A kind of synthetic method of thioctic acid

Abstract

The present invention belongs to the field of organic synthesis, and in particular to a method for synthesizing thioctic acid. The method for synthesizing thioctic acid includes hydrolyzing 6,8-dichlorooctanoic acid ethyl ester into 6,8-dichlorooctanoic acid sodium, and then 6,8-dichlorooctanoic acid sodium is subjected to thioreaction with sodium disulfide in the presence of an additive to obtain sodium thioctic acid, wherein the additive is selected from at least one of sodium octenyl succinate starch, cyclodextrin, mannitol and erythritol, and then sodium thioctic acid is acidified and purified to obtain thioctic acid. The method provided by the present invention can significantly improve the yield of thioctic acid.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing thioctic acid. Background Art

[0002] α-Lipoic acid (RLA), also known as lipoic acid, is a dithiol compound synthesized from octanoic acid by enzymatic reactions in mitochondria. Lipoic acid is a key coenzyme factor in the oxidative dehydrogenase complex of pyruvate and other α-keto acids in mitochondria, and plays a key role in mitochondrial energy metabolism. Lipoic acid has significant antioxidant capacity. Lipoic acid is widely used in the medical field to prevent and treat diabetes and its related complications. In the field of health products, it is mainly used to scavenge free radicals in the body, prevent lipid peroxidation, and protect cells from oxidative damage, so as to achieve the purpose of preventing and assisting in the treatment of diseases.

[0003] Lipoic acid is a white or light yellow, odorless powder or crystalline substance. It is an eight-carbon fatty acid with a chemical name of 1,2-dithiolane-3-pentanoic acid, in which a five-membered ring is formed by a disulfide bond between C6 and C8, and its structure is shown in the following formula (1). Since the disulfide bond in the molecular structure is unstable, it will cause the disulfide bond in the five-membered ring to break when exposed to heat or light, and it is easy to produce very unstable free radicals. At the same time, the disulfide bond also has the properties of a dynamic covalent bond, so lipoic acid is very easy to interact with other molecules of lipoic acid at the position of the disulfide bond to form a polymer of lipoic acid.

[0004]

[0005] At present, the main method for preparing lipoic acid in industry at home and abroad is a process using adipic acid as raw material, first synthesizing ethyl 6,8-dichlorooctanoate, then thiolation of ethyl 6,8-dichlorooctanoate with sodium disulfide, then alkaline hydrolysis to obtain sodium lipoate, then acidification to obtain crude lipoic acid, and finally crystallization to obtain lipoic acid product. It is precisely because of the instability of the disulfide bond in lipoic acid that lipoic acid polymerizes and impurities such as trisulfur byproducts are easily produced during its synthesis. For example, CN110003168A discloses a method for preparing lipoic acid using ethyl 6,8-dichlorooctanoate as raw material, which includes the synthesis of ethyl lipoate, the hydrolysis of ethyl lipoate, the acidification of sodium lipoate and the purification of crude lipoic acid. The yield of this method is generally only less than 70%. In view of the problems of existing lipoic acid synthesis methods such as many by-products, low reaction yields, long saponification reaction time, and complex post-treatment, it is still of great significance to develop a lipoic acid synthesis process with fewer by-products, higher reaction yields, and more environmental protection. Summary of the invention

[0006] The purpose of the invention is to overcome the defect of low yield when synthesizing lipoic acid by the existing method, and to provide a new lipoic acid synthesis method, which can significantly improve the lipoic acid yield.

[0007] Specifically, the synthesis method of thioctic acid provided by the present invention comprises hydrolyzing ethyl 6,8-dichlorooctanoate into sodium 6,8-dichlorooctanoate, and then subjecting the sodium 6,8-dichlorooctanoate to a thiolation reaction with sodium disulfide in the presence of an additive to obtain sodium thioctic acid, wherein the additive is selected from at least one of sodium octenyl succinate starch, cyclodextrin, mannitol and erythritol, and then acidifying the sodium thioctic acid and purifying it to obtain thioctic acid.

