反应详情

温度

0 °C

To a mechanically stirred solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid from the previous step (20 g, 52 mmol) in THF (104 mL) at −78° C. was added N-methyl morpholine (NMM) (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below −70° C. This mixture was stirred at −78° C. for 15 minutes and at 0° C. for 1 h. The white solid was filtered off and the filtrate containing the mixed anhydride cooled back to −78° C. for the subsequent reaction. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at −78° C. was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below −70° C. and stirred for 45 min. This metalated chiral auxiliary was cannulated to add to a reaction flask containing the anhydride solution at −78° C. The reaction was stirred and allowed to warm to 0° C. over 1.5 h. The resulting mixture was stirred further at 0° C. for 30 minute and quenched by adding excess saturated aqueous NH4Cl solution. The solution was diluted with EtOAc (200 mL) and the organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL). The solution was dried over MgSO4 and the solvent was removed in vacuo. The crude material was purified by ISCO silica gel column chromatography to yield 20.3 g (72%) of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid.

1. temperaturemaintaining the internal temperature below −70° C
2. filtrationThe white solid was filtered off
3. additionthe filtrate containing the mixed anhydride
4. temperaturecooled back to −78° C. for the subsequent reaction
5. temperaturemaintaining the internal temperature below −70° C.
6. stirringstirred for 45 min
7. additionto add to a reaction flask
8. stirringThe reaction was stirred
9. temperatureto warm to 0° C. over 1.5 h
10. stirringThe resulting mixture was stirred further at 0° C. for 30 minute
11. customquenched
12. additionby adding excess saturated aqueous NH4Cl solution
13. additionThe solution was diluted with EtOAc (200 mL)
14. washthe organic phase was washed with saturated aqueous NaHCO3 solution (3×100 mL) and brine (2×100 mL)
15. dry with materialThe solution was dried over MgSO4
16. customthe solvent was removed in vacuo
17. customThe crude material was purified by ISCO silica gel column chromatography