Nicotinic acid derivatives synthesis

Substituted nicotinic acid derivatives are useful in the synthesis of pesticides and pharmaceuticals as specific inhibitors of NAD and/or NADP dependent enzymes. 6-Hydroxynicotinic acid is a very useful intermediate in the synthesis of such inhibitors. 

C. Stirling, M. McAleer, and J.P.D. Reckless, et al.. Effects of acipimox, a nicotinic acid derivative, on lipolysis in human adipose tissue and on cholesterol synthesis in human jejunal mucosa, ain. Sci., 1985, 68, 83-88. 

Lefebvre, C.L. Ergot of Paspalum Phytopathology (1939) 29 365-367 Lehrfeld, J. Burkman, AM. Gearien, J.E. Synthesis of 6-Substi-tuted Nicotinic Acid Derivatives as Analogs of Ergot Alkaloids Journal of Medicinal Chemistry (1964) 7 150-154... 

Statins Ezitimibe Omega-3 triglycerides Bile acid sequestrants Fibrates Nicotinic acid derivatives Inhibit HMG-CoA reductase Inhibits absorption of cholesterol from the intestine Inhibit VLDL synthesis in the liver Bind bile acids in the intestine Lower levels of circulating VLDLs and LDLs by unknown mechanism Reduce the release of VLDLs from the liver... 

Substituted nicotinic acid derivatives, such as 6-hydroxy nicotinic acid are important building blocks for the synthesis of pesticides and pharmaceuticals, acting as specific inhibitors of NAD/NADP-dependent enzymes. In a process developed by Lonza (Switzerland), 6-hydroxy nicotinic acid is produced by whole-cell microbial hydroxylation of nicotinic acid with Achromobacter xylosoxidans (yield > 100 g 1 ) (Fig. 16). A similar process for the production of 6-hydroxypicolinic acid (98 g l-1) and derivatives from picolinic acid (derivatives), based on Alcaligenes faecalis, has also been established [174,175]. 

Sosnovskikh VY, Irgashev RA, Kodess MI (2008) One-pot three-component reaction of 3-(polyfluoroacyl)chromones with active methylene compounds and ammonium acetate regioselective synthesis of novel R -containing nicotinic acid derivatives. Tetrahedron 64 2997-3004... 

The interconversion, breakdown, and synthesis of the coenzymes have received much more study in yeasts than have other reactions of nicotinic acid derivatives. In distinction to the studies of these compounds in other organisms, which have been recounted above, the quantities of substances reacting in yeasts have in many ca.ses been estimated in defined enzyme systems after separation from nsaction mixtures (58,104). The methods are sensitive to the quantities of coenzymes associated with a few milligrams of microorganisms. 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

Craig s synthesis of nicotine (V to VII, p. 42) proceeds via nomicotine. Nicotinic acid nitrile reacts with the Grignard reagent derived from ethyl y-bromopropyl ether to give 3-pyridyl-y-ethoxypropyl ketone (V). This yields an oily oxime (VI) reducible to a-(3-pyridyl)-a-amino-8-ethoxy-w-butane (VII), which with 48 per cent, hydrobromic acid at 130-3° gives womicotine, and this on methylation yields dZ-nicotine. 

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-... 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

Vitamins must be derived from the diet because either they cannot be synthesized de novo in human beings or their rate of synthesis, e.g. the production of nicotinic acid from tryptophan, is inadequate for the maintenance of health. Only vitamin D can be manufactured by the body at a sufficient rate. 

A synthesis of pyrrolo[2,3-, ]pyridine derivatives from nicotinic acid or 2,6-dichloropyridine affords 1,3- and 1,3,6-substituted pyrrolo[2,3-, ]pyridines <2006JOC5538>. 

An iron-catalyzed reaction of an a,P-unsaturated oxime such as 68 with a P-oxo ester also gave pyridine derivatives such as nicotinic acid 69 [99]. Under the reaction conditions (150-160 °C, without solvent) first Michael adducts such as intermediate 70 are presumably formed, which further condense via intermediate 71. This method is not restricted to a centric symmetry in the substitution pattern, which is an advantage compared with the Hantzsch synthesis. Moreover, the method starts with hydroxylamine being two oxidation stages above ammonia therefore, no oxidation in the final stage from dihydro- to pyridine is necessary (Scheme 8.31). 

It is remarkable that the intermediates in the conversion of hydroxyanthranilic acid to nicotinic acid are still not known with certainty. Intermediates A and B of diagram 21 are plausible suggestions, but no synthesis of either has been reported. Both are extremely unlikely to be stable in the free state, but should be obtainable as simple derivatives. In the free state Intermediate A, for example, might be expected to tautomerize to the imino acid, and hence give keto acid and ammonia, or it could cyclize to a piperazine or to quinolinic acid. Tautomerism through the imino acid would eliminate the necessity for a fumaric —> maleic isomerization. It is quite possible that spontaneous cyclization explains the prominent part quinolinic acid plays in work on hydroxyanthranilic-nicotinic conversion. If the latter occurred in the following.way ... 

These compounds are derived from the vitamin niacin (nicotinic acid, nicotinamide) and require it for their synthesis. Small amounts of niacin are derived from the essential amino acid tryptophan. 

Good use is made of this chemistry in the synthesis of nifluminic acid 69, an analgesic with a pyridine ring. Disconnection of the C—N bond suggests a 2-chloropyridine 70 starting material easily derived from nicotinic acid 60 and a simple aromatic amine 72 available by functionalisation of trifluorobenzene 74. 69 Is actually available as niflumic acid from Aldrich. 

---