反应详情

温度

80 °C

To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (65 mg, 0.20 mmol) and 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine (60 mg, 0.24 mmol) in anhydrous DMF (1.0 mL) at room temperature was added anhydrous K2CO3 (66 mg, 0.48 mmol). The resulting suspension was stirred at 80° C. The reaction progressed slowly, and additional 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine (60 mg, 0.24 mmol) and K2CO3 (66 mg, 0.48 mmol) were added after 1.5 h. After stirring for additional 5 h, the same amounts of 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine and K2CO3 were again added. The reaction mixture was stirred at 80° C. for 1 h more before a few drops of diisopropylethylamine were added. The resulting black reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The EtOAc layer was washed with water twice, then saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (0-70%) in hexanes to afford the title compound (95% pure) as a yellow foam. This was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 10 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 35 mg (34%) of the title compound as a light yellow powder. HPLC/MS: retention time=3.07 min, [M+H]+=510.2. 1H NMR (CDCl3, 400 MHz): δ 8.55 (dd, J=1.8, 6.2 Hz, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.16 (d, J=1.8, 6.2 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.66 (d, J=7.5 Hz, 1H), 5.26 (s, 2H), 3.04 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).

1. stirringAfter stirring for additional 5 h
2. additionwere added
3. stirringThe resulting black reaction mixture was stirred at 80° C. overnight
4. temperatureThe reaction mixture was cooled to room temperature
5. custompartitioned between EtOAc and water
6. washThe EtOAc layer was washed with water twice
7. dry with materialsaturated aqueous NaCl, dried (Na2SO4)
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. customThe crude product was purified
11. washeluted with a gradient of ethyl acetate (0-70%) in hexanes