反应详情

To a methanol (20.0 mL) solution of 2-(3-fluoro-4-(2-nitro-ethyl)-phenoxymethyl)-pyridine (400 mg, 1.45 mmol) described in Manufacturing Example 95-1-3 was added lithium methoxide (110 mg, 2.90 mmol), which was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (20.0 mL) and anhydrous tetrahydrofuran (10.0 mL) were added to the residue. Titanium (IV) chloride (510 μL, 4.64 mmol) was added dropwise to the reaction mixture on a dry ice-ethanol bath (−78° C.), which was stirred for 60 minutes at room temperature. Water, ethyl acetate, and tetrahydrofuran 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 then filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (360 mg). To a tetrahydrofuran (5.00 mL) solution of 3-ethynyl-pyridin-2,6-diamine (40.0 mg, 0.300 mmol) described in Manufacturing Example 13-1-3 and this crude product (180 mg) was added triethylamine (125 μL, 0.900 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 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=2:1→3:1), 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 (3.20 mg, 1.72%) as a ditrifluoroacetic acid salt.

1. concentrationThe reaction mixture was concentrated under a reduced pressure, and anhydrous dichloromethane (20.0 mL) and anhydrous tetrahydrofuran (10.0 mL)
2. additionwere added to the residue
3. stirringwas stirred for 60 minutes at room temperature
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 (360 mg)
10. stirringwhich was stirred for 2 hours at room temperature
11. extractionwhich was 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=2:1→3:1)
16. customfurther purified by reverse-phase high performance liquid chromatography (
17. additioncontaining 0.1% trifluoroacetic acid)