Development of an Optimized Process for the Liver-Targeted Triantennary N-Acetylgalactosamine Ligand

Development of a scalable process for N-acetylgalactosamine (GalNAc) ligand 1 is discussed. Multikilogram-scale synthesis of the GalNAc ligand is achieved in four reaction steps, where each step is characterized via factorial design of experiments (DoE) and first-principles experiments. The reactions tolerate a wide range of input parameters without generating critical impurities, and noncritical impurities are removed or reduced via aqueous washes and organic extractions. The GalNAc ligand can be isolated as an off-white amorphous solid via lyophilization or spray drying.