反应详情

With cooling with ice, oxalyl chloride (262 μl, 3 mmol) and a catalytic amount of dimethylformamide were added to a dichloromethane (7 ml) suspension of picolinic acid (271 mg, 2.2 mmol), followed by stirring at the same temperature for 10 minutes and stirring at room temperature for 20 minutes. After again cooling with ice, a dichloromethane suspension of 4-amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (458 mg, 2.0 mmol) and diisopropylethylamine (697 μl, 4 mmol) were added, followed by stirring at room temperature for 2 hours. The reaction liquid was diluted with chloroform, then the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was heated under reflux for 30 minutes in toluene (20 ml) in the presence of a catalytic amount of p-tosylic acid with a Dean-Stark device. After cooling, the solvent was evaporated away, the resulting residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was heated under reflux in xylene (20 ml) in the presence of a catalytic amount of p-tosylic acid with a Dean-Stark device. After cooling, the solvent was evaporated away, the resulting residue was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was washed with a mixed solvent of ethyl acetate and isopropyl ether, the precipitated solid was collected by filtration. This was suspended in toluene (40 ml), and heated under reflux for 15 hours in the presence of a catalytic amount of pyridinium p-toluenesulfonate. Further, the solvent was changed to xylene, a catalytic amount of p-toluenesulfonic acid was added, followed by heating under reflux for 12 hours. After cooling, the solvent was evaporated away, and the resulting residue was dissolved in chloroform, washed with water, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform/methanol (100:10, v/v→98:2, v/v) to obtain a main product. This was dissolved in dimethyl sulfoxide (8 ml), and (3S)-3-(dimethylamino)pyrrolidine (129 μl, 1.02 mmol) and triethylamine (150 μl) were added.

1. stirringstirring at room temperature for 20 minutes
2. temperatureAfter again cooling with ice
3. additionwere added
4. stirringby stirring at room temperature for 2 hours
5. customThe reaction liquid
6. washthe organic layer was washed with water
7. dry with materialdried over anhydrous sodium sulfate
8. customthe solvent was evaporated away under reduced pressure
9. temperatureThe resulting residue was heated
10. temperatureunder reflux for 30 minutes in toluene (20 ml) in the presence of a catalytic amount of p-tosylic acid with a Dean-Stark device
11. temperatureAfter cooling
12. customthe solvent was evaporated away
13. dissolutionthe resulting residue was dissolved in chloroform
14. washwashed with water
15. dry with materialdried over anhydrous sodium sulfate
16. customthe solvent was evaporated away under reduced pressure
17. temperatureThe resulting residue was heated
18. temperatureunder reflux in xylene (20 ml) in the presence of a catalytic amount of p-tosylic acid with a Dean-Stark device
19. temperatureAfter cooling
20. customthe solvent was evaporated away
21. dissolutionthe resulting residue was dissolved in chloroform
22. washwashed with water
23. dry with materialdried over anhydrous sodium sulfate
24. customthe solvent was evaporated away under reduced pressure
25. washThe resulting residue was washed with a mixed solvent of ethyl acetate and isopropyl ether
26. filtrationthe precipitated solid was collected by filtration
27. temperatureheated
28. temperatureunder reflux for 15 hours in the presence of a catalytic amount of pyridinium p-toluenesulfonate
29. additiona catalytic amount of p-toluenesulfonic acid was added
30. temperatureby heating
31. temperatureunder reflux for 12 hours
32. temperatureAfter cooling
33. customthe solvent was evaporated away
34. dissolutionthe resulting residue was dissolved in chloroform
35. washwashed with water
36. dry with materialdried over anhydrous sodium sulfate
37. customthe solvent was evaporated away under reduced pressure
38. washeluted with a mixed solvent of chloroform/methanol (100:10
39. customv/v→98:2, v/v) to obtain a main product