X is selected from chloro, bromo, fluoro and iodo
  • R* and R" are same or different is selected from linear, branched and cyclic alkyl (C j -C 4 groups)
  • R' and R" are same or different and is selected from linear,branched and cyclic alkyl
  • R is selected from hydrogen, linear, branched or cyclic alkyl, aryl, substituted aryl, heteroaryl, haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl and halogen preferably chloro
  • Aromatic hydrocarbon is selected from benzene, toluene, o- xylene, m- xylene, p-xylene and mixture of xylenes and mixture thereof.
  • aromatic hydrocarbon is mixture of xylene.
  • Organic solvent is selected from the group comprising of dimethylsulphoxide (DMSO), dimethyl formamide(DMF), dimethyl acetamide (DMA), N-methyl pyrolidinone (NMP).
  • DMSO dimethyl sulphoxide
  • DMF dimethyl formamide
  • DMA dimethyl acetamide
  • NMP N-methyl pyrolidinone
  • organic solvent is dimethyl sulphoxide (DMSO).
  • the weak base used in the above embodiment is selected from the group comprising alkali metal carbonate or alkaline earth metal carbonate.
  • base is alkali metal carbonate comprising lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate and like. More preferably base is potassium carbonate.
  • Substituted nitrobenzene of formula III is preferably selected from the group comprising difluoro, dichloro, dibromo and diiodonitrobenzene
  • compound of formula III is dichloronitrobenzene
  • Dialkyl malonate of formula IIIA is selected from C r C alkyl malonate preferably dimethyl malonate.
  • Aromatic solvent is selected from the group comprising benzene, toluene, xylene including ortho, meta, para or mixture thereof.
  • organic solvent is mixed xylene.
  • potassium carbonate is contacted with aromatic hydrocarbon selected from toluene or xylene or mixture thereof to form a first slurry and the said first slurry is heated to reflux and water is removed azeotropically using the Dean Stark apparatus till the potassium carbonate is free from the moisture.
  • the contents are cooled followed by the addition of DMSO to obtain second slurry and the said second slurry is contacted with 2,5-dichloronitrobenzene and dimethyl malonate.
  • the contents of said second slurry are heated till HPLC shows dichloronitrobenzene be less than about 2%.
  • the said contents are heated to at about 90-95 °C.
  • the reaction mass is then cooled whilist stirring.
  • the contents are further chilled and finally dimethylnitrobenzene malonate separates out and is filtered off.
  • the said reaction mass is cooled to about to about 10-15°C.
  • R is selected from hydrogen, linear, branched
  • haloalkyl like CFj, alkoxy, haloalkoxy, thioalkyl
  • the compound of the formula II is contacted with acid in a solvent, which is then further contacted with a metal under heating resulting into the formation of third slurry ;the said third comprising compound of formula I and water insoluble metal generated impurity of formula M(OH)X.
  • the said third slurry is contacted with additional quantity of mineral acid to convert the water insoluble impurity of formula M(OH)X into water soluble salt of formula MX n .
  • Product of the formula I is filtered off and washed with water to get the compound of the formula I free from the metal generated impurities.
  • R is selected from hydrogen, linear, branched
  • haloalkyl like CF 3 , atkoxy, haloalkoxy, thioalkyl
  • R' and R" are same or different is selected f rom linear
  • Metal used in the above embodiment is any metal that can displace the hydrogen from the acidic solution.
  • Metal for the purpose is selected from tin, iron, zinc, and the like.
  • metal is selected from tin or iron.
  • Acid used in the above embodiment is any acid that will react with metal liberating hydrogen to be used for the reduction.
  • Acid for the purpose is selected from hydrochloric acid, sulphuric acid, acetic acid and the like, preferably acid is selected from hydrochloric acid and acetic acid.
  • Mineral acid used in the above embodiment is any mineral acid that converts water insoluble impurity of formula M(OH)X into water soluble salts of formula MX n .
  • mineral acid is selected from hydrochloric acid or sulphuric acid. More preferably mineral acid is hydrochloric acid.
  • methanol is charged with dimethylnitrobenzene malonate under stirring C. Hydrochloric acid is added keeping the temperature in the range of about 30-40°C followed by heating the contents at about 75-8CTC to get a clear solution.
  • Methanol is distilled off at about 90-95 °C compensating volume with water in the reaction mass.
  • acetic acid is charged with dimethylnitrobenzene malonate and xylene whilist stirring at about 25-30°C.Iron powder is added in lots during which temperature reaches at about 45-50°C due to exothermicity. Contents are heated slowly to reach at refluxion about (100- 105 °C) and maintained till cyclised mono ester of formulaVII is not more than 1% with 6-chloro oxindole as a major product. Reaction mass is cooled to about 30-35°C and water is added whilist stirring to obtain a slurry hereinabove and hereinbelow referred as third slurry. The said third slurry comprises oxyindole and water insoluble impurity. Hydrochloric acid is then added and kept under stirring followed by cooling the contents at about 10- 15°C. 6-chloro-2-oxindole is collected by filtration and optionally purified if required.
  • the reduction of dialkyl ester of 2-nitrophenylmalonate comprises using metal/acid reduction resulting into the formation of substituted or unsubstituted cyclised mono alkyl ester of formula VIII replacing costly catalytic hydrogenation.
  • the said intermediate of formula VIII is used for the preparation of substituted or unsubstituted oxindoles comprising of hydrolysis and decarboxylation as depicted below.
  • R is selected from hydrogen, linear, branched
  • haloalkyl like CF 3 , alkoxy, haloalkoxy, thioalkyl
  • cyclised methyl ester of formula VII is prepared comprising reduction of dimethyl ester of 2- nitrophenylmalonate using iron/acetic acid reduction.
  • the said compound is used for the preparation of 6-chloro-2-oxindole of formula I is shown in the following schematic representation.
  • Example 1 indicating azeotropic drying of potassium carbonate and insitu using for diester preparation:
  • reaction mass showed 0.35% moisture at this level. Adjusted the moisture content of reaction mass to 4% by adding water and contents were heated to 90-95°C and the reaction progress was monitored by HPLC. The reaction did not go to completion after prolonged maintenance. Reaction terminated due to very poor conversion.
  • Example-3 reaction using commercial potassium carbonate having 1% moisture content
  • Methanol is distilled off at 90-95 °C with compensating the mass with (6.8L) 5N HC1 under stirring at 92-95 °C with HPLC monitoring for content of nitro phenyl acetic acid and nitro phenyl methyl acetate to be less than 1%. Contents were cooled to 15- 20°C and product is filtered of, washed with water till free from acidity.

