2-Aminopyridine-3-carboxylic acid

Mendel44 found that reaction of 2-aminopyridine-3-carboxylic acid with ethyl acetoacetate or ethyl benzoylacetate gave rise to a decarboxylated product (36 R1 = Me, Ph R = R2 = H), whereas with ethyl 4,4,4-tri-fluoroacetoacetate, the product was ethyl 2-aminopyridine-3-carboxylate. Yale51 obtained 3-benzoyl-2-hydroxy-4-oxo-4ff-pyrido[ 1,2-a] pyrimidine in 4- 5%, yield from 2-amino-3-methylpyridine and ethyl benzoylacetate in diethylbenzene. 

N-Methylformamide converted 2-aminopyridine-3-carboxylic acid to 3-methylpyrido[2,3-d]pyrimidin-4-one (5 hr at 180°C) in good yield.290 The same reagent also made 3-methyl-6-nitroquinazolin-4-one from 2-amino-5-nitrobenzoic acid in excellent yield some slowly reacting 2-aminobenzoic acids were assisted with phosphoryl chloride.291 A moderate yield of 3-phenylquinazolin-4-one was obtained from the action of formani-lide on 2-aminobenzoic acid (90 min at 140°C).282... 

In 1872, Griess fused urea and 2-aminobenzoic acid and, although unaware of the nature of his product, had made quinazoline-2,4-dione. Since that time, the reaction has been frequently used for converting C-substituted 2-aminobenzoic acids to their corresponding quinazoline-2,4-diones in excellent yields, usually at 190°-200°C maintained for 1-5 hr.307,308 In addition, 2-aminopyridine-3-carboxylic acid and urea, slowly heated to 210°C, gave a good yield of pyrido[2,3-rf]pyrimidine-2,4-dione.286 Pyrido-[3,4-d]pyrimidine-2,4-dione was formed similarly (yield not given).288... 

Thiourea, although a successful reagent for the o-aminoamides, has yet to establish itself in the o-amino acid series. Of the few known examples of its use, 2-aminobenzoic acid and thiourea at 170°C gave 2-thioxoqui-nazolin-4-one,310 and IV-phenylthiourea produced the 3-phenyl derivative311 in unstated (but apparently low) yields. Again, 2-aminopyridine-3-carboxylic acid and thiourea, at 210°C for only 5 min, gave a low yield of 2-thioxo-pyrido[2,3-d]pyrimidin-4-one (see 3).286... 

Aminopyridine-3-carboxylic acid (2-aminonicotinic acid) (CgHgOzNa)... 

Aminopicolinic Acid or Aminopyridinecarboxy lie A ctt/( Amino-pyridin-carbonsaure, in Ger), HaN(CBNH3)COOH. Aminopicolinic acids are aminopyridine carboxylic acids in which the carboxyl group is attached in position 2 (next to the nuclear N). Two isomers, 3-amino- and 4-amino- are described in Beil 22,541 [463]. If the carboxyl is attached to position 3 of aminopyridinic acid, the compd is called aminonicotinic flcirf(qv)... 

Considerable interest has been shown in the formation of hydrogen bond-mediated (discrete) cyclic assemblies incorporating between three and ten component molecules. A few hydrogen bonding motifs have dominated these studies. These include cyanuric acid-melamine contacts, 2-aminopyridine-carboxylic acid contacts and carboxylic acid or pyridone dimer contacts. While individual hydrogen bonding interactions of this type are often weak (with association constants of... 

Nitriles and imidates have found little use, so far. Heating propionitrile and 2-aminobenzoic acid at 210°C in a closed vessel gave only a low yield of 2-methylquinazolin-4-one.297 Anthranilic add and 10 of its C-substituted derivatives were refluxed (5-50 hr) with ethyl acetimidate and benzimidate in methanol to give 2-methyl- and 2-phenylquinazolin-4-ones, respectively, in moderate yields three aminopyridine carboxylic acids behaved similarly.298 JV-Phenylbenzimidoyl chloride [PhC(NPh)Cl] and ammonium 2-aminobenzoate, in cold acetone, produced 2,3-diphenylquinazolin-4-one in good yield.299... 

Supplement 1953 3242-3457 Hydroxy-carboxylic acids, 190 In i doxylic acid, 226. Carbonyl-carboxylic acids, 284. i Sulphonic acids, 386 Quinoline sul-phonic acid, 390. Amines, 419 2-Aminopyridine, 428. Amino-carboxylic acids, 541 Tryp- tophane, 545. Hydrazines, 563. Azo. compounds, 572. Diazo compounds, 590. ... 

There has been considerable interest in hydroxy-3,3 -bipyridines and 3,3 -bipyridinones. Following from some very early work on the oxidation of citrazinic acid (2,6-dihydroxypyridine-4-carboxylic acid), which was considered to give some polyhydroxy-3,3 -bipyridines, it has been shown that the 3,3 -bipyridinone 59, a product of the hydrolysis of a natural blue pigment from Corynehacterium insidiosum, is obtained by oxidation of 2-hydroxy-5-aminopyridine (60) or 2,6-dihydroxypyridine-4-carboxylic acid 61) 80,83 similar oxidation of 2,6-dihydroxy-3-aminopyridine-4-carboxylic acid affords the natural product indigoidine (20). Numerous related oxidative condensations have been reported subsequently. Cyano-acetamide condensations analogous to those discussed in the synthesis of 2,3 -bipyridines afford, for example, the cyano-substituted 3,3 -bipyridinone 62 588 v, lereas condensation of 3-pyridylacetonitrile with ethyl phenyl-propiolate and ethanol affords compound 63. To complete the section on... 

