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 Ring Transformation of Pyrrolo[2,3-d][1,3]oxazine to Pyrrolo[2,3-d]Pyrimidines

A convenient route is reported for the synthesis of fused pyrrolo[2,3-d][1,3]oxazine and pyrrolo[2,3-d]-pyrimidine derivatives from 2-amino-1-benzyl-3-t-butoxycarbonyl]-4,5-dimethylpyrrole.     

Pyrido[2,3-d]pyrimidines. 1. Acylation of 2,4,5-trioxo-7-amino-8H-pyrido [2,3-d]pyrimidines

Reaction of 2,4,5-trioxo-7-aminopyrido[2,3-d]pyrimidines with acylating agents takes place both at the amino group and at the cyclic nitrogen atom. Reaction of these compounds with formic acid, chloroacetyl chloride in pyridine, cyanoacetic acid in the presence of acetic anhydride, and oxalyl chloride leads to monoacylation at the amino group but with methyl chloroformate it is the product of acylation at the cyclic nitrogen. Refluxing in acetic anhydride gave mono-, di-, and triacetyl derivatives. The structures of these compounds were proved using spectral data.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 811–814, June, 1990.     

Pyrido[2,3-d]pyrimidines 4. Synthesis and some transformations of oxo(hydroxy)pyrido[2,3-d]pyrimidines

The cyclization of 5-cyanoacetyl-6-aminouracils in acidic media was accomplished. The structures of the pyrido[2,3-d]pyrimidines obtained and their properties are discussed.See [1] for Communication 3.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 674–680, May, 1991.     

Pyrido[2,3-d]pyrimidines. 2. Reactions of 2,4,5-trioxo-7-amino-8H-pyrido[2,3-d]pyrimidines with electrophilic agents

1,3-Dimethyl-2,4,5-trioxo-7-amino-8H-pyrido[2,3-d]pyrimidine has been brominated, chlorosulfonated, treated with potassium nitrite in acidic medium, and with the Vilsmeier reagent. Acylation and alkylation of 1,3-dimethyl-2,4,5-trioxo-6-bromo-7-aminopyrido[2,3-d]pyrimidine is also discussed.For Communication 1, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 662–666, May, 1990.     

Pyrido[2,3-d]pyrimidines and pyrido[2,3-d; 5-d′]dipyrimidines as potential chemotherapeutic agents. VIII

Reactions of 5-dimethylaminomethylene-6-imino-1,3-dimethyluracil hydrochloride (1) with active methylene compounds 2 and 4 yielded bi- and tricyclic heterocyclic compounds 3 and 5 . All the prepared compounds were screened for chemotherapeutical activities but none were active.     

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.     

The synthesis and transformations of 3-ethoxycarbonyl-2-isothiocyanatopyridine. Pyrido[2,3-d]pyrimidines and some azolopyrido[2,3-d]pyrimidines

3-Ethoxycarbonyl-2-isothiocyanatopyridine ( 2 ), prepared from 2-amino-3-ethoxycarbonylpyridine ( 1 ) by the thiophosgene method, was converted into thiouretanes 3 and 4 , 1,4-disubstituted thiosemicarbazide 6 , thioamide 8 , and thioureas 15 and 18 . The compounds 2 and 3 were converted into bicyclic pyrido[2,3-d]pyrimidines 5, 9, 10, 11, 12, 16 , and 17 , and tricyclic azolopyrido[2,3-d]pyrimidines 13 and 14 .     

Novel Pyrrolo[2,3-d]pyrimidine Ring forming Methodology

A short, succinct route to biologically active and medicinally important pyrrolo[2,3-d]pyrimidines has been developed starting from readily available acyclic aldehydes. A very efficienttwo step sequence involving a Knoevenagel condensation followed by copper mediated 1,4-conjugate of vinyl magnesium bromide sets up the acyclic precursor. Then, guanidine cyclization followed by a palliduim catalyzed amination reaction or ozonolytic cleavage of the vinyl substituent followed by guanidine cyclization and intramolecular imine formation complete the synthesis.     

Fused pyrimidines. 5. Methylated pyrimido[4,5-d]pyrimidines

The Mannich reaction has been applied to pyrimidines possessing activating groups at positions 2, 4, and 6 and that have a methyl group attached at a ring nitrogen atom. The corresponding tetrahydropyrimido[4,5-d]pyrimidines were obtained. In one case there was a possibility of isomer formation. Chemical reactivity was not successful in determining the structure but through an nmr program called INAPT, a version of INEPT, we were able to assign the structure as that of 6 .     

Pyrido[2,3-d]pyrimidines Reactions of hydroxypyrido[2,3-d]pyrimidines with thionyl chloride in the presence of DMF

Depending on the reaction conditions, 5-hydroxy- and 5,7-dihydroxypyrido[2,3-d]pyrimidines react with thionyl chloride in the presence of DMF to give chlorination at position 6 along with replacement of the hydroxy groups at C(5) and C(7) with chlorine, while a nitro group at C(6) is ipsosubstituted by chlorine.For Communication 5, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1230–1233, September, 1992.     

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 thieno[2,3-d]pyrimidines from 4,6-dichloropyrimidine-5-carbaldehydes

Several thieno[2,3-d]pyrimidines have been prepared by intramolecular cyclisation of 6-(substituted methylthio)-5-pyrimidinecarbaldehyde and carbonitrile intermediates derived from 6-chloropyrimidine-5-carbaldehydes and 5-carbonitriles and methyl thioglycolate or 5-formylpyrimidine-4-(3H)-thiones and appropriate α-halogeno compounds. Thienopyrimidines 18 and 5c were nitrated to the corresponding nitro compounds 23 and 24 . Hydrolysis at position 4 of compound 18 also occurred during nitration. The ester 5g was hydrolysed in base to the acid 25 .     

