Studies On Synthesis And Quality Of The Antiosteoporosis Drug Strontium Ranelate

Strontium Ranelate (distrontiumsalt of 2-[N,N-di(carboxy-methyl)mino]-3-cyano-4-carbo-xymethylthiophene-5-carboxylic acid), a novel antiosteoporosis agent, was developed by L-es Laboratoires Servier. This drug has a unique mechanism whereby it simultaneously stimu-lates the formation of new bone tissue and decreases bone resorption, and is used for the trea-tment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. Curr-ently it has shown potentially huge market in various countries.This thesis focuses onthe design of Strontium Ranelate synthetic route, optimization of the synthesis conditions, and the study on the crystal structure and quality control of Strontium Ranelateprepared via novel passway. the novel synthetic route of Strontium Ranelate includes:citric acid was used as the starting material, concentrated sulfuric acid was employed as catalyst,3-oxopentanedioic acid was firstly generated by decarboxylation, then Diethy 1,3-acetonedicarboxylate is produced from esterification of 3-oxop-entanedioic-acid and ethanol,5-amino thiophene was prepared by Gewald reaction with diethyl-1,3-acetonedicarboxylate and malononitrile and sulfur in the presence of morpholine catalyst, ethyl bromoacetate as alkylating reagent reacted with amino substituted alkyl reaction,four ester groups of thiophene ester hydrolysis into sodium salt, finally with strontium chloride reaction to give the target product Strontium Ranelate. Strontium Ranelate tetrahydrate was further purified through crystallization.Throughthe new crystalline preparation process conditions, obtained the tetrahydrate. The new process for synthesis of Strontium Ranelate has several advantages such as high purity, high yield, easy operation etc. It’s structure is characterized by UV, IR,1H-NMR, 13C-NMR, XRD, DSC, TGA. In addition, we also studiedthe quality of Strontium Ranelatein prepared via the new sythetic route, and consequently established a simple, specific, sensitive method for impurity investigation, and content determination of product as well as strontium. This research not only provides basis for controlling the quality of the drug, but also lays a foundation for formulating the quality standard of Strontium Ranelate.