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

Abstract

Efforts toward the development of a reliable gram-scale synthesis of 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]­methyl}­benzamide (PBRM), a potent and selective steroidal covalent inhibitor of 17β-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 PBRM 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.

A Targeted-Covalent Inhibitor of 17β-HSD1 Blocks Two Estrogen-Biosynthesis Pathways: In Vitro (Metabolism) and In Vivo (Xenograft) Studies in T-47D Breast Cancer Models

“…PBRM, a targeted-covalent steroidal inhibitor of 17β-HSD1, was synthesized, as previously reported [ 66 ]. Compound 21 [ 57 ], a reversible steroidal inhibitor of 17β-HSD1 used in our study, was synthesized in our laboratory using published procedures.…”

Structural derivatization strategies of natural phenols by semi-synthesis and total-synthesis

“…However, it's not so applicable for complex polyphenols as it requires sufficient protection of active groups including phenolic hydroxyls. Furthermore, cross-coupling of arylhalide or aryltriflate with organoboron or organometal was also a potential strategy to introduce alkyl or aryl with a great diversity [31,32] (Scheme 1A-m). Introducing specific groups onto the phenolic ring may improve the bioactivity of natural phenols.…”

Recent Applications of Pd-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Couplings in Pharmaceutical Process Chemistry.

“…Maltais and coworkers 13 from Université Laval designed three new synthetic routes for PBRM, the first selective covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 14 17β-HSD1 is involved in the last step of estrogen biosynthesis, making PBRM a leading candidate to treat breast cancer.…”