Imine-enamine tautomerism of dihydroazolopyrimidines. 3. 5-Aryl-substituted 4,7(6,7)-dihydro-1,2,4-triazolo[1,5-a]pyrimidines

5-Aryl-substituted 4,7(6,7)-dihydro-1,2,4-triazolo[1,5-a]pyrimidines were obtained by condensation of 3-amino-1,2,4-triazole with -dimethylaminopropiophenone hydrochlorides or crotophenone. The effect of steric and electronic factors on the position of the imine-enamine equilibrium in solutions of the synthesized substances is examined. 5-Phenyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyriniidine was subjected to x-ray diffraction analysis.See [1] for Communication 2.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1539–1544, November, 1991.     

Synthesis and NMR spectroscopic study of derivatives of pyrazolo[1,5-a]pyrimidines

Reactions of 3,5-diamino-4-nitropyrazole with asymmetric -dicarbonyl compounds formed pyrazolo[1,5-a]pyrimidines, which in turn were used as the starting compounds in the reaction with dimethylformamide diethylacetal. The structure of the compounds obtained was studied by NMR spectroscopy in experiments involving the homonuclear Overhauser effect.Center for Chemistry of Medicinal Substances (TsKhLS-VNIKhFI), Moscow 119815. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 619–628, May, 1997.     

Reactions with heterocyclic amidines,VII: Synthesis of some new pyrazolo[1,5-c]-1,2,4-triazines,pyrazolo[1,5-a]-1,3,5-triazines and pyrazolo[1,5-a]pyrimidines

Diazotised 5-amino-3-methyl-4-phenyloyrazole (1) reacted with active methylene reagents and with -naphthol to yield the pyrazolo[1,5-c)-1,2,4-triazine derivatives2a-e and5. Compound1 reacted with benzoyl isothiocyanate and with phenyl isothiocyanate to yield the corresponding pyrazol-5-ylthiourea derivatives6a, b. 5a was converted into the thiourea derivative8 by the action of acids or alkalies. A synthesis of 2-methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidin-5-one from the reaction of -phenylacetoactonitrile (3-oxo-2-phenyl-butyric nitrile) and -cyanoethylhydrazine is reported.

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Reaktionen mit heterocyclischen Amidinen, VII: Synthese einiger neuer Pyrazolo[1,5-c]-1,2,4-triazine, Pyrazolo[1,5-a]-1,3,5-triazine und Pyrazolo[1,5-a]pyrimidine

Zusammenfassung Diazotiertes 5-Amino-3-methyl-4-phenylpyrazol (1) reagiert mit einer aktiven Methylenkomponente und -Naphthol zu den Pyrazolo[1,5-c]-1,2,4-triazin-Derivaten2a-e und5. 1 ergibt mit Benzoylisothiocyanat und Phenylisothiocyanat die entsprechenden Pyrazol-5-yl-thioharnstoffe6a, b. 5a wurde mittels Säure oder Base in das Thioharnstoffderivat8 umgewandelt. Es wird über eine Synthese von 2-Methyl-3-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidin-5-on aus -Phenylacetoacetonitril (3-Oxo-2-phenyl-butyronitril) und -Cyanoethylhydrazin berichtet.

     

Amination of isomeric bromo-1-methylnitropyrazoles

A method was developed for the synthesis of 5-bromo-1-methyl-4-nitropyrazole from 1-methylpyrazole. In the reaction with 25% aqueous ammonia at 180–190 °C, 5-bromo-1-methyl-4-nitropyrazole is readily converted to 5-amino-1-methyl-4-nitropyrazole; the production of 4-amino-1-methyl-5-nitropyrazole from 4-bromo-1-methyl-5-nitropyrazole requires the presence of a copper catalyst; under the same conditions in the amination of 4-bromo-1-methyl-3-nitropyrazole, 4-amino-1-methyl-3-nitro- and 1-methyl-3-nitropyrazoles are formed in a 23 ratio.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1672–1675, December, 1983.     

2-Methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-5- and -7-Ones

The cyclocondensation of methylcinnamates and arylidene derivatives of Meldrums acid with 3-amino-5-methylthio-1,2,4-triazole in DMF gives 2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidin-5-ones. The reaction involving arylidene derivatives of Meldrums acid or its synthetic equivalents in ethyl acetate with a catalytic amount of pyridine gives a mixture of 2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5- and -7-ones.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 246–251, February, 2005.     

Synthesis and reactions of sym-Triazolo-[1,5-a]-sym-Triazinonethiones

1-Carbethoxythiocarbamoyl-5-amino-1,2,4-triazoles and N-(1,2,4-triazol-5-yl)-N-carbethoxythioureas are formed in the reaction of 5-amino-1,2,4-triazoles with carbethoxyisothiocyanate. The triazole derivatives obtained are cyclized to substituted sym-triazolo-[1,5-a]-sym-triazines in alkaline media.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 276–280, February, 1973.See also [1,2].     

