1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

Participants

Reaction Conditions

Reaction Steps

In a round bottom flask under argon was placed 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (73 mg, 0.19 mmol) in dichloromethane (5 mL). To this mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (38 μL, 0.21 mmol) and 1-hydoxybenzotriazole (27 mg, 0.20 mmol) and was stirred at 25° C. for 2 h. After this time period, 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in US20080021032, Example 80, 36 mg, 0.23 mmol) was added and 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), a saturated aqueous sodium bicarbonate solution (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (12 g column, 40% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (40 mg, 40%) as a light orange solid as a mixture of diastereomers: HR-ES-MS m/z calculated for C27H32N4O4F2 [M+H]+ 515.2465, observed 515.2464; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.10-2.10 (m, 11H), 2.15 (br. s., 2H), 3.89 (s, 2H), 4.28 (d, J=19.3 Hz, 1H), 4.57-4.65 (m, 1H), 4.67 (s, 1H), 472-486 (2×m, 1H), 5.04 (s, 1H), 6.41-6.49 (m, 1H), 7.29-7.51 (m, 3H), 7.54 (s, 1H), 10.81 (2×s, 1H).

Provenance & Evidence