Reaction Steps
In a 10 mL seal tube, methyl (S)-1-((S)-4,4-difluoro-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (52 mg, 97.7 μmol), methyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (46.5 mg, 97.7 μmol) and sodium bicarbonate (sat. solution, 400 μl, excess) were combined with tert-butanol (2.00 ml) to give a light brown suspension and degassed for 5 min. PdCl2(DPPF) (7.15 mg, 9.77 μmol) was added and flushed with nitrogen. It was sealed heating at 90° C. for 4 hr, diluted with EtOAc (10 ml), filtered and concentrated in vacuo. The crude mixture was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2) to afford {(4S,7S)-4-[5-(4′-{2-[(S)-4,4-Difluoro-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-carbamic acid methyl ester as a light yellow solid (26 mg, 31.5%). ESI-LRMS m/e calcd for C40H45F2N9O7, [M+] 801. found 802 [M+H]. 1H NMR (DMSO-d6) δ: 12.23 (br. s., 1H), 11.98 (br. s., 1H), 7.72-7.84 (m, 4H), 7.62-7.72 (m, 5H), 7.57 (d, J=1.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 5.81 (br. s., 1H), 5.30 (t, J=7.5 Hz, 1H), 4.39-4.55 (m, 3H), 3.94 (t, J=8.2 Hz, 1H), 3.56 (s, 4H), 3.55 (br. s., 3H), 2.84-2.95 (m, 1H), 2.18-2.35 (m, 3H), 2.12 (dd, J=13.1, 6.5 Hz, 1H), 1.86-2.03 (m, 4H), 1.64 (d, J=13.3 Hz, 1H), 1.09-1.26 (m, 1H), 0.92 (d, J=6.5 Hz, 1H), 0.85 (d, J=6.5 Hz, 6H).
