Pyrimidines substitution

The versatility of pyrimidine substituted chloroquinazolines as intermediates is due to the ready replacement of the halogen atoms by hydrogen, alkyl, alkoxyl, amino, and mercapto groups (see Section VI, A). 

Reduction of pyrimidine substituted quinazoline 3-oxides, cata-lytically or with phosphorus trichloride, also leads to quinazolines. ... 

Brown has also predicted, from localization energy calculations, that pyrrole and glyoxaline should react with radicals mainly at the 2-position, whereas pyrazole should be most reactive at the 3-position. Browm and Heffernan s calculation that the orientation in pyrimidine substitution should be 4 > 2 > 5 is in agreement with the results from the p-nitrophenylation of pyrimidine. ... 

Benzo-fused pyrrolizines can be prepared from the palladium-catalyzed reaction of alkynes with imines of 2-halogenoanilines. Pyrimidine-substituted alkynes react in the same way, to produce the pyrimidine-fused pyrrolizines 161 <2001JOC412> (Scheme 48). 

The 1,2,4-oxadiazole dioxolanes 144 react with hydroxylamine and hydrazines to form the 5-pyrazole- and isoxazole-substituted 1,2,4-oxadiazoles 146 via the dioxolane ring-opened intermediates 145 (Scheme 17). Reaction of compounds 144 with amidine or guanidine salts allows access to pyrimidine substituted analogues 147, via intermediate 145 (X = C(NH)R1), albeit in lower yield <1996JHC1943, 1998JHC161>. 

Most of these studies relate to derivatives of one ring system triazolo[l,5-tf]pyrimidine. 13C and 1SN chemical shifts of some 5,7-disubstituted [l,2,4]triazolo[l,5- ]pyrimidines substituted in the pyrimidine ring (and also some of their Au(m) chloride complexes) were published by Sztyk et al. <2002MRC529> the data are shown in Table 1. 

Table 1 15N and 13C NMR data of some [1,2,4]triazolo[1,5-a]pyrimidines substituted in the pyrimidine ring... 

Substituted malondialdehydes form pyrimidines substituted in the 5-position with an alkyl, aryl, halo, or hetero substituent. The pyrimidine is unsubstituted in the 4- and 6-positions. /3-Dialdehyde equivalents are frequently used in these reactions, for example, 3-alkoxy- or 3-aminoacroleins. With aldehydo ketones, the pyrimidine carries a substituent in the 4- or 6-position. The formyl group in the ketone is normally masked as an alkoxymethylene ketone or as an aminomethylene ketone. A commonly used procedure involves the preparation of a dimethylaminomethyl-ene ketone 645 by reaction of a methyl ketone 644 with DMF dimethylacetal and subsequent reaction with an amidine or guanidine to form the target pyrimidine 646 <2003MI237, 2004JHC461>. 

Nucleophilic attack on the ring carbon atoms of pyrazine follows the pattern of pyridine and pyrimidine substitutions.158,157 Thus,... 

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy-6-heptenoic (-hep-tanoic) acids./. Med. Chem., 1990, 33, 52-60. 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Roth BD, Bocan TMA, Blankley CJ, Chucholowski AW, Creger PL, Creswell MW, Ferguson E, Newton RS, O Brien P (1991) Relationship between tissue selectivity and lipophili-city for inhibitors of HMG-CoA reductase. J Med Chem 34 463-466 Beck G, Kesseler K, Baader E, Bartmann W, Bergmann A, Granzer E, Jendralla H, von Kerekjarto B, Krause R (1990) Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3, 5-dihydroxy-6-hepte-noic (-heptanoic) acids. J Med Chem 33 52-60... 

During the past twelve months a number of new phosphonium betaines and zwitterions has been reported. Reaction of ylides with acylisocyanates or acylisothiocyanates in methanol proceeds via a cyclization yielding pyrimidine substituted triphenylphosphonium salts (5) which can be converted into the corresponding betaines. The crystal structures of triphenylphosphonium-car-boxylate betaines 6 and 7 have been reported. Betaines 6 and 7 were obtained... 

