Synthesis of Benzothiazinones from Benzoyl Thiocarbamates: Application to Clinical Candidates for Tuberculosis Treatment

Abstract

Benzothiazinones are a structural motif found in biologically active compounds, such as the clinical candidates BTZ-043 and Macozinone for the treatment of tuberculosis. We describe a robust, two-step method to synthesize 2-amino-substituted benzothiazinones from benzoyl thiocarbamates, which were prepared in a one-pot procedure from benzoyl chlorides. The intramolecular cyclization and ethoxy displacement steps were also amenable to adoption in continuous flow as exemplified by select substrates.

Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones

“…7). 52 Reaction with ammonium isothiocyanate gives benzoyl isothiocyanates 15 , which are reacted in situ with ethanol to obtain stable benzoyl thiocarbamates 16 . Intramolecular cyclization in the presence of DBU as a base then yields 2-ethoxy-BTZs 17 .…”

“…41 Connor et al reported isolated yields up to 75% for the 2-ethoxy replacement step using piperidine, as a model secondary amine substrate, under optimized microwave conditions. 52…”

“…41 Connor et al reported isolated yields up to 75% for the 2-ethoxy replacement step using piperidine, as a model secondary amine substrate, under optimized microwave conditions. 52 We established another S N Ar-based synthetic route to 2-amino-BTZs using 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid 2 as starting material (Fig. 8).…”