反应详情

温度

-25 °C

LHMDS (1M in THF, 0.36 mL, 0.360 mmol) was added to a solution of phenyl 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 11, 148 mg, 0.345 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 70 mg, 0.346 mmol) in THF (3 ml) at −70° C. and stirred for 35 min. The reaction mixture was allowed to warm to −25° C., stirred for 5 min and cooled to −70° C. while stirring for 30 min. The reaction mixture was allowed to warm to −15° C., stirred for 10 min, cooled to −70° C. and quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and ethyl acetate, layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient ethyl acetate (90-100%) in heptane. Product fractions were combined, evaporated and dried to yield the title compound as a yellow solid. (UPLC-MS 3) tR 1.16 min, ESI-MS 505.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 5.68 (s, 1H), 5.26-5.21 (m, 1H), 4.06-4.00 (m, 2H), 3.62 (t, 2H), 3.51-3.44 (m, 8H), 3.40 (s, 3H), 2.84 (t, 2H), 2.03-1.96 (m, 2H).

1. stirringstirred for 5 min
2. temperaturecooled to −70° C.
3. stirringwhile stirring for 30 min
4. temperatureto warm to −15° C.
5. stirringstirred for 10 min
6. temperaturecooled to −70° C.
7. customquenched with saturated aqueous NH4Cl
8. additionThe reaction mixture was diluted with water and ethyl acetate, layers
9. customwere separated
10. extractionthe aqueous layer was extracted with ethyl acetate
11. washThe combined organic layers were washed with water
12. customdried
13. filtrationfiltered
14. customevaporated
15. customThe crude product was purified by silica gel column chromatography
16. washeluting with a gradient ethyl acetate (90-100%) in heptane
17. customevaporated
18. customdried