Research On Clean Preparation Technology Development Of Dihudroxudibutyleter

Baodan Jiansu (dihudroxudibutyleter, DHBE) is a efficient cholagogue, gallstone dissolving and protect-liver drug which is developed and produced by the French Laphal. Its main ingredient is dihudroxudibutyleter. China has not yet been imported the bulk drugs and no report about domestic manufacturer for the production approval has been seen. Therefore, clean preparation technology of dihudroxudibutyleter has important significance for promoting domestic pharmaceutical industry development.Recently, DHBE is produced by1,3-butanediol intermolecular etherification dehydration under the condition of170℃using the catalysis of sulfuric acid and then get dihudroxudibutyleter by reduced pressure discharge (156-163℃/20mm Hg) with yield20%. But there are corrosion of equipment, waste volume, environmental pollutions and other issues in this process.First, the influencing factors of sulfuric acid-catalyzed1,3-butanediol generating DHBE were investigated. The optimum conditions were obtained by discussing the react effect of reaction time, catalyst dosage, concentration of catalyst. The optimal conditions were:the reaction was catalyzed by5mol/L sulfuric acid; amount of sulfuric acid was6.67%; reaction time was1.5hours; reaction temperature was151-154℃, with conversion33.5%and selectivity28.0%. At the same time we got the three isomers of compound by using triphenylchloromethane protection primary hydroxyl and then deprotection. The three isomers were prepared by that method with purity98%(GC) and characterized by NMR, IR.Secondly, investigating the acid effect on the yield when the acid was p-toluene sulfonic acid,y-activated alumina, solid phosphoric acid, D803-Ⅱ-type sulfonic acid resin, ZrO2-TiO2solid super acid.The yield was higher when the acid was D803-Ⅱ-type sulfonic acid resin or ZrO2-TiO2solid super acid. The reaction catalyzed by D803-Ⅱ-type sulfonic acid resin (ZrO2-TiO2solid super acid)with conversion rate77.7%(85.2%) and selectivity67.4%(41.1%.).Finally, based on the small pilot study,50L reactor scale reaction and purification was finished with1,3-butanediol as raw material to produce dihudroxudibutyleter. The pilot test results show that50L reactor scale final product purity of each batch achieved above96%. The average yield was26.46%, the maximum of production efficiency is3kg/h on average. The feasibility of the new process was verified by the results.