Convenient selective synthesis of pyrano[2,3-d]pyrimidines

A selective method for the synthesis of substituted and annulated pyrano[2,3-d]pyrimidines consisting in acylation of 2-amino-3-cyano-4H-pyrans with acetic anhydride has been developed. It was shown for the first time that acid catalysis is more efficient in this reaction, rather than base catalysis as it has been believed earlier.     

Pyrido[2,3-d]pyrimidines,II. One step synthesis of pyrido[2,3-d]pyrimidines and pyrimido[4,5-b]quinolines from 6-amino uracils

Summary Reduction of 6-azidouracils2 with hydrogen palladium or sodium dithionite afforded the corresponding 6-aminouracils5 which could also be obtained by reaction of2 with triphenylphosphanevia phosphazenes and subsequent hydrolysis (Staudinger reaction). The use of trimethylphosphite instead of phosphanes yields with2b the expected trimethoxyphosphazene3c, whereas2a reacts to the phosphonoaminopyrimidine4. The syntheses of 5-hydroxy pyrido[2,3-d]pryimidine-2,4,7-triones6, pyrido[2,3-d]pyrimidine-2,4,5-triones8, cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-triones7a,c, and tetrahydro-pyrimido[4,5-b]quinolin-2,4,5-triones7b,d by condensation of 6-aminouracils5 with malonates, ethylaceto/benzoylacetate, ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate, respectively, are described.

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Pyrido[2,3-d]pyrimidine, 2. Mitt. Einstufige Synthese von Pyrido[2,3-d]pyrimidinen und Pyrimido[4,5-b]chinolinen aus 6-Aminouracilen

Zusammenfassung Reduktion der 6-Azidouracile2 mit Wasserstoff/Palladium oder Natriumdithionit ergibt die entsprechenden 6-Aminouracile5, die auch durch Reaktion von2 mit Triphenylphosphin und anschließende Hydrolyse erhalten werden können (Staudinger-Reaktion). Die Verwendung von Trimethylphosphit anstelle von von Trimethylphosphin ergibt mit2b das erwartete Trimethoxyphosphazin3c, während2a zum Phosphonoaminopyrimidin4 reagiert. Die Synthesen der 5-Hydroxy-pyrido[2,3-d]pyrimidin-2,4,7-trione6, der Pyrido[2,3-d]pyrimidin-2,4,5-trione8, der Cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-trione7a,c und der Tetrahydro-pyrimido[4,5-b]chinolin-2,4,5-trione7b,d durch Kondensation der 6-Aminouracile5 mit Malonat, Acetat, Ethyl-2-oxocyclopentancarboxylat und Ethylcyclohexancarboxylat werden beschrieben.

     

Synthesis of new 6-Aroylpyrido[2,3-d]pyrimidines

The synthesis of 6-dimethylaminomethylenaminopyrimidin-4(3H)-ones 2 and its reaction with β-dimethyl-aminopropiophenone hydrochloride 3 is discussed in this work. The reaction of 6-aminopyrimidin-4(3H)-ones 1 with an excess of dimethylformamide dimethyl acetal gives rise to the formation of 6-dimethylaminomethyleneaminopyrimidines 2. The heating of equimolecular quantities of 2 and 3 in dimethylformamide leads to the 6-aroylpyrido[2,3-d]pyrimidines derivatives 4. The structures of compounds 2 and 4 were determined on the basis of nmr measurements.     

Solid-phase synthesis of tetrasubstituted pyrrolo[2,3-d]pyrimidines

A facile solid phase synthesis of 2,4,6,7-tetrasubstituted pyrrolo[2,3-d]pyrimidines is described. The synthesis involves a highly efficient five-step route starting from resin-bound dimeric peptoids. To demonstrate the versatility of our method, a representative library of 108 tetrasubstituted pyrrolo[2,3-d]pyrimidines of high quality was synthesized.     

Synthèse des pyrido[2,3-d] el [3,2-d] -s-triazolo[3,4-f] pyrimidines el de (pyrazolyl-1')-4 pyrido[2,3-d] et [3,2-d] pyrimidines

The synthesis of two new heterocycles is described: pyrido-[2,3-d]-.s-triazolo[ 3,4-f] pyrimidine and pyrido[3,2-d]-.s-triayzolo-[3,4-f] pyrimidine. 4-[I'-Pyrazolyl]pyrido[2,3-d]pyrimidines and 4-[1′-pyrazoly1] pyrido[ 3,2-d] pyrimidine are obtained by the action of 4-hydrazinopyrido[2,3-d]pyrimidine and 4-hydrazinopyrido-[3,2-d]pyrimidine with several β-diketones.     

An improved synthesis of pyrido[2,3-d]pyrimidines

An improved and efficient synthesis of 1,3-dialkylpyrido[2,3-d]pyrimidine-2,4-(1H,3H)-diones from 6-methylaminouracils and methyl propiolate or diethyl ethoxymethylenemalonate is described.     

Reaction of chloropyrido[2,3-d]pyrimidines with DBSO

Communication 5 from the series Pyrido[2,3-d]pyrimidines. See [1] for communication 4.