3-Bromopyridine → 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-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

Participants

Reaction Conditions

Reaction Steps

To a stirring suspension of 570 mg (0.90 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Part A, and 172 mg (2.71 mmol, 3.0 equiv) of Cu0 powder in 10 mL of DMF is added 117 mg (1.80 mmol, 2.0 equiv of potassium acetate, followed by 285 mg (1.80 mmol, 2.0 equiv) of 3-bromopyridine). The resulting mixture is heated to 120° C. for 4 h, then an additional 285 mg of 3-bromopyridine is added and the reaction heated to 120° C. for an additional 15 h. The reaction mixture is then cooled to RT and filtered through a pad of Celite to remove the Cu0 powder. The reaction mixture is then poured into 100 mL of EtOAc-Et2O (1:1) and extracted with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent afforded 450 mg of the title compound as a light tan solid: mp 223°-224° C.; 1H NMR (CDCl3, 400 MHz) δ8.47 (d, 1H, J=3.8), 8.31 (s, br, 1H), 8.04 (d, 1H, J=8.2), 7.51 (d, 1H, J=7.3), 7.38 (d, 1H, J=7.7), 7.31-6.93 (m, 15H), 6.64 (d, 1H, J=7.5), 5.52 (s, 2H), 5.04 (m, 1H), 4.46 (d, 1H, J=15.9), 4.26 (d, 1H, J=15.8), 4.00 (m, 2H), 3.84 (s, 3H), 3.15 (s, 3H), 1.11 (2×d, 6H, J=6.7); low resolution MS (FAB)m/e 709 (MH+), 293, 265; Anal. (C42H40N6O5) Calcd. C, 71.17; H, 5.69; N, 11.86; Found C, 70.90; H, 5.74; N, 11.65.

Provenance & Evidence