Analogs of pyrimidine nucleosides

The UV absorption spectra of 5-substituted N¹-(tetrahydrofuran-2-yl)- and N¹-(2oxotetrahydrofuran-3-yl)uracils have been studied and their protolysis constants have been determined by the spectrophotometric method. A comparison is given with the spectra and pKa values of the corresponding N¹-methyl derivatives and ribosides and deoxyribosides.For part IV see [11].The work was carried out with analytical samples of compounds obtained by us previously [9–12].     

Analogs of pyrimidine nucleosides

N₁-(-Tetrahydrofuranyl)- and N₁-(-tetrahydropyranyl)uracils and the corresponding 6-azauracils have been obtained by the condensation of bistrimethylsilyl derivatives of uracils and 6-azauracils with-chlorotetrahydrofuran and-chlorotetrahydropyran. The superiority of the silyl method over the mercury method used previously has been demonstrated.For part III, see [9].     

Analogs of pyrimidine nucleosides

A new method for the synthesis ofN₁-(dihydroxyalkyl)uracils by reduction of substituted α- (1-uracilyl)- and γ-[(1-uracilyl)methyl]-γ-butyrolactones with sodium borohydride was found.     

Analogs of pyrimidine nucleosides

A new method was developed for the synthesis of 1-(2-tetrahydrofuryl) derivatives of uracil, 5-substituted uracils, 6-azauracil, and cytosine by alkylation of 2,4-bis(trimethylsilyl) derivatives of pyrimidine bases with 2-acetoxytetrahydrofuran in the presence of Lewis acids. In contrast to 2-chlorotetrahydrofuran, which is used in a previously described method, 2-acetoxytetrahydrofuran is stable at room temperature and reacts under these conditions with silyl derivatives of uracils in the presence of SnCl₄ to give 1-(2-tetrahydrofuryl) derivatives of pyrimidine bases in 80–85% yields.See [1] for communication X.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedineaii, No. 9, pp. 1258–1259. September, 1977.     

Analogs of pyrimidine nucleosides

α-(1-Cytosinyl)-γ-butyrolactone was obtained by condensation of bis(trimethylsilyl)cytosine with α-bromobutyrolactone. The reduction of α-(1-cytosinyl)-γ-butyrolactone with sodium borohydride gave N₁-(1,4-dihydroxy-2-butyl)cytosine, the acylation of which with benzoyl chloride and subsequent partial hydrolysis gave N₁-(1,4-dihydroxy-2-butyl)-N₄-benzoylcytosine.     

Analogs of pyrimidine nucleosides

The reaction of alkoxy bromides with N₁-(-tetrahydrofuryl) derivatives of pyrimidine bases has given a series of 6-alkoxy-5-bromo-1-(-tetrahydrofuryl)-5, 6-dihydrouracils. The hydrogenation of the 1-(-tetrahydrofuryl) derivatives of uracil and of 5-fluorouracil has been studied. It has been shown that in both cases 1-(-tetrahydrofuryl)-5, 6-dihydrouracil is formed.     

Analogs of the pyrimidine nucleosides

The kinetics of the hydrolysis of the pseudoglycosidic C-N bond in the N¹-derivatives of uracil, thymine, and 5-fluorouracil at various pH values of the medium have been studied. The dependence of the rate of hydrolysis of N¹-(tetrahydrofuran 2-yl)-5-fluorouracil on the temperature has been investigated. The influence of substituants at C₅ and N₁ of the pyrimidine ring on the stability of the pseudoglycosidic C-N bond has been evaluated.For part V, see [10].     

Analogs of pyrimidine nucleosides. 13. 1-Substituted 4-thiouracils

4-Thiouracil derivatives with various oxygen-containing groupings as substituents attached to the N₁ atom were obtained by thionation of 1-substituted uracils with phosphorus pentasulfide. It is demonstrated that the yield of the 4-thiouracil derivative depends on the strength of the C-N pseudoglycoside bond in the starting 1-substituted uracil.See [1] for communication 12.Translated from Khimlya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1109–1113, August, 1980.     

Analogs of pyrimidine nucleosides. 20. Aminomethylation of 5-fluorouracil and thymine

Reactions were studied of 5-fluorouracil and thymine with formaldehyde and secondary amines (piperidine, morpholine) and also of their 2,4-bis(trimethylsilyl) derivatives with N-methoxymethylmorpholine and bis(amino)methanes. The N-aminomethylation products are slightly stable and in aqueous solutions decompose readily to the starting components; their structure was confirmed by PMR spectra.For Communication 19, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 90–93, January, 1987.     

