- 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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- Fluorescent Sensors for Molecules Guest-Responsive Monomer and Excimer Fluorescence of 6A,6B-; 6A,6C-; 6A,6D-; and 6A,6E-Bis(2-naphthylsulfonyl)-γ-cyclodextrins
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Flexible hosts, 6A,6B-; 6A,6C-; 6A,6D-; and 6A,6E-bis(2-naphthylsulfonyl)-γ-cyclodextrins (γ-1, γ-2, γ-3, and γ-4, respectively) were used as fluorescent sensors with which a variety of organic compounds were detected by naphthalene excimer and monomer emissions. In a 10 vol% ethylene glycol aqueous solution, γ-1 exhibits almost pure monomer fluorescence while γ-2, γ-3, and γ-4 exhibit both monomer and excimer emissions. The intensities of the emissions changed upon addition of guest species, particularly in the case of γ-2 and γ-3, and the guest-induced intensity variations were used as sensitivity factors of the sensors. When (-)-borneol (5), cyclohexanol (6), cyclododecanol (7), and 1-adamantanecarboxylic acid (8) were added to each host solution, γ-2, γ-3, and γ-4 increased the excimer emission intensity but decreased the monomer one, the absolute intensity variations being 6 5≈8 1. When geraniol (9), nerol (10), and (-)-menthol (11) were added, the hosts decreased intensities in both monomer and excimer emissions for 9 and 10 while their emission variations for 11 were similar to those of 5. For steroids such as cholic acid (12), deoxycholic acid (13), chenodeoxycholic acid (14), and ursodeoxycholic acid (15), γ-4 showed depression in the excimer emission and enhancement in the monomer one while γ-2 and γ-3 showed complicated features in which the excimer emission was enhanced with the order of 15 14 13≈12 but the monomer one was depressed or enhanced depending on the hosts. All these data demonstrate that the hosts can be used as sensors for molecular recognition.
- Hamada, Fumio,Minato, Shingo,Osa, Tetsuo,Ueno, Akihiko
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- Regioselective oxidation of cholic acid and its 7β epimer by using o-iodoxybenzoic acid
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Rational exploration directed by DFT (density functional theory) based atomic Fukui indices, lead to development of regioselective oxidation of cholic acid and its 7β epimer by o-iodoxybenzoic acid. In case of cholic acid only, 7α-hydroxyl underwent oxidation, where as in its 7β epimer the selectivity was towards 12α-hydroxy group. Since these oxidations are the key steps in synthesis of ursodeoxycholic acid starting from cholic acid these findings may be useful in devising a protection free synthetic route.
- Dangate, Prasad S.,Salunke, Chetan L.,Akamanchi, Krishnacharya G.
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- 7α- and 12α-Hydroxysteroid dehydrogenases from Acinetobacter calcoaceticus lwoffii: a new integrated chemo-enzymatic route to ursodeoxycholic acid
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We report the very efficient biotransformation of cholic acid to 7-keto- and 7,12-diketocholic acids with Acinetobacter calcoaceticus lwoffii. The enzymes responsible of the biotransformation (i.e. 7α- and 12α-hydroxysteroid dehydrogenases) are partially purified and employed in a new chemo-enzymatic synthesis of ursodeoxycholic acid starting from cholic acid. The first step is the 12α-HSDH-mediated total oxidation of sodium cholate followed by the Wolf-Kishner reduction of the carbonyl group to chenodeoxycholic acid. This acid is then quantitatively oxidized with 7α-HSDH to 7-ketochenodeoxycholic acid, that was chemically reduced to ursodeoxycholic acid (70% overall yield).
- Giovannini, Pier Paolo,Grandini, Alessandro,Perrone, Daniela,Pedrini, Paola,Fantin, Giancarlo,Fogagnolo, Marco
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- 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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- An effective synthesis of ursodeoxycholic acid from dehydroepiandrosterone
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A novel synthetic route of producing ursodeoxycholic acid (UDCA) was developed through multiple reactions from plant-source dehydroepiandrosterone (DHEA), with a Mistunobu reaction and regioselective allyl oxidationat as the key steps. The reaction conditions of the key allyl oxidation reaction were also investigated and optimized, including solvent, oxidant and reaction temperature. In this novel route for the preparation of UDCA, most of the reaction steps have high conversions and overall yield up to 35% for 8 steps. Since all starting materials are cost-effective, commercially available and effectively avoided the risk of animal derived raw materials, this promising synthetic route offers economical and efficient strategies for potential production of UDCA.
