Pyridopyrimidones

Hydrolyses of aminopyridopyrimidines to the corresponding pyridopyrimidones by means of acid, base, and nitrous acid have been reported. 4-Amino compounds are stable to nitrous acid, but are much more labile than the 2-amino derivatives toward acid- or base-catalyzed hydrolysis. The aminochloro-pyrido[2,3-d]pyrimidine (160) has been converted into the 2,4-dianilino analog (161) by reaction with aniline." ... 

Yoon and co-workers reported a methodology that yielded pyridopyrimidones 97 and 98 through the palladium-catalyzed coupling of iodouracil 94 with alkenes 95 and 96, respectively <00SC81>. It was noted that when the alkenes of type 95 (X = acetyl, ester, or nitrile) were employed, demethylated products 97 resulted, otherwise, the deaminated products 98 were favored. No mechanistic explanation of these results was supplied by the authors. 

Chloropyridopyrimidines readily undergo amination reactions with ammonia,9-11,13> 86>41, 48,50,78, 110,122,128,126,127aliphaticamines,9-11, i3,48,so,no,i2d, 127 and aromatic amines9, 11,48,50,110,122 to yield mono- or diaminopyridopyrimidines or 4-amino-2-ehloro derivatives. Selective replacement of chloro substituents, however, was not achieved with the reaction of dimethylamine and 2,4-dichloropyrido-[2,3-d]pyrimidine.110 Thionation reactions by means of thiourea,10, 36, no, 122 hydrosulfide ion, 9 13,48,°0,56 sodium ethyl sulfide,10 replacement by alkoxide,10,13,36,38,60 and hydrolysis9,10,13,60 to regenerate the pyridopyrimidone all take place readily. Reductive dehalogenation10 to yield pyrido[3,2-d]pyrimidine (2) has been claimed but disputed.33... 

The methotrexate (MTX) analog (145) is prepared by condensing pyridopyrimidone carboxylic acid (143) with glutamic acid dimethyl ester (144). Testing of amide 145 in vitro against CCRF-CEM leukemia cells revealed that it is... 

---