1-(2-bromoethyl)pyrrolidine-2,5-dione

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 11.5 g of 5,6-dichloro-1-ethyl-2-methylbenzoimidazole and 20.6 g of N-(2-bromoethyl)succinimide were put into a 200-ml three-necked flask equipped with a stirrer and a reflux condenser and heated for 2 hours on an oil bath which has been heated to a temperature of 130° C. 10 ml of anisole was added to the mixture. The admixture was then allowed to stand for cooling. 50 ml of ethyl acetate was added to the admixture. The admixture was then refluxed for 30 minutes. After being allowed to cool to room temperature, the resulting crystal was filtered off, washed with acetone, and then dried at a temperature of 50° C. for 5 hours. Yield: 18.7 g (86%). equipped with a stirrer and a reflux condenser heated for 2 hours on an oil bath which for cooling The admixture was then refluxed for 30 minutes to cool to room temperature the resulting crystal was filtered off washed with acetone dried at a temperature of 50° C. for 5 hours

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 11.5 g of 5,6-dichloro-1-ethyl-2-methylbenzoimidazole and 20.6 g of N-(2-bromoethyl)succinimide were put into a 200-ml three-necked flask equipped with a stirrer and a reflux condenser and heated for 2 hours on an oil bath which has been heated to a temperature of 130° C. 10 ml of anisole was added to the mixture. The admixture was then allowed to stand for cooling. 50 ml of ethyl acetate was added to the admixture. The admixture was then refluxed for 30 minutes. After being allowed to cool to room temperature, the resulting crystal was filtered off, washed with acetone, and then dried at a temperature of 50° C. for 5 hours. Yield: 18.7 g (86%). equipped with a stirrer and a reflux condenser heated for 2 hours on an oil bath which for cooling The admixture was then refluxed for 30 minutes to cool to room temperature the resulting crystal was filtered off washed with acetone dried at a temperature of 50° C. for 5 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 9.9 g of succinimide and 50 ml of N,N-dimethylformamide were put into a 200-ml three-necked flask equipped with a stirrer and a thermometer. 14 g of potassium carbonate was added to the mixture. The admixture was then stirred at room temperature for 30 minutes. 39.6 g of 1,2-dibromoethane was added to the admixture. The admixture was allowed to react at a temperature of 40° to 50° C. for 2 hours. The reaction mixture was poured into water. The aqueous mixture was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized with hexane. The resulting crystal was filtered off and then air-dried. Yield: 16.7 g (81%); m.p. 55° to 56° C. equipped with a stirrer to react at a temperature of 40° to 50° C. for 2 hours The aqueous mixture was then extracted with ethyl acetate The ethyl acetate layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was crystallized with hexane The resulting crystal was filtered off air-dried

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 49.5 g of succinamide was dissolved in 750 ml of 2-butanone under heating. 187.9 g of dibromoethane and 138 g of anhydrous potassium carbonate were added to the solution and the mixture was heated under reflux for 9.5 h. under heating the mixture was heated under reflux for 9.5 h.

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzene-sulfonamide (41.4 mg, 0.1 mmol) in dry DMF (2 ml) was added 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione (30.9 mg, 0.15 mmol) and NaH (60%, 6.00 mg, 0.15 mmol). The mixture was stirred for 8 hours at 90° C. After cooled to room temperature, the solvent was evaporated. The mixture was diluted with EtOAc (60 ml), washed with brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by preparative TLC (CH2Cl2/CH3OH=20/1) to give 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-N-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl]-benzenesulfonamide (44 mg, 81.6%) and the free base was converted into HCl salt by 4N HCl in dioxane. After cooled to room temperature the solvent was evaporated The mixture was diluted with EtOAc (60 ml) washed with brine dried over MgSO4 The solvent was evaporated the residue was purified by preparative TLC (CH2Cl2/CH3OH=20/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of dihydro-furan-2,5-dione (396 mg, 4.00 mmol) and 1,2-dibromo-ethane (1.50 g, 8.00 mmol) in CH3CN (20 ml) was added K2CO3 (829 mg, 6.00 mmol) at room temperature. The mixture was stirred at reflux overnight and the solvent was evaporated. The mixture was diluted with EtOAc (150 mL), washed with water, sat. Na2CO3aq., brine, and dried over MgSO4. The solvent was evaporated to give 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione that was used for next step without further purification (580 mg, 70.4%). at reflux overnight the solvent was evaporated The mixture was diluted with EtOAc (150 mL) washed with water, sat. Na2CO3aq , brine, and dried over MgSO4 The solvent was evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of dihydro-furan-2,5-dione (396 mg, 4.00 mmol) and 1,2-dibromo-ethane (1.50 g, 8.00 mmol) in CH3CN (20 ml) was added K2CO3 (829 mg, 6.00 mmol) at room temperature. The mixture was stirred at reflux overnight and the solvent was evaporated. The mixture was diluted with EtOAc (150 mL), washed with water, sat. Na2CO3aq., brine, and dried over MgSO4. The solvent was evaporated to give 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione that was used for next step without further purification (580 mg, 70.4%). at reflux overnight the solvent was evaporated The mixture was diluted with EtOAc (150 mL) washed with water, sat. Na2CO3aq , brine, and dried over MgSO4 The solvent was evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 49.5 g of succinamide was dissolved in 750 ml of 2-butanone under heating. 187.9 g of dibromoethane and 138 g of anhydrous potassium carbonate were added to the solution and the mixture was heated under reflux for 9.5 h. under heating the mixture was heated under reflux for 9.5 h.

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 11.5 g of 5,6-dichloro-1-ethyl-2-methylbenzoimidazole and 20.6 g of N-(2-bromoethyl)succinimide were put into a 200-ml three-necked flask equipped with a stirrer and a reflux condenser and heated for 2 hours on an oil bath which has been heated to a temperature of 130° C. 10 ml of anisole was added to the mixture. The admixture was then allowed to stand for cooling. 50 ml of ethyl acetate was added to the admixture. The admixture was then refluxed for 30 minutes. After being allowed to cool to room temperature, the resulting crystal was filtered off, washed with acetone, and then dried at a temperature of 50° C. for 5 hours. Yield: 18.7 g (86%). equipped with a stirrer and a reflux condenser heated for 2 hours on an oil bath which for cooling The admixture was then refluxed for 30 minutes to cool to room temperature the resulting crystal was filtered off washed with acetone dried at a temperature of 50° C. for 5 hours

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 9.9 g of succinimide and 50 ml of N,N-dimethylformamide were put into a 200-ml three-necked flask equipped with a stirrer and a thermometer. 14 g of potassium carbonate was added to the mixture. The admixture was then stirred at room temperature for 30 minutes. 39.6 g of 1,2-dibromoethane was added to the admixture. The admixture was allowed to react at a temperature of 40° to 50° C. for 2 hours. The reaction mixture was poured into water. The aqueous mixture was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized with hexane. The resulting crystal was filtered off and then air-dried. Yield: 16.7 g (81%); m.p. 55° to 56° C. equipped with a stirrer to react at a temperature of 40° to 50° C. for 2 hours The aqueous mixture was then extracted with ethyl acetate The ethyl acetate layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was crystallized with hexane The resulting crystal was filtered off air-dried