Microwave-assisted synthesis of pomalidomide building blocks for rapid PROTAC and molecular glue development

Abstract

Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via S_NAr on 4-fluorothalidomide. Here, we optimize a microwave-assisted synthesis (MAS) of pomalidomide building blocks, achieving high yields within 15 min - boosting yield by at least 14% at gram scale without the need for purification. Unlike conventional oil bath heating and overnight reactions, MAS streamlines degrader development. The method’s utility was demonstrated by synthesizing ARV-110, highlighting MAS as a powerful tool for accelerating pomalidomide PROTAC and molecular glue discovery programs.