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

作者：Fortunak Joseph M D^*; Byrn Stephen R; Dyson Brandon; Ekeocha Zita; Ellison Tiffany; King Christopher L; Kulkarni Amol A; Lee Mindy; Conrad Chelsea; Thompson Keeshaloy

来源：Tropical Journal of Pharmaceutical Research, 2013, 12(5): 791-798.

DOI：10.4314/tjpr.v12i5.20

• ACTs
• Dihydroartemisinin Piperaquine
• Dihydroartemisinin
• Green Chemistry
• Malaria
• Piperaquine

Purpose: To provide a robust, efficient synthesis of the malaria drug piperaquine for potential use in resource-poor settings. %26lt;br%26gt;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. %26lt;br%26gt;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 (%26gt; 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. %26lt;br%26gt;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.

• 出版日期2013-10