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

Abstract

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.