5-Pyrimidinecarboxylic ACID

The reaction is proposed to proceed from the anion (9) of A/-aminocatbonylaspattic acid [923-37-5] to dehydrooranate (11) via the tetrahedral activated complex (10), which is a highly charged, unstable sp carbon species. In order to design a stable transition-state analogue, the carboxylic acid in dihydrooronate (hexahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) [6202-10-4] was substituted with boronic acid the result is a competitive inhibitor of dibydroorotase witb a iC value of 5 ]lM. Its inhibitory function is supposedly due to tbe formation of tbe charged, but stable, tetrabedral transition-state intermediate (8) at tbe active site of tbe enzyme. 

Although it is seldom used, esterification of pyrimidinecarboxylic acids proceeds normally. Conditions are illustrated by the conversion of pyrimidine-4-carboxylic acid (181 R = H) into its methyl ester (181 R = Me) by methanol/sulfuric acid (47%), methanol/hydrogen chloride (80%), or by diazomethane (ca. 100%) (60MI21300). The isomeric methyl pyrimidine-2-carboxylate is formed by treatment of the silver salt of the acid with methyl iodide. Higher esters, e.g. (182 R = Bu), are usually made by warming the acid (182 R = H) with the appropriate alcohol and sulfuric acid (60JOC1950). 

In fact, most pyrimidinecarboxylic acids are made by hydrolysis of the corresponding esters, nitriles or sometimes amides, many of which can be made more easily by primary synthesis than can the acids themselves. Thus, pyrimidine-5-carboxylic acid may be made by alkaline hydrolysis of its ethyl ester (62JOC2264) and pyrimidin-5-ylacetic acid (789 ... 

Pyrimidinecarboxylic acid chlorides formation, 3, 80 Pyrimidinecarboxylic acids acidic pK , 3, 60 decarboxylation, 3, 80 esterification, 3, 80 esters... 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

When M-ethyl-M-[2-(4-benzylpiperazin-1 -yl)pyrimidin-4-yl]aminometh-ylenemalonate [1199, PhCH2N(CH2CH2)2] was heated in polyphosphoric acid at 190-200°C for 5 min, and the reaction mixture was treated with aqueous sodium hydroxide, pyrido[2,3-c/]pyrimidinecarboxylic acid [1200, R = R1 = PhCH2N(CH2CH2)2] was obtained in 20% yield [81JAP(K)99480]. 

Some sulphur-containing derivatives, such as 2-hydroxy-4-mercapto [36a] (X), 4-hydroxy-2-methylthio-[36a] (XI), 2-hydroxy-4-methylthio-[36a] (XII), and 2,4-bis(methylthio)-6-pyrimidinecarboxylic acid [36a] (XIII), can cause more than 50 per cent inhibition of orotic acid metabolism by cell-free extracts from mouse liver or L5178Y leukaemia cells at concentrations less than 2 x ICT M[207]. 5-Diazo-orotic acid (IX) has recently been found to possess good inhibitory activity against leukaemia L-1210 in mice [212]. 

Among 5-alkyl- or 5-aryl-substituted 4-pyrimidinecarboxylic acids screened for antiviral, antimalarial and antimicrobial activities [213], 2-mercapto-5-methyl-6-amino-4-pyrimidinecarboxylic acid (XlVa) is active against influenza... 

A number of 4-pyrimidinecarboxylic acids of the general formula (XVI) and their esters, amides and nitriles are claimed to possess cardiovascular, hypotensive, and spasmolytic properties [214]. Other biological activities and medicinal uses of 5-halo-substituted orotic acids, as well as those of uracil-6-sulphonic acid and related compounds, have been discussed in Part I of this review [215]. 

MERCAPTO-4-AMINO-5-CARBETHOXYPYRIMIDINE (6-Pyrimidinecarboxylic acid, 4-amino-2-mercapto-, ethyl ester)... 

The appropriateness of using of microwave-assisted organic synthesis to obtain pyridinecarboxylic acids and pyrimidinecarboxylic acids was also described in [202]. The application of microwave irradiation reduces significantly the reaction time from 2 h to 10 min, increases yields of the target compounds and also allows high-boiling and hard-to-remove solvents (DMF and acetic acid) to be replaced by ethanol. 

The application of arylpyruvic acids 256 in place of pyruvic acid in three-component reactions leads to dramatic changes in the direction of the process. Refluxing of starting compounds for 3 hours of irradiating with microwave at 170°C for 20 minutes in acetic acid yielded 3-hydroxy-4,5-diaryl-l-azolyl-2,5-dihydro-li/-2-pyrrolones 258 [203] (Scheme 3.73). Under ultrasonic irradiation in ethanol with the addition of catalytic amounts of hydrochloric acid or in acetic acid, the reaction proceeds in a different direction with the formation of pyrimidinecarboxylic acids 259. In the case of pyruvic acid the course of the three-component reaction does not so drastically depend on the activation method or solvent type as well as from temperature mode [202]. 

Chemical Name 4-Pyrimidinecarboxylic acid, l,2,3,6-tetrahydro-2,6-dioxo-... 

To investigate thiamine metabolism in mammals, thiamine (Rf values 0.16, 0.04, and 0.03), urinary excretion of thiamine metabolites [thiochirome (Rf values 0.31, 0.28, and 0.33), thiazole (Rf values 0.85, 0.79, and 0.81), and 2-methyl-4-amino-pyrimidinecarboxylic acid (Rf values 0.42, 0.21, and 0.26)], and related compounds [pyrimidinesulfonic acid (Rf values 0.48, 0.39, and 0.46), a-hydroxyethylthiamine (Rf values 0.23, 0.09, and 0.06), A -methylnicotinamide (Rf values 0.31, 0.06, and 0.05)] were analyzed and identified by TLC on silica gel with acetonitrile-water (40 10 vol/vol) adjusted to a pH of 2.54, 4.03, and 7.85 with formic acid as solvents, respectively.Although A -methylnicotinamide and thio-chrome could not be separated in single-phase chromatography at pH 2.54, a second phase at right angle, with a pH 4.03 solvent, separated these quite clearly without affecting the resolution of the other compounds. 

Atwal, K. S., O Reilly, B. C., Gougoutas, J. Z., Malley, M. F. Synthesis of substituted 1,2,3,4-tetrahydro-6-methyl-2-thioxo-5-pyrimidinecarboxylic acid esters. Heterocycles 1987, 26, 1189-1192. 

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