4-amino-2,5-difluorophenol

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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Amino-2,5-difluorophenol (4.95 g) was dissolved in dimethyl sulfoxide (50 ml) under a nitrogen stream, and potassium tert-butoxide (4.05 g) was added at room temperature, and the mixture was stirred for 25 minutes. 4-Chloropyridine-2-carboxamide (2.70 g) was added to the mixture, which was stirred at 80° C. for 2.5 hours. The reaction mixture was allowed to cool down to room temperature, and a 1N aqueous solution of sodium hydroxide (74.25 ml) was added, and the mixture was stirred for 10 hours. The precipitated solid was collected by filtration, and the resultant solid was washed with water. The solid was dried by hot air at 100° C. for 24 hours to give the title compound (3.38 g, 74%) as purple powder. was added at room temperature was stirred at 80° C. for 2.5 hours the mixture was stirred for 10 hours The precipitated solid was collected by filtration the resultant solid was washed with water The solid was dried by hot air at 100° C. for 24 hours

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

実験手順: After dissolving 4-amino-2,5-difluorophenol (4.95 g) in dimethyl sulfoxide (50 ml) under a nitrogen stream, potassium tert-butoxide (4.05 g) was added at room temperature and the mixture was stirred for 25 minutes. After adding 4-chloropyridine-2-carboxyamide (2.70 g) to the mixture, stirring was continued at 80° C. for 2.5 hours. After cooling the reaction mixture to room temperature, a 1N aqueous solution of sodium hydroxide (74.25 ml) was added and stirring was continued for 10 hours. The precipitated solid was collected by filtration and washed with water. The solid was dried with warm air at 100° C. for 24 hours to give the title compound (3.38 g, 74%) as purple powder. was added at room temperature stirring was continued at 80° C. for 2.5 hours stirring was continued for 10 hours The precipitated solid was collected by filtration washed with water The solid was dried with warm air at 100° C. for 24 hours

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

実験手順: To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) was added 10% palladium on carbon (921 mg), and the mixture was stirred at room temperature for 24 hours and 20 minutes under a hydrogen atmosphere. After terminating the reaction by substituting the atmosphere in the flask with nitrogen, the catalyst was filtered using Celite. The filtrate was distilled off under reduced pressure to give the title compound (4.96 g, 99%) as a brown solid. After terminating the reaction the catalyst was filtered The filtrate was distilled off under reduced pressure

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: To a solution of 4-amino-2,5-difluorophenol (0.190 g, 1.310 mmol) in DMF (10 mL) was added potassium tert-butoxide (0.168 g, 1.497 mmol). The mixture was stirred at RT for 30 min. 4-Chloro-5-iodopyrimidine (0.30 g, 1.248 mmol) was added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was quenched with water and the solution was extracted with EtOAc (3×). The organic solution was washed with 5% aqueous lithium chloride solution and brine. The organics were dried over MgSO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (10% to 50% EtOAc/hexane) to obtain 2,5-difluoro-4-(5-iodopyrimidin-4-yloxy)benzenamine (160 mg, 36.7% yield) which was used for the next reaction. MS (ESI) m/z: 349.9 (M+H+). the reaction mixture was heated at 80° C. overnight The reaction mixture was quenched with water the solution was extracted with EtOAc (3×) The organic solution was washed with 5% aqueous lithium chloride solution and brine The organics were dried over MgSO4 filtered concentrated The crude was purified by silica gel column chromatography (10% to 50% EtOAc/hexane)

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

実験手順: 42 g (0.18 mol) of 2,5-difluoro-4-(phenyidiazenyl)phenol from Example 5 and 1 g of Pd/C (10%) were initially charged in 650 ml of ethanol. The solution was degassed and aerated with hydrogen. The mixture was stirred at room temperature under a 1 bar hydrogen atmosphere for 18 hours. On completion of hydrogen uptake, the catalyst was filtered off and the filtrate distilled under reduced pressure, and dried under high vacuum at 70° C. for 4 hours. The residue (24 g) was recrystallized from ethanol and dried. 15 g (60%) of 4-amino-2,5-difluorophenol are obtained as orange-brown powder. The solution was degassed On completion of hydrogen uptake, the catalyst was filtered off the filtrate distilled under reduced pressure dried under high vacuum at 70° C. for 4 hours The residue (24 g) was recrystallized from ethanol dried

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

実験手順: To a mixture of 4-amino-2,5-difluorophenol (100 mg, 0.64 mmol), and 4-chloropicolinamide (110 mg, 0.71 mmol) in DMF (2 mL) was added NaH (80 mg, 1.3 mmol, 60% dispersed in mineral oil). The reaction mixture was microwaved at 120° C. for 1.5 hours, then cooled to rt, diluted with water (20 mL), and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (80 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography with (EtOAc/PE (v/v)=4/1) to afford the title compound as a brown solid (52 mg, 26%). The reaction mixture was microwaved at 120° C. for 1.5 hours extracted with EtOAc (30 mL×3) The combined organic phases were washed with brine (80 mL) dried over Na2SO4 concentrated in vacuo The residue was purified by flash column chromatography with (EtOAc/PE (v/v)=4/1)

反応条件: temp:32.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (50% Pd content, 185 mg). The reaction was stirred at 32° C. under H2 atmosphere for 10 hours. The mixture was filtered through a CELITE® pad and the filtrate was concentrated in vacuo. The residue was washed with DCM (15 mL) to give the title compound as a dark brown solid (500 mg, 86%). The mixture was filtered through a CELITE® pad the filtrate was concentrated in vacuo The residue was washed with DCM (15 mL)

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

実験手順: To a mixture of 4-amino-2,5-difluorophenol (100 mg, 0.64 mmol), and 4-chloropicolinamide (110 mg, 0.71 mmol) in DMF (2 mL) was added NaH (80 mg, 1.3 mmol, 60% dispersed in mineral oil). The reaction mixture was microwaved at 120° C. for 1.5 hours, then cooled to rt, diluted with water (20 mL), and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (80 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography with (EtOAc/PE (v/v)=4/1) to afford the title compound as a brown solid (52 mg, 26%). The reaction mixture was microwaved at 120° C. for 1.5 hours extracted with EtOAc (30 mL×3) The combined organic phases were washed with brine (80 mL) dried over Na2SO4 concentrated in vacuo The residue was purified by flash column chromatography with (EtOAc/PE (v/v)=4/1)