反应详情

温度

25 °C

In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid (575 mg, 1.52 mmol) in dichloromethane (25 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (296 μL, 1.67 mmol) and 1-hydoxybenzotriazole (216 mg, 1.59 mmol) and stirred at 25° C. for 2 h. After this time, 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in US20080021032, Example 80, 283 mg, 1.83 mmol) was added and the mixture stirred for 16 h at 25° C. After this time, the mixture was diluted with dichloromethane (10 mL) and washed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL) dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5,5-trifluoro-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (460 mg, 59%) as a yellow foam: HR-ES-MS m/z calculated for C23H26N4O4ClF3 [M+H]+ 515.1668, observed 515.1664; 1H NMR (300 MHz, CDCl3) δ ppm 1.15 (s, 3H), 1.16 (s, 3H), 1.20 (d, J=6.6 Hz, 3H), 1.89-2.19 (m, 2H), 2.30 (m, 1H), 3.94 (s, 2H), 4.28 (m, 1H), 4.31 (m, 1H), 4.90, 4.91 (2×s, 1H), 5.00 (dd, J=4.8, 10.9 Hz, 1H), 6.68 (br. s., 1H), 7.20-7.37 (m, 4H), 7.49 (d, J=7.9 Hz, 1H), 8.65, 8.89 (2×br. s., 1H).

1. customIn a round bottom flask under argon was placed
2. stirringthe mixture stirred for 16 h at 25° C
3. washwashed with a 1N aqueous hydrochloric acid solution (10 mL), water (10 mL)
4. dry with materiala saturated aqueous sodium bicarbonate solution (10 mL) dried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customPurification by AnaLogix IntelliFlash flash chromatography (12 g column, 20% ethyl acetate/hexanes to 80% ethyl acetate/hexanes)