FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10 rule 13)
1. TITLE OF THE INVENTION: A PROCESS FOR THE PREPARATION OF 2-OXINDOLES OF FORMULA .
2. APPLICANT:

(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: ARCH PHARMALABS LIMITED,
541-A, ARCH HOUSE, MAROL-MAROSHI ROAD, ANDHERI (EAST), MUMBAI-400059
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE
A process for the preparation of 2-oxindoles of formula I

FIELD OF TECHNOLOGY:
Disclosed herein is an improved, economical and ecofriendly process for the preparation of 2-oxindoles of formula I with less sulphated ash, high HPLC assay and high HPLC purity. Oxindole described herein particularly refers to 6-chloro-2-oxindole(s) of formula IA, which is a key raw material for the preparation of pharmaceutical drugs like Ziprasidone of formula II and its salts and intermediates thereof. 2-oxindoles is also known as 2-oxindolines or indole-2(3H)-ones. The process disclosed herein relates to a single step catalytic hydrogenation of compound of the formula III in a solvent to obtain compound of formula I. The process in particular comprises the use of raney nickel as a catalyst which can be recovered and repeatedly reused, capable of reducing the nitro group of compound of formula III into amino group suitably, followed by cyclisation of said amino compound to obtain oxindole of Formula I. The most advantageous feature is the cost

reduction of the process at least by about 25% by reusing the catalyst and recycling of recovered solvent and ecosafety as it avoids formation of sludge containing metals.

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 IA 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.l, page 51-53 discloses a three step process to prepare 6-chloro-2-oxindoles from 2-halonitrobenzenes with a malonate, usually dimethyl malonate, in the presence of sodium hydride, to obtain the nitro arylmalonate. The second step comprises Krapcho decarboxylation of the diester of the nitro arylmalonate with water and lithium chloride in dimethyl sulfoxide to obtain malonate monoester. The nitro group of the monoester is then reduced with iron and acetic acid to yield 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 drawback 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 in-situ process of reductive cyclisation nor mentions the purity profile of cyclised product. One of the major drawbacks associated with the said process is the use of metal-acid combination for reducing the nitro group into amino group that generates effluent problem by forming metallic sludge, disposal of which is a big issue.

The entire process as disclosed therein is depicted in the below given scheme.

US4721712 (hereinafter refered as '712) 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.
'712 also discloses the process for the preparation of similar 6-bromo-2-oxindole comprising the similar process as described in Qualich et.al., Synthesis, vol.1993, No.l, page 51-53 as give herein above. The entire process as disclosed therein is illustrated hereinbelow.


Simet, J. Org. Chem, vol. 28 (1963), p. 3580 discloses a similar process for preparing 6-trifluoromethyl-2-oxindole from 5-trifluoromethyl-2-chloronitrobenzene comprising reaction with a malonate diester anion, followed by caustic hydrolysis and decarboxylation to obtain the 4-trifluromethyl-2-nitrophenylacetic acid. After isolation 4-trifluromethyl-2-nitrophenylacetic acid was reduced to obtain 6-trifluoromethyl-2-oxindole with about a 5 mole ratio of mossy tin metal in 9N hydrochloric acid.
Kraynack et.al., Tetrahedron letters 39 (1998),7679-7682 discloses a process for the preparation of several 2-oxyindoles comprising reduction and decarboxylation of nitromalonates to afford 6-chloro-2-oxindole by the treatment with tin/HCI.

The said reference teaches the concept of in-situ reductive cyclisation of aryl malonates and comprises certain operations like pulverization 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. One of the major drawbacks associated with the said process is the use of tin -HC1

combination for reducing the nitro group into amino group that generates metallic sludge as an effluent disposal of which is a big issue.
US6469181 discloses two step hydrogenation of 2-nitrophenylacetic acids or esters to 2-oxindoles comprising catalytic 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 said process also mentions the evacuation of carbondioxide twice during the hydrogenation.
The said process comprises two catalytic hydrogenations for the preparation of compound of formula I. The entire process as disclosed therein is illustrated in the scheme given herein below.


