A continuous phase-transfer catalysis process for N-alkylation integrated with separation was developed. This approach circumvents the heat and mass transfer limitations encountered in batch scale-up, enabling a safer process and yielding a higher-quality product. Two continuous flow approaches are analyzed: a) an automated fill–empty reactor with an integrated gravity separator and b) a tubular flow reactor with an inline membrane separator. The fill–empty platform enabled the direct technology transfer from batch, achieving conversions >99% (by HPLC) and purities >90%. The tubular flow reactor allowed the reduction of the base solution requirements, yielding conversions of 91% and purities >88%. Both the setups provide a small process footprint with downstream integrated separation. The on-demand scale-up was efficiently and safely demonstrated using the fill–empty approach for the production of various substrates at the multigram scale.

中文翻译：

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使用相转移催化和流动相分离 的N烷基化反应规模放大†

氮的连续相转移催化过程开发了与分离结合的-烷基化。这种方法避免了批量放大过程中遇到的传热和传质限制，从而可以实现更安全的工艺并生产出更高质量的产品。分析了两种连续流方法：a）带有集成重力分离器的自动填充-空反应器，以及b）带有串联膜分离器的管式流反应器。填充为空的平台支持直接从批处理中转移技术，实现了> 99％的转化率（通过HPLC）和> 90％的纯度。管状流动反应器可以减少基本溶液的要求，转化率为91％，纯度> 88％。两种设置都提供了较小的工艺占用空间，并具有下游集成式分离功能。