Relationships between step and cumulative PMI and E-factors: Implications on estimating material efficiency with respect to charting synthesis optimization strategies

Abstract

This report describes mathematical relationships between step and cumulative process mass intensities (PMIs) for synthesis plans, and analogous parameters applied to E-factors. It is shown that both step E-factors and step PMIs are not additive for synthesis plans. It is also shown that a recursive calculation of cumulative PMIs from step PMIs is a rapid method of determining overall PMIs for synthesis plans, though cumulative PMIs are not sufficiently informative as step PMIs or step E-factors to identify bottlenecks in synthesis plans. Illustrations on the use of these metrics to track the material efficiency of published synthesis plans for the pharmaceutical, apixaban, are given as a template example. Advantages and disadvantages of each metric are discussed. A general algorithm to select the most promising candidate synthesis plans considered at the design stage for a given molecular target that most likely satisfy "green" material efficiency criteria is also presented.