5-(2-Chloroethyl)-6-chlorooxindole

6-chloro-5-(2-(4-(2, 3-dihydrobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)indolin-2-one Example 37 5-(2-(4-(benzo[b]thiophen-4-yl)piperidin-1-yl)ethyl)-6-chloroindolin-2-one The product of Reference Example 31 (120 mg, 0.553 mmol), Example 42 6-chloro-5-(2-(4-(thieno[2, 3-c]pyridin-4-yl)piperazin-1-yl)ethyl)indolin-2-one The product of Reference Example 26 (200 mg, 0.632 mmol), 5-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one hydrochloride A mixture of Preparation of 5-[2-[4-(1, 2-benzisothiazol-3-yl)-1-piperazinyl] ethyl]-6-chloro-1, 3-dihydro-2H-indol-2-one: (ii) Preparation of [5-(2-chloroethyl)-6-chlorooxindole] : Charge 650 ml of trifluoroacetic acid and 130 gm of step (i) product into a 3 litre three neck flask under nitrogen atmosphere at 25 to 30C. Stir the mixture for 15 mins and cool to 0 to 5C under stirring. Charge 142.46 gms of triethylsilane slowly keeping temperature between 0 to 5C over 30 mins. Stir the reaction mixture for 30 mins at 0 to 5C and allow it to gradually reach 30 to 35C. Stir the reaction for 6 hrs. Cool the reaction mixture to 5 to 10C and add chilled water slowly. Stir the mixture for 1 hr and filter the solids. Wash with demin water, 5% NaHCO3, demin water and hexane. Suck dry product and dry at 70 to 75C.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 45C. The reaction was maintained at 40-45C for 6 hours. The reaction mass was cooled to 0C TO-5C and maintained stirring for 90 minutes. The separated solid was filtered and washed with water (50 mL). Then the wet compound was further slurred in water (250 mL) for 90 minutes. The resultant solid was filtered, washed with water (50 mL) and dried at a temperature OF 70-75C to afford 5- (2-CHLOROETHYL)-6-CHLORO oxindole (43.5 gm).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 solid 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 4Preparation 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 30C. Stir the mixture for 15 minutes and cool to 0 to 5C under stirring. Charge 142.46 gms of triethyisilane slowly keeping temperature between 0 to 5C over 30 minutes. Stir the reaction mixture for 30 mins at 0 to 5C and allow it to gradually reach 30 to 35C. Stir the reaction for 6 hrs. Cool the reaction mixture to 5 to 10C 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- 45C.EXAMPLE 4 2 moles of Piperazine Benzisothiazole , 1 mole of 5-(2-chloroethyl)-6-chlorooxindole in water (20 times based on benzisothiazole) and in the presence of dispersing agent. All the reactants are charged in to the flask and refluxed under nitrogen, under stirring for 12-16 hr. After the completion of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurried in water and then in IPA and isolated by filtration. The solid is dried at 95-100 C.Yield: 92%, Purity 99% (min).2 moles of Piperazine Benzisothiazole , 1 mole of 5-(2-chloroethyl)-6- chlorooxindole in water (20 times based on benzisothiazole) and in the presence of dispersing agent. All the reactants are charged in to the flask and refluxed under nitrogen, -under stirring ^or^ r2-i6hr. After the completion 'of the reaction, the reaction mass is cooled to room temperature and the resulting mass is filtered. It is slurried inwater and then in IPA and isolated by filtration. The solid is dried at 95- 1000C.Yield: 92%, Purity 99 %( min).Preparation of 5-(2-(4-(l , 2-benzisothiazol-3-yl)-1 -piperazinyl)ethvD-6-chloro-l , 3-dihydro-2H-indol-2-one(Ziprasidone)In a 50 ml 3 necked round bottom flask there were placed 1 gram (4.56 mmol) of 3-piperazinylbenzo[d]isothiazole; 1.25 grams (5.43 mmol) of Preparation of 5-(2-(4-(l , 2-benzisothiazol-3-vD-1 -piperazinvl)ethyl)-6-chloro-1, 3-dihvdro-2H-indol-2-one(Ziprasidone)In a 50 ml 3 necked round bottom flask there were placed 1 gram (4.56 mmol) of 3-piperazinylbenzo[d]isothiazole; 2.5 grams (10.86 mmol) of Example 4. 