ethyl 5,5,5-trifluoro-4-oxopentanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a one-necked round-bottomed flask equipped with a distillation head and cooler, a mixture of 2-(2,2,2-trifluoro-acetyl)-succinic acid diethyl ester (54.6 g, 202 mmol) and boronic acid (12.5 g, 202 mmol) is heated to 170° C. Heating is continued for 4 h, during which time ethanol is gradually distilled off as it is formed. After cooling to room temperature, the reaction mixture is poured onto ice and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4 and concentrated at reduced pressure to afford a brown oil. The crude product is purified by distillation (60° C., 10 mbar) to afford the title compound as a colorless liquid (17.3 g, 87.3 mmol, 43%). 1H NMR (400 MHz, CDCl3, 298 K): δ=4.15 (q, J=7.1 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). MS (ES+): 199 (M(C7H9F3O3)+H)+. In a one-necked round-bottomed flask equipped with a distillation head and cooler Heating is gradually distilled off as it is formed After cooling to room temperature the reaction mixture is poured onto ice extracted twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 concentrated at reduced pressure to afford a brown oil The crude product is purified by distillation (60° C., 10 mbar)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+. heated at reflux for 18 h under an argon atmosphere After cooling to room temperature the reaction mixture is concentrated by rotary evaporation The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc The layers are separated the aqueous phase is extracted with twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 filtered concentrated at reduced pressure to afford a brown oil Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1)

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

実験手順: 45 g of the product of Step A, 10.3 g of boric acid and 1 g of p-toluenesulfonic acid were heated at 180° C. for 3 hours and the mixture was poured into ice and extracted with ethyl acetate. The mixture was decanted, dried and concentrated under reduced pressure and the residue was distilled to obtain 10.8 g of expected product. the mixture was poured into ice extracted with ethyl acetate The mixture was decanted dried concentrated under reduced pressure the residue was distilled

反応条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a one-necked round-bottomed flask equipped with a distillation head and cooler, a mixture of 2-(2,2,2-trifluoro-acetyl)-succinic acid diethyl ester (54.6 g, 202 mmol) and boronic acid (12.5 g, 202 mmol) is heated to 170° C. Heating is continued for 4 h, during which time ethanol is gradually distilled off as it is formed. After cooling to room temperature, the reaction mixture is poured onto ice and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4 and concentrated at reduced pressure to afford a brown oil. The crude product is purified by distillation (60° C., 10 mbar) to afford the title compound as a colorless liquid (17.3 g, 87.3 mmol, 43%). 1H NMR (400 MHz, CDCl3, 298 K): δ=4.15 (q, J=7.1 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). MS (ES+): 199 (M(C7H9F3O3)+H)+. In a one-necked round-bottomed flask equipped with a distillation head and cooler Heating is gradually distilled off as it is formed After cooling to room temperature the reaction mixture is poured onto ice extracted twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 concentrated at reduced pressure to afford a brown oil The crude product is purified by distillation (60° C., 10 mbar)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+. heated at reflux for 18 h under an argon atmosphere After cooling to room temperature the reaction mixture is concentrated by rotary evaporation The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc The layers are separated the aqueous phase is extracted with twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 filtered concentrated at reduced pressure to afford a brown oil Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+. heated at reflux for 18 h under an argon atmosphere After cooling to room temperature the reaction mixture is concentrated by rotary evaporation The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc The layers are separated the aqueous phase is extracted with twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 filtered concentrated at reduced pressure to afford a brown oil Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1)

反応条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a one-necked round-bottomed flask equipped with a distillation head and cooler, a mixture of 2-(2,2,2-trifluoro-acetyl)-succinic acid diethyl ester (54.6 g, 202 mmol) and boronic acid (12.5 g, 202 mmol) is heated to 170° C. Heating is continued for4 h, during which time ethanol is gradually distilled off as it is formed. After cooling to room temperature, the reaction mixture is poured onto ice and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4 and concentrated at reduced pressure to afford a brown oil. The crude product is purified by distillation (60° C., 10 mbar) to afford the title compound as a colorless liquid (17.3 g, 87.3 mmol, 43%). 1H NMR (400 MHz, CDCl3, 298 K): δ=4.15 (q, J=7.1 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). MS (ES+): 199 (M(C7H9F3O3)+H)+. In a one-necked round-bottomed flask equipped with a distillation head and cooler Heating is gradually distilled off as it is formed After cooling to room temperature the reaction mixture is poured onto ice extracted twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 concentrated at reduced pressure to afford a brown oil The crude product is purified by distillation (60° C., 10 mbar)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+. heated at reflux for 18 h under an argon atmosphere After cooling to room temperature the reaction mixture is concentrated by rotary evaporation The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc The layers are separated the aqueous phase is extracted with twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 filtered concentrated at reduced pressure to afford a brown oil Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1)

反応条件: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a one-necked round-bottomed flask equipped with a distillation head and cooler, a mixture of 2-(2,2,2-trifluoro-acetyl)-succinic acid diethyl ester (54.6 g, 202 mmol) and boronic acid (12.5 g, 202 mmol) is heated to 170° C. Heating is continued for4 h, during which time ethanol is gradually distilled off as it is formed. After cooling to room temperature, the reaction mixture is poured onto ice and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4 and concentrated at reduced pressure to afford a brown oil. The crude product is purified by distillation (60° C., 10 mbar) to afford the title compound as a colorless liquid (17.3 g, 87.3 mmol, 43%). 1H NMR (400 MHz, CDCl3, 298 K): δ=4.15 (q, J=7.1 Hz, 2H), 3.02 (t, J=6.4 Hz, 2H), 2.70 (t, J=6.4 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). MS (ES+): 199 (M(C7H9F3O3)+H)+. In a one-necked round-bottomed flask equipped with a distillation head and cooler Heating is gradually distilled off as it is formed After cooling to room temperature the reaction mixture is poured onto ice extracted twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 concentrated at reduced pressure to afford a brown oil The crude product is purified by distillation (60° C., 10 mbar)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5,5,5-trifluoro-4-oxo-pentanoic acid ethyl ester (6.00 g, 30.3 mmol) and p-tolylhydrazine hydrochloride (4.80 g, 30.3 mmol) in ethanol (25 mL) is cooled to 0° C. The solution is saturated with HCl gas and heated at reflux for 18 h under an argon atmosphere. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc. The layers are separated and the aqueous phase is extracted with twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown oil. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1) affords the title compound as orange crystals (5.14 g, 18.0 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.17 (bs, 1H), 7.63 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 4.06 (s, 2H), 2.57 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). MS (ES+): 286 (M(C14H14F3NO2)+H)+. heated at reflux for 18 h under an argon atmosphere After cooling to room temperature the reaction mixture is concentrated by rotary evaporation The residue is partitioned between a saturated aqueous NaHCO3 solution and EtOAc The layers are separated the aqueous phase is extracted with twice with EtOAc The combined organic layers are washed with brine dried over Na2SO4 filtered concentrated at reduced pressure to afford a brown oil Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 10:0 to 9:1)

反応条件: temp:0.00; pressure:0.00; stir: