反应详情

温度

50 °C

To a solution of 4-chloro-6-iodo-3-phenyl-2-(trifluoromethyl)quinoline (Intermediate 20: step b, containing about 13% molar of 4-chloro-3-phenyl-2-(trifluoromethyl)quinoline as impurity, 340 mg) in THF (4 mL) at −78° C. under N2 was added iPrMgCl (2.0 M in THF, 0.40 mL, 0.8 mmol). After stirring for 8 minutes, the cooling bath was removed, and stirring was continued for 20 minutes, then tert-butyl 4-nicotinoylpiperidine-1-carboxylate (225 mg, 0.770 mmol, Intermediate 21) was added in neat. After stirring at room temperature overnight, the mixture became clear brown and was heated at 50° C. for 1.5 hours. The mixture was quenched with saturated NH4Cl aqueous solution, and extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by flash column chromatography (silica gel, 20-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.17-9.35 (m, 1H), 8.50-8.88 (m, 2H), 8.29 (d, J=7.58 Hz, 1H), 8.24 (d, J=8.59 Hz, 1H), 7.82-8.00 (m, 1H), 7.47-7.57 (m, 4H), 7.21-7.33 (m, 2H), 4.08-4.26 (m, 2H), 2.69-2.99 (m, 3H), 1.82-1.92 (m, 1H), 1.53-1.80 (m, 3H), 1.47 (s, 4.5H), 1.41 (s, 4.5H); MS m/e 598.3 [M+H]+.

1. customthe cooling bath was removed
2. stirringstirring
3. waitwas continued for 20 minutes
4. stirringAfter stirring at room temperature overnight
5. customThe mixture was quenched with saturated NH4Cl aqueous solution
6. extractionextracted with EtOAc
7. dry with materialThe extracts were dried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated
10. customThe crude mixture was purified by flash column chromatography (silica gel, 20-100% EtOAc in heptanes)