Synthesis method of DL-lipoic acid

Abstract

The invention provides a method for synthesizing DL-lipoic acid, which comprises the following steps of: adding sodium persulfate and a catalyst into dihydrolipoic acid serving as a raw material in a neutral or weakly alkaline environment, heating to react, and purifying to obtain the DL-lipoic acid, the catalyst is a metal compound loaded on a microsphere carrier; the metal compound is selected from at least one of metal oxide and metal salt; the molecular formula of the microsphere carrier is MgCl2. N (ROH), n is 3-6, and R is C2-C6 saturated alkyl; the metal oxide adopts iron oxide or chromium oxide; the metal salt adopts ferric trichloride or chromium trichloride. According to the method, the metal compound loaded on the microsphere carrier is used as the catalyst, and in a neutral or weakly alkaline environment, dihydrolipoic acid is used as a raw material, and sodium persulfate is used as the catalyst, so that the yield and purity of the target product DL-lipoic acid are effectively improved, and the reaction time is shortened.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical drug preparation, and particularly relates to a method for synthesizing DL-lipoic acid. Background Art

[0002] DL-lipoic acid, also known as α-lipoic acid, is a water-insoluble white or pale yellow crystal that is widely distributed in biological tissues such as animals and plants. The structural formula of DL-lipoic acid is It contains a disulfide five-membered ring structure, exhibiting significant electrophilicity and the ability to react with free radicals. It can directly eliminate harmful hydroxyl and hydrogen radicals in aqueous solution. It also readily forms aggregates, exhibiting a stronger free radical scavenging ability than its monomeric counterpart. Due to its important physiological effects, DL-lipoic acid is widely used in clinical medicine and biomedicine, treating conditions such as diabetic peripheral neuropathy, osteoporosis, liver dysfunction, subacute necrotizing encephalopathy, radiation damage, and heavy metal poisoning such as arsenic, cadmium, and mercury. It is known as a "universal antioxidant" and has become an important pharmaceutical raw material. However, due to its extremely low content in plants and animals, chemical synthesis is currently the primary method for obtaining DL-lipoic acid.

[0003] In the existing process routes, different methods are used depending on the raw materials. For example, DL-lipoic acid is synthesized using adipic acid and its derivatives, cyclohexanone and its derivatives, etc. as raw materials. Although there are differences in the routes and intermediate products, most processes will produce dihydrolipoic acid, which is then used to produce DL-lipoic acid through a sulfonation and cyclization reaction.

[0004] Currently, the sulfonation and cyclization reaction conditions for preparing DL-lipoic acid from dihydrolipoic acid are: oxygen is introduced into dihydrolipoic acid and an alkaline solution, followed by heating to react. To improve reaction efficiency, existing methods generally add catalysts, such as ferric chloride, zinc chloride, manganese oxide, and copper chloride, or use activated carbon, graphene, and other carriers to support metal catalysts. Although this method improves yields slightly, the catalytic activity remains low, and the reaction is time-consuming, typically requiring more than 5 hours for the reaction to complete. Summary of the Invention

[0005] In view of this, the present invention aims to provide a method for synthesizing DL-lipoic acid, aiming to solve at least one technical problem among the background technology.

[0006] The present invention is achieved in that:

[0007] A synthetic method for DL-lipoic acid, wherein the reaction formula of the synthetic method is:

[0008]

[0009] In a neutral or weakly alkaline environment, dihydrolipoic acid is used as a raw material, sodium persulfate and a catalyst are added, heated to react, and DL-lipoic acid is obtained after purification;

[0010] The catalyst is a metal compound supported on a microsphere carrier;

[0011] The metal compound is selected from at least one of metal oxides and metal salts;

[0012] The molecular formula of the microsphere carrier is MgCl2·n(ROH), n=3-6, R=C2-C6 saturated alkyl;

[0013] The metal oxide is ferric oxide or chromium oxide; the metal salt is ferric chloride or chromium chloride.

