2-N-cyclopropyl-4,5-difluorobenzene-1,2-diamine

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

実験手順: Carbonyldiimidazole (4.3 g) was added to the solution of N1-cyclopropyl-4,5-difluorobenzene-1,2-diamine (3.2 g) in THF (30 ml). The mixture was stirred at rt for 20 hours, then diluted with ethyl acetate (200 ml) and washed with hydrochloric acid (1M, 200 ml). Organic layer dried over sodium sulphate, solvent removed to give expected product as a black solid (2.5 g). 1H NMR (CD3OD)δ: 7.20 (dd, 1H), 6.95 (dd, 1H), 2.86 (m, 1H), 1.11 (m, 2H), 0.94 (m, 2H). washed with hydrochloric acid (1M, 200 ml) Organic layer dried over sodium sulphate, solvent removed

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

実験手順: To a solution of the title compound from Step B (0.074 g, 0.40 mmol) in dichloromethane (2.1 mL) were added the title compound from Step C (0.080 g, 0.44 mmol), HATU (0.168 g, 0.442 mmol), HOAt (0.060 g, 0.44 mmol) and diisopropylethylamine (0.285 mL, 1.61 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 330.04 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1 H), 8.90 (d, J=7.2 Hz, 1 H), 8.35 (s, 1 H), 7.66 (br s, 1 H), 7.31 (d, J=10.7 Hz, 1 H), 7.04-7.00 (m, 1 H), 4.31 (br s, 1 H), 2.80 (br s, 1 H), 2.44 (t, J=6.1, 3.1 Hz, 1 H), 1.66 (s, 6 H), 0.78-0.77 (m, 2 H), 0.53-0.51 (m, 2 H). washed sequentially with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure Purification by flash chromatography on silica gel (50-100% ethyl acetate in hexanes)

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

実験手順: To the title compound from Step A (1.22 g, 5.69 mmol) were added 10% palladium on carbon (0.122 g, 1.15 mmol) and methanol (28.5 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was then filtered through CELITE® using dichloromethane, and the filtrate was concentrated. Purification by flash chromatography on silica gel (0-30% ethyl acetate in hexanes) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 6.83 (dd, J=12.4, 7.9 Hz, 1 H), 6.51 (dd, J=11.3, 7.8 Hz, 1 H), 3.82 (br s, 1 H), 3.15 (br s, 2 H), 2.40-2.37 (m, 1 H), 0.77-0.73 (m, 2 H), 0.52-0.50 (m, 2 H). The mixture was then filtered through CELITE® the filtrate was concentrated Purification by flash chromatography on silica gel (0-30% ethyl acetate in hexanes)

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

実験手順: Carbonyldiimidazole (4.3 g) was added to the solution of N1-cyclopropyl-4,5-difluorobenzene-1,2-diamine (3.2 g) in THF (30 ml). The mixture was stirred at rt for 20 hours, then diluted with ethyl acetate (200 ml) and washed with hydrochloric acid (1M, 200 ml). Organic layer dried over sodium sulphate, solvent removed to give expected product as a black solid (2.5 g). 1H NMR (CD3OD)δ: 7.20 (dd, 1H), 6.95 (dd, 1H), 2.86 (m, 1H), 1.11 (m, 2H), 0.94 (m, 2H). washed with hydrochloric acid (1M, 200 ml) Organic layer dried over sodium sulphate, solvent removed

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

実験手順: To a solution of the title compound from Step B (0.074 g, 0.40 mmol) in dichloromethane (2.1 mL) were added the title compound from Step C (0.080 g, 0.44 mmol), HATU (0.168 g, 0.442 mmol), HOAt (0.060 g, 0.44 mmol) and diisopropylethylamine (0.285 mL, 1.61 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with dichloromethane, washed sequentially with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (50-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 330.04 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1 H), 8.90 (d, J=7.2 Hz, 1 H), 8.35 (s, 1 H), 7.66 (br s, 1 H), 7.31 (d, J=10.7 Hz, 1 H), 7.04-7.00 (m, 1 H), 4.31 (br s, 1 H), 2.80 (br s, 1 H), 2.44 (t, J=6.1, 3.1 Hz, 1 H), 1.66 (s, 6 H), 0.78-0.77 (m, 2 H), 0.53-0.51 (m, 2 H). washed sequentially with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure Purification by flash chromatography on silica gel (50-100% ethyl acetate in hexanes)

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

実験手順: To the title compound from Step A (1.22 g, 5.69 mmol) were added 10% palladium on carbon (0.122 g, 1.15 mmol) and methanol (28.5 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was then filtered through CELITE® using dichloromethane, and the filtrate was concentrated. Purification by flash chromatography on silica gel (0-30% ethyl acetate in hexanes) provided the title compound: 1H NMR (500 MHz, CDCl3) δ 6.83 (dd, J=12.4, 7.9 Hz, 1 H), 6.51 (dd, J=11.3, 7.8 Hz, 1 H), 3.82 (br s, 1 H), 3.15 (br s, 2 H), 2.40-2.37 (m, 1 H), 0.77-0.73 (m, 2 H), 0.52-0.50 (m, 2 H). The mixture was then filtered through CELITE® the filtrate was concentrated Purification by flash chromatography on silica gel (0-30% ethyl acetate in hexanes)