Nicotinic acid derivatives, formation

Preparation of the first of these antiinflammatory prodrugs starts with the displacement of halogen on bromophthal ide 2 by the anion of the nicotinic acid derivative 1. Reaction of the intermediate 3 with aniline 4 leads to formation of talniflumate (5). ... 

Nicotinic acid derivatives occur in biologic materials as the free acid, as nicotinamide, and in two coenzymatic forms nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These coenzymes act in series with flavoprotein enzymes and, like them, are hydrogen acceptors or, when reduced, donors. Several plants and bacteria use a metabolic pathway for the formation of nicotinic acid that is different from the tryptophan pathway used by animals and man (B39). 

In a useful variant, it was demonstrated that nicotinic acid derivatives 90 can also be accessed (10CEJ428, 10EJO6582).The use of primary amines with good leaving groups attached to the nitrogen enables a subsequent elimination with formation of the pyridine core. This was realized using methoxyamine hydrochloride and sodium acetate in ethanol or iso-propanol at elevated temperatures in a microwave apparatus (Scheme 31). 

The formation of nicotinic acid derivatives by base-mediated nitrogen to carbon rearrangement of -substituted pyridine 2-sulfonamides (Scheme 189) has been reported. ... 

The indirect determination of certain organic substances can be made by complexometric titration methods. Such methods depend on the formation of an insoluble product between the organic material and a metal then, either the excess metal in solution is determined by a suitable titration with EDTA, or the metal-containing precipitate is decomposed and the liberated metal ions titrated. Thus, for example, narcotine, papaverine, codeine, strychnine and brucine have been determined by formation of iodobis-muthate complexes, chlorpromazine and quinine" as cadmium iodide complexes, purines and nicotinic acid derivatives by precipitation with mercury and barbiturates by precipitation with zinc. ... 

Nicotinic acid derivatives thus occur in all microorganisms examined, in similar quantities and in the organisms studied they participate in similar processes of hydrogen transport. Equally widespread are reactions of the millimicromolar order which result in their formation, interconversion, or inactivation (Table I). The much more rapid reaction by bacillus N.C., which derives its main material and energy from nicotinic acid, emphasizes the similarity between the rates of the other reactions. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

Vitamin Ba (pyridoxine, pyridoxal, pyridoxamine) like nicotinic acid is a pyridine derivative. Its phosphorylated form is the coenzyme in enzymes that decarboxylate amino acids, e.g., tyrosine, arginine, glycine, glutamic acid, and dihydroxyphenylalanine. Vitamin B participates as coenzyme in various transaminations. It also functions in the conversion of tryptophan to nicotinic acid and amide. It is generally concerned with protein metabolism, e.g., the vitamin B8 requirement is increased in rats during increased protein intake. Vitamin B6 is also involved in the formation of unsaturated fatty acids. 

In the formation of nicotine, a pyrrolidine ring derived from ornithine, most likely as the /V-methyl-A1 -pyrrolinium cation (see Figure 6.2) is attached to the pyridine ring of nicotinic acid, displacing the carboxyl during the sequence (Figure 6.31). A dihydronicotinic acid intermediate is likely to be involved allowing decarboxylation to the enamine 1,2-dihydropyridine. 

The Rutaceae oxazoles are evidently derived from /V-nicotinoyl-p-(p-hydroxy)-phenylethylamide (51), with the exception of balsoxin (25) and texamine (26) in which the nicotinoyl moiety is replaced by benzoyl. The condensation of these tyramine and nicotinic acid residues does not represent any major departure from the standard routes of alkaloid biosynthesis in the Rutaceae, for it has long been recognized that the alkaloids of this family are all derived from either phenylalanine (52), tyrosine, (53), or anthranilic acid (54) (22), the latter being the acknowledged precursor to nicotinic acid in most organisms (23). The formation of the putative oxazole precursor 51 or its equivalent therefore constitutes a convergence of the two predominant modes of alkaloid biosynthesis in the family. 

The formation of a monobenzoyl derivative and a mononitroso derivative, b.p. 176°/4 mm., [a]u — 155° (no solvent) shows that anabasine is a secondary-tertiary diacidic base. This conclusion is substantiated by the formation of an A-methylanabasine, b.p. 268°, when the base is heated with formaldehyde and formic acid (420). With potassium permanganate anabasine is oxidized to nicotinic acid whereas dehydrogenation either with silver acetate or with zinc dust causes the loss of six hydrogen atoms and the formation of 3, 2-dipyridyl, b.p. 293-294° (picrate, m.p. 151-152°)(423). These experiments support structure CLXXIV previously applied to anabasine (399), a formulation that is confirmed by the following experiments. When A-benzoylanabasine methiodide is oxidized with potassium ferricyanide, the 7V-benzoyl derivative of the corresponding pyridone,... 

Anions of CH-acidic compounds add to pyridinium ions mainly at C-4. Substituents already present on pyridine can bring about interesting reaction sequences. This is exemplified by the formation of the 2,7-naphthyridine derivative 53 from the quaternary salt of the nicotinic acid amide 52 and malonic... 