5-(2-(4-Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one. (I); A reactor is loaded with 200 g (0.86 mol) of 5-(2-(4-Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one hydrochloride. (I); A reactor is loaded with 131 g (0.57 mol) of 6-chloro-5-(2-chloro-ethyl)-1, 3-dihydro-indol-2-one, 125 g (0.57 mol) of piperazinyl benzoisothiazole, 260 ml of dimethylsulfoxide, 26 ml of water and 4.3 g (0.0285 mols) of Nal. The reaction mixture is added with 103 g (0.969 mol) of Na2CO3, with stirring under nitrogen atmosphere. The resulting mixture is heated to about 115-125 C. in 1 h and kept at said temperature under stirring for approx. 1 hr 45 min, then cooled and slowly added in about 25 min with isopropyl alcohol (650 ml), at a temperature of about 110 C., then slowly cooled at 25 C. The filtrate and the precipitate are washed with isopropyl alcohol (2×130 ml) to obtain 310 g of 5-(2-(4-benzo[d]isothiazol-3-yl) piperazin- 1-yl)ethyl)-6-chloro- 1, 3-dihydro-2H-indol-2-one free base, as a crystalline solid. The resulting product is placed in a 3 L beaker with 1500 ml of purified water, and 150 ml of 32% HCl are dropped therein with stirring. The reaction mixture is kept under stirring for 10 min, filtered, washed with purified water (2×500), dried to give 260 g of 5-(2-(4-benzo[d]isothiazol-3-yl) piperazin- 1-yl)ethyl)-6-chloro- 1, 3-dihydro-2H-indol-2-one hydrochloride, as a crystalline solid.Preparation of ziprasidone base To de-ionized water (2.0 Lit), was added 5- (2-chloroethyl)-6-chloro-oxindole (100 g) and 1- (1, 2-benzisothiazol-3-yl) piperazine (210 g) at 30-35C. The mixture was slowly heated under stirring to 98-100C over 60-80 minutes. The resultant mass was stirred for 10-15 hours at 98-100C. After completion of reaction as monitored by HPLC, the suspended solid material was filtered at 98-100C. The wet cake so obtained was suspended in de-ionized water (2.0 Lit) and heated to 90-95C and maintained at this temperature for 30 minutes. The solid suspension was filtered at 90-95C. The wet cake was further added to isopropyl alcohol (1.5 Lit) and stirred for 2 hours at 30-35C. The solids were filtered and washed with isopropyl alcohol (500 ml) and dried under vacuum at 50-55C for 7-8 hours till moisture content was not more than 1.0% w/w.; Preparation of ziprasidone base To de-ionized water (4.0 Lit), was added 5- (2-chloroethyl)-6-chloro-oxindole (200 g) and 1- (1, 2-benzisothiazol-3-yl) piperazine (419.8 g) at 30-35C. The mixture was slowly heated under stirring to 98-100C over 60-90 minutes. The resultant mass was stirred for 12-15 hours at 98-100C. After completion of reaction as monitored by HPLC, the suspended solid material was filtered at 98-100C. The wet cake so obtained was suspended in de-ionized water (4.0 Lit) and heated to 90-95C and further maintained at this temperature for 30 minutes. The solid suspension was filtered at 90-95C. The wet cake was further added to isopropyl alcohol (3.0 Lit) and the resultant mass was heated to reflux and maintained at reflux for 1 hour. The mass was further cooled to 30-35C and stirred for 1 hour at 30-35C. The solids were filtered and washed with isopropyl alcohol (1.0 Lit) and dried under vacuum at 50-55C for 10-12 hours till moisture content was not more than 1.0% w/w. The product so obtained was suspended in tetrahydrofuran (7.3 Lit) and de-ionized water (580 ml) and heated to reflux (65-67C). The resultant mass was maintained under reflux for 10-15 minutes at 65-67C and further stirred under reflux at 65-67C for 40-45 minutes to get a clear solution. Activated carbon (29 g) was added to the clear