Uracil methylation

A-Thiouracil 5-(M ethoxycarbonylmethyl)- 5-(Methoxycarbonyl-uracil methyl)-2-thiouraci I... 

Fig. 5. Separation of uracil, methyl and ethyl benzoates, toluene, ethylbenzene, triphenylene, and o-terphenyl in 80/20 (I /i ) methanol/water using two Cij columns for comments, see text.

The formation of the first nucleotide in the pyrimidine sequence, orotidylic acid (orotidine 5 -phosphate), was accomplished by the reaction of 5-phosphoribosyl-l-pyrophosphate (PRPP) with orotic acid 83) (Fig. 22). Other pyrimidines and carbamylaspartic acid did not react with PRPP in the presence of the enzyme, which has been named orotidine 5 -phosphate pyrophosphorylase. Several purine analogs, e.g., 6-uracilsulfonic acid, 6-uracil methyl sulfone, which inhibited the growth of several organisms (S78, 379), probably inhibited the formation of orotidylic acid. 

Methyl acetoacetate (MAA) and ethyl acetoacetate (EAA) are the most widely used esters they are found ia the pharmaceutical, agricultural, and allied industries. Both esters are used extensively as amine protecting agents ia the manufacture of antibiotics and synthetic sweeteners (Dane Salts) (147). Principal outiets for MAA are the manufacture of the organophosphoms insecticide dia2inon [33341-5] (148,149) and the uracil herbicides bromacil [31440-9] and terbacil [5902-51-2] (150,151) (see Insect conztiol technology Herbicides). 

Synthetic chemical approaches to the preparation of carbon-14 labeled materials iavolve a number of basic building blocks prepared from barium [ CJ-carbonate (2). These are carbon [ C]-dioxide [ CJ-acetjlene [U— C]-ben2ene, where U = uniformly labeled [1- and 2- C]-sodium acetate, [ C]-methyl iodide, [ C]-methanol, sodium [ C]-cyanide, and [ CJ-urea. Many compHcated radiotracers are synthesized from these materials. Some examples are [l- C]-8,ll,14-eicosatrienoic acid [3435-80-1] inoxn. [ CJ-carbon dioxide, [ting-U— C]-phenyhsothiocyanate [77590-93-3] ftom [ " CJ-acetjlene, [7- " C]-norepinephrine [18155-53-8] from [l- " C]-acetic acid, [4- " C]-cholesterol [1976-77-8] from [ " CJ-methyl iodide, [l- " C]-glucose [4005-41-8] from sodium [ " C]-cyanide, and [2- " C]-uracil [626-07-3] [27017-27-2] from [ " C]-urea. All syntheses of the basic radioactive building blocks have been described (4). 

Uracil reacts with hydrazine to give pyrazol-3(2if)-one (944) and urea N-methyl- and dimethyl-hydrazine behave similarly to give the 2-methyl- and 1,2-dimethyl derivatives. The reactions of hydrazines with uridine and related nucleosides and nucleotides is well studied (67JCS(C)1528). The tautomerism and predominant form of uracil are discussed in Section 2.13.1.8.4. 

Having a 5-methyl group, thymine is not nitrated or halogenated normally, but with aqueous bromine it does give the dihydropyrimidine (948) (25JBC(64)233) its other reactions parallel those of uracil although its behavior on irradiation is somewhat different (Section 2.13.2.1.4). 

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). 

Oxidative cyclization of the fully methylated 6-(benzylidenehydrazino)uracils (536) provides a 90% yield of the pyrazolo[3,4-J]pyrimidines (537) (75BCJ1484). 

Uracil, 6-dimethoxymethyl-3-methyl-2-thio-synthesis, 3, 113 Uracil, 1,3-dimethyl-dimers, 3, 74 Uracil, 3,6-dimethyl-synthesis, 3, 106, 110 Uracil, 5-fluoro-... 

Uracil, 5-methoxy-6-methoxymethyl-2-thio-synthesis, 3, 134 Uracil, 1-methyl-aminolysis, 3, 91 synthesis, 3, 110 Uracil, l-methyl-5,6-dihydro-synthesis, 3, 110 Uracil, 6-methyl-3-phenyl-synthesis, 3, 110 Uracil, 3-methyi-2-thio-synthesis, 3, 112 Uracil, 6-methyl-2-thio-oxidation, 3, 94 Uracil, 5-nitro-... 

The common naturally occurring pyrimidines are cytosine, uracil, and thymine (5-methyluracil) (Figure 11.3). Cytosine and thymine are the pyrimidines typically found in DNA, whereas cytosine and uracil are common in RNA. To view this generality another way, the uracil component of DNA occurs as the 5-methyl variety, thymine. Various pyrimidine derivatives, such as dihydrouracil, are present as minor constituents in certain RNA molecules. 

FIGURE 11.28 The 5-methyl group on thymine labels it as a special kind of uracil. 

Azauridine was also synthesized using the knowledge of the course of alkylation of 6-azauracil 2-methylmercapto derivatives (e.g., Section II,B,4,b). The 1-ribofuranosyl derivative obtained by reaction of the mercury salt of the 2-methylmercapto derivative with tri-O-benzoyl-jS-D-ribofuranosyl chloride on removal of the methyl-mercapto and then benzoyl groups yielded crystalline 6-azauridine, The main difference between uracil and 6-azauracil nucleosides consists in the preparation of cyclic nucleosides. It is known that uridine can be readily converted to cyclic nucleosides by the reaction of 2 (50-O-mesyl derivatives with nucleophilic agents, Analogous... 

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

Methyl- C]thymine ([ C]FMAU) could be obtained in modest radiochemical yields via cross-coupling of [ CJmethyl iodide with l-(2 -deoxy-2 -fluoro-/3-D-arabinofuranosyl)-5-(trimethylstannyl)uracil. Optimal power was found to be 70W, since an increase to 100 W as well as a decrease to SOW resulted in lower radiochemical yields (Scheme 6). 

Several syntheses of annulated uracils of biological value were recently reported. The key reaction was a microwave-assisted one-pot [4 -i- 2] cycloaddition of oxazino[4,5-d]-, pyrano-[2,3-d]-, pyrido[2,3-dj- and pyrimido[4,5-djpyrimidines, in the sohd state [134] and under solvent-free conditions [135]. The synthetic approach was based on the reaction of NJ -di-methyl-5-formylbarbituric acid 208 with maleimide in the sohd state for 5 min under microwave irradiation at 120 °C to give the pyrano[2,3-d]pyrimi-dine derivative 209 in 90% yield (Scheme 76). The reaction of 208 with phenyl isocyanate under microwave irradiation in the absence of solvent... 

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