Benzyl chloroformate → Benzyl 3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate

A solution of the 1-benzyl-4-hydroxymethyl-piperidin-3-ol from Step 1 above (13.5 g) in methanol (450 mL) was hydrogenated at 50 psi over 20% palladium hydroxide on charcoal (10 g) for 48 h in three batches. The combined reaction mixtures were filtered and the filtrate evaporated to give an oil. This was dissolved in water (100 mL) and dioxane (100 mL), cooled to 5° C., and benzyl chloroformate (7.8 mL) was added slowly, with addition of 1M NaOH to maintain a pH of 10–11. After 30 min, the cooling bath was removed and reaction mixture stirred for 30 min. The reaction mixture was concentrated to remove dioxane and the residue extracted with EtOAc (×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give a mixture of cis and trans 3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester products. Purification by flash column chromatography (80% EtOAc hexane to 5% MeOH EtOAc) gave the upper Rf cis isomer (major) and the lower Rf trans isomer (minor).

1. customThe combined reaction mixtures
2. filtrationwere filtered
3. customthe filtrate evaporated
4. customto give an oil
5. temperatureto maintain a pH of 10–11
6. customthe cooling bath was removed
7. customreaction mixture
8. concentrationThe reaction mixture was concentrated
9. customto remove dioxane
10. extractionthe residue extracted with EtOAc (×3)
11. washThe combined extracts were washed with brine
12. dry with materialdried over anhydrous sodium sulfate and solvent
13. customevaporated
14. customto give
15. customPurification by flash column chromatography (80% EtOAc hexane to 5% MeOH EtOAc)
16. customgave the upper Rf cis isomer (major)

ORD-Eintrag

ord-3b280626daff465f9b3fcaa674266f4f

Quelldatensatz

uspto-grants-2007_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07217716B2