Synthesis of alkyl- and phenyl-substituted 4-aminomethyl-2-buten-4-olides

4-Aminomethyl-2-buten-4-olides, 5-hydroxy-5,6-dihydro-2-pyridone, and isomeric 8,9-dihydro-4-cyano-2-oxofuro[2,3-c]piperidines were obtained by the base-catalyzed cyclization of 5-amino-4-hydroxy-4-alkyl-2-pentenoic acid esters. 5-Di-methylamino-3-methyl-4-oxovaleric acid ester and 4-dimethylamino-2-buten-4-olide, respectively, were isolated by isomerization of 5-dimethylamino-3-methyl-4-hydroxy-2-pentenoic acid ester and 4-dimethylamino-2-penten-5-olide in the presence of sodium isopropoxide.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1313–1319, October, 1987.     

Synthesis of Pyridazinone Derivatives

The reaction of methyl esters of 3-methyl-2-oxo- and 2-oxo-3-phenyl-3-pentenoic acids with hydrazine hydrate and phenylhydrazine was used to synthesize new pyridazinone derivatives. These products are formed through intermediate hydrazides with subsequent cyclization. 4-Hydroxy-3-oxotetrahydropyridazines are mainly formed using equimolar amounts of the starting reagents, while the corresponding hydrazones of 3,4-dioxohexahydropyridazines are formed in the case of a two-fold excess of hydrazine hydrate or phenylhydrazine. Evidence was obtained indicating the existence of a keto–enol tautomerism for 4-hydroxy-3-oxopyridazines.     

Synthese der diastereomeren 4-Amino- und 4-Hydroxy-3-(p-chlorphenyl)-valeriansäuren. Kristallstruktur von cis-4-(p-bromphenyl)-5-methyl-2-pyrrolidinon

Synthesis of 4-amino- and 4-hydroxy-3-(p-chlorophenyl)-valeric acids. X-ray structure of cis-4-(p-bromophenyl)-5-methyl-2-pyrrolidinone The syntheses of diastereomeric 4-amino- and 4-hydroxy-3-(p-chlorophenyl)-valeric acids and of their ring closure products (lactones and lactams), starting from 3-(p-chlorophenyl)-4-oxo-valeric acid, are described. A single-crystal X-ray structure analysis of cis-4-(p-bromophenyl)-5-methyl-2-pyrrolidinone is given. Some aspects of the biochemistry of threo-3-(p-chlorophenyl)-4-amino-valeric acid are presented.     

Acylpyruvic acid amides and hydrazides: XII. Reaction of 4-Aryl-2-hydroxy-4-oxo-2-butenic acids arylamides with triphenylphosphoranylideneacetic acid esters

4-Aryl-2-hydroxy-4-oxo-2-butenic (aroylpyruvic) acid arylamides react with triphenylphosphoranylidenacetic acid esters to form products of Wittig reaction at α-carbonyl group, the 5-aryl-3-arylaminocar-bonyl-5-oxo-3-pentenoic acid esters. Features in structure of the obtained compounds are discussed.     

Synthesis of 3-methyl-4-cyano-3-butenoic acid amides and their cyclization into 6-amino-2-pyridones

Two groups of amides, derivatives of 3-methyl-4-cyano- and 3-methyl-4-cyano-4-carbethoxy-3 acids were obtained from acetoacetamides in the form of mixtures of Z, E-isomers and the pure E-isomers were isolated. It was shown that amides from the first group are cyclized by bases into the corresponding 6-amino-4-methyl-2-pyridones and amides from the second group are cyclized into 6-hydroxy-5-cyano-4-methyl-2-pyridones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1636–1640, December 1992.     