[0008] After in-depth and extensive research, the inventors of the present invention found that the reason why the yield of synthesizing lipoic acid using the existing method is low is mainly attributed to the following four aspects: (1) the thiolation reaction is a two-phase system. The organic solution of 6,8-dichlorooctanoic acid ethyl ester and the sodium disulfide aqueous solution undergo a thiolation reaction under the action of a phase transfer catalyst, tetrabutylammonium bromide, to obtain lipoic acid ethyl ester. During the reaction, since the polarity of the generated product is greater than that of the raw material, it is easier to enter the aqueous phase under the action of the phase transfer catalyst to react with sodium disulfide. As the concentration of the product increases, the by-product with a trisulfide structure also gradually increases, resulting in a low yield of the thiolation reaction; (2) since the disulfide structure of lipoic acid is easily polymerized, (1) Due to the unstable nature of the reaction, the existing method adopts the method of increasing the amount of water to dilute the substrate to avoid the occurrence of polymerization reaction as much as possible. However, due to the low reaction concentration and reaction conversion rate caused by the increase of water, a large amount of polymerized lipoic acid will still be produced during the long-term high-temperature saponification and hydrolysis process, resulting in a low reaction yield; (2) Since lipoic acid is also very easy to polymerize under a low pH environment to form some obvious light yellow spherical colloid substances, it is difficult to avoid the production of the polymerized lipoic acid by-product in the traditional acidification process; (3) Due to the above reasons, there are many by-products, the reaction purification is difficult, the post-processing is complicated, and it is easy to cause the loss of the target product.

[0009] The key of the present invention is to first hydrolyze 6,8-dichlorooctanoic acid ethyl ester into 6,8-dichlorooctanoic acid sodium and place the thiolation and acidification reaction process in the presence of at least one of octenyl succinate starch sodium, cyclodextrin, mannitol and erythritol, thereby significantly improving the yield of thioctic acid. It is speculated that the reason may be that: on the one hand, if 6,8-dichlorooctanoic acid ethyl ester is hydrolyzed into 6,8-dichlorooctanoic acid sodium, the subsequent thiolation reaction system can be changed from a traditional two-phase system to a single-phase system, avoiding the use of a phase transfer catalyst, while avoiding the thiolation reaction product and sodium disulfide to generate a trisulfide structure by-product, thereby improving the reaction yield; on the other hand, octenyl succinate starch sodium, cyclodextrin, mannitol and erythritol can destroy the surface activity of sodium thioctic acid during the reaction process, thereby avoiding the generation of by-products such as polymerized thioctic acid, and at the same time, sodium thioctic acid can be prevented from being placed in a high temperature and strong base reaction system for a long time, thereby improving the reaction yield.

[0010] In a preferred embodiment, when the acidification method includes uniformly mixing the sodium thioctic acid aqueous solution and the organic solvent I, cooling to 5-10° C., slowly dropping the hydrochloric acid solution, stirring the reaction for 5-15 minutes after the dropwise addition is completed, and then standing for stratification, that is, when the organic phase-aqueous phase is used for acidification, the generated thioctic acid can be directly extracted into the organic phase during the reaction, which can avoid the thioctic acid from staying for a long time under strong acidic conditions, reduce the occurrence of side reactions, and is more conducive to improving the yield of thioctic acid. DETAILED DESCRIPTION

[0011] The lipoic acid synthesis method provided by the present invention comprises the following steps: hydrolyzing ethyl 6,8-dichlorooctanoate into sodium 6,8-dichlorooctanoate, and then subjecting the sodium 6,8-dichlorooctanoate to a thiolation reaction with sodium disulfide in the presence of an additive to obtain sodium lipoate, wherein the additive is selected from at least one of sodium octenyl succinate starch, cyclodextrin, mannitol and erythritol, and then acidifying the sodium lipoate and purifying it to obtain lipoic acid.

