1,2-Dichloroethane → HCID 22872968, compound

HRID 1781251Notes

Reaction equation

HRID 1781251 reaction equation
[NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH:19]([CH3:21])[CH3:20])[C:3]1=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([NH:44][C@@H:45]([C:53](O)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(OC(C)(C)C)=O>CN(C)C=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[NH2:44][C@H:45]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:53]([NH:1][CH:2]1[C:3](=[O:22])[N:4]([CH:19]([CH3:20])[CH3:21])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:54]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 637610Boc-D-phenylalanineHCID 10589821HCID 10589821, compound

Product 1

HCID 22872968HCID 22872968, compound

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a stirring solution of (+)-3-amino-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepine (40.8 g, 139 mmol) in dimethylformamide (140 mL) was added EDC (32.0 g, 167 mmol), HOBT (22.6 g, 167 mmol) and N-BOC-D-phenylalanine (44.3 g, 167 mmol). This was stirred at ambient temperature for 2 h. The reaction was diluted with saturated aqueous sodium hydrogen carbonate (1.5 L) and extracted with ethyl acetate (3×1 L). The organic layers were combined, dried with brine, anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil which was dissolved in ethyl acetate (700 mL), cooled in an ice/water bath. Hydrogen chloride gas was bubbled into the solution for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting foam was dissolved in ethyl acetate (1 L) and saturated aqueous sodium hydrogen carbonate (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate again (2×1 L). The organic layers were combined, dried with brine, anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a white solid, which was chromatographed over silica (2.5 kg) with ethyl acetate. The faster running diastereomer was recovered as a white solid (22.0 g, 72%). 1H NMR, CDCl3, δ 9.02 (d, J=8.6 Hz, 1H), 7.64-7.25 (m, 14H), 5.50 (d, J=8.6 Hz, 1H), 4.54 (septet, J=7.0 Hz, 1H), 3.70 (dd, J=3.9, 9.8 Hz, 1H), 3.34 (dd, J=3.9, 13.8 Hz, 1H), 2.82 (dd, J=9.8, 13.8 Hz, 1H), 1.51-1.40 (m, 5H), 1.27 (d, J=7.0 Hz, 1H).

Workup

  1. extractionextracted with ethyl acetate (3×1 L)
  2. dry with materialdried with brine, anhydrous magnesium sulfate
  3. filtrationfiltered
  4. customevaporated under reduced pressure
  5. customto give a yellow oil which
  6. temperaturecooled in an ice/water bath
  7. customHydrogen chloride gas was bubbled into the solution for 3 h
  8. concentrationThe reaction mixture was concentrated under reduced pressure
  9. dissolutionthe resulting foam was dissolved in ethyl acetate (1 L)
  10. customThe layers were separated
  11. extractionthe aqueous layer was extracted with ethyl acetate again (2×1 L)
  12. dry with materialdried with brine, anhydrous magnesium sulfate
  13. filtrationfiltered
  14. customevaporated under reduced pressure
  15. customto give a white solid, which
  16. customwas chromatographed over silica (2.5 kg) with ethyl acetate
  17. customwas recovered as a white solid (22.0 g, 72%)

Sources & evidence

ORD record
ord-9cc6bb4134da49a8b23b96d1e3d313cd
Source dataset
uspto-grants-1997_05
Patent number
US05633251

Reaction notes

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