Synthesis of 7-methyl-6-(nitroimidazolyl)thiopurines

We have studied the reactions of 7-methyl-6-thiopurine with 5(4)-halo-4(5)-nitroimidazoles and 6-chloro-7-methylpurine with sodium and ammonium salts of 5-mercapto-4-nitroimidazoles. We have obtained a series of 7-methyl-6-(nitroimidazolyl)thiopurines not previously described in the literature.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 217–220, February, 2000.     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

The dramatic effect of thiophenol on the reaction pathway of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with thiophenolates: ring expansion versus nucleophilic substitution

Ethyl 4-methyl-2-oxo-7-phenylthio-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylate and/or ethyl 6-methyl-2-oxo-4-(phenylthiomethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate were obtained in the reaction of ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with PhSNa or PhSK with or without PhSH, depending on the reagent ratio, reaction time, or temperature, as a result of ring expansion and/or nucleophilic substitution. The reaction pathway was affected strongly by the basicity-nucleophilicity of the reaction media. The results obtained were confirmed by reactions of 4-mesyloxymethyl-6-methyl-5-tosyltetrahydropyrimidin-2-one with PhSNa/PhSH and ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with NaCN/HCN or NaCH(COOEt)₂/CH₂(COOEt)₂.     

N1-Substitution in 2-methyl-4(5)nitroimidazole. III. New syntheses of 1-(2′-(ethylsulfonyl)ethyl)-2-methyl-5-nitroimidazole

Some new syntheses of 1-[2′-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole (IV), a new antitrichomonal agent are described. The most successful method proved to be alkylation of sodium ethanesulfinate (XXI) with 1-(2′-haloethyl)-2-methyl-5-nitroimidazoles (1a,b) in dimethylformamide.     

Synthesis of 2-amino-6-(nitroimidazolyl)thiopurines

We have synthesized a series of novel 2-amino-6-(nitroimidazolyl)thiopurines by reaction of thioguanine with 1-alkyl(1,2-dialkyl)-5-chloro-4-nitro-, 2-alkyl(1,2-dialkyl)-5-bromo-4-nitro-, and 1-alkyl(1,2-dialkyl)-4-chloro-5-nitroimidazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 221–224, February, 2000.     

Synthesis of novel isoxazolyl bis-thiazolo[3,2-a]pyrimidines

A new synthetic strategy for the synthesis of novel 3-(3-(3-methyl-4-nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl-7H-thiazolo[3,2-a]pyrimidin-3-yl)propyl)-5,7-diaryl-7H-thiazolo[3,2-a] pyrimidines(7a-i) analogues is described.Reaction of 3-(2(3-methyl-4-nitroisoxazole-5-yl)-1-phenylethyl)pentane-2,4-dione(3) with two moles of thiourea in presence of iodine and CuO afforded 4-(1-(2-aminothiazol-4-yl)-3-(3-methyl-4-nitroisoxazol-5-yl)-2-aryl propyl-thiazol-2-amine(5).Compound 5 on reaction with two moles of chalcone(6) furnished novel 3-(3-(3-methyl-4-nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl-7H-thiazolo[3,2a]pyrimidin-3-yl)propyl)-5,7-diaryl-7H-thiazolo[3,2-a] pyrimidines(7a-i).     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

冠醚苯并恶唑菁染料的合成

本文报道含冠迷苯并恶唑菁染料及半菁染料的合成,采用一种简便方法合成了关健中间体2-甲基6,7-二羟基苯并恶唑:从2,3,4-三羟基苯乙酮肟经beckmann重排而得到,将它再与三甘醇或四甘醇二氯化物反应 ,分别得到相应的冠醚化合物:2-甲基-6,7-并(12-冠-4)苯并恶唑和2-甲基-6,7-并(15-冠-5)苯并恶唑,将它们制成相应的季铵盐 ,然后分别与原甲酸乙酯或对二甲胺基甲醛作用,得到相应的冠醚恶唑菁染料,或半菁染料.     

