4-Methylmorpholine → Z-Lys(Z)-Leu-Leu-OMe

HRID 2298452Notes

Reaction equation

HRID 2298452 reaction equation
CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[NH2:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22].Cl.[NH:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:54](O)=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.CN(C=O)C>[NH:37]([C:57]([O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:58])[C@H:38]([C:54]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 7269422N2,N6-Bis[(phenylmethoxy)carbonyl]-L-lysineHCID 15598024L-Leucine, L-leucyl-, methyl ester, hydrochloride (1:1)

Product 1

HCID 12020551Z-Lys(Z)-Leu-Leu-OMeYield 99.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
19 °C

Procedure

4-Methylmorpholine (1.26 g, 12.5 mmol) and HOBt (1.69 g, 12.5 mmol) were added to a solution of H-Leu-Leu-OMe.HCl (4.04 g, 13.75 mmol) in ethyl acetate (160.0 g) and DMF (36.0 g) over 15 min. Z-Lys(Z)-OH (5.18 g, 12.5 mmol) was added to this stirred mixture over 15 min. A solution of DCC (3.10 g, 12.5 mmol) in ethyl acetate (10.0 g) was added dropwise at 18-20° C. over 30 min. The reaction mixture was stirred at 18-20° C. for 16 h and filtered. The filter cake was washed with ethyl acetate (100.0 g) and the combined filtrate was washed with aqueous NaHCO3. The resulting organic layer was washed with aqueous NaCI and concentrated under reduced pressure. The residue was dissolved in MeOH (80.0 g) at about 50° C. Water (160 g) was slowly added and the mixture was stirred for about 1 h at 20° C. The resulting solid was filtered, washed with H2O (80.0 g) and dried at 40° C. in a vacuum oven to give 8.16 g, 99.6% of the product Z-Lys(Z)-Leu-Leu-OMe.

Workup

  1. filtrationfiltered
  2. washThe filter cake was washed with ethyl acetate (100.0 g)
  3. washthe combined filtrate was washed with aqueous NaHCO3
  4. washThe resulting organic layer was washed with aqueous NaCI
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe residue was dissolved in MeOH (80.0 g) at about 50° C
  7. additionWater (160 g) was slowly added
  8. stirringthe mixture was stirred for about 1 h at 20° C
  9. filtrationThe resulting solid was filtered
  10. washwashed with H2O (80.0 g)
  11. customdried at 40° C. in a vacuum oven

Sources & evidence

ORD record
ord-69bf11fb3abe431498e15b49812a2915
Source dataset
uspto-grants-2002_12
Patent number
US06492490B1

Reaction notes

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