4-Methylmorpholine → Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate

HRID 988617Notes

Reaction equation

HRID 988617 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 10928Ethyl chloroformateHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 4311764Sodium borohydride

Product 1

HCID 2764081Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylateYield 92.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1-tert-butoxycarbonyl isonipecotic acid (40 g, 0.17 mol) and N-methylmorpholine (19 mL, 0.17 mol) in tetrahydrofuran (900 mL) at −10° C. was treated with ethyl chloroformate (17 mL, 0.17 mol). After 0.5 h, sodium borohydride was added (19.8 g, 0.5 mol) in one portion followed by slow addition of methanol. After gas evolution ceased, the mixture was concentrated and the residue was diluted with 10% aqueous acetic acid and partitioned between ethyl acetate and water. The aqueous layer was washed with EtOAc (2×) and the combined organic extracts were dried with magnesium sulfate, filtered, and concentrated to a solid residue which was purified by column chromatography (SiO2: 10 to 50% EtOAc:hexanes) providing the title compound (33.8 g, 90%) as a white solid.

Workup

  1. concentrationthe mixture was concentrated
  2. additionthe residue was diluted with 10% aqueous acetic acid
  3. custompartitioned between ethyl acetate and water
  4. washThe aqueous layer was washed with EtOAc (2×)
  5. dry with materialthe combined organic extracts were dried with magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to a solid residue which
  8. customwas purified by column chromatography (SiO2: 10 to 50% EtOAc:hexanes)

Sources & evidence

ORD record
ord-7d5746050f6948cb9a1d9e668e44fe98
Source dataset
uspto-grants-2003_10
Patent number
US06635657B1

Reaction notes

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