4-amino-2,3-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:

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

実験手順: 4-amino-2,3-difluorophenol (6 g, 41.4 mmol) and potassium tert-butoxide (4.9 g, 43.5 mmol) were suspended in DMAc (200 mL) and stirred at RT for 30 min under Ar atmosphere. 2,4-Dichloropyridine (6.1 g, 41.4 mmol) was added, and the resulting mixture was heated at 70° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography to afford 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (7 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, J=6.0 Hz, 1 H), 7.05 (s, 1 H), 6.95 (m, 1 H), 6.92 (m, 1 H), 6.62 (m, 1 H), 5.60 (s, 2 H); MS (ESI) m/z: 257.1[M+H]+. the resulting mixture was heated at 70° C. for 8 h The reaction mixture was filtered concentrated in vacuo purified by silica gel chromatography

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

実験手順: A solution of 1-benzyloxy-2,3-difluoro-4-nitro-benzene (14 g, 52.8 mmol) in MeOH (200 mL) was stirred with Pd/C (10%, 1.4 of 1.3 mmol) under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford 4-amino-2,3-difluorophenol (7 g, 92.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1 H), 6.45 (t, J=8.8 Hz, 1 H), 6.34 (t, J=9.2 Hz, 1 H), 4.67 (s, 2 H); MS (ESI) m/z: 146.1[M+H]+. The catalyst was removed by filtration the filtrate was concentrated in vacuo

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

実験手順: A solution of 1-benzyloxy-2,3-difluoro-4-nitro-benzene (14 g, 52.8 mmol) in MeOH (200 mL) was stirred with Pd/C (10%, 1.4 of 1.3 mmol) under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford 4-amino-2,3-difluorophenol (7 g, 92.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1 H), 6.45 (t, J=8.8 Hz, 1 H), 6.34 (t, J=9.2 Hz, 1 H), 4.67 (s, 2 H); MS (ESI) m/z: 146.1[M+H]+. The catalyst was removed by filtration the filtrate was concentrated in vacuo

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

実験手順: 61 g (0.26 mol) of 2,3-difluoro-4-(phenyldiazenyl)phenol from Example 3 and 1 g of Pd/C (10%) are initially charged in 800 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 was concentrated on a rotary evaporator, in the course of which the product already crystallized out. The resulting solid was filtered off, washed with a little cold ethanol and dried under high vacuum for 4 hours. 28 g (74%) of the desired compound were obtained as a light brown powder. The solution was degassed On completion of hydrogen uptake, the catalyst was filtered off the filtrate was concentrated on a rotary evaporator, in the course of which the product already crystallized out The resulting solid was filtered off washed with a little cold ethanol dried under high vacuum for 4 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 4-amino-2,3-difluorophenol (208 mg, 1.43 mmol) in DMF (4 mL) was added t-BuOK (257 mg, 2.29 mmol). The reaction was stirred at rt for 30 minutes, then 4-chloropicolinamide (249 mg, 1.59 mmol) was added. The mixture was microwaved at 120° C. for 3 hours, then cooled to rt and diluted with 25 mL of water. The resulted mixture was extracted with EtOAc (30 mL×3), and the combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as an orange solid (110 mg, 41.5%). The mixture was microwaved at 120° C. for 3 hours cooled to rt The resulted mixture was extracted with EtOAc (30 mL×3) the combined organic phases were washed with brine (30 mL×3) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/2)

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)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6% Pd content, 53%˜55% water content). The mixture was stirred at 32° C. for 13 hours under H2 atmosphere. The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH2Cl2 to give the title compound as a dark brown solid (0.89 g, 84%). The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc The filtrate was concentrated in vacuo washed with 30 mL of CH2Cl2

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)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6% Pd content, 53%˜55% water content). The mixture was stirred at 32° C. for 13 hours under H2 atmosphere. The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH2Cl2 to give the title compound as a dark brown solid (0.89 g, 84%). The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc The filtrate was concentrated in vacuo washed with 30 mL of CH2Cl2

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-2,3-difluorophenol (208 mg, 1.43 mmol) in DMF (4 mL) was added t-BuOK (257 mg, 2.29 mmol). The reaction was stirred at rt for 30 minutes, then 4-chloropicolinamide (249 mg, 1.59 mmol) was added. The mixture was microwaved at 120° C. for 3 hours, then cooled to rt and diluted with 25 mL of water. The resulted mixture was extracted with EtOAc (30 mL×3), and the combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as an orange solid (110 mg, 41.5%). The mixture was microwaved at 120° C. for 3 hours cooled to rt The resulted mixture was extracted with EtOAc (30 mL×3) the combined organic phases were washed with brine (30 mL×3) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/2)