- An improved synthesis of 6α-ethylchenodeoxycholic acid (6ECDCA), a potent and selective agonist for the Farnesoid X Receptor (FXR)
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The active, potent, and selective Farnesoid X Receptor (FXR) agonist 6α-ethylchenodeoxycholic acid (6ECDCA) has been synthesized in improved yield compared to the published methodologies. The synthesis employed selective oxidation of one of the two hydroxyls of the readily-available starting material chenodeoxycholic acid (CDCA) as a key step. After protection of the remaining hydroxyl, LDA/HMPA/EtI/PPTS provided an efficient deprotonation/ethylation/ deprotection sequence. The two synthetic improvements that allow a productive yield are the use of PCC in the oxidation step, and the use of HMPA/ethyl iodide in the stereoselective alkylation step. This synthesis offers an economical and efficient strategy which provides a simple and cost-effective procedure for potential large-scale production of this promising FXR agonist, which is a research tool and potential drug substance of current interest.
- Yu, Donna,Mattern, Daniell L.,Forman, Barry M.
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Read Online
- An expedient synthesis of 6α-fluoroursodeoxycholic acid
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Optimization of the synthesis of 6α-fluoroursodeoxycholic acid 1 is described starting from the commercially available 2. The penultimate intermediate 16 was made in eight synthetic steps but in only four operations in an overall yield of 57%. The highlights are flourination of hydroxyketo acid 11 using Selectfluor through the intermediacy of silyl enol ether 12, conversion of 13 to 14 via equilibration of fluoroketone, esterification, and acylation. The drug substance 1 was prepared from mesylate 16 using potassium superoxide followed by a mild reductive workup using methoxydiethylborane.
- Koenigsberger, Kurt,Chen, Guang-Pei,Vivelo, James,Lee, George,Fitt, John,McKenna, Joseph,Jenson, Todd,Prasad, Kapa,Repic, Oljan
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Read Online
- Engineering Regioselectivity of a P450 Monooxygenase Enables the Synthesis of Ursodeoxycholic Acid via 7β-Hydroxylation of Lithocholic Acid
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We engineered the cytochrome P450 monooxygenase CYP107D1 (OleP) from Streptomyces antibioticus for the stereo- and regioselective 7β-hydroxylation of lithocholic acid (LCA) to yield ursodeoxycholic acid (UDCA). OleP was previously shown to hydroxylate testosterone at the 7β-position but LCA is exclusively hydroxylated at the 6β-position, forming murideoxycholic acid (MDCA). Structural and 3DM analysis, and molecular docking were used to identify amino acid residues F84, S240, and V291 as specificity-determining residues. Alanine scanning identified S240A as a UDCA-producing variant. A synthetic “small but smart” library based on these positions was screened using a colorimetric assay for UDCA. We identified a nearly perfectly regio- and stereoselective triple mutant (F84Q/S240A/V291G) that produces 10-fold higher levels of UDCA than the S240A variant. This biocatalyst opens up new possibilities for the environmentally friendly synthesis of UDCA from the biological waste product LCA.
- Grobe, Sascha,Badenhorst, Christoffel P. S.,Bayer, Thomas,Hamnevik, Emil,Wu, Shuke,Grathwol, Christoph W.,Link, Andreas,Koban, Sven,Brundiek, Henrike,Gro?johann, Beatrice,Bornscheuer, Uwe T.
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supporting information
p. 753 - 757
(2020/12/01)
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- (E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells
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Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC50 = 15?μM/EC50 = 26?nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.
- Dracinsky, Martin,Drastik, Martin,Kaspar, Miroslav,Klepetarova, Blanka,Kronenberger, Thales,Kudova, Eva,Micuda, Stanislav,Pavek, Petr,Stefela, Alzbeta
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- Synthesis method of intermediate 3 α - hydroxyl -7 - ketone - 5 5 5 beta-cholestane -24 - acid of obeticholic acid
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The invention discloses a chemical synthesis method for an intermediate 7-ketone lithocholic acid(3alpha-hydroxy-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, and belongs to the field of organic chemical synthesis. The method comprises the following steps: cholic acid is taken as a raw material, and the intermediate 7- ketone lithocholic acid of the obeticholic acid is synthesized through the selective oxidation of 7alpha-hydroxy, the benzyl esterification of side chain carboxyl, the etherification of 3alpha-hydroxy, the methanesulfonic acid esterification of 12alpha-hydroxy, elimination, hydrogenation, hydrolysis and the like. The method disclosed by the invention has the advantages of novel synthetic method, low cost, high yield, environment friendliness and convenience in industrial production since the cheap cholic acid is taken as the raw material.
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Paragraph 0102; 0115-0116
(2021/01/24)
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- Preparation method of low-cost, high-yield and high-purity 7-ketolithocholic acid
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The invention discloses a preparation method of low-cost, high-yield and high-purity 7-ketolithocholic acid, which is characterized by comprising the following steps: adding chenodeoxycholic acid intoa mixed solution of an organic solvent and water, and performing stirring to dissolve; adding bromide and acid, and performing stirring and dissolving; adding bromate for reaction; adding a terminating agent, and performing stirring to terminate the reaction; adding water to crystallize the product; and carrying out solid-liquid separation, washing a solid product with water for multiple times, and performing drying to obtain 7-ketolithocholic acid. According to the method, a common and safe reagent is adopted, chenodeoxycholic acid is selectively oxidized into 7-ketolithocholic acid under arelatively mild condition, the product purity is greater than 98.0%, and the yield is greater than 85%. The method has the advantages of cheap reagents, simple operation, high process reproducibility,simple post-treatment, high product purity and the high yield, and can easily implement industrial production.
