TITLE

An improved process for preparing 2-oxindoles of formula I, a key raw material for making pharmaceutical drugs and intermediates thereof.

Formula I

FIELD OF TECHNOLOGY:

Disclosed herein is an improved process for preparing 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. Oxindole as used herein, refers to 2-oxindole(s).

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.

Formula II

During insitu reductive cyclisation of nitro arylmalonates of formula II using metal-acid combination to obtain corresponding oxindole of formula I, 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. Preferably 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. Preferably acid ion is selected from Cl, Br, I, SO4, -COOCH3 and the like.

The said impurities being insoluble in water do not get removed during work up and instead gets trapped in the product formed by the reduction step and gets carried forward into the final drug molecule formed therefrom adversely impacting the sulphated ash and thereby assay of the oxindole product of formula I and hence finished drug molecule therefrom.

Process described herein disclosed by the inventors provide a solution to overcome the problem by modifying the work-up strategy comprising addition of mineral acid to the reaction mixture which converts the water insoluble M(OH)X formed as an impurity into corresponding water soluble metal salt which being soluble in water gets removed at this stage itself and does not get carried forward thus producing pure final drug molecule in high yield free from said impurity thereby improving sulphated ash and hence HPLC assay. This invention is particularly examplified by considering Sn/HCl and Fe/CH3COOH combinations as reducing agents in the presence of a co-solvent.

BACKGROUND OF THE INVENTION
2-oxindoles are valuable pharmaceutical agents and/or intermediates for the production of pharmaceutical agents, including analgesic and anti-inflammatory 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.
Qualich et.al., Synthesis, vol.1993, No.1, page 51-53 discloses a three step process to prepare oxindoles from 2-halonitrobenzenes with a malonate, usually dimethyl malonate, in the presence of sodium hydride, to obtain the nitro arylmalonate. The second step involves Krapcho decarboxylation of the diester of the nitro arylmalonate with water and 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 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 is highly hazardous. Further, the yield reported by this process is about 50%. Another drawbak of the said process is that the monoester obtained in the reaction is purified by the column chromatography making it industrially non-feasible. Moreover the said reference neither teaches the concept of insitu process of reductive cyclisation nor mentions the purity profile of cyclised product.
The entire process as disclosed therein is depicted in the below given scheme.

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.

This patent also discloses the preparation of similar 6-bromo-2-oxindole comprising the similar process as described in Qualich et.al., Synthesis, vol.1993, No.1, page 51-53 as give herein above. The entire process as disclosed therein is depicted in the below given scheme.

Simet, J. Org. Chem, vol. 28 (1963), p. 3580 discloses a similar process for preparing 6-trifluoromethyl-2-oxindole from 5-trifluoromethyl-2-chloronitrobenzene, by reaction with a malonate diester anion, followed by caustic hydrolysis and decarboxylation to obtain the 4-trifluromethyl-2-nitrophenylacetic acid. After isolation, this was reduced to the 6-trifluoromethyl-2-oxindole with about a 5 mole ratio of mossy tin metal in 9N hydrochloric acid. This process likewise has the drawback of multiple process steps, however the said process does not teach the concept of insitu reductive cyclisation.
Kraynack et.al., Tetrahedron letters 39 (1998),7679-7682 discloses the preparation of several 2-oxyindoles comprising reduction and decarboxylation of nitromalonates to afford 6-chloro-2-oxindole by the treatment with tin/HCl.

Although the said reference teaches the concept of insitu reductive cyclisation of aryl malonates but involves certain operations like pulvarisation and hot filtration which are not feasible on plant scale. The process disclosed in the said prior art is used to prepare 2-oxindoles on scale of 1 to 140 mmole without indicating purity profile of 2-oxindoles.
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. It also discloses in-situ process for further catalytic hydrogenation of N-hydroxy-2-oxindole, cyclisation, hydrolysis and decarboxylation reactions to produce the 2-oxindole.The drawback of the said hydrogenation process is the formation of dehalogenated products as impurities as catalytic hydrogenation is susceptible to dehalogenation if similar process is applied for the preparation of 6-chloro-2-oxyindole.The entire process as disclosed therein is depicted in the below given scheme.

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. Moreover expensive 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. However 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. It also discloses that the use of mild base such as an alkali metal carbonate or an alkaline earth metal carbonate does not necessitates the use of absolute anhydrous reaction conditions. Moreover the said process disclosed therein isolates nitro phenyl acetic acid therefore it does not teach insitu concept of reductive cyclisation.

