Scale-up and Optimization of a Continuous Flow Synthesis of an α-Thio-β-chloroacrylamide

Abstract

Use of continuous flow processing to undertake a multistep chlorination cascade has been achieved with effective inline workup and end-of-line crystallization in batch, leading to isolation of α-thio-β-chloroacrylamide Z-3 in pure form from a complex reaction mixture, exploiting the advantage of efficient heat transfer in flow. During development of a continuous flow strategy for production of appreciable quantities of α-thio-β-chloroacrylamides, difficulties surrounding a labor and resource intensive workup followed by final product isolation were addressed. A greener solvent choice was applied to the chemical synthesis, which enabled inline purification and separation, resulting in the crystallization of pure product directly from the reaction mixture. This process was readily scalable and demonstrated control over impurity formation and removal, which is key in an industrial setting.

A Coalescing Filter for Liquid–Liquid Separation and Multistage Extraction in Continuous-Flow Chemistry

“…5 This has increased the potential applications of continuous processes in the fine chemical industries as more complex molecules with challenging workups can be realized via telescoped, multistep continuous flow synthesis. 1,3,6,7 Furthermore, the development of lab-scale flow technology has enabled the exploration and optimization of new and existing syntheses routes via automated technology and in-line analysis. 8−10 One purification step that has attracted significant attention in the flow chemistry community is the extraction of products or impurities based on their partitioning between immiscible liquids.…”

“…The development of in-line purification technology has expanded the scope of flow chemistry by allowing multiple reaction steps to be performed sequentially in flow . This has increased the potential applications of continuous processes in the fine chemical industries as more complex molecules with challenging work-ups can be realized via telescoped, multistep continuous flow synthesis. ,,, Furthermore, the development of lab-scale flow technology has enabled the exploration and optimization of new and existing syntheses routes via automated technology and in-line analysis. − …”