4-bromo-2,6-difluorobenzamide

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

実験手順: To a stirred solution of 4-bromo-2,6-difluorobenzamide (9 5 g) in DMF (1 L) at 0° C. was added cyanuric chloride (82 g) slowly, and the reaction mixture was stirred at 0° C. for 4 hours. Water (5 L) was added slowly to the reaction, and it was extracted with EtOAc (2 L). The organic layer was separated, dried over MgSO4, filtered and evaporated under vacuum to afford the crude product, which was purified by chromatography (SiO2, 300-400 mesh, petroleum ether:EtOAc=200:1) to provide 47 g of pure title compound and 17 g of impure title compound. 1H NMR (300 MHz, DMSO-d6): δ 7.90 (m, 2H). was extracted with EtOAc (2 L) The organic layer was separated dried over MgSO4 filtered evaporated under vacuum to afford the crude product, which was purified by chromatography (SiO2, 300-400 mesh, petroleum ether:EtOAc=200:1)

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

実験手順: To a stirred solution of 4-bromo-2,6-difluorobenzamide (9 5 g) in DMF (1 L) at 0° C. was added cyanuric chloride (82 g) slowly, and the reaction mixture was stirred at 0° C. for 4 hours. Water (5 L) was added slowly to the reaction, and it was extracted with EtOAc (2 L). The organic layer was separated, dried over MgSO4, filtered and evaporated under vacuum to afford the crude product, which was purified by chromatography (SiO2, 300-400 mesh, petroleum ether:EtOAc=200:1) to provide 47 g of pure title compound and 17 g of impure title compound. 1H NMR (300 MHz, DMSO-d6): δ 7.90 (m, 2H). was extracted with EtOAc (2 L) The organic layer was separated dried over MgSO4 filtered evaporated under vacuum to afford the crude product, which was purified by chromatography (SiO2, 300-400 mesh, petroleum ether:EtOAc=200:1)

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

実験手順: To a mixture of 4-bromo-2,6-difluorobenzoic acid (110 g) and triethylamine (65 g) in THF (1.5 L) at −50° C. was added ethylchloroformate (60 g) dropwise. After the addition, the reaction mixture was warmed to 0° C. and stirred at this temperature for 1 hour. Ammonia (2 L, 0.5 M in 1,4-dioxane) was added dropwise, and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated, and the resulting residue was partitioned between 1N HCl aqueous solution (2 L) and CH2Cl2 (1 L). The resulting solid was filtered and washed with CH2Cl2 to afford the title compound (60 g). The organic layer of the filtrate was separated, dried over MgSO4, filtered and evaporated under vacuum to afford another portion of the title compound (50 g). 1H NMR (300 MHz, DMSO-d6): δ 7.56 (m, 2H), 7.91 (s, 1H), 8.15 (s, 1H). After the addition the reaction mixture was stirred overnight at room temperature The mixture was concentrated the resulting residue was partitioned between 1N HCl aqueous solution (2 L) and CH2Cl2 (1 L) The resulting solid was filtered washed with CH2Cl2

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

実験手順: To a mixture of 4-bromo-2,6-difluorobenzoic acid (110 g) and triethylamine (65 g) in THF (1.5 L) at −50° C. was added ethylchloroformate (60 g) dropwise. After the addition, the reaction mixture was warmed to 0° C. and stirred at this temperature for 1 hour. Ammonia (2 L, 0.5 M in 1,4-dioxane) was added dropwise, and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated, and the resulting residue was partitioned between 1N HCl aqueous solution (2 L) and CH2Cl2 (1 L). The resulting solid was filtered and washed with CH2Cl2 to afford the title compound (60 g). The organic layer of the filtrate was separated, dried over MgSO4, filtered and evaporated under vacuum to afford another portion of the title compound (50 g). 1H NMR (300 MHz, DMSO-d6): δ 7.56 (m, 2H), 7.91 (s, 1H), 8.15 (s, 1H). After the addition the reaction mixture was stirred overnight at room temperature The mixture was concentrated the resulting residue was partitioned between 1N HCl aqueous solution (2 L) and CH2Cl2 (1 L) The resulting solid was filtered washed with CH2Cl2

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

実験手順: To a mixture of 4-bromo-2,6-difluorobenzoic acid (110 g) and triethylamine (65 g) in THF (1.5 L) at −50° C. was added ethylchloroformate (60 g) dropwise. After the addition, the reaction mixture was warmed to 0° C. and stirred at this temperature for 1 hour. Ammonia (2 L, 0.5 M in 1,4-dioxane) was added dropwise, and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated, and the resulting residue was partitioned between 1N HCl aqueous solution (2 L) and CH2Cl2 (1 L). The resulting solid was filtered and washed with CH2Cl2 to afford the title compound (60 g). The organic layer of the filtrate was separated, dried over MgSO4, filtered and evaporated under vacuum to afford another portion of the title compound (50 g). 1H NMR (300 MHz, DMSO-d6): δ 7.56 (m, 2H), 7.91 (s, 1H), 8.15 (s, 1H). After the addition the reaction mixture was stirred overnight at room temperature The mixture was concentrated the resulting residue was partitioned between 1N HCl aqueous solution (2 L) and CH2Cl2 (1 L) The resulting solid was filtered washed with CH2Cl2