Organic Process Research & Development 2003,7 ,309-312 discloses the process for preparing 6-chloro 5-(2-chloroethyl)oxindole (an advanced intermediate of Ziprsidone) comprising hydrolysis and decarboxylation of tetraethyl 2,2'-(4-chloro-6-nitro-1,3-phenylene)dimalonate resulting into the formation of 2-(2-chloro-5-(2-ethoxy-2-oxoethyl)-4-nitrophenyl)acetic acid followed by its esterification to prepare corresponding methyl ester which on catalytic hydrogenation with Raney nickel in acetic acid undergoes reductive cyclisation yielding methyl 2-(6-chloro-2-oxoindolin-5-yl)acetate.The drawback associated with this process is the use of tetraethyl 2,2'-(4-chloro-6-nitro-1,3-phenylene)dimalonate as a starting material, that requires extra mole of diethyl malonate. Moreover it involves hydrogenation for reductive cyclisation which generally forms dehlogenated 2-oxindole as an impurity.
Journal of Medicinal chemistry, vol. 36, nb.22, (1993), p.3386-3396 discloses the process for preparing methyl ester of 6-chloro 2-oxindole comprising catalytic hydrogenation using palladium over charcoal. The drawback associated with this process is the use of costly palladium. Another drawback of this process is the high probability of deschlorination resulting in the formation of methyl ester of 2-oxindole as an impurity.
IN185117 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. However 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.
Keeping the drawbacks associated with the prior art discussed herein above related to insitu preparation of compound of formula II and insitu reductive cyclisation of nitro arylmalonate of the formula II using metal-acid combination, the inventors of the present invention disclose herein suitable solutions to overcome the problems associated with the processes disclosed therein in the prior art and the improved process for the preparation of substituted oxindoles disclosed herein is suitable for plant scale production.
Process disclosed herein is represented by the following scheme:

WO03/099198 discloses that preparation of nitro arylmalonate of formula II does not require the use of absolute anhydrous reaction conditions. However, 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. Moreover 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. 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. Prior art neither teaches nor motivate a person of ordinary skill to ascertain the role of moisture content for the progress of said reaction and for insitu azeotropic drying of potassium carbonate that gives higher yield and high purity profile of nitro aryl malonate of formula II.

Formula III

To compare the effect of moisture content (M.C.) for the reaction comprising contacting compound of formula III with compound of formula IIIA in the presence of a base to obtain compound of formula II three parallel reactions were run w.r.t. reaction masses having various degrees of moisture content (TABLE 1) .

R, R, R’’ and X are same as described hereinabove

1. Reaction mass having about 4% moisture content results into incomplete reaction forming impure product of formula II with lower yield.

2. Azeotropically dried potassium carbonate in xylene and using it insitu results into a clean reaction.

3. By using the potassium carbonate (LOD- ~2-3%) as such corresponding moisture content of reaction mass to about 1% resulting into a cleaner reaction over that with 4% moisture in reaction medium.

Disclosure of abbreviations used in table 1:
DCNB (2,5-dichloronitrobenzene) of formula III wherein R and X are chloro groups (Raw material):

Formula III

Monoester intermediate is formula:

(Mono ester)

CNPM (Dimcthyl-(4-chloro-2-nitrophenyl) malonate) of formula II wherein R is chloro and R’ is methyl group

Formula II

TABLE 1
M.C=Moisture Content

% M.C.of reaction mass Temp.°C No hrs HPLC monitoring area%
- - - Mono ester CNPM(PDT) DCNB(SM )
4% 90-95 3 12.47 69.02 18.62
--do-- --do-- 6 19.07 57.8 8.92
--do-- --do-- 12 32.26 26.34 5.7
--do-- --do-- 19 32.08 10.58 3.7
Insitu dried azeo tropically 90-100 9 Below 2% Above 95% Below 5%
1% 90-95 4 0.65 81 15
--do-- --do-- 8* 2.4 85 2.5
* indicating slow conversion after 4 hrs
As per the classic chemistry when tin is used as a reducing metal in combination with hydrochloric acid it gets converted into tin chloride (SnCl2) and the hydrogen generated in the reaction is used for the reduction of nitro group of formula II. After the reduction the solvent is distilled off and HCl quantity in the reaction mass gets reduced. During the process SnCl2 formed in the reaction gets hydrolyzed to form Sn(OH)Cl and owing to low HCl content and as a result higher pH the Sn(OH)Cl being insoluble in water gets precipitated and trapped with the precipitated desired product of formula I and does not get removed by the aqueous mother liquor. 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 SnCl2).