Synthesis of 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-3,4′-bipyridine-3′-carboxylic and 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic esters and investigation of their stability. 2. Esters of 6′-carbamoylmethyl-thio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3-carboxylic acids

The stability of solutions of esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic acids was investigated by HPLC. The corresponding esters of 6′-carbamoylmethylthio-5′-cyano-4,4′-bipyridine-3′-carboxylic acids,esters of 8-cyano-5-methyl-3-oxo-7-(4-pyridyl)-2,3-dihydro-7H-thiazolo-[3,2-a]pyridine-6-carboxylic acids, methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate, and methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-thieno[2,3-b]pyridine-5-carboxylate were synthesized as standard compounds (typical impurities). Analysis by HPLC was realized under the conditions of reverse-phase chromatography. It was established that solutions of the investigated compounds (with mixtures of acetonitrile with phosphate buffer, having pH values of not less than 3 and not more than 5, as solvents) are stable for one month when the solutions are stored in a place protected against light. It is also necessary to use chromatographic systems in which the aqueous components have pH 3–5 during determination of the purity of the esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4, 4′-bipyridine-3′-carboxylic acid by HPLC in order to separate the analyzed sorbates and their typical impurities more completely. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 841–848, June, 2007.     

Synthesis of alkyl-substituted 2-halo-4-aminomethyl-2-buten-4-olides

The reaction of esters of alkyl-substituted (E)-5-amino-4-hydroxy-2,3,epoxyvaleric acids with some hydrohalic acids gave the corresponding 2-halo-4-amino-methyl-2-buten-4-olides, the hydrochlorides of which have diuretic activity.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1471–1474, November, 1985.     

Reaction of 2,6-dibutylaminohepta-2,5-dien-4-one with malononitrile

Malononitrile reacted with the title compound to give 6-amino-5-cyano-2-(3,3-dicyano-2-methylallylidene-4-methyl-2H-pyran (3). Treatment of 3 with hot 80% sulfuric acid yielded 4,7-dimethyl-56-hydroxy-2(1H)quinolone. With concentrated aqueous sodium hydroxide, 3 gave 5-amino-3,6-dicyano-4,7-dimethyl-2(1H)quinolone and 5-amino-6-carbamoyl-3-cyano-4,7-dimethyl-2(1H)quinolone. The reaction of 3 with hydrochloric in acetic acid gave a mixture of 6-amino-3,7-dicyano-2,8-dimethyl-4-quinolizone and 3-cyano-4-methyl-6-(3,3-dicyano-2-methylallyl)-2-pyrone. Compound 3 also reacted with methylamine, butylamine and piperidine to give 8-amino-5-cyano-4-methyl-2-pyridone, 6-bulylamino-5-cyano-4-methyl-2-pyridone and 5-eyano-4-methyl-6-piperidino-2-pyridone respectively.     

Synthesis of polyheterocyclic compounds derived from 6-amino- 4-aryl-2-r-4h-furo[2,3-<Emphasis Type="Italic">b</Emphasis>]pyran-5-carbonitriles

Syntheses were developed for 4-aryl-6-ethoxy-2-R-furo[2,3-b]pyridine-5-carbonitriles and ethyl esters of 5-amino-4-aryl-7-methyl-2-R-1,9-dioxa-8-azacyclopenta[b]naphthalene-6-carboxylic acids based on the reaction of 6-amino-4-aryl-2-R-4H-furo[2,3-b]pyran-5-carbonitriles with ethyl acetoacetate and nucleophilic recyclization. The mechanisms of these reactions are considered.     

Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles. VIII. Synthesis of ethyl and methyl 2,4-disubstituted 5-pyrimidinecarboxylates

Reaction of ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates with N-C-N dinucleophiles such as guanidine, acetamidine or benzamidine afforded in high yields the relative esters of 4-substituted 2-amino-, 2-methyl- or 2-phenyl-5-pyrimidinecarboxylic acids, respectively. These esters were hydrolyzed to the corresponding carboxylic acids, which were converted by heating to 4-substituted 2-pyrimidinamines, 2-methyl or 2-phenylpyrimidines, respectively, generally in excellent yields. The 4-unsubstituted ethyl 2-amino-, 2-methyl- and 2-phenyl-5-pyrimidinecarboxylates were obtained in moderate yields by reaction of the above dinucleophiles with ethyl 2,2-diformylacetate. These esters were hydrolyzed and the corresponding acids (with the exception of the 2-methyl derivative) were decarboxylated to give 2-pyrimidinamine and 2-phenylpyrimidine in satisfactory yields.     

