Quinoxaline-2-carboxylic acids

Isopropylidene 2-quinoxalinylaminomethylenemalonate was treated in methylene chloride with polyphosphoric acid at 60°C to give pyrimido[l, 2-a]quinoxaline-2-carboxylic acid (1201) in 97% yield (83EUP86723). 

Rapid and sensitive HPLC methods were developed for the detection of an antimicrobial growth promoter and its main metabolites containing quinoxaline-2-carboxylic acid <2005MI1495>. The major phenazine pigments of Pseudomonas aeruginosa such as 1-hydroxyphenazine and phenazine-l-carboxylic acid <1997JCH(A)(771)99>, and 2-aminophenazine as an impurity in a bactericide <1999MI632>, were also analyzed by HPLC methods. 

In swine, carbadox is metabolized rapidly to quinoxaline-2-carboxylic acid, with the intermediary formation of the aldehyde and the desoxy metabolite of the parent compound. Metabolism studies with radiolabeled carbadox showed that the parent compound and its three metabolites are present in plasma within hours after drug administration, but all four compounds can disappear within 24 h postdosing. The major urinary metabolite was shown to be the quinoxaline-2 -carboxylic acid, which was also excreted in the conjugated form. A -oxides were not found in urine. Feces also contained some quinoxaline-2-carboxylic acid but no unchanged carbadox (14). 

Quinoxaline-1,4-dioxides are synthetic antimicrobial agents the best-known members are carbadox and olaquindox. Both compounds are rapidly metabolized to monoxy- and desoxy- compounds. The final product from carbadox and the one most often determined, mainly in liver (target tissue), is quinoxaline-2-carboxylic acid. Carbadox and olaquindox are light-sensitive compounds and sample manipulations should be performed only under the minimum of indirect incandescent illumination. Carbadox and desoxycarbadox are insoluble in water but are soluble in chloroform and methanol, while olaquindox is slightly soluble in water and some organic solvents. The solubility, however, of quinoxaline-2-carboxylic acid can be easily monitored by adjusting the pH because it is a strong carboxylic acid (pK 2.88). 

After hydrolyzate acidification with hydrochloric acid at pH values lower than 1, quinoxaline-2-carboxylic acid is quantitatively extracted into ethyl acetate, chloroform, or dichloromethane, since at these strongly acidic conditions the ionization of their carboxylate moiety is suppressed (pK, 2.88), and then back-extracted into aqueous buffered solutions at pH 6.0 or higher. These liquid-liquid partitioning procedures isolate quinoxaline-2-carboxylic acid from a complex mixture of tissue hydrolysates, and provide an aqueous extract suitable for further purification by solid-phase extraction. This has been accomplished either with the strong cation-exchange resin AG MP-50 (419, 420) or with a polar silica column (422). 

Following extraction/cleanup, quinoxaline-2-carboxylic acid can be detected by electron capture, or mass spectrometric techniques, after gas chromatographic separation on capillary or conventional columns. A prerequisite of quin-oxaline-2-carboxylic acid analysis by gas chromatography is the derivatization of the molecule by means of esterification. Esterification has been accomplished with methanol (419, 420, 422), ethanol (421), or propanol (423) under sulfuric acid catalysis. Further purification of the alkyl ester derivative with solid-phase extraction on a silica gel column (422), thin-layer chromatography on silica gel plate (420), or liquid chromatography on Hypersil-ODS, 3 m, column (423), has been reported. 

Quinoxaline-2-carboxylic acid with thionyl chloride gives the acid chloride (79%), which undergoes the expected reactions.166 The gas-phase pyrolysis of quinoxaline-2,3-dicarboxylic anhydride (157) over a Nichrome coil gives o-phthalonitrile (158) (72%), probably via 2,3-quinoxalyne (159) which ring-cleaves, and the diisocyanide subsequently rearranges thermally to the dinitrile.167... 

Quinoxalinecarboxaldehydes on treatment with 60% ethanolic potassium cyanide yield quinoxaloins, which are thought to exist in the hydrogen-bonded tautomeric form 163. Aerial oxidation of quinoxaloin gives quinoxalil, and oxidation with concentrated nitric acid yields quinoxaline-2-carboxylic acid.170... 