In view of above during the work-up additional quantity of mineral acid preferably hydrochloric acid is added to the reaction mass containing water insoluble tin hydroxy chloride (Sn(OH)Cl) impurity compensating the previous loss of acid during the concentration. As a result the said water insoluble impurity gets converted into tin chloride SnCl2 which being highly water soluble gets flushed away during filtration of product obtained after quenching over water thereby resulting into the product free from said impurity which otherwise gets carried forward into the advanced intermediates and finished drug molecule. The product obtained with the said modification is free from impurity and produces a high purity drug molecule in high yield.
Chemistry of the above is given as below:

Similarly when iron is 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)SO4 or Fe(OH)(OOCH3) or Fe3O(CH3COO)6(H2O)3 which gets trapped in the required 2-oxindole thereby affecting the assay, sulphated ash and overall purity and yield.
According to the chemistry of iron and acetic acid combination; interaction of the two produces ferrous (II) acetate and hydrogen. 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 [Fe3O(CH3COO)6(H2O)3]+COOCH3-.Moreover when solution of ferric acetate is heated to boiling all of the iron is precipitated as basic ferric(III) acetate. (Inoganic Chemistry, International chemical series by Hamiltan Perkin Cady). 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. Under such conditions 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 HCl and H2SO4.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.


Chemistry of the above is given as below:

Also disclosed herein is the selectivity of co-solvent for the smooth reductive cyclisation. It has been observed that when acetic acid is used as the only reaction medium/ reactant, after 65-70% metal addition of iron; a sudden exotherm takes place and temperature reaches to about 100-105°C which is not easy to control by circulating chilled water through the jacket of the reactor thereby creates a risk at the plant level. Use of C1-C3 alcohol as major solvent does not provide the optimum temperature needed for the reaction which is around 90-95°C. Inventors of the present invention disclose herein an ideal solvent and reactant medium comprising acetic acid and an aromatic hydrocarbon that provides a constant boiling mixture and drives the reaction to completion in a smooth manner.
The inventors of the present invention disclose herein that the desired constant boiling mixture can be achieved by using toluene or xylene or mixture thereof as a co-solvent.
The reaction results based on use of toluene and xylene as a co-solvent are summarized below:

In view of above 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.
However, it is to be noted that extent of intermediates and impurities depend upon the metal used for the reduction. It has been observed that when tin is used in combination with hydrochloric acid as reducing agent along with methanol as co-solvent reaction proceeds as per the following sequence comprising preference to hydrolysis.

In this case 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.

Formula IV

Formula V
However, in case when iron is used in combination with anhydrous acetic acid; 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. One important observation in relation to this process is color development in the oxindole of formula I. As per the observation of the present inventors color development 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.

Prior reduction during reduction process avoids the formation of compounds of formulae V and VI as intermediates or as impurities. Reaction mass is heated to reach at refluxion; during which cyclised mono ester of formula VII undergoes hydrolysis and decarboxylation with simultaneous conversion into product of formula I thereby reducing the digestion period and hence improves the color.

SUMMARY OF DRAWBACKS ASSOCITED WITH INSITU REDUCTIVE CYCLISATION:
1.More sulphated ash and hence less assay of 2-oxindoles of formula I due to trapped metal generated impurities does not pass the required specifications.
2. Poor color and appearance hence does not pass the required specifications.
3. Poor yield and quality of advanced intermediates and finished drugs obtained comprising the use of contaminated 2-oxindolesof formula I thereby not meeting the pharmaceutical requirements.
4. Controlled exotherm during reductive cyclisation hence plant feasible.
TECHNICAL SOLUTIONS OVER DRAWBAKS OF THE PRIOR ART:
1. Removal of trapped water insoluble metal generated impurities represented by formula M(OH)X by converting the said water insoluble impurities into corresponding water soluble salts during the work-up comprising contacting the reaction mass with mineral acid thereby improving sulphated ash and hence assay.
2. Reducing the digestion period of the intermediates by accelerating rate of cyclisation.
3. Use of good quality 2-oxindole of formula I for the preparation of advanced intermediates and finished drugs therefrom in higher yield meeting specifications.
4. Use of aromatic hydrocarbon as a co-solvent that provides optimum temperature required for the reaction.
SULPHATED ASH AND HPLC ASSAY:
The determination of 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.

This can be best understood by the example: 60% solution of a material having 99.5% purity when injected in HPLC will result into 99.5% purity and 60% assay indicating material with high HPLC purity need not to have high HPLC assay also.
OBJECTS OF THE INVENTION:
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..

Formula I
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.