[0014] Preferably, the synthesis method comprises the following steps:

[0015] At room temperature, add alkaline solution to dihydrolipoic acid, stir evenly and dissolve, and adjust the pH to neutral or weak alkaline;

[0016] First add the catalyst, raise the temperature to 40°C to 60°C, then add sodium persulfate, and stir to react for 2h to 4h;

[0017] After the reaction is completed, the temperature is lowered to below 15° C., the organic phase is extracted with an organic solvent, and then impurities are removed by distillation, dried and crystallized to obtain high-purity DL-lipoic acid.

[0018] Preferably, the synthesis method is carried out in a water bath; after the reaction is completed, cooling water at 0°C to 10°C is continuously introduced into the water bath to rapidly reduce the temperature of the reaction system environment to below 15°C.

[0019] Preferably, the catalyst preparation step comprises:

[0020] The microsphere carrier is mixed with the metal compound by impregnation or high-energy ball milling;

[0021] Heat treating the mixture at 80°C to 120°C;

[0022] After repeated washing, vacuum drying is performed to obtain the catalyst.

[0023] Preferably, the amount of the catalyst used is based on the metal compound supported by the catalyst, and the amount of the metal compound used is 1 wt% to 5 wt% of the dihydrolipoic acid.

[0024] Preferably, the molar ratio of sodium persulfate to dihydrolipoic acid is 1.1 to 1.5:1.

[0025] Preferably, the organic solvent is chloroform or diethyl ether.

[0026] Preferably, the pH of the neutral or weakly alkaline environment is 7-9.

[0027] Preferably, the pH of the neutral or weakly alkaline environment is 7.5-8.

[0028] Preferably, the loading amount of the metal oxide and / or metal salt in the catalyst is 5% to 50%, preferably 15% to 30%.

[0029] Preferably, a complexing agent is added when the microsphere carrier is mixed with the metal compound.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. The present invention uses a metal compound supported on a microsphere carrier as a catalyst, dihydrolipoic acid as a raw material, and sodium persulfate as a catalyst under a neutral or weakly alkaline environment, effectively improving the yield and purity of the target product DL-lipoic acid and shortening the reaction time.

[0032] 2. The present invention adds a metal compound as a catalyst to improve the activity of sodium persulfate, and optimizes MgCl2·n(ROH) as a catalyst carrier to further improve the activity of sodium persulfate.

[0033] 3. The present invention adopts an impregnation method or a high-energy ball milling method to mix the microsphere carrier with the metal compound, and utilizes the complexation between the microsphere carrier and the metal compound to increase the specific surface area and improve the catalytic efficiency; at the same time, the amount of metal catalyst used is reduced. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific implementation cases described herein are only used to explain the present invention and are not intended to limit the present invention.

[0035] A method for synthesizing DL-lipoic acid, the reaction formula of which is as follows: in a neutral or weakly alkaline environment, dihydrolipoic acid is used as a raw material, sodium persulfate and a catalyst are added, heated to react, and DL-lipoic acid is obtained after purification;

[0036]

[0037] The synthesis method comprises steps S1-S3:

[0038] S1. At room temperature, add alkaline solution to dihydrolipoic acid, stir and dissolve it, and adjust the pH to neutral or weakly alkaline, preferably 7.5-8.

[0039] S2. First add the catalyst, raise the temperature to 40°C to 60°C, then add sodium persulfate, and stir to react for 2h to 4h.

[0040] The catalyst is a metal compound supported on a microsphere carrier; the preparation method is: mixing the microsphere carrier with the metal compound by an impregnation method or a high-energy ball milling method, in a preferred embodiment, adding a complexing agent during mixing; heat-treating the mixture at 80°C to 120°C to increase the specific surface area; repeatedly washing with a solvent such as ethanol and then vacuum drying to obtain the catalyst; in specific implementation, the impregnation method is suitable for water-soluble metal compounds, specifically, immersing the microsphere carrier in a metal compound solution for a period of time, and adding a complexing agent (such as EDTA), which can be assisted by ultrasound, and filtering to obtain the catalyst; all metal compounds are suitable for high-energy ball milling, specifically, using a high-energy ball mill to ball-mill the metal oxide / metal salt, the microsphere carrier and the complexing agent to mix them.

