PROCESS FOR PREPARING ZIPRASIDONE

INTRODUCTION

The present application relates to processes for the preparation of ziprasidone and its pharmaceutically acceptable salts. It also relates to novel synthetic intermediates useful in the preparation of ziprasidone.

Ziprasidone is chemically known as 5-[2-[4(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and is structurally represented by Formula I.

Ziprasidone (GEODON®) is an atypical antipsychotic. It is approved for the treatment of schizophrenia and for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. Ziprasidone intramuscular is also approved for the treatment of acute agitation in schizophrenic patients. The oral form of ziprasidone is marketed as ziprasidone hydrochloride monohydrate which is white to slightly pink powder. The intramuscular form is ziprasidone mesylate trihydrate and is provided as a lyophilized powder.

US Patent No. 4,831,031 discloses Ziprasidone and its derivatives, its pharmaceutically acceptable salts and process for their preparation involving condensation of 3-(1-piperazinyl)-1,2-benzisothiazole of Formula III with 5-(2-chloro ethyl)-6-chloro oxindole of Formula II in polar solvent such as methylisobutyl ketone and in presence of an acid neutralizing agent such as sodium carbonate and a catalyst such as sodium iodide. After completion of the reaction residue is purified with column chromatography to give purified ziprasidone.

5-(2-chloro ethyl)-6-chloro oxindole of Formula II is prepared by the reaction of 6-chloro oxindole of Formula IV with halo acetic acid followed by reduction of resultant chloroacetyl derivative of Formula V with triethyl silane and trifluoroacetic acid, and
3-(1-piperazinyl)-1,2-benzisothiazole of Formula III is prepared by the condensation of 3-chloro-1,2-benzisothiazole with excess moles of piperazine in hydrocarbon solvent at elevated temperature to give 3-(1-piperazinyl)-1,2-benzisothiazole of Formula III. The process may be depicted as follows:

The process suffers from the drawback of formation of impurities such as keto ziprasidone and bis piperazinyl benzisothiazole which is difficult to remove from the final compound and requires column chromatography to obtain purified ziprasidone.
US patent number 5,359,068 discloses the preparation of ziprasidone by final step
heterocyclization of ester derivative in the presence of a reducing agent such as
sodium hydrosulfite in a suitable solvent. After treatment with reducing agent, the
resulting product is further heated with a strong mineral acid such as hydrochloric
acid to give ziprasidone of Formula I.

The ester derivative is prepared from its diester derivative by treatment with an acid
followed by C1-C6 alkanol in the presence of acidic esterification catalyst such as
thionyl chloride to give ester derivative. It also discloses multiple step preparation of
diester derivative, which is time consuming and not suitable for large scale
production.

The process may be depicted as follows:

PCT application number WO 2006/080025 discloses an improved method for the
condensation of aryl-piperazinyl ring derivative of Formula III with heterocyclic ring
derivative of Formula II to give ziprasidone of Formula I.

The process involves the condensation of silylated aryl-piperazinyl ring derivative
with heterocyclic ring derivative II in the presence of sodium carbonate and sodium
iodide as catalyst.

Silylated aryl-piperazinyl ring derivative is prepared by the reaction of aryl-piperazinyl
ring derivative of Formula III with a silylating agent such as trimethylsilyl chloride in
the presence of triethylamine and tetrabutyl ammonium bromide.

The process may be depicted as follows:

Many other references in the prior art describe various processes for the preparation of ziprasidone with slight modifications over the existing methodologies.

As disclosed above, prior art processes are time consuming, commercially not viable and result in low yield of ziprasidone. Further, chromatographic technique for the purification is cumbersome, tedious and difficult to utilize on an industrial scale.

The above mentioned drawbacks motivates us to develop an alternative and novel processes for the preparation of ziprasidone that is cost effective, commercially viable, reproducible on industrial scale and meets the needs of regulatory agencies.
Thus, the present application provides an improved processes for the preparation of ziprasidone, which is unique with respect to its simplicity, cost effectiveness, and scalability by using mild reaction conditions and novel intermediates.

