1-Hydroxybenzotriazole → (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide

Participants

Reaction Conditions

Reaction Steps

To a stirred solution of (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (150 mg, 0.4 mmol) in dichloromethane (12 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (249 mg, 1.3 mmol) and N,N-diisopropylethylamine (280 mg, 2.2 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (200 mg, 1.31 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 67 mg, 0.4 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-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (105 mg, 50%) as a light brown sticky solid: NMR (400 MHz, CDCl3) δ ppm 0.89-1.06 (m, 2H), 1.14 (br. s., 6H), 1.17-1.29 (m, 3H), 1.56-1.94 (m, 8H), 2.58 (br. s., 3H), 3.76 (br. s., 1H), 3.92 (br. s., 2H), 4.09 (d, J=18.1 Hz, 1H), 4.33 (d, J=18.1 Hz, 1H), 4.81-4.93 (m, 1H), 4.96 (br. s., 1H), 6.67 (br. s., 1H), 7.20 (d, J=8.8 Hz, 1H), 7.28 (br. s., 1H), 7.41 (d, J=8.3 Hz, 1H), 8.39 (br. s., 1H), 8.74 (br. s., 1H).

Provenance & Evidence