Regioselective, Efficient and Sustainable Bromination Process for the Synthesis of the Antimicrobial Agent Bromiphen Bromide

Abstract

In the drug discovery process, the role of halogen atom substitution has greatly influenced outcomes in the hit-to-lead-to-candidate optimization. Useful reasons for halogen insertion have included increasing steric hindrance or improving lipophilicity, among many others; and a recent review reports that fully one-quarter of the total number of papers and patents in medicinal chemistry involves halogen atom substitution. As an example, during our recent studies on the degradation of domiphen bromide, we found that the p-bromo analogue (Scheme 1, 1, bromiphen bromide), which had initially been seen as an undesirable impurity deriving from harsh conditions, showed improved antimicrobial activity. As a result, compound 1 was patented as a new antimicrobial agent with good activity against both Gram negative and Gram positive bacteria and against fungi. The patented synthesis (Scheme 2) applied traditional organic procedures and gave an overall yield of about 57%. A key intermediate for the synthesis of bromiphen bromide is p-bromophenol, which is prepared via the bromination of phenol. Conventional preparations of bromophenol typically use strong oxidizing agents, a variety of metal catalysts and halogenated solvents. These reagents are corrosive and toxic therefore their use is less desirable. Moreover, the lack of regioselectivity is a drawback since the phenol contains an ortho/ para director which affords a mixture of isomers and requires a subsequent separation. Considering only regioselective procedures, to the best of our knowledge none is atomeconomical or sustainable. With a view to preparing larger quantities of bromiphen bromide for further biological and toxicological investigations, and based on our own past experience, we sought a more regioselective, eco-friendly and sustainable synthetic method. We considered protocols focused on ecologically more acceptable bromination and we now report the resulting regioselective procedure for bromiphen bromide, capitalizing on our observation that it could be formed from domiphen bromide. A source of bromide and an oxidizing agent were necessary to enhance the formation of Br2 in situ. The