Synthesis of 1H-pyrazolo[3,4-c]isoquinolin-1-ones by the condensation of cyclohexanone derivatives with 3-amino-1-phenyl-1H-pyrazol-5(4H)-one

The synthesis of 1H-pyrazolo[3,4-c]isoquinolin-1-ones was carried out by reacting 3-aryl(heteryl)-2,4-diacetyl-5-hydroxy-5-methylcyclohexanones with 3-amino-1-phenyl-1H-pyrazol-5(4H)-one. The structure of the 7-acetyl-2,4,6,7,8,9-hexahydro-8-hydroxy-5,8-dimethyl-2-phenyl-6-(fur-2-yl)-1H-pyrazolo[3,4-c]isoquinolin-1-one obtained was proved by X-ray diffraction analysis.     

Synthesis of Some New Thiazoles and Pyrazolo[1,5-a]pyrimidines Containing an Antipyrine Moiety

Ethyl 2-{2-[4-(2,3-dimethyl-5-oxo-1-phenyl-3-(pyrazolin-4-yl)]-2-cyano-1-(phenylamino)vinylthio}-acetate, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl-(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]2-(4-oxo-3-phenyl-(1,3-thiazoilidin-2-ylidene))ethanenitrile, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]-2-(4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))ethanenitrile, 2-(5-acetyl-4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))-2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]ethanenitrile, and ethyl 2-(cyano(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)methylene)-2,3-dihydro-4-methyl-3-phenylthiazole-5-carboxylate were synthesized by treatment of 2-(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)-3-mercapto-3-(phenylamino)-acrylonitrile with appropriate halo ketones or halo esters. Also, 4-{2-[5,7-dimethyl-2-(phenylamino)(7a-hydropyrazolo[1,5-a]pyrimidin-3-yl](1,-thiazol-4-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one derivatives were synthesized via reaction of 4-{2-[5-amino-3-(phenylamino)pyrazolin-4-yl](1,3-thiazol-2-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with β-diketone or β-keto ester. All synthesized compound were established by elemental analysis, spectral data, and alternative synthesis whenever possible.     

Heterocyclizations of 5-methylpyrazol-3-amine with unsaturated arylaliphatic carboxylic acid derivatives

Cyclocondensation of 5-methylpyrazol-3-amine with methyl cinnamate and arylmethylidenemalonic acids in DMF and methanol leads to the formation of 7-aryl-2-methyl-6,7-dihydropyrazolo[1,5-a]-pyrimidin-5(4H)-ones. Arylmethylidenemalonic acids react with the title amine at a ratio of 1:2 in nitrobenzene to give 4-aryl-3,5-dimethyl-1,7-dihydrodipyrazolo[3,4-b:4′,3′-e]pyridines. Heterocyclizations of 5-methylpyrazol-3-amine with 5-arylmethylidene-2,2-dimethyl-1,3-dioxane-4,6-diones or their precursors, para-substituted benzaldehydes and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) in all solvents (methanol, DMF, and nitrobenzene) give the corresponding 4-aryl-3-methyl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-ones. The structure of 3-methyl-4-(4-nitrophenyl)-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridin-6-one was proved by X-ray analysis.     

Three-Component Spiro Heterocyclization of Pyrrolediones with Indan-1,3-dione and Acyclic Enamines

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pynole-3-carboxylates reacted with indan-1,3-dione and 3-amino-1-phenylbut-2-en-1-one or 3-aminobut-2-enenitrile to give 3-benzoyl-2-methyl-2′,5-dioxo-5′-prienyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrroles] and 2-methyl-2′,5-dioxo-5′-phenyl-1,1′,2′,5-tetrahydrospiro[indeno[1,2-b]pyridine-4,3′-pyrrole]-3-carbonitriles, respectively.

     

Synthesis and alkylation of pyrazolo[3,4-c]isoquinolines and hexahydrocyclohepta[d]pyrazolo[3,4-b]pyridines

The condensation of 1-acyl-2-(morpholin-4-yl)cycloalkenes with 3-amino-1-phenyl-1H-pyrazol-5(4H)-ones gave the corresponding 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoline and 3,6,7,8,9,10-hexahydrocyclohepta[ d]pyrazolo[3,4-b]pyridine derivatives. Alkylation of 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]-isoquinolines with alkyl halides occurred at the nitrogen atom in the 3-position. The structure of 7-methyl-2,5-diphenyl-2,3,6,7,8,9-hexahydro-1H-pyrazolo[3,4-c]isoquinolin-1-one was proved by X-ray analysis.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 6. Naphthothienonaphthyridines

