تفاعل #833507

معادلة التفاعل

N-methyl pyrrolidinone

water

Sodium bicarbonate

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

→

product

المردود 86.0%

EKB-569

المردود 86.0%

المذيبات

NMP CH3CN

ظروف التفاعل

المعالجة

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

الإجراء التجريبي

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.

المصدر