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A kind of preparation method of lipoic acid oxidation impurity

A technology for oxidizing impurities and lipoic acid, applied in organic chemistry and other directions, can solve problems such as separation and purification

Active Publication Date: 2019-09-20
SHANDONG QIDU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

"Studies on the oxidation products of lipoic acid" (Journal of Vitaminology,1967,13(2):115-121), "Oxidation of.alpha.-lipoic acid"(Journal of Organic Chemistry,1975,40(1):58 -62), "Preparation and Separation of S-Oxides of a-Lipoic Acid" (Methods in Enzymology, 1979,62:137-145) also studied the synthesis of lipoic acid oxidation impurities, but did not study the four lipoic acid oxidation Separation and purification of impurity compounds

Method used

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  • A kind of preparation method of lipoic acid oxidation impurity
  • A kind of preparation method of lipoic acid oxidation impurity
  • A kind of preparation method of lipoic acid oxidation impurity

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Experimental program
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Effect test

Embodiment 1

[0026] A preparation method for lipoic acid oxidized impurities, characterized in that it comprises the following steps:

[0027] (1) Dissolve lipoic acid (1.00g, 4.9mmol, 1) in dichloromethane (5ml), then add N,N'-dicyclohexylcarbodiimide (0.95g, 4.9mmol), 4- Dimethylaminopyridine (0.60g, 4.9mmol) and methanol (0.47g, 14.7mmol) were stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was filtered. The filtrate was washed with 5% aqueous citric acid (10 ml), saturated sodium bicarbonate (10 ml), and saturated brine (10 ml), and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to obtain 0.90 g of a light yellow oily liquid, namely methyl lipoic acid (2i).

[0028] The reaction equation is:

[0029]

[0030] (2) Dissolve the crude lipoic acid methyl ester (2i, 0.90g, 4.1mmol) obtained in step (1) in dichloromethane (4.5ml), add m-chloroperoxybenzoic acid (0.83g, 4.1mmol, 85 %) stir...

Embodiment 2

[0037] (1) Lipoic acid (1.00g, 4.9mmol, 1) was dissolved in acetonitrile (10ml), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 0.94g, 4.9mmol), 4-dimethylaminopyridine (0.60g, 4.9mmol), benzyl alcohol (0.59g, 5.5mmol), stirred at room temperature for 4 hours, the reaction was completed, and the reaction solution was filtered. The filtrate was washed with 5% aqueous citric acid (10 ml), saturated sodium bicarbonate (10 ml), and saturated brine (10 ml), and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to obtain 1.30 g of benzyl lipoic acid (2ii) as a light yellow oily liquid.

[0038] The reaction equation is:

[0039]

[0040] (2) Dissolve the crude lipoic acid benzyl ester (2ii, 1.30g, 4.4mmol) obtained in step (1) in N,N-dimethylformamide (13ml), add tert-butyl hydroperoxide solution (1.6 ml, 8.8mmol, 5.5mmol / ml) was stirred at room temperature for 8 hours, the reaction was completed, and conce...

Embodiment 3

[0047] A preparation method for lipoic acid oxidized impurities, characterized in that it comprises the following steps:

[0048](1) Dissolve lipoic acid (1.0g, 4.9mmol, 1) in N,N-dimethylformamide (20ml), and then add N,N'-bis(2,6-diisopropylbenzene Base) carbodiimide (1.78g, 4.9mmol), 4-dimethylaminopyridine (0.60g, 4.9mmol), isopropanol (0.88g, 14.7mmol), stirred at room temperature for 4 hours, after the reaction was completed, filtered The reaction solution. The filtrate was washed with 5% aqueous citric acid (10 ml), saturated sodium bicarbonate (10 ml), and saturated brine (10 ml), and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to obtain 1.05 g of isopropyl lipoic acid (2iii) as a yellow oily liquid.

[0049] The reaction equation is:

[0050]

[0051] (2) The crude product of lipoic acid isopropyl ester (2iii, 1.05g, 4.2mmol) obtained in step (1) was dissolved in acetonitrile (21ml), added peracetic acid (8.9...

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Abstract

The invention relates to a chemical preparation method of thioctic acid oxidation impurities, and belongs to the technical field of medicine synthesis. The structural formula of the thioctic acid oxidation impurities is shown in the description. The preparation method of the thioctic acid oxidation impurities comprises the following steps: preparing an ester from thioctic acid and an alcohol in an organic solvent under the action of a condensing agent; dissolving the obtained alcohol ester compound of thioctic acid in an organic solvent, processing the obtained solution by an oxidant to generate four oxidation products of thioctate, and carrying out column chromatography purification according to the Rf vale difference of the compounds to obtain four intermediate compounds; and respectively hydrolyzing the four intermediate compounds in an alkaline aqueous solution to obtain the four thioctic acid oxidation impurity compounds I, II, III and IV. The preparation method of the thioctic acid oxidation impurity compounds has the advantages of obtaining of single oxidation impurities, simplicity, easiness in implementation, and easiness in enforcement.

Description

technical field [0001] The invention relates to a preparation method of lipoic acid oxidized impurities, belonging to the technical field of pharmaceutical synthesis. Background technique [0002] Alpha lipoic acid is a vitamin-like mitochondrial coenzyme that eliminates free radicals that accelerate aging and cause disease. Lipoic acid has both fat-soluble and water-soluble properties, can be absorbed by various tissues and organs, and provides comprehensive performance for the human body. It is an antioxidant with "the most functions and the strongest activity" among all antioxidants. [0003] Foreign studies have proved that lipoic acid can significantly improve the clinical symptoms caused by diabetic peripheral neuropathy, and it has been recommended as an adjuvant treatment for diabetic peripheral neuropathy in Germany for more than 30 years. In addition, lipoic acid can balance blood sugar, promote the absorption of glucose, improve the blood sugar control of diabeti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D339/04
Inventor 李宗涛张涛刘文坤郑亮张莉翟民康乐杨学谦任继波
Owner SHANDONG QIDU PHARMA