Quinolinic acid, synthesis

Oxidation. The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid [59-67-6] (7) has been accompHshed direcdy in 79% yield using a nitric—sulfuric acid mixture above 220°C (25). A wide variety of oxidants have been used in the preparation of quinoline N-oxide. This substrate has proved to be useful in the preparation of 2-chloroquinoline [612-62-4] and 4-chloroquinoline [611 -35-8] using sulfuryl chloride (26). The oxidized nitrogen is readily reduced with DMSO (27) (see Amine oxides). 

PyrimidoX4,5-6]quinoline-2-carboxylic acids synthesis, 3, 224-225 Pyrimido[4,5-6]quinoline-2,4-diones synthesis, 3, 224 Pyrimido[5,4-6]quinolinediones synthesis, 3, 219 Pyrimido[4,5-6]quinolines synthesis, 3, 219, 224, 227, 228, 230, 231 Pyrimido[4,5-c]quinolines synthesis, 3, 224, 227 tautomerism, 3, 205 Pyrimido[5,4-6]quinolines synthesis, 3, 227 Pyrimido[5,4-c]quinolines synthesis, 3, 219, 224, 227, 230 Pyrimido[5,4-6]quinoline-1,3,5-trione, 7-chloro-synthesis, 3, 221... 

Friedlander synthesis, 2, 444 Quinoline-2,4-dicarboxylic acids Pfitzinger synthesis, 2, 446 Quinoline-3,4-dicarboxylic acids synthesis... 

Carboxylic acids with labile a-methylene protons react with isatin in the presence of strong aqueous base. In the total synthesis of methoxatin, the coenzyme of methanol dehydrogenase and glucose dehydrogenase, Weinreb employs a Pfitzinger condensation of an isatin 37 and pyruvic acid as a key step to provide the 4-quinolinic acid 38 in 50% yield under the standard basic conditions. ... 

Further work was now directed toward the synthesis of analogs of this highly active herbicide. Substituted quinolinic acids are not readily available and these are usually obtained in poor yield by the oxidation of the appropriate quinoline ... 

L-tryptophane is the precursor of serotonin and other biological substances like tryptamine, kynure-nine and quinolinic acid. Furthermore, it is an essential substrate in the protein synthesis. The dietary intake of L-tryptophane might increase the production of serotonin. For this reason the aminoacid is used for the therapy of light sleeping disorders. 

In the original Doebner-von Miller synthesis of quinolines an arylamine condenses with two molecules of an aldehyde most of the variants have been dealt with in Section 2.08.2.2.3.ii since the intermediate (often used directly) is an a,-unsaturated aldehyde. Two further major variations, the Beyer modification and the Doebner cinchoninic acid synthesis, will be dealt with here, since intermediates are rarely isolated. 

An alternative pathway for synthesis of quinoli-nate from aspartate and a triose phosphate exists in bacteria and in plants and provides the major route of nicotinic acid synthesis in nature. In E. coli the reaction is catalyzed by two enzymes, one an FAD-containing L-aspartate oxidase which oxidizes aspartate to a-iminoaspartate.228 The latter condenses with dihydroxyacetone-P to form quinolinate (Eq. 25-13).229 There are at least two other pathways for synthesis of quinolinic acid as well as five or more salvage pathways for resynthesis of degraded pyridine nucleotide coenzymes.224/230/231... 

Precursors in the biosynthesis of niacin In animals and bacteria, tryptophan and in plants, glycerol and succinic acid. Intermediates in the synthesis include kynurenine, hydroxyanthranilic acid, and quinolinic acid. In animals, the niacin storage sites are liver, heart, and muscle. Niacin supplements are prepared commercially by (1) Hydrolysis of 3-cyanopyndine or (2) oxidation of nicotine, quinoltne, or collidine. 

The synthesis of quinolinic acid and its subsequent decarboxylation to nicotinic acid has been accomplished directly in 79% yield using a nitric-sulfuric acid mixture above 220°C. A wide variety of oxidants have been used in the preparation of quinoline iV-oxice. 

H,6H-Purine, l,7-dimethyl-6-oxo-UV spectra, 5, 517 7H,8H-Purine, 8-oxo-UV spectra, 5, 517 Purinecarboxamides reactions, 5, 550, 551 Purinecarboxylic adds reactions, 5, 550 Purine-6-carboxylic acids synthesis, 5, 593 Purine-8-carboxylic acids synthesis, 5, 593 Purine nucleotides biosynthesis, 1, 87-88 Purine[9,8-a]quinolines, 5, 566 Purines, 5, 499-605 aldehydes reactions, 5, 549 synthesis, 5, 593 alkylation, 5, 505, 528-538 amination, 5, 541-542 anions... 

