Tropical Journal of Pharmaceutical Research

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An Efficient, Green Chemical Synthesis of the Malaria Drug, Piperaquine

JMD Fortunak, SR Byrn, B Dyson, Z Ekeocha, T Ellison, CL King, AA Kulkarni, M Lee, C Conrad, K Thompson


Purpose: To provide a robust, efficient synthesis of the malaria drug piperaquine for potential use in resource-poor settings.
Methods: We used in-process analytical technologies (IPAT; HPLC) and a program of experiments to develop a synthesis of piperaquine that avoids the presence of a toxic impurity in the API and is optimized for overall yield and operational simplicity.
Results : A green-chemical synthesis of piperaquine is described that proceeds in 92 – 93 % overall yield. The chemistry is robust and provides very pure piperaquine tetraphosphate salt (> 99.5 %). The overall process utilizes modest amounts (about 8 kg/kg) of 2-propanol and ethyl acetate as the only organic materials not incorporated into the API; roughly 60 % of this waste can be recycled into the production process. This process also completely avoids the formation of a toxic impurity commonly seen in piperaquine that is otherwise difficult to remove.
Conclusion: An efficient synthesis of piperaquine is described that may be useful for application in resource-poor settings as a means of expanding access to and reducing the cost of ACTs.

Keywords: ACTs, Dihydroartemisinin Piperaquine, Dihydroartemisinin, Green Chemistry, Malaria, Piperaquine.
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