- Enantioselective Synthesis of R-(+)-α-Lipoic Acid
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The title compound has been synthesised in an enantioselective manner from achiral precursors using the Sharpless asymmetric epoxidation as the key step in the reaction sequence.
- Page, Philip C. Bulman,Rayner, Christopher M.,Sutherland, Ian O.
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- ASYMMETRIC SYNTHESIS VIA ACETAL TEMPLATES. 12. HIGHLY DIASTEREOSELECTIVE COUPLING REACTIONS WITH A KETENE ACETAL. AN EFFICIENT, ASYMMETRIC SYNTHESIS OF R-(+)-α-LIPOIC ACID.
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TiCl4 catalyzes the essentially quantitative coupling of chiral acetals 1 with 1-t-butoxy-1-t-butyldimethylsilyloxyethene 2 to generate β-alkoxycarboxylates in wich the new asymmetric center is formed with excellent diastereoselection. β-Hydrocarboxylic acids of high ee result from removal of the chiral auxiliary.The procedure has been appllied to the synthesis of R-(+)-α-lipoic acid 10.
- Elliott, John D.,Steele, John,Johnson, William S.
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- Coevolution of the Activity and Thermostability of an ?-Keto Ester Reductase for Better Synthesis of an (R)-α-Lipoic Acid Precursor
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In this work, we have identified a significantly improved variant (S131Y/Q252I) of the natural ?-keto ester reductase CpAR2 from Candida parapsilosis for efficiently manufacturing (R)-8-chloro-6-hydroxyoctanoic acid [(R)-ECHO] through co-evolution of activity and thermostability. The activity of the variant CpAR2S131Y/Q252I towards the ?-keto ester ethyl 8-chloro-6-oxooctanoate was improved to 214 U mg?1—from 120 U mg?1 in the case of the wild-type enzyme (CpAR2WT)—and the half-deactivating temperature (T50, for 15 min incubation) was simultaneously increased by 2.3 °C in relation to that of CpAR2WT. Consequently, only 2 g L?1 of lyophilized E. coli cells harboring CpAR2S131Y/Q252I and a glucose dehydrogenase (GDH) were required in order to achieve productivity similar to that obtained in our previous work, under optimized reaction conditions (530 g L?1 d?1). This result demonstrated a more economical and efficient process for the production of the key (R)-α-lipoic acid intermediate ethyl 8-chloro-6-oxooctanoate.
- Chen, Qi,Xu, Jian-He,Xu, Yao,Zhang, Zhi-Jun,Zheng, Gao-Wei
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- Stereocontrolled reactions induced by a thermolabile group. Synthesis of optically active 1,3-diols
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Wittig Horner-Michael reactions of phosphonates with optically active lactol 1 lead preferentially to one diastereoisomer. 2. Force field calculations conducted on one pair of diastereoisomers 2c and 2′c predict that these isomers must exist in different conformations of similar energies. 1H NMR data are in good agreement with these predictions. The dihydrofurans obtained by retro Diels-Alder reactions of 2 are easily transformed into optically pure 1,3-diols, precursors of R-(+)-α-lipoic acid and (-)-(1R,3R,5s)-1,3-dimethyl-2,9-dioxabicylco [3.3.1]nonane.
- Bloch, Robert,Bortolussi, Michel,Girard, Christian,Seck, Matar
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- Microwave-assisted resolution of α-lipoic acid catalyzed by an ionic liquid co-lyophilized lipase
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The combination of the ionic liquid co-lyophilized lipase and microwave irradiation was used to improve enzyme performance in enantioselective esterification of α-lipoic acid. Effects of various reaction conditions on enzyme activity and enantioselectivity were investigated. Under optimal condition, the highest enantioselectivity (E = 41.2) was observed with a high enzyme activity (178.1 μmol/h/mg) when using the ionic liquid co-lyophilized lipase with microwave assistance. Furthermore, the ionic liquid co-lyophilized lipase exhibited excellent reusability under low power microwave.
- Liu, Ning,Wang, Lei,Wang, Zhi,Jiang, Liyan,Wu, Zhuofu,Yue, Hong,Xie, Xiaona
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- Preparation method of R-lipoic acid
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The invention discloses a preparation method of R-lipoic acid, and belongs to the technical field of pharmaceutical chemistry synthesis. The method comprises the following steps: preparing an intermediate-1; preparing an intermediate-2; preparing an intermediate-3; preparing an intermediate-4; preparing an intermediate-5; preparing an intermediate-6; preparing an intermediate-7; and preparing a finished product, and performing hydrolysis reaction on the obtained intermediate-7 under an alkaline condition to obtain R-lipoic acid. The method has the advantages of mild process conditions, high optical purity of chiral intermediates and final products, and facilitation of quality control and improvement of bulk drugs of the final products; and reagent raw materials used in the process route are easy to obtain, the technical scheme is reasonable and environment-friendly, and the method can meet the use requirements through mass production and is suitable for industrial large-scale production.
