Of pyridopyrimidines

In addition to those cases recorded in (69AHC(10)149), NMR has been widely used in the solution of structural and regioisomeric problems in the field of pyridopyrimidines, their benzo fused derivatives (74CC308), and nucleosides. In some cases the NOE technique has proved especially useful (78JOC828, 74JCS(P1)122S). 

The mass spectra of pyridopyrimidines in general show many features in common with those of other related N-heterocycles, in particular quinazolines and pteridines. The pyridopyrimidines show strong molecular ions, and when breakdown of the hetero ring occurs, fragments arising from loss of CO, CN, HCN and HCNO are observed. 

As with the purines, the replacement of chloro groups by amino groups has been one of the major building blocks of pyridopyrimidine chemistry, being employed in a great variety of reactions too numerous to catalogue fully, particularly in the piromidic and pipemidic acid fields. 

No syntheses of pyridopyrimidines by formation of bonds between two heteroatoms are possible. 

The preparation and use of derivatized Meldrum s acid has led to an alternative preparation of 2-substituted quinolines (49 and 50) and the preparation of pyridopyrimidines (52). When Meldrum s acid derivatives are used (as shown in this example) decarboxylation occurred under the cyclization conditions. Three component coupling has been used to readily assemble the desired 3-anilino-acrylate from reaction of Meldrum s acid, (EtO)3CH and an aniline (e.g. 54 or 55).< ... 

Nucleab Magn etic Resonance Spectra of Pyridopyrimidines ... 

The mass spectra of a number of pyridopyrimidines have been determined in these laboratories. Pyridopyrimidin-4(3//)-ones showed features in their spectra common to the fragmentation patterns of other heterocyclic compounds " and more particularly... 

A large number of nucleophilic substitution reactions involving interconversions of pyridopyrimidines have been reported, the majority of which involve substituents in the pyrimidine ring. This subject has been reviewed previously in an earlier volume in this series which dealt with the theoretical aspects of nucleophilic re-activiti in azines, and so only a summary of the nucelophilic displacements of the substituent groups will be given here. In general, nucleophilic substitutions occur most readily at the 4-position of pyrido-... 

The mechanism of ring-opening of pyridopyrimidin-4(3H)-ones under alkaline conditions is presumably as follows ... 

E. C. Taylor and his co-workers have demonstrated an important principle in the ring-opening of pyridopyrimidines and other fused pyrimidine systems to o-aminonitriles. They have demonstrated that based-catalyzed cleavage of a 4-substituted pyrimidine will occur provided that (a) the anion formed by the attack by the base at the 2-position can be stabilized by appropriate structural features in the remainder of the molecule and (b) that the substituent attached to the 4-position is capable of departure with its bonding pair of electrons in... 

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3 T)-ones. Dehydrogenation of dihydropyrido[2,3-(i]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-diehloro-5,6-dicyano-p-benzo-quinone (DDQ) to yield the aromatic derivatives have been reported. Thus, 7-amino-5,6-dihydro-1,3-diethylpyrido[2,3-d]-pyri-midine-2,4(lif,3f/)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

With respect to R2 (the substituent at position 3 of pyridopyrimidine), the transformation is influenced in the following sequence Me < CH2COOEt following sequence applies COOEt = OH < alkyl < styryl < NHAc [77JCS(P1)789 ... 

Chichibabin96 prepared the first representatives of pyridopyrimidines of type 63. Instead of assuming the 63 zwitterionic form, Chichibabin used the 2,4-dioxo structure and named the compounds malonyl-a-aminopyridines. 

When 2,4-dioxopyrido[l,2-a]pyrimidines 391 were treated dropwise in acetonitrile with tetrachlorosilane in 1,2-dichloroethane in the presence of sodium iodide at room temperature, 2-acetamido-3,4-dihydro-2//-pyridopyrimidin-4-ones 396 were obtained after work-up [92MJ24 93IJC(B)637]. In the first step iodotrichlorosilane was formed, and 1,2-addition of iodotrichlorosilane to a 2-carbonyl group of pyridopyrimidine 391 led to the formation of a-iodosilyl esters 392, which reacted with acetonitrile. After the rearrangement of adduct 393 and a further reaction with a second mole of iodotrichlorosilane, the hydrolysis of disylylated intermediates 395 yielded 2-acetamido-3,4-dihydro-2//-pyridopyrimidin-4-ones 396 (see Scheme 24). 

Hydroxy-2-methyl-4.//-pyrido[l,2-a]pyrimidin-4-ones510 (R1 = Hor CN R2 = H, Me) reacted with dimethylthiocarbamoyl chloride in acetone to afford 9-dimethylthiocarbamoyloxy derivatives 511 (R1 = H, CN R2 = H, Me) (Scheme 30) (87EUP218423 89EUP329126). When compounds 511 were heated in Dowtherm A, the 9-dimethylthiocarbamoyloxy group rearranged to give 9-(dimethylcarbamoylthio)-2-methyl-4//-pyrido[l,2-a]pyrimidin-4-ones 512 in excellent yield. The treatment of pyridopyrimidin-4-one 512 (R1 = H, R2 = Me) with sodium hydride... 

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]. 

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