反应详情

To a mixture of 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.33 g) and tetrahydrofuran (20 mL) was added sodium borohydride (0.047 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (20 mL), sodium hydride (0.037 g) was added, and the mixture was stirred at room temperature for 10 min. Methyl iodide (0.046 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue was added 1N aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in dimethyl sulfoxide (5 mL), and the mixture was added to a mixture of hydroxylammonium chloride (0.46 g), sodium hydrogencarbonate (0.7 g) and dimethyl sulfoxide (10 mL), which had been stirred at 40° C. for 30 min in advance. The reaction mixture was stirred at 90° C. for 16 hr, diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.068 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.057 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.14 g, 36%).

1. concentrationThe reaction mixture was concentrated
2. extractionthe residue was extracted with ethyl acetate and saturated aqueous ammonium chloride solution
3. washThe ethyl acetate layer was washed with saturated brine
4. dry with materialdried over anhydrous magnesium sulfate
5. customThe solvent was evaporated under reduced pressure
6. dissolutionThe obtained residue was dissolved in N,N-dimethylformamide (20 mL)
7. additionsodium hydride (0.037 g) was added
8. stirringthe mixture was stirred at room temperature for 10 min
9. additionMethyl iodide (0.046 mL) was added to the reaction mixture
10. stirringthe mixture was further stirred at room temperature for 1 hr
11. additionThe reaction mixture was diluted with ethyl acetate
12. washwashed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine
13. dry with materialdried over anhydrous magnesium sulfate
14. customThe solvent was evaporated under reduced pressure
15. additionTo the obtained residue was added 1N aqueous sodium hydroxide solution (50 mL)
16. stirringthe mixture was stirred at 60° C. for 1 hr
17. extractionthe mixture was extracted with ethyl acetate
18. washThe obtained ethyl acetate layer was washed with saturated brine
19. dry with materialdried over anhydrous magnesium sulfate
20. customThe solvent was evaporated under reduced pressure
21. customThe residue obtained by silica gel column chromatography
22. stirringhad been stirred at 40° C. for 30 min in advance
23. stirringThe reaction mixture was stirred at 90° C. for 16 hr
24. washwashed successively with water and saturated brine
25. dry with materialdried over anhydrous magnesium sulfate
26. customThe solvent was evaporated under reduced pressure
27. dissolutionThe residue was dissolved in methylene chloride (30 mL)
28. additionN,N′-carbonyldiimidazole (0.068 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.057 mL) were added
29. stirringthe mixture was stirred at room temperature for 2 hr
30. additionThe reaction mixture was diluted with chloroform
31. washwashed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine
32. dry with materialdried over anhydrous magnesium sulfate
33. customThe solvent was evaporated under reduced pressure
34. filtrationThe precipitated solid was collected by filtration