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- Synthesis method R -lipoic acid
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A synthesis method of R -lipoic acid comprises N - (5 -bromopentyl) phthalimide and zinc powder. Lithium chloride, trimethylchlorosilane, 1,2 - dibromoethane and tetrahydrofuran are mixed, reacted to form a zinc bromide intermediate, and 3 - {[2 - (trimethylsilyl) ethoxy] methoxy} propionyl chloride is then reacted with a zinc bromide intermediate. The obtained intermediate -1 is subjected to a hydrazine decomposition reaction. The obtained intermediate -2 is subjected to a catalytic oxidation reaction. The obtained intermediate -3 is subjected to an esterification reaction. The nearly smooth Candida tropicalis is introduced into a fermentation medium for amplification culture, and the obtained resting cells are suspended in a buffer aqueous solution and the obtained intermediate -4 is added for enzyme-catalyzed chiral reduction reaction. The resulting intermediate -5 is subjected to deprotection reaction. The resulting intermediate -6 is subjected to a chlorination reaction. The resulting intermediate -7 was subjected to a cyclization reaction. The obtained intermediate -8 was subjected to a hydrolysis reaction to obtain a finished product.
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- Preparation method of R-lipoic acid tromethamine salt
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The invention relates to a preparation method of R-lipoic acid trometamol salt, which comprises the following steps: introducing candida parapsilosis into a fermentation culture medium for multiplication culture, and conducting centrifugal separation; suspending obtained resting cells in a buffer aqueous solution, adding ethyl 6-carbonyl-8-chlorocaprylate, glucose dehydrogenase, glucose and nicotinamide adenine dinucleotide, and carrying out a chiral reduction reaction; mixing the obtained ethyl S-6-hydroxy-8-chlorocaprylate with a chlorination reagent, a catalyst and a solvent, and carrying out a chlorination reaction; adding the obtained ethyl R-6,8-dichlorocaprylate into a system of sulfur, sodium sulfide, a phase transfer catalyst and water, and carrying out cyclization reaction; carrying out hydrolysis reaction on the obtained R-lipoic acid ethyl ester under an alkaline condition; and suspending the obtained R-lipoic acid and trometamol in an alcohol solvent, conducting heating and dissolving, and carrying out salt forming reaction to obtain a finished product. The method has the advantages of mild process conditions, low cost, high product purity, high yield and high optical purity.
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Paragraph 0028; 0036; 0038; 0045; 0047; 0054
(2021/05/12)
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- Preparation method of D-lipoic acid
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The invention relates to a preparation method of d-lipoic acid. The preparation method comprises the following steps: carrying out free reaction on a compound shown as a formula I under the action ofcitric acid, washing with water, concentrating, and eluting to obtain the d-lipoic acid. According to the scheme for preparing the d-lipoic acid, the generation of polymer related substances in the preparation process of the d-lipoic acid can be remarkably reduced.
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Paragraph 0040-0070
(2021/02/24)
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- Lipoic acid preparation method and application of lipoic acid in preparation of drug for treating oligospermia
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The invention provides a lipoic acid preparation method. The lipoic acid preparation method is characterized by comprising the following steps: (1) carrying out cyclization reaction on ethyl 6,8-dichloro caprylate to prepare lipoic acid ethyl ester; (2) converting 6,8-epitrithio-octanoic acid in the lipoic acid ethyl ester obtained in step (1) into lipoic acid ethyl ester by using sulfite; (3) hydrolyzing the lipoic acid ethyl ester under the effect of alkali to prepare a lipoic acid crude product; and (4) and carrying out recrystallization and drying on the lipoic acid crude product to prepare high-purity lipoic acid, wherein in step (4), recrystallization comprises carrying out heat dissolving on the lipoic acid crude product, filtering a hot lipoic acid solution through an adsorption layer, and crystallizing and filtering filtrate. By the method, known impurities B in the lipoic acid are controlled, the method is simple, and is easy to operate, the purity of the obtained product ishigh, the high-purity lipoic acid can be obtained by only one-time refining, and industrial production is facilitated. In addition, by the lipoic acid prepared by the method, oligospermia can be treated, the density of sperms is increased, and the activity of the sperms is improved.
