A novel approach for the synthesis of (S)-tolvaptan and (S)-desmethyltolvaptan

Abstract

A novel and concise approach has been developed for the total synthesis of (S)-tolvaptan, which is used for the treatment of hyponatremia. The key intermediate, benzazepinone has been synthesized in three steps through ortho-acylation of N-Pivalamide protected aryl amine followed by an intramolecular haloamine cyclization. The total synthesis of (S)-tolvaptan from p-chloroaniline has been accomplished in seven steps with 43% overall yield.