SUMMARY

One aspect of the present application relates to a novel, efficient and alternate process for the preparation of ziprasidone of Formula I, and pharmaceutical^ acceptable salts thereof, comprising:

a) condensing the chloroacetyl derivative of Formula V, with 3-(1-piperazinyl)-1,2-
benzisothiazole of Formula III, or salts thereof, in the presence of a base in a suitable solvent to form keto derivative of ziprasidone of Formula VI,

b) reducing the keto derivative of ziprasidone of Formula VI to form ziprasidone of
Formula I.

Another aspect of the present application relates to a novel process for the preparation of ziprasidone of Formula I, and pharmaceutically acceptable salts thereof, comprising:

a) reducing the chloroacetyl derivative of Formula V, to form 5-(2-chloro ethyl)-6-
chloro oxindole of Formula II,

b) reacting the 5-(2-chloro ethyl)-6-chloro oxindole of Formula II with piperazine to
form novel compound of Formula VII, or salts thereof,

c) condensing the compound of Formula VII, or salt thereof with 3-chloro-1,2-
benzisothiazole to give ziprasidone of Formula I.

Still another aspect of the present application relates to a novel and efficient process for the preparation of ziprasidone of Formula I, and pharmaceutically acceptable salts thereof which comprises:

a) reacting the 5-(2-chloro ethyl)-6-chloro oxindole of Formula II, with phthalimide in presence of a base to give N-alkyl amide of the Formula VIII,

b) hydrolyzing the compound of Formula VIII to give primary amine compound of
Formula IX,

c) condensing the primary amine compound of Formula IX with dihalo compound of Formula X, to afford ziprasidone of Formula I.

DRAWINGS

Fig. 1 is a synthetic scheme for the preparation of ziprasidone according to present application.

DETAILED DESCRIPTION

The present application provides alternative processes for the preparation of Ziprasidone of Formula I and its pharmaceutically acceptable salts using novel intermediates.
One embodiment of the present application provides a novel, efficient and alternate process to prepare ziprasidone of Formula I, and pharmaceutically acceptable salts thereof.

Novel methodology of the present application includes condensation of chloroacetyl derivative of Formula V, with 3-(1-piperazinyl)-1,2-benzisothiazole of Formula III, or salts thereof, to form keto derivative of ziprasidone of Formula VI.

Suitably, the reaction may be conducted in the presence of a base in suitable solvent at suitable temperature range for sufficient time or till the completion of the reaction. After completion of the reaction, the keto derivative of ziprasidone of Formula VI may be isolated and purified by techniques known in the prior art. Preferably, the keto derivative of ziprasidone of Formula VI may be isolated by the addition of a suitable solvent to the reaction mixture or it may be used for the next step without isolation or purification.
Typically, the chloroacetyl derivative of Formula V, alkali metal carbonate (base) and 3-(1-piperazinyl)-1,2-benzisothiazole of Formula III are present in a molar ratio of about 1-3:1-5:1-3.

Suitable bases which may be used for the reaction include, but are not limited to alkali metal bicarbonates or carbonates such as sodium carbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate and the like or hydroxides such as sodium hydroxide, potassium hydroxide and the like; optionally in the presence of alkali metal halides such as potassium bromide, potassium iodide, lithium iodide, lithium bromide, sodium iodide, sodium bromide and the like or organic base such triethylamine and the like or mixtures thereof.

The condensation reaction may optionally be performed in the presence of phase transfer catalyst or it may be used in combination with other suitable catalyst such as sodium iodide and the like.

The phase transfer catalysts which may be used include, but are not limited to tetralkylammonium or phosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulphate, crown ethers like 15-crown-5, 18-crown-6, and the like.

The keto derivative of ziprasidone of Formula VI is reduced to give ziprasidone with high purity and yield. It has been observed that during prior art condensation processes keto ziprasidone of Formula VI is transported up to final product as an impurity. This keto impurity is difficult to remove and require tedious chromatographic purification which results in low yield of final ziprasidone. Present application specifically employs the step of reduction at the final step to overcome this problem.