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Paragraph 0061-0072
(2019/04/17)
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- Preparation method of R-(+)-lipoic acid
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The invention discloses a preparation method of R-(+)-lipoic acid. The method comprises the following steps: performing salt formation on a raw material of racemic lipoic acid and a resolving agent ofR-phenylethylamine, so as to obtain diastereoisomeric R-phenylethylamine racemic lipoic acid salt; performing recrystallization separation on a raw material of the salt, so as to obtain a single enantiomer of R-phenylethylamine R-(+)-lipoic acid salt; finally, acidizing the single enantiomer of R-phenylethylamine R-(+)-lipoic acid salt, so as to obtain the target compound R-(+)-lipoic acid in a structure of the formula (I) at a yield of 40%. The method is simple in operation, lower in requirements on equipment, mild in conditions and higher in yield, so that the method is suitable for industrial production.
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Paragraph 0038; 0043; 0044; 0046; 0050; 0052; 0054
(2018/06/23)
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- Preparation method of R-lipoic acid tromethamine salt
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The invention discloses a preparation method of R-lipoic acid tromethamine salt and belongs to the field of organic medicinal chemistry. The method includes the steps that (S)-6,8-dichloro ethyl caprylate and sulphur are put into a reaction vessel, the temperature is raised, a cyclization reaction is carried out, the temperature is preserved, extraction is carried out with a first organic solvent, concentration is carried out, and cyclization liquid is obtained; then, a hydrolysis reaction is carried out, cooling is carried out, and hydrolysis liquid is obtained; a second organic solvent is added into the hydrolysis liquid, the pH value is regulated, extraction is carried out, an obtained organic layer is washed with water to be neutral, the second organic solvent is removed at reduced pressure, and an initial product is obtained; mixed liquor is added into the initial product, the temperature is raised, a first filter aid is added, stirring adsorption is carried out, filtration is carried out, and light yellow liquid is obtained; cooling is carried out to separate out crystals, and R-lipoic acid is obtained; R-lipoic acid is dissolved, trihydroxymethyl aminomethane is added, the temperature is raised for solution, a second filter aid is added for filtration, and light yellow liquid is obtained; cooling is carried out to separate out crystals, centrifugal drying is carried out, and the finished product is obtained. According to the method, few steps are needed, efficiency is high, energy is saved, and waste discharge is reduced.
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Paragraph 0025; 0026
(2016/10/31)
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- Preparation method of (R)-(+)-lipoic acid
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The invention discloses a preparation method of (R)-(+)-lipoic acid and belongs to the field of organic and medicinal chemistry. The preparation method comprises the following steps: (S)-ethyl 6,8-dichloro caprylate and sulfur are fed into a reaction container equipped with a stirring device, the mixture is heated, an aqueous sodium sulphide solution is added dropwise for a cyclization reaction, heat is preserved, then extraction and concentration are performed, and a cyclization liquid is obtained; the cyclization liquid is fed into the reaction container, an alkaline solution is added, a hydrolysis reaction is performed, and a hydrolysate is obtained through cooling; an organic solvent is added to the hydrolysate, pH is regulated with acid, extraction is performed, an organic layer obtained through extraction is washed to be neutral, then an organic solvent is removed through pressure reduction, a primary product is obtained, a mixed solvent is added to the primary product, the mixture is heated and dissolved, a filter aid is added, stirring and adsorption are performed, filtering is performed, a faint yellow liquid is obtained and cooled, crystals are precipitated, and a finished product is obtained. The steps are reduced, and the preparation efficiency is high; raw material consumption is reduced, the optical rotation of (R)-(+)-lipoic acid reaches 117-118 degrees, the ee value is 99.0%-99.5%, the content is higher than 99%, and waste emission is reduced.
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Paragraph 0064; 0065; 0066; 0067; 0068
(2016/11/17)
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- Preparation method of (R)-alpha-thioctic acid
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The invention relates to a preparation method of (R)-alpha-thioctic acid, and belongs to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: introducing Candida parapsilosis to a fermentation medium, carrying out multiplication culture, and centrifuging; introducing above obtained reductase catalyst to a system composed of 6-carbonyl-8-chloroctanoic acid, glucose dehydrogenase, glucose, nicotinamide adenine dinucleotide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and water, and carrying out a chiral reduction reaction; adding above obtained (S)-6-hydroxy-8-chloroctanoic acid to a system composed of a chlorination reagent, a catalyst and a solvent, and carrying out a chlorination reaction; and adding obtained (R)-6,8-dichloroctanoic acid to a system composed of sulfur, sodium sulfide, a phase transfer catalyst and water, and carrying out a cyclization reaction to obtain the finished product. The method has the advantages of mild technologic conditions, low cost, realization of high purity, high yield and high optical purity of the product, easy obtaining of reagents used in the above technologic route, and reasonable and environmentally-friendly technical scheme.