Formula II

Formula III

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.
Further aspects of the present invention are to provide processes having at least one of the following characteristics:
1) General method for preparing a variety of nitro aryl malonates of the formula II comprising drying of the base selected from the series of alkali metal carbonates, alkaline earth metal carbonates and the like comprising preparing a first slurry;first slurry comprising base and an aromatic hydrocarbon. Drying the base from the said first slurry using the concept of azeotropic drying and using the said dry base insitu for the reaction of substituted nitrobenzenes of formula III by contacting with dialkyl malonate of formula IIIA.
2) Selectivity of co-solvents selected from the series of aromatic hydrocarbon and mixture thereof for the preparation of constant boiling mixture as described hereinabove.
3) Converting water insoluble metal associated impurities represented by formula M(OH)X (which otherwise gets carried forward into advanced intermediates and the end drug molecule) into water soluble compounds of formula MXn(wherein M represents metal cation ,X represents anion and n is an integer like 1,2,3 etc) which gets removed and washed away into mother liquor during work up by using extra amount of mineral acid.
4) Minimizes the number of process reaction steps and unit operations.
5) Readily scalable for production of commercial scale quantities of oxindole and advanced intermediates and pharmaceutically acceptable drug molecules therefrom.
6) High purity 2-oxindole having cyclised mono ester of formula VII as an impurity not more than 0.1%.
7) Improved sulphated ash thereby increasing the assay.
8) 2-oxindole having sulphated ash less than about 0.1%.

SUMMARY OF THE INVENTION:

Disclosed herein is a process for the preparation of oxindoles of formula I comprising:
a) forming a first slurry, the first slurry comprising an inorganic base in a solvent;
b) removing the water from the inorganic base by distilling off the solvent from the first slurry by azeotropic distillation process to obtain a dried base:
c) add organic solvent to the said dried base to form a second slurry;
d) contacting compound of formula III and compound of formula IIIA with dry base in the said second slurry to obtain a compound of formula II;
e) contacting said compound of formula II with a metal and acid in a solvent to obtain third slurry; the third slurry comprising 2-oxyindole of formula I and water insoluble impurity of formula M(OH)X wherein M is a metal caion and X is an anion;
f) adding mineral acid to the said 3rd slurry to convert water insoluble impurity of formula M(OH)X into corresponding water soluble metal compound of formula MXn wherein M and X are same metal and acid moieties as in M(OH)X and n is equivalent to the valency of metal and the said water soluble metal compound gets removed during processing of reaction mass;
g) isolating the 2-oxindole of formula I free from metal compound impurities of formulae M(OH)X and MXn from the 3rd slurry.

purifying oxindole of formula I obtained from step g and isolating pure 2-oxindole of formula I

The invention is examplified with following processes. The process for the preparation of oxindole of formula I comprising:

1. Sn/HCl as reduction source:

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;
c)monitoring the reaction for the disappearance of 2,5-dichloronitrobenzene ;
d) quenching the reaction mass with water
e) cooling the contents and collecting diester of nitro phenylmalonate of formula II wherein R’ and R” is methyl group by filtration;
f) optionally purifying the product obtained from step e;
g) forming a slurry;the said slurry hereinbefore and hereinbelow refered as third slurrys; the said third slurry comprising diester of nitro phenylmalonate obtained in e or f, methanol ,hydrochloric acid tin to be used as reductant metal;
h) monitoring the reaction for the disappearance of diester of nitro phenylmalonate of formula II and formation of intermediates and the conversion of intermediates till the formation of required product of formula I;
i) contacted the reaction mass of step h with additional quantity of hydrochloric acid during the work-up of the said reaction mass
j) cooling the reaction mass and collecting the product by filtration;
k) optionally purifying the product.

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;
c)monitoring the reaction for the disappearance of 2,5-dichloronitrobenzene;
d) quenching the reaction mass with water;
e) cooling the contents and collecting diester of nitro arylmalonate by filtration;
f) optionally purifying the product obtained from step e’;
g) forming a slurry;the said slurry hereinbefore and hereinbelow refered as third slurrys;the said third slurry comprising diester of nitro phenylmalonate obtained in e or f, acetic acid,xylene and iron to be used as reductant metal;
h) monitoring the reaction for the disappearance of diester of nitro phenylmalonate of formula II and formation of intermediates and the conversion of intermediates till the formation of required product;
i) 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;
j) cooling the reaction mass and collecting the product by filtration;
k) optionally purifying the product.

Contacting hereinabove and hereinbelow comprises adding, mixing, heating, stirring, refluxing or combination thereof.
The term 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.
ADVANTAGES OVER THE PRIOR ART:

1) 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.

2) 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.

3) Use of selective aromatic hydrocarbon as a co-solvent not only alters the rate of reaction but also controls the temperature over the use of single solvent by forming the constant boiling mixture.

4) Metal/acid reduction minimizes the chances of forming dehalogenated product e.g. deschloro oxindole as an impurity over those of catalytic hydrogenation.

5) in-situ reaction reduces process unit operations.

6) High purity of diester of nitro aryl malonate improves the yield of oxindole and derivatives thereof which intern produces high purity advanced intermediates and drug molecule.

