Orotic acids

Orotic acid (2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid)... 

Orotic acid (971) has a chequered history. It was isolated in 1905 from the whey of cows milk in Italy and it was subsequently synthesized in the United States in 1907. However, the workers involved were discouraged by some difference in melting points and no direct comparison of specimens was ever made. To make matters worse, the same laboratories prepared the isomeric 5-hydroxy-2-oxo-l,2-dihydropyrimidine-4-carboxylic acid and announced it as orotic acid, again without any direct comparison. Only in 1930 did a German worker actually compare directly natural and the original synthetic orotic acid, thereby showing them to be identical (30CB1000). 

There are at least eight syntheses of orotic acid in the literature. The most practical in the laboratory is that involving the condensation of diethyl oxalacetate (972) with S-methylthiourea to give 2-methylthio-6-oxo-l,6-dihydropyrimidine-4-carboxylic acid (973) which undergoes either direct acidic hydrolysis or a less smelly oxidative hydrolysis, via the unisolated sulfone (974), to afford orotic acid (971) (B-68MI21303). 

Orotic acid undergoes 5-nitration, 5-bromination in hydrobromic acid with peroxide, 5,5-dibromination following decarboxylation in bromine water, esterification, methylation (rather complicated), conversion into its acid chloride (containing some anhydride) by treatment with thionyl chloride, and conversion into 2,6-dichloropyrimidine-4-carboxylic acid by phosphoryl chloride (62HC(16)422). 

C2H4N2 540-61-4) see Estazolam Orotic acid aminoacetonitrile monohydrochloride (C2H5CIN2 6077-/4-9) see Octopamine... 

C,Hi)BrO 79465-06-8) see Indinavir sulfate 5-bromodihydroorotic acid (CjH5BrN204 58668-21-6) see Orotic acid 9-bromo-lip,21-dihydroxy 16a-methylpregna-l,4-diene-3,20-dione 21-acetate... 

C4H4O2 674-82-8) see Aranidipine Bamidipine Benidipine Butoctamide Efonidipine hydrochloride ethanol Epirizole Ketazolam Leflunomide Lercanidipine hydrochloride Manidipine Nimodipine Orotic acid diloxanide... 

C2H2O3 298-12-4) see Allantoin Ethyl biscoumacetate Lamivudine Orotic acid gold iodide (Aul)... 

C, H4Mg05 109536-69-8) see Rofecoxib maleic acid monoureide (C5H6N2O4 105-61-3) see Orotic acid maleic anhydride... 

CNNaO 917-61-3) see Carisoprodol Hydroxycarbamide Orotic acid Prazosin sodium cyanide... 

CH4N2O 57-13-6) see Alfuzosin Allantoin Amobarbital Barbital Bromisoval Butalbital Carbasalate calcium Carbromal Cyclopentobarbital Dimethadione Dipyridamole Enoximone Ethotoin Heptabarb Metaxalone Methyclothiazide Orotic acid Paramethadione Pentobarbital Phenacemide Phenetuiide Phenobarbital Phenytoin Proquazone Secbutabarbital Secobarbital Sulfadimethoxine Thalidomide Trimethadione... 

While mammahan cells reutilize few free pyrimidines, salvage reactions convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides. ATP-dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2 "-de-oxycytidine, 2 -deoxyguanosine, and 2 -deoxyadenosine to their corresponding nucleoside triphosphates. In addition, orotate phosphoribosyltransferase (reaction 5, Figure 34-7), an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP). 

The orotic aciduria that accompanies Reye s syndrome probably is a consequence of the inabifity of severely damaged mitochondria to utifize carbamoyl phosphate, which then becomes available for cytosofic overproduction of orotic acid. Type I orotic aciduria reflects a deficiency of both orotate phosphoribosyltransferase and orotidylate decarboxylase (reactions 5 and 6, Figure 34—7) the rarer type II orotic aciduria is due to a deficiency only of orotidylate decarboxylase (reaction 6, Figure 34-7). 

Increased excretion of orotic acid, uracil, and uridine accompanies a deficiency in fiver mitocfiondrial or-nitfiine transcarbamoylase (reaction 2, Figure 29-9). 

The aerobic degradation of several azaarenes involves reduction of the rings at some stage, and are discussed in Chapter 10, Part 1. Illustrative examples include the degradation of pyridines (3-alkyl-pyridine, pyridoxal) and pyrimidines (catalyzed by dihydropyrimidine dehydrogenases). Reductions are involved in both the aerobic and the anaerobic degradation of uracil and orotic acid. 

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