Improving the Sustainability and Safety of Ursodeoxycholic Acid Synthesis in Continuous Flow Process with Water

• Hahyeon Kim^a
• Jonghyun Lee^b
• Seung Jae Lee^c
• Jeong Eun Oh^a
• Soo Dong Kim^a
• Yashwardhan R. Malpani^c
• Ye-Jin Hwang^d

• ^aDepartment of Biomedical and Pharmaceutical Science, Kyung Hee University, 26 Kyughee-daero, Dongdaemun-gu, Seoul 02447, Republic of Korea
• ^bDepartment of Basic Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyughee-daero, Dongdaemun-gu, Seoul 02447, Republic of Korea
• ^cAPI Synthesis Team, Daewoong-Bio, 29-Jeyakdanji-ro, Hyangnam-eup, Hwaseung-si, Hyeonggi-do 18608, Republic of Korea
• ^dDepartment of Chemistry and Chemical Engineering, Education and Research Center for Smart energy and Materials, Inha University 100 Inha-ro, Michugol-gu, Incheon, Republic of Korea

A clog-free sustainable method for the synthesis of ursodeoxycholic acid through selective hydrogenation was developed using Raney nickel in a continuous flow process. To increase the sustainability and safety of the continuous flow system, water as a green solvent was used to remove the salt compound causing serious clogging problems and to generate hydrogen gas by electrolysis. Furthermore, a real-time monitoring system was installed in the flow system to check the system pressure and collective volume of the reaction solution, allowing immediate confirmation of blockages. Eventually, the continuous flow system was successfully developed with a short residence time of 4 minutes, almost full conversion, and high selectivity of 94.0% dr. This continuous flow system lasts 10 consecutive days with lower catalyst loading (the ratio of Raney nickel to 7-oxo-LCA = 4.44 w/w) without clogging problems.

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