反应详情

To a solution of 3-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.5 mg) in tetrahydrofuran (20 ml) (Production Example 124) was added N,N-dimethylformamide (2 ml) under a nitrogen atmosphere, followed by evaporating the tetrahydrofuran under a reduced pressure. To the solution thus concentrated were added N-(4-fluorophenyl)malonic acid (42.6 mg), triethylamine (0.030 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (95.5 mg) at room temperature, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of ammonium chloride (15 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (15 ml), water (15 ml) and brine (15 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate-ethyl acetate:ethanol=95:5). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (1 ml) was added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (29.1 mg, 48.8%) as a pale green and yellow solid.

1. customby evaporating the tetrahydrofuran under a reduced pressure
2. concentrationTo the solution thus concentrated
3. additionwere added N-(4-fluorophenyl)malonic acid (42.6 mg), triethylamine (0.030 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (95.5 mg) at room temperature
4. customThe reaction mixture was partitioned between ethyl acetate (30 ml)
5. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (15 ml), water (15 ml) and brine (15 ml) in this order
6. dry with materialdried over anhydrous sodium sulfate
7. customThe solvent was evaporated
8. customto give a residue, which
9. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate-ethyl acetate:ethanol=95:5)
10. additionFractions containing the target compound
11. concentrationwere concentrated
12. customto give a residue
13. filtrationThe solid was filtered off
14. customdried under aeration