反应详情

2-(R)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)morpholine TsOH salt (1.83 assay Kg, 3.00 mol) was suspended in 10 L of DMF and potassium carbonate (1.04 Kg, 7.5 mol) was added in one portion to give a white slurry. Propargyl bromide (80 wt % in toluene, 535 g, 3.6 mol) was added dropwise over 30 minutes, the reaction was sligtly exothermic <30° C. (without cooling). The reaction mixture was stirred at room temperature for ~3 hours (~99.9% conversion) and then 40% aqueous dimethylamine was added, and aged for 30 minutes (to destroy excess propargyl bromide), then the reaction solution was partitioned between 20 L of toluene and 20 L of water. The organic layer was washed with water twice (2×18 L). The resulting organic layer was concentrated to 6 L with KF<250 μg/mL (additional toluene may need to be used to achieve this KF specifcation).

1. customto give a white slurry
2. customwas sligtly exothermic <30° C.
3. temperature(without cooling)
4. custom(to destroy excess propargyl bromide)
5. customthe reaction solution was partitioned between 20 L of toluene and 20 L of water
6. washThe organic layer was washed with water twice (2×18 L)
7. concentrationThe resulting organic layer was concentrated to 6 L with KF<250 μg/mL (additional toluene