Preparation and Properties of some Pyrido [3,4 - d] pyrimidines

Abstract

The chemistry of the few known pyrido[3,4-d] pyrimidines is reviewed, and the biological properties of related compounds are summarised. Two main routes are employed for the synthesis of the pyrido [3,4-d] pyrimidines. The pyrido[3,4-d] pyrimidin-4(3H)-ones and pyrido[3,4-d] pyrimidine-2,4(1H,3H) -diones are prepared from 3-aminopyridine-4-carboxylic acids, by condensation with amides or urea. Treatment of 3-aminopyridine-4-carboxylic acid and its 2,6-dimethyl derivative with acetic anhydride yields 2-methylpyrido[3,4-d] [1,3] oxazin-4-cnes. Replacement of the acetic anhydride by benzoyl chloride in pyridine gives the corresponding 2-pnenylpyrido [3,4-d] [1 ,3] oxazin-4-ones. The 2-methylpyrido-oxazines react readily with primary amines to form 3=substituted-2-methylpyridopyrimidines. Similar reactions with the 2-phenylpyrido-oxazines generally result in the isolation of the intermediate diamides, which cyclise to pyridopyrimidines on heating. The mechanisms of these reactions are discussed. Methylation of a series of pyrido[3,4-d] pyrimidin-4(3H)-ones and pyrido [3,4-d] pyrimidine-2,4( 1H, 3H)-diones, with dimethyl sulphate or methyl iodide, yields the N-methyl derivatives. The reluctance of 3,6,8-trimethylpyrido[3,4-d] pyrimidine-2,4(1H, 3H)-dione to undergo methylation at the 1-position is thought to be due to steric hindrance. Some ring-opening reactions of pyrido[3,4-d] pyrimidin-4( 3H) -ones and pyrido[3,4-d] pyrimidine-2,4(1H, 3H) -diones with nucleophiles are investigated and possible mechanisms for these reactions outlined. The reaction of 2,6,8-trimethyl-3-phenylpyrido[3,4-d] pyrimidin-4( 3H)-one with benzaldehyde and p-nitrobenzaldehyde yields a monostyryl derivative. The reduction of pyrido[3,4-d] pyrimiain-4(3H)-ones with lithium aluminium hydride results in reductive cleavage of the 2,3-bond in the pyrimidine ring. The products obtained are 3-alkylamino--alkyl (or aryl) aminomethylpyridines, which can be recyclised to pyridopyrimidines by the action of phosgene. Possible mechanisms are discussed; the reaction seems to be general for the pyrido[3,4-d] pyrimidin-4( 3H) -ones and the ease of cleavage appears to depend on the substituent at the 3-position. The infrared and n.m.r. spectra of the new pyrido [3,4-d] pyrimidines are recorded. The mass spectra of a selection of pyrido[3,4-d] pyrimidin-4(3H) -ones, pyrido[3,4-d] pyrimidine-2,4(1H, 3H) -diones and pyridine derivatives are recorded, and possible fragmentation pathways are suggested for many of these compounds.