Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 5-(2-(4-(1,2-BENZISOTHIAZOL-3-YL)-1-PIPERAZINYL) ETHYL)-6-CHLORO-1, 3-DIHYDRO-2H-INDOL-2-ONE HYDROCHLORIDE (ZIPRASIDONE HYDROCHLORIDE) AND IT'S INTERMEDIATE

Abstract The present invention relates to an improved, convenient, commercially viable, environment friendly and cost-effective processes for the preparation of 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV), which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V) and 5-(2-(4-(1,2-benzisothiazol- 3-yl)-1-piperazinyl) ethyl)-6-chloro-l, 3-dihydro-2H-indol-2-one hydrochloride, which is known as Ziprasidone hydrochloride of Formula (I), represented by the following structure. Formula (I) The process for the preparation of 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV) comprises the reaction of 6-Chloro-2-oxindole of Formula (II), chloroacetyl chloride of Formula (III) in presence of halogenated hydrocarbon solvents like dichloromethane and aluminum chloride as catalyst. Another main aspect of the present invention is to provide an improved process for the preparation of Ziprasidone hydrochloride of Formula (I), which comprises of refluxing the reaction mixture of 3-(I-piperazinyl)-1,2-benzisothiazole of Formula (VI), 5-(2- chloro ethyl)-6-chloro oxindole of Formula (V) and sodium iodide in a non polar solvents like cyclohexane in presence of a phase transfer catalyst like tetrabutyl ammonium bromide till the reaction completes. Then by subsequent steps washed the isolated compound with alkanone solvent like acetone to yield Ziprasidone Base (crude), which is purified by chloroform and methanol to yield the pure ziprasidone base, which is further acidified with HCI in acetic acid to yield the final ziprasidone hydrochloride salt.
Full Text

FIELD OF THE INVENTION
The present invention relates to improved processes for the preparation of 5-(2-(4-(l,2-benzisothiazol-3-yl)-l-piperazinyl) ethyl)-6-chloro-l, 3-dihydro-2H-indol-2-one and its hydrochloride, which is known as Ziprasidone hydrochloride of Formula (I) and 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV), which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V). It is marketed under brand names "GEODON". Ziprasidone hydrochloride of Formula (I) of the present invention is depicted by the following structure.
Ziprasidone, Ziprasidone hydrochloride and its other pharmaceutically acceptable salts are useful as antipsychotic agents in the treatment of Schizophrenia. BACK GROUND OF THE INVENTION
Several references disclosed the preparation of Ziprasidone, Ziprasidone hydrochloride salt; other salts including hydrochloride monohydrate, mesylate salts etc.
USF 4,831,031 incorporated here in by reference, described the synthesis of Ziprasidone hydrochloride salt. It generically disclosed the preparation of 5-(2-Chloro acetyl)-6-chloro oxindole, which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole (one of the key intermediate of Ziprasidone) in presence of carbon disulphide. The said patent also exempUfied generically the coupling reaction between 3-(l-piperazinyl)-1,2-benzisothiazole and 5-(2-chloro ethyl)-6-chloro oxindole for the preparation of Ziprasidone

base using polar solvents like lower alcohols, methylisobutylketone, and dichloromethane. The
said patent also disclosed the preparation of Ziprasidone hydrochloride by adding aqueous
hydrochloric acid to the Ziprasidone base.
USP 5,206,366, which also referred to an aqueous based process for preparing ziprasidone, its
hydrochloride salt and no where disclosed the non-polar solvents for the coupling reaction
between 3-(l-piperazinyl)-l,2-benzisothiazole and 5-(2-chloro ethyl)-6-chloro oxindole for the
preparation of Ziprasidone base.
USP 4,590,196 refers to l-(l,2-benzisothiazol-3-yl) piperazine, which is the penultimate
intermediate made by the processes of the present invention.
USP 5,312,925 disclosed preparation of the Ziprasidone hydrochloride monohydrate, which
involves refluxing the reaction mixture of 3-(l-piperazinyl)-l,2-benzisothiazole hydrochloride,
5-(2-chloro ethyl)-6-chloro oxindole, water and sodium carbonate at 100oC, followed by
isolating the required compound by washing with isopropanol and recrystallising from THF.
The objective of the present invention is to provide an improved process for the preparation of 5-(2-Chloro acetyl)-6-chloro oxindole, which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole (one of the key intermediate of Ziprasidone), Ziprasidone Base and its hydrochloride, which is cost effective, commercially viable and well suited for industrial scale up.

