Synthesis of 8-methyl-2-azainosine and related nucleosides

The synthesis of 6-methyl-7-(β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-4-one (8-methyl-2-azainosine ( 2) ) and 6-methyl-7-(β-D-glucopyranosyl)imidazo[4,5-d]-v-triazin-4-one ( 5 ) by diazotization of 5-amino-1-(β-D-ribofuranosyl)-2-methylimidazole-4-carboxamide ( 1 ) and diazotization of 5-amino-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-methylimidazole-4-carboxamide ( 3 ), followed by deacetylation of the resulting compound 4 , is described. The preparation of 6-methyl-5-(β-D-ribofuranosyl)imidazo[4,5-d]-v-triazin-4-one ( 10 ) and 6-methyl-5-(β-D-glucopyranosyl)imidazo[4,5-d]-v-triazin-4-one ( 11 ) by glycosylation of 6-methylimidazo[4,5-d]-v-triazin-4-one (8-methyl-2-azahypoxanthine, ( 7) ) is also described. Structural assignments were made on basis of analytical and ¹H-nmr and uv spectral data.     

Synthesis and biological evaluation of certain 4-alkylamino and 4-arylalkylamino derivatives of the imidazo[4,5-d]pyridazine and v-triazolo[4,5-d]pyridazine ring systems

Certain 4-alkylamino and 4-arylalkylamino derivatives of the imidazo- and v-triazolo[4,5-d]pyridazine ring systems were prepared and evaluated against two human colon carcinomas (DLD-1 and HCT-15) and one human lung carcinoma (LX-1), in vitro. 4-Methylthioimidazo[4,5-d]pyridazine ( 1 ) and 4-methylthio-v-triazolo-[4,5-d]pyridazine ( 9 ) served as precursors to the title compounds. Treatment of these heterocycles with the appropriate amine (ammonia, methylamine, dimethylamine, benzylamine and hydrazine) provided the desired derivatives of that ring system. 4-AIP ( 2 ) and 2-aza-4-AIP ( 10 ) served as precursors to the 4-dimethylaminomethyleneamino derivatives 6 and 14 , respectively. Likewise, the 4-hydrazino analogs ( 7 and 15 ) served as intermediates in the syntheses of benzaldehyde-p-[bis(2-chloroethyl)amino]amino[4,5-d]-pyridazin-4-yl-hydrazone ( 8 ) and benzaldehyde-p-[bis(2-chloroethyl)amino]amino-v-triazolo[4,5-d]pyridazin-4-yl-hydrazone ( 16 ), respectively.     

1,2,3-Triazolo[4,5-e]-1,2,4-triazolo[3,4-c]pyrimidines

Some new 1,2,3-triazolo[4,5-e]-1,2,4-triazolo[3, 4 -c]pyrimidmes were prepared starting from the corresponding 1,2,3-triazolo[4,5-d]pyrimidines via the formation of the 1,2,4-triazole ring. Thus suitable hydrazino derivatives 6 were condensed with triethyl orthoformate, triethyl orthoacetate and triethyl orthobenzoate to give the expected tricyclic derivatives 7 , 8 and 9 . Intramolecular cyclization of the ethoxycarbonylhydrazino derivatives 10 gave the tricyclic compounds 11 bearing an hydroxyl group in the 3 position. The v-triazolo-s-triazolopyrimidine derivatives were tested towards the A₁ and A_2A adenosine receptors in binding assays, but they did not show any receptor affinity.     

Synthesis of 1- and 3-amino-5-t-butyl-1H- and -3H-v-triazolo[4,5-d]pyrimidines as hetaryne precursors

The synthesis of the title compounds 6 and 8 has first been accomplished by reaction of O-mesitylsulfonyl-hydroxylamine with 5-t-butyl-3H-v-triazolo[4,5-d]pyrimidine ( 5 ) whose preparation is reported in detail. However the preferred route for the synthesis of the 3-amino derivative 8 is based upon the preparation of 3-benzylideneamino-5-t-butyl-3H-v-triazolo[4,5-d]pyrimidine ( 10 ), followed by the removal of the benzylidene protecting group. This critical step was effected by treatment of 10 with dilute hydrochloric acid, in the presence of 2,4-dinitrophenylhydrazine. The diazotization of 5-amino-4-hydrazino-2-t-butylpyrimidine gave predominantly the tetrazolo[1,5-c]-pyrimidine 13 along with a small amount of compound 8.     

