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

In 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.