Development of a Second-Generation Stereoselective Manufacturing Process for a Key <i>N</i> -Hydroxyamidine Intermediate of <b>GDC-6599</b> Enabled by Data Science and Mechanistic Understanding

We report the development of a second-generation manufacturing process for a key N -hydroxyamidine intermediate ( 3 ) en route to GDC-6599 ( 1 ). To obviate the safety hazards associated with a decakilogram-scale nucleophilic cyanation used in the first-generation route, we developed a sequence leveraging an enantioselective Pd-catalyzed Hayashi-Heck arylation followed by a stereo- and regioselective Rh-catalyzed hydroformylation reaction. This new route utilizes a synergistic high-throughput experimentation (HTE)/multivariate linear regression (MLR)-driven catalyst selection to establish the key stereochemical dyad of the tetrahydrofuran core. A detailed mechanistic understanding of the regioselective hydroformylation step was established and allowed for implementation on the manufacturing scale. The optimized 5-step sequence proceeds in 38% overall yield, avoiding the use of cyanide reagents and providing a robust control strategy for regio- and stereoisomeric impurities.