Synthesis and reduction of esters of N-(4-amino-5-nitro-6-pyrimidyl)amino acids

The reaction of esters of amino acids with 4-amino-6-chloro-5-nitropyrimidine has yielded esters of (4-amino-5-nitro-6-pyrimidyl)amino acids. The reduction of the esters of -(4-amino-5-nitro-6-pyrimidylamino) acids has yielded 4-amino-6-hydroxy-7,8-dihydropteridines. -(4-Amino-5-nitro-6-pyrimidylamino) acids and the ester of N-(4-amino-5-nitro-6-pyrimidyl)--alanine do not cyclize and on reduction give the corresponding diaminopyrimidine derivatives.     

Synthesis of 2-dialkylaminomethyltetrahydrofuran-3-ols

The reaction of esters of 4-R-3-methyl-2,3,4,5-diepoxyvaleric acids with secondary amines leads to the formation of esters of 4-R-5-dialkylamino-4-hydroxy-3-methyl-2,3-epoxyvaleric acids. The reduction of the latter with lithium tetrahydroaluminate and the cyclization of the reduction products in the presence of p-toluenesulfonic acid has given 2-dialkylaminoethyltetrahydrofuran-3-ols, the methiodides of which possess ganglion-blocking activity.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1443–1446, November, 1973.     

4-Hydroxy-2-quinolones. 90. Synthesis and antitubercular activity of 4-methyl-2-thiazolylamides of halo-substituted 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acids

Several variants were studied for the synthesis of esters of halogen derivatives of 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acids, whose reaction with 2-amino-4-methylthiazole gives the corresponding hetarylamides. Results are given for a study of the antitubercular activity of these products. Communication 89, see ref. [1]. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 71–76, January, 2006.     

Analogs of D(+)-pantothenic acid. VI. Synthesis of D-, L-, and DL-4′-amino-4′-deoxypantothenic acid

A new analog of pantothenic acid, DL-4-amino-2-hydroxy-3,3-dimethylbutanoic acid, has been synthesized and it has been separated into stereoisomer. D-, L-, and DL-N-(4-Amino-2-hydroxy-3,3-dimethylbutyryl)-β-alanines — amino analogs of pantothenic acid — have been synthesized by the condensation of the N-hydroxysuccinimide esters of N-BOC-D-, -L-, and -DL-4-amino-2-hydroxy-3,3-dimethylbutanoic acids with β-alanine, followed by the elimination of the protective groups.     

Homochiral 4-hydroxy-5-hexenoic acids and their derivatives and homologues from carbohydrates

Efficient routes to chiral 4-hydroxy-5-hexenoic acids and lactones from d-gluconic acid-δ-lactone and l-mannonic acid-γ-lactone are described. In this approach, the starting lactones are converted to 2,6-dibromo compounds that readily undergo zinc mediated elimination to generate the terminal alkene group in concert with 2-deoxygenation. The integrity of the remaining stereocenters is preserved during the reaction. The related important pharmaceutical intermediates (S)-3-hydroxy-4-pentenoic acid and (S)-1,3-dihydroxy-4-pentene were also prepared from 2-deoxyribose via the corresponding aldonolactone.     