Hydroxymethylation and cyanoethylation of nitroimidazoles

A series of nitroimidazoles were subjected to hydroxymethylations under a variety of conditions. Hydroxymethylation of 1-(2-hydroxyethyl), 1-(2-acetoxyethyl), and 1-(2-chloroethyl) substituted 5-nitroimidazoles with paraformaldehyde in dimethyl sulfoxide yielded the respective 2-hydroxymethyl analogs (5–7). However, attempts to hydroxymethylate 1-(2-hydroxyethyl), 1-(2-acetoxyethyl), 1-(2-cyanoethyl) substituted 4-nitroimidazoles and 1-(2-hydroxyethyl)-2-nitroimidazole were unsuccessful. Treatment of 1-(2-acetoxyethyl)-5-nitro-2-imidazolecar-baldehyde(10) with hydroxylamine-O-sulfonic acid afforded a mixture of corresponding 2-carbonitrile (12) and 2-(N-hydroxy)carboximidamide (13). Hydrolysis of 10 with ethanolic hydrochloric acid yielded 8-ethoxy-5,6-dihydro-3-nitro-8H-imidazo[2,1-c] [1,4]oxazine (11) which, on subsequent reaction with hydroxylamine-O-sulfonic acid, afforded 1-(2-hydroxyethyl)-5-nitroimidazole-2-(N-hydroxy)carboximidamide (15). Reaction of 4(5)-nitroimidazole with chloropropionitrile produced a mixture of the isomeric 1-(2-cyanoethyl) substituted 4- and 5-nitroimidazoles. Treatment of 2,4(5)-dinitroímidazole with chloropropionitrile afforded a mixture of 4(5)-chloro-5(4)-nitroimidazole and 1-(2-cyanoethyl)-4-nitro-5-chloroimidazoIe. Reaction of nitroimidazoles with acrylonitrile in the presence of Triton B yielded the corresponding 1-(2-cyanoethyl) substituted derivatives.     

Syntheses of substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles

Starting from readily available ethyl-4-nitropyrrole-2-carboxylate ( 1 ), substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles were prepared. The reaction of 1 with diazomethane gave ethyl 1-methyl-4-nitropyrrole-2-carboxylate ( 2 ). Reaction of compound 2 with hydrazine hydrate afforded the corresponding hydrazide 3 . The reaction of 3 with formic acid yielded 1-(1-methyl-4-nitropyrrole-2-carboxyl)-2-(formyl)hydrazine ( 7 ). Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 6 in 40% yield. Reaction of compound 7 with phosphorus pentoxide afforded compound 9 . Reaction of compound 3 with 1,1′-carboxyldiimidazole in the presence of triethylamine yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-oxadiazoline-4(H)-5-one ( 11 ). Refluxing compound 3 with cyanogen bromide in methanol gave compound 12 . Compound 13 could be obtained through the reaction of compound 3 with carbon disulfide in basic medium. Alkylation of compound 13 afforded the correspanding alkylthio derivative 14 . Reaction of 1-methyl-4-nitropyrrole-2-carboxylic acid ( 15 ) with thiosemicarbazide and phosphorus oxychloride gave 2-amino-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 16 ). Sandmeyer reaction of compound 16 yielded 2-chloro-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 17 ). Refluxing of the latter with thiourea afforded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazoline-4(H)-5-thione ( 18 ). Alkylation of compound 18 gave the corresponding alkylthio derivative 19 . Oxidation of the latter with hydrogen peroxide in acetic acid yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-5-methylsulfonyl-1,3,4-thiadiazole ( 20 ).     

Nitroimidazoles. V . Synthesis of 1-methyl-2-(2-methyl-4-thiazolyl)nitroimidazoles

Reaction of readily available 2-methyl-4-formylthiazole ( 1 ) with glyoxal and ammonia gave 2-(2-methyl-4-thiazolyl)imidazole ( 2 ). Nitration of 2 with a mixture of nitric acid-sulfuric acid at 100° yielded 2-(2-methyl-4-thiazolyl)-4,5-dinitroimidazole ( 3 ) as the sole reaction product, while nitration at 65° afforded 2-(2-methyl-4-thiazolyl)-4-(or 5)-nitroimidazole ( 4 ). N-Methylation of compound 4 in the presence of base gave 1-methyl-2-(2-methyl-4-thiazolyl)4-nitroimidazole ( 6 ), whereas N-methylation with diazomethane afforded 1-methyl-2-(2-methyl-4-thiazolyl)-5-nitroimidazole ( 5 ). N-Methylation of compound 3 yielded 1-methyl-2-(2-methyl-4-thiazolyl)-3,5-dinitroimidazole ( 7 ) in high yield.     

