A method for synthesizing lipoic acid esters using a buffer salt

Abstract

The application discloses a method for synthesizing lipoic acid ester (I) by using buffer salt. The method takes 6,8-dichlorooctanoic acid ester (II) as raw material, adds buffer salt to stabilize the pH value of the reaction system in the process of ring closing reaction with a sulfuration reagent, thereby inhibiting the hydrolysis of lipoic acid ester, and improving the yield and purity of the product lipoic acid ester (I). The application is simple, convenient and practical, and is suitable for industrialized large-scale production of lipoic acid ester (I).

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemistry, and relates to the synthesis of lipoic acid, in particular to a synthesis method of lipoic acid ethyl ester. BACKGROUND

[0002] Lipoic acid, also known as α-lipoic acid, has the chemical name of 1,2-dithiolane-3-pentanoic acid, and was isolated in 1951 as a racemic product. Lipoic acid is a coenzyme existing in mitochondria, and belongs to a class of compounds in the B group of vitamins, and is widely distributed in biological tissues of animals and plants. Lipoic acid has strong antioxidant properties and is known as "universal antioxidant", and can eliminate free radicals that accelerate aging and cause diseases; can improve the insulin function and heart rate variability of patients with diabetes; can treat hepatitis C, protect the kidneys and pancreas, and prevent cataracts, and thus has attracted widespread attention from researchers.

[0003]

[0004] One of the mainstream methods for preparing lipoic acid at present is to use 6,8-dichlorooctanoic acid ethyl ester as a raw material, to cyclize to obtain lipoic acid ethyl ester in the presence of a sulfuration reagent, and to hydrolyze lipoic acid ethyl ester to obtain lipoic acid. Due to the presence of two sulfur atoms in lipoic acid, lipoic acid and lipoic acid ethyl ester are prone to oxidation, ring opening, polymerization and other side reactions during preparation and storage, which has an important influence on the product quality of lipoic acid and also puts forward higher requirements for the preparation process of lipoic acid. Therefore, how to obtain lipoic acid with high purity has become an important topic.

[0005]

[0006] There are many literatures reported for synthesizing lipoic acid ester from 6,8-dichlorooctanoic acid ethyl ester. For example, Henan Chemical , 2006, 23(5), 19-20 reported that sodium sulfide and sulfur powder were first reacted to generate a sodium sulfide solution in an aqueous solution, and then 6,8-dichlorooctanoic acid ethyl ester was added to the system and heated to reflux to obtain lipoic acid ethyl ester, which was hydrolyzed by one-pot method to finally obtain lipoic acid with a total yield of 68%. Similar literatures include CN108774209, CN115772155, CN109574987 and Chemical Communications , 2012, 75(9), 837-841.

[0007] Due to the poor solubility of 6,8-dichlorooctanoic acid ethyl ester in water, the addition of a phase transfer catalyst in the reaction system is an important method to improve the reaction yield, such as Bioorganic & Medicinal Chemistry LettersCN110003168, WO2002030917, CN113429386, CN113185494, etc. added tetrabutylammonium bromide (TBAB), CN112778270 added triethylbenzylammonium chloride to promote the reaction. SUMMARY

[0008] The present inventors found that the conventional reaction conditions would cause partial hydrolysis of lipoic acid ester, and the hydrolysis product lipoic acid was further oxidized due to its poor stability, leading to side reactions such as ring opening and polymerization, making it difficult to improve the purity of the product lipoic acid ester (I), or causing a significant decrease in the purification yield.

[0009] After a large number of experiments, the present inventors surprisingly found that the addition of buffer salt in the reaction system can inhibit the hydrolysis of lipoic acid ester. Therefore, the present application proposes a method for synthesizing lipoic acid ester (I) using buffer salt, which uses 6,8-dichlorooctanoate (II) as raw material, and adds buffer salt to stabilize the pH value of the reaction system during the ring-closing reaction with the sulfurizing reagent, thereby inhibiting the hydrolysis of lipoic acid ester and improving the yield and purity of the product lipoic acid ester (I). The present application is simple, convenient and practical, and is conducive to the industrialized mass production of lipoic acid ester (I).

