Synthesis of Nicotinic Acid

Nicotinic acid is an important intermediate for pharmaceuticals and serves as a provitamin in food additives for animal feeding. It is produced by the Lonza process (involving oxidation of 2-methyl-5-ethyl pyridine using nitric acid) or by the Degussa process.The latter process involved hydrolysis of P-cyanopyridine, which in turn was produced by amminoxidation of P-picoline. A third process involving selective vapour phase oxidation of P-picoline catalysed by vanadium titanium oxide catalyst has also been described.  

A convenient process involving direct oxidation of P-picoline has been developed for the synthesis of nicotinic acid.  

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Pellagra is currently thought to be due to imbalance of dietary amino acids and deficiency of niacin. The common variety of maize is rich in leucine, which inhibits synthesis of nicotinic acid mononucleotide and causes deficiency of NAD+ and NADP+. A strain of maize known as opaque 2 contains less leucine and does not cause pellagra unless excess leucine is added to the diet. 

Chini EN, Chini CC, Kato I, Takasawa S, Okamoto H. CD38 is the major enzyme responsible for synthesis of nicotinic acid-adenine dinncleotide phosphate in mam-mahan tissues. Biochem J 2002 362(Part 1) 125-130. 

Ethyl-2-methylpyridine 164 (the educt in the industrial synthesis of nicotinic acid, see p 291) is formed from acetaldehyde or but-2-enal (crotonaldehyde) and aqueous NH3 in a similar process. 

The same stability principle applies to the historical synthesis of nicotinic acid from nicotine which, for example, upon oxidation with permanganate , chromic acid or fuming nitric acidi , loses four carbons and the N of the 5-membered ring. 

Similar reaction mechanisms are the bases for the synthesis of nicotinic acid from 3-methyl pyridine, 3-ethyl pyridine, 3-phenyl pyridine, and 3,3 -... 

Therefore, there is substantial evidence that 3-hydroxyanthranilic acid is an intermediate on the direct pathway of the synthesis of nicotinic acid from tryptophan. 

A. aerogenes, growing in simple media (114) Glucosi, phosphates, and inorganic salts 33 Inactivation and synthesis of nicotinic acid 0.5... 

A review of recent advances in transition-metal-catalysed oxidations by molecular oxygen has highlighted the scope and limitations, as well as the meehanisms of these reactions. " " An overview of the fundamental studies on a new method of synthesis of nicotinic acid by the gas-phase catalytic oxidation of -picoline by oxygen has been presented. The reactivity of vanadium species has been considered in order to discover the nature of the active catalyst. Kinetic equations for -picoline oxidation on vanadia-titania catalysts have been discussed. " The effect of quaternary ammonium salts or macrocyclic ethers on the autoxidation of ethylbenzene or the decomposition of the a-phenylethyl hydroperoxide intermediate catalysed by Ni(II) or Fe(III) acetylacetonates has been reviewed. ... 

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). 

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. 

H3. Handler, P., and Kohn, H. I., The mechanism of cozymase synthesis in the human erythrocyte a comparison of the role of nicotinic acid and nicotinamide. J. Biol. Chem. 150, 447-452 (1943). 

Neomycin/nicotinic acid combination therapy lowered Lp(a) markedly in some patients, but nicotinic acid alone was not effective (G35, Ml9). On the other hand, in a subgroup of patients with hypertriglyceridemia, Carlson (C2) and Seed (S27) reported a positive effect of nicotinic acid therapy on Lp(a) levels and ascribed it to an inhibition of synthesis of apo-B. 

Nitrilase-mediated conversion of 3-cyanopyridine into nicotinic acid is an attractive alternative to chemical methods of nicotinic acid synthesis.It has been synthesized using whole cells (containing nitrilase) of some microorganisms and involves the following reaction ... 

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. 

SYNTHESIS There have been three total syntheses of ibogaine reported in the chemical literature. The first of these was a thirteen step process published about 30 years ago. Although the chemistry lab can serve a fine function for both isolation and purification of ibogaine from plant sources. In other words, there is no practical way to start from a bottle of nicotinic acid and actually prepare useful amounts. The parent ring system contains two chiral centers, neither of which is amenable to easy manipulation. 

Niacin is found in unrefined and enriched grains and cereal, milk, aid lean meats, especially liver. Limited quantities of niacin can also be obtained from the metabolism of tryptophan. [Note The pathway is inefficient in that only about 1 mg of nicotinic acid is formed from 60 mg of tryptophan. Further, tryptophan is metabolized to niacin orty when there is a relative abundance of the amino acid—that is, alter the needs for protein synthesis and energy production have been met]... 

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... 

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. 

In this section the synthesis of coumalic acid (92), representing the a(2)-pyrone system, is described. a-Pyrones readily undergo a simple lactone-amide transformation, and the conversion of coumalic acid into the tautomeric 6-hydroxy-nicotinic acid (93) provides a further illustration of the conversion of a six-membered oxygen heterocycle into the corresponding nitrogen system. 

The methyl ester of nicotinic acid is selectively reduced to the 1,2-dihydropyridine 166 in a vast improvement over previous methods (Equation 87) <20010L201>. Low temperatures and choice of pyridinium-activating agent are crucial to avoid 1,4-dihydropyridine formation. A modification of Fowler s dihydropyridine synthesis was used to prepare the iV-acyldihydropyridine 167 (Equation 88) <20060L2961>. 

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