4-Methylmorpholine → N-(2-Acetylthiomethyl-4-phenylbutanoyl)-(L)-Leucine t-butyl ester

HRID 983675Notes

Reaction equation

HRID 983675 reaction equation
[C:1]1([CH2:7][CH2:8][CH:9]([CH2:13][S:14][C:15](=[O:17])[CH3:16])[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C1COCC1.C(Cl)Cl>[C:27]([O:26][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][C:10](=[O:12])[CH:9]([CH2:13][S:14][C:15](=[O:17])[CH3:16])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:30])([CH3:29])[CH3:28]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 27960291-Hydroxybenzotriazole hydrateHCID 7022311tert-butyl (2S)-2-amino-4-methylpentanoateHCID 101062544-Phenyl-2-[acetylthio-methyl]butyric acid

Product 1

HCID 54107687N-(2-Acetylthiomethyl-4-phenylbutanoyl)-(L)-Leucine t-butyl ester

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 4-phenyl-2-[acetylthio-methyl]butyric acid (3.57 g, 14.2 mmole) in 66 mL of THF at 0° C., was added (S)-leucine, t-butyl ester (2.91 g 15.6 mmole) and 1-hydroxybenzotriazole hydrate (HOBTH2O, 2.86 g, 21.2 mmole) and N-methylmorpholine (4.29 g, 42.4 mmole). The mixture was stirred at 0° C. for 15 minutes, then 5.42 g of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC′HCl, 28.3 mmol) was added and the mixture stirred overnight. The solution was worked up by adding 100 mL methylene chloride and the mixture extracted with 3×50 mL of 5% sodium bicarbonate and washed with 2×50 mL of brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluted with methylene chloride/ethyl acetate (95/5). The product was separated as diastereomeric (R,S) and (S,S) fractions. The absolute stereochemistry of each fraction was not determined. Higher Rf material=1.78 g; lower Rf material=1.90 g.

Workup

  1. stirringthe mixture stirred overnight
  2. extractionthe mixture extracted with 3×50 mL of 5% sodium bicarbonate
  3. washwashed with 2×50 mL of brine
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. customthe solvent removed under reduced pressure
  7. customThe residue was purified by flash chromatography on silica gel
  8. washeluted with methylene chloride/ethyl acetate (95/5)
  9. customThe product was separated as diastereomeric (R,S) and (S,S) fractions

Sources & evidence

ORD record
ord-b307d9bea1c941a786d6ddfc0385bc26
Source dataset
uspto-grants-2005_03
Patent number
US06864383B2

Reaction notes

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