[0010] A method for preparing lipoic acid ester (I) using 6,8-dichlorooctanoate (II) as raw material, and adding buffer salt during the ring-closing reaction with the sulfurizing reagent, thereby obtaining the product lipoic acid ester (I).

[0011] wherein R is methyl, ethyl or isopropyl.

[0012] In the preparation method, the buffer salt includes phosphate system, borate system, acetate system, carbonate system, ammonium formate, and amino acid.

[0013] In one embodiment, the phosphate system is used as the buffer salt, including phosphoric acid, dihydrogen phosphate, hydrogen phosphate, phosphate, and a mixture of any one or more of the above in any proportion.

[0014] In a preferred embodiment, sodium dihydrogen phosphate or a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate is used as the buffer salt.

[0015] In one embodiment, the borate system is used as the buffer salt, including boric acid, borax, and a mixture of the two in any proportion.

[0016] In a preferred embodiment, a mixture of boric acid and borax is used as the buffer salt.

[0017] In one embodiment, acetate system is used as the buffer salt, including acetic acid, acetate, and mixture of the two in any ratio.

[0018] In a preferred embodiment, mixture of acetic acid and sodium acetate is used as the buffer salt.

[0019] In a preferred embodiment, ammonium acetate is used as the buffer salt.

[0020] In one embodiment, carbonate system is used as the buffer salt, including carbonate, bicarbonate, and mixture of the two in any ratio.

[0021] In a preferred embodiment, sodium bicarbonate is used as the buffer salt.

[0022] In one embodiment, ammonium formate is used as the buffer salt.

[0023] In one embodiment, amino acid is used as the buffer salt, including glycine, alanine, lysine.

[0024] In a preferred embodiment, L-lysine is used as the buffer salt.

[0025] It should be understood that the buffer salt described herein not only includes buffer pair formed by two or more components, such as phosphate system, but also includes single compound, weak acid weak base salt or amphoteric compound with buffering effect itself, such as ammonium acetate, amino acid.

[0026] It should be understood that when expressing numerical characteristics herein, the term "about" or "approximately" means that the indicated number can have an error range or floating range of ±10%, ±9%, ±8%, ±7%, ±6%, or ±5%.

[0027] The synthesis method of lipoic acid ester provided by the present application effectively reduces the by-product of further hydrolysis of the product by adding buffer salt, so that the post-processing and purification steps of the reaction are simpler, and the final yield of the product is improved. The route has the advantages of economy and safe operation, and is suitable for industrial large-scale production. DETAILED DESCRIPTION

[0028] The present application is further illustrated by the following examples. It should be understood that these examples are for illustrative purposes only, and are not intended to limit the present application. Various changes or adjustments made by those skilled in the art based on the concept of the present application shall fall within the scope of the present application.

[0029] The amount of addition, content and concentration of various substances are referred to in this paper, wherein the percentage content refers to the mass percentage content unless otherwise specified.

[0030] In the examples herein, if no specific description is made for the reaction temperature or operating temperature, the temperature generally refers to room temperature (10-40℃). Examples

[0031] Reagents: The reactants and catalysts used in the examples of the present application are all of chemical purity, which can be used directly or purified simply according to the needs. The reagents are purchased from China Pharmaceutical (Group) Shanghai Chemical Reagent Company, Shanghai Aladdin Biochemical Technology Co., Ltd.

[0032] Detection instrument:

[0033] Nuclear magnetic resonance instrument: Bruker AV-500 and Brucker AV-600;

[0034] Gas chromatograph (GC), model: Shimadzu 2030, detector FID, gas chromatograph column model: 30-mG0301-31.

[0035] Example 1: Preparation of ethyl lipoate (compound I-1)

[0036]

[0037] Into the reaction kettle, 6,8-dichlorooctanoic acid ethyl ester (100 g, 0.41 mol, 1.0 eq), sulfur sublimation (17.3 g, 0.54 mol, 1.3 eq), tetrabutylammonium bromide (5.4 g, 0.016 mol, 0.04 eq) and 400 g of purified water were sequentially added, then buffer salt dipotassium hydrogen phosphate (11.3 g, 0.08 mol, 0.2 eq) was added, at this time the molar concentration of the buffer salt in the system was 0.2 mol / L, and the pH value was 8.2. Nitrogen was replaced, and the stirring was started to heat to an internal temperature of 70-75℃, which was solution A; sodium sulfide (109.6 g, 0.46 mol, 1.1 eq) was quickly added to 200 g of purified water, and under nitrogen protection, heated to an internal temperature of 45-55℃ for 1 hour of stirring to completely dissolve the system, which was solution B.

