Dicyclohexylcarbodiimide → HCID 178454159, compound

HRID 579900Notes

Reaction equation

HRID 579900 reaction equation
[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)[NH:5][CH3:6].[C:14]([O:18][C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16].[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)[NH:5][CH3:6]

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 77857L-Phenylalanine, N-[(1,1-dimethylethoxy)carbonyl]-HCID 27960291-Hydroxybenzotriazole hydrateHCID 178484879HCID 178484879, compound

Product 1

HCID 178454159HCID 178454159, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
0 °C

Procedure

N-Methyl-L-histidine methyl ester (1.05 g.) from step a was dissolved in dichloromethane and at 0° C., 1.25 ml of triethylamine was added, followed by N-t-butyloxycarbonyl-L-phenylalanine (1.14 g.), 1-hydroxybenzotriazole hydrate (1.04 g.) and dicyclohexylcarbodiimide (0.89 g.) the mixture was stirred at 0° C. and allowed to slowly warm to 20° C. over a 4-5 hour period. It was then stirred an additional 10 hours. The slurry was filtered, concentrated, redissolved in 100 ml of ethyl acetate, the additional precipitate was filtered, and the filtrate was washed with 1N sodium hydroxide (2×10 ml) dried over magnesium sulfate, and concentrated to give 0.84 g. of an off-white solid. Recrystallization of this material from ethyl acetate gave 0.47 g. of the title compound as a colorless powder. Additional material was obtained as follows. The combined filtered drying agent and second (from ethyl acetate) precipitate above were heated in methanol, and the resultant suspension was cooled, filtered and the filtrate was concentrated to give a solid which was chromatographed on silica in ethanol-dichloromethane to give 0.857 g. of the pure title substance. 1H NMR, CDCl3, 250 mHz, partial, 1.39 (s, 9H, Boc), 2.80 (S, 3H, N-CH3 ), 2.90 and 3.03 (m), 3.35 (m, 1H), 3.70 (s, 3H, OCH3), 4.75 (dt, 1H), 5.15 (dt, 1H), 5.3 (d, BOCNH), 6.84 and 7.68 (1H ea, imidazolyl CH), 7.1-7.4 (m, aromatic). Singlets at 7.55 and 6.74 suggested about 10% of the substance exists in another rotameric form (imidazolyl CH resonances).

Workup

  1. temperatureto slowly warm to 20° C. over a 4-5 hour period
  2. stirringIt was then stirred an additional 10 hours
  3. filtrationThe slurry was filtered
  4. concentrationconcentrated
  5. dissolutionredissolved in 100 ml of ethyl acetate
  6. filtrationthe additional precipitate was filtered
  7. washthe filtrate was washed with 1N sodium hydroxide (2×10 ml)
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated
  10. customto give 0.84 g
  11. customRecrystallization of this material from ethyl acetate
  12. customgave 0.47 g

Sources & evidence

ORD record
ord-13e190990e7945a3be2245c4ff7b9f94
Source dataset
uspto-grants-1988_06
Patent number
US04749687

Reaction notes

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