Hydrogen Peroxide → trans-1-Benzyl-4-(4-methoxyphenyl)piperidin-3-ol

HRID 1507241Notes

Reaction equation

HRID 1507241 reaction equation
[BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[CH2:12]([N:19]1[CH2:24][CH:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].OO>C1COCC1.O.C(O)C>[CH2:12]([N:19]1[CH2:20][CH2:21][C@@H:22]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C@H:23]([OH:9])[CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1

Participants

9

Reactant 5

HCID 784Hydrogen PeroxideHCID 8000Boron trifluoride etherateHCID 14798Sodium HydroxideHCID 4311764Sodium borohydrideHCID 106364031-Benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine

Product 1

HCID 118207341trans-1-Benzyl-4-(4-methoxyphenyl)piperidin-3-olYield 70.1%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent2×

Procedure

To a suspension of NaBH4 (2.7 g, 72 mmol) in THF (150 mL) at −10° C. was added boron trifluoride etherate (9.1 mL, 72 mmol) and the solution was stirred for 15 minutes. Then a solution of 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol) in 100 mL tetrahydrofuran was added and the mixture was stirred for an additional hour. Next were sequentially added 25 mL of water, 25 mL of 10% aqueous sodium hydroxide, 50 mL of ethanol, and 12.8 mL of 30% aqueous hydrogen peroxide (125 mmol) and the final mixture was heated to reflux overnight. The mixture was allowed to cool and was then diluted with 200 mL of water and extracted with 300 mL of ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was triturated with diethyl ether to yield 7.5 g (57%) (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol. LCMS (method A) RT 2.03 min, 81.5% AP, m/z 298.4 (M+H+), 1H NMR (300 MHz, DMSO-d6) δ ppm 7.28-7.35 (m, 5H) 7.14 (d, J=8.69 Hz, 2H) 6.83 (d, J=8.69 Hz, 2H) 4.43 (d, J=6.04 Hz, 1H) 3.51 (d, J=19.26 Hz, 4H) 3.33 (s, 3H) 2.97 (dd, J=10.01, 3.59 Hz, 1H) 2.81 (d, J=10.95 Hz, 1H) 2.19-2.29 (m, 1H) 1.96-1.98 (m, 1H) 1.78 (t, J=10.20 Hz, 1H) 1.58-1.68 (m, 2H).

Workup

  1. stirringthe mixture was stirred for an additional hour
  2. temperatureto reflux overnight
  3. temperatureto cool
  4. extractionextracted with 300 mL of ethyl acetate
  5. customThe organic layer was separated
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. customevaporated under reduced pressure
  9. customThe residue was triturated with diethyl ether

Sources & evidence

ORD record
ord-1548d668beb94ca8b040ec7eb40edb03
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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