Synthesis and Antiviral Activity of 1-{[2-(Phenoxy)ethoxy]methyl}uracil Derivatives

The synthesis of novel 1-{[2-(phenoxy)ethoxy]methyl}uracil derivatives with different substituents in positions and 6 of the pyrimidine ring has been carried out. It has been shown that the alkylation of trimethylsilyl derivatives of uracil with 2-(4-chlorophenoxy)- and 2-(4-methylphenoxy)ethoxymethyl chloride under Hilbert-Johnson reaction conditions gives N₍₁₎-substitution products. It was found that the 1-{ [2-(phenoxy)ethoxy]methyl}uracil derivatives show viral inhibition properties relative to human immunodeficiency type 1 virus in vitro. The most active compounds are 5-bromo-6-methyluracil derivatives which suppress viral reproduction by 50% at 7.2 and 7.8 micromolar concentrations.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 726–731, May, 2005.     

Synthesis of acyclic and macrocyclic analogs of Di-, Tri-, and tetranucleotides

Compounds consisting of two or three uracil fragments were synthesized by reaction of methyl-substituted uracil sodium salts with 1-(6-bromohexyl)-3,6-dimethyluracil or 1,6-dibromohexane. Treatment of these compounds with paraformaldehyde gave the corresponding pyrimidinophanes and acyclic compounds in which the uracil fragments are linked through methylene bridges. Uracil derivatives having no substituent on N³ were synthesized by reactions of silylated uracils with 1,3-bis(6-bromohexyl)uracil or 4,4′-(6-bromohexyloxy)diphenylmethane. The acyclic compound was converted into pyrimidinophane containing uracil fragments with N³H groups. A trinucleotide analog including uracil and two adenine fragments was synthesized from 1,3-bis(6-bromohexyl)uracil.     

Hydroxyethylation of uracil,adenine, and cytosine with ethylene carbonate

It was established that both 1-(2-hydroxyethyl)uracil and 3-(2-hydroxyethyl)-uracil, which are converted to 1, 3-bis (2-hydroxyethyl) uracil, are formed in the first step of the reaction of uracil with ethylene carbonate. The simultaneous formation of 9- (2-hydroxyethyl) adenine and 3- (2-hydroxyethyl) adenine occurs in the reaction of adenine with ethylene carbonate. The only product of hydroxyethylation of cytosine was 1-(2-hydroxyethyl) cytosine. Methods for the analytical separation of the hydroxyethylation products and the preparative isolation of the 1- and 9-hydroxyethyl derivatives are proposed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 684–689, May, 1978.     

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.     

A convenient, high-yield synthesis of 1-substituted uracil and thymine derivatives

Novel reagents for the synthesis of 1-substituted uracil and thymine derivatives have been developed. The aminolysis of 2- or 4-nitrophenyl 3-ethoxyacryloylcarbamate and 3-ethoxy-2-methylacryloylcarbamate with a variety of primary amino derivatives proceeded smoothly under very mild reaction conditions yielding almost quantitatively the 1,3-disubstituted urea derivatives. Their subsequent cyclization provided the 1-substituted uracil and thymine compounds, in almost quantitative yield.     

N1-(2-furoylmethyl) and N1-(5-nitro-2- furoylmethyl) derivatives of uracil and its 5-substituted derivatives

The corresponding N₁-(2-furoylmethyl) and N₁-(5-nitro-2-furoylmethyl) derivatives of uracil and its 5-substituted derivatives were obtained by the reaction of 2-bromo- and 5-nitro-2-bromoacetylfurans with uracil, 5-fluorouracil, and thymine. The structures of these compounds as N₁-substituted uracils were proved by a study of the UV spectra at various pH values. The computational method of expanding the UV spectra into individual bands was used.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1268–1270, September, 1971.     

