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.

中文翻译：

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开发和执行 ABBV-154 免疫学 ADC 药物连接器的可扩展路线


溴乙酰胺 1 是一种磷酸化糖皮质激素药物接头，用于与单克隆抗体 (mAb) 阿达木单抗缀合，产生抗体-药物缀合物 ABBV-154。已经开发出一种可扩展的药物接头 1 路线，该路线改进了第一代序列并允许生产数百克材料。新路线从缩醛形成开始，其中结合了结晶，消除了之前使用反相色谱法去除不需要的缩醛非对映异构体的需要。然后将接头片段的二肽部分安装在单个转化中。使用一锅亚磷酰胺置换和氧化序列将后续产物直接进行磷酸化。 Fmoc 基团的脱保护伴随着连续萃取以除去相关的副产物。胺与溴乙酸偶联，最后通过反相纯化对三个叔丁基进行整体脱保护，产生药物连接体。