Benzyl Chloride → 3-Carbomethoxy-1,3-dibenzyl-4-piperidone

HRID 967000Notes

Reaction equation

HRID 967000 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4].[H-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4]

Participants

5

Reactant 3

HCID 7503Benzyl ChlorideHCID 24758Sodium hydrideHCID 107480Methyl 1-benzyl-4-oxo-3-piperidinecarboxylate

Product 1

HCID 542328573-Carbomethoxy-1,3-dibenzyl-4-piperidoneYield 83.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (5.14 g, 20.8 mmol) in DMF (130 mL) at 0° C. was added sodium hydride (60% by weight in mineral oil, 0.874 g, 21.8 mmol) in four portions over 0.5 h. After stirring at 0° C. for an additional 0.5 h, benzyl chloride (2.87 mL, 25.0 mmol) was added and the reaction mixture was allowed to stir for 14 h while warming to room temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution, the organic layer was removed and the aqueous layer was washed four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 0.5% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step A as a pale yellow oil (5.89 g): +APcI MS (M+1)+ 338; 1H NMR (400 MHz, CDCl3) δ: 7.09-7.39 (arom, series of m, 10H), 3.60 (s, 3H), 3.56 (d, 2H), 3.38 (m, 1H), 3.20 (d, 1H), 2.93 (m, 2H), 2.78 (m, 1H), 2.42 (m, 2H), 2.31 (m, 1H).

Workup

  1. stirringto stir for 14 h
  2. temperaturewhile warming to room temperature
  3. customThe reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution
  4. customthe organic layer was removed
  5. washthe aqueous layer was washed four times with EtOAc
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under vacuum
  9. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-779959732e03400b978ce4cef86624cc
Source dataset
uspto-grants-2005_10
Patent number
US06953791B2

Reaction notes

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