Facile One-Pot Process for Large-Scale Production of Highly Pure Bosentan Monohydrate, an Endothelin Receptor Antagonist

Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4)...

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Bibliographic Details
Published in:Organic process research & development 2011-11, Vol.15 (6), p.1382-1387
Main Authors: Niphade, Navnath C., Jagtap, Kunal M., Gaikawad, Chandrashekhar T., Jachak, Madhukar N., Mathad, Vijayavitthal T.
Format: Article
Language:English
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Summary:Described is an efficient, economic, and one-pot process for the production of highly pure bosentan (1), an endothelin receptor antagonist. The synthesis comprises the reaction of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine (2) with 4-tert-butylbenzenesulfonamide (3) and ethylene glycol (4) in acetonitrile in the presence of potassium carbonate to yield bosentan (1) in the same pot. The present work also describes a novel purification method for the removal of critical dimer impurity (7) and 6-hydroxy impurity (8) in 1 by preparation of bosentan ammonium salt (6) using inexpensive ammonium hydroxide. Upon purification, bosentan monohydrate (1) with an overall yield of 68% and HPLC purity of 99.90% was achieved.
ISSN:1083-6160
1520-586X
DOI:10.1021/op200197z