反应详情

温度

5 °C

Sodium hydrogen carbonate (36.3 kg, 1.7 mol eq) was charged followed by iso-propylacetate (102.5 L, 2.5 rel vol). 3-(trifluoromethyl)aniline (41.0 kg, 1 mol eq, limiting reagent) charged followed by a line rinse of iso-propylacetate (20.5 L, 0.5 rel vol). The reaction was cooled to 5° C.-10° C. Methyl malonyl chloride (36.5 kg, 1.05 mol eq) was charged maintaining the temperature below 10° C. followed by a line rinse of iso-propylacetate (10.3 L, 0.25 rel vol). The mixture was stirred until the reaction was complete as judged by HPLC. The temperature was adjusted to 20° C. and further iso-propylacetate (71.8 L, 1.75 rel vol) charged followed by water (205 L, 5 rel vol). The layers were separated & the organic layer further extracted with brine (41 L, 1 rel vol). The solvent was swapped from iso-propylacetate to cyclohexane by reduced pressure distillation. Following seeding, cooling to 5° C. and stirring, the product was isolated by filtration, washed twice with cyclohexane (2×41 L, 2×1 rel vol) and dried to constant weight to yield the title compound (60.6 kg, 232.2 mol, 91%).

1. additioncharged
2. washrinse of iso-propylacetate (20.5 L, 0.5 rel vol)
3. temperatureThe reaction was cooled to 5° C.-10° C
4. temperaturemaintaining the temperature below 10° C.
5. washrinse of iso-propylacetate (10.3 L, 0.25 rel vol)
6. customwas adjusted to 20° C.
7. additionfurther iso-propylacetate (71.8 L, 1.75 rel vol) charged
8. customThe layers were separated
9. extractionthe organic layer further extracted with brine (41 L, 1 rel vol)
10. distillationThe solvent was swapped from iso-propylacetate to cyclohexane by reduced pressure distillation
11. stirringstirring
12. customthe product was isolated by filtration
13. washwashed twice with cyclohexane (2×41 L, 2×1 rel vol)
14. customdried to constant weight