Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O2 and light, and the output is pure, crystalline artemisinin. Everything else—solvents, photocatalyst and aqueous acid—can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.
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The authors acknowledge support from Sanofi, the University of Nottingham, the Bill and Melinda Gates Foundation (grant no. 1070294), and the Engineering and Physical Sciences Research Coucil (EPSRC; grant no. EP/L021889/1, ‘Continuous Chemical Manufacture with Light’). J.F.B.B. thanks the EPSRC for a studentship and M.W.G. thanks the Royal Society for a Wolfson Merit Award. The authors thank L. Hitchen for her contribution to batch studies in scCO2, M. Guyler, P. Fields, R. Wilson and D. Litchfield for technical support, G. Coxhill for MALDI analysis and W. Lewis for obtaining the crystal structure of 1 (shown in Fig. 3c). The authors thank D.B. Amabilino and P. Licence for helpful comments. Note that the production of semi-synthetic 1 at Sanofi is a not-for-profit venture, its development being supported in part by the Bill and Melinda Gates Foundation.
The authors declare no competing financial interests.
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Amara, Z., Bellamy, J., Horvath, R. et al. Applying green chemistry to the photochemical route to artemisinin. Nature Chem 7, 489–495 (2015). https://doi.org/10.1038/nchem.2261
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