Mechanochemistry for “no solvent, no base” preparation of hydantoin-based active pharmaceutical ingredients: nitrofurantoin and dantrolene

Abstract

The gram-scale mechanochemical preparation of marketed drugs Nitrofurantoin and Dantrolene is herein reported.

Mechanochemistry for Synthesis

“…Mechanochemistry permits aldimine condensations using protonated ammonium salts without as acrificial base,a s observed by Colacino et al who produced hydantoin-based hydrazones,i ncluding APIs Nitrofurantoin and Dantrolin (Figure 8d). [98] Wróblewska et al have shown that carbodiimide-mediated formation of amides,usually requiring abase, also proceeds by base-free milling. [99] Such reactivity is most likely due to proton mobility between close-spaced molecules in the milled solid, consistent with rapid H/D exchange observed in milling deuterated and non-deuterated organic acids [92]…”

Mechanoenzymatic Transformations in the Absence of Bulk Water: A More Natural Way of Using Enzymes

“…This observation is consistent with the ongoing change in our understanding of chemical transformations, with the growing realization that many reactions readily proceed in solvent‐less mechanochemical environments . Indeed, mechanochemistry, which was recently proposed to be involved in the emergence of small organic molecules on the early Earth, has successfully provided routes to chemical selectivity, as well as reactions or molecules that have otherwise been considered difficult or even impractical to access. Although mechanoenzymatic reactivity is in a very early stage of development, it has already sparked a significant amount of interest, and provided simple solutions to streamline industrial processing of, for example, lignocellulosic material.…”

“…It is our view that solvent-less environments found in liquidassistedg rinding and/ora ging in moist air,a re more effective than conventional dilute solutions in replicating the natural environmento fm any enzymes.M uch more akin to low h conditions of liquid-assisted mechanochemistry,e nzymes secreted by microorganisms thrive on moist surfaces, and intracellular enzymes functioni nh ighly concentrated, organized environments.T his observation is consistent with the ongoing change in our understanding of chemical transformations, [161] with the growingr ealization that many reactions readily proceed in solvent-less mechanochemicale nvironments. [18,115,[162][163][164][165][166][167][168] Indeed, mechanochemistry,w hichw as recently proposed to be involved in the emergence of small organic molecules on the early Earth, [169] has successfully provided routes to chemical selectivity, [19,170,171] as well as reactions [172,173] or molecules [174][175][176] that have otherwiseb een considered difficult or even impractical to access. Although mechanoenzymatic reactivity is in a very early stage of development, it has already sparked as ignificanta mount of interest, [177] and provided simple solutions to streamline industrial processing of, for example, lignocellulosic material.…”

Mechanochemie gasförmiger Reaktanten

“…In ähnlicher Weise führt Kugelmahlen von Reaktionsmischungen oft zur Bildung kleiner,gasfçrmiger Moleküle,wie HCl, [72] N 2 , [68,73] CO 2 oder anderer. In ähnlicher Weise führt Kugelmahlen von Reaktionsmischungen oft zur Bildung kleiner,gasfçrmiger Moleküle,wie HCl, [72] N 2 , [68,73] CO 2 oder anderer.…”

“…[72] Im Fall von Reaktionen, die gasfçrmige Reaktanten beinhalten, ist die Art, wie die Gase i) in den Mahlbecher eingeleitet und gehalten werden, ii)ins itu erzeugt werden oder iii)kontinuierlich durch den Mahlreaktor fließen, ebenso wichtig.Zusätzlich wird die Temperatur-und Druckkontrolle aus sicherheitstechnischer Sicht äußerst bedeutsam, wenn Gase durch Kugelmahlen reagieren. Obwohl in erster Linie Schwing-und Planetenkugelmühlen die bevorzugten mechanischen Konfigurationen sind, wurden gewçhnlich maßgeschneiderte Veränderungen an kommerziellen Geräten vorgenommen, um die Verwendung von gasfçrmigen Proben zu ermçglichen.…”