- Method for synthesizing deoxycholic acid
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The invention provides a method for synthesizing deoxycholic acid. The method comprises the steps of esterifying cholic acid to obtain a compound I, oxidizing to obtain a compound II, performing protection to obtain a compound III, brominating to obtain a compound IV, reducing to obtain a compound V, eliminating to obtain a compound VI, reducing and hydrogenating to obtain a compound VII, and performing ester hydrolysis to obtain deoxycholic acid. The reaction formula is shown in the description, wherein R1 in the formula III, the formula VI, the formula V, the formula VI and the formula VII is selected from benzoyl or p-toluenesulfonyl; and R2 is selected from methyl, ethyl or tertiary butyl. The synthesis method overcomes the defects of long reaction steps, expensive used reagents, difficulty in purification, low yield and the like in the prior art, and provides a novel method which is rapid in reaction, easy in purification, high in yield and suitable for commercial mass production.
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Paragraph 0038-0039
(2021/06/26)
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- Synthesis method of 3[alpha],6[alpha](beta),12[alpha]-trihydroxyl-5[beta]-cholic acid
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The invention discloses a preparation method of 3[alpha],6[alpha],12[alpha]-trihydroxyl-5[beta]-cholic acid and 3[alpha],6[beta],12[alpha]-trihydroxyl-5[beta]-cholic acid. 3[alpha],7[alpha],12[alpha]-trihydroxyl-5[beta]-cholic acid is taken as a raw material, and 3[alpha],6[alpha],12[alpha]-trihydroxyl-5[beta]-cholic acid and 3[alpha],6[beta],12[alpha]-trihydroxyl-5[beta]-cholic acid are obtainedthrough ten steps such as Mukaiyama aldol condensation reaction, oxidative cracking, reduction removal and the like . The synthesis method has the characteristics of green and high efficiency.
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Paragraph 0023; 0028
(2020/10/14)
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- PROCESS FOR THE PREPARATION OF DEOXYCHOLIC ACID
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The present invention provides a process for preparation of deoxycholic acid or salt thereof; the process comprises the steps of reacting the compound of formula II to obtain a compound of formula III; the compound of formula III is converted to a compound of formula IV and the compound of formula IV is converted to deoxycholic acid. The present invention also provides a process for the purification of deoxycholic acid or salt thereof.
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Paragraph 0121
(2018/12/13)
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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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- 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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- 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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- [...] synthetic method and intermediate (by machine translation)
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The invention discloses a method for synthesizing [...], 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, eliminate, selective hydrolysis of 3 bit ester group, with the three-a chlorosilane reaction to produce the silicon ether, with acetaldehyde to aldol condensation, and the hydrolysis, catalytic hydrogenation reduction olefinic bond, carbonyl reduction reaction such as, to synthesize states the aobeiaobei cholic acid. The method of the invention uses cheap cholic acid as raw materials, synthetic method is novel, low cost, high yield, mild reaction conditions, easy post treatment, environmental friendly, convenient to industrial production. (by machine translation)
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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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- 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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- Radical-mediated dehydrogenation of bile acids by means of hydrogen atom transfer to triplet carbonyls
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The aim of the present paper is to explore the potential of radical-mediated dehydrogenation of bile salts (BSs), which is reminiscent of the enzymatic action of hydroxysteroid dehydrogenase enzymes (HSDH). The concept has been demonstrated using triplet carbonyls that can be efficiently generated upon selective UVA-excitation. Hydrogen atom transfer (HAT) from BSs to triplet benzophenone (BP) derivatives gave rise to radicals, ultimately leading to reduction of the BP chromophore with concomitant formation of the oxo-analogs of the corresponding BSs. The direct reactivity of triplet BP with BSs in the initial step was evaluated by determining the kinetic rate constants using laser flash photolysis (LFP). The BP triplet decay was monitored (λmax = 520 nm) upon addition of increasing BS concentrations, and the obtained rate constant values indicated a reactivity of the methine hydrogen atoms in the order of C-3 2 than under O2, also supporting the role of the oxygen-quenchable triplet in the dehydrogenation process. Furthermore, irradiation of deaerated aqueous solutions of sodium cholate in the presence of KPMe provided the oxo-analogs, 3[O],7[O]-CA, 3[O]-CA and 7[O]-CA, arising from the HAT process.
- Miro,Marin,Miranda
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supporting information
p. 2679 - 2683
(2016/03/05)
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- Synthesis of various secosteroidal macrocycles by ring-closing metathesis
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We set out to describe an efficient and versatile method for preparing secosteroidal macrocycles from cholic acid, via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps. The characteristic 1H and 13C NMR spectroscopic features of the synthesized compounds are reported.
