تفاعل #554584

معادلة التفاعل

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

المردود 65.0%

المذيبات

DME

water

ظروف التفاعل

المعالجة

1. 1
   أخرىThe 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
   أخرىThe reaction solution was degassed
5. 5
   workup.ADDITIONcharged with nitrogen again three times
6. 6
   أخرىuntil consumption of the borane pinacol ester),
7. 7
   درجة الحرارةcooled to ambient temperature
8. 8
   workup.ADDITIONdiluted with EtOAc (200 mL)
9. 9
   ترشيحThe reaction mixture was filtered through a pad of celite
10. 10
    غسيلwashed with EtOAc
11. 11
    غسيلThe EtOAc solution was washed with brine
12. 12
    تجفيفdried over Na2SO4
13. 13
    تركيزconcentrated
14. 14
    أخرىThe crude product was purified on a silica gel column
15. 15
    غسيلeluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc)

الإجراء التجريبي

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)+.

المصدر