反应详情

To a methanol (5 mL) solution of 3-(2-nitro-ethyl)-5-phenoxy-pyridine (210 mg, 0.860 mmol) described in Manufacturing Example 145-1-4 was added lithium methoxide (65 mg, 1.72 mmol), which was stirred for 25 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (5 mL) ad methylene chloride (5 mL) was added titanium (IV) tetrachloride (236 μL, 2.15 mmol) under nitrogen atmosphere, which was stirred for 50 minutes at 0° C. Sodium hydrogencarbonate was added to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. To a tetrahydrofuran (4 mL) solution of this residue were added 3-ethynyl-pyridin-2,6-diamine (15 mg, 0.11 mmol) described in Manufacturing Example 13-1-3 and triethylamine (240 μL, 1.72 mmol), which was stirred for 1 hour and 15 minutes at 50° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.6 mg, 1.1%) as a ditrifluoroacetic acid salt.

1. concentrationThe reaction mixture was concentrated under a reduced pressure
2. additionTo a suspension of this residue in tetrahydrofuran (5 mL) ad methylene chloride (5 mL)
3. stirringwhich was stirred for 50 minutes at 0° C
4. extractionwhich was extracted with ethyl acetate
5. customThe organic layer was separated
6. washwashed with saturated aqueous sodium chloride
7. dry with materialdried over anhydrous magnesium sulfate
8. filtrationfiltered
9. concentrationThe filtrate was concentrated under a reduced pressure
10. stirringwas stirred for 1 hour and 15 minutes at 50° C
11. extractionwhich was extracted with ethyl acetate
12. customThe organic layer was separated
13. washwashed with saturated aqueous sodium chloride
14. dry with materialdried over anhydrous magnesium sulfate
15. filtrationfiltered
16. concentrationThe filtrate was concentrated under a reduced pressure
17. customthe residue was purified by reverse-phase high performance liquid chromatography (
18. additioncontaining 0.1% trifluoroacetic acid)