[0038] The solution B was slowly added to the solution A, and after the dripping was completed, the reaction was continued for 30 min. TLC monitoring showed that the raw material 6,8-dichlorooctanoic acid ethyl ester was substantially reacted. The temperature was reduced to 45°C, 300 mL of methyl tert-butyl ether was added for stirring, and after the water phase was separated, the water phase was extracted with 100 mL of methyl tert-butyl ether. The organic phases were combined, and the product ethyl thioctic acid was obtained by concentration. The HPLC purity was 97.75%, the hydrolysis impurity was 0.24%, the conversion to pure thioctic acid ethyl ester was 90.2 g, and the yield was 92.8%.

[0039] The above reaction operation was repeated without adding a buffer salt or changing different buffer salts and their molar concentrations to obtain the product purity and the proportion of hydrolysis impurities, and the molar yield of the converted product. The experimental results are shown in the following table.

[0040] No. Buffer salt Molar concentration mol / L Product purity Hydrolytic impurity Yield 1 None -- 89.17% 2.50% 77.4% 2 Dipotassium hydrogen phosphate 0.2 97.75% 0.24% 92.8% 3 Dipotassium hydrogen phosphate 0.1 95.76% 0.33% 90.7% 4 Dipotassium hydrogen phosphate: Monopotassium phosphate = 1:1 0.2 92.83% 0.18% 82.3% 5 Dipotassium hydrogen phosphate: Potassium phosphate = 1:1 0.2 88.27% 1.74% 75.5% 6 Disodium hydrogen phosphate 0.3 97.43% 0.35% 91.1% 7 Acetic acid 0.2 65.28% 0.15% 57.8% 8 Sodium acetate 0.2 87.61% 6.36% 65.2% 9 Ammonium acetate 0.2 79.78% 0.11% 78.9% 10 Sodium bicarbonate 0.2 83.34% 0.37% 82.8%

[0041] The above results show that the product purity is higher when a phosphate system is used, and the hydrolysis impurity is smaller when acetic acid or ammonium acetate is used.

[0042] Example 2: Preparation of methyl thioctic acid (compound I-2)

[0043]

[0044] Into the reaction kettle, 6,8-dichlorooctanoic acid methyl ester (47.1 g, 0.21 mol, 1.0 eq), sulfur (8.7 g, 0.27 mol, 1.3 eq), tetrabutylammonium bromide (2.8 g, 0.008 mol, 0.04 eq), and 200 g of purified water were sequentially added. Then, the buffer salt borax (15.2 g, 0.04 mol, 0.2 eq) was added, and the molar concentration of the buffer salt in the system was 0.2 mol / L, and the pH value was 8.0. Nitrogen was replaced, and the stirring was started. The temperature was increased to 70-75°C, which was solution A. Sodium sulfide (54.8 g, 0.23 mol, 1.1 eq) was quickly added to 100 g of purified water. Under nitrogen protection, the system was heated to 45-55°C and stirred for 1 hour until it was completely dissolved. This was solution B.

[0045] The solution B was slowly added to the solution A, and after the dripping was completed, the reaction was continued for 30 min. TLC monitoring showed that the raw material 6,8-dichlorooctanoic acid ethyl ester was substantially reacted. The temperature was reduced to 45°C, 300 mL of methyl tert-butyl ether was added for stirring, and after the water phase was separated, the water phase was extracted with 100 mL of methyl tert-butyl ether. The organic phases were combined, and the product ethyl thioctic acid was obtained by concentration. The HPLC purity was 97.75%, the hydrolysis impurity was 0.24%, the conversion to pure thioctic acid ethyl ester was 90.2 g, and the yield was 92.8%.

