1077-28-7

Basic information

• Product Name: DL-Thioctic acid
• Synonyms: 5 MG PNPP SUBSTRATE TABLETS REAGENT GR;(1)-ALPHA-LIPOIC ACID;DL-α-Lipoic acidUSP, 99.0-101.0% (Assay);5-(1,2)Dithiolan-3-yl-pentanoic acid for synthesis;TIMTEC-BB SBB003484;THIOOCTIC ACID;THIOCTIC ACID;(+-)-2-dithiolane-3-pentanoicacid
• CAS NO: 1077-28-7
• Molecular Formula: C₈H₁₄O₂S₂
• Molecular Weight: 206.33
• EINECS: 214-071-2
• Product Categories: Inhibitors;Pharmaceutical intermediates;Fatty & Aliphatic Acids, Esters, Alcohols & Derivatives;Substrates;Antioxidant;Biochemistry;Nutritional Supplements;Biochemics;Heterocycles;Sulfur & Selenium Compounds;Food & Flavor Additives;Miscellaneous Compounds
• Mol File: 1077-28-7.mol

Chemical Properties

• Melting Point: 60-62 °C
• Boiling Point: 160-165 °C(lit.)
• Flash Point: 160-165°C
• Appearance: Yellow/Crystals or Crystalline Powder
• Density: 1.2888 (rough estimate)
• Refractive Index: 1.5200 (estimate)
• Storage Temp.: 2-8°C
• Solubility: ethanol: 50 mg/mL
• PKA: 4.75±0.10(Predicted)
• Water Solubility: 0.9 g/L (20 ºC)
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,9326
• BRN: 81853
• CAS DataBase Reference: DL-Thioctic acid(CAS DataBase Reference)
• NIST Chemistry Reference: DL-Thioctic acid(1077-28-7)
• EPA Substance Registry System: DL-Thioctic acid(1077-28-7)

Safety Data

• Hazard Codes: Xn
• Statements: 22-20/21/22
• Safety Statements: 37/39-26-24/25-36-36/37/39
• WGK Germany: 3
• RTECS: JP1192000
• Hazardous Substances Data: 1077-28-7(Hazardous Substances Data)

Usage

Chemical Properties

Light-Yellow Solid

Originator

Neurium,Hexal

Uses

Different sources of media describe the Uses of 1077-28-7 differently. You can refer to the following data:
1. Lipoic acid [CAS: 1077-28-7] (6,8-dimercaptooctanoic acid), a lipophilic endogenous disulfide that can be reduced to the dithiol dihydrolipoic acid, protects against free-radical-mediated injury both in vivo and in vitro.
2. thioctic acid is also known as alpha lipoic acid. It is an anti-oxidant.
3. (±)-α-Lipoic acid has been used in in vitro lipoylation studies and in the pyruvate dehydrogenase complex (PDC)-pyruvate dehydrogenase kinase (PDHK) functional assay. It has also been used to investigate its antioxidative effect on developing cerebellum of rats exposed to arsenic during postnatal period.
4. A fat-metabolism stimulator

