Reaction Steps
In a 10 mL seal tube, methyl (2S)-3-methyl-1-oxo-1-(3-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)-8-oxa-2-azaspiro[4.5]decan-2-yl)butan-2-ylcarbamate (45 mg, 79.4 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 (37.8 mg, 79.4 μmol) and sodium bicarbonate (sat solution, 0.4 ml) were combined with tert-butanol (2.6 ml) to give a light brown suspension and deoxygenated for 5 min. PdCl2(DPPF) (5.81 mg, 7.94 μmol) was added and flushed with nitrogen. It was sealed heating at 90° C. for 4 hr. The reaction mixture was diluted with EtOAc (10 ml), filtered and concentrated in vacuo. The residue was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2) to afford {(4S,7S)-4-[5(4′-{2-[2-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-8-oxa-2-aza-spiro[4.5]dec-3-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 (30 mg, 42.9%). ESI-LRMS m/e calcd for C44H53N9O8, [M+] 835. found 836 [M+H]. 1H NMR (DMSO-d6) δ: 12.09-12.45 (m, 1H), 7.57-7.99 (m, 11H), 7.49 (d, J=8.3 Hz, 2H), 5.80 (br. s., 1H), 4.93-5.16 (m, 1H), 4.46 (d, J=11.3 Hz, 2H), 3.92-4.27 (m, 1H), 3.64 (br. s., 3H), 3.50-3.60 (m, 10H), 2.88 (t, J=10.3 Hz, 1H), 1.77-2.36 (m, 6H), 1.63 (br. s., 2H), 1.48 (d, J=11.5 Hz, 1H), 0.77-1.02 (m, 6H), 0.67 (d, J=6.5 Hz, 2H), 0.12 (d, J=6.8 Hz, 1H).
