反应详情

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100.0 mg) was dissolved in tetrahydrofuran (2.0 ml) under a nitrogen atmosphere, triethylamine (0.0630 ml) and phenyl chloroformate (0.0624 ml) were added dropwise at 0° C., followed by stirring for 30 min. The reaction mixture was stirred after addition of ethyl acetate (5 ml) and saturated sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered it. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2.0 ml). (S)-3-Hydroxypyrrolidine was added at room temperature under a nitrogen atmosphere, followed by stirring 22 hr. The reaction mixture was partitioned between ethyl acetate (10 ml) and saturated sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with twice in water (10 ml) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1), and fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added heptane:ethyl acetate=10:1 to suspend a solid. The solid was collected by filtration to provide the titled compound as white powder (63.7 mg, 51%).

1. stirringThe reaction mixture was stirred
2. customThe organic layer was separated
3. washwashed with brine
4. dry with materialdried over anhydrous sodium sulfate
5. filtrationfiltered it
6. concentrationThe solvent was concentrated under reduced pressure
7. dissolutionThe residue was dissolved in N,N-dimethylformamide (2.0 ml)
8. addition(S)-3-Hydroxypyrrolidine was added at room temperature under a nitrogen atmosphere
9. stirringby stirring 22 hr
10. customThe reaction mixture was partitioned between ethyl acetate (10 ml) and saturated sodium hydrogencarbonate (5 ml)
11. customThe organic layer was separated
12. washwashed with twice in water (10 ml) and brine in this order
13. dry with materialdried over anhydrous sodium sulfate
14. concentrationThe solvent was concentrated under reduced pressure
15. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
16. additionethyl acetate, then ethyl acetate:methanol=10:1), and fractions containing the target compound
17. concentrationwere concentrated under reduced pressure
18. additionTo the resultant residue was added heptane
19. filtrationThe solid was collected by filtration