4-Methylmorpholine → N-[1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidyl]-L-alanine 1,1-dimethylethyl ester

HRID 34491Notes

Reaction equation

HRID 34491 reaction equation
[Cl:1][C:2]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23])[CH2:3][N:4]1[CH:21]=[N:20][C:6]([CH2:7][C@@H:8]([C:17]([OH:19])=O)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:57][C:58]([O:61][C:62](=[O:66])[C@H:63]([CH3:65])[NH2:64])([CH3:60])[CH3:59].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:57][C:58]([O:61][C:62](=[O:66])[C@H:63]([CH3:65])[NH:64][C:17](=[O:19])[C@H:8]([CH2:7][C:6]1[N:20]=[CH:21][N:4]([CH2:3][C:2]([Cl:1])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[O:23])[CH:5]=1)[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([CH3:60])[CH3:59]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 11275390tert-Butyl alaninate hydrochlorideHCID 228392281-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine

Product 1

HCID 14211453N-[1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidyl]-L-alanine 1,1-dimethylethyl esterYield 89.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred mixture of 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (1.14 g), N-methylmorpholine (461 μl), 1-hydroxybenzotriazole hydrate (277 mg) and L-alanine 1,1-dimethylethyl ester hydrochloride (364 mg) in dichloromethane (30 ml) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (422 mg). The resulting mixture was stirred for 18 hours, and concentrated under reduced pressure to yield a residue which was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium hydrogen carbonate and then brine and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to yield a foam which was chromatographed on silica gel eluting with methanol/dichloromethane (1:24) to yield N-[1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidyl]-L-alanine 1,1-dimethylethyl ester as a white foam (1.25 g), and as a mixture of diastereoisomers, m.p. 85-90° C. (decomp), (Found: C, 55.57; H, 5.51; N, 7.86%; C33H39Cl3N4O6.H2O requires C, 55.66; H, 5.80; N, 7.87%), having the formula: ##STR35##

Workup

  1. concentrationconcentrated under reduced pressure
  2. customto yield a residue which
  3. customwas partitioned between ethyl acetate and water
  4. washThe organic phase was washed with saturated aqueous sodium hydrogen carbonate
  5. dry with materialbrine and dried over anhydrous magnesium sulphate
  6. customThe solvent was removed under reduced pressure
  7. customto yield a foam which
  8. customwas chromatographed on silica gel eluting with methanol/dichloromethane (1:24)

Sources & evidence

ORD record
ord-99d8bdbf181a4420bdc4c25e5c95cbb4
Source dataset
uspto-grants-1988_08
Patent number
US04761483

Reaction notes

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