Suitable reducing agents which may be used include, but are not limited to trialkyl silyl derivatives such as trimethyl silane, triethyl silane, tripropyl silane and the like optionally in the presence of mild acid such as acetic acid, propionic acid, methane sulfonic acid, ethane sulfonic acid and the like. The preferred combination as per the present application may be triethyl silane and methane sulfonic acid. The use of methane sulfonic acid along with triethyl silane produced ziprasidone with good yield and purity.
The chloroacetyl derivative of Formula V used in the reaction may be prepared by methods known in the prior art or by the Friedel crafts acylation of 6-chloro oxindole with a source of acetyl group in presence of a Lewis acid in a suitable solvent. After completion of the reaction, mixture is quenched with a suitable quenching agent and the product may be isolated and purified by any well known techniques of the prior art.
3-(1-piperazinyl)-1,2-benzisothiazole of Formula III or its salts used in the reaction may be prepared by reacting 3-chloro-1,2-benzisothiazole with suitable moles of piperazine in a suitable solvent.

Typically, the 3-chloro-1,2-benzisothiazole and piperazine may be in a molar ratio of about 1:7.

It is advantageous to add 3-chloro-1,2-benzisothiazole in small portion to the mixture of piperazine in suitable solvent. After completion of the reaction, so formed acid during the reaction may be neutralized with a suitable base and the product may be extracted in a suitable solvent such as toluene. 3-(1-piperazinyl)-1,2-benzisothiazole may be purified by any well known techniques of prior art such as recrystallisation, extraction, acid-base treatment and the like. 3-(1-piperazinyl)-1,2-benzisothiazole may be isolated as a free base or a salt.

Suitable solvents which may be used for the above reactions include but are not limited to high boiling point organic solvent, non polar solvent, polar protic or aprotic solvent such as linear or cyclic saturated or unsaturated hydrocarbon solvent, a saturated or unsaturated halogenated hydrocarbon solvent, a ketone e.g. acetone and the like or straight chain or branched C1-8 alcohol such as methanol, ethanol and the like; nitriles of general Formula RCN wherein R is C2-5 alkyl; water, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, sulfolane and/or mixtures thereof.

Another embodiment of the present application involves novel synthetic intermediates and their use for the preparation of ziprasidone of Formula I, and pharmaceutically acceptable salts thereof.

The process involves reduction of chloroacetyl derivative of Formula V, to give 5-(2-chloro ethyl)-6-chloro oxindole of Formula II,

The reduction may be conducted by the procedure known in the art such as involving the use of mixture of trifluoro acetic acid and triethyl silane.

The amount of acid used may be selected from a wide range depending on the reaction rate and other factors.

5-(2-chloro ethyl)-6-chloro oxindole of Formula II is further reacted with suitable moles of piperazine in a suitable solvent to give novel compound of Formula VII.

Generally portion wise addition of piperazine to the mixture of 5-(2-chloro ethyl)-6-chloro oxindole in a suitable solvent is preferred. The reaction may be carried out at ambient temperature to the reflux temperature of the solvent and may be completed in about 2 to 13 hours. Novel compound of Formula VII may be isolated as a free base or as an acid addition salt.

These salts are prepared in the usual manner, i.e., by reaction of the free base with a suitable organic or inorganic acid.

Novel compound of Formula VII is further condensed with 3-chloro-1,2-
benzisothiazole to give ziprasidone of Formula I.

It has been surprisingly found that condensation of Formula VII with 3-chloro-1,2-
benzisothiazole reduces the formation of bis piperazinyl benzisothiazole impurity
which was usually formed during the prior art processes and was difficult to remove
from the final ziprasidone.

Condensation may be carried out in the presence or absence of an organic or
inorganic base and in a suitable solvent. Optionally a catalytic amount of sodium
iodide or a phase transfer catalyst or both may be employed during condensation.
The reaction may be carried out at ambient temperature to the reflux temperature of
the solvent and/or reagent.

During the process of the present application formation of bis piperazinyl
benzisothiazole impurity is reduced significantly, which in turn increases the overall
yield and purity of ziprasidone.

Suitable solvents for conducting the reaction include but not limited to organic
solvents including alcohols such as C1-4 alcohols; aromatic hydrocarbons such as
benzene, toluene, xylene, ethylbenzene, petroleum ether and the like; aliphatic
hydrocarbons such as pentane, hexane, heptane, octane and the like; alicyclic
hydrocarbons such as cyclohexane, methylcyclohexane, cycloheptane and the like;
halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane
and the like; ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dioxane,
tetrahydrofuran and the like; esters such as methyl acetate, ethyl acetate, isopropyl
acetate and the like. Such solvents may be employed independently or in
combination.

