A new base-induced ring transformation of pyrido[2,3-d]pyrimidines

8-Substituted 5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates ( 3 ) rearranged to 8-substituted 7,8-dihydro-5-hydroxy-7-oxopyrido[2,3-d]pyrimidine-6-carboxaldehydes ( 5 ) when treated with sodium ethoxide in an aprotic polar solvent at room temperature. The 6-cyano analogue ( 18 ) also underwent ring transformation under the same mild conditions giving 7-amino-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxaldehyde ( 21 ). However, the ring transformations of the pyrido[2,3-d]pyrimidine bearing no N₈-substituent ( 12 ), ethyl 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine- ( 14 ) and -quinoline-3-carboxylates ( 16 ) failed to occur. A mechanism is discussed.     

Synthesis of thiopyrano[2,3-d] pyrimidines and thieno[2,3-d]pyrimidines

The reaction of 4-chloro-5-cyano-2-methylthiopyrimidine (I) with ethyl mercaptosuccinate (II) in refluxing ethanol containing sodium carbonate has afforded diethyl 3-amino-2-(methyl-thio)-7H-thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylate (IV). Displacement of the methylthio group in IV with hydrazine gave the corresponding hydrazino derivative which underwent Schiff base formation with benzaldehyde or 2,6-dichlorobenzaldehyde. Treatment of IV in refluxing acetic anhydride afforded the corresponding diacetylated amino derivative. Partial saponification of IV with sodium hydroxide gave 5-amino-2-(methylthio)-7H-thiopyrano-[2,3-d]pyrimidine 6,7-dicarboxylic acid 6 ethyl ester (VIII). The reaction of 4-amino-6-chloro-5-cyano-2-phenylpyrirnidine (XI) with II resulted in the formation of ethyl 4-amino-6-(ethoxy-carbonyl)-5,6-dihydro-5-amino-2-phenylthieno[2,3-d]pyrimidine-6-acetate (XIII) which when subjected to hydrolysis gave ethyl 4,5-diamino-2-phenylthieno[2,3-d]pyrimidine-6-acetate isolated as the hydrochloride (XIV). Diazotization of IV with sodium nitrite in acetic acid unexpectedly afforded diethyl 5-(acetyloxy)-6,7-dihydro-6-hydroxy-2-(methylthio)-5H-thio-pyrano[2,3-d]pyrimidine-6,7-diearboxylate (XV). Several structural ambiguities were resolved by ir and pmr spectra.     

Synthesis and properties of 1-Benzothiopyrano[2,3-d]-pyrimidine-2,4-(3H)diones (10-thia-5-deazaflavins)

Treatment of 6-arylthiouracils with the Vilsmeier reagent (dimethylformamide-phosphorus oxychloride) gave the corresponding 6-arylthio-5-formyluracils, which could alternatively be prepared by the condensation of 6-chloro-5-formyluracils with thiophenols. Dehydrative cyclization of the above 5-formyluracils with polyphosphoric acid gave 1-benzothiopyrano[2,3-d]pyrimidine-2,4-(3H)diones (10-thia-5-deazaflavins). These 10-thia-5-deazaflavins oxidized alcohols to give the corresponding carbonyl compounds with the aid of strong base, and they were hydrogenated to 1,5-dihydro-10-thia-5-deazaflavins. Treatment of 10-thia-5-deazaflavins with concentrated aqueous potassium hydroxide led to the exclusive formation of 1,5-dihydro-10-thia-5-deazaflavins and 1,5-dihydro-10-thia-5-deazaflavin-5-ones via intermolecular oxidation-reduction (disproportionation) between initially formed 1,5-dihydro-5-hydroxy-10-thia-5-deazaflavins and unchanged 10-thia-5-deazaflavins.     

Synthesis of 5-Oxo and 7-Oxopyrido[2,3-d]pyrimidines

The synthesis of 4-amino-2-methylthio-5-oxopyrido[2,3-d]pyrimidine 4 and its isomer, 4-amino-2-methyl-thio-7-oxopyrido[2,3-d]pyrimidine 6 is described. The regiochemistry of the reaction of 4,6-diamino-2-methyl-thiopyrimidine 9 and diethyl ethoxymethylene malonate 12 is discussed.     