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Paragraph 0023; 0026; 0029
(2017/05/23)
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- Identification of an ε-keto ester reductase for the efficient synthesis of an (R)-α-lipoic acid precursor
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Abstract A novel reductase (CpAR2) with unusually high activity toward an ε-keto ester, ethyl 8-chloro-6-oxooctanoate, was isolated from Candida parapsilosis. The asymmetric reduction of ethyl 8-chloro-6-oxooctanoate using Escherichia coli cells coexpressing CpAR2 and glucose dehydrogenase genes gave ethyl (R)-8-chloro-6-hydroxyoctanoate, a key precursor for the synthesis of (R)-α-lipoic acid, in high space-time yield (530 gL-1d-1) and with excellent enantiomeric excess (>99%). This bioprocess was shown to be viable on a 10-L scale. This method provides a greener and more cost-effective method for the industrial production of (R)-α-lipoic acid.
- Zhang, Yu-Jun,Zhang, Wen-Xia,Zheng, Gao-Wei,Xu, Jian-He
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p. 1697 - 1702
(2015/06/02)
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- Chirality induction and chiron approaches to enantioselective total synthesis of α-lipoic acid
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Abstract An efficient, short and convenient asymmetric synthesis of (R)-(+)-lipoic acid in seven steps from chiral hydroxy aldehyde with 32.5% overall yield is described. Synthesis of S and R enantiomers of α-lipoic acid from cis-1,4-butene diol derived chiral lactone is reported with 34 % overall yield. The present synthesis involves use of simple reaction conditions making it a convenient synthesis.
- Chavan, Subhash P.,Pawar, Kailash P.,Praveen, Ch.,Patil, Niteen B.
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p. 4213 - 4218
(2015/06/02)
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- Glycation Cross-link Breakers to Increase Resistance to Enzymatic Degradation
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The present invention relates to a method to treat a grafts, implant, scaffold, and constructs, including allografts, xenografts, autografts, and prosthetics comprising collagen, with an inhibitor of collagen cross-links and/or advanced glycation endproducts (AGE), in order to alleviate the mechanical weakness induced by the cross-links The invention also provides for kits for use in the operating theater during autograft, allograft or xenograft procedures, or for preparing allograft, xenografts or prosthetics that have not been already treated prior to packaging. The kit comprises a first agent or agents that inhibit collagen cross-links and/or advanced glycation endproducts, instructions for use, optionally a wash or rinse agent, and a device for containing the graft and first agent.
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- SURFACE ENHANCED RAMAN SPECTROSCOPY (SERS) COMPOUNDS AND METHODS OF THEIR PREPARATION
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A compound for detecting an analyte using Surface Enhanced Raman Spectroscopy (SERS) and a method of forming the compound is provided. The compound has Formula I: wherein W is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group; each Y independently is NR1R2, wherein R1 and R2 are independently selected from the group consisting of H and C1-C6 alkyl, or R1 and R2 combine to form together with the nitrogen to which they are attached a heterocyclic group with 4 to 5 carbon atoms, is used to denote a single or a double bond, and Z is NH, NH2, NH—(C═O)—(CH2)n—SH, wherein n=1 to 10, or or a tautomer or stereoisomer thereof, or a salt thereof. A method and device for detecting an analyte using Surface Enhanced Raman Spectroscopy (SERS) is also provided.
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- Enantioselective total synthesis of (R)-α- Lipoic acid: An application of thermodynamically controlled deracemization of (±)-2-(2-Methoxyethyl)cyclohexanone
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According to the concept of thermodynamically controlled deracemization, racemic 2-(2-methoxyethyl)cyclohexanone was converted into the R-isomer (99% ee) in 90% yield using (-)-(2R,3R)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4- dioxaspiro[5.4]decane as a host molecule under basic conditions. As an application, a short and enantioselective synthesis of (R) - lipoic acid was accomplished in 44% overall yield from (±)-2-(2-methoxyethyl) cyclohexanone.
