反应详情

温度

-52 °C

Preparation 13 ethyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate (108.5 g, 387.4 mmol) was dissolved in 1 L of THF and the resulting solution was cooled to −52° C. Isopropylmagnesium chloride (2 mol/L solution in THF, 200 mL, 400 mmol) was added over 27 minutes keeping the internal temperature <−39° C., followed by addition of zinc chloride (1.9 mol/L in 2-MeTHF, 120 mL, 230 mmol) over 15 minutes keeping the internal temperature <−39° C. The reaction was then warmed to 40° C. followed by addition of Preparation 10 tert-butyl (3R)-3-[(4-bromobenzoyl)(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (158.27 g, 319.9 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (4.60 g, 6.92 mmol). The reaction was warmed further to 55° C. and held for 2 h. After cooling to room temperature, the crude reaction mixture was filtered through Celite® and the filtrate was concentrated to give a foam. This material was re-dissolved in 1 L of 2-MeTHF and washed with 400 mL of water followed by filtration of the biphasic mixture and phase separation. 2-MeTHF was removed in vacuo and replaced with EtOH, then the solution was concentrated to a final volume of 1.5 L, resulting in precipitation of solids which were collected via filtration. After drying, the title compound was isolated as a tan solid (141.5 g, 78% yield).

1. customthe internal temperature <−39° C.
2. customthe internal temperature <−39° C
3. temperatureThe reaction was then warmed to 40° C.
4. temperatureThe reaction was warmed further to 55° C.
5. temperatureAfter cooling to room temperature
6. customthe crude reaction mixture
7. filtrationwas filtered through Celite®
8. concentrationthe filtrate was concentrated
9. customto give a foam
10. washwashed with 400 mL of water
11. filtrationfollowed by filtration of the biphasic mixture and phase separation
12. custom2-MeTHF was removed in vacuo
13. concentrationthe solution was concentrated to a final volume of 1.5 L
14. customresulting in precipitation of solids which
15. filtrationwere collected via filtration
16. customAfter drying