CN116102532B - Method for recovering lipoic acid from lipoic acid crystal mother liquor - Google Patents
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Abstract
本发明属于制药技术领域，涉及一种从硫辛酸结晶母液中回收硫辛酸的方法。所述方法包括：使用还原剂硼氢化钠或硼氢化钾将硫辛酸结晶母液中的硫辛酸、环三硫辛酸和硫辛酸聚合物均转化为二氢硫辛酸，而后使用环合剂三氯化铁将二氢硫辛酸氧化环合为硫辛酸。通过本发明方法回收得到的硫辛酸产品质量符合药典标准，不仅实现了硫辛酸结晶母液中硫辛酸的回收，还实现了副产物向主产物的转化。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
The invention belongs to the technical field of pharmacy, and relates to a method for recovering lipoic acid from lipoic acid crystallization mother liquor.
Background
Lipoic acid (C 8H14O2S2), which is an organic compound that can be used as a coenzyme to participate in acyl transfer in metabolism in the organism, and can eliminate free radicals that cause accelerated aging and pathogenicity. Meanwhile, lipoic acid is absorbed in the intestinal tract in vivo and then enters cells, the lipoic acid has the characteristics of fat solubility and water solubility, and sulfhydryl groups are easy to carry out oxidation-reduction reaction, so that the lipoic acid can protect sulfhydryl enzyme from poisoning by heavy metal ions. Lipoic acid has been widely used in clinical medicine, and has application range including liver dysfunction, subacute necrosis encephalopathy, nervous diseases, radiation injury, etc. and is known as universal antioxidant.
At present, lipoic acid is mainly synthesized by a chemical method, and a plurality of synthetic process routes related to lipoic acid are provided. Tao Naimin Shuoshi graduation paper, "technological study of lipoic acid Synthesis," has performed comprehensive carding on the synthetic route of lipoic acid. Among them, adipic acid and derivatives are the schemes for industrial production, and typical synthetic routes are as follows:
The quality of the lipoic acid product produced by the scheme accords with the pharmacopoeia standards of various countries. The process has yield of 65% or lower in the production process, and the reason for the lower yield is mainly that (1) lipoic acid has both fat-soluble and water-soluble characteristics, so that a large amount of products can be taken away by water phase in the post-hydrolysis treatment, and (2) a large amount of byproducts, mainly cyclotrislipoic acid and lipoic acid polymers, are produced in the reaction process. The production of these impurities not only reduces the yield but also affects the quality of the product, and the above impurities are also the main impurities recorded in pharmacopoeias of various countries. Aiming at the problem that a large amount of lipoic acid is carried away by the water phase in the post-treatment of the hydrolysis reaction, the article of research progress of lipoic acid production process and wastewater treatment process published by Zhang Tengxiao et al is carded and summarized, and a large amount of process schemes are summarized. However, there has been no report on the recovery and reuse of the mother liquor after the crystallization and separation of lipoic acid.
Analysis of the above-mentioned lipoic acid crystallization mother liquor components revealed that the contents of the impurity cyclotrishiooctanoic acid and lipoic acid polymers were very high in addition to lipoic acid. This presents a significant challenge for recovery of acceptable lipoic acid from lipoic acid crystallization mother liquor. The solvent contained in the mother liquor is mainly ethyl acetate, acetone, cyclohexane, petroleum ether and other solvents or combinations thereof, and the common scheme in the production is that the solvent is an acetone, ethyl acetate, an acetone/cyclohexane system, an ethyl acetate/cyclohexane system, an acetone/petroleum ether system, an ethyl acetate/petroleum ether system.
Disclosure of Invention
Accordingly, in view of the above-described lipoic acid crystallization mother liquor, an object of the present invention is to provide a method for recovering lipoic acid from lipoic acid crystallization mother liquor, in which lipoic acid, cyclotrisulfuric acid and lipoic acid polymers in lipoic acid crystallization mother liquor are all converted into dihydrolipoic acid using a reducing agent sodium borohydride or potassium borohydride, and then dihydrolipoic acid is oxidized and cyclized into lipoic acid using an cyclizing agent ferric trichloride, thereby efficiently recovering qualified lipoic acid.
According to the present invention, there is provided a method for recovering lipoic acid from lipoic acid crystallization mother liquor, comprising:
step 1, preparing the dihydrolipoic acid by reduction
Concentrating the lipoic acid crystallization mother liquor to obtain an oily concentrate, carrying out reduction reaction on the concentrate in water under the condition of pH of 7-8 in the presence of sodium borohydride or potassium borohydride serving as a reducing agent to generate dihydrolipoic acid, acidifying the reaction solution to pH of 1-2 by using acid after the reaction, and extracting the acidified reaction solution by using a first organic solvent to obtain an organic phase containing the dihydrolipoic acid;
step 2 preparation of lipoic acid
And (2) carrying out an oxidative cyclization reaction on the organic phase containing the dihydrolipoic acid obtained in the step (1) in the presence of water, ferric trichloride, sodium hydroxide and oxygen to obtain the lipoic acid.
