Self-optimising reactive extractions: towards the efficient development of multi-step continuous flow processes

Adam D Clayton,Luke A Power,A John Blacker,Caroline Ainsworth,William R Reynolds,David R J Hose,Martin F Jones,Thomas W Chamberlain,Richard A Bourne

doi:10.1007/s41981-020-00086-6

Adam D Clayton, Luke A Power + Show 7 more

Open Access

https://doi.org/10.1007/s41981-020-00086-6

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Abstract

Downstream purification of products and intermediates is essential for the development of continuous flow processes. Described herein, is a study on the use of a modular and reconfigurable continuous flow platform for the self-optimisation of reactive extractions and multi-step reaction-extraction processes. The selective extraction of one amine from a mixture of two similar amines was achieved with an optimum separation of 90%, and in this case, the black-box optimisation approach was superior to global polynomial modelling. Furthermore, this methodology was utilised to simultaneously optimise the continuous flow synthesis and work-up of N-benzyl-α-methylbenzylamine with respect to four variables, resulting in a significantly improved purity.

Highlights

The synthesis of active pharmaceutical ingredients (APIs) requires complex multi-step processing, involving chemical transformations, reaction quenching, work-ups, extractions and purifications
The system was comprised of three interchangeable modules: a variable temperature (−40 to 150 °C) microreactor; a miniature continuous stirred tank reactor (CSTR), fReactor, for flow rate independent mixing of liquid-liquid biphasic mixtures; [20] a membrane-based liquid-liquid separator fitted with a hydrophobic PTFE membrane (0.5 μm) [15]
We have successfully developed a modular and reconfigurable continuous flow platform for the self-optimisation of multistep reaction and extraction processes

Summary

Introduction

The synthesis of active pharmaceutical ingredients (APIs) requires complex multi-step processing, involving chemical transformations, reaction quenching, work-ups, extractions and purifications. Iterative step-by-step transformations in batch, where intermediates are purified and isolated between each synthetic step [1]. This process has a very high space-time demand, as large inventories of intermediates must be stored and transported between different manufacturing sites. Continuous flow offers in-line purification and the addition of reagents at set points in the processing sequence, providing a more productive uninterrupted reaction network [2]. There has been a rise in the use of modular flow platforms for the multi-step synthesis of APIs, minimising the impact of supply chain disruptions [3,4,5]

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