SUMMARY OF THE INVENTION:
The present invention relates to an improved, convenient, commercially viable, environment friendly and cost-effective processes for the preparation of 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV), which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V) and 5-(2-(4-(l,2-benzisothiazol-3-yl)-l-piperazinyl) ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one hydrochloride, which is known as Ziprasidone hydrochloride of Formula (I).
The process for the preparation of 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV) comprises the reaction of 6-Chloro-2-oxindole of Formula (II), chloroacetyl chloride of Formula (III) in presence of halogenated hydrocarbon solvents like dichloromethane and aluminum chloride as catalyst.
Another main aspect of the present invention is to provide an improved process for the preparation of Ziprasidone hydrochloride of Formula (I), which comprises of refluxing the reaction mixture of 3-(l-piperazinyl)-l,2-benzisothiazole of Formula (VI), 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V) and sodium iodide in less polar solvents like cyclohexane in presence of a phase transfer catalyst like tetrabutyl ammonium bromide till the reaction completes. Then by subsequent steps washed the isolated compound with alkanone solvent like acetone.
It is still a further object of the present invention is to provide a process for purification of Ziprasidone base, which comprises of recrystalising the Ziprasidone base in a mixture of chloroform and methanol to yield the pure ziprasidone base, which is further acidified with HCl in acetic acid to yield the final ziprasidone hydrochloride salt.

The processes of the present invention are simple, cost-effective, and non-hazardous and are
well suited for large-scale production.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV), which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V) comprises of:
i. refluxing the reaction mixture of 6-chloro-2-oxindole of Formula (II) and
chloro acetyl chloride of Formula (III) in presence of halogenated hydrocarbon solvents like dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride, preferably dichloromethane and Lewis acids like AICI3, BF3. (Et20)2, preferably AICI3 as catalyst till the reaction completes; ii. cooling the reaction mass obtained in step (i) and hydrolysed into chilled water at a temperature of 15-45^C, preferably to 25-35 ^C accompanied by stirring the reaction mass at the same temperature till the solid separates; iii. successive filtering and washing the solid obtained in step (ii) with water; iv. purifying 5-(2-Chloro acetyl) -6-chloro oxindole obtained by step (iii) or by different process in organic acids like acetic acid, formic acid, propionic acid preferably acetic acid by the process which comprises adding organic acid followed by heating the reaction mixture to a temperature of 60-100°C, preferably 70-80°C; V. adding activated carbon to the reaction mass of step (iv) and stirring at same
temperature for 30 minutes, preferably 10-15 minutes; vi. filtering the carbon from reaction mass obtained in step (v);

vii. maintaining the filtrate obtained in step (vi) to a temperature of 10-40^C,
preferably 18-22°C till the solid separates; viii. filtering and washing the solid obtained in step (vii) with water; ix. drying the soUd obtained step (viii) to a temperature of 50-100*^C, preferably 60-80°C to afford pure 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV). Accordingly the other important aspect of the present invention is to provide an improved process for the preparation of 5-(2-(4-(l,2-benzisothiazol-3-yl)-l-piperazinyl) ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one hydrochloride of Formula (I) (Ziprasidone hydrochloride) comprises of: A) Preparation of Ziprasidone Base of Formula (VII)
i. carrying out the reaction between the 3-(l-piperazinyl)-l,2-benzisothiazole of Formula (VI), 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V), sodium carbonate and sodium iodide in a less polar solvents comprises of Cyclohexane, toluene, benzene, hexanes, heptane preferably Cyclohexane in presence of a phase transfer catalyst comprises of tetrabutyl ammonium bromide, tetrabutyl phosphonim bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide preferably tetrabutyl ammonium bromide till the reaction completes at reflux or pressure conditions (autoclave); ii. CooHng the reaction mass obtained in step (i) to a temperature of 15-40^C,
preferably to 25-35 ^C; iii. filtering the compound obtained in step (ii); iv. adding water to the wet compound obtained in step (iii) accompanied by stirring;