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Paragraph 0048-0055
(2020/07/24)
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- A method of synthesis of ursodesoxycholic acid(UDCA) using bile salt hydrolase(BSH) from Porcine intestinal flora Bifidobacterium thermophilum
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The present invention relates to a method for synthesizing ursodesoxycholic acid (UDCA) from porcine bile acid by using bile salt hydrolase (BSH) derived from Bifidobacterium thermophilum in porcine gut microbiota. The present inventors have found that, compared to existing synthesis methods involving repeated purification processes, an UDCA synthesis method using the BSH of Bifidobacterium thermophilum in porcine gut microbiota is simple and time-saving; provides remarkable advantages in terms of high-throughput production and stability; is significantly more economical; and can increase an UDCA yield. In addition, the present invention is expected to provide a significant economic advantage in that it provides high-value added UDCA effective in improving hepatic functions, alleviating fatigue through liver improvement, cholesterol reduction, gallstone dissolution, primary biliary cirrhosis, and the like by utilizing porcine waste by-products.(AA) First step : Extract bile acid derived from by-products(BB) Second step : Extract BSH enzyme(CC) Third step : Extract CDCA(DD) Fourth step : Synthesize and purify UDCA(EE) Fifth step : Analyze UDCA(FF) Process of extracting bile acid for use in UDCA synthesis in by-products, Extract bile acid soluble by use of organic solvent methanol and evaporate methanol to obtain bile acid(GG) Extract BSH enzyme by expression and purification of BSH from lactic acid bacteria having BSH enzyme used in CDCA extraction(HH) Extract bile acid from CDCA as a measure to increase the purity and yield of UDCA from extracted bile acid(II) Synthesize UDCA by redox reaction using CDCA from the bile acid extracted from respective by-products(JJ) Analyze CLA via HPLC in order to confirm the synthesis and yield of synthesized UDCACOPYRIGHT KIPO 2020
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Paragraph 0045-0046
(2020/07/11)
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- SYNTHETIC DERIVATIVES OF CHOLIC ACID 7-SULFATE AND USES THEREOF
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The compositions and methods provided herein are related, in part, to the discovery of cholic acid 7-sulfate as a treatment for diabetes. Provided herein is a method for treating a metabolic disorder (e.g., diabetes, obesity), or an inflammatory disease (e.g., Crohn's disease, inflammatory bowel disease, ulcerative colitis, pancreatitis, hepatitis, appendicitis, gastritis, diverticulitis, celiac disease, food intolerance, enteritis, ulcer, gastroesophageal reflux disease (GERD), psoriatic arthritis, psoriasis, and rheumatoid arthritis) in a subject in need thereof comprising administering to a subject a compound of Formulae (I)-(XVII).
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Paragraph 00340-00341
(2020/07/05)
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- Preparation method of ursodeoxycholic acid
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The invention discloses a preparation method of ursodesoxycholic acid, which comprises the following steps:using chenodeoxycholic acid as a raw material, oxidizing with sodium hypochlorite to obtain an intermediate 3alpha-hydroxy-7beta-carbonyl-5 beta-cholanic acid, carrying out hydrogenation reduction hydrogenation by using Raney nickel as a catalyst to obtain an ursodesoxycholic acid crude product, and carrying out triethylamine salifying refining to obtain the ursodesodesoxycholic acid bulk drug. The preparation method of ursodesoxycholic acid is stable and reliable in raw material source,high in reaction selectivity, easy in finished product refining, high in quality and short in process route; the method has the advantages of short synthesis steps, mild reaction conditions and cleanprocess, and is suitable for industrial production.
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Paragraph 0023
(2020/06/24)
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- Flavin Oxidoreductase-Mediated Regeneration of Nicotinamide Adenine Dinucleotide with Dioxygen and Catalytic Amount of Flavin Mononucleotide for One-Pot Multi-Enzymatic Preparation of Ursodeoxycholic Acid
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Ursodeoxycholic acid (UDCA), a pharmaceutical ingredient widely used in clinics, can be prepared from chenodeoxycholic acid (CDCA) by the epimerization of the 7α-OH group. In this study, a nicotinamide adenine dinucleotide (NAD+) regeneration system was developed by using flavin oxidoreductase (FR) and flavin mononucleotide (FMN). Only catalytic amount of FMN is required for the effective NAD+ recycling. FR/FMN system was then applied in the oxidation of CDCA to 7-ketolithocholic acid (7-keto-LCA) by NAD+-dependent 7α-hydroxysteroid dehydrogenase (Bs-7α-HSDH) from Brevundimonas sp., which showed extremely high enzyme activity toward CDCA (kcat/Km=8050 s?1 ? mM?1). When Escherichia coli whole cells coexpressing Bs-7α-HSDH and FR genes were used as biocatalyst, CDCA (50 mM) was completely converted to 7-keto-LCA with the turnover number of FMN being 227 and 58.8 g ? L?1 ? d?1 space-time yield of 7-keto-LCA. For the reduction of 7-keto-LCA, nicotinamide adenine dinucleotide phosphate (NADPH)-dependent 7-β-hydroxysteroid dehydrogenase (Cm-7β-HSDH) from Clostridium sp. Marseille was employed with alcohol dehydrogenase from Thermoanaerobacter brockii (TbADH) and iso-propanol as co-factor regeneration system. When E. coli whole cells coexpressing Cm-7β-HSDH and TbADH genes were used as biocatalyst, 40 mM 7-keto-LCA was reduced to UDCA with 26.8 g ? L?1 ? d?1 space-time yield. The oxidation and reduction were then carried in a one-pot concurrent mode, 12.5 mM CDCA was completely converted to UDCA. The epimerization of CDCA to UDCA proceeded to completion at the substrate concentration of 30 mM in the one-pot sequential process. Therefore, the complete conversion of CDCA to UDCA in one-pot has been realized by employing 7α-HSDH and 7β-HSDH of different co-factor specificities with independent co-factor recycling systems. The cholic acids, especially UDCA, exert inhibitive effect on the activities of these enzymes, preventing the complete epimerization of 7α-OH at higher substrate loading. This inhibition issue should be solvable by engineering the involved enzymes, that is currently pursued in our laboratory. (Figure presented.).
