反应详情

温度

130 °C

tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.11 g, 0.30 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (73 mg, 0.30 mmol), and Cs2CO3 (0.11 g, 0.33 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (13 mg, 0.091 mmol) and copper iodide (75 mg, 0.39 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×30 mL). Activated charcoal was added to the organic solution, and the resulting suspension was filtered through a Celite® plug and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 4 column volumes) gave the title compound (70 mg, 43%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 7.22 (dd, J=7.5, 1.5 Hz, 1H), 4.60 (s, 2H), 3.77 (t, J=5.5 Hz, 2H), 3.71 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 527 [M+H]+.

1. customthe air was removed under vacuum for 15 min
2. additionwere added to the suspension
3. customThe evacuation/Ar flushing process
4. temperatureThe mixture was cooled
5. additiondiluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL)
6. filtrationThe resulting solids were collected by filtration
7. dissolutiondissolved in CH2Cl2 (30 mL)
8. washwashed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×30 mL)
9. additionActivated charcoal was added to the organic solution
10. filtrationthe resulting suspension was filtered through a Celite® plug
11. concentrationconcentrated to dryness under reduced pressure
12. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 4 column volumes)