Of 6-methyluracil

The synthesis of 6-methyluracil from ethyl acetoacetate and urea was described first by Behrend.i The substance has been obtained also by the action of lead hydroxide on methylthiouracil in an alkaline medium, and by boiling benzalmethylhydroxypyri-midinhydrazine with hydrochloric acid. ... 

Amidines react with P-keto esters to provide hydroxypyrimidines. The synthesis of the 2,6-dimethyl-4-hydroxylpyrimidine (9) has been improved dramatically by combining Pinner s procedure with that of Donleavy et al. for the synthesis of 6-methyluracil. 

Aqueous suspensions of 6-methyluracil, when administered orally to rats, accelerate and intensify the assimilation of alimentary carbohydrates and increase hepatic glycogen synthesis [267]. 

Gastric ulcers induced in rats by repeated administration of caffeine can be reduced by the administration of 6-methyluracil. Treatment is more effective when this compound is combined with either 2-methyl-4,6-dihydroxypyrimidine or cytosine [273]. In a study of the influence of 6-methyluracil and uracil on experimental blastomogenesis in mice, it was found that 6-methyluracil reduces the frequency of urethan-induced lung adenoma whereas uracil increases the instances [274]. 6-Methyluracil, like orotic acid, can restore experimentally induced infarction in rabbits [179-182]. 

The alkylation of the 1,2,6-thiadiazine (76) has been studied in detail (82H(l7)40l) because of its importance as an isostere of 6-methyluracil. Dimethyl sulfate in the presence of sodium hydroxide as base gives the 2-monomethyl derivative exclusively. Other reagents such as diazomethane and iodomethane give the 2,6-dimethyl derivative as the major product although substantial amounts of O-methylation and C-methylation at C-4 also occur, indicating that in systems where there are several possible sites for alkylation, the results are very much dependent on the reaction conditions. 

Oxidation [1, 993-994, at end]. Orotaldehyde (2) can be obtained in 58% yield by direct oxidation of 6-methyluracil (1) with selenium dioxide in acetic acid.102... 

Like pyridones, oxydiazines are readily deprotonated under mild conditions to give ambident anions which can be alkylated, conveniently by phase-transfer methods, alkylation usually occuring at nitrogen. 3-Pyridazinones alkylate cleanly on N-2 under phase-transfer conditions but the regiochemistry of uracil alkylation is sometimes difficult to control (see also below). Carbon substitution can also be effected in some cases via delocalised A -anions, as in the reaction of 6-methyluracil with formaldehyde, or with diazonium salts. ... 

Carbon substitution can also be effected in some cases via delocalised N-anions, as in the reaction of 6-methyluracil with formaldehyde, or with diazonium salts. ... 

The ab initio quantum-chemical method on the 6-31G basis has been used to study the mechanism of selenium oxide and selenous acid oxidation of 6-methyluracil to orotic aldehyde. The mixed anhydride of acetic and selenous acids, which possessed high activity and steric accessibility in electrophilic attack on position 5 of the pyrimidine ring, was formed with a gain of energy. The three-stage mechanism of the oxidation of the Me group in 6-methyluracil by the mixed anhydride of selenous and acetic acids had been analysed. ... 

Hydroxymethyl-6-methyluracil (1043) was prepared many years ago from 6-methyl-uracil and formaldehyde, or in other ways. Since 1956 it has received much attention in the USSR under the (transliterated) name pentoxyl or pentoxil. It is used in several anaemic and disease conditions. For example, a mixture of folic acid and pentoxyl quickly reduces the anaemia resulting from lead poisoning pentoxyl stimulates the supply of serum protein after massive blood loss it stimulates wound healing it stimulates the immune response in typhus infection and it potentiates the action of sulfonamides in pneumococcus infections (70MI21300). 

In 1962, bromacil (5-bromo-3-s-butyl-6-methyluracil 1047 R = Bu ), its homologue (isocil 1047 R = Pr ) and related iV-alkyluracils were shown to have valuable selective phytotoxic properties and vitually no mammalian toxicity. Thus, bromacil achieves a complete kill of most unwanted broad-leaf annuals or perennials along with some grasses... 

The dry, finely powdered, crude jS-uraminocrotonic ester is stirred into a solution of 80 g. (2 moles) of sodium hydroxide in 1200 cc. of water at 95 . The clear solution is then cooled to 65° and carefully acidified, while stirring, by the slow addition of concentrated hydrochloric acid. The 6-methyluracil precipitates almost immediately, and after the mixture is cooled the product is collected on a filter, washed with cold water, alcohol, and ether, and air-dried. The substance is obtained as a colorless... 

CASRN 314-40-9 molecular formula C9Hi3BrN202 FW 261.12 Soil Metabolites tentatively identified in soil were 5-bromo-3-(3-hydroxy-l-methylpropyl)-6-methyluracil, 5-bromo-3-5ec-butyl-6-hydroxymethyluracil, 5-bromo-3-(2-hydroxy-l-methylprop-yl)-6-methyluracil, and carbon dioxide. The presence of uracil products suggests that bromacil was degraded via hydroxylation of the side chain alkyl groups. In the laboratory, 25.3% of C-bromacil degraded in soil to carbon dioxide after 9 wk but mineralization in the field was not observed. The half-life of bromacil in a silt loam was 5-6 months (Gardiner et al, 1969). 

