Computational study on the mechanism for the synthesis of active pharmaceutical ingredients nitrofurantoin and dantrolene in both solution and mechanochemical conditions.

A combination of density functional theory (DFT) calculations and microkinetic simulations is applied to the study of condensation between -acyl-hydrazides and aldehydes in acidic media to produce the active pharmaceutical ingredients (API) nitrofurantoin and dantrolene. Previous experimental reports have shown that the use of ball milling conditions leads to a reduction in the reaction time, which is associated with a significant reduction of waste. This result is reproduced by the current calculations, which additionally provide a detailed mechanistic explanation for this behavior.

Sustainable Beckmann Rearrangement using Bead-Milling Technology: The Route to Paracetamol.

To address the growing demand for more sustainable and greener chemistry, mechanochemical methodologies are emerging as key players. However, to date there has been little data highlighting the benefits of these rising mechanochemical technologies with regard to process scale-up activities or implementation in commercial production scale. Herein, we report the first application of bead-mill technology (Dyno®-mill) for the sustainable mechanochemical synthesis of Acetaminophen, known under the brand name Paracetamol.

Scalability of Pharmaceutical Co-Crystal Formation by Mechanochemistry in Batch.

The development of mechanochemistry is considerably growing. Benign by design, this technology complies with several principles of green chemistry, contributing to the achievement of the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal objectives. Herein, we report the use of mechanochemical processes in batch to prepare kilogram-scale of the Active Pharmaceutical Ingredient (API): Ibuprofen-Nicotinamide (rac-IBP:NCT) co-crystal in an industrial eccentric vibration mill.

Green metrics in mechanochemistry.

The development of new green methodologies and their broader adoption for promoting sustainable development in chemistry laboratories and industry play a significant role in society, due to the economic importance of chemistry and its widespread presence in everyday life. Therefore, a sustainable approach to chemistry contributes to the well-being of the worldwide population and complies with the United Nations Sustainable Development Goals (UN SDGs) and the European Green Deal. The review highlights how batch and continuous mechanochemical methods are an eco-friendly approach for organic synthesis, with a lower environmental footprint in most cases, compared to solution-based procedures.

The first solid-state route to luminescent Au(I)-glutathionate and its pH-controlled transformation into ultrasmall oligomeric Au(SG) nanoclusters for application in cancer radiotheraphy.

There is still a need for synthetic approaches that are much faster, easier to scale up, more robust and efficient for generating gold(I)-thiolates that can be easily converted into gold-thiolate nanoclusters. Mechanochemical methods can offer significantly reduced reaction times, increased yields and straightforward recovery of the product, compared to the solution-based reactions. For the first time, a new simple, rapid and efficient mechanochemical redox method in a ball-mill was developed to produce the highly luminescent, pH-responsive Au(I)-glutathionate, [Au(SG)].

Mechanochemistry: New Tools to Navigate the Uncharted Territory of "Impossible" Reactions.

Mechanochemical transformations have made chemists enter unknown territories, forcing a different chemistry perspective. While questioning or revisiting familiar concepts belonging to solution chemistry, mechanochemistry has broken new ground, especially in the panorama of organic synthesis. Not only does it foster new "thinking outside the box", but it also has opened new reaction paths, allowing to overcome the weaknesses of traditional chemistry exactly where the use of well-established solution-based methodologies rules out progress.

Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine.

In recent years, mechanochemistry has enriched the toolbox of synthetic chemists, enabling faster and more sustainable access to new materials and existing products, including active pharmaceutical ingredients (APIs). However, molecular-level understanding of most mechanochemical reactions remains limited, delaying the implementation of mechanochemistry in industrial applications. Herein, we have applied in situ monitoring by Raman spectroscopy to the mechanosynthesis of phenytoin, a World Health Organization (WHO) Essential Medicine, enabling the observation, isolation, and characterization of key molecular-migration intermediates involved in the single-step transformation of benzil, urea, and KOH into phenytoin.

Mechanochemical Preparation of Protein : hydantoin Hybrids and Their Release Properties.

Mechanochemistry is a versatile methodology that can be employed both for covalent bond formation in organic synthesis as well as a mediator to allow preparation novel colloidal dispersions for drug delivery. Herein, ball-milling was employed for the solid-state preparation of fluorescent hydrophobic hydantoins, followed by the unprecedented mechanochemically-mediated complexation of hydrophobic hydantoins within hydrophilic protein β-lactoglobulin (BLG) and BLG nanofibrils (BLGNFs). These hydantoin:protein materials were in turn incorporated into hydrogels.

Mechanochemical synthesis of mononuclear gold(I) halide complexes of diphosphine ligands with tuneable luminescent properties.

A mechanochemical method is reported for the synthesis of Au(diphos)X complexes of diphosphine (diphos = XantPhos and -XantPhos) ligands and halide ions (X = Cl and I). The Au(XantPhos)X (1: X = Cl; 2: X = I) and Au(-XantPhos)Cl (3) complexes exhibited either yellowish green (1) or bluish green (2) emission, whereas 3 was seemingly non-emissive in the solid state at room temperature. Blue- (2B) and bluish green (2G) luminescent concomitant solvates of 2 were obtained by recrystallization.

Mechanochemical Rearrangements.

