Continuous-Flow Synthesis of Tramadol from Cyclohexanone

Abstract

A multioperation, continuous-flow platform for the synthesis of tramadol, ranging from gram to decagram quantities, is described. The platform is segmented into two halves allowing for a single operator to modulate between preparation of the intermediate by Mannich addition or complete the fully concatenated synthesis. All purification operations are incorporated in-line for the Mannich reaction. ‘Flash’ reactivity between meta-methoxyphenyl magnesium bromide and the Mannich product was controlled with a static helical mixer and tested with a combination of flow and batch-based and factorial evaluations. These efforts culminated in a rapid production rate of tramadol (13.7 g°h–1) sustained over 56 reactor volumes. A comparison of process metrics including E-Factor, production rate, and space-time yield are used to contextualize the developed platform with respect to established engineering and synthetic methods for making tramadol.