CN118126019A - Preparation method of alpha-lipoic acid - Google Patents

Abstract

The invention provides a preparation method of alpha-lipoic acid. According to the method, when the dissolution pH is 6.85-6.95, monoethyl adipate reacts to generate sodium salt, which is dissolved in water; diethyl adipate and toluene are dissolved in chloroform, and diethyl adipate and toluene can be removed in a targeted manner; during acid extraction, the sodium salt reacts with hydrochloric acid to generate monoethyl adipate, and according to the difference in solubility of monoethyl adipate in water at different pH values, a higher extraction yield is obtained, and the method avoids thermal degradation of the product caused by high-temperature distillation, and can obtain high-purity monoethyl adipate. The method is simple to operate, effectively reduces the production cost, not only solves the problem of removing diethyl adipate, but also solves the problem of residual toluene in monoethyl adipate participating in subsequent reactions, and finally can improve the yield of alpha-lipoic acid.

Description

A kind of preparation method of alpha-lipoic acid

Technical Field

The invention relates to the technical field of new materials, and in particular to a method for preparing alpha-lipoic acid.

Background technique

α-Lipoic acid, also known as lipoic acid (ALA), has a chemical name of 1,2-dithiolane-3-pentanoic acid. It is a coenzyme that exists in mitochondria. Due to its unique antioxidant properties, α-lipoic acid has attracted extensive attention from researchers in the field of new materials research. For example, relevant researchers used α-lipoic acid as a material, utilized the thermal response ring-opening polymerization characteristics of α-lipoic acid, formed polylipoic acid, prepared a polylipoic acid-based adhesive, and used the time-dependent self-enhancement effect of the adhesive to apply it in hot melt deposition 3D printing. Through the 3D printing of polylipoic acid, the model formation on different scales was fully realized. After 3D printing, the model printed by polylipoic acid showed mechanical enhancement characteristics over time. Studies have shown that this is caused by the microscopic self-assembly of polylipoic acid and lipoic acid. This work realizes the organic combination of self-assembly at the microscopic level and self-assembly at the macroscopic level. This study also provides a feasible method for the controllable manufacturing and mechanical enhancement of adhesive materials, paving the way for the application of the next generation of functional adhesive materials. In addition, α-lipoic acid can improve the insulin function and heart rate variability of diabetic patients; it can treat hepatitis C, protect the kidneys and pancreas, prevent cataracts and other diseases. α-lipoic acid can also be used in cosmetics, feed, photography technology and other fields. Therefore, the study of the preparation of α-lipoic acid is of great significance to the research and development of new materials.

At present, please refer to Figure 1. α-lipoic acid is mainly prepared by using adipic acid as the starting material, first preparing crude 6,8-dichlorooctanoic acid ethyl ester, and then preparing it through steps such as sulfidation, hydrolysis, and acidification after the crude 6,8-dichlorooctanoic acid ethyl ester is purified by distillation. Among them, monoethyl adipate is produced by using adipic acid as the starting material and toluene as the solvent through esterification reaction. Its main organic impurity is diethyl adipate, and the residual solvent is toluene. The residual solvent toluene in monoethyl adipate reacts with 6-oxo-6-chlorohexanoic acid ethyl ester under the catalytic condition of anhydrous AlCl ₃ to form impurity A (please refer to Figure 2 for the formation route of impurity A), which affects the purity of 6-oxo-6-chlorohexanoic acid ethyl ester and ultimately affects the yield of α-lipoic acid.

The related technology also uses a method of distilling monoethyl adipate, but in the distillation process of monoethyl adipate, since the boiling point of diethyl adipate is lower than that of monoethyl adipate, diethyl adipate is evaporated first. After a small amount of diethyl adipate is evaporated, a large amount of monoethyl adipate can only be evaporated by increasing the temperature in the reactor. Long-term distillation of monoethyl adipate in a high temperature environment is prone to thermal decomposition. The degree of decomposition is about 4% according to experimental tests, which affects the purity and yield of monoethyl adipate, and ultimately affects the yield of α-lipoic acid. In addition, high-temperature distillation not only poses a safety hazard to production, but also consumes a lot of energy.

Summary of the invention

Therefore, the present invention provides a method for preparing alpha-lipoic acid to solve the problem that the organic impurity diethyl adipate and the residual solvent toluene affect the purity and yield of monoethyl adipate, and further affect the yield of alpha-lipoic acid.