The synthesis of 3,5-dimethylpyrazol-1-yl-vl-v-triazolo[4,5-d]pyridazines and substituted 3,5-dimethylpyrazol-1 -ylimidazo[4,5-d]pyridazines

The synthesis of 4-(3,5-dimethylpyrazol-1-yl)-v-triazolo[4,5-d]pyridazine, 4-(3,5-dimethylpyrazol-1-yl)imid-azo[4,5-d]pyridazine and several S-substituted derivatives of 4-(3,5-dimethylpyrazol-1-yl)imidazo[4,5-d]pyrid-azine-2-thiol is reported. These syntheses were carried out to provide a variety of interesting compounds for biological screening.     

Pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazine-7,9(6H8H)-diones

Some 5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazine-7,9-(6H,8H)-diones (4 a–d) have been synthesised by the condensation of 3-alkyl-4-amino-5-mercapto-(1,2,4)-triazoles (1 a–d) with 5-bromobarbituric acid (2a). Similarly some 9a-nitro-5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazine-7,9(8H,9aH)-diones (5 a–d) have been obtained by the condensation of1 a–d with 5-bromo-5-nitrobarbituric acid (2b) and final cyclisation withPPA. The structures have been confirmed by PMR spectra and analytical results.

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Pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazin-7,9(6H,8H)-dione

Zusammenfassung Es wurden einige 5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazin-7,9(6H,8H)-dione (4 a–d) mittels Kondensation von 3-Alkyl-4-amino-5-mercapto-(1,2,4)-triazolen (1 a–d) mit 5-Brombarbitursäure (2 a) dargestellt. Des weiteren wurden einige 9a-Nitro-5H-pyrimido[4,5-e](1,2,4)-triazolo[3,4-b](1,3,4)-thiadiazin-7,9(8H,9aH)-dione (5 a–d) über die Kondensation von1 a–d mit 5-Brom-5-nitrobarbitursäure (2 b) und anschließender Cyclisierung mitPPA synthetisiert. Die angeführten Strukturen wurden mittels PMR-Spektren und analytischen Daten abgesichert.

     

Synthesis of 1H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazines, 8H-pyrazolo[3,4-e]tetrazolo[5,1-c]-as-triazine and 1,7-dihydro-8H-pyrazolo[3,4-e]-as-triazine derivatives

3-Hydrazino-7-methyl-5-phenyl-5H-pyrazolo[3,4-c]-as-triazine 1 underwent ring closure and/or condensation reaction with formic acid, acetic acid, acetic anhydride and benzoyl chloride to afford 1H-pyrazolo-[3,4-d]-s-triazolo[3,4-c]-as-triazines 2, 5 and 7a and/or N-acyl derivatives 3, 4 and 6 . N-Acyl derivatives 3 and 6 underwent cyclisation reaction on treatment with phosphoryl chloride to give 5 and 7a . 3-Methyl-1-phenyl-8-aryl-1H-pyrazolo[3,4-e]-s-triazolo[34,-c]-as-triazines 7 were also prepared by the reaction of the hydrazono derivatives 8 wit thionyl chloride. On treatment of 1 with nitrous acid gave the 8H-pyrazolo[3,4-e]tetrazolo-[5,1-c]-as-triazine 9 . Compound 1 underwent ring closure with carbon disulphide or ethyl chloroformate to 1,7-dihydro-8H-pyrazolo[3,4-e]-s-triazolo[3,4-c]-as-triazine derivatives 10 and 12 . Reaction of 1 with ethyl acetoacetate or acetylacetone gave 3-pyrazolo derivatives 13 and 14 .     

Ring Transformation of 7-Nitro-1-(4-nitrophenyl)-4,5-dihydro-1H-imidazo- and -[1,2,3]triazolo[4,5-c]pyridin-4-ones

Nitration of 1-phenyl-4,5-dihydroimidazo- and -1,2,3-triazolo[4,5-c]pyridin-4-ones initially occurs at the para position of the phenyl ring, and the subsequent nitration yields the corresponding 7-nitro-1-(4-nitrophenyl) derivatives. Treatment of the latter with hydrazine hydrate leads to formation of 1-(4-aminophenyl)-7-methyl-4,5-dihydroimidazo- and -1,2,3-triazolo[4,5-d]pyridazin-4-ones.     

