反应详情

温度

-10 °C

Dissolve (S)-5-Hydroxymethyl-dihydro-furan-2-one (1.21 g, 1 eq.) in THF (16 mL) and cool to −10° C. To this add dimethylethylamine (1.8 mL, 1.5 eq.) followed by the dropwise addition of TMS-Cl (1.46 mL, 1.1 eq.) Allow the reaction to stir for 1.5 hours at −10° C. Gas Chromatography confirms complete consumption of the (S)-5-Hydroxymethyl-dihydro-furan-2-one. Filter the mixture and wash with additional THF (25 mL). Cool the solution to −78° C. To this add LiHMDS (10 mL, 1.23 eq. to (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone) dropwise and allow to stir at −78° C. for 30 minutes. Add (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone (4 g, 0.76 eq. to (S)-5-Hydroxymethyl-dihydro-furan-2-one) and keep the reaction at −78° C. After 1 hour, TLC (50% EtOAc/Heptane) shows approximately 50% (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone. At the end of the day, add LiHMDS (3 mL) and allow to warm to room temperature overnight. TLC (50% EtOAc/Heptane) still shows a small amount of (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone. Quench the reaction with phosphoric acid:water (1:3) (50 mL) and allow to stir at room temperature for 1 hour. Extract the aqueous layer with EtOAc (3×100 mL). Combine the organic layers, dry and concentrate. Pass the crude oil through a silica gel plug (EtOAc) to give the titled compound (2.57 g, 60% yield).

1. customthe reaction
2. customconsumption of the (S)-5-Hydroxymethyl-dihydro-furan-2-one
3. filtrationFilter the mixture
4. washwash with additional THF (25 mL)
5. temperatureCool the solution to −78° C
6. stirringto stir at −78° C. for 30 minutes
7. customthe reaction at −78° C
8. waitAfter 1 hour
9. temperatureto warm to room temperature overnight
10. customQuench
11. customthe reaction with phosphoric acid:water (1:3) (50 mL)
12. stirringto stir at room temperature for 1 hour
13. extractionExtract the aqueous layer with EtOAc (3×100 mL)
14. customCombine the organic layers, dry
15. concentrationconcentrate