The acid strengths of the quinoxaline monocarboxylic acids can be correlated with the electron densities at the carbon atoms attached to the carboxyl group. Quinoxaline 2-carboxylic acid has a pAa of 2.88, compared with 4.03 and 3.64 for the 5- and 6-carboxylic acids. The calculated 7r-electron densities at C-2, C-5 and C-6 in the parent heterocycle are 0.866, 0.938, and 0.933, and thus the carboxyl group attached to C-2, the ring carbon that carries least electronic charge, is the most easily ionized.246... 

Oxidation of 9-hydroxy-5,6-dihydro-8//-pyrido[l,2-a]quinoxalin-8-one with KMn04 in H20 gave quinoxaline-2-carboxylic acid (75MI1). 

Quinoxaline 1,4-dioxides possess antibacterial activity, " as well as being fungicides, insecticides, and herbicides. Quinoxaline-2-carboxylic acid 1,4-dioxide has been isolated from cultures of Sireplomyces ambrofaciens and this compound has been shown to have antibiotic properties. Echinomycin, from the quinoxaline-peptide antibiotic family, contains one or more quinoxaline rings and is an antitumor agent. Quinoxaline derivatives are also antagonists at the jV-methyl-D-aspartate (NMDA) receptor of the glycine modulatory site. Poly(phenylquinoxalines) are used as high temperature polymers. 

Substituted quinoxaline-2-carboxylic acids can be prepared by reaction of benzene-1,2-diamines with oxopropanedioic acid or with its monocthyl or diethyl ester.The synthesis of quinoxalinccarboxamides has been achieved by condensation reactions involving a,/l-dioxo-carboxamides. The reaction is limited to the oxo carbonyl groups because of the reduced reactivity of the amide carbonyl function. 

Quinoxaline-2-carboxylic acids readily undergo decarboxylation. 3-Chloroquinoxaline-2-carb-oxylic acid undergoes decarboxylation at relatively high temperatures to give 2-chloroquinox-aline. ... 

Dccarboxylative chlorination can be achieved by photolysis of the benzophenone oxime ester of quinoxaline-2-carboxylic acid in carbon tetrachloride in 74% yield. 

Quinoxaline mono-iV-oxides result from the partial reduction of the di-N-oxides. Among reagents that have been used for this purpose are hydrogen and a metal catalyst, phosphorus trichloride, and sodium dithionite. Thus 2-methylquinoxaline 1-oxide has been prepared by partial hydrogenation of the di-JV-oxide quinoxaline-2-carboxyanilide 1-oxide has been prepared from the partial deoxygenation of the 1,4-dioxide with phosphorus trichloride and quinoxaline-2-carboxylic acid... 

Quinoxaline Antibiotics Containing Quinoxaline-2-carboxylic Acid Residues. 148... 

The earlier literature on quinoxaline-2-carboxylic acids and quinoxaline-2,3-dicarboxylic acids has been reviewed in Simpson s monograph. ... 

Most preparations of quinoxaline-2-carboxylic acids and their derivatives are based on the reaction of an o-phenylenediamine with a suitable... 

Quinoxaline-2-carboxylic acids substituted in the 3-position have been widely prepared by reaction of an o-phenylenediamine with mesoxalic acid or its diethyl ester. Mesoxalic acid ester condensation proceeds as shown in Scheme 1. The resulting quinoxalinone carboxylate can be... 

The 2-hydroxy-3-oxo-2,3-dihydrofuran 5 reacts with o-phenylene-diamine to give the quinoxaline-2-carboxylic acid ester 7. In this case the reaction may be envisaged as proceeding through the ring-opened tautomer (6) of the dihydrofuran/... 

The ready availability of alloxazines from reaction of 0-phenylenediamine hydrochlorides and alloxan makes them attractive starting materials for the preparation of quinoxaline-2-carboxylic acids. When the pyrimidine ring of the alloxazine is cleaved with ammonia, a 3-... 

Methylquinoxalines are converted into the corresponding carboxylic acids by condensation with an aromatic aldehyde and oxidation of the resulting styryl derivative with potassium permanganate. Quinoxaline-2-carboxylic acids are also conveniently prepared by oxidation of the readily available D-arabinotetrahydroxybutylquinoxalines with sodium peroxide in water or in a heterogeneous benzene-water system. ... 

Two groups of workers have measured the pKa value of quinoxaline-2-carboxylic acid and reported values of 2.87 and 2.80. 3-Chloro- and... 

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