Method for preparing high-purity ethyl lipoate by using ionic liquid

Abstract

The invention discloses a method for preparing high-purity ethyl lipoate by using ionic liquid. The method comprises the following steps: by taking 6, 8-dichloro ethyl caprylate as a raw material, carrying out cyclization reaction on the 6, 8-dichloro ethyl caprylate and a vulcanizing reagent consisting of sodium sulfide and sulfur by utilizing an ionic liquid, so as to obtain ethyl lipoate; and optionally adding sodium sulfite to remove trisulfide by-products. By adding the ionic liquid, the use of an organic solvent can be thoroughly avoided, the product is easy to separate, and the ionic liquid is a catalyst and a reagent stabilizer and can be recycled. The method has the advantages of mild reaction conditions, simple operation, high product purity (HPLC purity > = 95%), yield > = 95%, and substantial reduction of the discharge amount of three wastes. Meanwhile, the method can meet the requirements of large-scale industrial production, and has remarkable economic and environmental benefits.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis and green chemistry, and particularly relates to a method for preparing high-purity ethyl thioctic acid by using an ionic liquid. BACKGROUND

[0002] Lipoic acid (ALA) is a kind of vitamin-like antioxidant with amphiphilic properties (both water-soluble and fat-soluble). Its unique molecular structure enables it to effectively scavenge various free radicals, making it a universal antioxidant drug. As an important coenzyme cofactor, lipoic acid participates in various metabolic processes and plays a key role in energy production and immune regulation. Studies have shown that α-lipoic acid has potential value in the treatment of various diseases, including: 1) assisting in the treatment of type II diabetes by improving insulin sensitivity and beta cell function; 2) protecting nerve cells and delaying the progression of neurodegenerative diseases; 3) reducing liver oxidative damage; 4) as an adjunct therapy for HIV infection and certain tumor treatment; 5) preventing the occurrence of cataracts and exercise-induced muscle damage.

[0003]

[0004] 6,8-Dichlorooctanoic acid ethyl ester is a key intermediate in the synthesis of lipoic acid. Its synthesis route is usually as follows: 6,8-dichlorooctanoic acid ethyl ester is used as the starting material, and under the action of a sulfurizing agent, a cyclization reaction is carried out to obtain ethyl lipoate, and then through a hydrolysis reaction, lipoic acid is finally obtained. Due to the presence of two active sulfur atoms in the lipoic acid molecule, lipoic acid and ethyl lipoate are prone to oxidation, ring opening and polymerization during preparation and storage, which can significantly affect the quality of the final product. Therefore, how to effectively control the reaction conditions to obtain high-purity lipoic acid and its intermediate ethyl lipoate has become a key technical problem in the development of this process.

[0005]

[0006] There are many documents reporting the synthesis of ethyl lipoate from 6,8-dichlorooctanoic acid ethyl ester. For example, CN101759682 reports that sodium sulfide is first reacted with sulfur to generate sodium bisulfide in an aqueous solution, and then 6,8-dichlorooctanoic acid ethyl ester is heated and refluxed in a methanol-water mixed solvent with tetrabutylammonium bromide as a phase transfer catalyst, and finally ethyl lipoate is obtained by one-pot hydrolysis, with a total yield of 68%. α Similar documents include CN115772155, CN109574987 and Bioorganic & Medicinal Chemistry Letters, 2010, 20(10), 3078-3083, etc., but these methods respectively use ethanol, propanol, isopropanol or toluene and other organic solvents as reaction medium. From the perspective of industrial production, the existing process generally has the following defects: organic solvent dependence: the use of flammable and explosive solvents such as methanol, ethanol, toluene increases the safety risk and cost; environmental pressure: a large amount of organic solvents leads to difficulty in treating three wastes (especially VOC); by-product control difficulty: ethyl lipoic acid is easy to oxidize to generate a by-product (ethyl trithiolate), which affects the final purity. Therefore, it is of great practical significance to develop a more economical, safe and environmentally friendly synthesis process.

[0007] Based on the above limitations of the prior art, this research is dedicated to developing a new synthesis process of ethyl lipoate to solve the shortcomings of current methods in cost-effectiveness, safety and environmental compatibility. Under this research background, we propose the following technical solutions. SUMMARY

[0008] The purpose of the present application is to provide a safe, environmentally friendly and efficient synthesis method of ethyl lipoate, which replaces organic solvents with ionic liquids to achieve high-purity product preparation. This method has the following advantages: mild process conditions, easy to implement industrialization; low cost, raw materials are easy to obtain, high reaction efficiency; product purity and yield are significantly improved; green and environmentally friendly, reducing three waste emissions, meeting the requirements of sustainable development. This method can meet the needs of large-scale industrial production, and has significant economic and environmental benefits.

