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Svechnikova

et al. 2007

Chem Heterocycl Comp

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The high reactivity of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates is governed by the simultaneous presence of the 4-OH and 2-C=O groups in the pyridine part of the molecule.Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates are known to be quite powerful acylating agents. They readily react with primary and many secondary aliphatic, aromatic, and heterocyclic amines to form the corresponding amides in high yields [2][3][4][5]. The almost unlimited potential for modification of the quinolone and amide parts of the molecule allows a targeted change to the physicochemical and hence biological properties of the indicated compounds. This has led to increased interest from the viewpoint of chemists and pharmacologists engaged in a search for novel biologically active compounds based on them and which can give rise to medicinal compounds with improved properties There is also interest in the theoretical question regarding the reason for the high reactivity of the ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates which are key in such investigations because the reason remains unclear. Our report attempts to answer the question.The first step in our investigation was a comparative analysis of the steric structural features of the simplest member of the homologous series, i.e. ester 1 and of the isomers 4-ethoxycarbonyl-3-hydroxy-2-oxo-1,2-dihydroquinoline (2) and 3-ethoxycarbonyl-4-hydroxy-1-oxo-1,2-dihydroisoquinoline (3) stable to amidation. With this aim, all three esters were studied by X-ray structural analysis. Hence in the case of the isoquinoline derivative 3 it was found that the heterocyclic fragment is planar to within 0.022 Å (see Fig.

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confidence: 99%

4-Hydroxy-2-quinolones 130. The reactivity of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates

Svechnikova

et al. 2007

Chem Heterocycl Comp

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“…With benzylamine a similar reaction occurs under comparatively mild conditions (180°C), but leads only to 4-benzylaminoquinolone and only subsequent catalytic hydrogenation gives 4-amino derivatives [9]. It is evident that the methods given are unsuitable for obtaining amino esters 1 because of the thermal instability of the initial 4-hydroxy derivatives 7 [10] in the first case, and the high reactivity of their ester groupings [11] in the second, and consequently were not considered by us. It is more preferred to convert the 4-hydroxy esters 7 into chloro derivatives 8, the synthesis of which is also possible by alkylating 1H-4-chloro-2-oxoquinolines 9 [12].…”

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confidence: 99%

4-Hydroxyquinol-2-ones. 86. Synthesis of Methyl (Ethyl) Esters of 1-Substituted 4-Amino-2-oxoquinoline-3-carboxylic Acids

Gorokhova

2005

Chem Heterocycl Compd

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Esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic acids 1 are of interest as potentially biologically active substances and also as a basis for further chemical conversions with an adequately broad synthetic potential.The usual method of obtaining compounds of this family comprises acylation of anthranilonitrile 2 with the acid chloride of an appropriate acid, containing a fairly reactive methylene group, with subsequent closure of the 4-aminoquinoline ring under the action of basic catalysts [2,3]. This method gives good results in the synthesis of 3-alkoxycarbonyl-1H-4-amino-2-oxoquinolines 3 [4] and, in principle, may be used for obtaining 1-N-alkyl derivatives 1 (Scheme 1, method A). Regretably alkylation of anthranilonitrile 2 does not occur quantitatively and the N-alkyl derivatives obtained always contain contamination by the starting material, effective elimination of which is only possible by chromatography (especially in the case of the lower N-alkyl substituents). Using the available N-alkylanthranilic acids in the synthesis of anthranilonitriles 4 [5] may exclude chromatographic purification, but such a modification introduces several additional stages, esterification, amidation in an autoclave, dehydration of the amide, and removal of the N-protecting group [2,3], which is not always justified by far.A second possible variant for obtaining esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic acids 1 is the alkylation of the previously isolated 1H-derivatives 3 (method B). As a result of lactam-lactim, enamine-imine, and keto-enol tautomerism for esters 3 it is possible that five tautomeric forms exist (Scheme 2), in which both nitrogen atoms, the oxygen of the 2-C=O group, or the carbon atom at position 3 of the quinoline ring may potentially be nucleophilic centers.We noted previously [4] that the properties of the 4-amino group in esters 3, judging by the chemical shift of its protons in the 1 H NMR spectrum (8.3 ppm), are far closer to an amide than to a normal amine (for example, for anilines the mean value is ~4 ppm [6]). It is also known that in 1H-4-amino-2-oxo-3-phenylquinolines alkylation of the 4-amino group (chemical shift 5.9 ppm) is successfully effected only in the _______ * For Part 85 see [1].

“…It is interesting that under analogous conditions esters of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids behave differently. They are practically quantitatively condensed into 5,9-di-R-6,7,8-trioxodiquinolino[3,4-b;3',4'-e]-4H-pyranes [9].…”

Section: _______mentioning

confidence: 99%

4-hydroxy-2-quinolones. 95. Synthesis, structure, and antitubercular properties of hetarylamides of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid

Kolesnik

et al. 2006

Chem Heterocycl Compd

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More recently tuberculosis was considered to be an illness already finally conquered, but today it has become the most widespread infectious disease in the world. The reason for the position established now is concealed in the reduction of the set of antitubercular measures in the majority of developing and economically highly developed countries. As a result tuberculosis has emerged from being under control and at the beginning of the nineties of the last century approached a crisis point, in place of an annual fall in morbidity an impetuous deterioration in the epidemiological situation began [2,3]. In addition, seriously complicating the problem, the ability of Mycobacterium tuberculosis to mutate actively, has given it the possibility of producing resistance (frequently multiple) against many well-known antitubercular preparations. As a result there are now in the world several million people for whom classical medical treatment is no help. In connection with this the search for new medicinal agents with antimycobacterial action is a problem of paramount importance in contemporary international public health.Of undoubted interest in this project are anilides [4], hetarylamides [5][6][7], and hydrazides [8] of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, which show, in experiments in vitro, high activity in relation not only to Mycobacterium tuberculosis, but also to inducers of nontubercular mycobacterial disease, the Mycobacterium avium complex. With the aim of clarifying the rules of the chemical structureantitubercular action in the series of compounds being studied we have effected the synthesis and carried out microbiological screening of hydrogenated analogs of the compounds described previously and of the hetarylamides of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acids 1a-u.