A purification method for lipoic acid

Abstract

This invention discloses a method for purifying lipoic acid (I). The method uses crude lipoic acid obtained from the hydrolysis of ethyl lipoate as raw material. A mixed solution of crude lipoic acid in methanol and water is prepared, and the pH is adjusted with acid to slowly precipitate lipoic acid (I). After filtration, washing, and drying, the final product is obtained. This invention reduces the formation of polymers and impurities, improves product yield and purity, and is simple, convenient, and practical, making it suitable for large-scale industrial production of lipoic acid (I).

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, specifically the field of thioctic acid preparation, and more specifically to a method for purifying thioctic acid. Background Technology

[0002] Lipoic acid, also known as α-lipoic acid, chemically named 1,2-dithiopentane-3-pentanoic acid, is a natural product isolated in 1951. Lipoic acid is a coenzyme found in mitochondria and belongs to the B vitamins, widely distributed in biological tissues of animals and plants. It possesses strong antioxidant properties and is hailed as a "universal antioxidant," capable of eliminating free radicals that accelerate aging and cause disease; improving insulin function and heart rate variability in diabetic patients; treating hepatitis C; protecting the kidneys and pancreas; and preventing cataracts, among other benefits, thus attracting widespread attention from researchers.

[0003]

[0004] Currently, the final step in the preparation of lipoic acid typically involves alkaline hydrolysis of ethyl lipoate. However, the presence of two sulfur atoms in lipoic acid makes it susceptible to side reactions such as oxidation, ring-opening, and polymerization, significantly impacting the product quality. Therefore, obtaining high-purity lipoic acid after hydrolysis is a crucial research topic.

[0005]

[0006] Numerous studies have reported on the preparation of lipoic acid from ethyl thiochlorooctanoate via hydrolysis, most using ethanol or water as solvents and sodium hydroxide or potassium hydroxide as alkali. Examples include Chinese patents CN112778270, CN113429386, CN113185494, and other literature. Tetrahedron: Asymmetry Articles such as 2015, 26(5-6), 281-287 all use ethanol as a solvent, followed by alkaline hydrolysis, and then acidification with hydrochloric acid to precipitate a solid, thus obtaining thioctic acid. Whether using ethanol or water, viscous polymers are easily generated during purification, leading to problems such as poor solid properties, high impurity content, and low purification yield.

[0007] WO2002030917 reported an example of hydrolysis using methanol and water as solvents. After obtaining the crude product, it was purified using various solvents such as toluene, cyclohexane, and ethyl acetate, with an overall yield of 64%. This purification method has a low yield, and as lipoic acid is a nutrient, using multiple organic solvents for purification leads to a variety of solvent residues that are difficult to remove. Summary of the Invention

[0008] In the process of developing a purification process for lipoic acid (I), through extensive experiments, the inventors discovered that lipoic acid in a system of methanol and water in appropriate proportions can reduce the formation of viscous polymers, resulting in a product with better solid properties and higher purity. Therefore, this invention proposes a purification method for lipoic acid (I), using crude ethyl lipoate hydrolyzed as raw material. A mixed solution of crude lipoic acid in methanol and water is prepared, and the pH is adjusted with acid, causing lipoic acid (I) to slowly precipitate. After filtration, washing, and drying, the final product is obtained.

[0009] A method for purifying lipoic acid (I) includes the following steps:

[0010] A. Dissolve the crude thioctic acid shown in formula (I) in a mixed solvent of methanol and water to obtain a thioctic acid solution;

[0011] B. In the lipoic acid solution from step A, at a suitable temperature, an inorganic acid is added for acidification, and lipoic acid (I) is precipitated.

[0012] C, through filtration, washing, and drying, yields pure lipoic acid (I).

[0013]

[0014] In step A of the purification method, the purity of crude lipoic acid ranges from 80% to 99%, where purity refers to HPLC purity.

[0015] In one embodiment of step A, the weight of methanol is 10 to 40 times the weight of crude thioctic acid, and the weight of water is 5 to 20 times the weight of crude thioctic acid.

[0016] In a preferred embodiment, the weight of methanol is 25 to 25 times that of crude lipoic acid, and the weight of water is 8 to 15 times that of crude lipoic acid.

[0017] In one embodiment of step A, a filtration operation is added to remove solids that appear in the solution.

[0018] In step A of the purification method, the suitable operating temperature is 0~30℃.

[0019] In a preferred embodiment, the operating temperature is 0~5℃.

[0020] In step A of the purification method, the inorganic acid includes hydrochloric acid, sulfuric acid, phosphoric acid, and their aqueous solutions.

[0021] In a preferred embodiment, the inorganic acid is an aqueous solution of hydrochloric acid.

[0022] In step C of the purification method, the solvent used for washing includes water and methanol.

[0023] In a preferred embodiment, the solvent used for washing is water.

[0024] In step A of the purification method, the lipoic acid solution can be prepared by the following steps:

[0025] D, dissolve the ethyl lipoic acid ester shown in formula (II) in methanol, and then perform alkaline hydrolysis in the presence of an inorganic base to obtain a solution of lipoic acid (I):

[0026]

[0027] In step D, the inorganic base comprises sodium hydroxide, potassium hydroxide, sodium carbonate, and an aqueous solution thereof.

