Development of a Cyanide‐free and Scalable Route for the ADAMTS‐5 Inhibitor GLPG1972: Synthesis of an Advanced Key Chiral Intermediate

Abstract

AbstractIn this study we report a mild, efficient, scalable, cyanide‐free and environmentally‐benign procedure for synthesizing 5,5‐disubstituted hydantoins starting from alkylnitriles and diethyl carbonate. Synthesis of 5,5‐disubstituted hydantoins is typically carried out under harsh conditions with transition metal catalysts that are not preferable from a sustainability perspective. This procedure illustrates an elegant cyanide‐free synthesis of cyclopropyl‐substituted 5,5‐hydantoins starting from alkylnitriles that circumvent cyanide reagents. This process holds great synthetic relevance owing to the great potential shown by 5,5‐cyclopropyl substituted hydantoins towards treating human osteoarthritis.