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 short process for the preparation of Ziprasidone and intermediates thereof".
2. Applicant

(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road,
Chandivali, Andheri (East), Mumbai-400072, India.
PREAMBLE TO THE DESCREPTION

The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE:
A short process for the preparation of Ziprasidone and intermediates
thereof.
FIELD OF THE TECHNOLOGY:
The present invention relates to an efficient short process for the preparation of 6-chlorooxindole of formula III, an intermediate for the preparation of 5-(2-chloroethyl)-6-chlorooxindole of formula IV which is a key intermediate for the preparation of Ziprasidone of the formula I.

BACKGROUND OF THE INVENTION
Ziprasidone hydrochloride is a serotonin and dopamine antagonist and effective as an antipsychotic drug. Ziprasidone does not increase the weight of the patient, therefore, has a distinctive advantage.
US20090047354 (hereinafter described as '354) discloses a process for the preparation 5-(2-chloroacety)-6-chloro oxindole which is a key intermediate for the preparation of compound of formula I comprising reacting 6-chloro-oxindole with chloro acetyl chloride in halogenated hydrocarbon solvent in presence of A1CL3. It does not disclose the process for the preparation of 6-chloro-oxindole.

US7608711 (hereinafter described as '711) discloses a process for the preparation of 5-(2-chloroethyl)-6-chloro oxindole comprising reducing a compound of formula V to give a compound of formula VI which is reduced further to the said compound.

'711 also does not disclose the process for the preparation of 6-chloro-oxindole.
US20060089502 (hereinafter described as '502) discloses a process for the preparation 5-(2-chIoroethyl)-6-chloro oxindole comprising reacting 6-chloro-oxindole with chloro acetyl chloride to form 5-(2-chloroacetyl)-6-chloro-2-oxindole which is reduced with an excess of triethylsilane in the presence of a strong acid to form a mixture of 5-(2-chloroethyl)-6-chlorooxindole, 5-(2-chloroacetyl)-6-chloro-2-oxindole, and 5-(2-chlorohydroxylethyl)-6-chlorooxindoIe which is used as an intermediate to prepare ziprasidone.
'502 also does not disclose the process for the preparation of 6-chloro-oxindole.
WO2003099198 (hereinafter described as '198) discloses a process for the preparation of 5-(2-chloroethyl)-6-chloro oxindole comprising hydrolysis and decarboxylation of compound of formula IIa to give a corresponding substituted phenylacetic acid derivative of formula VII which is reacted with Fe and acetic acid to reduce and cyclise resulting into the formation of compound of formula III which is further converted into compound of formula IV which is a key intermediate for the preparation of compound of formula I



Process disclosed in '198 for the preparation of compound of formula III from compound of formula II comprises following 2 operational steps:
1. Hydrolysis of compound of formula II followed by decarboxylation using HC1 and after processing isolating the compound of formula VII.
2. Reducing the compound of formula VII from step 1 with Fe and acetic acid followed by its cyclisation to obtain a compound of formula III.
Organic Process Research & Development 2003,7 ,309-312 discloses the process for preparing of 5-(2-chloroethyl)-6-chloro oxindole which is used as an intermediate for the preparation of Ziprasidone. The process disclosed therein in the said reference has been represented in Scheme-I given below:
Scheme-I

The said references also discloses the process for the preparation of compound of formula D comprising hydrolysis of compound of formula A to obtain compound of formula B which is converted into compound of formula C which is then reduced and cyclised to give an oxindole of formula D. The process disclosed therein in the said references also comprises 3 steps starting from malonic acid substituted molecule of formula A to obtain the corresponding oxindole of formula D.
IN185117 discloses a process for the preparation of 6-chloro-oxindole comprising treating 5-halo-2-nitrophenyl malonyldiester with mineral

acid in presence of organic acid to obtain the corresponding 5-halo-2-nitrophenyl acetic acid which is converted into corresponding phenyl acetic ester. Substituted nitrophenylester is hydrogenated to obtain the corresponding oxindole. The process comprises the following operational steps to convert aryl malonic ester into corresponding oxindole:
1. Hydrolysis and decarboxylation to form phenyl acetic acid
derivative.
2. Esterification of phenyl acetic acid to obtain phenyl acid ester derivative.
3. Hydrogenation of nito Gp. Of
US4831031 (hereinafter described as '031) discloses the process for the preparation of Ziprasidone and its intermediate 5-(2-chloroethyl)-6-chloro oxindole. '031 do not disclose the process for the preparation of 6-chloro-oxindole of formula III.
US5206366 discloses a process for the preparation of Ziprasidone wherein process for the preparation of 6-chloro-oxindole of formula III comprises Wolf-Kishner reduction of 6-chloroisatin of formula H. The process is shown in scheme-II.