DEATAILED DESCREPTION OF THE INVENTION:

Disclosed herein is an efficient, economical and industrially viable process for the preparation of 2-oxindoles of formula (I) and its derivatives thereof free from metal generated impurities. The disclosure of the present invention has been described in detail under the following heads:

USE OF AZEOTROPICALLY DRIED ALKALI METAL CARBONATES PREFERABLY POTASSIUM CARBONATE:

It has been observed by the inventors of the present invention that use of commercial potassium carbonate after routine drying retains some moisture in it that retards the progress of reaction forming multiple numbers of impurities. 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. However as per WO03/099198; preparation of diester of aryl nitro malonate of the formula II does not necessitates the use of absolute anhydrous reaction conditions. But it has been confirmed by the inventors of the present invention that 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 I represents hplc progress of the reaction having 4% water content indicating unclean reaction

Figure I

Figure II represent hplc progress of the reaction using insitu dried potassium carbonate indicating clean reaction

Figure II

Figure III 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%.

Figure III

USE OF MINERAL ACID AND IMPROVISATION IN SULPHATED ASH AND HPLC ASSAY THEREBY:

It has been observed by inventors of present invention that sulphated ash content of 6-choloro-2-oxindole of formula I , if not treated with mineral acid as described in specification results into at least 5 times more sulphated ash content compared to the product obtained after treating the reaction mass with mineral acid. Improvisation in sulphated ash directly affects the HPLC assay also. As per the subjectabout 10%. Inventors of the present invention have been successful in getting 6-chloro-2-oxindole with sulphated ash less than about 0.1%, HPLC assay of at least 99% when treated with mineral acid preferably with Iron/acetic acid combination along with aromatic hydrocarbon co-solvent as reduction medium.

HPLC purity and HPLC assay and sulphated ash of 6-choloro-2-oxindole of formula I with and without treatment with mineral acid is given below in TABLE -2.

TABLE -2
Batch No. Treatment of mineral acid HPLC Purity % HPLC assay % Sulphated ash %

6CI/1101/ 076.
Sn/HCl
Yes
98.15
97.98
0.08

6CI/1111/134
Fe/CH3COOH
Yes
99.91
99.82
0.04

BDIND2090001
Sn/HCl
No
93.94
87.65
0.4

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.

Figure IV
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 V
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/1111/134.

Figure VI
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 VII
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 VIII
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.

Figure IX

USE OF AROMATIC SOLVENT FOR MAKING CONSTANT BOILING MIXTURE:
Use of acetic acid (in case when iron is used as a reducing metal) as only solvent for the purpose of reductive cyclisation is not satisfactory. It has been observed that after about 65-70% metal addition a sudden exotherm takes place and temperature reaches to about 100-105°C which cannot be controlled by circulating chilled water through the jacket of the reactor thereby creates a risk at the plant level. Optional use of C1-C3 alcohol as co-solvent as reported in WO2003/099198 does not provide the optimum temperature needed for the reaction which is around 90-95°C. To overcome the difficulties associated with the process disclosed therein in the prior art inventors disclose herein use of aromatic hydrocarbon as a co-solvent with acetic acid that provides a constant boiling mixture to the reaction mass which drives the reaction to completion in a safe and efficient manner.

SELECTIVITY OF AROMATIC SOLVENT FOR MAKING CONSTANT BOILING MIXTURE:

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 Cl 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. This may be owing to the fact that the decarboxylation of compound of formula VII to obtain compound of formula I is an endothermic reaction and this can be achieved at about 95°C. The desired reaction condition are not achievable when toluene is used as a co-solvent, therefore, takes a long time for the completion of reaction to form compound of formula I. When constant boiling mixture comprises xylene as a co-solvent; after the disappearance of compound of formula II (wherein R is chloro and R’ is methyl group) from the reaction mass in two hours, there remains 34% of cyclised monoester of formula VII and 62% of formula of oxindole of formula I (wherein R is chloro). Conversion of so formed cyclised monoester of formula VII into oxindole of formula I take about 11 hrs. The Process results disclosed hereinabove indicates that xylene is an ideal co-solvent to form constant boiling mixture for the said reaction.

CONTROL OVER THE COLOR DEVELOPMENT:

It has been observed that color of 6-choloro-2-oxindole of formula I is time and temperature dependent. Digestion of reaction mass after iron addition thereby accumulating cyclised mono ester of formula VII imparts various color shades to the product of the reaction. According to the findings of the present invention after the complete addition of iron, 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. When the reaction mass is heated to reflux the said process get accelerated resulting into formation of 6-chloro-2-oxindole with improved color.

