反应详情

温度

40 °C

[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 mL) in a 5000 mL flask fitted with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the internal temperature was raised to 40° C. When all the solids had dissolved and the solution temperature had reached 40° C., solid KHMDS (376.2 g, 1890 mmol) was added over a period of 5 minutes. When addition of the potassium base was complete, a heterogeneous yellow solution was obtained, and the internal temperature had risen to 62° C. After a period of 60 minutes, the internal temperature decreased back to 40° C., and the reaction was determined to be complete by HPLC (no starting material or uncyclized intermediate was present). The thick reaction mixture was then quenched by pouring it into H2O (6000 mL) and stirring the resulting mixture until it had reached room temperature. The mixture was then filtered, and the filter pad was washed with water (1000 mL 2×). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50° C. overnight providing 155.3 g (47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.

1. customfitted with a condenser, mechanical stirrer
2. customtemperature probe, and purged with argon
3. dissolutionWhen all the solids had dissolved
4. customhad reached 40° C.
5. customa heterogeneous yellow solution was obtained
6. customhad risen to 62° C
7. customdecreased back to 40° C.
8. customThe thick reaction mixture was then quenched
9. additionby pouring it into H2O (6000 mL)
10. customhad reached room temperature
11. filtrationThe mixture was then filtered
12. washthe filter pad was washed with water (1000 mL 2×)
13. customdried in a vacuum oven at 50° C. overnight