High-purity Compounds Research Articles

Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated Amide Synthesis

We describe a unified synthetic strategy for efficient assembly of four new heterocyclic libraries. The synthesis began by creating a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a simple one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. A newly developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic dienamides. The final stage of the process entailed diversification of each of the initially produced carboxylic acids using a fully automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity.

Piperazine Amide Linker for Cyclative Cleavage from Solid Support: Traceless Synthesis of Dihydroquinoxalin-2-ones

A piperazine amide linker for cyclative cleavage from solid support and its use in the traceless solid-phase synthesis of dihydroquinoxalinones are described. Piperazine was attached to Wang resin via a carbamate linkage and acylated with Fmoc-amino acids. Following Fmoc group removal, resin-bound amines were reacted with 1-fluoro-2-nitrobenzenes. The nitro group of the resulting 2-nitroanilines was reduced, and acyclic precursors, in contrast to traditional ester-type linkage, remained attached to the resin. Target dihydroquinoxalinones were obtained either by acid- or microwave-mediated cyclative cleavage. The synthesis provided crude compounds of high purity and enabled the preparation of stable immobilized linear intermediates. The linker is suitable for combinatorial synthesis of compound libraries.

Right-First-Time Isocratic Preparative Liquid Chromatography-Mass Spectrometry Purification

Preparative RP-LCMS is widely used to purify compounds from crude reaction mixtures in drug discovery today. Method development for preparative Liquid Chromatography-Mass Spectrometry (LCMS) consists of finding the right balance between speed and quality, often leading to the use of fast generic gradients (5-95% organic mobile phase) to purify compounds of various structures and polarity, which can be sometimes detrimental to the purity of the isolated compound. Isocratic elution is the best method to obtain high purity, but it usually requires a long trial and error method development to find the right eluent composition. Therefore it is mostly used to purify large quantities of product using for instance stack injections, but not for routine purification of structurally diverse compounds. Herein, we describe an empirical method that allows "right-first-time" purifications with isocratic elution on preparative RP-LCMS, permitting isolation of compounds in high purity and yield.

ChemInform Abstract: An Efficient and Convenient Approach for the Synthesis of Novel 2‐Hydroxy‐12‐aryl‐8,9,10,12‐tetrahydrobenzo[a]xanthene‐11‐ones Using p‐Toluenesulfonic Acid in Ethanol and Ionic Liquid.

AbstractThe presented method is operationally convenient, gives excellent yields of the title compounds in high purity with easy work‐up.

An uncatalyzed aldol reaction of thiazolidinediones

Thiazolidinediones have been used as aldol donors with aromatic aldehydes “on water” and in DMSO without using any catalyst to give the corresponding β-hydroxy carbonyl compounds in high yield and purity. The p-cyano and p-nitro substituted aldol products undergo syn/anti isomerization via an enolization mechanism providing an “on water” diastereoselectivity switch. Water molecules play a significant role in stabilizing the syn aldol products of pyridine and thiazole containing aldehydes.

Final report on key comparison CCQM-K55.a (estradiol): An international comparison of mass fraction purity assignment of estradiol