Synthesis of certain 3-alkoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidines structurally related to adenosine,inosine and guanosine

Several 3-alkoxysubstituted pyrazolo[3,4-d]pyrimidine ribonucleosides structurally related to adenosine, inosine and guanosine have been prepared by the direct glycosylation of preformed aglycon precursor containing a 3-alkoxy substituent. Ring closure of 5(3)-amino-3(5)-ethoxypyrazole-4-carboxamide ( 6b ) with either formamide or potassium ethyl xanthate gave 3-ethoxyallopurinol ( 7b ) and 3-ethoxy-6-thioxopyrazolo[3,4-d]-pyrimidin-4(5H,7H)-one ( 10 ), respectively. Methylation of 10 gave the corresponding 6-methylthio derivative 15 . Similar ring annulation of 5(3)-methoxypyrazole-4-carboxamide ( 6a ) with formamide afforded 3-methoxyallopurinol ( 7a ). Treatment of 5(3)-amino-3(5)-methoxypyrazole-4-carbonitrile ( 5a ) with formamidine acetate furnished 4-amino-3-methoxypyrazolo[3,4-d]pyrimidine ( 4 ). High-temperature glycosylation of 7b with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of boron trifluoride etherate gave a 2:1 mixture of N-1 and N-2 glycosyl blocked nucleosides 11b and 13b . Deprotection of 11b and 13b with sodium methoxide gave 3-ethoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one ( 12b ) and the corresponding N-2 glycosyl isomer 14b , respectively. Similar glycosylation of either 4 or 7a , and subsequent debenzoylation gave exclusively 4-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine ( 9 ) and 3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4-(5H)-one ( 12a ), respectively. The structural assignment of 12a was made on the basis of single-crystal X-ray analysis. Application of this general glycosylation procedure to 15 gave the corresponding N-1 glycosyl derivative 16 as the sole product, which on debenzoylation afforded 3-ethoxy-6-(methylthio)-1-(3-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one ( 17 ). Oxidation of 16 and subsequent ammonolysis furnished the guanosine analog 6-arnino-3-ethoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]-pyrimidin-4(5H)-one ( 19 ). Similarly, starting from 3-methoxy-4,6-bis(methylthio)pyrazolo[3,4-d]pyrimidine ( 20 ), 6-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one ( 23 ) was prepared.     

Syntheses of 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one,an isostere of oxanosine,and the guanosine analog 6-amino-1-(β-d-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one via ring closure of pyrazole-5-thioureido intermediates

6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 4 ), an isostere of the nucleoside antibiotic oxanosine has been synthesized from ethyl 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxylate ( 6 ). Treatment of 6 with ethoxycarbonyl isothiocyanate in acetone gave the 5-thioureido derivative 7 , which on methylation with methyl iodide afforded ethyl 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-ethoxycarbonyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxylate ( 8 ). Ring closure of 8 under alkaline media furnished 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 10 ), which on deisopropylidenation afforded 4 in good yield. 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 5 ) has also been synthesized from the AICA riboside congener 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxamide ( 12 ). Treatment of 12 with benzoyl isothiocyanate, and subsequent methylation of the reaction product with methyl iodide gave 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-benzoyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxamide ( 15 ). Base mediated cyclization of 15 gave 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 14 ). Deisopropylidenation of 14 with aqueous trifluoroacetic acid afforded 5 in good yield. Compound 4 was devoid of any significant antiviral or antitumor activity in culture.     

Regioselective synthesis of pyrido[2,3-d]pyrimidines

The reaction of diethyl ethoxymethylenemalonate ( 1 ) and 6-amino-1,3-dimethyluracil ( 2 ) was determined to be regioselective. Under acidic conditions the product was the previously isolated 7-oxopyrido[2,3-d]pyrimidine ( 3 ), while in the presence of one equivalent of base followed by thermal cyclization, the isomeric 5-oxopyrido[2,3-d]pyrimidine ( 5 ) is formed.     