- Ibrahim-Ouali, Malika,Romero, Eugénie
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p. 651 - 661
(2013/07/11)
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- Exploitation of a laccase/meldola's blue system for NAD+ regeneration in preparative scale hydroxysteroid dehydrogenase-catalyzed oxidations
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An enzymatic regeneration system consisting of laccase and the 2H +/2e- redox mediator Meldola's blue (MB) was developed for the efficient oxidation of reduced nicotinamide adenine dinucleotide (NADH) cofactor and employed in the gram-scale oxidation of cholic acid (1) to its 7-keto derivative (1a) by 7a-hydroxysteroid dehydrogenase (7a- HSDH) in an aqueous, buffered reaction system. The regenerating enzyme, laccase, reduces molecular oxygen as terminal 4H+/4e- acceptor to water and concomitantly reoxidizes NADH via MB at high turnover rates. The regeneration system was successfully applied to quantitatively convert 1 (50 mM, 20.4 g) into 1a with a space-time yield of 5.8 mmolL-1h-1. High total turnover numbers were achieved for 7a-HSDH (4.2×105) and laccase (1.1× 10.6). Alternatively, the regeneration system was employed on the conversion of the methyl ester derivative of cholic acid (2, 200 mM, 5.9 g) dissolved in isopropyl acetate as organic solvent in a biphasic system. Due to the high concentration of 2 and the excellent performance of the enzymatic cascade reaction even under the harsh process conditions, space-time yields of up to 20 mmolL-1h-1(8.5 gL-1h -1) of the produced 7-keto derivative 2a were obtained. The irreversibility and high driving force of the regenerating reaction allowed quantitative conversions and easy product recovery.
- Ferrandi, Erica Elisa,Monti, Daniela,Patel, Ilabahen,Kittl, Roman,Haltrich, Dietmar,Riva, Sergio,Ludwig, Roland
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p. 2821 - 2828
(2013/01/15)
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- Synthesis of cholic acid based calixpyrroles and porphyrins
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New cholic acid based calix[4]pyrroles and porphyrins were prepared and their properties were studied. It was confirmed by spectral measurements that the superassembly of 5,15-bis(3α,7α,12α-trihydroxy-5β- cholan-24-yl)-10,20-diphenylporphyrin, the best candidate for this study from the conjugates prepared, may be influenced not only by the solvent mixture composition (polar/non-polar component ratio) but by time as well.
- Nguyen Thi, Thu Huong,Cardova, Lenka,Dvorakova, Michaela,Rockova, Dagmar,Drasar, Pavel
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experimental part
p. 858 - 863
(2012/07/14)
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- POLYHYDROXYLATED BILE ACIDS FOR TREATMENT OF BILIARY DISORDERS
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The invention provides, in part, polyhydroxylated bile acids for treating biliary disorders, for example, biliary disorders arising out of cholestasis or portal hypertesion. The invention also provides, in part, polyhydroxylated bile acids for stimulating bile flow. New compounds 2α,3α,7α,12α-tetrahydroxy-5β-cholanoic acid and 3α,4α,7α,12α-tetrahydroxy-5β-cholanoic acid are disclosed, uses thereof and synthesis thereof.
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Page/Page column 37
(2011/04/14)
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- A ring-closing metathesis approach to secosteroidal macrocycles
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An efficient synthesis of secosteroidal macrocycles has been achieved via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps.
- Ibrahim-Ouali, Malika,Zoubir, Jamel,Romero, Eugénie
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p. 7128 - 7131
(2012/01/04)
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- Biotransformation of methyl cholate by Aspergillus niger
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Biotransformation of methyl cholate using Aspergillus niger was investigated. This led to the isolation of two derivatives: methyl 3α,7α,12α,15β-tetrahydroxy-5β-cholan-24-oate identified as a new compound, and a known compound methyl 3α,12α-dihydroxy-7-ox
- Al-Aboudi, Amal,Mohammad, Mohammad Y.,Haddad, Salim,Al-Far, Rawhi,Choudhary, M. Iqbal,Atta-ur-Rahman
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experimental part
p. 483 - 486
(2009/05/07)
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- Discovery of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a potent and selective agonist for the TGR5 receptor, a novel target for diabesity
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In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C23(S)-methyl group in the side chain of bile acids such as chenodeoxycholic acid (CDCA) and 6-ethylchenodeoxycholic acid (6-ECDCA, INT-747) affords selectivity for TGR5. Herein we report further lead optimization efforts that have led to the discovery of 6R-ethyl-23(S)- methylcholic acid (S-EMCA, INT-777) as a novel potent and selective TGR5 agonist with remarkable in vivo activity.