重氮萘酮在环醚中热解反应研究

三种带有不同取代基的重氮萘酮(la～1c)在THF和二氧六环中加热分解给出不同的产物。1-重氮-4-萘酮(1a)的热解产物主要是重氮萘酮热解后产生的烯酮卡宾(2a)与环醚开环后形成的聚合物;3-甲基-1-重氮-4-萘酮(1b)的热解产物比较复杂,除冠醚类产物之外,还有烯酮卡宾对四氢呋喃和二氧六环的C-H键的插入反应产物、螺环化合物、2-甲基萘酚以及难以分离的聚合物;3-硝基-1-重氮-4-萘酮(1c)的热解产物主要是聚合物,此外还有少量C－H键的插入反应产物和2-硝基萘酚。对重氮萘酮热解反应的机理作了讨论。     

Synthesis and structural modification of <Emphasis Type="Italic">tert</Emphasis>-butyl ester of 7α-chloro-2-(N,N-dimethylaminomethylene)-3-methyl-1,1-dioxoceph-3-em-4-carboxylic acid

The reaction of tert-butyl 7α-chloro-and 7-β-chloro-7α-isopropoxy-3-methyl-1,1-dioxoceph-3-em-4-carboxylates with the Vilsmeier reagent was carried out with introduction of N,N-dimethylaminomethylene group at position 2 in the E-and Z-isomeric forms. Prolonged treatment of tert-butyl 7α-chloro-3-methyl-2-(N,N-dimethylaminomethylene)-1,1-dioxoceph-3-em-4-carboxylate with hydroxylamine hydrochloride in acetonitrile at 40–50°C gave tert-butyl 10(S)-chloro-6-methyl-5-oxa-1,1,9-trioxo-1-thia-4,8-diazatricyclo[7,2,0,0^2,6]undecane-7(R)-carboxylate which isomerized into 1-tertbutoxycarbonylmethyl-3α-chloro-4-(5-methylisoxazole-4-sulfonyl)azetidin-2-one. In the case of tertbutyl 7β-chloro-7α-isopropoxy-3-methyl-2-(N,N-dimethylaminomethylen)-1,1-dioxoceph-3-em-4-carboxylate the analogous reaction gave tert-butyl 10β-chloro-(2S,6S,7S,10R,11R)-10α-isopropoxy-6-methyl-5-oxa-1,1,9-trioxo-1-thia-4,8-diazatricyclo[7,2,0,0^2,6]undecane-7(R)-carboxylate, the struc-ture of which was determined by 2D-NOESY two-dimensional spectroscopy. The compounds synthesized showed weak or no cytotoxic activity with respect to monolayers of cancer cells in vitro.     

Reaction of Aminobenzimidazoles with 4-Hydroxy-6-methyl-2-pyrone and 4-Hydroxycoumarine

6- and 7-(4-hydroxy-6-methyl-2-oxo-1-pyridyl)benzimidazoles and 1-(6- and 7-benzimidazolyl)-4-hydroxy-2-oxoquinolines were synthesized by reaction of aminobenzimidazoles with 4-hydroxy-6-methyl-2-pyrone and 4-hydroxycoumarine.     

Investigation of nitrogen- and sulfur-containing heterocycles

The reaction of 5-amino-4-chloro- and -4-methoxy-6~mercaptopyrimidines with 4-methoxy-, 4-amino-, and 2,4-diethoxyphenacyl chlorides has yielded 5-amino-4-chloro- and -4-methoxy-6-phenacylthiopyrimidines. The reaction of 2, 5-diamino-4-methyl-6-mercaptopyrimidine with 4-methoxyphenacyl chloride has yielded 2-amino-6-hydroxy-6-(4-methoxyphenyl)-4-methyl-5, 6-dihydropyrimido[4, 5-b]-1,4-thiazine, and that with 4-aminophenacyl chloride has yielded the corresponding 7H-pyrimido[4, 5-b]-1,4-thiazine.For part IV, see [1].     

