A method for obtaining (R)-α-lipoic acid by inclusion complexation and resolution

Abstract

The invention discloses a method for preparing (R)-α-lipoic acid, wherein racemic lipoic acid is used as a raw material, (S)-2,2'-binaphthol or a derivative of its ether is used as an inclusion resolving agent, and a target compound (R)-α-lipoic acid is obtained in high yield. The method is simple to operate, has low requirements on equipment, mild conditions, high yield, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic chemistry and relates to the separation of optical isomers, and specifically relates to a method for obtaining (R)-α-lipoic acid by inclusion separation. Technical Background

[0002] Lipoic acid is a natural product first isolated from pig liver in 1951. It belongs to the B vitamins and is soluble in both water and fat. Lipoic acid contains a disulfide five-membered ring structure, has a high electron density, has significant electrophilicity and the ability to react with free radicals, so it has antioxidant properties. It is known as the "universal antioxidant" and is the most effective natural antioxidant. Its English name is alphalipoic acid, abbreviated as ALA, and its chemical name is 1,2-dithiolane-3-pentanoic acid.

[0003] Lipoic acid is an indispensable substance in the tricarboxylic acid cycle in human metabolism. As a coenzyme factor of pyruvate decarboxylation dehydrogenase, it converts pyruvate into acetyl-CoA to generate FADH.

[0004] In the human body, lipoic acid not only participates in energy metabolism, but also can eliminate harmful substances such as active free radicals and reactive oxygen in the human body. From the structure of lipoic acid, it can be seen that lipoic acid contains a five-membered ring structure, which contains a disulfide atom with electrophilicity, has the ability to react with free radicals, and can remove reactive oxygen components. Vitamin C is water-soluble, while the molar mass of lipoic acid is higher than that of vitamin C, contains more carbon atoms, and has stronger fat solubility than vitamin C. Compared with fat-soluble vitamin E, the molar mass of lipoic acid is smaller, and its terminal group is carboxyl, so it has better water solubility. So far, it is one of the most powerful natural substances with antioxidant properties known to mankind, and is known as the "universal antioxidant". Its antioxidant capacity is more than four hundred times that of vitamin C and vitamin E. This compound can work synergistically with lipoic acid to reduce oxidative substances in the body. Lipoic acid can chelate heavy metal ions to achieve a detoxification effect.

[0005] At the same time, lipoic acid can react with other active substances in the body to reduce and regenerate other antioxidant substances, such as glutathione, vitamin E, etc., to protect the body from damage caused by cell oxidation.

[0006] Lipoic acid plays an important role in anti-oxidation, sugar metabolism, diabetic complications, inhibiting the spread of HIV-1 in cells, heavy metal poisoning and the treatment of many other diseases. It has received great attention from the biomedical community and is favored by the health care and functional food fields.

[0007] The global annual market demand for lipoic acid and related intermediates and derivatives is about 1,800 to 2,500 tons, with an average annual compound growth rate of 10%. At present, the racemic form of α-lipoic acid is mainly used in the market. Studies have shown that among the two enantiomers of lipoic acid (R)- and (S)-, natural (R)-α-lipoic acid has higher biological activity and has more important application value than the (S)-enantiomer with no obvious biological activity. Therefore, the research and development of a process route suitable for industrial production to obtain high-purity (R)-α-lipoic acid enantiomers is the focus of research on the synthesis of α-lipoic acid.

[0008] At present, there are three main methods for synthesizing (R)-α-lipoic acid: 1) starting from achiral raw materials, synthesizing by asymmetric synthesis methods catalyzed by enzymes and chemicals; 2) starting from racemic intermediates, synthesizing by chiral intermediates obtained by chiral resolution, or directly synthesizing by chiral resolution of racemic products; 3) starting from commercial chiral raw materials, synthesizing by asymmetric synthesis controlled by chiral substrates.

[0009] Among them, the chiral resolution synthesis of racemic products is a method used for a long time in the industry. In current production, α-phenylethylamine is mainly used as a resolution reagent. This resolution reagent is a classic alkaline resolution agent, and its resolution yield for racemic lipoic acid is about 30%. In 2003, F. Villani et al. reported a method for preparing (R)-α-lipoic acid by using chiral amines to resolve racemic α-lipoic acid. The yield was 27.5%, and the ee value was 99%, US. Patent 6670484.

[0010] The inclusion resolution method mainly utilizes the non-covalent bond interaction (including hydrogen bond, π-π interaction, van der Waals force, etc.) between the chiral host molecule and the guest molecule to be included, so that the chiral host molecule selectively reacts with one of the enantiomers of the guest molecule to form a selective chiral inclusion complex to obtain the target chiral isomer. Compared with traditional resolution agents, it does not crystallize by forming corresponding isomer salts, but crystallizes by the combination of host and guest. Although the chiral inclusion resolution method has been greatly developed, there is currently no mature theory for the enantiomeric recognition ability of the chiral host molecule in the process of inclusion complex formation, and the molecular structure of the host and guest will affect the resolution effect.

