Реакция #554584

Уравнение реакции

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

Выход 65.0%

Растворители

DME

water

Условия реакции

Обработка

1. 1
   ДругоеThe 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
   ДругоеThe reaction solution was degassed
5. 5
   workup.ADDITIONcharged with nitrogen again three times
6. 6
   Другоеuntil consumption of the borane pinacol ester),
7. 7
   Температураcooled to ambient temperature
8. 8
   workup.ADDITIONdiluted with EtOAc (200 mL)
9. 9
   ФильтрацияThe reaction mixture was filtered through a pad of celite
10. 10
    Промывкаwashed with EtOAc
11. 11
    ПромывкаThe EtOAc solution was washed with brine
12. 12
    Сушкаdried over Na2SO4
13. 13
    Концентрированиеconcentrated
14. 14
    ДругоеThe crude product was purified on a silica gel column
15. 15
    Промывкаeluting with EtOAc/hexane system (0% EtOAc to 100% EtOAc)

Методика

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)+.

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