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Preparation method of lipoic acid impurities

A technology of lipoic acid and impurities, applied in the field of preparation of lipoic acid impurities, to achieve a good reaction route, improve reaction conditions, and avoid the formation of impurities

Inactive Publication Date: 2021-03-12
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ethyl 5-thietanyl pentanoate is an impurity produced during sulfide cyclization in the lipoic acid synthesis process, which belongs to the key process impurity, but there are few reports on its preparation method at present, 5-thietanyl The structural formula of ethyl valerate is as follows:

Method used

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  • Preparation method of lipoic acid impurities
  • Preparation method of lipoic acid impurities

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Embodiment 1

[0053] The present embodiment provides a kind of preparation method of lipoic acid impurity, the preparation method of described lipoic acid impurity comprises the following steps:

[0054] (1)N 2 Under protection, ethyl 6,8-dichlorooctanoate (10g, 0.041mol), sodium sulfide pentahydrate (7.5g, 0.045mol), tetrabutylammonium bromide (0.7g, 0.002mol) and water (50mL) The mixture was stirred and reacted at 45°C for 4h; sodium sulfite (10g, 0.079mol) was added and the temperature was raised to 80°C and stirred for 0.5h;

[0055] Aftertreatment: after the reaction solution is down to room temperature, extract with 30g toluene, and the extract is concentrated to obtain 5.1g oily liquid (the purity of 5-thietanylvaleric acid ethyl ester in this oily liquid is 7.8%); Purified by column chromatography, eluting with an eluent with a volume ratio of ethyl acetate / n-heptane=1 / 10 to obtain 1.6 g of ethyl 6,8-dichlorooctanoate (purity 88.6%) and 5-sulfur A mixture of ethyl heterocyclobutan...

Embodiment 2

[0060] The present embodiment provides a kind of preparation method of lipoic acid impurity, the preparation method of described lipoic acid impurity comprises the following steps:

[0061] (1)N 2 Under protection, a mixture of ethyl 6,8-dichlorooctanoate (50g, 0.207mol), sodium sulfide pentahydrate (37.5g, 0.223mol), tetrabutylammonium bromide (2g, 0.006mol) and water (50mL) The reaction was stirred at room temperature for 24h. Sodium sulfite (50g, 0.397mol) was added and the temperature was raised to 80°C and the reaction was stirred for 1h;

[0062] Post-treatment: After the reaction liquid was lowered to room temperature, it was extracted with 100 g of toluene, and concentrated to obtain 16 g of oily liquid (the purity of ethyl 5-thietanylvalerate in the oily liquid was 7.9%);

[0063] (2) Sulfur (2.7g, 0.084mol), tetrabutylammonium bromide (1g, 0.003mol) and water (50mL) were added to the oily liquid obtained in step (1), heated to 80°C under stirring, and A solution o...

Embodiment 3

[0067] The present embodiment provides a kind of preparation method of lipoic acid impurity, the preparation method of described lipoic acid impurity comprises the following steps:

[0068] (1)N 2 Under protection, ethyl 6,8-dichlorooctanoate (50g, 0.207mol), sodium sulfide pentahydrate (37.5g, 0.223mol), tetrabutylammonium bromide (2g, 0.006mol) and water (50mL) The mixture was stirred at 25°C for 24h. Sodium sulfite (50g, 0.397mol) was added and the temperature was raised to 80°C and the reaction was stirred for 1h;

[0069] Post-processing: After the reaction liquid was lowered to room temperature, it was extracted with 30 g of toluene to obtain a toluene liquid;

[0070] (2) Sulfur (2.7g, 0.084mol), tetrabutylammonium bromide (1g, 0.003mol) and water (50mL) were added to the toluene liquid obtained in step (1), heated to 80°C under stirring, and A solution of sodium sulfide pentahydrate (12 g, 0.071 mol) in water (30 mL) was added dropwise at temperature. After droppin...

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Abstract

The invention provides a preparation method of a lipoic acid impurity, and the method comprises the following steps: (1) mixing ethyl 6, 8-dichlorocaprylate and sodium sulfide to react, mixing with sodium sulfite to continue the reaction, and obtaining a mixture; (2) mixing the mixture obtained in the step (1) with sulfur and sodium sulfide for reaction, and then mixing with sodium sulfite for continuous reaction to obtain the 5-thietanyl ethyl valerate. According to the preparation method, distribution and formation reasons of impurities in the lipoic acid preparation process can be known, explanation of sources and trends of the impurities in lipoic acid is facilitated, a reaction route can be better designed, reaction conditions are improved, formation of the impurities is avoided, andthe product quality is improved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of lipoic acid impurities. Background technique [0002] Alpha lipoic acid (alpha lipoic acid) is a coenzyme that exists in mitochondria, similar to vitamins, and can eliminate free radicals that lead to accelerated aging and disease. Alpha lipoic acid enters the cells after being absorbed by the intestines in the body, and has both fat-soluble and water-soluble properties. Lipoic acid belongs to a class of compounds in B vitamins, a growth factor for yeast and some microorganisms, and acts as a coenzyme in a multi-enzyme system, catalyzing the oxidative decarboxylation of pyruvate into acetic acid and the oxidative decarboxylation of α-ketoglutarate into succinic acid Transacyl effect. [0003] α-lipoic acid contains a disulfide five-membered ring structure, has a high electron density, has significant electrophilicity and the ability...

Claims

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Application Information

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IPC IPC(8): C07D331/04
CPCC07D331/04
Inventor 孟德超石晓青孙晓彤
Owner SUZHOU FUSHILAI PHARMA CO LTD
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