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.     

Pyrrolo[2,3-d] pyrimidines. I. 5-hydroxypyrrolo[2,3-d] pyrimidines

5-Hydroxy-7-alkyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriles (VIIb-d) and 5-hydroxy-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, ethyl ester (VIIa) were prepared from 5-carbethoxy-4-chloro-2-phenylpyrimidine (IV) via 4-[(cyanomethyl)alkylamino[-2-phenyl-5-pyrimidinecarboxylic acid, ethyl esters (Vb-d) and 4-[(carboxymethyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid, diethyl ester (Va), respectively. The hydroxy group of the pyrrolo-[2,3-d]pyrimidines could be methylated, acetylated and tosylated. Hydrolysis of 5-methoxy-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (IX) afforded the corresponding amide (X).     

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.     

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.     

Synthesis of pyrido[2,3-d]pyrimidines from aminopyrimidinecarbaldehydes

2-Methoxy-4-amino-5-pyrimidinecarbaldehyde ( 2a ) as well as its 6-methyl 2b and 6-phenyl derivatives 2c were prepared by reduction of the corresponding aminopyrimidinecarbonitriles 1 . Catalytic hydrogenation of 1a, 1b gives 5-hydroxymethylpyrimidines 3a, 3b ; under the same conditions 1c afforded 5-aminomethylpyrimidine 4 . Condensation of 2 with carbonitriles, ketones and polyfunctional carbonyl compounds bearing the -CH₂CO- moiety afforded the pyrido[2,3-d]pyrimidines and pyrimido-[4,5-b]quinoline derivatives.     

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

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

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.     

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.     

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 .     

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 furo[2,3-d]pyrimidines condensed with a tetrahydrothiopyran

Using o-iodobenzoic acid we synthesized 5-hydroxy-2,2-dimethyltetrahydrothiopyran-4-one. From the latter we synthesized 2-amino-5,5-dimethyl-3-cyano-4,5-dihydro-7H-furo[2,3-c]thiopyran; this is a starting material for the preparation of furo[2,3-d]pyrimidine condensed with tetrahydrothiopyran and triazole rings.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1403–1405, October, 1990.     

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.     

Pyrimidinylalkylthiols,furo[2,3-d]pyrimidines and derivatives

Several pyrimidinylalkylthiols and furo[2,3-d]pyrimidines and their derivatives have been prepared as potential radiation-protection agents.     

Synthesis of pyrrolo[2,3-d]pyrimidines with 3-amino-2-hydroxypropyl substituents

A novel route has been found for the synthesis of pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazines. They are promising reagents for the preparation of pyrrolo[2,3-d]pyrimidine-6-carboxylic acid amides which contain a 3-amino-2-hydroxypropyl substituent in position 7 of the heterocyclic ring.     

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.     

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.     

Synthesis and Reactions of Some New Heterocyclic Compounds Related to Pyrrolylthieno[2,3-d]pyrimidines and Thieno[2,3-d][4,5-d]dipyrimidines

Abstract

Condensation of ethyl-5-amino-2,4-diphenylthieno[2,3-d]pyrimidine-6-carboxylate (3a) with 2,5-dimethoxy tetrahydrofurane in acetic acid gives the corresponding 5-pyrrolyl derivative4, which in turn could be easily reacted with hydrazine hydrate in ethanol yielding the carbohydrazide derivative5. Reaction of5 with aromatic aldehydes, acetylacetone, carbon disulfide or phenylisothiocyanate gave pyrrolyl derivatives6,7,8,9 respectively. On the other hand, condensation of 5-(1-pyrrolyl)-6-acetyl-2,4-diphenylthieno[2,3-d]pyrimidine11 with benzaldehyde afforded the corresponding chalcone12, which on treatment with hydrazine hydrate, phenyl hydrazine, or thiourea gave the pyrazolinyl derivatives13,14 and pyrimidinyl derivative15, respectively. Furthermore some new pyrimidothienopyrimidne16,17a–d,19,20a–c were obtained using 5-amino-carboxamide3c as starting material.     

5-Acetyl-6-amino-4-methylthio-2-phenylpyrimidine and its use in the synthesis of functionalized pyrido[2,3-d]pyrimidines and pyrimido-[4,5-d]pyrimidines

Schemes for the synthesis of MeS-substituted pyrido[2,3-d]pyrimidin-5-one, pyrimido[4,5-d]pyrimidine, and 4-methylenepyrimido[4,5-d]pyrimidin-2-one based on 5-acetyl-6-amino-4-methylthio-2-phenylpyrimidine, which was prepared from the adduct of benzoyl isothiocyanate with acetylketeneN-benzoylaminal, were suggested.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1324–1328, July, 1995.The work was carried out with financial support from the Russian Foundation for Basic Research (Grant No. 94-03-08964).     

Novel animation reactions of dihydrofurano[2,3-d] pyrimidines

Although alkoxypyrimidines can be aminated to yield aminopyrimidines, monoamination of 2,4- or 4,6-chloroalkoxypyrimidines results in chlorine displacement. Preferential alkoxy displacement in such systems is unusual. We now have evidence of such a displacement in the dihydrofurano[2,3-d] pyrimidines (V). In some cases two types of products, formed by displacement of either the chlorine or alkoxy substituent, were obtained.     

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.