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

• Published in: Chemical communications (Cambridge, England) Vol. 61; no. 24; pp. 467 - 4673
• Main Authors: Abdallah, Diaaeldin I, Israelian, Johan, Hasan, Lina S, Patel, Naman H, Keillor, Jeffrey W, Wright, Timothy B, Saqib, Bilal, de Araujo, Elvin D, Gunning, Patrick T
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 19.03.2025
• Subjects: Microwaves; Molecular Structure; Thalidomide - analogs & derivatives; Thalidomide - chemical synthesis; Thalidomide - chemistry
• ISSN: 1359-7345; 1364-548X; 1364-548X
• DOI: 10.1039/d4cc03435j

Targeted protein degradation (TPD) is revolutionizing drug discovery, but PROTAC synthesis remains challenging due to multi-step synthesis and slow linker installation via S N Ar 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. A rapid and efficient microwave-assisted synthesis of pomalidomide analogs, improving upon prior methods to accelerate the discovery and optimization of degraders like clinical candidate ARV-110.