An eta(6)-dienyne transition-metal complex

The ruthenium complexes, [(eta5-C5R5)Ru(CH3CN)3]PF6 (1-Cp*, R = Me; 1-Cp, R = H), underwent reaction with both 1-(2-chloro-1-methylvinyl)-2-pentynyl-(Z)-cyclopentene (6-Z) and 1-(2-chloro-1-methylvinyl)-2-pentynyl-(E)-cyclopentene (6-E) to give (eta5-C5R5)Ru[eta6-(5-chloro-4-methyl-6-propylindan)]PF6 (7-Cp*, R = Me; 7-Cp, R = H). In a similar fashion, reaction of 1-Cp and 1-Cp* with 1-isopropenyl-2-pent-1-ynylcyclopentene (8) led to the formation of (eta5-C5R5)Ru(eta6-4-methyl-6-propylindan)]PF6 (9-Cp*, R = Me; 9-Cp, R = H). The reaction of 1-Cp* with 8 at -60 degrees C in CDCl3 solution led to observation of the eta6-dienyne complex, (eta5-C5Me5)Ru[eta6-(1-isopropenyl-2-pent-1-ynylcyclopentene)]PF6 (10), by 1H NMR spectroscopy. Complexes 7-Cp and 10 were characterized by X-ray crystallographic analysis.     

3-Formylchromones IV. The rearrangement of 3-formylchromone enamines as a simple, facile route to novel pyrazolo[3,4-b]pyridines and the synthetic utility of the latter

One-pot and facile preparations of 6-(2-hydroxy-5-R-benzoyl)-4-methyl-2-R1- pyrazolo[3,4-b]pyridines 4a-o are described, using the reaction of 3-formyl chromones 1 with 5-amino-1-R1-pyrazoles 2. An enamine-intermediate 2-ethyloxy-6-R-3-(3-methyl-1- phenylpyrazol-5-ylaminomethylene)chroman-4-one 3 was isolated at lower temperatures. Acyloxy-derivatives 5 of compounds 4 were obtained by acylation with acid chlorides or acid anhydrides. Coumarins 6 substituted at the 3- and 4-positions were prepared from the pyrazolo[3,4-b]pyridines 4 by condensation reactions and hydrazones 7 were formed from their reaction with 2,4-dinitrophenyl hydrazine. Reactions under microwave irradiation proceeded significantly faster and with high yields.     

Synthesis and comparative study of reactivities of δ-lactone,estor group and oxazinone ring in coumarin derivatives towards carbon or nitrogen nucleophiles

Condensation of methyl 7-methylcoumarin-4-acetate ( 2 ) with primary amines and with anthranilic acid gave 7-methyl-2-oxo-N-aryl-2H-[1]-benzopyran-4-acetamide ( 4a—d ) and (7), respectively. Compound 7 underwent cyclization to give 2-(7-methyl-2-oxo-2H-[1]-benzopyran-4-yl)-methyl-4H-3,1-benzoxazin-4-one ( 3 ). The reaction of 3 with aromatic amines gave the corresponding quinazolone derivatives 5 which tautomerises to the thermodynamically more stable isomer 6 , whereas its reaction with Grignard reagents and aromatic aldehydes gave 8a, 8b , and 9a, 9b , respectively.     

Investigations on imidazoles 98. Reactions of nitrohaloimidazoles with amino acids

The reaction of 5-chloro(bromo)-1-methyl(1,2-dimethyl)-4-nitroimidazoles and 4-chloro-1-methyl-5-nitroimidazole with amino acids has been studied. This has enabled a series of N-(4-nitro-5-imidazolyl)- and N-(5-nitro-4-imidazolyl)-substituted amino acids to be synthesized. Esters of some of these acids have been obtained.For Part 97 see [1].Center for Drug Chemistry, All-Russian Research Institute for Pharmaceutical Chemistry, Moscow 119815. Novokuznetsk Research Institute for Pharmaceutical Chemistry, Novokuznetsk 654034, Russia. Zaporozhye State Medical University, Zaporozhye 330074, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 48–53, January, 1999.     

A convenient synthesis of novel pyridazino[3,4-b]quinoxaline and pyrazolo[3,4-b]quinoxaline utilizing 1,3-dipolar cycloaddition reaction

The reaction of 2,6-dichloroquinoxaline 4-oxide 4 with methylhydrazine gave 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5, whose reaction with dimethyl acetylenedicarboxylate or 2-chloroacrylonitrile resulted in the 1,3-dipolar cycloaddition reaction to afford 7-chloro-3,4-bismethoxycarbonyl-1-methyl-1,2-dihydropyridazino[3,4-b]quinoxaline 6 or 6-chloro-3-hydroxymethylene-1-methyl-2,3-dihydro-1H-pyrazolo[3,4-b] quinoxaline hydrochloride 7, respectively.