A continuous flow process using a sequence of microreactors with in-line IR analysis for the preparation of N,N-diethyl-4-(3-fluorophenylpiperidin-4- ylidenemethyl)benzamide as a potent and highly selective δ-opioid receptor agonist

摘要

This article describes the design, optimisation and development of a continuous flow synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4- ylidenemethyl)benzamide, a potent δ-opioid receptor agonist developed by AstraZeneca. The process employs a sequence of flow-based microreactors, with integrated purification employing solid-supported reagents and in-line IR analytical protocols using a newly developed ReactIR flow cell. With this monitoring device, initiation of the fourth input flow stream can be precisely controlled during the synthesis. A four-step flow synthesis of a potent δ-opioid receptor agonist was developed (see scheme), using a continuation of pumping devices in combination with cartridges packed with appropriate scavengers to effect clean delivery of the product. We have also reported the use of in-line ReactIR monitoring to synchronise pumping of a late input stream to coordinate reactive components.