Still another embodiment of the present application relates to the preparation of ziprasidone of Formula I and pharmaceutically acceptable salts thereof using Gabriel synthesis mechanism of primary alkyl amine. Accordingly 5-(2-chloro ethyl)-6-chloro oxindole of Formula II, is reacted with phthalimide in presence of a base to give /V-alkyl amide of the Formula VIII, Preferably a mixture of phthalimide in a suitable solvent and in the presence of base is stirred at a suitable temperature for few minutes to few hours for the deprotonation of the imide proton by the base. Phthalimide proton is more acidic than the primary amine proton due to resonance stabilization of adjacent carbonyl groups thus it generates strong nucleophile.

Subsequently a solution of 5-(2-chloro ethyl)-6-chloro oxindole of Formula II in a
suitable solvent is added to the phthalimide solution and heated at about 80-140 °C
to provide N-alkyl amide of the Formula VIII.

Suitable solvents which may be used include, but are not limited to aliphatic amides
such as dimethylacetamide, dimethylformamide and the like.

The compound of Formula IX may be prepared by reacting A/-alkyl amide of Formula VIII with suitable amide hydrolyzing reagent in a suitable solvent at a suitable temperature.

Hydrolysis of amide group may be carried out at ambient temperature to the reflux temperature of the solvent and/or reagent.

Generally a mixture of aqueous hydrazine hydrate in an alcoholic solvent is added to the solution of A/-alkyl amide of the Formula VIII in an alcoholic solvent. The resulting mixture is refluxed for a sufficient time or till the completion of the hydrolysis. Solvent may be removed partially or completely after completion of the hydrolysis and the residue is again taken in a suitable solvent and refluxed for few minutes to hours to result the required compound in a solid form.

Novel primary amine compound of Formula IX, may be further condensed with dihalo compound of Formula X, to afford ziprasidone of Formula I.

Suitable solvents which may be used include, but are not limited to aliphatic amides such as dimethylacetamide, dimethylformamide and the like.

Suitably, the reaction may be conducted in the presence of a base, and suitable
temperatures for conducting the reaction range from about 0 to about 100 °C.
Novel dihalo compound of Formula X may prepared by reaction of 3-chloro-1,2-
benzisothiazole with diethanol amine to give dihydroxy compound of the following

Formula

Generally the reaction may be carried out at reflux temperature of the alcoholic solvent for a sufficient time or till the completion of the reaction. After completion of the reaction, the solvent is partially or completely removed and the residue is acidified with an alcohol acid solution while maintaining the pH around 1.0 to 3.0 of the reaction mixture to give acid addition salt of novel dihydroxy compound. Acid addition salt of novel dihydroxy compound is treated with a suitable base such as sodium hydroxide in polar protic solvent and the resulting compound is extracted in halogenated hydrocarbon solvent and further treated with halogenating agent at a suitable temperature to give dihalo compound of Formula X. Suitable halogenating agent may be include, but are not limited to phosgene, oxalyl dichloride, thionyl chloride, phosphorus pentachloride, phosphorous trichloride, phosphorus oxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide, phosphorous bromide and phosphorus oxybromide.

After the completion of the reaction, the reaction mixture is purified by the usual means such as concentration, thereby isolating the halogenating agent of the reaction. Alternatively, the reaction mixture containing the halogenating agent may be directly used for the next step, without purification.

According to present application ziprasidone may be isolated as free base and further converted to pharmaceutical acceptable salts thereof. These salts may be prepared in the usual manner by reacting free base with an appropriate amount of organic or inorganic acid. The base of Formula I is dissolved in a suitable solvent and acidified with an acid solution. The acid solution is added until the salt formation is complete.

Most preferred acid addition salt of ziprasidone is ziprasidone hydrochloride or ziprasidone mesylate.

Isolation and purification of the compounds and intermediates described above may be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phasic-transfer or chromatography, column chromatography, or by a combination of these procedures. Specific illustrations of suitable separation and isolation procedures may be described by reference to the examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.

