Pyridones methylation

It is found in practice that for a number of compounds reacting ma the predominant species an almost horizontal plot is obtained. For compounds presumed to be nitrated via the free bases, such as 2,6-lutidine i-oxide and 3- and 5-methyl-2-pyridone, slopes of approximately unity are obtained. Since this type of plot allows for the incomplete ionisation of nitric acid, it can be used at higher acidities than plots using — ( H + logio Hjo) which break down when the condition is no longer true. 

The similarity of their rate profiles, and the similarity of their rate constants for nitration at a particular temperature and acidity show that 4-pyridone, i-methyl-4-pyridone, and 4-methoxypyridine are all nitrated as their cations down to about 85 % sulphuric acid. The same is true of 2-methoxy-3-methylpyridine. In contrast, 3- and 5-methyl-2-pyridone, i,5-dimethyl-2-pyridone and 3-nitro-4-pyridone all react... 

Biosynthetic studies using acetate (Ac), propionate (Pr), and butyrate (Bu) revealed the polyketide nature of aurodox which has the composition Pr(Ac)g for the goldinamine skeleton C-7 to C-25 and the composition Bu(Ac) for the C-27 to C-39 carbon chain of goldinonic acid. In contrast to the methyl branch at C-8, those at C-19 and C-21 are methionine-derived as are all remaining methyl groups (52,53). The biogenetic origin of the pyridone moiety is not clear. 

Mocimycin has been chemically converted to aurodox by protection of the 4-hydroxy group at the pyridone moiety as the benzoylformate, followed by /V-methylation and hydrolytic removal of the protective group (1,55). Whereas aurodox esters are active growth promotors in animals, goldinamines that are A/-acylated by acids other than goldinonic acid, such as acetic, benzoic, or arylsulfonic acids, lack useful antimicrobial or growth-promoting activity (1). 

Methylpyridinium quaternary salts, such as (12), undergo oxidation in alkaline solution in the presence of potassium ferricyanide to give 2-pyridones, eg, A/-methyl-2-pyridone [694-85-9] (16). Frequendy nucleophilic attack at position 2 by excess hydroxide leads to ring opening this and synthetically useful recycli2ations have been reviewed (17). 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

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). 

Bromopyridine has been made by direct bromination of pyridine - from N-methyl-2-pyridone with phosphorus penta-bromide and phosphorus oxybromide from 2-aminopyridine by diazotization with amyl nitrite in 20% hydrobromic acid from sodium 2-pyridinediazotate by solution in concentrated hydrobromic acid and from 2-aminopyridinc by diazotization in the presence of bromine and concentrated hydrobromic acidd The method described here is essentially that of Craig. 

The procedure for preparing 6-hydroxynicotinic acid is also based on a method described by von Pechmann. 6-Hydroxynico-tinic acid has also been prepared by decarboxylation of 6-hy-droxy-2,3-pyridinedicarboxylic acid by heating 6-hydra-zinonicotinic acid or its hydrazide with hydrochloric acid by the action of carbon dioxide on the sodium salt of a-pyridone at 180-200 and 20 atmospheres by heating the nitrile of 6-chlo-ronicotinic acid with alcoholic sodium hydroxide or hydrochloric acid from 6-aminonicotinic acid and by the prolonged action of concentrated ammonium hydroxide on methyl cou-malate. ... 

R-methyl-2-pyridone- N-methyl-2-pyridone-3-carboxylic acid 3-carhoxylic acid amide... 

A third synthesis which has resulted in the preparation of rieinine and a number of its derivatives is due to Schroeter, Seidler, Sulzbacher and Kanitz,i2 who foimd that cyanoacetyl chloride polymerises spontaneously to 6-chloro-2 4-dihydroxy-3-cyano-pyridine. The di-sodium derivative of this with methyl sulphate produces A -methyl-6-chloro-4-hydroxy-3-cyano-2-pyridone (6-chlororicininic acid), the mono-sodium derivative of which, with methyl bromide or sulphate, is converted into 6-chlororicinine and the latter is reduced by zinc and sulphuric acid to rieinine. A fourth synthesis, starting from 3-nitro-4-pyridone, is due to Reitmann. ... 

