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<p>Clonidine•HCl is a clinically important imidazoline derivative whose manufacturing routes have seen little innovation since their development in the mid-to-late 20<sup>th</sup> century. Its widespread use as an antihypertensive and neuroactive agent underscores the need for more efficient, modern production strategies. Herein, we report the first continuous flow strategy for the synthesis of clonidine. By integrating telescoped multistep sequences, inline liquid-liquid workup, advanced solid handling, and machine learning, we developed an intensified process that delivers clonidine•HCl in only 24 min total residence time across 5 continuous transformations, achieving an overall yield of 54%. This approach significantly outperforms conventional batch protocols, which typically require more than 18 h. The platform enables efficient and precisely controlled isothiocyanate formation, thiourea hydrolysis, <i>S</i>-methylation, and imidazoline cyclisation, while reducing intermediate isolations, minimising reagent handling, and eliminating hazardous materials associated with legacy routes. These advances provide a scalable, data-driven manufacturing solution and establish a foundation for intensified production of clonidine and related APIs under continuous flow conditions.</p>

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Machine-learning-assisted continuous flow synthesis of clonidine

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月29日

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  • Cloudius R. Sagandira,
  • Sinazo Nqeketo,
  • Alexander Pomberger,
  • Daniel Wigh,
  • Christophe Len

摘要

Clonidine•HCl is a clinically important imidazoline derivative whose manufacturing routes have seen little innovation since their development in the mid-to-late 20th century. Its widespread use as an antihypertensive and neuroactive agent underscores the need for more efficient, modern production strategies. Herein, we report the first continuous flow strategy for the synthesis of clonidine. By integrating telescoped multistep sequences, inline liquid-liquid workup, advanced solid handling, and machine learning, we developed an intensified process that delivers clonidine•HCl in only 24 min total residence time across 5 continuous transformations, achieving an overall yield of 54%. This approach significantly outperforms conventional batch protocols, which typically require more than 18 h. The platform enables efficient and precisely controlled isothiocyanate formation, thiourea hydrolysis, S-methylation, and imidazoline cyclisation, while reducing intermediate isolations, minimising reagent handling, and eliminating hazardous materials associated with legacy routes. These advances provide a scalable, data-driven manufacturing solution and establish a foundation for intensified production of clonidine and related APIs under continuous flow conditions.