反应详情

To a methanol (5.00 mL) solution of 2-(4-fluoro-phenoxymethyl)-5-(2-nitro-ethyl)-pyridine (50.0 mg, 0.181 mmol) described in Manufacturing Example 72-1-3 was added lithium methoxide (13.7 mg, 0.362 mmol) under nitrogen atmosphere at room temperature, which was stirred for 30 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and anhydrous dichloromethane (4.00 ml) and anhydrous tetrahydrofuran (2.00 ml) were added to the residue. Titanium (IV) chloride (63.7 μL, 0.579 mmol) was added dropwise into the reaction mixture on a dry ice-ethanol bath (−78° C.), and stirred for 40 minutes at 0° C. Water and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (43.0 mg). To a tetrahydrofuran (5.00 mL) solution of this crude product (23.0 mg) and 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (3.44 mg, 0.029 mmol) was added triethylamine (12.2 μL, 0.083 mmol) at room temperature, which was stirred for 2 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2), the mixture was further purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (3.62 mg, 25.4%) as a ditrifluoracetic acid salt.

1. customThe solvent was evaporated from the reaction mixture under a reduced pressure, and anhydrous dichloromethane (4.00 ml) and anhydrous tetrahydrofuran (2.00 ml)
2. additionwere added to the residue
3. stirringstirred for 40 minutes at 0° C
4. extractionthe organic layer was extracted with ethyl acetate
5. washThis organic layer was washed with water and saturated aqueous sodium chloride
6. dry with materialdried over anhydrous magnesium sulfate
7. filtrationfiltered
8. concentrationThe filtrate was concentrated under a reduced pressure
9. customto obtain a crude product (43.0 mg)
10. stirringwhich was stirred for 2 hours at room temperature
11. extractionwhich was then extracted with ethyl acetate
12. washThe organic layer was washed with saturated aqueous sodium chloride
13. dry with materialdried over anhydrous magnesium sulfate
14. customthe solvent was evaporated under a reduced pressure
15. customThe residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2)
16. customthe mixture was further purified by reverse-phase high-performance liquid chromatography (
17. additioncontaining 0.1% trifluoracetic acid)