Development of a Manufacturing Process for a Key <i>(S)</i>-5-(2,2-Dimethyltetrahydro-2<i>H</i>-pyran-4-yl)-1<i>H</i>-indole Intermediate for Orforglipron. Part II. Development of a CSTR Process for Evans Auxiliary-Assisted Asymmetric 1,4-Addition

A scalable 8-step route incorporating Evans auxiliary-assisted asymmetric 1,4-addition was developed for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate of orforglipron. The main challenges of the batch process included the copper complex’s stability, the high exothermicity of the reaction, and the control of a key diastereomeric impurity. These challenges were addressed by developing a CSTR process to prepare the copper complex, enabling “on-demand” preparation and improved heat transfer to control the reaction temperature. A simple slurry purification was devised to isolate a metastable polymorph that effectively reduced the diastereomeric impurity to acceptable levels. The optimized process was successfully scaled up to >400 kg, demonstrating its robustness.