[0041] In a specific implementation, the molecular formula of the microsphere carrier is MgCl2·n(ROH), where n=3-6, and R=C2-C6 saturated alkyl; the metal compound is a metal oxide or / and a metal salt, and the metal oxide is ferric oxide or chromium oxide; the metal salt is ferric chloride or chromium chloride; the microsphere carrier is prepared by existing technical means in this field, such as mixing MgCl2 and anhydrous alcohol and then preparing it by spraying; or melting MgCl2 and anhydrous alcohol in an oxygen-free protective environment and mixing them with a dispersant (such as fumed silica), heating and stirring to emulsify, and finally extruding to shape.

[0042] In this step, sodium persulfate is used as an oxidant, which has a higher oxidizing property than oxygen and can cyclize two sulfhydryl groups (-SH) to SS. However, since the cyclization reaction of dihydrolipoic acid is an alkaline condition, the activity of sodium persulfate is inhibited. In the present invention, a metal compound is added as a catalyst to improve the activity of sodium persulfate, and MgCl2·n(ROH) is optimized as a catalyst carrier to further improve the activity of sodium persulfate.

[0043] The dosage of the catalyst of the present invention is calculated based on the metal compound supported thereon, and the dosage of the metal compound is 1wt% to 5wt% of dihydrolipoic acid, for example, it can be 1wt%, 2wt%, 3wt%, 4wt%, or 5wt%; but it is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; compared with conventional catalysts, the present invention greatly saves the dosage.

[0044] In terms of molar ratio, the ratio of sodium persulfate to dihydrolipoic acid is 1.1 to 1.5:1, for example, 1.1:1, 1.2:1, 1.3:1, 1.4:1, or 1.5:1; but the ratio is not limited to the values ​​listed, and other values ​​not listed within the numerical range are also applicable.

[0045] The loading amount of the metal oxide and / or metal salt in the catalyst is 5% to 50%, preferably 15% to 30%, for example, 5%, 10%, 15%, 30%, 50%; but it is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0046] In a specific implementation, the synthesis method of the present invention is carried out in a water bath, which is more conducive to the occurrence and uniformity of the reaction.

[0047] S3. After the reaction is completed, cooling water at 0°C to 10°C is continuously introduced into a water bath to reduce the temperature of the reaction system to below 15°C. The organic phase is extracted with chloroform or ether, and then impurities are removed by distillation, dried, and crystallized to obtain high-purity DL-lipoic acid.

[0048] In a specific implementation, since the reaction of dihydrolipoic acid to DL-lipoic acid is a reversible oxidation reaction, the reversible reaction can be inhibited by rapidly cooling the temperature after the reaction is completed, thereby improving the purity of the target product and further increasing the stability of the reaction.

[0049] Example 1

[0050] This embodiment is a method for synthesizing DL-lipoic acid, which comprises:

[0051] S1. At room temperature, add alkaline solution to dihydrolipoic acid (100 g, 0.480 mol, purity ≥ 99%), stir and dissolve, and adjust the pH to neutral or weak alkaline, pH 7.5.

[0052] S2. Using a high-energy ball milling method, the microsphere carrier MgCl2·3(EtOH) was mixed with ferric chloride and a complexing agent EDTA, and the mixture was heat-treated at 80°C for about 2 hours; the mixture was then repeatedly washed with a solvent such as ethanol and then vacuum-dried to obtain a catalyst with a ferric chloride loading of 5%; the catalyst (ferric chloride dosage was 3 g) was first added to the raw material solution prepared in step S1, the temperature was raised to 40°C in a water bath, and then sodium persulfate (125.71 g, 0.528 mol) was added, and the reaction was stirred for 3 hours to obtain crude DL-lipoic acid.

