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10percent palladium on carbon (921 mg) was added to a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzen (9.21 g) in methanol (300 ml), followed by stirring at room temperature under hydrogen atmosphere for 24 hours and 20 minutes. The air of the flask was replaced with nitrogen to stop the reaction, and the catalyst was removed by filtration using celite. The filtrate was distilled off under reduced pressure to give the title compound (4.96 g, 99percent) as a pale brown solid.1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03 (1H, s).
99%
With hydrogen In methanol at 20℃; for 24.33 h;
(Reference Example C-2) 4-Amino-2,5-difluorophenol To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) was added 10 percent palladium on carbon (921 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr and 20 min. The atmosphere in the reaction vessel was replaced with nitrogen to stop the reaction, and the catalyst was filtered through Celite. The filtrate was removed under reduced pressure to provide the titled compound as a brown solid (4.96 g, 99 percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03 (1H, s).
99%
With hydrogen In methanol at 20℃; for 24.3333 h;
(Production Example 95) 4-Amino-2,5-difluorophenol To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) was added 10 percent palladium on carbon (921 mg), followed by stirring under a hydrogen atmosphere at room temperature for 24 hr and 20 min. The atmosphere in the reaction vessel was replaced with nitrogen to stop the reaction, and the catalyst was filtered through Celite. The filtrate was removed under reduced pressure to provide the titled compound as a brown solid (4.96 g, 99 percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03 (1H, s).
86%
With palladium 10% on activated carbon In tetrahydrofuran; methanol at 32℃; for 10 h;
To a suspension of l-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (185 mg, 17percent). The reaction was stirred at 32 °C under atmosphere for 10 hours, and then filtered through a CELITE? pad. The organic phase was washed with MeOH (10 mL) and concentrated in vacuo. The residue was stirred in DCM (15 mL), filtered and washed with DCM (20 mL) to give the title compound as a dark brown solid (500 mg, 86percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; IH NMR (400 MHz, DMSO-i): δ 4.68 (s, 2H), 6.53-6.65 (m, 2H), 9.06 (br s, IH).
86%
With 50% palladium on charcoal; hydrogen In tetrahydrofuran; methanol at 32℃; for 10 h;
Step 2) 4-amino-2,5-difluorophenol [0181] To a suspension of l-(benzyloxy)-2,5-difluoro-4-nitrobenzene (1.06 g, 4 mmol) in CH3OH (25 mL) and THF (5 mL) was added Pd/C (50 percent Pd content, 185 mg). The reaction was stirred at 32 °C under 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 percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; NMR (400 MHz, DMSO-i): δ (ppm) 4.68 (s, 2H), 6.53-6.65 (m, 2H), 9.06 (br, 1H).
86%
With 50% palladium on charcoal; hydrogen In tetrahydrofuran; methanol at 32℃; for 10 h;
Step 2) 4-amino-2,5-difluorophenol 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 (50percent 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, 86percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 4.68 (s, 2H), 6.53-6.65 (m, 2H), 9.06 (br, 1H).
To a solution of 4-amino-2,5-difluorophenol (0.190 g, 1.310 mmol) in DMF ( 10 mL) was added potassium ter/-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 (3x). The organic solution was washed with 5% aqueous lithium chloride solution and brine. The organics were dried over gS04, 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+).
2,5-difluoro-4-((7-methoxyquinolin-4-yl)oxy)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 150℃; for 2h;Microwave irradiation;
To a mixture of 4-amino-2,5-difluorophenol (100 mg, 0.51 mmol) and 4- chloro-7-methoxyquinoline (114 mg, 0.72 mmol) in DMSO (2 mL) was added NaH (62 mg, 1.02 mmol, 60percent in mineral oil). The reaction was heated at 150 °C for 2 hours in microwave, then cooled to rt, quenched with water (20 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (80 mL), dried over Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as an orange solid (45 mg, 40percent). MS (ESI, pos. ion) m/z: 303.1 [M+H]+.
With N-nitromethylpyrrolidone; potassium tert-butylate; at 140℃; for 1h;Inert atmosphere;
4-Chloro-7-methoxyquinoline-6-carboxamide (200 mg, 845.12 mumol), 4 amino-2,5-difluorophenol(184.13 mg, 1.01 mmol) and potassium t-butoxide (113.80 mg, 1.01 mmol) were added to a microwave tube containing nitromethylpyrrolidone (5 mL), then heated to 140 ° C under a nitrogen sparge and stirred. Reaction for 1 hour.The reaction solution was added to 30 ml of water to precipitate a solid. The product was obtained without purification and used directly in the next step.
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