3,5-Bis(trifluoromethyl)benzyl alcohol → 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine

Temperatur

-75 °C

A solution of 0.500 g (1.87 mmole) of N-benzyl-3-(S)-phenylmorpholine-2-one (from Example 14) in 10 mL of dry THF was cooled to -75° C. under nitrogen and was treated dropwise with 2.06 mL (2.06 mmole) of a 1M solution of lithium tri(sec-butyl)-borohydride (L-Selectride®) in THF. After stirring the solution at -75° C. for 30 min, a solution of 3,5-bis(trifluoromethyl)benzyl alcohol, trifluoromethanesulfonate ester in toluene was added by cannula so that the internal temperature was maintained below -60° C. The resulting solution was stirred at -75° C. for 1 hr and then between -38° C. and -50° C. for 2 hr. The solution was then poured into a mixture of 25 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate, and the layers were separated. The aqueous phase was extracted with 2×30 mL of ethyl acetate, the combined organic layers were dried over sodium sulfate, the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on 130 g of silica eluting with 2 L of 100:5 hexanes:ethyl acetate to give 0.68 g (73%) of an oil, which by 1H NMR is a 20:1 mixture of cis:trans morpholines.

1. temperaturewas maintained below -60° C
2. stirringThe resulting solution was stirred at -75° C. for 1 hr
3. waitbetween -38° C. and -50° C. for 2 hr
4. customthe layers were separated
5. extractionThe aqueous phase was extracted with 2×30 mL of ethyl acetate
6. dry with materialthe combined organic layers were dried over sodium sulfate
7. filtrationthe mixture was filtered
8. concentrationthe filtrate concentrated in vacuo
9. customThe residue was purified by flash chromatography on 130 g of silica eluting with 2 L of 100:5 hexanes

ORD-Eintrag

ord-a5d344eae1664d6cbad12e28e40272b4

Quelldatensatz

uspto-grants-1999_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05922706