反应详情

Sodium hydride (60% dispersion in mineral oil, 6.07 g, 151.60 mmol) was added portionwise, under nitrogen atmosphere, at 0° C., to a mixture of benzotriazol-1-yl-(4-cyclohexylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanone (25.4 g, 68.95 mmol) and tert-butyl ethyl malonate (14.36 mL, 75.83 mmol) in anhydrous DMF (400 mL) and the resulting mixture was stirred at RT for 15 h. The reaction mixture was poured into a mixture of NaHSO4 (aq 10%, 1 L) and ice (200 mL) and then was carefully extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (2×100 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The yellow oil obtained was dissolved in DCM (30 mL) and trifluoroacteic acid (60 mL) was added. The reaction mixture was heated at reflux for 1 h. The resulting mixture was cooled and the solvent was evaporated under reduced pressure. NaHCO3 (sat'd aq) was added until pH 7 was reached and the resulting mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane 10/90 to 15/85) to afford 20.9 g (90% yield) of 3-(4-cyclohexylamino-2-methylsulfanyl-pyrimidin-5-yl)-3-oxo-propionic acid ethyl ester.

1. extractionwas carefully extracted with EtOAc (2×200 mL)
2. washThe combined organic extracts were washed with water (2×100 mL)
3. dry with materialdried over Na2SO4
4. filtrationfiltered
5. customevaporated under reduced pressure
6. customThe yellow oil obtained
7. temperatureThe reaction mixture was heated
8. temperatureat reflux for 1 h
9. temperatureThe resulting mixture was cooled
10. customthe solvent was evaporated under reduced pressure
11. additionNaHCO3 (sat'd aq) was added until pH 7
12. extractionthe resulting mixture was extracted with EtOAc (3×100 mL)
13. dry with materialThe combined organic extracts were dried over Na2SO4
14. filtrationfiltered
15. customevaporated under reduced pressure
16. customThe crude residue was purified by flash chromatography (EtOAc/hexane 10/90 to 15/85)