- Chen, Wang,Hu, Daihua,Feng, Zili,Liu, Zhaopeng
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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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- 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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- 7α-OH epimerisation of bile acids via oxido-reduction with Xanthomonas maltophilia
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The microbial 7α-OH epimerisation of cholic, chenodeoxycholic, and 12-ketochenodeoxycholic acids (7α-OH bile acids) with Xanthomonas maltophilia CBS 827.97 to corresponding 7β-OH derivatives with scarcity of oxygen is described. With normal pressure of oxygen the 7-OH oxidation products are obtained. No biotransformations are achieved in anaerobic conditions. The microbial 7α-OH epimerisation is achieved by oxidation of 7-OH function and subsequent reduction. Partial purification, in fact, of the enzymatic fraction revealed the presence of two hydroxysteroid dehydrogenases (HSDH) α- and β-stereospecific together with a glycocholate hydrolase. On the basis of these results a further application is the microbial reduction of 6α-fluoro and 6β-fluoro-3α-hydroxy-7-oxo-5β-cholan-24-oic acid methyl esters to the corresponding 7α-OH and 7β-OH derivatives.
- Medici, Alessandro,Pedrini, Paola,Bianchini, Ercolina,Fantin, Giancarlo,Guerrini, Alessandra,Natalini, Benedetto,Pellicciari, Roberto
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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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- A Facile Route to Ursodeoxycholic Acid Based on Stereocontrolled Conversion and Aggregation Behavior Research
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A facile route to ursodeoxycholic acid (UDCA) and its aggregation behavior in aqueous phase solution, which is rarely known, are reported. The starting material, hyodeoxycholic acid (HDCA), is a relatively less expensive material and more easily obtained compared with chenodeoxycholic acid (CDCA). A facile route was developed to synthesize UDCA from HDCA with a Shapiro reaction as the key step and in 26% overall yield. A new strategy using organosilane reagent considering its stability, nontoxicity, and abundance in nature was carried out for a more rapid route and higher yield. It was found that the critical micelle concentration value, which is a critical value for surfactants of bile salts, was influenced by the number of hydroxyl groups.
- Dou, Qian,Jiang, Zhongliang
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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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- Synthesis of ursodeoxycholic acid from plant-source (20S)-21-hydroxy-20-methylpregn-4-en-3-one
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A novel synthetic route of producing ursodeoxycholic acid (UDCA) was developed through multiple reactions from cheap and commercially available bisnoralcohol (BA). The key reaction conditions, including solvents, bases and reaction temperatures of the route were investigated and optimized. In the straightforward route for preparation of UDCA, most of the reaction steps have high conversions with average yields of 91%, and overall yield up to 59% (6 steps) from the plant-source BA. Especially in the last step of reduction and hydrolysis, there are five functional groups converted with calcd 97% per conversion in one-pot reaction. This promising route offers economical and efficient strategies for potential large-scale production of UDCA.
- Gu, Xiang-Zhong,He, Li-Ming,Li, Chen-Chen,Qiu, Wen-Wei,Wang, Jie
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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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- Microbial 7-OH epimerisation of bile acids
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The microbial 7-OH epimerisation of cholic and chenodeoxycholic acids with Xanthomonas maltophilia CBS 827.97 to ursocholic and ursodeoxycholic acids with scarsity of oxygen is described. With normal pressure of oxygen the 7-ketocholic and the 7-ketochenodeoxycholic acids are obtained. No biotransformation is achieved in anaerobic conditions.
- Dean, Mariangela,Fantin, Giancarlo,Fogagnolo, Marco,Medici, Alessandro,Pedrini, Paola,Poli, Silvia
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- STEREOCHEMISTRY OF REDUCTION OF CYCLIC KETONES BY ALKALI METALS AND BY SODIUM DITHIONITE.
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An opposite stereoselectivity is observed in the reduction of 3α-hydroxy-5β-7-oxo-cholanic acid by alkali metals and by sodium dithionite, contrary to the results reported with other cyclic or bicyclic ketones.An electron-transfer mechanism followed by coupling of the ketyl radical with SO2(1-). is suggested for the reduction by sodium dithionite.
