Pyrimidine derivatives

Salts of 4-aminothiazoles react with chlorovinyl ketone (82) or with /3-diketones (83) at 140°C to yield the thiazoio[3.4-u]pyrimidine derivatives (84) (Scheme 58) (240). 

Flucytosine. Flucytosine (17) or 5-fluorocytosine (4-amino-5-fluoro-2-pyrimidone, 5-FC), C H FN O, is a pyrimidine derivative, that is efficient against Candida albicans Cryptococcus neoformans and Torulopsis glabrata. 

Flucytosine [2022-85-7] is well absorbed in the digestive tract, which is why oral adraiinistration is preferable. Plasma levels of 30 —40 mg/L are obtained after a dose of 30 mg/kg body weight. Approximately 90% of the pyrimidine derivative is found unaltered in urine, indicating that it is highly suitable for the treatment of renal candidosis. High concentrations were also noted in cerebrospinal fluid the average concentration is approximately 75% of the plasma concentration. 

Interesting structures can be formed by combinations of ring and side-chain substituents in special relative orientations. As indicated above, structures (28) contain the elements of azomethine or carbonyl ylides, which are 1,3-dipoles. Charge-separated species formed by attachment of an anionic group to an azonia-nitrogen also are 1,3-dipoles pyridine 1-oxide (32) is perhaps the simplest example of these the ylide (33) is another. More complex combinations lead to 1,4-dipoles , for instance the pyrimidine derivative (34), and the cross-conjugated ylide (35). Compounds of this type have been reviewed by Ramsden (80AHCl26)l). 

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). 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

The 3- or 5-aminopyrazoles are the synthons used most frequently. The second heterocyclic ring is created between the amino group and the 1-position (if unsubstituted) or between the amino group and the 4-position. Thus 3-substituted 5-aminopyrazoles react with 1,3-difunctional compounds to afford pyrazolo[l,5-a]pyrimidine derivatives (538) (Table 34). Aminopyrazolinones (R = OH) can be used instead of aminopyrazoles. Similarly 3-aminoin-dazole yields pyrimido[l,2-h]indazoles (539). 

Highly activated pyrimidine derivatives such as the diquaternary salt (406) and the monoquaternary salt (407) underwent ring contraction at a lower temperature and gave isoxazole in much better yields. Pyrimidine iV-oxides (408) also underwent ring contraction in a similar fashion to give isoxazoles (338). It was found, using 1,3- N-labelled (408b) as... 

Trifluoromethyl-substituted dioxazine or pyrimidine derivatives are obtained oriK3.cliQn oihexafluoroacetone with cyanoguanidines [93] orcyanoacetamides... 

The reaction of 4,4-bis(tnfluoromethyl)-I,3-diaza-1,3-butadienes with certain a,P-unsaturated ketones yields pyrimidine derivatives A two-step mechanism, metathesis-electrocyclic ring closure and metathesis-intramolecular ene reaction, is a plausible explanation for the experimental results (pathway 4, equa-bon 25) [259]... 

Although the term nucleoside was once limited to the compounds in Table 28.2 and a few others, cunent use is more permissive. Pyrimidine derivatives of D-arabinose, for exfflnple, occur in the free state in certain sponges and are called spongonticleosides. The powerful antiviral drug ribavirin, used to treat hepatitis C and Lassa fever, is a synthetic nucleoside analog in which the base, rather than being a pyrimidine or purine, is a triazole. 

The common naturally occurring pyrimidines are cytosine, uracil, and thymine (5-methyluracil) (Figure 11.3). Cytosine and thymine are the pyrimidines typically found in DNA, whereas cytosine and uracil are common in RNA. To view this generality another way, the uracil component of DNA occurs as the 5-methyl variety, thymine. Various pyrimidine derivatives, such as dihydrouracil, are present as minor constituents in certain RNA molecules. 

