The invention discloses a preparation method of
pemetrexed disodium, which can directly hydrolyzing into salt after an
organic solvent is removed, rather than salifying together with p-toluenesulfonic acid and / or purifying a product by adopting a
crystallization method during the preparation process, thus omitting the step of salifying together with p-toluenesulfonic acid and / or
crystallization through
ethanol, effectively improving the total yield of drugs to 68-75%; in the preparation process,
a peptide condensing agent is firstly prepared and is fully reacted with pemedolac in the
organic solvent into transient-state acid ester, so that the generation of N-
methylation impurities can be effectively inhibited in the reaction together with L-
glutamic acid diethyl ester hydrochloride, the defect that the content of N-
methylation impurities during the one-pot preparation process in the prior art exceeds 0.1% can be avoided, the advantages for opening up Europe and America markets can be brought, the defect that the raw materials are not reacted thoroughly to cause high cost can also be overcome; the HPLC (High Performance Liquid Chromatograph) of the finished
pemetrexed disodium obtained by adopting the method is more than or equal to 99.8%, and the content of single impurities is less than 0.1%.