Mechanochemistry for "no solvent, no base" preparation of hydantoin-based active pharmaceutical ingredients: Nitrofurantoin and dantrolene

The eco-compatible, base- and waste-free, energy-efficient, low-environmental-impact, gram-scale, mechanochemical preparation of marketed drugs such as nitrofurantoin (Furantin©), dantrolene (Dantrium©) and their structurally related derivatives is herein reported. Not a drop of organic solvent was used for the entire process and high yields of pure compounds were obtained without post-reaction work-up. Hydrazones were stable in the presence of water and gaseous HCl, formed as by-products 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.