Pyrimidine hydroxymethylation

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

The pathways for thiamine biosynthesis have been elucidated only partiy. Thiamine pyrophosphate is made universally from the precursors 4-amino-5-hydroxymethyl-2-methylpytimidinepyrophosphate [841-01-0] (47) and 4-methyl-5-(2-hydroxyethyl)thiazolephosphate [3269-79-2] (48), but there appear to be different pathways ia the eadier steps. In bacteria, the early steps of the pyrimidine biosynthesis are same as those of purine nucleotide biosynthesis, 5-Aminoimidazole ribotide [41535-66-4] (AIR) (49) appears to be the sole and last common iatermediate ultimately the elements are suppHed by glycine, formate, and ribose. AIR is rearranged in a complex manner to the pyrimidine by an as-yet undetermined mechanism. In yeasts, the pathway to the pyrimidine is less well understood and maybe different (74—83) (Fig. 9). 

The phenomenon of 5-hydroxymethylation is a standard case of electrophilic attack. Thus uracil (83 R = H) and paraformaldehyde in aqueous alkali furnish 5-hydroj(ymethyl-pyrimidine-2,4(l//,3//)-dione (83 R = CH20H) in good yield (59JA2521). Aromatic aldehydes react differentiy to yield 5-benzylidene derivatives of, for example, 1-methylbar-bituric acid (78CC764). 

The concept and use of free radical attack on pyrimidines has been little developed. However, pyrimidine does react slowly with p-nitrobenzenediazonium chloride to yield some 2- and 4-p-nitrophenylpyrimidines (51JCS2323) in addition, 2,4-and 4,6-dimethyl-pyrimidine are converted by hydroxymethylene radicals (from ammonium peroxydisul-fate/methanol) into 6- and 2-hydroxymethyl derivatives, respectively (77H(6)525). Certain bipyrimidine photoproducts appear to be formed from two similar or dissimilar pyrimidinyl radicals (see Section 2.13.2.1.4). 

The simplest pyrimidine antibiotic is bacimethrin, 5-hydroxymethyl-2-methoxypyrimidin-4-amine (985), which was isolated in 1961 from Bacillus megatherium and is active against several yeasts and bacteria in vitro as well as against staphylococcal infections in vivo it has some anticarcinoma activity in mice (69MI21301). It may be synthesized by LAH reduction of ethyl 4-amino-2-methoxypyrimidine-5-carboxylate (984) which may be made by primary synthesis in poor yield, or better, from the sulfone (983) (B-68MI21304). 

H,4H-Oxazolo[5,4,3-y]pyrido[3,2-g]quinolin-4-one, 8-hydroxymethyl-6-methyl — see Nybomyein 5H-Oxazolo[2,3-[Pg.731]

The terc-butyldimethylsilyl groups of pyrido[l,2-c]pyrimidine 154 was eliminated with BU4NF to afford 6-hydroxy-8-hydroxymethyl derivative 155 (00TL1849). Compound 155 gave tricyclic derivative 156 under Mitsunobu conditions. 

Hydrolysis of 3-[(2,6-dimethoxy-4-pyrimidinyl)hydroxymethyl]perhydro-pyrido[l,2-c]pyrimidin-l-iminium salts 174-177 in boiling cone. HCl afforded the appropriate 3-[(2-hydroxy-6-oxo-l,6-dihydropyrimidin-4-yl) hydroxymethyl] derivative (98TL7021, 00JA5017). 

Thiamine is present in cells as the free form 1, as the diphosphate 2, and as the diphosphate of the hydroxyethyl derivative 3 (Scheme 1) in variable ratio. The component heterocyclic moieties, 4-amino-5-hydroxymethyl-2-methylpyrimidine (4) and 4-methyl-5-(2-hydroxyethyl)thiazole (5) are also presented in Scheme 1, with the atom numbering. This numbering follows the rules of nomenclature of heterocyclic compounds for the ring atoms, and is arbitrary for the substituents. To avoid the use of acronyms, compound 5 is termed as the thiazole of thiamine or more simply the thiazole. This does not raise any ambiguity because unsubstituted thiazole is encountered in this chapter. Other thiazoles are named after the rules of heterocyclic nomenclature. Pyrimidine 4 is called pyramine, a well established name in the field. A detailed account of the present status of knowledge on the biosynthesis of thiamine diphosphate from its heterocyclic moieties can be found in a review by the authors.1 This report provides only the minimal information necessary for understanding the main part of this chapter (Scheme 2). 

