Pyridopyrimidines from pyridines

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 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 in the pyrido[2,3-rf]pyrimidine field (e.g. 73GEP2248497, 74MI21502) but also in [3,4-d] and [4,3-rf] cases (74GEP2348U1). Sometimes pyridooxazine intermediates similar to (113) are involved, especially in the few examples with pyrido[3,2-rf]pyrimidines (65JCS4240). 

This is the least investigated system and the few known derivatives have been synthesized from 3,4-disubstituted pyridines (routes i or ii). The first recorded pyridopyrimidine of any system was pyrido[3,4-d]-... 

In addition to several general reviews on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines, enaminones, the photochemistry of enamides , heterocyclic jS-enamino esters , enamino thiones , the synthesis of indole alkaloids via enamines , formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamines , synthesis of lactams , formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones, the synthesis of 3-cyano-2(l -pyrimidine-thiones and -selenones from jS-enamino ketones and the chemistry of cyclic en-aminonitriles. ... 

Unfortunately, Vertex s initial foray into varying the quinolinone moiety on 2 (ECso = 2.1 aM) came empty-handed. Replacing the quinolinone with quinolone, pyridine, alkylation of the NH on quinolone 2, and replacing the quinolinone moiety with pyridopyrimidine core structure all yielded analogs with inferior potentiator activities. Meanwhile, the naphthanol derivative 3 retained the potentiator activity (ECso = 3.5 jM). The lesson learnt from this SAR exercise is that the two features are essential to the potentiator activity (i). The hydrophobic phenyl ring is needed, and (ii). The quinolinol tautomer 2 (which is more stabilized via hydrogen bond) is favored. 

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