奥贝胆酸的合成及制备工艺研究

Synthesis of obeticholic acid and optimization of the preparation process

目的制备奥贝胆酸并对其合成工艺进行优化。方法以(E)-3α-羟基-6-亚乙基-7-酮-5β-胆烷-24-酸为原料,经过双键氢化还原、α-乙基构型翻转、羰基立体选择性还原等反应制备奥贝胆酸。结果制备的化合物经过1H NMR、13C NMR、MS进行结构确证,对合成工艺路线的关键步骤进行了优化,总收率为69%。结论设计出符合工业化生产的奥贝胆酸制备工艺,保证原料药的安全性及质量可控性,提升药品质量,达到国家药品评审中心(CDE)申报要求。

Objective To synthesize obeticholic acid and optimize the preparation process. Method Obeticholic acid was synthesized from(E)-3α-hydroxyl-6-ethylidene-7-keto-5β-cholane-24-acid via the reactions in cluding the double bound hydrogenation,inversion of α-ethyl′s configuration,and stereospecific reduction of the carbonyl group. Results The structures of the compounds were confirmed by1 H NMR,13 C NMR and MS data. The preparation process was optimized,with the overall yield about 69%.Conclusion An industrial process for the preparation of obeticholic acid has been developed,available for the safety and quality control as well as the quality improvement of final products,which could meet the registration requiremens of Center for Drug Evalution(CDE).