Identifying a kinetic model for the acid-catalyzed sequence of the artemisinin partial synthesis

This is the authors' abstract. We don't add key points for this paper.

Artemisinin derivatives, recognized as the most potent antimalarial agents with extensive biological activity, can be produced via semi-synthetic conversion of dihydroartemisinic acid through a hydroperoxide intermediate ( PO 1 ). However, modeling and optimizing this synthesis, particularly the acid-catalyzed transformation of PO 1 into artemisinin, has been challenging due to complex and partly unknown reaction pathways, and coupled mass-transfer processes. Extending our previous work, we present the first semi-empirical kinetic model describing the partial synthesis of artemisinin. Our developed identification approach integrates chemical domain expertise, mathematical optimization, and rigorous model evaluation against experimental data. Data were collected from a milliscale photo-flow and a batch reactor, leveraging both the efficient mass transfer of the continuous system and the frequent sampling capability of the batch setup. Numerical analysis revealed that the acid catalyst influences reaction kinetics more significantly than previously assumed. The identified kinetic model features apparent reaction orders greater than two with respect to the concentration of the added acid, and it contains different intermediates and byproducts depending on whether the operation is conducted in the presence of oxygen or under anaerobic conditions. Although the semi-empirical nature of the approach necessitates careful interpretation of these mechanistic conclusions, the developed process model accurately reproduces the behavior of the reaction system, providing parameter estimates crucial for process optimization.