Reaction Steps
To a solution of the intermediate from step D (0.39 g, 1.0 mmol) in DMF (2 mL) was added 4-tert-butyl cyclohexylamine (268 μL, 1.5 mmol), HOAt (0.2 g, 1.5 mmol), DIEA (0.52 mL, 3.0 mmol) and EDC (0.29 g, 1.5 mmol). The resulting solution was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate and washed with IN HCl, saturated NaHCO3, and saturated NaCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on Biotage Quad 3 system using 30% ethyl acetate-hexanes. The trans and cis isomers were obtained in a 3:1 ratio. Isomer A (trans isomer): 1H NMR (CDCl3, 500 MHz): 8.02 (d, J=8.4 Hz, 2H), 7.46 (dd, J=6.7, 7.9 Hz, 2H), 7.41 (d, J=8.2Hz, 2H), 6.75 (s, 1H), 5.86 (s, 2H), 5.83 (d, J=8.2 Hz, 1H), 3.93 (s, 3H), 3.8 (m, 1H), 2.11 (bm, 2H), 1.18 (bm, 2H), 1.2-1.0 (m, 3H), 0.91 (s, 9H). LC-MS: 3.07 min; (M+H)=528.2. Isomer B (cis isomer): 1H NMR (CDCl3, 500 MHz): 8.01 (d, J=8.0 Hz, 2H), 7.48 (t, J=6.6 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 6.73 (s, 1H), 6.08 (d, J=7.1 Hz, 1H), 5.84 (s, 2H), 4.23 (m, 1H), 3.92 (s, 3H), 1.94 (d, J=14.2 Hz, 2H), 1.71 (d, J=11.2 Hz, 2H), 1.61 (m, 211), 1.1 (m, 2H), 0.89 (s, 9H). LC-MS: 3.07 min; (M+H)=528.2.