Degradative ring opening of pyrido and pyrazino 3-benzenesulfonyloxyuracils and their conversion to condensed pyrazolones and triazolones

Ring opening, followed by an immediate Lossen rearrangement, of 3-benzenesulfonyloxypyrido[3,2-d, 3,4-d and 4,3-d]pyrimidine-2,4(1H,3H)diones with sodium methoxide in methanol furnished good yields of the methyl esters of 3-[2-(methoxycarbonyl)hydrazino]-2-, 3-[2-(methoxycarbonylhydrazino]-4- and 4-[2-(methoxycarbonyl)hydrazino]-3-pyridinecarboxylic acids, respectively. These hydrazino esters were cyclized to the corresponding pyridopyrazolones. However, the reaction of 3-benzenesulfonyloxypyrido[2,3-d]pyrimidine-2,4(1H,3H)dione with sodium methoxide produced 8-methoxycarbonyl-s-triazolo[4,5-a]pyridin-3(2H)one. In similar fashion, sodium methoxide converted 3-benzenesulfonyloxylumazine to 8-methoxycarbonyl-s-triazolo[4,3-a]pyrazin-3(2H)one.     

Synthesis of certain N- and C-alkyl purine analogs

A number of N- and C-alkyl derivatives of selected guanine analogs have been synthesized as potential antiviral agents. n-Pentyl, n-hexyl and 6-hydroxyhexyl derivatives in the imidazo[1,2-α]-s-triazine, 9–11 , imid-azo[1,2-α]pyrimidine, 13–17 , and thiazolo[4,5-d]pyrimidine, 19–21, ring system have been prepared by the direct alkylation of the sodium salt of the appropriate aglycon with the respective alkylbromides. Dehydra-tive coupling of 3-amino-6-hydrazino-1,2,4-triazin-5(4H)-one ( 22 ) with either hexanoic acid or heptanoic acid, and further ring closure of the reaction products 24a and 24b provided the n-pentyl and n-hexyl derivatives of 6-amino-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one 25a and 25b , respectively. A similar condensation of 3-amino-6-aminomethyl-1,2,4-triazin-5(4H)-one ( 23 ) with heptanoic acid, followed by ring annulation, readily gave 2-amino-7-n-hexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one ( 25c ). Bromination of 25c with N-bromosuccini-mide afforded the corresponding 5-bromo derivative 26 . Alkylation of the in situ generated sodium salt of 4-methoxycarbonylmethyl-5-methoxycarbonyl-2-oxo-1H,3H-imidazole ( 27 ) with 1-bromohexane gave the N-1 alkylated product 31 . Manipulation of the functional groups in 31 and further hydrazine mediated ring annulation furnished 5,6-diamino-1-n-hexyl-3-methylimidazo[4,5-c]pyridine-2,4-dione ( 39 ). Catalytic hydrogena-tion of 39 gave 7-methyl-8-oxo-9-hexyl-3-deazaguanine ( 40 ), a congener of the immunostimulator 7-methyl-8-oxoguanosine.     

Regioselective synthesis of 9-substituted-8-azaguanines (5-amino-3-substituted-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one)

By modifying previously described methods for the synthesis of 9-substituted-guanines from imidazoles, we have developed a new procedure for the regioselective synthesis of 9-substituted-8-azaguanines (5-amino-3-substituted-3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one) from triazoles in high yields. The method seems suitable for the introduction of a variety of substituents including sugars, carbocyclic, acyclic and carboacyclic chains.     