Synthesis of novel dihydrothiazolo[3,2-a]pyrimidinone derivatives

Condensation of 2-amino-4-hydroxy-2-mercaptopyrimidine (2) hydrate and ethyl 4-bromocrotonate gave a mixture of ethyl 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-acetate (4) and 2a,3-dihydro-1-thia-5,8,8b-triazaacenaphthylene-4,7(2H)-dione (5) whereas reaction of 2 with 4-bromocrotononitrile afforded only 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a] pyrimidine-3-acetonitrile. Reaction of the tricycle 5 (which was isolated as a hemihydrate) with excess methyl iodide/potassium carbonate in dimethylformamide resulted in both ring hydrolysis and methylation to give 3,4-dihydro-1,7-dimethyl-4- [(methylthio)methyl]-2H-pyrimido[1,6-a]pyrimidine-2,6,8(1H,7H)-trione (10). Methylating 5 with excess methyl iodide/sodium methoxide in methanol also resulted in ring fragmentation and methylation but instead afforded methyl 7-methyl-amino-2,3-dihydro-5-oxo-7H-thiazolo[3,2-a]pyrimidine-3-acetate. The mechanistic aspects of these reactions are discussed.     

Synthese von 2,4-Diamino-thieno[2,3-d]pyrimidin-Derivaten

Synthesis of 2,4-Diamino-thieno[2,3-d]pyrimidines Condensation of 2-aminothiophene-3-carbonitrile ( 4 ) with guanidine or sequential addition of CS₂ and NH₃ to 4 provides 2,4-diaminothieno[2,3-d]pyrimidine ( 7 ). This compound yields, after sequential addition of sec-BuLi and either [3-(trifluoromethyl)benzene]sulfenyl chloride ( 8 ) or the corresponding disulfide 9 , followed by acidic work up, 2,4-diamino-6-{[3-(trifluoromethyl)phenyl]thio}thieno[2,3-d]pyrimidine ( 10 ). In another approach, 2-amino-5-{[3-(trifluoromethyl)phenyl]thio}thiophene-3-carbonitrile ( 11 ) obtained from 4 and 8 is transformed to 10 by condensation with guanidine. Corresponding to the second route, 2,4-diamino-6-[(naphth-2-yl)thio]thieno-[2,3-d]pyrimidine ( 16 ) is synthesized. Oxidation of 10 with m-chloroperbenzoic acid gives 2,4-diamino-6-{[3-(tri-fluoromethyl)phenyl]sulfinyl}thieno[2,3-d]pyrimidine ( 13 ).     

Acetylenic chemistry: Part 15 [1]. Reactions of 1,2,3,4-Tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine with 3-bromoprop-1-yne

Reaction of 1,2,3,4-tetrahydro-2,4-dioxopyrido[2,3-d]pyrimidine with 3-bromoprop-1-yne gave 1-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4a ), 3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4b ), and 1,3-diprop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 4c ). Subsequent boiling of 1,3-diprop-2′-ynylpyrido-[2,3-d]pyrimidine-2,4-dione ( 4c ) in formic acid afforded 1-methylimidazo[1,2-a]pyridyl-N-prop-2′-ynylamide ( 5 ) and 1-acetonyl-3-prop-2′-ynylpyrido[2,3-d]pyrimidine-2,4-dione ( 6 ).     

Synthesis of 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acids and the reinvestigation of the thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate

Diethyl [2-(3- or 4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonates 5 prepared by the reaction between 2-(3- or 4-pyridinyl)-4-pyrimidinamines 3 and diethyl ethoxymethylenemalonate ( 4 ) were thermally cyclized to afford ethyl 5,8-dihydro-5-oxo-2-(3- or 4-pyridinyl)pyrido[2,3-d]pyrimidine-6-carboxylates 6 . The later were alkylated with ethyl iodide and then saponified to give 5,8-dihydro-8-ethyl-5-oxo-2-(3- or 4-pyridinyl)pyrido-[2,3-d]pyrimidine-6-carboxylic acids 2 . Thermal cyclization of diethyl (2-hydroxy-4-pyrimidinyl)amino-methylenemalonate ( 8 ) gave ethyl 1,6-dihydro-4,6-dioxo-4H-pyrimido[1,6-a]pyrimidine-3-carboxylate ( 10 ) instead of ethyl 5,8-dihydro-2-hydroxy-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate ( 9 ) as previously claimed.     

