Aryl Phosphate Derivatives of Bromo-Methoxy-Azidothymidine: MATERIALS AND METHODS(1)
Chemical Synthesis of AZT Derivatives
We synthesized three new analogues of AZT (WHI-01, -02, and -03) with 5-bromo and 6-methoxy groups on the thymine ring and azido/amino substitution in the C-3 position of the pentose ring using published procedures. The chemical compositions of these three AZT analogues are shown in Figure 1. Similarly, 9 novel aryl phosphate derivatives of AZT (WHI compounds 04, 05, 06, 07, 08, 09, 10, 11, and 12) were prepared using phosphorochlori-date chemistry. In brief, reaction of appropriately substituted phenols with phosphorous oxy chloride in the presence of triethylamine yielded the phosphorodichloridate derivative. buy prednisone
Condensation with AZT in anhydrous tetrahy-drofuran containing A-methylimidazole as base yielded the target aryl phosphoramidate derivative of AZT. Further modifications in the structure were achieved by reaction with bromine in anhydrous methanol to obtain the desired target compounds (Fig. 2). For each compound, the purity was > 95%, as determined by the proton (Щ) nuclear magnetic resonance spectra (Varian 300 MHz; Varian Associates, Palo Alto, CA) and HPLC. For each compound, the characterization included carbon (13C) NMR, Fourier transform infrared spectra (FT-Nicolet model Protege 460; Ni-colet Corporation, Madison, WI), UV-visible spectra (Beckman model DE 7400 spectrophotometer; Beckman Instruments, Fullerton, CA), HPLC (Hewlett Packard model 1100 series; Hewlett-Packard Co., Wilmington, DE), and mass spectra (Hewlett Packard Matrix Assisted Laser Desorption Time-of-Flight spectrometer model G2025A) analysis. Azidothymidine/zidovudine was purchased from Aldrich Chemical Co. (Milwaukee, WI).