The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to the present invention is described in more detail as follows.
In the invention, the lipoic acid crystallization mother liquor is crystallization mother liquor obtained after separating lipoic acid crude product in lipoic acid preparation, or crystallization mother liquor generated in the lipoic acid crude product refining process, or a mixed liquor of the lipoic acid crude product and the crystallization mother liquor. The crystallization mother liquor is analyzed by HPLC, as shown in figure 1, the content of the thiooctanoic acid in the crystallization mother liquor is 5% -20%, the content of the cyclotrisulfoisooctanoic acid is 1% -7%, the content of the lipoic acid polymer is 0.1% -2% based on the total weight of the crystallization mother liquor, and the solvent is one or more selected from ethyl acetate, acetone, cyclohexane and petroleum ether. For example, as a specific example, the lipoic acid crystallization mother liquor may be the mother liquor of CN109574987a examples 1-4 after separation of lipoic acid.
In the step 1 of preparing the dihydrolipoic acid by reduction, the lipoic acid crystal mother liquor is concentrated to obtain oily concentrate. The concentration is not limited, and for example, reduced pressure distillation concentration may be employed to obtain an oily concentrate.
And then the oily concentrate is subjected to reduction reaction in water under the condition that the pH value is 7-8 and in the presence of a reducing agent sodium borohydride or potassium borohydride to generate the dihydrolipoic acid. The reduction reaction using sodium borohydride or potassium borohydride as a reducing agent is known in the art and can be performed using conventional process conditions. Specifically, water is added into the oily concentrate, the water consumption is 5-30 times, preferably 10-20 times, the weight of the oily concentrate, then inorganic alkali is added into the oily concentrate to adjust the pH to 7-8, the oily concentrate is stirred until the oily concentrate is uniformly dispersed, and then a reducing agent sodium borohydride or potassium borohydride is added into the oily concentrate to perform a reduction reaction at 30-60 ℃, preferably 40-50 ℃, and the reaction time is generally 5-10 hours. The inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide, preferably sodium carbonate, and the reducing agent sodium borohydride or potassium borohydride is used in an amount which is 0.3-0.8 times, preferably 0.5-0.7 times, the weight of the oily concentrate.
After the reduction reaction, acidizing the reaction liquid to pH 1-2 by using acid, and extracting the acidized reaction liquid by using a first organic solvent to obtain an organic phase containing the dihydrolipoic acid. The method comprises the steps of adjusting the pH of a reaction solution to be 1-2 by using hydrochloric acid, phosphoric acid or sulfuric acid solution and the like, preferably hydrochloric acid solution, extracting the acidified reaction solution once or more times by adopting a first organic solvent, and combining the extracts to obtain an organic extract phase containing the dihydrolipoic acid. The organic extract phase may be washed with water, if desired. The first organic solvent is selected from dichloromethane, ethyl acetate and toluene, preferably dichloromethane, and the total dosage of the first organic solvent is 1-2 times of the water dosage by volume.
In the step 2 of preparing lipoic acid, the organic phase containing the dihydrolipoic acid obtained in the step 1 is subjected to an oxidative cyclization reaction in the presence of water, ferric trichloride, sodium hydroxide and oxygen to obtain lipoic acid. Specifically, in the step 2, the water is 0.8-1.2 times of the volume of the organic phase containing the dihydrolipoic acid, the ferric trichloride is 0.3-0.6 times, preferably 0.35-0.45 times, of the weight of the concentrate in the step 1, the sodium hydroxide is used for adjusting the pH of the reaction solution to 8-9, and oxygen is continuously introduced until the reaction is complete. The temperature of the oxidation cyclization reaction is 30-60 ℃, preferably 40-50 ℃ and the reaction time is 6-15 hours.
The method for recovering the lipoic acid from the lipoic acid crystallization mother liquor further comprises the steps of standing and layering at-5-10 ℃ and preferably 0-5 ℃ after the oxidation cyclization reaction is completed, separating to obtain a water phase, adjusting the pH of the water phase to 1-2 by using hydrochloric acid, crystallizing and separating the lipoic acid, and filtering, washing and drying to obtain the lipoic acid.
