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

Efforts toward the development of a reliable gram-scale synthesis of 3-{[(16 beta,17 beta)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl}benzamide (PBRM), a potent and selective steroidal covalent inhibitor of 17 beta-hydroxysteroid dehydrogenase type 1, are described. Among the three synthetic routes (C-E) developed herein, route E is the most efficient one with only six 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 previously 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 PBRIVI structure. This work now makes it possible to start a proof-of-principle in a nonhuman primate model for the treatment of endometriosis, while supporting its future pharmacological development.