4- Methyl-5 nicotinic acid

Methylation of nicotine to the pyridinium iodide with methyl iodide, followed by its conversion to the hydroxide with silver oxide in water, oxidation with potassium permanganate to the A -methyl nicotinic acid hydroxide and subsequent deprotonation with silver oxide yielded Trigollenine as colorless needles (1897CB2117). In a later publication, the formation of nicotinic acid from nicotine was described. Esterification followed by aminolysis and methylation yielded the A -methylnicotinamide... 

Carboxylic acid iV-hydroxy-succinimide ester iV-Methyl-nicotinic acid iV-hydroxysuccinimide ester [21] Phenolic OH LC-ESP/MS/ MS... 

Carboxylic acid /V-hydroxysuccinimidc ester, e.g., iV-methyl-nicotinic acid /V-hydroxysuccinimide ester [21]... 

Likewise, SOCL chlorinates 6-methylnicotinic acid (51) to trichloroni-cotinoyl chloride (52) (36JPRI88), whereas 4-methyl-nicotinic acid (53) is transformed by SOCL into the dichlorothio lactone 54 (44JAI456 ... 

Besson M, Debleqc F, Gallezot P, Neto S, Pinel C (2000) Diastereoselective heterogeneous catalytic hydrogenation of 2-methyl nicotinic acid using pyroglutamate chiral auxiliary. C Chem Eur J 6 949... 

An improved method to synthesize 25 involves the reduction of the methylated nicotinic acid ester 179 with sodium borohydride [126a]. 

An improved synthesis of pyridoxol has appeared and 5-hydroxy-6-methyl-nicotinic acid (X-20S), a metabolite of pyridoxal in Pseudomonas MA has been prepared. ... 

Other urinary excretion products of niacin include nicotinuric acid (nicotinoyl glycine) nicotinamide N-oxide, and trigonelline (N -methyl nicotinic acid) the latter may arise from bacterial action in the gut or from the absorption of this substance from foods. The pattern of the different turnover metabolites varies between species, between diets (depending partly on the ratio of nicotinamide to nicotinic acid in the diet), and partly with niacin status thus there are complex regulatory mechanisms to be considered. 

Derivatives of nicotinic acid which were ineffective for Staph, aureus, Proteus vulgaris and pea roots —pyridine-3,4-dicarboxylic acid (cinchomeronic acid) pyridine-3,5-dicarbo.xylic acid (dinicotinic acid) 3-amino-pyridine trigonelline are-coline. 6-Methyl-nicotinic acid was inactive for dysentery bacilli. Derivatives differing in structure more widely were inactive. 

The result of this biosynthesis is that the product is nicotinic acid mononucleotide rather than free nicotinic acid. Ingested nicotinic acid is converted to nicotinic acid mononucleotide which, in turn, is converted to nicotinic acid adenine dinucleotide. Nicotinic acid adenine dinucleotide is then converted to nicotinamide adenine dinucleotide. If excess nicotinic acid is ingested, it is metabolized into a series of detoxification products (Fig. 4). Physiological metabohtes include /V-methylnicotinamide (19) and A/-methyl-6-pyridone-2-carboxamide (24) (1). 

In the case of nicotinamide, the color yield is often low. This problem can be circumvented by either hydrolysis to nicotinic acid or by conversion of the amide to a fluorescent compound. Treatment of nicotinamide with methyl iodide yields the quaternary ammonium salt, /V-methyl nicotinamide (5). Reaction of this compound with acetophenone yields a fluorescent adduct (49). Other carbonyl compounds have also been used (50—54). 

For more specific analysis, chromatographic methods have been developed. Using reverse-phase columns and uv detection, hplc methods have been appHed to the analysis of nicotinic acid and nicotinamide in biological fluids such as blood and urine and in foods such as coffee and meat. Derivatization techniques have also been employed to improve sensitivity (55). For example, the reaction of nicotinic amide with DCCI (AT-dicyclohexyl-0-methoxycoumarin-4-yl)methyl isourea to yield the fluorescent coumarin ester has been reported (56). After separation on a reversed-phase column, detection limits of 10 pmol for nicotinic acid have been reported (57). 

When trigonelline is heated in closed tubes with baryta water at 120°, it gives rise to methylamine, whilst similar treatment with hydrochloric acid at 260° furnishes methyl chloride and nicotinic acid (pyridine-3-carboxylic acid), indicating that it is the methylbetaine of nicotinic acid. 

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. 

Pyridine 210 is oxidized by 20% nitric acid at the acetyl group to 2-methyl-5-pyridinecarboxylic acid, while its ozonation gives cinchomeronic acid [pyridine-2,5-dicarboxylic acid (215)] (75DIS) which is decarboxylated (200°C, 2 h) to nicotinic acid 216 in 97% yield (75DIS). 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

In two publications [36, 37] and a subsequent review [38], a closely related alternative procedure for conversion of pyridine-N-oxides into cyanopyridines was reported in 1983. This used a combination of the mild Lewis acid Me2NCOCl and trimethylsilyl cyanide 18 for the cyanation of pyridine N-oxides such as 860, affording, in CH2CI2, via 932 and 933, 2-cyanopyridine 862 in 94% yield and apparently no 4-cyanopyridine 864 [36-38] (Scheme 7.13). With 3-substituted pyridine N-oxides such as methyl nicotinate N-oxide a mixture of 40% methyl 2-cyanonico-tinate and 60% methyl 6-cyanonicotinate is obtained. 

The group C counterirritants methyl nicotinate and histamine dihydrochloride produce vasodilation.24 Methyl nicotinate is a nicotinic acid derivative that produces prostaglandin-mediated vasodilation.46 NSAIDs and aspirin block the production of prostaglandins and decrease methyl nicotinate-induced vasodilation. Application over a large area has been reported to cause systemic symptoms and syncope, possibly due to vasodilation and a decrease in blood pressure.47 Patients should be educated to apply only scant amounts to the affected area to avoid this effect. 

The coordination modes found in Ni11 complexes with 2-(diphenylphosphino)nicotinic acid and its methyl ester and 2-(diphenylphosphino)benzoic acid and its methyl ester are surprising.696 The complex with the benzoic acid derivative shows the expected P,0 coordination with a six-membered chelate ring (252), while the nicotinic acid analogue forms a four-membered chelate ring with P,N binding (251). 

The reason for the absence of an additive response to nicotinic acid plus nicotinamide, seen with whole blood and in recovery experiments, remains obscure. Nicotinic acid and nicotinamide seem to interfere with each other s utilization. There may exist a competition between nicotinic acid and nicotinamide for methylation growth therefore would not reach an algebraic sum when the two are combined because of the limited number of methyl groups available for these compounds. 

In view of the biological importance of nicotinic acid, it was decided to prepare a quaternary salt from the acid or ester and bromofluoroethane. S Carbethoxy- N-2-fluoroethylpyridinium bromide (XIX) was therefore prepared and examined. The l.d. 50 for subcutaneous injection into mice was 200 mg. /kg., i.e. it was relatively non-toxic compared with methyl fluoroacetate. 

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