Under the auspices of the Organic Analysis Working Group (OAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a key comparison, CCQM K55.a, was coordinated by the Bureau International des Poids et Mesures (BIPM) in 2009/2010. Eleven national measurement institutes and the BIPM participated. Participants were required to assign the mass fraction of estradiol present as the main component in the comparison sample (CCQM-K55.a) which consisted of a bulk estradiol hemihydrate material obtained from a commercial supplier that had been extensively but not exhaustively dried prior to sub-division into the units supplied for the comparison.Estradiol was selected to be representative of the performance of a laboratory's measurement capability for the purity assignment of organic compounds of medium structural complexity [molar mass range 300–500 Da] and low polarity (pKOW < −2) for which related structure impurities can be quantified by capillary gas phase chromatography (GC) or by high performance liquid chromatography (LC).The majority of participants used a mass balance approach to determine the estradiol content. The key comparison reference value (KCRV) for estradiol in CCQM-K55.a was assigned by combination of KCRVs assigned by consensus from participant results for each orthogonal impurity class. This allowed participants to demonstrate the efficacy (or otherwise) of their implementation of the mass balance approach and to demonstrate that their assigned value for the main component agreed with the KCRV through use of internally consistent contributing methods.The KCRV for the estradiol content of the material was 984.3 mg/g with a combined standard uncertainty of 0.42 mg/g. The individual participant results showed that a relative expanded uncertainty for the purity assignment of 0.2% is a reasonable estimate of the best achievable result by an individual laboratory for a material of this complexity available in this amount at this level of purity. The relative expanded uncertainties reported by laboratories having results consistent with the KCRV ranged from 0.2% to 0.8%.The review of results that were biased from the KCRV showed that two major analytical challenges are posed by the material: the measurement of its water content and controlling for related substance artefact formation during the analysis process. The results displaying a positive bias relative to the KCRV (overestimation of estradiol content) were due to underestimation of the water content of the material, while those with a negative bias (underestimation of estradiol) overestimated the total related substance impurities through a failure to detect and control for artefact formation arising from in situ oxidative dimerization of estradiol in neutral solution prior to analysis. There was however good agreement between all participants in the identification and the quantification of the individual related structure impurities actually present in the sample.The comparison also demonstrated the utility of high-field 1H NMR for both quantitative and qualitative analysis of high purity compounds. It is noted that all the participants who used qNMR as a major or contributing technique and included it as part of, combined it or confirmed it with a conventional 'mass balance' data estimate, obtained results consistent with the KCRV.Main text.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Microwave-Assisted Synthesis of New N1,N4-Substituted Thiosemicarbazones

We present an efficient procedure for the synthesis of thirty-six N1,N4-substituted thiosemicarbazones, including twenty-five ones that are reported for the first time, using a microwave-assisted methodology for the reaction of thiosemicarbazide intermediates with aldehydes in the presence of glacial acetic acid in ethanol and under solvent free conditions. Overall reaction times (20–40 min when ethanol as solvent, and 3 min under solvent free conditions) were much shorter than with the traditional procedure (480 min); satisfactory yields and high-purity compounds were obtained. The thiosemicarbazide intermediates were obtained from alkyl or aryl isothiocyanates and hydrazine hydrate or phenyl hydrazine by stirring at room temperature for 60 min or by microwave irradiation for 30 min, with lower yields for the latter. The preliminary in vitro antifungal activity of thiosemicarbazones was evaluated against Aspergillus parasiticus and Candida albicans.

An efficient and convenient approach for the synthesis of novel 2‐hydroxy‐12‐aryl‐8,9,10,12‐tetrahydrobenzo[a]xanthene‐11‐ones using p‐toluenesulfonic acid in ethanol and ionic liquid

AbstractA novel series of 2‐hydroxy‐12‐aryl‐8,9,10,12‐tetrahydrobenzo[a]xanthene‐11‐ones were synthesized by the one‐pot multicomponent condensation of 2,7‐dihydroxynaphthalene, aromatic aldehydes, and cyclic 1,3‐dicarbonyl compounds in the presence of a catalytic amount of p‐toluenesulfonic acid in ethanol and in ionic liquid butyl methyl imidazolium tetrafluroborate ([bmim]BF4). The newly developed protocol is operationally convenient, widely applicable, and gives excellent yields of the diversely substituted title compounds in high purity by easy workup. J. Heterocyclic Chem., (2011).

ChemInform Abstract: An Improved Method for the Preparation of 4,5‐Diaminochrysazin.

AbstractThe title method affords the title compound (V) in high purity and is suitable for scale‐up.

Stable isotopic characterization of ammonium metavanadate (NH4VO3)

This paper describes hydrogen ((2)H/(1)H), nitrogen ((15)N/(14)N), and oxygen ((18)O/(16)O) isotopic characterization of ammonium metavanadate (NH(4)VO(3)), a toxic industrial chemical (TIC). We analyzed nineteen high purity compounds obtained from nine suppliers, which show large ranges in trivariate stable isotope compositions, nearly 100-fold greater than analytical uncertainty. Covariation between δ(2)H and δ(15)N values indicates these ratios can be used to trace ammonia compounds, which are critical for the industrial purification of vanadyl ions and precipitation of ammonium metavanadate crystals. δ(2)H and δ(18)O plot far from the Meteoric Water Line (MWL), and suggest materials and industrial processing may lead to decoupling of H and O isotopes. We show how stable isotope characterization is a valuable forensic tool that discriminates between NH(4)VO(3) samples due to differences in source materials, modes of production, and facility location.