Reactions of regioisomeric 3,3-dimethyl- and 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyrones with N-nucleophiles

Reactions of 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyrone with ethylenediamine, hydrazine, or hydroxylamine yield 5-methyl-7-trifluoromethyl-2,3-dihydro-1H-1,4-diazepine, 3(5)-(2-hydroxy-2-methylpropyl)-5(3)-trifluoromethylpyrazole, and 5-hydroxy-3-(2-hydroxy-2-methylpropyl)-5-triflouromethyl-Δ², respectively. The same compounds were obtained from 2-amino-1,1,1-trifluoro-6-hydroxy-6-methylhept-2(Z)-en-4-one and 2-hydroxy-6, 6-dimethyl-2-trifluoromethyltetrahydro-4-pyrone.     

Naphth[1,2-d]oxazole intermediates in the preparation of 3-hydroxy-4-(1-alkyl-3-methyl-5-hydroxy-4-pyrazolyl)-azo-1-naphthalenesulfonamide dyes

Acylation of 4-amino-3-hydroxy-1-naphthalenesulfonic acid ( 3 ) with benzoyl chloride in pyridine gave pyridinium 3-hydroxy-4-(N-benzoylamino)-1-naphthalenesulfonate ( 12 ) which was converted by thionyl chloride followed by diethylamine into N,N-diethyl-2-phenylnaphth[1,2-d]oxazole-5-sulfonamide ( 14 ). The naphthoxazole moiety was hydrolyzed with potassium hydroxide and the resulting N,N-diethyl-4-amino-3-hydroxy-1-naphthalenesulfonamide ( 11 ) coupled with 1-alkyl-3-methyl-5-pyrazolones. The 2-phenylnaphth[1,2-d]oxazole intermediates and various by-products were investigated.     

New 4-quinaldinol derivatives XVII. 2-Methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxyquinoline-6-carboxylic acid and some of its transformations

1-(2-Methyl-4-hydroxy-6-carboxy-3-quinolinyl)-3-butanone and 1-(2-methyl-4-chloro-6-carboxy-3-quinolinyl)-3-butanone were obtained by the acid hydrolysis of 2-methyl-3-(3-chloro-2-buten-1-yl)-4-hydroxy(chloro)quinoline-6-carboxylic acids and their esters.See [6] for communication XVI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1681–1682, December, 1971.     

On the formation of homo-azasteroidal esters of N,N-bis(2-chloroethyl)aminobenzoic acid isomers and their antitumor activity

The N, N-bis(2-chloroethyl)aminobenzoate isomers and the 4-methyl-3-N, N-bis(2-chloro-ethyl)aminobenzoate of 3β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5-androsten-17-oic-13,17-lactam and 17β-hydroxy-3-aza-A-homo-4α-androsten-4-one, have been prepared and their biological activity evaluated against P388 leukemia in vivo and Ehrlich Ascites tumor (EAT), P388 and L1210 leukemias and Baby Hamster cells (BHK) in vitro. The esters in which the alkylating congener is linked to the lactam alcohol in the axial position are inactive in vivo in P388 leukemia, while compounds 1, 4, 6, 13, 14 and the alkylating congeners 17, 18 and 20 are active. The effect of the homo-azasteroidal of N, N-bis(2-chloroethyl)aminobenzoic acid isomers and of 4-methyl-3-N, N-bis(2-chloroethyl)aminobenzoic acid on the incorporation of the radioactive precursor into the DNA of L1210, P388 leukemias, Ehrlich ascites tumor and, baby Hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursor was obtained with the ortho derivatives, yielding <70% inhibition of thymidine incorporation in all tumor lines tested.     

Synthesis of N-substituted 3-hydroxy-2-methyl-4-pyridones and -pyridonimines

Carbohydrates with 1,4 glycosidic bonds like maltose, lactose, dextrin or starch react with primary amines as well as amino acids or proteins to give i.e. 3-hydroxy-2-methyl-4-pyridones 5 and 3-hydroxy-2-methyl-4-pyridonimines 7. A generally applicable synthesis of compounds of this type is described. The pyridones 5 and pyridonimines 7 are strongly complexing agents. Molybdenum-derivatives, for instance, are suitable as fairly stable oxidation catalysts.