Synthesis of Molibresib

Key words

molibresib - BET inhibitor - thiolactams - oxidative activation - 1,4-benzodiazepine ring formation - triazole ring formation

Significance

Molibresib (GSK525762) is an inhibitor of the interaction between bromo and extra-terminal (BET) bromodomain proteins that is of interest for the treatment of solid tumors. The concise synthesis of molibresib depicted started with the commercially available ketone A and delivered 52 kg of product in 41% yield and 99.9% ee. For the discovery synthesis of molibresib, see: E. Nicodeme et al. Nature 2010, 468, 1119.

Comment

Construction of the core methyltriazolo[1,4]benzodiazepine H was achieved by oxidative activation of the thiolactam F via a sulfenic acid (RS–OH) that underwent substitution by acetyl­hydrazide (G), followed by an acid-catalyzed cyclocondensation. The mild conditions for the methyltriazole formation avoided racemization of the sensitive stereocenter.

Publication History

Article published online:
20 April 2022