Pyridopyrimidines. Synthesis of the 5-Deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N10-Methylfolic Acid

Article abstract of DOI:10.1021/jo00344a002

Reaction of bromoacetic acid with N,N-dimethylformamide and phosphorus oxychloride gave a triformylmethane derivative, which was condensed with 2,4-diaminopyrimidin-6(1H)-one (2) in water at reflux to give 2-amino-4(3H)-oxopyrido<2,3-d>pyrimidine-6-carboxaldehyde (4).The structure of 4 was confirmed by conversion to the 2,4-dinitrophenylhydrazone and oxidation to the known 6-carboxylic acid (6).Similarly, condensation of 1 with 2,4,6-triaminopyrimidine gave 2,4-diaminopyrido<2,3-d>pyrimidine-6-carboxaldehyde (5).Reductive alkylation of diethyl (p-aminobenzoyl)-L-glutamate (9) with 5 in 70percent acetic acid over Raney nickel gave diethyl N-<4-<<(2,4-diaminopyrido<2,3-d>pyrimidin-6-yl)methyl>amino>benzoyl>-L-glutamate (10), which was saponified with base to give the corresponding glutamic acid 11 (5-deazaaminopterin).The latter was methylated with formaldehyde and sodium cyanoborohydride to give 5-deazamethotrexate (12).Reductive alkylation of 9 with 4 gave diethyl N-<4-<<(2-amino-4(3H)-oxopyrido<2,3-d>pyrimidin-6-yl>methyl>amino>benzoyl>-L-glutamate (13), which was converted to the corresponding glutamic acid 14 (5-deazafolic acid).The preferred route for the preparation of 14 involved the hydrolysis of 10 with base at reflux, which resulted in replacement of the 4-amino group and saponification of the ester groups.Methylation of 14 with formaldehyde and sodium cyanoborohydride gave 5-deaza-10-methylfolic acid (15), which was also prepared by alkaline hydrolysis of the 4-amino group of 12.