The drawback of the said hydrogenation process is the formation of dehalogenated products in case of halo substituted 2-oxindoles as impurities as catalytic hydrogenation specifically using Pt/C as it has been used in examples 2 and 6 is susceptible to dehalogenation when similar process is applied for the preparation of 6-chloro-2-oxyindole.
Since the said process comprises two catalytic hydrogenations therefore there are two probabilities for dechlorination at two stages during the process; when same process is applied for the preparation of 6-chloro-2-oxindole


Example 2 of the said application discloses reduction in acetic acid using Pt/C.
Example 6 of the said application discloses reduction using sulphided Pt/C in non acidic solvent like ethanol as well as cyclisation without using any external acidic source.
Inventors of the present invention have studied the preparation of 6-chloro-2-oxindole of formula IA by hydrogenation using Pt/C and Pd/C. However as per their finding; these reactions of reduction and even cyclisation are not clean as confirmed by the HPLC chromatographs (figures I and II) showing multiple numbers of peaks shown herein below. In case when poisoned catalyst is used with the intension of minimizing dechlorination, it has been observed that dechlorination certainly gets minimized but the reduction of nitro group gets hindered at N-hydroxy compound rather than getting amino compound and may require higher temperature for completion. On the other hand when normal catalyst is used the amount of dechlorination increases along with the formation of desired amino compound. Furthermore N-hydroxy compound thus formed does not convert into 2-oxindol on further prolonged hydrogenation at the same temperature. Moreover, even after the external cyclisation chromatographs shows extra peaks indicating non conversion of intermediates formed during hydrogenation into required product.

FIGURE I
Furthermore, inventors of the present invention have observed that the use of acidic source is necessary to push the cyclisation, in absence of which cyclised product is formed upto the extent of 4% only as indicated in figure III (use of Pt/C) and 11.8% figure VI( use of Pd/C).




FIGURE HI
FIGURE IV
In view of above it can be stated that Pt/C or poisoned Pt/C? is not satisfactory catalyst for the preparation of 6-chloro-2-oxindole. Similar results are also for Pd/C figure IV (reduction) and V (cyclisation) indicating it to be non satisfactory for the preparation of compound of formula IA.


FIGURE V


FIGURE VI
Figure I represents reduction of compound of formula III into compound of formula IA using Pt/C, in acetic acid.

Figure II represents cyclisation having multiple peaks resulting from Pt/C indicating non conversion of intermediates formed during hydrogenation into required product of formula IA.
Figure III represents formation of cyclised product of formula IA in absence of non acidic solvent and condition.
Figure IV represents reduction of compound of formula III into compound of formula IA using Pd/C, in acetic acid.
Figure V represents cyclisation having multiple peaks resulting from Pd/C indicating non conversion of intermediates formed during hydrogenation into required product of formula IA.
Figure VI represents formation of cyclised product of formula IA in absence of non acidic solvent.
US4160032 discloses the preparation of 6-chloro-2-oxindole comprising reacting 4-chloro-2-nitrotoluene with sodium ethoxide and diethyl oxalate followed by refluxing it with hydrogen peroxide and acidification to obtain 4-ehloro-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 resulting in the formation of impurities.
WO02/14275 discloses a process for the preparation 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 a 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. Moreover use of Zinc and sulphuric acid creates effluent problem resulting from sludge formation.
WO03/099198 discloses a three step process to prepare oxindoles from 2-halonitrobenzenes comprising 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 arylmalonate is subjected to hydrolysis and decarboxylation to obtain nitro aryl acetic acid which is isolated and then subjected to reductive cyclisation using iron-acetic acid optionally using methanol as a co-solvent to obtain 2- oxindole of formula IA. However, use of iron and acetic acid creates effluent problem resulting from sludge formation.

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-l,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. Though the said reference discloses the hydrogenation of nitro group into amino group (well known in the art) for an advanced Ziprasidone intermediate by using raney Nickel in acetic acid, it does not give the satisfactory results when it is applied for the hydrogenation of nitro group into amino group for the preparation of compound of formula IA from compound of formula III under the same conditions as described therein in the prior art. It results into a incomplete reaction leaving behind about 40-50% unreacted starting material of formula III as confirmed by HPLC chromatographs of two reaction samples given herein below in figures VII and VIII:


FIGURE VII

FIGURE VIII
Journal of Medicinal chemistry, vol. 36, nb.22, (1993), p.3386-3396 discloses a 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 dechlorination resulting in the formation of methyl ester of 2-oxindole as an impurity as discussed in details herein above.

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 to the reductive cyclisation.
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 the presence of a solvent. However, the drawback associated with this process is formation of huge sludge resulting from metal acid reduction like tin, iron etc.
Process disclosed therein is represented by the following scheme:

Solution to the technical problems associated with the processes disclosed therein in the prior art is the object of the present invention. Taking into consideration the said objective the present invention

provides an industrially viable, safe and economical process thereby eliminating all the shortcomings of the processes disclosed therein in the prior art.

