Liu Delong

The development on the research of industrial production of artemisinin

Artemisinin (also named as Qinghaosu) has a significant therapeutic effect against chloroquine-resistant malaria with minimal side effects. It is an active compound existing in Artemisia annua L. and was isolated as a sesquiterpene lactone by Chinese investigators in 1972. Chinese scientist Youyou Tu won the 2015 Nobel Prize in Physiology or Medicine for her discoveries concerning a novel treatment against Malaria. Now, the artemisinin-derived compounds, dihydroartemisinin, artemether and artesunate, are the most effective drugs for the treatment of malaria. However, the artemisinin currently on sale is extracted from sweet wormwood Artemisia annua L. and research towards an industrial production of artemisinin under simple and mild reaction conditions is ongoing. Since its first synthesis in the 1980s, it has taken chemists more than 30 years to develop a feasible synthetic approach to artemisinin, including total synthetic and semi-synthetic procedures. The key step of these procedures is the peroxidation process which utilizes singlet oxygen to promote reaction. However, the majority of these peroxidation processes occur via a photochemical reaction, which is considered a difficult procedure to use in large-scale industrial processes. Many research groups and companies are engaged in the design of suitable equipment in order to meet the necessary requirements for use in photochemical reactions. Seeberger developed continuous flow apparatus in which the reaction occurs while the chemicals are flowing through a thin tube-wrapped light source, dramatically increasing the volume of available reactive oxygen. However, each set of apparatus only produces less than 1 kg artemisinin and column chromatography is needed to provide the pure product in a total yield of 39%. Sanofi employed a series of steps in big vats enabling the photochemical reaction to be performed in a specially developed glass reactor; however, this pathway is expensive due to equipment depreciation. A procedure that does not rely on any photochemical conditions is considered to be more suitable for the large-scale synthesis of artemisinin. Wanbin Zhang, a professor at Shanghai Jiao Tong University, has been investigating this topic for many years and has recently developed a simple and mild synthetic approach for the synthesis of artemisinin. At first, his group developed a peroxidation process which does not require photochemical conditions. The desired artemisinin is obtained in high yield from dihydroartemisinic acid (DHAA). In addition, a highly efficient asymmetric hydrogenation of artemisinic acid (AA) has been realized for the synthesis of DHAA using planar chiral RuPHOX-Ru complex developed within the Zhang’s group. The optimized procedure has been applied to a 10-kg production scale with a competitive price and shows potential for use in industry application prospects. Due to the large number of published papers concerning the synthesis of artemisinin, this review only summarizes the chemical synthetic development of artemisinin synthesis from the viewpoint of industrialization. We wish to provide a clear and concise outline of the industrial production of artemisinin for the chemical community.