A novel synthesis of N(1)-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

A new synthesis of N₁-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R₁ substituents.     

A novel synthesis of substituted 3-amino and 3-thio pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

Fervenulin is a natural product that has been extensively studied due to its molecular features and breadth of biological activities. Published studies have reported the generation of numerous analogues of the bicyclic pyrimidotriazinodione core. One underrepresented subclass are compounds with electron releasing atoms bonded directly to the C-3 position. We report an efficient and straightforward synthesis of compounds with substituted amino and thio functionality attached to the C-3 position. These are derived from a common 3-chloro precursor that is made in six steps in 15.8% overall yield from a starting chlorouracil. Our methodology should be applicable to the synthesis of C-3 ether congeners also, and through previously described chemistry be expandable to incorporating diversity at the N-6 position of the pyrimidotriazinodione core. The chemistry reported herein expands possibilities for the generation of diverse libraries of substituted pyrimidotriazinediones for future studies.     

Pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazine-7,9(6H8H)-diones

Some 5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazine-7,9-(6H,8H)-diones (4 a–d) have been synthesised by the condensation of 3-alkyl-4-amino-5-mercapto-(1,2,4)-triazoles (1 a–d) with 5-bromobarbituric acid (2a). Similarly some 9a-nitro-5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazine-7,9(8H,9aH)-diones (5 a–d) have been obtained by the condensation of1 a–d with 5-bromo-5-nitrobarbituric acid (2b) and final cyclisation withPPA. The structures have been confirmed by PMR spectra and analytical results.

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Pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazin-7,9(6H,8H)-dione

Zusammenfassung Es wurden einige 5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazin-7,9(6H,8H)-dione (4 a–d) mittels Kondensation von 3-Alkyl-4-amino-5-mercapto-(1,2,4)-triazolen (1 a–d) mit 5-Brombarbitursäure (2 a) dargestellt. Des weiteren wurden einige 9a-Nitro-5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazin-7,9(8H,9aH)-dione (5 a–d) über die Kondensation von1 a–d mit 5-Brom-5-nitrobarbitursäure (2 b) und anschließender Cyclisierung mitPPA synthetisiert. Die angeführten Strukturen wurden mittels PMR-Spektren und analytischen Daten abgesichert.

     

Synthesis of selected 3-substituted-pyrimido[5,4-e]1,2,4-triazine-5,7-diamines as potential folate antagonists

3-(Anilinomethy1) 3-[(arylthio)methy1]pyrimido[5,4-e]-1,2,4-triazine-5,7-diamines were prepared by ring closure of 6-hydrazino-4-[(phenylmethy1)thio]-2.5-pyrimidinediamine. these nonclassical analogs of known potent dihydrofolate reductase inhibitors were inactive against malarial infections in mice and L1210 leukemia in vitro.     

Facile and efficient synthesis of 5,7-disubstituted thiazolo[5,4-d] pyrimidine-4,6(5H,7H)-diones

A facile and efficient approach was developed to access 5,7-disubstitued thiazolo[5,4-d]pyrimidine-4,6(5H,7H)-diones through condensation of N-substituted 5-amino-4-carbethoxythiazole with structurally diverse isocyanates in the presence of sodium hydride.The easy availability of substrates and tolerance of structural diversity in this reaction make it attractive to be used for construction of libraries in drug discovery process.     

Sequence of the conversion of pyrimido [5,4-e]-1,2,4-triazinediones to imidazo[4,5-e]-1,2,4-triazinones

The conversion of pyrimido[5,4-e]-1,2,4-triazinediones to imidazo[4,5-e]-1,2,4-triazinones is a multistage process including the hydrolysis of the C₍₅₎-N₍₆₎ amide bond, the closure of the ureido group to the imidazolidinone ring, decarboxylation, acid oxidation.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1252–1259, September, 1987.     

A novel synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones

An improved synthesis of 3-(substituted)pyrimido[4,5-c]pyridazine-5,7(1H,6H)-diones, a known subclass of 4-deazatoxoflavins, is reported. The approach involves treatment of 3-methyl-6-(1-methylhydrazinyl)uracil with representative phenyl and alkyl glyoxal monohydrates, which in turn are obtained by selenium dioxide oxidation of the corresponding phenyl and alkyl methyl ketones. The first entry into 4-monosubstituted isomers is also reported.     

Synthesis of pyrido[2,3-d]pyrimidine-2,4-diones from pyrimido-[4,5-e]-1,2,4-triazine-6,8-diones by reversed azadiene synthesis

It was shown that pyrimido[4,5-e]-1,2,4-triazine-6,8-diones enter the reversed azadiene synthesis reaction with ketones and vinyl ethyl ether in the presence of diethylamine or boron trifluoride etherate, and also with enamines. As a result of the reaction, pyrido[2,3-d]pyrimidine-2,4-diones are formed in good yield. Pyrimido[5,4-e]-1,2,4-triazine-5,7-diones do not undergo such reactions with acetone. The reasons for the unique behavior of the isomeric pyrimidotriazinediones in the reaction with acetone are discussed.For a preliminary communication, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 224–233, February, 1990.     

