Diisopropylethylamine → (S)-N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamide

Participants

Reaction Steps

A stirred solution of (S)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanoic acid (150 mg, 0.4 mmol) in DMF (15 mL) was treated with HATU (253 mg, 0.5 mmol) and DIPEA (0.3 mL, 1.7 mL mmol). After 15 min, 1-cyanocyclopropane hydrochloride (61 mg, 0.5 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere for 2 h. Once the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate & washed with 1HCl solution and brine, dried over Na2SO4, filtered and was concentrated. The crude compound was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane followed by re-crystallization from DCM and pentane to provide (S)-N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-phenylethylamino)pentanamide (65 mg, 37%) as white solid. 1H-NMR (500 MHz, DMSO-d6): 8.88 (1H, s, NH), 7.38 (5H, s, Ar—H), 4.23 (1H, m, CHCF3), 3.39 (1H, m, CH), 3.18 (1H, m, NH), 2.23 (2H, m, CH2), 1.94 (2H, m, CH2), 1.32 (2H, m, CH2), 0.82 (2H, m, CH2), 0.57 (1H, m, CH), 0.45 (2H, m, CH2), 0.12 (2H, m, CH2). 19F-NMR (500 MHz, CD3OD): −74.609 (CF2), 95.308, −95.507 (CF3). EIMS (m/z): 416 (M+H). HPLC: 97.37% (RT 16.39)Column used zorbax SB, C8, 250×4.6 mm, 5uMobile Phase: ACN (B): 0.1% TFA in water (A)Flow rate: 1.0 mL/Min

Provenance & Evidence