芬戈莫德的合成及质量研究

发布时间：2018-12-18 08:23

【摘要】：免疫抑制剂是对机体的免疫反应具有抑制作用的药物，有能抑制与免疫反应有关细胞的增殖和功能，降低抗体免疫反应的作用。免疫抑制剂是一类结合免疫病理学、临床免疫学等多种学科的理论基础发展而来的新型药物。因其独特的影响免疫应答反应而抑制机体的免疫功能，可广泛应用于在器官移植中的抗排斥反应和自身免疫病的治疗。常用的免疫抑制剂主要有五类：（1）糖皮质激素类，如可的松和强的松；（2）微生物代谢产物，如环孢菌素和藤霉素等；（3）抗代谢物，如硫唑嘌呤和6-巯基嘌呤等；（4）多克隆和单克隆抗淋巴细胞抗体，，如抗淋巴细胞球蛋白和OKT3等；（5）烷化剂类，如环磷酰胺等。另外还有中药类的免疫抑制剂和新开发的小分子类型的免疫抑制剂。芬戈莫德是日本三菱（Mitsubishi）制药公司研制开发的。Fujita教授等从科虫夏草培养液中提取得到的一种新型免疫抑制制剂，为抗生素ISP-1经化学修饰合成。可经口服给药用于治疗复发－缓解型多发性硬化症（multiplesclerosis,MS）。研究表明，其免疫抑制机制与其它药物完全不同，可改变淋巴细胞的趋向，促使淋巴细胞滞留于淋巴组织内，淋巴细胞离开淋巴组织的几率被降低，达到免疫抑制的效果。本文查阅大量有关芬戈莫德合成方法的文献，列举了国内的两条合成路线及国外文献中的三条合成路线。本试验在合成工艺研究方面，结合了工业生产的需要，设计的合成路线以β-苯乙醇为原料，经卤化反应、傅克酰化反应，缩合，羰基还原，酯基还原，水解去乙酰基，最终成盐得到目标分子。总收率达到22.4%。与文献中的合成路线相比，本试验所得到的合成路线工艺简化，成本降低，反应条件温和，收率高，适合于工业化规模生产。关键中间体与最终的目标产物的结构经紫外光谱、红外光谱、核磁共振氢谱及碳谱等均得到确证。本文建立了HPLC法测定盐酸芬戈莫德原料药的含量和有关物质的方法。含量测定HPLC法试验结果表明：盐酸芬戈莫德在0.055~0.165mg/mL范围内呈良好的线性关系，Y＝158490160X－51837.4，r2＝0.9998；精密度RSD为0.11%，表明仪器精密度良好；重复性RSD为0.09%，表明含量测定重复性良好；稳定性RSD为0.13%，表明供试品溶液至少在12h内稳定；加样回收率RSD为1.37%，表明此方法可行；样品耐受性良好。有关物质HPLC法试验结果表明：稳定性RSD为0.022%，表明供试品溶液至少在12h内稳定；耐受性良好。由以上数据显示测定结果准确，可靠，表明所建立的HPLC法能有效的控制本品的质量。
[Abstract]:Immunosuppressant is a kind of drug which can inhibit the immune response of the body. It can inhibit the proliferation and function of the cells related to the immune reaction and reduce the immune response of antibody. Immunosuppressant is a new kind of medicine which combines with immunopathology, clinical immunology and so on. Because of its unique effect on immune response, it can be widely used in the treatment of autoimmune diseases and anti-rejection in organ transplantation. There are five main types of immunosuppressants: (1) glucocorticoids, such as cortisone and prednisone; (2) microbial metabolites, such as cyclosporin and tenomenine; (3) antimetabolites, such as azathioprine and 6-mercaptopurine; (4) polyclonal and monoclonal anti-lymphocyte antibodies, such as antilymphocyte globulin and OKT3, (5) alkylates, such as cyclophosphamide, etc. There are also traditional Chinese medicine immunosuppressants and newly developed small molecule type immunosuppressants. Fengomod was developed by Mitsubishi (Mitsubishi) Pharmaceutical Company of Japan. Professor Fujita and others obtained a new immunosuppressive preparation from the culture medium of Herba Compositae. It is a chemically modified synthesis of antibiotic ISP-1. It can be used orally in the treatment of recurrent-remission multiple sclerosis (multiplesclerosis,MS). The results showed that the immunosuppressive mechanism was completely different from that of other drugs, which could change the tendency of lymphocytes, promote the retention of lymphocytes in lymphoid tissues, and reduce the probability of lymphocytes leaving lymphoid tissues, so as to achieve the effect of immunosuppression. In this paper, a large number of literatures on the synthesis of Fingomod are reviewed, and two synthetic routes at home and three synthetic routes in foreign literature are listed. In the aspect of synthesis technology, the synthetic route was designed with 尾 -phenylethanol as raw material through halogenation reaction, Fourier acylation reaction, condensation, carbonyl reduction, ester reduction, hydrolysis and deacetylation. The target molecule is eventually formed into salt. The total yield was 22. 4%. Compared with the synthetic route in the literature, the synthetic route obtained in this paper has the advantages of simple process, low cost, mild reaction conditions and high yield, which is suitable for industrial scale production. The structures of the key intermediates and the final target products were confirmed by UV, IR, NMR and C spectra. A HPLC method for the determination of the content and related substances of fengormod hydrochloride was established. The results of HPLC method showed that Fengomod hydrochloride had a good linear relationship in the range of 0.055~0.165mg/mL, YC158490160X-51837.4X ~ (2) 0.9998, and the precision RSD was 0.11, which indicated that the precision of the instrument was good. The reproducibility RSD was 0.09, which indicated that the content determination was reproducible, the stable RSD was 0.13, the sample solution was stable in at least 12 hours, the sample recovery RSD was 1.37, which indicated that the method was feasible and the sample tolerance was good. The results of HPLC test showed that the stability of RSD was 0.022, which indicated that the solution of the sample was stable in at least 12 hours and had good tolerance. The above data show that the determination results are accurate and reliable, which indicates that the established HPLC method can effectively control the quality of this product.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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