In-line separation of multicomponent reaction mixtures using a new semi-continuous supercritical fluid chromatography system

Abstract

A new bespoke semi-continuous parallel column supercritical fluid chromatography unit has been developed that solves the problem of effective separation of continuous, multicomponent reaction mixtures. It enables the rapid in-line separation of crude mixtures produced during batch and continuous flow reactions. It overcomes limitations inherent to other systems, enabling it to collect up to five individual fractions from mixtures with any number of constituent components, and adds new machinery to aid the modern synthetic chemist. The success of the system was exemplified using two Appel-type reactions, enabling the recovery of 81 % of 1-bromoethylbenzene (with a first pass purity of 92 %) and 89 % of an intermediate to the anti-cancer drug candidate AZ82 (>99 % purity) from batch mixtures. As a notable example, the system was also used in a telescoped flow process to separate an intermediate during the synthesis of isoniazid. In this case, the three-stage synthesis was operated at steady state for four hours during which time 96 % recovery of the intermediate, isonicotinamide, was attained (with a purity of >99 %).