反应详情

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (75 mg) was dissolved in tetrahydrofuran (1.8 ml) under a nitrogen atmosphere, and triethylamine (0.074 ml) and phenyl chloroformate (0.0488 ml) were added dropwise in this order at room temperature, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.8 ml). This solution was added to a mixture of a crude product of 3-methoxyazetidine trifluoroacetate (209.8 mg, corresponds to 0.671 mmol) and triethylamine (0.450 ml), followed by stirring at room temperature for 13 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, ethyl acetate, ethyl acetate:methanol=50:1, then 20:1). Fractions containing the target compound were concentrated. To the resultant residue was added diethyl ether:heptane=1:2 to suspend a solid. The solid was collected by filtration and washed with heptane. This was dried under aeration to provide the titled compound as white powder (46.5 mg, 48.9%).

1. customThe reaction mixture was partitioned between ethyl acetate and water
2. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order
3. dry with materialdried over anhydrous sodium sulfate
4. concentrationThe solvent was concentrated under reduced pressure
5. dissolutionThe residue was dissolved in N,N-dimethylformamide (1.8 ml)
6. stirringby stirring at room temperature for 13 hr
7. customThe reaction mixture was partitioned between ethyl acetate and water
8. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order
9. dry with materialdried over anhydrous sodium sulfate
10. customThe solvent was removed
11. customthe residue was purified by silica gel column chromatography (eluent
12. additionFractions containing the target compound
13. concentrationwere concentrated
14. additionTo the resultant residue was added diethyl ether
15. filtrationThe solid was collected by filtration
16. washwashed with heptane
17. customThis was dried under aeration