V. washing the compound obtained in step (iv) with water; vi. suspending the compound obtained in step (v) in alkanone solvents Uke acetone,
2-butanone, propanone, methylethyl ketone, dimethyl ketone, diethyl ketone,
preferably acetone accompanied by stirring; vii. isolating the sohd obtained in step (vi); viii. drying the isolated compound of step (vii) at 50-100*^C, preferably 70-75 ^C to
afford the Ziprasidone base of Formula (VII); B) Purification of Ziprasidone Base
i. dissolving the Ziprasidone Base of Formula (VII) in mixture of alcoholic and
halogenated hydrocarbon solvents like methanol, ethanol, propanol, butanol,
isopropanol, isobutanol, preferably methanol and halogenated hydrocarbon
solvents like methylene chloride, chloroform, ethylene dichloride, carbon
tetrachloride, preferably chloroform at reflux temperature; ii. charging carbon to the reaction solution of step (i) and followed by maintaining
at reflux condition for 30 minutes, preferably 10-15 minutes; iii. filtering the carbon from reaction mass obtained in step (ii); iv. optionally distilling off the solvent from the filtrate of step (iii) to about half of
the volume; V. adding alcohohc solvents like methanol, ethanol, propanol, butanol, isopropanol,
isobutanol, preferably methanol to the residue of step (iv) at a temperature of 20-
60*^C for 30 minutes, preferably 10-15 minutes;

vi. cooling the reaction mass of step (v) to of 0-40^C, preferably to 25-35 ^C
accompanied by maintaining the reaction mass at the same temperature till the
solid separates out; vii. filtering and washing the solid obtained in step (vi) with alcoholic solvents like
methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably
methanol; viii. drying the isolated compound of step (vii) at 50-100*^C, preferably 65-75^C to
afford Ziprasidone base of Formula (VIII); C) Preparation of Ziprasidone hydrochloride of Formula (I)
i. dissolving Ziprasidone base of Formula (VIII) in organic acids like acetic acid,
formic acid, preferably acetic acid or a mixture of organic acids and alcohols at
room temperature; ii. charging carbon to the reaction solution of step (i) accompanied by stirring 30
minutes, preferably 10-15 minutes; iii. filtering the carbon from reaction mass obtained in step (ii) accompanied by
adding hydrochloric acid in organic solvents like acetic acid, isopropanol,
methanol, preferably HCl in acetic acid or HCl in isopropanol to the filtrate or
altematively adding the solution obtained step (ii) to the mixture of hydrochloric
acid in organic solvents like acetic acid, Isopropanol or mixture of acetic acid
and isopropanol; iv. maintaining the reaction mixture at 30-35^C till the solid separates out; V. isolating the solid obtained in step (iv);

vi. optionally slurrying the isolated compound from alcoholic solvents like methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably isopropanol;
vii. drying the solid obtained in step (vi) at 50-100*^C, preferably 70-80*^0 to afford ziprasidone hydrochloride of Formula (I).
An improved process for the preparation of Ziprasidone hydrochloride of the present invention by above-disclosed method can be depicted by the following synthetic scheme.
Synthetic scheme:


Thus, the present invention is directed to an improved process for the preparation of ziprasidone hydrochloride, which renders it well suited for pharmaceutical formulations. The processes of the present invention are simple, cost-effective, environment friendly, commercially viable and non-hazardous and are well suited for large-scale production

