反応 #833507

反応方程式

N-methyl pyrrolidinone

water

Sodium bicarbonate

4-[3-chloro-4-fluorophenyl]amino-6-amino-3-cyano-7-ethoxy quinoline

→

product

収率 86.0%

EKB-569

収率 86.0%

溶媒

NMP CH3CN

反応条件

後処理

1. 1
   その他A 3 L multi-neck flask was equipped with an agitator
2. 2
   その他At ambient temperature
3. 3
   workup.ADDITION6,002,008] was added
4. 4
   温度The flask was cooled to 0-10° C
5. 5
   その他was transferred via dip tube
6. 6
   workup.WAITpositive nitrogen pressure to the 3 L flask over 30-45 min
7. 7
   温度while maintaining 0-10° C
8. 8
   その他was kept at 0-10° C. for a minimum of 2 h
9. 9
   その他A 12 L multi-neck flask equipped with agitator
10. 10
    workup.STIRRINGstirred until a solution
11. 11
    その他was obtained
12. 12
    温度The solution was cooled to 20-24° C
13. 13
    workup.WAITpositive nitrogen pressure, to the 12 L flask over 45-60 min
14. 14
    温度while maintaining 20-24° C
15. 15
    温度The mixture was maintained at 20-24° C. for a minimum of 1 h
16. 16
    ろ過filtered on a Buchner funnel
17. 17
    洗浄rinsed with water (3×0.40 kg, 3×0.40 L) with suction
18. 18
    温度being maintained
19. 19
    その他The product was dried in a vacuum oven at 50° C.

実験手順

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.

出典