Vol. 13 No. 2(50) (2015)
Published:
2015-06-10
Full Issue
Original Researches
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Heterocyclization of amides of alkenylcarboxylic acids
The latest published data on heterocyclization of amides of alkenylcarboxylic acids have been systematized. It has been proven that the electrophilic intramolecular cyclization reaction of functionally substituted olefins opened in the 70s of the last century is a convenient way of constructing different oxygen-, nitrogen- and sulfurcontaining heterocyclic compounds. It has been noted that anilides of unsaturated carboxylic acids as bifunctional nucleophilic systems containing alkenyl and aminocarbonyl functions are useful models to study the electrophilic cyclization reaction, which leads to formation of O- and N-containing heterocycles (lactones and lactams). The last of them belong to the important types of compounds used as key blocks in the synthesis of biologically ctive alkaloids and their analogues, pharmaceutical and agrochemical products. The effective approaches to the synthesis of new types of functionalized lactones and lactams have been developed; amides of 3-butenoic, 4-pentenoic and 5-hexenoic acids are often used as substrates for their design. Along with classical methods of synthesis of lactones and lactams the literary sources relating to the use of original catalytic electrophilic systems (Nolan, Grubbs, Hoveyda), the metathesis reaction and radical processes in regio- and stereoselective cyclization of amides under mild conditions have been analyzed and summarized in the article. The synthetic versions considered are general in nature and allow to perform the targeted functionalization of O-, N-, S-containing heterocyclic small and medium-sized systems along with the cyclization processes.
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Synthesis and alkylation of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-ones
The one-step method for preparation of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-ones by interaction of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid with ortho-pnenylediamines using 1,1’-carbonyldiimidazole as a coupling-reagent has been developed. The procedure proposed allows to obtain easily the target products using common reagents and solvents; and it also requires the simple isolation methods. The selectivity of 6-(1H-benzimidazol-2-yl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one interaction with benzyl chlorides in DMF – K2CO3 conditions has been studied using the NOESY spectroscopic method and alternative synthetic approaches; it has been determined that the reaction occurs at position 3 of the thieno[2,3-d] pyrimidine system. The study of the antimicrobial activity by the agar diffusion method for the compounds obtained has shown that 6-(1H-benzimidazol-2-yl)-3-benzyl-5-methylthieno[2,3-d]pyrimidin-4(3H)-ones reveal the antimicrobial activity against the strains of Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa; while the compound with unsubstituted position 3 appeared to be inactive against these strains of microorganisms. However, this compound exhibited the higher inhibitory activity against the Candida albicans fungi.
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Polymorphism and the analgesic activity of N-(3-pyridylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide
The advanced study of the analgesic activity of N-(3-pyridylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide selected by the results of the primary pharmacological screening as the leading structure has revealed a significant change in anesthetic properties in different samples of this compound. Since the substance under study was not soluble in water, and animals received it orally as a thin aqueous suspension, the most likely cause of the effect observed was thought to be the changes in the crystalline structure of N-(3-pyridylmethyl)-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide occurring in it under the influence of external factors. This assumption has been fully confirmed by the thorough microscopic investigation of righ – and low-active samples, as well as more objective data, the methods of powder and single crystal X-ray diffraction analysis. Thus, in particular, it has been found that with all the variety of crystalline and amorphous forms included in the samples studied their qualitative composition appeared to be quite similar. At the same time the quantitative content of some of the phases varies greatly, and obviously, it was the factor determining the size of the analgesic effect.
