Dimethylformamide → 6-ethyl-3-{2-[4-(2-hydroxyethoxy)phenyl]-2-oxoethyl}-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

Temperature

60 °C

To a mixture of 4′-{[6-ethyl-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.49 g), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.40 mL) and N,N-dimethylformamide (5 mL) was added cesium carbonate (0.6 g), and the mixture was stirred at 60° C. for 5 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and added to a mixture of hydroxylammonium chloride (0.52 g), sodium hydrogencarbonate (0.78 g) and dimethyl sulfoxide (5 mL) stirred at 50° C. for 30 min, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.2 g) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.18 g, 31%).

1. temperatureto cool to room temperature
2. extractionthe mixture was extracted with ethyl acetate
3. washThe organic layer was washed successively with water and saturated brine
4. dry with materialdried over anhydrous magnesium sulfate
5. customThe solvent was evaporated under reduced pressure
6. customThe obtained residue was purified by silica gel column chromatography
7. additionadded to a mixture of hydroxylammonium chloride (0.52 g), sodium hydrogencarbonate (0.78 g) and dimethyl sulfoxide (5 mL)
8. stirringstirred at 50° C. for 30 min
9. stirringthe mixture was stirred at 90° C. for 20 hr
10. temperatureto cool to room temperature
11. additionethyl acetate and water were added to the reaction mixture
12. extractionthe mixture was extracted with ethyl acetate
13. washThe organic layer was washed successively with water and saturated brine
14. dry with materialdried over anhydrous magnesium sulfate
15. customThe solvent was evaporated under reduced pressure
16. customThe residue was purified by silica gel column chromatography
17. dissolutiondissolved in tetrahydrofuran (3 mL)
18. additionN,N′-Carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added
19. stirringthe mixture was stirred at room temperature for 2 hr
20. additionThe reaction mixture was diluted with ethyl acetate
21. washwashed successively with 1N hydrochloric acid and saturated brine
22. dry with materialdried over anhydrous magnesium sulfate
23. customThe solvent was evaporated under reduced pressure
24. dissolutionThe residue was dissolved in tetrahydrofuran (3 mL)
25. additiontetrabutylammonium fluoride (0.2 g) was added
26. stirringthe mixture was stirred at room temperature for 3 hr
27. additionTo the reaction mixture were added ethyl acetate and water
28. extractionthe mixture was extracted with ethyl acetate
29. washThe organic layer was washed successively with water and saturated brine
30. dry with materialdried over anhydrous magnesium sulfate
31. customThe solvent was evaporated under reduced pressure
32. customThe obtained residue was purified by silica gel column chromatography

ORD record

ord-ffc596b769074c27b571974730ecdea1

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08501750B2