Continuous Synthesis and Purification by Direct Coupling of a Flow Reactor with Simulated Moving-Bed Chromatography

摘要

Continuous-flow reactors have increased the scale of reactions that can be carried out in the laboratory, and can ease the transition from the research to production environment. Performing a reaction in flow can be advantageous in cases where heat, mass, or light-transfer influence reactivity, or where hazardous reagents are used at high temperature and pressure. However, purification is often a bottleneck in synthesis and can negate the benefits ascribed to flow reactors, unless side-products can be removed by crystallization or liquid-liquid extraction. In-line solid-supported reagents that scavenge undesired byproducts' have finite lifetimes and cannot be operated in a continuous manner without regeneration. Additionally, separating complex mixtures of products often necessitates recourse to batch column chromatography. Simulated moving-bed (SMB) chromatography, a form of continuous counter-current chromatography widely used industrially, offers a solution. Based on efforts to integrate both enzymatic and crystallization processes with SMB chromatography we envisioned that a flow reactor could be coupled with SMB chromatography to synthesize and purify complex molecules in a single, continuously operated system. Herein, we report the first successful coupling of flow synthesis and SMB chromatography to continuously produce pure product.