Erickson GA,
Hatcher MA,
Journet M,
Kowalski JA,
Lovelace TC,
Pink CJ,
Xie S.
*
GlaxoSmithKline, Collegeville, USA
Preparation of Methyltriazolo[1,4]benzodiazepine via Oxidative Activation of a Thiolactam
for the Synthesis of BET Inhibitor Molibresib.
J. Org. Chem. 2022;
87: 1961-1970
DOI:
10.1021/acs.joc.1c00563
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.