The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to the present invention further comprises purifying lipoic acid obtained as described above. The method comprises the steps of adding the obtained lipoic acid into a second organic solvent, dissolving at 30-40 ℃, preferably 32-36 ℃, adding active carbon and silica gel after dissolving, decoloring, filtering to remove the active carbon and the silica gel after decoloring, cooling filtrate to-20-0 ℃, preferably-10-5 ℃, crystallizing and separating lipoic acid, growing crystals, filtering, washing and drying to obtain lipoic acid. The second organic solvent is one or a combination of more 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 1:4-7, or an ethyl acetate/cyclohexane system in which the volume ratio of ethyl acetate to cyclohexane is 1:4-7.
Advantageous effects
In the method for recovering the lipoic acid from the lipoic acid crystallization mother liquor, the used reducing agent sodium borohydride or potassium borohydride can completely convert lipoic acid, cyclotrislipoic acid and lipoic acid polymers in the lipoic acid crystallization mother liquor into the dihydrolipoic acid, and the process is simple and convenient, thereby laying a foundation for recovering and obtaining the qualified lipoic acid. And then the ferric trichloride serving as a cyclization agent is used for oxidatively cyclizing the dihydrolipoic acid into lipoic acid, so that the qualified lipoic acid is effectively recovered.
The quality of the lipoic acid product recovered by the method meets the pharmacopoeia standard, so that the recovery of lipoic acid in lipoic acid crystallization mother liquor is realized, and the conversion of byproducts to main products is also realized.
Drawings
FIG. 1 is an HPLC analysis chart of lipoic acid crystallization mother liquor;
figure 2 is a typical HPLC profile of the finished lipoic acid recovered in example 1.
Detailed Description
The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to the present invention will be described more specifically by examples, but the scope of the present invention is not limited to these examples.
Example 1
1Kg of lipoic acid crystallization mother liquor was taken, and fig. 1 is an HPLC analysis chart of the lipoic acid crystallization mother liquor, wherein the content of lipoic acid (rt=20.8 min) was 10wt%, the content of cyclotrisulfur octanoic acid (rt=6.4 min) was 3wt%, and the content of lipoic acid polymer (rt=2.3 min) was 0.2wt%, and the lipoic acid crystallization mother liquor was concentrated under reduced pressure to obtain about 160g of oily concentrate. To the concentrate was added 2.5L of water, 41g of sodium carbonate was added in portions to adjust the pH of the solution to 7.9, and stirred until the oil was completely dissolved. 83g of sodium borohydride was added, and the reaction was allowed to proceed at 50℃for 7 hours. After the reaction, slowly adding 3N hydrochloric acid until the pH of the feed liquid is 1.1, adding 1.5L of dichloromethane, fully stirring, standing for layering, adding 1L of dichloromethane again into the water phase, fully stirring, and standing for layering. The dichloromethane phases of the two extractions are collected and combined, 1L of water is added, and after the mixture is fully stirred, the mixture is stood for layering, so that 2.8L of dichloromethane solution containing the dihydrolipoic acid is obtained.
2.5L of water and 65g of ferric trichloride are added into the dichloromethane containing the dihydrolipoic acid, and after uniform stirring, 32% sodium hydroxide is added, and the pH value of the feed liquid water phase is adjusted to 9. Then the temperature is raised to 50 ℃, and oxygen is continuously introduced to react for 8 hours. And cooling to 10 ℃ after the reaction is finished, and then standing and layering to remove a dichloromethane phase. Concentrated hydrochloric acid was added dropwise to the aqueous phase to a pH of 1.2, during which time a solid precipitated. And (3) after crystallization, carrying out solid-liquid separation, and washing with water to obtain a lipoic acid crude product.
The crude lipoic acid is added into a mixed solvent of 100mL of acetone and 700mL of cyclohexane, the temperature is raised to 40 ℃, and the mixture is stirred until the materials are completely dissolved. After the solution is cleared, adding 5g of active carbon and 15g of silica gel for decoloring, and filtering to remove the active carbon and the silica gel after decoloring. The filtrate was slowly cooled to-15 ℃ during which time solids precipitated. Keeping the crystal growing temperature at-15 ℃ for 2 hours, carrying out solid-liquid separation after the crystal growing is finished, and drying to obtain 103g of lipoic acid, wherein the yield is 64.3% (calculated by concentrating oily matters), and the purity is 99.4% (see figure 2).
