反应详情

温度

23 °C

To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (250 mg, 0.6 mmol) in dichloromethane (12 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (344 mg, 1.8 mmol) and N,N-diisopropylethylamine (387 mg, 3.0 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (275 mg, 1.9 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 93 mg, 0.6 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[2-oxo-4-(3-trifluoromethoxy-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionamide (70 mg, 21%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ PPM 0.81-1.09 (m, 2H), 1.15 (s, 6H), 1.16-1.32 (m, 3H), 1.60-1.97 (m, 8H), 3.60 (s, 1H), 3.93 (s, 2H), 4.08 (d, J=18.1 Hz, 1H), 4.28 (d, J=18.1 Hz, 1H), 4.88 (dd, J=9.0, 6.6 Hz, 1H), 5.02 (s, 1H), 6.67 (d, J=2.1 Hz, 1H), 7.07 (s, 1H), 7.10-7.16 (m, 2H), 7.29 (d, J=2.1 Hz, 1H), 7.44 (t, J=8.3 Hz, 1H), 8.49 (s, 1H).

1. customat room temperature
2. washwashed with a saturated aqueous ammonium chloride solution
3. washThe organic layer was then washed with a saturated aqueous sodium chloride solution
4. customseparated
5. dry with materialdried over sodium sulfate
6. concentrationconcentrated in vacuo
7. customto afford the crude product, which
8. customwas purified by flash column chromatography (silica gel (100-200 mesh)) which