Synthesis of 4-[(1,3-diaminopyrrolo[3',4':4,5]pyrido[2,3-d]pyrimidin-8- yl)benzoyl]-L-glutamic acid as a potential antifolate

Article abstract of DOI:10.1002/jhet.5570300542

The synthesis of 4-[(1,3-diaminopyrrolo[3',4':4,5]pyrido[2,3-d]pyrimidin- 8-yl)benzoyl]-L-glutamic acid (18), a potential antifolate and anticancer agent, has been achieved starting from 1,4-dibromobutan-2-ol with alkyl p- aminobenzoic acids. Condensation of these two agents gave 1-(4- alkoxycarbonylphenyl)pyrrolidin-3-ols 7a,b, which were oxidized to the corresponding pyrrolidin-3-one derivatives 8a,b. Compounds 8a,b were converted into 1,3-diamino-8-(4-alkoxycarbonylphenyl)-7,8-dihydro-9H- pyrrolo[3',4':4,5]pyrido[2,3-d]pyrimidines 12a,b in 4 steps. Saponification of 12b the benzoate ester and coupling with di-tert-butyl glutamate afforded a mixture of 7,8-dihydro product 16 and its aromatized derivative 17. Finally hydrolysis of esters 16 or 17 gave only the title compound 18. The 7,8- dihydro tricyclic derivatives were easily air-oxidized to form their fully aromatized compounds. The title compound 18 was one tenth less active than MTX against HL-60 cells in culture.