In 1931 Ing pointed out that formula (II) and (III) do not contain methyl or potential methyl groups in j ositions 6 and 8 which they occupy in cytisoline. Further, a partially reduced quinoline ought to oxidise easily to a benzenecarboxylic acid and so far the only simple oxidation, products recorded from cytisine were ammonia, oxalic acid and isovaleric acid. Distillation of cytisine with zinc dust or soda-lime yields pyrrole and pyridine, but no quinoline. On these grounds Ing suggested that cytisine should be formulated without a quinoline nucleus, and that the reactions which indicate the presence of an aromatic nucleus in the alkaloid can be accounted for by an a-pyridone ring. This a-pyridone nucleus can... 

The importance of ring size holds also for tautomerism of -pyrrol-5-ones and. d -dihydro-6-pyridones. While the former compounds behave as cyclic 1-methyl-2-alkyl-2-hydroxy-5-pyrrolidones 179) (76) [or, on distillation, as the dehydrated l-methyl-2-alkyl-J -pyrrolones (77)], the latter compounds exist as acyclic N-methylamides of 8-oxo-acids (78) [as shown by infrared spectroscopy (/80)j. The dehydration of 78 during distillation to form l-methyl-2-alkyl-. -dihydro-6-pyridones (79) is achieved only with difficulty. 

Cyclic hydroxamic acids and V-hydroxyimides are sufficiently acidic to be (9-methylated with diazomethane, although caution is necessary because complex secondary reactions may occur. N-Hydroxyisatin (105) reacted with diazomethane in acetone to give the products of ring expansion and further methylation (131, R = H or CH3). The benzalphthalimidine system (132) could not be methylated satisfactorily with diazomethane, but the V-methoxy compound was readil3 obtained by alkylation with methyl iodide and potassium carbonate in acetone. In the pyridine series, 1-benzyl-oxy and l-allyloxy-2-pyridones were formed by thermal isomeriza-tion of the corresponding 2-alkyloxypyridine V-oxides at 100°. 

The corresponding [5,4-6]-compound (107) was prepared similarly and treated with methyl iodide to give a quaternary salt which was shown to have structure 108, because mild alkaline hydrolysis gave 3-acetamido-l-methyl-2-pyridone. Again, quaternization took place on the pyridine-nitrogen, which is different from the behavior of the corresponding 1,4-diazaindene mentioned above. 

Activated compounds such as 5-nitropyrimidin-2-one and 1-methyl-5-nitro-2-pyridone form the 2-chloro analogs with thionyl chloride 223b. 312b displacement of the —O—SO—Cl group. In reactions... 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

Chemistry, pharmacology, and clinical efficacy of the Chinese nootropic agent huperzine A, alkaloid from Hupenia sermta with annulated 2-pyridone and l-amino-3-methyl-9-ethylidenebicyclo[3.3.l]nona-2,6-diene fragments 99ACR641. 

The cyclization of the 1,3-enyne amines with cyanacetamide in the presence of bases (55°C, H2O, 2 h) leads to 3-cyano-6-methyl-2-pyridones (155), yield 77% (69ZOR1179). 

From monoalkylammobutenones and diketene at —5°C in benzene 3-acetyl-4-methyl-2(l//)-pyridones 300 are formed via the intermediate amides 299 (80MI1). 

Methyl- and 3-phenyl-4-hydroxy-2-oxo-2//-pyrido[2,1 -Z)]oxazinium inner salts were prepared in the reaction of 2-pyridone and 2-substituted malonyl chloride, prepared in situ from 2-substituted malonic acid with PCI5 in CH2CI2 (00JCS(P2)2096). 

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