Method for recovering lipoic acid from lipoic acid crystal mother liquor

Abstract

The invention belongs to the field of pharmaceutical technology and relates to a method for recovering lipoic acid from a lipoic acid crystal mother liquor. The method comprises: using a reducing agent, sodium borohydride or potassium borohydride, to convert lipoic acid, cyclotrilipoic acid and lipoic acid polymer in the lipoic acid crystal mother liquor into dihydrolipoic acid, and then using a cyclizing agent, ferric chloride, to oxidize and cyclize the dihydrolipoic acid into lipoic acid. The quality of the lipoic acid product recovered by the method of the invention meets the pharmacopoeia standard, and not only the recovery of lipoic acid in the lipoic acid crystal mother liquor is achieved, but also the conversion of byproducts into main products is achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals and relates to a method for recovering thioctic acid from thioctic acid crystal mother liquor. Background Art

[0002] Lipoic acid, molecular formula is C8H 14 O2S2 is an organic compound that can act as a coenzyme to participate in the acyl transfer in the metabolism of substances in the body, and can eliminate free radicals that accelerate aging and cause disease. At the same time, after lipoic acid is absorbed through the intestine and enters the cells in the body, it has the characteristics of both fat solubility and water solubility, and the sulfhydryl group is easy to undergo redox reactions, so it can protect the sulfhydryl enzyme from the poisoning of heavy metal ions. Lipoic acid has been widely used in clinical medicine, and its scope of application includes: the treatment of liver dysfunction, subacute necrotic encephalopathy, neurological diseases, radiation injury, arsenic, cadmium, mercury and other heavy metal poisoning and other diseases, and is known as the "universal antioxidant".

[0003] At present, lipoic acid is mainly synthesized by chemical methods, and there are many synthetic routes for lipoic acid. Tao Naimin's master's thesis "Technology Research on the Synthesis of Lipoic Acid" comprehensively sorted out the synthetic routes of lipoic acid. Among them, the synthesis method of adipic acid and its derivatives is a scheme that has been realized in industrial production. The typical synthetic route is:

[0004]

[0005] The quality of the lipoic acid product produced by this scheme meets the standards of various pharmacopoeias. The yield of this process during the production process is around 65%, or even lower. The main reasons for the low yield are the following two aspects: (1) Since lipoic acid has both fat-soluble and water-soluble properties, the aqueous phase will take away a large amount of the product during the post-hydrolysis reaction treatment; (2) The reaction process produces a large number of by-products, mainly cyclotrilipoic acid and lipoic acid polymers. The generation of these impurities not only reduces the yield, but also affects the quality of the product. The above impurities are also the main impurities included in the pharmacopoeias of various countries. In response to the problem of "a large amount of lipoic acid is taken away by the aqueous phase during the post-hydrolysis reaction treatment", Zhang Tengxiao et al. published an article titled "Research Progress in Lipoic Acid Production Process and Wastewater Treatment Process" to sort out and summarize a large number of process schemes. However, no reports have been found on the recycling and reuse of the crystallization mother liquor after the crystallization and separation of lipoic acid.

[0006] The above-mentioned thioctic acid crystallization mother liquor components are analyzed, and it is found that in addition to thioctic acid, the content of impurity cyclotrithioic acid and thioctic acid polymer is also very high. This brings a huge challenge to recover qualified thioctic acid from the thioctic acid crystallization mother liquor. The solvent contained in the mother liquor is mainly a solvent or a combination of ethyl acetate, acetone, cyclohexane, petroleum ether, etc., and the commonly used schemes in production are: acetone, ethyl acetate, acetone / cyclohexane system, ethyl acetate / cyclohexane system, acetone / petroleum ether system, ethyl acetate / petroleum ether system. Summary of the invention

[0007] Therefore, for above-mentioned thioctic acid crystalline mother liquor, the object of the present invention is to provide a kind of method that reclaims thioctic acid from thioctic acid crystalline mother liquor, wherein use reducing agent sodium borohydride or potassium borohydride that thioctic acid, cyclotrithioic acid and thioctic acid polymer in thioctic acid crystalline mother liquor are all converted into dihydrolipoic acid, and then use cyclizing agent ferric chloride that dihydrolipoic acid is oxidized cyclization to thioctic acid, thereby effectively reclaim qualified thioctic acid.