The condensation of 1,3-dicarbonyl compounds 1 with amidines 2 catalyzed by acids or bases to give pyrimidine derivatives 3 is regarded as the Pinner pyrimidine synthesis. ... 

Many pyrimidine derivatives have been prepared via the Pinner procedure. Amidines react with 1,3-dicarbonyl compounds to form 2, 4, 6-trisubstituted pyrimidines. ... 

For the preparation of triazolopyrimidines three main types of synthesis are in use. The first of these proceeds from a pyrimidine derivative (especially the 4,5-diamino derivatives) and closes the triazole ring. The second method proceeds, on the contrary, from derivatives of u-triazole to close the pyrimidine ring. The third method finally is one which yields the derivatives through substitution or replacement of substituents in compounds prepared by one of the first-named procedures. 

Various nucleophilic reactions of polysubstituted 5-halopyri-midines are described in Section II,E,2,e with postulates to explain the degree of reactivity. For pyrimidine derivatives, the effect of the following on nucleophilic substitution is included in earlier sections hydrogen bonding and cationization in Section II, C, the leaving group in Section II, D, and the nucleophile in Sections II,E,2,e and II, F. 

A fairly large number of l,2,4-triazolo[l,5-c]pyrimidine derivatives were prepared via transformation of substituents attached to the skeleton of the parent system. The reported examples of such substituent transformation may collectively be categorized into the following types. 

A series of interesting pyrazolo[3,4-(f pyrimidine derivatives was obtained by a thermal denitrocyclization reaction of hydrazones, e.g. 164 or 166, easily formed from the corresponding aldehyde or ketone hydrazones with halo-nitrouracil derivatives, e.g. 163 (71CC1442, 72CC298). Intermediates 164 or 166 can be isolated and their cyclization in suitable solvents (methanol, DMF, DMSO) provided high yields of the products. Aldehyde hydrazones yielded the corresponding l,7-dihydropyrazolo[3,4-J]pyrimidines, e.g. 165, whereas ketone hydrazones gave l,5-dihydropyrazolo[3,4-pyrimidine derivatives, e.g. spirocyclic compound 167 (Scheme 26). 

The only known derivative of this class was prepared from ethyl 8-anilinecrotonate, ethyl acetoacetate, and benzaldehyde. In the first instance, a pyrimidine derivative is formed, this is then subjected to partial hydrolysis to form the 3,4-dihydro-l,3-2H-oxazine derivative (42). 

Moreover, with a change of solvent, a new tautomeric form can arise owing to formation of intermolecular hydrogen bonds in place of the previously existent intramolecular hydrogen bonds. This situation is characteristic, for example, for pyrimidine derivatives 49, for which the use of polar (DMSO, DMF, MeOH, HMPT) solvents or specifically solvating cosolvents (S) (e.g., a small amount of water or A-methylpyrrolidinone) leads to the appearance of ylidene tautomer 49b with the p-quinonoid disposition of the double bonds (Scheme 18) [88KGS521 90UK457]. 

In tautomeric equilibria of some functionalized pyrimidine derivatives, such as isocytosine 52 (R = H) [77ZN(C)894] or pseudocytidine 52 (R = furanosyl) (99MI1), the potentially tautomeric oxo and amino groups are practically not involved, and only annular tautomeric interconversions N(1)H N(3)H are ob-... 

Extension of this work by studying the reaction of 3-methyl-5-nitro-pyrimidin-4(3//)-one with -X-arylketones in the presence of ammonium acetate surprisingly revealed the formation of a mixture of 4-arylpyrimidines and 6-arylpyridin-2(l//)-ones (00JCS(P1)27). The ratio between pyridine and pyrimidine formation is dependent on the substituent X. With electron-donating substituents the formation of the pyridin-2(l//)-ones is favored, with electron-attracting substituents the formation of the pyrimidine derivatives (Scheme 21) In the formation of the 6-arylpyridin-2(l//)-ones the C-4- C-5-C-6 part of the pyrimidone-4 is the building block in the construction of the pyridine ring. Therefore, the pyrimidone can be considered as an activated o -nitroformylacetic acid (Scheme 21). 

