Integration of Solventless Reaction in a Multi-Step Process: Application to an Efficient Synthesis of PA-824

Abstract

In order to improve redundant synthetic processes, the integration of a solventless reaction has proved to be useful for gaining high reaction mass efficiency (RME) as well as reducing the amount of solvents. This concept was applied to synthesis of PA-824, a potential antituberculosis drug. Thus, the solventless ring-opening reaction of glycidyl silyl ether with dinitroimidazole was connected to succeeding solution reactions. The ring-opening of glycidol followed by selective silylation of the primary hydroxy group under solventless conditions was also feasible. As a consequence, the overall yield of the target compound was nearly tripled, and thus the RME values were increased more than 2.5 times while the amount of necessary solvents was decreased to less than 1/3.