1-benzyl-3,3-difluoropyrrolidine-2,5-dione

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

実験手順: To a solution of 1-benzyl-3,3-difluoropyrrolidine-2,5-dione (325 mg, 1.44 mmol) in acetonitrile (3.6 mL), LiF (56 mg, 1.50 eq) and a stir bar were added. The reaction mixture was sonicated for 2.5 hr at rt. N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.4 mL, 1.59 mmol, 1.10 eq) and LiF (37 mg, 1.44 mmol, 1 eq) were added and continued to sonicate for 0.5 hr. The reaction mixture was concentrated and the salt was removed by filtration. The crude residue was purified by column chromatography and eluted with 2 to 20% EtOAc/heptane and purified further with 2 to 10% EtOAc/heptane. The desired fractions were faintly ultraviolet active but were visualized with KMNO4 stain. The title compound was isolated as a yellow oil (196 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.43 (m, 10 H) 4.57-4.75 (m, 2 H) 3.63 (s, 2 H) 3.56-3.65 (m, 1 H) 3.33-3.41 (m, 1 H) 3.13 (d, J=9.29 Hz, 1 H) 2.74 (dd, J=9.35, 7.03 Hz, 1 H) 2.57-2.70 (m, 1 H). m/z (APCI+) for C20H20FN2O2 339.20 (M+H)+. The reaction mixture was sonicated for 2.5 hr at rt to sonicate for 0.5 hr The reaction mixture was concentrated the salt was removed by filtration The crude residue was purified by column chromatography eluted with 2 to 20% EtOAc/heptane purified further with 2 to 10% EtOAc/heptane

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

実験手順: To a solution of 1-benzyl-3,3-difluoropyrrolidine-2,5-dione (325 mg, 1.44 mmol) in acetonitrile (3.6 mL), LiF (56 mg, 1.50 eq) and a stir bar were added. The reaction mixture was sonicated for 2.5 hr at rt. N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.4 mL, 1.59 mmol, 1.10 eq) and LiF (37 mg, 1.44 mmol, 1 eq) were added and continued to sonicate for 0.5 hr. The reaction mixture was concentrated and the salt was removed by filtration. The crude residue was purified by column chromatography and eluted with 2 to 20% EtOAc/heptane and purified further with 2 to 10% EtOAc/heptane. The desired fractions were faintly ultraviolet active but were visualized with KMNO4 stain. The title compound was isolated as a yellow oil (196 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.43 (m, 10 H) 4.57-4.75 (m, 2 H) 3.63 (s, 2 H) 3.56-3.65 (m, 1 H) 3.33-3.41 (m, 1 H) 3.13 (d, J=9.29 Hz, 1 H) 2.74 (dd, J=9.35, 7.03 Hz, 1 H) 2.57-2.70 (m, 1 H). m/z (APCI+) for C20H20FN2O2 339.20 (M+H)+. The reaction mixture was sonicated for 2.5 hr at rt to sonicate for 0.5 hr The reaction mixture was concentrated the salt was removed by filtration The crude residue was purified by column chromatography eluted with 2 to 20% EtOAc/heptane purified further with 2 to 10% EtOAc/heptane

