Ferenc Darvas

High-Efficiency Aminocarbonylation by Introducing CO to a Pressurized Continuous Flow Reactor

Halogenated aryl carboxylic acids were efficiently converted to the corresponding dicarboxylic acid monoamides by a one-step Pd-catalyzed aminocarbonylation in a micro/meso fluidic continuous flow reactor (X-Cube) operated at high pressure and high temperature with CO gas introduction. Reaction parameters (solvent, base, catalyst, pressure, temperature) were rapidly optimized in the reactions, which required less than 2 min. The method gave improved results over comparable batch techniques and is also suited to automated parallel syntheses of compound libraries.

A quantitative approach to optical resolution

Abstract Significant statistical relationships have been found between the parameters characterizing the results and circumstances of the resolutions of seventeen phenylglycine derivatives. The successful predictions given for the results of six independent resolutions prove the utility of these relationships.

In Silico and Ex silico ADME approaches for drug discovery.

The high attrition rate of drug candidates during clinical trials for poor pharmacokinetic and metabolic properties has created a need to do these studies as early as it is possible during the drug discovery process. In addition the most successful drug is often not the most potent one but the one that has the suitable level of potency, safety, and pharmacokinetics. Science and technology development during the last few years and the generation of last databases and information has created the basis for doing early experimental PK and ADME studies in addition to eADME. Similarly, testing safety features as early as possible is key to affordable drug discovery and development. Throughput and cost are crucial for early application. In silico methods have by far the highest throughput, followed by the in vitro and in vivo approaches. On the other hand, with regard to relevance and reliability of data the ranking is the opposite. The great challenge for in silico methods is generation of models that correlate more closely with in vivo systems. For the in vitro assays increasing the throughput is an absolute must. Ex silico methods that combine in silico predictions with experimental methods are new additions to the scientific repertoire (e.g. Chromatographic Hydrophobicity Index that is deduced from the reverse phase HPLC data can be used for calculation of lipophilicity). The emerging new approaches have clear impact on the design of early stage screening and combinatorial libraries. In addition to the Lipinskis rules descriptors such as number of rotatable bonds, number of aromatic rings, branching behavior and polar surface area (PSA) are commonly used is the drug design process.

Solution-phase parallel synthesis of 4,6-diaryl-pyrimidine- 2-ylamines and 2-amino-5,5-disubstituted-3,5-dihydro-imidazol- 4-ones via a rearrangement

The reaction of chalcones and guanidine was investigated in the presence of an oxidizing agent. Depending on the order of the addition either a 4,6-diaryl-pyrimidine-2-ylamine or 2-amino-5,5-disubstituted-3,5-dihydro-imidazol-4-one was obtained. The structures of the imidazolinones were elucidated by NMR spectroscopy and X-ray crystallography and for its formation a mechanism was proposed.

Synthesis of γ-valerolactone using a continuous-flow reactor

This study describes the heterogeneous catalysed continuous synthesis of γ-valerolactone (GVL) using a continuous-flow reactor, H-Cube® and H-Cube Pro™, equipped with 5% Ru/C, 10% Pd/C and RANEY® Ni CatCart®. The highest yield of GVL was achieved by using 5% Ru/C in the presence of 0.015 mol L−1 Bu-P(C6H4-m-SO3Na)2 ligand under 100 bar H2 at 100 °C.

Recent Advances in Chemical Genomics

Chemical genomics, which utilizes specially designed small chemical compounds early in the discovery phase of new drugs to explore the life science at various levels, can address biological questions that are not amenable to genetic manipulation or functional genomics/proteomics approaches. Following the development of HT phenotypic assays and DNA expression analysis, the integration of cell-based assays with activity / affinity-based approaches allows us to interrogate the cells by analyzing phenotypic alterations, changes of transcript signature or detecting the differences in protein expression levels. Furthermore, activity / affinity-based techniques directly provide a druggable subset of gene products, which interact with small molecules, greatly reducing the complexity of analyzing the proteome. In this paper, we give an account of the recent advances (approaches and strategies) in the field of chemical genomics, and discuss how these approaches enable the investigator to obtain a novel therapeutically relevant target as well as drug candidates acting on them in a target-specific manner. This novel post-genomic discovery strategy, where target identification/ validation is carried out by interactions with small molecules, could significantly reduce the time-scale for early drug discovery, and increase the success rate of finding novel, druggable targets, as well as more specific drug candidates.

