p-Bromochlorobenzene → Tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3-methylpiperidine-1-carboxylate

Temperatur

-78 °C

A solution of 1-bromo-4-chlorobenzene (21.87 g, 114 mmol) in anhydrous THF (250 mL) was cooled to −78° C. and treated dropwise with n-butyllithium (43.5 mL, 109 mmol, 1.6 M in hexanes). The mixture was stirred at −78° C. for 45 minutes, during which time a precipitate was observed, then the slurry was treated dropwise with a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (11.6 g, 54.4 mmol) in anhydrous THF (50 mL). The reaction was stirred at −78° C. for 2 hours, then allowed to slowly warm to −20° C. and quenched with saturated ammonium chloride. The layers were separated, and the organic phase was concentrated in vacuo. The aqueous phase was extracted once with ethyl acetate (300 mL), and the organic phase was combined with the residue from the original organic phase. The mixture was washed 3 times with water, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was digested in boiling hexanes (200 mL) for 1 hour, and then the mixture was cooled to room temperature. The solids were collected by filtration, rinsed with a small amount of hot hexanes, and dried under vacuum to yield tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3-methylpiperidine-1-carboxylate (13.96 g, 42.8 mmol, 79% yield) as a powder. m/z=252.2 (M-tBuO)+.

1. stirringThe reaction was stirred at −78° C. for 2 hours
2. temperatureto slowly warm to −20° C.
3. customquenched with saturated ammonium chloride
4. customThe layers were separated
5. concentrationthe organic phase was concentrated in vacuo
6. extractionThe aqueous phase was extracted once with ethyl acetate (300 mL)
7. washThe mixture was washed 3 times with water
8. dry with materialonce with brine, then dried over sodium sulfate
9. concentrationconcentrated in vacuo
10. customfor 1 hour
11. temperaturethe mixture was cooled to room temperature
12. filtrationThe solids were collected by filtration
13. washrinsed with a small amount of hot hexanes
14. customdried under vacuum

ORD-Eintrag

ord-035dad7749d447afa785c8a128f1dbe1

Quelldatensatz

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08642622B2