反应详情

A suspension of Example A5 (0.154 g, 0.444 mmol) in EtOAc (2.5 mL) was treated with satd. NaHCO3 (2.5 mL) and isopropenyl chloroformate (0.046 mL, 0.422 mmol) and the biphasic mixture stirred vigorously at RT for 3.5 h. Additional isopropenyl chloroformate (20 μL) was added and the mixture was stirred at RT overnight. The mixture was diluted with additional EtOAc and satd. NaHCO3 and the layers separated. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The resulting residue was dissolved in pyridine (1.5 mL), cooled to 0° C., treated with isopropenyl chloroformate (15 μL) and allowed to warm to RT. The mixture was re-cooled to 0° C., treated with additional isopropenyl chloroformate (7 μL) and allowed to warm to RT. The mixture was once again cooled to 0° C., treated with isopropenyl chloroformate (5 μL), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, treated with brine and extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (141 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.55 (d, J=10.5 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H), 6.23 (s, 1H), 4.73 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), MS (ESI) m/z: 431.1 [M+H]+.

1. customNaHCO3 and the layers separated
2. washThe organic layer was washed with brine
3. dry with materialdried over MgSO4
4. concentrationconcentrated to dryness
5. dissolutionThe resulting residue was dissolved in pyridine (1.5 mL)
6. temperaturecooled to 0° C.
7. additiontreated with isopropenyl chloroformate (15 μL)
8. temperatureto warm to RT
9. temperatureThe mixture was re-cooled to 0° C.
10. additiontreated with additional isopropenyl chloroformate (7 μL)
11. temperatureto warm to RT
12. temperatureThe mixture was once again cooled to 0° C.
13. additiontreated with isopropenyl chloroformate (5 μL)
14. temperatureto warm to RT
15. stirringstirred overnight
16. concentrationThe mixture was concentrated to dryness
17. additiontreated with brine
18. extractionextracted with EtOAc (2×)
19. dry with materialThe combined organics were dried over MgSO4
20. concentrationconcentrated to dryness
21. custompurified via silica gel chromatography (EtOAc/Hex)