Syntheses Of Organic Impurities Of Antineoplastic Pemetrexed Disodium

Pemetrexed disodium, that contains the fused pyrrole pyrimidine structure, is a kind of folic acid antagonist that inhibits tumor growth by inhibition of cell replication through destruction of the normal metabolism of intracellular folic acid dependent process. However, some side reactions concurrent with the formation of residual impurities can occur during the process of production and storage, that will directly or indirectly affects the quality of this drug. As a consequence, it necessitates qualitative and quantitative research on impurities of pemetrexed disodium in order to ensure the safety of drug quality and patient. Among the known impurities of pemetrexed disodium, impurity A and D, namely sodium (S)-2-(4-(2-(2-amino-1-methyl-4-oxo-4,7-dihydro-1H-pyrrolo [2,3-d] pyrimidm-5-yl) ethyl) benzamido) pentanedioate and sodium (5)-2-((5)-4-(4-(2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl) benzamido)-4-arboxylatobutanamido) pentanedioate, are two common ones but they are very expensive if purchased commercially. The main body of this work is aiming at producing these two compounds as impurity references that meet the requirements for quality control of pemetrexed disodium. In this work, impurity A and D have been successfully prepared by exploring and optimizing the literature synthetic routes. Impurity A was obtained by direct methylating reaction and finally isolated by HPLC technique. Access to impurity D involves two key steps, that is, synthesis of side chain of glutamic acid dimer and amide coupling of side chain. The target structures of both compounds have been unambiguously confirmed by comprehensive micro-analytical method including ESI-MS, NMR and HPLC etc.