4-hydroxy-2-quinolones. 22.* Synthesis and biological properties of 1-alkyl(aryl)-2-oxo-3-carbethoxy-4-hydroxyquinolines and their derivatives

Gorokhova

et al. 2006

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Keywords: 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, cyanoacetic ester, 4-chloroquinoline, amidation, hydrolysis, decarboxylation, X-ray structural analysis.In organic chemistry the method of forming new carbon-carbon bonds based on the ability of carbanions, obtained from active methylene compounds, to react readily by substitution with alkylating agents and other reactive halogen-containing substances, has been known for a long time and is widely used for preparative purposes. Hydrolysis of the substituted malonic, cyanoacetic, or acetoacetic esters synthesized in such a way, gives the corresponding acids, distinguished by an inclination to decarboxylate on heating. The whole chain of conversions based on these reactions in fact represents a simple and effective means of substituting halogen in a molecule by CH 2 COOH or CH 2 COR [2].We noted previously the ease of forming 4-alkyl(or aryl)amino-substituted 3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolines on interacting the ethyl ester of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (1) with alkylamines [3], or anilines [4]. This circumstance permits the suggestion that the 4-chloro-substituted ester 1 also possesses adequate reactivity for reaction with C-nucleophiles, such as the carbanion generated in the presence of bases from cyanoacetic ester.As experiments carried out by us showed this reaction is indeed feasible and the ethyl ester of 4-(cyanoethoxycarbonylmethyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2) is formed in the system DMF/K 2 CO 3 without any difficulty. Theoretically subsequent alkaline hydrolysis must lead to 2-(3-carboxy-2-oxo-1,2-dihydroquinolin-4-yl)malonic acid (3) which, in its turn, on thermal decarboxylation must form 4-carboxymethyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (4). However, according to data of chromatomass spectrometry, the product of hydrolysis of ester 2 unexpectedly proved to be not the substituted malonic acid 3 but a pure compound with molecular mass 203 units. The 1 H NMR spectrum shows the presence in the sample being investigated of COOH and NH groups (broadened singlets at low field), a quinoline nucleus (four signals with typical multiplicity in the aromatic region), and a C-methyl group (singlet of intensity 3H at _______ * For Part 95 see [1]. __________________________________________________________________________________________

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confidence: 93%

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confidence: 93%

4-hydroxy-2-quinolones. 96. Synthesis and properties of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Gorokhova

et al. 2006

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“…We have used the same principle as in obtaining 4-hydroxyquinolones-2, i.e., the acylation of amino esters with ethoxymalonyl chloride with subsequent closing of the ring under Dieckman reaction conditions. It is known [10] that N-acylanthranilates unambiguously form 3-ethoxycarbonyl-4-hydroxyquinolones -2 under these conditions. However after acylation of ethyl aminocrotonates 1 the cyclization of the diesters 2 is theoretically possible by two routes since both carbonyl and active methylene groups are present in both the malonyl and crotonyl fragments.…”

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confidence: 98%

“…The substituent at N (1) is in the ap-conformation and is rotated practically perpendicular relative to the mean-square plane of the ring (torsion angles C (1) -N (1) -C (7) -C (8) 84.9(2)° and N (1) -C (7) -C (8) -C (9) 180.0(2)°). Conjugation between the π-systems of the pyridine ring and the ester group is considerably decreased as a result of rotation of the latter about the C (4) -C (10) [12].…”

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confidence: 99%

4-Hydroxyquinolones-2. 91. Synthesis and properties of ethyl 1-R-4-hydroxy-6-methyl-2-oxo-dihydropyridine-5-carboxylates

