反应详情

温度

90 °C

A 2-L four neck round bottom flask equipped with mechanical stirrer, reflux condenser with nitrogen outlet, positive pressure nitrogen inlet and thermocouple was charged with N-(3-amino-6-(2-chlorophenyl)-2-methoxypyridin-4-yl)-3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide (156.2 g, 0.346 mol) and AcOH (glacial, 780 mL). The resulting mixture was heated to 90° C. for 2 h. The resulting mixture was then was cooled to 50° C., transferred to a one-neck round bottom flask and concentrated on a rotary evaporator (bath at 50° C.). The resulting orange pasty solid was dissolved in EtOAc (1.5 L) and added to a separatory funnel containing saturated aqueous sodium bicarbonate (2 L) and EtOAc (1.5 L). The pH of the aqueous was still acidic, and was adjusted with 50% wt/wt NaOH (˜10 mL) to pH 8-9, then back to neutral with aqueous HCl (2 M, 120 mL) to a final pH of 6-8. The turbid organic layer was separated and the aqueous layer extracted with EtOAc (2×500 mL). The combined turbid organic layers were warmed in a 50° C. bath with gentle stirring and within 1-2 min, a clear orange solution resulted. The warm organic layer was quickly washed with brine (500 mL), dried (MgSO4) with occasional warming throughout the drying process, filtered and the volatiles removed under reduced pressure. The resulting residue crystallized on standing and then redissolved with dichloromethane to yield a turbid mixture. The resulting concentrate was loaded onto BIOTAGE 150M (2.5 kg silica, prewetted with 4 L heptane) and eluted with heptane (4 L), 10% EtOAc in heptane (12 L), and finally 20% EtOAc in heptane (16 L), whereby fractions of suitable purity were collected and concentrated to yield the title compound.

1. temperaturereflux condenser with nitrogen outlet, positive pressure nitrogen inlet
2. temperatureThe resulting mixture was then was cooled to 50° C.
3. customtransferred to a one-neck round bottom flask
4. concentrationconcentrated on a rotary evaporator (bath at 50° C.)
5. dissolutionThe resulting orange pasty solid was dissolved in EtOAc (1.5 L)
6. additionadded to a separatory funnel
7. additioncontaining saturated aqueous sodium bicarbonate (2 L) and EtOAc (1.5 L)
8. customThe turbid organic layer was separated
9. extractionthe aqueous layer extracted with EtOAc (2×500 mL)
10. temperatureThe combined turbid organic layers were warmed in a 50° C. bath
11. customa clear orange solution resulted
12. washThe warm organic layer was quickly washed with brine (500 mL)
13. dry with materialdried (MgSO4)
14. temperaturewith occasional warming throughout the drying process
15. filtrationfiltered
16. customthe volatiles removed under reduced pressure
17. customThe resulting residue crystallized
18. dissolutionredissolved with dichloromethane
19. customto yield a turbid mixture
20. concentrationThe resulting concentrate
21. washeluted with heptane (4 L), 10% EtOAc in heptane (12 L), and finally 20% EtOAc in heptane (16 L), whereby fractions of suitable purity
22. customwere collected
23. concentrationconcentrated