基于绿色化学策略的核苷类化合物的设计合成

发布时间：2018-06-01 01:41

本文选题：绿色介质 + 水　；参考：《河南师范大学》2014年博士论文

【摘要】：化学工业促进了国民经济的发展，同时也带来了严重的环境污染。其中，反应溶剂不绿色，反应过程不绿色，反应策略不绿色是造成污染的重要因素。因而最大程度地使用绿色的溶剂，不用、少用传统有机溶剂或者使用无毒、无害的溶剂，开发绿色的反应过程，应用绿色的反应策略，是化学工业可持续发展的必由之路。其中，原子经济性反应和以水为溶剂的绿色合成因其独特的绿色性能受到了越来越多的关注。核苷类药物是应用非常广泛的抗肿瘤、抗艾滋病的一线药物，市场份额和国内外需求量巨大。但是，现有的生产与合成方法往往存在着使用有机溶剂、重金属催化剂和原子不经济等问题，严重制约了核苷工业的发展。核苷类药物的绿色化研究不仅能够解决核苷生产引起的污染问题，而且能够突破技术瓶颈，促进核苷工业的可持续发展，是国际前沿的研究课题。本文以绿色化学策略为指导，将绿色化学与核苷制备结合起来，开发绿色的反应路线，最终实现核苷类物质的环境友好生产。主要内容如下： 1.首次以水为反应介质合成了重要的抗白血病和抗乙型肝炎药物阿糖腺苷，并进行绿色性评价。以水为反应介质、空气作为氧化剂，代替传统方法当中使用的二氧六环等有机溶剂，避免使用过量的氧化汞或氧化银等重金属催化剂，绿色地得到目标产物。不仅小试时能很好地反应，在将反应规模扩大到公斤级时仍然非常高效，显示出较好的应用前景。巧妙设计实验，对其绿色化反应的机理和本质进行了深入研究，为进一步拓展该反应的应用范围奠定了理论基础。并通过原子经济性、反应质量效率、质量强度、环境因子、环境商、溶剂以及操作和消耗等七个方面对合成路线进行绿色评价。该方法具有广泛的普适性，也可以用于类似药物的制备。这是目前为止最为绿色的阿糖腺苷的合成工艺，具有原创性和自主知识产权，具有广阔的应用前景。 2.首次以水为反应介质实现了嘌呤类化合物6位的烷基化反应，并进行绿色性评价。该方法以水为反应介质，以5%的FeSO4为催化剂，使用廉价易得且性质稳定的羧酸为烷基化试剂，在室温条件下搅拌，即可实现嘌呤核苷6位的烷基化反应。羧酸的使用避免了传统方法当中使用的有机硼、有机镁、有机锌等金属试剂，水的使用避免了大量的四氢呋喃所带来的潜在污染，FeSO4的使用避免了钯、镍等剧毒重金属的污染。并设计实验对其绿色化反应的机理和本质进行了深入研究，得到了基础研究的理论成果。并通过原子经济性、反应质量效率、质量强度、环境因子、环境商、溶剂以及操作和消耗等七个方面对合成路线进行了绿色性评价。该方法普适性好、原子经济性高、反应条件温和、产率高、操作及后处理简便，为生产和应用奠定了基础。 3.首次应用国际前沿的绿色化学理念C-H键活化的概念，提高嘌呤核苷8位烷基化反应的原子经济性，并进行绿色性评价。该方法避免了传统方法中对底物进行卤代和转变为金属试剂的繁琐步骤，避免使用重金属催化剂，以廉价易得且便于后处理的氧化剂促进底物双C-H键的直接偶联，副产物仅为一分子氢。合成过程原子经济性好，反应产率高，不使用额外的有机溶剂。方法具有广泛的普适性。通过原子经济性、反应质量效率、质量强度、环境因子、环境商、溶剂以及操作和消耗等七个方面对合成路线进行了绿色评价。文章还对其反应机理进行了深入研究。通过对得到产物的活性筛选，我们得到一个具有良好抗HL-60细胞活性的化合物。 4.首次实现了嘌呤二烷基化反应的原子经济性提高和选择性提高。该方法通过对反应时间和底物配比的控制，高选择性地得到单一的6烷基化和6,8-二烷基化的嘌呤核苷。反应直接使用商品化的嘌呤底物和廉价的烷烃为原料，通过双C-H活化实现直接的偶联。通过对绿色性的评价，反应原子经济性得到很大提高，反应具有高选择性且高效便捷，操作简便，，收率高。通过对得到产物的活性筛选，我们得到一个具有良好抗HL-60细胞活性的化合物。论文的研究成果均为独创性的，具有自主知识产权。研究扩大了绿色化学在核苷类化合物中的应用范围，为绿色化学在核苷生产中的应用提供了理论依据，也为绿色化学策略在药物合成中的广泛应用提供了有益启示。
[Abstract]:The chemical industry has promoted the development of the national economy and also brought serious environmental pollution. Among them, the reaction solvent is not green, the reaction process is not green and the reaction strategy is not green is an important factor in the pollution. Therefore, the maximum use of green solvents, the use of the traditional organic solvents, or the use of non-toxic and harmless solvents, is opened. The green reaction process and the application of green reaction strategy are the only way for the sustainable development of the chemical industry. Among them, the atomic economic reaction and the green synthesis with water as solvents have attracted more and more attention because of their unique green properties.
Nucleoside drugs are one of the most widely used antitumor and anti AIDS front-line drugs. The market share and domestic and foreign demand are huge. However, existing production and synthesis methods often exist in the use of organic solvents, heavy metal catalysts and atomic diseconomies, and the development of nucleoside industry. The research not only can solve the problem of the pollution caused by the nucleoside production, but also can break through the technical bottleneck and promote the sustainable development of the nucleoside industry. It is the research subject of the international frontier.
This paper, guided by green chemical strategy, combines green chemistry with nucleoside preparation, develops a green reaction route, and finally realizes the environmental friendly production of nucleosides. The main contents are as follows:
1. an important anti leukemia and anti HBV adenosine adenosine was synthesized by water as the reaction medium.