In a general embodiment of the invention 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. The said third slurry is then contacted with additional quantity of mineral acid to convert the water insoluble impurity of formula M(OH)X into water soluble salt of formula MXn (n=valency of metal M). 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..

In a preferred embodiment of the invention 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. Temperature is then slowly raised to reflux and the maintained for about 2-3 hrs to obtain third slurry. Methanol is distilled off and compensating volume with 5N HCl with continued heating at about 90-95°C. Reaction is monitored for oxindole as a major product and other intermediates namely nitro phenyl acetic acid and nitro phenyl methyl acetate. The reaction mass is cooled and product is collected by filtration and optionally purified if required.
In another embodiment of the invention 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.


Formula III

Formula II
Aromatic hydrocarbon is selected from benzene, toluene, o- xylene, m-xylene, p-xylene and mixture of xylenes and mixture thereof. Preferably aromatic hydrocarbon is mixture of xylene.

There is no particular restriction on the nature of the organic solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved. Organic solvent is selected from the group comprising of dimethylsulphoxide (DMSO), dimethyl formamide(DMF), dimethyl acetamide (DMA), N-methyl pyrolidinone (NMP). Preferably 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. Preferably 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 Preferably compound of formula III is dichloronitrobenzene. Dialkyl malonate of formula IIIA is selected from C1-C4 alkyl malonate preferably dimethyl malonate. Aromatic solvent is selected from the group comprising benzene, toluene, xylene including ortho, meta, para or mixture thereof. Preferably organic solvent is mixed xylene.

In a preferred embodiment 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%. Preferably 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. Preferably the said reaction mass is cooled to about to about 10-15°C.

Schematic representation for the preparation of isolated diester of nitroarylmalonate of formula II

In a general embodiment of the invention 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 MXn. 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.
M and x are same as described herein above.
Schematic representation for the preparation of 2-oxindole of formula I:

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. Preferably 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 MXn. selected from the group comprising hydrochloric acid, sulphuric acid, phosphoric acid and the like. Preferably mineral acid is selected from hydrochloric acid or sulphuric acid. More preferably mineral acid is hydrochloric acid.

In a preferred embodiment of the present invention 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 75-80°C to get a clear solution. Methanol is distilled off at about 90-95°C compensating volume with water in the reaction mass. Heating is continued till HPLC shows dimethylnitrobenzene malonate to be less than about 2%.Contents are cooled to about 40-45°C and methanol is added. Tin metal is then added in lots into third slurry comprising water, acid, oxindole of formula I and water insoluble impurity of formula M(OH)X keeping the temperature in the range of about 45-50°C. Temperature is then slowly raised to reach at about 70-75°C (reflux) and maintained for about 2-3 hrs. Methanol is distilled off at about 90-95°C and compensating the volume with 5N HCl whilist heating at about 90-95°C. Reaction is monitored for oxindole as major product and other intermediates namely Nitro phenyl acetic acid and Nitro phenyl methyl acetate. The reaction mass is cooled and product is collected by filtration and optionally purified if required.

Schematic representation for the preparation of 6-chloro-2-oxindole when Tin is reductant metal:

In another preferred embodiment of the present invention 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.

Schematic representation for the preparation of 6-chloro-2-oxindole when iron is reductant metal:

In a general embodiment of the present invention 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.

Schematic representation for the preparation of 2-oxindole via cyclised mono ester intermediate:

In a preferred embodiment of the present invention 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.

Schematic representation for the preparation of 6-chloro-2-oxindole via cyclised mono ester(methyl) intermediate:

The invention can be best understood by the following illustrative examples.

Example 1 indicating azeotropic drying of potassium carbonate and insitu using for diester preparation:

200 g potassium carbonate was added with 600 ml of xylene and water was removed azeotropically by heating the contents at reflux till water is completely removed and is further confirmed by moisture content. After distillation of xylene as much as possible, 300 ml DMSO was added under stirring at around 60°C followed by addition of dimethyl malonate (126.1g,0.98mol) and 125 g ( 0.65mol) of 2, 5-dichloronitrobenzene. Reaction mass was heated at 90-105°C till reaction mass is left with less than 2% of 2,5-dichloronitrobenzene and monoester below ~4%. Reaction mass is quenched with water, product is filtered off, washed with water till it becomes free from basicity. Weight of dry product: 170-175g cream colored solid with HPLC assay of 94-95% which accounts for 85-90% molar yield.

