4-Aminopyridine-3-carboxylates

When pyrimidinone 3 is treated with ethyl 3-oxobutanoate 19a in the presence of ammonium acetate, a different type of TCRT proceeds, giving ethyl 4-aminopyridine-3-carboxylate 41a (Table 10) [59]. In this reaction, pyrimidinone 3 behaves as the synthetic equivalent of activated diformylamine 5, and the amino group at the 4-position is derived from ammonium acetate. Since 3-ethoxycarbonyl-4-pyridone 14a prepared in Sect. 5.2 is intact under the same conditions, aminopyridine 41a is not formed via pyridone 14a. Furthermore, ammonium ion also causes no change on ethyl 3-oxobutanoate 19a, which indicates enamine is not dinucleophilic reagent in the present reaction. Hence, the keto ester moiety is converted to the enaminone after the addition of 19a to pyrimidinone 3. 

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... 

With p-ketoesters, 5,6-cycloalkeno-4-aminopyridine-3-carboxylates 32 are obtained. 

A new metabolite, 4-aminopyridine-2,3-dicarboxylic acid, was recently isolated from C. acromelalga in a yield of 0.000056% based on the weight of frozen fruiting bodies (41)5). A lethal effect of this compound on mice has not been observed however, bioactivity is still expected because of the similarity of its structure to the physiologicaUy active pyridine-2,3-dicarboxylic acid. The structure of this compound was deduced from H-NMR, C-NMR, and mass spectra, and the position of the substituents was assumed from comparison with clitidine, which contains a 4-aminopyridine-3-carboxylic acid moiety. The structural proposal was confirmed by synthesis from 2,3-dimethyl-4-nitropyridine 1-oxide (Scheme 91) when this compound was subjected to successive reduction and oxidation it yielded a product identical to the one occurring naturally. 

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. ... 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

Reaction of 2-aminopyridine with ethyl 2-cyano-3-ethoxy-3-methyl-, -3-ethyl-, -3-phenylacrylates and ethyl 2-ethoxycarbonyl-3-ethoxy-3-methyl-, -3-phenylacrylates in boiling xylene yielded 2-substituted 4/f-pyrido[l,2-u]pyrimidine-3-carbonitriles and -3-carboxylates (99MI7). Similar reactions of 2-aminopyridine with 2-cyano-3-ethoxyacrylonitrile and its 3-methyl, 3-ethyl, -3-phenyl derivatives in boiling MeCN afforded 4-imino-4//-pyrido[l,2-u]-pyrimidine-3-carbonitrile and its 2-substituted derivatives. 

Reaction of pyridinium-A -(2-pyridyl)amidine (402) and alkyl haloace-tates in the presence of K2CO3 afforded a mixture of 4-oxo-4/f-pyrido[l, 2-u]pyrimidine-2-carboxylates 407 and 2-aminopyridine derivatives 406 through intermediers 403- 05, as depicted in Scheme 15 (00TL5837). Compound 406 could be cyclized on the action of heat or silica gel into 407. The best yield was achieved in the case of ethyl bromoacetate. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

The reactions of ethyl 2-aminopyridine-4- and-5-carboxylates, ethyl orthoformate, and diethyl malonate in the presence of ZnCl, at 100-120°C for 15 min afforded 2-pyridylaminomethylenemalonates (264) in 53-71% yields (78MI5). 

Aminopyridine was reacted with diethyl bis(methylthio)methylene-malonate at 150°C for 24 hr, then at 180°C for 6 h, to give 2-methylthiopyri-do[l,2-a]pyrimidine 3-carboxylate (351) in 29% yield (88CP1232904). 

When 3-aminopyridine was reacted with EMME in Dowtherm A, first at 150°C for 1 hr and then at boiling temperature for 1 hr, ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate was obtained in 73-82% yields (46JA-1317). 

Shvo and Israelstam obtained pyrido[l,2-a]pyrimidine-3-carboxylate (1002, R = R1 = H), when 2-aminopyridine was reacted with EMME in polyphosphoric acid at 110-120°C for 2-3 hr (68JOC3015). 

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). 

Solventless reaction of 6-bromo-8-cyclopentyl-2-methylsulfinyl-8//-pyrido[2,3-r7 pyrimidin-7-one 195 with tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l-carboxylate 196 at 120 °C for 1 h followed by deprotection in the presence of gaseous HCl afforded the amine derivative 197 (Equation 14) <2003W02003062236>. 

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