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

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