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Synthesis and N-alkylation of diethyl 4,7-dihydroazolo[1,5-a]pyrimidin-5,6-dicarboxylates
It has been shown that the ternary condensation of oxaloacetic ester (diethyl 2-oxosuccinate), aromatic aldehydes and 3-amino-1,2,4-triazole or 5-aminotetrazole in dimethylformamide results in formation of the corresponding diethyl 7-aryl-4,7-dihydroazolo[1,5-a]pyrimidin-5,6-dicarboxylates. By 1H NMR spectroscopy (according to the data of the chemical shifts of C(2)H-protons for the corresponding N(4)H- and N(4)-methylderivatives of 7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5,6-dicarboxylate) it has been found that alkylation of 4,7-dihydro[1,2,4]azolo[1,5-a]pyrimidin-5,6-dicarboxylates in the acetonitrile–saturated water alkali system leads selectively to formation of N(4)-alkyl derivatives. Both the starting compounds obtained and their N(4)-methylsubstituted analogues together with relative diethyl 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5,6-dicarboxylates, 6-unsubstituted 4-aryl-3,4-dihydropyrimidin-2(1H)-on-5-dicarboxylates and the derivatives of 6-COR-7-aryl-4,7-dihydro[1,2,4] triazolo[1,5-a]pyrimidines are the promising objects for studying benzyl C(7)-functionalization of 4,7-dihydroazolo 1,5-a]pyrimidines, as well as of reactions associated with the presence of double C=C-bonds activated by two electron withdrawing groups. Obtaining of the key N(4)H- and N(4)Me-derivatives of 7-phenyl-4,7-dihydro[1,2,4] triazolo- and tetrazolo[1,5-a]pyrimidin-5,6-dicarboxylates also opens the way to the research of biological properties of the compounds of this class. It is noteworthy that being a three-component one the reaction studied, without any doubts, are appropriate for the synthesis of the derivatives of 7-aryl-4,7-dihydro[1,2,4]triazolo- and tetrazolo[1,5-a]pyrimidines containing two electron withdrawing substituents in positions 5 and 6.
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Multicomponent synthesis of substituted N-aryl-4-aryl(3-pyridinyl-5-cyano)-6-(3,4-dihydroxybenzoylmethylsulphanyl)-2-methylnicotinamides, 6-allyl(carbamoylmethyl)sulphanyl-N-(4-chlorophenyl)-3-cyano-4-hetaryl-2-methyl-1,4-dihydronicotinamides and their antiradical and membrane-stabilizations properties
The multicomponent condensation of aromatic aldehydes, acetoacetanilides, cyanothioacetamide, alkylating agents and morpholine in ethanol at 20°C was first synthesized to formation of substituted 4-aryl-N-aryl(3-pyridinyl)-5-cyano-6-(3,4-dihydroxybenzoylmethylsulphanyl)-2-methylnicotinamides, 6-allylsulphanyl-N-(4-chlorophenyl)-5-cyano-2-methyl-4-(3-pyridinyl)-1,4-dihydronicotinamide and 6-carbamoylmethylsulphanyl-N-(4-chlorophenyl)- 5-cyano-2-methyl-4-(4-pyridinyl)-1,4-dihydronicotinamide. In the first step Knoevenagel reaction produces the alkene which is then reacted with a Michael anilide acetoacetate to form the corresponding adduct. Last reaction conditions chemoselectively intramolecularly cyclized to substituted morpholinium tetrahydropyridinthiolate. Elimination of the water the latter leads to the formation of salt, the arises capable aromatization and alkylation of 3,4-dihydroxyphenacylbromide. Introduction this condensation as alkylating reagent allylbromide or α-chloroacetamide ends form the corresponding 1,4-dihydronicotinamide. The structure of the synthesized compounds was proved by IR-, 1H NMR- and chromatommas-spectrometry. Synthesized substances tested for anti-radical and membrane-stabilizing action. Revealed their high antiradical activity at a concentration of 10-1-10-3 mol/L compared with nicotinamide.
