Synthesis and selective ²H-, ¹³C-, and ¹⁵N-labeling of the Tau protein binder THK-523

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• 作者：Karoline T. Neumann ; Anders T. Lindhardt ; Benny Bang-Andersen and Troels Skrydstrup
• 刊名：Journal of Labelled Compounds and Radiopharmaceuticals
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：60
• 期：1
• 页码：30-35
• 全文大小：983K
• ISSN：1099-1344

文摘

A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to ¹³C- 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 ¹³C-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 ¹⁵N-THK-523 variant with the isotope label in the quinoline ring system.