Synthesis of ethoxycarbonyl-1,4- and -1,2-dihydropyridinecarboxylic acid amides

3-Carbamoyl derivatives of 4-phenyl-5-ethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine were obtained by cyclocondensation of 2-benzylideneacetoacetic ester with -aminocrotonic acid amide or anilides. In the alkylation of 4-phenyl-5-ethoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid anilides the amido group is initially alkylated, after which the ring NH group is alkylated, while the thiocarbamoyl group is converted to a cyano group. Reduction of the pyridinium salts gave 3- and 5-carbamoyl derivatives of 4-phenyl-1,2,6-trimethyl-1,2-dihydropyridine-5- and -3-carboxylic acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1665–1673, December, 1991.     

Bridgehead nitrogen heterocycles. VI. The reaction of 1-amino- and 1,2-diaminopyridinium salts with β-dicarbonyl compounds

1,2-Diaminopyridinium iodide underwent reaction with ethyl acetoacetate to form 1,4-dihydro-2-methyl-4-oxopyrido[1,2-a]pyrimidin-1-ium iodide, and with acetyl acetone it gave 2,4-dimethylpyrido[1,2-a]pyrimidin-5-ium iodide. Though 2-acetylcyclohexanone gave the corresponding 5-methyl-1,2,3,4-tetrahydropyrido[1,2-a]quinazolin-11-ium iodide, no reaction was observed with 2,6-dimethyl-3,5-heptanedione, 1-benzoylacetone, 1,3-diphenyl-1,3-propanedione and its p-methoxyphenyl derivative. However, 1-aminopyridinium iodide and acetyl acetone in the presence of base gave 3-acetyl-2-methylpyrazolo[1,5-a]pyridine and 1-amino-2-methylpyridinium iodide yielded the corresponding 3-acetyl-2,7-dimethylpyrazolo[1,5-a]pyridine. With ethyl acetoacetate, the latter salt formed 3-ethoxycarbonyl-2,7-dimethylpyrazolo[1,5-a]pyridine but with 2,6-dimethyl substituents in the pyridine ring no condensation occurred. Reaction of 1-amino-2-methylpyridinium iodide with benzaldehyde gave N-benzalimino-2-methylpyridinium iodide which, on treatment with base, resulted in the formation of 2-picoline and benzonitrile, providing a convenient method of deamination.     

Synthesis of bisarylmethyl-substituted pyrimidines and quinolines

The condensation of 2-chloro-8-methylquinoline-3-carbaldehyde, 2-chloroand 2-chloro-7,8,9,10-tetrahydrobenzo[h]quinoline-3-carbaldehydes, 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde, 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde, and 2-chloropyrido[1,2-a]pirimidine-3-carbaldehyde with N-substituted anilines gave the corresponding diaryl(hetaryl)methanes.     

Synthesis and hydrazinolysis of β-(1,3,4-oxadiazol-2-yl)pyridines

Cyclization of the hydrazide of 5-ethoxycarbonyl-2,6-dimethylpyridine-3-carboxylic acid by acylation with aromatic or aliphatic acid chlorides with subsequent boiling in POCl₃ or heating in orthoformic acid gave the corresponding ethyl 2,6-dimethyl-5-(5-R-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate. The cyclization of the reaction products with hydrazine hydrate has been studied. Cyclization of the dihydrazide of 2,6-dimethyl-3,5-pyridinedicarboxylic acid under analogous conditions gave only 3,5-bis-(5-R-1,3,4-oxadiazol-2-yl)-2,6-dimethylpyridines, containing R = 2-FC₆H₄, H.     

Synthesis of 2,2-dimethyl-1,2-dihydrobenzo[<Emphasis Type="Italic">f</Emphasis>]-isoquinolines displaying antifungal activity

The reaction of 2,2-dimethyl-1,2-dihydrobenzo[f]isoquinoline with malonic acid gave (2,2-dimethyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-4-yl)acetic acid, the acid chloride of which readily forms esters with alcohols and phenols. Reaction of the same azomethine with thioglycolic acid leads to (2,2-di-methyl-1,2,3,4-tetrahydro-benzo[f]isoquinolin-4-yl)thioacetic acid. Activation of the initial azomethine by iodomethylation enables reaction with 1,3-indanedione to be carried out. The obtained substances display antifungal action.     

