Computational study on the mechanism for the synthesis of the active pharmaceutical ingredients nitrofurantoin and dantrolene in both solution and mechanochemical conditions

Abstract

A combination of density functional theory (DFT) calculations and microkinetic simulations is applied to the study of the condensation in acidic media between N-acyl-hydrazides and aldehydes to produce the active pharmaceutical ingredients (API) nitrofurantoin and dantrolene. Previous experimental reports by some of us had shown that the use of ball milling conditions led to a reduction in reaction time which came associated with significant reduction of waste. This result is reproduced by the current calculations, which, moreover, provide a detailed mechanistic explanation for this behavior.