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题名	新型高血压药aliskiren的合成研究
作者	李乐乐
学位类别	博士
答辩日期	2015-05
授予单位	中国科学院研究生院
授予地点	中国科学院长春应用化学研究所
导师	高连勋 ; 韩福社
关键词	高血压药 肾素抑制剂 阿利吉仑 对甲苯磺酰腙 烷基四唑硫醚
中文摘要	Aliskiren是已经上市的新型高血压药，是唯一的肾素抑制剂类高血压药。Aliskiren分子拥有独特的结构，即四个S型手性中心位于同一条碳链上，这给其合成带来极大的挑战。本论文以aliskiren的高效合成为目标，开展了aliskiren的合成研究，主要包括两部分内容： 首先，本论文重点关注合成aliskiren的关键中间体(2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethylnon-4-enamide。本论文基于Julia-Kocienski烯化策略，开发了一条合成此中间体的新路线。此路线具有实用性、高效性等优势：从商品化的原料出发，使用便宜易得的原料；用10步直线步骤以33%的总产率合成了此中间体，所有反应都可以实现克级规模；用Evans不对称烷基化反应引入手性中心时，具有非常卓越的立体选择性（>97% ee）；用Julia-Kocienski烯化构建双键时，具有很好的产率（81%）和双键反式选择性（E:Z = 14.41:1）。随后，从此中间体出发，完成了aliskiren的合成。 其次，本论文关注合成烷基四唑硫醚：Julia-Kocienski烯化策略的中间体。基于对甲苯磺酰腙与四唑硫醇之间的无过渡金属的C-S还原偶联反应，本论文开发了一条合成烷基四唑硫醚的新方法：醛与对甲苯磺酰肼形成腙后，原位与四唑硫醇进行偶联反应，一锅反应合成烷基四唑硫醚。迄今为止，这是从醛合成烷基四唑硫醚最直接的方法，克服了已有方法中步骤多的缺点。对醛和四唑硫醇这两个底物，此方法都有广泛的适用性。其中，带有保护的氨基或羟基官能团的醛，能够合成带有双官能团的四唑硫醚，这为进一步转化提供了可能性。在合成aliskiren的路线中，进行Julia?Kocienski烯化反应所使用的烷基四唑硫醚前体，也能用此方法合成，这将进一步提高合成aliskiren的效率。最后，本论文通过对照实验，研究了添加剂LiI在反应体系中的作用，确定了此偶联反应的机理。
英文摘要	Aliskiren has been marketed as an novel antihypertensive drug, which is the only orally available, highly specific, and efficient renin inhibitor. Aliskiren features the presence of four chiral centers in an aliphatic carbon chain, which renders the synthesis of this molecule extremely challenging. The dissertation developed the study on the synthesis of aliskiren with the target of its efficient synthesis. The following two parts are included: Firstly, the dissertation focuses on an efficient pathway for the synthesis of (2S,7R,E)-2-isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethylnon-4-enamide, which has been used as the advanced intermediate toward aliskiren. We have established an alternative, efficient, and practicable protocol for its synthesis. From the commercially readily available starting materials, it could be synthesized in 33% overall yield via a ten-step procedure in muti-gram scale. The key transformations were the Evans chiral auxiliary-aided asymmetric allylation for the installation of the appropriate chiral center in excellent enantiomeric purity (>97% ee) and Julia–Kocienski olefination for the construction of the intermediate in high yield (81%) with high selectivity (E:Z = 14.41:1). Then, aliskiren was synthesized from the intermediate. Secondly, the dissertation focuses on an straightforward protocol for the synthesis of 1H-Tetrazol-5-yl thioethers which served as precursors of Julia–Kocienski olefination in our synthesis of aliskiren. Based on the metal-free reductive cross-coupling of tosylhydrazones with 1H-tetrazol-5-yl thiols, we have established the most straightforward protocol for the synthesis of alkyl 1H-tetrazol-5-yl thioethers from aldehydes. Namely, the aldehydes were first condensed with N-tosylhydrazine to generate the N-tosylhydrazones, which were then reductively coupled in situ with 1H-tetrazole-5-thiols to afford the thioethers in one-pot with high to excellent yields. The method is compatible to a broad range of both substrates. Notablely, the thioethers from the aldehydes decorated by protected amine or hydroxyl groups, are very important due to their double functional groups. The practical use of this method was elaborated by the synthesis of the key intermediate for accessing aliskiren. Finally, we investigated the role played by LiI additive in the metal-free reductive cross-coupling reaction by the control experiments, and verified the mechanism proposed by us.
语种	中文
公开日期	2016-05-03
内容类型	学位论文
源URL	[http://ir.ciac.jl.cn/handle/322003/64492]
专题	长春应用化学研究所_长春应用化学研究所知识产出_学位论文
推荐引用方式 GB/T 7714	李乐乐. 新型高血压药aliskiren的合成研究[D]. 中国科学院长春应用化学研究所. 中国科学院研究生院. 2015.

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