Facile synthesis of 5-amino- and 7-amino-6-azaoxindole derivatives

An efficient approach for the formation of 5-amino- and 7-amino-6-azaoxindole derivatives was developed. 2-Amino-4-chloro-3-nitropyridine (8), and its 5-nitro-substituted regioisomer (9), respectively, were obtained by reaction with ethyl malonate. The resulting 2-amino-3/5-nitropyridine derivatives substituted in the 4-position with malonic acid diethyl ester (10, 11) were subjected to reductive cyclization yielding 3-ethoxycarbonyl-6-azaoxindole derivatives 4a and 5a. Protection of the amino function was not required. Intermediates 10 and 11 could also be converted to the corresponding 4-acetic acid ethyl esters 12 and 13 by dealkoxycarbonylation with LiCl, and subsequently cyclized under reductive conditions yielding 3-unsubstituted 5-/7-aminooxazindoles.     

Azaindole derivatives. 67. Synthesis of N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles

N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles have been synthesized from the respective 1-benzyl-4-methyl-5-cyano-6-chloro(and 6-hydroxy)-7-azaindoles. The effect of the 5-cyano group on the oxidation-reduction processes accompanying nucleophilic replacement of chlorine in 6-chloro-7-azaindoles by primary and secondary amines has been considered. 7-Azaindoline compounds were dehydrogenated by chloranil to N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles.For communication 66, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 91–96, January, 1986.     

Synthesis and properties of sym-triazine derivatives. 7. Synthesis of pyridyl-substituted 2-amino- and 2,4-diamino-sym-triazines

N-Substituted 2,4-diamino-6-pyridyl-sym-triazines were synthesized by cyclocondensation of pyridinecarboxylic acid esters with biguanides. 4,6-Disubstituted 2-amino-sym-triazines containing pyridyl residues were obtained by the reaction of pyridinecarboxylic acid nitriles with guanidine or of pyridinecarboxylic acid esters with N-imidoylguanidines. Aminotriazines of this type are also formed in the condensation of N-acylguanidines with nitriles or imino esters. The general principles of the fragmentation of 2-amino-4-dialkylamino-6-pyridyl-sym-triazines under the influence of electron impact were established.See [1] for Communication 6.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 674–680, May, 1988.     

N8-芳基取代4-氨基-6-氯-7(8H)-蝶啶酮的合成

通过N4-芳基取代4,5,6-三氨基嘧啶与草酸二水合物环合, 得到N8-芳基取代4-氨基-5,8二氢-6,7-蝶啶二酮, 再经氯代, 得到新型N8-芳基取代4-氨基-6-氯-7(8H)-蝶啶酮, 用红外光谱、核磁共振氢谱、核磁共振碳谱、质谱和元素分析确证了其结构. 用X-ray单晶衍射测定了4-氨基-6-氯-8-对甲苯基-7(8H)-蝶啶酮(3a)的晶体结构, 证明了环合反应的区域选择性.     

Synthesis and properties of carbamoyl derivatives of 5-hydroxy-3,3,5-trimethylisoxazolidine

The reaction of 5-hydroxy-3,3,5-trimethylisoxazolidine with alkyl (or aryl) isocyanates gives N-alkyl(aryl)-carbamoyl-5-hydroxy-3,3,5-trimethylisoxazolidines, which react with methanol in the presence of p-toluenesulfonic acid to give 5-methoxy-1-carbamoyl derivatives of isoxazolidine. When arylcarbamoyl-5-hydroxy-3,3,5-trimethylisoxazolidines are heated in carbon tetrachloride, they are converted to O-arylcarbamoyl-N-(2-methyl-4-oxo-2-pentyl)hydroxylamines, the treatment of which with hydrogen chloride in benzene made it possible to isolate 1,2,6-oxadiazepin-7-ones along with the hydrochloride of the given compounds.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 746–750, June, 1979.     

