Sodium borohydride → 1,1-Dimethylethyl 3-hydroxy-4-(hydroxymethyl)-1-piperidinecarboxylate

HRID 2168646Notes

Reaction equation

HRID 2168646 reaction equation
C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]1=[O:19])=O)C.[BH4-].[Na+]>C1COCC1.CO>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH:7]([OH:19])[CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]

Participants

5

Reactant 2

HCID 4311764Sodium borohydrideHCID 158529891-tert-Butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate

Product 1

HCID 154810601,1-Dimethylethyl 3-hydroxy-4-(hydroxymethyl)-1-piperidinecarboxylateYield 77.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of 3-Oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (10 g) in a mixture of THF (100 mL) and MeOH (50 mL) was added NaBH4 in 10 lots over 1 h period. At the end of 1 h, TLC analysis (eluant: EtOAC) showed complete consumption of starting material. Removed solvent under reduced pressure, to the residue was added saturated NH4Cl solution (200 mL) and stirred for 1 h at rt. The aqueous layer was extracted with DCM (4×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated the filtrate. The product was purified by silica gel column chromatography (Eluant 8:2 EtOAc/Hexanes) to give 3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, cis/trans mixture). The cis/trans mixture (5 g) was separated on ISCO (Combiflash instrument) on a silica gel column (300 g) by eluting with ethyl acetate in hexanes to get (±)-trans-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, HRf) and (±)-cis-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, LRf).

Workup

  1. customAt the end of 1 h, TLC analysis (eluant: EtOAC)
  2. customconsumption of starting material
  3. additionRemoved solvent under reduced pressure, to the residue was added saturated NH4Cl solution (200 mL)
  4. extractionThe aqueous layer was extracted with DCM (4×100 mL)
  5. dry with materialThe combined organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated the filtrate
  8. customThe product was purified by silica gel column chromatography (Eluant 8:2 EtOAc/Hexanes)

Sources & evidence

ORD record
ord-425d05216251418788dc9caff5e11700
Source dataset
uspto-grants-2015_06
Patent number
US09045461B2

Reaction notes

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