Pyrimidine acids with

Heating 5-amino-4-mercapto pyrimidines (61) with formic acid affords the corresponding thiazolo[5,4d]pyrimidines (62) (Scheme 28) (357, 382, 411, 431). 

The direct formation of dipyrimidin-5-yl sulfides occurs on treatment of appropriate 5-unsubstituted pyrimidine substrates with sulfur mono- or di-chloride. Thus, reaction of uracil (83 R = H) with sulfur monochloride in boiling formic acid gives diuracil-5-yl sulfide in good yield sulfur dichloride gives a poor yield. Simple derivatives of uracil and barbituric acid undergo similar reactions but not cytosine, isocytosine, 2,4-bismethylthiopyrimidine or pyrimidine-4,6-dione (59). The mechanism is unknown (72AJC2275). 

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). 

The cyclization of 5-(2-carboxyanilino)pyrimidine (170) with sulfuric acid/phosphoric acid leads to the 7-chloropyrimido[5,4-A]quinolinetriones (171) (57JCS4997, 74KGS131), the 2,4,10-trichloro compounds being obtained with phosphoryl chloride (72JHC91), whilst a formally similar cyclization of 4(6)-arylamino-5-ethoxycarbonylpyrimidines gives... 

Aromatic aldehydes give 2-aryl-4-oxo derivatives (181) in the presence of concentrated sulfuric acid (70EGP73039), whilst pyrimidine derivatives (182) give octahydropyrido[4,3-with formaldehyde (e.g. 66M52). A similar reaction is observed with 6-methylpyrimidinones (e.g. 70M1415). 

The 6-methyl derivative (98, R = Me) was an important intermediate in the synthesis of analogs (e.g., 183) of folic acid. Korte has shown that 2-aminopyrido[3,2-guanidine carbonate with 3-aminopicolinic acid and that treatment of the same acid with ammonium thiocyanate or potassium cyanate yields the thioureido and ureido derivatives (100, X = S and X = 0). In contrast to the pyrido[2,3-d]pyrimidine system bsoth of these compounds could be cyclized by heat and the latter (100, X = O) is a likely intermediate in the synthesis of the dione (98) by the fusion with urea. 

Hydrolytic fragmentation of the C5-N6 part took place upon heating 7-methyl-5-propyl-2-thioxo-l,2,4-triazolo[l,5-c]pyrimidine (129) with hydrochloric acid. 3-Acetonyl-5-mercapto-l,2,4-triazole (130) and butanoic acid were obtained as a result of N4-C5, C5-N6, and N6-C7 bond cleavages (65JCS3369) (Scheme 50). 

Oxidation of 2-mercapto-l,2,4-triazolo[l,5-c]pyrimidines (174) with chlorine or bromine in water (64BRP951652 65JCS3369), with hydrogen peroxide and chlorine (95MIP1), as well as with sodium chlorate in hydrochloric acid (94JMC2371) gave the corresponding 2-sulfonyl halide derivatives 175. Oxidation of the 2-alkylmercapto compounds 176 to the 2-alkylsufonyl derivatives 177 was made with ammonium peroxodisulfate and sulfuric acid... 

Heating the 8-amino-7-chloro-2-oxo-l,2,4-triazolo[l,5-c]pyrimidine 189 with hydrochloric acid caused hydrolysis of the chloro group yielding the 2,7-dioxo derivative 190 (68JOC530) (Scheme 72). 

In addition to pyridine, the six-membered diamine pyrimidine is also found commonly in biological molecules, particularly as a constituent of nucleic acids. With a pKa of 1.3, pyrimidine is substantially less basic than pyridine because of the inductive effect of the second nitrogen. 

Pyrazino[l,2-z]pyrimidine-6,8-dionc was prepared from [3+3] atom fragments by reacting 6-hydroxypyrimidine-4-carboxylic acid with 2-aminoacetaldehyde dimethyl acetal <2005W02005/016927>. 

A regiospecific strategy to A-7-substituted purines 65 and its application to a library of 2,6,8-trisubstituted purines has been reported. The three-step synthetic strategy involves cyclization reactions of suitably substituted pyrimidines 63 with either a carboxylic acid or an aldehyde <06JC0410>. 

Serine (Ser or S) ((S)-2-amino-3-hydroxypropanoic acid) is a polar, neutral, uncharged amino acid with the formula H00CCH(NH2)CH20H. It has an aliphatic hydroxyl side chain and can be seen as a hydroxylated version of Ala. Ser participates in the biosynthesis of purines and pyrimidines and is also the precursor to several amino acids including Gly, Cys, and Trp (in bacteria). In addition, it is the precursor to numerous other metabolites, including sphingolipids and is present in enzymes such as a-chymotrypsin. Ser, Asn, and aspartate disrupt a helices. 

The first example in Figure 11.1 shows a pyrimidine trione compound bound to the active site of stromelysin. In order to get the interaction of one of the acidic pyrimidine nitrogens with the zinc cation correctly, the deprotonated negatively charged isomer has to be considered. 

Formation of UTP requires successive phosphorylations using ATP. CTP is, in turn, formed from UTP by an amination reaction in the pyrimidine ring, with the amino acid glutamine supplying the nitrogen this is also an ATP-dependent reaction. 

Destroying the aromatic character of the thiophene ring has been accomplished by heating the 5-ammothieno[2,3-tf -pyrimidine 66 with orthophosphoric acid (Equation 27) the 5-oxo product 67 is obtained <2005CHJ211>. 

Reaction of 4-chloro-6-fluoropyrido[3,4- pyrimidine 59 with [3-methyl-4-(pyridin-3-yloxy)phenyl]amine 60, followed by coupling the formed amine 61 with (3-azabicyclo[3.1.0]hex-6-yl)carbamic acid fi r7-butyl ester, afforded the substituted derivative 62 <2002EPP1249451>. Compound 59 was also reacted with 3-bromoaniline to give the 4-anilino derivative 63 that upon treatment with either methyl- or dimethylamine gave the corresponding 4,6-diamino derivatives 64 (Scheme 2) <1997W09726259, 1995W09519774>. 

Diamino-5-oxo-l,2,4-triazolo[l,5-a]pyrimidine together with nitrous acid affords a fused triazolo-TP. 

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