Process intensification toward galanthamine: continuous flow N-methylation of demethylbromonarwedine

Abstract

A continuous flow process for the N-methylation of demethylbromonarwedine employing Eschweiler-Clarke conditions is reported for the synthesis of methylbromonarwedine, an intermediate of the anti-Alzheimer’s drug (−)-galanthamine. By intensifying this reaction by performing the N-methylation at elevated temperature and pressure, the reaction time was drastically reduced from 3 h in batch to only 40 s. The robustness of this process was demonstrated by operating it for 4.5 h, resulting in a product throughput of 20 g/h. Methylbromonarwedine was obtained not only in high yield (83%) but also with an excellent product content of 90%, which is a crucial factor in this route toward (−)-galanthamine.

Graphical Abstract