Asymmetric hydrogenation of C=C double bonds using Rh-complex under homogeneous, heterogeneous and continuous mode conditions

A green process for enantioselective hydrogenation of dehydroamino acid derivatives and dimethyl itaconate with a rhodium catalyst modified by a new phosphine–phosphoramidite has been developed providing 97.7–99.8% enantioselectivity in green solvents such as ethylene carbonate and propylene carbonate. The L-DOPA precursor was obtained by simple filtration in 71% yield with 99.5% ee. Dimethyl itaconate was hydrogenated under solvent-free condition at 50 °C with 98.7% ee. The new rhodium complex was heterogenized on a mesoporous Al2O3 support using phosphotungstic acid (PTA) as an anchoring agent and tested in heterogeneous batch and flow reaction modes. The supported catalyst was reused eight times in the batch mode with over 97% ee and used over 12 hours in the flow reaction mode with an average of 97% ee in the asymmetric hydrogenation reaction of (Z)-α-acetamidocinnamic acid methyl ester.

Development of chemically modified glass surfaces for nucleic acid, protein and small molecule microarrays

Microarrays have become a widely used tool to investigate the living cell at different levels. DNA microarrays enable the expression analysis of thousand of genes simultaneously, while protein arrays investigate the properties and interactions of proteins with other proteins and with non-proteinaceous molecules. One crucial step in producing such microarrays is the permanent immobilization of samples on a solid surface. Our goal was to develop diverse linker systems capable of anchoring different biological samples, especially DNA and drug-like small molecules. We developed 6 different chemical surfaces having a 3-D-like linker system for biomolecule immobilization, and compared them to previously described immobilization strategies. The attachment chemistry utilizes the amino reactive properties of acrylic and epoxy functions. The capacity of the support was increased by creating a branching structure holding the reactive functions.The method of anchoring was investigated through a model reaction. From HPLC and mass spectrometry measurements we concluded that the covalent binding of DNA occurs through nucleobases. The tested systems offer the capability to permanently immobilize several biomolecular species in an array format.

Analysis of pyridinium aldoximes - a chromatographic approach.

Pyridinium aldoximes are used as antidotes to organophosphorus cholinesterase inhibitors. All pyridinium aldoximes (oximes) are highly polar quaternary ammonium compounds showing low to minimal blood-brain-barrier (BBB) penetration. Oximes are separated using reversed-phase (RP) HPLC methods and/or thin-layer chromatography (TLC). The chemical structures, elementary compositions, molecular sizes and the calculated logP values of several mono- and bis-pyridinium aldoximes are given. Chromatographic and electrophoretic analyses of oximes are detailed, including the stationary and mobile phase composition and the mode of detection. Degradation pathways and products are also discussed. To characterize oximes lipophilicity/hydrophilicity an in silico method was used and expanded as to describe organophosphorus compound adducts with several pyridinium aldoximes.

Stepwise aromatic nucleophilic substitution in continuous flow. Synthesis of an unsymmetrically substituted 3,5-diamino-benzonitrile library.

Aromatic or heteroaromatic ring precursors with 2–3 identical functionalities are often used in sequential derivatization depending on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. Continuous flow chemistry offers an enhanced parameter space (pressure and temperature) with rapid parameter optimization that ensures selectivity in many cases. We developed a flow chemistry procedure to carry out a stepwise aromatic nucleophilic substitution of difluoro-benzenes having an activating group in meta position to the fluorines. The mono-aminated products were obtained in high yield and selectivity in an extremely short reaction time, while applying higher temperature, longer reaction zone (or time), and employing higher excess of another amine reactant, the subsequent introduction of the second amino group was also successfully achieved leading to an unsymmetrically substituted 3,5-diamino-benzonitrile library.