New organic nitrates. II. Synthesis of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazin-2,4(3H)-diones

The preparation and the physico-chemical characterization of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazine-2,4(3H)-diones are reported.     

New Facile Route to Synthesize Furo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine and Furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives

A new facile route for synthesis of 3-(aryl)-8,9-diphenylfuro[3,2-e][1,2,4]triazolo pyrimidines derivative from the same starting material, 2-amino-4,5-diphenylfuran-3-carbonitrile, has been developed through heterocyclization of the corresponding arylidene-hydrazono-5,6-diphenylfuro[2,3-d]pyrimidine and N-(arylmethylene)-4-imino-5,6-diphenylfuro[2,3-d]pyrimidin-3(4H)-amine under refluxing condition with acetic anhydride followed by air oxidation. The products were obtained in good yield with an easy workup along with the purification of products by a nonchromatographic method. This general synthetic procedure can be extended to the preparation of a wide range of isomeric triazoles using 2-amino 3-carbonitrile bifunctional derivatives.     

Bisindoles. 20. Synthesis of 3H,8H-indolo[4,5-e]- and -[5,4-e]indole systems

New heterocyclic systems, viz., 3H,8H-indolo[4,5-e]indole and 3H,8H-indolo-[5,4-e]indole, which were also obtained from the corresponding pyruvic acid dihydrazones, were synthesized by cyclization of ethyl pyruvate 2,7- and 2,6-naphthylenedihydrazones and subsequent saponification and decarboxylation of the cyclization products. The syn-syn, syn-anti, and anti-anti forms of the dihydrazones were isolated and characterized.See [1] for Communication 19.Translated from Khimiya Geterotsiklcheskikh Soedinenii, No. 3, pp. 352–357, March, 1984.     

A study of the products of the reduction of the antibiotic reumycin (6-methylpyrimido [5,4-e][1,2,4]triazine-5,7-dione)

The structures of the products of the reduction of the antibiotic reumycin (I), which is a specific autooxidizable acceptor of reducing equivalents from certain flavin dehydrogenases of the respiratory chain of the mitochondria of yeast and animal tissues, have been established with the aid of physicochemical methods (UV, IR, and PMR spectroscopy and mass spectrometry). In the determination of the structures of five reduction products of reumycin effective use has been made of high-resolution mass spectrometry and a consideration of the spectra of metastable ions (the DADI technique). It has been shown that only the asym-triazine ring in the initial (I) undergoes reduction and ring-opening.All-Union Scientific-Research Institute of Antibiotics, Moscow Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 85–95, January–February, 1981.     

Bisindoles. 25. Properties of 3h,8h-indolo[4,5-e]- and -[5,4-e]indole

Electrophilic-substitution reactions for 3H,8H-indolo[4,5-e]- and -[5,4-e]indole were studied. Mono- and disubstituted compounds were isolated as a result of formylation and acetylation, whereas only monosubstitution products were isolated in the case if diazo coupling. It is shown that in the dimethylaminomethylation of 3H,8H-indolo[4,5-e]indole steric factors hinder the formation of a disubstituted compound, while the formation of \-substitution products is hindered in the case of diazo coupling of 3H,8H-indolo[4,5-e]- and-[5,4-e]indole.See [1] for Communication 24.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1205–1212, September, 1988.     

Condensed isoquinolines. 19. Synthesis of 1′-R-spiro[6a,11b-diazabenz[e]aceanthrylene-6(7H),4′ (1′H)-pyridine]-5,7(12H)-diones

During acylation of 7-isonicotinoyl-6,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one or its alkylation followed by treatment with organic bases, spirocyclization occurs with formation of derivatives of a novel heterocyclic system: 1′-acyl-and 1′-alkylspiro[7H,12H-6a,11b-diazabenz[e]aceanthrylene-6(5H),4′(1′ H)-pyridine]-5,7-diones. We have studied the spectral properties of the synthesized spirans. We have shown that 7-nicotinoyl-6,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one does not undergo an analogous reaction of repeated acylation, while treatment of its quaternary salt with bases leads to a complex mixture of unidentified products. For Communication 18, see [1]. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 113–122, January, 2006.     

Electron ionization mass spectra of aryl- and benzyl-substituted 2,3-dihydroimidazo[1,2-a]pyrimidine-5,7(1H,6H)-diones

The electron ionization mass spectra of the 1-phenyl-, 1-benzyl- and 6-benzyl-1-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidine-5,7(1H,6H)-dione derivatives were recorded at 70 eV to find out the effects of substituents on their fragmentations. Fragmentation pathways were studied using B/E and B(2)/E scans. Some fragmentations involved the loss of C(3)HO(2) or carbon suboxide. The possibility of keto-enol tautomerism was also studied. For comparison selected compounds were studied using (1)H and (13)C NMR spectroscopy to reveal the presence of possible tautomerism. Some ions including [M-OH](+) and [M-HCO](+) and NMR results indicate that the enol form is predominant both in the gas and in the liquid phase.