Five novel polycyclic heterocyclic ring systems are reported via photocyclization. The specific final products in these ring systems are: naphtho[1′,2′:4,5]thieno[2,3-c][1,8]naphthyridin-6(5H)-one ( 5 ), naphtho-[1′,2′:4,5]thieno[2,3-c][1,6]naphthyridin-6(5H)-one ( 6 ), naphtho[1′,2′:4,5]thieno[2,3-c]-1,5-naphthyridine ( 9 ), naphtho[1′,2′:4,5]thieno[2,3-c][1,2,4]triazolo[4,3-a]-1,5-naphthyridine ( 12 ), and naphtho[2′,1′:4,5]thieno[2,3-c]-1,5-naphthyridine ( 17 ). The direction of photocyclization to produce 9 was established from a zero quantum two-dimensional nmr spectroscopy experiment (ZQCOSY) using 6-chloronaphtho[1′,2′:4,5]thieno[2,3-c]-1,5-naphthyridine ( 8 ) as the model compound.     

Synthesis of 1H-thieno[3,4-c]pyrazoles,thieno[3,4-b]furans,selenolo[3,4-b]furans and pyrrolo[3,4-d]thiazoles

Starting from the readily available aryl 2-methyl-5-phenyl-3-furyl ketones, 5-methyl-1H-1-phenylpyrazole-4-yl ketones and 4-methyl-2-phenyl-5-thiazolylcarboxaldehyde, a series of 2-phenyl-4-arylthieno[3,4-b]-furan, 2-phenyl-4-(p-methoxyphenyl)selenolo[3,4-b]furan, 4-aryl-1H-1-phenylthieno[3,4-c]pyrazole and 5-benzyl-2-phenylpyrrolo[3,4-d]thiazole were prepared in high yield.     

Tautomerism of Aza heterocycles: V. Structure of the spontaneous transformation products of 5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo-[4,3-c]pyridin-3-one in crystal and solution

5-Methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one exists as zwitterion with a proton localized on the nitrogen atom of the piperidine ring and negative charge delocalized over the pyrazololate fragment. The compound is stable in crystal but ustable in solution. Its chromatographic purification and attempts to recrystallize or synthesize by condensation of phenylhydrazine with alkyl 1-methyl-4-oxopiperidin-3-carboxylate on heating in alcohols or benzene lead to the formation of a complex mixture of products. Among these products, we isolated and identified 3a,3a′-methylenebis(5-methyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one), 1-methyl-3-(2-phenylhydrazinylidene)pyrrolidin-2-one, and 5-methyl-2-phenyl-3,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. The structure of methyl 3-(2-phenylhydrazinylidene)-4,5-dihydro-3H-pyrrole-2-carboxylate and 3a,5-dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was proved by NMR spectroscopy. 3a,5-Dimethyl-2-phenyl-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-3-one was isolated as hydrochloride hydrate whose structure was determined by X-ray analysis.     

Intramolecular cyclization of ketene containing both acyl andN-alkylimidoyl substituents. Synthesis and crystal and molecular structure of 3-benzoyl-5-phenyl-2H,4H-furo[3,2-c] isoquinolin-2-one

Thermal decarbonylation of 1-benzyl-4,5-dibenzoyl-2,3-dihydropyrrole-2,3-dione yields benzoyl[N-benzyl(phenylglyoxalimidoyl)]ketene. The latter undergoes intramolecular cyclization to 3-benzoyl-5-phenyl-2,3,4,5-tetrahydrofuro[3,2-c]isoquinolin-2-one. Which is oxidized to 3-benzoyl-5-phenyl-2H,4H-furo[3,2-c]isoquinolin-2-one under the reaction conditions. The crystal and molecular structure of the title compound was studied by X-ray structural analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 563–565, March, 1997.     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

Studies on the synthesis of heterocyclic compounds. Part I. The pschorr reaction in the pyrazole series

Preparation and structural evidence of N-methyl-(1,3-R,R'-pyrazol-5-yl)-o-nitrobenzamides (VIIIa, b) are discussed. Diazotisation of related o-aminobenzamides XIa,b followed by the Pschorr reaction afforded a very complex mixture from which pyrazolo[3,4-c]isoquinolin-5-ones XIIa.b in 7–10% yields together with N-methyl-(1,3-R,R'-pyrazol-5-yl)-o-hydroxybenzamides (XIIIa) in 15–20% yields were isolated.     