The present invention provides a method for preparing alpha-lipoic acid, comprising the following steps:

Step 1, controlling the temperature at 20-25° C., adding crude monoethyl adipate and deionized water to a dissolving kettle in sequence, and adjusting the pH to 6.85-6.95 using 10% sodium bicarbonate;

Step 2, controlling the temperature at 20-25°C, adding chloroform to the dissolution kettle for extraction, stirring for 25-30 minutes, standing for stratification, and transferring the aqueous phase to the acidification kettle for acidification;

Step 3, add deionized water to the chloroform phase, then use 10% sodium bicarbonate to adjust the pH to 6.85-6.95, stir and back extract for 10-15 minutes, transfer the upper aqueous phase to the acidification kettle, wait for acid adjustment, and recover chloroform from the organic phase;

Step 4, controlling the temperature at 20-25°C, and adjusting the pH of the aqueous phase in the acidification kettle to 2.5-3.5 with 15% hydrochloric acid;

Step 5, controlling the temperature at 20-25°C, standing and separating the layers, the lower layer is monoethyl adipate, and the upper layer is water to be extracted;

Step 6, extracting the upper aqueous phase of the acidified kettle with chloroform three times, and standing and stratifying after each extraction;

Step 7, after the aqueous phase is extracted for the third time, the aqueous phase is discharged, the chloroform phase is combined with the monoethyl adipate obtained in step 5, and then the chloroform phase is washed with a saturated sodium chloride solution with stirring for 25 to 30 minutes, and the organic phase is concentrated after standing for stratification;

Step 8, controlling the temperature at 20-40° C., vacuum concentrating the organic phase of step 7 to recover chloroform, and obtaining pure monoethyl adipate;

Step 9, preparing monoethyl adipate chloride based on pure monoethyl adipate;

Step 10, preparing α-lipoic acid based on ethyl adipic acid chloride.

The preparation method of alpha-lipoic acid provided by the invention comprises the following steps: when the dissolution pH is 6.85-6.95, monoethyl adipate (acidity coefficient 4.69±0.1) reacts to generate sodium salt, which is dissolved in water; and diethyl adipate and toluene are dissolved in chloroform, so that diethyl adipate and toluene can be removed in a targeted manner; during acid extraction, the sodium salt reacts with hydrochloric acid to generate monoethyl adipate, and at the same time, according to the difference in solubility of monoethyl adipate in water at different pH values, a higher extraction yield is obtained, and the method avoids thermal degradation of the product caused by high-temperature distillation, so that high-purity monoethyl adipate can be obtained. The method is simple to operate, effectively reduces the production cost, solves the problem of removing diethyl adipate, and solves the problem of residual solvent toluene of monoethyl adipate participating in the reaction to generate impurities, and finally improves the yield of alpha-lipoic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a synthetic route diagram of α-lipoic acid;

FIG2 is a formation route diagram of impurity A;

Fig. 3 is a liquid chromatography result diagram of Example 1;

Fig. 4 is a gas chromatography result diagram of Example 1;

Fig. 5 is a liquid chromatography result diagram of Example 2;

Fig. 6 is a gas chromatography result diagram of Example 2;

Fig. 7 is a diagram of the liquid chromatography results of Example 3;

FIG8 is a gas chromatography result diagram of Example 3;

FIG9 is a liquid chromatography result diagram of Comparative Example 1;

Figure 10 is a gas chromatography result diagram of Comparative Example 1;

Figure 11 is a liquid chromatography result diagram of Comparative Example 2;

Figure 12 is a gas chromatography result diagram of Comparative Example 2;

Figure 13 is a liquid chromatography result diagram of Comparative Example 3;

Figure 14 is a gas chromatography result diagram of Comparative Example 3;

Figure 15 is a liquid chromatography result diagram of Comparative Example 4;

Figure 16 is a gas chromatography result diagram of Comparative Example 4;

Figure 17 is a liquid chromatography result diagram of Comparative Example 5;

Figure 18 is a gas chromatography result diagram of Comparative Example 5;

Figure 19 is a liquid chromatography result diagram of Comparative Example 6;

Figure 20 is a gas chromatography result diagram of Comparative Example 6;

Figure 21 is a liquid chromatography result diagram of Comparative Example 7;

Figure 22 is a gas chromatography result diagram of Comparative Example 7;

Figure 23 is a liquid chromatography result diagram of Comparative Example 8;

Figure 24 is a graph showing the gas chromatography results of Comparative Example 8.

