Hydrogen Peroxide → 4-(4-Fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

HRID 1518967Notes

Reaction equation

HRID 1518967 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:21].[Na+].OO>C1COCC1>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C@@H:13]([OH:21])[CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]

Participants

5

Reactant 3

HCID 784Hydrogen PeroxideHCID 14798Sodium HydroxideHCID 157514261,1-Dimethylethyl 4-(4-fluorophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate

Product 1

HCID 897142794-(4-Fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl esterYield 95.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

Add borane tetrahydrofuran complex (171 mL, 171 mmol) to a solution of tert-butyl 4-(4-fluorophenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (54 g, 186 mmol) in THF (544 mL) under a nitrogen atmosphere. Stir overnight at 40° C., then add 2M sodium hydroxide (36.8 g, 70.8 mmol) and stir for 12 minutes at ambient temperature. Add hydrogen peroxide (31.1 mL, 357.8 mmol) while maintaining the internal temperature at 19-21° C. through the use of an ice-water bath. After addition is complete, remove the ice bath and stir at ambient temperature for 3 hours. Dilute the reaction mixture with water (250 mL) and extract twice with methyl tert-butyl ether (500 mL). Combine organic extracts, and sequentially wash with brine, sodium bisulfate then brine again. Dry the organics over magnesium sulphate; filter; collect the filtrate; and concentrate under vacuum. Purify the crude material via flash column chromatography using hexane/ethyl acetate (4:1, then 3:1) followed by DCM/EtOAc (1:1, then 0:100). Combine product fractions and dry under vacuum to give a white solid. Separate enantiomers using chromatography conditions “L” (see below), collecting the first eluting isomer to give the title compound (20.02 g, 36.4%) as a white solid. MS (m/z): 196 (M+1-Boc).

Workup

  1. stirringstir for 12 minutes at ambient temperature
  2. additionAfter addition
  3. customremove the ice bath
  4. stirringstir at ambient temperature for 3 hours
  5. additionDilute the reaction mixture with water (250 mL)
  6. extractionextract twice with methyl tert-butyl ether (500 mL)
  7. washCombine organic extracts, and sequentially wash with brine, sodium bisulfate
  8. dry with materialDry the organics over magnesium sulphate
  9. filtrationfilter
  10. customcollect the filtrate
  11. concentrationand concentrate under vacuum
  12. customPurify the crude material via flash column chromatography
  13. customCombine product fractions and dry under vacuum
  14. customto give a white solid
  15. customcollecting the first eluting isomer

Sources & evidence

ORD record
ord-088c71ef4f77490fb1588441647c382e
Source dataset
uspto-grants-2015_07
Patent number
US09073856B2

Reaction notes

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