α,β-Unsaturated nitriles in heterocyclic synthesis: Synthesis of some new pyrazolo[1,5-a]pyrimidine derivatives

3-Antipyrinyl-5-aminopyrazole (1) reacted with acrylonitrile to afford 5-amino-1--cyanoethyl-3-antipyrinylpyrazole (2). Compound2 could also be obtained from the reaction of -cyanoethylhydrazine (3) and compound4.2 was readily cyclized into 2-antipyrinyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-one (5) by acetic-hydrochloric acid.5 could be also obtained from the reaction of1 and methyl acrylate. The reaction of1 and cinnamonitrile derivatives7 a–e resulted in the formation of pyrazolo[1,5-a]pyrimidine derivatives9,11 and12.

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,-Ungesättigte Nitrile in der Heterocyclen-Synthese: Synthese einiger neuer Pyrazolo[1,5-a]pyrimidin-Derivate

Zusammenfassung 3-Antipyrinyl-5-aminopyrazol (1) reagierte mit Acrylnitril zu 5-Amino-1--cyanoethyl-3-antipyrinylpyrazol (2).2 konnte ebenfalls aus der Reaktion von -Cyanethylhydrazin (3) und Verbindung4 erhalten werden.2 wurde mittels Essigsäure-Salzsäure glatt zu 2-Antipyrinyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidin-5-on (5) cyclisiert.5 konnte auch aus der Reaktion von1 mit Methylacrylat erhalten werden. Die Reaktion von1 mit Zimtsäurenitrilderivaten7 a–e ergab die Pyrazolo[1,5-a]pyrimidin-Derivate9,11 und12.

     

3-α-Halocarbonyl derivatives of pyrazolo[1,5-a] benzimidazole and their reactions

3-(-haloacyl)-2,4-dialkylpyrazolo[1,5-a]benzimidazoles can be obtained either by brominating 3-acetylpyrazolo[1,5-a]benzimidazoles with bromine in acetic acid, or by acylating the 3-unsubstituted pyrazolobenzimidazoles with haloacetic halides. Halogenation of 3-acetylpyrazolo[1,5-a]benzimidazoles with bromine in acetic acid in the presence of sodium acetate, and bromination with N-bromosuccinimide or 1-chlorobenzotriazole, result in deacylation to give 3,6(7)-dibromo- and 3-chloropyrazolo[1,5-a]benzimidazoles. The mono- and trihaloketones obtained have been used to prepare the corresponding aminoketones, the 3-carboxylic acid, and its derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 43–48, January, 1988.     

Synthesis of 3-amino-4-nitropyrazoles

3-Bromo-1,5-dimethyl-4-nitropyrazole does not react upon heating with aqueous ammonia, while 1,5-dimethyl-3,4-dinitropyrazole under the same conditions yields 3-amino-1,5-dimethyl-4-nitropyrazole, which is formed from 3-bromo-1,5-dimethyl-4-nitropyrazole in the presence of a copper catalyst. The amination of 1-methyl-3,4-dinitropyrazole-5-carboxylic acid is accompanied by decarboxylation, which is characteristic for 4-substituted 1-methylpyrazole-5-carboxylic acids upon heating in aqueous ammonia or water.     

Interaction of aminoazoles with Meldrum’s acid and dialkyl ketones or cyclohexanone

Interaction of 3-amino-5-methylpyrazole, 3-amino-5-methylthio-, and 3,5-diamino-1,2,4-triazole with Meldrum’s acid, acetone, ethyl methyl ketone, and cyclohexanone leads to alkyl-substituted pyrazolo[3,4-b]pyridin-6-ones and 1,2,4-triazolo[1,5-a]pyrimidin-7-ones respectively. The structure of 5,5-dimethyl-2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-7-one was demonstrated by an X-ray structural investigation. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 595–601, April, 2007.     

Recyclization of Condensed Carbethoxypyrimidines Accompanied by Substitution of a Carbon Atom into the Heterocycle

Condensation in ethanol of ethyl ethoxymethyleneacetoacetate with systems containing an amidine fragment (substituted 3-aminopyrazoles and 3-amino-1,2,4-triazole) gave 6-carbethoxy-7-methylpyrazolo[1,5-a]pyrimidines. Addition of base to solutions of the obtained bicyclic carbethoxy derivatives in the course of several minutes caused rearrangement to 6-acetyl-7-hydroxypyrazolo[1,5-a]pyrimidine and 6-acetyl-7-hydroxy-1,2,4-triazolo[1,5-a]pyrimidine respectively. A more prolonged refluxing in 15% aqueous alcohol solution of base caused 6-carbethoxy-7-methyl-2-phenylpyrazolo[1,5-a]pyrimidine and 6-acetyl-7-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidine to recyclize to 7-methylpyrazolo[1,5-a]pyrimidine.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 569–576, April, 2005.     

Three component condensation of 3-amino-1,2,4-triazole with carbonyl compounds. A new synthesis of 1,2,4-triazolo[1,5-a]pyrimidines

Three component condensation of 3-amino-1,2,4-triazole with an aromatic aldehyde and ketone gives 1,2,4-triazolo[1,5-a]-pyrimidines. An x-ray structural investigation of 5-phenyl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]benzo[h]quinazoline was undertaken in order to determine the course of this reaction.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 481–485, April, 1993.     