[0009] The preparation method of ethyl lipoate comprises the following steps: taking 6,8-dichloroethyl octanoate as a raw material, and performing cyclization reaction with a sulfurizing agent in an ionic liquid at 30-45 ℃ to obtain ethyl lipoate. Optionally, sodium sulfite is added to reduce the trithiolate by-product.

[0010] The ionic liquid is one of 1-butyl-3-methylimidazolium bistrifluoromethylsulfonylimide [BMIM][NTf2], 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4], 1-butyl-3-methylimidazolium bromide [BMIM]Br, and 1-hexyl-3-methylimidazolium tetrafluoroborate [HMIM][BF4].

[0011] The molar volume ratio of 6,8-dichloroethyl octanoate, sulfurizing agent and ionic liquid is 1:1:0.2-0.8 (mmol:mmol:ml).

[0012] The sulfurizing agent is sodium sulfide and sulfur. The molar ratio of sodium sulfide to sulfur is 1:1-1.5.

[0013] The reaction time after adding the sulfurizing agent to the reaction system is 30-180 minutes. After the cyclization reaction is completed, sodium sulfite is added to the reaction system to carry out the desulfurization reaction.

[0014] The molar ratio of ethyl 6,8-dichlorooctanoate to sodium sulfite is 1:0.5-1.5.

[0015] In some embodiments, the method for preparing ethyl thiocate includes the following steps: Weigh out sodium sulfide and place it in a container. Add an ionic liquid and stir in a constant temperature water bath at 30-40℃ until completely dissolved. Then add a measured amount of sulfur powder and continue stirring until the sulfur is completely dissolved, yielding a clear solution A.

[0016] Ethyl 6,8-dichlorooctanoate and ionic liquid are added sequentially to the reaction vessel, and the mixture is stirred and heated to 30-45 °C. This is solution B.

[0017] Using a constant-pressure dropping funnel, solution A is slowly added dropwise to solution B, controlling the dropping rate to complete the addition within a certain time. After the addition is complete, the reaction is continued at this temperature for 30-180 minutes. During this time, the reaction progress is monitored by thin-layer chromatography. The reaction is complete when the starting material, ethyl 6,8-dichlorooctanoate, has essentially disappeared. The resulting product is then desulfurized to obtain ethyl thiooctanoate.

[0018] Furthermore, the products obtained after the reaction need to undergo post-processing, which includes a desulfurization reaction.

[0019] The desulfurization reaction includes: adding a measured amount of sodium sulfite to the reaction system; stirring the reaction continuously at 30-45 °C for 30-120 minutes; after the reaction is terminated, performing liquid-liquid extraction with ethyl acetate; collecting and combining the organic phases, drying and concentrating under reduced pressure to obtain the target product, ethyl thiocate.

[0020] The recovery process of ionic liquids includes the following steps: First, the ionic liquid phase is washed multiple times with deionized water until no chloride ions are detected with silver nitrate solution. Then, the washed ionic liquid is dried under high temperature and high vacuum conditions for at least 12 hours to completely remove moisture. Finally, the dried ionic liquid is sealed and stored for future recycling.

[0021] This invention provides a method for synthesizing ethyl thiocate, which in turn can be used to synthesize thioctic acid. The synthesis is carried out using green solvents, resulting in mild process conditions that are easy to implement industrially; the cost is low, and the purity and yield of the product are significantly improved. This route can meet the needs of large-scale industrial production and has significant economic and environmental benefits.

[0022] The beneficial effects are specifically manifested as follows: Absolutely green: Completely eliminates organic solvents, reducing waste at the source; High yield and high purity: Yield ≥95%, HPLC purity ≥95%; Significantly reduced cost: Solvent cost reduced by >90%; Suppression of side reactions: Stable temperature control of the ionic liquid system, combined with sodium sulfite desulfurization, effectively reduces trisulfide residues. Detailed Implementation

[0023] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. The purity of the products in all embodiments was determined by high-performance liquid chromatography (HPLC). Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0024] Example 1 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of ionic liquid [BMIM][NTf2] was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a reddish-brown Na2S2 solution (solution A).

[0025] Ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g) and 20 mL of ionic liquid [BMIM][NTf2] were added sequentially to the reaction vessel. The system was stirred and heated to an internal temperature of 30 °C to obtain solution B.

