Synthesis of Danuglipron: Design and Development of a Robust Telescoped C–O Coupling─Deprotection Sequence

Danuglipron tromethamine (1), a glucagon-like peptide-1 receptor (GLP-1R) agonist candidate, was investigated by Pfizer for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Given the anticipated high clinical and commercial demand for danuglipron tromethamine, the development of a robust, efficient, and sustainable manufacturing process was critical. This work describes the optimization and development of a telescoped process for the initial steps of the synthesis, featuring a Pd-catalyzed C–O coupling and an acidic t-butoxycarbamate deprotection. This is the first of two papers describing the commercial route for danuglipron tromethamine.