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Phosphonomethylated derivatives of dinitroanilines
A number of dinitroanilines derivatives previously unknown has been synthesized. The alkylamino groups and aminomethylphosphonic groups have been introduced as acids and esters in their structure. The synthesis has been carried out by Kabachnik-Fields reaction and its modification – Moedritzer-Irani reaction, in which formaldehyde and phosphonic acids are used in a highly acidic medium. However, we have not found any other examples of successful application of this reaction to aniline derivatives in the literature. Thus, the possibility to use Moedritzer-Irani reaction to dinitrosubstituted anilines has been found. Obviously, the fact that two nitrogroups reactivate the aromatic ring of aniline is enough to fully avoid adverse polymerization associated with the interaction of formaldehyde with the benzene ring in this case. This polymerization makes it impossible to use Moedritzer-Irani reaction for other compounds with the aniline moiety. Benzylaminophosphonic acids esters have been also synthesized based on dialkyl phosphites and Schiff bases using Kabachnik-Fields reaction with subsequent hydrolyzation to the acids. The required aminosubstituted dinitroanilines with aliphatic aminogroups have been synthesized by the reaction of aliphatic diamines with dinitrochlorbenzenes. The structure of the compounds obtained has been confirmed by the methods of 1H and 31P NMR spectroscopy and elemental analysis. As a result, the application of Moedritzer-Irani reaction has been expanded, and due to it aminomethylphosphonic acids that are previously unknown and structurally similar to the known herbicides have been synthesized.
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Screening of the antiviral activity in the range of C5 and N3 substituted 4-thiazolidinone derivatives
Prospects for the search of antiviral agents among 4-thiazolidinone derivatives, as well as the optimal directions of the main core structure optimization – namely C5 and N3, have been described. As the result of the screening performed (within the Antimicrobial Acquisition and Coordinating Facility programme), the values of the antiviral activity of the target 5-substituted-4-thiazolidinones with the carboxylic group (or its derivatives) in the N3 residue on relation to a wide range of the viral panels have been determined. The active compounds, which can be regarded as promising structures in the anti-flu agent design, have been identified, as well as 3-{5-[2-chloro-3-(4-nitrophenyl)-allylidene]-4-oxo-2-thioxothiazolidine-3-yl}-propionic (1) and –succinic acids (3) have been identified has hit-compounds with a marked anti-VZV activity (SI values – 27 and 38, respectively).
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Development of the quantitative determination method of the active ingredients in Altabor substance
The method of quantitative determination of active ingredients in Altabor substance based on absorption of the ellagitannin complex by ions of iron (II) has been developed. The linear characteristics of the method developed have been identified. The linear dependence of absorbance of the ellagitannin complex of Altabor with ions of iron (II) on the concentration of Altabor has been proven. The accuracy of ellagitannin determination in Altabor substance has been studied. It has been found that the method proposed is characterized by acceptable accuracy and can be used to quantify the active ingredients in Altabor substance.
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Development of the methods for identification and quantitative determination of Epifine – a new perspective anticonvulsant
According to the results of the pharmacological testing the substance of 4-methoxy-3-chloroanilide 1-(3’-fluorophenyl)-5-methyl-1,2,3-triazole (1H)-4-carboxylic acid has shown a pronounced anticonvulsant activity that exceeds the level of the reference drug – Depakine. It is recommended for further profound studies under conditional name Epifine. Development of methods for the quality control of a substance occupies an important place among the stages of drug introduction.For preparation of the substance to introduction we have developed the methods for identification and quantitative determination of the promising substance Epifine. Standardization has been performed in accordance with the existing requirements for development of modern methods for analysis of pharmaceutical substances possessing the pharmacopoeial quality. For identification a set of physical, physicochemical (NMR 1H, IR and UV spectroscopy) and chemical methods has been proposed. The physical and chemical properties of Epifine have been investigated, and the intervals of melting point and solubility in different solvents have been determined. As expected, in the IR spectrum the characteristic absorption bands confirming the presence of aromatic rings, in particular benzene and triazole, carbonyl groups (amide-1, amide-2), substituted amino group, methyl and methoxy groups, were observed. We have also proposed the chemical methods of identification of this compound conditioned by the presence of the anilide residue, the triazole ring, and covalently bound halogens. The non-aqueous acid-base titration has been developed for the quantitative analysis of Epifine.
