Study On The Synthesis Of Strontium Ranelate

Osteoporosis is a group of systemic lupus, systemic bone disease caused by avariety of reasons. When osteoporosis occurs, the bone tissue is calcified at normallevel, and the ratio of calcium salt and stroma is represented to be normal.Osteoporosis is a metabolic bone disease based on the reduction of bone tissue perunit volume. For most of the osteoporosis, the bone tissue reduction is mainly due tothe increase in bone absorption. Osteoporosis will lead to the increasing of bothbone fragility and the risk of fracture. Currently the drugs for treating osteoporosiscan be divided into three categories by the mechanism: First, the bone absorptioninhibitor, inhibiting the further reduction of bone mass, such as estrogen receptormodulators, calcitonin, bisphosphonates, and isopropoxycarbonyl flavonoids. Second,the bone formation accelerator, increasing bone mass, such as fluoride parathyroidhormone, insulin-like growth factor, and vitamin K. Third, the bone mineralizationaccelerator, promoting osteocalcin calm and increasing bone mass, such as vitamin Dand calcium. However, the mode of the action of these drugs is single, and hormonereplacement therapy is no longer used as first-line therapy for osteoporosis. Forwomen of menopausal osteoporosis fractures, the drugs also can not play the role ofprevention and treatment.Strontium ranelate chemically named5-[N,N-bis (carboxymethyl) amino]-3-carboxymethyl-4-cyano-2-thiophene carboxylic distrontium salts, is the new uniqueanti-osteoporosis drug which have a dual mechanism of action of stimulating boneformation and inhibiting bone absorption. As it can reduce the risk of fractures,increase bone strength and bone density, it overcomes the drawbacks of the single mechanism drug in the past, with no effect on bone mineralization or the bonestructure of the crystal. Therefore, the effect of Strontium ranelate in reducing the riskof fractures, enhancing bone strength and bone density is obvious. Because its littleadverse reactions and good tolerance, it is widely recognized as the first new drug forthe prevention and treatment of menopausal fracture due to osteoporosis.The basic strontium ranelate synthetic methods reported in the literature is basedon citric acid as a raw materialand generated by the following process: firstly,cyclization5-amino-thiophene is prepared after decarboxylation and esterificationand; then after alkylation,5-aminothiophene tetraethyl is prepared; at last,5-aminothiophene tetraethyl is hydrolyzed and salified in an alkaline environment togetstrontium ranelate. The chlorosulfonic acid used in the decarboxylation of citricacid is toxic and drastic is a kind of highly toxic chemical, and it is difficult topurchase. This project uses hair fuming sulfuric acid and concentrated sulfuric acidinstead of chlorine acid, the result is turned out to be that the yield is slightlyincreased and the cost is significantly lower (reagent products). The synthetic methodof5–aminothiophene reported in literature are different in reaction time, temperatureand types of organic base. This project compares these reaction condition, selects andcombines the best reaction condition.5-aminothiophene tetraethyl is from5-aminothiophene after alkylation reaction, this project contrasts variety of catalysts onthe reaction, and compares different reaction time and ratios of acid-binding agent andalkylating agent. Otherwise, we test the combine catalysts, and present the bestsynthetic scheme. The yield in this project compared to that in the literature has agreat improvement. For these intermediate products, we test differentpost-processings, choose the one with highest yield. Because strontium ranelate isdifficult to purify, this project also introduces intermediate ranelate lithium, to find amethod for purifying the obtained strontium ranelate in order to achieve high purity,stable process, and highly independent on the purity of former product5- aminothiophene tetraethyl. It solves the reported problem that recrystallization ofhigh purity5-aminothiophene tetraethyl is complicated.For strontium ranelate and intermediate products of every step, the qualitativeand quantitative analysis method is employed to determine the structure and purity.We analysis the solubility, UV absorption, water content of strontium ranelate and itshydrates, we also confirm its structure. Otherwise, we test the purity of differentbatches of strontium ranelate and its hydrates. The results show that the productionfrom the new processes has a high purity, the organic impurities content is less than0.1%, impurity content meets the requirements, and it provides the basis for thequality control of the drug. At last, we pre-amplify the synthetic method, provide thereliable lab-scheme for the coming pilot production.