Machine-learning-assisted continuous flow synthesis of clonidine
- 1Pharmaceutical Technologies, Council for Scientific and Industrial Research (CSIR)
- 2ReactWise Technologies Ltd
- 3Institute of Chemistry for Life and Health Sciences, Chimie ParisTech, CNRS, PSL Research University
Abstract
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.
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BibTeX
@article{sagandira2026machinelearningassisted,
title = {{Machine-learning-assisted continuous flow synthesis of clonidine}},
author = {Cloudius R. Sagandira and Sinazo Nqeketo and Alexander Pomberger and Daniel Wigh and Christophe Len},
journal = {Communications Chemistry},
year = {2026},
month = jun,
doi = {10.1038/s42004-026-02096-2},
url = {https://doi.org/10.1038/s42004-026-02096-2},
note = {CC BY},
}
RIS
TY - JOUR
TI - Machine-learning-assisted continuous flow synthesis of clonidine
AU - Cloudius R. Sagandira
AU - Sinazo Nqeketo
AU - Alexander Pomberger
AU - Daniel Wigh
AU - Christophe Len
PY - 2026
DA - 2026/06/01
JO - Communications Chemistry
DO - 10.1038/s42004-026-02096-2
UR - https://doi.org/10.1038/s42004-026-02096-2
AB - 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.
SN - 2399-3669
ER -