反应详情

温度

-78 °C

Under argon and at −78° C., 14.0 ml (1.0M in THF, 14.0 mmol, 1.05 eq.) of bis(trimethylsilyl)lithium amide were added dropwise to a solution of 5.0 g (13.3 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 100 ml of tetrahydrofuran, and the mixture was stirred at −78° C. for 15 min. 2.6 g (14.7 mmol, 1.1 eq.) of neat ethyl trifluoromethanesulphonate were then added dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for another 1 h. The reaction mixture was cooled to 0° C., and saturated aqueous ammonium chloride solution was added. After phase separation, the aqueous phase was extracted twice with methyl tert-butyl ether. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by flash chromatography (340 g of silica gel, mobile phase: cyclohexane/ethyl acetate mixtures 8:1, 4:1). The product-containing fractions were combined and concentrated under reduced pressure. The residue was dissolved in hot methyl tert-butyl ether and the solution was left to stand without any cover, and after 10 min the mixture had crystallized almost completely. The crystals were filtered off and washed twice with methyl tert-butyl ether. The combined filtrates were concentrated under reduced pressure and the residue was re-crystallized as described. The two crystal batches were combined and dried under reduced pressure. Yield: 4.2 g (78% of theory)

1. customThe cooling bath was removed
2. stirringthe reaction mixture was stirred at RT for another 1 h
3. temperatureThe reaction mixture was cooled to 0° C.
4. additionsaturated aqueous ammonium chloride solution was added
5. customAfter phase separation
6. extractionthe aqueous phase was extracted twice with methyl tert-butyl ether
7. dry with materialThe combined organic phases were dried (sodium sulphate)
8. filtrationfiltered
9. concentrationconcentrated under reduced pressure
10. customThe crude product was then purified by flash chromatography (340 g of silica gel, mobile phase: cyclohexane/ethyl acetate mixtures 8:1, 4:1)
11. concentrationconcentrated under reduced pressure
12. dissolutionThe residue was dissolved in hot methyl tert-butyl ether
13. waitthe solution was left
14. customafter 10 min the mixture had crystallized almost completely
15. filtrationThe crystals were filtered off
16. washwashed twice with methyl tert-butyl ether
17. concentrationThe combined filtrates were concentrated under reduced pressure
18. customthe residue was re-crystallized
19. customdried under reduced pressure