Methanamine, N-methoxy-, hydrochloride (1:1) → 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide

HRID 579581Notes

Reaction equation

HRID 579581 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:21]([O:22][CH3:23])[CH3:20])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 90423Ethyl 1-benzylpiperidine-4-carboxylateHCID 178418918HCID 178418918, compound

Product 1

HCID 211930301-benzyl-N-methoxy-N-methylpiperidine-4-carboxamideYield 84%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (6.12 g, 62.6 mmol) in THF (80 mL) was cooled to 0° C. prior to the addition of i-PrMgCl (121.2 mmol, 60.6 mL, 2 M in THF) dropwise. The reaction was stirred for 1 h, then quenched by addition of saturated aqueous ammonium chloride (90 mL). The aqueous and organic layers were separated. The separated aqueous phase was further extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (2-18% methanol in dichloromethane) to afford the desired product (8.88 g, 84%). Rf 0.45 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.20 (m, 5H), 3.69 (s, 3H), 3.51 (s, 2H), 3.17 (s, 3H), 2.94 (d, 2H, J=11.4 Hz), 2.63-2.66 (m, 1H), 2.01 (td, J=11.7, 2.9 Hz, 2H), 1.83 (qd, J=12.8, 3.7 Hz, 2H), 1.72-1.67 (m, 2H). ESI MS found for C15H22N2O2 m/z [263.3 (M+1)].

Workup

  1. customquenched by addition of saturated aqueous ammonium chloride (90 mL)
  2. customThe aqueous and organic layers were separated
  3. extractionThe separated aqueous phase was further extracted with ethyl acetate
  4. washThe combined organic layers were washed with saturated aqueous sodium chloride
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was chromatographed on silica gel (2-18% methanol in dichloromethane)

Sources & evidence

ORD record
ord-0598326e64e84f2ebe3e263899fdf100
Source dataset
uspto-grants-2015_05
Patent number
US09040703B2

Reaction notes

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