The present invention will be explained in more detail with following examples but don't limit it in any way.
EXAMPLE - 1: Preparation of 5-(2-ChIoro acetyl) "6-chloro oxindole
Cooled the reaction mixture of dichloromethane (250 ml) and aluminum chloride (159.0 gm) to a temperature of 4^C. To the cold reaction mixture 6-chloro-2-oxindole (50 gm) was added portion wise over 30 minutes. Heated the resulting reaction mixture to a temperature of 26^C. To the reaction mixture chloro acetyl chloride (53.9 gm) was slowly added over 40 minutes, then refluxed the reaction mixture for 9 hours. The reaction completion is monitored by TLC. Then the reaction mass was cooled to a temperature of 28*^C and poured into a mixture of ice (900 gm) and hydrochloric acid (45 ml) and accompanied by stirring the reaction mass for 45 minutes. The separated solid was filtered and washed with water and further slurred in water (250 ml). To the resulting wet compound acetic acid (1190 ml) was added and heated to a temperature of 76°C followed by addition of carbon (2.5 gm) to the hot reaction mass. Then the reaction mass was stirred for 15 minutes at the same temperature. Carbon was filtered off and washed with acetic acid (10 ml). Then the filtrate was cooled to a temperature of 18 - 20°C and continued stirring at the same temperature for 2 hours. Then the separated solid was filtered, washed with water (2x100 ml) and dried at a temperature of 60-65*^C to afford the pure 5-(2-Chloro acetyl) -6-chloro oxindole (48.2 gm).
EXAMPLE - 2: Preparation of 5-(2-Chloro ethyl) -6-chloro oxindole
Triethylsilane (57.2 gm) was added slowly to the reaction mixture of 5-(2-Chloro acetyl) -6-chloro oxindole (50.0 gm) and trifluoroacetic acid (175 ml) below the temperature of 45*^C,

Maintained the reaction at 40-45*^C for 6 hours. The reaction mass was cooled to 0 to -5^C and maintained stirring for 90 min. The separated sohd was filtered and washed with water (50 ml). Then the wet compound was further slurred in water (250 ml) for 90 min. The resultant solid was filtered, washed with water (50 ml) and dried at a temperature of 70-75^C to afford the 5-(2-Chloro ethyl) -6-chloro oxindole (43.5 gm).
EXAMPLE - 3: Preparation of Ziprasidone base (Crude)
Refluxed the reaction mixture of 5-(2-Chloro ethyl) -6-chloro oxindole (100 gm), 3-(l-piperazinyl)-l,2-benzisothiazole (104.7 gm), sodium carbonate (92.2 gm), sodium iodide (6.4 gm), tetra butyl ammonium bromide (28 gm) and cyclohexane (1000 ml) till the reaction completes. The reaction mass was cooled to a temperature of BO^C and filtered the sohd. To the wet compound added water (1000 ml) and continued stirring for 45 minutes. The solid was filtered and washed with water (100 ml). To the water wet compound added acetone (500 ml) and stirred for 2 hours at room temperature. Filtered the compound and washed with acetone (200 ml) and dried at a temperature of 70 - 75*^C to afford the Crude Ziprasidone base (156.9 gm)
EXAMPLE -4: Preparation of Ziprasidone base (Crude)
Charged 5-(2-Chloro ethyl) -6-chloro oxindole (50 gm), 3-(l-piperazinyl)-l,2-benzisothiazole (47.5 gm) and cyclohexane (500 ml) in to autoclave. To this sodium carbonate (46 gm), sodium iodide (3.2 gm), tetra butyl phosphonium bromide (14.8 gm) was added and maintained the reaction at temperature 95 - 102°C and the pressure was 2.5 kg/cm2 till the reaction complete. The reaction mass was cooled to 30*^C and added water (250 ml), filtered the compound.

