A method for preparing lipoic acid

Abstract

The invention discloses a method for preparing thioctic acid, belongs to the technical field of organic synthesis, and includes desulfurization and acidification; in the desulfurization step, in a sodium thioctic acid system containing sulfide ions, acid and a compound containing metal ions are added, filtered after reaction, and a metal chelate of thioctic acid is obtained; then the metal chelate of thioctic acid is reacted with sodium hydroxide to obtain pure sodium thioctic acid; then the pure sodium thioctic acid is acidified to obtain thioctic acid. The present invention utilizes the property that thioctic acid is easy to chelate with metal ions to form a solid, removes sulfide ions while chelating thioctic acid, greatly suppresses the generation of impurity 1,2,3-trithiocyclohexane-4-pentanoic acid, and the thioctic acid obtained by the method of the present invention has low impurity content, high purity, and high yield, and greatly improves the quality of thioctic acid.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing thioctic acid. Background Art

[0002] Lipoic acid is an antioxidant and a free radical scavenger. It binds to iron, copper and other transition metal ions such as Mn 2+ 、Cd 2+ 、Zn 2+ It can chelate with other substances, reduce the production of hydroxyl free radicals, and then block the lipid oxidation reaction of nerve tissue, prevent the glycosylation of protein, inhibit aldose reductase, and prevent the conversion of glucose or galactose into sorbitol. Therefore, it can prevent diabetes, control blood sugar and prevent neural mutations caused by high blood sugar. It can be seen that lipoic acid is an important chemical drug.

[0003] At present, the more mature and stable industrial production route of lipoic acid in the industry is to use 6,8-dichlorooctanoic acid ethyl ester, sulfur and sodium sulfide as starting materials, and obtain lipoic acid through cyclization, hydrolysis, acidification and purification, with a total yield of about 50%. The production process flow chart is as follows Figure 1 As shown. However, the disadvantage of this process is that a lot of viscous materials are easily produced during the acidification process, resulting in a decrease in the yield of the product and a decrease in purity. In addition, a large amount of impurity 1,2,3-trithiocyclohexane-4-pentanoic acid is generated during the acidification process, and its content is even as high as 10-20%. Analysis of the acidification process found that the SS bond formed during the cyclization process is very easy to open during the acidification process, and the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid is formed after the divalent sulfide ions in the system are inserted.

[0004] In actual production, in order to avoid the excessive generation of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid, the intermediate ethyl thioate is usually separated from water after the cyclization reaction, and the wastewater containing a large amount of divalent sulfide ions is discarded, and then the ethyl thioate is hydrolyzed and acidified. The pharmacopoeia stipulates that the content of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid should be below 0.2%. However, it is impossible to completely separate the intermediate from water during production, which results in a small amount of sulfur-containing wastewater entering the subsequent hydrolysis and acidification steps, thereby increasing the content of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid and reducing the yield and purity of thioctic acid. Therefore, how to inhibit the generation of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid plays a vital role in improving the yield and purity of thioctic acid. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing thioctic acid to solve the technical problems in the above-mentioned background technology.

[0006] In order to achieve the above object, the present invention discloses a method for preparing lipoic acid, comprising desulfurization and acidification;

[0007] In the desulfurization step, an acid and a compound containing metal ions are added to a sodium thioctic acid system containing sulfide ions, and the reaction is followed by filtration to obtain a metal chelate of thioctic acid; the metal chelate of thioctic acid is then reacted with sodium hydroxide to obtain pure sodium thioctic acid;

[0008] The pure sodium lipoate is then acidified to obtain lipoic acid.

[0009] Furthermore, the preparation method of the sodium thioctic acid system containing sulfide ions is: using sulfur, sodium sulfide, and ethyl dichlorooctanoate as raw materials, heating and reacting in an organic solvent to synthesize ethyl thioctic acid, and then adding sodium hydroxide to react to obtain the sodium thioctic acid system containing sulfide ions.