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

実験手順: To a stirred solution of the above benzamide intermediate (9.4 g, 40 mmol) in DMF (15 mL) was added cyanuric chloride (7.24 g, 40 mL) at 0° C. The reaction was stirred at 0° C. for 3 h. Water was added slowly to the reaction and it was extracted with CH2Cl2 (3×100 mL). The solvent was washed with brine and dried over Na2SO4. The solvent was removed to give 4-bromo-2,6-difluorobenzonitrile (7.57 g, 86.9%). was extracted with CH2Cl2 (3×100 mL) The solvent was washed with brine dried over Na2SO4 The solvent was removed

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of the above benzoic acid intermediate (18 g, 76 mmol) in THF (150 mL)), at −20° C., was added triethylamine (7.6 g, 76 mmol) and ethyl chloroformate (9.8 g, 91 mmol. The reaction was stirred at −20° C. for 20 min. Then it was warmed up to room temperature and an ammonia solution (0.5 M in dioxane, 150 mL, 76 mmol) was added. The reaction was stirred at room temperature overnight. It was then concentrated, diluted with dichloromethane, washed with 1 N HCl and brine, and dried over Na2SO4. The solvent was removed to give the crude product as a solid. It was washed with dichloromethane to give 4-bromo-2,6-difluorobenzamide (9.4 g, 52.4%). Then it was warmed up to room temperature The reaction was stirred at room temperature overnight It was then concentrated diluted with dichloromethane washed with 1 N HCl and brine dried over Na2SO4 The solvent was removed to give the crude product as a solid It was washed with dichloromethane

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

実験手順: To a solution of 4-bromo-2,6-difluoro-benzoic acid (2.77 g, 11.7 mmol) and 1-hydroxybenzotriazole (1.74 g, 12.8 mmol) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.46 g, 12.9 mmol) and the solution is stirred at room temperature for 2 hours. After cooling at 0° C. is added aq. NH3 (1.74 mL) and the reaction mixture is stirred for an additional 20 hours. The solvent is evaporated in vacuo and the residue partitioned between diethyl ether and water. The aqueous phase is extracted several times with Et2O, the organic layers are then combined, washed with 1M HCl, sat. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the benzamide as a white solid (2.56 g, 93%). After cooling at 0° C. the reaction mixture is stirred for an additional 20 hours The solvent is evaporated in vacuo the residue partitioned between diethyl ether and water The aqueous phase is extracted several times with Et2O washed with 1M HCl, sat. NaHCO3 dried over MgSO4 filtered concentrated in vacuo

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

実験手順: To a solution of 4-bromo-2,6-difluoro-benzoic acid (2.77 g, 11.7 mmol) and 1-hydroxybenzotriazole (1.74 g, 12.8 mmol) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.46 g, 12.9 mmol) and the solution is stirred at room temperature for 2 hours. After cooling at 0° C. is added aq. NH3 (1.74 mL) and the reaction mixture is stirred for an additional 20 hours. The solvent is evaporated in vacuo and the residue partitioned between diethyl ether and water. The aqueous phase is extracted several times with Et2O, the organic layers are then combined, washed with 1M HCl, sat. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the benzamide as a white solid (2.56 g, 93%). After cooling at 0° C. the reaction mixture is stirred for an additional 20 hours The solvent is evaporated in vacuo the residue partitioned between diethyl ether and water The aqueous phase is extracted several times with Et2O washed with 1M HCl, sat. NaHCO3 dried over MgSO4 filtered concentrated in vacuo

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

実験手順: To a solution of 4-bromo-2,6-difluoro-benzoic acid (2.77 g, 11.7 mmol) and 1-hydroxybenzotriazole (1.74 g, 12.8 mmol) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.46 g, 12.9 mmol) and the solution is stirred at room temperature for 2 hours. After cooling at 0° C. is added aq. NH3 (1.74 mL) and the reaction mixture is stirred for an additional 20 hours. The solvent is evaporated in vacuo and the residue partitioned between diethyl ether and water. The aqueous phase is extracted several times with Et2O, the organic layers are then combined, washed with 1M HCl, sat. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the benzamide as a white solid (2.56 g, 93%). After cooling at 0° C. the reaction mixture is stirred for an additional 20 hours The solvent is evaporated in vacuo the residue partitioned between diethyl ether and water The aqueous phase is extracted several times with Et2O washed with 1M HCl, sat. NaHCO3 dried over MgSO4 filtered concentrated in vacuo