反应详情

温度

-68 °C

To tetrahydrofuran (THF) (180 mL) was added a 2.0M lithium diisopropylamide/THF-ethylbenzene-heptane solution (272 mL), the mixture was cooled to −68° C. in a dry ice-methanol bath, and a solution of methyl isobutyrate (55.38 g) in THF (180 mL) was added dropwise at −64° C. or lower for 50 minutes. The mixture was stirred at around −65° C. for 1 hour, and then a solution of [(4-bromobutoxy)methyl]benzene (40.0 g) and hexamethylphosphoric acid triamide (29.48 g) in THF (90 mL) was added dropwise at −62° C. or lower for about 30 minutes. After the mixture was stirred at the same temperature for 30 minutes, the dry ice bath was removed, followed by stirring for about 1.5 hours. The reaction solution was placed into an aqueous saturated ammonium chloride solution (1.4 L), followed by extraction with a mixed solution (1.6 L) of hexane:ethyl acetate (3:1). The extract solution was washed with water and an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting orange liquid was treated with a silica gel column (hexane:ethyl acetate=15:1). The resulting compound (82.0 g) was dissolved in methanol (820 mL), a 4N hydrogen chloride/1,4-dioxane solution (82 mL) and 10% palladium carbon (50% hydrous product, 8.2 g) were added, and hydrogen was blown into the solution for 3.5 hours while stirring on a hot bath at 50° C. After cooled to room temperature, the system was replaced with nitrogen, and the catalyst was filtered off using Celite, followed by concentration under reduced pressure. Operation of adding toluene to the residue, and concentrating this again under reduced pressure was performed two times, followed by purification with a silica gel column (hexane:ethyl acetate=4:1→2:1). The resulting compound (23.88 g), carbon tetrachloride (170 mL) and sodium periodate (65.9 g) were added to a mixed solution of water (255 mL) and acetonitrile (170 mL), and then ruthenium trichloride (n-hydrate) (716 mg) was added for about 3 minutes in portions. After stirred at room temperature for 4 hours, the reaction mixture was dispersed in water (0.8 L), followed by extraction with ethyl acetate. After the extract solution was washed with water, an aqueous saturated sodium chloride solution was added, the mixture was stirred and filtered with Celite, and layers were separated. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in toluene, and concentration operation was performed two times to obtain the title compound (27.2 g) having the following physical property values.

1. stirringAfter the mixture was stirred at the same temperature for 30 minutes
2. customthe dry ice bath was removed
3. stirringby stirring for about 1.5 hours
4. extractionfollowed by extraction with a mixed solution (1.6 L) of hexane:ethyl acetate (3:1)
5. washThe extract solution was washed with water
6. dry with materialan aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate
7. concentrationconcentrated under reduced pressure
8. additionThe resulting orange liquid was treated with a silica gel column (hexane:ethyl acetate=15:1)
9. dissolutionThe resulting compound (82.0 g) was dissolved in methanol (820 mL)
10. additiona 4N hydrogen chloride/1,4-dioxane solution (82 mL) and 10% palladium carbon (50% hydrous product, 8.2 g) were added
11. waithydrogen was blown into the solution for 3.5 hours
12. stirringwhile stirring on a hot bath at 50° C
13. temperatureAfter cooled to room temperature
14. filtrationthe catalyst was filtered off
15. concentrationfollowed by concentration under reduced pressure
16. concentrationOperation of adding toluene to the residue, and concentrating this again under reduced pressure
17. customfollowed by purification with a silica gel column (hexane:ethyl acetate=4:1→2:1)
18. additionThe resulting compound (23.88 g), carbon tetrachloride (170 mL) and sodium periodate (65.9 g) were added to a mixed solution of water (255 mL) and acetonitrile (170 mL)
19. additionruthenium trichloride (n-hydrate) (716 mg) was added for about 3 minutes in portions
20. stirringAfter stirred at room temperature for 4 hours
21. additionthe reaction mixture was dispersed in water (0.8 L)
22. extractionfollowed by extraction with ethyl acetate
23. washAfter the extract solution was washed with water
24. additionan aqueous saturated sodium chloride solution was added
25. stirringthe mixture was stirred
26. filtrationfiltered with Celite, and layers
27. customwere separated
28. dry with materialThe organic layer was dried with anhydrous sodium sulfate
29. concentrationconcentrated under reduced pressure
30. dissolutionThe resulting residue was dissolved in toluene
31. concentrationconcentration operation