Application of\nExperimental Design (DoE) to Improve\na Very Dilute Workup Procedure

A three-level face-centered central composite experimental\ndesign\nwas applied to the reaction parameters (concentration, stoichiometry,\ntemperature) of an acid-catalyzed rearrangement of a morphine derivative,\nwith the aim of reducing the very dilute workup procedure required\nfor isolation of the aporphine product without compromising yield,\nquality, or other parameters. This enabled the concentration of starting\nmaterial in the acid catalyst to be increased 2-fold while maintaining\nother parameters, resulting in nearly 60% overall volume reduction\non workup. This formal experimental design study required only 17\ntube-scale experiments, yielding a more robust process overall, and\nadditionally provided a greater understanding of the reaction design\nspace for potential future scale-up.