- Kaku, Hiroto,Okamoto, Natsuko,Nishii, Takeshi,Horikawa, Mitsuyo,Tsunoda, Tetsuto
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experimental part
p. 2931 - 2934
(2010/10/21)
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- ALPHA-LIPOIC ACID DERIVATIVES AND THEIR USE IN DRUG PREPARATION
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The present invention concerns an enantiomer R of a compound of Formula (I), wherein X is -NH-R1 or of Formula (V) or (VI), R1 is -(CH2)n-R2, R2 is a linear, branched or cyclic C1C6 aliphatic group, -O-(CH2)n-CH3, -NH-CO- (CH2)n-CH3, a 5- or 6-membered aliphatic or aromatic ring optionally comprising a heteroatom, a 5- or 6-membered aromatic ring substituted by one or two substituents, said substituents being selected from the group consisting of -OH, - O(alkyl C1C3) and -OCO(alkyl C1C3), or of Formula (V), R3 is H or a C1-C3 aliphatic group and R4 is a linear C1-C3 or a branched C3-C12 aliphatic group, or R3 is a C1-C3 aliphatic group and R4 is a linear C1-C12 aliphatic group, Y is O, CH-(CH2)n-CH3 or N(CO)(CH2)n-CH3, and n is an integer from O to 6. It has been found that the enantiomers of the invention are able to release (R)- alpha-lipoic acid, ensuring a longer permanence in the body for the pharmacologically active principle than that obtainable by its direct administration, or to simulate the pharmacological action of alpha-lipoic acid itself, while exhibiting a much more intense and lasting activity.
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Page/Page column 34-37
(2010/06/11)
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- Method of preparing R-(+)-alpha-lipoic acid and its salt
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The present invention discloses a method for preparing R-(+)-LA as well as its metal salts including sodium salt, potassium salt, calcium salt, magnesium salt, zinc salt, ferric salt, cooper salt , lithium salt and its organic salt, wherein a racemic Ethyl 6, 8-Dichlorooctanoic acid is employed as starting agents, followed by a hydrolysis and resolution processes to obtain (+)DCA, and then through sulfuration and cyclization process to obtain R-(+)-LA as well as its varied salts. A method for converting the (?)DCA to (+)DCA is also introduced.
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Page/Page column 2
(2008/06/13)
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- An efficient, highly enantioenriched route to L-carnitine and α-lipoic acid via hydrolytic kinetic resolution
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A general and practical approach for the synthesis of C-4 chiral building blocks using Jacobsen's hydrolytic kinetic resolution technique to resolve terminal epoxides and diols in high enantiomeric excess and excellent yields is described. The utilization of these building blocks for the synthesis of biologically important natural products L-carnitine and α-lipoic acid is illustrated. Georg Thieme Verlag Stuttgart.
- Bose, D. Subhas,Fatima, Liyakat,Rajender, Salla
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p. 1863 - 1867
(2008/01/27)
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- Enantioselective synthesis of R-(+)-α and S-(-)-α-lipoic acid
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An efficient synthesis of α-lipoic acid from the readily available cis-2-butene-1,4-diol employing a Claisen orthoester rearrangement and Sharpless asymmetric dihydroxylation as the key steps, is described.
- Chavan, Subhash P.,Praveen, Cherukupally,Ramakrishna,Kalkote
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p. 6027 - 6028
(2007/10/03)
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- Synthesis of r(+)alpha-lipoic acid
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Process for the synthesis of R(+)α-lipoic acid comprising the following stages: a) Salifying of racemic 6,8-halo-octanoic acid with S(?)α-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(?)α-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(?)α-methylbenzylamine; (d) separation of the diastereoisomeric salt to obtain R(+)6,8-di-halo-octanoic acid by reation of said salt with strong mineral acids in an aqueous solution with a dilution between 2 and 10% by weight; e) esterification of R(+)6,8-di-halo-octanoic acid to obtain the corresponding alkyl ester; f) reaction of the alkyl ester of R(+)6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis; g) hydolysis of the ester of R(+)α-lipoic acid.
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- METHOD FOR THE PURIFICATION OF LIPONIC ACID
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The invention relates to a method for the purification of liponic acid wherein at least O.1 times the amount of an adsorption agent is added to a solution of liponic acid in relation to the mass of liponic acid to be purified and the adsorption agent is then separated. As a result, it is possible to produce racemic or non-racemic liponic acid with less than 1 wt. % oligomers, e.g. 0.11 wt. %.
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Page/Page column 4-5
(2008/06/13)
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- The synthesis of R (+) α-lipoamino acid
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Process for the synthesis of R(+)alpha-lipoic acid comprising the following stages: a) Salifying of racemic 6,8-halo-octanoic acid with S(-)alpha-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(-)alpha-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(-)alpha-methylbenzylamine; (d) separation of the diastereoisomeric salt to obtain R(+)6,8-di-halo-octanoic acid by reation of said salt with strong mineral acids in an aqueous solution with a dilution between 2 and 10% by weight; e) esterification of R(+)6,8-di-halo-octanoic acid to obtain the corresponding alkyl ester; f) reaction of the alkyl ester of R(+)6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis; g) hydolysis of the ester of R(+)alpha-lipoic acid.