washed with water (100 ml). The wet compound was further slurred in water (500 ml), filtered and washed with water (100 ml). To the water wet compound added acetone (500 ml) and stirred at room temperature for 2 hours and 30 minutes. The solid was fihered, washed with acetone (100 ml) and dried at a temperature of 60-65^C to afford the Ziprasidone base (65.7 gm)
EXAMPLE - 5: Purification of Ziprasidone base
Ziprasidone base (40 gm), methanol (250 ml) and chloroform (750 ml) were heated to reflux till clear solution is obtained. Carbon (2 gm) was added to the resulting reaction solution and maintained at reflux temperature for 15 minutes. Then the carbon was filtered and the filtrate was heated to distill and collected the distillate around 400 ml. To the reaction mass added Methanol (400 ml) slowly in 45minutes. Cooled the reaction mixture to a temperature of 35'^C and stirred at the same temperature for 2.0 hours. Then the solid was filtered, washed with methanol (200.0 ml) and dried at a temperature of 70^C to afford the pure Ziprasidone base (31.5 gm).
EXAMPLE - 6: Preparation of Ziprasidone Hydrochloride
Dissolved the Pure Ziprasidone base (100 gm) in acetic acid (3000 ml) at temperature of 30*^C. Carbon (5) was added to the resulting reaction solution, stirred the reaction mixture for 15 minutes at the same temperature. Filtered carbon and washed with acetic acid (30 ml). Then add filtrate slowly to the mixer of isopropyl alcohol (500ml) and Isopropyl alcohol-HCI (220 ml) at the temperature of 30°C for 35min. Stirred the reaction mixture for 2.5hours at the same temperature. Fihered the compound and washed with Isopropyl alcohol (100ml). To the wet

compound added isopropyl alcohol (1000), stirred at 30°C for 90min. Then soHd was filtered and washed with Isopropanol (100ml) and dried at the temperature of 70-75^C to afford the Ziprasidone hydrochloride of Formula (1) of the present invention (93.9gm)
EXAMPLE -7: Preparation of Ziprasidone Hydrochloride
Dissolved the Pure Ziprasidone base (10 gm) in acetic acid (50 ml) at temperature of 32*^C. Carbon (0.5gm) was added to the resulting reaction solution, stirred the reaction mixture for 10 minutes at the same temperature. Then filtered carbon and washed with acetic acid (5 ml). Then added 20ml of acetic acid -HCI slowly for 15min to the filtrate. Stirred the reaction mixture for 90 min. filtered the separated compound and washed with acetic acid (10 ml). To the acetic acid wet added isopropyl alcohol (100), stirred at 32°C for 60min. Then solid was filtered and washed with Isopropanol (10ml) and dried at the temperature of 75-80*^C to afford the Ziprasidone hydrochloride of Formula (1) of the present invention. (9.8 gm)






we Claim:
1. An improved process for the preparation of 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV), which is an intermediate for the preparation of 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V) comprises of:
i. refluxing the reaction mixture of 6-chloro-2-oxindole of Formula (II) and
chloro acetyl chloride of Formula (III) in presence of halogenated hydrocarbon solvents like dichloromethane, chloroform, ethylene dichloride, carbon tetrachloride, preferably dichloromethane and Lewis acids like AICI3, BF3. (Et20)2, preferably AICI3 as catalyst till the reaction completes; ii. cooling the reaction mass obtained in step (i) and hydrolysed into chilled water at a temperature of 15-450C, preferably to 25-35 0C accompanied by stirring the reaction mass at the same temperature till the solid separates; iii. successive filtering and washing the compound 5-(2-Chloro acetyl) -6-chloro
oxindole obtained in step (ii) with water; iv. Purifying 5-(2-Chloro acetyl) -6-chloro oxindole obtained by step (iii) or by different process in organic acids like acetic acid, formic acid, propionic acid preferably acetic acid by the process which comprises adding organic acid followed by heating the reaction mixture to a temperature of 60-100°C, preferably 70-80°C; V. adding activated carbon to the reaction mass of step (iv); vi. filtering the carbon from reaction mass obtained in step (v); vii. maintaining the filtrate obtained in step (vi) to a temperature of 10-40oC, preferably 18-22°C till the solid separates;