US4831031 (hereinafter described as'031) and 5338846 (hereinafter described as'846) disclose the preparation of 5- [2-[4-(l,2-benzisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l, 3-di hydro-2H-indol-2-one, compound of formula I, ,Ziprasidone. '03land '846 do not disclose the process for the preparation of 6-chloro-oxindole.
G. J. Quallich discloses a process (Synthesis, 51, January 1993) comprising the reaction of a substituted halo nitrobenzene with a malonate, usually dimethyl malonate, in the presence of sodium hydride, to obtain the diester of arylmalonate. The second step involves Krapcho decarboxylation of the diester of the arylmalonate with lithium chloride in dimethyl sulfoxide to obtain the malonate monoesten The nitro group of the monoester is then reduced with iron and acetic acid to yield the substituted oxindole derivative. The process disclosed therein in the said reference involves the following two steps of operations for converting

substituted arylmalonate of formula II into corresponding oxindole of formula III
1. Krapcho decarboxylation of substituted diarylmalonate of formula II
2. Reduction of nitro group using iron and acetic acid followed by cyclization to obtain oxindole of formula III.
Disadvantages of the process disclosed therein in the said reference are use of sodium hydride which is moisture sensitive and pyrophoric compound as a base for the preparation of arylmalonate ester of formula II and two separate operations of Krapcho reduction of substituted aryl ester compound of formula II into corresponding monoester and the reduction of monoester and cyclization to obtain the desired oxindole of formula III.
US4160032 discloses the preparation of 6-chloro-oxindoIe, wherein 4-chloro-2-nitrotoluene is treated with sodium ethoxide and diethyl oxalate, followed by refluxing it with hydrogen peroxide and acidification, to obtain 4-chloro- 2-nitrophenylacetic acid. The 4-chloro-2-nitrophenylacetic acid is then subjected to reductive cyclisation using hydrogen gas under pressure, in the presence of Pt02, to obtain 6-chloro-oxindole.
Collins et al reported a process (J. Am. Chem. Soc, 221, 78, 1956) wherein nitrophenyiacetic acids were prepared from o-nitrotoluenes through pyruvic acids.
These nitro phenylacetic acids were further subjected to reduction using zinc and sulfuric acid to yield the oxindoles. The disadvantage of this process is that, the nitrophenyiacetic acids were obtained in moderate yields, and in the case of 4-chloro- 2-nitrophenylacetic acid, a precursor of 6-chloro-oxindole, a yield as low as 4% was reported.
WO02/14275 also discloses the synthesis of 6-halosubstituted oxindoles using 4-halo-2-nitrophenylacetic acid as the starting materia]. The starting material is subjected to reductive cyclisation using 50% sulfuric acid and zinc dust in the presence of ethanol as the solvent. The entire process is carried out at high temperature under a nitrogen blanket. Such a process is not feasible at industrial scale because the working up of the reaction involves extraction in organic solvents, followed by chromatographic separation of the final product.

CZ191777 also discloses the process for the preparation of halo substituted oxindoles wherein 3-halosubstituted aniline is reacted with chloroacetyl chloride, followed by refluxing the mixture with aluminum chloride in a suitable solvent to obtain the 6-halosubstituted oxindole. The disadvantage of this process is that it could also lead to formation of the regioisomer, viz. 4-chloro- oxindole that needs to be separated from the final product.
JP56068668 and JP62028133 disclose the process for the preparation of unsubstituted oxindole using 2-chlorophenylacetic acid as the starting material. The 2-chlorophenylacetic acid is cyclised to the oxindole, using aqueous ammonia in the presence of CuCl. Such a procedure may not be feasible for dihalo compounds, wherein the dihalo compound could lead to the formation of a mixture of products, such as the undesired mono and/or diaminohalo compounds. Hence, the process is undesirable for the synthesis of substituted oxindoles.
In view of shortcomings in the processes disclosed therein in the prior art for preparing 6-chloro-oxindoIe molecule of formula III comprising hydrolysis of substituted arylmalonate compound of formula II using a mineral acid to obtain a corresponding phenyl acetic acid molecule of formula VII which is isolated and then subjected to reductive cyclization using Fe and acetic acid in a separate operational step to obtain 6-chloro-oxindole molecule of formula III, there is a scope to improve the process wherein the conversion of arylmalonate compound of formula II can be converted into corresponding 6-chloro-oxindole compound of formula III in a single step using one set of reagent.
The present invention discloses an improved, short and an efficient process for the preparation of 6-chloro-oxindole molecule of formula III in a single step by treating substituted arylmalonate compound of formula II with metal or their compounds and mineral acid. The metal or their compounds is selected from the group of Titanium, Cadmium, Zinc, and Tin. Preferably metal is tin and mineral acid is hydrochloric acid with variable concentration depending upon the requirement to obtain 6-chloro-oxindole molecule of formula III as shown below in scheme-Ill. 6-chloro-oxindole molecule of formula III is an intermediate for the preparation of 5-(2-chloroethyl)-6-chlorp oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone.


