Synthesis of derivatives of pyrazolo[3,4-d]pyrimidin-3-ylacetic acid and their nucleosides

3-Cyanomethyl-4,6-dimethylmercaptopyrazolo[3,4-d]pyrimidine was synthesized on the basis of 3-cyanomethyl-4-cyano-5-aminopyrazole. Ribosylation of this product gave 1-(2,3,5-tri-O-acetyl--D-ribofuranosyl)-3-cyanomethyl-4,6-dimethylmercaptopyrazolo[3,4-d]pyrimidine in 63% yield and small amounts of the 1- and 2- isomers. A number of derivatives of 6-methylmercaptopyrazolo[3,4-d]pyrimidin-3-ylacetic acid and their 1-ribosides were synthesized. The 4-methylmercapto group was replaced by amino, hydrazino, oxo, N-piperidino, and N-morpholino groups. The nitrile group was saponified in an alkaline medium to carbamoyl and carboxy groups. The corresponding 4-morpholino and 4-piperidino derivatives were obtained by the reaction of 3-cyano-4,6-dimethylmercaptopyrazolo[3,4-d]pyrimidine per-O-acetylated 1--D-ribofuranoside with secondary cyclic amines. The high resistance of the 6-methylmercapto group to the action of nucleophilic agents and the higher reactivity of the 4-methylmercapto group as compared with the nitrile group are discussed. Data on the cytotoxic activity of the synthesized compounds were obtained.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 536–545, April, 1981.     

Pyrazolopyrimidine nucleosides. Part VIII The synthesis of certain 4-substituted pyrazolo[3,4-d]pyrimidine nucleosides

1-(β-D-Ribofuranosyl)pyrazolo[3,4-b]pyrimidine-4-thione ( 6 ), obtained by a three-step synthesis from allopurinol riboside (3), was treated with certain alkyl and aryl halides to provide the corresponding 4-alkylthio derivatives. The nucleoside 4-methylthio-1-(β-D-ribofuranosyl)pyra-zolo[3,4-d]pyritnidine ( 7 ) has served as the precursor for the preparation of the 4-methylamino ( 11 ), 4-dimethylamino ( 12 ), 4-hydrazino ( 13 ), and the 4-hydroxylamino ( 14 ) analogs.     

Synthesis of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4-b]pyridines

The synthesis and characterization of a number of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4–6]pyridines from common precursors, 5-benzoyl-4-chloro-1H-pyrazolo-[3,4-b]pyridines, has been described. The structures were determined by unambiguous chemical synthesis and by isolation and ¹³C nmr analysis of some key, isolated, intermediates. The ability of these compounds to displace [3H]flunitrazepam from CNS binding sites was also observed.     

吡唑并嘧啶-4-酮衍生物的合成与除草活性

吡唑并嘧啶-4-酮衍生物的合成与除草活性;吡唑[3; 4-d]并嘧啶酮;苯氧丙酸酯;aza-Wittig反应;合成;除草活性     

Synthesis and Vasodilatory Activities of New Pyrazolo[3,4—d] pyrimidin—4—one Derivatives

A series of pyrazole[3,4-d] pyrimidin-4-one derivatives were synthesized and tested for vasodilatory activities. All of them were new compounds and their structures were confirmed by IR,^1H NMR,MS and elemental analysis.     

Synthesis of novel isoxazolines and isoxazoles of N-substituted pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives through [3+2] cycloaddition

3,6-Dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one 3 was prepared by an intramolecular cyclization of N-(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl) acetamide 2 in ethanol in the presence of piperidine. N-allylation and N-propargyl alkylation of N-substituted pyrazolo[3,4-d] pyrimidin-4(5H)-one 3 yielded the corresponding dipolarophiles 4 and 5 which afford by condensation with arylnitrile oxides in toluene the expected new isoxazolines 6 and isoxazoles 7, respectively. On the other hand, the aminopyrazole 1 in refluxing with ethanol in the presence of sodium hydroxide afforded the corresponding carboxamide 8, which then, was converted to its ethyl 3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d] pyrimidine-6-carboxylate 9 with neat diethyl oxalate. The dipolarophile 10 on regiospecific 1,3-dipolar cycloaddition with arylnitrile oxides affords isoxazoles 11 and the unexpected deethoxycarbonylated isoxazoles 12. The target compounds were completely characterized by ¹H NMR, ¹³C NMR, IR and HRMS.     

