Hydrochloric Acid → N-[4-(2-cyanoethyl)cyclohexyl]-N-cyclopropyl-4-[(2S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzamide

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Reaction Steps

To a solution of (S)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (0.33 g, 1.4 mmol), HBTU (0.64, 1.7 mmol), and HOBt (0.24 g, 1.8 mmol) in DMF (3.3 mL) was added Hünig's base (0.58 mL, 3.4 mmol). The solution was stirred for 5 minutes prior to the addition of 3-(4-(cyclopropylamino)cyclohexyl)propanenitrile prepared in step g (0.32 g, 1.7 mmol). The reaction was stirred at room temperature for 5 h followed by quenching with 3-(dimethylamino)-propylamine (0.1 mL). The reaction contents were poured into 1 N HCl (30 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with 0.5 N NaOH (10 mL), dried with Na2SO4, and concentrated in vacuo. Silica gel chromatography (60% MTBE in hexanes) separated cis and trans isomers with the desired trans isomer eluting last to provide (S)-N-(4-(2-cyanoethyl)cyclohexyl)-N-cyclopropyl-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide. 1H NMR (500 MHz, CDCl3): δ 0.40-0.48 (bs, 2H), 0.58 (bd, J=6 Hz, 2H), 1.05-1.20 (m, 2 H), 1.42-1.56 (m, 1H), 1.60-1.64 (m, 3H), 1.81 (s, 3H), 1.85-1.92 (m, 4H), 1.97-2.00 (m, 2H), 2.41 (t, J=7 Hz, 2H), 2.56-3.00 (m, 1 H), 2.69 (bs, 1H), 4.13 (bs, 1H), 7.48 (d, J=8 Hz, 2H), 7.60 (d, J=8 Hz, 2H).

Provenance & Evidence