Hexane → Benzyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate

Temperatur

-78 °C

A solution of 3-bromopyridine (9.09 mL, 94.31 mmol) in diethyl ether (50 mL) was added dropwise to a stirred solution of 1.6M n-butyl lithium in hexane (58.9 mL, 94.31 mmol) in diethyl ether (500 mL) cooled to −78° C., over a period of 15 minutes under nitrogen. The resulting suspension was stirred at −78° C. for 1 hour. A solution of benzyl 4-oxopiperidine-1-carboxylate (20 g, 85.74 mmol) in diethyl ether (50 mL) and THF (50 mL) was added dropwise over 15 minutes. The reaction mixture was stirred at −78° C. for 1 hour, warmed to 0° C. over 2.5 hours and quenched with saturated ammonium chloride solution (500 ml). The mixture was extracted with ethyl acetate (2×500 mL) and the combined extracts were washed with brine (200 mL) then dried over MgSO4 and filtered through a short pad of silica. The silica pad was washed through with ethyl acetate (4×250 mL) and the filtrate was concentrated under vacuum. The residue was purified by flash silica chromatography eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford benzyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate (12.8 g, 48%) as an oil.

1. stirringThe reaction mixture was stirred at −78° C. for 1 hour
2. temperaturewarmed to 0° C. over 2.5 hours
3. customquenched with saturated ammonium chloride solution (500 ml)
4. extractionThe mixture was extracted with ethyl acetate (2×500 mL)
5. washthe combined extracts were washed with brine (200 mL)
6. dry with materialthen dried over MgSO4
7. filtrationfiltered through a short pad of silica
8. washThe silica pad was washed through with ethyl acetate (4×250 mL)
9. concentrationthe filtrate was concentrated under vacuum
10. customThe residue was purified by flash silica chromatography
11. washeluting with ethyl acetate
12. customPure fractions were evaporated to dryness

ORD-Eintrag

ord-785266b4f5264dc381a84af4eb9853a3

Quelldatensatz

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08003649B2