1,4-二氮杂环庚烷-6-胺(DAZA)可以用三个2-羟基苄基侧臂烷基化,产生适合于放射性金属如68Ga配位的六齿螯合剂。这些螯合剂,N,1,4-三(烷氧基-2-羟基苄基)-DAZA,可以通过一锅法合成生产,第一步是DAZA与两种各自的4-烷氧基-2-羟基苯甲醛的羰基胺缩合,然后用硼氢化钠进行还原胺化。虽然这个反应的第一步是可以预测的,随后的还原胺化可能导致两种单体,二-或三(烷氧基-羟基苄基)-DAZA化合物。寻求确定可能允许对三种可能产物中的任何一种的形成进行特定反应控制的依赖性,特别是对偏爱的三烷基化DAZA化合物,进行了各种合成试验。此外,采用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形成的。随后,建立了一种合成方法,导致三烷基化DAZA化合物的百分比增加,这使得这些六齿螯合剂的成功分离。此外,通过量子化学计算评估了通过aminalC-N键插入攻击的第三个羰基部分进行的替代途径,但到目前为止仍然完全是假设的。
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 68Ga. These chelators, N,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.