反应详情

温度

87 °C

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 (15.22 g, 35.64 mmol) and 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (14.12 g, 42.77 mmol) in DME (143 mL) was added a solution of Na2CO3 (11.33 g, 10692 mmol) in water (36 mL). The solution was degassed and charged with nitrogen three times. To the solution was added Pd(PPh3)2Cl2 (1.25 mg, 1.782 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 (600 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 (Biotage 90+Column: equilibrium 600 mL 100% Hexanes, segment 1: 2250 mL 50% EtOAc/Hexanes Linear, segment 2: 4500 mL 75% EtOAc/Hexanes Linear, segment 3: 4500 mL 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 (11.8 g, 60% yield, ˜95% purity) with a Rf of 0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)+.

1. customThe solution was degassed
2. additioncharged with nitrogen three times
3. customThe reaction solution was degassed
4. additioncharged with nitrogen again three times
5. customuntil consumption of the borane pinacol ester),
6. temperaturecooled to ambient temperature
7. additiondiluted with EtOAc (600 mL)
8. filtrationThe reaction mixture was filtered through a pad of celite
9. washwashed with EtOAc
10. washThe EtOAc solution was washed with brine
11. dry with materialdried over Na2SO4
12. concentrationconcentrated
13. customThe crude product was purified on a silica gel column
14. washeluting with EtOAc/Hexane system (Biotage 90+Column: equilibrium 600 mL 100% Hexanes, segment 1: 2250 mL 50% EtOAc/Hexanes Linear, segment 2: 4500 mL 75% EtOAc/Hexanes Linear, segment 3: 4500 mL 100% EtOAc)