Manufacturing Process

To a suspension of 106 g of anhydrous aluminum chloride in 450 ml of carbontetrachloride is added dropwise, with vigorous stirring, 70 g of ethyl 8- chloroformylvalerate (H. Bergs, C. Wittfeld and H. Frank, Ber., 67B, 1622 (1947)). The temperature is maintained at 25°C. The cooling bath is removed and ethylene is passed in for a period of 2 hours. The reaction mixture is poured onto cracked ice, the organic layer separated, and the aqueous layer extracted with 200 ml of chloroform. The combined organic extracts are dried over anhydrous sodium sulfate and the solvent removed in vacuo. The dark colored oil remaining, crude ethyl 8-chloro-6-oxooctanoate is distilled in vacuo through a 6 in. Vigreaux column. After small forerun, the main fraction, 48-54 g (72-80%), B.P. 112-114°C (2 mm.); n25 D1-4485, is collected.Redistilled thiolacetic acid (14.7 g) is cooled in an ice-bath and neutralized to the phenolphthalein end-point with a 10% solution of potassium hydroxide in ethanol (approximately 135 ml required). To this solution is added 29 g of ethyl-6,8-dibromooctanoate and the mixture is stirred and heated under reflux in an atmosphere of nitrogen for 5 hours. The reaction mixture, which contains ethyl 6,8-diacetyl-mercaptooctanoate, is cooled and 35 g of potassium hydroxide (85%) is added. The reaction mixture is stirred at room temperature in an atmosphere of nitrogen for 17 hours, then acidified (pH less than 1) with 6 N hydrochloric acid. Ethanol is removed in vacuo, sufficient water is added to dissolve the inorganic solids and the mixture is extracted with two 150 ml portions of chloroform. To the combined organic extracts, which contain 6,8-dimercaptooctanoic acid , is added 575 ml of chloroform and 210 ml of water. This mixture is stirred vigorously in an atmosphere of nitrogen While sufficient iodoform reagent (R. L. Shriner and R. C. Fuson, "Identification of Organic Compounds," 2nd. Ed., John Wiley and Sons, New York, N.Y., 1940, p. 53) is added dropwise during a 6 hour period to give a permanent brown color. Approximately 185 ml of iodoform reagent is required. The organic layer is separated, washed with 500 ml of 1% sodium thiosulfate solution, and then extracted with two 250 ml portions of 5% sodium bicarbonate solution. The aqueous extracts are acidified (pH less than 1) with 6 N hydrochloric acid and extarcted with two 125 ml portions of chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and the solvent is then removed in vacuo. The yellow viscous oil remaining solidifies when cooled and scratched. This solid material is extracted with three 300 ml portions of boiling Skelly B solvent (essentially nhexane). The combined extracts are seeded with crystalline DL-α-lipoic acid and allowed to stand at room temperature overnight and then in a refrigerator for several hours. Large yellow crystals separate, M.P. 60.5-61.5°C. The yield of product is 10.8-12.3 g (60-68%). 1,2-Dithiolane-3-pentanoic acid was recrystallized from Skelly B solvent, M.P. 61-62°C.

Brand name

Liposan;Thioactacid.

Therapeutic Function

Growth factor, Lipotropic, Detoxicant

Synthesis Reference(s)

Journal of the American Chemical Society, 79, p. 6483, 1957 DOI: 10.1021/ja01581a033

General Description

Oxidized form. Has antioxidant properties. Growth factor for many bacteria and protozoa.

Flammability and Explosibility

Notclassified

Pharmaceutical Applications

Lipoic acid(ALA), also known as α-lipoic acid (alpha-lipoic acid) or thioctic acid, has the formula C8H14S2O2 and systematic name 5-(1,2-dithiolan-3-yl)pentanoic acid. It contains a disulfide group, which can be transformed in the body to a dithiol group. ALA has been on the market since the 1950s as a dietary supplement. It is a natural antioxidant usually made by the body. The advantage of ALA over other antioxidants such as vitamin C and E is that it is soluble both in water and in fat. Researchers in the former Soviet Union found that ALA can chelate mercury once it is transformed into the dithiol-containing compound. ALA can penetrate both the blood–brain barrier and the cell membrane and therefore would be a very interesting chelating agent. Nevertheless, there is much debate about its mode of action, side effects and effectiveness. Other antidotes, such as BAL and DMSA, are more efficient in the removal of heavy metals. ALA has not received FDA approval as a chelating agent, but it is still sold as a food supplement.

Biochem/physiol Actions

Antioxidant and coenzyme needed for the activity of enzyme complexes such as those of pyruvate dehydrogenase and glycine decarboxylase. Exogenous thioctic acid is reduced intracellularly by two or more enzymes. The reduced form then influences a number of cell processes by direct radical scavenging, recycling of other antioxidants, increasing glutathione synthesis, and modulating transcription factor activity particularly that of NF-κB. Decreases the phagocytosis of myelin by macrophages.

