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Phosgene → N-[N2-[[3-oxo-2-[(1-oxoheptyl)amino]-1-methyl-3-(phenylmethoxy)-propoxy]carbonyl]-N6-[(phenylmethoxy)carbonyl]-(R)-6-[(phenylmethoxy)carbonyl]-L-lysyl]-D-Alanine Phenylmethyl Ester

HRID 2258046
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 2258046
[C:1]1([CH2:7][O:8][C:9](=[O:23])[C@@H:10]([C@@H:20]([CH3:22])[OH:21])[NH:11][C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](Cl)(Cl)=[O:25].[C:28]1([CH2:34][O:35][C:36](=[O:69])[C@@H:37]([CH3:68])[NH:38][C:39](=[O:67])[C@@H:40]([CH2:42][CH2:43][CH2:44][CH:45]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[NH:46][C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[NH2:41])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.CC#N.CCOC(C)=O.O>[C:28]1([CH2:34][O:35][C:36](=[O:69])[C@@H:37]([CH3:68])[NH:38][C:39](=[O:67])[C@@H:40]([CH2:42][CH2:43][CH2:44][CH:45]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[NH:46][C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[NH:41][C:24]([O:21][CH:20]([CH3:22])[CH:10]([NH:11][C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9](=[O:23])[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

7

Edukt 3

HCID 6371PhosgeneHCID 11034596N-(1-oxoheptyl)-D-allo-Threonine Phenylmethyl EsterHCID 67798175HCID 67798175, Verbindung

Produkt 1

HCID 86749716N-[N2-[[3-oxo-2-[(1-oxoheptyl)amino]-1-methyl-3-(phenylmethoxy)-propoxy]carbonyl]-N6-[(phenylmethoxy)carbonyl]-(R)-6-[(phenylmethoxy)carbonyl]-L-lysyl]-D-Alanine Phenylmethyl Ester

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6342AcetonitrileLösungsmittel
HCID 8028TetrahydrofuranLösungsmittel
HCID 22728543Water ethylacetateLösungsmittel

Versuchsvorschrift

A solution of 2e-1 (173.6 mg, 0.54 mmol) in THF (Sure/Seal solvent redried over 3 MS, 1.45 mL) is added to excess cold phosgene (1.92M solution in toluene; 1.40 mL, 2.63 mmol), alternately with TEA (81 μl, 0.58 mmol) over a period of 15 min at 0° C. The resulting milky mixture is stirred for an addition 15 min at the same temperature and for 5 h at room temperature. The mixture is degassed with argon for 30 min and stirred under aspirator pressure for 30 min. The residue is treated with a solution of freshly prepared 3b (0.37 mmol) in CH3CN (redried as for THF, 2.9 mL) and then TEA (81 μl, 0.58 mmol), both added all at once. The white slurry is stirred overnight at ambient temperature. The mixture is taken up in EtOAc/H2O and the layers separated. The aq. phase is extracted with EtOAc twice and the combined organic phase is washed with brine, dried, filtered, and evaporated. Purification of the product by chromatography (3×30 cm column, gradient of 2:1-1:2 hexane/EtOAc) gaves a white wax which is identified as 1a-1: NMR δ 0.86 (m, 3 H), 1.11 (d, J=6.4, 3 H), 1.20-1.40 (m, 8 H), 1.42 (d, J=7.3, 3 H), 1.50-1.75 (m, 4 H, with overlapping H2O signal), 1.75-2.05 (br d, 2 H), 2.20 (m, 2 H), 4.15 (br s, 1 H), 4.47 (br s, 1 H), 4.62 (apparent quintet, 1 H), 4.87 (apparent br d, J≃6, 1 H), 5.00-5.20 (m, 9 H), 5.23 (m, 1 H), 5.37 (br d, 1 H), 6.40 (br d, 1 H), 7.33 (m, 20 H), 7.77 (br d, 1 H); MS (HR-FAB) m/z 923.4420 (M+H, calcd. for C51H63N4O12, 923.4442).

Aufarbeitung

  1. customThe mixture is degassed with argon for 30 min
  2. stirringstirred under aspirator pressure for 30 min
  3. additionThe residue is treated with a solution
  4. stirringThe white slurry is stirred overnight at ambient temperature
  5. customthe layers separated
  6. extractionThe aq. phase is extracted with EtOAc twice
  7. washthe combined organic phase is washed with brine
  8. customdried
  9. filtrationfiltered
  10. customevaporated
  11. customPurification of the product by chromatography (3×30 cm column, gradient of 2:1-1:2 hexane/EtOAc)

Quellen und Nachweise

ORD-Eintrag
ord-a6a526a9baa442d98931292bd556112e
Quelldatensatz
uspto-grants-1997_08
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US05658945

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