Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

Abstract

The mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins was investigated in the presence of various poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under dry-grinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG grinding agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures.

Liquid‐Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals

“…This successful protocol was further applied to the preparation of antiepileptic drug phenytoin (Phenytek®), using trimethylsilyl isocyanate (TMS‐NCO) as superior cyanate and cesium carbonate as a base for cyclization (Scheme 6b‐5) [55c] . After a simple and eco‐friendly workup, phenytoin could be obtained in a very nice yield without any chromatographic or recrystallization purification.…”

“…in catalyzing and directing polymorphism of APIs cocrystal to avoid the solvate formation, here PEG polymer acted as a chelation matrix of the potassium cations in ethotoin preparation, inducing the enhancement of both reactivity and solubility of the naked CO 3 2− , and finally responsible for the improvement of the reaction. Control experiments highlighted that the change in the “physical state of the system” intrigued by amount, length and viscosity of PEG polymer had exerted great impaction on the reaction efficiency [55c] …”

Multicomponent mechanochemical synthesis

“… 42 Subsequent work by the same researchers proved that a liquid-assisted grinding protocol based on the addition of polyethylene glycols led to cleaner reaction profiles. 43 …”

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

“…We previously demonstrated how this approach was successfully used for the mechanochemical preparation of imidazoline-2,4-diones, or hydantoins, a scaffold of synthetic 2 and pharmaceutical interest for its many biological properties, 3 leading to clinical candidates [4][5] and marketed drugs. 6 Several added-value hydantoin-based molecules for the industry, including Active Pharmaceutical Ingredients (API) such as Phenytoin 1 7 and Ethotoin 2, 8 antibacterial agents for polymer textiles 3-5, [8][9] or the precursor 6 10 an inhibitor of the dihydroorodotase enzyme, were already described by us ( Figure 1). Very recently, we described the first "mechanochemical sol-gel process" to prepare silicon-based biohybrid nanomaterials containing hydantoins.…”