Development of a tandem microfluidic two-phase extraction device for continuous arylboronic acid phase-switching purification

The last 20 years has witnessed a surge in the development of fluidic devices and techniques aimed at the generation of novel tools for chemical transformations, chemical analysis, bioassays, therapeutics, medical diagnostics, and in vivo tissue research. A growing area of research involves the use of microfluidics to facilitate reaction optimization and chemical synthesis on a large scale. Although there have been significant gains such as the incorporation of microwave heating, better mass-heat transport, and reduction of impurities through accurate control of reagent addition and reaction parameters, there is a lack of continuous purification techniques to accompany these processes. The development of continuous in-line purification processes is required for the wide scale adoption of continuous flow synthesis. It is necessary since multistep syntheses generally require changing solvents and removal of spent reagents and salts for downstream unit operations or analysis. Developing homogeneous in-line purification processes for flow synthesis would be a boon for industry by enhancing multistep fluidic processes by streamlining unit operations, enabling on demand synthesis of pharmaceuticals for market, resulting in lower costs from storage, spoilage and consignment returns. To achieve this, a method must continuously purify reaction mixtures of salts and by-products for mass spectrometric analysis to produce real-time second by second analysis of flow reactions. We have developed a microfluidic device to perform a tandem extraction process utilizing reversible acid/base phase switching properties of stable arylboronic acids. Using the complexation of boronic acids to 1,3 diol containing sugars, such as glucitol to produce boronic esters with strong hydrogen bonding ability, an aliphatic boronic acid functionalized molecule can be phase transferred from organic to aqueous media and vice versa, to facilitate the removal of impurities under continuous flow conditions. The current project involved the design and optimization of a simple hybrid device composed of perfluoropolymer film and stainless steel to construct a cheap, easily fabricated and configurable for rapid phase partitioning of boronic acids as a proof of concept methodology for continuous flow purification. Although continuous flow synthesis using fluidic systems has shown promise for single step synthesis, there is considerable difficulty in performing sequential steps to build complex small molecules. However, with the development of a continuous flow purification method this may be ameliorated so that a general method of multistep synthesis can be developed. The use of extraction techniques to facilitate purifications in continuous flow systems may prove to be a reliable and sustainable method for small scale as well as industrial scale synthesis as opposed to the use of liquid chromatography of intermediates, which introduces greater unit operations, steps and exponentially increases costs of APIs. Although the current project was not successful in generating a fully optimized device with a total arylboronic acid recovery of ~95%, we did achieve a high recovery of 75%. The proof of concept device demonstrated the utility and promise this system holds for developing multistep inline synthesis and analysis in-flow but requires further work to fabricate a more suitable microfluidic device to conduct arylboronic acid phase-switching purifications.

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