High Throughput Experimentation Using DESI-MS to Guide Continuous-Flow Synthesis

Bradley P Loren,Tiago J P Sobreira,Kathryn Yammine,R Graham Cooks,Larisa Avramova,H Samuel Ewan,Huiying Liao,Christina R Ferreira,David H Thompson

doi:10.1038/s41598-019-50638-7

Abstract

We demonstrate the use of accelerated reactions with desorption electrospray ionization mass spectrometry (DESI-MS) as a tool for predicting the outcome of microfluidic reactions. DESI-MS was employed as a high throughput experimentation tool to provide qualitative predictions of reaction outcomes, so that vast regions of chemical reactivity space may be more rapidly explored and areas of optimal efficiency identified. This work is part of a larger effort to accelerate reaction optimization to enable the rapid development of continuous-flow syntheses of small molecules in high yield. In order to build confidence in this approach, however, it is necessary to establish a robust predictive connection between reactions performed under analogous DESI-MS, batch, and microfluidic reaction conditions. In the present work, we explore the potential of high throughput DESI-MS experiments to identify trends in reactivity based on chemical structure, solvent, temperature, and stoichiometry that are consistent across these platforms. N-alkylation reactions were used as the test case due to their ease of reactant and product detection by electrospray ionization mass spectrometry (ESI-MS) and their great importance in API synthesis. While DESI-MS narrowed the scope of possibilities for reaction selection among some parameters such as solvent, others like stoichiometry and temperature still required further optimization under continuous synthesis conditions. DESI-MS high throughput experimentation (HTE) reaction evaluation significantly reduced the search space for flow chemistry optimization, thus representing a significant savings in time and materials to achieve a desired transformation with high efficiency.

Highlights

high throughput experimentation (HTE) is transforming the drug development process[16,17,18,19]
We have recently reported an extension of this approach to a high throughput format using desorption electrospray ionization mass spectrometry (DESI-MS)[27]
We report the application of this HTE method to guide the optimization of microfluidic reactions

Summary

Introduction

HTE is transforming the drug development process[16,17,18,19]. In much the same way that these tools have accelerated drug discovery, HTE in organic reaction exploration is poised to drastically boost the efficiency of reaction discovery, route selection, and step optimization. Several different approaches have been used to screen reactions in both batch[13,14] and continuous-flow[11,15,20] under high throughput conditions. Information from smaller more focused screens in bulk microtiter and continuous flow reactors may both serve as a validation of the DESI-MS results, as well as serving to refine subsequent DESI-MS HTE (Fig. 1). Data from this series of experiments can be used to guide reaction optimization to achieve the highest yielding transformations under continuous-flow conditions in an efficient manner. Scale up of a reaction in continuous-flow based on the outcome of this larger experiment was demonstrated

Methods

Results

Conclusion