Synthesis of 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones. I. 3-unsubstituted compounds

Synthesis of 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones via a Pechmann condensation of 3-carbethoxy-1-methyl-4-piperidone with various phenols is described. The limitations of this method are discussed. Synthesis of the parent ring system 3a via reduction of 1,2,3,4-tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H-[1]benzopyrano[3,4-c]pyridin-5-one ( 5 ) is also described.     

New process for the synthesis of UP 269-6, a 1,2,4-triazolo[1,5-c]pyrimidine derivative as a potent orally active angiotensin ii antagonist

A new synthetic route to prepare the 2-hydroxy-5-methyl-7-n-propyl-8-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-[1,2,4]triazolo[1,5-c]pyrimidine ( UP 269-6 , Ripisartan) is described. UP 269-6 is a non-peptide angiotensin II antagonist currently in phase II clinical trials for the treatment of hypertension and chronic heart failure. Its development needed a suitable process for industrial production. The laboratory scale synthesis was optimized and particularly two key steps: 4-hydrazinopyrimidine formation without isolation of the 4-chloro intermediate and its cyclization into triazolo[1,5-c]pyrimidine derivative without isolation of the triazolo[4,3-c]pyrimidine isomer using urea in N-methylpyrrolidone at 160°C. This cyclization process affords a new and efficient way to prepare directly 2-hydroxytriazolo[1,5-c]pyrimidine without isolation of the corresponding triazolo[43-c]pyrimidine.     

Studies on the synthesis of heterocyclic compounds. III. Preparation of some pyrazolo[3,4-C] [1,5]benzodiazocin-10(11H)one derivatives

Starting from the readly available N-melhyl-N-(1-phenyl-3-R-pyrazol-5-yl)-2-nitrobenzamides (1a,b), the pyrazoles, 4-aeetyl substituted 2a,b, were prepared in high yield. Reduction of 2a gave the amino derivative 4a, which was eyclized to the desired pyrazolo[3,4-c][1,5]benzodiazo-cin-10(11H)one (5a). Compound 2b afforded 5b directly. Compound 5b was also prepared by the action of phosphorus oxychloride on N-methyl-N-(1,3-diphenylpyrazol-5-yl)-2-acetamido-benzamide (6b).     

Synthesis and Antimicrobial Activities of Some 6-Methyl-3-Thioxo-2,3-Dihydro-1,2,4-Triazine Derivatives

Abstract

4-Arylidene-imidazole derivatives (4a,b) were readily prepared by reacting 4-am- ino-6-methyl-3–thioxo-2,3–dihydro[1,2,4]triazin-5(4H)-one (1) with 4-arylidene-2-phenyl- 4H-oxazol-5-one (2). Reaction of 1 with some aromatic aldehydes in presence of triethylphosphite exclusively afforded the corresponding aminophosphonates 5a-c. Reaction of 1 with 3-phenyl-1H-quinazoline-2,4-dione (6a) and/or 3-phenyl-2-thioxo-2,3-dihydro- 1H-quinazolin-4-one (6b) gave 2-(6-methyl-5-oxo-3-thioxo-2,5-dihydro-3H-[1,2,4]triazin-4-ylimino)-3-phenyl-2,3-dihydro-1H-quinazolin-4-one (7). Moreover, on treating 1 with 2-phenylbenzo[d][1,3]thiazine-4-thione (8), 6-methyl-4-(2-phenyl-4-thioxo-4H-quinazolin-3-yl)-3-thioxo-3,4-dihydro-2H-[1,2,4]triazine-5-one (9) was obtained in 65% yield. Reaction of 1 with 4-sulfonylaminoacetic acid derivatives (10a,b) afforded the corresponding sulfonamides (11a,b), respectively. Acid hydrolysis of 11a afforded 7-aminomethyl-3-methyl[1,3,4]thiadiazole[2,3-c][1,2,4]triazin-4-one (12). 4-Amino-6-methyl-3-(morpholine-4-ylsulfanyl)-4H-[1,2,4]triazin-5-one (14) was prepared by reacting compound 1 with morpholine in presence of KI/I₂, while 3,3′-bis(4-amino-6-methyl-5-oxo-triazinyl)disulfide (16) was obtained by oxidation of 1 with lead tetraacetate. The antimicrobial activity of the products was evaluated against Gram-positive and Gram-negative bacteria as well as the fungus Candida albicans.

[Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures, and tables.]     

New approaches to synthesis of tris[1,2,4]triazolo[1,3,5]triazines

Thermal cyclization of 3-R-5-chloro-1,2,4-triazoles (R = Cl, Ph) afforded 2,6,10-tri-R- tris[1,2,4]triazolo[1,5-a:1′,5′c:1″,5″-e][1,3,5]triazines 5 (R = Ph) and 7 (R = Cl). These compounds are first representatives of this class of heterocycles, whose structures were unambiguously established. Treatment of these compounds with nucleophiles (H₂O/NaOH, NH₃) results in the triazine ring opening to give compounds consisting of three 1,2,4-triazole rings linked in a chain. For example, treatment of cyclic compound 5 with aqueous alkali affords 3-phenyl-1-3-phenyl-1-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,2,4-triazol-5-yl-1H-1,2,4-triazol-5-one. Treatment of 3,7,11-triphenyltris[1,2,4]triazolo[4,3-a:4′,3′c:4″,3″-e][1,3,5]triazine (2) with HCl/SbCl₅ leads to the triazine ring opening giving rise to 5-(3-chloro-5-phenyl-1,2,4-triazol-4-yl)-3-phenyl-4-(5-phenyl-1H-1,2,4-triazol-3-yl)-1,2,4-triazole. Thermal cyclization of the latter produces 3,7,10-triphenyltris[1,2,4]triazolo[1,5-a:4′,3′c:4″,3″-e][1,3,5]triazine (13). Thermolysis of both cyclic compound 2 and cyclic compound 13 is accompanied by the Dimroth rearrangement to yield 3,6,10-triphenyl-tris[1,2,4]triazolo[1,5-a:1′, 5′-c:4″,3″-e][1,3,5]triazine (14). Compounds 13 and 14 are the first representatives of cyclic compounds with this skeleton. ¹³C NMR spectroscopy allows the determination of the isomer type in a series of tris[1,2,4]triazolo[1,3,5]triazines.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 706–712, March, 2005.     

A new method for the synthesis of 6H,11H-indolo[3,2-c]-isoquinolin-5-ones/thiones and their reactions

The synthesis of 8-substituted and unsubstituted 6H,11H-indolo[3,2-c]isoquinolin-5-ones/thiones 3a-c and 4a-c and their derivatives viz, ethyl (8-substituted-6H,11H-indolo[3,2-c]isoquinolin-5-on-6-yl)acetates 5a-c , (8-substituted-6H,11H-indolo[3,2-c]isoquinolin-5-on-6-yl)acetyl hydrazides 6a-c , 3,5-disubstituted-pyrazoles 7a-c and 8a-c , 3-substituted-pyrazol-5-ones 9a-c and 5-(8-substituted-6H,11H-indolo[3,2-c]isoquinolin-5-on-6-yl)methyl-1,3,4-oxadiazole-2-thiones 10a-c , also ethyl (8-substituted-11H-indolo[3,2-c]isoquinolin-5-ylthio)ace-tates 11a-c , (8-substituted-11Hindolo[3,2-c]isoquinolin-5-ylthio)acetyl hydrazides 12a-c , 3,5-disubstituted-pyrazoles 13a-c and 14a-c , 3-substituted-pyrazol-5-ones 15a-c and 5-(8-substituted-11H-indolo[3,2-c]isoquin-olin-5-yl)thiomethyl-1,3,4-oxadiazole-2-thiones 16a-c is described.     

A new procedure for the synthesis of 4H-pyrazolo[1,5-c][1,3,5]thiadiazine-4-thiones

Thiation of N-(1-tert-butyl-3-methylpyrazol-5-yl)carboxamides 2 with the Lawesson reagent afforded the corresponding thiocarboxamides 3 . Heating of 3 in formic acid gave the N-dealkylated thiocarboxamides 4 which were cyclized into 4H-pyrazolo[1,5-c][1,3,5]thiadiazine-4-thiones 5 by treatment with thiophosgene.     

Synthesis of some new 3-pyrazolyl-substituted-4(3H)quinazolinones

N-(1-Phenyl-3-methylpyrazol-5-yl)-o-aminobenzamide reacted with orthoesters to yield some new 3-pyrazolyl-substituted-4(3H)quinazolinones (VIIa,b,c,d). An alternative synthesis of Vllb was accomplished by reaction of acetylanthranyl with l-phenyl-3-methyl-5-aminopyrazole.