本文選題：硅替代新藥研發(fā) + 氮雜環(huán)卡賓��； 參考：《山東大學(xué)》2017年碩士論文

【摘要】："硅替代"新藥研發(fā)是指對現(xiàn)有藥物結(jié)構(gòu)進(jìn)行硅修飾以獲得具有有效生物活性的藥物。硅元素與碳元素相比,它的親脂性,電負(fù)性,原子大小以及共價鍵半徑是不同的。這些差異使硅替代藥物表現(xiàn)出優(yōu)越的性質(zhì):1,硅替代藥物里含有硅醇官能團(tuán),硅醇官能團(tuán)與甲醇官能團(tuán)相比,前者的氫鍵鍵能更加大,親和力被加強(qiáng),選擇性被提高;2,硅替代藥物具有更高的親脂性,它們具有非常強(qiáng)的組織滲透能力,而且能明顯增加藥物的分布容積。它們還能提高表觀油水分配系數(shù),改善藥物血腦屏障的通透性,從而進(jìn)一步影響中樞神經(jīng)系統(tǒng)活動,可以顯著提高藥物的療效;3,硅替代藥物的毒性低,從而提高了安全性。含硅類化合物的合成方法研究吸引越來越多人的注意,如何方便有效地合成硅類化合物成為研究人員亟待解決的問題。我們對醛與硅試劑的加成比較感興趣,因?yàn)樗鼈兊漠a(chǎn)物為α-羥基硅烷,而含有羥基的α-羥基硅烷以及它們的衍生物已經(jīng)被廣泛應(yīng)用在C-C鍵的構(gòu)建和重排中。我們將三氮唑卡賓與[2.2]環(huán)仿進(jìn)行結(jié)合,得到一類新穎的催化劑并且成功地應(yīng)用在醛的硅基化反應(yīng)里,得到一系列α-羥基硅烷產(chǎn)物。本論文包括以下幾個方面:第一章,研究背景分別對硅替代新藥研究、不對稱硅基化反應(yīng)研究、氮雜環(huán)卡賓(NHC)在不對稱催化反應(yīng)中的應(yīng)用以及[2.2]PCP在不對稱催化里的應(yīng)用分別進(jìn)行綜述。第二章,目標(biāo)配體的設(shè)計(jì)、合成和表征合成目標(biāo)配體需要先合成兩個原料,分別是基于面手性[2.2]環(huán)仿甲�；蔓}以及手性氨基醇衍生的亞胺醚。一方面我們以對甲基芐基三甲基氯化銨為原料,通過消除聚合得到[2.2]PCP。然后進(jìn)行溴代,高溫轉(zhuǎn)位。接著單亞胺化,酸解堿化。然后與Boc保護(hù)的L型脯氨酸反應(yīng),柱層析拆分,酸解堿化分別得到到RP/SP光學(xué)純產(chǎn)物。然后重氮化,溴代。接著單腙化,甲�；�。然后經(jīng)過Suzuik反應(yīng),酸解得到甲�；蔓}。另一方面我們以L-苯甘氨醇為原料,經(jīng)過酰胺化,關(guān)環(huán)以及甲基化得到亞胺醚。最后甲�；蔓}與亞胺醚反應(yīng)關(guān)環(huán)得到目標(biāo)配體。第三章,目標(biāo)配體(S,Sp)-4在醛的不對稱硅基化反應(yīng)中的應(yīng)用我們以對氯苯甲醛作為模板底物,經(jīng)過條件優(yōu)化以及配體篩選,得到最優(yōu)反應(yīng)條件。在最優(yōu)條件下,我們研究了各種芳香醛的不對稱硅基化反應(yīng),得到一系列α-羥基硅產(chǎn)物。本論文的創(chuàng)新點(diǎn):1,第一次合成出目標(biāo)配體(R,Rp)-13;2,利用實(shí)驗(yàn)室里現(xiàn)有的配體庫,研究了醛的不對稱硅基化反應(yīng),開創(chuàng)了第一例無金屬催化的醛的不對稱硅基化反應(yīng)。
[Abstract]:New drug R & D for silicon substitution refers to the modification of existing drug structures to obtain effective bioactive drugs. Compared with carbon, silicon has different lipophilicity, electronegativity, atomic size and covalent bond radius. These differences make silicon substitute drugs show superior properties: 1. Silicon substitute drugs contain silyl functional groups. Compared with methanol functional groups, the former has higher hydrogen bond energy and stronger affinity. The selectivity is improved and the silicon-substituted drugs have higher lipophilic properties. They have very strong tissue permeability and can obviously increase the distribution volume of the drugs. They can also improve the apparent distribution coefficient of oil and water, improve the permeability of the blood-brain barrier, and further affect the central nervous system activities. They can significantly improve the efficacy of the drug and the toxicity of silicon substitute drugs, thus improving the safety. More and more attention has been paid to the synthesis method of silicon-containing compounds. How to synthesize silicon compounds conveniently and effectively has become an urgent problem to be solved. We are interested in the addition of aldehydes and silicon reagents because their products are 偽 -hydroxysilane and their derivatives have been widely used in the construction and rearrangement of C-C bonds. A series of 偽 -hydroxysilane products were obtained by combining triazole carbene with [2.2] cycloform to obtain a new kind of catalyst and successfully applied to the silicylation of aldehydes. This paper includes the following aspects: chapter 1, the background of the research on silicon substitute new drugs, asymmetric silicylation reaction research, The applications of PCP in asymmetric catalysis and [2.2] PCP in asymmetric catalysis were reviewed. In chapter 2, the design, synthesis and characterization of the target ligands require the synthesis of two raw materials, one is based on [2.2] cycloimidyl hydrazide and the other is imide derived from chiral amino alcohol. On the one hand, we use p-methyl benzyl trimethylammonium chloride as raw material and get [2.2] PCPs by eliminating polymerization. Then brominate, high temperature transposition. Then monoimide, acidolysis and alkalination. Then, RP/SP optical pure products were obtained by reaction with L-type proline protected by Boc, separation by column chromatography and Alkalization of acidolysis. Then diazotization, bromination. Then monohydrazone, formylation. Then the formyl hydrazide salt was obtained by Suzuik reaction and acidolysis. On the other hand, we have amidation, ring closing and methylation of L-phenylglycinol as raw material to obtain imine ether. Finally, the target ligand was obtained by the reaction of formyl hydrazide with imine ether. In chapter 3, the application of the target ligand, SznSp-4, in the asymmetric silicylation of aldehydes, the optimal reaction conditions were obtained by using p-chlorobenzaldehyde as the template substrate, and the optimum conditions were obtained by optimizing the conditions and screening the ligand. Under the optimal conditions, asymmetric silicylation of aromatic aldehydes has been studied and a series of 偽 -hydroxysilicon products have been obtained. The innovation point of this thesis is: 1: 1, the target ligand RPN-13 / 2 was synthesized for the first time. Using the existing ligands in the laboratory, the asymmetric silicylation of aldehydes was studied, and the first non-metal-catalyzed asymmetric silicylation of aldehydes was initiated.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R914

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1 安平;手性α-羥基硅類化合物的合成研究[D];山東大學(xué);2017年

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本文編號：1822832