- Pellicciari, Roberto,Gioiello, Antimo,Macchiarulo, Antonio,Thomas, Charles,Rosatelli, Emiliano,Natalini, Benedetto,Sardella, Roccaldo,Pruzanski, Mark,Roda, Aldo,Pastorini, Elisabetta,Schoonjans, Kristina,Auwerx, Johan
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supporting information; experimental part
p. 7958 - 7961
(2010/08/22)
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- Chemical modifications of bile acids under high-intensity ultrasound or microwave irradiation
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High-intensity ultrasound (HIU) and microwave (MW) irradiation, having emerged as effective promoters of organic reactions, were exploited for the synthesis of bile acids derivatives. Esterification, amidation, hydrolysis, oxidation, and reduction were investigated. Compared to conventional methods, both techniques proved much more efficient, increasing product yields and dramatically cutting down reaction times. Scaled-up studies are now under way.
- Cravotto, Giancarlo,Boffa, Luisa,Turello, Marta,Parenti, Massimo,Barge, Alessandro
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- Cholanic acid ring based 4-(trifluoroacetyl)phenyl derivatives, process for preparation and use thereof
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The present invention relates to a cholanic acid ring based 4-(trifluoroacetyl)phenyl derivatives of the following formula 1, process for preparation and use thereof. The cholanic acid ring based 4-(trifluoroacetyl)phenyl derivatives of the present invention may be used as a host material in the host-guest chemistry, in detail as a material for ion sensors, optical sensors, gas sensors, biosensors, chromatographies, photostimulated ion-binding resins, ion exchange resins and organic reactions. (In the above formula 1, R, R1, R2, R3and n are defined in the specifications).
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- Synthesis of both enantiomers of 1-phenylethane-1,2-diol via chirality transfer from bile acid derivatives
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Both enantiomers of 1-phenylethane-1,2-diol were synthesized with good to excellent enantioselectivities via selective reduction of the phenylglyoxalates derived from bile acids, followed by reductive cleavage. Copyright (C) 2000 Elsevier Science Ltd.
- Bandyopadhyaya,Sangeetha,Radha,Maitra, Uday
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p. 3463 - 3466
(2007/10/03)
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- Selective dimethyldioxirane oxidation of bile acid methyl esters
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DMDO oxidation of the hydroxy groups of bile acid methyl esters establishes the positional order of reactivity as 3-7 > 6 > 12 and supports a mechanism involving C-H oxygen insertion through a planar intramolecularly hydrogen bonded transition state.
- Buxton, P. Christopher,Marples, Brian A.,Toon, Richard C.,Waddington, Victoria L.
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p. 4729 - 4732
(2007/10/03)
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- Design, Synthesis, and Evaluation of Bile Acid-Based Molecular Tweezers
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A family of bile acid-based molecular tweezers (7-9) has been constructed readily from simple precursors.Binding experiments with various electron deficient aromatic compounds showed that tweezer 8 binds trinitrofluorenone 10e with an association constant of 220 M-1 in CDCl3.Single-crystal X-ray analysis of compound 8 shows aromatic-aromatic interactions producing a two-dimensional lattice of pyrene units.Tweezer 8 was immobilized on Merrifield resin, and binding studies have shown that these data compare well with those of the solution state studies.
- D'Souza, Lawrence J.,Maitra, Uday
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p. 9494 - 9502
(2007/10/03)
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- Cholic Acid Derived Novel Chiral Auxiliaries for Asymmetric Diels-Alder Reactions
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Cholic acid-based chiral acrylate 5 yields a Diels-Alder adduct with cyclopentadiene in the presence of BF3*OEt2 with 88 percent diastereoselectivity
- Maitra, Uday,Mathivanan, Packiarajan
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p. 1469 - 1471
(2007/10/02)
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- An efficient synthesis of 4β and 6α-hydroxylated bile acids
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An efficient method for the preparation of 4β- and 6α-hydroxylated bile acids has been developed.It involved a highly stereoselective acetoxylation at the 4β and 6α positions of 3- and 7-oxo bile acids, respectively, with lead tetraacetate in the presence of boron trifluoride etherate in acetic acid.Reduction of the resulting α-acetoxy ketones with sodium borohydride or tert-butylamine borane complex, and alkaline hydrolysis, provided the desired bile acids in good yields. Keywords: sterols; bile acid; 4β-hydroxylated bile acid;6α-hydroxylated bile acid; acetoxylation; lead tetraacetate oxidation
- Yoshimura, Teruki,Mahara, Reijiro,Kurosawa, Takao,Ikegawa, Shigeo,Tohma, Masahiko
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- Potential Bile Acid Metabolites. 7. 3,7,12-Trihydroxy-5β-cholanic Acids and Related Compounds
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With this work, the complete set of the eight possible stereoisomeric (5β)-3,7,12-trihydroxy acids are now known and characterized.The key intermediates methyl 3α,7β-dihydroxy-12-oxo- and 3β,7β-dihydroxy-12-oxocholanate have been synthesized, and their reductions by tert-butylamine-borane complex and by NaBH4 are described.
- Iida, Takashi,Chang, Frederic C.
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p. 2972 - 2978
(2007/10/02)
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