[0010] Furthermore, the metal ions include Fe 3+ , Cu 2+ , Mn 2+ , Ca 2+ 、Cd 2+ and Zn 2+ One or more of the .

[0011] Furthermore, the compound containing metal ions includes one or more of ferric chloride, zinc chloride, anhydrous copper sulfate and calcium chloride.

[0012] Furthermore, the acid is an inorganic acid, including one or more of hydrochloric acid, sulfuric acid and nitric acid.

[0013] Furthermore, the organic solvent includes one or more of methanol, ethanol, isopropanol, n-propanol, acetone, benzene, toluene, pentane, ether, ethyl acetate and carbon tetrachloride.

[0014] Furthermore, the lipoic acid obtained after acidification is post-treated, and the post-treatment includes dissolving with cyclohexane and then crystallizing.

[0015] Compared with the prior art, the method for preparing lipoic acid of the present invention has the following beneficial effects:

[0016] (1) The present invention utilizes the property that thioctic acid easily chelates with metal ions to form a solid. A compound containing metal ions is added to a sodium thioctic acid system containing a large amount of sulfur-containing wastewater to form a solid metal chelate of thioctic acid. At the same time, sulfur ions also form a precipitate with the metal ions. The precipitate is then dissociated with alkaline water. The metal chelate of thioctic acid re-forms sodium thioctic acid and returns to fresh water, while the sulfur ions are separated and removed in the form of a precipitate. As a result, there is almost no divalent sulfur ion in the aqueous solution of sodium thioctic acid, and the generation of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid is greatly suppressed.

[0017] (2) The preparation method of the present invention is an improvement made on the basis of the existing production process, and there is no need to modify the production equipment, and the equipment investment is low.

[0018] (3) The lipoic acid obtained by the preparation method of the present invention has low impurity content, high purity and high yield, which greatly improves the quality of lipoic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 :The current industrial production process flow chart of lipoic acid in the industry.

[0020] Figure 2 : Partial chemical process flow diagram of preparation thioctic acid of the present invention. DETAILED DESCRIPTION

[0021] The embodiments of the present invention will be described in detail below in conjunction with specific examples. The following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or the conditions recommended by the manufacturer.

[0022] A method for preparing lipoic acid is based on a sodium lipoate system containing sulfide ions, and high-purity lipoic acid is obtained through desulfurization and acidification steps. The method specifically comprises the following steps:

[0023] First, synthesize sodium thioctic acid. This step adopts the existing process. In the reaction container, sulfur and ethyl dichlorooctanoate are added to the organic solvent in sequence, heated to 60-70°C (reflux), and then sodium sulfide is added at this temperature to obtain ethyl thioctic acid after reaction; the temperature is lowered to 55-60°C, sodium hydroxide is added, and the organic solvent is removed after the reaction is completed to obtain the sodium thioctic acid system. At this time, a large amount of sulfide ions remain in the reaction system, so it is called a sodium thioctic acid system containing sulfide ions;

[0024] In this step, the organic solvent includes one or more of methanol, ethanol, isopropanol, n-propanol, acetone, benzene, toluene, pentane, ether, ethyl acetate and carbon tetrachloride, preferably methanol.

[0025] Then, desulfurization is performed. The desulfurization process is divided into two steps: (1) In the sodium thioctic acid system containing sulfur ions, acid is added to adjust the pH of the system to 6-7, and then a compound containing metal ions is added. At this time, a large amount of solids gradually appear in the system. After stirring, the system is filtered to obtain a filter cake. The filtrate after filtration contains unreacted raw materials and other impurities, forming wastewater, which is discarded. The filter cake contains metal chelates of thioctic acid and metal compounds of sulfur; (2) The filter cake is reacted with sodium hydroxide, and the metal chelates of thioctic acid therein dissociate when exposed to alkali to form sodium thioctic acid, which is then filtered to remove the filter residue (the filter residue is a metal compound of sulfur), and the filtrate is retained. The filtrate is a sodium thioctic acid solution after the sulfur ions are removed, that is, pure sodium thioctic acid, completing the desulfurization process. There are almost no sulfur ions in the filtrate after desulfurization, which inhibits the formation of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid, greatly reducing the impurity content in the final product.

