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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.

This article describes the design,optimisation and development of a Suzuki cross-coupling protocol mediated by an efficient palladium-en- capsulated catalyst (Pd EnCat TM ) under microwave irradiation. The methodolo- gy has been used in both batch mode for classical library preparation and in continuous-flow applications furnishing multigram quantities of material. De- scribed is a method that uses direct fo- cused microwave heating whilst apply- ing an external cooling source. This en- ables a lower than normal bulk temper- ature to be maintained throughout the reaction period leading to significant improvements in the overall yield and purity of the reaction products. Addi- tional aspects of this novel heating pro- tocol are discussed in relation to the prolonged lifetime and enhanced reac- tivity of the immobilised catalyst system.