α-Lipoic Acid Standardized herbal extract Pharmaceutical intermediates 6,8-Thioticacid

Description:

DL-α-Lipoic acid is a cyclic disulfide antioxidant that interconverts with its reduced dithiol form. It is an essential cofactor for decarboxylation reactions of the citric acid cycle, and acts as a general antioxidant. DL-α-lipoic acid can act as a direct radical scavenger, as a cofactor to regenerate reduced glutathione, and as a metal chelator.

Chemical Formula:

Basic Parameters:

Melting point	60-62 °C
Product category	Dietary supplement   Nutritional supplement
Solubility	ethanol: 50 mg/mL
MW	206.33
Water solubility	0.9 g/L (20 ºC)

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 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.

Synthetic route:

The Common Uses

● 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.

● Thioctic acid is also known as alpha lipoic acid. It is an anti-oxidant.

● A fat-metabolism stimulator

● 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.

Pharmaceutical Applications:

α-Lipoic Acid 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.