The term contacting herein means dissolving, slurring, stirring, adding, reacting and the like or combination thereof.
OBJECT OF THE INVENTION
The present invention discloses an efficient, short, simple, cost effective and non-hazardous process for the preparation of 6-chloro-oxindole of formula III which is an intermediate for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone.
First aspect of the invention is to disclose an efficient, short, simple, cost effective and non-hazardous process for the preparation of compound of formula IlIa which is an intermediate for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone

Third aspect of the present invention is to provide an efficient, short, simple, cost effective and non-hazardous process for the preparation of
Second aspect of the invention is to disclose an efficient, short, simple, cost effective and non-hazardous process for the preparation of 6-chloro-oxindole of formula III which is an intermediate for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone.


5-(2-chloroethyI)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone.

Fourth aspect of the invention is to provide an efficient, short, simple, cost effective and non-hazardous process for the preparation of Ziprasidone hydrochloride of formula I which is a serotonin and dopamine antagonist and effective as an antipsychotic drug. Ziprasidone does not increase the weight of the patient, therefore, has a distinctive advantage.
Formula (I)

ADVANTAGES OF THE PRESENT INVENTION
1. Reduction in number of unit operations
2. Use of one set of reagents responsible for four chemical changes
including hydrolysis, decarboxylation, reduction and cyclisation in a
single step of operation.
SUMMARY OF INVENTION
The invention discloses an efficient, short, simple, cost effective and non-hazardous process for the preparation of 6-chloro-oxindole of formula III which is an intermediate for the preparation of 5-(2-chloroethyl)-6-chloro oxindole compound of formula IV which is a key intermediate for the preparation of compound of formula-1, Ziprasidone, comprising contacting arylmalonate of formula II with a metal or its compound and mineral acid to obtain 6-chloro-oxindole of formula III in a single step.

DETAILED DESCRIPTION OF THE INVENTION
Disclosed herein in the present invention is a single step process for the preparation of oxindole derivative of formula III

Wherein substituted aryl maolnate ester of formula Ila is used as a starting material.

Compound of formula Ila is contacted with a metal or its compound and mineral acid in an organic solvent at reflux temperature to obtain the corresponding substituted oxindole derivative of formula Ilia. The metal or their compounds are selected from Titanium (TiC13), Cadmium, Zinc, and Tin. Preferably metal is tin. Preferably mineral acid is hydrochloric acid. The process disclosed herein in the present invention converts the starting material of formula Ila into corresponding substituted oxyindole derivatives of formula IlIa in a single step comprising a single unit operation using one set of reagents comprising metal or its compound/ mineral acid as compared to the process disclosed in WO200309918 wherein the same starting material of formula Ila is converted into the corresponding substituted oxyindole in 2 operational steps process comprising first converting the starting material of formula Ila into corresponding substituted phenylacetic acid of formula Vila by treating with HC1 in combination with acetic acid.;


The substituted phenyl acetic acid derivative of formula Vila is isolated and in a second separate step is used as a starting material and is treated with a second set of reagents comprising iron and acetic acid to obtain the corresponding substituted oxindole derivative of formula Ilia.
In the present invention starting material of formula Ha is contacted with only one set of reagent comprising metal and minereal acid that directly forms compound of formula Ilia devoid of isolation of any intermediate at any stage during the formation of compound of formula Ilia.

Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of the skill in the art, the invention may be embodied as a method, system or process.
In an embodiment the substituted oxyindole derivative is 6-chloro-oxindole also known as 6-chloro-indol-2-one of formula III. The said 6-chloro-oxindole derivative of formula III is prepared by contacting arylmaionate diester of formula II with metal or metal compound and mineral acid at temperature about 5 C to about 80°C in an organic solvent.

The metal is selected from Titanium (TiC13), Cadmium, Zinc, and Tin. Preferably metal is tin and mineral acid is HC1. Preferably organic solvent is aliphatic alcohol. More preferably aliphatic alcohol is methanol.
In another embodiment disclosed herein in the present invention is the process for the preparation of compound of formula IVa


comprising contacting compound of formula IlI a with chloroacetyl chloride in an organic solvent in the presence of lewis acid to provide 5-(2-chloroacetyl)-6-chloroxyindoIe of formula V. Preferably lewis acid is AICI3 Organic solvent is selected from halo or nitro substituted alkanes or benzene such as methylene dichloride, nitromethane, nitrobenzene, chloroform, carbon tetrachloride and the like. Preferably organic solvent is halogenated hydrocarbon. More preferably solvent is dichloro ethane.
5-(2-chloroacetyl)-6-chloroxyindole of formula V is subjected to reduction with trialkyl silane in the presence of an organic acid in an organic solvent to form 5-(2-chloroethyI)-6-chloroxyindole of formula IV. Preferably trialkyl silane is triethyl silane. Preferably organic acid is trifluoroacetic acid. Preferably organic solvent is n-hexane.The process for the preparation of compound of formula IV wherein X is CI has been summarized in scheme-IV.
5-(2-chloroacetyl)-6-chloro-oxindole IIlb 5-(2-chloroethyl)-6-chloro-oxindole IV
The overall scheme of the present invention is depicted as follows:
Scheme-IV

