Novel and Practical Synthesis of Triantennary N-Acetylgalactosamine Ligands for Liver-Targeted Delivery of siRNA Therapeutics

A novel and efficient synthetic approach for triantennary N-acetylgalactosamine is presented. A strategically designed convergent synthetic route was developed, successfully completing the target molecule in 16 steps. The key innovation is a pioneering amide condensation reaction between building blocks 46 and 48, yielding intermediate 40 with a significantly enhanced yield (77.6%) compared to that of conventional methods. This optimized protocol exhibits remarkable operational simplicity. Most intermediates required simple purification or were directly used in subsequent reactions without isolation. The target compound was ultimately obtained in outstanding yield (10.2%) with excellent purity (99.66%). Comprehensive structural verification was conducted via 1H NMR and HRMS analyses for all synthesized compounds, complemented by 13C NMR characterization for critical intermediates.