Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part III. Development of a Telescoped Phase-Transfer-Catalyzed Alkylation and Cyclopropanation Process

A scalable 8-step route for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate for orforglipron was developed to support clinical trials. Highlights of process development results in this contribution include the following: (1) approximately 50% reduction of a key des-carbonyl impurity in the reductive removal of the Evans auxiliary by the introduction of MgCl2 as a chelating agent for the reduction with LiBH4, (2) a telescoped process for PTC alkylation with chloroacetonitrile and subsequent cyclopropyl ring formation with an asymmetric cyclic sulfate avoiding the problematic isolation of the alkylation product, and (3) significantly improved isolated yield and stereoselectivity of the cyclopropyl ring formation by replacing KHMDS with LiOt-Bu as the base for the reaction. The developed process was successfully scaled up to >400 kg scale for each step to deliver a high-quality product in an overall yield of 22%, demonstrating the robustness of the optimized process.