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

HRID 2084316Notes

Reaction equation

HRID 2084316 reaction equation
[C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]

Participants

6

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 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-10 °C

Procedure

To a solution of Boc-isonipecotic acid (40 g, 0.17 mol) and N-methylmorpholine (19 mL, 0.17 mol) in tetrahydrofuran (900 mL) stirring at −10° C., ethyl chloroformate was slowly added (17 mL, 0.17 mol) via addition funnel. After 30 min, sodium borohydride was added (19.8 g, 0.5 mol) in one portion. The reaction mixture was stirred at −10° C. for 1 h; then it was slowly quenched with methanol. The solvent was removed in vacuo: the resulting residue was diluted with 10% aqueous acetic acid and partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with additional ethyl acetate (2×500 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid residue which was chromatographed on silica gel. Elution with ethyl acetate-hexanes (1:9 to 1:1) provided the title compound (33.8 g, 90%) as a white solid.

Workup

  1. additionvia addition funnel
  2. customthen it was slowly quenched with methanol
  3. customThe solvent was removed in vacuo
  4. additionthe resulting residue was diluted with 10% aqueous acetic acid
  5. custompartitioned between ethyl acetate and water
  6. customThe aqueous layer was separated
  7. extractionextracted with additional ethyl acetate (2×500 mL)
  8. dry with materialThe combined organic extracts were dried with magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo to a solid residue which
  11. customwas chromatographed on silica gel
  12. washElution with ethyl acetate-hexanes (1:9 to 1:1)

Sources & evidence

ORD record
ord-7bd0aeed12b1479c9845083ec3b97d2a
Source dataset
uspto-grants-2004_04
Patent number
US06716855B2

Reaction notes

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