[0008] According to the present invention, the method for recovering thioctic acid from thioctic acid crystallization mother liquor provided by the present invention comprises:

[0009] Step 1: Reduction to dihydrolipoic acid

[0010] The lipoic acid crystal mother liquor is concentrated to obtain an oily concentrate, and the concentrate is subjected to a reduction reaction in water at a pH of 7 to 8 in the presence of a reducing agent, sodium borohydride or potassium borohydride, to generate dihydrolipoic acid; after the reaction, the reaction solution is acidified with an acid to a pH of 1 to 2, and the acidified reaction solution is extracted with a first organic solvent to obtain an organic phase containing dihydrolipoic acid;

[0011] Step 2: Prepare Lipoic Acid

[0012] The organic phase containing dihydrolipoic acid obtained in the above step 1 is subjected to an oxidative cyclization reaction in the presence of water, ferric chloride, sodium hydroxide and oxygen to obtain lipoic acid.

[0013] The method for recovering lipoic acid from lipoic acid crystallization mother liquor of the present invention is described in more detail below.

[0014] In the present invention, the thioctic acid crystallization mother liquor is the crystallization mother liquor after separating the thioctic acid crude product in the preparation of thioctic acid, or the crystallization mother liquor produced in the refining process of the thioctic acid crude product, or the mixture of the above two. The crystallization mother liquor is analyzed by HPLC, such as Figure 1The crystallization mother liquor comprises 5% to 20% thioctic acid, 1% to 7% cyclotrithioic acid, 0.1% to 2% thioctic acid polymer, and the solvent is selected from one or more of ethyl acetate, acetone, cyclohexane and petroleum ether. For example, as a specific example, the thioctic acid crystallization mother liquor can be the mother liquor after thioctic acid is separated from Examples 1-4 of CN109574987A.

[0015] In the step 1 of reducing and preparing dihydrolipoic acid, the lipoic acid crystallization mother liquor is concentrated to obtain an oily concentrate. There is no limitation on the concentration, for example, reduced pressure distillation can be used to concentrate to obtain an oily concentrate.

[0016] Then the oily concentrate is subjected to reduction reaction in water at a pH of 7 to 8 in the presence of sodium borohydride or potassium borohydride as a reducing agent to generate dihydrolipoic acid. The reduction reaction using sodium borohydride or potassium borohydride as a reducing agent is a known reaction in the art and its conventional process conditions can be used. Specifically, water is added to the oily concentrate in an amount of 5 to 30 times, preferably 10 to 20 times, of the weight of the oily concentrate, and then an inorganic base is added thereto to adjust the pH to 7 to 8, and the oily concentrate is stirred until it is uniformly dispersed, and then sodium borohydride or potassium borohydride as a reducing agent is added, and the reduction reaction is carried out at 30°C to 60°C, preferably 40°C to 50°C, and the reaction time is generally 5 to 10 hours. Wherein, the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide, and sodium carbonate is preferred; the amount of the reducing agent sodium borohydride or potassium borohydride is 0.3 to 0.8 times the weight of the oily concentrate, and preferably 0.5 to 0.7 times.

[0017] After the reduction reaction, the reaction solution is acidified with an acid to a pH of 1 to 2, and the acidified reaction solution is extracted with a first organic solvent to obtain an organic phase containing dihydrolipoic acid. Specifically, hydrochloric acid, phosphoric acid or sulfuric acid solution, etc., and preferably hydrochloric acid solution, are used to adjust the pH of the reaction solution to control between 1 and 2; then, the acidified reaction solution is extracted once or multiple times with a first organic solvent, and the extracts are combined to obtain an organic extraction phase containing dihydrolipoic acid. The organic extraction phase can be washed with water as needed. Wherein, the first organic solvent is selected from dichloromethane, ethyl acetate and toluene, and dichloromethane is preferred; the total amount of the first organic solvent is 1 to 2 times the amount of water used above, by volume.

[0018] In the step 2 for preparing lipoic acid, the organic phase containing dihydrolipoic acid obtained in the above step 1 is subjected to an oxidative cyclization reaction in the presence of water, ferric chloride, sodium hydroxide and oxygen to obtain lipoic acid. Specifically, in step 2, the amount of water used is 0.8 to 1.2 times the volume of the organic phase containing dihydrolipoic acid; the amount of ferric chloride used is 0.3 to 0.6 times the weight of the concentrate in step 1, preferably 0.35 to 0.45 times; the amount of sodium hydroxide used is to adjust the pH of the reaction solution between 8 and 9; oxygen is continuously introduced until the reaction is complete. The oxidative cyclization reaction temperature is 30°C to 60°C, preferably 40°C to 50°C; the reaction time is 6 to 15 hours.

