反应详情

温度

70 °C

To a solution of 5.5 g (22 mmol) ethyl(3-chloro-2,5,6-trifluoro-4-pyridinyl)acetate 1-1 in 75 mL DMF was added 3 g (19 mmol) 2,2-difluoro-2-(2-pyridinyl)ethylamine and 4 g (40 mmol) CaCO3 and the reaction mixture was heated to 70° C. for 18 hours. The reaction mixture was then cooled, diluted w. 400 mL ether, washed 2×300 mL water, and 1×300 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (90 g silica cartridge, linear gradient 5-50% EtOAc/hex over 30 min, 70 mL/min flow rate.) afforded ethyl (3-chloro-6-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-2,5-difluoro-4-pyridinyl)acetate 1-2 as a white solid. 1H NMR (400 mHz, CDCl3) δ8.66 (br d, 1H, J=4.94 Hz); 7.84 (ddd, 1H, J=7.7, 7.7, and 1.64 Hz); 7.70 (d, 1H, J=7.88 Hz); 7.41 (dd, 1H, J=4.95, 7.14 Hz); 5.40 (br m, 1H); 4.36 (dt, 2H, J=13.9, 6.22 Hz); 4.19 (q, 2H, J=7.14 Hz); 3.77 (d, 2H, J=1.83 Hz); 1.27 (t, 3H, J=7.14 Hz). Mass Spectrum (electrospray) M+H=392.0.

1. temperatureThe reaction mixture was then cooled
2. additiondiluted w
3. wash400 mL ether, washed 2×300 mL water, and 1×300 mL brine
4. dry with materialdried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated
7. customPurification by automated flash chromatography (90 g silica cartridge, linear gradient 5-50% EtOAc/hex over 30 min, 70 mL/min flow rate.)