Annelated piperazinyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidines

Tricyclic analogs of piperazinylthiopyrano[3,2-d]pyrimidine hypoglycemic agents were prepared. The angular tricyclic systems, 8,9-dihydro-7H-thiopyrano[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine and 8,9-dihydro-7H-tetrazolo[1,5-a]thiopyrano[2,3-e]pyrimidine derivatives were synthesized from 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine in three step sequences. Derivatives of the linear tricyclic system, 5,6-dihydro-7H-thiopyrano[3,2-d][1,2,4]triazolo[2,3-a]pyrimidine, were prepared by condensation of 3-amino-1,2,4-triazole with ethyl 3-oxo-tetrahydropyran-2-carboxylate. The tricyclic heteroaryl-piperazines lacked significant hypoglycemic activity.     

Synthesis of 4,6-disubstituted-7-β-D-ribofuranosyl- and arabinofuranosylpyrazolo[3,4-d]pyrimidines and certain related ribonucleosides

Several disubstituted pyrazolo[3,4-d]pyrimidine, pyrazolo[1,5-a]pyrimidine and thiazolo[4,5-d]pyrimidine ribonucleosides have been prepared as congeners of uridine and cytidine. Glycosylation of the trimethylsilyl (TMS) derivative of pyrazolo[3,4-d]pyrimidine-4,6(1H,5H,7H)-dione ( 4 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 5 ) in the presence of TMS triflate afforded 7-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo-[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 6 ). Debenzoylation of 6 gave the uridine analog 7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 3 ), identical with 7-ribofuranosyloxoallopurinol reported earlier. Thiation of 6 gave 7 , which on debenzoylation afforded 7-β-D-ribofuranosyl-6-oxopyrazolo[3,4-d]pyrimidine-4(1H,5H)-thione ( 8 ). Ammonolysis of 7 at elevated temperature gave a low yield of the cytidine analog 4-amino-7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-6(1H)-one ( 11 ). Chlorination of 6 , followed by ammonolysis, furnished an alternate route to 11 . A similar glycosylation of TMS-4 with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride ( 12 ) gave mainly the N7-glycosylated product 13 , which on debenzylation provided 7-β-D-arabinofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 14 ). 4-Amino-7-β-D-arabinofuranosyl-pyrazolo[3,4-d]pyrimidin-6(1H)-one ( 19 ) was prepared from 13 via the C4-pyridinium chloride intermediate 17 . Condensation of the TMS derivatives of 7-hydroxy- ( 20 ) or 7-aminopyrazolo[1,5-a]pyrimidin-5(4H)-one ( 23 ) with 5 in the presence of TMS triflate gave the corresponding blocked nucleosides 21 and 24 , respectively, which on deprotection afforded 7-hydroxy- 22 and 7-amino-4-β-D-ribofuranosylpyrazolo[1,5-a]pyrimidin-5-one ( 25 ), respectively. Similarly, starting either from 2-chloro ( 26 ) or 2-aminothiazolo[4,5-d]pyrimidine-5,7-(4H,6H)-dione ( 29 ), 2-amino-4-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-5,7(6H)-dione ( 28 ) has been prepared. The structure of 25 was confirmed by single crystal X-ray diffraction studies.     

