本文選題：綠色介質(zhì) + 水��； 參考：《河南師范大學(xué)》2014年博士論文

【摘要】：化學(xué)工業(yè)促進(jìn)了國(guó)民經(jīng)濟(jì)的發(fā)展，同時(shí)也帶來了嚴(yán)重的環(huán)境污染。其中，反應(yīng)溶劑不綠色，反應(yīng)過程不綠色，反應(yīng)策略不綠色是造成污染的重要因素。因而最大程度地使用綠色的溶劑，不用、少用傳統(tǒng)有機(jī)溶劑或者使用無毒、無害的溶劑，開發(fā)綠色的反應(yīng)過程，應(yīng)用綠色的反應(yīng)策略，是化學(xué)工業(yè)可持續(xù)發(fā)展的必由之路。其中，原子經(jīng)濟(jì)性反應(yīng)和以水為溶劑的綠色合成因其獨(dú)特的綠色性能受到了越來越多的關(guān)注。 核苷類藥物是應(yīng)用非常廣泛的抗腫瘤、抗艾滋病的一線藥物，市場(chǎng)份額和國(guó)內(nèi)外需求量巨大。但是，現(xiàn)有的生產(chǎn)與合成方法往往存在著使用有機(jī)溶劑、重金屬催化劑和原子不經(jīng)濟(jì)等問題，嚴(yán)重制約了核苷工業(yè)的發(fā)展。核苷類藥物的綠色化研究不僅能夠解決核苷生產(chǎn)引起的污染問題，而且能夠突破技術(shù)瓶頸，促進(jìn)核苷工業(yè)的可持續(xù)發(fā)展，是國(guó)際前沿的研究課題。 本文以綠色化學(xué)策略為指導(dǎo)，將綠色化學(xué)與核苷制備結(jié)合起來，開發(fā)綠色的反應(yīng)路線，最終實(shí)現(xiàn)核苷類物質(zhì)的環(huán)境友好生產(chǎn)。主要內(nèi)容如下： 1.首次以水為反應(yīng)介質(zhì)合成了重要的抗白血病和抗乙型肝炎藥物阿糖腺苷，并進(jìn)行綠色性評(píng)價(jià)。 以水為反應(yīng)介質(zhì)、空氣作為氧化劑，代替?zhèn)鹘y(tǒng)方法當(dāng)中使用的二氧六環(huán)等有機(jī)溶劑，避免使用過量的氧化汞或氧化銀等重金屬催化劑，綠色地得到目標(biāo)產(chǎn)物。不僅小試時(shí)能很好地反應(yīng)，在將反應(yīng)規(guī)模擴(kuò)大到公斤級(jí)時(shí)仍然非常高效，顯示出較好的應(yīng)用前景。巧妙設(shè)計(jì)實(shí)驗(yàn)，對(duì)其綠色化反應(yīng)的機(jī)理和本質(zhì)進(jìn)行了深入研究，為進(jìn)一步拓展該反應(yīng)的應(yīng)用范圍奠定了理論基礎(chǔ)。并通過原子經(jīng)濟(jì)性、反應(yīng)質(zhì)量效率、質(zhì)量強(qiáng)度、環(huán)境因子、環(huán)境商、溶劑以及操作和消耗等七個(gè)方面對(duì)合成路線進(jìn)行綠色評(píng)價(jià)。該方法具有廣泛的普適性，也可以用于類似藥物的制備。這是目前為止最為綠色的阿糖腺苷的合成工藝，具有原創(chuàng)性和自主知識(shí)產(chǎn)權(quán)，具有廣闊的應(yīng)用前景。 2.首次以水為反應(yīng)介質(zhì)實(shí)現(xiàn)了嘌呤類化合物6位的烷基化反應(yīng)，并進(jìn)行綠色性評(píng)價(jià)。 該方法以水為反應(yīng)介質(zhì)，以5%的FeSO4為催化劑，使用廉價(jià)易得且性質(zhì)穩(wěn)定的羧酸為烷基化試劑，在室溫條件下攪拌，即可實(shí)現(xiàn)嘌呤核苷6位的烷基化反應(yīng)。