ethyl 2,2-difluoro-2-phenylacetate

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

実験手順: A stirred mixture of 2.2 g of difluoro-2-phenyl acetic acid ethyl ester (W. J. Middleton, E. M. Bingham, J. Org. Chem., 45, 2883-2887 (1980)), and 0.6 g of sodium borohydride in 75 mL of ethanol was kept at room temperature overnight, concentrated to near dryness under reduced pressure carefully acidified with 20 mL of 5% HCl and extracted into 3×50 mL of dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave 1.7 g of product as an oil: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 4.0 (t, 2H). concentrated extracted into 3×50 mL of dichloromethane The combined extracts were dried over magnesium sulfate concentrated under reduced pressure Drying under vacuum

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

実験手順: A stirred mixture of 2.2 g of difluoro-2-phenyl acetic acid ethyl ester (W. J. Middleton, E. M. Bingham, J. Org. Chem., 45, 2883-2887 (1980)), and 0.6 g of sodium borohydride in 75 mL of ethanol was kept at room temperature overnight, concentrated to near dryness under reduced pressure carefully acidified with 20 mL of 5% HCl and extracted into 3×50 mL of dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave 1.7 g of product as an oil: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 4.0 (t, 2H). concentrated extracted into 3×50 mL of dichloromethane The combined extracts were dried over magnesium sulfate concentrated under reduced pressure Drying under vacuum

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

実験手順: A suspension of ethyl 2,2-difluoro-2-phenylacetate (6.0 g, 30 mmol), as prepared in the preceding step, in 1 N NaOH (36 mL, 36 mmol) was stirred at ambient temperature. After 36 hours, the reaction became almost homogeneous. The mixture was acidified with 1N HCl (36 mL), and extracted with DCM twice. The extracts were combined, washed with H2O, dried over Na2SO4, and concentrated to give the title compound (3.85 g, 81% yield) as a pale yellow solid, that was used without further purification. extracted with DCM twice washed with H2O dried over Na2SO4 concentrated

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

実験手順: A stirred mixture of 2.2 g of difluoro-2-phenyl acetic acid ethyl ester (W. J. Middleton, E. M. Bingham, J. Org. Chem., 45, 2883-2887 (1980)), and 0.6 g of sodium borohydride in 75 mL of ethanol was kept at room temperature overnight, concentrated to near dryness under reduced pressure carefully acidified with 20 mL of 5% HCl and extracted into 3×50 mL of dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum gave 1.7 g of product as an oil: 1H NMR (400 MHz, CDCl3) 7.5 (m, 5H), 4.0 (t, 2H). concentrated extracted into 3×50 mL of dichloromethane The combined extracts were dried over magnesium sulfate concentrated under reduced pressure Drying under vacuum

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

実験手順: A solution of the above difluoro-phenyl-acetic acid ethyl ester and NH3 in MeOH (7 M, 10 mL) is heated to 60° C. for 2 h in a pressure tube. The mixture is cooled to room temperature, and concentrated to afford 2,2-difluoro-2-phenyl-acetamide (0.33 g). LCMS: RT=1.7 minutes; MS: 172 (M+H). concentrated

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

実験手順: A solution of the above difluoro-phenyl-acetic acid ethyl ester and NH3 in MeOH (7 M, 10 mL) is heated to 60° C. for 2 h in a pressure tube. The mixture is cooled to room temperature, and concentrated to afford 2,2-difluoro-2-phenyl-acetamide (0.33 g). LCMS: RT=1.7 minutes; MS: 172 (M+H). concentrated

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

実験手順: A suspension of ethyl 2,2-difluoro-2-phenylacetate (6.0 g, 30 mmol), as prepared in the preceding step, in 1 N NaOH (36 mL, 36 mmol) was stirred at ambient temperature. After 36 hours, the reaction became almost homogeneous. The mixture was acidified with 1N HCl (36 mL), and extracted with DCM twice. The extracts were combined, washed with H2O, dried over Na2SO4, and concentrated to give the title compound (3.85 g, 81% yield) as a pale yellow solid, that was used without further purification. extracted with DCM twice washed with H2O dried over Na2SO4 concentrated

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

実験手順: A solution of the above difluoro-phenyl-acetic acid ethyl ester and NH3 in MeOH (7 M, 10 mL) is heated to 60° C. for 2 h in a pressure tube. The mixture is cooled to room temperature, and concentrated to afford 2,2-difluoro-2-phenyl-acetamide (0.33 g). LCMS: RT=1.7 minutes; MS: 172 (M+H). concentrated

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

実験手順: Obtained from Intermediate 5 (13.2 g, 66 mmol) by the procedure described in Intermediate 2. The title compound was obtained (6.88 g, 66%) as oil.

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

実験手順: To a solution of difluoro-phenyl-acetic acid ethyl ester (5.0 g, 25.0 mmol) in ethanol (150 mL) was added sodium borohydride (1.37 g, 36 mmol) at rt. The mixture was stirred for 2.5 h at room temperature. HCl aqueous (1N) was added and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the product 2,2-difluoro-2-phenyl-ethanol (3.4 g, 86.1%), which was used to the next step without further purification. the resulting mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated

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

実験手順: To a solution of difluoro-phenyl-acetic acid ethyl ester (5.0 g, 25.0 mmol) in ethanol (150 mL) was added sodium borohydride (1.37 g, 36 mmol) at rt. The mixture was stirred for 2.5 h at room temperature. HCl aqueous (1N) was added and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the product 2,2-difluoro-2-phenyl-ethanol (3.4 g, 86.1%), which was used to the next step without further purification. the resulting mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate concentrated

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

実験手順: A solution of the title compound of Step (A) (6.00 g; 30 mmol) in 50 ml of EtOH was saturated with anhydrous NH3. An exothermic reaction was observed. After stirring the reaction mixture 60 hr at room temperature, the volatiles were removed in vacuo and the solid residue was taken up in a minimal amount of hot ethyl acetate. A small amount of insoluble material was filtered off and hexane was added to the filtrate until slightly turbid. After cooling to room temperature and standing several hr, the crystals were filtered and dried to afford 4.68 g (91%) of the title compound of this step as a colorless crystalline solid. An exothermic reaction the volatiles were removed in vacuo A small amount of insoluble material was filtered off hexane was added to the filtrate until slightly turbid After cooling to room temperature standing several hr the crystals were filtered dried