Detailed ways

In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to various embodiments, but the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thorough and comprehensive.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and/or" used herein includes any and all combinations of one or more of the related listed items.

The following is a further description of the embodiments of the present invention in multiple embodiments. The embodiments of the present invention are not limited to the following specific embodiments. Within the scope of the unchanged main rights, appropriate changes can be made to the implementation.

Example 1

Step 1, controlling the temperature at 20-25° C., adding crude monoethyl adipate and deionized water to a dissolving kettle in sequence, wherein the mass ratio of crude monoethyl adipate to deionized water is 1:3, and adjusting the pH to 6.9 using 10% sodium bicarbonate;

Step 2, controlling the temperature at 20-25°C, adding chloroform to the dissolving kettle for extraction, the mass ratio of chloroform to the crude monoethyl adipate being 1:1, stirring for 25-30 minutes, standing for stratification, transferring the aqueous phase to the acidifying kettle for acidification;

Step 3, adding deionized water to the chloroform phase, the mass ratio of chloroform to deionized water is 1:1, and then adjusting the pH to 6.9 with 10% sodium bicarbonate, stirring and back-extracting for 10-15 minutes, transferring the upper aqueous phase to an acidification kettle, waiting for acid adjustment, and recovering chloroform from the organic phase;

Step 4, controlling the temperature at 20-25°C, and adjusting the pH of the aqueous phase in the acidification kettle to 3.0 with 15% hydrochloric acid;

Step 5, controlling the temperature at 20-25°C, standing and separating the layers, the lower layer is monoethyl adipate, and the upper layer is water to be extracted;

Step 6, extracting the upper aqueous phase of the acidified kettle with chloroform three times, standing and stratifying after each extraction, and the mass ratio of the chloroform used in each extraction to the mass ratio of the crude monoethyl adipate in step 1 is 1:1;

Step 7, after the aqueous phase is extracted for the third time, the aqueous phase is discharged, the chloroform phase is combined with the monoethyl adipate obtained in step 5, and then the chloroform phase is stirred and washed for 25 to 30 minutes with a saturated sodium chloride solution, wherein the mass ratio of the saturated sodium chloride solution to the crude monoethyl adipate in step 1 is 0.5:1, the organic phase is allowed to stand and the layers are separated, and the organic phase is to be concentrated;

Step 8, controlling the temperature at 20-40° C., vacuum concentrating the organic phase of step 7 to recover chloroform, and obtaining pure monoethyl adipate;

Step 9, preparing monoethyl adipate chloride based on pure monoethyl adipate;

Step 9 specifically includes:

Step 9.1, add chloroform and pure monoethyl adipate into the reaction kettle and cool to 0°C;

Step 9.2, controlling the temperature at 0-10°C, adding chloroform and thionyl chloride;

Step 9.3, after the addition of thionyl chloride, the temperature was controlled at 5-10°C and the reaction was carried out for 2 hours;

Step 9.4, raise the temperature to 40±2°C and keep the reaction for 2h;

Step 9.5, raise the temperature to 70±2°C and keep the reaction for 1 hour;

Step 9.6, after the reaction is completed, the mixture is cooled to 15-20° C. to obtain ethyl adipic acid chloride;

Step 10, preparing α-lipoic acid based on ethyl adipic acid chloride;

Step 10 specifically includes:

Anhydrous aluminum chloride is added to ethyl adipic acid monochloride, the temperature is controlled at 15-20°C, and the complex reaction is carried out for 2 hours to obtain 6-oxo-6-chlorohexanoic acid ethyl ester complex reaction liquid, and then ethylene is introduced for addition reaction. After the addition reaction is completed, deionized water is added for hydrolysis, and the organic phase is obtained by layering. Ethanol and potassium borohydride are added to the organic phase for reduction reaction, and then chlorination reaction, cyclization reaction, hydrolysis and acidification are carried out in sequence to prepare α-lipoic acid.

