Reaction Steps
3,8-Difluoro-5-(4-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—A stirred solution of 4-methoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzamide (0.95 g, 2.46 mmol) in tetrahydrofuran was treated under nitrogen with a 1.0 M solution of lithium bis(trimethylsilyl) amide in tetrahydrofuran (5 mL, 5.0 mmol) and heated at 70° C. for fifteen hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo to afford a residue. The residue was dissolved in ethyl acetate and washed sequentially with a 1 N hydrochloric acid solution and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to afford a crude solid. The crude solid was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 3% and 15% methyl tert-butyl ether in hexane to afford, after crystallization from ethyl acetate-hexane, the title compound (0.36 g, 0.99 mmol, 40%) as a homogeneous, colorless, crystalline solid, m.p. 98-100° C.; MS [(+ESI), m/z]: 366 [M+H]+; IR (Solid), vmax: 2920, 1630, 1600, 1580, 1510, 1495, 1385, 1320, 1250, 870, 840, 810 cm−1; 1H NMR (400 MHz, DMSO-d6) δ: 1.22 (d, J=7.0 Hz, 3H), 3.77 (s, 3H), 5.73 (q, J=6.7 Hz, 1H), 6.59 (dd, J=10.3, 2.3 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.07 (td, J=8.6, 2.7 Hz, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.27 (td, J=8.5, 3.2 Hz, 1H), 7.39 (dd, J=9.2, 2.7 Hz, 1H), 7.98 (dd, J=8.9, 6.3 Hz, 1H), 8.02 (dd, J=8.5, 5.4 Hz, 1H); Anal. calcd for C22H17F2NO2: C, 72.32; H, 4.69; N, 3.83. Found: C, 71.82; H, 4.52; N, 3.76.
