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...

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Bibliographic Details
Published in:Synlett 2020-12, Vol.31 (19), p.1888-1893
Main Authors: Monos, Timothy M., Jaworski, Jonathan N., Stephens, John C., Jamison, Timothy F.
Format: Article
Language:English
Subjects:
cluster
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Summary: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.
ISSN:0936-5214
1437-2096
DOI:10.1055/s-0039-1690884