Synthesis of pyrido[2,3-d]pyrimidin-4-one derivatives

This paper describes one-pot synthesis of 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one 4 , 5H-dipyri-do[1,2-a:3′,2′-e]pyrimidin-5-one 10 and 5H-pyrido[3,2-e]pyrimido[1,2-a]pyrimidin-5-one 15 and some of their derivatives, starting with 2-chloro-3-pyridine carboxilic acid 1. Compounds 4 and 10 reacted with phosphorus pentasulfide to give the respective 5-thione analogues, 5 from 4 and 11 from 10 . Boiling the 5-thione derivatives with hydrazine hydrate, the respective 5-hydrazono derivatives 6 from 5 and 12 from 11 were obtained. The 5-acetyl hydrazono, 7 , and the 5-isopropylidenehydrazono, 8 , derivatives were also prepared from 6 , and the 5-propionylhydrazono derivatives, 13 , from 12 . Compound 4 reacted with hydrazine to give an adduct with two molecules of hydrazine and the probable structure 16 . Treating this adduct with acetone a monohydrazone 17 was obtained. Boiling a suspension of this adduct in DMF, it gave 6,10-dihydro-6H-pyrido[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazin-5-one 20 .     

Synthesis of 5-glycopyranosylamino-pyrano[2,3-d]pyrimidin-2-one derivatives

Summary Three series of 3-substituted 5-glycopyranosylamino pyrano[2,3-d]pyrimidin-2-one derivatives,3 a–c,4 a–c, and5 a–c have been prepared by treatment of the corresponding 1,4-dihydro-6-glycopyranosylamino pyrimidin-4-ones1 a–c with malonic, methyl malonic and ethyl malonic acids, respectively.

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Synthese von Derivaten des 5-Glucopyranosylaminopyrano[2,3-d]pyrimidin-2-on

Zusammenfassung Es wurden drei Serien von 3-substituierten 5-Glucopyranosylaminopyrano[2,3-d]pyrimidin-2-onen (3 a–c,4 a–c und5 a–c) mittels Behandlung der entsprechenden 1,4-Dihydro-6-glucopyranosylamino-pyrimidin-4-one (1 a–c) mit Malon-, Methylmalon- bzw. Ethylmalonsäure dargestellt.

     

Synthesis of pyrazolo[3,4-d]pyrimidine derivatives using ketene dithioacetals

The cyclization of 5-amino-3-methylthiopyrazole-4-carbonitriles or 4-carboxamides 3a-j , which were prepared by the reaction of ketene dithioacetals 1a,b [1a : bis(methylthiomethylenemalononitrile; 1b : bis(methylthio)methylenecyanoacetamide] with hydrazines (hydrazine hydrate, phenylhydrazine, p-chlorophenylhydrazine, p-nitrophenylhydrazine), with formamide or carbon disulfide proceeded to give the corresponding 4-amino- or 4-hydroxy-3-methylthiopyrazolo[3,4-d]pyrimidines 6a-h in good yields. 3-Aminopyrazolo[3,4-d]pyrimidine derivatives 6i-1 were also obtained by the application of the cyclization reaction of 3,5-diaminopyrazoles with formamide.     

Synthesis of pyrano[3,4-c]pyrazole and pyrazolo[3,4-d][1,2]diazepine derivatives

By the action of thionyl chloride on 3(5)-R-4-phenacylpyrazole-5(3)-carboxylic acid ( 3c,d ), 3-R-5-phenylpyrano[3,4-c]pyrazole-7-(1H)ones ( 4c,d ) were obtained. When 4c,d were treated with hydrazine hydrate followed by refluxing in ethanol containing acetic acid, 4,7-dihydro-3-R-5-phenylpyrazolo[3,4-d][1,2]-diazepin-8-(1H)ones ( 6c,d ) were formed. Compounds 6c,d , in turn, were refluxed in ethanol saturated with hydrochloric acid to yield 6-amino-1,6-dihydro-3-R-5-phenyl-7H-pyrazolo[3,4-c]pyridin-7-ones ( 7c,d ). Compounds 7c,d could be obtained directly from 5c,d. The starting materials 3c,d were prepared by hydrolysis of the oxime of 3(5)-R-4-phenacyl-5(3)carboalcoxypyrazoles ( 1a,b ). Structural assignments rested on correct elemental analysis, molecular weights determined by mass spectrometry, and spectroscopic evidence.     

Nitroxyl derivatives of pyrazolo [3,4-d]pyrimidine

Conclusions Pyrazolo[3,4-d]pyrimidine nitroxyl derivatives having different distances between the paramagnetic center and the pyrazolopyrimidine ring have been prepared for the first time.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 12, pp. 2763–2766, December, 1982.     

Synthesis of 2-Trihalomethyl-3,4-dihydrothieno[2,3-d]pyrimidin-4-ones

At room temperature, N-(1-chloro-2,2,2-trihaloethylidene)-O-methyl urethanes react with 2-aminothiophenes to form N-(2-thienyl)-N'-(methoxycarbonyl)trihaloacetamidines, which when heated in boiling toluene undergo ring closure to form 2-trihalomethyl-3,4-dihydrothieno[2,3-d]pyrimidin-4-ones.     