[0026] Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 30 °C and stirred for 1 h.

[0027] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was continued at this temperature for 1 h before being terminated. The system was extracted with ethyl acetate, and the lower ionic liquid phase was recovered and reused. The organic phases were combined, dried, and concentrated to obtain ethyl thiocate product with a yield of 99% and a purity of 97%.

[0028] Recovery of ionic liquids: First, the ionic liquid phase is washed multiple times with deionized water until no chloride ions are detected with silver nitrate solution. Then, the washed ionic liquid is dried under high temperature and high vacuum conditions for at least 12 hours to completely remove moisture. Finally, the dried ionic liquid is sealed and stored for future recycling. The recovery rate is 98%.

[0029] Ionic liquids can be recycled multiple times while maintaining high catalytic performance. As shown in the table below, even in the 6th cycle, ethyl thiocate can still be obtained with a yield of 95% and a purity of 95%, demonstrating its excellent stability.

[0030]

[0031] Example 2 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 60 mL of ionic liquid [BMIM][NTf2] was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a reddish-brown Na2S2 solution (solution A).

[0032] Ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g) and 40 mL of ionic liquid [BMIM][NTf2] were added sequentially to the reaction vessel. The system was stirred and heated to an internal temperature of 30 °C to obtain solution B. Solution A was then slowly added dropwise to solution B.

[0033] After the addition is complete, the reaction system is kept at 30 °C and stirred for another 1 h.

[0034] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and ethyl thiocate was obtained in 98% yield and with 95% purity.

[0035] Example 3 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of ionic liquid [BMIM][BF4] was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a reddish-brown Na2S2 solution (solution A).

[0036] Ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g) and 20 mL of ionic liquid [BMIM][BF4] were added sequentially to the reaction vessel. The system was stirred and heated to an internal temperature of 30 °C to obtain solution B.

[0037] Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 30 °C and stirred for 1 h.

[0038] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated to obtain ethyl thiocate product with a yield of 98% and a purity of 96%.

[0039] Example 4 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of ionic liquid [HMIM][BF4] was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a reddish-brown Na2S2 solution (solution A).

[0040] Ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g) and 20 mL of ionic liquid [HMIM][BF4] were added sequentially to the reaction vessel. The system was stirred and heated to an internal temperature of 30 °C to obtain solution B. Solution A was then slowly added dropwise to solution B.

[0041] After the addition is complete, the reaction system is kept at 30 °C and stirred for another 1 h.

[0042] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated to obtain ethyl thiocate product with a yield of 95% and a purity of 95%.

[0043] Example 5 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of ionic liquid [BMIM][NTf2] was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a reddish-brown Na2S2 solution (solution A).

[0044] Ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g) and 20 mL of ionic liquid [BMIM][NTf2] were added sequentially to the reaction vessel. The system was stirred and heated to an internal temperature of 45 °C to obtain solution B.

[0045] Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 45 °C and stirred for 1 h.

[0046] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and ethyl thiocate was obtained in 96% yield and with 99% purity.

[0047] Example 6 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of ionic liquid [BMIM][NTf2] was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a reddish-brown Na2S2 solution (solution A).

[0048] Ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g) and 20 mL of ionic liquid [BMIM][NTf2] were added sequentially to the reaction vessel. The system was stirred and heated to an internal temperature of 45 °C to obtain solution B.

[0049] Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 45 °C and stirred for 1 h.

[0050] Sodium sulfite (1.2 eq., 120 mmol, 15.12 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and ethyl thiocate was obtained in 95% yield and with 98% purity.

[0051] Comparative Example 1 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of pure water was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a clear, reddish-brown Na₂S₂ solution (solution A).

[0052] Add the following to the reaction vessel in sequence: ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g), tetrabutylammonium bromide (0.04 eq., 4 mmol, 1.29 g), 10 mL of pure water, and 10 mL of ethanol.

[0053] The system was stirred and heated to an internal temperature of 80 °C to obtain solution B. Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 80 °C and stirred for another 1 h.

[0054] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and ethyl thiocate was obtained in 93% yield and with 92% purity.

[0055] Comparative Example 2 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of pure water was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a clear, reddish-brown Na₂S₂ solution (solution A).

[0056] The following were added sequentially to the reaction vessel: ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g), tetrabutylammonium chloride (0.04 eq., 4 mmol, 1.11 g), 10 mL of pure water, and 10 mL of methanol. The system was stirred and heated to an internal temperature of 80 °C to obtain solution B.

