5-Pyrimidinecarboxylic ACID ESTER

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. 

Atwal,K.S.,Rovnyak,G.C., Kimball, S.D.,Floyd,D.M.,Moreland, S.,Swanson,B.N.,Gougoutas, J.Z., Schwarts, J., Smillie, K.M. and Malley, M.F. 1990. Dihydropyrimidine calcium channel blockers. 2. 3-Substituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. J. Med. Chem. 33(9) 2629-2635. 

Atwal, K.S., Swanson, B.N., Unger, S.E., Floyd, D.M., Moreland, S., Hedberg, A. and O Reilly, B.C. 1991. Dihydropyrimidine calcium channel blockers. 3. 3-Carbamoyl-4-aryl-l,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. J. Med. Chem. 34(2) 806-811. 

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... 

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)... 

Many carboxy derivatives are available by primary syntheses. Otherwise the best route to simple pyrimidinecarboxylic acid derivatives is oxidative. This statement is even more applicable to our present situation with readily available acyl-, alkenyl-, or alkynylpyrimidine substrates from the coupling procedures, which serve as excellent substrates for oxidative reactions. The normal carboxylic acid reactions are observed ester formation, ester hydrolysis, aminolysis, acid chloride formation and reactions. A carboxy group in an electrophilic position may readily be lost when the pyrimidine ring is further depleted of 7t-electrons by its substitution pattern selective decarboxylation can be effected in pyrimidinedicarboxylic acids. 

Ethyl 2-ethylthio-4-chloro-5-pyrimidinecarboxylate (XXIIa), as well as the corresponding4-hydroxy-(XXIIb) and 4-amino-(XXIIIa) derivatives, possess-anti-cytogenic activity on Neurospora crassa [223, 224]. Compounds (XXIIIa, b and c) were found to inhibit the conversion of orotic acid to the uridine nucleotides [202]. Ethyl 2-methylthio-4-(halo-substituted anilino)-5-pyrimidinecarboxylates (XXIV), particularly the o-bromo- and the o-chloro- derivatives, substantially inhibit the growth of five experimental mouse tumours (Krebs-2 ascites carcinoma, Ehrlich carcinoma clone 2, leukaemia L-1210, carcinoma 755 and lymphocytic neoplasm P-288) [225]. Compounds of this type are usually prepared by the base catalysed condensation of ethoxymethylenemalonic esters or related derivatives with urea, thiourea, guanidine, or substituted amidine-type analogues [212, 225-237]. 

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