具有螺环结构的2-哌啶酮及吡咯烷酮的合成分析.docx

同济大掌硕士掌位论文 摘要
摘 要
本论文从既知的哌啶和吡咯烷类螺环化合物出发,通过直接氧化的方法,将其结构的哌啶或毗咯烷部分转换成为具有酰胺结构的哌啶酮或吡咯烷酮,进而改变整个螺环分子的特性,提高分子的生物活性,为基于组合化学的药物研发设计、合成了一种新型的具有螺环结构的2一哌啶酮及吡咯烷酮类“药物模板”化合物。论文共分为三个部分:
1。从3一苯丙醇出发,经过溴化、格氏化反应后,
,中间体2在90%硫酸水溶液中关环合成关键的螺环中间体3,然后再经过脱苄、上Boc、氧化、脱保护等系列反应,最终合成得到了一种新型结构的螺[苯并环一4’一哌啶一2’-酮】类化合物一螺[1,2,3,4-四氢一1一萘
酮一4,4'-哌啶一2’-酮】6b,%。
(苯并二氢吡喃一4一酮-2,4’-哌啶)8和螺(2,3-二氢-1一茚酮一3,4'-哌啶)lO为原料,通过KMnOjCuS04氧化、TFA/DCM脱Boc两步反应, 以较好的收率得到了两种结构新颖的螺环模板化合物~螺(
·2,4'-2’一哌啶酮)9b和螺(2,3一二氢一1一茚酮-3,4'-哌啶一2’一酮)llb。
,[】十—‘烷、2,8一二氮螺[]癸烷和螺[1,2一二氢一吲哚一3,4’_哌啶]为研究对象,从不同酰基保护基、氧化剂用量、分子立体构型三方面,对KMn04/CuS04混合氧化剂氧化合成具有二氮螺坏结构的2一哌啶酮及吡咯烷酮类化合物时,其氧化成酰胺结构的选择性进行了讨论。其中,合成了3,9一二氮螺[55]|I—。烷一2一酮、螺[】,2一二氢一吲哚一3,4’.蹶啶一2’.酮]和螺[1,2一二氢吲哚一2一酮一3。4’一哌啶一2’.酮]。
关键词:氮螺环化合物; 药物模板; 2一哌啶酮; ; 组合化学化合物库; 氧化
⑧同济大掌硕士掌位论文摘要
Abstract
In the present paper,a novel type of drug templates of spiropiperidin-2-ones and spiropyrrolidin·-2-·ones were designed and synthesized for drug R&D binatorial Chemistry,starting from a series of known and potent spiropiperidines
mad spiropyrrolidines by direct -aided“Accelrys’’molecular modeling system showed that the molecular property and biological activity of pounds contmning spiropiperidin-2一ones and spiropyrrolidin-2一ones have been changed pared with the original spiropiperidines and spiropyrro- 一lidines by modeling the pound library ofthis class oftemplates.
from 3-Phenyl-propan一1一ol,the Grignard reagent by bromization and Grignardation reacted with 1一Benzyl-piperidin一4一one to afford intermediate alcohol 3, which was cyclized in the presence of 90%H2S04 aqueous solution,then followed by benzyl-removal、Boc-protection、oxidation and deprotection series ofreacfions to give a novel structural pound·一spiro[1,2,3,4-tetrahydronaphthalen-1·one
·4,4’-piperidin一2一one】6b,total yield ofnine steps was %.
novel spirocyclic templates一一spiro(chroman一4一one·2,4'-piperidin一2’·one)
9b and spiro(2,3一dih