[0011] A search revealed that the prior art did not report a method for splitting (R)-α-lipoic acid using an inclusion splitting method. The applicant unexpectedly discovered during the research and development process that a suitable guest molecule could form a selective inclusion complex with (R)-α-lipoic acid, thereby obtaining a higher yield of (R)-α-lipoic acid. Summary of the invention

[0012] The invention provides an inclusion separation method, which can obtain (R)-alpha-lipoic acid with a higher yield.

[0013] The invention adopts (S)-2,2'-binaphthol and its derivatives as inclusion resolving agents to selectively resolve the racemic form of lipoic acid, thereby obtaining (R)-alpha-lipoic acid with a higher yield.

[0014] The (S)-2,2'-binaphthol and its derivatives of the present invention are preferably one of (S)-2,2'-binaphthol, (S)-2,2'-binaphthol-14-crown-4 and (S)-2,2'-binaphthol-18-crown-6.

[0015] Beneficial effects of the present invention:

[0016] 1. The present invention adopts (S)-2,2'-binaphthol and its derivatives as inclusion resolving agents to resolve racemic lipoic acid, thereby obtaining a high yield of (R)-α-lipoic acid.

[0017] 2. The splitting conditions adopted in the present invention have low requirements on equipment and are mild, and are suitable for industrial production. DETAILED DESCRIPTION

[0018] The specific implementation methods of the present invention are further described in detail below in conjunction with the examples. In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "including" or its variations such as "comprising" or "including" will be understood to include the stated components and steps, without excluding the presence of other material components or steps.

[0019] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0020] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0021] The "reaction solvent" of the present invention refers to the solvent used in the process of reacting racemic lipoic acid with an inclusion resolving agent to form a complex crystal of (R)-α-lipoic acid and an inclusion resolving agent.

[0022] The "exchange solvent" of the present invention is also called "crystallization solvent" and refers to dissolving and crystallizing the complex to obtain the target compound.

[0023] The present invention provides a method for preparing (R)-α-lipoic acid, using (S)-2,2'-binaphthol or its crown ether derivative as an inclusion resolution agent, and the method comprises the following specific steps:

[0024] Step 1: reacting racemic lipoic acid with an inclusion resolving agent in a reaction solvent to form a complex crystal of (R)-α-lipoic acid and the inclusion resolving agent;

[0025] Step 2: Add the complex crystals obtained in step 1 to the exchange solvent, heat to reflux, cool and crystallize, and filter to obtain (R)-α-lipoic acid.

[0026] The (S)-2,2'-binaphthol crown ether derivative is one of (S)-2,2'-binaphthol-14-crown-4, (S)-2,2'-binaphthol-17-crown-5 and (S)-2,2'-binaphthol-18-crown-6. Particularly preferably, the inclusion resolution agent is (S)-2,2'-binaphthol-14-crown-4.

[0027] Preferably, in the above preparation method, the reaction temperature in step 1 is -20°C-60°C, preferably -10°C-0°C; and the reaction time is 1 to 8 hours, preferably 1 to 4 hours.

[0028] Preferably, in the above preparation method, the molar ratio of the inclusion resolving agent to racemic lipoic acid in step 1 is (0.5-1.1):1, preferably (0.5-0.7):1.

[0029] Preferably, the reaction solvent and the exchange solvent (crystallization solvent) in the above preparation method may be the same or different, and are selected from one or more of methanol, ethanol, dichloromethane, chloroform, ether, isopropyl ether, methyl tert-butyl ether, acetone, toluene, ethyl acetate, cyclohexane, n-hexane or n-heptane.

[0030] It is particularly preferred that the reaction solvent is one or more of toluene, isopropyl ether, diethyl ether and methyl tert-butyl ether, and the exchange solvent (crystallization solvent) is selected from one or more of toluene, isopropyl ether, diethyl ether, methyl tert-butyl ether, cyclohexane, n-hexane or n-heptane.

[0031] Hereinafter, embodiments of the present invention are described in detail. However, these embodiments are exemplary, the present invention is not limited thereto, and the present invention is defined by the scope of the claims.

[0032] In the present invention, the percentage content, unless otherwise specified, generally refers to the percentage content by weight. In the examples, raw materials can generally be purchased from the market unless otherwise specified.

[0033] Example 1 Preparation of (R)-α-lipoic acid

[0034] Dissolve racemic lipoic acid (10.0 g, 0.05 mol) in the reaction solvent toluene, and slowly drop a certain proportion of (S)-2,2'-binaphthol-14-crown-4 (0.035 mol) dissolved in the reaction solvent toluene into the system. After the dropwise addition, control the reaction temperature to -10-0°C and stir for 3 hours. Filter to obtain light yellow solid (S)-2,2'-binaphthol-14-crown-4 lipoic acid crystals.

