Evaluation of pyrimido[5,4-d]pyrimidine derivatives as peroxyoxalate chemiluminescence reagents using a flow injection system

Eighteen kinds of pyrimido[5,4-d]pyrimidines together with several commercially available fluorescent compounds such as perylene, Rhodamine B, etc., were evaluated as the reagents for a peroxyoxalate chemiluminescence (CL) detection system by using a flow injection method. The peroxyoxalate CL reaction employed consists of bis(2,4,6-trichlorophenyl)oxalate, hydrogen peroxide, triethylamine, and a fluorophore. Under the conditions used, 2,6-bis[di-(2-hydroxyethyl)amino]-4,8- dipiperidinopyrimido[5,4-d]pyrimidine (Dipyridamole) and 2,4,6,8-tetrathiomorpholinopyrimido[5,4-d]pyrimidine (1i) gave very intense chemiluminescence intensities which were larger than those of any other commercially available fluorescent compounds tested (e.g., 10 times larger than that of perylene).     

Sequential approach to the synthesis of 'U and Z' shaped polycyclic heteroarenes

The synthesis of three new classes of heteroarenes, built through the sequential fusion of naphthalene, benzo/naphtho[b]oxepine and thiochromene rings with pyran and pyrimidine ring systems to give 'U and Z' shaped structural frameworks is reported. The methodology is based on the synthesis of pyran fused intermediates, 1-methylthio-3-oxo-5,6-dihydro-3H-benzo[f]chromene-2-carbonitrile (3), 4-methylthio-2-oxo-5,6-dihydro-2H-benzo/naphtho[b]pyrano[2,3-d]oxepine-3-carbonitriles (10, 20) and 4-methylthio-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles (15) from the reaction of 2-tetralone, benzo/naphtho[b]oxepin-5-ones and thiochromen-4-ones with methyl 2-cyano-3,3-dimethylthioacrylate respectively. Further condensation of intermediates 3, 10, 20 and 15 with amidines led to the formation of tetracyclic 'U' shaped 4-amino-2-aryl-7,8-dihydro-5-oxo-5H-naphtho[2,1-b]pyrimido[4,5-d]pyrans (8) and 'Z' shaped 4-amino-2-aryl-5-oxo-12,13-dihydro-5H-benzo/naphtho[b]oxepino[5,4-b]pyrimido[4,5-d]pyrans (12, 22) and 4-amino-2-aryl-5-oxo-5,12-dihydrothiochromeno[4,3-b]pyrimido[4,5-d]pyrans (17). Compound 12f forms a chain of dimers through N-HO interactions as indicated by the X-ray structure analysis, and the quantum chemical calculations performed at the MP2 level indicate that this interaction energy is 10 kJ mol(-1).     

Study of Nitrogen- and Sulfur-Containing Heterocycles. 57. Synthesis and Conversion of 4′-Substituted 5-(5-Amino-6-Pyrimidylthio)-2,2-Dimethyl-4,6-Dioxo-1,3-Dioxanes

By reaction of 4-substituted 5-amino-6-mercaptopyrimidines with 5-bromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, we have obtained 4′-substituted 5-(5-amino-6-pyrimidylthio)-2,2-dimethyl-4,6-dioxo-1,3-dioxanes. We have studied diazotization of these compounds by isoamyl nitrite. In the case of 4′-methoxy- and 4′-dimethylamino-substituted derivatives, we have obtained derivatives of novel heterocyclic systems: pyrimido[5,4-e][1,3,4]thiadiazine and pyrimido[5,4-e][1,3,4]thiadiazine-7-spiro-5′-1,3-dioxane, and in the case of the 4′-isopropylamino-substituted derivative we obtained 4-isopropyl-7-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1,2,3-triazolo[5,4-d]pyrimidin-7-ylidene.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 613–623, April, 2005.     

Study of the nucleophilic substitution reactions of 2,4,10-trichloropyrimido[5,4-b]quinoline

A number of pyrimido[5,4-b]quinoline derivatives were synthesized. It is shown that in the reaction of 2,4,10-trichloropyrimido[5,4-b]quinoline (II) with strong nucleophilic reagents (OCH₃ and SH) both of the halogens of the pyrimidine ring are replaced, while with amines substitution of the halogens of the pyrimidine ring proceeds successively; under more severe conditions, all three halogen atoms of II are replaced by amine residues.     