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of the crude 4-(benzylamino)-3,3-difluoro-4-oxobutanoic acid in iPrOAc (40 mL), SOCl2 (2.04 mL, 27.9 mmol, 2 eq) was added at ambient temperature. The reaction solution was stirred at 55° C. for 4 hr. The reaction was cooled to 0-5° C. Half saturated brine (50 mL) was added slowly to quench the excess SOCl2. The organic phase was washed with brine (70 mL) and 2 M Na2CO3 (about 50 mL) to pH=8-9, extracted two times with EtOAc. The combined organic layer was washed with brine (50 mL), the organic phase was dried over MgSO4, filtered and concentrated. The crude residue was diluted with CH2Cl2 and filtered to remove precipitate. The concentrated filtrate was purified by column chromatography and eluted with 2-20% EtOAc/Heptane to obtain the title compound as a clear oil (1.74 g, 65%)1H NMR (400 MHz, CDCl3) δ ppm 7.30-7.43 (m, 5 H) 4.76 (s, 2 H) 3.18 (t, J=12.53 Hz, 2 H). The reaction was cooled to 0-5° C to quench the excess SOCl2 The organic phase was washed with brine (70 mL) and 2 M Na2CO3 (about 50 mL) to pH=8-9 extracted two times with EtOAc The combined organic layer was washed with brine (50 mL) the organic phase was dried over MgSO4 filtered concentrated The crude residue was diluted with CH2Cl2 filtered to remove precipitate The concentrated filtrate was purified by column chromatography eluted with 2-20% EtOAc/Heptane

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

実験手順: To a solution of 1-benzyl-3,3-difluoropyrrolidine-2,5-dione (325 mg, 1.44 mmol) in acetonitrile (3.6 mL), LiF (56 mg, 1.50 eq) and a stir bar were added. The reaction mixture was sonicated for 2.5 hr at rt. N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.4 mL, 1.59 mmol, 1.10 eq) and LiF (37 mg, 1.44 mmol, 1 eq) were added and continued to sonicate for 0.5 hr. The reaction mixture was concentrated and the salt was removed by filtration. The crude residue was purified by column chromatography and eluted with 2 to 20% EtOAc/heptane and purified further with 2 to 10% EtOAc/heptane. The desired fractions were faintly ultraviolet active but were visualized with KMNO4 stain. The title compound was isolated as a yellow oil (196 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.10-7.43 (m, 10 H) 4.57-4.75 (m, 2 H) 3.63 (s, 2 H) 3.56-3.65 (m, 1 H) 3.33-3.41 (m, 1 H) 3.13 (d, J=9.29 Hz, 1 H) 2.74 (dd, J=9.35, 7.03 Hz, 1 H) 2.57-2.70 (m, 1 H). m/z (APCI+) for C20H20FN2O2 339.20 (M+H)+. The reaction mixture was sonicated for 2.5 hr at rt to sonicate for 0.5 hr The reaction mixture was concentrated the salt was removed by filtration The crude residue was purified by column chromatography eluted with 2 to 20% EtOAc/heptane purified further with 2 to 10% EtOAc/heptane

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of the crude 4-(benzylamino)-3,3-difluoro-4-oxobutanoic acid in iPrOAc (40 mL), SOCl2 (2.04 mL, 27.9 mmol, 2 eq) was added at ambient temperature. The reaction solution was stirred at 55° C. for 4 hr. The reaction was cooled to 0-5° C. Half saturated brine (50 mL) was added slowly to quench the excess SOCl2. The organic phase was washed with brine (70 mL) and 2 M Na2CO3 (about 50 mL) to pH=8-9, extracted two times with EtOAc. The combined organic layer was washed with brine (50 mL), the organic phase was dried over MgSO4, filtered and concentrated. The crude residue was diluted with CH2Cl2 and filtered to remove precipitate. The concentrated filtrate was purified by column chromatography and eluted with 2-20% EtOAc/Heptane to obtain the title compound as a clear oil (1.74 g, 65%)1H NMR (400 MHz, CDCl3) δ ppm 7.30-7.43 (m, 5 H) 4.76 (s, 2 H) 3.18 (t, J=12.53 Hz, 2 H). The reaction was cooled to 0-5° C to quench the excess SOCl2 The organic phase was washed with brine (70 mL) and 2 M Na2CO3 (about 50 mL) to pH=8-9 extracted two times with EtOAc The combined organic layer was washed with brine (50 mL) the organic phase was dried over MgSO4 filtered concentrated The crude residue was diluted with CH2Cl2 filtered to remove precipitate The concentrated filtrate was purified by column chromatography eluted with 2-20% EtOAc/Heptane