In a preferred embodiment the compound of 5- [2- [4- (1, 2-benzisothiazol-3-yl)-l-piperazinyl ethyl]-6-chloro-l, 3-di hydro-2H-indol-2-one, compound of formula I or ziprasidone is prepared from compound of formula IV by any known prior art such as United States Patent No. 4831031 or United States Patent No. 5338846 The free base may be converted to its salt or hydrate form by using processes as disclosed in United States Patent No. 5312925.

The oxindole derivatives of formula II and IV prepared by the process steps of the present invention can be used as intermediates for the synthesis of pharmaceutically active antipsychotic compounds and other pharmaceutically active compounds bearing the following general structure:

It will be apparent to those skilled in the art that the various modifications and variations can be made in the present invention and specific examples

provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
The following examples are for illustrative purposes only and are not intended, or should they be interpreted to limit the scope of the invention.
Example 1:
Preparation of dimethyl-(4-chloro-2-nitrophenvl) malonate -
Dimethyl malonate (312.5g) is added to a mixture of anhydrous
potassium carbonate (535.5g) and dimethyl sulfoxide (0.4 liters) under a
nitrogen atmosphere at 25-30°C. The reaction mixture is heated to 60-
65°C and 2,5-dichloronitrobenzene (250gm,) diluted in 0.25 litre 2,5-
dichloronitrobenzene is added to it in portions over a period of one hour
and the contents are maintained first at 40-45°C for 5 hrs . The
temperature of the reaction mixture is then raised to 60-65°C and
maintained so for another 5 hours. The temperature of the reaction
mixture is further raised to 80-85°C. and maintained so for another 5
hours and cooled to 40-45 °C.
The reaction mass is quenched with water at 2-5°C.The dimethyl-(4-
chloro-2-nitrophenyl) malonate formed is filtered and washed with water
till the mother liquor shows a pH of 6.5-7. The product is finally washed
with methanol and
dried at 40-45°C. Purify the solid with methanol if required.
Example 2
Preparation of 6-chIoroxyindoIe:
Dimcthyl-(4-chloro-2-nitrophenyl)malonate (68gm) obtained in example 1 is charged with methanol(500 ml) at 20-25°C and tin metal (50gm), followed by slow addition of concentrated hydrochloric acid (216gm) at around 10°C. The reaction mixture is maintained first at 18-20°C followed by heating slowly to reflux at 65-70°C, maintained at this temperature for 6 hours and Filter hot to remove insolubles if any, Methanol is removed under vacuum till solid cake is obtained. Quench the solid with water, stir the solid at 0-5°C and filter off the solid and wash with water till it is free from acid. Purify the solid using ethyl acetate if required.Dry it under vacuum at 40-45°C.

Example 3
Preparation of 6-chloro-5-(chloroacetyl)oxindole :
Charged with 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 stirred 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 distlation 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 4
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 mins 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 undr vacuum at 40-45°C.
Example 5
Preparation of 5-[2-[4-(l,2-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-chIoroethvl)-6-chlorooxindole product, 122.4 gm 3-(I-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-yI)-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. FiJter 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 5
Preparation of 5- [2-[4'(l,2-benzisothiazol-3-yl)-l-piperaz'myn]ethyl]-6-chloro-l,3-di hydro-2H- indol-2-one hydrochloride:
Charge 1.56 It of demin 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. 15 mins.
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
is dried under vacuum at 55°C.

Claims:
a) contacting compound of formula Ha
1. Process for the preparation of compound of formula I comprising


wherein X is a halogen; R is C1-C4 straight chain , branched or cyclic alkyl Group
with metal or metal compound and mineral acid to give a compound of formula Ilia in a single step

wherein X is same as in Ha;
b) contacting the compound of formula IlIa with chloroacetyl chloride to
obtain a compound of formula IIIc

wherein X is same as in Ha and IlIa ;
c) reducing compound IIIc obtained in b to obtain compound IVa;


d) contacting compound IVa obtained in c with compound of formula VIII to obtain compound of formula I or its pharmaceutically acceptable salts

2. Process of claim 1 wherein metal is tin.
3. Process of claim 1 wherein mineral acid is HC1.