Liquid‐Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals

Abstract

Mechanochemical reactions by milling, grinding or other types of mechanical action have emerged as a salient green approach because of its wide applications towards academic and industrial chemical communities in sustainable solvent‐free/solvent‐less processes. Liquid‐assisted grinding (LAG) as an extension of traditional solvent‐free mechanochemical techniques by which a small amount of liquid is used as an additive to enhance and/or control reactivity, has been fruitfully applied in the screening of inclusion compounds, cocrystals, salts, solvates, and polymorphs. However, utilization of this important technique in the synthesis of pharmaceutically and biologically relevant targets was not adequately investigated. This review article summarizes an overview of the latest development of LAG mechanochemical approaches in the synthesis of active pharmaceutical ingredients (API) and drug‐like fragments, highlights its superiority versus conventional syntheses.

Atomically dispersed Mn–N4 electrocatalyst with high oxygen reduction reaction catalytic activity from metal–organic framework ZIF-8 by minimal-water-assisted mechanochemical synthesis

“…25 Minimal-liquid-assisted mechanochemical milling or grinding has been widely applied in industries for environmentally friendly synthesis or processing of materials. [30][31][32][33][34] In recent years, this method has been transferred to large-scale preparation of metal-organic frameworks with quantitatively high yields. 35,36 Considering the low Mn-N-C pyrolytic yield from metal ion-loaded MOF precursors (typically 10-20 wt%) and the ease of large-scale and high-yield synthesis of MOFs in an environmentally benign way by liquid-assisted grinding (LAG), 37 it is worthwhile to explore this method to prepare MOF precursors for Mn-N-C preparation.…”

Mechanochemical Organocatalysis: Do High Enantioselectivities Contradict What We Might Expect?

“…They then carried out solvent (water) and neat/concentrated comparisons, using catalyst C7 , finding that reaction times of 48 h were required to achieve comparable yields, although with lower stereoselectivity (Scheme 3B). This study appears to mark the first example where ball‐milling leads to improved enantioselectivity in an organocatalyzed reaction and also features the use of water as a LAG agent [26] …”

“…Typically, applied forces are either opposing in direction and result in the application of pulling forces to a mechanophore (using sonication devices or atomic force microscopes) or the forces converge on the reaction centre through impact [1–9] . Such converging forces can be achieved with a mortar and pestle, a simple hammer, a diamond anvil cell or perhaps most typically by a ball mill [10–31] . Ball‐milled reactions are conducted in jars using the displacement, movement and impact of balls to input energy into a sample.…”

Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates

“…4,5 In this regard, mechanochemistry [6][7][8] as an essentially solvent-free technique can beneficially contribute to the ongoing green renovation of the pharma industry. [9][10][11] Despite the rapid development of mechanochemical organic synthesis over the past decades, [12][13][14][15] its synthetic portfolio still does not entirely cover the diverse range of transformations required for API production and needs to be expanded.…”