Purification Methods

It forms yellow needles from cyclohexane or hexane and has been distilled at high vacuum; and sublimes at ~90o and very high vacuum. It is insoluble in H2O but dissolves in alkaline solution. [Lewis & Raphael J Chem Soc 4263 1962, Soper et al. J Am Chem Soc 76 4109, Reed & Niu J Am Chem Soc 77 416 1955, Tsuji et al. J Org Chem 43 3606 1978, Calvin Fed Proc USA 13 703 1954.] The S-benzylisothiuronium salt has m 153-154o (evacuated capillary, from MeOH), 132-134o, 135-137o (from EtOH). The dand lforms have m 45-47.5o and [] D 23 ±113o (c 1.88, *C6H6) and have UV in MeOH with max at 330nm ( 140). [Beilstein 19/7 V 237.] The reduced form, (±)-6,8-dimercaptooctanoic acid, [7516-48-5] M 208.3, is a light yellow liquid which is sold in sealed ampoules.

Synthetic route

1,2-dithiolane-3-pentanoic acid (1077-28-7) + water (7732-18-5) + zinc(II) oxide → [Zn(II)(DL-α-lipoate)2(H2O)2]

Conditions	Yield
In water pouring ligand soln. over compressed pellet of Zn-compd.; crystn. on surface of pellet (several d); hand sepn.; elem. anal.;

smithsonite (743369-26-8) + 1,2-dithiolane-3-pentanoic acid (1077-28-7) + water (7732-18-5) → [Zn(II)(DL-α-lipoate)2(H2O)2]

Conditions	Yield
In water pouring ligand soln. over compressed pellet of Zn-compd.; crystn. on surface of pellet (several d); hand sepn.;

hydrozincite + 1,2-dithiolane-3-pentanoic acid (1077-28-7) + water (7732-18-5) → [Zn(II)(DL-α-lipoate)2(H2O)2]

Conditions	Yield
In water pouring ligand soln. over compressed pellet of Zn-compd.; crystn. on surface of pellet (several d); hand sepn.;

1,2-dithiolane-3-pentanoic acid (1077-28-7) + copper(II) oxide → [Cu(II)(DL-α-lipoate)2]2 (172372-30-4)

Conditions	Yield
In water pouring ligand soln. over compressed pellet of Cu-compd.; crystn. on surface of pellet (several d); hand sepn.;

1,2-dithiolane-3-pentanoic acid (1077-28-7) + copper(l) chloride → catena-poly-[Cu(I)(DL-α-lipoic acid)Cl] (185566-77-2)

Conditions	Yield
With HCl In hydrogenchloride N2-atmosphere; addn. of excess CuCl (in 4 M HCl) to ligand (in 0.5 M HCl) at 60°C; crystn. after cooling to room temp.; elem. anal.;
In water N2-atmosphere; pouring ligand soln. over compressed pellet of CuCl; crystn. on surface of pellet (several d); hand sepn.;

malachite + 1,2-dithiolane-3-pentanoic acid (1077-28-7) → [Cu(II)(DL-α-lipoate)2]2 (172372-30-4)

Conditions	Yield
In water pouring ligand soln. over compressed pellet of Cu-compd.; crystn. on surface of pellet (several d); hand sepn.;

malachite + 1,2-dithiolane-3-pentanoic acid (1077-28-7) → [Cu(II)(DL-α-lipoate)2]2 (172372-30-4)

Conditions	Yield
In water pouring ligand soln. over compressed pellet of Cu-compd.; crystn. on surface of pellet (several d); hand sepn.; elem. anal.;

Upstream product

• 462-20-4 dihydrolipoic acid 
• 41324-23-6 methyl 6-oxooct-7-enoate 
• 100053-64-3 8-acetylsulfanyl-6-oxo-octanoic acid methyl ester 
• 101277-59-2 8-benzylsulfanyl-6-oxo-octanoic acid methyl ester 
• 1077-28-7 Thioctic acid 
• 46236-19-5 1,2-dithiolane-3-pentanoic acid methyl ester 
• 1892-29-1 bis(2-hydroxyethyl) disulfide 
• 16096-98-3 trans-1,2-dithiane-4,5-diol 
• 131760-68-4 1,2-dimethyl-3,8-dioxo-1,2,5,6-diazadithiocane 
• 138152-63-3 6,8-Dibromoctansaeure 
• 88987-43-3 5-(2,2-Dimethyl-3-oxo-3λ⁴-[1,3]dithian-4-yl)-pentanoic acid 
• 114113-97-2 5-((7R,10S)-7-Isopropyl-10-methyl-1-oxo-1λ⁴,5-dithia-spiro[5.5]undec-2-yl)-pentanoic acid 
• 462-20-4 (+)-Dihydrolipoic acid 
• 462-20-4 (-)-Dihydrolipoic acid 