Pyrazolopyrimidine nucleosides. Part VII. The synthesis of certain pyrazolo [3,4-d] pyrimidine nucleosides related to the nucleoside antibiotics toyocamycin and sangivamycin

The condensation of 4-acetamido-3-cyanopyrazolo[3,4-d]pyrimidine ( 5 ) with crystalline 2,3,5-tri-O-acetyl-β- D -ribofuranosyl chloride ( 6 ) has furnished a good yield of nucleoside material ( 7 ) which on treatment with sodium methoxide in methanol provided a high yield of nucleoside which was subsequently established as methyl 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]-pyrimidine-3-formimidate monohydrate ( 11 ). The formimidate function of 11 was found to be highly reactive and 11 was readily converted into the corresponding carhoxamidine ( 8 ), carboxamidoxime ( 14 ) and carboxamidrazone ( 15 ) when treated with the appropriate nucleophiles. Treatment of the imidate ( 11 ) with sodium hydrogen sulfide gave a high yield of the thiocarboxamide ( 12 ) which was then readily converted into 4-amino-3-cyano-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 16 ). Aqueous base transformed 11 into 4-amino-1-(β- D -ribofuranosyl)-pyrazolo[3,4-d]pyrimidine-3-carboxamide ( 10 ) while more vigorous basic hydrolysis provided the corresponding carboxylic acid ( 9 ) in nearly quantitative yield. Decarboxylation of 9 proceeded smoothly in hot sulfolane to provide the known 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 13 ) in 68% yield which unequivocally established the site of ribosylation and anomeric configuration for all nucleosides reported in this investigation.     

新型5-芳甲酰胺基-6-芳胺基-吡唑并[3,4-d] 嘧啶-4-酮衍生物的合成及其除草活性

以吡唑膦亚胺、芳基异氰酸酯和芳基甲酰肼为原料,通过串联氮杂Wittig反应关环合成了12种新型的5-芳甲酰胺基-6-芳胺基-吡唑并[3,4-d]嘧啶-4-酮衍生物(3a~3l),其结构经¹H NMR, ¹³C NMR, IR和HR-MS(ESI)表征。对单双子叶除草活性的初步测试结果发现：部分化合物具有优异的除草活性,特别是浓度为100 mg·L^-1时,5-(4-氟苯甲酰胺基)-6-(4-氯苯胺基)-3-甲硫基-1-苯基-1H-吡唑[3,4-d]-嘧啶-4(5H)-酮3i和5-(4-吡啶苯甲酰胺基)-6-(4-氯苯胺基)-3-甲硫基-1-苯基-1H-吡唑[3,4-d]-嘧啶-4 (5H)-酮3k对油菜和稗草的茎和根的抑制率高达100%。     

Synthesis of pyrazolo[4,3-d]oxazoles

1-Phenyl-3-methyl-5-pyrazolone-4-oxime reacted with benzylamine, methylamine, methyl- and ethyl ioides to give 3-methyl-1,5-diphenyl-1H-, 3-methyl-1-phenyl-1H- and 3,5-dimethyl-1-phenyl-1H-pyrazolo[4,3-d]oxazoles I, II. The structure of I was elucidated authentically through other routes by interaction of 1-phenyl-3-methyl-4,5-dioxopyrazolone with benzylamine and/or benzaldehyde and ammonium acetate. Various 3-meth-yl-5-aryl-1-phenyl-1H-pyrazolo[4,3-d]oxazoles IV were synthesized by the reaction of 4,5-dioxopyrazolone with aromatic aldehydes in the presence of ammonium acetate. Also, the structure of I was elucidated authentically via other routes by the reaction of 1-phenyl-3-methyl-4-imino-5-pyrazolone with each of benzylcyanide, benzylamine, benzaldehyde and benzalaniline.     

Synthesis of 3-Cyano-4,6-bis(methylthio)pyrazolo[3,4-d]pyrimidine 1-riboside

3-Cyano-4,6-bis(methylthio)pyrazolo[3,4-d]pyrimidine was synthesized by cyclization of 3,4-dicyano-5-aminopyrazole with CS₂ in pyridine with subsequent Dimroth rearrangement and methylation of the resulting 3-cyano-4,6-dimercaptopyrazolo[3,4-d]-pyrimidine with methyl iodide. Glycosylation of the product by fusion with 1,2,3,5-tetra-O-acetyl--D-ribofuranose in the presence of iodine gave 1-(2,3,5-tri-O-acetyl--D-ribofuranosyl)-3-cyano-4,6-bis(methylthio)pyrazolo[3,4-d]pyrimidine, the deacetylation of which with a 1% solution of hydrogen chloride in methanol led to 3-cyano-4,6-bis(methylthio)pyrazolo[3,4-d]pyrimidine 1-fiboside. The structures of the compounds were established by IR, UV, circular dichroism, PMR, and ¹³NMR spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1687–1692, December, 1979.Original article submitted March 29, 1979.