[0026] In this step, the acid is an inorganic acid, including one or more of hydrochloric acid, sulfuric acid and nitric acid, preferably hydrochloric acid.

[0027] Then, acidification is performed. Acid is added to the sodium thioctic acid solution after the sulfide ions are removed, and the sodium thioctic acid is acidified to generate a crude thioctic acid product.

[0028] Then, post-treatment is performed. First, the crude thioctic acid is vacuum dried, and then the dried crude thioctic acid is dissolved in cyclohexane and crystallized, and the precipitated crystals are filtered and vacuum dried to obtain pure thioctic acid.

[0029] The partial chemical process flow of preparing thioctic acid of the present invention is as follows Figure 2 As shown, since the preparation of the sodium lipoate system containing sulfide ions is a conventional technique, this step is omitted.

[0030] In the lipoic acid prepared by the method of the present invention, the content of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid is greatly reduced, which meets the requirements of the pharmacopoeia, and in the preparation process, after multiple filtration and washing steps, the yield of the product and the purity of the final product are greatly improved. After testing, the yield of the final product lipoic acid is ≥70%, the content of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid is ≤0.15%, and the contents of other impurities are all <0.1%.

[0031] Example 1

[0032] (1) Synthesis of sodium thioctic acid: 50.0 mL of methanol, 1.74 g of sulfur, and 10.88 g of ethyl 6,8-dichlorooctanoate were added to a 250 mL four-necked flask in sequence, and the temperature was raised to 65°C (reflux). At this temperature, a sodium sulfide aqueous solution (5.62 g of sodium sulfide dissolved in 20.0 mL of water) was slowly added dropwise. After the addition was completed, the reaction was kept warm for 3 h. At this time, the content of ethyl 6,8-dichlorooctanoate had dropped to below 0.5%, and the reaction was stopped.

[0033] The temperature was lowered to 55-60°C, and a sodium hydroxide aqueous solution (3.6 g of sodium hydroxide dissolved in 33 mL of water) was added to a four-necked flask. The reaction was kept warm for 4 hours. At this time, the content of ethyl lipoate was lower than 0.5%, and the reaction was stopped. Methanol was removed by decompression to obtain sodium lipoate. The sodium lipoate in the water layer was calibrated, and the calibration yield was 90% and the purity was 91%.

[0034] (2) Desulfurization: Then cool to 15-20°C, add 6M HCl solution into the four-necked flask until the pH of the system is 6-7, stir for 0.5h, and re-measure the pH if it remains unchanged;

[0035] Then the temperature was lowered to 0-5°C, and 3.7 g of zinc chloride was added to the four-necked flask. A large amount of white solid gradually appeared in the system. After stirring for 0.5 h, the system was filtered to obtain filter cake 1.

[0036] Add 20 mL of ice water to filter cake 1 for slurrying, and filter again after 0.5 h to obtain filter cake 2; then add 10 mL of water to filter cake 2 and stir until it becomes porridge-like, heat to 15-20 ° C, and then add 10% sodium hydroxide aqueous solution dropwise until the pH of the system is 10-11, the system gradually becomes thinner, and filter after stirring for 0.5 h to obtain a light yellow filtrate.

[0037] (3) Acidification: Control the temperature at 15-20°C and slowly add 2M HCl solution to the filtrate until the pH of the system reaches 1-2. At this time, a large amount of solid precipitates in the system. Stir for 0.5h at this temperature. If the pH remains unchanged after retesting, filter and obtain crude lipoic acid.

