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

HRID 2395898Notes

Reaction equation

HRID 2395898 reaction equation
[C:1]1([CH2:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](OCC)=[O:33])#[N:28].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:27]([CH2:29][C@@H:30]([OH:37])[CH2:31][C:32](=[O:33])[CH2:10][C:9]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])#[N:28]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 82657Acetamide, N,N-bis(phenylmethyl)-HCID 2724682Lithium diisopropylamideHCID 2733879Ethyl (3R)-4-cyano-3-hydroxybutanoate

Product 1

HCID 15294357(R)-6-cyano-5-hydroxy-3-oxo-N,N-bis(phenylmethyl)hexanamide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 21263495Tetrahydrofuran heptaneSolvent

Procedure

To a stirred -10° C. solution of N,N-bis(phenylmethyl)acetamide (prepared from N, N-bis(phenylmethyl)amine and acetyl chloride by refluxing for 2 hours in toluene) (120 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 -30° C. to -45° 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 of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -35° 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-5-hydroxy-3-oxo-N,N-bis(phenylmethyl)hexanamide as an oil. This oil, approximately 0.1 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL) under a nitrogen atmosphere. The solution is cooled to -20° C., and a 50% solution of methoxydiethylborane in tetrahydrofuran (50 mL) is added. The reaction is cooled to -78° C., and sodium borohydride (12 g, 0.32 mol) is added over 30 minutes. The reaction is maintained at -78° C. for 5 hours and allowed to warm to room temperature and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of acetic acid (20 mL) and concentrated by vacuum distillation to an oil. The residue is dissolved with methanol (300 mL), concentrated by vacuum distillation, redissolved with methanol (300 mL), and reconcentrated by vacuum distillation to give a yellow oil. The oil is taken up in ethyl acetate (300 mL) and washed with deionized water (300 mL). The ethyl acetate solution is concentrated by vacuum distillation to give crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-bis(phenylmethyl)hexanamide as an oil which is used without further purification;

Workup

  1. temperaturewhile maintaining the temperature between -30° C. to -45° C.
  2. stirringThe reaction mixture is stirred for 30 minutes at -35° 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-98656a9976404e959fd20f30681ed1b9
Source dataset
uspto-grants-1996_02
Patent number
US05489691

Reaction notes

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