The Mannich reaction in the synthesis of N,S-containing heterocycles 3. Unexpected direction of the aminomethylation reaction of N-methylmorpholinium 1-amino-2,4-dicyano-4-ethoxycarbonyl-1,3-butadienethiolate. One stage cascade synthesis of new derivatives of pyrido[1,2-<Emphasis Type="Italic">a</Emphasis>][1,3,5]triazine

The interaction of N-methylmorpholinium 1-amino-2,4-dicyano-4-ethoxycarbonyl-1,3-butadienethiolate with primary amines and formaldehyde leads to the formation of ethyl esters of 7-cyano-6-thioxo-1,3,4,6-2H-pyrido[1,2-a][1,3,5]triazine-9-carboxylic acid in place of the expected derivatives of pyrido[2,1-b][1,3,5]thiadiazine. The structure of the ethyl ester of 7-cyano-3-phenyl-6-thioxo-1,3,4,6-2H-pyrido[1,2-a][1,3,5]triazine-9-carboxylic acid was demonstrated by X-ray structural analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1075–1081, July, 2007.     

Synthesis and properties of ethyl esters of some 1,2-dihydropyridine-3,5-dicarboxylic acids

The oxidation of diethyl 1-methyl- or 1-aryl-2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylates with hydrogen peroxide in the presence of perchloric acid gave the perchlorates of the corresponding pyridinium ions, the reduction of which with NaBH₄ is a preparative method for the synthesis of diethyl esters of 1-substituted 2,6-dimethyl-1,2-dihydropyridine-3,5-dicarboxylic acids. Derivatives of the 5-carboxylic acid of the corresponding 1,2-dihydropyridine are formed by alkaline hydrolysis of these esters.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1225–1228, September, 1982.     

A novel synthetic route to 1,2-dimethyl-5-phenyl-1H-imidazo[4,5-b]pyridin-7-ol

Heating a mixture of 4-amino-1,2-dimethyl-1H-imidazole-5-carboxylic acid ethyl ester with ethyl benzoyl acetate resulted in the formation of 8-ethoxycarbonyl-6,7-dimethyl-4-oxo-2-phenylimidazo[1,5-a]pyrimidin-5-ium, hydroxide, inner salt. This compound was then transformed into 1,2-dimethyl-5-phenyl-1H-imidazo-[4,5-b]pyridin-7-ol via several intermediates. A number of structurally interesting compounds were also isolated during the course of this work. Thus, the target ring system was formed by a circuitous series of ring-chain tautomerizations/rearrangements.     

Reduction and alkaline hydrolysis of 5-oxoindeno[1,2-b]pyridinium salts

5,9b-Dihydro derivatives of indeno[1,2-b]pyridine were obtained by the reduction of the corresponding 1,2-dimethyl-4-aryl-5-oxoindeno[1,2-b]pyridinium perchlorates. 1,2-Dimethyl-3-ethoxycarbonyl-4-phenyl-5-oxoindeno[1,2-b]pyridinium perchlorate forms in alkaline medium with splitting, recyclization and deamination products.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp 86–89, January, 1987.     

