Application of Experimental Design (DoE) to Improve a Very Dilute Workup Procedure

A three-level face-centered central composite experimental design was applied to the reaction parameters (concentration, stoichiometry, temperature) of an acid-catalyzed rearrangement of a morphine derivative, with the aim of reducing the very dilute workup procedure required for isolation of the aporphine product without compromising yield, quality, or other parameters. This enabled the concentration of starting material in the acid catalyst to be increased 2-fold while maintaining other parameters, resulting in nearly 60% overall volume reduction on workup. This formal experimental design study required only 17 tube-scale experiments, yielding a more robust process overall, and additionally provided a greater understanding of the reaction design space for potential future scale-up.