A greatly improved procedure for the synthesis of an antibiotic-drug candidate 2,4-diacetylphloroglucinol over silica sulphuric acid catalyst: multivariate optimisation and environmental assessment protocol comparison by metrics

Abstract

Efforts toward the development of a straightforward greener Gram-scale synthesis of the antibiotic compound 2,4-diacetylphloroglucinol (DAPG) have been developed. This beneficial procedure was accomplished through the Friedel–Crafts acylation of phloroglucinol over inexpensive heterogeneous silica sulphuric acid (SSA) catalyst via ultrasound-assisted (US) synthesis under solvent-free condition. The influences of various parameters such as temperature, catalyst loading, and reaction time on the reaction performance were analysed using a multivariate statistical modelling response surface methodology (RSM). A high yield of DAPG (95%) was achieved at 60 °C after 15–20 min reaction with the presence of 10% (w/w) SSA as the catalyst. Column chromatography-free and a Gram scale-up reaction also exhibited the practical applicability of this newly developed protocol. The SSA catalyst was recovered and recycled up to 10 consecutive runs with no appreciable loss of activity. A plausible mechanism for the Friedel–Crafts acylation of phloroglucinol is proposed. Moreover, an environmental assessment has been carried out over this present method and compared with several established literature using the EATOS software and the Andraos algorithm to assess the consumption of the substrates, solvents, catalysts, and the production of coupled products or by-products. In addition, their energy consumptions were also determined. The data collected showed that the present method is the most promising one, characterised by the highest environmental impact profile against all the other reported methods. The physicochemical properties of the synthesised DAPG were assessed and exhibited reasonable oral bioavailability drug property as determined by Lipinski's rules.