solution at 65-67C with stirring for 1 hour at 65-67C. The reaction mass was filtered while hot under vacuum through celite bed at 65-67C. The celite bed was washed with tetrahydrofuran (580 ml). The solvent was recovered under vacuum at 50-55C leaving behind about 2.2 Lit of the reaction mass. The resultant suspension was cooled under stirring slowly to 35C and maintained for further 30 minutes. It was further cooled to 3- 5C and maintained for 2 hours under stirring at 3-5C. The solid separated was filtered and the wet cake was slurry washed with isopropyl alcohol (870 ml). The product was then dried under vacuum at 50-55C for 7-8 hours till the moisture was less than 0.5 % w/w. Yield : 267 g (68%) Purity: 99.96% by HPLC Impurity : Single known or unknown impurity 0.03% by HPLCRefluxed the reaction mixture of 5- (2-chloroethyl)-6-chloro oxindole (100 GM), 3- (1-piperazinyl)-1, 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 was completed. The reaction mass was cooled to a temperature of 30C and the solid was filtered. To the wet compound was 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 was added acetone (500 mL) and there was stirring for 2 hours at room temperature. The compound was filtered and washed with acetone (200 mL) and dried at a TEMPERATURE OF70-75C to afford the CRUDE Ziprasidone base (156.9 g)Charged 5- (2-chloroethyl)-6-chloro oxindole (50 GM), 3- (1-PIPERAZINYL)- 1, 2-BENZISOTHIAZOLE (47.5 gm) and cyclohexane (500 mL) into an autoclave. To this sodium carbonate (46 GM), sodium iodide (3.2 GM), tetra butyl phosphonium bromide (14.8 gm) was added and the reaction was maintained at a temperature OF 95-102C and the pressure was kept at 2.5 KG/CM2 TILL the reaction was completed. The reaction mass was cooled to 30C and water (250 mL) was added. The resulting compound was filtered and 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 was added acetone (500 mL) and was stirred at room temperature for 2 hours and 30 minutes. The solid was filtered, washed with acetone (100 mL) and dried at a TEMPERATURE OF 60-65C to afford the Ziprasidone base (65.7 gm).Sodium carbonate (56.3 g) and 500 mL of water were placed into a round bottom flask. Added was 50 g OF 3- (1-PIPERAZINYL)-1, 2-BENZISOTHIAZOLE hydrochloride and 50 g of 6-CHLORO-5- (2-CHLOROETHYL) OXINDOLE. The reaction mixture was then refluxed for 15 hours. The reaction completion was monitored by TLC. The reaction mass was cooled to room temperature. The resulting compound was filtered and washed with 50 mL of water. The wet compound and 250 mL of acetone were placed into a flask and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to give a solid cake, which was washed with 50 mL of acetone. The wet cake and 750 mL of methanol were placed into a flask, which was heated to 50C, and 14 mL of methane sulfonic acid was added to the solution over 20 minutes. The resulting reaction mass was cooled to room temperature and was subjected to a filtration to give a solid compound, which was washed with methanol. The wet compound and 750 mL of water were placed into a flask, and then pH of the solution was adjusted to pH 9 with caustic lye. The reaction mixture was then stirred at room temperature for 1 hour and filtered. The filtered compound was washed with water and dried at 70C to give 65 g of crystalline form Ziprasidone base.Refluxed the reaction mixture of 5-(2-Chloro ethyl)-6-chloro oxindole (100 gm), 3-(1-piperazinyl)-1, 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 30 C. and filtered the solid. To the wet compound added was 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)Charged 5-(2-Chloro ethyl)-6-chloro oxindole (50 gm), 3-(1-piperazinyl)-1, 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 