合成路线1

A novel synthetic route to pemetrexed disodium has been reported: The reaction of 3,4-dimethoxybenzylamine with methyl chloroformate gives the corresponding carbamate (II), which is alkylated with 2-butenyl bromide (III) yielding the N-alkyl carbamate (IV). The cleavage of (IV) with hydrazine and KOH affords the secondary amine (V), which is condensed with dimethyl malonate to give the malonamic ester (VI). The radical cyclization of (VI) by means of manganese triacetate dihydrate/copper acetate hydrate affords the pyrrolidinone (VII), which is treated with P2S5 in THF to give the thione (VIII). The cyclization of (VIII) with guanidine (IX) yields the pyrrolopyrimidinone (X), which is condensed with N-(4-iodobenzoyl)-L-glutamic acid diethyl ester (XI) by means of palladium diacetate to afford the ethano-bridged pyrrolopyrimidine (XII). Elimination of the dimethoxybenzyl-protecting group of (XII) with TFA/H2SO4 gives the diethyl ester of pemetrexed (XIII), which is finally saponified with NaOH in THF/water.