Ammonium Hydroxide → (R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate

Temperatur

-78 °C

A solution of tert-butyl pyrrolidine-1-carboxylate (20 g, 116.8 mmol) and (−)-sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to −78° C. and sec-BuLi (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduced drop-wise via cannula, keeping the internal temperature under −70° C. The resulting solution was stirred for 3 hours at −78° C., followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, 1M in Et2O) drop-wise with rapid stirring, keeping the internal temperature below −65° C. The resulting light suspension was stirred at −78° C. for 30 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 2-bromo-1,4-difluorobenzene (14.5 mL, 128 mmol), Pd(OAc)2 (1.31 g, 5.8 mmol) and t-Bu3P—HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (10.5 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite and the filter cake washed with Et2O (1 L). The filtrate was washed with a 1M aqueous HCl solution (0.5 L) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate as yellow oil (23.9 g, 72% yield).

1. customunder −70° C
2. customthe internal temperature below −65° C
3. stirringThe resulting light suspension was stirred at −78° C. for 30 minutes
4. temperaturewarmed to ambient temperature
5. stirringAfter stirring overnight at ambient temperature
6. stirringthe reaction was stirred for 1 hour
7. filtrationThe resulting slurry was filtered through Celite
8. washthe filter cake washed with Et2O (1 L)
9. washThe filtrate was washed with a 1M aqueous HCl solution (0.5 L) and brine
10. filtrationThe organic layer was filtered
11. concentrationconcentrated
12. customthe crude product was purified by silica column chromatography
13. washeluting with 5-10% EtOAc/hexanes

ORD-Eintrag

ord-d097c27bf25d432f86dda92aff3690e4

Quelldatensatz

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08791123B2