[0012] In a preferred embodiment, the hydrolysis method comprises mixing 6,8-dichlorooctanoic acid ethyl ester and phosphate buffer solution evenly, adjusting the pH value to 6.5-7.5, adding immobilized lipase for hydrolysis, maintaining the pH value of the reaction system in the range of 6.5-7.5, filtering after the hydrolysis is completed, and obtaining a hydrolyzate containing 6,8-dichlorooctanoic acid sodium. The phosphate buffer solution is a solution composed of sodium dihydrogen phosphate and disodium hydrogen phosphate. Among them, the concentration of the sodium dihydrogen phosphate can be 0.01-0.2 mol / L. The amount of the phosphate buffer solution is based on adjusting the pH value of the reaction system to 6.5-7.5. The immobilized lipase can be various existing substances that bind lipase to solid materials and have the catalytic reaction characteristics of catalyzing the conversion of 6,8-dichlorooctanoic acid ethyl ester into 6,8-dichlorooctanoic acid sodium, which is preferably selected from at least one of Lipozyme TLIM, LipasePSIM, Novozym 435 and Novozyme 40086. The amount of the immobilized lipase can generally be 20% to 50% of the weight of 6,8-dichlorooctanoic acid ethyl ester, such as 20%, 30%, 40%, 50% and any value therebetween. The immobilized lipase can be repeatedly applied to the reaction more than 20 times after simple filtration recovery. The hydrolysis conditions preferably include a temperature of 20 to 40° C., a pH of 6.5 to 7.5, and a time of 8 to 20 hours.

[0013] In a preferred embodiment, the thiolation method comprises adding additives and water to a hydrolyzate containing sodium 6,8-dichlorooctanoate, then dripping sodium disulfide aqueous solution into the reaction system, continuing the reaction for 5 to 50 minutes after the dripping is completed, standing and stratifying, and the resulting aqueous phase is a sodium thioctic acid aqueous solution. The additive is selected from at least one of sodium octenyl succinate starch, cyclodextrin, mannitol and erythritol, which can destroy the surface activity of sodium thioctic acid, inhibit sodium thioctic acid aggregation to produce micelles, and reduce the solubility of thioctic acid in water, thereby avoiding the production of by-products such as polymerized thioctic acid; at the same time, sodium thioctic acid is prevented from being placed in a high temperature and strong base reaction system for a long time, thereby improving the reaction yield. The cyclodextrin can be selected from at least one of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. The amount of the additive is preferably 1% to 5% of the weight of 6,8-dichlorooctanoic acid ethyl ester, such as 1%, 2%, 3%, 4%, 5% and any value therebetween.

[0014] The sodium disulfide aqueous solution can be obtained commercially or prepared according to various existing methods. In a preferred embodiment, the sodium disulfide aqueous solution is prepared according to the following method: sodium sulfide is dissolved in water and sulfur powder is added, and then the temperature is raised to 65-85°C. After the sulfur powder is completely dissolved, the sodium disulfide aqueous solution is obtained by stirring and reacting for 45-60 minutes. Among them, the molar ratio of the sodium sulfide to the sulfur powder is preferably (1-1.1):1. The sodium sulfide can be used in the form of its hydrate, such as sodium sulfide nine water, sodium sulfide five water, etc. Relative to 100g of sodium sulfide, the amount of water can be 150-250mL. The amount of the sodium disulfide aqueous solution is preferably 150% to 250% v / w (such as 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250% v / w and any value therebetween) of the weight of 6,8-dichlorooctanoic acid ethyl ester, that is, relative to 100 kg of 6,8-dichlorooctanoic acid ethyl ester, the amount of the sodium disulfide aqueous solution is 150 to 250 L. The sodium disulfide aqueous solution is added to the reaction system in a dropwise manner, and the dropwise addition time can generally be 1.5 to 2.5 hours.

[0015] In a preferred embodiment, the acidification is carried out by organic phase-aqueous phase two-phase acidification. At this time, the generated thioctic acid can be directly extracted into the organic phase during the reaction, which can avoid thioctic acid from staying for a long time under strong acidic conditions, reduce the occurrence of side reactions, and is more conducive to the improvement of thioctic acid yield. Specifically, the acidification method includes mixing sodium thioctic acid aqueous solution and organic solvent I evenly, cooling to 5-10 ° C, slowly dripping hydrochloric acid solution, stirring the reaction for 5-15 minutes after the dropwise addition is completed, and then standing and stratifying, and the resulting organic phase is a thioctic acid-containing solution. Wherein, specific examples of the organic solvent I include, but are not limited to: at least one of toluene, xylene, ethyl acetate, tetrahydrofuran and ether. The amount of the organic solvent I is preferably 100% to 200% v / w (such as 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200% v / w and any value therebetween) of the weight fraction of 6,8-dichlorooctanoic acid ethyl ester, that is, relative to 100 kg of 6,8-dichlorooctanoic acid ethyl ester, the amount of the organic solvent I is 100 to 200 L. The amount of the hydrochloric acid solution is preferably based on adjusting the pH value of the system to 2 to 3.