[0053] S3. After the reaction, ice water was continuously introduced until the temperature of the reaction system dropped to 10° C. and the temperature was kept constant. The organic phase was extracted with chloroform and the extraction was repeated three times. The organic phases were combined and then distilled to remove impurities, dried and crystallized to obtain high-purity DL-lipoic acid (96.97 g, 0.470 mol). The yield was 97.9% based on the molar ratio of dihydrolipoic acid; the purity was detected to be 98.4%.

[0054] Example 2

[0055] In this example, based on Example 1, the molecular formula of the microsphere carrier in the catalyst was adjusted, that is, the number of R groups and n in MgCl2·n(ROH) was changed. The other reaction conditions and steps were consistent with those in Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 1.

[0056] Table 1

[0057]

[0058]

[0059] From the data in Table 1, it can be seen that when the components of the microsphere carrier in the catalyst are changed, the yield and purity of the target product change significantly;

[0060] Comparison of Examples 1 and 2-1 to 2-6 shows that when the alkyl group of the alcohol in the microsphere carrier is C2 to C6, the yield of the target product is above 96%. When the alkyl group is C1 or C7, the yield of the target product drops below 90%. The reason is that when the chain of the alkyl alcohol is too long or too short, the catalyst component (metal compound) is not easily complexed with it, and thus cannot fully exert its function of promoting catalyst activity.

[0061] From the comparison of Example 1, Example 2-7 to Example 2-11, it can be seen that when the n value representing the alcohol content in the microsphere carrier is 3 to 6, the yield of the target product is above 97%; when the n value is 2 or 7, the yield of the target product drops to below 91%. The reason is that: when the alcohol content is too low, the complexation effect with the catalyst component (metal compound) is poor; when the alcohol content is too high, the alcohol group is easily removed after subsequent heat treatment, causing irregularity and collapse of the carrier surface, resulting in reduced catalytic effect.

[0062] Example 3

[0063] In this example, based on Example 1, the type of metal compound in the catalyst was adjusted. Other reaction conditions and steps were consistent with Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 2.

[0064] Table 2

[0065]

[0066]

[0067] It can be seen from the data in Table 2 that when the composition of the metal compound in the catalyst changes, the yield and purity of the target product also change.

[0068] Among them, by comparing Example 1 and Example 3-1 with Example 3-2 and Example 3-3, it can be seen that the catalytic efficiency of the iron compound is better than that of the chromium compound;

[0069] Comparisons between Example 1 and Example 3-1, and between Example 3-2 and Example 3-3 show that metal salts are superior to metal oxides.

[0070] Comparison between Example 1, Example 3-1 to Example 3, and Example 3-4 to Example 3-7 shows that the metal composite compound is superior to a single compound.

[0071] Example 4

[0072] In this example, based on Example 1, the reaction environment, specifically the pH, was adjusted. Other reaction conditions and steps were consistent with those in Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 3.

[0073] Table 3

[0074]

[0075]

[0076] As shown in Table 3, the yield of the target product was above 92% when the reaction environment was neutral or weakly alkaline. In particular, the yield of the target product was above 97% when the pH was between 7.5 and 8. The yield of the target product decreased significantly when the reaction environment was acidic, as sulfhydryl cyclization is more likely to occur in an alkaline environment. When the pH was greater than 9, the increased alkalinity, while beneficial for sulfhydryl cyclization, reduced the activity of the oxidant, sodium persulfate.

[0077] Example 5

[0078] In this example, based on Example 1, the reaction temperature of step S2 was adjusted, and the yield of the product after different reaction times (1 h, 2 h, 3 h, 4 h, 5 h) was detected. The other reaction conditions and steps were consistent with those in Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 4.

[0079] Table 4

[0080]

[0081] As shown in Table 4, as the reaction temperature increases, the oxidant activity increases, and the reaction rate of the cyclization reaction increases. However, after a reaction time of 3 hours, the yield of the target product does not increase significantly. Considering factors such as cost and energy consumption, the reaction time of the present invention is set to 2 to 4 hours, preferably 2 to 3 hours; and the reaction temperature is set to 40°C to 60°C. When the temperature is too high, the reaction yield decreases with time because the high temperature reduces the activity of the catalyst.