The application of the Friedlander reaction to 3-aminopyridine-2-carbaldehyde (135) gives good yields of the 2,3-disubstituted 1,5-naphthyridines (136) (75CR(C)(280)38l). The intramolecular cyclization of /3- (3-aminopyridinyl)acrylic acid (137) results in the formation of l,5-naphthyridin-2-one (138) (66JHC357), whilst the condensation of 3-aminopyridine-2-carboxylic acid or its esters (139) with active methylene compounds yields 4-oxo (132) and 4-hydroxy-2-oxo compounds (134 R = H) after hydrolysis and decarboxylation of the intermediates (140) and (134 R = C02Et). Reductive cyclization of the 3-nitropyridine derivative (141) gives the 1,5-naphthyridine (142) (71JOC450). 

Aminopyridine has been prepared by heating nicotinamide in an alkaline potassium hypobromite solution at 70° by hydrolysis of 8-pyridylurethan with oleum by heating 3-amino-pyridine-2-carboxylic acid at 250° by reduction of 3-nitro-pyridine with zinc and hydrochloric acid and by heating 3-bromopyridine with ammonia and copper sulfate in a sealed tube. ... 

The synthesis of a number of substituted thioureides by treatment of isothiocyanates 2 and 30-32 with aniline, 2-aminopyridine, 1-adamantyl-amine, benzylamine, 2-aminobenzimidazole, 2-aminobenzothiazole, o-bromoaniline, 2-aminopyridine, 5-amino-1 -phenylpyrazole-4-carboxylic acid, and various classes of sulfamines, in benzene or xylene solution, has been reported.54... 

Adams and Pachter found that the reaction of 2-aminopyridine and 2-bromoacrylic acid yields a mixture of 2-oxo-2//-pyrido[ l,2-a]pyrimidine (18) and 3,4-dihydroimidazo[l,2-a]pyridine-2-carboxylic acid (17). The product ratio was dependent upon the reaction conditions.18... 

Depending on the reaction conditions, alkaline hydrolysis of the 3-alkoxycarbonylpyrido[l,2-a]pyrimidines (71) afforded the corresponding pyrido [ 1,2- ]pyrimidine-3-carboxylic acids,18148 pyridylaminoacrylates (73 R = H)256 or 2-aminopyridines.126 Acidic hydrolysis produced the half-ester of 70.75 133-148... 

Aminopyridine and isopropylidene (methylthio)methylenemalonates 184 were reacted in refluxing ethanol to give 2-substituted 4-oxo-4H-pyridof 1,2-a]pyrimidine-3-carboxylic acids 185 (89S317). 2-Methylthio-4-oxo-47/-pyrido[ 1,2-a]pyrimidine-3-nitrile was formed in the reaction of 2-aminopyridine and ethyl bis(methylthio)methylenecyanoacetate (91MI17). 

The electrochemical behavior of malonyl-a-aminopyridines 661 was investigated by Gullu et al. in acetonitrile or a mixture of trifluoroacetic acid and dichloromethane containing tetrabutylammonium tetrafluoro-borate or triethylammonium trifluoroacetate in a water-jacketed, two-compartment glass cell equipped with a platinum disk anode at 1.50 V (Ag/ Ag+) and a carbon-rod secondary electrode (91T675). Controlled potential anodic oxidation of 661 afforded labile coupled carboxylic acids 662 (R2 = COOH), which easily decarboxylated to compounds 662 (R2 = H) under the work-up conditions. Sometimes, the carboxylic acid 662 (R2 = COOH) could be isolated or when the reaction mixture was treated with methanol, methyl ester 662 (R = H, R1 = Bu, R2 = COOMe) was obtained in 40% yield. 

On the basis of the above experimental facts, enaminones 42 are considered to be usable as the dinucleophilic reagents for the RTF reaction leading to 4-aminopyridine-3-carboxylic acid derivatives 41 (Table 11) [60]. Enaminones 42 are readily prepared by only mixing 1,3-dicarbonyl compounds 19 and amines without solvent. When enaminone 42i derived from ethyl ace-toacetate 19a and propylamine is used, the RTF reaction proceeds to afford ethyl AT-propyl-4-aminopyridine-3-carboxylate 41i in 88% yield. The amino group of 41 is easily modified by changing amine, and pyridine-3-carboxylic... 

Since the introduction in 1963 of nalidixic acid (N -ethyl-7-methyl-4-oxo-l,4-dihydro[l,8]-naphthyridinyl-3-carboxylic acid) as a systemic Gram-negative antibacterial agent, many related derivatives have been synthesized. These types of compounds have received much attention and interest by virtue of their chemical and clinical properties. The methods reported in the chemical literature for preparing C-6- and C-3-substituted 4-oxo[1.8]naphthyridines are somewhat limited. These methods involve the condensation of substituted 2-aminopyridines with suitable 3-ethoxyacrylates, followed by cyclization. Recently, such substituted 4-oxo-l,4-dihydro[1.8]naphthyridines have been obtained using the Suzuki reaction (Eq. (38)) [69]. 

The presence of electron-withdrawing substituents at C(4) facilitates reactions with nucleophiles, which may well be initiated by attack at C(5). Thus oxazole-4-aldehydes undergo ring-fission on treatment with aqueous alkali to form (acylamino)malondialdehydes (equation 3), and 2-pentyloxazole-4-carboxylic acid yields 2-pentylimidazole, with concomitant decarboxylation, when heated with ammonia at 150 °C. An example of a more complex ring transformation is the formation of 3-aminopyridines (131) by the action of malononitrile on 4-acetyloxazoles under alkaline conditions (equation 4). 

Fig. 14 Robust hydrogen bonding observed between a carboxylic acid and an aminopyridine...

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