抗抑郁药维拉佐酮中间体3-（4-氯丁基）-5-氰基吲哚的合成研究

发布时间：2019-06-14 04:49

【摘要】：本文综述了抑郁症与抗抑郁药物的发展历程，并着重介绍了新型抗抑郁药维拉佐酮。维拉佐酮于2011年获FDA批准成为成人重度抑郁症的临床治疗药物，因具有SSRI与5-HT1A受体激动剂双药效团，与传统抗抑郁药相比起效更快、选择性更好、药效更强。鉴于其良好的应用前景，本文对合成维拉佐酮的关键中间体3-(4-氯丁基)-5-氰基吲哚的合成进行了研究。首先采用路线一“吲哚-吲哚啉-吲哚”合成法，以吲哚、亚硫酸氢钠为原料，经过加成、N-酰基保护、溴化和脱酰基保护得到了5-溴吲哚，，但在继续以氰化亚铜为氰化试剂反应时未能成功制备5-氰基吲哚。采用路线二L-B吲哚合成法，以间甲基苯胺为原料经N-酰基保护、硝化、重氮化、Sandmeyer氰基化和还原环化最终合成了5-氰基吲哚。最后以5-氰基吲哚为原料、4-氯丁酰氯为酰基化试剂经Friedel-Crafts酰基化反应合成了3-(4-氯丁酰基)-5-氰基吲哚。本文分别对采用的路线一、路线二的各步反应的影响因素及相关机理进行了探讨，对已得到的产物及中间体结构经IR、1HNMR等进行了表征。
[Abstract]:In this paper, the development of depression and antidepressants was reviewed, and the new antidepressant verazodone was introduced. Verazodone was approved by FDA in 2011 as a clinical drug for severe depression in adults. Because of its dual drug efficacy of SSRI and 5-HT1A receptor agonists, verazodone is more effective, more selective and more effective than traditional antidepressants. In view of its good application prospect, the synthesis of 3-(4-chlorobutyl)-5-cyanoindole, a key intermediate for the synthesis of verrazolone, was studied in this paper. Firstly, 5-bromoindole was synthesized from indole and sodium bisulfite by route 1 "indole-indoline-indole" synthesis method. 5-bromoindole was obtained by addition, N-acyl protection, bromination and deacylation protection, but 5-cyanoindole could not be successfully prepared when cuprous cyanide was used as cyanide reagent. 5-cyanoindole was synthesized by route diL-B indole synthesis with m-methylaniline as raw material under N-acyl protection, nitrification, diazotization, Sandmeyer cyclization and reductive cyclization. Finally, 3-(4-chlorobutyryl)-5-cyanoindole was synthesized by Friedel-Crafts acylation with 5-cyanoindole as raw material and 4-chlorobutyryl chloride as acylation reagent. In this paper, the influencing factors and related mechanisms of each step of route 1 and route 2 were discussed, and the structures of the obtained products and intermediates were characterized by IR,1HNMR and so on.
【学位授予单位】：天津理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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