A new synthesis of pyrimidines substituted at position 5 was reported by van der Stoel and van der Plas175,176,208 via photochemical rearrangement of 4-substituted l,4(l,6)-dihydropyrimidines (100) to the corresponding 5-substituted 1,2-dihydropyrimidines (125), which on oxidation yielded 5-substituted pyrimidines [Eq. (56)]. 

Acyl(or cyano)pyrimidines substituted at the 4-position with chlorine, methoxy or methylsulf-anyl have also been used as intermediates in the preparation of pyrimido[4,5-rf]pyrimidines by reaction with guanidine, urea, or amidines.110114 139,140 Thus, 5-phenylpyrimido[4,5-<7]-pyrimidine-2,4,7-triamine (35) is obtained by reaction of 2-amino-4-methoxy-6-phenylpyrimi-dine-5-carbonitrile (34) with guanidine.114... 

Tautomeric studies on dihydropyrimidines have usually been carried out on pyrimidines substituted by strongly conjugative groups or on geminally disubstituted derivatives to reduce the number of tautomeric forms. X-ray structure analysis is often used for information in the solid phase. NMR is most frequently used for tautomeric equilibrium studies in solution. A short summary is available B-94MI 602-01 >, p. 817). 

The best preparative method for mercaptopyrimidines varies from position to position from thioureas and their equivalents. Thiones in any of the electrophilic positions are prepared by thiolysis of halo-pyrimidines, or commonly by thiation of pyrimidinones using phosphorus pentasulfide or, more recently, the superior Lawesson reagent 2,4-bis-/ -methoxyphenyl-l,3,2,4-dithiadiphosphetane 2,4-disulfide. Thiolysis in the 5-position requires a metal sulfide and a 5-bromide under vigorous conditions. Alternatively, pyrimidines substituted with strongly electron-donating substituents may be sulfonated, for example, by chlorosulfonic acid, in the 5-position with subsequent reduction to thiol. 

In the synthesis of 173, the relative stereochemistry is set in the addition of a 4-(l-metallo-ethyl)-5-fluoropyrimidine derivative to l-(2,4-difluorophenyl)-2-(17/-l,2,4-triazol-l-yl)-l-ethanone 174 (Scheme 12.27). The diastereocontrol of this can be controlled by pyrimidine substitution pattern and reaction conditions of the metalation step. Good diastereoselectivity (12 1) is obtained using an zinc derivative of 175. After removal of the chlorine from the pyrimidine ring, of the desired stereoisomer of 173 is isolated via a diastereomeric resolution using salt (l/ )-10-camphorsulfonic acid (10-CSA). Synthetic routes to the pyrimidine partner have also been evaluated. Shown in Scheme 12.28, the initial six-step route from 5-fluorouracil 177 can be replaced by a four-step process, involving fluorination of methyl 3-oxopentanoate and cyclization with formami-dine acetate. ... 

Aryl Ring. When the significant improvement in activity was found with 4,6-dimethyl pyrimidine substitution, we prepared sulfonylureas with this heterocyclic system held constant while varying the aiyl portion. We expanded this part of the program to include 4-methoxy-6-methyl and 4,6-dimethoxy pyrimidines and their triazine analogs as well, when these heterocyclic groups were found to promote activity. 

Nontautomeric derivatives of pyrimidine" absorb strongly at 1580-1520 cm" and absorb near 990 and 810 cm . Amino-substituted pyrimidines show NH2 absorption bands at 3500-3100 and 1680-1635 cm in addition to the strong absorption at 1600-1500 cm . Pyrimidines substituted with hydroxyl groups are generally in the keto form with C=0 absorption near 1700... 

Shepherd proposed a colorimetric method for pyrimidines substituted in the 2-position based on the red colour formed with 2-thio-barbituric acid. Since no colour is produced when the pyrimidine is substituted in either the 4- or the 6-position this reaction may be used for the determination of sulphadiazine in the presence of other sulphonamides, including sulphamerazine and sulphadimidine. 

---