羧酸的使用避免了傳統(tǒng)方法當(dāng)中使用的有機(jī)硼、有機(jī)鎂、有機(jī)鋅等金屬試劑，水的使用避免了大量的四氫呋喃所帶來的潛在污染，F(xiàn)eSO4的使用避免了鈀、鎳等劇毒重金屬的污染。并設(shè)計(jì)實(shí)驗(yàn)對(duì)其綠色化反應(yīng)的機(jī)理和本質(zhì)進(jìn)行了深入研究，得到了基礎(chǔ)研究的理論成果。并通過原子經(jīng)濟(jì)性、反應(yīng)質(zhì)量效率、質(zhì)量強(qiáng)度、環(huán)境因子、環(huán)境商、溶劑以及操作和消耗等七個(gè)方面對(duì)合成路線進(jìn)行了綠色性評(píng)價(jià)。該方法普適性好、原子經(jīng)濟(jì)性高、反應(yīng)條件溫和、產(chǎn)率高、操作及后處理簡(jiǎn)便，為生產(chǎn)和應(yīng)用奠定了基礎(chǔ)。 3.首次應(yīng)用國(guó)際前沿的綠色化學(xué)理念C-H鍵活化的概念，提高嘌呤核苷8位烷基化反應(yīng)的原子經(jīng)濟(jì)性，并進(jìn)行綠色性評(píng)價(jià)。 該方法避免了傳統(tǒng)方法中對(duì)底物進(jìn)行鹵代和轉(zhuǎn)變?yōu)榻饘僭噭┑姆爆嵅襟E，避免使用重金屬催化劑，以廉價(jià)易得且便于后處理的氧化劑促進(jìn)底物雙C-H鍵的直接偶聯(lián)，副產(chǎn)物僅為一分子氫。合成過程原子經(jīng)濟(jì)性好，反應(yīng)產(chǎn)率高，不使用額外的有機(jī)溶劑。方法具有廣泛的普適性。通過原子經(jīng)濟(jì)性、反應(yīng)質(zhì)量效率、質(zhì)量強(qiáng)度、環(huán)境因子、環(huán)境商、溶劑以及操作和消耗等七個(gè)方面對(duì)合成路線進(jìn)行了綠色評(píng)價(jià)。文章還對(duì)其反應(yīng)機(jī)理進(jìn)行了深入研究。通過對(duì)得到產(chǎn)物的活性篩選，我們得到一個(gè)具有良好抗HL-60細(xì)胞活性的化合物。 4.首次實(shí)現(xiàn)了嘌呤二烷基化反應(yīng)的原子經(jīng)濟(jì)性提高和選擇性提高。 該方法通過對(duì)反應(yīng)時(shí)間和底物配比的控制，高選擇性地得到單一的6烷基化和6,8-二烷基化的嘌呤核苷。反應(yīng)直接使用商品化的嘌呤底物和廉價(jià)的烷烴為原料，通過雙C-H活化實(shí)現(xiàn)直接的偶聯(lián)。通過對(duì)綠色性的評(píng)價(jià)，反應(yīng)原子經(jīng)濟(jì)性得到很大提高，反應(yīng)具有高選擇性且高效便捷，操作簡(jiǎn)便，，收率高。通過對(duì)得到產(chǎn)物的活性篩選，我們得到一個(gè)具有良好抗HL-60細(xì)胞活性的化合物。 論文的研究成果均為獨(dú)創(chuàng)性的，具有自主知識(shí)產(chǎn)權(quán)。研究擴(kuò)大了綠色化學(xué)在核苷類化合物中的應(yīng)用范圍，為綠色化學(xué)在核苷生產(chǎn)中的應(yīng)用提供了理論依據(jù)，也為綠色化學(xué)策略在藥物合成中的廣泛應(yīng)用提供了有益啟示。
[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.
【學(xué)位授予單位】：河南師范大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：TQ464.6

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