Downstream Products

• 119365-69-4 (R)-6,8-dimercaptooctanoic acid 
• 1365619-36-8 2-(2-(4-N-(4-(1,2-dithiolane)pentanecarboxy)aminophenyl))ethylamino-N⁽⁶⁾-(2,2-diphenylethyl)adenosine-5'-N-ethylcarboxamide 
• 1365619-29-9 2-(2-(4-N-(4-(1,2-dithiolane)pentanecarboxy)aminophenyl))ethylamino-2',3'-isopropylideneadenosine-5'-N-ethylcarboxamide 
• 940-69-2 lipoamide 
• 462-20-4 dihydrolipoic acid 
• 25631-51-0 4-(5-[1,2]dithiolan-3-yl-valerylamino)-benzoic acid ethyl ester 
• 1200-22-2 (R)-1,2-dithiolane-3-pentanoic acid 
• 16096-98-3 trans-1,2-dithiane-4,5-diol 
• 131760-68-4 1,2-dimethyl-3,8-dioxo-1,2,5,6-diazadithiocane 
• 138715-29-4 (4S,5R)-3-<5-(1,2-dithiolan-3-yl)-1-oxopentyl>-4-methyl-5-phenyloxazolidine-2-selone 
• 78010-69-2 5-[1,2]Dithiolan-3-yl-pentanoic acid 1-(4-chloro-benzoylamino)-2-(4-chloro-phenyl)-2-oxo-ethyl ester 
• 1892-29-1 bis(2-hydroxyethyl) disulfide 
• 62-46-4 α-lipoic acid radical cation 
• 184045-25-8 5-[1,2]Dithiolan-3-yl-pentanoic acid 2-{2-[2-(methoxy-phenyl-methyl)-4-methyl-thiazol-5-yl]-ethoxymethyl}-benzyl ester 

Relevant articles and documents

Catalytic Oxidation of Dithiols by a Semisynthetic Enzyme

The semisynthetic enzyme flavopapain (1C), obtained from the alkylation of Cys-25 of papain with 8α-(bromoacetyl)-10-methylisoalloxazine (1B), was found to be an effective catalyst for the oxidation of dithiols to disulfides.The k2/Ks values for the oxidation of d,l-dihydrolipoamide and d,l-dihydrolipoic acid determined from anaerobic single-reaction stopped-flow kinetics were 4400 and 3400 M-1 s-1, respectively.These values were, respectively, 126 and 200 times larger than the second-order rate constants for oxidation of d,l-dihydrolipoamide and d,l-dihydrolipoic acid by the model flavin 8-acetyl-10-methylisoalloxazine (1A).Under aerobic turnover conditions using the synthetic dye MTT as an electron acceptor, the kcat and Km values for the oxidation of d,l-dihydrolipoamide by 1C were in approximate agreement with the k2 and Ks values, indicating that the rate-limiting step of catalytic cycle is substrate oxidation rather than oxidation of dihydroflavopapain.When compared with flavopapains 2C and 3C , flavopapain 1C is the most efficient catalyst.The circular dichroic spectra of flavopapains 1C, 2C and 3C were recorded, and the dissociation constants of the sulfite addition complexes of 1C and 2C were determined.From these kinetic and physical studies, the differences in catalytic activity of 1C, 2C, and 3C were judged to be due to changes in the flavin orientation within the active site and the ability to fit the substrate into a productive reaction conformation.

A Reagent for Reduction of Disulfide Bonds in Proteins That Reduces Disulfide Bonds Faster Than Does Dithiothreitol

We have synthesized a new reagent - N,N'-dimethyl-N,N'-bis(mercaptoacetyl)hydrazine (DMH) - for the reduction of disulfide bonds in proteins.DMH reduces disulfide bonds 7 times faster than does dithiothreitol (DTT) in water at pH 7.DMH reduces mixed disulfides of cysteine proteases (papain and ficin) especially rapidly (30 times faster than DTT).DMH (ε0 = -0.300 V) reduces noncyclic disulfides completely, although it is less strongly reducing than DTT (ε0 = -0.356 V).