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

Abstract

La présente invention concerne des procédés améliorés ayant une utilité pratique dans la préparation de 2-oxindoles de formule I comprenant la préparation de diester de 2-nitroarylmalonate de formule II en tant que premier intermédiaire et la cyclisation réductive in situ ultérieure en utilisant une combinaison d'acides métalliques et son traitement conclusif modifié pour former un composé de formule I exempt d'impuretés générées par du métal de formule M(OH)X, où M est un cation métallique et X est un anion. R est choisi parmi l'hydrogène, un groupe alkyle linéaire, ramifié ou cyclique, un groupe aryle, un groupe aryle substitué, un groupe hétéroaryle, un groupe haloalkyle semblable au CF3, un groupe alcoxy, un groupe haloalcoxy, un groupe thioalkyle et un halogène, de préférence du chloro de formule I, où R' et R" sont identiques ou différents et sont choisis parmi un groupe aryle linéaire, ramifié et cyclique (groupes C1C4), de préférence un groupe méthyle, R est choisi parmi l'hydrogène, un groupe alkyle linéaire, ramifié ou cyclique, un groupe aryle, un groupe aryle substitué, un groupe hétéroaryle, un groupe haloalkyle semblable au CF3, un groupe alcoxy, un groupe haloalcoxy, un groupe thioalkyle et un halogène, de préférence du chloro de formule II.
PCT/IN2012/000137 2011-12-20 2012-02-29 Procédé amélioré de préparation de 2-oxindoles de formule i, une matière première clé pour la fabrication de médicaments et de leurs intermédiaires Ceased WO2013093928A1 (fr)

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CN104045592A (zh) * 2014-05-07 2014-09-17 华东理工大学 制备5-氟吲哚-2-酮的方法
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
CN116020495A (zh) * 2022-10-11 2023-04-28 合肥工业大学 酯化用Ag:Sn(OH)Cl@Ag@AC可循环催化材料、制备方法及应用

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US4160032A (en) 1973-11-21 1979-07-03 Sandoz, Inc. Oxindoles as sleep-inducers
US4721712A (en) 1984-06-12 1988-01-26 Pfizer Inc. 1,3-disubstituted 2-oxindoles as analgesic and anti-inflammatory agents
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WO2002014275A2 (fr) 2000-08-11 2002-02-21 Eli Lilly And Company Derives sulfonamides heterocycliques
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104045592A (zh) * 2014-05-07 2014-09-17 华东理工大学 制备5-氟吲哚-2-酮的方法
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
CN116020495A (zh) * 2022-10-11 2023-04-28 合肥工业大学 酯化用Ag:Sn(OH)Cl@Ag@AC可循环催化材料、制备方法及应用
CN116020495B (zh) * 2022-10-11 2024-05-28 合肥工业大学 酯化用Ag:Sn(OH)Cl@Ag@AC可循环催化材料、制备方法及应用

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