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- Process for the production of a racemic thioctic acid
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Process for the synthesis of racemic thiotic acid comprising the following stages: a) reaction of the alkyl ester of 6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis selected from the group consisting of quaternary ammonium or phosphonium salts having the following general formula: where: A is nitrogen of phosphorus, X is selected from the group consisting of Cl, Br, I, HSO4, and H2PO4 and the substitutents R1, R2, R3 and R4 are selection from the group consisting of linear or branched alkyl radicals having one to twenty carbon atoms (C1-C20), said substituents being identical or different one from the other, or only one of said substituents is selected from the group consisting of arylalkyl radicals having the following formula —(CH2)nC6H5 in which n=1-16; b) followed by the hydrolysis of the ester of racemic thiotic acid.
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- Liver function improvement formulation
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A food supplement formulation effective to improve the function of the liver comprises selenium, milk thistle seed, phosphatidyl choline, dandelion root, l-methionine, l-taurine, N-acetyl-cysteine, alpha lipoic arid, artichoke leaf, green tea leaf, turmeric root, belleric myrobalan fruit, boerhavia diffusa, eclipta alba, wedelolactones tinospora cordifolia, andrographis paniculata, and picrorhiza kurroa.
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- Process for the production of r(+) alpha-lipoic acid
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Process for the synthesis of R(+)α-lipoic acid comprising the following stages: a) Salifying of racemic thioctic acid with R(+)α-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(+)α-lipoic acid-R(+)α-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(+)α-lipoic acid-R(+)α-methylbenzylamine, in which the re-crystallization solvent consists of a mixture of non-polar/polar solvents; d) separation of the diastereoisomeric salt to obtain R(+)α-lipoic acid by reaction of said salt with acids selected from the group consisting of aliphatic hydroxy-carboxylic acids having 3 to 6 carbon atoms and aqueous phosphoric acid.
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- Compositions of matter having bioactive properties
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Particles of coordinated complex comprising a basic, hydrous polymer and a capacitance adding compound, as well as methods for their production, are described. These complexes exhibit a high degree of bioactivity making them suitable for a broad range of applications through their incorporation into conventional vehicles benefiting from antimicrobial and similar properties.
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- Asymmetric dihydroxylation and hydrogenation approaches to the enantioselective synthesis of R-(+)-α-lipoic acid
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The asymmetric synthesis of methyl (S)-6,8-dihydroxyoctanoate (5) and (S)-6,8-dimethylsulfonyloxyoctane-1-carboxylic acid (13), key precursors to R-(+)-α-lipoic acid (6) is described using OsO4-catalyzed asymmetric dihydroxylation and Ru-catalyzed asymmetric hydrogenation, respectively, as the key steps in the reaction sequence. These methods lead to an efficient formal synthesis of R-(+)-α-lipoic acid in 90% ee.
- Upadhya,Nikalje,Sudalai
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p. 4891 - 4893
(2007/10/03)
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- A short and productive synthesis of (R)-α-Lipoic acid
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(R)-α-Lipoic acid is synthesized in seven steps from the base chemicals methyl acetoacetate or Meldrum's acid and monomethyl adipate. The key steps are the introduction of the stereogenic center by fermentative or homogeneously catalyzed hydrogenation of 3-oxooctanedioic acid diester to (3S)-3-hydroxyoctanedioic acid diester and its regioselective reduction to (6S)-6,8-dihydroxyoctanoic acid ester. The overall yield of (R)-α-lipoic acid, starting from 3-oxooctanedioic acid diester, is 40%.
- Bringmann, Gerhard,Herzberg, Daniela,Adam, Geo,Balkenhohl, Friedhelm,Paust, Joachim
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p. 655 - 661
(2007/10/03)
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- Alpha-lipoic acid with novel modification
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The invention is relative to a thioctic acid with a predominant amount of an enantiomer and a novel modification, in the case of which the X-ray powder diffractograms show a characteristic reflex in the range of 23.4 to 22.7° 2 theta(Cu) which shifts in the direction of the smaller angular values as the enantiomer content increases.
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- Lipase catalyzed regio- and stereospecific hydrolysis: Chemoenzymatic synthesis of both (R)- and (S)-enantiomers of α-lipoic acid
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Native lipase of Candida rugosa (EC 3.1.1.3) enantioselectively and regiospecifically hydrolyses the n-butyl ester of 2,4-dithioacetyl butanoic acid either at the carboxylic acid terminus or at the α-thioacetate to provide enantiomerically pure (R)-2,4-dithioacetyl butyric acid and (S)- butyl 2-thio-4-thioacetyl butyrate (ee >98%) while the lipase modified by treatment with diethyl p-nitrophenyl phosphate attacks only the α- thioacetate giving enantiomerically pure (S)-butyl 2-thio-4-thioacetyl butyrate. These enantiomerically pure intermediates can be used as chiral building blocks to obtain both(S)- and (R)-enantiomers of α-lipoic acid and their analogues.
