Reaction Steps
To a solution of the intermediate from step F (464 mg, 0.90 mmol) in DMF (10 mL) was added HOAt (244 mg, 1.79 mmol), tert-butyl-cyclohexylamine (426 μL, 2.39 mmol), DIEA (623 μL, 3.57 mmol) and EDC (343 mg, 1.79 mmol). The resulting slurry was left stirring at room temperature overnight. The reaction was stirred to 50° C. for 3 hours. It was cooled to room temperature, diluted with ethyl acetate, washed with 1N HCl, saturated NaHCO3 solution, and dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate-hexanes. The trans and cis isomers were obtained in a 2:1 ratio. Isomer A (trans isomer): 1H NMR (CDCl3, 500 MHz): 9.16 (d, J=1.8 Hz, 1H), 8.31 (dd, J=2.1, 8.3 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.61 (dd, J=2.1, 8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 6.92 (s, 1H), 5.89 (s, 2H), 3.97 (s, 3H), 3.9 (m, 1H), 2.14 (bd, J=11.3 Hz, 2H), 1.87 (bd, J=12.6 Hz, 2H), 1.0-1.4 (m, 5H), 0.88 (s, 9H). LC-MS: 2.81 min; (M+H)=529.2. Isomer B (cis isomer): 1H NMR (CDCl3, 500 MHz): 9.18 (d, J=2.1 Hz, 1H), 8.33 (dd, J=2.0, 8.2 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.64 (dd, J=2.1, 8.3 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.9 (s, 1H), 5.88 (s, 2H), 4.3 (m, 1H), 3.97 (s, 3H), 2.01 (d, J=13.8 Hz, 2H), 1.73 (m, 2H), 1.65 (m, 2H), 1.29 (m, 2H), 0.89 (s, 9H). LC-MS: 2.81 min; (M+H)=529.2.
