1-Hydroxybenzotriazole → (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

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence