2,6-二氟苯肼盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride (12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added 2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed by triethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for 10 min and then heated to reflux for 1.5 h. The contents were cooled to RT and solvents removed under reduced pressure. The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAc layer was separated, washed with 50 mL of brine, dried and concentrated. The concentrated solid was stirred in 50 mL of hexanes for 5 min, filtered through a flitted funnel, and dried in a vacuum oven at 45° C. for 2 h to afford 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brown solid. This material was used without further purification. MS (ES+): 221.1 (M+H)+. (B): A mixture of 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64 mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reaction mixture was concentrated to half of its volume, cooled with an ice bath, pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL of EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as a brown amorphous solid. This material was used without further purification. MS (ES+): 196.1 (M+H)+. heated to reflux for 1.5 h The contents were cooled to RT solvents removed under reduced pressure The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc The EtOAc layer was separated washed with 50 mL of brine dried concentrated The concentrated solid was stirred in 50 mL of hexanes for 5 min filtered through a flitted funnel dried in a vacuum oven at 45° C. for 2 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride (12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added 2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed by triethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for 10 min and then heated to reflux for 1.5 h. The contents were cooled to RT and solvents removed under reduced pressure. The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAc layer was separated, washed with 50 mL of brine, dried and concentrated. The concentrated solid was stirred in 50 mL of hexanes for 5 min, filtered through a flitted funnel, and dried in a vacuum oven at 45° C. for 2 h to afford 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brown solid. This material was used without further purification. MS (ES+): 221.1 (M+H)+. (B): A mixture of 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64 mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reaction mixture was concentrated to half of its volume, cooled with an ice bath, pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL of EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as a brown amorphous solid. This material was used without further purification. MS (ES+): 196.1 (M+H)+. heated to reflux for 1.5 h The contents were cooled to RT solvents removed under reduced pressure The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc The EtOAc layer was separated washed with 50 mL of brine dried concentrated The concentrated solid was stirred in 50 mL of hexanes for 5 min filtered through a flitted funnel dried in a vacuum oven at 45° C. for 2 h

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-iodo-2-methoxynicotinic acid (1.00 g) obtained in Step C of Example 6 in DMA (10 mL) were added (2,6-difluorophenyl)hydrazine hydrochloride (647 mg), EDCI hydrochloride (824 mg) and HOBt (581 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (1.32 g). the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-iodo-2-methoxynicotinic acid (1.00 g) obtained in Step C of Example 6 in DMA (10 mL) were added (2,6-difluorophenyl)hydrazine hydrochloride (647 mg), EDCI hydrochloride (824 mg) and HOBt (581 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give the title compound (1.32 g). the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride (12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added 2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed by triethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for 10 min and then heated to reflux for 1.5 h. The contents were cooled to RT and solvents removed under reduced pressure. The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAc layer was separated, washed with 50 mL of brine, dried and concentrated. The concentrated solid was stirred in 50 mL of hexanes for 5 min, filtered through a flitted funnel, and dried in a vacuum oven at 45° C. for 2 h to afford 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brown solid. This material was used without further purification. MS (ES+): 221.1 (M+H)+. (B): A mixture of 5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64 mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reaction mixture was concentrated to half of its volume, cooled with an ice bath, pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL of EtOAc. The combined organic layers were washed with brine, dried and concentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as a brown amorphous solid. This material was used without further purification. MS (ES+): 196.1 (M+H)+. heated to reflux for 1.5 h The contents were cooled to RT solvents removed under reduced pressure The resulting brown solid was stirred with 50 mL of water and 250 mL of EtOAc The EtOAc layer was separated washed with 50 mL of brine dried concentrated The concentrated solid was stirred in 50 mL of hexanes for 5 min filtered through a flitted funnel dried in a vacuum oven at 45° C. for 2 h