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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 1781340
Notes
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Reaction equation

HRID 1781340 reaction equation
[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
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

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

Product 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

Reagents, catalysts & solvents 3

HCID 6342
Acetonitrile
Solvent
HCID 8028TetrahydrofuranSolvent
HCID 22728543Water ethylacetateSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-d896f7bdfcab4970950d4d3e8a62ba2c
Source dataset
uspto-grants-1997_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05633280

Reaction notes

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