[Improved synthesis process of diethyl N-[4-[(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamate].

Objective: To establish a new approach to synthesis of diethyl N-[4-[(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamate.

Methods: Target compound (5) was synthesized by the use of (2,4-dioxo-tetrahydropyridopyrimidin-6-yl)methyl acetate (1) as starting material via hydrolysis, chlorination, condensation with diethyl (p-aminobenzoyl)glutamate and aminolysis.

Results: A new approach to synthesis of diethyl N-[4-[(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamate was established. This synthetic route has hydrolysis reaction, chlorination, diethyl N-(p-aminobenzoyl)-L-glutamate condensation reaction and ammonolysis reaction. The total yield is 36.7%.The structures of those compounds have identified by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance and mass spectrometry. This synthetic route avoid the unstable brominated reaction product and improves the harsh condition of ammonolysis reaction.

Conclusion: The new synthetic route has improved the reaction condition and the stability of the intermediate, and increased the extent of the derivative compounds, which has great significance to anti-folic acid of anti-tumor inhibitor synthesis.