- Chen, Xi,Cui, Yunfeng,Feng, Jinhui,Wang, Yu,Liu, Xiangtao,Wu, Qiaqing,Zhu, Dunming,Ma, Yanhe
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p. 2497 - 2504
(2019/03/28)
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- NAD+-Dependent Enzymatic Route for the Epimerization of Hydroxysteroids
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Epimerization of cholic and chenodeoxycholic acid (CA and CDCA, respectively) is a notable conversion for the production of ursodeoxycholic acid (UDCA). Two enantiocomplementary hydroxysteroid dehydrogenases (7α- and 7β-HSDHs) can carry out this transformation fully selectively by specific oxidation of the 7α-OH group of the substrate and subsequent reduction of the keto intermediate to the final product (7β-OH). With a view to developing robust and active biocatalysts, novel NADH-active 7β-HSDH species are necessary to enable a solely NAD+-dependent redox-neutral cascade for UDCA production. A wild-type NADH-dependent 7β-HSDH from Lactobacillus spicheri (Ls7β-HSDH) was identified, recombinantly expressed, purified, and biochemically characterized. Using this novel NAD+-dependent 7β-HSDH enzyme in combination with 7α-HSDH from Stenotrophomonas maltophilia permitted the biotransformations of CA and CDCA in the presence of catalytic amounts of NAD+, resulting in high yields (>90 %) of UCA and UDCA.
- Tonin, Fabio,Otten, Linda G.,Arends, Isabel W. C. E.
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p. 3192 - 3203
(2018/11/10)
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- SYNTHESIS OF OBETICHOLIC ACID AND SYNTHESIS INTERMEDIATE
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The present invention relates to a new intermediate for the synthesis of obeticholic acid, the compound of formula (I) or a geometric isomer thereof, a process for obtaining the same, as well as the use of said intermediate in the synthesis of obeticholic acid.
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Page/Page column 35; 36
(2019/10/01)
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- Ketone-7- based cholic acid intermediate as well as preparation method and application thereof (by machine translation)
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The preparation method comprises the 7 - following steps: firstly, carrying out an esterification reaction on pig cholic acid as a starting raw material, and selectively protecting a leaving group 2,2 - through a special space 7 structure of the 6,7 pig cholic acid 3 6 7 - 7 - 7 7 6 α 6 6 7 7 . The method provided by the invention has 7 - the advantages of high purity, simple process flow and no special purification mode in the preparation process, and is suitable for industrial production. (by machine translation)
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- 7-ketolithocholic acid intermediate and preparation process and application thereof
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The invention discloses a 7-ketolithocholic acid intermediate and a preparation process and an application thereof. Hyocholic acid is utilized as a starting material, an esterification reaction is carried out first, then a silane protection group protects a 3-hydroxyl group with high selectivity, then a specific spatial structure of 6,7-hydroxyl group of the hyocholic acid is utilized, a conventional protection method can be selectively connected to a strong leaving group at 6-position to obtain the 7-ketolithocholic acid intermediate, and the 7-ketolithocholic acid intermediate is subjected to oxidation, removal, reduction, and hydrolysis to remove a protection group to obtain a target product 7-ketolithocholic acid. The 7-ketolithocholic acid prepared by the process is high in degree ofpurity, is also simple in process step, enables a synthetize route to be greatly simplified, and enables the industrialization cost to be saved.
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- Process Research and Impurity Control Strategy for Obeticholic Acid, a Farnesoid X Receptor Agonist
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The process to obtain ICH-grade quality obeticholic acid (OCA) was improved, and the overall yield was 25.9%. The critical process parameters were established to reduce or avoid process-related impurities. The formation mechanisms, purge pathways, and control strategies for these impurities were also discussed for the first time. An high-performance liquid chromatography instrument utilizing the charged aerosol detection technique was applied for an impurity content assay in OCA for the first time. The developed process was robust and suitable for manufacturing scale-up.
- Feng, Wei-Dong,Zhuo, Song-Ming,Zhang, Fu-Li
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p. 1979 - 1989
(2019/10/11)
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- Preparation method of ursodesoxycholic acid
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The invention discloses a preparation method of ursodesoxycholic acid. Cholic acid is adopted as a raw material, and the ursodesoxycholic acid is prepared through 3 alpha-hydroxyl selective protection, 7 alpha-hydroxyl selective oxidation, ester group protection, 12 alpha-hydroxyl methanesulfonic acid esterification, 3 and 24 site protecting group selective hydrolysis, eliminating and catalytic hydrogenation. According to the preparation method, the low-cost cholic acid is adopted as the raw material, a synthesizing method is novel, low in cost, high in yield and mild in reaction condition, operation is easy and convenient, environmental friendliness is achieved, and industrial production is convenient.
