反应详情

温度

100 °C

EXAMPLE 94. To a stirred solution of 4-(6-fluoropyridin-3-yl)-5,6,9,10-tetrahydro-[1,4]diazepino[1,7-h][1,7]naphthyridine-8,11-dione (31 mg, 0.096 mmol) in 1,2-dichloroethane (2 mL) POCl3 (29.3 mg, 0.19 mmol) was added and the resulting suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. For complete removal of POCl3 the residue was taken up in toluene and evaporated twice again and dried under high vacuo. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (5 mL), 4-isopropyl-1H-imidazole (53 mg, 0.48 mmol) was added and the mixture was stirred at 100° C. for 1 h. The reaction mixture was allowed to warm to rt and diluted with DCM. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by SFC (column: DEAP 5 μm, 250×30 mm, 60A, Princeton; eluent: from 6% MeOH/CO2 to 11% MeOH/CO2 in 11 min; flow 100 mL/min; UV detection at 220 nm) and yielded the title compound as beige powder (11 mg). UPLC-MS: MS 417.2 (M+H+); UPLC rt 0.87 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17-1.34 (m, 6 H), 2.81-2.98 (m, 3 H), 4.05 (br. s., 2 H), 4.40 (s, 2 H), 7.09 (dd, J=8.3, 2.8 Hz, 1 H), 7.22-7.36 (m, 2 H), 7.77 (td, J=7.9, 2.1 Hz, 1 H), 7.96 (s, 1 H), 8.03 (s, 1 H), 8.23 (d, J=1.5 Hz, 1 H), 8.68 (d, J=4.8 Hz, 1 H).

1. temperatureThe reaction mixture was cooled to rt
2. concentrationconcentrated under reduced pressure to dryness
3. customFor complete removal of POCl3 the residue
4. customevaporated twice again
5. customdried under high vacuo
6. dissolutionThe resulting crude chloro compound was dissolved in 1,2-dichloroethane (5 mL)
7. stirringthe mixture was stirred at 100° C. for 1 h
8. temperatureto warm to rt
9. extractionthe mixture was extracted twice with DCM
10. dry with materialThe combined organic layers were dried with sodium sulfate
11. filtrationfiltered
12. customthe solvent was removed under reduced pressure
13. customThe crude product was purified by SFC (column: DEAP 5 μm, 250×30 mm, 60A, Princeton; eluent: from 6% MeOH/CO2 to 11% MeOH/CO2 in 11 min; flow 100 mL/min; UV detection at 220 nm)