filtered, washed with acetone (100 ml) and dried at a temperature of 60-65 C. to afford the Ziprasidone base (65.7 gm)5-(2-(4-(1, 2-benzisothiazol-3-yl)-piperazinyl)ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one A clean and dry 20-gallon glass lined tank was charged with 19 L of water and 4.44 Kg of sodium carbonate, after the carbonate had dissolved 4.29 Kg (17.5 moles) of 5-(2-chloroethyl)-6-chloro-oxindole and 3.62 Kg (1 6.5 moles) of 1-(1, 2-benzisothiazol-3-yl) piperazine were added. The aqueous slurry was heated to reflux and the temperature maintained for 14 hours. When the reaction was complete the solution was cooled to 20 C. and filtered. The wet product was reslurried in 23 L of isopropyl alcohol at room temperature for 2 hours. The product was collected by filtration on 2 large Buchner funnels, each was washed with 3.4 L of fresh isopropyl alcohol. The product was vacuum dried at 30 to 40 C. until no isopropyl alcohol remained, giving 5.89 Kg (86.4% yield) of the desired free base which matched a standard sample by high performance liquid chromatography (HPLC).5-(2-(4-Benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one hydrochloride. (I); A reactor is loaded with 131 g (0.57 mol) of 6-chloro-5-(2-chloro-ethyl)-1, 3-dihydro-indol-2-one, 125 g (0.57 mol) of piperazinyl benzoisothiazole, 260 ml of dimethylsulfoxide, 26 ml of water and 4.3 g (0.0285 mols) of Nal. The reaction mixture is added with 103 g (0.969 mol) of Na2CO3, with stirring under nitrogen atmosphere. The resulting mixture is heated to about 115-125 C. in 1 h and kept at said temperature under stirring for approx. 1 hr 45 min, then cooled and slowly added in about 25 min with isopropyl alcohol (650 ml), at a temperature of about 110 C., then slowly cooled at 25 C. The filtrate and the precipitate are washed with isopropyl alcohol (2×130 ml) to obtain 310 g of 5-(2-(4-benzo[d]isothiazol-3-yl) piperazin- 1-yl)ethyl)-6-chloro- 1, 3-dihydro-2H-indol-2-one free base, as a crystalline solid. The resulting product is placed in a 3 L beaker with 1500 ml of purified water, and 150 ml of 32% HCl are dropped therein with stirring. The reaction mixture is kept under stirring for 10 min, filtered, washed with purified water (2×500), dried to give 260 g of 5-(2-(4-benzo[d]isothiazol-3-yl) piperazin- 1-yl)ethyl)-6-chloro- 1, 3-dihydro-2H-indol-2-one hydrochloride, as a crystalline solid.Synthesis of Ziprasidone To a 125 mL round bottom flask equipped with an N2 inlet and condenser are added 0.73 g (3.2 mmol) 5-(2-chloroethyl)-6-chloro-oxindole, 0.70 g (3.2 mmol) N-(1, 2-benzisothiazol-3-yl)piperazine, 0.68 g (6.4 mmol) sodium carbonate, 2 mg sodium iodide, and 30 mL methylisobutyl ketone. The reaction is refluxed for 40 hours, cooled, filtered, and evaporated. The residue is chromatographed on silica gel, eluding the by-products with ethyl acetate (1 L) and the product with 4% methanol in ethyl acetate (1.5 L). The product fractions (Rf=0.2 in 5% methanol in ethyl acetate) are evaporated, taken up in methylene chloride, and precipitated by addition of ether saturated with HCl; the solid is filtered and washed with ether, dried, and washed with acetone. The latter is done by slurrying the solid with acetone and filtering.Example 3 Preparation of 5- [2- [4- (1, 2- benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1, 3- dihydro-2H-indol-2-one (Ziprasidone base) In a round bottom flask 1 g of 6-Chloro-5-(2-Chloroethyl)-1, 3-Dihydro-2H-Indol-2-One (INT 1), 1.1 g of (3-(1-piperazinyl)1, 2-benzisothiazole), 1.46 g of Na2CO3 and 8 ml of 1-ethyl-3-methylimidazolium methyl sulfate were placed, heated to 100 C and stirred for 24 hours. After the completion of the reaction the presence of 5- [2- [4- (1, 2- benzisothiazol-3-yl)-1-piperazinyl] ethyl] -6-chloro-1, 