Palladium-Catalyzed Allylic Coupling of 1,2,3-Triazolo[4,5-d]pyrimidines (8-Azapurines)

The palladium-catalyzed coupling of the sodium salt of 7-amino-1,2,3-triazolo[4,5-d]pyrimidine (8-azaadenine, 1) with allylic phosphates or carbonates resulted in mixtures of 2- and 3-substituted 1,2,3-triazolopyrimidines, which were separated by chromatography. 1-Substituted triazolopyrimidines were not isolated from these reactions. Regioselectivity (and stereoselectivity) was also observed for substitution of the allylic moiety when more than one isomer is possible from the reaction. The use of 5-amino-1,2,3-triazolo[4,5-d]pyrimidin-7-ones (8-azaguanine, 2), instead of 8-azaadenine, also resulted in mixtures. Alternate syntheses of the 3-allyl-1,2,3-triazolo[4,5-d]pyrimidines confirmed the structures of these compounds.     

1, 3-dipolar cycloaddition of diazomethane to azolopyridazines. The synthesis of 8-methyl-8H- and 9-methyl-9H-pyrazolo[3, 4-d]-s-triazolo[4, 3-b]pyridazine and 1-methyl-1H- and 2-methyl-2H-imidazo[1, 2-b]pyrazolo[3, 4-b]pyridazine derivatives

The transformations of 7-methyl-7H- and 8-methyl-8H-pyrazolo[4, 3-d]tetrazolo[1, 5-b]pyridazines 1, 2, 9 and 10 into 8-methyl-8H- and 9-methyl-9H-pyrazolo[3, 4-H]-s-triazolo[4, 3-b]pyridazines 7 and 8 , and 1-methyl-1H-and 2-methyl-2H-imidazo[1, 2-b]pyrazolo[3, 4-d]pyridazines 13 and 14 are described.     

Transaminations of enaminones:A Synthesis of tricyclic,N-aryl, 1,2,3-triazole-fused pyridones

1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylated the pyrrolidine enamines of cyclopentanone and cyclohexanone, and the resulting enaminones underwent transaminations with aryl amines under acidic conditions. The products then cyclized under basic conditions to linearly fused, tricyclic 3-phenylmethyl- and 3-(4-methoxyphenylmethyl)-4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[6]-1,2,3-triazolo[4,5-e]pyridines, and to 5,6,7,8-tetrahydro-4-aryl-3H-1,2,3-triazolo[4,5-b]quinolin-9(4H)-ones. Similar transaminations afforded the related 8-phenyl- and 8-(3-chlorophenyl)-1,5,7,8-tetrahydro-1-(phenylmethyl)-4H-thieno[3,4-e]-1,2,3-triazolo[4,5-b]pyridin-4-ones. Phase-transfer and catalytic hydrogenolyses of some of these intermediates furnished 4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[b]-1,2,3-triazolo[4,5-e]pyridines and 4-aryl-5,6,7,8-tetrahydro-3H,2,3-triazolo[4,5-b]quinoline-9-(4H)-ones. The 3-(4-methoxyphenylmethyl)-4-aryl intermediates were sterically crowded. Two protons from the methoxyphenylmethylphenylmethylgroups were dramatically shielded because of anisotropic effects exerted by the 4-aryl substituents.     

Synthesis and transformations of (±)-trans-4aβ(H), saα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one

Hydrogenation of 4,7-dimethylcoumarin ( 1 ) in alkaline medium has been shown to furnish a mixture of (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one ( 2 ), (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 3 ) and (±)-cis-4aα(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 4 ) in 40:25:35:ratio, respectively. The stereochemistry of the major hydrogenation product 2 , has been established by transforming it to p-menthane derivatives e.g. (±)-2 (R)-[2′(R)hydroxy-4′(R) methylcyclohex-(1′S)-yl]propan-1-ol ( 20 ) and (±)-trans-3α,6β-dimethyl-3aβ(H),7aα(H)-octahydrobenzofuran ( 12 ). Starting from a mixture of lactones 2, 3 and 4 , lactone 3 has been obtained in pure state employing a sequence of reactions.     