Photolytic. When a dilute aqueous solution (1-10 mg/L) of bromacil was exposed to sunlight for 4 months, the TV-dealkylated photoproduct, 5-bromo-6-methyluracil, formed in small quantities. This compound is less stable than bromacil and upon further irradiation, the de-brominated product, 6-methyluracil was formed (Moilanen and Crosby, 1974). Acher and Dunkelblum (1979) studied the dye-sensitized photolysis of aerated aqueous solutions of bromacil using sunlight as the irradiation source. After 1 h, a mixture of diastereoisomers of 3-5ec-butyl-5-acetyl-5-hydroxyhydantoin formed in an 83% yield. In a subsequent study, another minor intermediate was identified as a 5,5 -photoproduct of 3-5ec-butyl-6-methyluracil. In this study, the rate of photooxidation increased with pH. The most effective sensitizers were riboflavin (10 ppm) and methylene blue (2-5 ppm) (Acher and Saltzman, 1980). Direct photodegradation of bromacil is not significant (Acher and Dunkelblum, 1979 Ishihara, 1963). 

Orotic acid or 6-methyluracil vide infra), when administered to rabbits with myocardial infarction induced by ligation of the anterior descending branch of the left coronary artery, can decrease the incidence of necrosis and increase the rate of regeneration for healthy cellular and fibrous connective tissue in the infarct region [182]. Rats with induced aortal stenosis which are treated with... 

Methyluracil was found to decrease the toxic effects of large doses of potassium benzylpenicillin or Bicillin 5 and to eliminate the undesirable effect of dichlorotetracycline on tissue cells [268, 269]. The combination of one of these antibiotics with 6-methyluracil decreases the number of degenerating cells... 

When administered into the newly developed chicken embryo, 6-methyluracil was found to possess strong teratogenic activity. The compound produces abnormalities in 85 per cent of the embryos at 4 mg/kg [270]. In pregnant rats this pyrimidine causes damage to 10-day-old embiyos. Microanatomical examination reveals urogenital system abnormalities (e.g. hydronephrosis, uretal oedema) [271]. 

Nitro-6-methyluracil, like 6-methyluracil, was reported to produce abnormalities in 75 per cent of the embryos by intermpting basic development of the organs [270]. 

The uracils with herbicidal activity do not necessarily contain 5-halo substituents. 3-Cyclohexyl-5-methyluracil [354] (XLIV), l,3-di-isopropyl-6-methyl-uracil [352] (XLV) and 3-s-butyl-5-thiocyanato-6-methyluracil [353] (XLVI), for example, are cited as having this type of activity. 3-Butyl-6-methyluracil (XLlllc) possesses interesting selective activities. For instance, this pyrimidine kills many annual weed species without damage to peas and peanuts, even when applied at twice the concentration needed to kill the weeds [346]. On the other hand, the related 5-bromo derivatives, such as (XLlIlb), are useful as industrial herbicides where it is desirable to kill all plants [346]. 

Orotic acid readily forms dimers even when irradiated in liquid medium [582, 583]. 5-Bromouracil (5-BrU) in DNA is dehalogenated, rather than forming cyclobutane-type dimers. Such DNA derivatives are more sensitive to ultraviolet irradiation than normal DNAs [584-594], Irradiation of 5-bromo-uracil and derivatives in aqueous medium produces 5,5 -diuracil [590, 591]. However, derivatives such as 3-sbutyl-5-bromo-6-methyluracil have been reported to yield cyclobutane dimers either by irradiation of frozen aqueous solutions, or by catalysis with free radical initiators, such as aluminium chloride, ferric chloride, peroxides or azonitriles [595]. 5-Hydroxymethyluracil is reported to dimerize very slowly in frozen water at 2537 A [596]. The fundamental research in the photochemistry of the nucleic acids, the monomeric bases, and their analogues has stimulated new experiments in certain micro-organisms and approaches in such diverse fields as template coding and genetic recombination [597-616]. 

Among the dihydro analogues of thiouracil, 2-mercapto-6-methyl-5,6-dihydro-uracil (LXXX) retains some of the antithyroid activity exhibited by 2-thiouracils [642] (see Part 1 of this review. Volume 6). This compound can be obtained either by the condensation of thiourea with ethyl crotonate or by the hydrogenation of 2-mercapto-6-methyluracil. 

Methyluracils 947 are readily prepared by reaction of ureas with diketene 945 in acetic acid, and although mixtures of products are obtained with substituted ureas, this procedure has been used synthetically to prepare a variety of 1-substituted and 1,3-disubstituted 6-methyluracils, using both solution- and solid-phase procedures <2000TL1487, 2003CPB1025, 2004JME1259>. 

A series of pyrido[2,3-rf pyrimidine-2,4-diones bearing substituents at C-5 and/or C-6 were synthesized using palladium-catalyzed coupling of uracil derivative 417 with vinyl substrates or allyl ethers to give the regioisomeric mixtures of 418/419 and 420/421, respectively. The ratio of the isomeric structures was dependent on the substituent R. In the case of the reaction with -butyl vinyl ether, only the product 419 was obtained. However, the reactions with acrylonitrile, ethyl acrylate, 2-trifluoromethylstyrene, and 3-nitrostyrene afforded only 418. Also, reaction with allyl phenyl ether gave only 420. The key intermediate 417 was prepared by the reaction of 6-amino-l-methyluracil with DMF-DMA (DMA = dimethylacetamide), followed by N-benzylation with benzyl chloride and vinyl iodination with iV-iodosuccinimide (NIS) (Scheme 15) <2001BML611>. 

Reaction of 3-(5-acetoxyhexyl)-6-amino-l-methyluracil with diketene in boiling dichloroethane gave the cyclized pyrido[2,3-,71pyrimidine-2,4,5-trione 501 <2002W02002094824>. Also, reaction of 6-amino-1-phenyluracil with methoxyvinyl cyanide gave 7-amino-tetrahydropyrido[2,3-,7]pyrimidinedione 502 <2001EPP1145716>. The cyano... 

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