[0019] The method for recovering thioctic acid from thioctic acid crystal mother liquor of the present invention also includes, after the oxidative cyclization reaction is completed, standing and stratifying at -5°C to 10°C, preferably 0°C to 5°C, to separate and obtain an aqueous phase; adjusting the pH of the aqueous phase to 1 to 2 with hydrochloric acid, allowing thioctic acid crystals to precipitate, filtering, washing and drying to obtain thioctic acid.

[0020] In the method for recovering thioctic acid from thioctic acid crystal mother liquor of the present invention, it also includes purifying the thioctic acid obtained above. Specifically, the thioctic acid obtained above is added to a second organic solvent, dissolved at 30°C to 40°C, preferably 32°C to 36°C, and activated carbon and silica gel are added for decolorization after dissolving. After decolorization, the activated carbon and silica gel are filtered to remove the activated carbon and silica gel; the filtrate is cooled to -20°C to 0°C, preferably -10°C to -5°C, and thioctic acid crystals are precipitated, and the crystals are grown, filtered, washed, and dried to obtain thioctic acid. The second organic solvent is one or a combination of several of acetone, ethyl acetate, cyclohexane, n-heptane and petroleum ether, preferably an acetone / cyclohexane system or an ethyl acetate / cyclohexane system, specifically, an acetone / cyclohexane system in which the volume ratio of acetone to cyclohexane is 1:4 to 7, or an ethyl acetate / cyclohexane system in which the volume ratio of ethyl acetate to cyclohexane is 1:4 to 7.

[0021] Beneficial Effects

[0022] In the method for recovering thioctic acid from thioctic acid crystal mother liquor of the present invention, the reducing agent sodium borohydride or potassium borohydride can convert thioctic acid, cyclotrithioic acid and thioctic acid polymer in the thioctic acid crystal mother liquor into dihydrothioctic acid, and the process is simple, which lays a foundation for recovering qualified thioctic acid. Then, the cyclizing agent ferric chloride is used to oxidize and cyclize dihydrothioctic acid into thioctic acid, thereby effectively recovering qualified thioctic acid.

[0023] The quality of the lipoic acid product recovered by the method of the invention meets the pharmacopoeia standard, and not only the recovery of lipoic acid in the lipoic acid crystal mother liquor is achieved, but also the conversion of the by-product into the main product is achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the HPLC analysis spectrum of lipoic acid crystal mother liquor;

[0025] Figure 2 The following is a typical HPLC spectrum of the lipoic acid product recovered in Example 1. DETAILED DESCRIPTION

[0026] Below, the method for reclaiming thioctic acid from thioctic acid crystallization mother liquor of the present invention is more specifically described by examples, but protection scope of the present invention is not limited to these examples.

[0027] Example 1

[0028] Take 1kg of lipoic acid crystal mother liquor, Figure 1 The HPLC analysis spectrum of the thioctic acid crystal mother liquor, wherein the content of thioctic acid (Rt = 20.8min) is 10wt%, the content of cyclotrithioic acid (Rt = 6.4min) is 3wt%, and the content of thioctic acid polymer (Rt = 2.3min) is 0.2wt%, which is concentrated under reduced pressure to obtain about 160g of an oily concentrate. 2.5L of water is added to the concentrate, 41g of sodium carbonate is added in batches to adjust the solution pH to 7.9, and stirred until the oil is completely dissolved. 83g of sodium borohydride is added, and the temperature is raised to 50°C for 7 hours. After the reaction is completed, 3N hydrochloric acid is slowly added to the feed liquid to pH 1.1, 1.5L of dichloromethane is added, and the mixture is allowed to stand for stratification after sufficient stirring, and 1L of dichloromethane is added to the aqueous phase again, and the mixture is allowed to stand for stratification after sufficient stirring. Collect and merge the two extracted dichloromethane phases, add 1L of water and allow to stand for stratification after sufficient stirring, and obtain 2.8L of a dichloromethane solution containing dihydrolipoic acid.

[0029] Add 2.5L of water and 65g of ferric chloride to the dichloromethane containing dihydrolipoic acid, stir evenly, add 32% sodium hydroxide, and adjust the pH of the aqueous phase of the feed liquid to 9. Then heat it to 50°C, and continuously introduce oxygen to react for 8 hours. After the reaction is completed, cool it to 10°C, and then stand and separate to remove the dichloromethane phase. Add concentrated hydrochloric acid to the aqueous phase until the pH is 1.2, during which solids are precipitated. After crystallization, solid-liquid separation is completed, and crude lipoic acid is obtained after washing with water.

