Acetic Acid → ethyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate

HRID 2046656Notes

Reaction equation

HRID 2046656 reaction equation
C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[CH:19]([C@@H:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:22]([CH3:24])[CH3:23])=[O:20].[C:36]([OH:39])(=[O:38])[CH3:37]>O1CCCC1.CCCCCC.O>[CH2:28]([O:27][C:26]([NH:25][C@@H:21]([CH:22]([CH3:24])[CH3:23])[C@@H:19]([OH:20])[CH2:14][C:13]([O:16][CH2:17][CH3:18])=[O:15])=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:28]([O:27][C:26]([NH:25][CH:37]([CH:13]([OH:15])[CH2:14][CH:5]([CH3:6])[CH3:7])[C:36]([O-:39])=[O:38])=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1

Participants

10

Reactant 5

HCID 176Acetic AcidHCID 7912DiisopropylamineHCID 8857Ethyl AcetateHCID 11009915benzyl [(1S)-1-formyl-2-methylpropyl]carbamateHCID 178418339Butyllithium

Product 2

HCID 59370506ethyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoateHCID 131731055([(Benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution (40 mL) of diisopropylamine (4.6 mL) in tetrahydrofuran was added 1.6 mol/L solution (20.19 mL) of n-butyllithium in hexane, and the mixture was cooled to −78° C. A solution (5 mL) of ethyl acetate (3.16 mL) in tetrahydrofuran was added dropwise to the mixture at a rate to maintain the reaction mixture at −70° C. or below. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr, a solution (10 mL) of benzyl [(1S)-1-formyl-2-methylpropyl]carbamate (1.9 g) in tetrahydrofuran was added dropwise thereto at a rate to maintain the reaction mixture at −70° C. or below. The reaction mixture was once warmed to −30° C., and cooled again to −78° C. Acetic acid (2.3 mL) was added to the mixture, and the temperature of the mixture was raised to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→2:1) to give the title compound (yield: 800 mg) and ethyl (3R,4S)-4-{([(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate (yield: 550 mg) both as a colorless oil.

Workup

  1. temperatureto maintain the reaction mixture at −70° C. or below
  2. additionAfter the completion of the dropwise addition
  3. temperatureat a rate to maintain the reaction mixture at −70° C. or below
  4. temperatureThe reaction mixture was once warmed to −30° C.
  5. temperaturecooled again to −78° C
  6. temperaturethe temperature of the mixture was raised to room temperature
  7. extractionthe mixture was extracted with ethyl acetate
  8. washThe extract was washed with saturated brine
  9. dry with materialdried over anhydrous sodium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→2:1)

Sources & evidence

ORD record
ord-972484da68c24c768cbd3f837d393ee4
Source dataset
uspto-grants-2013_11
Patent number
US08592452B2

Reaction notes

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