Example 2

Step 1, controlling the temperature at 20-25° C., adding crude monoethyl adipate and deionized water to a dissolving kettle in sequence, wherein the mass ratio of crude monoethyl adipate to deionized water is 1:3, and adjusting the pH to 6.85 using 10% sodium bicarbonate;

Step 2, controlling the temperature at 20-25°C, adding chloroform to the dissolving kettle for extraction, the mass ratio of chloroform to the crude monoethyl adipate being 1:1, stirring for 25-30 minutes, standing for stratification, transferring the aqueous phase to the acidifying kettle for acidification;

Step 3, adding deionized water to the chloroform phase, the mass ratio of chloroform to deionized water is 1:1, and then adjusting the pH to 6.85 with 10% sodium bicarbonate, stirring and back-extracting for 10-15 minutes, transferring the upper aqueous phase to an acidification kettle, waiting for acid adjustment, and recovering chloroform from the organic phase;

Step 4, controlling the temperature at 20-25°C, and adjusting the pH of the aqueous phase in the acidification kettle to 2.5 with 15% hydrochloric acid;

Step 5, controlling the temperature at 20-25°C, standing and separating the layers, the lower layer is monoethyl adipate, and the upper layer is water to be extracted;

Step 6, extracting the upper aqueous phase of the acidified kettle with chloroform three times, standing and stratifying after each extraction, and the mass ratio of the chloroform used in each extraction to the mass ratio of the crude monoethyl adipate in step 1 is 1:1;

Step 7, after the aqueous phase is extracted for the third time, the aqueous phase is discharged, the chloroform phase is combined with the monoethyl adipate obtained in step 5, and then the chloroform phase is stirred and washed for 25 to 30 minutes with a saturated sodium chloride solution, wherein the mass ratio of the saturated sodium chloride solution to the crude monoethyl adipate in step 1 is 0.5:1, the organic phase is allowed to stand and the layers are separated, and the organic phase is to be concentrated;

Step 8, controlling the temperature at 20-40° C., vacuum concentrating the organic phase of step 7 to recover chloroform, and obtaining pure monoethyl adipate;

Step 9, preparing monoethyl adipate chloride based on pure monoethyl adipate;

Step 9 specifically includes:

Step 9.1, add chloroform and pure monoethyl adipate into the reaction kettle and cool to 0°C;

Step 9.2, controlling the temperature at 0-10°C, adding chloroform and thionyl chloride;

Step 9.3, after the addition of thionyl chloride, the temperature was controlled at 5-10°C and the reaction was carried out for 2 hours;

Step 9.4, raise the temperature to 40±2°C and keep the reaction for 2h;

Step 9.5, raise the temperature to 70±2°C and keep the reaction for 1 hour;

Step 9.6, after the reaction is completed, the mixture is cooled to 15-20° C. to obtain ethyl adipic acid chloride;

Step 10, preparing α-lipoic acid based on ethyl adipic acid chloride;

Step 10 specifically includes:

Anhydrous aluminum chloride is added to ethyl adipic acid monochloride, the temperature is controlled at 15-20°C, and the complex reaction is carried out for 2 hours to obtain 6-oxo-6-chlorohexanoic acid ethyl ester complex reaction liquid, and then ethylene is introduced for addition reaction. After the addition reaction is completed, deionized water is added for hydrolysis, and the organic phase is obtained by layering. Ethanol and potassium borohydride are added to the organic phase for reduction reaction, and then chlorination reaction, cyclization reaction, hydrolysis and acidification are carried out in sequence to prepare α-lipoic acid.

Example 3

Step 1, controlling the temperature at 20-25° C., adding crude monoethyl adipate and deionized water to a dissolving kettle in sequence, wherein the mass ratio of crude monoethyl adipate to deionized water is 1:3, and adjusting the pH to 6.95 using 10% sodium bicarbonate;

Step 2, controlling the temperature at 20-25°C, adding chloroform to the dissolving kettle for extraction, the mass ratio of chloroform to the crude monoethyl adipate being 1:1, stirring for 25-30 minutes, standing for stratification, transferring the aqueous phase to the acidifying kettle for acidification;

Step 3, adding deionized water to the chloroform phase, the mass ratio of chloroform to deionized water is 1:1, and then adjusting the pH to 6.95 with 10% sodium bicarbonate, stirring and back-extracting for 10-15 minutes, transferring the upper aqueous phase to an acidification kettle, waiting for acid adjustment, and recovering chloroform from the organic phase;

Step 4, controlling the temperature at 20-25°C, and adjusting the pH of the aqueous phase in the acidification kettle to 3.5 with 15% hydrochloric acid;

Step 5, controlling the temperature at 20-25°C, standing and separating the layers, the lower layer is monoethyl adipate, and the upper layer is water to be extracted;

