反应详情

温度

-25 °C

The intermediate from example 1 step G (10.95 g, 17.0 mmol) was combined with (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (4.39 g, 17.0 mmol) and dissolved in 170 mL DCM. The vessel was cooled to −25° C. followed by the addition boron trifluoride etherate (0.48 g, 3.4 mmol). The reaction vessel was maintained at −25° C. for 1 hr. The reaction was quenched by the addition of a saturated solution of NaHCO3 and the mixture was allowed to warm to ambient temperature. The aqueous mixture was extracted several times with EtOAc and washed with brine, dried over Na2SO4, filtered through a fritted funnel and concentrated in vacuo. The crude residue was purified on silica gel and eluted toluene. The first component collected off the column was the unwanted diastereomer. The second component collected was the desired diastereomer and was determined to be 85% pure as determined by 1HNMR. The product was recrystallized from cold methanol to provide the pure title compound. 1H-NMR (CDCl3): δ 1.41 (d, 3H, J=6.5 Hz), 1.76-1.84 (m, 1H), 2.50-2.62 (m, 1H), 3.02 (dd, 1H, J=9.0, 12.0 Hz), 3.07 (dd, 1H, J=3.0, 9.5 Hz), 3.41 (dd, 1H, J=2.5, 10.0 Hz), 3.54 (dd, 1H, J=11.5, 11.5 Hz), 4.26-4.36 (m, 5H), 4.56 (dd, 1H, J=3.5, 11.0 Hz), 4.99 (q, 1H, J=6.5 Hz), 6.92-7.06 (m, 4H), 7.20-7.36 (m, 7H), 7.71 (s, 1H), 8.19 (d, 2H, J=9.0 Hz), 8.31 (d, 2H, J=9.0 Hz) ppm.

1. temperatureThe reaction vessel was maintained at −25° C. for 1 hr
2. customThe reaction was quenched by the addition of a saturated solution of NaHCO3
3. temperatureto warm to ambient temperature
4. extractionThe aqueous mixture was extracted several times with EtOAc
5. washwashed with brine
6. dry with materialdried over Na2SO4
7. filtrationfiltered through a fritted funnel
8. concentrationconcentrated in vacuo
9. customThe crude residue was purified on silica gel
10. washeluted toluene
11. customThe first component collected off the column
12. customThe second component collected
13. customThe product was recrystallized from cold methanol