FIGURE IX
In the present invention the inventors have studied different modes for the preparation of 6-chloro-2-oxindol of formula IA comprising reduction of nitro group into amino group by hydrogenation including catalytic hydrogenation and catalytic transfer hydrogenation. However, catalytic hydrogenation using Pt/C and Pd/C was not found to be satisfactory owing to their unclean reaction, impure cyclised product as discussed herein above in the specification. Second attempt was to prepare 6-chloro-2-oxindole comprising reduction of nitro group into amino group by catalytic transfer hydrogenation using ammonium formate/ Pd/C (Figure VII), hydrazine/ FeCl3(Figure VIII). However the, results were not found to be satisfactory as the reactions were unclean as confirmed by the following chromatographs given herein below:


FIGURE X Description of Figures:
Figure IX represents reduction of compound of formula III into compound of formula IA using catalytic transfer hydrogenation using ammonium formate/ Pd/C indicating 59.69% unreacted starting material of formula III.
Figure X represents reduction of compound of formula III into compound of formula IA using catalytic transfer hydrogenation using hydrazine/ FeCl3 indicating formation of product only to the extent of 1.36% and 59.69% unknown compound at 16.35 RT.

None of the process disclosed therein in the prior art describes any probability of reusing the catalyst and thereby making the process economically inefficient.
The process proposed herein comprises catalytic hydrogenation of compound of formula III in a solvent into compound of formula IA using non acidic solvent comprising preparation of corresponding amino compound followed by insitu cyclisatioh using mineral acid as illustrated herein below. The process in particular comprises the use of raney nickel as a catalyst capable of reducing nitro group of compound of formula III (when R is CI) to obtain the corresponding amino compound avoiding dechlorination and formation of deschloro impurities; the said amino compound of formula III is cyclised insitu yielding oxindole of formula I. The said nickel catalyst capable of reducing nitro group of compound of formula III to obtain corresponding amino compound can be repeatedly reused along with use of recovered solvent making the process economically efficient. As regards reuse of recovered solvent it is to be noted that the reduction of nitro group into amino group is accompanied by the water generation. Therefore removal of the water from the solvent by the traditional modes and reuse remains under the scope of the invention. Presence of water acts as antisolvent resulting into the precipitation of the amino product. Similarly addition of a polar solvent to dissolve the precipitated amino product also remains under the scope of the invention.


SUMMARY OF DRAWBACKS ASSOCITED WITH PRIOR ART:
1. More sulphated ash and hence less assay of 2-oxindoles of formula I when reduction is carried out by metal acid reduction due to trapped metal generated impurities and hence does not pass the required specifications.
2. Huge amount of sludge formation in case of metal acid reduction and tedious work-up.
3. Poor color and appearance hence does not pass the required
specifications.
4. Poor yield and quality of advanced intermediates and finished drugs
obtained comprising the use of contaminated 2-oxindoles of formula I
thereby not meeting the pharmaceutical requirements.

5. Dehalogenation of the compound of formula III (when R is halo) resulting into deshalo impurities of intermediate and finished product when reduction is achieved by catalytic hydrogenation using noble metals/C like Pt/C, Pd/C, Pt02 and the like.
6. Evacuation of carbondioxide from the hydrogenator during the hydrogenation itself.
TECHNICAL SOLUTIONS OVER DRAWBARS OF THE PRIOR ART:
1. Use of raney nickel as a catalyst with an intension of its repeated reuse; capable of reducing the nitro group into amino group of compound of formula III suitably under the non drastic conditions in a non acidic solvent avoiding dehalogenation (when R is halo group) which forms deshalo impurity followed by its in-situ cyclisation using a mineral acid.
2. Use of good quality 2-oxindole of formula IA for the preparation of advanced intermediates and finished drugs free from deshalo impurity therefrom in higher yield meeting specifications.
3. Less sulphated ash thereby enhancing HPLC assay of compound of formula I A.
4. No evacuation of carbon dioxide is required as the process involves external cyclisation after hydrogenation has occurred.

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 but 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.
ADVANTAGES OT THE PRESENT INVENTION:
1. The proposed process produces the compound of formula I particularly IA with less sulphated ash thereby enhancing HPLC assay and HPLC purity.

2. Repeated reuse of raney nickel catalyst, there by reducing the cost of the process at least by about 25% over the processes disclosed in the prior art.
3. Simple work up compared to tedious work-up in case of metal/ acid reduction.
4. No formation of effluent wastage thereby having the ecological balance.