- Fadnavis,Babu, Ravi Luke,Vadivel, S. Kumara,Deshpande, Ashlesha A.,Bhalerao
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p. 4109 - 4112
(2007/10/03)
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- Production and use of salts of 6, 8-bis (amidiniumthio) -octanoic acid
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The invention relates to the production and purification of salts of 6,8-bis(amidiniumthio) octanoic acid, its enantiomers (+)-6,8-bis(amidiniumthio)octanoic acid and (-)-6,8-bis (amidiniumthio)octanoic acid and of the esters of these compounds as well as to their use to produce dihydrolipoic acid and α-lipoic acid.
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- The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step
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2-(2-Acetoxyethyl)cyclohexanone (4) was converted into the lactone (-)-(5) regio- and enantioselectively using 2-oxo-Δ3-4,5,5-trimethylcyclopentenyl acetyl-CoA monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from camphor grown Pseudomonas putida NCIMB 10007. The lactone (-)-(5) was converted into (R)-(+)-lipoic acid in six steps. In contrast cyclopentanone monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from cyclopentanol-grown Pseudomonas sp. NCIMB 9872 selectively oxidized the (S)-enantiomer of the ketone (4) giving better access to optically enriched, naturally occurring lipoic acid.
- Adger, Brian,Bes, M. Teresa,Grogan, Gideon,McCague, Raymond,Pedragosa-Moreau, Sandrine,Roberts, Stanley M.,Villa, Raffaella,Wan, Peter W. H.,Willetts, Andrew J.
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p. 253 - 261
(2007/10/03)
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- Labeling nucleic acids
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Reagents and methods for multi-step labeling of nucleic acids allow the addition of relatively insoluble or unstable labels to nucleic acid in the final step. Nucleic acids can be stored as a stable intermediate capable of reacting with a label conjugated to a thiol-reactive group.
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- Interaction of α-Lipoic acid Enantiomers and Homologues with the Enzyme Components of the Mammalian Pyruvate Dehydrogenase Complex
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Lipoic acid (α-lipoic acid, thioctic acid) is applied as a therapeutic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic acid for the pyruvate dehydrogenase complex and its component enzymes from different sources has been studied. The dihydrolipoamide dehydrogenase component from pig heart has a clear preference for R-lipoic acid, a substrate which reacts 24 times faster than the S-enantiomer. Selectivity is more at the stage of the catalytic reaction than of binding. The Michaelis constants of both enantiomers are comparable (Km = 3.7 and 5.5 mM for R- and S-lipoic acid, respectively) and the S-enantiomer inhibits the R-lipoic acid dependent reaction with an inhibition constant similar to its Michaelis constant. When three lipoic acid homologues were tested, RS-1,2-dithiolane-3-caproic acid was one carbon atom longer than lipoic acid, while RS-bisnorlipoic acid and RS-tetranorlipoic acid were two and four carbon atoms shorter, respectively. All are poor substrates but bind to and inhibit the enzyme with an affinity similar to that of S-lipoic acid. No essential differences with respect to its reaction with lipoic acid enantiomers and homologues exist between free and complex-bound dihydrolipoamide dehydrogenase. Dihydrolipoamide dehydrogenase from human renal carcinoma has a higher Michaelis constant for R-lipoic acid (Km = 18 mM) and does not accept the S-enantiomer as a substrate. Both enantiomers of lipoic acid are inhibitors of the overall reaction of the bovine pyruvate dehydrogenase complex, but stimulate the respective enzyme complexes from rat as well as from Escherichia coli. The S-enantiomer is the stronger inhibitor, the R-enantiomer the better activator. The two enantiomers have no influence on the partial reaction of the bovine pyruvate dehydrogenase component, but do inhibit this enzyme component from rat kidney. The implications of these results are discussed.
- Loeffelhardt, Sabine,Bonaventura, Christoph,Locher, Mathias,Borbe, Harald O.,Bisswanger, Hans
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p. 637 - 646
(2007/10/03)
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- Application of Enzymic Baeyer-Villiger Oxidations of 2-Substituted Cycloalkanones to the Total Synthesis of (R)-(+)-Lipoic Acid
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Oxidation of ketones 1a-h using a monooxygenase from Pseudomonas putida NCIMB 10007 gave the lactones 2a-h in optically active form: lactone 2h was converted into (R)-(+)-lipoic acid 9.