Quinolinic acid (133) was prepared by methods similar to those described for the monocarboxylic acids.182,183,189-191,196-202 In many cases the resulting diacid was decarboxylated to nicotinic acid (126). Quinoline (130) was simultaneously oxidized to the diacid (133) and reduced to tetrahy-droquinoline (134) in one of the rare reports of paired synthesis of pyridine compounds (Scheme 44).189 An attempt was made to delineate some of the electrode processes for the diacid (133).200... 

Carrigan CN, Esslinger CS, Bartlett RD, Bridges RJ, Thompson CM (1999) Quinoline-2,4-dicarboxylic acids synthesis and evaluation as inhibitors of the glutamate vesicular transport system. Bioorg Med Chem Lett 9 2607-2612. 

In an example of the Combes synthesis of quinolines, acid-catalyzed condensation of 4(7)-aminobenzimidazole with excess acetylacetone afforded 5,7-dimethylimidazo[4,5-A]quinoline (81), albeit in low yield (Equation (44)) <91T7459>. 

As shown in Figure 8.2, NAD(P) can be synthesized from the tryptophan metaboUte quinolinic acid. The oxidative pathway of tryptophan metabolism is shown in Figure 8.4. Under normal conditions, almost aU of the dietary intake of tryptophan, apart from the small amount that is used for net new protein synthesis, is metabolized by this pathway, and hence is potentially available for NAD synthesis. About 1% of tryptophan metabolism is by way of 5-hydroxylation and decarboxylation to 5-hydroxytryptarnine (serotonin), which is excreted mainly as 5-hydroxyindoleacetic acid. 

As shown in Figure 8.4, the synthesis of NAD from tryptophan involves the nonenzymic cyclization of aminocarhoxymuconic semialdehyde to quinolinic acid. The alternative metahoUc fate of aminocarhoxymuconic semialdehyde is decarboxylation, catalyzed hy picolinate carboxylase, leading into the oxidative branch of the pathway, and catabolism via acetyl coenzyme A. There is thus competition between an enzyme-catalyzed reaction that has hyperbolic, saturable kinetics, and a nonenzymic reaction thathas linear, first-order kinetics. 

Figure 8.2. Synthesis of NAD from nicotinamide, nicotinic acid, and quinolinic acid. Qiiinolinate phosphoribosyltransferase, EC 2.4.2.19 nicotinic acid phosphoribosyl-transferase, EC 2.4.2.11 nicotinamide phosphoribosyltransferase, EC 2.4.2.12 nicotinamide deamidase, EC 3.5.1.19 NAD glycohydrolase, EC 3.2.2.5 NAD pyrophosphatase, EC3.6.1.22 ADP-ribosyltransferases, EC 2.4.2.31 and EC 2.4.2.36 and poly(ADP-ribose) polymerase, EC 2.4.2.30. PRPP, phosphoribosyl pyrophosphate.

Animals and yeasts can synthesize nicotinamide from tryptophan via hydroxyanthranilic acid (52) and quinolinic acid (53, Fig. 6A) (31), but the biosynthetic capacity of humans is limited. On a diet that is low in tryptophan, the combined contributions of endogenous synthesis and nutritional supply of precursors, such as nicotinic acid, nicotinamide, and nicotinamide riboside, may be insufficient, which results in cutaneous manifestation of niacin deficiency under the clinical picture of pellagra. Exogenous supply of nicotinamide riboside was shown to promote NAD+-dependent Sir2-function and to extend life-span in yeast without calorie restriction (32). 

Beagles KE, Morrison PF, Heyes MP. Quinolinic acid in vivo synthesis rates, extracellular concentrations, and intercompartmental distributions in normal and immune activated brain as determined by multiple isotope microdialysis. J Neurochem 1998 70 281-91. 

Rare earth metal triflates are recognized as a very efficient Lewis acid catalysts of several reactions including the aldol reaction, the Michael reaction, allylation, the Diels-Alder reaction, the Friedel-Crafts reaction, and glycosylation [110]. A polymer-sup-ported scandium catalyst has been developed and used for quinoline library synthesis (Sch. 8) [111], because lanthanide triflates were known to be effective in the synthesis of quinolines from A-arylimines [112,113]. This catalyst (103) was readily prepared from poly(acrylonitrile) 100 by chemical modification. A variety of combinations of aldehydes, amines, and olefins are possible in this reaction. Use of the polymer-supported catalyst has several advantages in quinoline library construction. 

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