Evaluation of safe mixed solvents in N-phenylbenzamide synthesis for alteration of hazardous dipolar aprotic solvents in amide drug syntheses

Abstract

N-phenylbenzamide (N-PBA) was synthesized with the solvent-pair mixtures (1:1 v/v) containing hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) to investigate the replacement/limitation of hazardous dipolar aprotic solvents in amide drug synthesis. Pure solvents: dimethylformamide (DMF), dichloromethane (DCM), acetonitrile (ACN), acetone (Ace), tetrahydrofuran (THF), ethyl acetate (EtAc), dimethyl sulfoxide (DMSO), and mixed solvents: H2O-THF, H2O-DMSO, H2O-Ace, H2O-DMF, H2O–EtOH, H2O-IPA, EtOH-DMF, EtOH-DMSO were selected based on Kamlet-Taft (KT) parameters, GSK 2016 health-safety scores. Syntheses were carried out with an amide coupling system at 25 °C to evaluate the reaction yield observed with high-performance liquid chromatography (HPLC). The percent yield of 72.68 ± 0.35 (H2O-THF), 71.24 ± 1.93 (H2O-Ace), 80.27 ± 1.67 (EtOH-DMF), 67.27 ± 0.64 (EtOH-DMSO), 65.38 ± 1.55 (H2O-IPA) were found by adjusting the pH 10.8 in solvent mixtures for synthesis. A ninefold increase in the N-PBA yield was obtained by adjusting the pH 10.8 in mixed solvents. Besides, (77.12 ± 1.66, DMSO), and (92.44 ± 0.82, DMF) %yields in N-PBA were found using pure solvents. The aforementioned findings indicate that safe solvent mixtures can be utilized in amide drug synthesis to avoid/limit hazardous dipolar aprotic solvents.