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 (1 ml) under a nitrogen atmosphere, and triethylamine (0.0630 ml) and phenyl chloroformate (0.0624 ml) were added dropwise at 0° C. in this order, followed by stirring for 30 min. The reaction mixture was stirred after addition of ethyl acetate (5 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.0 ml). 3-Hydroxyazetidine hydrochloride (99.0 mg) and triethylamine (0.315 ml) were added at room temperature, followed by stirring for 22 hr and 5 min. The reaction mixture was partitioned between ethyl acetate (10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. To the resultant residue were added ethyl acetate (1 ml) and heptane (1 ml) to precipitate a solid. The solid was collected by filtration. The resultant solid 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 provide the titled compound as white powder (71.1 mg, 58%).

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. concentrationThe solvent was concentrated under reduced pressure
6. dissolutionThe residue was dissolved in N,N-dimethylformamide (1.0 ml)
7. addition3-Hydroxyazetidine hydrochloride (99.0 mg) and triethylamine (0.315 ml) were added at room temperature
8. stirringby stirring for 22 hr and 5 min
9. customThe reaction mixture was partitioned between ethyl acetate (10 ml)
10. washThe organic layer was washed with brine
11. dry with materialdried over anhydrous sodium sulfate
12. concentrationThe solvent was concentrated under reduced pressure
13. additionTo the resultant residue were added ethyl acetate (1 ml) and heptane (1 ml)
14. customto precipitate a solid
15. filtrationThe solid was collected by filtration
16. customThe resultant solid was purified by silica gel column chromatography (Fuji Silysia NH, eluent
17. additionethyl acetate, then ethyl acetate:methanol=10:1), and fractions containing the target compound
18. concentrationwere concentrated under reduced pressure