Acetamido-l//-l,5-benzodiazepine-3-carbonitrilc forms the pyrimidine derivative 10 by reaction with methylamine.290... 

It was known that the K+ -competitive imidazopyridine compound, SCH28080, inhibits acid secretion. Then, many reversible inhibitors were developed. These contain protonatable nitrogens but have a variety of core structures such as imidazopyiidines, piperidinopyr-idines, substituted 4-phenylaminoquinolines, pyrrolo [3,2-c]quinolines, guanidinothiazoles, and 2,4-diamino-pyrimidine derivatives. Several reversible inhibitors have been in clinical trials. 

In a similar way, 1,3-dinitrogen systems such as diamines, amidines, guanidines, aminothiazoles, aminopyridines, ureas and thioureas react with alkynyl-carbene complexes generating the corresponding heterocycles. Of particular interest is the reaction with ureas, as the process can be applied to the easy synthesis of pyrimidine derivatives [88] (Scheme 41). 

Microwave-Promoted Synthesis of Bicyclic Pyrimidine Derivatives on Solid-Phase... 

The hydrazine 70 reacts with triethyl orthoformate, sodium nitrite in acetic acid, or pyruvic acid, to yield l,2,4-triazolo[4,3-c]-, tetrazolo[l,5-c]- and l,2,4-triazino[5,6-c]pyrano [4 ,3 4,5]pyrrolo[3,2-e]pyrimidine derivatives 71(X= CH), 71(X= N) and 72 respectively <95KGS700 96CA(124)176023>. 

Many 5-alkyl-, 5-alkenyl-, and 5-alkynyl-l-(2-deoxy-2-fluoro- 5-D-arabin-ofuranosyl)pyrimidines (750 - 752 and 765 - 767) were prepared - " by condensation of 742 (or the equivalent, such as 743) with C-5-substituted pyrimidine derivatives, or by attachment of a C-fragment to C-5 of the existing nucleosides through their 5-iodo or 5-chloromercuri derivatives, or by further conversion of the attached C-5 substituent into another one. ... 

Among the simplest compounds of this series are l-(2-deoxy-2-fluoro- -D-arabinofuranosyl)thymine (758, FMAU) and 1-(2-deoxy-2-fluoro-)S-D-arabinofuranosyl)-5-methylcytosine (749, FMAC). Later FIAU (757) and FMAU (758) were prepared in high yields (>95% the ratio of Plot an-omers being 7/1 and 4/1, respectively) by condensation using 743 and 2,4-bis(0-trimethylsilyl)-5-iodouracil (769), and 743 and 2,4-bis(0-trimethylsi-lyl)thymine (770), respectively. Likewise, 753, 757, 758, and 765 (this was described later) were prepared in high yields using pyrimidine derivatives... 

Durre P, JR Andreesen (1982) Anaerobic degradation of uric acid via pyrimidine derivatives by selenium-starved cells of Clostridiumpurinolyticum. Arch Microbiol 131 255-260. 

Another pyrimidine derivative, RA-642, has been found to inhibit ferrous-induced lipid peroxidation in cell... 

Bellido, L, de la Cruz, J.P. and de la Cuesta, S. (1991). The pyrimido pyrimidine derivative RA642 a potent inhibitor of ferrous induced lipid peroxidation. Meth. Find. Exp. Clin. Pharmacol. 13, 371-375. 

It has been reported that nickel catalyzed the reactions of 6-amino-1,3-dimethyluracil with substituted alkynylketones in water to give substituted 2,4-dioxopyrido[2,3-f/ pyrimidine derivatives in quantitative yields at room temperature (Eq. 4.70).134 The products have potential pharmacological and biological activities. The reaction may have proceeded through an ionic process. 

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