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- Synthesis method of obeticholic acid and intermediate
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The invention discloses a synthesis method of obeticholic acid and an intermediate. The method specifically comprises seven steps: an oxidation reaction, an esterification reaction, a protection reaction, an Aldol reaction, hydrogenation reduction, hydrolysis and a carbonyl reduction reaction with raw materials including chenodeoxycholic acid, NBS, concentrated sulfuric acid, methanol, sodium iodide, trimethyl silicon chloride, trimethylamine, acetaldehyde, boron trifluoride diethyl etherate, palladium on carbon, hydrogen, NaOH and NaBH4. The synthesis method of obeticholic acid and the intermediate is high in yield, low in cost, environmentally friendly, easy to operate and suitable for industrialization.
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Paragraph 0019-0022
(2018/05/16)
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- STEROID DERIVATIVE FXR AGONIST
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The present invention relates to a compound represented by formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, and relates to applications thereof in the preparation of drugs for treating FXR related diseases.
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Paragraph 0098-0100
(2018/12/13)
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- Continuous Production of Ursodeoxycholic Acid by Using Two Cascade Reactors with Co-immobilized Enzymes
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Ursodeoxycholic acid (UDCA) is an effective drug for the treatment of hepatitis. In this study, 7α-hydroxysteroid dehydrogenase (7α-HSDH) and lactate dehydrogenase (LDH), as well as 7β-hydroxysteroid dehydrogenase (7β-HSDH) and glucose dehydrogenase (GDH), were co-immobilized onto an epoxy-functionalized resin (ES-103) to catalyze the synthesis of UDCA from chenodeoxycholic acid (CDCA). Through optimizing the immobilization pH, time, and loading ratio of enzymes to resin, the specific activities of immobilized LDH-7αHSDH@ES-103 and 7βHSDH-GDH@ES-103 were 43.2 and 25.8 U g?1, respectively, which were 12- and 516-fold higher than that under the initial immobilization conditions. Continuous production of UDCA from CDCA was subsequently achieved by using immobilized LDH-7αHSDH@ES-103 and 7βHSDH-GDH@ES-103 in two serial packed-bed reactors. The yield of UDCA reached nearly 100 % and lasted for at least 12 h in the packed-bed reactors, which was superior to that of the batchwise reaction. This efficient continuous approach developed herein might provide a feasible route for large-scale biotransformation of CDCA into UDCA.
- Zheng, Ming-Min,Chen, Fei-Fei,Li, Hao,Li, Chun-Xiu,Xu, Jian-He
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p. 347 - 353
(2018/02/27)
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- Method for preparing obeticholic acid, ursodeoxycholic acid and 7-ketolithocholicacid
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The invention discloses a method for preparing obeticholic acid, 7-ketolithocholicacid and ursodeoxycholic acid. Cholic acid is used as a raw material for preparing obeticholic acid through selectiveprotection by a 3-alpha-hydroxyl group, selective oxidation of a 7-alpha-hydroxyl group, esterification of a 24th carboxyl group, methanesulfonation of a 12-alpha-hydroxyl group, elimination, hydrolysis, silylation, condensation, hydrolysis, catalytic hydrogenation, carbonyl reduction and other reactions; an intermediate is subjected to catalytic hydrogenation to prepare the 7-ketolithocholicacidand then is reduced to prepare the ursodeoxycholic acid. The method provided by the invention uses cheap cholic acid as the raw material, and has advantages of novel synthesis method, low cost, high yield, mild reaction condition, high simplicity in operation, environmental friendliness and high convenience in industrial production.
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- Synthesis method of intermediate 7-ketolithocholic acid of ursodeoxycholic acid
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The invention discloses a chemical synthesis method of intermediate 7-ketolithocholic acid (3alpha-hydroxy-7-one-5beta-cholestan-2-4-acid) of ursodeoxycholic acid, and belongs to the field of organic chemical synthesis. According to the method, cholic acid is adopted as a material, and is subjected to reactions including selective oxidation of 7alpha-hydroxy, benzyl esterification of a side chain carboxyl group, esterification of 3alpha-hydroxy, methanesulfonic acid esterification of 12alpha-hydroxy, elimination, hydrogenation and hydrolysis to synthesize the intermediate 7-ketolithocholic acid of the ursodeoxycholic acid; the cheap cholic acid is adopted as the material, the synthesis method has the advantages of being novel, low in cost, high in yield and environment-friendly and industrial production is facilitated.
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Paragraph 0116-0117
(2017/08/31)
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- Synthesis method for obeticholic acid intermediate 7-ketolithocholic acid
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The invention discloses a chemical synthesis method for an obeticholic acid intermediate 7-ketolithocholic acid (3alpha-hydroxy-7-keto-5beta-cholestane-24-acid), and belongs to the field of organic chemical synthesis. The method adopts cholic acid as a raw material, and through 7alpha-hydroxyl selective oxidation, side chain carboxyl esterification, 3alpha-hydroxyl etherification, 12alpha-hydroxyl methanesulfonic acid esterification, elimination, hydrogenation, hydrolysis and other reactions, the obeticholic acid intermediate 7-ketolithocholic acid is synthesized. The synthesis method for 7-ketolithocholic acid adopts cheap cholic acid as the raw material, and has the advantages of novel synthesis method, low cost, high yield, environmental friendliness and convenience in industrialized production.
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- Synthetic method of 7-keto-lithocholic acid
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The invention discloses a chemical synthetic method of an intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, and belongs to the field of organic chemical synthesis. According to the chemical synthetic method of the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, cholic acid is adopted as a raw material, and through reactions of selective oxidization of 7alpha-hydroxyl, esterification of side chain carboxyl groups, esterification of 3alpha-hydroxyl, methanesulfonic acid esterification, elimination, hydrogenation, and hydrolysis of 12alpha-hydroxyl, the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid is synthesized. According to the chemical synthetic method of the intermediate 7-keto-lithocholic acid (3alpha-hydroxyl-7-ketone-5beta-cholestane-24-acid) of obeticholic acid, cheap cholic acid is adopted as the raw material, the synthesis method is novel, low in cost, high in yield and environmentally friendly, which facilitates industrialized production.
