Diethyl Ether → HCID 131719360, compound

HRID 1720014Notes

Reaction equation

HRID 1720014 reaction equation
[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:25].[CH3:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[CH2:33](OCC)C>>[N:27]1([CH3:26])[CH2:32][CH2:31][CH2:33][C@H:28]1[C:29]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:30].[ClH:25]

Participants

4

Reactant 3

HCID 3283Diethyl EtherHCID 79724-MethylmorpholineHCID 74889902L-Tryptophan, L-leucyl-, methyl ester, hydrochloride (1:1)

Product 1

HCID 131719360HCID 131719360, compound

Procedure

A suspension of 1.0 g (7.74 mmoles) of N-Me-(L)-Pro,OH (Sigma) in 60 ml of dry methylene chloride (CH2Cl2) was brought, in an argon atmosphere, to the temperature of an ice and salt bath. The following were then added in succession: 1.250 g (7.74 mmoles) of commercial 1-hydroxybenzotriazole (HOBt) and 1.600 g (7.75 mmoles) of N,N'-dicyclohexylcarbodiimmide (DCC), leaving the system under stirring and maintaining control of the temperature for a further 30 minutes. To the reaction mixture was then added with 2.800 g (7.61 mmoles) of (L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.840 ml (7.62 mmoles) of 4-methylmorpholine (NMM), leaving the system under stirring for 12 hours with the temperature free to rise to room temperature. The fine white precipitate was then filtered away and washed with a little CH2Cl2. The latter was put back into the filtered reaction solution, which was concentrated under vacuum to approximately half its original volume, filtering away the new white precipitate. It was then extracted in succession using 5% NaHCO3 (3×30 ml) and saturated aqueous NaCl (2×30 ml), discarding the aqueous phases. The organic phase was then extracted with acetate buffer at pH 4 (3×30 ml), discarding the organic phase. The aqueous phase was brought to pH 6 and extracted using CH2Cl2 (3×30 ml). The organic phase, extracted with saturated aqueous NaCl (2×30 ml), was left in a cold chamber, under argon atmosphere and anhydrous Na2SO4 for 24 hours. The desiccant was then filtered away, the organic solution concentrated to a small volume and the residual yellowish liquid added dropwise under energetic stirring to an excess of dry petroleum ether (30/50), obtaining an abundant white precipitate. After several hours in a cold chamber the white solid was filtered and, taken up at the limit of solubility with anhydrous dioxane, was precipitated again in an excess of a solution of 1.0 M of gaseous HCl in anhydrous ethyl ether. After leaving the suspension to rest in a cold chamber for approximately 1 hour, the excess of acid was eliminated under a flow of dry nitrogen, then adding a large excess of anhydrous ethyl ether. The abundant fine milk-white precipitation, filtered under vacuum and washed in a little anhydrous ethyl ether, was left for 24 hours under vacuum on P2O5 . 2.550 g (70.0%) of an analytically pure semi-crystalline white solid were recovered.

Workup

  1. temperaturemaintaining control of the temperature for a further 30 minutes
  2. customleaving the system
  3. stirringunder stirring for 12 hours with the temperature free
  4. customto rise to room temperature
  5. filtrationThe fine white precipitate was then filtered away
  6. washwashed with a little CH2Cl2
  7. customThe latter was put back into the filtered reaction solution, which
  8. concentrationwas concentrated under vacuum to approximately half its original volume
  9. filtrationfiltering away the new white precipitate
  10. extractionIt was then extracted in succession
  11. extractionThe organic phase was then extracted with acetate buffer at pH 4 (3×30 ml)
  12. extractionextracted
  13. extractionThe organic phase, extracted with saturated aqueous NaCl (2×30 ml)
  14. waitwas left in a cold chamber, under argon atmosphere
  15. filtrationThe desiccant was then filtered away
  16. concentrationthe organic solution concentrated to a small volume
  17. additionthe residual yellowish liquid added dropwise
  18. stirringunder energetic stirring to an excess of dry petroleum ether (30/50)
  19. customobtaining an abundant white precipitate
  20. filtrationAfter several hours in a cold chamber the white solid was filtered
  21. customwas precipitated again in an excess of a solution of 1.0 M of gaseous HCl in anhydrous ethyl ether
  22. customAfter leaving the suspension
  23. waitto rest in a cold chamber for approximately 1 hour
  24. customThe abundant fine milk-white precipitation
  25. filtrationfiltered under vacuum
  26. washwashed in a little anhydrous ethyl ether
  27. waitwas left for 24 hours under vacuum on P2O5
  28. custom2.550 g (70.0%) of an analytically pure semi-crystalline white solid were recovered

Sources & evidence

ORD record
ord-440c8161da1c4dc482244cab9536eefe
Source dataset
uspto-grants-1996_04
Patent number
US05504071

Reaction notes

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