[0035] The obtained (S)-2,2'-binaphthol-14-crown-4-lipoic acid crystals were added to the solvent n-hexane, refluxed for 4 hours, dissolved and then cooled to room temperature for crystallization, filtered to obtain (R)-α-lipoic acid solid.

[0036] Investigating the effect of temperature on splitting

[0037] The reaction temperature was changed, and the other conditions were the same as in Example 1. The results are shown in Table 1.

[0038] Table 1 Effect of temperature on splitting effect

[0039]

[0040]

[0041] From the results in Table 1, it can be seen that the splitting temperature has a certain influence on the splitting yield. The method of the present invention can achieve a good splitting effect at -10-60°C, especially at -10-30°C.

[0042] Investigating the effect of solvent on the resolution

[0043] The reaction solvent and crystallization solvent in Example 1 were changed, and other conditions remained unchanged. The results are shown in Table 2

[0044] Table 2 Effect of solvent on separation effect

[0045]

[0046] It can be seen from Table 2 that different solvents have a greater impact on the resolution effect, among which toluene and isopropyl ether have better effects.

[0047] Investigating the effect of molar ratio on resolution

[0048] The molar ratio of the resolving agent and racemic lipoic acid in Example 8 was changed, and other conditions remained unchanged. The results are shown in Table 3. Table 3 Effect of the molar ratio of the resolving agent and racemic lipoic acid on the resolution effect

[0049]

[0050]

[0051] It can be seen from Table 3 that the molar ratio of the resolving agent to racemic lipoic acid in the range of 0.5-1.2:1 has a good resolving effect.

[0052] Investigating the effect of time on splitting

[0053] The reaction time of Example 8 was changed to investigate the effect of the reaction time on the resolution effect. The results are shown in Table 4.

[0054] Table 4 Effect of split time on split effect

[0055] Example No. Reaction time Yield % ee value% 24 1 30.2 99.1 25 2 32.9 99.3 26 3 33.4 99.5 27 4 33.1 89.1 28 5 34.2 88.2 29 6 33.7 89.6 30 7 31.5 89.5 31 8 32.6 88.6

[0056] It can be seen from Table 4 that a better resolution effect can be obtained when the reaction time is 1-8 hours, and 1-3 hours is particularly preferred.

[0057] Effects of different resolving agents on resolution

[0058] The resolving agent in Example 8 was changed, and the other conditions remained unchanged. The results are shown in Table 5.

[0059] Table 5 Effect of the resolving agent on the resolving effect

[0060]

[0061]

[0062] It can be seen from Table 5 that different resolving agents have a significant effect on the resolving effect. The resolving agents in Examples 32-34 are (S)-2,2'-binaphthol, (S)-2,2'-binaphthol-18-crown-6, and (S)-2,2'-binaphthol-17-crown-5, respectively. Although Examples 32-34 show certain resolving abilities, there is a large difference in effect compared to the resolving agent (S)-2,2'-binaphthol-14-crown-4 in Example 8. (S)-2,2'-binaphthol-14-crown-4 shows a relatively excellent resolving effect as a resolving agent.

[0063] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing (R)-α-lipoic acid, characterized in that Using (S)-2,2'-binaphthol crown ether derivative as inclusion resolution agent, the method comprises the following specific steps: Step 1: racemic lipoic acid reacts with an inclusion resolving agent in a reaction solvent to form a complex crystal of (R)-α-lipoic acid and the inclusion resolving agent; Step 2: Add the complex crystals obtained in step 1 to the exchange solvent, heat to reflux, cool and crystallize, and filter to obtain (R)-α-lipoic acid. The (S)-2,2'-binaphthol crown ether derivative is one of (S)-2,2'-binaphthol-14-crown-4, (S)-2,2'-binaphthol-17-crown-5 and (S)-2,2'-binaphthol-18-crown-6.

2. The preparation method according to claim 1, characterized in that: The inclusion resolution agent is (S)-2,2'-binaphthol-14-crown-4.

3. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step 1 is -20°C to 60°C; the reaction time is 1 to 8 hours.

4. The preparation method according to claim 1 or 2, characterized in that: The reaction temperature of step 1 is -10°C to 30°C; the reaction time is 1 to 4 hours.

5. The preparation method according to claim 4, characterized in that: The molar ratio of the inclusion resolving agent to racemic lipoic acid in step 1 is (0.5-1.2):

1.

6. The preparation method according to claim 4, characterized in that: The reaction solvent and the exchange solvent may be the same or different and may be selected from one or more of methanol, ethanol, dichloromethane, chloroform, ether, isopropyl ether, methyl tert-butyl ether, acetone, toluene, ethyl acetate, cyclohexane, n-hexane or n-heptane.

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