Study on Preparation and Crystal Modification of Flupirtine Maleate

摘要

A five-step procedure for synthesis of ethyl 2-amino-6-{[(4- fluorophenyl)methyl] amino}-3-pyridinyl carbamic acid ethyl ester maleate (Ⅵ),flupirtine maleate was developed. The synthesis started with 2,6-dichloro-3- nitropyridine (Ⅰ) and anhydrous ammonia gas making the following intermediates: 2-amino-3-nitro-6-chloropyridine (Ⅱ), 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine (Ⅲ), 2,3-diamino-6-(p-fluorobenzylamino)pyridine (Ⅳ), and 2-amino-6-{[(4-fluorophenyl)-methyl]amino}-3-pyridinyl carbamic acid ethyl ester (Ⅴ). The one-pot procedure for was tried, and the two Ⅲ-step yield was improved to 90%. Hydrogenation and acetylation reacted in the same reactor, and ethanol replaced the toxic dioxane as solvent, the total yield of the five-step up to 81.2%. Besides, crystal modification of was studied, Various crystal forms were Ⅵ analyzed by infrared spectrum and identified by X-ray diffractometry. It is shown how to obtain the modification wanted by infrared spectrum monitoring.