An expedient synthesis of novel,fused pyrimido[4,5‐d]pyrimidine and pyrimido [5,4‐e] [1,2,4]triazolo[4,3‐c]pyrimidine analogues from 4‐amino‐2,6‐dichloro‐pyrimidine

A number of potent pyrimido[4,5‐d]pyrimidine have efficiently been synthesized by the condensation of 4‐amino‐2,6‐dichloropyrimidine with various substituted benzaldehyde followed by cyclization with ammonium thiocyanate. Also, these newly synthesized derivatives were utilized for the construction of novel pyrimido[5,4‐e][1,2,4]triazolo[4,3‐c]pyrimidine analogues via oxidative cyclization involving 1,5‐hydrogen abstraction. Structure of all the newly constructed derivatives was corroborated by the elemental and spectral data. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:245–253, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20177     

噻唑并嘧啶类化合物的合成研究进展

综述了在医药和农药领域具有广泛用途的噻唑并嘧啶类化合物近二十年来合成方法上的研究进展. 结合本研究组在这一领域的工作介绍了噻唑并嘧啶类化合物的三种主要结构类型: 噻唑并[3,2-a]嘧啶、噻唑并[4,5-d]嘧啶、噻唑并[5,4-d]嘧啶类化合物的相关合成方法及新进展.     

多聚磷酸存在下取代6-苄硫基嘧啶与羧酸的环合反应研究

以多聚磷酸(PPA)为催化剂, 对取代6-苄硫基嘧啶与羧酸的反应进行了研究. 当羧酸为脂肪酸时, 在60-80 ℃下反应, 可选择性地得到6-苄硫基嘌呤衍生物; 改用芳香酸时, 则得到硫上的苄基被脱除的6-巯基嘌呤和嘧啶并[5,4-d]噻唑; 如果将嘧啶4-位上伯胺取代基变成仲胺取代基, 只得到嘧啶并[5,4-d]噻唑. 通过双途径反应机理对上述现象进行了解释.     

Synthesis and reactions of 2,4-disubstituted benzo[b]furano-, benzo[b]thieno- and indolo[3,2-d]-1,3-oxazinium salts

Under acid catalyzed acylation 3-acetamidobenzo[b]furan, -benzo[b]tkiophene, and indole undergo heterocyclization to condensed 1,3-oxazinium salts. Treatment of the salts with ammonium acetate in acetic acid gives the corresponding benzo[b]furano- and benzo[b]thieno[3,2-d]pyrimidines and 2-acetyl-3-acetamidoindole gives pyrimido [5,4-d] indole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1569–1571, November, 1990.     

2-Alkyl-4-oxohexahydropyrimido[4,5-<Emphasis Type="Italic">d</Emphasis>]- and -[5,4-<Emphasis Type="Italic">d</Emphasis>]azocines

It has been established that 2-R-4-oxotetrahydropyrido[4,3-d]pyrimidines, under the action of activated alkynes in methanol, form a mixture of 2-R-4-oxohexahydropyrimido[4,5-d]azocines and products of decomposition of the tetrahydropyridine ring, the 2-R-5-methoxymethyl-4-oxo-6-vinylaminoethyl-pyrimidines. Tetrahydropyrido[3,4-d]pyrimidine, isomeric at the junction of the pyrimidine and tetrahydropyridine rings, forms only the corresponding pyrimido[5,4-d]azocine, the product of expansion, under the action of methyl propiolate.     

3,4-二胺-1H-吡唑并[5,4-d]嘧啶的固相合成

用固相合成技术合成了吡唑并[5,4-d]嘧啶的一类衍生物8.以Merrifield树脂为原料,与化合物3反应得到树脂4.4经过还原胺化、取代、分子内亲核加成反应得到树脂7,再由三氟醋酸断裂得到化合物3,4-二胺-1H-吡唑并[5,4-d]嘧啶.     

2-Benzazepines. 7. Synthesis of pyrimido[5,4-d][2]benzazepines

Two novel syntheses of pyrimido[5,4-d][2]benzazepines are described. The first synthesis started with 3-phenylphthalide which in three steps was converted to a functionalized pyrimidine which was cyclized to give the 2-benzazepine ring system. The second approach used o-benzoylbenzoic acid methyl ester as the starting material, which in four steps was converted to a functionalized pyrimidine which was cyclized to give a 2-benzazepine. Pyrimido[5,4-d][2]benzazepines have been found to have activity in standard central nervous system (CNS) pharmacological tests.     

