The final step in the preparation of the ABBV-154 drug-linker is a global acidic deprotection of three tert-butyl protecting groups that proceeds through several intermediates and is complicated by acetal epimerization, which generates an undesired diastereomer. This complex reaction was initially optimized in a batch setup, but scaling issues prompted the development of a flow process with an impinging jet mixing element. Initial studies utilized commercially available Y-mixers for small-scale experiments; however, clogging of the mixer was difficult to avoid. A three-dimensional (3D) printed Y-mixer impinging jet was created for lab development to avoid this issue and scale down the geometry of the plant-scale jet. The impinging process was executed in the manufacturing environment at kilogram scale, maintaining the desired diastereoselectivity, and reversed-phase chromatography enabled purification of the drug-linker. This paper discusses the key parameters examined to ensure successful scale-up of a mixing-sensitive reaction that demonstrated superior selectivity in flow compared to the batch process.

中文翻译：

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使用冲击射流提高 ABBV-154 药物连接体制备中的可扩展性


制备 ABBV-154 药物连接体的最后一步是三个叔丁基保护基团的整体酸性脱保护，该过程通过几个中间体进行，并因缩醛差向异构化而变得复杂，从而产生不需要的非对映异构体。这种复杂的反应最初是在批量设置中进行优化的，但结垢问题促使开发了带有冲击射流混合元件的流动工艺。最初的研究使用市售的 Y 型混合器进行小规模实验；然而，混合器的堵塞是难以避免的。为实验室开发创建了三维 (3D) 打印的 Y 型混合器冲击射流，以避免此问题并缩小工厂规模射流的几何形状。撞击过程在公斤级的制造环境中执行，保持所需的非对映选择性，并且反相色谱能够纯化药物连接体。本文讨论了为确保成功放大混合敏感反应而检查的关键参数，该反应在流动过程中表现出比间歇过程更优异的选择性。