2-(2,2-difluoropropylamino)ethanol

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

実験手順: 4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (581.0 g, 1.48 mol) was dissolved in 10 liters of methylene chloride to give a pale yellow, slightly opaque solution. The solution was filtered through Celite® to give a clear green colored solution. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (296.8 g, 1.64 mol) was added in one portion as a solid at room temperature to give an opaque suspension (addition is slightly endothermic). 4-Methylmorpholine (182.9 g, 1.80 mol) was added over 15 minutes while keeping the temperature between 18–22° C. (reaction returned to being yellow in color). Reaction stirred for 3 hours at room temperature, then 2-(2,2-difluoropropylamino)-ethanol (228.3 g, 1.64 mol) was added neat over 10 minutes while keeping the temperature between 20–25° C. The reaction was stirred for 15 hours, then washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine. The crude product solution was concentrated in vacuo to a thick orange oil, then reconstituted in 4 liters of isopropyl ether. After removing 1 liter of distillates precipitate began to form. To the crude product suspension was added 1.5 liters of isopropyl ether and then the mixture was stirred at room temperature for 1 hour. The precipitated solids were collected by filtration and the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether, followed by air-drying for 16 hours. Acetic acid 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(2,2-difluoro-propyl)-(2-hydroxyethyl)-carbamoyl]-1H-pyrazol-4-yl ester I-6e (603.0 g, 78%) was isolated as a granular off-white solid. to give a pale yellow, slightly opaque solution The solution was filtered through Celite® to give a clear green colored solution to give an opaque suspension ( addition between 18–22° C. (reaction returned to being yellow in color) Reaction between 20–25° C The reaction was stirred for 15 hours washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine The crude product solution was concentrated in vacuo to a thick orange oil After removing 1 liter of distillates precipitate to form the mixture was stirred at room temperature for 1 hour The precipitated solids were collected by filtration the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether by air-drying for 16 hours

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

実験手順: 4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (581.0 g, 1.48 mol) was dissolved in 10 liters of methylene chloride to give a pale yellow, slightly opaque solution. The solution was filtered through Celite® to give a clear green colored solution. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (296.8 g, 1.64 mol) was added in one portion as a solid at room temperature to give an opaque suspension (addition is slightly endothermic). 4-Methylmorpholine (182.9 g, 1.80 mol) was added over 15 minutes while keeping the temperature between 18–22° C. (reaction returned to being yellow in color). Reaction stirred for 3 hours at room temperature, then 2-(2,2-difluoropropylamino)-ethanol (228.3 g, 1.64 mol) was added neat over 10 minutes while keeping the temperature between 20–25° C. The reaction was stirred for 15 hours, then washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine. The crude product solution was concentrated in vacuo to a thick orange oil, then reconstituted in 4 liters of isopropyl ether. After removing 1 liter of distillates precipitate began to form. To the crude product suspension was added 1.5 liters of isopropyl ether and then the mixture was stirred at room temperature for 1 hour. The precipitated solids were collected by filtration and the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether, followed by air-drying for 16 hours. Acetic acid 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(2,2-difluoro-propyl)-(2-hydroxyethyl)-carbamoyl]-1H-pyrazol-4-yl ester I-6e (603.0 g, 78%) was isolated as a granular off-white solid. to give a pale yellow, slightly opaque solution The solution was filtered through Celite® to give a clear green colored solution to give an opaque suspension ( addition between 18–22° C. (reaction returned to being yellow in color) Reaction between 20–25° C The reaction was stirred for 15 hours washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine The crude product solution was concentrated in vacuo to a thick orange oil After removing 1 liter of distillates precipitate to form the mixture was stirred at room temperature for 1 hour The precipitated solids were collected by filtration the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether by air-drying for 16 hours

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-3c (15 g, 40 mmol) and 2-(2,2-difluoro-propylamino)-ethanol (16.5 g, 120 mmol) were heated at 125° C. for 18 hours. The reaction solution was cooled, diluted into ethyl acetate, washed with 1 N aq. HCl, brine, dried (Na2SO4) and concentrated in vacuo. The resulting oil was chromatographed on silica gel (20% to 40% ethyl acetate/hexanes) to afford the title compound (I-3d) as an oil, 10 g. The reaction solution was cooled washed with 1 N aq. HCl, brine dried (Na2SO4) concentrated in vacuo The resulting oil was chromatographed on silica gel (20% to 40% ethyl acetate/hexanes)

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-3c (15 g, 40 mmol) and 2-(2,2-difluoro-propylamino)-ethanol (16.5 g, 120 mmol) were heated at 125° C. for 18 hours. The reaction solution was cooled, diluted into ethyl acetate, washed with 1 N aq. HCl, brine, dried (Na2SO4) and concentrated in vacuo. The resulting oil was chromatographed on silica gel (20% to 40% ethyl acetate/hexanes) to afford the title compound (I-3d) as an oil, 10 g. The reaction solution was cooled washed with 1 N aq. HCl, brine dried (Na2SO4) concentrated in vacuo The resulting oil was chromatographed on silica gel (20% to 40% ethyl acetate/hexanes)