Traceless solid-phase synthesis of bicyclic dihydropyrimidones using multidirectional cyclization cleavage

Solid-phase and solution-phase protocols for the synthesis of furo[3,4-d]pyrimidines, pyrrolo[3,4-d]pyrimidines, and pyrimido[4,5-d]pyridazines are reported. The multistep solid-phase sequence involves the initial high-speed, microwave-promoted acetoacetylation of hydroxymethylpolystyrene resin with methyl 4-chloroacetoacetate. The immobilized 4-chloroacetoacetate precursor was subsequently subjected to three-component Biginelli-type condensations employing urea and a variety of aromatic aldehydes. The resulting 6-chloromethyl-functionalized resin-bound dihydropyrimidones served as common chemical platforms for the generation of the desired heterobicyclic scaffolds using three different traceless cyclative cleavage strategies. The corresponding furo[3,4-d]pyrimidines were obtained by microwave flash heating in a rapid, thermally triggered, cyclative release. Treatment of the chloromethyl dihydropyrimidone intermediates with a variety of primary amines followed by high-temperature microwave heating furnished the anticipated pyrrolo[3,4-d]pyrimidine scaffolds via nucleophilic cyclative cleavage. In a similar way, reaction with monosubstituted hydrazines resulted in the formation of pyrimido[4,5-d]pyridazines. All compounds were obtained in moderate to good overall yields and purities.     

Functionalization of 2-Amino-3-benzyl-6-(benzylthio)pyrimidin-4(3H)-one: An Efficient Access to the Synthesis of Polycyclic Pyrimidine Scaffolds

Russian Journal of General Chemistry - 2-Aminouracil is used in the synthesis of a new series of tri- and tetracyclic pyrimidine scaffolds as the precursor. Thiazolo[5,4-d]triazolo[4,3-a]pyrimidine...     

Studies with Heterocyclic β‐Enaminoniriles: A Simple Route for the Synthesis of Polyfunctionally Substituted Thiophene,Imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene and Thieno[3,2‐d]pyrimidine Derivatives

Reaction of 3,5‐diaminothiophene‐2‐carbonitrile derivatives 3a‐c with ethoxycarbonylmethyl isothiocyanate and/or N‐[bis(methylthio)methylene]glycine ethyl ester led to formation of 7‐substituted‐8‐amino‐5‐thioxo‐6H‐imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one derivatives 6a‐c and 7‐substituted‐8‐amino‐5‐(methylthio)imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one 7a‐c , respectively. Also, the synthetic potential of the β‐enaminonitrile moiety in 3a‐c has been explored; it proved to be a promising candiate for the synthesis of 1,6‐disubstituted‐2,4‐diamino‐7,8‐dihydro‐8‐oxopyrrolo[1,2‐a]thieno[2,3‐e]pyrimidine derivatives 10a‐f and pyrido[2′,3′:6,5]pyrimido[3,4‐a]benzimidazole derivatives 12a,b .     

Synthesis of novel benzo[b]pyrimido[4',5':5,4]thieno[2,3-e][1,6]naphthyridine-8-ones via Pictet–Spengler cyclization

An efficient method for the synthesis of novel benzo[b]pyrimido[4',5':5,4]thieno[2,3e]-[1,6]naphthyridine-8-one derivatives via Pictet–Spengler cyclization is reported. The reaction of 4-(3-aminopyrimido[4,5-d]thieno-2-yl)quinoline-2-ones, which could be obtained from Thorpe–Ziegler isomerization of 4-bromomethylquinoline-2-ones and 5-cyano-1,6-dihydro-4-methyl-2-phenyl-6-thioxopyrimidine,with aromatic aldehydes in the presence of BF_3·OEt_2 gives pyrimidothieno[1,6]naphthyridines in good yields.     