[0046] The above reaction operation was repeated without adding buffer salt or changing different buffer salts and their molar concentrations to obtain the product purity and hydrolysis impurity ratio, and the molar yield of the purified product, and the experimental results are shown in the following table.

[0047] No. Buffer salt Molar concentration mol / L Product purity Hydrolytic impurity Yield 1 None -- 85.22% 3.83% 75.1% 2 Borax 0.2 98.30% 0.21% 89.7% 3 Boric acid 0.2 75.33% 0.15% 66.5% 4 Boric acid: Borax = 1:1 0.2 91.15% 0.20% 81.7% 5 Ammonium formate 0.2 83.54% 0.12% 82.4% 6 Glycine 0.3 93.77% 0.35% 90.1% 7 Glycine 0.2 95.82% 0.32% 91.4% 8 L-alanine 0.2 93.35% 0.29% 90.3% 9 L-lysine 0.2 96.78% 0.22% 93.4%

[0048] The above results show that the use of borax and amino acids can obtain higher product purity and less hydrolysis impurities.

[0049] Example 3: Preparation of lipoic acid isopropyl ester (compound I-3)

[0050]

[0051] Into the reaction kettle, 6,8-dichlorooctanoic acid isopropyl ester (52.9 g, 0.21 mol, 1.0 eq), sulfur (8.7 g, 0.27 mol, 1.3 eq), tetrabutylammonium bromide (2.8 g, 0.008 mol, 0.04 eq) and 200 g of purified water were sequentially added, and then borax (15.2 g, 0.04 mol, 0.2 eq) was added, at this time the molar concentration of the buffer salt in the system was 0.2 mol / L, and the pH value was 8.0. Nitrogen was replaced, and the stirring was started to heat to an internal temperature of 70-75°C, which was solution A; sodium sulfide (54.8 g, 0.23 mol, 1.1 eq) was quickly added to 100 g of purified water, and under nitrogen protection, it was heated to an internal temperature of 45-55°C and stirred for 1 hour until the system was completely dissolved, which was solution B.

[0052] Solution B was slowly added to solution A, and after 30 min of reaction after the drop was completed, TLC monitoring showed that the raw material 6,8-dichlorooctanoic acid isopropyl ester was basically reacted; the temperature was lowered to 45°C, 150 mL of methyl tert-butyl ether was added and stirred, and after the layers were separated, the aqueous phase was extracted with 60 mL of methyl tert-butyl ether, and the organic phases were combined and concentrated to obtain the product lipoic acid isopropyl ester, with an HPLC purity of 97.97% and a hydrolysis impurity of 0.20%. The equivalent pure lipoic acid isopropyl ester was 47.4 g, and the yield was 92.1%.

[0053] The above reaction operation was repeated without adding buffer salt or changing different buffer salts and their molar concentrations to obtain the product purity and hydrolysis impurity ratio, and the molar yield of the purified product, and the experimental results are shown in the following table.

[0054] No. Buffer salt Molar concentration mol / L Product purity Hydrolytic impurity Yield 1 None -- 80.22% 2.07% 73.1% 2 Borax 0.2 97.97% 0.20% 92.1% 3 Dipotassium hydrogen phosphate 0.2 97.65% 0.23% 91.8% 4 Ammonium formate 0.2 82.44% 0.15% 80.4% 5 Ammonium acetate 0.2 83.73% 0.10% 81.9% 6 L-lysine 0.2 94.39% 0.25% 91.1%

[0055] The specific embodiments of the present application are described above. It needs to be understood that the present application is not limited to the specific embodiments described above, and various modifications or changes can be made by those skilled in the art within the scope of the claims, which do not affect the essential content of the present application, and should be included in the scope of the present application.

Claims

1. A process for the preparation of a lipoic acid ester (I) characterized in that, In the process of ring-closing reaction of 6,8-dichlorooctanoate (II) with sulfuration reagent, a buffer salt is added to obtain product thioctic ester (I); R is methyl, ethyl or isopropyl; The buffer salt is selected from phosphate system, borate system and amino acid; The phosphate system is selected from dihydrogen phosphate, hydrogen phosphate and mixture of one or more of the above in any ratio; The borate system is selected from borax; The amino acid is selected from glycine, alanine and lysine.

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