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

実験手順: To a stirred solution of lithium aluminum hydride (5.5 g, 146 mmol) in diethyl ether (85 ml) was added a solution of 2,2-difluoro-N-(2-hydroxy-ethyl)-propionamide (11.2 g, 73 mmol) in diethyl ether (55 ml) dropwise at such a rate to maintain a gentle reflux. After an additional 1.5 hours, the reaction was quenched with sodium sulfate decahydrate, diluted with ethyl acetate and allowed to stir for 18 hours. The mixture was filtered with the aid of diatomaceous earth, washing with ethyl acetate. The filtrate was concentrated in vacuo and fractionally distilled (11 torr, collecting fractions distilling at 75–88° C.) to afford the title compound (I-3c) as a colorless oil, 4.5 g. to maintain a gentle reflux the reaction was quenched with sodium sulfate decahydrate diluted with ethyl acetate The mixture was filtered with the aid of diatomaceous earth washing with ethyl acetate The filtrate was concentrated in vacuo fractionally distilled (11 torr, collecting fractions distilling at 75–88° C.)

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

実験手順: 4-Acetoxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6d (581.0 g, 1.48 mol) was dissolved in 10 liters of methylene chloride to give a pale yellow, slightly opaque solution. The solution was filtered through Celite® to give a clear green colored solution. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (296.8 g, 1.64 mol) was added in one portion as a solid at room temperature to give an opaque suspension (addition is slightly endothermic). 4-Methylmorpholine (182.9 g, 1.80 mol) was added over 15 minutes while keeping the temperature between 18–22° C. (reaction returned to being yellow in color). Reaction stirred for 3 hours at room temperature, then 2-(2,2-difluoropropylamino)-ethanol (228.3 g, 1.64 mol) was added neat over 10 minutes while keeping the temperature between 20–25° C. The reaction was stirred for 15 hours, then washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine. The crude product solution was concentrated in vacuo to a thick orange oil, then reconstituted in 4 liters of isopropyl ether. After removing 1 liter of distillates precipitate began to form. To the crude product suspension was added 1.5 liters of isopropyl ether and then the mixture was stirred at room temperature for 1 hour. The precipitated solids were collected by filtration and the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether, followed by air-drying for 16 hours. Acetic acid 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-[(2,2-difluoro-propyl)-(2-hydroxyethyl)-carbamoyl]-1H-pyrazol-4-yl ester I-6e (603.0 g, 78%) was isolated as a granular off-white solid. to give a pale yellow, slightly opaque solution The solution was filtered through Celite® to give a clear green colored solution to give an opaque suspension ( addition between 18–22° C. (reaction returned to being yellow in color) Reaction between 20–25° C The reaction was stirred for 15 hours washed twice with 6 liter portions of 10% citric acid and once with 5 liters of brine The crude product solution was concentrated in vacuo to a thick orange oil After removing 1 liter of distillates precipitate to form the mixture was stirred at room temperature for 1 hour The precipitated solids were collected by filtration the resulting filtercake was rinsed with 2 liters of room temperature isopropyl ether by air-drying for 16 hours

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester I-3c (15 g, 40 mmol) and 2-(2,2-difluoro-propylamino)-ethanol (16.5 g, 120 mmol) were heated at 125° C. for 18 hours. The reaction solution was cooled, diluted into ethyl acetate, washed with 1 N aq. HCl, brine, dried (Na2SO4) and concentrated in vacuo. The resulting oil was chromatographed on silica gel (20% to 40% ethyl acetate/hexanes) to afford the title compound (I-3d) as an oil, 10 g. The reaction solution was cooled washed with 1 N aq. HCl, brine dried (Na2SO4) concentrated in vacuo The resulting oil was chromatographed on silica gel (20% to 40% ethyl acetate/hexanes)

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

実験手順: To a stirred solution of lithium aluminum hydride (5.5 g, 146 mmol) in diethyl ether (85 ml) was added a solution of 2,2-difluoro-N-(2-hydroxy-ethyl)-propionamide (11.2 g, 73 mmol) in diethyl ether (55 ml) dropwise at such a rate to maintain a gentle reflux. After an additional 1.5 hours, the reaction was quenched with sodium sulfate decahydrate, diluted with ethyl acetate and allowed to stir for 18 hours. The mixture was filtered with the aid of diatomaceous earth, washing with ethyl acetate. The filtrate was concentrated in vacuo and fractionally distilled (11 torr, collecting fractions distilling at 75–88° C.) to afford the title compound (I-3c) as a colorless oil, 4.5 g. to maintain a gentle reflux the reaction was quenched with sodium sulfate decahydrate diluted with ethyl acetate The mixture was filtered with the aid of diatomaceous earth washing with ethyl acetate The filtrate was concentrated in vacuo fractionally distilled (11 torr, collecting fractions distilling at 75–88° C.)