5. No evacuation of carbon dioxide as the process involves cyclisation after hydrogenation has occurred instead of reductive cyclisation as disclosed in the prior art.
6. Avoiding dechlorination thereby eliminating formation of deschloro impurity.
OBJECTS OF THE INVENTION:
First aspect of the invention is to provide a process for the preparation of compound of formula I particularly IA by single step catalytic hydrogenation comprising the use of raney Nickel catalyst with the intension of its repeated use; capable of reducing the nitro group into amino group of compound of formula III suitably in non acidic solvent

followed by its cyclisation resulting into the formation of compound of formula IA free from deshalo impurity.
Second aspect of the invention is repeated reuse of the catalyst and reuse of recovered solvent thereby reducing cost by about 25% over the processes disclosed therein in the prior art.
Third aspect of the invention is to provide a process that will reduce the effluent problem by eliminating the formation of sludge there by making the process ecofriendly.
Fourth aspect of the invention is to provide a process that is having a simple work-up procedure like filtration.
Fifth aspect of the invention is to provide a process that reduces the time required for the entire process till the isolation of the final product.
Sixth aspect of the invention is to provide a process that will reduce the sulphated ash thereby enhancing the HPLC assay and hence HPLC purity of compound of formula I and particularly IA.
Seventh aspect of the invention is to establish the formation of compound of formula IA by the process under the invention by its IR, NMR and mass spectra.

Eighth aspect of the invention is to use the compound of formula IA made by the process under the invention for the preparation of Ziprsidone.
Ninth aspect of the invention is to provide a process for the preparation of compound of formula I particularly IA by hydrogenation comprising steps of:
i) contacting compound of formula III in a non acidic solvent with
raney Nickel; ii) heating the reaction mass of step i whilist passing of hydrogen gas
under pressure; iii) monitor the reaction by HPLC for the disappearance of starting
material of compound of formula III; iv) reaction mass of step iii is carefully filtered off under the nitrogen
to remove the catalyst which can be reused for the same purpose; v) filtrate collected from the step iv is contacted with mineral acid
and the said reaction mass is heated; vi) monitor the reaction by HPLC for the disappearance of
intermediates formed during hydrogenation and formation of
compound of formula I and particularly IA when R is chloro; vii) crude material is collected by filtration and optionally purified to
get the compound of formula I with desired impurity profile.

The term suitably used hereinabove and hereinbelow for raney nickel catalyst refers to the material that does not lead to dehalogenation thereby avoiding the formation of dehalogenated product known as deshalo as an impurity.
SUMMARY OF THE INVENTION:
Disclosed herein is a process for the preparation of compound of formula I particularly IA by a single step catalytic hydrogenation (compared to multistep as disclosed in US6469181) comprising the use of raney nickel as a catalyst capable of reducing nitro group of compound of formula III to obtain the corresponding amino compound avoiding dechlorination (when R is CI) and formation of deschloro impurities; the said amino compound of formula III is cyclised insitu yielding oxindole of formula I. The said nickel catalyst capable of reducing nitro group of compound of formula III to obtain corresponding amino compound can be repeatedly reused along with use of recovered solvent making the process economically efficient.
The compound of formula IA is used as a key raw material for the preparation of Ziprasidone of formula II. The process disclosed herein comprises:
i) contacting compound of formula III in a non acidic solvent with raney Nickel;

ii) heating the reaction mass of step I whilist passing of hydrogen gas
under pressure; iii) monitor the reaction by HPLC for the disappearance of starting
material of compound of formula III; iv) reaction mass is carefully filtered off under the nitrogen to remove
the catalyst which can be reused for the same purpose; v) filtrate collected from the step iv is contacted with mineral acid
and the said reaction mass is heated; vi) monitor the reaction by HPLC for the disappearance of
intermediates formed during hydrogenation and appearance of
compound of formula I, particularly IA when R is CI; vii) crude material is collected by filtration and optionally purified to
get the compound of formula I, particularly IA with desired
impurity profile.
Schematic representation of the proposed process is illustrated below:


DETAILED DISCREPTION OF THE INVENTION:
Disclosed herein is an efficient, economical and industrially viable process for the preparation of compound of formula (I) particularly IA.
The disclosure of the present invention has been described herein below
in detail in non limiting embodiments.
In a general embodiment of the instant invention disclosed herein is a
process for the preparation of compound of formula (I) comprising the
steps of:
i) contacting compound of formula III in a non acidic solvent with
raney Nickel; ii) heating the reaction mass whilist passing of hydrogen gas under
pressure; iii) monitor the reaction by HPLC for the disappearance of starting
material of compound of formula III; iv) reaction mass is carefully filtered off under the nitrogen to remove
the raney nickel catalyst which can be reused for the same
purpose; v) filtrate collected from the step iv is contacted with acid and the
said reaction mass is heated; vi) monitor the reaction by HPLC for the disappearance of
intermediates formed during hydrogenation and appearance of
compound of formula I,;

vii) crude material is collected by filtration and optionally purified to get the compound of formula I with desired impurity profile.
Schematic representation of the proposed process is illustrated below:
General representation:

