Tetrahydrofuran → 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid methoxy-methyl-amide

HRID 228493Notes

Reaction equation

HRID 228493 reaction equation
[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])C.C1COCC1.Cl.[CH3:27][NH:28][O:29][CH3:30].C([Mg]Cl)(C)C>C(OCC)(=O)C>[NH3:8].[CH3:1][OH:3].[CH3:30][O:29][N:28]([CH3:27])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:7]1)=[O:5]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 3160450Ethyl 1-(4-methoxybenzyl)piperidine-3-carboxylateHCID 178418918HCID 178418918, compound

Product 2

HCID 21705897Ammonia methanolYield 3%HCID 597300371-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid methoxy-methyl-amideYield 186.4%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid ethyl ester (9.3 g, 33.5 mmol), THF (200 mL), N,O-Dimethylhydroxylamine hydrochloride (4.9 g, 50.3 mmol) at −10° C. (Acetone/ice bath) under a Nitrogen atmosphere. By dropwise addition, add Isopropylmagnesium chloride (50.3 mL, 100.6 mmol). Stir the reaction for 6 hours allowing the reaction mixture to warm to room temperature. Quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 1:1 Hexanes:Ethyl acetate and then 1:1 Hexanes:Ethyl acetate with 3% 1N NH3 MeOH to give 9.13 g (93% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.4-1.7 (3H, m), 1.8 (1H, d), 1.9 (1H, t), 2.1 (1H, t), 2.8-3.0 (3H, m), 3.1 (3H, s), 3.5 (2H, d), 3.6 (3H, s), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 293 (M+1).

Workup

  1. customat −10° C.
  2. additionBy dropwise addition
  3. customthe reaction for 6 hours
  4. customQuench the reaction mixture with sat NH4Cl (aq)
  5. extractionextract product from the water
  6. washWash the organic layer with brine
  7. dry with materialdry over Na2SO4
  8. concentrationConcentrate under reduced pressure and flash chromatograph

Sources & evidence

ORD record
ord-7c6236249c2f4418845e1a9fa3d49f7f
Source dataset
uspto-grants-2009_07
Patent number
US07560463B2

Reaction notes

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