Nucleosides CV. Synthesis of the 8-((β-D-ribofuranosyl)pyrazolo[1,5-a]-1,3,5-triazine isosteres of adenosine and inosine

Reaction of ethyl N-cyanoformimidate ( 3 ) and of ethyl N-carbelhoxyformimidate ( 5 ) with 3-aminopyrazole ( 2 ) gave 4-amino- and 4-oxo-3H-pyrazolo[1,5-a]-1,3,5-triazine ( 4 and 7 ), respectively. Reaction of 3-amino-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)pyrazole ( 8 ) with the same reagents similarly gave the blocked 4-amino-8-ribosyl- and 4-oxo-3H-8-ribosyl-pyrazolo[ 1,5-a]-1,3,5-triazine ( 9 and 15 ), respectively. Deblocking in acid finally afforded the unblocked products 10 (an isostere of adenosine and formycin) and 16 (an isostere of inosine and formycin B). The corresponding derivatives in the a series were made by identical procedures for confirming all structural assignments. Preliminary in vitro testing results of 10 are included.     

The synthesis of 7,8-dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]triazines

Cyclic hydrazino amidines were converted to the corresponding aminopyrazolyl derivatives. Ring closure between the amino groups of pyrazoline moieties and NH groups of cyclic amidines afforded the following ring systems: 7,8-Dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines.     

New synthesis of 2,4-dialkyl(or diaryl)pyrazolo[1,5-a]-1,3,5-triazines

Reactions of monothiodiacylamines or N-aroylthioimidates with 3-aminopyrazoles gave pyrazolo[1,5-a]-1,3,5-triazines in good yields.     

Synthesis of Functionalized 2-(2-Pyrrolyl)pyrazolo[1,5-a]pyrimidines

Reactions of 5-amino-3-(2-pyrrolyl)pyrazoles with -dicarbonyl compounds (acetylacetone and ethyl acetoacetate) lead to formation of up to 90% of polysubstituted pyrazolo[1,5-a]pyrimidines.     

A facile synthesis of 8-(β-D-ribofuranosyl)-4-thioxo-3H-pyrazolo[1,5-a]-1,3,5-triazine and its α-anomer

A versatile intermediate 2 for C-nucleoside synthesis was treated with thiosemicarbazide to obtain thiosemicarbazone 6 , which was then converted to 3-aminopyrazol-2N-thiocarboxamide derivatives 7 and 8 by the reaction of 6 and sodium ethoxide. 4-Thioxo-4H-pyrazolo[1,5-a]-1,3,5-triazine C-nucleosides 11 and 12 were obtained by the ring closure reaction of 7 and 8 with triethyl orthoformate. Brief treatment of 11 and 12 with 10% methanolic hydrogen chloride afforded C-nucleosides 4 and 13 , respectively, without anomerization. Identification of compounds 4 and 13 was made on the basis of ¹H nmr and uv spectra, as well as chemical conversion to known compounds with established configurations. Model compounds were also synthesized in order to confirm the heterocyclic moieties.     

1,2,4-Triazines VIII. The synthesis of 1,2,4-triazino[2,3-e]pyrazolo[1,5-a]-1,3,5-triazines and 1,2,4-triazino[4,3-e]pyrazolo[],5-a] -1,3,5-triaziness

Substituted 2,5-dihydro-3[3-methyI(or phenyl)-5-aminopyrazolyl]-1,2,4-triazin-5-ones reacted with orthoesters to yield exclusively 1,2,4-triazino[2,3-e]pyrazolo[1,5-a]-1,3,5-triazin-5-ones. The structure elucidation was supported by independent synthesis of the isomeric 1,2,3-triazino-[4,3-e]pyrazolo[1,5-α]-1,3,5-triazin-7-one as well as by spectroscopical methods.     