[0030] Add crude lipoic acid to a mixed solvent of 100 mL acetone and 700 mL cyclohexane, heat to 40°C, and stir until the material is completely dissolved. After the solution is clear, add 5 g of activated carbon and 15 g of silica gel for decolorization. After decolorization, filter to remove the activated carbon and silica gel. Slowly cool the filtrate to -15°C, during which solids precipitate. Keep the crystal temperature at -15°C for 2 hours. After crystallization, separate the solid and liquid. After drying, 103 g of lipoic acid is obtained, with a yield of 64.3% (calculated as concentrated oil) and a purity of 99.4% (see Figure 2 ).

[0031] Example 2

[0032] Take 5kg of the above-mentioned lipoic acid crystal mother liquor and concentrate under reduced pressure to obtain 720g of oily concentrate. Add 11L of water to the concentrate, add 247g of sodium carbonate in batches to adjust the pH of the solution to 7.3, and stir until the oil is completely dissolved. Add 480g of sodium borohydride, warm to 42°C and react for 9 hours. After the reaction is complete, slowly add 2N hydrochloric acid until the pH of the feed liquid is 1.6. Add 6L of dichloromethane, stir well and let stand for stratification, add 6L of dichloromethane to the aqueous phase again, stir well and let stand for stratification. Collect and combine the two extracted dichloromethane phases, add 5L of water and stir well and let stand for stratification to obtain 12.9L of dichloromethane solution containing dihydrolipoic acid.

[0033] Add 13L of water and 320g of ferric chloride to the dichloromethane containing dihydrolipoic acid, stir evenly, add solid sodium hydroxide, and adjust the pH of the aqueous phase of the feed liquid to 8.2. Heat to 45°C, and continuously introduce oxygen to react for 12 hours. After the reaction is completed, cool to 0°C, and then stand and separate to remove the dichloromethane phase. Add concentrated hydrochloric acid to the aqueous phase until the pH is 1.8, during which solids precipitate. After crystallization, solid-liquid separation is completed, and crude lipoic acid is obtained after washing with water.

[0034] Add the crude thioctic acid to a mixed solvent of 0.6L ethyl acetate and 3L cyclohexane, heat to 30°C, and stir until the material is completely dissolved. After the solution is clear, add 20g of activated carbon and 70g of silica gel for decolorization. After decolorization, filter to remove the activated carbon and silica gel. The filtrate is slowly cooled to -5°C, during which solids are precipitated. Keep the crystal temperature at -5°C for 2 hours, separate the solid and liquid after crystal growth, and obtain 520g of thioctic acid after drying, with a yield of 72.2% (calculated as concentrated oil) and a purity of 99.1%.

Claims

1. A method for recovering thioctic acid from thioctic acid crystallization mother liquor, comprising: Step 1: Reduction to dihydrolipoic acid The lipoic acid crystal mother liquor is concentrated to obtain an oily concentrate, and the concentrate is subjected to a reduction reaction in water at a pH of 7 to 8 in the presence of a reducing agent, sodium borohydride or potassium borohydride, to generate dihydrolipoic acid; after the reaction, the reaction solution is acidified with an acid to a pH of 1 to 2, and the acidified reaction solution is extracted with a first organic solvent to obtain an organic phase containing dihydrolipoic acid; Step 2: Prepare Lipoic Acid The organic phase containing dihydrolipoic acid obtained in the above step 1 is subjected to an oxidative cyclization reaction in the presence of water, ferric chloride, sodium hydroxide and oxygen to obtain lipoic acid. The method further comprises: After the oxidation cyclization reaction is completed, the mixture is allowed to stand at -5°C to 10°C to separate the layers and obtain an aqueous phase; the pH of the aqueous phase is adjusted to 1 to 2 with hydrochloric acid, thioctic acid crystals are precipitated, and the thioctic acid is obtained by filtering, washing and drying; The thioctic acid obtained above is purified by the following steps: adding the thioctic acid obtained above into a second organic solvent, dissolving it at 30°C to 40°C, adding activated carbon and silica gel to decolorize it after the solution is clear, filtering to remove the activated carbon and silica gel after the decolorization is completed; cooling the filtrate to -20°C to 0°C, allowing the thioctic acid to crystallize, growing the crystals, filtering, washing and drying to obtain the thioctic acid, wherein the second organic solvent is one or a combination of several of acetone, ethyl acetate, cyclohexane, n-heptane and petroleum ether.

2. The method for recovering thioctic acid from thioctic acid crystallization mother liquor according to claim 1, characterized in that, Based on the total weight of the lipoic acid crystal mother liquor, the content of lipoic acid is 5% to 20%, the content of cyclotrilipoic acid is 1% to 7%, the content of lipoic acid polymer is 0.1% to 2%, and the solvent is selected from one or more of ethyl acetate, acetone, cyclohexane and petroleum ether.

