Methanol → (R)-tert-butyl 3-(4-bromo-N-(3-chloropyridin-2-yl)benzamido)piperidine-1-carboxylate

Temperature

-10 °C

Preparation 1 tert-Butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (214.4 g, 687.7 mmol) was dissolved in 260 mL of THF and the resulting suspension was cooled to −10° C. Lithium bis(trimethylsilyl)amide (1 mol/L in THF, 687.7 mL, 687.1 mmol) was added over 25 min followed by warming to 20° C. and stirring for 1 h before cooling back to −10° C. 4-Bromobenzoyl chloride (140.0 g, 625.2 mmol) was added as a solution in 230 mL of THF over 1.5 h, maintaining the internal temperature at less than −7° C. After complete addition, the reaction mixture was warmed to 0° C. at which point HPLC indicated the reaction was complete. MeOH was added (101 mL), then the reaction was warmed to room temperature and concentrated in vacuo to a low volume. The solvent was then exchanged to 2-MeTHF. The crude product solution (700 mL in 2-MeTHF) was washed with 700 mL of half-saturated aqueous NaHCO3, followed by 200 mL of half-saturated brine. The 2-MeTHF solution was concentrated to a low volume followed by addition of 400 mL of heptane resulting in precipitation of solids which were collected via filtration. The collected solids were dried to afford the title compound as a tan powder (244 g, 79% yield).

1. temperatureby warming to 20° C.
2. temperaturebefore cooling back to −10° C
3. temperaturemaintaining the internal temperature at less than −7° C
4. additionAfter complete addition
5. temperaturethe reaction mixture was warmed to 0° C. at which point HPLC
6. temperaturethe reaction was warmed to room temperature
7. concentrationconcentrated in vacuo to a low volume
8. washThe crude product solution (700 mL in 2-MeTHF) was washed with 700 mL of half-saturated aqueous NaHCO3
9. concentrationThe 2-MeTHF solution was concentrated to a low volume
10. additionfollowed by addition of 400 mL of heptane resulting in precipitation of solids which
11. filtrationwere collected via filtration
12. customThe collected solids were dried

ORD record

ord-bded389482b0408db05afd6a19a970d0

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09227956B2