[0028] In a preferred embodiment, the inorganic base is an aqueous solution of sodium hydroxide.

[0029] It should be understood that in this article, when describing numerical characteristics, the terms "about" or "approximately" mean that the expressed number may have an error range or fluctuation range of ±10%, ±9%, ±8%, ±7%, ±6%, or ±5%.

[0030] The present invention provides a purification method for lipoic acid, which reduces the generation of polymers and impurities during acidification, improves the yield and purity of the product, is simple to operate, convenient and practical, and is suitable for large-scale industrial production of lipoic acid (I). Detailed Implementation

[0031] The present invention is further illustrated below by way of examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the invention. Various changes or modifications made by those skilled in the art based on the concept of the present invention should fall within the protection scope of the present invention.

[0032] This article involves the addition amount, content and concentration of various substances. Unless otherwise specified, the percentage content mentioned refers to the mass percentage.

[0033] In the embodiments described herein, unless otherwise specified, the temperature generally refers to room temperature (10-40°C).

[0034] Example 1: Purification of lipoic acid – Methanol / water scheme

[0035] 50g of lipoic acid (HPLC purity 90%) was dissolved in 750g of methanol, followed by slow addition of 500g of purified water. The mixture was heated to an internal temperature of 55-60℃ and maintained at this temperature for 1 hour. A small amount of insoluble matter was removed by filtration. The filtrate was then cooled to 0-5℃, and 2mol / L dilute hydrochloric acid was added dropwise, producing a large amount of solid. After the pH of the system stabilized at 1-2, the mixture was filtered, washed with water, and vacuum dried at 38℃ for 24 hours. 42.2g of lipoic acid was obtained, with a purification yield of 84.4%, HPLC purity of 99.80%, and a maximum single impurity of 0.08%.

[0036] Repeat the above reaction procedure, take 50g of lipoic acid with HPLC purity of 90%, change the amount of methanol and water, the type of acid, and the acidification temperature, and obtain the product yield, HPLC purity and maximum single impurity. The experimental results are shown in the table below.

[0037] Serial Number Methanol (g) Water (g) Types of acids acidification temperature yield purity Maximum single hybrid 1 750 500 2mol / L hydrochloric acid 0-5℃ 84.4% 99.80% 0.08% 2 750 500 2mol / L hydrochloric acid 5-10℃ 80.5% 99.77% 0.10% 3 750 500 4 mol / L hydrochloric acid 10-20℃ 78.3% 99.83% 0.13% 4 750 500 4 mol / L hydrochloric acid 0-5℃ 82.7% 99.87% 0.07% 5 1500 500 4 mol / L hydrochloric acid 0-5℃ 87.4% 99.90% 0.05% 6 1500 500 6mol / L hydrochloric acid 0-5℃ 83.3% 98.20% 0.09% 7 1500 500 4mol / L sulfuric acid 0-5℃ 85.2% 99.93% 0.04% 8 1500 500 2mol / L sulfuric acid 0-5℃ 83.7% 98.78% 0.11% 9 1500 500 4 mol / L phosphoric acid 0-5℃ 86.1% 99.88% 0.07% 10 1500 500 2 mol / L phosphoric acid 0-5℃ 84.2% 98.91% 0.09%

[0038] The results show that when using 1500g methanol and 500g water, 4mol / L acid, and controlling the acidification temperature at 0~5℃, the product yield and purity are high, and the number of single impurities is small.

[0039] Example 2: Purification of Lipoic Acid – Comparative Example

[0040] 50g of lipoic acid (HPLC purity 90%) was dissolved in 1500g of ethanol, followed by slow addition of 500g of purified water. The mixture was heated to an internal temperature of 55-60℃ and maintained at this temperature for 1 hour. A small amount of insoluble matter was removed by filtration. The filtrate was then cooled to 0-5℃, and 4mol / L dilute hydrochloric acid was added dropwise, producing a large amount of solid. After the pH of the system stabilized at 1-2, the mixture was filtered, washed with water, and vacuum dried at 38℃ for 24 hours. 30.7g of lipoic acid was obtained, with a purification yield of 61.4%, HPLC purity of 97.44%, and a maximum single impurity of 0.53%.

[0041] Repeat the above reaction procedure, take 50g of lipoic acid with HPLC purity of 90%, and use ethanol or water, or a mixture of ethanol and water as solvents to obtain the product yield, HPLC purity and maximum single impurity. The experimental results are shown in the table below.

[0042] Serial Number Ethanol (g) Water (g) yield purity Maximum single hybrid 1 1500 500 61.4% 97.44% 0.53% 2 2000 0 54.7% 95.53% 0.83% 3 0 2000 68.5% 98.25% 0.32% 4 1000 1000 64.39% 94.43% 0.64%

[0043] The results show that regardless of whether pure ethanol, pure water, or a mixture of ethanol and water is used, the product yield and purity are poor, and the amount of single impurities is large.

