反应详情

170 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 719 mmol, 1 equivalent) were initially charged in 3800 ml of ethanol, and 151 g of powdered molecular sieve 3 Å and 623 g of ethyl 2-chloroacetoacetate (3.6 mol, 5 equivalents) were added. The reaction mixture was heated at reflux for 24 h and then filtered off through silica gel and concentrated under reduced pressure. The mixture was kept at RT for 48 h, and the solid formed was filtered off. The solid was then stirred three times with a little isopropanol and then filtered off and washed with diethyl ether. This gave 60.8 g (23% of theory) of the title compound. The combined filtrates of the filtration steps were concentrated and the residue was chromatographed on silica gel using cyclohexane/diethyl ether as mobile phase. This gave a further 46.5 g (18% of theory; total yield: 41% of theory) of the title compound.

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 24 h
3. filtrationfiltered off through silica gel
4. concentrationconcentrated under reduced pressure
5. customthe solid formed
6. filtrationwas filtered off
7. filtrationfiltered off
8. washwashed with diethyl ether
9. filtrationThe combined filtrates of the filtration steps
10. concentrationwere concentrated
11. customthe residue was chromatographed on silica gel