5-Acetyl-6-amino-4-methylthio-2-phenylpyrimidine and its use in the synthesis of functionalized pyrido[2,3-d]pyrimidines and pyrimido-[4,5-d]pyrimidines

Schemes for the synthesis of MeS-substituted pyrido[2,3-d]pyrimidin-5-one, pyrimido[4,5-d]pyrimidine, and 4-methylenepyrimido[4,5-d]pyrimidin-2-one based on 5-acetyl-6-amino-4-methylthio-2-phenylpyrimidine, which was prepared from the adduct of benzoyl isothiocyanate with acetylketeneN-benzoylaminal, were suggested.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1324–1328, July, 1995.The work was carried out with financial support from the Russian Foundation for Basic Research (Grant No. 94-03-08964).     

Synthesis of 2,4-diamino-5-acetyl(ethoxycarbonyl)pyrimidines from β-dicarbonyl compounds and dicyandiamide and their use for building a pyrimido[4,5-d]pyrimidine system

2,4-Diamino-5-acetyl(ethoxycarbonyl)-6-methyl(phenyl)pyrimidines were obtained by the reaction of acetylacetone and -ketocarboxylic acid esters with dicyandiamide in the presence of Ni(OAc)₂. It was shown that annelation of the pyrimidine ring with this compound provides a convenient method for building the pyrimido[4,5-d]-pyrimidine system. New derivatives of 2-aminopyrimido[4,5-d]pyrimidine, 7-amino-3H-pyrimido[4,5-d]-pyrimidin-4-one, and 7-amino-1H,3H-pyrimido[4,5-d]-pyrimidine-2,4-dione were synthesized.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, pp. 159–164, January, 1991.     

The synthesis of pyrimido[4,5-c]pyridazines and pyrimido[5,4-c]pyridazines

The Hofmann reaction on 6-methylpyridazine-3,4-dicarboxamide (1) gave a mixture of 3-methylpyrimido[4,5-c]pyridazine-5,7-dione (2), 3-methylpyrimido[5,4-c]pyridazine-6,8-dione (3) and an acid (4) of unknown structure. The Hofmann reaction on pyridazine-3,4-dicarboxamide (9) gave a mixture of pyrimido[4,5-c]pyridazine-5,7-dione ( 10 ) and an acid ( 11 ) of unknown structure. The reaction of 3-amino-6-methylpyridazine-4-carboxamide ( 18 ) with ethyl orthoformate gave 3-methylpyrimido[4,5-c]pyridazin-5-one ( 21 ). 4-Aminopyridazine-3-carboxamide ( 36 ) upon fusion with urea gave pyrimido[5,4-c]pyridazine-6,8-dione ( 37 ) while with ethyl orthoformate 36 gave pyrimido[5,4-c]pyridazin-8-one ( 38 ). Pyrimido[5,4-c]-pyridazine-8-thione ( 39 ) was obtained by the action of phosphorus pentasulfide on 38. 4-Amino-3-cyanopyridazine ( 16 ) when treated with formamide produced 8-aminopyrimido[5,4-c]-pyridazine ( 41 ). The synthesis of 4-aminopyridazine-3-carboxamide ( 36 ) and 4-amino-3-cyanopyridazine ( 16 ), both key intermediates in the synthesis of the novel pyrimido[5,4-c]pyridazine ring system was accomplished by the Reissert reaction of 4-aminopyridazine-2-oxides and subsequent conversion of the nitrile to the amide.     

A simple and efficient one-pot novel synthesis of pyrazolo[3,4-b][1,8]naphthyridine and pyrazolo[3,4-d]pyrimido[1,2-a]pyrimidine derivatives as anti-inflammatory agents

Research on Chemical Intermediates - An efficient one-pot synthesis of novel pyrazolo[3,4-b][1,8]naphthyridine and pyrazolo[3,4-d]pyrimido[1,2-a]pyrimidine derivatives has been investigated from...     

Synthesis of pyrido[2,3-b]indoles and pyrimidoindoles via Pd-catalyzed amidation and cyclization

Biologically and pharmaceutically active core structures containing a new class of 4-hydroxy-α-carbolines, dihydropyrido[2,3-b]indoles, pyrimido[4,5-b] and [5,4-b]indoles have been synthesized in good yields via Pd-catalyzed amidation and cyclizations. The keto-enol tautomerism in 4-hydroxy-α-carbolines has been investigated by DFT calculations and spectroscopic techniques. The fluorescence studies of pyrimido[4,5-b] and [5,4-b]indoles were carried out with good quantum yields.