2-Carbethoxymethyl-4H-3,1-benzoxazin-4-one. 3. Condensation of o-phenylenediamive

Украинец, И. В.; Bezuglyi, P. A.; Treskach, V. I.; Туров, А. В.

doi:10.1007/bf00473945

Cited by 4 publications

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“…In the first two cases the reaction products unexpectedly proved to be 2-ethoxycarbonyl-(5) and the 2-carboxy- (6) anilides of 1H-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, and in the latter case the N,N'-di-2-carboxyanilide of malonic acid (7). The structures of the obtained compounds were confirmed by 1 H NMR and mass spectra, and also by a contrary synthesis, by amidation of 1H-3-ethoxycarbonyl-4-hydroxy-2-oxoquinoline (8) with ethyl anthranilate and anthranilic acid respectively or thermolysis of ethyl ester of 2-carboxymalonanilic acid (9 It is difficult to give an unequivocal explanation of the mechanism for these chemical processes.…”

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4-Hydroxy-2-quinolones. 112. Reaction of 2-ethoxycarbonylmethyl-4H-3,1-benzoxazin-4-one with active methylene compounds

Украинец

Сидоренко

Gorokhova

et al. 2007

Chem Heterocycl Compd

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Keywords: 4H-3,1-benzoxazin-4-one, 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, active methylene compounds.Under the action of active methylene compounds (acetoacetic, cyanoacetic, or malonic esters) in dry pyridine 2-substituted 4H-3,1-benzoxazin-4-ones (acylanthranils) usually recyclize into 2-R-4-oxo-3,4-dihydroquinoline-3-carboxylates [2]. Occasionally the reaction stops at the acyclic esters of 3-(2-acylaminophenyl)-3-oxopropionic acid [3].Proceeding from this, it seemed of interest to study the behavior of 2-ethoxycarbonylmethyl-4H-3,1-benzoxazin-4-one (1) under the described reaction conditions. Interest in such a family of investigations is caused, primarily, by the fact that the given acylanthranil itself contains an active methylene group, affording the possibility of the occurrence of more profound, occasionally unexpected, heterocyclizations [4][5][6][7].With the highly nucleophilic carbanion generated from malononitrile, benzoxazinone 1 reacts similarly with isatoic anhydride [8], i.e. the acylmalononitrile 2 formed initially is cyclized into the aminoquinolone 3. However, to isolate it was unsuccessful since under the conditions of the synthesis, boiling pyridine, the amino group is subject to intramolcular acylation with the formation of 1-hydroxy-3,6-dioxo-4,6-dihydro-3H-pyrimido[1,2-a]quinoline-5-carbonitrile (4).A completely different picture is observed on using acetoacetic, cyanoacetic, and malonic esters. In the first two cases the reaction products unexpectedly proved to be 2-ethoxycarbonyl-(5) and the 2-carboxy-(6) anilides of 1H-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, and in the latter case the N,N'-di-2-carboxyanilide of malonic acid (7). The structures of the obtained compounds were confirmed by 1 H NMR and mass spectra, and also by a contrary synthesis, by amidation of 1H-3-ethoxycarbonyl-4-hydroxy-2-oxoquinoline (8) with ethyl anthranilate and anthranilic acid respectively or thermolysis of ethyl ester of 2-carboxymalonanilic acid (9).

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“…Interest in such a family of investigations is caused, primarily, by the fact that the given acylanthranil itself contains an active methylene group, affording the possibility of the occurrence of more profound, occasionally unexpected, heterocyclizations [4][5][6][7].…”

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4-Hydroxy-2-quinolones. 112. Reaction of 2-ethoxycarbonylmethyl-4H-3,1-benzoxazin-4-one with active methylene compounds

Украинец

Сидоренко

Gorokhova

et al. 2007

Chem Heterocycl Compd

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“…This concerns the spectrum of the benzimidazol-2-ylamide 1k in which the signals for the H-4 and H-7 protons of the benzimidazole ring appear as a totally unresolved broadened multiplet of overall intensity 2H while the protons H-5 and H-6 show the usual, well resolved sextet with spin-spin coupling constant of 3.0 Hz, typical of benzimidazoles. The 1 H NMR spectra of the very closely structurally related 3-(benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinolines [8,9] do not show similar anomalies hence the only source of this observed effect has to be the carbamide group separating the quinolone and benzimidazole fragments. More precisely it is not this group but the whole 2-aminobenzimidazole fragment which is not overall a conventional amine (as reported in [10]) and in some respects resembles an imino derivative of benzimidazolone.…”

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confidence: 72%

4-hydroxy-2-quinolones. 153*. Synthesis of hetarylamides of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Украинец

Bereznyakova

Паршиков

2009

Chem Heterocycl Comp

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Keywords: 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, amidation, intramolecular cyclization.We have previously proposed the preparation of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamides and this has been introduced satisfactorily into the synthesis of N-alkyl-[2], arylalkyl- [3], and aryl-[4] substituted derivatives. There are differences in some details of carrying out the experiment but a common feature is shared, i.e. all are based on the initial separation of the corresponding quinoline-3-carboxylic acid. In most cases such a course was justified even though the method of activating the carbonyl carbon atom of the carboxyl group in the starting quinoline-3-carboxylic acid has to be modified each time based on the properties of the starting amine.One of the reported methods can evidently also be used for synthesis of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid hetarylamides 1. It should immediately be noted, however, that when 2-oxo-1,2-dihydroquinoline-3-carboxylic acid chlorides react with azahetarylamines they frequently form stable N-acylhetarylamine salts rather than the amides [5]. For this reason we have not studied the "acid chloride" variant in this work. The use here of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid imidazolide (2) as the acylating agent appears more promising and, in fact, shows fully satisfactory results (method A, Table 1). None the less it has been noted before [4] that the imidazolide 2 is unusually unreactive and thus needs the use of high boiling solvents and in some cases has led to serious complications. Hence, for example, with acylation of the thermally unstable 2-amino-5-isobutyl-1,3,4-thiadiazole under these conditions the corresponding hetarylamide 1n could be obtained, but due to the low reaction rate it proved to be so strongly charged with gray-brown colored degradation products of the free amine that purification of the final product proved impossible even

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“…The initial method involved the reaction of anthranilic acid esters ( 6a and 6b ) with methyl malonyl chloride. The products ( 7a and 7b ) were then condensed with phenylenediamine at elevated temperatures in the absence of solvent − to yield the 4-hydroxy-3-benzimidazol-2-ylhydroquinolin-2-ones ( 8a and 8b ) in low to moderate yields (Scheme , a). The synthesis of 8c started from anthranilonitrile and used the same conditions as for the preparation of 8a and 8b to yield the 4- amino -3-benzimidazol-2-ylhydroquinolin-2-one 8c in poor yield (Scheme , a).…”

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Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

Renhowe¹,

Pecchi²,

Shafer³

et al. 2008

J. Med. Chem.

129

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The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

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2-Carbethoxymethyl-4H-3,1-benzoxazin-4-one. 3. Condensation of o-phenylenediamive

Cited by 4 publications

References 3 publications

4-Hydroxy-2-quinolones. 112. Reaction of 2-ethoxycarbonylmethyl-4H-3,1-benzoxazin-4-one with active methylene compounds

4-Hydroxy-2-quinolones. 112. Reaction of 2-ethoxycarbonylmethyl-4H-3,1-benzoxazin-4-one with active methylene compounds

4-hydroxy-2-quinolones. 153*. Synthesis of hetarylamides of 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Design, Structure−Activity Relationships and in Vivo Characterization of 4-Amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A Novel Class of Receptor Tyrosine Kinase Inhibitors

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