Optimization and Impurity Control Strategy for Lithocholic Acid Production Using Commercially Plant-Sourced Bisnoralcohol

In this study, lithocholic acid (LCA) was prepared using
commercially
available plant-sourced bisnoralcohol (BA), and the overall yield
of the product was 70.6% for five steps. To prevent process-related
impurities, the isomerizations of catalytic hydrogenation in the C4–C5
double bond and reduction of the 3-keto group were optimized. The
double bond reduction isomerization was improved (5β-H:5α-H
= 97:3) using palladium–copper nanowires (Pd–Cu NWs)
instead of Pd/C. The reduction of the 3-keto group was 100% converted
to a 3α-OH product by 3α-hydroxysteroid dehydrogenase/carbonyl
reductase catalysis. Moreover, the impurities during the optimization
process were comprehensively studied. Compared with the reported synthesis
methods, our developed method significantly improved the isomer ratio
and overall yield, affording ICH-grade quality of LCA, and it is more
cost-effective and suitable for large-scale production of LCA.

本研究以市售植物源双去甲醇（bisnoralcohol, BA）为原料制备石胆酸（lithocholic acid, LCA），五步反应总收率达70.6%。为避免工艺相关杂质的产生，本研究对C4-C5双键催化加氢中的异构化反应以及3-酮基还原反应进行了优化。采用钯铜纳米线（Pd–Cu NWs）替代钯碳（Pd/C）催化剂，使双键还原异构化反应的立体选择性得到显著提升，5β-H与5α-H的比例达到97:3；通过3α-羟类固醇脱氢酶/羰基还原酶催化，可将3-酮基还原反应完全转化为3α-羟基产物。此外，本研究对优化过程中产生的杂质进行了全面研究。与已报道的合成方法相比，本研究开发的合成策略显著提升了异构体比例与总收率，所得产物达到ICH级（人用药品注册技术要求国际协调会，International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH）的LCA质量标准，且具备更高的成本效益，更适合石胆酸的规模化生产。