Quinoline was converted in good yield to nicotinic acid (Sturrock et al., 1960). With indoles, the pyrrole ring opens to give aniline derivatives, as in the formation of 2-aminobenzaldehyde and anthranilic acid from indole (Equation 5.44) (Jurs, 1966). 

Ricinine.—Ricinine (49), the alkaloid of castor bean plants, is derived from nicotinic acid (28) and quinolinic acid (48), and its formation is intimately associated with the pyridine nucleotide cycle cf. ref. 6. Quinolinic acid is built from a C3 fragment that is formed from glycerol via glyceraldehyde and a C4 unit that is related to succinic or aspartic acids. A recent investigation has confirmed this pathway for ricinine (49) and indicated that dihydroxyacetone phosphate lies between glycerol and glyceraldehyde (loss of tritium from C-2 of labelled glycerol). ... 

Nicotine.—Nicotine (33) is assembled in Nicotiana species from nicotinic acid (31) and N-methyl-A -pyrroline (32). Administration to Nicotiana plants of 5-fluoronicotinic acid and derivatives of (32) methylated at C-2 and C-3 has resulted in the formation in vivo of unnatural nicotine analogues.In contrast, 4-methylnicotinic acid has been found not to be transformed in vivo into 4-methylnicotine, presumably because this particular methyl group interferes sterically with the appropriate enzyme reactions involved in nicotine biosynthesis. ... 

Nicotine is the main alkaloid of tobacco Nicotiana tabacum) of the Solana-ceae. Anabasine is the main alkaloid of Anabasis aphylla (Chenopodiaceae), although trace amounts are also present in tobacco. Both nicotine and anabasine possess strong insecticidal activity. The structures of these alkaloids also have similarities in that one contains a pyrrolidine ring derived from ornithine and the other a piperidine ring derived from lysine, both of which are joined at C-3 of the pyridine ring, itself derived from nicotinic acid [1]. These alkaloids were described in detail in Chapters 3 and 4 on ornithine-and lysine-derived alkaloids, respectively. The procedure for the formation of nicotine and anabasine by condensation of A -pyrrolidine and A -piperidine with a nicotinic acid moiety is shown in the figure [2]. 

The approximately 80 known pyrrolidine alkaloids possess a 5-membered nitrogen-containing ring (Massiot and Delaude, 1986 Binder, 1993). Several subgroups of pyrrolidine alkaloids arise by condensation of these units with other molecules, Pyrrolidine bases usually are modified by additional Schiff-base formation, Mannich condensation, and aldol-type processes to yield other alkaloids of tiiis general class. For example, condensation of pyrrolidine derivatives with nicotinic acid is involved in the formation of pyridine alkaloids such as nicotine see Chapter 28). Pyrrolidine units react with acetyl- or malonyl-CoA and condense via a Mannich condensation to form compounds such as hygrine and cuscohygrine and tropane alkaloids see below). 

As a simple indole derivative, the aromatic amino acid tryptophan (2-amino-3-(3-indolyl)-propionic acid) plays an important part in animal and plant metabolism. Its degradation via kynurenine leads, e. g., to formation of nicotinic acid and its amide or of ommochromes which have been found as pigments especially in crustaceans and insects. Observations made on mutant strains of insects and of the mould Neurospora crassa, in which the biosynthetic routes mentioned are blocked, have given a profound insight into the physiology of gene activity [6]. 

Tropane alkaloids are found mainly in the Solanaceae [14] plant family. First biosynthetic step of tropane alkaloids starts with iV-methylation of putrescine (derived from L-omithine) to form Al-methylputrescine. After the conversion to 1-methyl-Al pyrrolinium cation, its condensation with nicotinic acid gives rise to nicotine synthesis, while other chemical conversions lead to the formation of tropinone, the precursor of many tropane alkaloids through branched pathways (Fig. 8.8a) [15]. 

Nicotinic Add Metabolism. The sequence of reactions leading to the formation of pyridine compounds is of particular interest as a source of nicotinic acid. Nutritional, isotopic, and genetic experiments have all shown that tryptophan and its metabolic derivatives including 3-hydroxy-anthranilic acid are precursors of nicotinic acid in animals and in Neuro-spora. The terminal steps in this sequence are not known. Under certain physiological conditions an increase in picolinic carboxylase appears to reduce nicotinic acid synthesis. This implies a common pathway as far as the oxidation of 3-hydroxyanthranilic acid. Whether quinolinic acid is a precursor of nicotinic acid is still uncertain. The enzyme that forms the amide of nicotinic acid also has not been isolated. Subsequent reactions of nicotinamide include the formation of the riboside with nucleoside phosphorylase and methylation by nicotinamide methyl-kinase. In animals W-methylnicotinamide is oxidized to the corresponding 6-pyridone by a liver flavoprotein. Nicotinic acid also forms glycine and ornithine conjugates. Both aerobic and anaerobic bacteria have been found to oxidize nicotinic acid in the 6-position. ... 

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