反应详情

温度

105 °C

A mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (20.0 g, 71.5 mmol, Intermediate 3: step b) and 4-bromo-2-methylaniline (13.3 g, 71.5 mmol) in phosphorus oxychloride (66.8 mL, 712 mmol) was heated at 105° C. After 5 hours, the mixture was cooled to 23° C. and added to water (600 mL) with cooling so that the internal temperature did not exceed 35° C. The pH of the mixture was adjusted to 8-9 by the slow addition of saturated aqueous ammonia solution such that the internal temperature did not exceed 35° C. After 30 minutes of stirring at room temperature, the mixture was filtered and the solid material was suspended in acetonitrile (200 mL), sonicated and filtered. The solid material was collected and suspended in DCM (80 mL), sonicated, filtered and washed with ether (40 mL). The filtrate was concentrated, suspended in DCM (40 mL), sonicated and filtered to provide more of the title compound. To 5 g of the isolated solid, DCM (300 mL) and saturated aqueous NaHCO3 (100 mL) were added and the mixture was transferred to a separatory funnel, and the layers were separated. The DCM layer was further washed with brine (100 mL), dried (MgSO4), filtered and the solvents were removed under reduced pressure. The crude material was purified using flash-column chromatography on silica gel eluting with DCM to provide the title compound as an off-white solid.

1. temperaturethe mixture was cooled to 23° C.
2. temperaturewith cooling so that the internal temperature
3. customdid not exceed 35° C
4. customdid not exceed 35° C
5. filtrationthe mixture was filtered
6. customsonicated
7. filtrationfiltered
8. customThe solid material was collected
9. customsonicated
10. filtrationfiltered
11. washwashed with ether (40 mL)
12. concentrationThe filtrate was concentrated
13. customsonicated
14. filtrationfiltered