Alpha Lipoic Acid (ALA) is a new type of
antioxidant and an important coenzyme in organism. Its chemical name is 1,2-dithiolane-3-pentanoic acid. It is soluble in both water and fat. It acts as a coenzyme in the tricarboxylic acid cycle reaction in organism, especially in the decarboxylation reaction of pyruvate and other α - ketoacids. It catalyzes the process in mitochondria that sugars, fats and proteins are converted from metabolites produced by anaerobic oxidation to starting substances of aerobic oxidation [1].
α -
Lipoic Acid is a kind of vitamin drugs. Its antioxidant effect is better than vitamins A, C and e. it can directly eliminate harmful hydroxyl radicals and reactive oxygen species in
Aqueous Solution [1]. It is the most effective natural antioxidant known by human beings. It is known as "universal antioxidant". It is mainly used in the treatment of liver diseases in clinic, with antiviral effect and small side effects [2,3].
This product is light yellow crystalline powder, almost tasteless, insoluble in water, soluble in ethanol, chloroform, ether. The synthesis methods include adipic acid method, cyclohexanone method, heptanoic acid-6-ene method [1-6]. These methods are not satisfactory either because the raw materials are not easy to obtain, or the steps are cumbersome, or the residual solvent in the product is high. α - lipoic acid was synthesized from ethyl 6,8-dichlorooctanoate by cyclization, hydrolysis and purification. The total yield was 42.6%. The method has the advantages of easy to obtain raw materials, less reaction steps, simple operation, high yield, and low residual
Solvents in the products, which can meet the needs of customers at home and abroad
Demand, with good market prospects.
1 experimental part
1.1 instruments and reagents
Lc-20at high performance liquid chromatograph, Shimadzu, Japan; gc9160 gas chromatograph, Hangzhou Kangdi instrument and Equipment Co., Ltd.; 79-1 magnetic stirring, Jintan medical instrument factory, Jiangsu Province; jj-1 mechanical stirrer, Jiangsu Jintan ronghua Instrument Manufacturing Co., Ltd.; SHB-B95 circulating water vacuum pump, Beijing kekejia Experimental Instrument Co., Ltd.; wrs-1b melting point tester, Shanghai sildake Science Instrument Co., Ltd.
Ethyl 6,8-dichlorooctanoate, industrial product (produced by Suzhou Bolin Industrial Co., Ltd., 95%); sodium sulfide, industrial product; sulfur powder, ethanol, toluene, sodium hydroxide and hydrochloric acid, all of which are chemically pure; α - lipoic acid, standard product (produced by sigma Aldrich, USA, 99.5%).
1.2 analysis method
HPLC: chromatographic system: using octadecyl bonded silica gel as stationary phase, chromatographic column was 4.6 mm × 250 mm, detection wavelength was 215 nm, flow rate was 1.2 ml / min, column temperature was 35 ℃, column effect was not less than 1500 theoretical plates, tailing factor was less than 2, RSD of repeated injection was less than 2.0%; flow matching ratio was methanol ∶ 0.005 1 mol / L potassium dihydrogen phosphate solution: acetonitrile = 1160 ∶ 920 ∶ 180, adjust pH to 3.0 ~ 3.1 with phosphoric acid; buffer solvent: 0.005 mol / L potassium dihydrogen phosphate solution: acetonitrile = 1 ∶ 1; inject equal volume (20 μ L) of standard solution and sample solution respectively, record the main peak area.
GC: chromatographic system - packed column with 0.25-0.18 mm diameter divinylbenzene ethyl vinyl benzene polymer porous beads as stationary phase, column temperature 110 ℃, headspace temperature 110 ℃, headspace equilibrium time 60 ℃ The relative standard deviation (RSD) of repeated injection was less than 10%; the solvent was dimethyl sulfoxide, and the standard solution and sample solution were determined respectively
The sample was injected 2-3 times and the peak area was calculated.
1.3 experimental methods
1.3.1 preparation of ethyl lipoate (cyclization)
Put 120 ml ethanol, 40 g ethyl 6,8-dichlorooctanoate, 30 g sodium sulfide and 7.2 g sulfur powder into 1000 ml reaction flask, heat and reflux for 3 h, evaporate 1 / 3 ethanol, cool and filter to obtain clear cyclization solution.
1.3.2 preparation of sodium lipoate (hydrolysis)
Add 32.5 g of liquid alkali and 250 g of water into the cyclization solution, heat and reflux for 4 h to obtain the hydrolysate.
1.3.3 preparation of crude lipoic acid
Add 10% hydrochloric acid to the hydrolysate, adjust the pH to 1-2, extract with 400 ml toluene in three times, wash the organic layer with water, combine the toluene layers and evaporate all the toluene to obtain yellow crystal. 0% (HPLC).
1.3.4 refining of lipoic acid
Add 22 g crude product into 1000 ml reaction flask, add appropriate amount of dilute alkali, adjust to pH = 10, add appropriate amount of activated carbon after heating and dissolving, and filter. The filtrate was adjusted to pH = 2 with dilute hydrochloric acid, and 20 g of light yellow crystal was obtained with a yield of 42.6%. MP 60 ~ 62 ℃, content ≥ 99.5% (HPLC), residual solvent (GC): toluene ≤ 5ppm, ethyl acetate ≤ 5ppm, cyclohexane ≤ 5ppm, acetone ≤ 5ppm, all meet the requirements of customers.
2 Conclusion
α - lipoic acid was synthesized from
Ethyl 6.8-Dichlorooctanoate. The route was simple and the raw material was easy to obtain. The yield was 42.6%. The purity of α - lipoic acid prepared by this method is high. The HPLC analysis and melting point determination show that the content of α - lipoic acid is more than 99.5%, MP is 60 ~ 62 ℃. This method can be used for the synthesis of α - lipoic acid. The residual solvent of α - lipoic acid prepared by this method is less than 5 ppm, which meets the requirements of domestic and foreign customers and has a good market prospect.
