Pyridine compounds synthesis

By-Products. Almost all commercial manufacture of pyridine compounds involves the concomitant manufacture of various side products. Liquid- and vapor-phase synthesis of pyridines from ammonia and aldehydes or ketones produces pyridine or an alkylated pyridine as a primary product, as well as isomeric aLkylpyridines and higher substituted aLkylpyridines, along with their isomers. Furthermore, self-condensation of aldehydes and ketones can produce substituted ben2enes. Condensation of ammonia with the aldehydes can produce certain alkyl or unsaturated nitrile side products. Lasdy, self-condensation of the aldehydes and ketones, perhaps with reduction, can lead to alkanes and alkenes. 

Raw Material and Energy Aspects to Pyridine Manufacture. The majority of pyridine and pyridine derivatives are based on raw materials like aldehydes or ketones. These are petroleum-derived starting materials and their manufacture entails cracking and distillation of alkanes and alkenes, and oxidation of alkanes, alkenes, or alcohols. Ammonia is usually the source of the nitrogen atom in pyridine compounds. Gas-phase synthesis of pyridines requires high temperatures (350—550°C) and is therefore somewhat energy intensive. 

The synthesis of these derivatives from the appropriate pyridine compound is usually more convenient than by alkylation of an indolizine, and almost any pattern of alkyl or alkylidene substitution can be achieved using the methods of synthesis already described. 

Whereas the first synthesis of chemicals by electrolysis dates back over 180 years, the equipment and techniques to understand the fundamentals of these reactions were not developed until recently. This review of electrochemical citations of pyridine compounds of industrial interest is keyed to the functionality of the starting pyridine hence the electrochemistry of pyridines is indexed and not their preparation by electrolysis. 

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... 

A native of Long Island, New York, Timothy P. Meagher received his B.A. from SUNY Potsdam, Potsdam, New York, in 1981. Following a brief stint in industry, he earned his Ph.D. at Ohio State University in 1988. He joined the research department at Reilly Industries, Inc. in 1988. During his tenure there he worked in the area of pyridine chemistry. In particular, projects involved gas phase synthesis, ammoxidation, chlorination, and hydrogenation of pyridine compounds. Publications include contribution to Chemistry of Heterocyclic Compounds II and a patent on hydrogenation of 2-ethanol pyridine. He left Reilly Industries, Inc. in 2001 and is currently a consultant for TEKA Consulting. 

The general synthetic scheme of Eq.(15) has been applied to the three isomers of l-methyI-(benzimidazolylvinyl)pyridinium salts 93-95, which are examples of compounds of type 74 mentioned in Section II, A, 1 [see Eq.(l 1)] and in Eq.(17). Synthesis of the 4-pyridinio and 3-pyridinio derivatives 93, 94 can be achieved either via (i) from Eq.(15) [(92S395), Eq.(17)] or via (ii) and (hi) [(91CL2151 92UP1), Eq.(ll)]. A different situation holds for the 2-pyridinio compound 95, which was only prepared by via (i) owing to the steric and electronic interference to quaternization of ort/zo-substitute pyridine compounds (92UP1) [Eq.(ll), Section II,A,1],... 

Thomas, A. D., Josemin, K. N. N., Asokan, C. V. Viismeier-Haack reactions of carbonyl compounds synthesis of substituted pyrones and pyridines. Tetrahedron 2004, 60, 5069-5076. 

Ohler, E., El-Badawi, M., and Zbiral, E., Dialkyl (l,2-epoxy-3-oxoalkyl)phosphonates as synthons for heterocyclic carbonyl compounds. Synthesis of acyl-substituted thiazoles, indolizines, imidazo[ 1,2-fii]pyridines and imidazo[l,2-fii]pyrimidines, Chem. Ber., 118, 4099, 1985. 

Numerous 3-(2-cyanovinyl)-substituted 1,8-naphthyridines 392 were prepared by refluxing l,8-naphthyridine-3-carbaldehydes 393 with substituted acetonitriles in alcohol in the presence of catalytic amounts of pyridine. Compounds 392 were covered by a patent as promising starting compounds for the synthesis of new drugs for the treatment of cancer, psoriasis and atherosclerosis (1996FRP2706898). 

Synthesis of 1,2-Benzisothiazolin-3-ones from Thermal Decomposition of H-Substituted 2-(Methylthio)benzamides. The compounds 2-MeSC6H4CON-(Bu )OCOR (R = Ph or 4-MeCeH4) are prepared by acylating Bu NHOCOR with 2-MeSC6H4COCl in the presence of pyridine. Compound (56 R = Me,... 

The 3,6-diposition-substituted pyridine compounds are important intermediates for industrial synthesis, especially for production of some agricultural chemicals. This compound can be obtained by chemically synthesized from pyridine, but the process is accompanied by some by-products. Microbial hydroxylation of aromatic compounds is a very efficient method of regioselective reaction. Several methods have been reported for the preparation of 3,6-disubstituted pyridine using microorganisms. In 1985, Lehky et al. reported the microbial production of 6-hydroxynicotinic acid (6-HNA) from nicotinic acid (NA) by Achromobacter xylosoxydans Nagasawa et al. also prepared 6-HNA from NA by using Pseudomonas fluorescens TN5. 

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. ... 

Research on pyridine compounds has led to the discovery of the fungicide pyrifenox. Structure activity relationships are presented and the efforts to establish an efficient technical synthesis for pyrifenox are described. 

Deamidation of Nicotinic Add. Enzymes from microorganisms (185-188), insects (189), and birds have been found to deamidate nicotinamide to nicotinic acid (190). Recently, Sundaram et al. (191) have shown that a strain of Leuconostoc mesenteroides which will grow on nicotinic acid but not on nicotinamide, does not possess the deamidase and will not convert the pyridine amide to DPN. On the other hand, Saccharomyces cerevisiae will grow on both pyridine compounds, and the yeast contains the deamidase. These observations suggest that the route of synthesis of DPN from nicotinamide may involve the Preiss-Handler pathway, and that deamidation of nicotinamide occurs during the synthesis, which is also indicated by studies in the intact mouse (see Section III, A). 

Shestopalov AM, Shestopalov AA, Rodinovskaya, Gromova AV (2009) Synthesis of ring fluorinated pyridines. In Petrov VA (ed) Fluorinated heterocyclic compounds synthesis, chemistry, and apphcations part I. Wiley, Hoboken, pp 243-271... 

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