Development and Production of an Enantioselective Tetrahydroisoquinoline Synthesis Enabled by Continuous Cryogenic Lithium–Halogen Exchange

Abstract

Route invention, process development, and production of 185 kg of a key tetrahydroisoquinoline intermediate for the dopamine D1 receptor positive allosteric modulator mevidalen are reported. The synthesis leveraged widely commercially available chiral starting materials to build a challenging 1,3-trans-tetrahydroisoquinoline. Two cryogenic lithiations were used to forge C–C bonds, and the heterocycle was formed by an intramolecular nucleophilic displacement. Because of a significant exotherm and instability of the aryllithium intermediate, one lithiation was shown to be scalable only in continuous flow mode. The processes were scaled up using a combination of batch and flow technologies, and the challenges that were encountered during production are described. After the successful pilot-plant campaign, the new route was analyzed from several perspectives to guide future development.