Synthesis of a Human Urate Transporter-1 Inhibitor, an Arginine Vasopressin Antagonist, and a 17β-Hydroxysteroid Dehydrogenase Type-3 Inhibitor, Using Ring-Expansion of Cyclic Ketoximes with DIBALH

Abstract

Synthesis of three clinical candidates for medicines, a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17β-hydroxysteroid dehydrogenase type-3 inhibitor, is described. These compounds were synthesized via construction of their 3,4-dihydro-2H-benzo[b][1,4]oxazine, dibenzodiazepine, and dibenzazocine skeletons, respectively, using the reductive ring-expansion reaction of the corresponding bicyclic or tricyclic oximes with diisobutylaluminum hydride.

A concise and efficient concurrent synthesis of 6,11-dihydrodibenzo[b,e]azepines and 5,6,11,12-tetrahydrodibenzo[b,f]azocines and their conversion to 4-oxo-8,13-dihydro-4H-benzo[5,6]azepino[3,2,1-ij]quinoline-5-carboxylates and N-acetyl-5,6,11,12-tetrahydrodibenzo[b,f]azocines: synthetic sequence, spectroscopic characterization and the structures of two products

“…The dibenzo[b,e]azepine (A) and dibenzo [b,f]azocine (B) ring systems (see Scheme 1) form the core of a variety of bioactive compounds (André s et al, 2002;Wikströ m et al, 2002;Al-Qawasmeh et al, 2009), including a range of useful therapeutic agents (Schreiber et al, 1998;Jung et al, 2001;Liu et al, 2004;Fink et al, 2005Fink et al, , 2006Dinesh et al, 2014). Accordingly, considerable efforts have been made in the development of new methods for accessing these tricyclic scaffolds (Stappers et al, 2002;Polonka-Bá lint et al, 2008;Majumdar et al, 2010;Qin et al, 2011;Cho et al, 2010Cho et al, , 2011Cho et al, , 2014Guastavino & Rossi, 2012;Chadwick et al, 2013;Xie et al, 2018). However, there still remains a need for alternative approaches for their construction with full control of the substitution patterns, starting from readily accessible materials, and exhibiting high atom efficiency and low cost.…”