Cumulative Green Chemistry Principle Score for Objective Assessment of Drug Synthesis

Abstract

Green chemistry guides the sustainable drug synthesis. Classical metrics (AE, E-factor, and process-mass-intensity) cover only 2 of the 12 green chemistry principles (GCPs) (prevention and AE). Other important GCPs are grossly ignored (benign solvents, reagents, and catalysis). Recently newer metrics green aspiration level (GAL) and improved (iGAL) were proposed. These metrics consider the E-factor but miss other important principles, such as the use of benign solvents, reagents, and catalysis. The recently proposed principle-specific score also requires proprietary data. Thus, a simple and novel metric/score that includes additional GCPs for objective assessment of environmental impacts, safety, and greenness of the synthesis routes is urgently required. This article proposes novel metrics, principle-specific, and average green chemistry principle scores (AGCPx and AGCP) and a cumulative green chemistry principle score (CGCP score) that considers four GCPs (x = 2, 3, 5, and 9) to allow objective and quantitative assessments of the different routes for an API. CGCP score has been quantitatively benchmarked against the classical metrics for sildenafil which is known for its green synthesis procedures. Additionally, the AGCP and CGCP scores have been validated by using the US-EPA and ACS-GCI awarded green chemistry routes for a chemically and therapeutically diverse set of drugs. Although the process-chemistry green synthesis routes tend to have an average CGCP score of 0.59, a synthesis route with the AGCP score of ∼0.53 can be considered green (e.g., discovery route for carbimazole). We also demonstrate the utility of CGCP score for the discovery (medchem) and process-chemistry routes for four FDA-approved PARP-1 drugs. CGCP score allows the objective comparison and assessment of synthesis schemes for a given drug and between multiple drugs. CGCP correctly identifies the greenness (or lack thereof) of known synthesis routes (talazoparib and niraparib, respectively) and offers novel green chemistry insights for further improvements. CGCP score is a useful synthesis design tool and valuable addition to the armory of discovery and process chemists.