2,6-Lutidine → (5)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

Participants

Reaction Conditions

Reaction Steps

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol) in methylene chloride (2.9 mL) at 0° C. was treated with oxalyl chloride (0.03 mL, 0.34 mmol) followed by N,N-dimethylformamide (5 drops). The resulting solution was stirred at 0° C. for 30 min. At this time, the solution was warmed to room temperature and stirred for 30 min. The reaction was then concentrated in vacuo. The residue was re-suspended in methylene chloride (2×5 mL) and then concentrated in vacuo. The residue was then dissolved in methylene chloride (1 mL) and was added to a pre-cooled solution of 1-methyl-1H-pyrazol-3-ylamine (Matrix, 30 mg, 1.05 mmol) and 2,6-lutidine (0.05 mL, 0.47 mmol) in methylene chloride (3 mL) at 0° C. The reaction was allowed to gradually warm to room temperature and was stirred at room temperature overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×100 mL) and water (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (50-75% ethyl acetate/hexanes) afforded (5)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 77%) as a white solid; ES−-HRMS m/e calcd for C21H23N4O2F3 (M+H)+ 421.1846 found 421.1844. 1H-NMR (300 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.01 (t, J=8.6 Hz, 2H), 7.68-7.81 (m, 1H), 7.54 (d, J=1.9 Hz, 1H), 6.39 (d, J=1.9 Hz, 1H), 5.02-5.15 (m, 1H), 5.03 (d, J=18.5 Hz, 1H), 4.71 (d, J=18.5 Hz, 1H), 3.73 (s, 3H), 0.98-2.12 (m, 11H).

Provenance & Evidence