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<p>A continuous flow process for the <i>N</i>-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 <i>N</i>-methylation at elevated temperature and pressure, the reaction time was drastically reduced from 3&#xa0;h in batch to only 40&#xa0;s. The robustness of this process was demonstrated by operating it for 4.5&#xa0;h, resulting in a product throughput of 20&#xa0;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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月25日

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  • Niklas Sulzer,
  • Elena Pusca,
  • Johanna Pfnier,
  • Martin Seifert,
  • Stefan Welzig,
  • Doris Dallinger,
  • C. Oliver Kappe

摘要

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