Development of a packed-bed flow process for the production scale hydrogenation of 7-oxo-lithocholic acid to ursodeoxych
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Development of a packed-bed flow process for the production scale hydrogenation of 7-oxo-lithocholic acid to ursodeoxycholic acid Seung Jae Lee 1,2 & Yashwardhan R. Malpani 2 & Il Won Kim 1 Received: 14 June 2020 / Revised: 4 August 2020 / Accepted: 11 August 2020 # Akadémiai Kiadó 2020
Abstract A continuous flow process for the synthesis of ursodeoxycholic acid (UDCA) from 7-oxo-lithocholic acid (7-oxo-LCA) through catalytic hydrogenation was developed from the lab scale to the final production scale. Various parameters, such as catalyst, solvent, base equivalence, feed flow rate, temperature, and pressure, were optimized under the flow conditions suitable for the final production in the pilot and production scale. Heterogeneous Raney-Ni catalyst was optimal in terms of conversion ratio and stereoselectivity when solvent and base equivalence were 2-propanol and > 1.5, respectively. It was employed under the packedbed flow conditions with hydrogen gas. The scale-up was carried out up to 155 kg lot production scale. The developed process has an advantage over the widely used alkali metal reduction of 7-oxo-LCA to UDCA being more convenient and safer. Also, it produces UDCA with high stereoselectivity (> 23) and a fast production rate (> 4 kg/h). The synthesized product is suitable for the recrystallization to generate a high purity UDCA (> 99.5%) in a sufficient isolation yield (ca. 70%). Overall a production scale continuous process for UDCA was realized in a highly efficient manner. Keywords Continuous flow . Packed-bed reactor carbonyl reduction . Raney-nickel hydrogenation UDCA
Introduction In the last two decades, flow chemistry has seen immense growth in the field of organic transformations [1–5]. Especially, continuous flow process development of pharmaceutical drugs has emerged as one of the spotlighted research areas at production levels [6, 7]. Since 2018, regulatory authorities, such as US Food and Drug Administration (FDA) and European authorities, also have favored the incorporation of the flow process in drug development [8]. This is due to the Electronic supplementary material The online version of this article (https://doi.org/10.1007/s41981-020-00108-3) contains supplementary material, which is available to authorized users. * Seung Jae Lee [email protected] * Il Won Kim [email protected] 1
Department of Chemical Engineering, Soongsil University, 369 Sangdo-ro, Dongjak-gu 06978 Seoul, Republic of Korea
2
API Synthesis Team, Daewoong-Bio, 29-Jeyakdanji-ro, Hyangnam-eup, Hwaseung-si, Gyeonggi-do 18608, Republic of Korea
consistency of the results, safety, better operation control, ease of handling hazardous chemicals, production size flexibility, and most importantly, its applicability in large scale photo/ electro/microwave chemistry. In many cases, it has also been found to be a greener approach. Thus, global pharmaceutical companies such as Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Vertex, and Johnson & Johnson have disclosed reports for realizing the commercial manufactu
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