반응 #1256888

반응 방정식

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

수율 60.1%

용매

DME

water

반응 조건

후처리

1. 1
   기타The solution was degassed
2. 2
   workup.ADDITIONcharged with nitrogen three times
3. 3
   기타The reaction solution was degassed
4. 4
   workup.ADDITIONcharged with nitrogen again three times
5. 5
   기타until consumption of the borane pinacol ester),
6. 6
   온도cooled to ambient temperature
7. 7
   workup.ADDITIONdiluted with EtOAc (600 mL)
8. 8
   여과The reaction mixture was filtered through a pad of celite
9. 9
   세척washed with EtOAc
10. 10
    세척The EtOAc solution was washed with brine
11. 11
    건조dried over Na2SO4
12. 12
    농축concentrated
13. 13
    기타The crude product was purified on a silica gel column
14. 14
    세척eluting 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)

실험 절차

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)+.

출처