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- Chenodeoxycholic acid synthesis method
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The invention discloses a chenodeoxycholic acid synthesis method, wherein cholic acid is used as a raw material, and 7[alpha]-hydroxyl selective oxidation, side-chain carboxyl esterification, 3[alpha]-hydroxyl esterification, 12[alpha]-hydroxymethanesulfonic acid esterification, elimination, hydrolysis, reduction and other reactions are performed to prepare the chenodeoxycholic acid. According to the present invention, the chenodeoxycholic acid synthesis method has advantages of simple step, less side reaction, high yield and easily available raw materials, is suitable for industrial production, can solve the problems of high synthesis cost, low yield and the like in the prior art, and is suitable for industrial mass-production.
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- METHODS FOR PREPARATION OF BILE ACIDS AND DERIVATIVES THEREOF
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The present application relates to a method of preparing compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, R1 is H, α-OH, β-ΟΗ, or an oxo group.
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- Synthesis method of obeticholic acid
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The invention discloses a synthesis method of obeticholic acid. The synthesis method takes 3alpha,7alpha-dihydroxyl-5beta-cholestane-24-acid as a starting material and comprises the following steps: carrying out hydroxyl oxidation and carboxylic acid ethyl esterification, and reacting with trimethylsilyl chloride to synthesize silyl enol ether; then enabling the silyl enol ether and acetaldehyde to subject to Mukaiyama hydroxyaldehyde condensation to obtain 6-ethylidene-3alpha-hydroxyl-7-one-5beta-cholestane-24-ethyl; carrying out catalytic hydrogenation, hydroxyl protection and ester group hydrolysis; carrying out selective reduction through sodium borohydride; finally, carrying out de-protection to obtain the obeticholic acid. By optimizing synthesis steps and selecting different protection reagents to protect hydroxyl and carboxyl for a plurality of times, and adopting a selective hydrogenation reduction reaction, the problems in a synthesis reaction of the obeticholic acid that more impurities are caused, a structure is easy to overturn, the yield in a 6alpha-ethylation process is low, purification is difficult to realize and the like are effectively solved; the total yield of an obeticholic acid product is greatly improved; the synthesis method has good economical efficiency and is suitable for industrial production.
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Paragraph 0044; 0045; 0046
(2017/07/21)
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- Method for synthesizing lithocholic acid from chenodeoxycholic acid as raw material
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The invention discloses a method for synthesizing lithocholic acid from chenodeoxycholic acid as a raw material. According to the method, chenodeoxycholic acid is adopted as an initial raw material, and the lithocholic acid is prepared through two steps of synthesis of selective oxidation with 7alpha-OH and Huang Min-lon reduction. The method is low in price and easy in initial raw material obtaining, short in synthesis step, simple in aftertreatment, high in total yield and applicable to industrial production.
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Paragraph 0036; 0037; 0038; 0039
(2017/10/13)
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- Synthetic method of medicine intermediate for treating liver disease
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The invention discloses a synthetic method of a medicine intermediate for treating a liver disease. The intermediate is 3 alpha-hydroxy-7-keto-5 beta-cholanic acid methyl ester (II) and prepared by performing esterification reaction on raw materials such as 3 alpha-hydroxy-7-keto-5 beta-cholanic acid (I), methyl alcohol and sulfuric acid with the mass fraction of 98%. Compared with the prior art, the synthetic method has the advantages that the sulfuric acid directly replaces methane sulfonic acid, strong irritation caused by the methane sulfonic acid is decreased, harm to bodies is reduced, a product is precipitated by tap water, industrial production cost is reduced, 2mol/L sodium hydroxide solution is directly used for adjusting the pH (potential of hydrogen) of a reaction system, dosage is less, no gas is discharged, the danger of stamping is avoided, a crystallization mode is finally optimized, yield is improved, the product is purified, a column purification product is omitted, a crystallization purification product is directly used, operation is simplified while the yield and product purity are improved, time is saved, the yield can reach 96%, and the purity can reach 99%.
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Paragraph 0043-0054
(2017/08/31)
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- A high-purity aobeiAobei cholic acid preparation method (by machine translation)
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The invention relates to a method for preparing high-purity aobeiAobei cholic acid. As shown in formula II compound chenodeoxycholic acid (CDCA) as the starting material, through oxidation, esterification, hydroxyl protection, ethylidene, catalytic hydrogenation, and carbonyl reduction of an ester of a reaction to obtain high-purity aobeiAobei cholic acid. The present invention provides a method of preparing aobeiAobei cholic acid with low toxicity, low pollution, high purity, stereoselectivity is good, there is little impurity content, mild reaction conditions, high safety, production simple operation and the like, and is suitable for industrial production. (by machine translation)
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Paragraph 0051-0053
(2017/07/20)
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- Sulfonylurea derivative and pharmaceutical composition and application thereof
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The invention relates to a preparation method and application of a sulfonylurea compound and a composition containing the same component as FXR and / or TGR5 agonist, the FXR and / or TGR5 agonist is a compound shown as a formula (I), or a pharmaceutically acceptable salt, a solvate, a prodrug, an isomer and a stable isotope derivative thereof. The compounds can be used for treatment of FXR and / or TGR5 mediated diseases including primary biliary cirrhosis, nonalcoholic fatty liver, portal hypertension, bile acid diarrhea and cholestasis, type II diabetes and obesity and other field.
