Reaction screening and optimization of continuous-flow atropine synthesis by preparative electrospray mass spectrometry

Abstract

Preparative electrospray (ES) exploits the acceleration of reactions in charged microdroplets to perform a small scale chemical synthesis. In combination with on-line mass spectrometric (MS) analysis, it constitutes a rapid screening tool to select reagents to generate specific products. A successful reaction in preparative ES triggers a refined microfluidic reaction screening procedure which includes the optimization for stoichiometry, temperature and residence time. We apply this combined approach for refining a flow synthesis of atropine. A successful preparative ES pathway for the synthesis of the phenylacetyl ester intermediate, using tropine/HCl/phenylacetyl chloride, was optimized for solvent in both the preparative ES and microfluidics flow systems and a base screening was conducted by both methods to increase atropine yield, increase percentage conversion and reduce byproducts. In preparative ES, the first step yielded 55% conversion (judged using MS) to intermediate and the second step yielded 47% conversion to atropine. When combined in two discrete steps in continuous-flow microfluidics, a 44% conversion of the starting material and a 30% actual yield of atropine were achieved. When the reactions were continuously telescoped in a new form of preparative reactive extractive electrospray (EES), atropine was synthesized with a 24% conversion. The corresponding continuous-flow microfluidics experiment gave a 55% conversion with an average of 34% yield in 8 min residence time. This is the first in depth study to utilize telescoped preparative ES and the first use of dual ESI emitters for multistep synthesis.