Step 6, extracting the upper aqueous phase of the acidified kettle with chloroform three times, standing and stratifying after each extraction, and the mass ratio of the chloroform used in each extraction to the mass ratio of the crude monoethyl adipate in step 1 is 1:1;

Step 7, after the aqueous phase is extracted for the third time, the aqueous phase is discharged, the chloroform phase is combined with the monoethyl adipate obtained in step 5, and then the chloroform phase is stirred and washed for 25 to 30 minutes with a saturated sodium chloride solution, wherein the mass ratio of the saturated sodium chloride solution to the crude monoethyl adipate in step 1 is 0.5:1, the organic phase is allowed to stand and the layers are separated, and the organic phase is to be concentrated;

Step 8, controlling the temperature at 20-40° C., vacuum concentrating the organic phase of step 7 to recover chloroform, and obtaining pure monoethyl adipate;

Step 9, preparing monoethyl adipate chloride based on pure monoethyl adipate;

Step 9 specifically includes:

Step 9.1, add chloroform and pure monoethyl adipate into the reaction kettle and cool to 0°C;

Step 9.2, controlling the temperature at 0-10°C, adding chloroform and thionyl chloride;

Step 9.3, after the addition of thionyl chloride, the temperature was controlled at 5-10°C and the reaction was carried out for 2 hours;

Step 9.4, raise the temperature to 40±2°C and keep the reaction for 2h;

Step 9.5, raise the temperature to 70±2°C and keep the reaction for 1 hour;

Step 9.6, after the reaction is completed, the mixture is cooled to 15-20° C. to obtain ethyl adipic acid chloride;

Step 10, preparing α-lipoic acid based on ethyl adipic acid chloride;

Step 10 specifically includes:

Anhydrous aluminum chloride is added to ethyl adipic acid monochloride, the temperature is controlled at 15-20°C, and the complex reaction is carried out for 2 hours to obtain 6-oxo-6-chlorohexanoic acid ethyl ester complex reaction liquid, and then ethylene is introduced for addition reaction. After the addition reaction is completed, deionized water is added for hydrolysis, and the organic phase is obtained by layering. Ethanol and potassium borohydride are added to the organic phase for reduction reaction, and then chlorination reaction, cyclization reaction, hydrolysis and acidification are carried out in sequence to prepare α-lipoic acid.

Comparative Example 1

Comparative Example 1 is substantially the same as Example 1, except that in Comparative Example 1, both Step 1 and Step 3 use 10% sodium bicarbonate to adjust the pH to 6.80.

Comparative Example 2

Comparative Example 2 is substantially the same as Example 1, except that in Comparative Example 2, both Step 1 and Step 3 use 10% sodium bicarbonate to adjust the pH to 7.0.

Comparative Example 3

Comparative Example 3 is substantially the same as Example 1, except that in Comparative Example 3, the pH of the aqueous phase in the acidification kettle in step 4 is adjusted to 2.3 with 15% hydrochloric acid.

Comparative Example 4

Comparative Example 4 is substantially the same as Example 1, except that in Comparative Example 4, the pH of the aqueous phase in the acidification kettle in step 4 is adjusted to 3.7 with 15% hydrochloric acid.

Comparative Example 5

Comparative Example 5 is substantially the same as Example 1, except that, in Comparative Example 5, in step 2, the temperature is controlled at 20-25° C., chloroform is added to the dissolving kettle for extraction, and the mass ratio of chloroform to the crude monoethyl adipate is 1:2.

Comparative Example 6

Comparative Example 6 is substantially the same as Example 1, except that in Comparative Example 6, step 1 uses 10% sodium hydroxide to adjust the pH to 6.9.

Comparative Example 7

Comparative Example 7 is substantially the same as Example 1, except that in Comparative Example 7, step 3 uses 10% sodium hydroxide to adjust the pH to 6.9.

Comparative Example 8

First, monoethyl adipate was prepared according to the process technology route disclosed in the Chinese invention patent with authorization announcement number CN107043327B, and then α-lipoic acid was prepared by using steps 9 and 10 in Example 1.

Experimental test

The purity of monoethyl adipate and the content of diethyl adipate obtained in each embodiment and comparative example were detected by liquid chromatography, the purity of ethyl 6-oxo-6-chlorohexanoate and the content of impurity A in each embodiment and comparative example were detected by gas chromatography, and the yield of monoethyl adipate and the yield of α-lipoic acid were calculated.

