Pyridopyrimidine

All four possible pyridopyrimidine systems, pyrido[2,3-Chemical Abstracts nomenclature is used throughout this Chapter. For the reasons given above (Section 2.15.1), the pyrido[2,3-fused systems, e.g. (5) and (6) (numbering shown), are also known. The linear benzo fused derivatives of pyrido[3,2-[Pg.201]

Conformational behaviour of reduced pyridopyrimidines does not appear to have been systematically investigated. 

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. 

REACTIVITY AT RING ATOMS IN PYRIDOPYRIMIDINES 2.15.3.1 Electrophilic Attack at Ring Carbon... 

REACTIVITY OF SUBSTITUENTS IN PYRIDOPYRIMIDINES 2.15.4.1 Electrophilic Attack on Substituents... 

Alkyl groups attached to pyridopyrimidines adjacent to a nitrogen are activated , i.e. they are readily deprotonated and react with electrophilic reagents as their anions, or resonance stabilized equivalents, e.g. (64). This ready deprotonation, of course, leads to facile exchange of the alkyl protons for deuterium (Sections 2.15.2.2.1, 2.15.4.2), but, in... 

Carboxylic acid derivatives on pyridopyrimidine rings appear to undergo normal reactions with electrophilic reagents, e.g. the 6-amide (70) is dehydrated to the 6-nitrile with phosphorus oxychloride. 

A useful reaction in early preparations of parent pyridopyrimidines was the McFadyen-Stevens decomposition of tosyl hydrazides, e.g. (93) -> (3) (62JCS4094). 

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. 

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). 

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

No examples of simple pyridopyrimidines formed in this way have been reported, although some [4 + 2] reactions may involve intermediates of this type. 

The vast majority of this type of cyclization start from pyridines. One obvious route converts o- acylaminopyridine acids, esters or their equivalents to pyridopyrimidines using a one-atom ammonia or amine fragment, e.g. (173) (174). Examples are known mainly... 

The field of pyridopyridazines, although potentially a rich one, has been little explored compared with that of the pyridopyrimidines. This is due partly to the difficulty of preparation of several of the member systems, to the relatively small number of different syntheses utilized for those systems which have been explored, and the relative lack of interesting biological activity, or pharmaceutical and other uses found with them. 

Again, as with pyridopyrimidines, the main reaction is oxidation of di- or poly-hydro derivatives to fully aromatic structures, often merely by air or oxygen. In some cases the reagent of choice is mercury(II) oxide, whilst other reagents used include sulfur, bromine, chloranil, chromium trioxide-acetic acid, hydrogen peroxide, and potassium ferricyanide, which also caused oxidative removal of a benzyl group in the transformation (306) (307)... 

As in the pyridopyrimidines, the MacFadyen-Stevens degradation of tosylhydrazino derivatives has been used to prepare the parent [2,3-tf] compound (63JCS6073), and 1,4-bishydrazinopyrido[3,4-tf] pyridazines are reduced to the 1,4-diamino derivatives by Raney nickel (68AJC1291). 

As in the pyridopyrimidines, selective nucleophilic substitution reactions at reactive ring positions have been a fruitful source of pyridopyridazines. 

The only example from a pyridazine intermediate is of the Dieckmann-type used so widely in the pyridopyrimidine field (Section 2.15.5.4.2). The 3-carboxyalkylamino-4-ester (365) is cyclized by strong base to give the pyrido[2,3-c]pyridazine-6-carboxylate (366) (77JAP(K)7733695). 

The only syntheses of this type noted are analogues of corresponding [3 + 3] reactions in the pyridopyrimidine field. 

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). 

The greatest medicinal interest in pyridopyrimidines has been in another type of antibacterial derivative, the analogues of nalidixic acid, piromidic (68) (71CPB1426) and pipemidic (69) acids (75JMC74). 

Nonmedical uses claimed for pyridopyrimidines include uses as growth promoters, cytokinins, herbicides, agricultural fungicides, coccidiostats, dyestuffs intermediates, UV absorbants and corrosion inhibitors. 

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