- Adger, Brian,Bes, M. Teresa,Grogan, Gideon,McCague, Ray,Pedragosa-Moreau, Sandrine,et al.
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p. 1563 - 1564
(2007/10/02)
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- Preparation of R/S-γ-lipoic acid or R/S-α-lipoic acid
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A process for preparing R/S-γ-lipoic acid of the formula I or R/S-α-lipoic acid of the formula II STR1 is disclosed.
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- Preparation and use of salts of the pure enantiomers of alpha-lipoic acid
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The pure enantiomers of alpha-lipoic acid are obtained by formation of the diastereomeric salt pairs with the optical antipodes of alpha-methylbenzylamine in solution.
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- An Enantioselective Synthesis of R-(+)-α-Lipoic Acid
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R-(+)-α-Lipoic acid (1), D +107 deg, has been prepared in a six-step enantioselective synthesis from 6-bromohex-1-ene; the enantioselectivity is controlled by a Sharpless asymmetric epoxidation of the intermediate allyl alcohol (2).
- Page, Philip C. Bulman,Rayner, Christopher M.,Sutherland, Ian O.
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p. 1615 - 1618
(2007/10/02)
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- SYNTHESES OF α-(R)-AND α-(S)-LIPOIC ACID FROM (S)-MALIC ACID
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(S)-Malic acid has been converted into α-(R)-and α-(S)-lipoic acid via (R)-and (S)-(2-phenylmethoxyethyl)oxirane .The (R)-oxirane (2a) was cleaved with but-3-enylmagnesium bromide (cuprate catalysis) to give (S)-1-(phenylmethoxy)oct-7-en-3-ol (4a).This was converted into methyl (S)-6,8-dihydroxyoctanoate (5a), the di-O-methanesulphonate (6a) of which was treated with sodium sulphide and sulphur in dimethylformamide to yield methyl α-(R)-lipoate (7a), that was saponified to α-(R)-lipoic acid (1a).The (S)-oxirane (2b) was similarly converted into α-(S)-lipoic acid (1b).
- Brookes, Michael H.,Golding, Bernard T.,Hudson, Alan T.
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- SYNTHESIS OF (3R,4R)-1,5-HEXADIEN-3,4,-DIOL AND ITS UNSYMMETRICAL DERIVATIVES : APPLICATION TO (R)-(+)-α-LIPOIC ACID
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(3R,4R)-1,5-Hexadien-3,4-diol and its umsymmetrical derivatives were prepared starting from D-mannitol and their utility in the synthesis of (R)-(+)-α-lipoic acid has been explored.
- Rama Rao, A. V.,Mysorekar, S. V.,Gurjar, M. K.,Yadav, S. J.
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p. 2183 - 2186
(2007/10/02)
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- ENANTIOSPECIFIC SYNTHESIS OF (R)-(+)-α-LIPOIC ACID FROM D-GLUCOSE
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The first enantiospecific synthesis of natural (R)-(+)-α-lipoic acid in 13 steps starting from D-glucose is described.
- Rao, A. V. Rama,Gurjar, Mukund K.,Garyali, Kamini,Ravindranathan, T.
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- One-electron Redox Potentials of RSSR(1+.)-RSSR Couples from Dimethyl Disulphide and Lipoic Acid
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One-electron redox potentials have been measured for three (RSSR)(1+.)/RSSR couples by reference to (SCN)2(1-.)/2 SCN(1-) and/or I2(1-.)/2 I(1-) in pulse radiolysis experiments: E0 (CH3SSCH3(1+.)/CH3SSCH) +(1.391 +/- 0.003) V; E0 COOH(1+.)/lip(SS)COOH> +(1.13 +/- 0.01) V; and E0 COO(1-)(1+.)/lip(SS)COO(1-)> +(1.10 +/- 0.01) V .The paper also includes equilibrium constants for the underlying RSSR + X2(1-.) RSSR(1+.) + 2 X(1-) equilibria (X=SCN or I), and rate constants for the respective back and/or forward reactions.The results are discussed in the light of structural considerations and in relation to other redox couples involving sulphur-centred radial species.
- Bonifacic, Marija,Asmus, Klaus-Dieter
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p. 1805 - 1810
(2007/10/02)
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- Proof that the Absolute Configuration of Natural α-Lipoic Acid is R by the Synthesis of its Enantiomer from (S)-Malic Acid
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The absolute configuration of natural (+)-α-lipoic acid is confirmed to be R by the synthesis of its enantiomer from (S)-malic acid.
- Brookes, Michael H.,Golding, Bernard T.,Howes, David A.,Hudson, Alan T.
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p. 1051 - 1053
(2007/10/02)
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