反应详情

To a solution of N-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)malonamide (35 mg) in tetrahydrofuran (2.8 ml) was added triethylamine (0.0245 ml), and then phenyl chloroformate (0.0221 ml) was added dropwise thereto while cooling in an ice water bath, followed by stirring for 30 min. The reaction mixture was concentrated under a reduced pressure. To a suspension of the residue in N,N-dimethylformamide (1.4 ml) was added dimethylamine (0.175 ml, 2.0 M solution in tetrahydrofuran), followed by stirring at room temperature for 5 hrs. Diethylamine hydrochloride (35.8 mg) and triethylamine (0.2 ml) were added further, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a 1 N aqueous solution of sodium hydroxide (30 ml). The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then subjected to silica gel filtration (FUJI Silysia NH). The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated to give a solid, which was then suspended in ethanol (0.5 ml)-diethyl ether (2.5 ml), filtered off, and dried under aeration to provide the titled compound (12.4 mg, 30%) as pale brown powder.

1. temperaturewhile cooling in an ice water bath
2. concentrationThe reaction mixture was concentrated under a reduced pressure
3. additionTo a suspension of the residue in N,N-dimethylformamide (1.4 ml)
4. additionwas added dimethylamine (0.175 ml, 2.0 M solution in tetrahydrofuran)
5. stirringby stirring at room temperature for 5 hrs
6. additionDiethylamine hydrochloride (35.8 mg) and triethylamine (0.2 ml) were added further
7. stirringby stirring at room temperature for 2 hrs
8. customThe reaction mixture was partitioned between ethyl acetate (50 ml)
9. washThe organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order
10. dry with materialdried over anhydrous sodium sulfate
11. customThe solvent was evaporated
12. customto give a residue, which
13. filtrationwas then subjected to silica gel filtration (FUJI Silysia NH)
14. concentrationThe filtrate was concentrated under a reduced pressure
15. customto give a residue, which
16. customwas then purified by silica gel column chromatography (eluent
17. additionFractions containing the target compound
18. concentrationwere concentrated
19. customto give a solid, which
20. filtrationfiltered off
21. customdried under aeration