免疫抑制剂论文：免疫抑制剂 氨基甲醇 合成 Suzuki反应

免疫抑制剂：免疫抑制剂 氨基甲醇 合成 Suzuki反应 【关键词】免疫抑制剂 氨基甲醇 合成 Suzuki反应 【英文关键词】Immunosuppressant Amino Alcohol Synthesis Suzuki reaction 免疫抑制剂论文:两个6-取代-2-氨基-1，2，3，4-四氢-2-萘甲醇类化合物的合成研究 【中文摘要】免疫抑制剂作为一种具有抑制人体免疫作用的药物，广泛应用于器官移植排斥反应和人体自身免疫疾病的临床治疗中。目前临床常用的免疫抑制剂大多具有很强的毒副作用，在治疗疾病的同时会诱发感染和肿瘤，因此医药工作者在不断开发新型的免疫抑制剂。特别是随着酶、受体等多种与免疫相关的新靶点的不断发现，人们开发了多种针对这些不同药物作用靶点的高效特异性的新型免疫抑制剂。本文根据药物的不同作用靶点分类，分别介绍了二氢乳清酸脱氢酶抑制剂、Janus激酶3抑制剂、蛋白激酶C抑制剂和鞘氨醇-1-磷酸受体激动剂等四类新型免疫抑制剂，其中由日本三菱制药公司研发的FTY-720属于鞘氨醇-1-磷酸受体激动剂类药物，具有独特的药理特点和良好的疗效，毒副作用少，在许多疾病的临床治疗方面发挥着重要作用，是一种极具潜力的免疫抑制剂，且它具有新颖的化学结构，可以作为先导化合物用于新型免疫抑制剂的进一步开发。本文根据FTY-720的构效关系研究以及本实验室自主研发的新型免疫 抑制剂FC系列化合物的研究经验，并合成了目标产物:6-苯基 -2-氨基-1,2,3,4-四氢-2-萘甲醇和6-(6-甲氧己基)-2-氨基 -1,2,3,4-四氢-2-萘甲醇。目标化合物都是以四氢萘为母体，2位为 羟甲基和氨基，6位含取代基的分子，与之前设计合成的7位含取代 基的分子一脉相承，为进一步研究化合物结构与活性的关系提供了物 质基础，同时也为新型免疫抑制剂的研发提供了科学依据。本文对有 机硼试剂，α-氨基酸，钯催化C-C键偶联的合成等进行了 简单叙述，并详细介绍了经典C-C键偶联方法Suzuki反应的特点， 分别从亲电试剂、硼酸试剂、催化剂、碱及反应条件等多方面介绍了 影响Suzuki反应效果的因素，为实验过程中方法改进提供了坚实的 理论依据。本实验以对溴苯乙酸为原料，6-溴-2-四氢萘酮为重要中 间体，采用Suzuki反应、Bucherer-Beg’s反应、酰胺水解及羰基 【英文摘要】The immunosuppressants were a kind of im-munosuppressive drugs, that were widelyused in organ transplant rejection reaction and autoimmune disease. They play an importantrole in the clinical treatment. But at present most of the immunosuppressants that werecommonly used have strong side effects.They may induce infection and tumor so themedical workers are constantly committed to the development of new immunosuppressiveagents.Especially with the discovery of enzymes, receptors and the other new targets thatrelated to the immune function we have developed many kinds of specific newimmunosuppressants with high activity.In this paper，we introduced four kinds of new immunosuppressants according to theirdifferent targets and mechanismas. They are the inhibitors of dihydroorotate dehydrogenase,Janus kinase3and protein kinase C and sphingosine-1-phosphate agonists. FTY-720synthesized by Professor Fujita with Yoshitomi Pharmaceutical Company was a kind ofsphingosine-1-phosphate agonists. It has unique pharmacological characteristics, goodcurative effect and less toxic side effect than conventional immunosuppressants.It plays animportant role in the clinical treatment of many diseases. It is a promising immuno suppress-ant. furthermore it has a novel structure that can be used as lead compounds for furtherdevelopment of new immunosuppressive agents.According to the studies on structure-activity relationship of FTY-720and the researchexperience of new immunosuppressive agents FC in our laboratory, we designed andsynthesized two target compounds:[2-amino-6-phenyl-1,2,3,4-Tetrahydronaphthalen-2–yl]methanol and [2-amino-6-(6-methoxyhexyl)-1,2,3,4-Tetrahydronaphthalen-2- yl] methanol.The basing structure of the target compounds was tetralin, the2position was substitutedby hydroxymethyl and amino. They are in the same strain with the other2-amino-6-substituted-1,2,3,4-tetrahydro-2-naphthalene methanol and2-amino-7-substituted-1,2,3,4-tetrahydro-2-naphthalene methanol. They are useful for the further study of the compoundstructure-activity relationships and lay a good foundation for the development of newimmunosuppressants. This paper briefly introduces the synthesis method of organic boron reagent, α-aminoacid, palladium catalyzed C-C bond coupling and details the characteristics of Suzukireaction which is a classic C-C bond coupling method. Moreover I analyzes and summarizedvarious factors that influence the effect of the Suzuki reaction such as electrophiles, boricacid, alkali reagent, catalyst and reaction conditions. This provides a solid theoretical basisfor the improvement of methods in the experiment.The two target compounds were synthesized by6-bromo-2-tetralone as starting material,6-substituted-2-tetralone as intermediate and Suzuki reaction, Bucherer-Berg’s reaction,hydantoin hydrolysis and carbonyl reduction as key steps. The key intermediates and targetcompound are identified by1H-NMR,13C-NMR, MS and IR. 【目录】两个6-取代-2-氨基-1，2，3，4-四氢-2-萘甲醇类化 合物的合成研究 中文摘要 4-6 ABSTRACT 6-7 第1章 绪论 9-19 1.1 新型免疫抑制剂的研究进展 9-12 1.2 基于 FTY720 构效关系设计的新型免疫抑制剂 12-19 第2章 实验路线的设计 19-21 2.1 6-溴-2-萘满酮的合成设计 19 2.2 6 位取代基的合成设计 19 2.3 α-氨基酸的合 成设计 19-20 2.4 目标分子合成路线设计 20-21 第3 章 6-取代-2-氨基-1，2，3，4-四氢-2-萘甲醇的合成 21-31 3.1 实验部分 21-29 3.2 实验结果与讨论 29-31 第4章 结 论 31-32 参考文献 32-37 附图 37-58 作者简介 及在学期间所取得的科研成果 58-59 致谢 59