Non acidic solvent used in step I is selected from the group with non reducible character (which itself will not undergo the reduction imparting impurity that will be difficult to be removed) selected from the group comprising alcohol, ether, ester and mixture thereof.
Alcoholic solvent is linear or branched chain alcohol selected from group comprising methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol,t-butanol and mixture thereof and the like. Preferable alcohol is isopropanol.
Ester solvent is selected from the group comprising ethyl acetate, methyl acetate, propyl acetate, butyl acetate and the mixture thereof and the like. Preferable ester solvent is ethyl acetate.

Ether solvent is selected from the group comprising tetrahydrofuran, 1,2-dimethoxy ethane, methyl tertiary butyl ether and mixture thereof and the like. Preferably ether solvent is tetrahydrofuran.
Raney Nickel catalyst used in step i comprises Nickel content more than 84% and settled density upto 0.8% that is capable of reducing nitro group into amino group of compound of formula III suitably.
Acid used in step v is selected from organic and inorganic acids selected from the group comprising acetic acid, formic acid, hydrohalic acid, sulphurous acid, sulphuric acid and the like that can bring about the cyclisation of amino compound of the formula IV. Preferably acid is hydrochloric acid or sulphuric acid.
The term suitably used hereinabove and herein below refers to a concept that does not lead to dehalogenation when substituent in phenyl ring is halo group thereby avoiding the formation of dehalogenated product as an impurity.
The term contacting means reacting, heating, mixing, treating, stirring refluxing and the like.

In a preferred embodiment of the instant invention disclosed herein is a process for the preparation of compound of formula IA comprising the steps of: i) contacting compound of formula III; wherein R is chloro in
isopropanol as a non acidic solvent with raney Nickel; ii) heating the reaction mass of step I at about 55-60°C whilist
passing of hydrogen gas under about 5-6 kg/cm pressure ; iii) monitor the reaction by HPLC for the disappearance of starting
material of compound of formula III wherein R is chloro; iv) reaction mass is carefully filtered off under the nitrogen to remove
the catalyst which can be reused for the same purpose; v) filtrate collected from the step iv is contacted with hydrochloric
acid and the said reaction mass is heated at about 85-95°C; vi) monitor the reaction by HPLC for the disappearance of
intermediates formed during hydrogenation and formation of
compound of formula IA; vii) crude material is isolated by filtration from reaction mass of step
vi and optionally purified to get the compound of formula IA with
desired impurity profile.
Schematic representation of the proposed process is illustrated below:


D
escription of the figures related to process under the present invention: Figure XI represents the reaction monitoring for the process under the invention indicating the disappearance of compound of formula III, wherein R is chloro and R' is methyl and formation of intermediates during hydrogenation.
Figure XII represents reaction monitoring for the conversion of intermediates into cyclised product of formula IA. Figure XIII represents purity of isolated product of formula IA.

FIGURE XIII
In another preferred embodiment of the instant invention disclosed herein is a process for the preparation of compound of formula IA comprising the steps of:

i) contacting compound of formula III; wherein R is chloro in
isopropanol as a non acidic solvent with reusable raney nickel
used once in the preceding embodiment; ii) heating the reaction mass at of step i at about 55-60°C whilist
passing of hydrogen gas under about 5-6 kg/cm2 pressure ; iii) monitor the reaction by HPLC for the disappearance of starting
material of compound of formula III wherein R is chloro; iv) reaction mass of step iii is filtered off under the nitrogen to
remove the catalyst which can be reused for the same purpose; v) filtrate collected from the step iv is contacted with hydrochloric
acid and reaction mass is heated at about 85-95°C; vi) monitor the reaction by HPLC for the disappearance of
intermediates formed during hydrogenation and appearance of
compound of formula IA, particularly IA; vii) crude material is collected by filtration and optionally purified to
get the compound of formula IA with desired impurity profile.
Schematic representation of the proposed process is illustrated below:
Preferred:

Description of the figures related to process under the present invention: Figure XIV represents the reaction monitoring for the process under the invention indicating the disappearance of compound of formula III,


FIGURE XIV

FIGURE XV
wherein R is chloro and R' is methyl and formation of intermediates during hydrogenation using recycled raney nickel (once used catalyst). Figure XV represents reaction monitoring for the conversion of intermediates into cyclised product of formula IA using recycled (once used catalyst).

