【作者】 李岩；

【导师】 高章华；

【作者基本信息】 浙江大学 ， 化学工程（专业学位）， 2022， 硕士

【摘要】 氘是氢同位素的一种,被广泛应用于核磁分析、化学反应机理的研究和生物代谢过程的追踪。另外,相对于一般的药和材料,氘的引入大大提高了药物分子的代谢稳定性和有机发光材料的耐久性,推动了近年来氘代药物和材料研发的高速发展。芳香烃和吡啶环作为有机合成的关键中间体,以其为底物,能够衍生出各类药物和有机材料分子。本篇论文以简单芳香烃和吡啶环作底物,对于其氘代反应展开系统研究。第一部分,对吡啶类化合物β-和γ-位置的选择性氘代反应进行了较为全面和深入的研究。采用的方法为碱(tBuOK)促进C-H活化,引入氘代二甲基亚砜作为氘源,完成吡啶类化合物选择性氘代的目标。通过进一步对碱的种类和用量、反应时间的优化,其模型底物总氘代度可达2.97D。随后在较优条件下,进行了吡啶类化合物的拓展。实验数据显示,大部分底物可以获得中等以上的氘代度,并成功将这一反应条件应用于几种常见药物的氘代。最后,通过动力学实验、控制实验(加入自由基捕获剂或加入二甲基亚砜阴离子)指明了反应机理,即阴离子机理。第二部分,对简单芳香烃的全氘代进行研究,目标为常压下的温和氢同位素交换反应。分别尝试了过渡金属催化法和酸催化法进行全氘代苯的合成,其中过渡金属催化法(Pd,Ir)未能在温和条件下实现苯的全氘代反应(常压,<80℃),而采用酸催化法在高浓度的三氟甲磺酸的条件下得到了苯和萘的全氘代产物。随后,为实现酸的浓度的降低,氘代效率的提升,进行了微波实验,然而只有反应速度显著提升(高达4倍),未能突破实验条件中的酸的浓度极限。最终设计了一种新型油水双循环模型反应器实现了氘代效率的提升,并通过实验完成了可行性验证。更多还原

【Abstract】 Deuterium,as a stable isotope of hydrogen,is widely used in nuclear magnetic resonance analysis,chemical reaction mechanisms exploration,and biological metabolic processes tracking.In addition,compared with ordinary pharmaceutical and material molecules,the introduction of deuterium has increased the metabolic stability of drugs and the durability of organic luminescent materials,which has boosted the vigorous development of deuterium drugs and materials research in recent years.Aromatic hydrocarbons and pyridine rings are important intermediates for organic synthesis,and various types of organic compounds,including many pharmaceuticals and organic materials,can be derived from these two substrates.This thesis uses aromatic hydrocarbons and pyridine rings as substrates to study their deuteration reactions.In the first part,the selective deuteration reactions at the β-and y-positions of pyridine compounds were comprehensively and in-depth studied.By promoting C-H activation by alkali(tBuOK),deuterated dimethyl sulfoxide is introduced as a source of deuterium to achieve selective deuteration of pyridine compounds.Through the systematic optimization of the type and dosage of the base,and reaction time,the total deuteration degree of the model substrate reached 2.97D.After determining the preferred conditions,the substrate scope was expanded to a range of pyridine compounds.Experimental results show that moderate to high deuterium incorporation degree was given for most substrates.Further,the method was successfully applied to the deuteration of several common drugs.Finally,kinetic study and control experiments(adding free radical trappers or adding dimethyl sulfoxide anions)indicated the reaction mechanism as an anion mechanism.In the second part,an exploratory study of the full deuterium incorporation of fundamental aromatic hydrocarbons was conducted,targeting a mild HIE process under atmosphere pressure.The transition metal catalysis method and acid catalysis method were tried to produce benzene-d,in which the transition metal catalysis(Pd,Ir)method failed to achieve satisfactory benzene deuteration under desired mild conditions(atmospheric pressure,<80℃)of,while the acid catalyzed method gave the deuterated benzene and naphthalene at high concentration of trifluoromethanesulfonic acid.Subsequently,microwave experiments were conducted to reduce the acidity and to increase deuteration efficiency.While the reaction rate significantly increased(～4 times),and the minimum acidity remained as the bottle neck of the acid catalyzed HIE reaction.Finally,a novel oil-water dual-cycle model reactor was designed to improve the efficiency of deuteration,with prove-of-concept experimental results.更多还原