反应详情

温度

-25 °C

A solution of LHMDS in THF (1M, 500 μL, 0.500 mmol) was added drop wise to a solution of 7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 321, 130 mg, 0.474 mmol) and diphenylcarbonate (105 mg, 0.490 mmol) in THF (2.2 ml) at −25° C. The reaction mixture was stirred for 85 minutes at −25° C., then warmed to room temperature and stirred for 45 min, placed in a fridge and stored over the weekend at 4° C. The reaction mixture was then cooled to −65° C. and further LHMDS (500 μl, 0.500 mmol) was added and it was allowed to warm to −45° C. to −35° C. and stirred for 80 min. The reaction mixture was quenched with saturated aqueous NH4Cl, diluted with ethyl acetate and water. Phases were separated and the water phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-5%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.78 min; ESI-MS 395.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.44-7.34 (m, 3H), 7.25-7.15 (m, 5H), 5.11 (s, 1H), 4.04-3.96 (m, 2H), 3.34 (s, 6H), 2.90 (t, 2H), 2.15-2.04 (m, 2H).

1. temperaturewarmed to room temperature
2. stirringstirred for 45 min
3. customstored over the weekend at 4° C
4. temperatureThe reaction mixture was then cooled to −65° C.
5. temperatureto warm to −45° C. to −35° C.
6. stirringstirred for 80 min
7. customThe reaction mixture was quenched with saturated aqueous NH4Cl
8. additiondiluted with ethyl acetate and water
9. customPhases were separated
10. extractionthe water phase was extracted with ethyl acetate
11. washThe combined organic layers were washed with brine
12. customdried
13. filtrationfiltered
14. customevaporated
15. customThe crude product was purified by silica gel column chromatography
16. washeluting with a gradient of MeOH (1-5%) in DCM
17. customevaporated
18. customdried