Hydrogen Peroxide → rac-tert-butyl (4R,5R)-4-fluoro-5-hydroxyazepane-1-carboxylate

Temperatur

-5 °C

To a tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved in THF (430 mL) solution and the solution was cooled to −5° C. L-selectride (112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture was gradually warmed to ambient temperature over 3 hours and stirred for an additional 20 hours. The resulting cloudy mixture was diluted with 110 mL of MeOH which was followed by the addition of NaOH (355 mL, 355 mmol, 1.0M aqueous). The mixture was cooled in a water bath, and H2O2 (80.4 mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over 30 minutes. The mixture was stirred vigorously for 1 hour, then diluted with water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and 1N KHSO4 (2×150 mL), and the combined aqueous phases were back-extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, then dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes) to provide the product as a thick colorless oil which slowly became a white solid (13.9 g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis).

1. temperatureThe mixture was gradually warmed to ambient temperature over 3 hours
2. temperatureThe mixture was cooled in a water bath
3. stirringThe mixture was stirred vigorously for 1 hour
4. extractionextracted with EtOAc (3×200 mL)
5. washThe combined organic layers were washed with water and 1N KHSO4 (2×150 mL)
6. extractionthe combined aqueous phases were back-extracted with EtOAc (200 mL)
7. washThe combined organic layers were washed with saturated aqueous NaHCO3
8. dry with materialdried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated
11. customThe crude product was purified via column chromatography (15% to 60% EtOAc/hexanes)

ORD-Eintrag

ord-28e37197cae049f6b67ebe9011648c5e

Quelldatensatz

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08575145B2