Reaction Steps
To a solution of 0.400 g of 2-(7-fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part E, (0.839 mmol) in 5 mL dimethylformamide at 0° C. under nitrogen is added 2.01 mL (1.01 mmol, 1.2 equiv) potassium bis(trimethylsilyl)amide (0.5M in toluene) dropwise over 5 min. After stirring 10 min., 287 mg of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole (0.923 mmol, 1.1 equiv) is added. After 15 min., the reaction is added to a mixture of ethyl acetate, saturated aqueous brine, and water with vigorous agitation. The mixture is transferred to a separatory funnel and the layers were separated. The organic layer is washed with 1:1 water/saturated aqueous brine, saturated aqueous brine, and then dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue is purified on flash grade silica with 2:3 ethyl acetate/hexane (500 mL) followed by 3:2 ethyl acetate/hexane (1000 mL). The appropriate fractions were combined, evaporated in vacuo to a residue, and triturated with hexane. Hexane is removed in vacuo to provide 388 mg of the title compound as a white solid: 1H NMR (300 MHz, CDCl3) δ8.69 (s, br, 1H), 8.58 (d, 1H, J=4.6), 8.20 (s, br, 1H), 8.02 (d, 1H, J=8.2), 7.84 (d, 1H, J=7.9), 7.57 (s, 1H), 7.50 (m, 1H), 7.32 (m, 2H), 7.14 (d, 2H, J=8.8), 7.05 (m, 1H), 6.97 (m, 2H), 6.61 (dd, 1H, J=2.8, 9.2), 4.92 (m, 1H), 4.52 (d, 1H, J=18.4), 4.40 (dd, 1H, J=5.1, 8.7), 4.04 (d, 1H, J=18.4), 3.85 (s, 3H), 3.81 (m, 1H), 3.53 (dd, 1H, J=5.2, 16.7), 1.66 (s, 9H), 1.03 (m, 6H). TLC Rf =0.50 (ethyl acetate/hexane 7/3).
