Tuesday, September 24, 2019

Development of a Gram-Scale Synthesis of PBRM, an Irreversible Inhibitor of 17beta-Hydroxysteroid Dehydrogenase Type 1

René Maltais and Donald Poirier
Organic Process Research & Development 2019
DOI: 10.1021/acs.oprd.8b00402

Efforts toward the development of a reliable gram scale synthesis of PBRM, a potent and selective steroidal covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), are described. Among the three synthetic routes (C-E) developed herein, route E is the most efficient one with only 6 chemical steps from commercially available estrone, and an overall yield of 13% leading to PBRM with a high HPLC grade purity (99.7%) after recrystallization. Important improvements have been achieved in this sequence from previous reported routes (A and B). Notably, we used a palladium catalyzed Suzuki-Miyaura cross-coupling reaction to rapidly install the requested C3 chain on estrone. Also, catalytic hydrogenation of the C16-enone was shortened by half using Pearlman’s catalyst. Finally, we used a selective bromination through deoxygenation of alcohol at the last step of the sequence to provide PBRM without dehydration of its carboxamide functionality, a persistent problem observed in other routes. Crystals of PBRM were also obtained from recrystallization in acetonitrile and submitted to x-ray analysis, which confirmed the PBRM structure. This work now makes it possible to start a proof-of-principle in a non-human primate model for the treatment of endometriosis, while supporting its future pharmacological development.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 https://doi.org/10.1080/17460441.2023.2218642 Covalent drug discovery has ...