Synthesis of the antimalarial API artemether in a flow reactor

• Catalytic flow synthesis of artemether was shown for the first time.
• A stable etherification catalyst was found.
• LCA study highlighted critical stages of the process.
• Tandem reduction-etherification in flow is feasible.

The earlier developed flow protocol for stoichiometric reduction of an important biologically derived pharmaceutical precursor, artemisinin, to dihydroartemisinin was extended to a sequential reaction to produce one of the final APIs, artemether. A highly active heterogeneous catalyst was found for the etherification reaction. The use of QuadraSil catalyst allows to eliminate one step of reaction workup. A comparative Life Cycle Assessment of both reactions has shown advantages of the flow process over the optimized literature batch protocols. Results of LCA highlight the significance of solvents in pharmaceuticals manufacture and the advantage of flow technology, enabling small solvent inventories to be used.

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