In a still more preferred embodiment of the instant invention disclosed herein is a process for the preparation of compound of formula IA comprising the steps of: i) contacting compound of formula III; wherein R is chloro in
isopropanol as a non acidic solvent with reusable raney nickel
used twice in the preceding embodiments; ii) heating the reaction mass at of step i at about 55-60°C whilist
passing of hydrogen gas under about 5-6 kg/cm2 pressure ; iii) monitor the reaction by HPLC for the disappearance of starting
material of compound of formula III wherein R is chloro; iv) reaction mass is filtered off under the nitrogen to remove the
catalyst which can be reused for the same purpose; v) filtrate collected from the step iv is contacted with hydrochloric
acid and reaction mass is heated at about 85-95°C; vi) monitor the reaction by HPLC for the disappearance of
intermediates formed during hydrogenation and appearance of
compound of formula IA, particularly IA; vii) crude material is collected by filtration and optionally purified to
get the compound of formula I with desired impurity profile. Schematic representation of the proposed process is illustrated below:
Preferred:



FIGURE XVI
Description of the figures related to process under the present invention: Figure XVI represents the reaction monitoring for the process under the invention indicating the disappearance of compound of formula III, wherein R is chloro and R' is methyl and formation of intermediates during hydrogenation using recycled raney nickel (twice used catalyst). Figure XVII represents reaction monitoring for the conversion of intermediates into cyclised product of formula IA using recycled (twice used catalyst).

FIGURE XVII
In one of the general embodiment the disclosed herein is a process for
the preparation of Ziprasidone of formula II and its pharmaceutically
acceptable salt preferably hydrochloride of formula IIA comprising steps
of:
i) preparing the compound of formula IA as disclosed hereinabove in the
preceeding embodiments;
ii) employing the said compound of formula IA for the preparation of
compound 6-chloro 5-(2-chloroefhyl)oxindole of formula V by the
standard process known in the art;

iii) employing the compound of formula V for the preparation of Ziprasidone of formula II by the standard process known in the art.


iv) employing Ziprasidone of formula II for the preparation of pharmaceutical^ acceptable acid salt preferably hydrochloride salt.
The invention is best understood by the following non limiting examples.
Example 1: Solution of compound of formula III (150g) in isopropyl alcohol (1050ml) is charged to hydrogenater with Raney/Ni (15g on dry basis). Reaction mass is heated to 50-55°C under 5-6 Kg hydrogen pressure. The reaction is monitored by HPLC (absence of compound of formula III). Once the reaction is completed, catalyst is separated and kept aside. The filtrate is concentrated partially under reduced pressure and 2N HC1 (525 ml) is added to the resulting residual mass and heated to 80-85°C. Isopropyl alcohol and methanol are removed (formed in the reaction) by distillation and compensating the same with 2N HC1. During this process the temperature is gradually raised to 90-95°C and finally the reaction mass is held at 90-95 °C for 4-5h. The reaction is monitored by HPLC (absence of intermediates formed during hydrogenation and formation of 6-Chloro-2-oxindole) After termination of reaction, the reaction mass is cooled to 10-15°C. The Crude product

was isolated by filtration. The crude product further purified from ethyl acetate. The product of formula IA prepared by the process under the invention is confirmed by it NMR values and overlapping IR with authentic sample as illustrated herein below (figure XVIII): 'H-NMR, 8 values in ppm (DMSO): 7.2 (1H), 6.95(1H), 6.79(1H), 10.42(1H), 3.45(2H)

FIGURE XVIII
Example 2: Solution of compound of formula III (150g) in isopropyl alcohol (1050ml) is charged to hydrogenater with once used Raney/Ni (15g on dry basis). Reaction mass is heated to 50-55°C under 5-6 Kg hydrogen pressure. The reaction is monitored by HPLC (absence of compound of formula III).Once the reaction complete, catalyst is separated and kept aside. The filtrate is concentrated partially under