[0038] (4) Post-treatment: The crude lipoic acid was vacuum dried to obtain 7.65 g of the crude lipoic acid, with a yield of 82.17% and a purity of 98.5%;

[0039] Suspend the dried crude lipoic acid in 75 mL of cyclohexane, heat to reflux, keep warm for 0.5 h after dissolution, then stop heating and slowly cool down. After crystallization, slowly cool down to 15-20°C, keep warm for 0.5 h, and then filter to obtain pure lipoic acid;

[0040] The pure lipoic acid was vacuum dried to obtain 7.0 g of lipoic acid with a yield of 75.18% and a purity of 99.3%. The impurity 1,2,3-trithiocyclohexane-4-pentanoic acid content was 0.05%, and the other impurities were all less than 0.1%.

[0041] Example 2

[0042] (1) Synthesis of sodium thioctic acid: 50.0 mL of methanol, 1.74 g of sulfur, and 10.88 g of ethyl 6,8-dichlorooctanoate were added to a 250 mL four-necked flask in sequence, and the temperature was raised to 65°C (reflux). At this temperature, a sodium sulfide aqueous solution (5.62 g of sodium sulfide dissolved in 20.0 mL of water) was slowly added dropwise. After the addition was completed, the reaction was kept warm for 3 h. At this time, the content of ethyl 6,8-dichlorooctanoate had dropped to below 0.5%, and the reaction was stopped.

[0043] The temperature was lowered to 55-60°C, and a sodium hydroxide aqueous solution (3.6 g of sodium hydroxide dissolved in 33 mL of water) was added to a four-necked flask. The reaction was kept warm for 4 hours. At this time, the content of ethyl lipoate was lower than 0.5%, and the reaction was stopped. Methanol was removed by decompression to obtain sodium lipoate. The sodium lipoate in the water layer was calibrated, and the calibration yield was 88.5% and the purity was 92.5%.

[0044] (2) Desulfurization: Then cool to 15-20°C, add 6M HCl solution into the four-necked flask until the pH of the system is 6-7, stir for 0.5h, and re-measure the pH if it remains unchanged;

[0045] Then the temperature was lowered to 0-5°C, and 2.93 g of ferric chloride was added to the four-necked flask. A large amount of brick red solid gradually appeared in the system. After stirring for 0.5 h, the system was filtered to obtain filter cake 1.

[0046] Add 20 mL of ice water to filter cake 1 for slurrying, and filter again after 0.5 h to obtain filter cake 2; then add 10 mL of water to filter cake 2 and stir until it becomes porridge-like, heat to 15-20 ° C, and then add 10% sodium hydroxide aqueous solution dropwise until the pH of the system is 10-11, the system gradually becomes thinner, and filter after stirring for 0.5 h to obtain a light yellow filtrate.

[0047] (3) Acidification: Control the temperature at 15-20°C and slowly add 2M HCl solution to the filtrate until the pH of the system reaches 1-2. At this time, a large amount of solid precipitates in the system. Stir for 0.5h at this temperature. If the pH remains unchanged after retesting, filter and obtain crude lipoic acid.

[0048] (4) Post-treatment: The crude lipoic acid was vacuum dried to obtain 7.9 g of the crude lipoic acid, with a yield of 84.85% and a purity of 97.5%;

[0049] Suspend the dried crude lipoic acid in 75 mL of cyclohexane, heat to reflux, keep warm for 0.5 h after dissolution, then stop heating and slowly cool down. After crystallization, slowly cool down to 15-20°C, keep warm for 0.5 h, and then filter to obtain pure lipoic acid;

[0050] The pure lipoic acid was vacuum dried to obtain 7.15 g of lipoic acid with a yield of 76.8% and a purity of 99.1%. The impurity 1,2,3-trithiocyclohexane-4-pentanoic acid content was 0.08%, and the remaining impurities were all less than 0.1%.

[0051] Example 3

[0052] (1) Synthesis of sodium thioctic acid: 50.0 mL of methanol, 1.74 g of sulfur, and 10.88 g of ethyl 6,8-dichlorooctanoate were added to a 250 mL four-necked flask in sequence, and the temperature was raised to 65°C (reflux). At this temperature, a sodium sulfide aqueous solution (5.62 g of sodium sulfide dissolved in 20.0 mL of water) was slowly added dropwise. After the addition was completed, the reaction was kept warm for 3 h. At this time, the content of ethyl 6,8-dichlorooctanoate had dropped to below 0.5%, and the reaction was stopped.