DOTA derivatives for site-specific biomolecule-modification via click chemistry: Synthesis and comparison of reaction characteristics

Due to the high stability of its complexes with many M 2+ and M 3+-ions, DOTA (1,4,7,10-tetraazacyclododecane- N, N′, N″, N‴-tetraacetic acid) is the most commonly used chelator for the derivatization and radiolabeling of bioactive molecules. Most of the currently used DOTA derivatives comprise amine-reactive functionalities, limiting their application to the derivatization of fully protected molecules or otherwise resulting in randomly distributed conjugation sites of undefined number. Click chemistry reactions are a valuable alternative to this unspecific conjugation as they proceed efficiently and chemoselectively under mild conditions allowing a site-specific derivatization of unprotected biomolecules. In this work, we describe straightforward syntheses of DOTA derivatives containing thiol, maleimide, aminooxy, aldehyde, alkyne, and azide functionalities, amenable to the currently most often used click chemistry reactions. Furthermore, the efficiency of the respective click reactions introducing DOTA into bioactive molecules was investigated. For each of the synthesized DOTA synthons, the site-specific and efficient conjugation to Tyr 3-octreotate could be shown. Among these, the addition and oxime formation reactions proceeded fast and without side reactions, giving the products in high yields of 64–83% after purification. The copper-catalyzed triazole formation reactions produced some side-products, giving the desired products in lower, but still reasonable overall yields of 19–25%. All synthesized peptide–DOTA-conjugates were labeled with 68Ga in high radiochemical yields of 96–99% and high specific activities providing compounds of high purity, demonstrating the applicability of all synthons for biomolecule modification and subsequent radiolabeling.

Synthesis of [13C5] and [carbonyl-14C]-5-chlorofuran-2-carboxylic acid

The inventory of labeled compounds and methods for their preparation are constantly growing, but still more building blocks of biologically relevant compounds need to be developed. Furans are frequently encountered in bioactive molecules, and a good synthesis of labeled furan is found in the literature. We required a relatively uncommon labeled furan, 5-chloro-2-furoic acid, for investigative work labeled with C-13 and C-14. Carboxylation of the lithium anion of [13C4]furan with 13CO2 followed by chlorination using benzyltrimethylammonium dichloroiodate provided the target compound in modest yield and high purity. The same procedure was then repeated with unlabeled furan and 14CO2 to give [carbonyl-14C]-5-chlorofuran-2-carboxylic acid. Copyright © 2010 John Wiley & Sons, Ltd.

Diversity-oriented synthesis of N-aryl- N-thiazolyl compounds

An efficient approach toward the parallel solid-phase synthesis of highly diversified N-aryl- N-thiazolyl compounds is presented. The treatment of resin-bound aniline derivatives with Fmoc-isothiocyanate generated aryl thioureas which, following Hantzsch’s reaction with a variety of α-haloketones and cleavage of the solid support, led to the desired N-aryl- N-thiazolyl compounds in good yield and high purity.

Resolving rotamers

A peptide-catalysed bromination provides access to an important class of chiral compounds in high enantiomeric purity.

Scalable Preparation of High Purity Rutin Fatty Acid Esters

AbstractInvestigations into expanded uses of modified flavonoids are often limited by the availability of these high purity compounds. As such, a simple, effective and relatively fast method for isolation of gram quantities of both long and medium chain fatty acid esters of rutin following scaled‐up biosynthesis reactions was established. Acylation reactions of rutin and palmitic or lauric acids were efficient in systems containing dried acetone and molecular sieves, yielding from 70–77% bioconversion after 96 h. Thereafter, high purity isolates (&gt;97%) were easily obtained in significant quantities following a two‐step solvent purification procedure whereby excess fatty acid substrate was first removed in a heptane/water (4:1, v/v) system, followed by selective ester extraction using an ethyl acetate/water system (1:6, v/v) at elevated temperature.

