2,4-Difluoro-benzoic acid tert-butyl ester

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At −78° C., 17.62 ml of 1.59 M n-butyl lithium-THF solution was added dropwise to 100 ml of THF solution containing 4.73 ml of tetramethylpiperidine. This was stirred at −10° C. for 10 minutes, cooled to −78° C., mixed with 5.00 g of tert-butyl 2,4-difluorobenzoate dissolved in 20 ml of THF and then stirred for 1 hour. Subsequently, 7.23 ml of DMF was added dropwise thereto, and the mixture was stirred for 1 hour, mixed with 5.34 ml of acetic acid and then risen to room temperature. This was mixed with an appropriate amount of purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 5.65 g (100%) of tert-butyl 2,4-difluoro-3-formylbenzoate (Reference Example 4-1) from a hexane-ethyl acetate (20:1-10:1) eluate. cooled to −78° C. stirred for 1 hour the mixture was stirred for 1 hour risen to room temperature extracted with ethyl acetate dried with anhydrous magnesium sulfate After concentration the thus formed residue was purified by a silica gel column chromatography

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At −78° C., 17.62 ml of 1.59 M n-butyl lithium-THF solution was added dropwise to 100 ml of THF solution containing 4.73 ml of tetramethylpiperidine. This was stirred at −10° C. for 10 minutes, cooled to −78° C., mixed with 5.00 g of tert-butyl 2,4-difluorobenzoate dissolved in 20 ml of THF and then stirred for 1 hour. Subsequently, 7.23 ml of DMF was added dropwise thereto, and the mixture was stirred for 1 hour, mixed with 5.34 ml of acetic acid and then risen to room temperature. This was mixed with an appropriate amount of purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 5.65 g (100%) of tert-butyl 2,4-difluoro-3-formylbenzoate (Reference Example 4-1) from a hexane-ethyl acetate (20:1-10:1) eluate. cooled to −78° C. stirred for 1 hour the mixture was stirred for 1 hour risen to room temperature extracted with ethyl acetate dried with anhydrous magnesium sulfate After concentration the thus formed residue was purified by a silica gel column chromatography

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A satured solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3 times). The organic phase was washed twice with water then with brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1). The title compound (33.38 g, 84%) was obtained as oil. the mixture was extracted with dichloromethane (3 times) The organic phase was washed twice with water with brine, dried over sodium sulfate filtered evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1)

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×). The organic phase was washed with water (2×), brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane-EtOAc 9:1). The title compound (33.38 g, 84%) was obtained as oil. the mixture was extracted with dichloromethane (3×) The organic phase was washed with water (2×), brine dried over sodium sulfate filtered evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane-EtOAc 9:1)

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×). The organic phase was washed with water (2×), brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane-EtOAc 9:1). The title compound (33.38 g, 84%) was obtained as oil. the mixture was extracted with dichloromethane (3×) The organic phase was washed with water (2×), brine dried over sodium sulfate filtered evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane-EtOAc 9:1)

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3 times). The organic phase was washed twice with water then with brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1). The title compound (33.38 g, 84%) was obtained as oil. the mixture was extracted with dichloromethane (3 times) The organic phase was washed twice with water with brine, dried over sodium sulfate filtered evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1)

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At −78° C., 17.62 ml of 1.59 M n-butyl lithium-THF solution was added dropwise to 100 ml of THF solution containing 4.73 ml of tetramethylpiperidine. This was stirred at −10° C. for 10 minutes, cooled to −78° C., mixed with 5.00 g of tert-butyl 2,4-difluorobenzoate dissolved in 20 ml of THF and then stirred for 1 hour. Subsequently, 7.23 ml of DMF was added dropwise thereto, and the mixture was stirred for 1 hour, mixed with 5.34 ml of acetic acid and then risen to room temperature. This was mixed with an appropriate amount of purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 5.65 g (100%) of tert-butyl 2,4-difluoro-3-formylbenzoate (Reference Example 4-1) from a hexane-ethyl acetate (20:1-10:1) eluate. cooled to −78° C. stirred for 1 hour the mixture was stirred for 1 hour risen to room temperature extracted with ethyl acetate dried with anhydrous magnesium sulfate After concentration the thus formed residue was purified by a silica gel column chromatography

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: At −78° C., 17.62 ml of 1.59 M n-butyl lithium-THF solution was added dropwise to 100 ml of THF solution containing 4.73 ml of tetramethylpiperidine. This was stirred at −10° C. for 10 minutes, cooled to −78° C., mixed with 5.00 g of tert-butyl 2,4-difluorobenzoate dissolved in 20 ml of THF and then stirred for 1 hour. Subsequently, 7.23 ml of DMF was added dropwise thereto, and the mixture was stirred for 1 hour, mixed with 5.34 ml of acetic acid and then risen to room temperature. This was mixed with an appropriate amount of purified water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. After concentration, the thus formed residue was purified by a silica gel column chromatography to obtain 5.65 g (100%) of tert-butyl 2,4-difluoro-3-formylbenzoate (Reference Example 4-1) from a hexane-ethyl acetate (20:1-10:1) eluate. cooled to −78° C. stirred for 1 hour the mixture was stirred for 1 hour risen to room temperature extracted with ethyl acetate dried with anhydrous magnesium sulfate After concentration the thus formed residue was purified by a silica gel column chromatography

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2,4-difluoro-benzoic acid tert-butyl ester (30 g, 140.05 mmol) and (S)-2-methoxy-1-methyl-ethylamine (100 mL) was stirred at 65° C. for 2 days. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3 times). The organic phase was washed twice with water then with brine, dried over sodium sulfate filtered and evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1). The title compound (33.38 g, 84%) was obtained as oil. the mixture was extracted with dichloromethane (3 times) The organic phase was washed twice with water with brine, dried over sodium sulfate filtered evaporated to dryness to obtain a crude, which was purified by column chromatography on silica gel (exane/ethyl acetate 9:1)