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Paragraph 0138-0141
(2017/04/25)
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- BILE ACID DERIVATIVES AND METHODS FOR SYNTHESIS AND USE
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Provided herein, inter alia, are methods for the preparation of modulators of farnesoid X receptor (FXR), and compositions and uses of the modulators of FXR.
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Paragraph 0409-0410
(2017/12/27)
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- METHODS FOR PREPARATION OF BILE ACIDS AND DERIVATIVES THEREOF
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The present application relates to a method of preparing compounds of Formula (A) or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof.
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Page/Page column 72
(2017/03/08)
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- Process for preparing aobeiAobei cholic acid (by machine translation)
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The invention application discloses a process for preparing aobeiAobei cholic acid, includes the following steps: AB - 1 — AB - 2 — AB - 3 — AB - 4 — AB - 5 — AB - 6 — AB - 7 — AB - 8 — AB - 9 — AB - 10, the preparation process in the process of preparing a simple and highly efficient reaction conditions, so as to ensure that the quality of the final product aobeiAobei cholic acid can be controlled. (by machine translation)
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Paragraph 0059; 0061; 0064; 0065
(2017/07/21)
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- PROCESS FOR PREPARATION OF OBETICHOLIC ACID
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The invention of the present application relates to the process for the preparation of intermediates of obeticholic acid and their conversion to obeticholic acid. The process involves the conversion of compound of formula (VI) to compound of formula (VII) in presence of an organic base.
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Page/Page column 17; 18
(2018/01/17)
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- Single crystal of OCA-E, and preparation method and application thereof
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The invention relates to a single crystal of OCA-E, and a preparation method and application thereof. In the X-ray powder diffraction pattern of the single crystal of OCA-E, characteristic peaks appear when the diffraction angle 2theta is equal to 6.1 DEG, 11.5 DEG, 12.3 DEG, 14.0 DEG, 15.6 DEG, 16.8 DEG, 17.9 DEG, 18.4 DEG, 23.1 DEG and 24.1 DEG. The single crystal has not been reported. According to determination results, the crystal structure of the single crystal belongs to a prismatic crystal system; the space group of the single crystal is P2(1)2(1)2(1); the number Z of molecules in a unit cell is 8; and the single crystal is a light yellow flaky crystal at normal temperature and has good morphology and purity of as high as 99.0%. The preparation method enables OCA-E to be perfectly separated from other impurities and has good reproducibility.
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Paragraph 0025; 0035; 0036
(2017/08/28)
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- Chenodeoxycholic acid method for preparing derivatives of
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The invention relates to a preparing method of a chenodeoxycholic acid derivative, and particularly relates to a preparing method of a compound shown as a formula I. The method includes (1) subjecting a compound shown as a formula 1 to Swern oxidation to obtain a compound shown as a formula 2; (2) subjecting the compound shown as the formula 2 to hydroxy protection to obtain a compound shown as a formula 3; (3) bringing the compound shown as the formula 3 into contact with iodoethane to obtain a compound shown as a formula 4; (4) subjecting the compound shown as the formula 4 to a reduction reaction to obtain a compound shown as a formula 5; and (5) bringing the compound shown as the formula 5 into contact with hydrogen under the existence of palladium/carbon that is a catalyst to obtain the compound shown as the formula I. The method is short in steps, simple in operation, and suitable for industrial production, and raw materials are easily available.
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Paragraph 0036-0038; 0042; 0044
(2018/02/04)
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- Preparation method of 3Alpha-hydrol-7-oxo-5Beta-cholanic acid
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The invention discloses a preparation method of 3Alpha-hydrol-7-oxo-5Beta-cholanic acid. Particularly, in the preparation method, hydrogen peroxide is used as an oxidant to oxidize chenodeoxycholic acid in the presence of an acid catalyst so as to obtain 3Alpha-hydrol-7-oxo-5Beta-cholanic acid, wherein a weight ratio of the chenodeoxycholic acid to the hydrogen peroxide is 1:0.05-0.15. The preparation method has the advantages of mild and safe reaction conditions, operation safety and controllability, low cost, high yield, low pollution and the like and has a promising development and application prospect.
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Paragraph 0019; 0020; 0021
(2016/11/28)
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- Preparation method for obeticholic acid and intermediate thereof
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The invention relates to a preparation method for obeticholic acid and an intermediate thereof. The intermediate 3alpha-hydroxy-6alpha-ethyl-7-keto-5beta-cholanic acid is obtained by subjecting 3alpha-hydroxy-6-ethylidene-7-keto-5beta-cholanic acid benzyl ester compounds to a reaction under the action of a catalyst and a hydrogen donor. The catalyst is selected from Pd/C or PtO2 or Raney Ni. The hydrogen donor is selected from cyclohexene or cyclohexadiene or tetrahydronaphthalene. According to the method, the yield is high, the stereoselectivity is high, safety is good, the reaction condition is mild, and the method is applicable to industrial production.
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Paragraph 0037; 0038; 0039
(2016/10/17)
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- SULFONYLAMINOCARBONYL DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USES THEREOF
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This disclosure is related to a sulfonylaminocarbonyl derivative of formula (I) and/or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the sulfonylaminocarbonyl derivatives of formula (I) and/or a pharmaceutically acceptable salt thereof, preparation methods thereof, and use thereof in treating FXR and/or TGR5 mediated diseases, including primary biliary cirrhosis, nonalcoholic fatty liver, portal hypertension, bile acid diarrhea and cholestasis, type II diabetes and obesity, etc.
