Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates

Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5′-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.

被掩蔽为磷酰胺（phosphoramidate）衍生物的治疗性核苷单磷酸前药（Prodrugs），作为可在体外及体内递送核苷酸的抗病毒药物类别，在药物研发领域的重要性日益凸显。传统制备手段中，磷酰胺衍生物通常以两种非对映异构体（diastereomers）的混合物形式获得。本研究报道了一类稳定的磷酰化试剂，其结构包含氨基酸酯与两个酚基：一个为未取代酚基，另一个带有吸电子取代基。该试剂可作为单一非对映异构体分离，并通过取代酚的选择性亲核取代反应，与核苷的5'-羟基发生反应，从而制备得到单一非对映异构体的磷酰胺产物。该方法已被成功用于以高收率和高非对映异构体纯度制备丙型肝炎病毒（HCV）临床候选药物PSI-7977。