Neumann Karoline T, Lindhardt Anders T, Bang-Andersen Benny, Skrydstrup Troels
Carbon Dioxide Activation Center (CADIAC), Department of Chemistry and the Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark.
Interdisciplinary Nanoscience Center (iNANO), Department of Engineering, Aarhus University, Aarhus, Denmark.
J Labelled Comp Radiopharm. 2017 Jan;60(1):30-35. doi: 10.1002/jlcr.3470. Epub 2016 Nov 13.
A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to C- and D-isotope labeling. The synthesis proceeds via two key reactions, namely, a Pd-catalyzed carbonylative Sonogashira coupling and a reductive ring-closing step with hydrogen or deuterium gas. By carrying out these reactions in a 2-chamber reactor we reported previously, ex situ-generated carbon monoxide and hydrogen/deuterium can be applied in stoichiometric quantities, thereby facilitating isotope labeling of this Tau-binding compound. Iridium-catalyzed hydrogen isotope exchange (HIE) reactions were performed on THK-523 and its C-labeled analog providing access to 4 additional analogues labeled with deuterium as well. Finally, by applying a Buchwald-Hartwig coupling, we were able to prepare a N-THK-523 variant with the isotope label in the quinoline ring system.
本文公开了一种合成Tau蛋白结合剂THK-523的新路线，该路线可轻松适用于碳和氘同位素标记。合成过程通过两个关键反应进行，即钯催化的羰基化Sonogashira偶联反应和用氢气或氘气进行的还原闭环步骤。通过在我们之前报道的双室反应器中进行这些反应，可以按化学计量使用异位生成的一氧化碳和氢气/氘气，从而便于对这种Tau蛋白结合化合物进行同位素标记。对THK-523及其碳标记类似物进行了铱催化的氢同位素交换（HIE）反应，还得到了另外4种用氘标记的类似物。最后，通过应用Buchwald-Hartwig偶联反应，我们能够制备在喹啉环系统中带有同位素标记的N-THK-523变体。
