Zeng Chunling, Xu Shitang, Yin Zhenlong, Cui Yue, Xu Xinhua, Li Ningbo
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China.
ACS Omega. 2023 Jun 14;8(25):23130-23141. doi: 10.1021/acsomega.3c02548. eCollection 2023 Jun 27.
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.
在本研究中，使用市售的植物源双降醇（BA）制备石胆酸（LCA），五步反应产物的总收率为70.6%。为防止与工艺相关的杂质产生，对C4-C5双键催化氢化的异构化反应以及3-酮基的还原反应进行了优化。使用钯-铜纳米线（Pd-Cu NWs）代替Pd/C，双键还原异构化得到改善（5β-H:5α-H = 97:3）。通过3α-羟基类固醇脱氢酶/羰基还原酶催化，3-酮基的还原反应100%转化为3α-OH产物。此外，还对优化过程中的杂质进行了全面研究。与已报道的合成方法相比，我们开发的方法显著提高了异构比和总收率，得到了符合人用药品注册技术要求国际协调会议（ICH）质量标准的LCA，且更具成本效益，适合LCA的大规模生产。
