4-Methylmorpholine → Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl

HRID 1700081Notes

Reaction equation

HRID 1700081 reaction equation
[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57]>C1COCC1>[NH:1]([C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[C@H:2]([C:7]([NH:9][C@H:10]([C:19]([NH:21][C@H:22]([C:27]([NH:55][C@H:56]([C:58]([CH2:60][Cl:61])=[O:59])[CH3:57])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 53787392(3S)-3-amino-1-chlorobutan-2-oneHCID 131721135Z-Leu-Asp(OtBu)-Leu-OH

Product 1

HCID 131721136Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

Boc-Ala-CH2Cl (2 g) in 5 equiv of HCl in dioxane was stirred at room temp for 1 h. After removal of solvent, the residue was triturated with diethyl ether to give crude H-Ala-CH2Cl (1.41 g). The Z-Leu-Asp(OtBu)-Leu-OH (2.68 g) and N-methylmorpholine (0.54 mL) were dissolved in THF (25 mL), the cooled to −20° C. Isobutyl chloroformate (0.64 mL) was added to generate the mixed anhydride, which was transferred to the H-Ala-CH2Cl (1.41 g in 10 mL of DMF) solution at −20° C. The resulting mixture was allowed to come to room temp and reaction was completed in 3 h. The salt was removed by filtration. The filtrate was concentrated, redissolved in ethyl acetate (100 mL). The solution was washed with 0.2 N HCl, 5% NaHCO3, sat. NaCl; dried over Na2SO4, filtered, and concentrated to yield crude solid of 3.19 g. The crude Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl was purified by Sephadex LH20 column chromatography.

Workup

  1. customto come to room temp
  2. customreaction
  3. customThe salt was removed by filtration
  4. concentrationThe filtrate was concentrated
  5. dissolutionredissolved in ethyl acetate (100 mL)
  6. washThe solution was washed with 0.2 N HCl, 5% NaHCO3, sat. NaCl
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto yield crude solid of 3.19 g
  11. customThe crude Z-Leu-Asp(OtBu)-Leu-Ala-CH2Cl was purified by Sephadex LH20 column chromatography

Sources & evidence

ORD record
ord-a8255e3df63e417bbdf36a2df25e9c23
Source dataset
uspto-grants-2002_02
Patent number
US06350573B1

Reaction notes

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