[0016] In a preferred embodiment, the purification method comprises mixing the organic phase and the organic solvent II uniformly, filtering the obtained mixture to remove insoluble matter, cooling to -15 to -20°C and keeping warm for 16 to 24 hours, and then filtering and drying the obtained crystals to obtain pure lipoic acid. Specific examples of the organic solvent II include, but are not limited to, at least one of cyclohexane, n-hexane and petroleum ether. The amount of the organic solvent II is preferably 400% to 800% v / w of the weight fraction of ethyl 6,8-dichlorooctanoate (such as 400%, 420%, 450%, 480%, 500%, 520%, 550%, 580%, 600%, 620%, 650%, 680%, 700%, 720%, 750%, 780%, 800% v / w and any value therebetween), that is, relative to 100 kg of ethyl 6,8-dichlorooctanoate, the amount of the organic solvent II is 400 to 800 L.

[0017] The present invention will be described in detail below by way of examples. The examples of the embodiments are intended to explain the present invention and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0018] Preparation Example 1 Preparation of sodium disulfide aqueous solution

[0019] Add 32.7 g of solid sodium sulfide nonahydrate and 60 mL of water into a reaction bottle and stir to dissolve, add 4.2 g of sulfur powder, raise the temperature to 85°C, and stir and react for 45 minutes after the sulfur powder is completely dissolved to obtain a sodium disulfide aqueous solution for use.

[0020] Embodiment 1 Synthesis of lipoic acid

[0021] S1. Hydrolysis: In a reaction flask, add 30 g of ethyl 6,8-dichlorooctanoate and 60 mL of 0.01 M phosphate buffer solution and mix evenly, adjust the solution pH to 7.5, add 6.0 g of commercial immobilized lipase Lipozyme TLIM, keep the reaction system pH at 6.5-7.5, react at room temperature for 16 hours, filter and remove the solidified lipase, and obtain a hydrolyzate containing sodium 6,8-dichlorooctanoate. HPLC detection shows that ethyl 6,8-dichlorooctanoate is completely hydrolyzed.

[0022] S2, thiolation reaction: add 0.9 g of sodium starch octenyl succinate (3% dosage) and 30 mL of water to the hydrolyzate containing sodium 6,8-dichlorooctanoate obtained in step S1, slowly drop the sodium disulfide aqueous solution obtained in Preparation Example 1 into the system, and control the dropping time to be 2 h. After the dropwise addition is completed, continue the reaction for 5 min, stand and separate, and the obtained aqueous phase is a sodium thioctic acid aqueous solution. HPLC determination shows that the obtained aqueous phase is a sodium thioctic acid aqueous solution.

[0023] S3, acidification: add the sodium thioctic acid aqueous solution obtained in step S2 and 60 mL of toluene (organic solvent I) into the reactor and mix them evenly, cool to 8°C, slowly drop 175 mL of 1 M hydrochloric acid solution to adjust the pH value of the system to 2-3, after the dropwise addition is completed, stir the reaction for 10 min, then stand for stratification, separate the water phase, and the obtained organic phase is a toluene solution containing thioctic acid.

[0024] S4, purification: add 150 mL of cyclohexane (organic solvent II) to the toluene solution containing thioctic acid and mix well, filter to remove insoluble matter, cool to -15°C and keep warm for 20 hours, filter, dry the obtained crystals to obtain 22.90 g of thioctic acid product, with a yield of 89.1% and a purity of 99.8%.

[0025] Embodiment 2 Synthesis of Lipoic Acid

[0026] S1. Hydrolysis: In a reaction flask, add 30 g of ethyl 6,8-dichlorooctanoate and 60 mL of 0.01 M phosphate buffer solution and mix evenly, adjust the solution pH to 6.5, add 15.0 g of commercial immobilized lipase Lipase PSIM, keep the reaction system pH at 6.0-7.0, react at room temperature for 8 hours, filter and remove the solidified lipase, and obtain a hydrolyzate containing sodium 6,8-dichlorooctanoate. HPLC detection shows that ethyl 6,8-dichlorooctanoate is completely hydrolyzed.