Equilibrium Constants for Thiol-Disulfide Interchange Reactions: A Coherent, Corrected Set

Equilibrium constants (Keq) for the thiol-disulfide interchange reactions between dithiothreitol (DTT) and lipoic acid (14.2 +/- 0.7), lipoic acid (Lip) and mercaptoethanol (13.3 M +/- 1.0 M), and mercaptoethanol (ME) and glutathione (GSH or GSSG) (1.20 +/- 0.10) were measured in D2O at pD 7.0 by 1H NMR spectroscopy.Two of these equilibrium constants were also measured in D2O/CD3OD.These values are compared with those obtained by other methods.A coherent set of values for the equilibrium constants between DTT or ME and thiols having a range of structures was assembled (Table III).The recommended value for the equilibrium constant between DTT and GSH is 210 M (Keq = ox>2/(red>)).

Thiolates of arsenic(III), antimony(III), and bismuth(III) with dl-α-dihydrolipoic acid

Lipoic acid can be reduced to dihydrolipoic acid free of lipoic acid without using deoxygenated solvents. Dihydrolipoic acid reacted with phenylarsine oxide, As2O3, and AsCl3, SbCl 3 but not Sb2O3, and Bi2O 3, BiCl3, and Bi(NO3)3· 5H2O in various solvents giving thiolates. When the reactions were done in methanol, the HCl and HNO3 released caused esterification of the -COOH group. The reaction with As(III) compounds was sensitive to dioxygen, leading to production of lipoic acid derivatives as well, arsenite being particularly active for the autoxidation. Physical (1H NMR) and chemical [reactivity of >M-Cl and >Bi(NO3)] properties of the adducts are described. The six-membered dihydrolipoic acid complexes reacted with stoichiometric amounts of British Anti-Lewisite releasing the dihydrolipoic acid by forming the corresponding complexes of British Anti-Lewisite. Graphical Abstract: [Figure not available: see fulltext.]

A lipoic acid injection and its preparation method (by machine translation)

The present invention to provide a high safety of the thioctic acid preparation, including lipoic acid, the solvent component, characterized in that the vinyl octoate in preparation, containing lipoic acid ethylenediamine double-substituent, wherein the lipoic acid ethylenediamine double-substituent content are not higher than 0.2%. The lipoic acid preparation high safety, low toxicity, can be better clinical efficacy of lipoic acid. (by machine translation)

Preparation method of R-(+)-lipoic acid

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.

Oxidation-triggered aggregation of gold nanoparticles for naked-eye detection of hydrogen peroxide

Naked-eye detection of H2O2 was realized based on the color change of gold nanoparticles upon aggregation. The removal of polyethylene glycol chains from the nanoparticle surface under H2O2 treatment let to the exposure of inner hydrophobic ligands, causing the nanoparticle aggregation in aqueous medium. This detection system shows a wide dynamic range in the μM scale and a distinguishable limit of 10 μM.

Chirality induction and chiron approaches to enantioselective total synthesis of α-lipoic acid

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.

Polyphenolic Bioprecursors

Cosmetic and therapeutic, in particular dermatological bioprecursors have the formula [A]n—PP—[B]m wherein PP is a polyphenol radical in which each hydroxyl function is protected by a group A or a group B, A is a saturated or unsaturated, substituted or unsubstituted alkyl radical having 1 to 20 carbon atoms which is bonded to the polyphenol, n is an integer not less than 1, and B is a precursor of a biologically active molecule, which is also bonded to the polyphenol, and m is an integer also not less than 1.

Process For Purifying Thioctic Acid in Water

Process for purifying thioctic acid in water comprising the following steps: a) dissolving the thioctic acid in an aqueous alkaline solution or alternatively dissolving a thioctic acid salt, if necessary adjusting the pH to alkaline values, b) acidifying the solution from step (a) with an acid chosen from the class consisting of sulfuric acid, phosphoric acid, methanesulfonic acid to a pH between 5.4 and 5.8. c) isolating the thioctic acid precipitated in step (b) by conventional methods.