Pyrido [4, 3 - d] Pyrimidines

Abstract

The methods available for the synthesis of tetrahydro-, octahydro- and fully aromatic pyrido[4, 3-d]pyrimidines are reviewed. Three new routes for the syntheses of pyridol 4, 3-d]pyrimidines are described. Treatment of 4-aminonicotinic acid, or 4-acetamidonicotinicacid with acetic anhydride yields 2-methylpyrido|4, 3-d] - [1,3] -oxazin-4-one. 2-Methylpyrido-oxazinereacts readily with aliphatic and aromatic primary amines to yield directly 3-substituted 2-methylpyrido[4,3-d]pyrimidin-4(3H)-ones without the necessity for the isolation of the intermediate diamides. Unsuccessful attempts to prepare 2-phenylpyrido[4,3-d] - [1,3] -oxazin-4-one are described. 4-Benzamidonicotinicacid undergoes transacylation with acetic anhydride, to give in the first instance 4-acetamidonicotinicacid, which is then cyclised to 2-methylpyrido[4,3-d]-oxazin-4-one. The possible reason for the transacylation is outlined.2,3-Disubstituted pyrido [4,3-d] pyrimidin-4 (3H) -ones are more conveniently prepared from ethyl 4-amidonicotinates.Ethyl 4-amidonicotinates are produced in excellent yieldsfrom ethyl 4-aminonicotinate and the appropriate acylchloride in pyridine. Ethyl 4-amidonicotinates react withprimary aliphatic amines under different conditions. The product of the reaction of the 4-amidonicotinate with the amine is either a 2,3-disubstituted pyrido| 4,3-d|pyrimidin-4(3H)-one or the diamide. The majority of the diamides are readily cyclised to the corresponding pyrido|4,3-d]pyrimidines by heat. The mechanism for the cyclisation of ethyl 4-amidonicotinateto 2,3-disubstituted pyrido[4,3-d]pyrimidin-4(3H)-one is described. Infrared spectra of ethyl 4-amidonicotinates,diamides and 2,3-disubstituted pyrido| 4, 3-d| pyrimidin-4(3H)-ones are discussed. Nuclear magnetic resonance spectra of 2,3-disubstitutedpyrido (4, 3-d| pyrimidin-4 (3H) -ones are described and analysed. A new synthesis of pyrido| 4, 3-d] pyrimidines, from pyrimidines, has been developed. Treatment of 2-phenyl-4styrylpyrimidine-5-carboxylic acid with bromine in acetic acid yields 2,7-diphenylpyrano[4,3-d] pyrimidin-5-one, which is the first recorded example of the pyrano [4, 3-d] pyrimidine ring system. 2,7-Diphenylpyrano[4, 3-d]pyrimidin-5-one reacts with primary aliphatic amines to give directly 6-substituted 2,7-diphenylpyrido[4,3-d]pyrimidin-5(6H)-ones. Unsuccessful attempts to prepare2,7-diphenylpyrido[4,3-d] pyrimidine from 5-substituted2,7-diphenylpyrido[ 4, 3-d] pyrimidines are described. The preparation of 7-phenylpyrano[4, 3-d] pyrimidin-2, 5(3H)-dione from 4-styrylpyrimidine-2(1H)-one-5-carboxylic acid and bromine is described. The product is less reactive towards amines than 2,7-diphenylpyrano|4,3-d| pyrimidine.) The fragmentation patterns in the mass spectra of a selected number of pyrido| 4, 3-d] pyrimidines are described. The results of primary neuropharmacological and cardiovascular tests of a selected number of intermediate compounds and pyrido| 4, 3-d|pyrimidines are presented.