Synthesis of 6-substituted 5-cyano-7-hydroxy-2-carboxybenzofurans

Methods for the synthesis of 5-cyano-7-hydroxy-2-carboxybenzofurans bearing a variety of substituents at the 6-position are outlined. The scope and limitations of lithiation processes, electrophilic substitutions, and pericyclic reactions are investigated.     

The tautomerism of 6-hydroxy-, 6-amino- and 6-acylamino-7-azaindolines

The lactam-lactim tautomerism of 6-hydroxy-7-azaindolines and amino-imine tautomerism of 6-amino- and 6-acylamino-7-azaindolines has been studied by IR and UV spectroscopy. It is shown that the lactam-lactim tautomeric equilibrium of 6-hydroxy-7-azaindolines in contrast to the other analogous N-heteroaromatic compounds is not completely shifted for the lactam. The commensurable amounts of both tautomeric forms can be observed in the solutions of 6-hydroxy-7-azaindolines and it is possible to elucidate the influence of the solvent polarity upon the lactam-lactim tautomeric equilibrium. The tautomeric equilibrium of 6-amino- and 6-acylamino-7-azaindolines is practically completely shifted for the amino form, and even acylation with p-toluene-sulfonic acid does not result in a noticeable shift of the tautomeric equilibrium for the amino form in contrast to the other N-heterocyclic amines.     

Synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone

The synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone is described. A new chromylation method of β-ketosulfoxide 9 leading to the Michael acceptor 12 has been developed. Dilithium tetrachlorocuprate was shown to be a very efficient catalyst for the conjugate addition reaction of phenyl magnesium bromide to the α,β-unsaturated sulfoxide 12. The instability of the obtained adducts 10 represents a limitation in terms of yield. It was confirmed that the natural flavanone leridol does not possess the structure of title compound 1.     

Synthesis of 7-oxo- and 7-hydroxy- derivatives of stigmasterol

The phytosteroids 3ß-hydroxy-(24S)-stigmast-5, 22E-dien-7-one and (24S)-stigmasta-5, 22E-diene-3\, 7ß-diol have been synthesized from stigmasterol.     

Synthesis of 8-demethyl-8-hydroxy-5-deazariboflavins

1-Deoxy 1-(3,4-dihydro-8-hydroxy-2,4-dioxopyrimido[4,5-b]quinolin-10-(2H)-yl)-D-ribitol (7,8-didemethyl-8-hydroxy-5-deazariboflavin), the flavin moiety of Methanobacterium coenzyme F₄₂₀, and its 7-methyl analog were prepared by acid-catalyzed reaction of appropriately substituted 6-(N-D-ribitylanilino)uracils with trimethyl or triethyl orthoformate followed by deprotection.     

Synthesis and properties of derivatives of 7-aroylalkylxanthinyl-8-thioacetic acid

When 7-aroylalkyl-8-bromo-3-methyl- and 1,3-dimethylxanthines are boiled with an excess of thioglycolic acid, a reductive dehalogenation takes place, while reaction with an equimolar amount of thioglycolic acid in DMFA leads to 7-aroylalkyl-3-methyl- and 1,3-dimethylxanthinyl-8-thioacetic acids. Cyclization of the latter with acetic anhydride in the presence of anhydrous sodium acetate results in the formation of 3-aryl-1,4-dihydro-9-methyl- and-7,9-dimethylthiazino[3,2-f]xanthine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 967–970, July, 1990.     

Synthesis of 7-hydroxy-6-alkoxy derivatives of 3,4-dihydroisoquinoline by ritter reaction

1-Substituted 6,7-dialkoxy-3,4-dihydroisoquinolines containing in the position 7 of the isoquinoline ring propoxy- or butoxy groups in the course of maintaining in the concentrated sulfuric acid are converted into 1-substituted 6-alkoxy-7-hydroxy-3,4-dihydroisoquinolines.     

