反应详情

温度

42.5 °C

A 3 L multi-neck flask was equipped with an agitator, thermometer, dip tube, and nitrogen protection. The flask was charged with N-methyl pyrrolidinone (0.77 kg, 0.75 L, d=1.033 g/mL). At ambient temperature, 4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline (0.0748 kg) [see, U.S. Pat. No. 6,002,008] was added and the mixture stirred while heating to 40-45° C. and hold for 15 min. The flask was cooled to 0-10° C. The mixture containing 4-N,N-dimethylaminocrotonoyl chloride hydrochloride was transferred via dip tube and positive nitrogen pressure to the 3 L flask over 30-45 min, while maintaining 0-10° C. The mixture was kept at 0-10° C. for a minimum of 2 h. The reaction was checked for completion by HPLC. The reaction is complete when there is ≦2% of the starting material (4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline) present. A 12 L multi-neck flask equipped with agitator, thermometer, dip tube, and nitrogen protection was charged with water (2.61 kg, 2.61 L). Sodium bicarbonate (0.209 kg) was added and stirred until a solution was obtained. The solution was cooled to 20-24° C. The NMP-CH3CN mixture was transferred, via dip tube and positive nitrogen pressure, to the 12 L flask over 45-60 min, while maintaining 20-24° C. The mixture was maintained at 20-24° C. for a minimum of 1 h, and filtered on a Buchner funnel, and rinsed with water (3×0.40 kg, 3×0.40 L) with suction being maintained until dripping stops. The product was dried in a vacuum oven at 50° C. and 10 mm Hg for 28-30 h to give 78.5 g (86% yield) of product.

1. customA 3 L multi-neck flask was equipped with an agitator
2. customAt ambient temperature
3. addition6,002,008] was added
4. temperatureThe flask was cooled to 0-10° C
5. customwas transferred via dip tube
6. waitpositive nitrogen pressure to the 3 L flask over 30-45 min
7. temperaturewhile maintaining 0-10° C
8. customwas kept at 0-10° C. for a minimum of 2 h
9. customA 12 L multi-neck flask equipped with agitator
10. stirringstirred until a solution
11. customwas obtained
12. temperatureThe solution was cooled to 20-24° C
13. waitpositive nitrogen pressure, to the 12 L flask over 45-60 min
14. temperaturewhile maintaining 20-24° C
15. temperatureThe mixture was maintained at 20-24° C. for a minimum of 1 h
16. filtrationfiltered on a Buchner funnel
17. washrinsed with water (3×0.40 kg, 3×0.40 L) with suction
18. temperaturebeing maintained
19. customThe product was dried in a vacuum oven at 50° C.