反应详情

6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (200 mg) was dissolved in tetrahydrofuran (8 ml) under a nitrogen atmosphere, and then triethylamine (0.334 ml) and phenyl chloroformate (0.301 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 1.5 hrs. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added N,N-dimethylformamide (8 ml). 4-(Pyrrolidin-1-ylmethyl)piperidine dihydrochloride (771 mg) and triethylamine (0.896 ml) were added thereto, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 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, heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (350 mg) as a pale yellow oil.

1. temperaturewhile cooling in an ice water bath
2. customThe reaction mixture was partitioned between ethyl acetate (200 ml)
3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (100 ml) in this order
4. dry with materialdried over anhydrous sodium sulfate
5. customThe solvent was evaporated
6. customto give a residue
7. stirringby stirring for 4 hrs
8. customThe reaction mixture was partitioned between ethyl acetate (100 ml)
9. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 ml) in this order
10. dry with materialdried over anhydrous sodium sulfate
11. customThe solvent was evaporated
12. customto give a residue, which
13. customwas then purified by silica gel column chromatography (Fuji Silysia NH, heptane
14. additionFractions containing the target compound
15. concentrationwere concentrated