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

Zeng, Chunling; Xu, Shitang; Cui, Yue; Xu, Xinhua

doi:10.1021/acsomega.3c02548

Cited by 3 publications

(7 citation statements)

References 36 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…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 .…”

Section: Resultsmentioning

confidence: 99%

“…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 …”

Section: Methodsmentioning

confidence: 99%

“…(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.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Zeng,

Liu,

Sun

et al. 2024

Org. Process Res. Dev.

Self Cite

View full text Add to dashboard Cite

Ursodeoxycholic acid (UDCA) was synthesized from commercially available phytosterol-derived bisnoralcohol with an overall yield of 57% by a six-step process. The absolute configuration of the 3,5,7-stereogenic centers in UDCA was determined using Pd-catalyzed and hydroxysteroid dehydrogenase (HSDH)-catalyzed hydrogenation conducted under normal temperature and atmospheric pressure conditions. To investigate the stereoselectivity and regioselectivity of the catalyst and assess the final purity of the product, all potential impurities were synthesized and analyzed using HPLC with charged aerosol detection (CAD). The developed process demonstrated cost-effectiveness and suitability for large-scale production of UDCA with an ICH-grade quality. Our Pd-catalyzed and HSDH-catalyzed hydrogenation techniques could also be applied in the synthesis of alphaxalone and brexanolone.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Zeng,

Liu,

Sun

et al. 2024

Org. Process Res. Dev.

Self Cite

View full text Add to dashboard Cite

show abstract

Hydroxysteroid Dehydrogenase-Catalyzed Highly Regio-, Chemo-, and Enantioselective Hydrogenation of 3-Keto in Steroids

Zeng,

Xu,

Shen

et al. 2023

Org. Lett.

Self Cite

View full text Add to dashboard Cite

A highly selective hydrogenation of 3-keto in steroids to 3-hydroxyl steroids catalyzed by hydroxysteroid dehydrogenases (HSDHs) was demonstrated. The Ct3α-HSDH-catalyzed hydrogenation generated 3α-hydroxyl steroids as the main enantiopure isomers in high yields, while the Ss3β-HSDH catalytic system afforded 3β-hydroxyl steroids in excellent yields. In both catalytic systems, the hydrogenation proceeded regioselectively at 3-keto with 7-, 11-, 17-, and 20-keto almost unreacted, and chemoselectively with the C�C bond and ester group unattacked. Our HSDH-promoted hydrogenation showed advantages like high regio-, chemo-, and enantioselectivity, good yields, mild conditions, a wide substrate scope, and being suitable for gram-scale synthesis. Notably, bioactive molecules like dehydroepiandrosterone, brienolone, and alfaxalone were obtained facilely in high yields via our hydrogenation approach.

show abstract

3-Benzylaminomethyl Lithocholic Acid Derivatives Exhibited Potent and Selective Uncompetitive Inhibitory Activity Against Protein Tyrosine Phosphatase 1B (PTP1B)

Mendoza-Jasso,

Pérez-Villanueva,

Alvarado-Rodríguez

et al. 2024

ACS Omega

View full text Add to dashboard Cite

Protein tyrosine phosphatase 1B (PTP1B) is a promising drug target for treating type 2 diabetes (T2DM) and obesity. As a result, developing new therapies that target PTP1B is an attractive strategy for treating these diseases. Herein, we detail the synthesis of 15 lithocholic acid (LA) derivatives, each containing different benzylaminomethyl groups attached to the C3 position of the steroid skeleton. The derivatives were assessed against two forms of PTP1B enzyme (hPTP1B 1−400 and hPTP1B 1−285 ), and the most potent compounds were then tested against T-cell protein tyrosine phosphatase (TCPTP) to determine their selectivity. The results showed that compounds 6m and 6n were more potent than the reference compounds (ursolic acid, chlorogenic acid, suramin, and TCS401). Additionally, both compounds exhibited greater potency over hPTP1B 1−400 . Furthermore, enzyme kinetic studies on hPTP1B 1−400 revealed that these two lithocholic acid derivatives have an uncompetitive inhibition against hPTP1B 1−400 with K i values of 2.5 and 3.4 μM, respectively. Interestingly, these compounds were around 75-fold more selective for PTP1B over TCPTP. Finally, docking studies and molecular dynamics simulations (MDS) were conducted to determine how these compounds interact with PTP1B. The docking studies revealed hydrophobic and H-bond interactions with amino acid residues in the unstructured region. MDS showed that these interactions persisted throughout the 200 ns simulation, indicating the crucial role of the unstructured zone in the biological activity and inhibition of PTP1B.

show abstract

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

Cited by 3 publications

References 36 publications

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

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

Hydroxysteroid Dehydrogenase-Catalyzed Highly Regio-, Chemo-, and Enantioselective Hydrogenation of 3-Keto in Steroids

3-Benzylaminomethyl Lithocholic Acid Derivatives Exhibited Potent and Selective Uncompetitive Inhibitory Activity Against Protein Tyrosine Phosphatase 1B (PTP1B)

Contact Info

Product

Resources

About