Gorokhova

et al. 2006

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The reaction of ethyl aminocrotonates with derivatives of malonic acid is a suitable method for the preparation of ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-5-carboxylates. One of the synthesized materials has been studied by X-ray crystallography.Keywords: 4-hydroxy-2-oxopyridinecarboxylic acids, 1,2-dihydropyridin-2-ones, ethyl 3-aminocrotonic acids, X-ray crystallography.6-Alkyl-substituted 1,2-dihydropyridin-2-ones are used in medicine as selective inhibitors of phosphodiesterases [2,3] and AMPA-receptors* 2 [4]. Highly effective vasodilators [5], anticoagulants [6], fungicides [7], and anti-HIV agents [8] have been created based on them. To obtain these compounds a three component condensation of the corresponding ketone, a dimethyl acetal of DMF or ethyl formate, and a substituted amide of acetic acid is normally required. The ketone determines the nature of the substituents at positions 5 and 6 of the ring formed, the substituted formic acid is the source of C (4) , and the substituted acetamide forms the N (1) -CO-C (3) -R unit of the dihydropyridine ring. In some cases an alternative route -the reaction of pyran-2-ones with amines -is used [9].In a continuation of our study of the physicochemical and biological properties of 4-hydroxyquinolones-2, we have connected reports of molecular systems similar to ours -1-R-4-hydroxy-2-oxo-1,2-dihydropyridine. We have used the same principle as in obtaining 4-hydroxyquinolones-2, i.e., the acylation of amino esters with ethoxymalonyl chloride with subsequent closing of the ring under Dieckman reaction conditions. It is known [10] that N-acylanthranilates unambiguously form 3-ethoxycarbonyl-4-hydroxyquinolones -2 under these conditions. However after acylation of ethyl aminocrotonates 1 the cyclization of the diesters 2 is theoretically possible by two routes since both carbonyl and active methylene groups are present in both the malonyl and crotonyl fragments. Consequently the end products of the reaction studied may be ethyl 4-hydroxy-6-methyl-2-oxo-1-propyl-1,2-dihydropyridine-3-carboxylate (3) or the isomeric ethyl 4-hydroxy-6-methyl-2-oxo-1-propyl-1,2-dihydropyridine-5-carboxylate (4). Unfortunately neither 1 H NMR spectroscopy nor chromatomass spectrometry permitted an unambiguous conclusion on the structure of this substance. Nevertheless a failure to prepare the benzamide 5 under normal conditions suggested that the ester produced is a _______ * For part 90, see [1]. * 2 AMPA -α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. __________________________________________________________________________________________

“…It should be noted that in the cases of the anilides 1f-i and the 4-bromo analogs 2f-i the substances with N-isoalkyl chains were somewhat more active that those with a normal chain structure. (3) was prepared as in the reported method [21].…”

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confidence: 99%

4-hydroxy-2-quinolones. 110. Bromination of 1-r-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides

Ткач

et al. 2006

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1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides have been prepared. It has been shown experimentally that these compounds are brominated by molecular bromine in glacial acetic acid at position 4 of the anilide fragment. The antitubercular properties of the compounds synthesized are discussed.Keywords: 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid amides, bromination, X-ray analysis, antitubercular activity.1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides possess a broad spectrum of biological activity. They include substances with antithyroid [2], antitubercular [3,4], analgesic, antiinflammatory [5], and antioxidant properties [6]. In medicine, the antineoplastic linomide (roquinimex, 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid N-methylanilide [7]) is used. Many investigation of the modification of the structure of this medicinal compound have revealed potential compounds with antinephritic [8] and anti-angiogenic [9, 10] properties in a given series as well as novel synthetic immunomodulators [11].In this report we continue our work studying the physicochemical and biological properties of 4-hydroxyquinol-2-ones and have investigated 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid anilides 1 and their 4-bromo-substituted analogs 2. The target compounds (Tables 1-3) were prepared by amidation of the ethyl esters 3 with aniline and 4-bromoaniline respectively according to a previously developed method [12].It is known that 3-alkyl-, 3-phenyl-, and 3-alkoxycarbonyl-substituted 4-hydroxy-2-oxo-1,2-dihydroquinolines (including N-phenyl) are brominated by molecular bromine in glacial acetic acid at position 3 to give 3-bromo-3-R-2,4-dioxo-1,2,3,4-tetrahydroquinolines [13,14].However, we later showed that with completely anhydrous solvents and reagents the indicated reaction occurs differently with electrophilic attack exclusively at position 6 of the quinolone [15]. With the anilides 1 a still further possible center for halogenation occurs (the phenylamide ring).