Dicyclohexylcarbodiimide → N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-[1-hydroxy-2-(1-methylethoxy)-2-oxoethyl]-3-methylbutyl]-1-(triphenylmethyl)-L-histidinamide

HRID 846469Notes

Reaction equation

HRID 846469 reaction equation
[CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].ON1C2C=CC=CC=2N=N1.[NH2:30][CH:31]([CH2:48][C:49]1[N:50]=[CH:51][N:52]([C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=1)[C:32]([NH:34][CH:35]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:19][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:16]([NH:30][C@H:31]([C:32]([NH:34][CH:35]([CH:36]([OH:43])[C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:33])[CH2:48][C:49]1[N:50]=[CH:51][N:52]([C:54]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:53]=1)=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:3]

Participants

6

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 77857L-Phenylalanine, N-[(1,1-dimethylethoxy)carbonyl]-HCID 572117653-[[2-amino-1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]amino]-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester

Product 1

HCID 70051836N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-[1-hydroxy-2-(1-methylethoxy)-2-oxoethyl]-3-methylbutyl]-1-(triphenylmethyl)-L-histidinamideYield 69.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a mixture of 1.1 g (4 mmol) of N-[(1,1dimethylethoxy)carbonyl]-L-phenylalanine and 0.568 g (4.2 mmol) of 1-hydroxybenzotriazole in 5 ml of dimethylformamide at 0° C. is added 2.4 g (4.1 mmol) of 3-[[2-amino-1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]amino]-2-hydroxy-5-methylhexanoic acid, 1-methylethyl ester (mixture of [2R-[2R*,3S*(S*)]] and [2S-[2R*,3R*(R*)]]-isomers) in 15 ml of dimethylformamide. The solution is stirred for five minutes, treated with 0.867 g (4.2 mmol) of dicyclohexylcarbodiimide, stirred at 0° C. for one hour, warmed to room temperature, stirred overnight, filtered and the dimethylformamide evaporated in vacuo. The resulting oil is dissolved in ethyl acetate and washed successively with 30 ml of 1N citric acid solution, 30 ml of saturated solution of sodium bicarbonate and 30 ml of saturated solution of sodium chloride. The organic layer is separated, dried (magnesium sulfate) and evaporated in vacuo to a foam. The foam is chromatographed over 250 g of silica gel (230-400 mesh), eluted with 5% methanol 95% chloroform, the combined fractions evaporated in vacuo and the residue dried under high vacuum overnight to afford 2.3 g of the title compound as a white foam.

Workup

  1. stirringstirred at 0° C. for one hour
  2. stirringstirred overnight
  3. filtrationfiltered
  4. customthe dimethylformamide evaporated in vacuo
  5. dissolutionThe resulting oil is dissolved in ethyl acetate
  6. washwashed successively with 30 ml of 1N citric acid solution, 30 ml of saturated solution of sodium bicarbonate and 30 ml of saturated solution of sodium chloride
  7. customThe organic layer is separated
  8. dry with materialdried (magnesium sulfate)
  9. customevaporated in vacuo to a foam
  10. customThe foam is chromatographed over 250 g of silica gel (230-400 mesh)
  11. washeluted with 5% methanol 95% chloroform
  12. customthe combined fractions evaporated in vacuo
  13. customthe residue dried under high vacuum overnight

Sources & evidence

ORD record
ord-15c479a2e27244d791c78aacb5c29e9f
Source dataset
uspto-grants-1992_08
Patent number
US05135914

Reaction notes

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