Hydrogen Peroxide → Trans-1-benzyl-4-isopropyl-piperidin-3-ol

Temperature

0 °C

Add boron trifluoride etherate (4.6 mL, 36.2 mmol) slowly to a solution of 1-benzyl-4-isopropyl-3,6-dihydro-2H-pyridine (6.7 g, 30.2 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under a nitrogen atmosphere. Stir the mixture for 15 minutes and then dropwise add borane-tetrahydrofuran complex (1M in tetrahydrofuran, 42.3 mL, 42.2 mmol). Allow the mixture to reach ambient temperature and stir for 6 hours. Then add slowly borane-tetrahydrofuran complex (24.1 mL, 24.1 mmol) and stir the mixture overnight. Cool the mixture at 0° C. and add methanol (54 mL) slowly. Stir the mixture at ambient temperature for one hour. Cool the mixture to 0° C. and add a solution of 10% CaCl2 in HCl (0.2M) slowly until the mixture has a pH of 1-2. Stir the mixture at ambient temperature for 1.5 hours. Cool the mixture at 0° C. and add a solution of 35% hydrogen peroxide (3.1 mL, 36.2 mmol). Stir the mixture at ambient temperature over the weekend. Add an aqueous solution of 10% Na2SO3 (15 mL) and methyl tert-butyl ether (50 mL). Add NaOH (5M) to pH 11-12. Separate the organic layer and extract the aqueous layer with methyl tert-butyl ether. Combine the organic layers and wash with brine; dry over MgSO4; filter; collect the filtrate; then remove the solvent under vacuum. Purify the residue by chromatography on a silica gel cartridge eluting with hexane:ethyl acetate (100% to 50% hexane) to obtain the title compound (2.6 g, 37%). MS (m/z): 234 (M+1).

1. customto reach ambient temperature
2. stirringstir for 6 hours
3. additionThen add slowly borane-tetrahydrofuran complex (24.1 mL, 24.1 mmol)
4. stirringstir the mixture overnight
5. stirringStir the mixture at ambient temperature for one hour
6. temperatureCool the mixture to 0° C.
7. stirringStir the mixture at ambient temperature for 1.5 hours
8. temperatureCool the mixture at 0° C.
9. stirringStir the mixture at ambient temperature over the weekend
10. customSeparate the organic layer
11. extractionextract the aqueous layer with methyl tert-butyl ether
12. washwash with brine
13. dry with materialdry over MgSO4
14. filtrationfilter
15. customcollect the filtrate
16. customthen remove the solvent under vacuum
17. customPurify the residue by chromatography on a silica gel cartridge
18. washeluting with hexane

ORD record

ord-a490cd78f1ca4c13b7964995cd3b77d3

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09073856B2