1-(2,4,5-trifluorophenyl)ethanone

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

実験手順: 40.8 g (0 3 mol) of sulphuryl chloride were added dropwise at room temperature (22° C.) to 48 g (0.275 mol) of 2,4,5-trifluoroacetophenone (obtained according to Example 110)dissolved in 400 ml of dichloromethane and the mixture was stirred until evolution of hydrogen chloride had ended (about 2 hours). The reaction mixture was then added to 600 ml of water, the organic phase was separated off, this was washed until neutral with sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvent was stripped off in a water pump vacuum. 48.6 g of 2,4,5-trifluorophenacyl chloride were obtained as an oily residue, which corresponds to 84.5% of theory. The characterization of the product carried out as in Examples 113 to 119 yielded a & value of 5.29 ppm. obtained (about 2 hours) the organic phase was separated off this was washed until neutral with sodium hydrogen carbonate solution dried over magnesium sulphate

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

実験手順: 194.5 g (1 mol) of 2,4,5-trifluorobenzoyl chloride were initially introduced into 100 ml of diethyl ether and heated to boiling under reflux. 1.1 mol of ethoxymagnesium malonic ester dissolved in 100 ml of ethanol and 125 ml of diethyl ether were then allowed to drop in in the course of 30 minutes and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was stirred into 500 ml of ice water and adjusted to a pH of 1 with concentrated sulphuric acid, and the organic material (345 g) was separated off. This organic material was dissolved in 300 ml of acetic acid and, after adding 37.5 ml of concentrated sulphuric acid, heated to reflux until evolution of CO2 had ended, which took 6 hours. The reaction mixture was then cooled and poured into water, and the organic phase was separated off and distilled. 83 g of product having a boiling point at 10 mbar of 63° to 64° C. were obtained. This corresponds to a yield of 47% of theory. heated under reflux to drop in in the course of 30 minutes under reflux After cooling the organic material (345 g) was separated off This organic material was dissolved in 300 ml of acetic acid after adding 37.5 ml of concentrated sulphuric acid heated to reflux until evolution of CO2 which took 6 hours The reaction mixture was then cooled poured into water the organic phase was separated off distilled at 10 mbar of 63° to 64° C. were obtained

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

実験手順: 194.5 g (1 mol) of 2,4,5-trifluorobenzoyl chloride were initially introduced into 100 ml of diethyl ether and heated to boiling under reflux. 1.1 mol of ethoxymagnesium malonic ester dissolved in 100 ml of ethanol and 125 ml of diethyl ether were then allowed to drop in in the course of 30 minutes and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was stirred into 500 ml of ice water and adjusted to a pH of 1 with concentrated sulphuric acid, and the organic material (345 g) was separated off. This organic material was dissolved in 300 ml of acetic acid and, after adding 37.5 ml of concentrated sulphuric acid, heated to reflux until evolution of CO2 had ended, which took 6 hours. The reaction mixture was then cooled and poured into water, and the organic phase was separated off and distilled. 83 g of product having a boiling point at 10 mbar of 63° to 64° C. were obtained. This corresponds to a yield of 47% of theory. heated under reflux to drop in in the course of 30 minutes under reflux After cooling the organic material (345 g) was separated off This organic material was dissolved in 300 ml of acetic acid after adding 37.5 ml of concentrated sulphuric acid heated to reflux until evolution of CO2 which took 6 hours The reaction mixture was then cooled poured into water the organic phase was separated off distilled at 10 mbar of 63° to 64° C. were obtained

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

実験手順: 40.8 g (0.3 mole) of sulphuryl chloride were added dropwise at room temperature (22° C.) to 48 g (0.275 mole) of 2,4,5-trifluoroacetophenone (obtained according to Example 6), dissolved in 400 ml of dichloromethane, and the mixture was stirred until the end of the evolution of hydrogen chloride (about 2 hours). 600 ml of water were then added to the reaction mixture, the organic phase was separated off, and this was washed until neutral with sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvent was stripped off in a water pump vacuum. 48.6 g of 2,4,5- trifluoro-phenacyl chloride were obtained as an oily residue, which corresponds to 84.5 % of theory. The characterization of the product carried out as in Examples 9 to 15 gave a δ value of 5.29 ppm. the organic phase was separated off this was washed until neutral with sodium hydrogen carbonate solution dried over magnesium sulphate