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Page/Page column 23
(2016/11/17)
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- Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease
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Metabolic disorders such as diabetes are known risk factors for developing cholesterol gallstone disease (CGD). Cholesterol gallstone disease is one of the most prevalent digestive diseases, leading to considerable financial and social burden worldwide. Ursodeoxycholic acid (UDCA) is the only bile acid drug approved by FDA for the non-surgical treatment of gallstones. However, the molecular link between UDCA and CGD is unclear. Previous data suggest that the farnesoid X receptor (FXR), a bile acid nuclear receptor, may protect against the development of CGD. In studies aimed at identifying the role of FXR, we recently identify a novel chemical tool, 6EUDCA (6-αethyl-ursodeoxycholic acid), a synthetic derivative of UDCA, for studying FXR. We found that 6EUDCA binds FXR stronger than UDCA in a TR-FRET binding assay. This result was supported by computational docking models that suggest 6EUDCA forms a more extensive hydrogen bound network with FXR. Interestingly, neither compound could activate FXR target genes in human nor mouse liver cells, suggesting UDCA and 6EUDCA activate non-genomic signals in an FXR-dependent manner. Overall these studies may lead to the identification of a novel mechanism by which bile acids regulate cell function, and 6EUDCA may be an effective targeted CGD therapeutic.
- Yu, Donna D.,Andrali, Sreenath S.,Li, Hongzhi,Lin, Min,Huang, Wendong,Forman, Barry M.
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p. 3986 - 3993
(2016/08/23)
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- Chenodeoxycholic acid compound and preparation method and application thereof
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The invention discloses a compound with a structural formula (I) and a pharmaceutically-acceptable salt, solvate or amino acid conjugate thereof (shown in the description). Six substituent groups are respectively located at alpha or beta positions, the R1 represents COOH or OSO3H, and the R2 represents a halogen alkyl group, a naphthenic base, a naphthenic-alkyl group, a heterocyclic group, a heterocyclic-alkyl group, a heterocyclic aryl group, a heterocyclic aryl-alkyl group, an acyl group or an alkoxyalkyl group.
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Paragraph 0022
(2016/10/07)
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- Synthetic method of 6-ethylchenodeoxycholic acid
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The invention discloses a synthetic method of 6-ethylchenodeoxycholic acid. The synthetic method comprises steps as follows: chenodeoxycholic acid and an oxidizing agent are subjected to an oxidizing reaction and an esterification reaction, and a compound with a structure represented as a formula III is prepared; hydroxyl and carbonyl on rings of the compound with the structure represented as the formula III are protected with tert-butyldimethylsilyl chloride, and a compound with a structure represented as a formula IV is obtained; the compound with the structure represented as the formula IV and paraldehydeare are subjected to an electrophilic addition reaction and then are subjected to deprotection, and a compound with a structure represented as a formula V is obtained; the compound with the structure represented as the formula V is subjected to catalytic hydrogenation and is subjected to reduction and hydrolysis finally, and the compound 6-ethylchenodeoxycholic acid with a structure represented as a formula VI is obtained. The method is simple and convenient to operate, adopts mild conditions, has higher yield and is suitable for being popularized to industrial production.
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Paragraph 0045; 0046
(2017/01/02)
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- DEUTERATED BILE ACIDS
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This disclosure relates to deuterated bile acid compositions. A deuterated compound is selected from the disclosed groups of bile acids and their derivatives, analogs and salts. At least one of the hydrogen atoms in the compound is replaced with deuterium.
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- Two-step enzymatic synthesis of ursodeoxycholic acid with a new 7β-hydroxysteroid dehydrogenase from Ruminococcus torques
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7β-Hydroxysteroid dehydrogenase (7β-HSDH) is a key enzyme for the efficient biosynthesis of ursodeoxycholic acid (UDCA), an effective pharmaceutical for primary biliary cirrhosis and human cholesterol gallstones. In this work, a new 7β-HSDH from Ruminococcus torques ATCC 35915, designated as 7β-HSDHRt, was identified and heterologously overexpressed in Escherichia coli for the enzymatic synthesis of ursodeoxycholic acid from chenodeoxycholic acid (CDCA). 7β-HSDHRt was firstly employed in one-pot mode together with 7α-HSDHCa, another NADPH-dependent 7α-HSDH from Clostridium absonum, to convert CDCA into UDCA without additional coenzyme regeneration. However, the final yield was limited to merely 73%, probably due to chemical equilibrium. Therefore, to enhance the UDCA yield, we alternatively adopted a two-step reaction strategy where the enzymes involved in the first reaction were simply heat-inactivated between the 1st-step reaction (dehydrogenation) and the 2nd-step reaction (hydrogenation), in order to prevent the undesired bioreduction of 7-oxo-LCA into CDCA in the 2nd step. Consequently, the analytic yield of UDCA was significantly improved up to above 98% at a substrate load of 10 mM (ca. 4 g L-1), without any detectable intermediate (7-oxo-LCA) as observed in the case of one-pot reaction.
- Zheng, Ming-Min,Wang, Ru-Feng,Li, Chun-Xiu,Xu, Jian-He
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p. 598 - 604
(2015/03/04)
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- PROCESS FOR PREPARING HIGH PURITY URSODEOXYCHOLIC ACID
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The present invention describes a process for the synthesis of ursodeoxycholic acid wherein the purification of the crude ursodeoxycholic acid (containing approximately 13-15% of chenodeoxycholic acid impurity) takes place first passing through a salification with imidazole and a subsequent purification via "methyl ester", which allows a finished product with an extremely low content of known "cheno and "litho" impurities to be obtained. The present invention also describes the recovery steps of cholic acid and 3α-hydroxy-7-ketocholanic acid from the mother liquors of process intermediates.
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Page/Page column 5; 9; 10
(2014/02/16)
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- Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors
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Bile acids exert genomic and nongenomic effects by interacting with membrane G-protein-coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions; thus, GP-BAR1/FXR dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.