EXAMPLES

EXAMPLE 1: PREPARATION OF ZIPRASIDONE (FORMULA I)

Step 1: Preparation of 3-(1-Piperazinyl)-1,2-benzisothiazole (Formula III):

To a stirred mixture of piperazine (50.0 g, 0.58 mol) in tertiary butanol (50.0 ml), 3-
chloro-1,2-benzisothiazole (20.0 g, 0.11 mol) was added in small portions at 90-100
°C over a period of 30 minutes. The reaction was heated to 110-120°C and stirred
for reaction completion. Demineralized water (200.0 ml) was added; pH of the mass
was adjusted to 12.0 with caustic lye and extracted with toluene (150.0 x 2 ml). The
organic layer was washed with water, concentrated and stirred at 0-5 °C. Filtered the

solid, washed with toluene and dried. The dried compound was recrystallised from toluene to afford the title compound. (18.7 g, yield: 73.0%, HPLC purity 99 %). Step 2: Preparation of 5-(2-chloro acetyl)-6-chloro oxindole (Formula V): To a stirred mixture of aluminum chloride (30.0 g, 0.22 mol) in dichloromethane (50.0 ml), 6-chloro oxindole (10.0 g, 0.06 mol) was added at 0-5 °C. To the resulting mixture, chloroacetyl chloride (11.0 g, 0.09 mol) was added at 25-35°C, heated to reflux and stirred till the reaction completion. The reaction mass was decomposed into a mixture of ice and hydrochloric acid. The precipitated solid was filtered, washed several times with water and dried. The resultant compound was recrystallised from acetic acid to afford the title compound. (12.0 g, yield: 88.0%, HPLC purity: 99.2%)

Step 3: Preparation of 5-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)acetyl)-6-chloroindolin-2-one (Formula VI):

To a stirred solution of 3-(1-piperazinyl)-1,2-benzisothiazole (III, 8.9 g, 0.04 mol) in cyclohexane (100.0 ml), sodium carbonate (8.5 g, 0.08 mol), sodium iodide (0.6 g, 0.003 mol), tetrabutyl ammonium bromide (2.6 g, 0.008 mol) and 5-(2-chloro acetyl)-6-chloro oxindole (V, 10.0 g, 0.047 mol) were added sequentially at ambient temperature. The resulting mixture was slowly heated to reflux and stirred for reaction completion. Demineralized water (100.0 ml) was added to the reaction mixture at ambient temperature and stirred to isolate the title compound. The separated solid was washed with water, methanol and dried to give title compound. (15.0 g, 83.0%, HPLC Purity: 98.4%) Step 4: Preparation of ziprasidone (Formula I):

Triethyl silane (10.0 g, 0.086 moles) was added slowly to the reaction mixture containing 5-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl)acetyl)-6-chloroindolin-2-one (VI, 10.0 g, 0.023 moles) and methane sulfonic acid (20.0 g, 0.20 moles) at below 25°C. Heated the reaction mass to 50-55°C and stirred for reaction completion. The reaction mass cooled to 0-5°C and stirred for 1 hour to isolate the compound. The isolated compound was filtered, washed with water (50.0 ml). The wet compound further slurred in water (100.0 ml), filtered, washed with water and dried. The resultant crude ziprasidone was recrystallized from a mixture of methanol and chloroform (Yield: 7.3 g, 76%, Purity: 99.8%).

EXAMPLE 2: PREPARATION OF ZIPRASIDONE (FORMULA I)

Step 1: Preparation of 6-Chloro-5-(2-piperazin-1-yl-ethyl)-oxindole (Formula VII):