[0082] Example 6

[0083] In this example, based on Example 1, the amount of the metal compound in the catalyst was adjusted. Other reaction conditions and steps were consistent with those in Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 5.

[0084] Table 5

[0085] Detection object Amount of metal compound in catalyst / g Yield / % purity / % Example 6-1 1 95.6 96.7 Example 6-2 2 96.1 97.3 Example 1 3 97.9 98.4 Example 6-3 4 98.2 98.7 Example 6-4 5 98.5 99.3 Example 6-5 6 98.4 99.5

[0086] As can be seen from the data in Table 5, as the amount of metal compound in the catalyst increases, the yield and purity of the target product are optimized; however, when it increases to a certain value, the change is not significant. In view of this, the amount of metal compound in the catalyst is 1% to 5% of the raw material.

[0087] Example 7

[0088] In this example, based on Example 1, the loading amount of the metal compound in the catalyst was adjusted (the amount of the metal compound remained unchanged). Other reaction conditions and steps were consistent with those in Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 6.

[0089] Table 6

[0090] Detection object Loading amount / % Yield / % purity / % Example 1 5 97.9 98.4 Example 7-1 15 98.4 98.6 Example 7-2 20 99.2 99 Example 7-3 30 99.5 99.4 Example 7-4 40 99.3 99.3 Example 7-5 50 98.4 99.5

[0091] As can be seen from the data in Table 6, as the loading amount of the metal compound in the catalyst increases, the yield and purity of the target product are optimized; however, after it increases to a certain value, the change is not significant. In view of this, the loading amount of the metal compound in the catalyst is 5% to 50%, preferably 15% to 30%.

[0092] Example 8

[0093] In this example, based on Example 1, the amount of the oxidant sodium persulfate was adjusted. Other reaction conditions and steps were consistent with those in Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 7.

[0094] Table 7

[0095] Detection object Sodium Persulfate: Dihydrolipoic Acid Yield / % purity / % Example 8-1 1:1 91.3 92.2 Example 1 1.1:1 97.9 98.4 Example 8-2 1.2:1 98.3 98.7 Example 8-3 1.3:1 98.9 99.3 Example 8-4 1.4:1 99.1 98.9 Example 8-5 1.5:1 99.1 98.5 Example 8-6 1.6:1 99.0 98.1

[0096] As can be seen from the data in Table 7, as the amount of sodium persulfate increases, the yield and / or purity of the target product are optimized; however, after it increases to a certain value, the change is not significant. In view of factors such as cost, the amount of the oxidant sodium persulfate is sodium persulfate: dihydrolipoic acid = 1:1 to 1.5:1.

[0097] Comparative Example 1

[0098] This comparative example is based on Example 1. The catalyst is adjusted according to whether a carrier is present and the composition of the carrier. Other reaction conditions and steps are consistent with Example 1. The yield and purity of the target product are calculated. The results are shown in Table 8.

[0099] Table 8

[0100]

[0101] As shown in Table 8 data, in the absence of catalyst, the efficiency that dihydrolipoic acid ring-closure reaction generates DL-lipoic acid is very low, and the highest productive rate is only 53.7%; Adopt FeCl Under the situation of catalyst, efficiency improves, but the highest productive rate is only 70.9%; Adopt silica gel microspheres, graphene oxide, molecular sieve etc. and FeCl Compound as catalyst, ring-closure reaction efficiency improves significantly, but is still lower than the embodiment of the present invention, and consuming time is longer. In organic chemical reaction, magnesium chloride microspheres also can be used as catalyst such as catalytic heterocycle, protective functional group and condensation reaction etc., but the effect of its catalysis dihydrolipoic acid ring-closure reaction is very low.

[0102] Comparative Example 2

[0103] In this comparative example, based on Example 1, the order of adding the catalyst, heating, and adding sodium persulfate was adjusted. Other reaction conditions and steps were consistent with Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 9.

