反应详情

温度

25 °C

A solution of (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (151 mg, 0.55 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (63 mg, 0.39 mmol) and 1-hydroxybenzotriazole (52 mg, 0.38 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 67 mg, 0.43 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified on Gilson HPLC system (C18 column, 10-99% acetonitrile/water gradient) to afford (S)-3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1-H-pyrazol-3-yl]-propionamide (47 mg, 24%) as a white solid: HR-ES-MS m/z calculated for C29H38N4O6 [M+H]+ 539.2864, observed 539.2865; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.99 (m, 2H) 1.05 (s, 3H) 1.07-1.30 (m, 4H) 1.50-1.83 (m, 7H) 3.89 (s, 2H) 3.98 (dd, J=18.1, 4.0 Hz, 1H) 4.09 (dd, J=11.3, 7.5 Hz, 1H) 4.18-4.34 (m, 2H) 4.34-4.45 (m, 1H) 4.53-4.63 (m, 1H) 4.67 (s, 1H) 4.86 (dd, J=11.3, 4.0 Hz, 1H) 5.25 (s, 1H) 6.42 (d, J=2.1 Hz, 1H) 6.79-6.99 (m, 4H) 7.52 (d, J=2.1 Hz, 1H) 10.70 (s, 1H).

1. stirringThe reaction mixture was stirred for 18 h at 25° C., under nitrogen
2. washwashed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
3. dry with materiala saturated sodium chloride solution and dried over magnesium sulfate
4. concentrationThe organic layer was concentrated
5. customthe crude product was purified on Gilson HPLC system (C18 column, 10-99% acetonitrile/water gradient)