反应详情

温度

60 °C

To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.1 mg, 12%) as a trifluoro acetic acid salt.

1. dissolutionwas dissolved
2. customby irradiating ultrasonic wave for 1 minute
3. concentrationThe reaction solution was concentrated under a reduced pressure, which
4. customgave a white solid
5. temperatureThis reaction mixture was cooled to room temperature
6. custompartitioned into water and ethyl acetate
7. customThe organic layer was separated
8. washwashed with water and saturated aqueous sodium chloride
9. dry with materialdried over anhydrous magnesium sulfate
10. filtrationfiltered
11. concentrationThe filtrate was concentrated under a reduced pressure
12. customThe residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:2)
13. customfurther purified by reverse-phase high performance liquid chromatography (
14. additioncontaining 0.1% trifluoroacetic acid)