7-Deazapurines II. Syntheses and reactions of 5-aminopyrrolo[2,3-d] pyrimidine-6-carbonitrile and related compounds

The reaction of 4-chloro-2-phenyl-5-pyrimidinecarbonitrile (III) with N-methylglycinonitrile gave 4-[(eyanomethyl)methylamino]-2-phenyl-5-pyrimidinecarbonitrile (VIa), which upon cycli-zation under Dieckmann conditions afforded 5-amino-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]-pyrimidine-6-carbonitrile (VIIa). Other examples (VIIb and VIIc) were prepared similarly from the reactions of III with glycinamide and ethyl glycinate, respectively. The preparation of simple 5-amino derivatives of the pyrrolo[2,3-d] pyrimidines thus synthesized is described. The alkyla-tion of VIIc with N-cyeloheptylchloroacetamide took place at the ring nitrogen, giving XII. The reaction of VIIa with formamide gave 4-amino-5-methyl-7-phenyl-5H-pyrrolo[2,3-d:4,5-d′ ]-dipyrimidine (XIII), the first member of a new ring system. Treatment of VIIa with carbon disulfide and pyridine afforded another example of this new ring system, 1,5-dihydro-5-methyl-7-phenyl-2H-pyrrolo[2,3-d:4,5-d′] dipyrimidine-2,4-(3H)dithione (XIV).     

Synthesis of S-5-pyrrolo[2,3-b]pyridinemethyl and S-5- and S-6-pyrrolo[2,3-d]pyridinemethyl derivatives of 5′-deoxy-5′-thioadenosine

Reaction of 5-dimethylaminomethylpyrrolo[2,3-b]pyridine methiodide or 5-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one methiodide with 5′-deoxy-5′-S-thioacetyl-N⁶-formyl-2′,3′-O-isopropylideneadenosine in ethanolic sodium hydroxide solution, followed by deprotection of the resulting thioether in 80% formic acid, afforded 5′-deoxy-5′-(5-pyrrolo[2,3-b]pyridinemethylthio)adenosine or 5′-deoxy-5′-[5-(pyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine, respectively. Similarly, the metiodide salt of the iso-gramine analog, 2-amino-6-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one afforded 5′-deoxy-5′-[6-(2-aminopyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine.     

Synthesis of 8-amino-4-methylthio-6-methyl-2-(β-D-ribofuranosyl)-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene and an unusual reductive ring-opening of the 1,2,3,5,6,7-hexaazaacenaphthylene ring system

The tricyclic nucleoside 8-amino-4-methylthio-6-methyl-2-(β-D-ribofuranosyl)-1,2,3,5,6,7-hexaazaacenaphthylene ( 3 ) was synthesized from 3-cyano-4,6-bis(methylthio)-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 1 ). Attempts to synthesize 8-amino-6-methyl-2-(β-D-ribofuranosyl)-1H-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene ( 5 ) ([an aza analog of 6-amino-4-methyl-8-(β-D-ribofuranosyl)-1,3,4,5,8-pentaazaacenaphthylene (TCN)], which is a potent antitumor agent), by the treatment of 3 with Raney nickel did not afford the desired aza analog of TCN. Instead, it was established that a reductive cleavage of the pyridazine moiety of 3 had occurred to give 4-methylamino-6-methylthio-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 6 ). Assuming that solubility was a problem in the reductive step, the isopropylidene derivative of 3 , 8-amino-6-methyl-4-methylthio-2-(2,3-O-isopropylidene-β-D-ribofuranosyl)-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene ( 8 ), was treated with Raney nickel, only to observe that a similar reductive ring cleavage of 8 had occurred to afford 4-methylamino-6-methylthio-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 10 ) and 4-methylamino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 11 ). Structural assignments for all products were established by physico-chemical procedures.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.     

