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

Abstract

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 3keto 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.

High Enantioselective and Large-Scale Production of Ursodeoxycholic Acid by Combination of Pd- and Hydroxysteroid Dehydrogenase-Catalyzed Hydrogenation

“…20 Subjection of BA-2 to the Wittig reaction with methylene triphenylphosphine formed 2 in 98% yield with 99.6% HPLC purity. 18 Protection of the 3-keto group in 2 with glycol ketal generated 3 in 97% yield and 98.6% purity. 21 The ester 5 was synthesized successfully in 81% yield with 98.2% purity from 3 via benzoyl peroxide (BPO)/N-hydroxyphthalimide (NHPI) catalyzed oxidation of C-7, 22 followed by deprotection of the ketal with hydrochloric acid (Scheme 3).…”

“…First, TEMPO-catalyzed oxidation of bisnoralcohol ( BA-1 ) was carried out to form BA-2 in 97% yield and 98.7% HPLC purity . Subjection of BA-2 to the Wittig reaction with methylene triphenylphosphine formed 2 in 98% yield with 99.6% HPLC purity . Protection of the 3-keto group in 2 with glycol ketal generated 3 in 97% yield and 98.6% purity .…”

“…The contents of stable carbon isotope ratio mass spectrometry detection were quantified by IsoPrime100 mass spectrometer (RuiYuan Co., Ltd. Nanjing, China). (20S)-3-Oxopregn-4-ene-20-carboxaldehyde ( BA-2 ) and methyl (22E)-3-oxochola-4,22-dien-24-oate ( 2 ) were synthesized according to our previously reported methods …”

“…(20S)-3-Oxopregn-4-ene-20-carboxaldehyde (BA-2) and methyl (22E)-3-oxochola-4,22-dien-24-oate (2) were synthesized according to our previously reported methods. 18 Procedure for Synthesis of Methyl (22E)-3,3-[1,2-Ethanediylbis(oxy)]-cholan-5,22-dien-24-oate (3). In a 20 L glass reactor, a mixture of ethylene glycol (3.33 kg), triethyl orthoformate (0.93 kg, 6.31 mol), 2 (1.50 kg, 3.90 mol), and p-toluenesulfonic acid (15.0 g, 87 mmol) was added.…”

“…However, the substrate concentration was low (1.0 g, 14 gL –1 , and 37 mM). Recently, we reported on the production of lithocholic acid derived from BA and the highly selective hydrogenation of 3-ketones in steroids catalyzed by hydroxysteroid dehydrogenase. , Herein, we presented an improved route to synthesize UDCA from commercially available BA (CNY 300/kg, from Norchem) (Scheme b). The main considerations for the preparation of plant-derived UDCA are cost and quality, as well as the requirement for high yield, excellent enantioselectivity, and safe and stable process conditions.…”