反应详情

温度

25 °C

A solution of 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21, 200.4 mg, 0.50 mmol) in methylene chloride (5.0 mL, 0.10 M) at 25° C. was treated with N,N′-diisopropylcarbodiimide (80 μL, 0.51 mmol) and 1-hydroxybenzotriazole (70.3 mg, 0.52 mmol). The solution was stirred at 25° C. for 45 min. After this time, the reaction was added to a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 95.3 mg, 0.61 mmol) in methylene chloride (2.0 mL) at 25° C. The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×50 mL), a saturated aqueous sodium bicarbonate solution (2×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 40 g, 1-4% methanol/methylene chloride) followed by silica gel column chromatography (AnaLogix 40 g, 1-3% methanol/methylene chloride) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide (144.2 mg, 53%) as a white solid; ES+-HRMS m/e calcd for C26H30N5O4F3 [M+H+] 534.2323, found 534.2321. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.07 (m, 1H), 1.27-1.77 (m, 8H), 1.92 (m, 1H), 2.25 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=4.4, J=10.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.53-7.63 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 8.18 (d, J=2.8 Hz, 1H), 10.84 (s, 1H).

1. stirringThe reaction was stirred at 25° C. overnight
2. washwas washed with a 1N aqueous hydrochloric acid solution (2×50 mL)
3. dry with materiala saturated aqueous sodium bicarbonate solution (2×50 mL), water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo