[4-(氯甲基)哌啶-1-基]-苯基甲酮

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 10 ml of N,N-dimethylformamide was dissolved 1.50 g (6.32 mmol) of N-benzoyl-4-chloromethylpiperidine (D). The resulting solution was cooled to 5° C. and thereto was added 1.36 g (25.28 mmol) of sodium methoxide. After stirring at 60° C. for 4 hours, the reaction mixture was cooled down to room temperature and then poured into a mixed liquid of 40 ml of toluene and 40 ml of iced water. An organic layer was separated and dried over 2 g of anhydrous magnesium sulfate and, thereafter, the solvent was removed by distillation. The residual liquid was subjected to silicagel column chromatography (stationary phase: 50 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (2:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.00 g of N-benzoyl-4-methylenepiperidine (E) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 4. the reaction mixture was cooled down to room temperature An organic layer was separated dried over 2 g of anhydrous magnesium sulfate the solvent was removed by distillation The fraction eluted with a hexane/ethyl acetate mixture (2:1 (v/v)) was collected The solvent was removed by distillation from the obtained fraction

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 20 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution was added 2.08 g (10 mmol) of phosphorus pentachloride. The resulting mixture was stirred at room temperature for 1 hour. After the completion of the reaction, thereto was added 20 ml of chloroform and the resulting mixture was poured into 50 ml of iced water to separate an organic layer. The organic layer was washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and dried over 4 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.03 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 50 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.33 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3. After the completion of the reaction to separate an organic layer The organic layer was washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate dried over 4 g of anhydrous magnesium sulfate Then, the solvent was removed by distillation to obtain 3.03 g of an oily matter The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected The solvent was removed by distillation from the obtained fraction

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 10 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution were added 0.81 ml (10 mmol) of pyridine and 1.4 ml (15 mmol) of phosphorus oxychloride. The resulting mixture was stirred at room temperature for 24 hours. After the completion of the reaction, thereto was added 10 ml of chloroform and the resulting mixture was poured into 20 ml of iced water to separate an organic layer. The organic layer was washed with 20 ml of water and dried over 3 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.18 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 40 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.27 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3. After the completion of the reaction to separate an organic layer The organic layer was washed with 20 ml of water dried over 3 g of anhydrous magnesium sulfate Then, the solvent was removed by distillation to obtain 3.18 g of an oily matter The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected The solvent was removed by distillation from the obtained fraction

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 10 ml of chloroform was dissolved 2.19 g (10 mmol) of N-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solution were added 0.81 ml (10 mmol) of pyridine and 1.4 ml (15 mmol) of phosphorus oxychloride. The resulting mixture was stirred at room temperature for 24 hours. After the completion of the reaction, thereto was added 10 ml of chloroform and the resulting mixture was poured into 20 ml of iced water to separate an organic layer. The organic layer was washed with 20 ml of water and dried over 3 g of anhydrous magnesium sulfate. Then, the solvent was removed by distillation to obtain 3.18 g of an oily matter. The oily matter was subjected to silica gel column chromatography (stationary phase: 40 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.27 g of N-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 3. After the completion of the reaction to separate an organic layer The organic layer was washed with 20 ml of water dried over 3 g of anhydrous magnesium sulfate Then, the solvent was removed by distillation to obtain 3.18 g of an oily matter The fraction eluted with a hexane/ethyl acetate mixture (1:1 (v/v)) was collected The solvent was removed by distillation from the obtained fraction

反应条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 1 l of N,N-dimethylformamide was dissolved 248.96 g (about 1 mol) of N-benzoyl-4-chloromethyl-piperidine (D) obtained in Example 3. The resulting solution was cooled to 5° C. and thereto was added 168.32 g (1.5 mol) of potassium tert-butoxide in five portions at 10° to 20° C. over about 1 hour. After the addition, the mixture was stirred at 10° to 20° C. for 40 minutes. Then, the reaction mixture was poured into a mixed liquid of 500 ml of 1N hydrochloric acid and 500 g of fragmentary ice. Subsequently, thereto was added 200 ml of toluene to separate an organic layer. The aqueous layer was extracted with 200 ml of toluene and the organic layers were combined. The combined organic layer was washed with 500 ml of water. The solvent was removed by distillation under reduced pressure to obtain 193.78 g of N-benzoyl-4-methylenepiperidine (E) as a yellowish brown oily matter. The NMR spectrum of the obtained compound was measured. The result is shown below. After the addition to separate an organic layer The aqueous layer was extracted with 200 ml of toluene The combined organic layer was washed with 500 ml of water The solvent was removed by distillation under reduced pressure

