Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189

A general and efficient method for the synthesis of pronucleotide (ProTide) 5'-phosphoramidate monoesters is reported. This method consists of a highly stereoselective 5'-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing 3'-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated.Fil: Simmons, Bryon. Merck & Co.; Estados UnidosFil: Liu, Zhuqing. Merck & Co.; Estados UnidosFil: Klapars, Artis. Merck & Co.; Estados UnidosFil: Bellomo Peraza, Ana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias ; Argentina. Merck & Co.; Estados UnidosFil: Silverman, Steven M.. Merck & Co.; Estados Unido