viii. filtering and washing the soUd obtained in step (vii) with water; ix. drying the soUd obtained step (viii) to a temperature of 50-100oC, preferably 60-80°C to afford pure 5-(2-Chloro acetyl) -6-chloro oxindole of Formula (IV). 2. An improved process for the preparation of 5-(2-(4-(l ,2-benzisothiazol-3-yl)-1 -
piperazinyl) ethyl)-6-chloro-l, 3-dihydro-2H-indol-2-one (Ziprasidone Base) of Formula (VII) comprises of:
i. carrying out the reaction between the 3-(l -piperazinyl)-l ,2-benzisothiazole of Formula (VI), 5-(2-chloro ethyl)-6-chloro oxindole of Formula (V), sodium carbonate and sodium iodide in a less polar solvents comprises of Cyclohexane, toluene, benzene, hexanes, heptane preferably Cyclohexane in presence of a phase transfer catalyst comprises of tetrabutyl ammonium bromide, tetrabutyl phosphonim bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide preferably tetrabutyl ammonium bromide till the reaction completes at reflux or pressure conditions (autoclave); ii. Cooling the reaction mass obtained in step (i) to a temperature of 15-40*^C,
preferably to 25-35 ^C; iii. filtering the compound obtained in step (ii); iv. adding water to the wet compound obtained in step (iii) accompanied by
stirring; V. washing the compound obtained in step (iv) with water;

vi. suspending the compound obtained in step (v) in alkanone solvents like acetone, 2-butanone, propanone, methylethyl ketone, dimethyl ketone, diethyl ketone, preferably acetone accompanied by stirring; vii. isolating the solid obtained in step (vi);
viii. drying the isolated compound of step (vii) at 50-lOO^C, preferably 70-75 *^C to afford the Ziprasidone base of Formula (VII). 3. Process for the purification of Ziprasidone Base of Formula (VII), prepared according to the claim 2 comprises of:
i. dissolving the Ziprasidone Base of Formula (VII) in mixture of aliphatic alcoholic solvents like methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably methanol and halogenated hydrocarbon solvents like methylene chloride, chloroform, ethylene dichloride, carbon tetrachloride, preferably chloroform at reflux temperature; ii. charging carbon to the reaction solution of step (i) and followed by maintaining
at reflux condition for 30 minutes, preferably 10-15 minutes; iii. filtering the carbon from reaction mass obtained in step (ii); iv. optionally distilling off the solvent from the filtrate of step (iii)to about half of
the volume; V. adding alcoholic solvents like methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably methanol to the residue of step (iv) at a temperature of 20-60 ^C for 30 minutes, preferably 10-15 minutes;

vi. cooling the reaction mass of step (v) to of 0-40*^C, preferably to 25-35 *^C
accompanied by maintaining the reaction mass at the same temperature till the solid separates out; vii. filtering and washing the sohd obtained in step (vi) with alcoholic solvents like methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably methanol; viii, drying the isolated compound of step (vii) at 50-lOO^C, preferably 65-75*^C to afford pure ziprasidone base of Formula (VIII). 4. Process for the preparation of Ziprasidone hydrochloride of Formula (I) from ziprasidone base of Formula (VIII), prepared according to the claim 3 comprises of:
i. dissolving Ziprasidone base of Formula (VIII) in organic acids like acetic acid, formic acid, preferably acetic acid or a mixture of organic acids and alcohols at room temperature; ii. charging carbon to the reaction solution of step (i) accompanied by stirring
30 minutes, preferably 10-15 minutes; iii. filtering the carbon from reaction mass obtained in step (ii) accompanied by adding hydrochloric acid in organic solvents like acetic acid, isopropanol, methanol, preferably HCl in acetic acid or HCl in isopropanol to the filtrate or altematively adding the solution obtained step (ii) to the mixture of hydrochloric acid in organic solvents like acetic acid, Isopropanol or mixture of acetic acid and isopropanol; iv. maintaining the reaction mixture at 30-35*^C till the solid separates out; V. isolating the solid obtained in step (iv);