Stereoselective Chemoenzymatic Synthesis of Enantiopure 1‐(Heteroaryl)ethanamines by Lipase‐Catalysed Kinetic Resolutions

AbstractThe efficient chemical synthesis and enzymatic kinetic resolution of a family of 1‐(heteroaryl)ethanamines have been performed with lipases responsible for the preparation of nitrogenated compounds in high optical purity. Thus, Candida antarctica lipase type B has been identified as an excellent biocatalyst for the stereoselective production of the corresponding enantiomerically enriched (R)‐acetamides and (S)‐amines. A similar effect of the heteroatom in the cyclic ring has been observed in terms of reactivity and enantioselectivity, with benzoxazole, benzothiazole and benzimidazole derivatives being obtained with excellent enantiopurities after one day of reaction. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2009)

An international comparison of mass fraction purity assignment of theophylline: CCQM Pilot Study CCQM-P20.e (Theophylline)

Under the auspices of the Organic Analysis Working Group (OAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a laboratory comparison, CCQM-P20.e, was coordinated by the Bureau International de Poids et Mesures (BIPM) in 2006/2007. Nine national measurement institutes, two expert laboratories and the BIPM participated in the comparison. Participants were required to assign the mass fraction of theophylline present as the main component in two separate study samples (CCQM-P20.e.1 and CCQM-P20.e.2).CCQM-P20.e.1 consisted of a high-purity theophylline material obtained from a commercial supplier. CCQM-P20.e.2 consisted of theophylline to which known amounts of the related structure compounds theobromine and caffeine were added in a homogenous, gravimetrically controlled fashion. For the CCQM-P20.e.2 sample it was possible to estimate gravimetric reference values both for the main component and for the two spiked impurities.In addition to assigning the mass fraction content of theophylline for both materials, participants were requested but not obliged to provide mass fraction estimates for the minor components they identified in each sample.The results reported by the study participants for the mass fraction content of theophylline in both materials showed good levels of agreement both with each other and with the gravimetric reference value assigned to the CCQM-P20.e.2 material. There was also satisfactory agreement overall, albeit at higher levels of uncertainty, in the quantification data reported for the minor components present in both samples. In the few cases where a significant deviation was observed from the consensus values reported by the comparison participants or gravimetric reference values where these where available, they appeared to arise from the use of non-optimal chromatographic separation conditions.The results demonstrate the feasibility for laboratories to assign mass fraction content with associated absolute expanded uncertainties in the range 0.05% to 0.5% for solid organic compounds of high purity (mass fraction of main component >995 mg/g) and in the range 0.1% to 1% for compounds of lower purity (mass fraction of main component >980 mg/g).Main text.To reach the main text of this paper, click on Final Report.The final report has been peer-reviewed and approved for publication by the CCQM Working Group on Organic Analysis.

Thermodynamics of electrolyte solutions

The theoretical description of the thermodynamic properties of electrolyte solutions is of great importance for predictions and practical calculations related to the production of high-purity chemical compounds and materials with preset properties. In the present study, the general principles of the construction of electrolyte solution models are developed on the basis of the general statistical approach to the description of interactions in solutions. Let us consider dilute solutions (without loss of generality, aqueous solutions) containing N particles of the

Technological aspects of preparation of high-purity compounds for sol-gel and pyrolytic synthesis methods

A number of aspects associated with the synthesis of high-purity compounds used in the gas-phase and sol-gel methods for preparing coatings and finely dispersed powders of oxides and oxide composites are considered.

Magnetic Parameters of R2Fe14B Compounds with Nanograin Structure

High-purity compounds R2Fe14B (R = Y, Gd, Tb, Dy, Ho and Er) were prepared by arc melting using rare-earth metals purified by vacuum distillation-sublimation. The compounds R2Fe14B are single-phase and have well-defined directional structure. Nanocrystalline structure was formed by severe plastic deformation of the samples by means of torsion for 5 turns on the Bridgeman anvil under the pressure of 4 GPa at room temperature. The performed investigations of magnetic properties of these compounds allowed us to obtain reliable quantitative data on the intrinsic magnetic parameters, such as saturation magnetization, Curie temperature, the remanent magnetization and coercive force. The enhancement of the remanent magnetization was observed for R2Fe14B in nanocrystalline states compared with the crystalline samples due to the intercrystalline exchange interactions.