用分子筛催化合成四种尿嘧啶衍生物

尿嘧啶类衍生物多具有生物活性,特别5-氟尿嘧啶具有抗癌活性,疗效较好,但毒副作用严重。以尿嘧啶为基体合成有生物活性的衍生物,或对5-氟尿嘧啶进行化学修饰,如酰化等,则可降低毒性,增加抗癌能力。此课题近几年来已引起人们关注。     

A convenient method for N-1 arylation of uracil derivatives

1-(4-Nitrophenyl)- and 1-(2,4-dinitrophenyl)uracil derivatives have been obtained by direct arylation of uracil and its 5-substituted derivatives using 1-fluoro-4-nitrobenzene or 1-fluoro-2,4-dinitrobenzene in the presence of a base. The application of the newly obtained uracil derivatives in further synthesis is also presented.     

Trace level determination of phenols as pentafluorobenzyl derivatives by gas chromatography-negative-ion chemical ionization mass spectrometry.

A method for the trace level determination of 11 phenols as pentafluorobenzyl (PFB) derivatives by gas chromatography-mass spectrometry (GC-MS) with negative-ion chemical ionization (NICI) is described. First, the conditions for the PFB derivatisation of phenols were optimized and were found to be reaction temperature 80 degrees C and reaction time 5 h. Second, the detection limits using selected ion monitoring (SIM) were compared between trimethylsilylated (TMS) derivatives in the electron ionization (EI) mode and PFB derivatives in the NICI mode. The responses for the PFB derivatives in the NICI mode were 3.3-61 times higher than those of the TMS derivatives in the EI mode. The instrumental detection limits using NICI-SIM ranged from 2.6 to 290 fg. This method was applied to the analysis of phenols in river water using solid-phase extraction. The recoveries of the phenols from a river water sample spiked with standards at 100 ng l-1 with 2-chlorophenol, 4-chloro-3-methylphenol and pentachlorophenol and at 1000 ng l-1 with phenol, 2,4-dimethylphenol, 2,4-dichlorophenol, 2-nitrophenol, 2,4,6-trichlorophenol and 4-nitrophenol were 81.2-106.3% (RSD 5.1-8.0%), except for 2-methyl-4,6-dinitrophenol and 2,4-dinitrophenol, for which the recoveries were 5.8 and 4.2%, respectively, because water contained in the acetone eluate interfered with the derivatisation of these compounds with two electrophilic nitro groups.     

Michael versus retro-Michael reaction in the regioselective synthesis of N-1 and N-3 uracil adducts

By controlling the temperature or reaction time in the base-catalysed Michael-type addition of 5-substituted uracil derivatives we were able to synthesise N-1 or N-3 uracil adducts using methyl acrylate and acrylonitrile as acceptors. The mechanism of this chemical inequivalence was established using ¹H NMR spectroscopic studies. The investigations revealed that formation of the N-1 adduct was achievable under kinetically controlled conditions irrespective to the type of the base used (TEA, DBU). In turn, synthesis of the N-3 adducts proceeded from the initially formed N-1,N-3 diadduct via a retro-Michael reaction which dominates at elevated temperature or prolonged reaction time.     

New approach for the synthesis of 1-aryl- and 1-heteroaryl-5-nitrouracil derivatives

1-(2,4-Dinitrophenyl)-5-nitrouracil and its 3-methyl derivatives were synthesized and used as substrates in reaction with aromatic amines and amino pyridines. In the reaction of aniline with 1-(2,4-dinitrophenyl)-5-nitrouracil, only the acyclic adduct was isolated. When 1-(2,4-dinitrophenyl)-3-methyl-5-nitrouracil was treated with aniline and other aromatic amines or amino pyridines, the desired 1-aryl-5-nitrouracil derivatives were obtained in satisfactory yield. The influence of the free H-3 proton present in the uracil ring on the course of the reaction is discussed.     

Synthesis of [2-(vinyloxy)ethyl]uracil and [2-(allyloxy)ethyl]uracil

A synthesis is reported for N¹-mono- and N¹,N³-disubstituted uracil derivatives containing a terminal carbon-carbon double bond in the side-chain. Alkylation of vinyl 2-chloroethyl ether by uracil potassium salts leads to a mixture of 1-[2-(vinyloxy)ethyl] and 1,3-di[2-(vinyloxy)ethyl] derivatives while treatment of 2,4-bis(trimethylsilyloxy)pyrimidines by vinyl 2-chloroethyl ether leads exclusively to N¹-monosubstituted products. Alkylation of cytosine by this chloroether gave 1-[2-(vinyloxy)ethyl]cytosine. The synthesis of 1-[2-(allyloxy)ethyl]uracil derivatives was carried out by treatment of uracil potassium salts by 1-(allyloxy)-2-(p-toluenesulfonyloxy)ethane.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 393–397, March, 1993.     