Example 2
5Kg of the lipoic acid crystallization mother liquor was concentrated under reduced pressure to obtain 720g of an oily concentrate. To the concentrate was added 11L of water, 247g of sodium carbonate was added in portions to adjust the pH of the solution to 7.3, and the mixture was stirred until the oil was completely dissolved. 480g of sodium borohydride was added thereto, and the temperature was raised to 42℃for 9 hours. After the reaction, 2N hydrochloric acid is slowly added until the pH of the feed liquid is 1.6. Adding 6L of dichloromethane, fully stirring, standing for layering, adding 6L of dichloromethane into the water phase again, fully stirring, and standing for layering. The dichloromethane phases of the two extractions are collected and combined, 5L of water is added, and the mixture is fully stirred and then is stood for layering, so as to obtain 12.9L of dichloromethane solution containing the dihydrolipoic acid.
13L of water and 320g of ferric trichloride are added into the dichloromethane containing the dihydrolipoic acid, solid sodium hydroxide is added after uniform stirring, and the pH of a feed liquid water phase is adjusted to 8.2. Heating to 45 ℃, and continuously introducing oxygen to react for 12 hours. Cooling to 0 ℃ after the reaction is finished, and then standing and layering to remove a dichloromethane phase. Concentrated hydrochloric acid was added dropwise to the aqueous phase to a pH of 1.8, during which time a solid precipitated. And (3) after crystallization, carrying out solid-liquid separation, and washing with water to obtain a lipoic acid crude product.
The crude lipoic acid is added into a mixed solvent of 0.6L of ethyl acetate and 3L of cyclohexane, the temperature is raised to 30 ℃, and the mixture is stirred until the materials are completely dissolved. After the solution is cleared, 20g of active carbon and 70g of silica gel are added for decolorization, and the active carbon and the silica gel are removed by filtration after the decolorization is finished. The filtrate was slowly cooled to-5 ℃ during which time solids precipitated. Keeping the crystal growing temperature at-5 ℃ for 2 hours, carrying out solid-liquid separation after the crystal growing, and drying to obtain 520g of lipoic acid, wherein the yield is 72.2% (calculated by concentrated oily matter) and the purity is 99.1%.
Claims (7)
1. A method for recovering lipoic acid from lipoic acid crystallization mother liquor, comprising:
step 1, preparing the dihydrolipoic acid by reduction
Concentrating the lipoic acid crystallization mother liquor to obtain an oily concentrate, carrying out reduction reaction on the concentrate in water under the condition of pH of 7-8 in the presence of sodium borohydride or potassium borohydride serving as a reducing agent to generate dihydrolipoic acid, acidifying the reaction solution to pH of 1-2 by using acid after the reaction, and extracting the acidified reaction solution by using a first organic solvent to obtain an organic phase containing the dihydrolipoic acid;
step 2 preparation of lipoic acid
The organic phase containing the dihydrolipoic acid obtained in the step 1 is subjected to an oxidative cyclization reaction in the presence of water, ferric trichloride, sodium hydroxide and oxygen to obtain lipoic acid,
The method further comprises the steps of:
standing and layering at-5 ℃ to 10 ℃ after the oxidation cyclization reaction is completed, and separating to obtain a water phase, adjusting the pH of the water phase to 1-2 by hydrochloric acid, crystallizing and separating lipoic acid, and filtering, washing and drying to obtain lipoic acid;
The obtained lipoic acid is purified, and the steps are that the obtained lipoic acid is added into a second organic solvent, dissolved at 30-40 ℃, activated carbon and silica gel are added after the solution is cleared, decolored, the activated carbon and the silica gel are removed after the decoloration is finished, the filtrate is cooled to-20-0 ℃, the lipoic acid is crystallized, the crystallization is carried out, the lipoic acid is obtained after filtration, washing and drying, wherein the second organic solvent is one or the combination of more of acetone, ethyl acetate, cyclohexane, n-heptane and petroleum ether.
2. The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to claim 1, wherein the lipoic acid content is 5% -20%, the cyclotrisulfoxin acid content is 1% -7%, the lipoic acid polymer content is 0.1% -2% based on the total weight of the lipoic acid crystallization mother liquor, and the solvent is one or more selected from the group consisting of ethyl acetate, acetone, cyclohexane and petroleum ether.
3. The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to claim 1 or 2, wherein in the step 1 reduction preparation of the dihydrolipoic acid, reduced pressure distillation concentration is adopted for the lipoic acid crystallization mother liquor to obtain oily concentrate, water is added into the oily concentrate, the water amount is 5-30 times of the weight of the oily concentrate, then inorganic base is added into the oily concentrate to adjust pH to 7-8, the oily concentrate is stirred until the oily concentrate is uniformly dispersed and dissolved, then reducing agent sodium borohydride or potassium borohydride is added, reduction reaction is carried out at 30-60 ℃ for 5-10 hours, wherein the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide, and the reducing agent sodium borohydride or potassium borohydride is 0.3-0.8 times of the weight of the oily concentrate.
