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.
CITATION STYLE
Bennett, N. B., Mlinar, L. B., Moschetta, E. G., Ellis, R. G., Chung, R., Manjrekar, O., … Wang, Z. (2024). Use of Impinging Jet to Improve Scalability in the Preparation of the ABBV-154 Drug-Linker. Organic Process Research and Development, 28(7), 2518–2533. https://doi.org/10.1021/acs.oprd.4c00143
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