Example-2 indicating unclean reaction for diester preparation with 4% moisture content:

To a suspension of DMSO (350ml) and commercially available potassium carbonate (143g: 2m/m, LOD -2%) added dimethyl malonate (101g 1.5m/m) and 2,5-dichloromethane (100g). 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)

To a suspension of DMSO (350ml), xylene (300ml) and commercially available potassium carbonate (143g 2m/m, LOD -2%) added dimethyl malonate (101g 1.5m/m) and 2,5-dichloromethane (100g). Reaction mass was showed to have 0.60 to1% moisture content .Reaction mass was heated to 90-95°C and the reaction progress was monitored by HPLC. A sample after 4h showed 81% of the required product and 15% unreacted 2,5-dichloronitrobenzene and 0.65% monoester. Reaction continued to 12h and showed 85% dimethyl ester of 2-nitrophenylmalonate with 3.8% unreacted 2,5-dichloronitrobenzene and 2.4% monoester. The progress of the reaction was found to be very slow after 4h.

Example- 4: Preparation of 6-chloro 2-oxindole (Tin as reductant metal):
8.8 L methanol is charged with 1.1 kg dimethyl ester of 2-nitrophenylmalonate under stirring at ambient temperature followed by the addition of 4.8 L concentrated hydrochloric acid keeping the temperature in the range of 30-40°C. Contents are heated to reach at 75-80°C till clear solution is obtained. Methanol is distilled off at 90-95°C reaction mass is compensated with 4Lwater and the reaction mass is maintained at 90-95°C till HPLC showed malonate to be less than 2%. Reaction mass is cooled to 45-50°C and 4L methanol is added followed by adding 0.975g tin in lots keeping the temperature in the range of 45-50°C. Temperature is brought to 75-80°C by gradual heating and maintained for 2-3 hours. Methanol is distilled off at 90-95°C with compensating the mass with (6.8L) 5N HCl 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.

Wt of crude =0.7kg, Area% = 96, HPLC assay= 86%

The crude mass is further purified from ethyl acetate.

Dry weight = 0.5kg, yield 75%, area: 98%, HPLC assay 97.98%, , sulphated ash 0.08%

Example- 4: Preparation of 6-chloro 2-oxindole (iron as reductant)

3.5L acetic acid is charged with 1 kg of dimethyl ester of 2-nitrophenylmalonate, 4.5L xylene under stirring at 25-30°C. 0.573 kg iron powder is added in lots keeping the temperature at 25-30°C. Stirring is continued when temperature reaches at 45-50°C. Reaction mass is then heated to reach at 100-105°Ctill HPLC showed cyclized monoester to be less than 1%.Reaction mass is gradually cooled to reach at 30-35°C and 10L water is added slowly under stirring followed by addition of 6L of con HCl keeping the temperature below 40°C. Contents are cooled to 10-15°C and 6-choloro 2-oxindole is collected by filtration, washed with water till free from free acid.

Crude weight: 0.7kg, area%= 96%, assay=93%

Crude is purified from ethyl acetate.

Dry weight: 0.43kg, yield=75% area%=99.91%, assay 99.82% , sulphated ash:0.04%

Example- 5: Preparation of cyclised mono ester of formula VII
3.5L acetic acid is charged with 1 kg of dimethyl ester of 2-nitrophenylmalonate, 4.5L xylene under stirring at 25-30°C. 0.573 g iron powder is added in lots keeping the temperature at 25-30°C. Stirring is continued and temperature is maintained at 50-55°C. Reaction mass is quenched over the water and product is isolated by the work-up as described under example 4.

WE CLAIM:

1. A process for the preparation of 2-oxindoles of formula I comprising the steps:

h) forming a first slurry, the first slurry comprising an inorganic base in a solvent;
i) removing the water from the inorganic base by distilling off the solvent from the first slurry by azeotropic distillation process to obtain a dried base:
j) add organic solvent to the said dried base to form a second slurry;
k) contacting compound of formula III and compound of formula IIIA with dry base in the said second slurry to obtain a compound of formula II;
l) contacting said compound of formula II with a metal and acid in a solvent to obtain third slurry; the third slurry comprising 2-oxyindole of formula I and water insoluble impurity of formula M(OH)X wherein M is a metal caion and X is an anion;
m) adding mineral acid to the said 3rd slurry to convert water insoluble impurity of formula M(OH)X into corresponding water soluble metal compound of formula MXn wherein M and X are same metal and acid moieties as in M(OH)X and n is equivalent to the valency of metal and the said water soluble metal compound gets removed during processing of reaction mass;
n) isolating the 2-oxindole of formula I free from metal compound impurities of formulae M(OH)X and MXn from the 3rd slurry.
o) purifying oxindole of formula I obtained from step g and isolating pure 2-oxindole of formula I

2. The process of claim 1 wherein solvent used to form first slurry is selected from aromatic hydrocarbons comprising benzene, toluene, o-xylene, m-xylene, p-xylene, mixture of xylenes and mixture thereof.