reduced pressure and HC1 (525ml) is added to the resulting residual mass and heated to 80-85°C. Removed isopropyl alcohol and methanol (formed in the reaction) by distillation and compensating the same with 2N HC1. During this process the temperature is gradually raised to 90-95°C and finally the reaction mass is held at 90-95°C for 4-5h. The reaction is monitored by HPLC (absence of intermediates formed during hydrogenation and formation of 6-Chloro-2-oxindole).After termination of reaction, the reaction mass is cooled to 10-15°C. The Crude product was isolated by filtration. The crude product was further purified using ethyl acetate.
Example 3:
Solution of compound of formula III (150g) in isopropyl alcohol (1050ml) is charged to hydrogenater with twice used Raney/Ni (15g on dry basis). Reaction mass is heated to 50-55°C under 5-6 Kg hydrogen pressure. The reaction is monitored by HPLC (absence of compound of formula III).Once the reaction complete, catalyst is separated and kept aside. The filtrate is concentrated partially under reduced pressure and HC1 (525ml) is added to the resulting residual mass and heated to 80-85°C. Removed isopropyl alcohol and methanol (formed in the reaction) by distillation and compensating the same with 2N HC1. During this process the temperature is gradually raised to 90-95°C and finally the reaction mass is held at 90-95°C for 4-5h. The reaction is monitored by HPLC (absence of intermediates formed during hydrogenation and

formation of 6-Chloro-2-oxindole).After termination of reaction, the reaction mass is cooled to 10-15°C. The Crude product was isolated by filtration. The crude product was further purified using ethyl acetate.
Example 4: Preparation of 6-chloro-5-(chloroacetyl) oxindole : Charge 500 ml of ethylene dichloride and A1C13 (250gm) in a 3 litre there-neck flask under nitrogen atmosphere at 25 to 30°C. Add 84.19 gm of chloroacetyl chloride slowly at RT controlling the exotherm and stir for 30 minutes. Contents are further added with 100 gm of 6-chloro-oxindoie at 35-37°C in an hour. Stirring is continued at 35-37°C for 10-12 hrs. Cool gradually to 0 to 5°C and pour into ice, and water under stirring over 30 minutes. Stir for 30 minutes, remove ethylene dichloride by distillation under vacuum, cool the mass and filter off the product wash with water till it is neutral. Purify the product using 1,4-dioxane if required.
Example 5: Preparation of 5-(2-chloroethvl)-6-chlorooxindole: Charge 650 ml of trifluoroacetic acid and 130 gm of 6-chloro-5-(chloroacetyl) oxindole into a 3 litre three neck flask under nitrogen atmosphere at 25 to 30°C. Stir the mixture for 15 minutes and cool to 0 to 5°C under stirring. Charge 142.46 gms of triethyisilane slowly keeping temperature between 0 to 5°C over 30 minutes. Stir the reaction mixture for 30 minutes at 0 to 5°C and allow it to gradually reach 30 to 35°C. Stir the reaction for 6 hrs. Cool the reaction mixture to 5 to 10°C and add chilled

water slowly. Stir the mixture for 1- hr and filter the solids. Wash with water till it is neutral. Suck dry product and dry it under vacuum at 40-
45°C.
Example 5: Preparation of 5-[2-[4-(l2-benzisothiazol-3-yl)-l-
piperazinyn]ethyl]-6-chloro-l,3-di hydro-2H- indol-2-one: Charge 1.0 litre water, 100 gm of 5-(2-chloroethvl)-6-chlorooxindoIe product, 122.4 gm 3-(l-piperazinyl)-l,2-benzisothiazole HCI and 138.2 gm of sodium carbonate into a 3 litre three neck flask at 25 to 30 C. Stir for 15 minutes and heat to reflux temperature 95 to 100 C. Maintain at reflux temperature for 15 hrs. Cool the reaction mixture to 45 - 50°C. Add 1.0 It of water into the reaction mixture and stir for 30 minutes. Filter at 45 to 50 C and wash with water. Suck dry for 30 minutes to yield crude product. Charge 2 It of water and above crude product and heat the mixture gradually to 45 to 50°C and stir for 30 minutes. Filler the product at 45 to 50°C and wash with water. Suck dry the product for 30 minutes. Charge 2.0 It of water and 300 gm of crude product into a 1.0 litre three neck flask at 25 to 30°C and heat the mixture gradually to 45 to 50°C. Stir for 30 mins. Filter the product at 45 to 50°C and wash with water till about neutral pH (6.5 to 7.0). Suck dry the product for 30 minutes to get wet crude base 5-[2-[4-(l,2-benzisothiazo!-3-yl)-l-piperazinyl]ethylj-6-chloro-i,3-di hydro-2H- indol-2-one. Add 300.-gms of wet crude base and 1.0 It of isopropanol at 25 to 30°C. Warm the reaction mixture to 50 to 55°C and stir for 1.0 hr. Cool the reaction

