Aiming for a standardized protocol for preparing a process green synthesis report and for ranking multiple synthesis plans to a common target product

Abstract

This paper proposes a standardized format for the preparation of process green synthesis reports that can be applied to chemical syntheses of active pharmaceutical ingredients (APIs) of importance to the pharmaceutical industry. Such a report is comprised of the following eight sections: a synthesis scheme, a synthesis tree, radial pentagons and step E-factor breakdowns for each reaction step, a tabular summary of key material efficiency step and overall metrics for a synthesis plan, a mass process block diagram, an energy consumption audit based on heating and cooling reaction and auxiliary solvents, a summary of environmental and safety-hazard impacts based on organic solvent consumption using the Rowan solvent greenness index, and a cycle time process schedule. Illustrative examples of process green synthesis reports are given for the following pharmaceuticals: 5-HT2B and 5-HT7 receptors antagonist (Astellas Pharma), brivanib (Bristol-Myers Squibb), and orexin receptor agonist (Merck). Methods of ranking synthesis plans to a common target product are also discussed using 6 industrial synthesis plans of apixaban (Bristol-Myers Squibb) as a working example. The Borda count method is suggested as a facile and reliable computational method for ranking multiple synthesis plans to a common target product using the following 4 attributes obtained from a process green synthesis report: process mass intensity, mass of sacrificial reagents used per kg of product, input enthalpic energy for solvents, and Rowan solvent greenness index for organic solvents.

Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra-ortho-Substituted Biaryl Pyridone

“…Overall, the first-generation route generated API in 10% yield over 9 transformations with a longest linear sequence of 7 steps. The cumulative process mass intensity (PMI) of the synthesis was 1,160, with the biaryl pyridone core accounting for 5 out of 9 steps with 71% of the total PMI. − …”

A proposed sustainability index for synthesis plans based on input provenance and output fate: application to academic and industrial synthesis plans for vanillin as a case study

“…Once numerical values of PMI, SR, IEE, RSGI, and SI are available for a given set of synthesis plans to a common target product, it is possible to use some kind of ranking algorithm to identify which ones have the highest overall performances based on these five attributes. From our previous work [ 20 ] we compared and contrasted the Borda positional counting method [ 21 – 24 ], established in 1781 by Jean-Charles de Borda (1733–1799), and the poset pairwise dominance analysis method [ 25 ] on 6 synthesis plans for the pharmaceutical apixaban. In implementing the Borda count method we first list the plans in ascending order of PMI, SR, IEE, and RSGI so that plans having the lowest values for these attributes are ranked highest; and we list the plans in descending order of SI so that plans having the highest values of SI are ranked highest.…”

“…In our past work [ 20 ] describing a presentation of a “standardized process green synthesis report” for chemical syntheses of pharmaceutical compounds we were able to demonstrate the Borda count [ 21 – 24 ] and poset (partially ordered set) pairwise dominance [ 25 ] ranking algorithms based on the four attributes PMI, SR, IEE, and RSGI. In the present work, we can now add SI as a fifth key attribute as part of those ranking algorithm analyses which takes into account sustainability potential as well as material and energy consumption and environmental and safety-hazard impacts.…”

“…Once numerical values of PMI, SR, IEE, RSGI, and SI are available for a given set of synthesis plans to a common target product, it is possible to use some kind of ranking algorithm to identify which ones have the highest overall performances based on these five attributes. From our previous work [20] we compared and contrasted the Borda positional counting method [21][22][23][24] fonic acid liquor (87), and Mottern four-step chemical synthesis from guaiacol (87). The lowest ranking plan was found to be the Lampman synthesis from sawdust, which had the highest overall process mass intensity (PMI = 32,540 kg/kg), second highest energy consumption requirements (IEE = 2,398,980 kJ/kg), fourth-highest solvent impact ranking (RSGI = 112,106 kg/kg), and lowest sustainability index value (SI = 0.3676).…”

Green One-Pot Asymmetric Synthesis of Peptidomimetics via Sequential Organocatalyzed Aziridination and Passerini Multicomponent Reaction

“…Green chemistry metrics have been used by synthetic organic and process chemists to estimate the material efficiency, environmental impact, and safety-hazard impact of their synthesis plans and chemical processes to a desired target molecule. 23 As for example, in a previous work using the organocatalytic asymmetric epoxidation-Passerini reaction, green metrics have been calculated in order to compare the tandem one-pot with the conventional two-step strategies to synthesize epoxy--acyloxycarboxamides. 24 For the synthesis of compound 4b, using this new sequential organocatalyzed aziridination/Passerini reactions, the calculated metrics have shown good atom economy (AE, 70.1 %) and reaction mass efficiency (RME, 45.0).…”