- Castaldi, Graziano,Perdoncin, Giulio,Giordano, Claudio
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- Purification method of ursodesoxycholic acid
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The invention discloses a purification method of ursodesoxycholic acid. The purification method comprises the following steps: step A, preparing 4-dimethyl pyridine ammonium salt of ursodesoxycholic acid; and step B, performing hydrolysis of 4-dimethyl pyridine ammonium salt of ursodesoxycholic acid. The method is simple and convenient to operate, the used solvent and reagent are cheap and easy to obtain, the method is suitable for industrial production, and the obtained ursodesoxycholic acid is high in purity.
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Paragraph 0071-0082
(2021/10/11)
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- METHOD FOR PREPARING BILE ACID DERIVATIVE BY USING CONTINUOUS FLOW REACTION
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Provided herein is a method of preparing a bile acid derivative using a continuous flow reaction. When bile acid derivatives are synthesized using a continuous flow reaction according to the present invention, the reaction is very safe compared to an existing batch-type reaction, the reaction time is significantly reduced, and high-quality bile acid derivatives may be synthesized with high efficiency. In particularly, according to the present invention, a hydrogenation reaction proceeds under substantially water-free reaction conditions, and thus the conversion rate (UDCA:CDCA) of a UDCA hydrogenation reaction may be significantly enhanced.
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Paragraph 0070-0082
(2020/09/22)
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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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- 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 0024-0027
(2020/06/24)
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- Method for synthesizing ursodeoxycholic acid by taking BA as raw material
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The invention discloses a synthesis method of ursodeoxycholic acid, and the method comprises the following steps: by using a botanical compound BA as a raw material, carrying out ethylene glycol protection, oxidation, side chain extension reaction, ethylene glycol removal protection, reduction, hydrolysis and the like to synthesize the ursodeoxycholic acid. Raw materials for synthesizing the ursodeoxycholic acid are cheap and easy to obtain, synthesis steps are easy and convenient to operate, the yield is high, environmental friendliness is achieved, and industrial production is facilitated.
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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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Paragraph 0136; 0143-0145
(2019/05/08)
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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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Paragraph 0152; 0189-0191
(2018/11/03)
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- A facile synthesis of ursodeoxycholic acid and obeticholic acid from cholic acid
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A novel synthetic route of producing ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) was developed through multiple reactions from cheap and readily-available cholic acid. The reaction conditions of the key elimination reaction of mesylate ester group were also investigated and optimized, including solvent, base and reaction temperature. In the straightforward synthetic route for preparation of UDCA and OCA, most of the reaction steps have high conversions with average yields of 94% and 92%, and overall yield up to 65% (7 steps) and 36% (11 steps) from cholic acid, respectively. This promising route offers economical and efficient strategies for potential large-scale production of UDCA and OCA.
- He, Xiao-Long,Wang, Li-Ting,Gu, Xiang-Zhong,Xiao, Jie-Xin,Qiu, Wen-Wei
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p. 173 - 178
(2018/11/10)
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- Method for preparing ursodeoxycholic acid
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The invention provides a method for preparing ursodeoxycholic acid; with 7-carbonyl lithocholic acid ester as a raw material, a zinc powder/ammonium formate system is used for catalytic hydrogenation,hydrolysis and recrystallization to prepare ursodeoxycholic acid; the reaction routes and the process conditions are optimized, and the purity and the yield of the product are improved.