Molecular rearrangements are a powerful tool for constructing complex structures in an atom- and step-economic manner, translating multistep transformations into an intrinsically more sustainable process. Mechanochemical molecular rearrangements become an even more appealing eco-friendly synthetic approach, especially for preparing active pharmaceutical ingredients (APIs) and natural products. Still in their infancy, rearrangements promoted by mechanochemistry represent a promising approach for chemists to merge molecular diversity and green chemistry perspectives toward more selective and efficient syntheses with a reduced environmental footprint.

Mechanochemical Preparation of Active Pharmaceutical Ingredients Monitored by Raman Spectroscopy.

The mechanochemical preparation of silver sulfadiazine and dantrolene, two marketed active pharmaceutical ingredients, was investigated by Raman spectroscopy. For the first time, the mechanochemical transformations involving highly fluorescent compounds could be studied with a high-resolution Raman system combined with a unique suitable Raman probe. Moreover, the kinetic features of the mechanochemical process were examined by a mathematical model allowing to describe the chemical changes under mechanical stress.

Kinetics of mechanochemical transformations.

The use of mechanical forces to activate and drive chemical transformations in solid particulate is attracting remarkable interest in the light of its promising application in a wide spectrum of strategic areas ranging from materials science to fine chemical synthesis and pharmaceutical ingredient production. The capability of enabling solventless processes and fabricating unique materials inaccessible otherwise has made mechanochemistry one of the ten chemical innovations with the highest potential of changing the world. As in the past, so again now, the development of reliable technologies based on mechanochemical transformations cannot be separated from the understanding of the underlying mechanisms, their description and their control.

Processing and Investigation Methods in Mechanochemical Kinetics.

The present work focuses on the challenges that emerge in connection with the kinetics of mechanically activated transformations. This is an important topics to comprehend to enable the full exploitation of mechanical processing in a broad spectrum of areas related to chemistry and materials science and engineering. Emerging challenges involve a number of facets regarding materials and material properties, working principles of ball mills and milling conditions, and local changes occurring in series in processed materials.

Metal-free mechanochemical oxidations in Ertalyte jars.

Aimed at eliminating or at least significantly reducing the use of solvents, sodium hypochlorite pentahydrate crystals (NaOCl·5HO) in the presence of a catalytic amount of a nitrosyl radical (TEMPO or AZADO) have been successfully used to induce mechanochemical oxidative processes on several structurally different primary and secondary alcohols. The proposed redox process is safe, inexpensive and performing effectively, especially on the macroscale. Herein, an Ertalyte jar has been successfully used, for the first time, in a mechanochemical process.

High throughput mechanochemistry: application to parallel synthesis of benzoxazines.

We describe herein an unprecedented mechanochemical "parallel synthesis" of 3,4-dihydro-2H-benzo[e][1,3]oxazine derivatives via a one pot three component reaction. The new milling system uses a multiposition jar (variable sizes are possible), allowing for the processing of up to 12 samples simultaneously, leading to the formation of a fungicide and a building block for polymer preparation with higher throughput compared to standard milling devices.

Mechanically induced oxidation of alcohols to aldehydes and ketones in ambient air: Revisiting TEMPO-assisted oxidations.

The present work addresses the development of an eco-friendly and cost-efficient protocol for the oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones by mechanical processing under air. Ball milling was shown to promote the quantitative conversion of a broad set of alcohols into carbonyl compounds with no trace of an over-oxidation to carboxylic acids. The mechanochemical reaction exhibited higher yields and rates than the classical, homogeneous, TEMPO-based oxidation.

Influence of the milling parameters on the nucleophilic substitution reaction of activated β-cyclodextrins.

The present work focuses on the mechanochemical preparation of industrially important β-cyclodextrin (CD) derivatives. Activated CDs have been reacted with nitrogen and sulfur nucleophiles using a planetary mill equipped with stainless steel, zirconia and glass milling tools of different sizes. It is shown that the milling frequency and the number as well as the size of the milling balls have an effect on the nucleophilic reaction.

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold.

The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates.

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

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.

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives.

5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1'-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.

Novel 1H-Pyrrolo[3,2-c]quinoline Based 5-HT6 Receptor Antagonists with Potential Application for the Treatment of Cognitive Disorders Associated with Alzheimer's Disease.

Modulators of the serotonin 5-HT6 receptor (5-HT6R) offer a promising strategy for the treatment of the cognitive deficits that are associated with dementia and Alzheimer's disease. Herein, we report the design, synthesis, and characterization of a novel class of 5-HT6R antagonists that is based on the 1H-pyrrolo[3,2-c]quinoline core. The most active compounds exhibited comparable binding affinity to the reference compound, SB-742457, and markedly improved selectivity.

Mechanochemical preparation of hydantoins from amino esters: application to the synthesis of the antiepileptic drug phenytoin.

The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps.

Solventless mechanosynthesis of N-protected amino esters.

Mechanochemical derivatizations of N- or C-protected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates.

Ultrasounds in melted poly(ethylene glycol) promote copper-catalyzed cyanation of aryl halides with K(4)[Fe(CN)(6)].

Melted poly(ethylene glycols) (PEGs) were used for the first time as solvent for the sonochemically promoted cyanation of aryl halides employing inexpensive and safe K4[Fe(CN)6] and a relatively low amount of Cu-based catalyst. The Mw (weight-average polymer molecular weight) of PEG proved to notably influence the substrate conversion, which is indicative of a strong dependence of the sonication efficacy on solvent properties. Gel permeation chromatography (GPC), X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM) contributed to the characterization of the polymer and the elucidation of the catalytic system.