Study On The Synthesis And Crystallization Process Of Antineoplastic Drug Lonidamine

Lonidamine (LND) is an anticancer and thermosensitive drug which mechanism of action is different with the other drug. LND is effective against a number of tumors, including head, neck and breast cancers, due to the inhibition of mitochondrial electron transport and the enzyme hexokinase and to the induction of apoptosis. Recently, Lonidamine has received increasing research , which is regarded as an important anti-tumor drug .A novel synthetic route for Lonidamine based on the literature record was presented in this dissertation. Lonidamine (LND) was synthesized from acetylphenylhydrazine by the reaction with chloral hydrate, hydroxylamine hydrochloride and sodium sulphate to give N-Acetylaminoisonitrosoacetanilide, which was subsequently hydrolyzed to form 1H-indazole-3-carboxylic acid after Beckmann rearrangement and ring closing reaction. 1H-indazole-3-carboxylic acid was further reacted with 2, 4-dichlorobenzyl chloride to give the objective product. The optimized parameters of the whole synthetic process were determined by experiment , obtained a inversion rate reaching 60.2%. Component and Structure of Lonidamine and its intermediate were determined by element analysis, IR and 1HNMR.Compared with the synthetic processes in the literature, the improved approach shows more advantages through simple operation, such as excellent yields, lower cost, small wastage etc. Therefore it is suitable for application in industry.The pilot study on crystal process of Lonidamine was executed aiming at the quality assurance to meet the demand of medical market.1. solubility of Lonidamine at different temperature and variable volume ratio of water/acetic solution acid was respectively studied by the phase equilibrium.2. the variable cooling rate in crystallization meta region of Lonidamine in acetic acid has been studied.3. A crystallization kinetics model adapt to industrial application was presented from a population and quality balance equation and simulated by numeric method .This dissertation provide basic research data for designing of industrial crystallizer and controlling of industrial process.