反应详情

(5-Bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (700 mg) is dissolved in N,N-dimethylformamide (5 ml), and thereto is added sodium hydride (60%) (88 mg) under nitrogen atmosphere at −10° C., and the mixture is stirred at the same temperature for 5 minutes, and thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (771 mg), and the mixture is stirred under ice-cooling for 1 hour and 40 minutes. To the reaction solution are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated, and the organic layer is washed twice with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) and (hexane:ethyl acetate=49:1→9:1). The residue is dissolved in diethyl ether, and filtered. The filtrate is concentrated under reduced pressure, and the residue obtained above (630 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added morpholine (119 μl) and triethylamine (190 μl), and the mixture is stirred at 50° C. for 4 hours, and the reaction solution is cooled to room temperature, and stirred at same temperature overnight. To the reaction solution are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with water and a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give 3-{[(5-bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (440 mg). MS (m/z): 662/664 [M+H]+

1. stirringthe mixture is stirred under ice-
2. temperaturecooling for 1 hour and 40 minutes
3. customa saturated aqueous citric acid solution, and the mixture is separated
4. washthe organic layer is washed twice with a saturated brine
5. dry with materialthe mixture is dried over magnesium sulfate
6. concentrationis concentrated under reduced pressure
7. customThe resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) and (hexane:ethyl acetate=49:1→9:1)
8. dissolutionThe residue is dissolved in diethyl ether
9. filtrationfiltered
10. concentrationThe filtrate is concentrated under reduced pressure
11. customthe residue obtained above (630 mg)
12. stirringthe mixture is stirred at 50° C. for 4 hours
13. stirringstirred at same temperature overnight
14. customthe mixture is separated
15. washthe organic layer is washed with water
16. dry with materiala saturated brine, and the mixture is dried over magnesium sulfate
17. concentrationis concentrated under reduced pressure
18. customThe resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3)