反应详情

Sodium hydride (1.1 g) was suspended in dimethyl sulfoxide (60 ml) under a nitrogen stream, and 4-chloro-2-pyridinamine (2.9 g) described in WO 02/32872 and then 4-amino-3-fluorophenol (3.6 g, 28 mmol) were added thereto at room temperature while stirring, followed by stirring under a nitrogen stream at 150° C. for 9 hrs. The reaction mixture was cooled down to room temperature, and partitioned between 10% aqueous ammonia (150 ml) and ethyl acetate (350 ml). The organic layer was washed twice with 10% aqueous ammonia (150 ml). The combined aqueous layer was extracted with ethyl acetate (150 ml) again. The combined organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Crude fractions containing the target compound were concentrated to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound (1.3 g, 26%) as a purple solid.

1. stirringby stirring under a nitrogen stream at 150° C. for 9 hrs
2. temperatureThe reaction mixture was cooled down to room temperature
3. custompartitioned between 10% aqueous ammonia (150 ml) and ethyl acetate (350 ml)
4. washThe organic layer was washed twice with 10% aqueous ammonia (150 ml)
5. extractionThe combined aqueous layer was extracted with ethyl acetate (150 ml) again
6. washThe combined organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (100 ml)
7. dry with materialdried over anhydrous sodium sulfate
8. customThe solvent was evaporated
9. customto give a residue, which
10. customwas then purified by silica gel column chromatography (eluent
11. additionCrude fractions containing the target compound
12. concentrationwere concentrated
13. customto give a residue, which
14. customwas then purified by silica gel column chromatography (eluent; ethyl acetate)
15. additionFractions containing the target compound
16. concentrationwere concentrated