Synthesis of Diethyl N-{4-[N-Methyl-N-(3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)amino-2-hydroxypropyl)amino]-benzoyl}-L-glutamate and Its Derivatives

A new practical approach to prepare diethyl N-{4-[N-methyl-N-(3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)amino-2-hydroxypropyl)amino]benzoyl}-L-glutamate and its derivatives has been realized from ethyl 4-aminobenzoate (4a) and diethyl N-(4-aminobenzoyl)-L-glutamate (4b). Six novel 5-(substituted)amino pyrimidines 9 similar to 11 were synthesized via methylation, allylation, bromohydroxylation, epoxidation, ring-opening, deprotection reaction and so on, and were characterized by H-1 NMR, C-13 NMR and MS techniques. The inhibitory activities against human dihydrofolate reductase of the compounds have been determined. The results showed that the bioactivities of the compounds were related with L-glutamate side chain.