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

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).

1. stirringThe reaction was stirred at room temperature for 5 h
2. customby quenching with 3-(dimethylamino)-propylamine (0.1 mL)
3. customThe reaction contents
4. extractionextracted with CH2Cl2 (2×10 mL)
5. washThe organic layer was washed with 0.5 N NaOH (10 mL)
6. dry with materialdried with Na2SO4
7. concentrationconcentrated in vacuo
8. customSilica gel chromatography (60% MTBE in hexanes) separated cis and trans isomers with the desired trans
9. washisomer eluting last

ORD record

ord-c5442ffce8a740f49ccb191f3b5de1aa

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08637576B2