Succinct Synthesis of Bosentan Utilizing Glycol Mono-THP Ether

Abstract

A concise synthetic method for bosentan, a nonpeptide orally active dual endothelin (ET-1_A/B) receptor antagonist used for the treatment of pulmonary artery hypertension (PAH), was developed. We developed a new succinct synthetic route for bosentan by employing an acid-labile tetrahydropyran (THP)–protected glycol. THP group is advantageous over the previously known protection groups used in bosentan synthesis in that it provides a clean and quantitative deprotection. Bosentan was constructed via two parallel reaction pathways, yet the better product yield was obtained from a pathway via 6. Deprotection of THP ether was achieved under a mild acidic condition to afford bosentan.

GRAPHICAL ABSTRACT

Keywords:

• Bosentan
• endothelin receptor antagonist
• pulmonary arterial hypertension
• tetrahydropyran ether