Hydrochloric Acid → (R)-6-cyano-N-(1,1-dimethylethyl)-5-hydroxy-3-oxo-N-(phenylmethyl)hexanamide

HRID 2395903Notes

Reaction equation

HRID 2395903 reaction equation
[C:1]1([CH2:7][NH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-][CH:16]([CH3:18])[CH3:17])(C)C.[Li+].[C:20]([CH2:22][C@@H:23]([OH:30])[CH2:24][C:25](OCC)=[O:26])#[N:21].Cl.O1CCC[CH2:33]1>O1CCCC1.CCCCCCC>[C:20]([CH2:22][C@@H:23]([OH:30])[CH2:24][C:25](=[O:26])[CH2:10][C:9]([N:8]([C:16]([CH3:17])([CH3:18])[CH3:33])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11])#[N:21]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8028Tetrahydrofuran2×HCID 11500N-BenzylacetamideHCID 2724682Lithium diisopropylamideHCID 2733879Ethyl (3R)-4-cyano-3-hydroxybutanoate

Product 1

HCID 53869197(R)-6-cyano-N-(1,1-dimethylethyl)-5-hydroxy-3-oxo-N-(phenylmethyl)hexanamide

Reagents, catalysts & solvents 1

HCID 21263495Tetrahydrofuran heptaneSolvent

Procedure

To a stirred -10° C. solution of N-1,1-dimethylethyl, N-phenylmethylacetamide (prepared from N-1,1-dimethylethyl, N-phenylmethyl amine, and acetyl chloride by refluxing for 2 hours in toluene) (102.5 g, 0.5 mol) in tetrahydrofuran (0.5 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.25 L of 2M) while maintaining the temperature between -40° C. to -50° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (20 g, 0.125 mol) as a solution in 200 mL or tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -25° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (0.5 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-N-(1,1-dimethylethyl)-5-hydroxy-3-oxo-N-(phenylmethyl)hexanamide as an oil.

Workup

  1. temperaturewhile maintaining the temperature between -40° C. to -50° C.
  2. stirringThe reaction mixture is stirred for 30 minutes at -25° C. to -20° C.
  3. extractionThe aqueous layer is extracted with 300 mL of ethyl acetate
  4. customthe aqueous layer is separated
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-055da2f4e2114d54909840aec9e490da
Source dataset
uspto-grants-1996_02
Patent number
US05489691

Reaction notes

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