[0027] S2, thiolation reaction: add 0.3 g of sodium starch octenyl succinate (1% dosage) and 30 mL of water to the hydrolyzate containing sodium 6,8-dichlorooctanoate obtained in step S1, slowly drop the sodium disulfide aqueous solution obtained in Preparation Example 1 into the system, and control the dropping time to be 1.5 h. After the dropwise addition is completed, continue the reaction for 5 min, stand and separate, and the obtained aqueous phase is a sodium thioctic acid aqueous solution. HPLC determination shows that the obtained aqueous phase is a sodium thioctic acid aqueous solution.

[0028] S3, acidification: add the sodium thioctic acid aqueous solution obtained in step S2 and 30 mL of toluene (organic solvent I) into the reactor and mix them evenly, cool to 10°C, slowly dropwise add 175 mL of 1 M hydrochloric acid solution to adjust the pH value of the system to 2-3, after the dropwise addition is completed, stir the reaction for 10 min, then stand for stratification, separate the water phase, and the obtained organic phase is a toluene solution containing thioctic acid.

[0029] S4, purification: add 180 mL of cyclohexane (organic solvent II) to the thioctic acid-containing toluene solution and mix well, filter out insoluble matter, cool to -20°C and keep warm for 16 h, filter, and dry the resulting crystals to obtain 22.57 g of thioctic acid product with a yield of 87.7% and a purity of 99.7%.

[0030] Embodiment 3 Synthesis of Lipoic Acid

[0031] S1. Hydrolysis: In a reaction flask, add 30 g of ethyl 6,8-dichlorooctanoate and 60 mL of 0.05 M phosphate buffer solution and mix evenly, adjust the solution pH to 7.0, add 6.0 g of commercial immobilized lipase Novozym435, keep the reaction system pH at 6.8-7.5, react at room temperature for 20 hours, filter and remove the solidified lipase, and obtain a hydrolyzate containing sodium 6,8-dichlorooctanoate. HPLC detection shows that ethyl 6,8-dichlorooctanoate is completely hydrolyzed.

[0032] S2, thiolation reaction: add 0.3 g of sodium starch octenyl succinate (1% dosage) and 30 mL of water to the hydrolyzate containing sodium 6,8-dichlorooctanoate obtained in step S1, slowly drop the sodium disulfide aqueous solution obtained in Preparation Example 1 into the system, and control the dropping time to be 2.5 h. After the dropwise addition is completed, continue the reaction for 45 min, stand and separate, and the obtained aqueous phase is a sodium thioctic acid aqueous solution. HPLC determination shows that the obtained aqueous phase is a sodium thioctic acid aqueous solution.

[0033] S3, acidification: add the sodium thioctic acid aqueous solution obtained in step S2 and 45 mL of toluene (organic solvent I) into the reactor and mix them evenly, cool to 5°C, slowly drop 175 mL of 1 M hydrochloric acid solution to adjust the pH value of the system to 2-3, after the dropwise addition is completed, stir the reaction for 5 min, then stand for stratification, separate the water phase, and the obtained organic phase is the thioctic acid-containing toluene solution.

[0034] S4, purification: add 120 mL of cyclohexane (organic solvent II) to the toluene solution containing thioctic acid, mix well, filter to remove insoluble matter, cool to -18°C and keep warm for 24 hours, filter, dry the obtained crystals to obtain 21.57 g of thioctic acid product, with a yield of 83.7% and a purity of 99.6%.

[0035] Embodiment 4-10

[0036] Thioctic acid was synthesized according to the method of Example 1, except that the type and amount of the additive were changed, as shown in Table 1. The other conditions were the same as those of Example 1 to obtain a thioctic acid product. The results are shown in Table 1.

[0037] Comparative Example 1

[0038] Thioctic acid was synthesized according to the method of Example 1, except that no additive was added. The remaining conditions were the same as those of Example 1 to obtain a thioctic acid product. The results are shown in Table 1.

