Pyridopyrimidines synthesis

There appear to be no reports of direct radical attack on the pyridopyrimidine ring system, but radical bromination of methyl substituents in the 7-position of the pyridine ring has been utilized in the synthesis of deaza analogues of natural products (62JCS4678, 79JHC133). 

The first example of this type also mimics a synthesis used in the pyridopyrimidine field, in which the quinoxaline diester (427) is cyclized in Dieckmann fashion to the pyri4o[2,3-]quinoxaline (428) (76CR(C)(282)861). 

Barbituric acid — see also Pyrimidine-2,4,6-trione, perhydro-acidic pK, 3, 60 bromination, 3, 70 fluorination, 3, 70 structure, 3, 68 tautomerism, 2, 27 in thermography, 1, 392 Barbituric acid, iV-alkyl-chlorination, 3, 70 Barbituric acid, 5-aminomethylene-synthesis, 3, 524 Barbituric acid, 5-arylidene-pyridopyrimidines from, 3, 227 Barbituric acid, 1,3-dicyclohexyl-synthesis, 3, 113 Barbituric acid, 2-thio-sensitizing dye... 

Pyrido[3,4-d]pyrimidine-2,4-dione synthesis, 3, 215 Pyridopyrimidines, 3, 201 iV-alkylations, 3, 206 biological activity, 3, 260-261 1-electron reductions, 3, 207 IR spectra, 3, 204 mass spectra, 3, 204 MO calculations, 3, 204 NMR, 3, 202, 203 nucleophilic substitution, 3, 213 8-nucleosides synthesis, 3, 206 physical properties, 3, 201-205 protonation, 3, 206 radical reactions, 3, 215 reactions with water, 3, 207 reduced... 

Synthesis from pyrido[7,2-a/pyrimidines. Reaction of the disubstituted pyridopyrimidinone 416 with hydrazine gives the aminopyrazole-fused product 417 (Equation 153) <1996FA781, 2003JIC311, 2004IJB1561>. Similarly, substituent interaction in the pyridopyrimidine 418 with amines in toluene at reflux gives, in various proportions, diastereomeric mixtures of the pyrrolopyridopyrimidines 419 and 420 (Equation 154) <2003T4581>. 

JME696>. Construction of the five-membered ring is also the key step in the synthesis of the pyrazole- and isoxazole-fused pyridopyrimidines 470 (Equation 198) <2004HC089>. 

Synthesis of these fused systems by formation of the five-membered ring is exemplified by the reaction of the pyridopyrimidine 505 with an arylacetyl chloride (Equation 228) <1999JPR332>. 

Another type of synthesis involves cyclization of ketonitrile 107 into fused pyridopyrimidine 108 in the presence of Et3N (Equation 9) <1998CHE1442, 2000T5185>. 

Two complementary routes to the synthesis of pyrido[, y-i/ pyridazines have been developed, the first of which begins by constructing the pyridine ring, and the second by constmcting the pyridazine ring. In addition, ring transformations of pyrrolopyridine, pyridooxazine, pyridopyrimidine, and tetrazine derivatives to the pyrido[x,y-t7 pyridazines have also been reported. 

The synthesis of pyrido[4,3-rf]pyrimidine-2,4-diones was carried out by thermal fusion of enamine 601 with A-methylurea at 180 °C to give the pyridopyrimidines 156 and 607 in addition to the unexpected a,/3-unsaturated esters 608, which were separated chromatographically in very poor yield (Equation 51). Alternatively, 156 was obtained in 59% yield by treatment of 601 with methyl isocyanate and EtsN to give the corresponding uriedo intermediate which was cyclized in situ with NaOH <1994JHC1569>. 

Pyridopyrimidine systems may also be accessed by in situ generation of pyridylisocyanates <2003TL2745>. Treatment of 2,3-pyridinccarboxylic anhydride with methanol leads to the formation of 2-(methoxycarbonyl)nicotinic acid that undergoes Curtius rearrangement on conversion to the 3-acyl azide with sodium azide and ethyl chloro-formate. Condensation of the resulting isocyanate with a series of amino acids leads to the synthesis of pyrido[3,2- T pyrimidines in good to excellent yield (Scheme 19). 

Another application of the Hantzsch reaction involved the identification of pyridopyrimidine derivatives such as 91 as inhibitors of stable toxin a (STA) induced cGMP synthesis (Fig. 13) [53]. 

Tanifum EA, Kots AY, Choi B-K et al (2009) Novel pyridopyrimidine derivatives as inhibitors of stable toxin a (STa) induced cGMP synthesis. Bioorg Med Chem Lett 19 3067-3071... 

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