8-Hydroxyquinoline → tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

Participants

Reaction Conditions

Reaction Steps

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.18 g, 0.48 mmol), 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (0.11 g, 0.51 mmol), and Cs2CO3 (0.20 g, 0.63 mmol) were suspended in DMSO (2.8 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (21 mg, 0.15 mmol) and copper iodide (0.23 mg, 1.2 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 110° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (20 mL), and the resulting solution was stirred at ambient temperature for 6 h. The resulting solution was diluted with CH2Cl2, the resulting layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×25 mL). Activated charcoal was added to the combined organic extracts, and the resulting suspension was filtered through a silica gel plug. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 10 column volumes and held for 4 column volumes, then increased to 0:100 over 10 column volumes and held for 4 column volumes) gave the title compound (0.12 mg, 56%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.72-7.67 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.30 (s, 2H), 3.69-3.67 (m, 5H), 3.60-3.57 (m, 2H), 3.08-3.05 (m, 2H), 2.98-2.96 (m, 2H), 1.44-1.42 (m, 9H).

Provenance & Evidence