Synthesis of 6-substituted pyrimidines by the wittig reaction. I. Via 2-amino-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde

Condensation of isopropyl 6-phenylhexanoate with ethyl diethoxyacetate followed by guanidine afforded 2 - amino-6-diethoxymethyl-5-phenylbutyl-4-pyrimidinol (VII). Acid hydrolysis of VII gave an excellent yield of 2-amino-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde (IV); the latter could be condensed with stabilized Wittig reagents such as carbethoxymethylene triphenyl phosphorane and cinnamylidene triphenyl phosphorane, but not unstabilized Wittig reagents such as carbethoxypropylene or cyano-propylene triphenyl phosphorane. Reduction of the Wittig products afforded pyrimidines with functionalized side-chains in the 6-position such as the 6-phenylbutyl (XVIII) and 6-carboxyethyl (XV) derivatives of 2-amino-5-phenylbutyl-4-pyrimidinol.     

Novel reaction of carbon suboxide. Synthesis of 6-amino-4-hydroxy-2(1H)-pyridone derivatives

The reaction of 2-cyanoacetamidines 1 with carbon suboxide 2 afforded 6-amino-4-hydroxy-2(1H)-pyri-dones 4 . Compounds 4 were also obtained by reaction of amidines 1 and 2,4,6-trichlorophenylmalonates 3 .     

Chemoselective synthesis of 5-amino-7-bromoquinolin-8-yl sulfonate derivatives and their antimicrobial evaluation

Abstract

A series of new 5-amino-7-bromoquinolin-8-ol sulfonate derivatives 5(a–j) were synthesized from 8-hydroxyquinoline through multi-step process with high yields using mild, efficient and conventional methods. Chemoselectivity was observed during the transformation of 5-amino-7-bromoquinolin-8-ol to 5-amino-7-bromoquinolin-8-ol sulfonate with various sulfonylchlorides exclusively to afford sulfonate derivatives. Also, the products were investigated for their in vitro antimicrobial activities and compared with the standard drugs. Among all the synthesized compounds 5-amino-7-bromoquinolin-8-yl biphenyl-4-sulfonate (5b) and 5-amino-7-bromoquinolin-8-yl 2-hydroxy-5-nitrobenzenesulfonate (5g) have showed potent antibacterial activity, whereas 5-amino-7-bromoquinolin-8-yl biphenyl-4-sulfonate (5b) and 5-amino-7-bromoquinolin-8-yl 2-hydroxy-5-nitrobenzenesulfonate (5g) possessed potent antifungal activities among all the tested pathogens.     

Purines. XIV. Synthesis and properties of 8-nitroxanthine and its N-methyl derivatives

Xanthine ( 1 ) and its N-methyl derivatives 2–16 have been nitrated to the corresponding 8-nitro derivatives 17–32 under different reaction conditions. Nitration in glacial acetic acid with nitric acid works well with the N-7 unsubstituted and some of the 9-methylxanthines, respectively, whereas the 7-methylxanthine derivatives react best with nitronium tetrafluoroborate in sulfolane or glacial acetic acid. The 8-nitro group can be displaced nucleophilically to form 8-chloro-, 33, 34 , 8-ethoxy-, 35,36 , and uric acid derivatives 37–40 , respectively. The newly synthesized 8-nitroxanthines have been characterized by elemental analyses, pK-determinations and uv and ¹H-nmr spectra.     

Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol

Background  

The anticancer drug, 6-mercaptopurine (6MP) is subjected to metabolic clearance through xanthine oxidase (XOD) mediated hydroxylation, producing 6-thiouric acid (6TUA), which is excreted in urine. This reduces the effective amount of drug available for therapeutic efficacy. Co-administration of allopurinol, a suicide inhibitor of XOD, which blocks the hydroxylation of 6MP inadvertently enhances the 6MP blood level, counters this reduction. However, allopurinol also blocks the hydroxylation of hypoxanthine, xanthine (released from dead cancer cells) leading to their accumulation in the body causing biochemical complications such as xanthine nephropathy. This necessitates the use of a preferential XOD inhibitor that selectively inhibits 6MP transformation, but leaves xanthine metabolism unaffected.