Enzyme-Mediated Preparation of (+)- and (–)-cis-α-Irone and (+)- and (–)-trans-α-Irone

The preparation of (−)- and (+)-trans-α-irone ( 1a and 1b , resp.) and of (+)- and (−)-cis-α-irone ( 1c and 1d , resp.) from commercially available Irone alpha ^® is reported. The relevant step in the synthetic sequence is the initial chromatographic separation of crystalline (±)-4,5-epoxy-4,5-dihydro-cis-α-irone ((±)- 5 ) from oily (±)-4,5-epoxy-4,5-dihydro-trans-α-irone ((±)- 4 ). The latter was subsequently converted, after NaBH₄ reduction, into the crystalline 3,5-dinitrobenzoate ester (±)- 8 , thus allowing a complete separation of the two corresponding diastereoisomeric alcohol derivatives. Suitable enantiomerically pure precursors of the desired products 1a – d were obtained by kinetic resolution of the racemic allylic alcohols derived from (±)- 5 and (±)- 8 , mediated by lipase PS (Amano). The last steps consisted of MnO₂ oxidation and removal of the epoxy moiety with Me₃SiCl/NaI in MeCN. External panel olfactory evaluation showed that (−)-cis-α-irone ( 1d ) has the finest and most distinct `orris butter' character.     

Herstellung von Dihydro-, Tetrahydro- und Hexahydrochelidamsäure-Derivaten

Preparation of dihydro-, tetrahydro- and hexahydro-chelidamic-acid derivatives. Three methods for the preparation of 4-oxo-2,6-piperidine-dicarboxylic acid ( 3 ) and derivatives, required as a synthon for betalaine pigments, were explored. The best method was found to be the catalytic hydrogenation of chclidamic acid ( 1 ) with 5% Rh/Alox in water under 2.7 atm. H₂ for 33 h at 70° and subsequent esterification with methanol which gave 42% of cis, cis-4-hydroxy-2,6-piperidine- ( 7 ) and 10% of 2,6-cis-piperidine-dicarboxylic acid dimethyl ester ( 8 ), readily separable by chromatography. Oxidation of 7 with dimethylsulfoxide and a carbodiimide attached to a polymer afforded 90% of 4-oxo-2,6-cis-piperidine-dicarboxylic acid dimethyl ester ( 19 ). Other methods of oxydizing 7 to 19 were less successful. The electrochemical reduction of 1 followed by esterification with methanol led in a low yield to a mixture of 4-oxo-0-2,6-trans-piperidine-dicarboxylic acid dimethylester ( 24 ), its dimethyl acetal 25 and presumably trans-4-hydroxy-r-2, cis-6-piperidine-dicarboxylic acid dimethyl ester ( 26 ). Reaction of 4-oxo-hepta-2E, 5E-dienoic acid ( 35 ) with aqueous ammonia gave a 98% yield of a 3 : 2 mixture of cis- and trans-ammonium-4-oxo-2, 6-piperidine-dicarboxylate ( 39 and 40 ). The above mentioned catalytic hydrogenation method was also applied to N-ethyl-chelidamic acid ( 16 ) to give a 4:6 mixture of the N-ethyl derivatives 17 and 18 . Furthermore, a number of functional derivatives of 5 , of 19 , of 39 and of 40 were prepared. Oxidation of the hydroxy-diester 7 with dimethylsulfoxide and a carbodiimidc derivative in the presence of trifluoroacetic acid afforded 4-oxo-1,2,3,4-tetrahydro-2, 6-pyridine-dicarboxylic acid dimethyl ester ( 50 ). This ester was also obtained under the same conditions from thc keto-diester 19 .     

A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones

Abstract  

The reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or its 2-methylthio derivative with hydrazonoyl halides, in the presence of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The structure of the latter compounds was further confirmed by reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one with the appropriate active chloromethylenes followed by coupling of the products with benzenediazonium chloride to afford the non-isolable azo-coupling products which converted, in situ, to 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The reaction mechanism was proposed and the products were screened for their biological activity. Some of the newly synthesized compounds had a moderate effect against some bacterial and fungal species.     

A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-<Emphasis Type="Italic">d</Emphasis>]-1,2,4-triazolo[4,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-5-ones

Abstract  The reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or its 2-methylthio derivative with hydrazonoyl halides, in the presence of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The structure of the latter compounds was further confirmed by reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one with the appropriate active chloromethylenes followed by coupling of the products with benzenediazonium chloride to afford the non-isolable azo-coupling products which converted, in situ, to 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The reaction mechanism was proposed and the products were screened for their biological activity. Some of the newly synthesized compounds had a moderate effect against some bacterial and fungal species. Graphical abstract