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

実験手順: Compound 2d (0.22 g, 0.78 mmol), 1-(2,4,5-trifluoro-phenyl)-ethanone (0.22 mL), DIEA (0.22 mL, 1.33 mmol), and DMSO (2 mL) were combined and heated at 130° C. for 20 h. The mixture was cooled to room temperature and purified by flash chromatography (eluent: 10 to 40% EtOAc+0.1% triethylamine in hexane) to afford 211 mg (62% yield) of 4-[1-(4-acetyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 50a: LC-MS 438.0 (MH+). The mixture was cooled to room temperature purified by flash chromatography (eluent: 10 to 40% EtOAc+0.1% triethylamine in hexane)

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 L 3-neck round bottom flask was charged with 1-(2,4,5-trifluorophenyl)ethanone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at about 23° C. Ice water was added to the reaction flask and the layers were stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method b) Rt=2.20 min; MS m/z 251.0/253.0 (M+H)+. The flask was equipped with a 250 mL This solution was added to the reaction flask over about 1 h at about 23° C Once addition of the solution the layers were stirred for about 15 min The layers were separated the organic solution was then washed with water and brine dried over MgSO4 filtered the solvent was removed under reduced pressure

反応条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 L 3-neck round bottom flask was charged with 1-(2,4,5-trifluorophenyl)ethanone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at about 23° C. Ice water was added to the reaction flask and the layers were stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method b) Rt=2.20 min; MS m/z 251.0 (M+H)+. The flask was equipped with a 250 mL This solution was added to the reaction flask over about 1 h at about 23° C Once addition of the solution the layers were stirred for about 15 min The layers were separated the organic solution was then washed with water and brine dried over MgSO4 filtered the solvent was removed under reduced pressure

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

実験手順: 40.8 g (0 3 mol) of sulphuryl chloride were added dropwise at room temperature (22° C.) to 48 g (0.275 mol) of 2,4,5-trifluoroacetophenone (obtained according to Example 110)dissolved in 400 ml of dichloromethane and the mixture was stirred until evolution of hydrogen chloride had ended (about 2 hours). The reaction mixture was then added to 600 ml of water, the organic phase was separated off, this was washed until neutral with sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvent was stripped off in a water pump vacuum. 48.6 g of 2,4,5-trifluorophenacyl chloride were obtained as an oily residue, which corresponds to 84.5% of theory. The characterization of the product carried out as in Examples 113 to 119 yielded a & value of 5.29 ppm. obtained (about 2 hours) the organic phase was separated off this was washed until neutral with sodium hydrogen carbonate solution dried over magnesium sulphate

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

実験手順: 194.5 g (1 mol) of 2,4,5-trifluorobenzoyl chloride were initially introduced into 100 ml of diethyl ether and heated to boiling under reflux. 1.1 mol of ethoxymagnesium malonic ester dissolved in 100 ml of ethanol and 125 ml of diethyl ether were then allowed to drop in in the course of 30 minutes and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was stirred into 500 ml of ice water and adjusted to a pH of 1 with concentrated sulphuric acid, and the organic material (345 g) was separated off. This organic material was dissolved in 300 ml of acetic acid and, after adding 37.5 ml of concentrated sulphuric acid, heated to reflux until evolution of CO2 had ended, which took 6 hours. The reaction mixture was then cooled and poured into water, and the organic phase was separated off and distilled. 83 g of product having a boiling point at 10 mbar of 63° to 64° C. were obtained. This corresponds to a yield of 47% of theory. heated under reflux to drop in in the course of 30 minutes under reflux After cooling the organic material (345 g) was separated off This organic material was dissolved in 300 ml of acetic acid after adding 37.5 ml of concentrated sulphuric acid heated to reflux until evolution of CO2 which took 6 hours The reaction mixture was then cooled poured into water the organic phase was separated off distilled at 10 mbar of 63° to 64° C. were obtained

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

実験手順: 40.8 g (0.3 mole) of sulphuryl chloride were added dropwise at room temperature (22° C.) to 48 g (0.275 mole) of 2,4,5-trifluoroacetophenone (obtained according to Example 6), dissolved in 400 ml of dichloromethane, and the mixture was stirred until the end of the evolution of hydrogen chloride (about 2 hours). 600 ml of water were then added to the reaction mixture, the organic phase was separated off, and this was washed until neutral with sodium hydrogen carbonate solution and dried over magnesium sulphate, and the solvent was stripped off in a water pump vacuum. 48.6 g of 2,4,5- trifluoro-phenacyl chloride were obtained as an oily residue, which corresponds to 84.5 % of theory. The characterization of the product carried out as in Examples 9 to 15 gave a δ value of 5.29 ppm. the organic phase was separated off this was washed until neutral with sodium hydrogen carbonate solution dried over magnesium sulphate