Large-scale synthesis of Notum inhibitor 1-(2,4-dichloro-3-(trifluoromethyl)-phenyl)-1H-1,2,3-triazole (ARUK3001185) employing a modified Sakai reaction as the key step

06 July 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


1-Phenyl-1H-1,2,3-triazole 1 (ARUK3001185) was prepared on large scale from aniline 4 by application of both (1) a copper catalyzed azide-alkyne cycloaddition (CuAAC) with (trimethylsilyl)acetylene, and (2) a Clark modification of the Sakai reaction. The one-pot Sakai-Clark method with (MeO)2CHCH=NNHTos (2b) proved to be superior as it was operationally simple, metal-free, and avoided the use of aryl azide 7. The Sakai-Clark method has been reliably performed on large scale to produce >100 g of 1 in good efficiency and high purity.


copper catalyzed azide-alkyne cyclisation
Sakai reaction

Supplementary materials

Spectroscopic and analytical data
Spectroscopic and analytical data for 1 (DSC, 1H NMR, 13C and DEPT NMR, HPLC, LCMS). Table of pilot reactions for the chlorination of 2-chloro-3-(trifluoromethyl)aniline (3) with N-chlorosuccinimide in various solvents.


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