青蒿素可工业化合成研究进展

The development on the research of industrial production of artemisinin

中国科学家屠呦呦由于在发现青蒿素和治疗疟疾新型疗法上的贡献而获得了2015年诺贝尔生理或医学奖.现如今以青蒿素为先导化合物衍生得到的蒿甲醚和青蒿琥酯等青蒿素类药物是治疗疟疾唯一有效的药物.但目前市售的青蒿素仍是依靠植物黄花蒿的提取,其高效人工合成依然是合成化学领域的一个挑战.由于生物合成青蒿酸的成功实现,使得从青蒿酸到青蒿素的高效化学合成,特别是无光照化学合成工艺的开发,成为人工合成青蒿素能否工业化生产的关键所在.本文从可工业化的角度,简要综述了青蒿素化学合成的研究进展.主要讨论的内容包括青蒿素化学合成的背景、仿生合成的探索以及无光照人工合成的研究等方面,为青蒿素的合成及其相关领域的科研工作者提供一个简单明了的概括.

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 1980 s, 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 Ru PHOX-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.