Evolution of the Synthetic Process to an Advanced GPR40 Agonist

Herein we describe a series of synthetic efforts to prepare an advanced GPR40 agonist (compound 1), with focus on phase-appropriate processes that circumvented key reagents with short supply in the original synthesis. The key transformations refined for large-scale production were an asymmetric aldol reaction, O-alkylation of an unstable intermediate, selective (Z)-olefination, and reduction of a Weinreb amide to aldehyde. Additionally, the new route circumvented stability issues of the core pyrrolidine fragment through de novo synthesis, achieving high d.r. during ring formation. The new improved route was efficiently scaled up to prepare more than 100 g API for toxicology studies.