- D'Amore, Claudio,Di Leva, Francesco Saverio,Sepe, Valentina,Renga, Barbara,Del Gaudio, Chiara,D'Auria, Maria Valeria,Zampella, Angela,Fiorucci, Stefano,Limongelli, Vittorio
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p. 937 - 954
(2014/03/21)
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- Hydroxylation of lithocholic acid by selected actinobacteria and filamentous fungi
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Selected actinobacteria and filamentous fungi of different taxonomy were screened for the ability to carry out regio- and stereospecific hydroxylation of lithocholic acid (LCA) at position 7β. The production of ursodeoxycholic acid (UDCA) was for the first time shown for the fungal strains of Bipolaris, Gibberella, Cunninghamella and Curvularia, as well as for isolated actinobacterial strains of Pseudonocardia, Saccharothrix, Amycolatopsis, Lentzea, Saccharopolyspora and Nocardia genera. Along with UDCA, chenodeoxycholic (CDCA), deoxycholic (DCA), cholic (CA), 7-ketodeoxycholic and 3-ketodeoxycholic acids were detected amongst the metabolites by some strains. A strain of Gibberella zeae VKM F-2600 expressed high level of 7β-hydroxylating activity towards LCA. Under optimized conditions, the yield of UDCA reached 90% at 1 g/L of LCA and up to 60% at a 8-fold increased substrate loading. The accumulation of the major by-product, 3-keto UDCA, was limited by using selected biotransformation media.
- Kollerov,Monti,Deshcherevskaya,Lobastova,Ferrandi,Larovere,Gulevskaya,Riva,Donova
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p. 370 - 378
(2013/03/28)
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- Conicasterol E, a small heterodimer partner sparing farnesoid X receptor modulator endowed with a pregnane X receptor agonistic activity, from the marine sponge Theonella swinhoei
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We report the isolation and pharmacological characterization of conicasterol E isolated from the marine sponge Theonella swinhoei. Pharmacological characterization of this steroid in comparison to CDCA, a natural FXR ligand, and 6-ECDCA, a synthetic FXR agonist generated by an improved synthetic strategy, and rifaximin, a potent PXR agonist, demonstrated that conicasterol E is an FXR modulator endowed with PXR agonistic activity. Conicasterol E induces the expression of genes involved in bile acids detoxification without effect on the expression of small heterodimer partner (SHP), thus sparing the expression of genes involved in bile acids biosynthesis. The relative positioning in the ligand binding domain of FXR, explored through docking calculations, demonstrated a different spatial arrangement for conicasterol E and pointed to the presence of simultaneous and efficient interactions with the receptor. In summary, conicasterol E represents a FXR modulator and PXR agonist that might hold utility in treatment of liver disorders.
- Sepe, Valentina,Ummarino, Raffaella,Dauria, Maria Valeria,Chini, Maria Giovanna,Bifulco, Giuseppe,Renga, Barbara,Damore, Claudio,Debitus, Cécile,Fiorucci, Stefano,Zampella, Angela
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experimental part
p. 84 - 93
(2012/03/26)
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- NOVEL METHOD OF SYNTHESIZING ALKYLATED BILE ACID DERIVATIVES
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A novel, improved method of synthesizing alkylated bile acid derivatives is provided. Such derivatives include, but are not limited to the active, potent, and selective FXR receptor agonist such as 6-ECDCA and other CA, DCA and CDCA derivatives. The first step of the synthesis selectively oxidates CDCA, CD, or DCA related starting material. An efficient combined deprotonation, trapping, ethylation, deprotection and reduction system is used to produce the desired alkylated bile acid derivatives. This practical synthesis offers a simple and economical pathway suitable for a large-scale manufacturing of alkylated bile acid derivatives including, but not limited to, 6-ECDCA.
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Page/Page column 3
(2009/04/24)
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- Chemical synthesis of 3β-sulfooxy-7β-hydroxy-24-nor-5-cholenoic acid: An internal standard for mass spectrometric analysis of the abnormal Δ5-bile acids occurring in Niemann-Pick disease
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In Niemann-Pick disease, type C1, increased amounts of 3β,7β-dihydroxy-5-cholenoic acid are reported to be present in urinary bile acids. The compound occurs as a tri-conjugate, sulfated at C-3, N-acetylglucosamidated at C-7, and N-acylamidated with taurine or glycine at C-24. For sensitive LC-MS/MS analysis of this bile acid, a suitable internal standard is needed. We report here the synthesis of a satisfactory internal standard, 3β-sulfooxy-7β-hydroxy-24-nor-5-cholenoic acid (as the disodium salt). The key reactions involved were (1) the so-called "second order" Beckmann rearrangement (one-carbon degradation at C-24) of hyodeoxycholic acid (HDCA) 3,6-diformate with sodium nitrite in a mixture of trifluoroacetic anhydride and trifluoroacetic acid, (2) simultaneous inversion at C-3 and elimination at C-6 of the ditosylate derivatives of the resulting 3α,6α-dihydroxy-24-nor-5β-cholanoic acid with potassium acetate in aqueous N,N-dimethylformamide, and (3) regioselective sulfation at C-3 of an intermediary 3β,7β-dihydroxy-24-nor-Δ5 derivative using sulfur trioxide-trimethylamine complex. Overall yield of the desired compound was 1.8% in 12 steps from HDCA.
- Kakiyama, Genta,Muto, Akina,Shimada, Miki,Mano, Nariyasu,Goto, Junichi,Hofmann, Alan F.,Iida, Takashi
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scheme or table
p. 766 - 772
(2009/09/05)
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