Benzyl Bromide → (SR)-1,4-dibenzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester

HRID 382791Notes

Reaction equation

HRID 382791 reaction equation
[H-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13](=[O:22])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:20]([O:19][C:17]([C:14]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:16][N:11]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:12][C:13]1=[O:22])=[O:18])[CH3:21]

Participants

7

Reactant 4

HCID 7498Benzyl BromideHCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 2723880Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride

Product 1

HCID 15511748(SR)-1,4-dibenzyl-3-oxo-piperidine-4-carboxylic acid ethyl esterYield 75.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

To a suspension of 30.9 g NaH (55%, 772 mmol) in 1000 ml DMF was added under argon atmosphere portionwise 115 g ethyl (SR)-N-benzyl-3-oxo-4-piperidine-carboxylate hydrochloride (386 mmol, commercially available) at 0-5° C. The reaction mixture was stirred for 1 h at r.t. and a solution of 45.9 ml benzylbromide (66.0 g, 386 mmol) in 200 ml DMF was added at 0° C. The reaction mixture was stirred for 1.5 h at r. t. and 200 ml sat. NaHCO3 solution were added at 0-10° C. The reaction mixture was reduced to 500 ml and 1000 ml water were added. The aqueous phase was extracted three times with 1000 ml ethyl acetate and the combined organic phases were washed with water (3×200 ml) and brine (3×200 ml). The organic phase was dried over MgSO4, filtrated and the solvent was removed under reduced pressure. The crude product was purified by chromatography over silica gel (ethyl acetate/hexane 1/8, then 1/4) to give 101 g of the product (290 mmol, 75%) as a brown oil.

Workup

  1. customat 0-5° C
  2. stirringThe reaction mixture was stirred for 1.5 h at r
  3. additionwere added
  4. extractionThe aqueous phase was extracted three times with 1000 ml ethyl acetate
  5. washthe combined organic phases were washed with water (3×200 ml) and brine (3×200 ml)
  6. dry with materialThe organic phase was dried over MgSO4
  7. filtrationfiltrated
  8. customthe solvent was removed under reduced pressure
  9. customThe crude product was purified by chromatography over silica gel (ethyl acetate/hexane 1/8

Sources & evidence

ORD record
ord-e92df26074d7456883d1a4002cd6aef4
Source dataset
uspto-grants-2001_10
Patent number
US06310213B1

Reaction notes

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