[0104] Table 9

[0105]

[0106] As can be seen from the data in Table 9, adjusting the order of adding the catalyst, heating, and adding sodium persulfate results in a higher yield of the final target product. However, only the embodiment of the present invention takes the shortest time to complete the reaction.

[0107] Comparative Example 3

[0108] In this comparative example, based on Example 1, the oxidant sodium persulfate was replaced by other oxidants, such as oxygen and hydrogen peroxide. The other reaction conditions and steps were consistent with those in Example 1. The yield and purity of the target product were calculated, and the results are shown in Table 10.

[0109] Table 10

[0110]

[0111]

[0112] It can be seen from the data in Table 10 that in terms of the final yield effect, oxygen ≈ sodium persulfate > hydrogen peroxide, but the time required for sodium persulfate as an oxidant to achieve the ideal yield is much lower than that of oxygen.

[0113] Comparative Example 4

[0114] In this comparative example, based on Example 1, the cooling program in S3 was adjusted to natural cooling. Other reaction conditions and steps were consistent with Example 1. The yield and purity of the target product after 3 hours of reaction were calculated. The results are shown in Table 11.

[0115] Table 11

[0116]

[0117] It can be seen from the data in Table 11 that the yield and purity of the target product are reduced with the natural cooling temperature reduction program.

[0118] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be determined by the appended claims.

Claims

1. A method for synthesizing DL-lipoic acid, characterized in that, The reaction formula of the synthesis method is: The synthesis method comprises the following steps: At room temperature, add alkaline solution to dihydrolipoic acid, stir and dissolve it evenly, and adjust the pH of the solution to neutral or weak alkaline; First add the catalyst, mix well and heat to 40℃~60℃, then add the oxidant sodium persulfate, stir and keep warm for 2h~4h; After the reaction is completed, the temperature is dropped to below 15°C, and the organic phase is extracted with an organic solvent. Then, high-purity DL-lipoic acid is obtained by distillation, removal of impurities, drying and crystallization. Wherein, the catalyst is a metal compound supported on a microsphere carrier; the metal compound is selected from at least one of metal oxides and metal salts; The molecular formula of the microsphere carrier is MgCl2·n(ROH), wherein n=3-6, R=C2-C6 saturated alkyl; The metal oxide is ferric oxide or chromium oxide; the metal salt is ferric chloride or chromium chloride.

2. A synthetic method for DL-lipoic acid according to claim 1, characterized in that, The synthesis method is carried out in a water bath; after the reaction is completed, cooling water at 0°C to 10°C is continuously introduced into the water bath to rapidly reduce the temperature of the reaction system environment to below 15°C.

3. A synthetic method for DL-lipoic acid according to claim 1, characterized in that, The steps of preparing the catalyst include: The microsphere carrier is mixed with the metal compound by impregnation or high-energy ball milling; Heat treating the mixture at 80°C to 120°C; After repeated washing, vacuum drying is performed to obtain the catalyst.

4. A method for synthesizing DL-lipoic acid according to claim 1, characterized in that, The amount of the catalyst used is calculated based on the metal compound supported by the catalyst, and the amount of the metal compound used is 1 wt% to 5 wt% of dihydrolipoic acid.

5. A method for synthesizing DL-lipoic acid according to claim 1, characterized in that, According to the molar ratio, the ratio of sodium persulfate to dihydrolipoic acid is 1.1 to 1.5:

1.

6. A method for synthesizing DL-lipoic acid according to claim 1, characterized in that, The organic solvent is chloroform or ether.

7. A method for synthesizing DL-lipoic acid according to claim 1, characterized in that, The pH of the neutral or weakly alkaline environment is 7-9.

8. A method for synthesizing DL-lipoic acid according to claim 7, characterized in that, The pH of the neutral or weakly alkaline environment is 7.5-8.

9. A method for synthesizing DL-lipoic acid according to claim 1, characterized in that, The loading amount of the metal oxide and / or metal salt in the catalyst is 5% to 50%.

10. The method for synthesizing DL-lipoic acid according to claim 3, wherein: When the microsphere carrier is mixed with the metal compound, a complexing agent is also added.

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