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 ) 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.