4. The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to claim 1 or 2, wherein in the step 1 reduction preparation of the dihydrolipoic acid, 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 after the reduction reaction, then the acidified reaction solution is extracted one or more times by using a first organic solvent, and the extraction solutions are combined to obtain an organic extraction phase containing the 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 water by volume.
5. The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to claim 1 or 2, wherein in the step 2 of preparing lipoic acid, the water is 0.8-1.2 times of the volume of an organic phase containing dihydro lipoic acid, the ferric trichloride is 0.3-0.6 times of the weight of the concentrate in the step 1, the sodium hydroxide is used for adjusting the pH of a reaction solution to 8-9, oxygen is continuously introduced until the reaction is complete, the oxidation cyclization reaction temperature is 30-60 ℃, and the reaction time is 6-15 hours.
6. The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to claim 1, wherein the second organic solvent is an acetone/cyclohexane system with a volume ratio of 1:4-7 of acetone to cyclohexane or an ethyl acetate/cyclohexane system with a volume ratio of 1:4-7 of ethyl acetate to cyclohexane.
7. The method for recovering lipoic acid from lipoic acid crystallization mother liquor according to claim 1 or 2, wherein in the step 1 reduction preparation of the dihydrolipoic acid, reduced pressure distillation concentration is adopted for the lipoic acid crystallization mother liquor to obtain oily concentrate, water is added into the oily concentrate, the water dosage is 5-30 times of the weight of the oily concentrate, then inorganic base is added into the oily concentrate to adjust pH to 7-8, the oily concentrate is stirred until the oily concentrate is uniformly dispersed and dissolved, then reducing agent sodium borohydride or potassium borohydride is added into the oily concentrate, reduction reaction is carried out at 30-60 ℃ for 5-10 hours, wherein the inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and sodium hydroxide, and the reducing agent sodium borohydride or potassium borohydride is 0.3-0.8 times of the weight of the oily concentrate;
In the reduction preparation of the dihydrolipoic acid in the step 1, hydrochloric acid, phosphoric acid or sulfuric acid solution is used for regulating the pH value of the reaction solution to be controlled between 1 and 2 after the reduction reaction, then, the acidified reaction solution is extracted for one or more times by adopting a first organic solvent, and the extraction solutions are combined to obtain an organic extraction phase containing the dihydrolipoic acid, wherein the first organic solvent is selected from dichloromethane, ethyl acetate and toluene, and the total dosage of the first organic solvent is 1 to 2 times of the dosage of the water by volume;
In the preparation of the lipoic acid in the step 2, the water consumption is 0.8-1.2 times of the volume of an organic phase containing the dihydrolipoic acid, the ferric trichloride consumption is 0.3-0.6 times of the weight of the concentrate in the step 1, the sodium hydroxide consumption is used for adjusting the pH value of a reaction solution to be 8-9, oxygen is continuously introduced until the reaction is complete, the oxidation cyclization reaction temperature is 30-60 ℃, and the reaction time is 6-15 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607955A (en) * | 2008-06-18 | 2009-12-23 | 上海津力化工有限公司 | A kind of preparation method of low residual lipoic acid |
| CN102603709A (en) * | 2012-03-02 | 2012-07-25 | 海南灵康制药有限公司 | Thioctic acid compound and preparation method thereof |
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| EP1307442A2 (en) * | 2000-08-02 | 2003-05-07 | Basf Aktiengesellschaft | Method for producing lipoic acid and dihydrolipoic acid |
| CN100375745C (en) * | 2005-12-21 | 2008-03-19 | 重庆药友制药有限责任公司 | Method for refining lipoic acid |
| CN109574987A (en) * | 2017-09-29 | 2019-04-05 | 辽宁远大诺康生物制药有限公司 | Application of the preparation method and lipoic acid of lipoic acid in the drug of preparation treatment aspermia or oligospermia |
| CN113292533B (en) * | 2021-05-25 | 2024-04-16 | 四川智强医药科技开发有限公司 | Method for purifying polymer impurities in lipoic acid |
| CN113234059B (en) * | 2021-05-26 | 2023-08-15 | 四川智强医药科技开发有限公司 | Preparation method of lipoic acid impurity A |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101607955A (en) * | 2008-06-18 | 2009-12-23 | 上海津力化工有限公司 | A kind of preparation method of low residual lipoic acid |
| CN102603709A (en) * | 2012-03-02 | 2012-07-25 | 海南灵康制药有限公司 | Thioctic acid compound and preparation method thereof |
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