Single-Pot Solution Phase Synthesis Optimization Using Fully Automated Systems for Combinatorial Screening

Abstract

The optimization of synthesis conditions plays an important role in chemistry and life sciences. A wide variety of reaction parameters should be explored to minimize the use of educts and maximize the yields of desired products in high purity. A fully automated system for combinatorial synthesis has been developed and used for the optimization of synthesis conditions of a multicomponent single-pot reaction. In order to explore optimal reaction conditions for the synthesis of pure endo isomer of 3-(2-bromo-benzoylamino)-cyclohex-4-ene1,2-dicarboxylic acid diethyl ester, an intermediate in the synthesis route of lycorizidine analogues, several hundred experiments were carried out with varying reaction temperature, times, concentrations, and ratios of educts. In this case study, financial aspects also were considered in order to minimize synthesis costs. The system was integrated using a Zymate XP robot as a system integrator. In addition to a GC/MS and an HPLC system, a multicomponent solid dispenser workbench and a liquid handling system are located within this fully automated system.