4-Amino-2-methyl-5-hydroxymethyl

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). 

Hydrochlorid E2, 130 [(Benzyl-carboxymethyl-amino)-methyl]-hydroxymethyl- E2, 129... 

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. 

Pliotolytic. Bussacchini et al. (1985) studied the photolysis (7, = 254 nm) of phenmedipham in ethanol, ethanol/water, and hexane as solvents. In their proposed free radical mechanism, homolysis of the carbon-oxygen bond of the carbamate linkage gave the following photoproducts 3-(hydroxylphenyl)carbamic acid methyl ester, m-toluidine, 2-hydroxy-4-aminomethyl benzoate, 3-hydroxy-5-aminomethyl benzoate, 2-amino-4-hydroxymethyl benzoate, and 2-amino-6-hydroxymethyl benzoate. 

Wright et al. [46] pointed out that apart from the compound (VII) nitrolysis of hexamine may also lead to the transient formation of l-di(hydroxymethyl)-amino-methyl-3,5-dinitro-l,3,5-triazacyclohexane (XIII) [(VI) is the dinitrate of (XIII)] through the nitrolysis of the bonds K and M ... 

Ames and co-workers have reported the synthesis of some aminoethyl indolizines.141 Workers at Keele University have investigated the preparation of hydroxymethyl and aminomethyl derivatives.142 They obtained the 2-, 3-, and 6-hydroxymethyl compounds by lithium aluminum hydride (LAH) reduction of the esters. However, compound 93 gave inseparable mixtures on reduction, and whereas the 2-amino-methyl compound could be made by reduction of the corresponding... 

Chemical Name Prosta-5,13-dien-l-oic acid, 9,ll,15-trihydroxy-15-methyl-, (5Z,9a,lla,13E,15S)-, compd. with 2-amino-2-(hydroxymethyl)-l,3-propanediol (1 1)... 

As already mentioned, one of the products of action of hydroxyl radicals on proteins is protein hydroperoxides (G6). Valine and lysine residues are particu-larily susceptible to hydroperoxide formation. Reduction of hydroperoxides produces respective hydroxy derivatives of amino acids. Three valine hydroxides derived from hydroperoxides of this amino acid have been characterized structurally as p-hydroxyvaline [(2S)-2-amino-3-hydroxy-3-methyl-butanoic acid], (2S,3S)-y-hydroxyvaline [(2S,3S)-2-amino-3-hydroxymethyl-butanoic acid], and (2S,3R)-y -hydroxyvaline [(2S,3R)-2-amino-3-hydroxymethyl-butanoic acid (Fig. 12). They are suggested to be possible markers of protein peroxidation (F21). 

Hydroperoxid [(N-Methyl-nitros-amino)-methyl]- E13/1, 572 (O-CO-R -> O-OR) Nitramin Hydroxymethyl-methyl-E14a/2, 73 (CH20 + R -... 

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>. 

Carbamoylpyrazines have been hydroxymethylated with formaldehyde and potassium carbonate, and aminomethylated with formaldehyde and amine. In this way the following have been prepared 2-Af-hydroxymethylcarbamoylpyrazine (138) 2W-(diethylaminomethyl)carbamoylpyrazine (1413-1416) 2W-(morpho-linomethyl)carbamoylpyrazine (1414, 1416) and 2-A -[piperidino(pyrrolidino or other amino)methyl]carbamoylpyrazines(1414,1416). 2-7V-(Diethylaminomethyl)-carbamoylpyrazine refluxed with morpholine afforded 2-A -(morpholinomethyl)-carbamoylpyrazine (1415), and 2-carbamoylpyrazine with TV-(morpholinomethyl)-benzenesulfonamide gave 2-7V-(morpholinomethyl)carbamoylpyrazine (1417). 

The nature of the solvent exerts only a moderate influence on the position of signals in this series. For example, 4-amino-5-hydroxymethyl-2-methyl-l,2,3-triazole gave a 2-Me signal at d 3.91 in perdeuterated dimethyl sulfoxide, at... 

The esters have also been reduced to alcohols, e.g., methyl 4-amino-2-methyltriazole-5-carboxylate and lithium aluminum hydride, stirred in tetra-hydrofuran, produced 4-amino-5-hydroxymethyl-2-methyltriazole (20°C, 6 hr, 60%), and the 3-benzyl analog gave 70% [73JCS(P1)1629]. 

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]. 

CH=N0H ho-chj.1oh "n CHs Pt02 Athanol/konz. HC1 1 20 3 -Hydroxy-2 -methyl-4 -amino -methyl-5-hydroxymethyl-pyridin 96 5... 

Similar solubility behavior of polyhydroxy compounds was shown in fused acetates by Burton and Crowell. Burton observed that solubility of several organic compounds at 200°C, in (Li, Na, K) acetate eutectic (mp 180°C) increases with the number of hydroxyl groups and with acidity. In weight percent the following approximate solubilities were determined methanol, 0.05% 2,4-dinitroaniline and 4-nitroaniline, < 0.5% hydroquinone and resorcinol, 1% 2-amino-2-hydroxymethyl-l, 3-propanediol and 2-amino-2-methyl-l,3-propanediol, I0% trimethylolethane and pentaerythritol were miscible in all proportions above their melting points. 

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). 

A synthesis of all four stereoisomers [(15,25)-, (1R,2R)-, (15,2/ )- and (l/ ,25)-] of l-amino-2-(hydroxymethyl)cyclobutanecarboxylic acid was presented. The synthesis is based on the chiral glycine equivalent, employed in both enantiomeric forms. The key step involves the cyclization of the silyl-protected iodohydrins to the corresponding sprro derivatives with the aid of the phosphazene base Bu-P4. The final compounds were found to display moderate potency as ligands for the glycine binding of the A-methyl-D-aspartate (NMDA) receptor [43] (Scheme 5.25). 

However, at zero buffer concentration the maximum stability was shifted to a pH of 5.85. Ampicillin was stable in solutions at pH 3 - 9 when stored for 24 hours at 5°C and 25°C. Ampicillin was unstable in solutions at pH 10 when stored at above conditions. Bundgaard demonstrated a metastable intermediate in iso-meration of penicillin to penicillenic acid in aqueous solutions. The degradation of ampicillin trihydrate in solution is greatly influenced not only by pH, but also by the types of buffer salts used j. 2-Amino-2 (hydroxymethyl)-1,3-propanediol (Tris) buffer of pH 7 is highly deleterious to the stability of ampicillin, but not at pH 5.0. Citrate presents a converse pattern in that ampicillin is relatively stable at pH 7 but not so at pH 5. Phosphate is intermediate in action but tends to resemble the Tris pattern. Jacobson and Russo-Alesi prepared ampicillin trihydrate solutions at a concentration of 5 mg/ml by dissolving it in buffer solutions of pH 5.0 or pH 7.0 prepared from O.lM sodium acetate and acetic acid and in buffers of pH 8.0 or pH 8.8 prepared from O.lM 2-amino-2 (hydroxy methyl)- ,... 

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