[0044] Example 3: Purification of Lipoic Acid – Effect of Raw Material Purity

[0045] 50g of lipoic acid (HPLC purity 80%) was dissolved in 1500g of methanol, followed by slow addition of 500g of purified water. The mixture was heated to an internal temperature of 55-60℃ and maintained at this temperature for 1 hour. A small amount of insoluble matter was removed by filtration. The filtrate was then cooled to 0-5℃, and 4mol / L dilute hydrochloric acid was added dropwise, producing a large amount of solid. After the pH of the system stabilized at 1-2, the mixture was filtered, washed with water, and vacuum dried at 38℃ for 24 hours. 37.8g of lipoic acid was obtained, with a yield of 81.0% and an HPLC purity of 99.53%, and a maximum single impurity of 0.09%.

[0046] Repeat the above reaction procedure, take 50g of lipoic acid with different HPLC purities, and obtain the product weight, yield, HPLC purity and maximum single impurity. The experimental results are shown in the table below.

[0047] Serial Number Raw material purity Product (g) Content Yield purity Maximum single hybrid 1 80% 32.4 81.0% 99.53% 0.09% 2 85% 37.8 88.9% 99.60% 0.10% 3 90% 42.2 93.8% 99.66% 0.07% 4 92% 43.1 93.7% 99.85% 0.08% 5 95% 46.8 98.5% 99.90% 0.05% 6 97% 47.9 98.8% 99.94% 0.03%

[0048] The results show that the higher the purity of the raw materials, the higher the product yield and purity, and the smaller the amount of single impurities.

[0049] Example 4: Preparation of lipoic acid by hydrolysis of ethyl lipoate

[0050]

[0051] Ethyl lipoate (100.0 g, 0.43 mol, 1.0 eq) and methanol (3000 g, w / w = 30:1) were added sequentially to the reaction flask and stirred to dissolve. The mixture was heated to an internal temperature of 40-45℃ and stirred for 30 minutes. Sodium hydroxide (19.0 g, 0.48 mol, 1.1 eq) was dissolved in 200 g of water to prepare an aqueous sodium hydroxide solution, which was then rapidly added dropwise to the ethyl lipoate system. The mixture was heated to an internal temperature of 55-60℃ and reacted for 4 hours. The reaction was stopped when the HPLC concentration of ethyl lipoate in the reaction solution was less than 0.1%, and the HPLC purity of the product lipoic acid was 96.25%.

[0052] Slowly add 800g of purified water to the above reaction solution, and start heating until the internal temperature reaches 55-60℃, then maintain this temperature for 1 hour. Filter to remove a small amount of insoluble matter, and continue cooling the filtrate to 0-5℃. Add 4mol / L dilute hydrochloric acid dropwise, producing a large amount of solid. After the pH of the system stabilizes at 1-2, filter under vacuum, wash with water, and dry under vacuum at 38℃ for 24 hours. Weigh 68.5g of lipoic acid, with a molar yield of 77.2%, HPLC purity of 99.90%, and a maximum single impurity of 0.04%.

[0053] Repeat the above reaction procedure, changing different inorganic bases, to obtain the product molar yield, HPLC purity, and maximum single impurity. The experimental results are shown in the table below.

[0054] Serial Number Inorganic base molar yield purity Maximum single hybrid 1 Sodium hydroxide 77.2% 99.90% 0.04% 2 potassium hydroxide 75.9% 99.63% 0.07% 3 Sodium carbonate 68.4% 98.97% 0.10%

[0055] The results show that sodium hydroxide and potassium hydroxide have better hydrolysis effects, while sodium carbonate has slightly worse results.

[0056] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims. These modifications or variations do not affect the essence of the present invention and should all be included within the scope of the present invention.

Claims

1. A method for purifying lipoic acid (I) characterized by, The method comprises the following steps: A. dissolving crude lipoic acid shown in formula (I) in a mixed solvent of methanol and water, to obtain a lipoic acid solution; the weight of methanol is 10-40 times of the weight of crude lipoic acid, and the weight of water is 5-20 times of the weight of crude lipoic acid; increasing the operation of filtration to remove possible solid in the solution; B. in the lipoic acid solution of step A, increasing the temperature to 55-60℃, and keeping the temperature for 1 hour; filtering to remove a small amount of insoluble substance; adding an inorganic acid to the filtrate at a suitable temperature to acidify and precipitate lipoic acid (I); the suitable temperature is 0-30℃; the inorganic acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, and aqueous solution thereof; the concentration of hydrochloric acid, sulfuric acid, and phosphoric acid is 4 mol / L; C. obtaining pure lipoic acid (I) by filtration, washing, and drying: the solvent used for washing comprises water and methanol.

2. The method of claim 1, wherein, The crude lipoic acid of step A has a purity in the range of 80%-99%.

3. The method of claim 1, wherein, The lipoic acid solution in step A can be prepared by the following steps: D. dissolving ethyl lipoate shown in formula (II) in methanol, and performing alkaline hydrolysis in the presence of an inorganic base, to obtain a lipoic acid (I) solution:

4. The method of claim 3, wherein, the inorganic base of step D comprises sodium hydroxide, potassium hydroxide, sodium carbonate, and aqueous solution thereof.

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