mixture gradually to 10 to 15°C and stir for 30 mins. Filter the product and wash with chilled isopropanol. Suck dry for 30 minutes. Charge 300gm of wet crude base and 6 It of tetrahydrofuran (THF). Heat the reaction mixture gradually to reflux temperature 65-70°C. Reflux till clear solution. Cool to 50 to 55°C and add charcoal and stir for 30 min at 50 to 55dC. Filter the charcoal and wash with hot THF. Distill out THF at 50 to 55 C under vacuum till residual volume is 1 It and cool the reaction mixture gradually to 5 to 10°C and stir for 1 hr. Filter the product and wash with chilled THF. Suck dry the product for 30 minutes. Dry the product at 60 to 65°C.
Example 6: Preparation of 5-[2-[4-(l,2-benzisothiazol-3-yl)-l-
piperazinyn]ethyl]-6-chloro-l,3-di hydro-2H- indol-2-one
hydrochloride:
Charge 1.56 It of DM water, 173 ml of cone, hydrochloric acid in a 3 It three neck flask and stir for 15 mins at 25 to 30°C. Charge 115 gm of 5-[2-[4-(l,2-benzisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l,3-di hydro-2H- indol-2-one free base to the above HC1 solution and stir for. 15mins. Heat the reaction mixture gradually to 65 to 70°C and stir, for 24 hrs. Cool, the reaction mixture to 25 to 30°C and stir for 30 minutes. Charge 230 ml of IN HC1 solution to the reaction mixture and stir for 3 hrs. Filter the product and wash with 1150 ml of water till pH of mother liquor becomes 5 to 7.5. Suck dry the product for 30 minute and Dry the product

CLAIMS:
We claim:
1. A process f or the preparation of oxindole of formula I

comprising steps of:
i) hydrogenating the compound of formula III in a solvent using raney Nickel as a catalyst;

ii) filtering the reaction mass of step i;
iii) filtrate collected from the step ii is contacted with acid and heating the reaction mixture to obtain compound of formula I; iv) isolating the compound of formula I from the reaction mass of step iii.
2. A process f or the preparation of 6-chloro-2-oxindole of formula IA


comprising steps of:
i) hydrogenating the compound of formula III; wherein R is CI in a solvent using raney Nickel as a catalyst;

ii) filtering the reaction mass of step I; iii) filtrate collected from the step ii is contacted with acid and heating
the reaction mixture to obtain compound of formula IA; iv) isolating the compound of formula IA from the reaction mass of
step iii. 3. A process for synthesizing Ziprasidone of formula II comprising the steps of:
i) hydrogenating the compound of formula III; wherein R is CI in a solvent using raney Nickel as a catalyst;

ii) filtering the reaction mass of step I;
iii) filtrate collected from the step ii is contacted with acid and heating the reaction mixture to obtain compound of formula IA;

iv) employing the compound of formula IA to synthesize Ziprasidone of formula II.
4. A process for synthesizing Ziprasidone hydrochloride of formula II comprising the steps of: i) hydrogenating the compound of formula III; wherein R is CI in a solvent using raney Nickel as a catalyst;

ii) filtering the reaction mass of step I;
iii) filtrate collected from the step ii is contacted with acid and heating
the reaction mixture to obtain compound of formula IA; iv) employing the compound of formula IA to synthesize Ziprasidone
of formula II; v) contacting the said ziprasidone of formula II with HC1 acid to
obtain hydrochloride salt of ziprasidone.
5. The process of proceeding claims 1 to 4 wherein Solvent is non acidic solvent.
6. The process of claim 6 wherein non acidic solvent is selected from the group comprising alcohol, ether, ester and mixture thereof.

7. The process of claim 6 wherein non acidic solvent is selected from the group comprising linear or branched chain alcohol selected from group comprising methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, t-butanol, ethyl acetate, methyl acetate, propyl acetate, butyl acetate , tetrahydrofuran, 1,2-dimethoxy ethane, methyl tertiary butyl ether and mixture thereof.
8. The process of claim 7 wherein non acidic solvent is selected from the group comprising isopropanol, ethyl acetate, tetrahydrofuran and mixture thereof.
9. The process of preceding claims 1 to 4 wherein acid is selected from organic and inorganic acids selected from the group comprising acetic acid, formic acid, hydrohalic acid, sulphurous acid, sulphuric acid.
10. The process of preceding claims 9 wherein acid is hydrochloric acid
or sulphuric acid.