本发明属有机化学中萜类化合物青蒿素衍生物及其制备方法。

青蒿(菊科植物黄花蒿Artemisia annua)是常用中药。李时珍“本草纲目”记载，青蒿苦、寒、无毒，主治疥疮痂痒、恶疮、疟疾寒热、虚劳寒热、骨蒸烦热、心痛热黄、赤白痢下等病。七十年代初，中国科学家从青蒿中提取分离到抗疟有效成份青蒿素，它的化学结构式为：天然青蒿素具有抗疟活性，但由于它有溶解度小，制剂困难和复燃率高的不足，致使它的广泛应用受到了限制，这就促使科学家们致力于青蒿素的结构改造工作，以解决上述问题。中国科学家发明了抗疟活性高于青蒿素的蒿甲醚和青蒿琥酯的新抗疟药。前者溶于油，后者的钠盐溶于水，但这一水溶液稳定性差。欧洲专利[EP0362730(1989年)]报道了二氢青蒿素的醚类及硫醚类衍生物(其中包括含碱性基团的青蒿醚类)的抗疟作用、提及它们兼有抗阿米巴和抗球虫作用。美国专利[US4816478(1989年)]提到二氢青蒿素的醚类，酯类衍生物有抗艾滋病及其相关病的作用，但无具体化学结构。中国专利[CN 89109562.4(1989年)]报道了一类含有碱性基团可制成盐的水溶性青蒿素衍生物。

近年的药学杂志报道，中国科技人员对青蒿及青蒿素类除抗疟外的其他生物活性作了广泛的探索，有的已在临床上试用成功，例如对急性上感高热的退烧作用，红斑狼疮的治疗、鸡球虫病的防治、牛羊焦虫病的防治、牛血吸虫病的防治、猪弓形虫病的治疗等，这些研究结果给人启迪。

为探索青蒿素类化合物的潜在药用价值，本发明旨在设计新的合成路线，合成并提供更多类型的青蒿素衍生物。

The invention belongs to terpenoid artemisinin derivative and preparation method thereof in the organic chemistry.

Sweet wormwood (feverfew Herba Artemisiae annuae Artemisia annua) is a conventional Chinese medicine.LI Shi-Zhen " Compendium of Materia Medica " record, sweet wormwood hardship, cold, nontoxic cures mainly the scabies scab and itches, dislikes sore, malaria fever and chills, consumptive disease fever and chills, hectic fever due to yin dysphoria with smothery sensation, yellow, the inferior disease of dysentery with red and white feces of pained heat.Early seventies, extraction separation is to antimalarial effective ingredient Artemisinin from sweet wormwood for the Chinese science man, and its chemical structural formula is: Natural Artemisinin has antimalarial active, but because it has solubleness little, preparation difficulty and the high deficiency of recrudescence rate cause its widespread use to be restricted, and this just impels scientists to be devoted to the structure of modification work of Artemisinin, to address the above problem.The Chinese science man has invented antimalarial active and has been higher than the Artemether of Artemisinin and the new antimalarial drug of Artesunate.The former is dissolved in oil, and the latter's sodium salt is water-soluble, but this aqueous stability is poor.European patent [EP0362730 (1989)] reported the ethers of Dihydroartemisinin and thioether analog derivative (comprising the sweet wormwood ethers that contains basic group) the antimalarial effect, mention that they have anti-amoeba and anticoccidial effect concurrently.United States Patent (USP) [US4816478 (1989)] is mentioned the ethers of Dihydroartemisinin, and ester derivative has the effect of anti-AIDS and related diseases thereof, but does not have particular chemical.Chinese patent [CN 89109562.4 (1989)] has reported that a class contains the water-soluble arteannuin derivant that basic group can be made into salt.

In recent years pharmaceutical journal report, the Chinese science and technology personnel to sweet wormwood and artemisine the other biological activity except that antimalarial done widely to explore, what have tries out successfully clinically, for example to the acute effect of bringing down a fever of going up the high heat of sense, the treatments of the control of the treatment of lupus erythematosus, the control of coccidiosis of chicken, cattle and sheep babesiasis, the control of bos sinicus, pig toxoplasmosis etc., these results of study edify to the people.

Be to explore the potential pharmaceutical use of artemisine compounds, the present invention is intended to design new synthetic route, and is synthetic and more eurypalynous artemisinin derivative is provided.

https://patents.google.com/patent/CN1038416C/en