一些药物中间体的氧化反应动力学及机理之分析-analysis of oxidation kinetics and mechanism of some drug intermediates.docxVIP

摘要四氢吡咯(pyrrolidine)和 1-(2-羟乙基)-哌啶(HEP)用来合成很多药物，是重要的药 物中间体，同时还是很多药物的前导物，它们的氧化反应机理却很少被研究。本文系 统的研究了[Ag(HIO6)2]5?氧化四氢吡咯和 1-(2-羟乙基)-哌啶的动力学与反应机理。我们在 15.0-30.0oC 的温度范围内的碱性介质中研究了[Ag(HIO6)2]5?氧化四氢吡咯的反应动力学，动力学实验表明：反应遵循二级反应，对 Ag(III)和四氢吡咯各为一级 反应；二级表观速率常数 k′随着[IO4?]的增大而缓慢地减小，随[OHˉ]增大而略微增大； 此外我们还研究了 k′与离子强度的关系。四氢吡咯在氧化反应中发生了脱氨现象，生 成了 4-羟基-丁酸。四氢吡咯的反应机理包含了[Ag(HIO6)2]5?和[Ag(HIO6)2(OH)(H2O)]2? 的前期平衡，这两种形态的 Ag(III)配合物在两个平行的反应速控步中分别与四氢吡咯 反应。基于实验数据，我们提出了反应机理并推导出了速率方程，得出了速控步的速 率常数和反应活化参数。我们在碱性介质中 25.0oC-40.0oC 的温度范围内研究了[Ag(HIO6)2]5?氧化 1-(2-羟乙 基)-哌啶(HEP)的反应动力学及机理。通过质谱分析法确定了哌啶和甲醛为主要的反应 产物。由实验数据和现象得出：Ag(III)在反应中遵循一级反应，HEP 遵循分数级反应； 我们通过实验分析了[OHˉ]和[IO4ˉ]tot 与表观速率常数 kobsd 的依赖关系，其中[IO4ˉ]tot 为 高碘酸根的总浓度。基于这些依赖关系，我们提出了反应机理，其中包括了形成 Ag(III)- 高碘酸根-HEP 的三元配合物的前期平衡。三元配合物通过两个平行的速率控制步骤解 离而还原为 Ag(I)；其中，一步骤为水分子帮助解离，而另一步骤 OHˉ促使三元配合物 的解离。最后推导计算出此反应速率控制步骤的速率常数、平衡常数和反应活化参数。关键词药物中间体四氢吡咯1-(2-羟乙基)-哌啶Ag(III)氧化反应 动力学及机理AbstractPyrrolidine and 1-(2-Hydroxyethyl) piperidine (HEP) are important drug intermediates, being involved in many drugs and drug leads; while their oxidation mechanisms are poorly understood. The oxidation of pyrrolidine and HEP by bis(hydrogenperiodato)argentate(III) complex anion ([Ag(HIO6)2]5?) were thus characterized kinetically and mechanistically in present work.The kinetics of oxidation of pyrrolidine by [Ag(HIO6)2]5? was studied in alkalinemedium, and the reaction temperatures were controlled in the range of 15.0-30.0 oC. The kinetic experiments indicated that the oxidation follows an overall second-order reaction with first-order in Ag(III) and pyrrolidine, respectively. In addition, it was found that observed second-order rate constants, k′, decreased with increasing [IO4?], and increased slightly when [OH?] was increased. The influence of ionic strength on the reaction rate was also investigated. The oxidation resulted in deamination of pyrrolidine, giving rise to the product of 4-hydroxybutyrate after pyrrolidine being oxidized. A reaction mechanism proposed includes an equilibriu