[0039] Table 1

[0040] serial number additive Additive dosage Yield content Example 4 Sodium starch octenylsuccinate 1％ 82.4％ 99.5％ Example 5 Sodium starch octenylsuccinate 5％ 88.5％ 99.7％ Example 6 α-Cyclodextrin 3％ 87.5％ 99.6％ Example 7 β-Cyclodextrin 3％ 81.3％ 99.8％ Example 8 γ-Cyclodextrin 3％ 85.9％ 99.4％ Example 9 Mannitol 3％ 84.2％ 99.6％ Example 10 Erythritol 3％ 82.2％ 99.7％ Comparative Example 1 none 0％ 65.3％ 97.2％

[0041] Examples 11-16

[0042] Thioctic acid was synthesized according to the method of Example 1, except that the types and amounts of organic solvent I and organic solvent II were changed, as shown in Table 2. The remaining conditions were the same as those of Example 1 to obtain a thioctic acid product. The results are shown in Table 2.

[0043] Table 2

[0044] serial number Organic Solvent I Organic Solvents II Addition volume I / II mL Yield content Embodiment 11 Xylene Cyclohexane 60mL / 150mL 85.5％ 99.4％ Example 12 Ethyl acetate Cyclohexane 30mL / 150mL 75.3％ 99.3％ Embodiment 13 Tetrahydrofuran Cyclohexane 30mL / 150mL 71.2％ 98.9％ Embodiment 14 Ether Cyclohexane 60mL / 150mL 82.4％ 99.2％ Embodiment 15 Toluene n-Hexane 60mL / 150mL 83.5％ 98.7％ Example 16 Toluene Petroleum ether 60mL / 150mL 81.7％ 98.4％

[0045] Embodiment 17

[0046] Thioctic acid was synthesized according to the method of Example 1, except that no organic solvent I was added during the acidification process. The specific process steps are as follows:

[0047] S1. Hydrolysis: In a reaction flask, add 30 g of ethyl 6,8-dichlorooctanoate and 60 mL of 0.01 M phosphate buffer solution and mix evenly, adjust the solution pH to 7.5, add 6.0 g of commercial immobilized lipase Lipozyme TLIM, keep the reaction system pH at 6.5-7.5, react at room temperature for 16 hours, filter and remove the solidified lipase, and obtain a hydrolyzate containing sodium 6,8-dichlorooctanoate. HPLC detection shows that ethyl 6,8-dichlorooctanoate is completely hydrolyzed.

[0048] S2, thiolation reaction: add 0.9 g of sodium starch octenyl succinate (3% dosage) and 30 mL of water to the hydrolyzate containing sodium 6,8-dichlorooctanoate obtained in step S1, and slowly drop the sodium disulfide aqueous solution obtained in Preparation Example 1 into the system, and the dropping time is controlled to be 2 h. After the dropwise addition is completed, continue the reaction for 5 min, stand and separate, and the obtained aqueous phase is the sodium thioctic acid aqueous solution.

[0049] S3, acidification: add the sodium thioctic acid aqueous solution obtained in step S2 into the reactor, cool to 8 ° C, slowly add 175 mL of 1 M hydrochloric acid solution dropwise to adjust the pH value of the system to 2-3. During the dropwise addition, a large amount of yellow precipitate is produced. After the dropwise addition is completed, stir the reaction for 10 minutes, filter and separate the water layer, and dry the solid to obtain 21.0 g of crude thioctic acid solid, with a yield of 76.5% and a purity of 93.5%.

[0050] S4, purification: the crude lipoic acid solid was dissolved in 30 mL of ethyl acetate, 150 mL of cyclohexane (organic solvent II) was added and mixed evenly, insoluble matter was removed by filtration, the temperature was lowered to -15°C and kept warm for 20 h, filtered, and the obtained crystals were dried to obtain 18.1 g of lipoic acid product with a yield of 70.3% and a purity of 99.7%.

[0051] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention without departing from the principles and intent of the present invention.

Claims

1. A method for synthesizing lipoic acid, characterized in that, The method comprises the steps of hydrolyzing ethyl 6,8-dichlorooctanoate into sodium 6,8-dichlorooctanoate, and then subjecting the sodium 6,8-dichlorooctanoate to a thiolation reaction with sodium disulfide in the presence of an additive to obtain sodium thioctic acid, wherein the additive is selected from at least one of sodium octenyl succinate starch, cyclodextrin, mannitol and erythritol, and then acidifying the sodium thioctic acid and purifying it to obtain thioctic acid.