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Paragraph 0006; 0026; 0027
(2018/03/25)
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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 0415-0417
(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 (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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- A synthesis method of ursodeoxycholic acid (by machine translation)
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The invention discloses a method for synthesizing of ursodeoxycholic acid, the cholic acid as the raw material, after 7 α - hydroxy selective oxidation, side chain carboxyl ester, 3 α - hydroxy ester, 12 α - hydroxy methanesulfonic acid esterification, elimination, hydrolysis, reduction of synthesis of ursodeoxycholic acid. The invention of ursodeoxycholic acid synthesis method, simple steps, less side reaction, high yield, raw materials are easy, is suitable for industrial production, solved in the prior art synthesis cost high, the yield is low and the like, and has a wide application. (by machine translation)
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- Method for preparing ursodeoxycholic acid
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The invention belongs to the field of medicine, and particularly relates to a method for preparing an ursodeoxycholic acid. The method comprises the following steps: performing esterification reaction to obtain a compound shown in formula II by taking an HDCA (hyodeoxycholic acid) as a starting raw material; performing selective hydroxy protection reaction to obtain a compound shown in formula III; performing hydroxy protection reaction to obtain a compound shown in formula IV; performing elimination reaction to obtain a compound shown in formula V; performing oxidation reaction on the compound shown in formula V under the action of tert-butyl hydroperoxide and pyridinium chlorochromate to obtain a compound shown in formula VI; performing hydrolysis to obtain a compound shown in formula VII; performing reduction to obtain the ursodeoxycholic acid shown in formula I. According to the method, the ursodeoxycholic acid is prepared by taking the HDCA as the starting raw material, so that not only can the problem of raw material shortage be solved, but also the method is convenient to operate, low in byproduct rate and cost, mild in reaction condition and suitable for large-scale production of the ursodeoxycholic acid.
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Paragraph 0081; 0082; 0083; 0084; 0085
(2017/07/20)
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- Method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through copper-carrying active carbon catalytic oxidation-reduction method
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The invention discloses a method for synthesizing ursodeoxycholic acid from chenodeoxycholic acid through a copper-carrying active carbon catalytic oxidation-reduction method. Adopted copper-carrying active carbon efficiently promotes an oxidation-reduction reaction of chenodeoxycholic acid methyl ester under the adsorption of active carbon and the catalysis of copper. According to the preparing method, under the catalysis of copper-carrying active carbon, reaction conditions are mild, and reaction efficiency is high. The purity of ursodeoxycholic acid prepared through the preparing method is high and can reach 98% or above, and the yield of ursodeoxycholic acid is 53% or so.
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Paragraph 0059; 0060
(2016/10/24)
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- Method for synthesizing ursodesoxycholic acid with chenodeoxycholic acid by photochemical method
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The invention discloses a method for synthesizing ursodesoxycholic acid with chenodeoxycholic acid by a photochemical method. The method comprises the following steps: preparing chenodeoxycholic acid methyl ester, preparing 3alpha-hydroxyl-7-keto-5beta-methyl cholanate by a photochemical oxidation process, preparing ursodesoxycholic acid methyl ester by a photochemical reduction method, and preparing ursodesoxycholic acid. The method mainly uses the photochemical method for converting chenodeoxycholic acid to ursodesoxycholic acid, the method has the advantages of mild reaction condition, high reaction efficiency and high selectivity; and the prepared ursodesoxycholic acid has the advantages of high yield, high purity and stable quality.
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Paragraph 0029; 0030; 0043; 0044
(2016/11/21)
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- A process for the preparation of ursodesoxycholic acid (by machine translation)
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A process for the preparation of ursodeoxycholic acid, relates to biochemical field of pharmacy. A prior art method for preparing ursodeoxycholic acid during the reduction reaction in the hydrogenation of the stereo-selectivity is poor, and the method for producing the route is long, the product yield is high, relatively poor quality of the product. The invention comprises the following steps: the 7-keto deoxycholic acid is dissolved in a solvent, adding chiral catalyst, under alkaline conditions, the pressure-keeping 0-20MPa, the hydrogen gas 15-81 °C hydrogenation reduction reaction is carried out, after the completion of reaction solvent; adding 13-95 times purified water, then adding acid after the hydrogenation reduction reaction of the crystalline product; separating the solid and liquid, after washing, drying, the resulting solid powder is ursodeoxycholic acid. Short production line of this invention, high product yield, the product quality is good. (by machine translation)
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Paragraph 0027; 0028
(2016/10/27)
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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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- CO2 incubator ozone sterilization device
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PROBLEM TO BE SOLVED: To provide an apparatus that ensures sterilization of a COincubator, has no leakage of fed ozone gas to the outside, uniformly circulates ozone in a storage and constantly and continuously controls an ozone concentration.SOLUTION: The apparatus for ozone sterilization of a COincubator includes: a sterilization tent 1 with an airtight hole 8a for airtightly protruding a leading end part of a tube connection part 14a provided in the COincubator 11 to the outside and a discharge part 9a for discharging ozone gas to the outside, for covering the COincubator 11 airtightly; an ozone gas generator 18 for applying circulating sterilization to the inside and the outside of the COincubator 11 covered by the sterilization tent 1 by pressure-feeding the ozone gas to the tube connection part 14a; and an ozone gas neutralization unit 26 for neutralizing and eliminating the ozone gas discharged from the discharge part 9a.