The synthesis and chemical reactions of certain pyrazolo[1,5-a]-1,3,5-triazines

3-Aminopyrazole was utilized as a starting material for the preparation of certain pyrazolo-[1,5-a]-1,3,5-triazines. 4-Chloro-2-methylthiopyrazolo[1,5-a]-1,3,5-triazine was prepared and used for studies of nucleophilic displacement reactions, and it has been found that both the chloro and methylthio groups may be displaced by nucleophiles. By modifications of these procedures we have prepared the adenine, hypoxanthine, and xanthine analogs of the pyrazolo-[1,5-a]-1,3,5-triazine ring system. Electrophilic substitution occurs in the 8-position of this ring system. The methyl group was introduced into the 4-position by a novel ring opening and ring closing of the 1,3,5-triazine ring.     

Synthesis of unsymmetrical 2,4-dialkylpyrazolo[1,5-a]-1,3,5-triazines

The reaction of 3-aminopyrazole with imidate esters such as ethyl acetimidate, gave N-(pyrazol-3-yl)acetamidine (1) rather than the isomeric 2-acetamidoyl-3-aminopyrazole. Ring closure of 1 with orthoesters such as ethyl propionimidate, afforded unsymmetrically substituted 2.4-dialkylpyrazolo[1,5-a]-1,3,5-triazines such as 4-ethyl-2-methylpyrazolo[1,5-a]-1,3,5-triazine (3). The structure of 1 was confirmed by several alternate syntheses. The unique feature of this two-step synthetic approach to the synthesis of pyrazolo[1,5-a]-1,3,5-triazines is that it is a convenient method of preparing fused triazines based on available pyrazoles rather than the less accessible dialkyltriazines.     

Crystal and molecular structure of 7-phenyl-1,2,4-triazolo[1,5-a]-1,3,5-triazine

The crystal and molecular structure of 7-phenyl-1,2,4-triazolo[1,5-a]-1,3,5-triazine were determined. It was shown that the amine nitrogen atom (N¹) of the triazole ring acts as a nucleophilic center in the cyclization of N-(1,2,4-triazol-5-yl)amidines with electrophilic reagents.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 6, pp. 1386–1389, June, 1992.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 2

A series of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-6-ones was obtained by reaction of ammonium acetate with ethyl 7-dimethylaminovinylpyrazolo[1,5-a]pyrimidine-6-carboxylates and these had been prepared from ethyl 7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylates by reaction with dimethylformamide dimethylacetal. Under these conditions the compounds bearing a 2-hydroxy group were also O-alkylated. During the preparation of the ethyl 2-hydroxy-7-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate the corresponding 5-methyl isomer was isolated and identified.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 1

A series of 7-methylpyrazolo[1,5-a]pyrimidines were reacted with dimethylformamide dimethylacetal to give the corresponding dimethylaminovinyl derivatives. These were reacted with ammonium acetate affording, through a ring closure, a number of 6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidines bearing various substituents on the pyrazole ring. The 6-acetyl-2-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine was used as starting material for obtaining some O-alkyl derivatives. Catalytic transfer hydrogenation of 2-benzyloxy-6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine led to the 2-hydroxy derivative.     

A new general synthesis of functionally substituted pyrazolo[1,5-a]pyrimidines

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Acid-catalyzed reaction of pyrazolo[1,5-a]pyridines with aldehydes: Formation of bis(pyrazolo[1,5-a]pyrid-3-yl)methane

Reaction of pyrazolo[1,5-a]pyridines with aldehydes in the presence of trifluoroacetic acid gave bis[pyrazolo[1,5-a]pyrid-3-yl)methanes in high yields.     

Synthesis of some new purine-related compounds: Regioselective one-pot synthesis of new tetrazolo[1,5-a]pyrimidine,pyrazolo[1,5-a]pyrimidine and pyrimido[1,6-a]pyrimidine derivatives

An easy and efficient route for the synthesis of some tetrazolo[1,5-a]-, pyrazolo[1,5-a]- and pyrimido[1,6-a] pyrimidine derivatives was described through the reaction of sodium salts of formyl ketones with 5-aminotetrazole, 5-aminopyrazole derivatives and 6-aminothiouracil, respectively. The antimicrobial screening of some derivatives of the prepared compounds has been achieved, and it exhibited a moderate activity against the tested microorganisms.     

