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

HRID 131041Notes

Reaction equation

HRID 131041 reaction equation
C(O[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>[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

6

Reactant 4

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

Product 1

HCID 597300371-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid methoxy-methyl-amideYield 93.2%

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 NH3MeOH 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-523afb6a94f84498b6b4754769410c4c
Source dataset
uspto-grants-2008_06
Patent number
US07381719B2

Reaction notes

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