Imine-enamine tautomerism of dihydroazolopyrimidines 5. Steric effects and the tautomeric equilibrium for dihydro-1,2,4-triazolo[1,5-a]pyrimidines

The reaction of 3-amino-1,2,4-triazole with -dimethylaminopropiophenones or unsaturated ketones gives 5,7-disubstituted 4,7(6,7)-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. An increase in the bulk of the substituent at C₍₇₎ in the bicyclic system leads to relative stabilization of the enamine tautomer of these compounds. An x-ray diffraction structural analysis of 7-tert-butyl-5-(4-methoxyphenyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine showed that the introduction of a tert-butyl group into the dihydropyrimidine ring leads to significant loss of planarity of this system.For Communication 4, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1357–1363, October, 1993.     

Cyclocondensation of α,Β-unsaturated ketones with 3-amino-1,2,4-triazole

Dihydro-1,2,4-triazolo[1,5-a]pyrimidine derivatives were obtained by condensation of 3-amino-1,2,4-triazole with 1,3-diaryl-1-propen-3-ones. The structure of 5-phenyl-7-(4-methylphenyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine was established by x-ray diffraction analysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 229–233, February, 1988.     

Azide-tetrazole tautomerism of diazidodiazines and their benzo analogs

It has been discovered with the aid of IR and NMR spectroscopy that 5-azidotetrazolo [1,5-a]quinazoline exists in solutions in a tautomeric equilibrium with ditetrazolo [1,5-a:1,5-c]quinazoline, and the thermodynamic and kinetic characteristics of the equilibrium have been determined. Azide-tetrazole tautomerism is not observed under these conditions for ditetrazolo[1,5-a:5,1-c]pyrazine, 6-azidotetrazolo [1,5-b]pyridazine, and their benzo analogs.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2002–2007, September, 1989.     

Imine-enamine tautomerization of dihydroazolopyrimidines 4. Synthesis and tautomerization of 5-(2-hydroxyphenyl)-dihydro-1,2,4-triazolo[1,5-a]pyrimidines

The condensation of 3-amino-1,2,4-triazole with 2-hydroxychalcones gives 7-aryl-5-(2-hydroxyphenyl)-4,7(6,7)-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. Both tautomeric forms were isolated for a number of these compounds. PMR spectroscopy was used to show that the enamine form is predominant in DMSO in contrast to the case in CHCl₃.For Communication 3, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1353–1356, October, 1993.     

Discovery of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives as c-Src kinase inhibitors for the treatment of acute ischemic stroke

We synthesized a series of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives and evaluated their ability to inhibit c-Src kinase; 7-(2-amino-2-methylpropylamino)-5-cyclopropyl-2-(3,5-dimethoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 7o and 7-(2-amino-2-methylpropylamino)-2-(3,5-dimethoxyphenylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide 7f showed potent inhibitory activity. Compound 7f inhibited c-Src selectively and exhibited satisfactory central nervous system (CNS) penetration. Furthermore, 7f.HCl reduced the infarct volume in vivo in a rat middle cerebral artery (MCA) occlusion model when administrated intraperitoneally.     

Synthesis of Novel 2-Methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one and Derivatives

A novel 2-methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one was synthesized using dimethyl-n-cyanoimidodithiocarbonate and 2-hydrazinobenzoic acid as building blocks. Chemical transformation of the inherent lactam moiety in the targeted 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazolin-5-one offered access to a variety of derivatives.     

2-amino-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidines: Synthesis and reactions with electrophilic reagents

The hydrogenation of 2-amino-5-R-7-R′-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines with NaBH₄ led to the formation of 2-amino-5-R-7-R′-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidines. Acylation, sulfonylation, and alkylation of these compounds depending on conditions and the reagent character occur at the amino group, atoms N³ or N⁴. The treatment with alkali of 2-amino-3-benzyl-5-R-7-R′-4,5,6,7-tetrahydro-1,2,4-triazolo-[1,5-a]pyrimidinium bromide resulted in 2-amino-3-benzyl-5-R-7-R′-3,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidine, similar reaction of 2-acetamido-3-benzyl-5-R-7-R′-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidinium bromide gave a mesoionic product of a hydrogen elimination from the amide nitrogen atom.     

Reactions of 3-aroylacrylates with α-aminoazoles*

Dihydro derivatives of pyrazolo[3,4-b]pyridine-, pyrazolo[1,5-a]pyrimidine-, and [1,2,4]triazolo-[1,5-a]pyrimidinecarboxylates have been prepared by cyclocondensation of β-aroylacrylates with 5-aminopyrazoles and 3-amino-1,2,4-triazole. Heating dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylates with hydrazine hydrate led to recyclization of the pyrimidine ring to form 6-arylpyridazin-3(2H)-ones.