Abstract
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.
Highlights
IntroductionRME = reaction mass efficiency RSGI = Rowan solvent greenness index, kg SD = skin dose, mg SF = stoichiometric factor SFP = smog forming potential, unitless SR = sacrificial reagents STY = space-time-yield, kg/m3/h or kg/L/h VTO = volume time output, h m3/kg W = waste Y = yield
The following five variables are depicted in radial pentagons: atom economy (AE), reaction yield, inverse of stoichiometric factor (SF) indicating excess reagent consumption, material recovery parameter (MRP) indicating auxiliary material consumption, and reaction mass efficiency (RME)
The most benign solvent is water and the most impactful solvent is benzene. These overall solvent index (OSI) values are multiplied by the corresponding scaled masses of solvents used as reaction solvents, workup solvents, and purification solvents determined in the SYNTHESIS spreadsheet in order to obtain the overall Rowan solvent greenness index (RSGI) score for the synthesis plan according to Eq 1
Summary
The pharmaceutical industry has been at the forefront of implementing green chemistry principles in the manufacture of active pharmaceutical ingredients over the last two decades [1,2,3,4,5,6,7,8,9,10,11]. In this work we present a simplified yet comprehensive “process green synthesis report” protocol that aims to achieve the following goals: (a) present a succinct summary analysis of a given process synthesis according to mass, impact, and energy metrics that are deemed to be essential in assessments of efficiency so that holistic decision-making can be accomplished; (b) present accompanying simple visual aids to each of these metrics analyses to quicken the identification of metric pros and cons for a given process synthesis; and (c) present all of this information in a manner that can be understood by both chemists and chemical engineers so that both groups of scientists who have different training and technical vocabulary backgrounds can come together and communicate in order to solve a given optimization problem while implementing green chemistry principles With this tool in hand, any chemist or chemical engineer can quickly glean the strengths and weaknesses of a given synthesis plan and act on those results to initiate further improvements that address any shortcomings and “hot spots” with respect to material and energy consumption, and environmental and safety-hazard issues that have been identified. We show that the Borda count method yields the same ranking results as the poset method using simpler and faster computation, but are different from the results of the inferior VMR method
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