The chromatographic column used for liquid chromatography was Superlu C18-AQ 5um, 250mm×4.6mm, column temperature 30°C, wavelength 210nm, injection volume 20μL, running time 40min, flow rate 1.0mL/min, and the mobile phase was as shown in Table 1.

The content of diethyl adipate (RRT1.3) was calculated by area normalization method.

Table 1

The gas chromatography column used was SE-54 (30m×0.32mm, 1µm), the vaporization temperature was 300°C, the detector temperature was 300°C, the injection volume was 20μL, the split ratio was 1:5, the running time was 29.75min, the nitrogen flow rate was 30mL/min, the hydrogen flow rate was 40mL/min, the air flow rate was 400mL/min, and the column flow rate was 3.23mL/min. Column temperature: initial temperature was 130°C and maintained for 3min, then increased to 200°C at 8°C/min and maintained for 7min, then increased to 250°C at 10°C/min and maintained for 6min.

The content of impurity A (RRT3.8) was calculated using the area normalization method.

Figures 3 to 24 show the results of liquid chromatography and gas chromatography of each embodiment and each comparative example, and the relevant data are statistically shown in Table 2.

Table 2

As can be seen from Table 2, the purity of monoethyl adipate, the yield of monoethyl adipate, and the yield of α-lipoic acid in Examples 1 to 3 are significantly higher than those in the comparative examples, especially higher than the purity of monoethyl adipate, the yield of monoethyl adipate, and the yield of α-lipoic acid in Comparative Example 8. The content of diethyl adipate and the content of impurity A in Examples 1 to 3 are significantly lower than the content of diethyl adipate and the content of impurity A in Comparative Example 8.

Among them, compared with Comparative Examples 1 and 2, in Example 1, the pH in Step 1 and Step 3 is not within the range of 6.85 to 6.95. When the pH is low, the solubility of diethyl adipate in water increases; when the pH is high, monoethyl adipate is hydrolyzed to generate adipic acid, which ultimately leads to a decrease in the purity and yield of monoethyl adipate and the yield of α-lipoic acid.

Compared with Comparative Examples 3 and 4, in Example 1, the pH in step 4 is not within the range of 2.5 to 3.5. When the pH is low (stronger acidity), monoethyl adipate is hydrolyzed to generate adipic acid under acidic conditions; when the pH is high (weaker acidity), the solubility of diethyl adipate in chloroform increases, resulting in a decrease in the purity and yield of monoethyl adipate and the yield of α-lipoic acid.

Compared with Comparative Example 5, in Example 1, since the mass ratio of chloroform to crude monoethyl adipate in step 2 is not 1:1, the amount of chloroform used is reduced, and diethyl adipate is not fully extracted, resulting in reduced purity and yield of monoethyl adipate and yield of α-lipoic acid.

Compared with Comparative Examples 6 and 7, in Example 1, 10% sodium hydroxide was used in step 1 of Comparative Example 6, and 10% sodium hydroxide was used in step 3 of Comparative Example 7. Since sodium hydroxide has a strong alkalinity, it is easy to cause local alkalinity. Monoethyl adipate is hydrolyzed under alkaline conditions and adipic acid is produced after acidification, resulting in a decrease in the purity and yield of monoethyl adipate and the yield of α-lipoic acid.

In summary, the preparation method of alpha-lipoic acid provided by the present invention is that when the dissolution pH is 6.85-6.95, monoethyl adipate (acidity coefficient 4.69±0.1) reacts to generate sodium salt, which is soluble in water; diethyl adipate and toluene are dissolved in chloroform, and diethyl adipate and toluene can be removed in a targeted manner; during acid extraction, the sodium salt reacts with hydrochloric acid to generate monoethyl adipate, and at the same time, according to the difference in solubility of monoethyl adipate in water at different pH values, a higher extraction yield is obtained, and the method avoids thermal degradation of the product caused by high-temperature distillation, and can obtain high-purity monoethyl adipate. The method is simple to operate, effectively reduces the production cost, not only solves the problem of removing diethyl adipate, but also solves the problem of residual solvent toluene of monoethyl adipate participating in the reaction to generate impurities, and finally can improve the yield of alpha-lipoic acid.

Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

Claims (8)

1. A method for preparing alpha-lipoic acid, which is characterized by comprising the following steps of;

Step 1, controlling the temperature to be 20-25 ℃, sequentially adding a monoethyl adipate crude product and deionized water into a dissolution kettle, and adjusting the pH to 6.85-6.95 by using 10% sodium bicarbonate;

Step 2, controlling the temperature at 20-25 ℃, adding chloroform into a dissolution kettle for extraction, stirring for 25-30 min, standing for layering, transferring a water phase into an acidification kettle, and waiting for acid adjustment;

Step 3, adding deionized water into the chloroform phase, then using 10% sodium bicarbonate to adjust the pH to 6.85-6.95, stirring and back-extracting for 10-15 min, transferring the upper water phase into an acidification kettle, waiting for acid adjustment, and recovering chloroform from the organic phase;

Step 4, controlling the temperature to be 20-25 ℃, and adjusting the pH value of the water phase in the acidification kettle to 2.5-3.5 by using 15% hydrochloric acid;

Step 5, controlling the temperature at 20-25 ℃, standing for layering, wherein the lower layer is monoethyl adipate, and the upper layer is water phase to be extracted;

Step 6, extracting the upper water phase of the acidification kettle with chloroform for three times, and standing for layering after each extraction;

step 7, discharging waste after the third extraction of the water phase, combining the chloroform phase with the monoethyl adipate obtained in the step 5, stirring and washing for 25-30 min by using a saturated sodium chloride solution, standing for layering, and concentrating an organic phase;

Step 8, controlling the temperature at 20-40 ℃, and vacuum concentrating the organic phase in the step 7 to recover chloroform to obtain a pure product of the monoethyl adipate;

Step 9, preparing adipic acid monoethyl ester acyl chloride based on adipic acid monoethyl ester pure product;

Step 10, lipoic acid is prepared based on monoethyl adipate chloride.

2. The method for preparing alpha-lipoic acid according to claim 1, wherein in the step 1, the mass ratio of the crude product of monoethyl adipate to deionized water is as follows:

Crude monoethyl adipate: deionized water = 1:3.

3. The method for preparing alpha-lipoic acid according to claim 1, wherein in the step 2, the mass ratio of chloroform to monoethyl adipate crude product is:

chloroform: crude monoethyl adipate = 1:1.

4. The method for preparing alpha-lipoic acid according to claim 1, wherein in the step 3, the mass ratio of chloroform to deionized water is as follows:

Chloroform: deionized water = 1:1.

5. The method for preparing alpha-lipoic acid according to claim 1, wherein in the step 6, the mass ratio of chloroform used in each extraction to the crude product of monoethyl adipate in the step 1 is:

chloroform: crude monoethyl adipate = 1:1.

6. The method for preparing alpha-lipoic acid according to claim 1, wherein in the step 7, the mass ratio of the saturated sodium chloride solution to the crude product of the monoethyl adipate in the step 1 is as follows:

Saturated sodium chloride solution: crude monoethyl adipate = 0.5:1.

7. The method for preparing alpha-lipoic acid according to claim 1, wherein the step 9 specifically comprises:

step 9.1, adding pure chloroform and monoethyl adipate into a reaction kettle, and cooling to 0 ℃;

9.2, controlling the temperature to be 0-10 ℃, and feeding chloroform and thionyl chloride;

step 9.3, after the end of the thionyl chloride feeding, controlling the temperature to be 5-10 ℃ and reacting for 2 hours;

step 9.4, heating to 40+/-2 ℃, and reacting for 2 hours at a temperature;

Step 9.5, heating to 70+/-2 ℃, and reacting for 1h with heat preservation;

And 9.6, after the reaction is finished, cooling to 15-20 ℃ to obtain the adipic acid monoethyl ester acyl chloride.

8. The method for preparing alpha-lipoic acid according to claim 1, wherein the step 10 specifically comprises:

Adding anhydrous aluminum trichloride into adipic acid monoethyl ester acyl chloride, controlling the temperature at 15-20 ℃ for complexation reaction for 2 hours to obtain 6-oxo-6-chlorohexanoic acid ethyl ester complexation reaction liquid, then introducing ethylene for addition reaction, transferring deionized water for hydrolysis after the addition reaction is finished, layering to obtain an organic phase, adding ethanol and potassium borohydride into the organic phase for reduction reaction, and then sequentially carrying out chlorination reaction, cyclization reaction, hydrolysis and acidification to obtain alpha-lipoic acid.