The Development of Conveniently Formatted Solid-Supported Reagents for Flow-Based Synthesis

The pharmaceutical discovery process is changing rapidly generating a greater need for conduct chemistry in a more efficient and timely fashion. As the global emphasis towards achieving the highest safety standards and sustainable practices unfolds, it is becoming necessary to re-evaluate how chemical synthesis is conducted. In medicinal chemistry in particular the acceleration of cycle times through high-throughput assaying and fast iterative design has put new emphasis on the reliability of processes and compound preparation times. A more integrated and continuous relay of information regarding the ongoing synthesis and its products in terms of basic characterization, physical properties and their functions needs to be captured. These requirements coupled with a desire for flexible synthetic implementation seem ideally suited to a flow-based approach to chemical synthesis. It is therefore our conclusion that future MedChem programmes will make increasing use of flow techniques and many of these will benefit from the use of solid-supported reagents and scavengers.Monoliths have been proposed and developed for use in solid-supported continuous flow synthesis. Monoliths are a single continuous piece of porous material which can be made from either organic or inorganic materials. These monoliths can be readily generated from various polymers or polymer blends and posses permanent, well-defined porous structures that are independent of the solvent or reagents used. In addition such constructs offer significantly higher mass transfer compared to oval beads as they rely on convective flow instead of diffusion factors (key for reproducible optimisation and small scale synthesis). They also have a higher loading than polymers prepared by suspension polymerization due to the fact that polymerisation occurs within a single phase avoiding the problem of partitioning. It is also possible to prepare these polymer units in any shape and size which is very advantageous for the translation between micro- and meso-flow systems by readily enabling scale up in a more consistent manner.This proposal describes the preparation and use of a series of active reagent functionalized monoliths to be used in flow base synthesis.