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

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 p...

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Bibliographic Details
Published in:European journal of organic chemistry 2022-09, Vol.2022 (34), p.n/a
Main Authors: Connors, William, DeKorte, Ryan, Lucas, Simon C. C., Gopalsamy, Ariamala, Ziegler, Robert E.
Format: Article
Language:English
Subjects:
API
Continuous flow
Isothiocyanate
Substrates
Sulfur heterocycles
Synthetic methods
Tuberculosis
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Summary: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. We report a strategy for the synthesis of amino‐substituted benzothiazinones using an intramolecular cyclization and ethoxy displacement approach. This resulted in a two‐step synthesis of the anti‐tuberculosis clinical candidates BTZ‐043 and Macozinone without the use of toxic carbon disulfide.
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.202200684