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 800 ml of the dichloromethane solution of N-benzoyl-4-hydroxymethylpiperidine (C) obtained in Example 2, which contains about 1 mol of N-benzoyl-4-hydroxymethylpiperidine, there was added dropwise 109 ml (1.5 mol) of thionyl chloride over 2 hours with keeping the reaction temperature at 25° to 30° C. Then the obtained reaction mixture was stirred at room temperature for 1 hour and at 35° C. for 8 hours. After the completion of the reaction, the solvent and the excess of thionyl chloride were removed by distillation to obtain 248.96 g of N-benzoyl-4-chloromethylpiperidine (D) as a yellowish brown oily matter. The NMR spectrum of the obtained compound was measured. The result is shown below. at 25° to 30° C Then the obtained reaction mixture After the completion of the reaction the solvent and the excess of thionyl chloride were removed by distillation

反应条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 800 ml of the dichloromethane solution of N-benzoyl-4-hydroxymethylpiperidine (C) obtained in Example 2, which contains about 1 mol of N-benzoyl-4-hydroxymethylpiperidine, there was added dropwise 109 ml (1.5 mol) of thionyl chloride over 2 hours with keeping the reaction temperature at 25° to 30° C. Then the obtained reaction mixture was stirred at room temperature for 1 hour and at 35° C. for 8 hours. After the completion of the reaction, the solvent and the excess of thionyl chloride were removed by distillation to obtain 248.96 g of N-benzoyl-4-chloromethylpiperidine (D) as a yellowish brown oily matter. The NMR spectrum of the obtained compound was measured. The result is shown below. at 25° to 30° C Then the obtained reaction mixture After the completion of the reaction the solvent and the excess of thionyl chloride were removed by distillation

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 28 ml of 30% sdium methanolate solution and 50 ml of methanol are added 14.1 g (0.15 mole) of phenol. The reaction mixture is evaporated in a vacuum and the residue is taken up in 120 ml of N,N-dimethyl formamide, 35.5 g (0.15 mole) of N-benzoyl-4chloromethylpiperidine are added thereto and the reaction mixture is stirred for 12 hours at 60°-70° C. After cooling, the reaction mixture is mixed with diethyl ether, washed with water and dilute aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and evaporated in a vacuum. The oily residue is triturated with diethyl ether/ligroin. There are obtained 23.0 g of N-benzoyl-4-phenoxymethylpiperidine (52% of theory); m.p. 95°-96° C. The reaction mixture is evaporated in a vacuum After cooling washed with water and dilute aqueous sodium hydroxide solution dried over anhydrous sodium sulfate evaporated in a vacuum The oily residue is triturated with diethyl ether/ligroin

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-Hydroxymethylpyridine is hydrogenated in methanol at 140° C. under 200 atmospheres of hydrogen pressure in the presence of ruthenium oxide, producing 4-hydroxymethylpiperidine, b.p. 126°-130° C./14 mm Hg; m.p. 55°-56° C. Reaction with benzoyl chloride produces N-benzoyl-4-hydroxymethylpiperidine (m.p. 83°-85° C.). A mixture of 135.0 g of N-benzoyl-4-hydroxymethyl-piperidine, 90 ml of thionyl chloride and 900 ml of chloroform is heated under reflux for 4 hours. Thereafter, the reaction mixture is mixed with water, while cooling with ice, and the organic phase is washed neutral with an aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. There are obtained 132.0 g (90% of theory) of N-benzoyl-4-chloromethylpiperidine; m.p. 68°-70° C. is heated under reflux for 4 hours while cooling with ice the organic phase is washed neutral with an aqueous solution of sodium bicarbonate dried over anhydrous sodium sulfate evaporated