Accelerating Antiretroviral Lead Optimization: One-Pot Synthesis and Solid-Phase Extraction-Mediated Purification of a Tenofovir Exalidex Congeneric Library

We report a rapid, one-pot synthesis and purification protocol for the HIV/HBV drug candidate tenofovir exalidex (TXL) and its congeners. The method employs polymer-supported triphenylphosphine (PS-TPP), trichloroacetonitrile, and alcohol promoieties to prepare tenofovir (TFV) prodrugs in high yields (64-98%) and high purities (>95%). This streamlined approach enables facile parallel synthesis and efficient isolation of the target compounds using solid-phase extraction (SPE), accelerating the discovery and development of novel TFV-based lipid prodrugs.