3. The process of claim 2 wherein aromatic hydrocarbon used to prepare first slurry is xylene.

4. The process of claim 1 wherein base used in first slurry is selected from alkali metal carbonate or alkaline earth metal carbonate.

5. The process of claim 4 wherein base used in first slurry is potassium carbonate.

6. The process of claim 1 wherein organic solvent used to form the second slurry is dimethylsulphoxide (DMSO).

7. The process of claim 1 wherein R and X substituents in compound of formula III are chloro groups.

8. The process of claim 1 wherein R’ and R” substituents in compound of formula IIIA are methyl groups.

9. The process of claim 1 wherein metal is any metal that liberates hydrogen from the acidic solution.

10. The process of claim 9 wherein metal is selected from the group comprising tin, iron, zinc.

11. The process of claim 1 wherein acid is any acid that reacts with metal liberating free hydrogen to be used for the reduction.

12. The process of claim 11 wherein acid is selected from group comprising hydrochloric acid, sulphuric acid, acetic acid.

13. The process of claim 1 wherein mineral acid to be added to 3rd slurry is selected from the group comprising hydrochloric acid, sulphuric acid and phosphoric acid.

14. Compound of formula IA produced according to the process of claim 1

with

a) sulphated ash less than 0.1%

b) HPLC assay more than 97.5%

15. A process for the preparation of compound of the formula II comprising the steps:

a) forming a first slurry, the first slurry comprising an inorganic base in an solvent;
b) removing the water from the inorganic base by distilling off the solvent from the first slurry by azeotropic distillation process to obtain a dried base:
c) add organic solvent to the said dried base to form a second slurry;
d) contacting compound of formula III and compound of formula IIIA with dry base in the said second slurry to obtain compound of formula II;
e) isolating the compound of formula II from the said second slurry.

16. The process of claim 15 wherein the solvent used to form first slurry is selected from aromatic hydrocarbons comprising benzene, toluene, o-xylene, m- xylene, p-xylene, mixture of xylenes and mixture thereof.

17. The process of claim 16 wherein aromatic hydrocarbon used to prepare first slurry is xylene.

18. The process of claim 15 wherein base used in first slurry is selected from alkali metal carbonate or alkaline earth metal carbonate.

19 The process of claim 18 wherein base used in first slurry is potassium carbonate

20. The process of claim 15 wherein organic solvent used to form the second slurry is dimethylsulphoxide (DMSO).

21. The process of claim 15 wherein R and X substituents in compound of formula III are chloro groups.

22. The process of claim 15 wherein R’ and R” substituents in compound of formula IIIA are methyl groups.

23. A process for the preparation of compound of the formula I with sulphated ash less than 0.1% comprising the steps:

a) contacting compound of formula II with a metal and acid in a solvent to obtain a slurry of 2-oxyindole of formula I and water insoluble metal oxy compound impurity of formula M(OH)X wherein M is a metal caion and X is an anion, quenching reaction mass over water ;
b) adding mineral acid to the said slurry to convert water insoluble impurity of formula M(OH)X into corresponding water soluble metal compound of formula MXn wherein M and X are same metal and acid moieties as in M(OH)X and n is equivalent to the valency of metal ion and the said water soluble metal compound gets removed during the processing of reaction mass;
a) isolating the oxindole of formula I Free from metal compound impurities of formulae M(OH)X from the said slurry.
b) Purifying oxindole of formula I and isolating the pure solid.

24. 2-oxindoles of formula I with sulphated ash less than 0.1%

24. 6-chloro -2-oxindoles of formula I with HPLC assay of at least 99%.

25. 6-choloro - 2-oxindoles of formula I with impurity of formula VIII less than 0.1%

26. A process for the preparation of compound of the formula I with HPLC assay not less than 97.5% comprising of the steps:

c) contacting compound of formula II with a metal and acid in a solvent to obtain slurry of 2-oxyindole of formula I and ; water insoluble metal oxy compound impurity of formula M(OH)X wherein M is a metal cation and X is anion, quenching reaction mass with water
d) adding mineral acid to the said slurry to convert water insoluble impurity of formula M(OH)X into corresponding water soluble metal compound of formula MXn wherein M and X are same metal and acid moieties as in M(OH)X and n is equivalent to the valency of metal ion and the said water soluble metal compound gets removed during the processing of reaction mass;
c) isolating the oxindole of formula I Free from metal compound impurities of formulae M(OH)X from the said slurry.
d) Purifying oxindole of formula I and isolating the pure solid

27. A process of claim 26; wherein use of iron/acetic acid as reduction medium produces 2-oxindole of formula I with HPLC assay not less than 97.5%.

28. A process of claim 26; wherein use of tin/HCl as reduction medium produces 2-oxindole of formula I with HPLC assay not less than 99%