Process Control Limits from a Laboratory Study on the Ni(0)-Mediated Coupling of Ethyl Acrylate with a C-22 Steroidal Iodide: A Case Study on the Role of Experimental Design in Highly Developed Processes

Abstract

An experimental design was used to assess the process robustness in the Ni(0)-mediated coupling of the C-22 steroidal iodide 15 with ethyl acrylate to yield the coupled product 16. Although the reaction conditions were optimized by empirical means, an experimental design was employed to assess the process sensitivity to certain key factors. Within the experimental space defined by the experimental parameters: moles of ethyl acrylate, moles of water, and moles of nickel chloride hexahydrate, moles of ethyl acrylate was the only significant factor, and no interactive effects were found. The selection of factors was based on mechanistic considerations and from an analysis of competing pathways. The design demonstrated that a potentially capricious reaction was very robust. The predictive equation from the experimental design was used to determine the control limits of the process with respect to the design response, the corrected yield. Process control limits determined from the predictive equation in an ex...