FIELD: chemistry.
SUBSTANCE: invention relates to a method of producing pemetrexed salt, having general formula I, where B+ denotes Na+ or protonated lysine, and having anticancer activity. Method includes following stages: a) reaction of 4-(2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoic acid (2) with diethyl-L-glutamate hydrochloride in presence of a binding agent to produce pemetrexed diethyl ester (3); b) hydrolysis of pemetrexed diethyl ester (3) to pemetrexed acid (5); c) forming salts with a base selected from NaOH or lysine, to produce corresponding pemetrexed salt. Method is characterized by that, that at step a) acid (2) is pre-converted in situ into corresponding sodium carboxylate or morpholine carboxylate, which can be separated or directly react, wherein used reaction solvent consists of water-alcohol mixture of solvents, where alcohol is selected from methanol, ethanol, isopropanol and n-propanol, and an intermediate compound of pemetrexed diethyl ester (3) is directly precipitated from reaction mixture with purity >98 %. Invention also relates to a (bi)lysine salt of N-[4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (pemetrexed) of formula (1), which is more stable, synthesis method thereof and a pharmaceutical composition containing said salt.
EFFECT: method enables to directly precipitate intermediate pemetrexed diethyl ester into a reaction mixture, obtaining said ester with high purity.
15 cl, 9 dwg, 3 tbl, 20 ex
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