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- OPHTHALMIC COMPOSITIONS COMPRISING dDC
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A composition comprising dDC and a polymer, wherein the composition is an aqueous liquid with a viscosity which increases upon contact with a surface of an eye is disclosed herein. An aqueous composition comprising a therapeutically effective concentration of dDC, wherein the concentration of dDC is less than 1% is also disclosed. An eye drop comprising a therapeutically effective amount of dDC, wherein the amount of dDC is less than 300 μg is also disclosed. A method comprising administering an effective amount of dDC topically to an eye of a person suffering from viral conjunctivitis a viral infection, wherein less than 300 μL of dDC is administered to said eye is also disclosed. A kit comprising a composition and a dispenser, wherein said dispenser dispenses a drop comprising a therapeutically effective amount of dDC, wherein the amount of dDC is less than 300 μg is also disclosed.
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- Xanthomonas maltophilia CBS 897.97 as a source of new 7β- and 7α-hydroxysteroid dehydrogenases and cholylglycine hydrolase: Improved biotransformations of bile acids
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The paper reports the partial purification and characterization of the 7β- and 7α-hydroxysteroid dehydrogenases (HSDH) and cholylglycine hydrolase (CGH), isolated from Xanthomonas maltophilia CBS 897.97. The activity of 7β-HSDH and 7α-HSDH in the reduction of the 7-keto bile acids is determined. The affinity of 7β-HSDH for bile acids is confirmed by the reduction, on analytical scale, to the corresponding 7β-OH derivatives. A crude mixture of 7α- and 7β-HSDH, in soluble or immobilized form, is employed in the synthesis, on preparative scale, of ursocholic and ursodeoxycholic acids starting from the corresponding 7α-derivatives. On the other hand, a partially purified 7β-HSDH in a double enzyme system, where the couple formate/formate dehydrogenase allows the cofactor recycle, affords 6α-fluoro-3α, 7β-dihydroxy-5β-cholan-24-oic acid (6-FUDCA) by reduction of the corresponding 7-keto derivative. This compound is not obtainable by microbiological route. The efficient and mild hydrolysis of glycinates and taurinates of bile acids with CGH is also reported. Very promising results are also obtained with bile acid containing raw materials.
- Pedrini, Paola,Andreotti, Elisa,Guerrini, Alessandra,Dean, Mariangela,Fantin, Giancarlo,Giovannini, Pier Paolo
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p. 189 - 198
(2007/10/03)
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- Preparative separation of steroids by reverse phase HPLC
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Budesonide C22R epimer is more active than C22S epimer. In so far the preparative separation of the two molecules from the mixture has not been made suitable at industrial level. The present invention describes the procedure to separate at preparative scale the epimers of certain synthetic steroid mixture. The present invention has based on isocratic reverse phase HPLC method and some devices as the procedure to dissolve the mixture and load it on the column, the choice of solvent and the physic-chemical condition of the chromatography, the recovery of the solvents. The whole of these devices to make the process to separate epimers from steroid mixtures, practicable at industrial level. More in particular the present invention describes the separation of the (22 R, S) 16α,17α-butyldenedioxy-11β, 21-dihydroxypregna-1,4-diene-3,20-dione (Budesonide), at preparative scale, into C22R and C22S epimers. The Budesonide has dissolved in a some organic solvent and each epimer has eluted in a water solution, permitting a highly easily recovery of the molecules also useful to pharmaceutical formulations.
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- Biodegradable polanhydrides derived from dimers of bile acids, and use thereof as controlled drug release systems
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New biodegradable polyanhydrides are disclosed, which are prepared by homopolymerization of dimer of bile acid, especially lithocholic acid, or bycopolymerization with linear dicarboxylic acid, especially sebacic acid. These biodegradable polyanhydrides have degradation kinetics and a release rate that make them particularly useful for controlled drug release. More specifically, the degradation kinetics of such anhydrides and the release rate of molecules embedded therein make them useful as matrices for controlled drug release systems. The rates of degradation and release can be adjusted by the copolymer composition. The near zero-order kinetrics of release of the drug embedded in the matrices made of such anhydrides, make the same particularly useful since they can deliver an active ingredient at a constant rate for long period of time, avoiding the inauspicious saw-tooth pattern of conventional systemic administration.