Nucleosides. 117. Synthesis of 4-oxo-8-(β-D-ribofuranosyl)-3H-pyrazolo[1,5-a]-1,3,5-triazine (OPTR) via 3-amino-2N-carbamoyl-4-(β-D-ribofuranosyl)pyrazole (ACPR) derivatives

Reaction of 2-formyl-2-(2,3-O-isopropylidene-5-O-trityl-D-ribofuranosyl)acetonitrile (VII) with semicarbazide hydrochloride followed by sodium ethoxide treatment afforded an α,β-mixture of 3-amino-2N-carbamoyl-4-(2,3-O-isopropylidene-5-O-trityl-D-ribofuranosyl)pyrazole (IX). Conversion of IX to 4-oxo-8-(2,3-O-isopropylidene-5-O-trityl-D-ribofuranosyl)-3H-pyrazolo[1,5-a]-1,3,5-triazine (XIII) was achieved by treatment of IX with ethylorthoformate. The β-isomer IXb gave only the β-isomer XIIIb, and the α-isomer IXa was converted exclusively into the α-isomer XIIIa. Upon deprotection with 3% n-butanolic hydrogen chloride, both IXa and IXb gave the same mixture of the α- and β-isomers of 3-amino-2N-carbamoyl-4-(D-ribosyl)pyrazole, which were separated by chromatography. The syntheses of the hitherto unknown compounds, 3-amino-2N-carbamoylpyrazole (IVa) and its 4-methyl analog (IVb) are also reported. Experimental details of the synthesis of 3-amino-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)pyrazole (XIIb), an important intermediate for “purine-like” C-nucleosides, are also described.     

Synthesis and electrophilic substitutions of novel pyrazolo[1,5-c]-1,2,4-triazolo[4,3-a]pyrimidines

5-Aryl-7-hydrazino-2-phenylpyrazolo[1,5-c]pyrimidines 1 were used as precursors for the preparation of a new series of 5-aryl-8-phenylpyrazolo[1,5-c]-1,2,4- triazolo[4,3-a]pyrimidines 2. The reactions of 2 with certain electrophilic reagents gave the respective 6-substituted derivatives 3-5 rather than the 7-isomeric products. Formylation of the key compounds 1 with ethyl formate yielded the formyl derivatives 6. Furthermore, boiling of compounds 1 with acetic acid afforded 7-acetylhydrazino-5-aryl-2-phenylpyrazolo[1,5-c]pyrimidines 7. Bromination of 7 yielded the dibromo- derivatives 8, while their iodination and nitration gave the monosubstituted derivatives 9 and 10, respectively. Also, treatment of 1 with boiling acetic anhydride yielded the triacetyl derivatives 11. The structure of synthesized products was confirmed by elemental analyses, IR, 1H NMR and MS spectra.     

Ring transformation reactions of C-nucleosides: Facile synthesis of pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]triazine C-nucleosides

1,3-Dimethyluracil ( 1 ), a versatile synthon for the synthesis of various heterocycles, reacted readily with 3-aminopyrazoles 2 in sodium ethoxide to give pyrazolo[1,5-a]pyrimidines 3 . Under similar conditions, 3-aminopyrazole C-nucleosides 4 and the synthon 1 gave a mixture of pyrazolo[1,5-a]pyrimidine C-nucleosides, which was separated on a silica gel column. Attempts to remove the protecting groups yielded pyranose derivative 10 . Another synthon 1,3-dimethyl-5-azauracil and 3-aminopyrazoles 12 gave pyrazolo[1,5-a]triazines 13 . In a similar reaction with 3-aminopyrazole C-nucleosides 4 gave the corresponding pyrazolo[1,5-a]-triazine C-nucleosides 14 and 15 .