Development and Execution of a Scalable Route to an Immunology ADC Drug-Linker for ABBV-154

Bromoacetamide 1 is a phosphorylated glucocorticoid drug-linker used in conjugation with the monoclonal antibody (mAb) adalimumab to produce the antibody-drug conjugate ABBV-154. A scalable route to drug-linker 1 has been developed that improves upon the first-generation sequence and allows the production of hundreds of grams of material. The new route begins with an acetal formation that incorporates a crystallization eliminating the previous need for reversed-phase chromatography to reject the undesired acetal diastereomer. The dipeptide portion of the linker fragment is then installed in a single transformation. The subsequent product is taken directly into a phosphorylation using a one-pot phosphoramidite displacement and oxidation sequence. Deprotection of a Fmoc group is accompanied by a continuous extraction to remove associated byproducts. The amine is coupled with bromoacetic acid, and a final global deprotection of three t-butyl groups with a reversed-phase purification yields drug-linker.