Water is used as the reaction medium and air is used as an oxidant to replace the organic solvent such as the two oxygen six ring used in the traditional method, and to avoid heavy metal catalysts such as mercuric oxide or silver oxide and so on. In order to further expand the application scope of the reaction, the mechanism and nature of the reaction are further studied, and the synthesis of the reaction is based on seven aspects: atomic economy, mass efficiency, quality strength, environmental factors, environmental quotient, solvent and operation and consumption. This method has extensive universality and can also be used in the preparation of similar drugs. This is the most green synthesis process of adenosine adenosine, which has original and independent intellectual property rights, and has a broad application prospect.
2. for the first time, the alkylation reaction of purine compounds at 6 sites was carried out with water as the reaction medium.
The method uses water as the reaction medium, with 5% FeSO4 as the catalyst, and the use of cheap and stable carboxylic acids as alkylation reagents. The alkylation of 6 bits of purine nucleosides can be achieved at room temperature. The use of carboxylic acids avoids the use of organic boron, organic magnesium, organic zinc and other metal reagents used in traditional methods, and the use of water. The potential pollution caused by a large number of tetrahydrofuran is avoided. The use of FeSO4 avoids the pollution of highly toxic heavy metals such as palladium and nickel. The mechanism and nature of its green reaction are studied in detail, and the theoretical results of basic research are obtained. Through the atomic economy, the reaction quality efficiency, quality strength, environmental factors, and rings are used. The green evaluation of the synthetic route is carried out in seven aspects, such as boundary quotient, solvent, operation and consumption. This method has the advantages of good universality, high atomic economy, mild reaction conditions, high yield, easy operation and post treatment, which lays a foundation for production and application.
3. for the first time, the concept of C-H bond activation was applied in the forefront of international green chemistry concept to improve the atomic economy of purine nucleoside 8 position alkylation reaction and to carry out green evaluation.
This method avoids the tedious steps of halogenation and transformation of substrates in traditional methods, avoids the use of heavy metal catalysts, and promotes the direct coupling of the substrate double C-H bonds with cheap and easy to treat oxidizers, and the by-products are only one molecule hydrogen. The synthesis process has good atomic economy, high yield and no extra use. Organic solvents. The method has extensive universality. Through the seven aspects of the atomic economy, the reaction quality efficiency, the quality strength, the environmental factor, the environment quotient, the solvent and the operation and consumption and so on, the synthetic route is evaluated. The reaction mechanism is further studied. To a compound with good anti HL-60 cell activity.
4. for the first time, the atomic economy and selectivity of purine two alkylation were improved.
By controlling the reaction time and substrate ratio, a single purine nucleoside with 6 alkylation and 6,8- two alkylation is highly selective. Direct use of commercialized purine substrates and cheap alkanes is used to direct coupling through double C-H activation. The reaction has high selectivity, high efficiency, high efficiency, easy operation and high yield. By screening the activity of the products, we get a compound with good anti HL-60 cell activity.
The research results of the paper are original and have independent intellectual property rights. The research expands the application scope of green chemistry in nucleoside compounds, provides theoretical basis for the application of green chemistry in the production of nucleoside, and also provides useful inspiration for the wide application of green chemical strategy in drug synthesis.
【学位授予单位】：河南师范大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：TQ464.6

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