虫草素的合成及工艺优化

Synthesis and process optimization of cordycepin

目的开发并优化一条经济、安全、高效的虫草素半合成工艺路线,深入分析反应机制。方法以廉价的腺苷为起始原料,与2-乙酰氧基异丁酰溴反应生成溴代中间体3,再经二氢双(2-甲氧乙氧基)铝酸钠(Red-Al)还原脱卤得虫草素,利用HRMS、^(1)H-NMR、^(13)C-NMR、HPLC、旋光和熔点进行结构确认及纯度鉴定,分析反应机制及生成的副产物。结果通过两步反应实现了虫草素的合成,其中脱卤反应在常温常压下进行,避免了昂贵金属试剂(Pd/C)和危险源(高压氢气)的使用,极大降低了生产成本,提高了反应安全性。结论本实验报道的两步法是目前虫草素最简洁高效的半合成路线,分离纯化简单,机制明确清晰,具有良好的市场化前景。

Objective To develop and optimize a economic,safe,and efficient method to semisynthesize cordycepin,and to define the reaction mechanism.Methods Firstly,cheap adenosine was used to react with 2-acetoxyisobutyryl bromide to furnish the bromide intermediate 3.Secondly,the bromide was reduced by sodium bis(2-methoxyethoxy)aluminium hydride(Red-Al)to get cordycepin.Finally,the product was determined and confirmed by HRMS,^(1)H-NMR,^(13)C-NMR,HPLC,optical rotation and melting point.The side-product and possible mechanism were also proposed.Results Cordycepin was synthesized in two steps,for which the dehalogenation was conducted under ambient temperature and normal pressure without using expensive metal(Pd/C)and dangerous reagent(high-pressure hydrogen).Therefore,this protocol reduced the cost and improve the safety greatly.Conclusion Two-step semi-synthesis of cordycepin is now the most efficient protocol with sample purification and clear mechanism,which facilitates the industrial production of cordycepin.