Synthesis and reactions of ethyl 3-acetyl-8-cyano-6,7-dimethylpyrrolo[1,2-a]pyrimidine-4-carboxylate and related compounds

The reactions of 3-acetyl-4-ethoxycarbonyl- or 3,4-diethoxycarbonylpyrrolo[1,2-a]pyrimidine derivatives 7a,b , which were prepared by condensation of the 2-aminopyrrole ( 4 ) with ethyl 3-ethoxymethylene-2,4-dioxovalerate ( 5a ) or ethyl ethoxymethyleneoxaloacetate ( 5b ), with diazomethane are described. Thus, reaction of 7a , with diazomethane gave ethyl 2a-acetyl-7-cyano-2a,3a-dihydro-5,6-dimethyl-3H -cyclopropa[e]pyrrolo[1,2-a]pyrimidine-3a-carboxylate ( 11 ) in 74% yield, which was readily transformed into the 1-pyrrol-2-yl-pyrrole ( 18 ) by treatment with potassium hydroxide. On the other hand, reaction of 7b with diazomethane afforded three products whose structures were assigned as diethyl 7-cyano-2a,3a-dihydro-5,6-dimethyl-3H-cyclopropa[e]pyrrolo[1,2-a]pyrimidine-2a,3a-carboxylate ( 20 ), 6-cyano-7,8-dimethyl-3a,3b,5,9a-tetrahydro-4H -aziridino[c]-1H or 3H-pyrazolo[3,4-e]pyrrolo[1,2-a]pyrimidine-3a,9a-dicarboxylates ( 21,22 ). Ring Transformation of 20 to 25 was not observed.     

4-Hydroxy-2-quinolones. 97. Simple synthesis of the esters of 4-halo-substituted 2-oxo-1,2-dihydroquinoline-3-carboxylic acids

Short term treatment of 3-ethoxycarbonyl-4-morpholino-2-oxo-1,2-dihydroquinoline with aqueous solutions of hydrohalogen acids leads to the formation of the ethyl esters of 4-halo-substituted 2-oxo-1,2-dihydroquinoline-3-carboxylic acids. Hydrolysis in HF is possible on extended boiling only to the 4-hydroxy derivative. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1022–1025, July, 2006.     

Synthesis and properties of amides of 2-substituted 3-aryl- and 3-pyridylaminoacrylic acids

The reaction of aryl- or pyridylamines with ethyl orthoformate and malonanilic acid gave amides of 2-(N-arylcarbamoyl)-, 2-cyano-, 2-ethoxycarbonyl-3-arylaminoacrylic acids and their corresponding 3-pyridyl analogs. IR and PMR spectroscopy indicates that these compounds exist in the enamine form with strong intramolecular hydrogen bonds. Amides of 3-(2-pyridylamino)-2-ethoxycarbonylacrylic acid cyclize to give amides of pyrido[1,2-a]pyrimidine-3-carboxylic acid, which react with hydrazine hydrate to give amides of 3-aminopyrazole-4-carboxylic acid.Perm Pharmaceutical Institute, 614000 Perm. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 629–633, May, 1994. Original article submitted February 8, 1994.     

An oxidation with thionyl chloride

The reaction of the 2-methylquinoline-3-carboxylic acid 1b with thionyl chloride gave the dichlorothiolactone 2 , the structure of which was confirmed by chemical transformations.     

Synthesis of Derivatives of 8-Cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridine and 9-Alkoxycarbonyl- (or 9-Carboxy)-3-ethoxycarbonyl-2-methyl-10H-benzo[b]-1,8-naphthyridine-5-one from the Reaction of 2-Chloro-5-ethoxycarbonyl-6-methylnicotinonitrile with Amino Acids

2-Substituted 8-cyano-6-ethoxycarbonyl-3-hydroxy-5-methylimidazo[1,2-a]pyridine was formed from the interaction of 2-chloro-5-ethoxycarbonyl-6-methylnicotinonitrile with -amino acids in DMF. The same nitrile on boiling with anthranilic acid or its esters in butanol gave, respectively, 2-(2-carboxyanilino)- or 2-(2-alkoxycarbonylanilino)-5-ethoxycarbonyl-6-methylnicotinonitriles which cyclized on heating in PPA to give 9-alkoxycarbonyl(or 9-carboxy)-3-ethoxycarbonyl-2-methyl-10H-benzo[b]-1,8-naphthyridin-5-ones.     

