反应详情

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (150 mg) was dissolved in tetrahydrofuran (1.5 ml) under a nitrogen atmosphere, and triethylamine (0.181 ml) and phenyl chloroformate (0.163 ml) were added while stirring and cooling in an ice water bath, followed by stirring at the same temperature for 15 min. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added N,N-dimethylformamide (1.5 ml), and (R)-(−)-3-pyrrolidinol hydrochloride (175 mg) and triethylamine (0.198 ml) were added, followed by stirring at room temperature for 5 hr. The reaction mixture was partitioned after addition of ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:5, ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and to the residue (130 mg) were added tert-butyl methyl ether (2 ml) and heptane (2 ml) to suspend a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (123.6 mg, 65.0%).

1. temperaturecooling in an ice water bath
2. stirringby stirring at the same temperature for 15 min
3. customThe reaction mixture was partitioned between ethyl acetate (30 ml)
4. washThe separated organic layer was washed with brine (30 ml)
5. dry with materialdried over anhydrous sodium sulfate
6. customThe solvent was removed under reduced pressure
7. additionTo the residue was added N,N-dimethylformamide (1.5 ml), and (R)-(−)-3-pyrrolidinol hydrochloride (175 mg) and triethylamine (0.198 ml)
8. additionwere added
9. stirringby stirring at room temperature for 5 hr
10. customThe reaction mixture was partitioned
11. additionafter addition of ethyl acetate (30 ml)
12. washThe separated organic layer was washed with brine (30 ml)
13. dry with materialdried over anhydrous sodium sulfate
14. customThe solvent was removed under reduced pressure
15. customthe residue was purified by silica gel column chromatography (eluent
16. additionFractions containing the target compound
17. concentrationwere concentrated under reduced pressure
18. additionto the residue (130 mg) were added tert-butyl methyl ether (2 ml) and heptane (2 ml)
19. filtrationThe solid was collected by filtration
20. customdried under aeration