Thiamine can be considered to be the product of the quatemization of 4-methyl-5-(2-hydroxymethyl)thiazole (5) by an active derivative of 4-amino-5-(hydroxymethyl)-2-methyl pyrimidine (4) (Scheme 2). In living cells, pyramine can be activated by conversion into the diphosphate 7, via monophosphate 6, and the substrate of the enzyme responsible for the quatemization is not the thiamine thiazole, but its phosphate 8. The product of the condensation, thiamine phosphate (9), is finally converted into diphosphate 2—the biochemically active derivative—by hydrolysis to free thiamine, followed by diphosphorylation, or more directly, in some cases. Enzymes are known for all of the steps depicted in Scheme 2, and adenosine triphosphate (ATP) is, as usual, the phosphate donor. 

Scheme 32.—Decarboxylation of 4-amino-2-carboxymethyl-5-hydroxymethyl-pyrimidine.

Zhou S, Breitenbach JM, Borysko KZ, Drach JC, Kern ER, GuUen E, Cheng YC, Zemhcka J (2004) Synthesis and antiviral activity of (Z)- and (E)-2,2-[bis(hydroxymethyl) cyclopropylidene]methylpurines and -pyrimidines second-generation methylenecyclopropane analogues of nucleosides. J Med Chem 47 566-575... 

The bromine atom of 4-aryl-2-(4-bromobutyl)-2,3,5,6,7,8-hexahydro-177- ancj -perhydropyrido[l,2-c]pyrimidine-l,3-diones was displaced with 4-substituted piperazines <2002FES959, 2004APH139, 2004PHA99>. Heating 3-hydroxymethyl derivatives of epimeric 6-methyl-l,3,4,6,7,llb-hexahydro-277-pyrimido[6,l-,2]isoquinolin-2-ones 152 resulted in the formation of the 3-unsubstituted derivatives 153 by loss of CH20 (Equation 26) <1997LA1165>. 

For various reasons, the generalizations mentioned above must be regarded as strictly provisional. Analyses utilizing formic acid indicate the presence of more than one phosphorus atom per purine or pyrimidine residue. This discrepancy, it is pointed out, could equally well result from an apparent deficiency of bases, due to error in the analytical technique.160 It is also necessary to consider that some nucleic acids are now known to contain more bases than was previously realized. Thus, 5-(hydroxymethyl)-cytosine is present in various viruses,181-182 and 5-methylcytosine occurs in various animal and plant deoxyribonucleic acids but is absent from those of microbial origin.17-160-1M- 184- 186 Certain microbial deoxyribonucleic acids also contain 6-methylaminopurine.186a Various bacteriophage deoxyribonucleic acids have been found to contain a component which is believed to consist of a D-glucoside186b of 5 -(hydroxymethyl)cytidylic acid. 

TEP TL TLC TMB TMP TMP TMPG TNS TPB TRIS TRITC TTAB UA USDA-FSIS Triethylphosphine Total luminescence Thin layer chromatography T etramethylbenzidine 2,4,6,8-Tetrathiomorpholinopyrimido [5,4-d] pyrimidine Trimethylphosphine S S -Trimethoxyphenylglyoxal Potassium 2-p-toluidinylnaphthalene-6-sulfonate Tetradecylpyridine bromide Tris (hydroxymethyl) aminomethane Tetramethylrhodamine isothiocyanate Tetradecyltrimethyl ammonium bromide Uric acid U.S. Department of Agriculture-Food Safety and Inspection Service... 

Chloro-2,3-dihydro-7-(hydroxymethyl)-3,3-dimethyl-5//-oxazolo[3,2-a]pyrimidin-5-one, see Terbacil 6-Chloro-2,3-dihydro-7-methyl-3,3-dimethyl-5//-oxazo lo[3,2-a]pyrimidin-5-one, see Terbacil Chlorodihydroxybiphenyl, see TCDD... 

Plant The major degradation products of [2- C]terbacil identified in alfalfa using a mass spectrometer were (% of applied amount) 3-/er/-butyl-5-chloro-6-hydroxymethyluracil (11.9) and 6-chloro-2,3-dihydro-7-(hydroxymethyl)-3,3-dimethyl-5//-oxazolo[3,2-a]pyrimidin-5-one (41.2). Two additional compounds tentatively identified by TLC were 3-/er/-butyl-6-hydroxy-methyluracil and 6-chloro-2,3-dihydro-7-methyl-3,3-dimethyl-5//-oxazolo[3,2-a]pyrimidin-5-one (Rhodes, 1977). 

Figure 1. Molecular structures of sulfadimidine (SDM), its 5-hydroxy-4,6-dimethyl-pyrimidine (SOH), its 6-hydroxymethyl-4-...

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