Synthesis of some bifunctional derivatives of 8-methylquinoline-5-carboxylic acid

Derivatives of 8-methylquinoline-5-carboxylic acid were synthesized. Alcoholysis of 8-methyl-5-cyanoquinoline gave methyl and ethyl 8-methylquinoline-5-carboxylates, which were converted to the corresponding 8-bromomethyl derivatives. The latter were used for the introduction of a methylamino group and the synthesis of N-acyl derivatives. The hydrazide, amide, and anilide of 8-methylquinoline-5-carboxylic acid were obtained as model compounds.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 785–788, June, 1982.     

Synthesis and reactions of esters of 3-cyano-2-OXO-5,6-tri(tetra)methylene-1,2-dihydroisonicotinic and 2-amino-3-Ethoxycarbonyl-5,6-tri(tetra)-methyleneisonicotinic acids

Esters of 3-cyano-2-oxo-5, 6-tri (tetra)-methylene-1, 2-dihydroisonicotinic and 2-amino-3-ethoxycarbonyl-5, 6-tri (tetra)methyleneisorticotinic acids have been obtained by the reaction of 2-oxocyclopentyl(hexyl)glyoxylic acid esters with malonic acid derivatives. Boiling the esters containing a tetramethylene ring with 75% sulfuric acid gave hydrolysis of the ester and cyano groups to carboxyl with subsequent decarboxylation at the 3 position and the formation of 2-oxo-5, 6-tetramethylene-1, 2-dihydroisonicotinic acid (2-oxo-1, 2, 5, 6, 7, 8-hexahydroquinoline-4-carboxylic acid).Perm Pharmaceutical Institute, Perm, 614000. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 370–373, March, 1996. Original article submitted July 10, 1995, revision submitted December 26, 1995.     

Naphthyridine studies. 15. 2-Styrylquinoline-3-carboxamides and their cyclization to 3-aryl-1-oxo-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines

Condensation of 2-methylquinoline-3-carboxamides or the acid nitrile with benzaldehydes gave 2-styrylquinoline-3-carboxamides or the nitrile. It was shown that these compounds cyclize to the 2-substituted 3-aryl-1-oxo-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines using pofyphosphoric acid or sulfuric acid.For Communication 14, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 92–94, January, 1992.     

New derivatives of quinaldin-4-ol

The synthesis and chemical reactions of 3-(3,3-dichloroallyl)-4-hydroxy-2-methylquinoline-6-carboxylic acid, 3-(2-carboxyethyl)-4-hydroxy-2-methylquinoline-6-carboxylic acid, and of derivatives of these acids are described.For Communication XVIII, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 6, No. 7, pp. 966–968, July, 1970.     

Study of the acylation reaction of 2,6-dimethyl-3,5-pyridinedicarboxylic acid hydrazides

Acylation of 3-ethoxycarbonyl-2,6-dimethyl-5-pyridinecarboxylic acid hydrazide and 2,6-dimethyl-3,5-pyridinedicarboxylic acid dihydrazide using aromatic acid chlorides gave the corresponding N-aroyl hydrazides. It was found that the hydrazinolysis of 3-ethoxycarbonyl-2,6-dimethyl-5-pyridinedicarboxylic acid N-aroyl hydrazides occurred not at the ester group but as a rehydrazinolysis reaction at the dihydrazide fragment. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1834–1845, December, 2005.     

Synthesis and alkylation of 4-aryl-5-oxo-1h-2,3,4,5-tetrahydroindeno[1,2-<Emphasis Type="Italic">b</Emphasis>]pyridines*

Reduction of 5-oxo-4-phenyl-1H-4,5-dihydroindeno[1,2-b]pyridines with triethylsilane in trifluoro-acetic acid gave the corresponding 1,2,3,4-tetrahydroindeno[1,2-b]pyridines predominatly with the trans-configured substituents at atoms C(2), C(3), and C(4). Alkylation of the anionic form of the tetrahydroindenopyridines gives the N- and C(4a)-alkyl derivatives.