反应详情

To a solution of 2-(trimethylsilyl)ethyl [4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]carbamate (222 mg) in tetrahydrofuran (7.0 ml) was added 10% palladium carbon (71.2 mg), followed by stirring under a hydrogen atmosphere at room temperature for 25 hrs. The reaction mixture was filtered to remove the catalyst, which was then washed with methanol (5.0 ml). 4-Fluorophenyl acetic acid (103 mg) and thionyl chloride (0.448 ml) were put in another vessel, stirred at 90° C. for 30 min, and concentrated under a reduced pressure. The resultant residue was dissolved in acetonitrile (5.0 ml), and then potassium thiocyanate (130 mg, 1.34 mmol) was added thereto, followed by stirring at 50° C. for 1 hr. The reaction mixture was added to the above filtrate, followed by stirring at room temperature for 1 hr. To the reaction mixture were added ethyl acetate (50 ml) and brine (30 ml) to partition. The organic layer was washed with brine (30 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then dissolved in tetrahydrofuran (5.0 ml), and then 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.891 ml) was added thereto, followed by stirring at room temperature for 30 min. The reaction mixture was concentrated, and then 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.1 ml) was further added thereto, followed by stirring at room temperature for 30 min. Then, 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.5 ml) was further added thereto, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate (50 ml) and brine (30 ml) to partition. The organic layer was washed with brine (30 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1) to provide the target compound (75.4 mg, 43.5%) as a pale yellow oil.

1. filtrationThe reaction mixture was filtered
2. customto remove the catalyst, which
3. washwas then washed with methanol (5.0 ml)
4. custom4-Fluorophenyl acetic acid (103 mg) and thionyl chloride (0.448 ml) were put in another vessel
5. stirringstirred at 90° C. for 30 min
6. concentrationconcentrated under a reduced pressure
7. dissolutionThe resultant residue was dissolved in acetonitrile (5.0 ml)
8. stirringby stirring at 50° C. for 1 hr
9. additionThe reaction mixture was added to the above filtrate
10. stirringby stirring at room temperature for 1 hr
11. customto partition
12. washThe organic layer was washed with brine (30 ml×3)
13. dry with materialdried over anhydrous sodium sulfate
14. customThe solvent was evaporated
15. customto give a residue, which
16. stirringby stirring at room temperature for 30 min
17. concentrationThe reaction mixture was concentrated
18. addition1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.1 ml) was further added
19. stirringby stirring at room temperature for 30 min
20. additionThen, 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.5 ml) was further added
21. stirringby stirring at room temperature overnight
22. additionTo the reaction mixture were added ethyl acetate (50 ml) and brine (30 ml)
23. customto partition
24. washThe organic layer was washed with brine (30 ml×3)
25. dry with materialdried over anhydrous sodium sulfate
26. customThe solvent was evaporated
27. customto give a residue, which
28. customwas then purified by silica gel column chromatography (Fuji Silysia NH, eluent