2. The synthetic method of thioctic acid according to claim 1, characterized in that, The hydrolysis method comprises the steps of uniformly mixing 6,8-dichlorooctanoic acid ethyl ester with a phosphate buffer solution, adjusting the pH value to 6.5-7.5, adding immobilized lipase for hydrolysis, and then filtering to obtain a hydrolyzate containing sodium 6,8-dichlorooctanoate.

3. The synthetic method of thioctic acid according to claim 2, characterized in that, The immobilized lipase is at least one selected from Lipozyme TLIM, Lipase PSIM, Novozym 435 and Novozyme 40086.

4. The synthetic method of thioctic acid according to claim 2, characterized in that, The dosage of the immobilized lipase is 20% to 50% of the weight of 6,8-dichlorooctanoic acid ethyl ester.

5. The synthetic method of lipoic acid according to claim 2, characterized in that, The hydrolysis conditions include a temperature of 20 to 40° C., a pH value of 6.5 to 7.5, and a time of 8 to 20 hours.

6. The synthetic method of lipoic acid according to claim 2, characterized in that, The thiolation reaction method comprises adding additives and water to a hydrolyzate containing sodium 6,8-dichlorooctanoate, then dripping a sodium disulfide aqueous solution into the reaction system, continuing the reaction for 5 to 50 minutes after the dripping is completed, standing and stratifying, and the obtained aqueous phase is a sodium thioctic acid aqueous solution.

7. The synthetic method of lipoic acid according to claim 6, characterized in that, The sodium disulfide aqueous solution is prepared according to the following method: sodium sulfide is dissolved in water, sulfur powder is added, the temperature is raised to 65-85° C., and after the sulfur powder is completely dissolved, the sodium disulfide aqueous solution is obtained by stirring and reacting for 45-60 minutes.

8. The synthetic method of lipoic acid according to claim 6, characterized in that, The cyclodextrin is selected from at least one of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

9. The synthetic method of lipoic acid according to claim 6, characterized in that, The dosage of the additive is 1% to 5% of the weight of 6,8-dichlorooctanoic acid ethyl ester.

10. The synthetic method of lipoic acid according to claim 6, characterized in that, The dosage of the sodium disulfide aqueous solution is 150% to 250% v / w of the weight of 6,8-dichlorooctanoic acid ethyl ester.

11. The synthetic method of lipoic acid according to claim 6, characterized in that, The dropping time is 1.5 to 2.5 hours.

12. The synthetic method of lipoic acid according to claim 6, characterized in that, The acidification method comprises uniformly mixing the sodium lipoate aqueous solution and the organic solvent I, cooling to 5-10° C., slowly dropping the hydrochloric acid solution, stirring and reacting for 5-15 minutes after the dropping is completed, and then standing and stratifying. The obtained organic phase is the lipoic acid-containing solution.

13. The synthetic method of lipoic acid according to claim 12, characterized in that, The organic solvent I is selected from at least one of toluene, xylene, ethyl acetate, tetrahydrofuran and diethyl ether.

14. The method for synthesizing lipoic acid according to claim 12, characterized in that: The amount of the organic solvent I is 100% to 200% v / w of the weight fraction of 6,8-dichlorooctanoic acid ethyl ester.

15. The method for synthesizing lipoic acid according to claim 12, characterized in that: The amount of the hydrochloric acid solution used is based on adjusting the pH value of the system to 2-3.

16. The method for synthesizing lipoic acid according to claim 12, characterized in that: The purification method comprises mixing the organic phase and the organic solvent II uniformly, filtering the obtained mixture to remove insoluble matter, cooling to -15 to -20°C and keeping the temperature for 16 to 24 hours, filtering again and drying the obtained crystals to obtain pure lipoic acid.

17. The method for synthesizing lipoic acid according to claim 16, characterized in that: The organic solvent II is selected from at least one of cyclohexane, n-hexane and petroleum ether.

18. The method for synthesizing lipoic acid according to claim 16, characterized in that: The amount of the organic solvent II is 400% to 800% v / w of the weight fraction of 6,8-dichlorooctanoic acid ethyl ester.

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