Synthesis of 1-(5,6-dihydro-2H-thiopyran-2-yl)uracil by a Pummerer-type thioglycosylation reaction: the regioselectivity of allylic substitution

1-(5,6-Dihydro-2H-thiopyran-2-yl)uracil derivatives, a new 4′-thio-D4-nucleoside analogue, were synthesized by reacting 5,6-dihydro-2H-thiopyran sulfoxide and persilylated uracil in a Pummerer-type thioglycosylation reaction. The reaction of 5-alkyl substituted dihydrothiopyran sulfoxide 7 only gave 1-(dihydrothiopyran-2-yl)uracil 9. On the other hand, the reaction with a 5-siloxy substituted derivative of 7 resulted in a mixture of products with the uracil moiety at either the α- or the γ-position. The use of a prolonged reaction time resulted in the exclusive formation of the 4-substituted dihydrothiopyran derivative 10. The result suggests that an equilibrium is operative in the formation of the α- and γ-adducts and that the latter should be more thermodynamically stable than the former. This conclusion was also supported by theoretical calculations.     

An Efficient Method for the Synthesis of N‐uracil‐4‐oxo‐thiazolidines without Catalyst

We have developed highly efficient, one‐pot three component reaction of 5‐amino‐uracil and aromatic aldehydes with thioglycolic acid for the synthesis of N‐uracil‐thiazolidinones in excellent yields. The same products were also prepared by the reaction of Schiff bases of 5‐amino‐uracil with thioglycolic acid. In addition, benzylation of thiazolidinone derivatives and Schiff bases by using benzyl chloride was investigated. The results obtained from elemental microanalysis and different spectral data are in agreement with the assigned structures.     

Synthesis of 1-(dihydroxypropyl)-5-substituted uracils

Novel 1-(dihydroxypropyl)-5-substituted uracils were synthesized in the reaction of 1-(4-nitrophenyl)-5-substituted uracil derivatives with appropriate aminopropanediols under mild conditions. In the case of 3-amino-1,2-propanediol both racemic and enantiomerically enriched products were obtained. These compounds may be considered as new building blocks for oligonucleotide synthesis.     

A novel strategy for the synthesis of uracil derivatives using bis(pentafluorophenyl)imidodicarbonate

The disclosure herein describes a novel strategy for the synthesis of uracil derivatives via a solvent-free microwave cyclocondensation reaction using bis(pentafluorophenyl)imidodicarbonate.     

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.     

Nucleoside synthesis from 3-alkylated sugars: role of 3beta-oxy substituents in directing nucleoside formation

Using Vorbrüggen's protocol, reaction of persilylated uracil with xylofuranose derivatives having 3beta-oxy-3alpha-alkyl substitution produced both alpha- and beta-nucleosides. Only the beta-nucleosides were formed from substrates having the reverse stereochemistry at C-3 or lacking the 3-alkyl substituent. Participation of the 3beta-oxy substituent in stabilizing the incipient C-1 carbonium ion (or oxonium ion) intermediate has been suggested from analysis of energy-minimized conformations.     

An efficient one‐pot synthesis of pyrimido[2,1‐b][1,3]oxazine derivatives via the reaction of isocyanides with dialkyl acetylenedicarboxylates in the presence of 5‐substituted uracils

The reactive 1:1 intermediate produced in the reaction between alkyl isocyanides and dialkyl acetylenedicarboxylates was trapped by uracil and its 5‐substituted derivatives to yield highly functionalized pyrimido[2,1‐b][1,3]oxazine derivatives in fairly good yields. J. Heterocyclic Chem.,(2011).