Pyrimidine 2 -methyl-4-amino-5-hydroxymethyl

Folic acid or the folate coenzyme [6] is a nutritional factor both for the parasites and the hosts. It exists in two forms, viz. dihydro- and tetrahydrofolic acids [4,5] which act as cofactors involved in the transfer of one carbon units like methyl, hydroxymethyl and formyl. The transfer of a one carbon unit is associated with de novo synthesis of purines, pyrimidines and amino acids. Mammals can not synthesize folate and, therefore, depend on preformed dietary folates, which are converted into dihydrofolate by folate reductase. Contrary to this, a number of protozoal parasites like plasmodia, trypanosomes and leishmania can not utilize exogenous folate. Consequently, they carry out a de novo biosynthesis of their necessary folate coenzymes [12]. The synthesis of various folates follows a sequence of reactions starting from 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine (1), which is described in Chart 4 [13,14]. 

Vitamin Bi is an essential co-factor for several enzymes of carbohydrate metabolism such as transketolase, pyruvate dehydrogenase (PDH), pyruvate decarboxylase and a-ketoglutarate dehydrogenase. To become the active co-factor thiamin pyrophosphate (TPP), thiamin has to be salvaged by thiamin pyrophosphokinase or synthesized de novo. In Escherichia coli and Saccharomyces cerevisiae thiamin biosynthesis proceeds via two branches that have to be combined. In the pyrimidine branch, 4-amino-5-hydroxymethy-2-methylpyrimidine (PIMP) is phosphorylated to 4-amino-2-methyl-5-hydroxymethyl pyrimidine diphosphate (PIMP-PP) by the enzyme HMP/HMP-P kinase (ThiD) however, the step can also be catalyzed by pyridoxine kinase (PdxK), an enzyme also responsible for the activation of vitamin B6 (see below). The second precursor of thiamin biosynthesis, 5-(2-hydroxyethyl)-4-methylthiazole (THZ), is activated by THZ kinase (ThiM) to 4-methyl-5-(2-phosphoethyl)-thiazole (THZ-P), and then the thia-zole and pyrimidine moieties, HMP-PP and THZ-P, are combined to form thiamin phosphate (ThiP) by thiamin phosphate synthase (ThiE). The final step, pyrophosphorylation, yields TPP and is carried out by thiamin pyrophosphorylase (TPK). 

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). 

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. 

Aliphatic and aromatic aldehydes condensed with 2-amino-(62BRP898414), 5-amino- (80AJC1147), or 8-amino-l,2,4-triazolo[l,5-c]pyrimidines (68JOC530) to give the related Schiff bases. Treatment of the 2-amino-5-methyl-l,2,4-triazolo[l,5-c]quinazoline 11 with formaldehyde and piperidine in the presence of acetic acid gave the 2-hydroxymethyl-amino-5-(2-piperidinoethyl) derivative 172. Utilization of aromatic aldehydes and piperidine in this reaction gave the 2-arylideneamino-5-styryl derivatives 173 (68CB2106) (Scheme 67). 

Figure 4 Biosynthesis of thiamine (vitamin ). 37, aminoimidazole ribotide 38, 2-methyl-4-amino-5-hydroxymethyl-pyrimidine phosphate 39, pyridoxal 5 -phosphate 40, histidine 41, 2-methyl-4-amino-5-hydroxymethyl-pyrimidine pyrophosphate 42, 4-methyl-5-p-hydroxyethylthiazole phosphate 43,1 -deoxy-D-xylulose 5-phosphate 44, 5-ADP-D-ribulose 45, thiamine phosphate 46, thiamine pyrophosphate.

The thiamin phosphate synthase-catalyzed formation of thiamin phosphate from 4-amino-5-(hydroxymethyl)-2-methylpyrimidine pyrophosphate and 4-methyl-5-( 1 -hydroxyethyl)thiazole phosphate has been studied. A mechanism was proposed, and the substituent effects of the pyrimidine ring upon the TS discussed <2001B10095>. 

Ohne Cosolvens gelingt die Cyclisierung von 5-Amino-4,6-dimercapto-2-methyl-pyrimidin mit Acetoxy-acetylchlorid das primar gebildete 2-( Acetoxy-methyl)-4-mercapio-6-melhyl-(j>yrimi-do 5,4-d]-J, 3-thiazol ) wird nach Hydrolyse als 2-Hydroxymethyl-4-mercapto-6-methyl-(pyrimi-do[5,4-d]-1,3-thiazof) (68% Schmp. 267-268 )204 isoliert ... 

Toxopyrlmidtne. 4-Amino-2-melhyl-S-pyrimi-dinemethanol 6 -amino -5 -hydroxymethyl -2-methylpyrimi -dine 4 -amino -5 -hydroxymethyl -2 -methylpyrimidine pyra -min pyramine. t 6H9N30, mol wt 139.16. C 51.78%, H 6.S2%, N 30.20%, O 11.50%. A metabolite of thiamine. Prepd from 4 -amino-5 -aminomethy 1-2 -methyl pyrimidine dibydrochloride or ethyl 4-amino-2-methyl-5-pyrimidine-carboxylate Dornow, petsch, Ber. 86, 1404 (1953) DiBella, Hennessy, J. Org, Chem. 26, 2017 (1961). 

Biosynthesis of the pyrimidine ring of thiamin (vitamin Bi) from aminoimidazoleribonucleotide. The 2-methyl-4-amino-5-hydroxymethyl-pyrimidine ring present in thiamin is synthesized from aminoimida-zoleribomlcleotide, which is an intermediate in purine biosynthesis (Fig. 4). 

Thiamine monophosphate is built from 2-methyl-4-amino-5-hydroxymethyl pyrimidine pyrophosphate and 4-methyl-5-(j8-hydroxyethyl)-thiazole (Fig. 183). The pyrimidine part is derived from 5-aminoimidazole ribonucleotide, an intermediate of purine biosythesis (D 10.4). As yet the origin of C-5 and the CH2OH-group as well as that of the CHg-group is stiU unknown. The thiazole moiety is derived from the precursors given in Fig. 184. Intermediates were not identified. 

Vitamin Bi (also called thiamine) is a water-soluble vitamin of B complex present in many foods as a natural nutrient. It is a biologically and pharmaceutically important compound containing a pyrimidine and a thiazole moiety such as 4-amino-5-hydroxymethyl-2-methyl-pyrimidine and 5-(2-hydroxyethyl)-4-methylthiazole linked by a methylene bridge (Figure 15.1). It is necessary for carbohydrate metabolism and for the maintenance of neural activity because most of the humans and mammals cannot synthesize vitamin Bi. Nerve cells need vitamin BI for their normal function because vitamin Bi has diphosphate-active sites which serve as a cofactor for several enzymes (Leopold et al. 2005). Vitamin Bi is employed for the prevention and treatment of beriberi, neuralgia, etc. and played a vital role in enzymatic mitochondrial... 

Difluorophenyl)methyl]thio -7- [(1 S,2S)-2-hydroxy-l-(hydroxymethyl)propyl] amino thiazolo [4,5 -d]pyrimidin-2(3H)-one 126 (Seheme 56) which are useful for treating a chemokine mediated diseases sueh as asthma, allergic rhinitis, COPD, inflammatory bowel disease, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis, cancer, etc., was prepared in a 7-step process, starting from 4-amino-6-hydroxy-2-mercaptopyrimidine and 2,3-difluorobenzyl bromide [82],... 

---