反应 #554584

反应方程式

3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine

4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

Na2CO3

→

4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester

收率 65.0%

溶剂

DME

water

反应条件

后处理

1. 1
   其他The solution was degassed
2. 2
   workup.ADDITIONcharged with nitrogen three times
3. 3
   workup.ADDITIONTo the solution was added Pd(PPh3J2CI2 (351 mg, 0.50 mmol)
4. 4
   其他The reaction solution was degassed
5. 5
   workup.ADDITIONcharged with nitrogen again three times
6. 6
   其他until consumption of the borane pinacol ester),
7. 7
   温度cooled to ambient temperature
8. 8
   workup.ADDITIONdiluted with EtOAc (200 mL)
9. 9
   过滤The reaction mixture was filtered through a pad of celite
10. 10
    洗涤washed with EtOAc
11. 11
    洗涤The EtOAc solution was washed with brine
12. 12
    干燥dried over Na2SO4
13. 13
    浓缩concentrated
14. 14
    其他The crude product was purified on a silica gel column
15. 15
    洗涤eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc)

实验过程

To a stirred solution of 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (4.2711 g, 10.0 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na2CO3 (3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3J2CI2 (351 mg, 0.50 mmol). The reaction solution was degassed and charged with nitrogen again three times. The reaction solution was stirred at 87° C. oil bath for about 16 hours (or until consumption of the borane pinacol ester), cooled to ambient temperature and diluted with EtOAc (200 mL). The reaction mixture was filtered through a pad of celite and washed with EtOAc. The EtOAc solution was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified on a silica gel column eluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc) to afford 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4167 g, 65% yield, −95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.

来源