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- Compositions containing salts of bile acid-aminosalicylate conjugates
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Disclosed are compositions containing bile acid-aminosalicylate conjugates having the formula, or a pharmaceutically acceptable salt thereof STR1 wherein R1 is OH either the α or the β position; R2 is OH; R3 is H or OH; and R4 is H or acetyl, the process for their preparation and method of treating/preventing gastrointestinal disorders, impaired liver function, autoimmune diseases of the liver and biliary tract, colon cancer, inflammatory bowel diseases, Crohn's disease, cystic fibrosis, dissolving gallstones, and regulating dietary cholesterol absorption by administering said compositions to a mammal in need of such treatment.
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- Stereocontrolled Conversion of Hyodeoxycholic Acid into Chenodeoxycholic Acid and Ursodeoxycholic Acid
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The first conversion of methyl hyodeoxycholanate into methyl chenodeoxycholanate and ursodeoxycholic acid in a stereocontrolled manner, by means of a 1,2-carbonyl transposition.
- Zhou, Wei-Shan,Wang, Zhong-Qi,Jiang, Biao
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- Stereoselective reduction of the keto group at 7-position of a bile keto acid
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The keto group at 7-position of a bile keto acid is stereoselectively reduced to beta-hydroxy group with hydrogen in the presence of nickel, of a base the quantity of which is of at least 0.3 mole to each mole of keto acid, and of an alcohol, having from 3 to 10 C atoms, selected from the group consisting of secondary alcohols, tertiary alcohols and beta-branched alcohols.
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- Process for preparing high purity ursodeoxycholic acid
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A process for preparing very pure ursodeoxycholic acid starting from cholic acid (I) by: (a) selectively oxidizing it to 3 alpha, 12 alpha-dihydroxy-7-ketocholanic acid (II) (b) reducing acid (II) to 3 alpha, 7 beta, 12 alpha-trihydroxy-cholanic acid (III) (c) oxidizing a 3,7-ester of acid (III) to 3 alpha, 7 beta-dihydroxy-12-keto-5-beta-cholanic acid (IV) by treatment with hypochlorite followed by hydrolysis (d) preparing the tris-trimethylsilyl derivative of acid (IV) (e) eliminating the trimethylsilyl groups (f) reducing the very pure acid (IV) by the Wolff-Kishner method to ursodeoxycholic acid. Alternatively, the Wolff-Kishner method can be applied directly to the tris-trimethylsilyl derivative, and the trimethylsilyl groups can be eliminated from the final product.
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- Process for preparing high purity ursodeoxycholic acid
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A process for preparing 3α, 7β-dihydroxy-cholanic acid (I) from 3α, 7α-dihydroxy-Δ11 -cholenic acid. This starting substance is converted by oxidation and successive reduction into 3α, 7β-dihydroxy-Δ11 -cholenic acid, which is separated in the form of the tris-trimethylsilyl derivative of high purity. The product (I) is obtained by hydrogenating and hydrolyzing the trisilyl derivative.
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- Potential Bile Acid Metabolites. 6. Stereoisomeric 3,7-Dihydroxy-5β-cholanic Acids
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New synthetic routes to the four possible 3,7-dihydroxy acids are described.The principal reactions involved were inversions with DMF and Me2SO-crown ether and reduction of 12-oxo tosylhydrazones.Inversion of 3α-tosylates by the Me2SO-crown ether method succeeded but that of the corresponding mesylates did not.A table of 1H NMR chemical shift reference data of monosubstituted methyl cholanates pertinent to bile acid characterization has been expanded.
- Iida, Takashi,Chang, Frederic C.
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p. 2966 - 2972
(2007/10/02)
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- Introducing Δ11 unsaturation into steroid compounds
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A process for the introduction of Δ11 unsaturation into steroid compounds having a C-12 sulfonate ester group is described. Dehydrosulfonation is carried out by reacting the sulfonate with a hexaalkylphosphoric triamide. The process is particularly useful with steroid compounds that also contain a blocked C-7 hydroxy group. The process yields the 11-enate in preference to the 6,11-dienate. The yield of the process can be increased by carrying out the reaction in the presence of a weak base.
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