罗氟司特的合成及质量标准研究

发布时间：2018-03-19 16:41

本文选题：慢性阻塞性肺疾病　切入点：罗氟司特　出处：《南华大学》2014年硕士论文　论文类型：学位论文

【摘要】：目的：探索罗氟司特的最优工艺路线，合成其可能存在的杂质并进行质量标准研究，为罗氟司特原料药临床前申报资料的撰写奠定基础。方法：以3-羟基-4-二氟甲氧基苯甲醛为原料，依次经过烷基化、氧化、酰胺化反应得到目标产物，采取HPLC、IR、MS及NMR相结合的方法对所合成化合物进行结构定性；通过中试放大试验确定其工业生产参数；分析罗氟司特中的潜在杂质并合成，，选用HPLC法或GC法对罗氟司特及其有关物质进行质量标准研究；采用GC法对罗氟司特中残留溶剂进行质量标准研究。结果：采取所选工艺路线得到的目标产物，其HPLC、IR、MS及NMR数据与文献报道一致；完成三批中试放大试验，工艺稳定且纯度均大于99.7%；合成罗氟司特有关物质共17个，其中新化合物8个；方法学研究结果表明，所选HPLC方法及GC方法线性范围好，准确度高。结论：所选工艺路线及进行质量标准研究所选用的检测方法合理，完成了罗氟司特原料药临床前申报资料中的相关试验。
[Abstract]:Objective: To explore the optimal process route of roflurost, synthesize the possible impurities and conduct quality standard research, so as to lay the foundation for the writing of preclinical application materials of rofluster.
Methods: 3- two fluorine hydroxy -4- methoxy benzaldehyde as raw materials, followed by alkylation, oxidation, amidation reaction to obtain the target product, take HPLC, IR, MS and NMR by combining the qualitative structure of the synthetic compounds; through the pilot test to determine the parameters of industrial production of fluorine Luo; for the potential impurities and synthesis, using HPLC method or GC method of roflumilast and related substances of quality standard; GC was used to study the quality standard of residual solvent roflumilast.
Results: the target product, the selected process route by the HPLC, IR, MS and NMR data are consistent with the literature; the completion of the three batch of pilot test, process stability and the purity was more than 99.7%; the synthesis of roflumilast related substances in a total of 17, including 8 new compounds; the study results show that the selected, HPLC method and GC method of linear range, high degree of accuracy.
Conclusion: the selected process route and the method of quality standard selection were reasonable, and completed the related tests in the clinical application of roflustar raw material.

【学位授予单位】：南华大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

【参考文献】