[0053] The temperature was lowered to 55-60°C, and a sodium hydroxide aqueous solution (3.6 g of sodium hydroxide dissolved in 33 mL of water) was added to a four-necked flask. The reaction was kept warm for 4 hours. At this time, the content of ethyl lipoate was lower than 0.5%, and the reaction was stopped. Methanol was removed by decompression to obtain sodium lipoate. The sodium lipoate in the water layer was calibrated, and the calibration yield was 87% and the purity was 92%.

[0054] (2) Desulfurization: Then cool to 15-20°C, add 6M HCl solution into the four-necked flask until the pH of the system is 6-7, stir for 0.5h, and re-measure the pH if it remains unchanged;

[0055] Then the temperature was lowered to 0-5°C, and 6.76 g of copper sulfate pentahydrate was added to the four-necked flask. A large amount of blue solid gradually appeared in the system. After stirring for 0.5 h, the system was filtered to obtain filter cake 1.

[0056] Add 20 mL of ice water to filter cake 1 for slurrying, and filter again after 0.5 h to obtain filter cake 2; then add 10 mL of water to filter cake 2 and stir until it becomes porridge-like, heat to 15-20 ° C, and then add 10% sodium hydroxide aqueous solution dropwise until the pH of the system is 10-11, the system gradually becomes thinner, and filter after stirring for 0.5 h to obtain a light yellow filtrate.

[0057] (3) Acidification: Control the temperature at 15-20°C and slowly add 2M HCl solution to the filtrate until the pH of the system reaches 1-2. At this time, a large amount of solid precipitates in the system. Stir for 0.5h at this temperature. If the pH remains unchanged after retesting, filter and obtain crude lipoic acid.

[0058] (4) Post-treatment: The crude lipoic acid was vacuum dried to obtain 7.5 g of the crude lipoic acid, with a yield of 80.55% and a purity of 98.8%;

[0059] Suspend the dried crude lipoic acid in 75 mL of cyclohexane, heat to reflux, keep warm for 0.5 h after dissolution, then stop heating and slowly cool down. After crystallization, slowly cool down to 15-20°C, keep warm for 0.5 h, and then filter to obtain pure lipoic acid;

[0060] The pure lipoic acid was vacuum dried to obtain 6.84 g of lipoic acid with a yield of 73.5% and a purity of 99.5%. The impurity 1,2,3-trithiocyclohexane-4-pentanoic acid content was 0.01%, and the other impurities were all less than 0.1%.

[0061] Example 4

[0062] (1) Synthesis of sodium thioctic acid: 50.0 mL of methanol, 1.74 g of sulfur, and 10.88 g of ethyl 6,8-dichlorooctanoate were added to a 250 mL four-necked flask in sequence, and the temperature was raised to 65°C (reflux). At this temperature, a sodium sulfide aqueous solution (5.62 g of sodium sulfide dissolved in 20.0 mL of water) was slowly added dropwise. After the addition was completed, the reaction was kept warm for 3 h. At this time, the content of ethyl 6,8-dichlorooctanoate had dropped to below 0.5%, and the reaction was stopped.

[0063] The temperature was lowered to 55-60°C, and a sodium hydroxide aqueous solution (3.6 g of sodium hydroxide dissolved in 33 mL of water) was added to the four-necked flask. The reaction was kept warm for 4 hours. At this time, the content of ethyl lipoate was lower than 0.5%, and the reaction was stopped. Methanol was removed by decompression to obtain sodium lipoate. The sodium lipoate in the water layer was calibrated, and the calibration yield was 86.5% and the purity was 93.5%.

