Branched Hetero Monodisperse PEG Purification for ADC Linkers

The patent introduces a branching unit with multiple hydroxyl groups (such as glycerol, pentaerythritol, or tris(hydroxymethyl)aminomethane) as an intermediary substance. This branching unit reacts with monodispersed polyethylene glycol to form a branched structure, while the excess monodispersed polyethylene glycol can be removed through purification steps. The branching unit serves as a mediator that enables branched structure formation while providing a pathway for purifying the final product by removing unreacted linear PEG.

The patent ensures that the hetero type monodispersed polyethylene glycol has different functional groups at each terminal (such as carboxyl at one end and amine or hydroxyl at the other end). This local differentiation of functional groups at each end of the molecule allows selective conjugation: one end conjugates to the drug while the other end conjugates to the antibody. This prevents formation of inactive dimers where two drugs or two antibodies would be conjugated to the same PEG molecule, thereby maintaining ADC effectiveness while preserving drug transport efficiency.

The patent employs simple separatory extraction for purification, which relies on changing physical parameters such as solvent polarity, pH, and temperature to separate the desired branched hetero PEG from excess linear PEG and other impurities. By carefully controlling reaction conditions (stoichiometry, solvent system, pH, temperature) during the synthesis, the product achieves sufficient polarity differences that allow effective separation through straightforward extraction methods, avoiding complex purification techniques while maintaining high purity.