Pyrimidines. 21. Novel reactions of 5-cyano-1,3-dimethyluracil with carbon nucleophiles. A facile preparation of certain pyrido[2,3-d]pyrimidines

Treatment of 5-cyano-1,3-dimethyluracil ( 8 ) with an activated acetonitrile, such as malononitrile, ethyl cyanoacetate or cyanoacetamide, in base afforded 7-amino-6-cyano-, 7-amino-6-ethoxycarbonyl-, and 7-amino-6-aminocarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18b, 18c and 18d , respectively) in high yields. On the other hand, reaction of 8 with acetonitrile in base gave the Michael adduct, 5-cyano-6-cyanomethyl-5,6-dihydrouracil ( 15 , R = H), and the hydrated product, 1,3-dimethyluracil-5-carboxamide ( 9 ) as the major products, and 7-amino-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 18a ) in only very low yield. Similar reaction with butanone gave 7-ethyl-1,3-dimethyl- and 1,3,6,7-tetramethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 10b and 10c ) in low yields. When 8 was treated with diethylmalonate in base, only a small amount of 6-ethoxycarbonyl-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione ( 19 ) was obtained together with 1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ( 20 ) and 18c (also in low yields). Treatment of 8 in ethanolic sodium ethoxide without added carbon nucleophile gave significant amounts (14%) of 20 and a small amount of 18c .     

Synthesis of certain pyrazolo[3,4-d]pyrimidin-3-one nucleosides

Synthesis of the pyrazolo[3,4-d]pyrimidin-3-one congeners of guanosine, adenosine and inosine is described. Glycosylation of 3-methoxy-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 13 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 16 ) in the presence of boron trifluoride etherate gave 3-methoxy-6-methylthio-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 17 ) which, after successive treatments with 3-chloroperoxybenzoic acid and methanolic ammonia, afforded 6-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)one ( 18 ). The guanosine analog, 6-amino-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 21 ), was made by sodium iodide-chlorotrimethylsilane treatment of 6-amino-3-methoxy-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)one ( 19 ), followed by sugar deprotection. Treatment of the adenine analog, 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( 11 ), according to the high temperature glycosylation procedure yielded a mixture of N-1 and N-2 ribosyl-attached isomers. Deprotection of the individual isomers afforded 4-amino-3-hydroxy-1-βribofuranosylpyrazolo-[3,4-d]pyrimidine ( 26 ) and 4-amino-2-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-3(7H)-one ( 27 ). The structures of 26 and 27 were established by single crystal X-ray diffraction analysis. The inosine analog, 1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 28 ), was synthesized enzymatically by direct ribosylation of 1H-pyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 8 ) with ribose-1-phosphate in the presence of purine nucleoside phosphorylase, and also by deamination of 26 with adenosine deaminase.     

9-Deazapurine nucleosides. The synthesis of certain N-5-β-d-ribofuranosylpyrrolo[3,2-d]pyrimidines

Several N-5 ribofuranosyl-2,4-disubstituted pyrrolo[3,2-d]pyrimidine (9-deazapurine) nucleosides were prepared by the single phase sodium salt glycosylation of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine ( 3 ) using 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dirnethylsilyl-α-D-ribofuranose ( 2 ). Use of 2 for the glycosylation avoided the formation of “orthoamide” products 1 and provided an excellent yield of the β nucleoside, 2,4-dichloro-5-[2,3-O-isopropylidene-5-O-(t-butyl)dimethylsilyl-β-D-ribofuranosyl]-5H-pyrrolo[3,2-d]pyrimidine ( 4 ), along with a small amount of the corresponding α anomer, 5 . Compound 4 served as the versatile intermediate from which the N-7 ribofuranosyl analogs of the naturally-occurring purine nucleosides adenosine, inosine and guanosine were synthesized. Thus, controlled amination of 4 followed by sugar deprotection and dehalogenation yielded the adenosine analog, 4-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidine ( 8 ) as the hydrochloride salt. Base hydrolysis of 4 followed by deprotection gave the 2-chloroinosine analog, 10 , and subsequent dehalogenation provided the inosine analog, 5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]-pyrimidin-4(3H)-one ( 11 ). Amination of 10 furnished the guanosine analog, 2-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one ( 12 ). Finally, the α anomer in the guanosine series, 16 , was prepared from 5 by the same procedure as that used to prepare 12 . The structural assignments were made on the basis of ultraviolet and proton nmr spectroscopy. In particular, the isopropylidene intermediates 9 and 14 were used to assign the proper configuration as β and α, respectively, according to Imbach's rule.