3. according to claim 1 and 2, reclaim the method for thioctic acid from thioctic acid crystallization mother liquor, it is characterized in that, In the step 1 of reducing and preparing dihydrolipoic acid, the lipoic acid crystal mother liquor is concentrated by vacuum distillation to obtain an oily concentrate; water is added to the oily concentrate, the amount of water being 5 to 30 times the weight of the oily concentrate, and then an inorganic base is added thereto to adjust the pH to 7 to 8, and the oily concentrate is stirred until the oily concentrate is uniformly dispersed and dissolved, and then a reducing agent, sodium borohydride or potassium borohydride, is added, and a reduction reaction is carried out at 30° C. to 60° C. for 5 to 10 hours, wherein the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide; and the amount of the reducing agent, sodium borohydride or potassium borohydride, is 0.3 to 0.8 times the weight of the oily concentrate.

4. according to claim 1 and 2, reclaim the method for thioctic acid from thioctic acid crystallization mother liquor, it is characterized in that, In the step 1 of preparing dihydrolipoic acid by reduction, after the reduction reaction, hydrochloric acid, phosphoric acid or sulfuric acid solution is used to adjust the pH of the reaction solution to be controlled between 1 and 2; then, the acidified reaction solution is extracted once or multiple times with a first organic solvent, and the extracts are combined to obtain an organic extraction phase containing dihydrolipoic acid, wherein the first organic solvent is selected from dichloromethane, ethyl acetate and toluene, and the total amount of the first organic solvent is 1 to 2 times the amount of the water, by volume.

5. according to claim 1 and 2, reclaim the method for thioctic acid from thioctic acid crystallization mother liquor, it is characterized in that, In the step 2 for preparing lipoic acid, the amount of water used is 0.8 to 1.2 times the volume of the organic phase containing dihydrolipoic acid; the amount of ferric chloride used is 0.3 to 0.6 times the weight of the concentrate in step 1; the amount of sodium hydroxide used is to adjust the pH of the reaction solution between 8 and 9; oxygen is continuously introduced until the reaction is complete; the oxidation cyclization reaction temperature is 30° C. to 60° C.; and the reaction time is 6 to 15 hours.

6. The method for recovering thioctic acid from thioctic acid crystal mother liquor according to claim 1, characterized in that: The second organic solvent is an acetone / cyclohexane system in which the volume ratio of acetone to cyclohexane is 1:4-7, or an ethyl acetate / cyclohexane system in which the volume ratio of ethyl acetate to cyclohexane is 1:4-7.

7. The method for reclaiming thioctic acid from thioctic acid crystal mother liquor according to claim 1 or 2, characterized in that, In the step 1 of reducing and preparing dihydrolipoic acid, the mother liquor of lipoic acid crystals is concentrated by vacuum distillation to obtain an oily concentrate; water is added to the oily concentrate, the amount of water being 5 to 30 times the weight of the oily concentrate, and then an inorganic base is added thereto to adjust the pH to 7 to 8, and the oily concentrate is stirred until the oily concentrate is uniformly dispersed and dissolved, and then a reducing agent, sodium borohydride or potassium borohydride, is added, and a reduction reaction is carried out at 30° C. to 60° C. for 5 to 10 hours, wherein the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide; the amount of the reducing agent, sodium borohydride or potassium borohydride, is 0.3 to 0.8 times the weight of the oily concentrate; In the step 1 of reducing and preparing dihydrolipoic acid, after the reduction reaction, the pH of the reaction solution is adjusted to be controlled between 1 and 2 using hydrochloric acid, phosphoric acid or sulfuric acid solution; then, the acidified reaction solution is extracted once or multiple times using a first organic solvent, and the extracts are combined to obtain an organic extract phase containing dihydrolipoic acid, wherein the first organic solvent is selected from dichloromethane, ethyl acetate and toluene, and the total amount of the first organic solvent is 1 to 2 times the amount of the water, by volume; In the step 2 for preparing lipoic acid, the amount of water used is 0.8 to 1.2 times the volume of the organic phase containing dihydrolipoic acid; the amount of ferric chloride used is 0.3 to 0.6 times the weight of the concentrate in step 1; the amount of sodium hydroxide used is to adjust the pH of the reaction solution between 8 and 9; oxygen is continuously introduced until the reaction is complete; the oxidation cyclization reaction temperature is 30° C. to 60° C.; and the reaction time is 6 to 15 hours.

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