6,7-Disubstituted pyrido pyrimidines

With aryldiazonium chlorides the pyrido[l,2-a]pyrimidines (63 R = H) yielded the 3-arylazo derivatives.253 The 3-methyl derivative of 63 (R = H) was also subjected to diazo coupling, but the product, a 3,3-disubstituted pyrido[l,2-a]pyrimidine, underwent immediate transformation involving hydrolysis of the C-4—N-5 bond253 (see also Section III.C,4). 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

A series of 2,3-disubstituted pyrido[4,3-rf]pyrimidin-4(3//)-ones (154) showed more complicated fragmentation patterns. Here again, however, strong molecular ions were invariably present and m/2e peaks were common, as were M-l peaks. The nature of the group Rx... 

Suitable cyclization partners are 2-(acylamino)nicotinic acids and primary amines, giving 2,3-disubstituted pyrido[2,3-r7]pyriinidin-4(3//)-ones. Thus, 3-aryl-2-methylpyrido[2,3-c/]pyrimidin-4(3/f)-ones 22 are synthesized by fusion of 2-acetamidonicotinic acid with arylamines.33... 

Aminopyrimidine-5-carboxaldehyde 284 with aromatic ketomethy-lenes provides 7- and 6,7-disubstituted pyrido[2,3-d]pyrimidines 285. Facile ring opening of the pyrimidine moiety of this heterocyclic system gives substituted 2-aminonicotinaldehydes 286 (Scheme 62) (75J(3C1438). 

Narsaiah and co-workers employed the Dimroth rearrangement in their preparation of novel 4-substituted-amino-5-trifluormethyl-2,7-disubstituted pyrido[2,3-< pyrimidines and evaluated their potential as antibiotics against Gram-positive and Gram-negative bacteria. Treatment of iminoether 121 with methyl amine in ethanol at room temperature for 3 h gave rise to 7V-methyl-2-methyl-7-phenyl-5-(trifluoromethyl)pyrido[2,3-i/)pyrimidin-4-amine 122 in 84% yield. This compound showed significant... 

The syntheses of pyrido[3,2-d]pyrimidines from pyridines utilize a 2,3-disubstituted pjrridine and insert the C-2 and N-3 atoms, either previously linked (route i) or in separate stages (route ii). 

Amino-4//-pyrido[],2-rz]pyrimidin-4-ones 184 were obtained from 3-(2,2-disubstituted ethenylamino) derivatives 183 with H2NNH2 H2O or HONH2 HCI m good yields, and from 183 (R = COOCH2Ph, R = acetyl) by treatment with NaBH4 in moderate yields (97H(45)2349,... 

AJC287>. From a complex reaction mixture of BuCH(COCl)2 and 2- 4-[(4-hydroxy-3-carboxyphenyl)hydrazi-no]phenylsulfonylamino pyridine at elevated temperature, tf yr/r >-(3-butyl-2-hydroxy-4-oxo-4//-pyrido[l,2-tf]pyrimi-din-3-ylium)hydroxide was isolated <2001MI53>. Reaction of 2-aminopyridines and diethyl alkylidenemalonates at 175 °C yielded 3-(2,2-disubstituted vinyl)-2-hydroxy-4//-pyrido[l,2-tf]pyrimidin-4-ones from the initially formed... 

Several studies deal with the reactivity of 2,4-disubstituted-6-aminopyrimidines, which have competing sites for ring formation with 1,3-biselectrophiles. Treatment of 2,4,6-triaminopyrimidine with ethyl acetoacetate in acetic acid formed the pyrimido[l,6-tf]pyrimidin-4-one 216, while the expected pyrido[2,3-r/]pyrimidin-7-one 217 was obtained under thermal conditions (Scheme 34) <1999JOC634>. 

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>. 

When N-[6-(disubstituted amino)-4-pyrimidinyl]aminomethylenema-lonates (1038) were cyclized by heating in Dowtherm A at 250°C for 15 min, both 4-(disubstituted amino)pyrido[2,3-c/]pyrimidine-6-carboxyl-ates (1039) and the 4-ethoxy derivative (1040) were prepared (70CPB1385). 

By hydrogenating 2.9-disubstituted 4-oxo-4H-pyrido[l,2-a]pyrimidines or their 6,7,8,9-tetrahydro derivatives over platinum(IV) oxide, Yale and Spitzmiller obtained a mixture of diastereomeric perhydro compounds.58 Separation was not attempted. 

On prolonged reaction with aryl isocyanates, the pyrido [ 1,2-a]pyrimidines (262) give pyrido[l,2-a]-s-triazines (266) in poor yield.328 The suggested pathway is the addition of the aryl isocyanate to form the 3,3-disubstituted product (263), which eliminates the ketene (265) the residual part of the molecule (264) reacts with an additional mol of aryl isocyanate to give 266. The ketene (265) forms the quinoline (267), by ring closure, which gives 268 by aryl isocyanate addition. The quinoline (267 R = CH2Ph, X = H) could be isolated. 

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