Green Synthesis of Alzheimer′s Disease Probes Aftobetin and Analogues Enabled by Flow Technology and Heterogeneous Photocatalysis

• Published in: ChemSusChem
• Main Authors: Li, Yongjiu, Liu, Xin, Liu, Qiong, Wang, Yuchen, Liu, Chenguang, Chen, Fener
• Format: Journal Article
• Language: English
• Published: 06.09.2024
• ISSN: 1864-5631; 1864-564X
• DOI: 10.1002/cssc.202401214

Abstract Aftobetin is a non‐invasive diagnosis of Alzheimer′s disease, that can bind with aggregated β‐amyloid peptide in eye′s lenses, used for early diagnosis of Alzheimer′s disease in a rapid and painless mode. The reported synthesis of this probe fell short in the aspects of greenness and economy due to the involvement of toxic Chromium(IV) oxidant, noble palladium catalyst, elevated reaction temperature, the long reaction time as well as the cumbersome workup. Herein, a holistic optimization of the synthetic process was achieved via the employment of flow technology and heterogenous photocatalysis. Firstly, the integration of heterogenous carbon nitrides photocatalysis and circulation flow technology furnished the air oxidation of alcohol and nickel catalyzed C−N coupling at 20 g scale, thus avoiding the use of toxic Chromium and precious palladium species respectively. Flow‐intensified esterification between acyl chloride and alcohol, just taking 30 seconds replaced the Steglich esterification of 6 hours, also avoiding the generation of difficult‐to‐remove dicyclohexylurea. Finally, C−N coupling, esterification and Knoevenagel condensation were telescoped together, thus simplifying the reaction workup. This fully‐flow protocol led to the on‐demand synthesis of eight probes.