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

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence