Zenner Anne, Steinmetzer Johannes, Ueberschaar Nico, Freesmeyer Martin, Weigand Wolfgang, Greiser Julia
Working Group for Translational Nuclear Medicine and Radiopharmacy, Clinic of Nuclear Medicine, Jena University Hospital, Jena, Germany.
Institute of Physical Chemistry and Abbe Center of Photonics, Friedrich Schiller University Jena, Jena, Germany.
R Soc Open Sci. 2024 Jul 3;11(7):240293. doi: 10.1098/rsos.240293. eCollection 2024 Jul.
1,4-Diazepane-6-amine (DAZA) can be alkylated with three 2-hydroxybenzyl pendant arms, resulting in hexadentate chelators suitable for coordination of radiometals like Ga. These chelators, ,1,4-tri(alkoxy-2-hydroxybenzyl)-DAZA, can be produced via a one-pot synthesis, with the first step being a carbonyl amine condensation of DAZA with two respective 4-alkoxy-2-hydroxybenzaldehydes, followed by reductive amination with sodium borohydride. While the first step of this reaction is predictable, the subsequent reductive amination can result in either mono-, di- or tri(alkoxy-hydroxybenzyl)-DAZA compounds. Seeking to identify dependencies that might allow a specific reaction control towards the formation of either of the three possible products, and particularly towards the favoured trialkylated DAZA compounds, a variety of synthesis trials were performed. Additionally, computational methods were employed to evaluate the underlying reaction mechanism. Synthesis trials verified that the trialkylated DAZA compounds are formed via direct reductive amination of the dialkylated DAZA compounds. Subsequently, a synthetic method was established, leading to an increase in the percentage of the trialkylated DAZA compounds, which allowed the successful isolation of those hexadentate chelators. Additionally, an alternative pathway proceeding via aminal C-N bond insertion of an attacking third carbonyl moiety was evaluated by means of quantum chemical calculations but so far remains entirely hypothetical.
1,4 - 二氮杂环庚烷 - 6 - 胺（DAZA）可以与三个2 - 羟基苄基侧链进行烷基化反应，生成适用于镓等放射性金属配位的六齿螯合剂。这些螯合剂，即1,4 - 三（烷氧基 - 2 - 羟基苄基）- DAZA，可以通过一锅法合成，第一步是DAZA与两个相应的4 - 烷氧基 - 2 - 羟基苯甲醛进行羰基胺缩合反应，然后用硼氢化钠进行还原胺化反应。虽然该反应的第一步是可预测的，但随后的还原胺化反应可能会生成单（烷氧基 - 羟基苄基）- DAZA、二（烷氧基 - 羟基苄基）- DAZA或三（烷氧基 - 羟基苄基）- DAZA化合物。为了确定可能有助于特定反应控制以形成三种可能产物中的任何一种，特别是有利于生成三烷基化DAZA化合物的依赖性，进行了各种合成试验。此外，还采用了计算方法来评估潜在的反应机理。合成试验证实，三烷基化DAZA化合物是通过二烷基化DAZA化合物的直接还原胺化反应形成的。随后，建立了一种合成方法，提高了三烷基化DAZA化合物的百分比，从而成功分离出那些六齿螯合剂。此外，通过量子化学计算评估了经由进攻性的第三个羰基部分的缩醛胺C - N键插入的替代途径，但到目前为止仍然完全是假设的。