3- dihydro-2H-indol-2-one was confirmed by HPLC. The reaction mixture was cooled to room temperature and 30 ml of methanol was added to precipitate the product. Reaction mixture was stirred for about 1 h and filtered. An amount of 1.8 g of wet crude Ziprasidone base was obtained (Purity 88.0 % was determined by HPLC). A whole sample was further placed in a 50 ml round bottom flask with 20 ml of demineralised water and heated at the 79C for 30 minutes, filtrated and cooled to room temperature. A 2.65 g of precipitated wet Ziprasidone base was dried in a vacuum drier for 1 h at the temperature 50 C and overnight at the room temperature. An amount of 1.03 g of Ziprasidone base was obtained.Preparation of 5- [2-[4-(1, 2- benzisothiazol-3-yl) -1-piperazipyl] ethyl] -6-chloro-1, 3- dihydro-2H-indol-2-one (Ziprasidone base) was repeated with the exception that 1-butyl-3-methylimidazolium tetrafluoroborate was used instead of 1-ethyl-3-methylimidazolium methyl sulfate. After the completion of the reaction the presence of 5- [2- [4- (1, 2- benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1, 3- dihydro-2H-indol-2-one was confirmed by HPLC.Example 5 Preparation of 5- [2- [4- (1, 2- benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1, 3-dihydro-2H-indol-2-one (Ziprasidone base) was repeated with the exception that 10 ml of 1-butyl-3-methylimidazolium bromide was used instead of 8 ml of 1-ethyl-3-methylimidazolium methyl sulfate. After the completion of the reaction the presence of 5- [2- [4- (1, 2- benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1, 3- dihydro-2H-indol-2-one was confirmed by HPLC.i. Synthesis of 5- [2- [4- (1, 2- benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1, 3-dihydro-2H-indol-2-one (Ziprasidone base) An amount of 5.00 g (0.023 mol) of 3-(1-piperazinyl)1, 2-benzisothiazole, 5.77 g (0.025 mol) of 6-Chloro-5-(2-Chloroethyl)-1, 3-Dihydro-2H-Indol-2-One, 2.44 g (0.023 mol) of Na2CO3 and 37.5 ml of 1-ethyl-3-methylimidazolium ethylsulfate were mixed to obtain homogenous suspension. The suspension was heated to about 100 C and maintained at the same temperature until the end of reaction. The reaction mixture was then cooled to room temperature and precipitated with 50 ml of MeOH, mixed for 1 hour and filtrated. Finally, 10 g of product containing 97.6 area % (by HPLC) of Ziprasidone base were obtained. ii. Synthesis of 5- [2- [4- (1, 2- benzisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1, 3-dihydro-2H-indol-2-one (Ziprasidone base) Example 13.i. was repeated with the exception that 50 ml of 2-propanol were used instead of methanol for precipitation. 10.1 g of wet product containing 97.6 area % (by HPLC) of Ziprasidone base was obtained.; iii. Synthesis of 5- [2- [4- (1, 2- benzisothiazol-3-yl) -1-piperazinyll ethyl] -6-chloro-1, 3-dihydro-2H-indol-2-one (Ziprasidone base) Filtrate (mixture of ionic liquid and methanol) as obtained according to Example 13.i. was reused for reaction in such way that methanol was evaporated. Example 13.i. was repeated with the exception that reused 1-ethyl-3-methylimidazolium ethylsulfate was added. Purity of the obtained product was > 90 area % (by HPLC).A process for the preparation of ziprasidone comprising the steps of: (a) mixing 5-(2-chloroethyl)-6-chloro-1, 3-dihydroindole-2(2H)-one with either a free base or salt form of 1, 2-benzisothiazole-3-piperazinyl in the presence of a base and an organic solvent, (b) heating the mixture obtained in step (a) and stirring for a sufficient amount of time to obtain ziprasidone formation, (c) cooling the mixture obtained in step (b) and adding water, and(d) isolating crude ziprasidone.General procedure: Equimolar mixture of General procedure: Equimolar mixture of