[0064] (2) Desulfurization: Then cool to 15-20°C, add 6M HCl solution into the four-necked flask until the pH of the system is 6-7, stir for 0.5h, and re-measure the pH if it remains unchanged;

[0065] Then the temperature was lowered to 0-5°C, and 3.0 g of calcium chloride was added to the four-necked flask. A large amount of white solid gradually appeared in the system. After stirring for 0.5 h, the system was filtered to obtain filter cake 1.

[0066] Add 20 mL of ice water to filter cake 1 for slurrying, and filter again after 0.5 h to obtain filter cake 2; then add 10 mL of water to filter cake 2 and stir until it becomes porridge-like, heat to 15-20 ° C, and then add 10% sodium hydroxide aqueous solution dropwise until the pH of the system is 10-11, the system gradually becomes thinner, and filter after stirring for 0.5 h to obtain a light yellow filtrate.

[0067] (3) Acidification: Control the temperature at 15-20°C and slowly add 2M HCl solution to the filtrate until the pH of the system reaches 1-2. At this time, a large amount of solid precipitates in the system. Stir for 0.5h at this temperature. If the pH remains unchanged after retesting, filter and obtain crude lipoic acid.

[0068] (4) Post-treatment: The crude lipoic acid was vacuum dried to obtain 7.58 g of the crude lipoic acid, with a yield of 81.5% and a purity of 97%;

[0069] Suspend the dried crude lipoic acid in 75 mL of cyclohexane, heat to reflux, keep warm for 0.5 h after dissolution, then stop heating and slowly cool down. After crystallization, slowly cool down to 15-20°C, keep warm for 0.5 h, and then filter to obtain pure lipoic acid;

[0070] The pure lipoic acid was vacuum dried to obtain 6.7 g of lipoic acid with a yield of 72% and a purity of 99.1%. The impurity 1,2,3-trithiocyclohexane-4-pentanoic acid content was 0.15%, and the other impurities were all less than 0.1%.

[0071] It can be seen that the thioctic acid obtained by the preparation method of the present invention has high yield, low impurity content, high purity, and the content of the impurity 1,2,3-trithiocyclohexane-4-pentanoic acid meets the requirements of the pharmacopoeia, which solves the technical problem of low yield and high impurity content of thioctic acid obtained by the existing production process.

[0072] The above description is only a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, improvements, etc. made within the design concept of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing thioctic acid, characterized in that: Includes desulfurization and acidification; In the desulfurization step, an acid and a compound containing metal ions are added to a sodium thioctic acid system containing sulfide ions, and the reaction is followed by filtration to obtain a metal chelate of thioctic acid; the metal chelate of thioctic acid is then reacted with sodium hydroxide to obtain pure sodium thioctic acid; Then the pure sodium lipoate is acidified to obtain lipoic acid; The metal ion is Fe 3+ , Cu 2+ , Ca 2+ and Zn 2+ One or more of the following; In the desulfurization step, acid is added to the sodium lipoate system containing sulfide ions until the pH of the system is 6-7; The preparation method of the sodium thioctic acid system containing sulfide ions is as follows: sulfur, sodium sulfide and ethyl dichlorooctanoate are used as raw materials, and ethyl thioctic acid is heated and reacted in an organic solvent to synthesize ethyl thioctic acid, and then sodium hydroxide is added to react to obtain the sodium thioctic acid system containing sulfide ions; The organic solvent is one or more of methanol, ethanol, isopropanol, n-propanol, acetone, benzene, toluene, pentane, ether, ethyl acetate and carbon tetrachloride.

2. The method for preparing thioctic acid as claimed in claim 1, wherein: The compound containing metal ions is one or more of ferric chloride, zinc chloride, anhydrous copper sulfate and calcium chloride.

3. The method for preparing thioctic acid as claimed in claim 1, wherein: In the desulfurization step, the added acid is an inorganic acid, which is one or more of hydrochloric acid, sulfuric acid and nitric acid.

4. The method for preparing thioctic acid as described in any one of claims 1 to 3, characterized in that: The lipoic acid obtained after acidification is post-treated, and the post-treatment includes dissolving with cyclohexane and then crystallizing.

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