Mechanochemistry for 'no solvent, no base, no waste' preparation of Hydantoin-based Active Pharmaceutical Ingredients: Nitrofurantoin and Dantrolene

The eco-compatible, energy-efficient, low environmental impact, gram scale, mechanochemical preparation of marketed drugs such as Nitrofurantoin (Furantin©, antibacterial agent), Dantrolene (Dantrium©, a muscle relaxant also used for prevention of malignant hyperthermia) and their structurally related derivatives, is herein reported. The solvent-, base- and waste-free stoichiometric ball-milling of 1-amino-hydantoin chlorohydrate and various aldehydes led to the more stable E-regioisomers selectively, in high yield and pure form without post-reaction work-up. Not a drop of organic solvent was used for the entire process and hydrazones were stable in the presence of water and gaseous HCl, formed during the synthesis. Comparative mechanochemical experiments were performed using diverse milling devices and jar materials, the Active Pharmaceutical Ingredients were analyzed by PXRD and green metrics are calculated.