vi. optionally slurrying the isolated compound from alcoholic solvents like methanol, ethanol, propanol, butanol, isopropanol, isobutanol, preferably isopropanol;
vii. drying the solid obtained in step (vi) at 50-100*^C, preferably 70-80^C to afford ziprasidone hydrochloride of Formula (I).
5. The process according to claim 1 of step (i), where in the halogenated hydrocarbon solvent is Dichloromethane.
6. The process according to claim 1 of step (iv), where in the organic acid used is acetic acid
7. The process according to claim 2 of step (i), where in the less polar solvent is Cyclohexane.
8. The process according to claim 2 of step (i), where in the phase transfer catalyst is tetrabutyl ammonium bromide.
9. The process according to claim 2 of step (vi), where in the alkanone solvent is acetone.
10. The process according to claim 2 of step (vii), where in the isolating solvent is acetone.
11. The process according to claim 3 of step (i), where in the mixture of alcohoHc and halogenated hydrocarbon solvents used in which alcohols are methanol, ethanol, propanol, butanol, isopropanol, isobutanol etc, and halogenated hydrocarbons are methylene chloride, chloroform, ethylene dichloride, carbontetrachloride etc.
12. The process according to claim 11, where in the alcoholic solvent is methanol.
13. The process according to claim 11, where in the haogenated hydrocarbon is chloroform.
14. The process according to claim 3 of step (vii), where in the alcoholic solvent is methanol
15. The process according to claim 4 of step (i), where in the organic acid is acetic acid.
16. The process according to claim 4 of step (iii), where in the acidifying agent is HCl in acetic acid.

17. The process according to claim 4 of step (vi), where in the solvent is used for slurrying is
isopropanol.
18. The improved processes for the preparation of 5-(2-Chloro acetyl) "6-chloro oxindole of
Formula (IV), 5-(2-(4-(l,2-benzisothiazol-3-yl)-l-piperazinyl) ethyl)-6-chloro-l, 3-
dihydro-2H-indol-2-one and its hydrochloride (Ziprasidone hydrochloride) of Formula (I)
are substantially as here in described and exempUfied.


Documents:

488-che-2003 form-3 25-01-2011.pdf

488-che-2003 form-5 25-01-2011.pdf

488-che-2003 amended claims 25-01-2011.pdf

488-che-2003 amended pages of specification 25-01-2011.pdf

488-che-2003 examination report reply received 25-01-2011.pdf

488-che-2003-abstract.pdf

488-che-2003-claims.pdf

488-che-2003-correspondnece-others.pdf

488-che-2003-description(complete).pdf

488-che-2003-form 1.pdf

488.jpg

abs-488-che-2003.jpg


Patent Number 246521
Indian Patent Application Number 488/CHE/2003
PG Journal Number 09/2011
Publication Date 04-Mar-2011
Grant Date 02-Mar-2011
Date of Filing 12-Jun-2003
Name of Patentee Dr.REDDY'S LABORATORIES LIMITED
Applicant Address 7-1-27, AMEERPET, HYDERABAD-560 016
Inventors:
# Inventor's Name Inventor's Address
1 Dr.MANNE SATYANARAYANA REDDY H.NO.8-3-167/D/16/ KALYAN NAGAR, NEAR AG COLONY, ERRAGADDA, HYDERABAD-500 038
2 SRINIVASAN THIRUMALAI RAJAN PLOT NO.12, LAKE VIEW ENCLAVE, MIYAPUR, HYDERABAD-500 050
3 UPPALA VENKATA BHASKAR RAO MIG-53, DHARMA REDDY COLONY, PHASE-1, KPHB, HYDERABAD-500 072
4 MUMMADI VENKATESH H.NO.2-42, PARWATHAPUR, GANDHI NAGAR-UPPAL, HYDERABAD-500 039
PCT International Classification Number A61K31/495
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA