Process Development and Pilot-Scale Synthesis of New Cyclization Conditions of Substituted Phenylacetamides to Tetrahydroisoquinoline-2-ones Using Eaton’s Reagent

Tetrahydroisoquinoline is a ubiquitous structural framework presented in numerous pharmacologically relevant molecules. Although accessible by the Pictet−Spengler cyclization, conditions commonly used for such cyclizations are often difficult to implement on scale. Herein, we report the development of a scaleable approach utilizing Eaton’s reagent for the cyclization of substituted phenylacetamide analogues to tetrahydroisoquinoline-2-one. The development, optimization, and safety hazard evaluations, which outline the benefits and ease of workup of this new process, are discussed.