Continuous-Flow Synthesis of Tramadol from Cyclohexanone

• Timothy M. Monos^a
• Jonathan N. Jaworski^a
• John C. Stephens^{b, c}
• Timothy F. Jamison*^a

• ^aDepartment of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
• ^bDepartment of Chemistry, Maynooth University, Maynooth, Co. Kildare, Ireland
• ^cThe Kathleen Lonsdale Institute of Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland

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.

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