[0057] Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 80 °C and stirred for 1 h.

[0058] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and ethyl thiocate was obtained in 94% yield and with 92% purity.

[0059] Comparative Example 3 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of pure water was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a clear, reddish-brown Na₂S₂ solution (solution A).

[0060] The following were added sequentially to the reaction vessel: ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g), tetrabutylammonium bromide (0.04 eq., 4 mmol, 1.29 g), 10 mL of pure water, and 10 mL of dimethyl sulfoxide. The system was stirred and heated to an internal temperature of 80 °C to obtain solution B.

[0061] Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 80 °C and stirred for 1 h.

[0062] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated to obtain ethyl thiocate product in 90% yield and 85% purity.

[0063] Comparative Example 4 Sodium sulfide (1.12 eq., 112 mmol, 8.74 g) and sulfur (1.12 eq., 112 mmol, 3.58 g) were weighed into an Erlenmeyer flask, and 30 mL of pure water was added. The solution was heated and stirred at 40 °C for 0.5 h to dissolve, yielding a clear, reddish-brown Na₂S₂ solution (solution A).

[0064] The following were added sequentially to the reaction vessel: ethyl 6,8-dichlorooctanoate (1.0 eq., 100 mmol, 24.61 g), tetrabutylammonium bromide (0.04 eq., 4 mmol, 1.29 g), 10 mL of pure water, and 10 mL of toluene. The system was stirred and heated to an internal temperature of 80 °C to obtain solution B.

[0065] Solution A was slowly added dropwise to solution B. After the addition was complete, the reaction system was kept at 80 °C and stirred for 1 h.

[0066] Sodium sulfite (1.5 eq., 150 mmol, 18.91 g) was weighed and added to the reaction system. The reaction was terminated after stirring at the same temperature for 1 h. The system was extracted with ethyl acetate, the organic phases were combined, dried and concentrated, and ethyl thiocate was obtained in 93% yield and with 92% purity.

Claims

1. A process for the preparation of ethyl lipoate, characterized in that, The method comprises the following steps: taking ethyl 6,8-dichlorooctanoate as a raw material, and performing cyclization reaction on the ethyl 6,8-dichlorooctanoate by using an ionic liquid and a sulfuration reagent to obtain ethyl thioctic acid.

2. The method of claim 1, wherein: The ionic liquid is one of 1-butyl-3-methylimidazolium bistrifluoromethylsulfonylimide [BMIM][NTf2], 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4], 1-butyl-3-methylimidazolium bromide [BMIM]Br and 1-hexyl-3-methylimidazolium tetrafluoroborate [HMIM][BF4].

3. The method according to claims 1 and 2, characterized in that: The molar volume ratio of ethyl 6,8-dichlorooctanoate, the sulfuration reagent and the ionic liquid is 1:1:0.2-0.8 (mmol:mmol:ml).

4. The method of claim 1, wherein: The sulfuration reagent is sodium sulfide and sulfur.

5. The method of claim 4, wherein: The molar ratio of the sodium sulfide and the sulfur is 1:1-1.

5.

6. The method of claim 1, wherein, The reaction temperature is 30-45 DEG C.

7. The method of claim 1, wherein, The reaction time after the sulfuration reagent is added into the reaction system is 30-180 minutes.

8. The method of claim 1, wherein: After the cyclization reaction is completed, sodium sulfite is added into the reaction system to perform desulfurization reaction.

9. The method of claim 8, wherein: The molar ratio of the ethyl 6,8-dichlorooctanoate and the sodium sulfite is 1:0.5-1.

5.

10. The method according to any one of claims 1 to 9, characterized in that, The method for preparing ethyl thioctic acid comprises the following steps: The ionic liquid is added into sodium sulfide, and the mixture is stirred in a constant-temperature water bath at 30-40 DEG C until the sodium sulfide is completely dissolved, then sulfur powder is added, and the mixture is continuously stirred until the sulfur is completely dissolved to obtain a clear solution A; Ethyl 6,8-dichlorooctanoate and the ionic liquid are sequentially added into a reaction kettle, and the mixture is stirred and heated to 30-45 DEG C to obtain solution B; Solution A is slowly added into solution B by using a constant-pressure dropping funnel, the dropping speed is controlled to complete the dropping in a period of time, after the dropping is completed, the mixture is continuously kept at a constant temperature for 30-180 minutes, and then ethyl thioctic acid is obtained after desulfurization operation.

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