反应详情

温度

40 °C

tert-Butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 4 above; 108.1 g, 273.3 mmol), 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (35.6 g, 287 mmol) and palladium on charcoal (3.09 g, 1.37 mmol) were charged to a suitable pressure vessel. Tetrahydrofuran (920 ml), water (54 ml) and acetic acid (32.8 g, 546.7 mmol) were charged and the stiffed mixture heated to 60° C. under 3 bar of hydrogen until the reaction deemed complete. The mixture was then cooled to 40° C. and 2 M sodium hydroxide solution (410 ml, 820 mmol) added. On cooling to 25° C. the mixture was filtered to remove catalyst before tetrahydrofuran (650 ml) was added and the organic phase separated. The organic phase was partially concentrated by distillation before toluene (575 ml) was added. The distillation was continued whilst maintaining the reaction volume with further addition of toluene (690 ml). The reaction mixture was allowed to cool to ambient temperature over about 3 hours during which the product crystallizes. The solid was collected by filtration, washed with toluene (460 ml), then ethyl acetate (230 ml) before being dried in vacuo at 45° C. to constant weight to give the title compound (114.9 g, 83%).

1. temperatureOn cooling to 25° C. the mixture
2. filtrationwas filtered
3. customto remove catalyst before tetrahydrofuran (650 ml)
4. additionwas added
5. customthe organic phase separated
6. concentrationThe organic phase was partially concentrated by distillation before toluene (575 ml)
7. additionwas added
8. distillationThe distillation
9. temperaturewhilst maintaining the reaction volume
10. additionwith further addition of toluene (690 ml)
11. temperatureto cool to ambient temperature over about 3 hours during which the product
12. customcrystallizes
13. filtrationThe solid was collected by filtration
14. washwashed with toluene (460 ml)
15. dry with materialethyl acetate (230 ml) before being dried in vacuo at 45° C. to constant weight