Synthesis Of Pemetrexed Disodium

In this paper, We put special emphasise on the synthesize methods of pemetrexed disodium. . A reasonable route was developed that pemetrexed disodium was prepared by 4-bromobenzoic acid via esterification, condensation, bromination, cyclization reaction and so on The overall yield of lab research was 13.9% and 12.7% with the scale-up. The structure of pemetrexed disodium and all intermediates was verified by 1H-NMR ,IR and MS.Process of pemetrexed disodium and intermediates were improved and optimized. water was used as solvent instead of 3A alcohol/water and"one pot"synthesis was adopted which was more easy to be handled in the preparation of intermediate 4(1-Hydroxy-4-(4-caromethyoxyphenyl)butanesulfonic Acid Sodium). Acetonitrile was used as solvent instead of dichloromethane and"one pot"synthesis was adopted in the preparation of intermediate 5 (4-[2-(2-Amino-4,7-Dihydro-4-Oxo-1H-Pyrrolo[2,3-d] pyrimidin-5-yl)ethyl]benzoic Acid Methyl Ester), and the reaction was performed in homogeneous system. At the same time, The manipulation was more easily to be handled and the yield increased. Ethanol-acetone combined solvent was used to purify intermediate 7(N-(4-[2-(2-Amino-4,7-Dihydro-4-Oxo-1H-Pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl)-L-Glutamic Acid Diethyl), avoiding column chromatography or the transformation to unstable toluenesulfonate. Hydrolyzation of intermediate 7 and preparation of pemetrexed disodium were combined into"one step"and manipulation was simplified . Additionally, HPLC method which was used to monitor reaction was changed into TLC which was more easy to handle.The improved synthesis reduced the process steps . lab research and scale-up research showed synthesize methods of pemetrexed disodium which was described in this paper was suitable for industrial producing.