4-bromo-2-fluoro-N-methylbenzamide

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:; See reaction.notes.procedure_details.

実験手順: The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and methylamine hydrochloride.

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 4 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purification of the residue by flash column chromatography (0-20% ethyl acetate/heptanes) gave the title compound (520 mg, 97%) as a yellow solid. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.09 (t, J=8.58 Hz, 1H), 8.03 (br. s., 1H), 7.35 (dd, J=8.19, 2.15 Hz, 1H), 7.27 (dd, J=11.41, 1.85 Hz, 1H), 3.36 (dd, J=4.88, 0.78 Hz, 3H). The reaction was cooled to room temperature filtered The filtrate was concentrated purification of the residue by flash column chromatography (0-20% ethyl acetate/heptanes)

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

実験手順: A solution of 4-bromo-2-fluorobenzoic acid (0.8 g, 3.7 mmol), methylamine (3.65 mL, 7.3 mmol), EDC (1.4 g, 7.3 mmol), triethylamine (1.0 mL, 7.3 mmol) dissolved in CH2Cl2(15 mL) was stirred under N2 for 24 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to give the title compound as a white solid (0.27 g, 32%). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layers were washed with saturated NaHCO3, brine dried over dried over Na2SO4 concentrated The residue was purified by silica gel chromatography (40% EtOAc in hexanes)

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

実験手順: A solution of 4-bromo-2-fluorobenzoic acid (0.8 g, 3.7 mmol), methylamine (3.65 mL, 7.3 mmol), EDC (1.4 g, 7.3 mmol), triethylamine (1.0 mL, 7.3 mmol) dissolved in CH2Cl2(15 mL) was stirred under N2 for 24 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to give the title compound as a white solid (0.27 g, 32%). The reaction mixture was partitioned between 1N HCl and EtOAc The organic layers were washed with saturated NaHCO3, brine dried over dried over Na2SO4 concentrated The residue was purified by silica gel chromatography (40% EtOAc in hexanes)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 4 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purification of the residue by flash column chromatography (0-20% ethyl acetate/heptanes) gave the title compound (520 mg, 97%) as a yellow solid. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.09 (t, J=8.58 Hz, 1H), 8.03 (br. s., 1H), 7.35 (dd, J=8.19, 2.15 Hz, 1H), 7.27 (dd, J=11.41, 1.85 Hz, 1H), 3.36 (dd, J=4.88, 0.78 Hz, 3H). The reaction was cooled to room temperature filtered The filtrate was concentrated purification of the residue by flash column chromatography (0-20% ethyl acetate/heptanes)

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

実験手順: Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4-bromo-2-fluoro-N-methylbenzamide (200 mg, 0.54 mmol) as a brown solid. M.P.: 116-120° C. MS (m/z): 440.3 [M+H]+.

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

実験手順: Following the General Procedure-3, the titled compound (80 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4-bromo-2-fluoro-N-methylbenzamide (200 mg, 0.54 mmol) as a brown solid. M.P.: 116-120° C. MS (m/z): 440.3 [M+H]+.

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-fluoro-N-methylbenzamide (0.80 g), vinylboronic acid pinacol cyclic ester (0.80 g) and 2M aqueous sodium carbonate solution (3.45 mL) in DME (17.3 mL) was argon-purged. Bis(triphenylphosphine)palladium(II) dichloride (0.12 g) was added thereto, and the mixture was stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to short silica gel column chromatography, and the solvent was evaporated under reduced pressure to give the title compound (0.74 g). purged Bis(triphenylphosphine)palladium(II) dichloride (0.12 g) was added The reaction solution was diluted with ethyl acetate the mixture was washed with water and saturated brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure the solvent was evaporated under reduced pressure

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-2-fluoro-N-methylbenzamide (0.80 g), vinylboronic acid pinacol cyclic ester (0.80 g) and 2M aqueous sodium carbonate solution (3.45 mL) in DME (17.3 mL) was argon-purged. Bis(triphenylphosphine)palladium(II) dichloride (0.12 g) was added thereto, and the mixture was stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to short silica gel column chromatography, and the solvent was evaporated under reduced pressure to give the title compound (0.74 g). purged Bis(triphenylphosphine)palladium(II) dichloride (0.12 g) was added The reaction solution was diluted with ethyl acetate the mixture was washed with water and saturated brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure the solvent was evaporated under reduced pressure

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Bromo-2-fluoro-N-methylbenzamide (155 mg, 0.66 mmol), isoaminobutyric acid (103 mg, 1.0 mmol), CuI (3 mg, 0.015 mmol), triethylamine (0.1 mL, catalytic amount) and K2CO3 (353 mg, 2.5 mmol) were dissolved in DMF (4 mL) and water (1 mL) stirred at RT for 5 min. 2-Acetylcyclohexanone (100 mg, 0.7 mmol) was added and the mixture heated at 100° C. for 18 h. The reaction mixture was acidified with 1 M citric acid (to pH 4) and extracted with ethyl acetate (50 mL, 2 times). The organic layer was dried over Na2SO4 and concentrated to obtain 200 mg of 2-(4-(methylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid. extracted with ethyl acetate (50 mL, 2 times) The organic layer was dried over Na2SO4 concentrated