Analogs of pyrimidine nucleosides. 15. Synthesis of 3′-hydroxy- and 4′-hydroxyftorafur

A method for the synthesis of ftorafur metabolites, viz., 3-hydroxy- and 4-hydroxyftorafur, from 3-benzoxytetrahydrofuran, which is chlorinated in the presence of UV irradiation, was developed. The resulting mixture of -chloro ethers is alkylated by 2,4-bis(trimethylsilyl)-5-fluorouracil. The alkylation products are separated by fractional crystallization and column chromatography on silica gel, and the benzoyl protective group is removed, cis-4-Hydroxyftorafut, trans-3-hydroxyftorafur, and cis-3-hydroxyftorafur, which were identified from the PMR spectra and by comparison with the literature data, were obtained.See [1] for Communication 14.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1094–1096, August, 1981.     

Analogs of pyrimidine nucleosides. 16. Racemic 2′,3′-dideoxynucleosides and their derivatives

The chlorination of 2-halomethyltetrahydrofurans and acyl derivatives of tetrahydrofuryl alcohol wasstudied; mixtures of 2,5- and 2,2-disubstituted tetrahydrofurans are formed as a result of the reaction. 2,4-Bis(trimethylsilyl) derivatives of uracil, 5-substituted uracils, and cytosine are alkylated by the resulting mixtures of -chloro ethers without separation, and mixtures of cis and transisomers of 1-(5-substituted-2-tetrahydrofuryl) and 1-(2-substituted-2-tetrahydrofuryl) derivatives of uracil, 5-substituted uracils, and cytosine are obtained. The reaction products were identified onthe basis of their PMR spectra.See [1] for Communication 15.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 101–110, January, 1982.     

Analogs of pyrimidine nucleosides. 14. Synthesis and antitumorigenic activity of alkoxyalkyl derivatives of 5-fluorouracil

A number of alkoxyalkyl derivatives of 5-fluorouracil were synthesized by alkylation of 2,4-bis(trimethylsilyl)-5-fluorouracil with -chloro ethers or by the addition of 5-fluorouracil to vinyl ethers. It was established that the synthesized compounds are capable of increasing the lifetimes of mice with L-1210 leukemia and La hemocytoblastosis. The UV and NMR spectra of the synthesized compounds are presented.See [9] for Communication 13.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1541–1544, November, 1980.     

Analogs of pyrimidine mono- and polynucleotides

Phosphorylation of N₁-(1,4-dihydroxy-2-butyl) derivatives of uracil and thymine with polyphosphoric acid or Β-cyanoethyl phosphate in the presence of dicyclohexylcarbodiimide gives the corresponding diphosphates as the chief reaction products.     

Analogs of pyrimidine mono- and polynucleotides

The corresponding monophosphates, cyclophosphates, and , -diphosphates were obtained by phosphorylation of 1-(1, 4-dihydroxy-2-pentyl) thymine, 1-(1, 3-dihydroxy-2-propyl) uracil, and their derivatives with selective protection of one of the hydroxyl groups. 2-Cyanoethyl phosphate (CEP) in the presence of N, N-dicyclohexylcarbodiimide (DCC), polyphosphoric acid, and pyrophosphoryl chloride were used as phosphorylating agents. The dependence of the yields of the products of phosphorylation of 1-(1, 4-dihydroxy-2-pentyl) thymine with CEP on the ratio of the reacting substances and the reaction time was studied. The monophosphates were cyclized under the influence of DCC. In the case of 1-(1, 3-dihydroxy-2-propyl) uracil 1-phosphate a dimeric phosphate was obtained in addition to a cyclophosphate. The acid hydrolysis of the cyclophosphates was investigated.See [1] for communication V; see [2] for a preliminary communication.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 678–683, May, 1978.     

Analogs of pyrimidine mono- and polynucleotides

The phosphorylation of N₁-(l,4-dihydroxy-2-butyl) thymlne with β-cyanoethyl phosphate in the presence of dicyclohexylcarbodiimide was investigated. The optimum conditions for the specific synthesis of the diphosphate, the isomeric monophosphates, and the cyclophosphate of N₁-(l,4-dihydroxy-2-butyl)thyimine were found. A number of side products were identified, and the fundamental ideas regarding the reaction mechanism are given. It is shown that the “pseudoglycoside” bond in the synthesized compounds is more resistant to acid hydrolysis than the analogous bond in the natural prototypes.     

Analogs of purine nucleosides and purine mono-and polynucleotides

A number of 6-substituted 9-(1,5-dihydroxy-3-pentyl)purines were obtained from 5-amino-4,6-dichloropyrimidine. 5-Amino-4,6-dichloropyrimidine reacts with 2-hydroxymethylpyrrolidine to give 4-chloro-5-amino-6-(2-hydroxymethylpyrrolidino)pyrimidine.See [1] for communication IV.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 552–555, April, 1976.