Reaction Steps
To a solution of 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (200 mg, 0.31 mmol) and 2-chloro-4-fluoro-benzene boronic acid (98 mg, 0.62 mmol) in toluene (3 mL) and ethanol (0.3 mL) was added sodium carbonate (2M solution, 0.39 mL) and tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0155 mmol). The flask was evacuated and purged with nitrogen a few times. The reaction mixture was heated to reflux for 2 h and diluted with methylene chloride. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 5% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 3H), 1.08 (s, 3H), 1.64 (m, 2H), 2.40 (m, 1H), 2.57 (brs, 1H), 2.83 (t, 1H, J=7.3 Hz), 2.90 (brs, 1H), 3.14 (s, 1H), 3.53 (m, 2H), 3.63 (t, 1H, J=13.2 Hz), 3.81 (s, 3H), 4.11 (abq, 2H, J=14.9 Hz), 4.55 (abq, 2H, J=14.9 Hz), 6.22 (s, 1H), 6.78 (s, 1H), 6.84 (d, 2H, J=8.4 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.12 (dd, 1H, J1=8.4 Hz, J2=6.0 Hz), 7.21 (d, 3H, J=8.7 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.54 (m, 2H). MS (API-ES+): 695 (M+H).
