反应详情

To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclohexyloxy)ethoxy)benzyl)benzene (intermediate AE) (0.3 g, 0.64 mmol) in anhydrous toluene/THF (v/v=2:1, 6 mL), n-BuLi (2.5 N, 0.39 mL, 0.96 mmol) was added dropwise at −78° C. and stirred for 1 h. Then the mixture was transferred to a solution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (0.447 g, 0.96 mmol) in anhydrous toluene (5 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and the mixture was allowed to warm to room temperature and stirred overnight. Then 20 mL of water was added. The organic phase was separated, and the water phase was extracted with EtOAc. The organic phases were combined, washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in anhydrous CH3CN (4 mL), Et3SiH (0.2 mL, 1.25 mmol) was added and the mixture was cooled to −20° C. Then BF3.Et2O (0.12 mL, 0.94 mmol) was added dropwise, and the mixture was allowed to warm to 20° C. and stirred overnight. After the reaction reached completion, it was quenched with saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with EtOAc and washed with water and brine. The product was dried with anhydrous Na2SO4, filtered, concentrated to a solid, and purified by preparative HPLC to obtain compound AF as a white powder upon freeze-drying. 1H NMR (400 MHz, CD3OD): δ 7.37-7.30 (m, 3H), 7.12 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.11-4.03 (m, 5H), 3.87-3.79 (m, 4H), 3.47-3.33 (m, 4H); 3.32-3.30 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.75 (m, 2H), 1.60-1.50 (m, 1H), 1.33-1.28 (m, 5H); MS ESI (m/z): 508 (M+H)+, calc. 507.

1. customat −78° C
2. stirringThe mixture was stirred at −78° C. for 2 h
3. customwas consumed
4. customThe reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH)
5. stirringstirred overnight
6. additionThen 20 mL of water was added
7. customThe organic phase was separated
8. extractionthe water phase was extracted with EtOAc
9. washwashed with saturated NaHCO3, water and brine
10. dry with materialdried with anhydrous Na2SO4
11. filtrationfiltered
12. concentrationconcentrated
13. dissolutionThe residue was dissolved in anhydrous CH3CN (4 mL)
14. temperaturethe mixture was cooled to −20° C
15. temperatureto warm to 20° C.
16. stirringstirred overnight
17. customwas quenched with saturated aqueous NaHCO3
18. customThe solvent was removed under reduced pressure
19. extractionthe residue was extracted with EtOAc
20. washwashed with water and brine
21. dry with materialThe product was dried with anhydrous Na2SO4
22. filtrationfiltered
23. concentrationconcentrated to a solid
24. custompurified by preparative HPLC
25. customto obtain compound AF as a white powder
26. customupon freeze-drying