去氧胆酸的合成工艺研究

Study on the synthesis process of deoxycholic acid

目的根据质量源于设计的理念对去氧胆酸的合成工艺进行工艺优化,以保证产品的安全和质量。方法在查阅文献和参考原研专利基础上,通过分析每条合成路线优缺点,从而选定了植物源9-羟基雄烯二酮作为起始物料,对合成去氧胆酸关键中间体化合物7的制备工艺进行系统研究。针对每步反应产生的工艺杂质和光学异构体杂质,对关键工艺参数进行了详细的研究筛选,同时对每步反应后处理及精制工艺进行了系统的研究,为制定化合物7的质量标准提供了理论依据。结果在质量源于设计的思维指导下,以单因素设计实验为基础优化了反应工艺参数,合理地控制了手性异构体的含量同时提高了反应收率。以此为基础设计出化合物7合理的质量标准,并且通过多批次得到合格的去氧胆酸样品的实验证明了对化合物7质量标准设计的合理性和可行性。结论整个工艺过程稳定、可操作性强,完全可以满足工业化生产要求,为合成原料药去氧胆酸奠定了基础。

Objective To optimize the synthesis process of deoxycholic acid according to the concept of the quality-based de sign(QBD)to ensure the safety and quality of the product.Methods Based on a large number of literature and the referenced origi nal patents,the plant sourced 9-hydroxyandrostenedione was selected and used as the starting material for the deoxycholic acid synthe sis,in view of the advantages and disadvantages of each of the reported synthetic routes,and the synthesis process of the key interme diate 7 was investigated systematically with the particular attention.For the process impurities and optical isomer impurities generated in each reaction,the key parameters of the synthetic process were investigated and optimized in detail.At the same time,each step of post-reaction treatment and refining process was systematically investigated to provide the quality standard for the key intermediate 7.Results Under the guidance of QBD,the reaction process parameters were optimized based on the single factor design experiments,by which the content of chiral isomers was reasonably controlled and the reaction yield was largely improved.Based on the results,a quality standard was designed for the key intermediate 7,and the reasonability and feasibility of the quality standard was proved by the successful synthesis of deoxychloic acid from 7 to obtain multiple batches of qualified deoxycholic acid samples.Conclusion The whole process is stable and simply operable,and well matches the industrial requirement for the raw material deoxycholic acid synthe sis.