反应详情

A solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.3 M, 0.986 mL, 1.28 mmol) was added dropwise to an ice-water cooled, stirring suspension of 5-bromo-1-methyl-1H-imidazole (241 mg, 1.50 mmol) in dry tetrahydrofuran (6 mL). After 5 minutes, the flask was removed from the cooling bath and the white suspension was stirred at 23° C. After 10 minutes, the Grignard suspension was added to an ice-water cooled, stirring mixture containing 4-(3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-2-methoxyquinoline-6-carbonyl)benzonitrile (205 mg, 0.427 mmol, Intermediate 16: step e) and lanthanum(III) chloride bis(lithium chloride) complex (0.6 M solution in tetrahydrofuran, 1.42 mL, 0.854 mmol) in dry tetrahydrofuran (8 mL). After 20 minutes, 1 M aqueous citric acid solution (1 mL) was added. The flask was removed from the cooling bath and then ethyl acetate (100 mL) was added. Additional 1 M aqueous citric acid solution (˜15 mL) was added until the mixture was comprised of two homogeneous layers, at which point saturated aqueous sodium bicarbonate solution was added until the pH of the aqueous layer was ˜8 by litmus paper test. The layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined and the combined solution was dried over sodium sulfate. The dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash-column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.45 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 8.06 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.58-7.51 (m, 5H), 7.44-7.38 (m, 3H), 6.41 (d, J=1.1 Hz, 1H), 4.33 (s, 2H), 4.09 (s, 3H), 3.94 (s, 1H), 3.38 (s, 3H); MS (ESI): mass calcd. C31H24ClN7O2, 561.2. m/z found, 562.1 [M+H]+.

1. temperaturecooled
2. customthe flask was removed from the cooling bath
3. stirringthe white suspension was stirred at 23° C
4. waitAfter 10 minutes
5. additionthe Grignard suspension was added to an ice-water
6. temperaturecooled
7. stirringstirring mixture
8. waitAfter 20 minutes
9. customThe flask was removed from the cooling bath
10. additionethyl acetate (100 mL) was added
11. additionAdditional 1 M aqueous citric acid solution (˜15 mL) was added until the mixture
12. additionwas added until the pH of the aqueous layer
13. customThe layers were separated
14. extractionThe aqueous layer was extracted with ethyl acetate (20 mL)
15. dry with materialthe combined solution was dried over sodium sulfate
16. filtrationThe dried solution was filtered
17. additionSilica gel (5 g) was added to the filtrate
18. concentrationthe mixture was concentrated by rotary evaporation
19. customto afford a free-flowing powder
20. customThe powder was loaded onto a silica gel column for flash-column chromatography purification
21. washElution with dichloromethane initially