Hydrochloric Acid → cyclo-(Gly-Ala-DAla-Gly-Gly-)

HRID 1683244Notes

Reaction equation

HRID 1683244 reaction equation
[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=O)=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].Cl.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[NH:1]1[C:21](=[O:23])[CH2:20][NH:19][C:17](=[O:18])[CH2:16][NH:15][C:13](=[O:14])[C@@H:11]([CH3:12])[NH:10][C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[CH2:2]1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 199401P,P-Diphenylphosphinic azideHCID 131719919Gly-Ala-DAla-Gly-Gly

Product 1

HCID 14942554cyclo-(Gly-Ala-DAla-Gly-Gly-)Yield 60%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
-25 °C

Procedure

This compound was synthesized by the method of Veber, D. F. et al, J. Org. Chem., 44, 3101-5 (1979). To a solution of Gly-Ala-DAla-Gly-Gly.circle-solid.HCl prepared as in Example 33D (12.9 g, 35.0 mmol) in anhydrous DMF (4400 ml) was added enough TEA to adjust the pH to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the resulting mixture was cooled to -25° C. To this mixture was added DPPA (9.20 ml, 43.0 mmol) dropwise over 5 min. The reaction was stored at -25° C. (internal temperature) for 48 h thereafter. During this time the pH was monitored periodically (as described above) and maintained at ~8 by the addition of TEA. After this time the reaction mixture was allowed to stand at 0° C. for 48 h. Again the pH was monitored periodically and maintained at ~8 by the addition of TEA. After this time the reaction mixture was diluted with water (4400 ml) and stirred with Bio-Rad AG 501-X8 (mixed-bed) resin (200 g) for 6 h. The resin was separated by filtration and the solution was concentrated to dryness. Trituration of the residue with refluxing THF (250 ml) for 3 h, filtration of the hot THF and drying at high vacuum afforded 6.61 g (60% yield) of the product as a white powder: 1H NMR (DMSO-d6) δ 1.15-1.32 (m, 6H), 3.45-4.00 (m, 6H), 4.10-4.38 (m, 2H), 7.81 (d, J=7.8 Hz, 1H), 7.97 (t, J=6.6 Hz, 1H), 8.10 (m, 2H), 8.18 (d, J=7.5 Hz, 1H).

Workup

  1. customThis compound was synthesized by the method of Veber, D
  2. additionwas added enough TEA
  3. customwas stored at -25° C.
  4. customfor 48 h
  5. temperaturemaintained at ~8 by the addition of TEA
  6. temperaturemaintained at ~8 by the addition of TEA
  7. customThe resin was separated by filtration
  8. concentrationthe solution was concentrated to dryness
  9. waitTrituration of the residue with refluxing THF (250 ml) for 3 h
  10. filtrationfiltration of the hot THF
  11. customdrying at high vacuum

Sources & evidence

ORD record
ord-08bb072952464bd8a88cacaf2ccdd279
Source dataset
uspto-grants-1997_06
Patent number
US05637578

Reaction notes

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