反应详情

4-(4-Amino-3-chlorophenoxy)pyridin-2-ylamine (750 mg, 3.18 mmol) was dissolved in tetrahydrofuran (30 ml), and then triethylamine (0.444 ml, 4.77 mmol) was added thereto. Phenyl chloroformate (0.399 ml, 4.77 mmol) was added dropwise thereto while ice-cooling, followed by stirring at room temperature for 4 hrs and 45 min. Triethylamine (0.222 ml) and phenyl chloroformate (0.200 ml) were further added thereto, followed by stirring for 40 min. Triethylamine (0.111 ml) and phenyl chloroformate (0.100 ml) were further added thereto, followed by stirring for 40 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (10 ml) and 3-(1-methylpiperazin-4-yl)propylamine (2.32 ml, 15.9 mmol) were added, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, 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, ethyl acetate, then ethyl acetate:methanol=10:1 to 20:3). The crude purified fraction was concentrated, and purified again by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1 to 20:3) to provide the titled compound (691 mg, 1.65 mmol, 51.9%) as colorless powder.

1. temperaturewhile ice-cooling
2. stirringby stirring for 40 min
3. stirringby stirring for 40 min
4. concentrationThe reaction mixture was concentrated under a reduced pressure
5. customto give a residue
6. stirringby stirring at room temperature for 2 hrs
7. customThe reaction mixture was partitioned between ethyl acetate (50 ml) and water (20 ml)
8. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate
9. dry with materialdried over anhydrous sodium sulfate
10. customThe solvent was evaporated
11. customto give a residue, which
12. customwas then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate
13. customThe crude purified fraction
14. concentrationwas concentrated
15. custompurified again by silica gel column chromatography (Fuji Silysia NH, hexane