To a stirred mixture of 5-(2-chloroethyl)-6-chloro oxindole (II, 5.0 g, 0.021 moles) in tertiary butanol (50.0 ml), piperazine (9.0 g, 0.10 moles) was added in three different portions at reflux temperature. The reaction mass was stirred at reflux temperature for about 6 hours to complete the reaction. Distilled off tertiary butanol completely, demineralized water (100.0 ml) was added to the residual mass to dissolve and extracted with dichloromethane. The dichloromethane layer was washed with water and distilled off completely. The residual mass was triturated with hexane to separate the solid. The separated solid was filtered off, washed with hexane and dried to give title compound (Yield: 4.0 g, 66.0%, Purity: 95.0%). Step 2: Preparation of ziprasidone (Formula I):
To stirred mixture of 6-Chloro-5-(2-piperazin-1-yl-ethyl)-oxindole (VII, 3.0 g, 0.010 moles), sodium carbonate (1.2 g, 0.011 moles) and tert. butanol (10 ml) was added a solution of 3-chloro-1,2-benzisothiazole (1.7 g, 0.010 moles) in tert. butanol (10 ml). The reaction mass slowly heated to reflux and maintained for 20-22 hours for reaction completion. Tert. butanol was concentrated under vacuum and water (50.0 ml) was added and stirred for 30 minutes. The solid was filtered, washed with water and dried. The resultant crude compound was further recrystallized from a mixture of methanol and chloroform (Yield: 3.5 g, 80.0%, HPLC Purity: 99.2%)

EXAMPLE 3: PREPARATION OF ZIPRASIDONE (FORMULA I)

Step 1: Preparation of 2-(2-(6-Chloro-2-oxoindolin-5-yl)ethyl)isoindoline-1,3-dione (Formula VIII):

To a stirred mixture of phthalimide (6.3 g, 0.043 moles) in dimethylformamide (20.0 ml), anhydrous potassium carbonate (6.0 g, 0.043 moles) was added and stirred at 60-70 °C for about 1-2 hours. The solution of 5-(2-chloro ethyl) -6-chloro oxindole (II, 10.0 g, 0.043 moles) in dimethylformamide (20.0 ml) was added to the reaction mass and heated to 100-120 °C to complete the reaction. The mass was cooled to ambient temperature and decomposed into chilled water. The reaction mixture was extracted with ethyl acetate (100ml x 3) and the combined organic layer was washed with demineralized water (50.0 ml). The solvent was distilled off, residual mass was triturated with hexane, filtered off the solid and dried. The crude compound was recrystallized from dichloromethane to afford title compound (Yield: 9.6 g, 65.0%, HPLC Purity 92.0%)

Step 2: Preparation of 5-(2-aminoethyl)-6-chloroindolin-2-one (Formula IX): 2-(2-(6-Chloro-2-oxoindolin-5-yl)ethyl)isoindoline-1,3-dione (5.0 g, 0.0147), 40% aqueous monomethylamine solution (20.0 mL) and water (20.0 mL) were stirred at 45-50°C for about 60-90 minutes. Water (25.0 mL) was added and extracted into dichloromethane (50x3 mL). The dichloromethane was distilled completely and the residual mass was triturated with hexane. The resulting crude compound was purified from acetone to afford title compound (1.9 g. 61.5%, HPLC Purity: 98.25%). Step 3: Preparation of 2,2'-(Benzo[d]isothiazol-3-ylazanediyl)diethanol hydrochloride: A solution of 3-Chloro-1,2-benzisothiazole (10.0 g, 0.058 moles), diethanol amine (6.1 g, 0.058 moles) and n-butanol (100.0 ml) were heated to reflux overnight to complete the reaction. n-Butanol was distilled off completely under vacuum and the residual mass was dissolved in isopropyl alcohol (25.0ml). The reaction mass was cooled to 0-5 °C, isopropyl alcohol containing hydrochloric acid was added till pH of the mass attains to 2.0 and stirred the mass for 15 minutes. The light yellow colored solid was filtered off, washed with chilled isopropyl alcohol and dried to afford title compound (12.6 g, 78.0%, HPLC Purity: 98.4%)

Step 4: Preparation of ziprasidone (Formula I):

2,2'-(Benzo[d]isothiazol-3-ylazanediyl)diethanol hydrochloride (2.0 g, 0.007 mol) was taken in water (20.0 mL) and pH adjusted to 10.0 with 10% aqueous sodium hydroxide solution, and the liberated free base extracted into chloroform (50 mL). The chloroform layer was dried over sodium sulfate, thionyl chloride (3.0 g, 0.025 mol) was added and stirred at 50-60°C till the reaction completion to get chloro derivative. The organic layer concentrated under vacuum and the residual mass dissolved in dimethyl formamide (10.0 ml). In another flask, 5-(2-aminoethyl)-6-chloroindolin-2-one (4.0 g, 0.0190 moles), dimethyl formamide (10 ml) was taken, cooled to 0-5°C and 60% NaH (2.3 g, 0.057 moles) was added in three different portions and stirred for 30 minutes. The above dimethyl formamide solution containing chloro derivative was added slowly at 0-5°C. The temperature of the reaction mass was raised to 10-15°C and stirred for reaction completion. Methanol (10.0 mL) was added to decompose excess sodium hydride and stirred at room temperature for 10-15 minutes. Water (100.0 mL) was added and stirred for solid separation. The separated solid was filtered, washed with water, further slurry washed with water and dried. The crude compound was recrystallized from a mixture of methanol and chloroform. (Yield: 2.0 g, 72.0%, HPLC Purity: 99.12%)

