反应详情

Dissolve commercially available (S)-5-hydroxymethyl-dihydro-furan-2-one (33.0 g, 284 mmoles) in 450 mL of THF, and then add 31.2 g (427 mmoles) of dimethylethylamine along with 50 mL of THF (rinse). Place the mixture under nitrogen and cool in an ice/water bath. Add trimethylsilyl chloride 39.8 mL (313 mmoles) while maintaining the temperature below 13° C. Filter the mixture and rinse the cake with THF (2×100 mL). Cool the solution of TMS (trimethylsilyl) protected lactone to −78° C. and add 4-bromomethyl-3,5-dichloro-4′-fluoro-biphenyl (71.2 g, 213 mmoles). Add a 1 M solution of lithium hexamethyldisilazide in THF (264 mL, 264 mmoles) over 1 h at −65 to −78° C. After stirring for 1 h, add a 600 mL solution of 120 mL of conc. phosphoric acid in water. After stirring for 10 min at room temperature, add 1 L of ethyl acetate and stir the mixture for 10 min. The layers separate. Wash the organic layer with water (2×500 mL). Evaporate the solvent down to a solution of approximately 250 mL and add an additional 250 mL of EtOAc. Evaporate the solvent until a solution of approximately 300-350 mL remains. Heat the mixture to reflux and add 494 mL of heptane. Allow the slurry to cool to room temperature, collect the solids by filtration, and rinse with heptane (2×100 mL). Dry the solid under vacuum to afford 62.1 g (59%) of the titled compound. MS (m/z): 369 (M+1, 35Cl), 371 (M+1, 37Cl).

1. temperaturecool in an ice/water bath
2. filtrationFilter the mixture
3. washrinse the cake with THF (2×100 mL)
4. temperatureCool the solution of TMS (trimethylsilyl)
5. customto −78° C.
6. stirringAfter stirring for 10 min at room temperature
7. stirringstir the mixture for 10 min
8. customThe layers separate
9. washWash the organic layer with water (2×500 mL)
10. customEvaporate the solvent down to a solution of approximately 250 mL
11. additionadd an additional 250 mL of EtOAc
12. customEvaporate the solvent until a solution of approximately 300-350 mL
13. temperatureHeat the mixture
14. temperatureto reflux
15. additionadd 494 mL of heptane
16. customcollect the solids
17. filtrationby filtration
18. washrinse with heptane (2×100 mL)
19. customDry the solid under vacuum