We Claims:

Claim 1: A process for preparing ziprasidone of Formula I, and pharmaceutically
acceptable salts thereof, which comprises:

a) condensing the chloroacetyl derivative of Formula V, with 3-(1-piperazinyl)-
1,2-benzisothiazole of Formula III, or salts thereof, in the presence of a base in a suitable solvent to form keto derivative of ziprasidone of Formula VI,

b) reducing the keto derivative of ziprasidone of Formula VI to form ziprasidone
of Formula I.

c) optionally, converting the ziprasidone to pharmaceutically acceptable salt.

Claim 2: The process of claim 1, wherein base in step a) is selected from sodium
carbonate, lithium carbonate, potassium carbonate, potassium bicarbonate,
ammonium carbonate, ammonium bicarbonate, sodium hydroxide, potassium
hydroxide and triethylamine or mixtures thereof.

Claim 3: The process of claim 1, wherein suitable solvent in step a) is selected from
high boiling point organic solvent, non polar solvent, polar protic or aprotic solvent, a
saturated or unsaturated halogenated hydrocarbon solvent, a ketone, straight chain
or branched C1-8 alcohol, nitriles of general Formula RCN wherein R is C2-5 alkyl,
water, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, N-
methylpyrrolidone and sulfolane or mixtures thereof.

Claim 4: The process of claim 1, wherein reducing agent in step b) is selected from
trimethyl silane, triethyl silane and tripropyl silane.

Claim 5: A process for preparing ziprasidone of Formula I, and pharmaceutically
acceptable salts thereof, which comprises:

a) reducing the chloroacetyl derivative of Formula V with triethylsilane in
presence of trifluoroacetic acid to form 5-(2-chloro ethyl)-6-chloro oxindole of
Formula II,

b) reacting the 5-(2-chloro ethyl)-6-chloro oxindole of Formula II with piperazine
in a suitable solvent to form novel compound of Formula VII, or salts thereof,

c) condensing the compound of Formula VII, or salt thereof with 3-chloro-1,2-
benzisothiazole in a suitable solvent to give ziprasidone of Formula I. d) optionally, converting ziprasidone to pharmaceutical^ acceptable salt. Claim 6: The process of claim 5, wherein suitable solvent in step b) and c) is selected from C1-4 alcohols; benzene, toluene, xylene, ethylbenzene, petroleum ether, pentane, hexane, heptane, octane, cyclohexane, methylcyclohexane, cycloheptane, chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, diisopropyl ether, dibutyl ether, dioxane, tetrahydrofuran, methyl acetate, ethyl acetate and isopropyl acetate or mixtures thereof.

Claim 7: A process for preparing ziprasidone of Formula I, and pharmaceutically acceptable salts thereof, which comprises:

a) reacting the 5-(2-chloro ethyl)-6-chloro oxindole of Formula II, with phthalimide in presence of a base in a suitable solvent to give /V-alkyl amide of the Formula VIII,

b) hydrolyzing the compound of Formula VIII to give primary amine compound of Formula IX,

c) condensing the primary amine compound of Formula IX in a suitable solvent with dihalo compound of Formula X, to afford ziprasidone of Formula I.

d) optionally, converting ziprasidoneto pharmaceutically acceptable salt.

Claim 8: The process of claim 7, wherein suitable solvent in step a) and c) is
selected from dimethylacetamide and dimethylformamide.

Claim 9: The process of claim 7, wherein base in step a) is selected from sodium carbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate and ammonium bicarbonate or mixtures thereof.

Claim 10: Compounds of following formula or its salts thereof: