A kind of preparation method of dihydrolipoic acid

Abstract

This invention discloses a method for preparing dihydrolipoic acid, relating to the field of pharmaceutical synthesis technology. The invention comprises the following steps: a) using a low-carbon alcohol as a reaction solvent, adding 6,8-dichlorooctanoic acid methyl ester, sodium sulfide nonahydrate, and sulfur, heating to reflux, and cooling and filtering after the reaction is completed; b) adding water and a metal reducing agent to the filtrate, heating to reflux under nitrogen protection, and then cooling to room temperature; c) adjusting the solution pH to 1-2 with dilute hydrochloric acid or the like, and recovering the alcoholic reaction solvent under reduced pressure; d) extracting the product with an organic solvent, and finally distilling under reduced pressure to obtain the product. This invention uses inexpensive 6,8-dichlorooctanoic acid methyl ester as the base raw material and readily available and inexpensive metal reducing agents, which can effectively reduce costs, have low requirements for reaction conditions, and reduce the difficulty of preparation.

Description

Technical Field

[0001] The present application relates to the technical field of drug synthesis, and in particular to a method for preparing dihydrolipoic acid. Background Art

[0002] Thioctic acid, also known as dithioctic acid, is systematically named 1,2-dithio-pentane-3-pentanoic acid, with a molecular formula of C8H 14 O2S2, with a relative molecular mass of 206.3182, acts as a coenzyme in acyl transfer during metabolism, eliminating free radicals that accelerate aging and cause disease. Lipoic acid is absorbed through the intestines and enters cells, possessing both fat- and water-soluble properties.

[0003] Several clinical reports and pharmaceutical research articles suggest that lipoic acid exhibits strong biological activity, acting as a repair factor in various biological systems. Early on, it was used to treat various conditions, including liver poisoning and cirrhosis. In recent years, lipoic acid's potent antioxidant properties and safety have regained recognition, and scientists have begun research on its pharmacology and clinical applications, with findings appearing in relevant journals.

[0004] The antioxidant effect of lipoic acid is mainly manifested in: chelating metal ions, removing active oxygen, and also regenerating some endogenous antioxidants such as vitamin C, vitamin E and glutathione.

[0005] Currently, the most widely used clinical application of lipoic acid is in the treatment of type 2 diabetes and its neurological complications. It is also used to protect the body and reduce DNA damage caused by ionizing radiation. Due to its excellent antioxidant properties, lipoic acid is also used as a dietary supplement in healthy individuals.

[0006] Lipoic acid has two enantiomers, but their biological activities are distinct. The R-enantiomer is more potent than the S-enantiomer. Existing data suggest that the superiority of the R-enantiomer may be due to its greater permeability through cell membranes and mitochondria during lipoic acid metabolism. Upon entry into the mitochondria, it is reduced to dihydrolipoic acid. In contrast, the S-enantiomer enters cell membranes in much smaller quantities. Dihydrolipoic acid possesses even stronger antioxidant capacity than lipoic acid. Both the regeneration of endogenous antioxidants and the repair of oxidative damage require the presence of dihydrolipoic acid, which explains the greater effectiveness of R-lipoic acid.

[0007] If dihydrolipoic acid is used directly, it can work directly without entering the mitochondria for reduction, and may have greater application value than R-lipoic acid in the future. The current methods for preparing dihydrolipoic acid mainly include the following methods:

[0008] 1. JACS-1955-77-416 describes a method for preparing dihydrolipoic acid, which involves reacting 6,8-dichlorooctanoate with benzyl mercaptan, followed by reduction of the product in sodium / liquid ammonia. However, due to the hazardous nature of metallic sodium, large-scale production is not feasible.

[0009] 2. Patents CN01813578.1 and US6906210 describe a method for preparing dihydrolipoic acid, wherein 6,8-dimethylsulfonyloxyoctanoate is reacted with a mixture of sodium sulfide and sulfur, followed by reduction with sodium borohydride. The reducing agent, sodium borohydride, is relatively expensive, and the raw material 6,8-dimethylsulfonyloxyoctanoate is much more expensive than 6,8-dichlorooctanoate, resulting in high overall production costs.

[0010] 3. WO / 2018 / 137874A1, CN201780059952 and US10532978 describe methods that are almost the same as the previous ones, but the heating and pressurizing in the first step and the large excess of sodium borohydride reduction in the second step also use heating reactions, which have certain requirements for the reaction conditions.

[0011] Existing methods for preparing dihydrolipoic acid are either dangerous and unfavorable for expanding production scale, or have high requirements for preparation conditions, or have complicated preparation processes. In view of this, the present application proposes a method for preparing dihydrolipoic acid with low preparation cost and safety. Summary of the Invention

[0012] The purpose of this application is to solve the problems raised in the above background technology, and to provide a method for preparing dihydrolipoic acid.

[0013] In order to achieve the above-mentioned purpose, this application specifically adopts the following technical solutions:

[0014] A method for preparing dihydrolipoic acid comprises:

[0015] Use low-carbon alcohols as reaction solvents, add methyl 6,8-dichlorooctanoate, sodium sulfide nonahydrate and sulfur, heat to reflux, cool and filter after the reaction is completed;

[0016] Add water and a metal reducing agent to the filtrate, heat to reflux under nitrogen protection, and then cool to room temperature;

[0017] Adjust the pH of the solution to 1-2 with dilute hydrochloric acid, etc., and recover the alcohol reaction solvent under reduced pressure;

[0018] The product is extracted with an organic solvent, and the solvent is recovered under normal pressure and then distilled under reduced pressure to obtain the product.

[0019]

[0020] That is the above formula (I).

[0021] Furthermore, in step b), the metal reducing agent includes a first type of metal reducing agent and a second type of metal reducing agent, wherein:

[0022] When a type of metal reducing agent is selected, a promoter needs to be added;

[0023] When a Class II metal reducing agent is selected, no promoter is needed.

[0024] Furthermore, the first type of metal reducing agent is zinc and iron, and the second type of metal reducing agent is magnesium and aluminum.

[0025] Furthermore, the accelerator is ammonium chloride.

[0026] Furthermore, the alcohol reaction solvent in step a) is a mixed solution of methanol, ethanol or propanol and water.

[0027] Furthermore, the acidic solution in step c) is one of nitric acid, sulfuric acid or hydrochloric acid.

[0028] Furthermore, the extraction in step d) is performed twice.

[0029] The beneficial effects of this application are as follows:

[0030] 1. This application uses cheap 6,8-dichlorooctanoic acid methyl ester to prepare dihydrolipoic acid, which can first reduce costs, and the use of a metal reducing agent can further reduce the preparation cost, thereby meeting low-cost production requirements.

[0031] 2. The preparation method of the present application is simple and has low requirements for reaction conditions, which reduces the difficulty of preparation.

[0032] 3. The raw materials used in the preparation method of this application are less dangerous than those in the prior art, thereby improving the safety of the preparation process. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the embodiments of the present application.

[0034] The present application proposes a method for preparing dihydrolipoic acid, comprising:

[0035] a) methyl 6,8-dichlorooctanoate, sodium sulfide nonahydrate (Na2S·9H2O), and sulfur (S) are sequentially added to an alcoholic reaction solvent, the mixture is first heated to reflux, then cooled and filtered to obtain a filtrate. This application uses methyl 6,8-dichlorooctanoate as the raw material for preparing 6,8-dihydrolipoic acid because it is cheaper than 6,8-dihydroxyoctanoate, thereby reducing preparation costs.

[0036] b) adding water and a metal reducing agent to the filtrate in sequence, heating the mixture to reflux under nitrogen protection, and then cooling the mixture to room temperature to obtain a reduced solution. Unlike the prior art for preparing dihydrolipoic acid, the present invention uses a metal reducing agent and selects a cheap and readily available active metal for reduction, thereby further reducing the preparation cost;

[0037] c) adding an acidic solution to the reducing solution to lower the pH to 1-2, and recovering the alcohol reaction solvent under reduced pressure to obtain a mother liquor;

[0038] d) The mother liquor is extracted with isopropyl acetate, etc., and the solvent is recovered under normal pressure and then distilled under reduced pressure to obtain dihydrolipoic acid:

[0039]

[0040] That is the above formula (I).

[0041] In some embodiments, in step b), the metal reducing agent includes a first type of metal reducing agent and a second type of metal reducing agent, wherein:

[0042] When a type of metal reducing agent is selected, a promoter needs to be added;

[0043] When a Class II metal reducing agent is selected, no promoter is needed.

[0044] In some embodiments, the first type of metal reducing agent is zinc and iron, and the second type of metal reducing agent is magnesium and aluminum.

[0045] In some embodiments, the accelerator is ammonium chloride.

[0046] In some embodiments, the alcohol reaction solvent in step a) is a mixed solution of methanol, ethanol or propanol and water.

[0047] In some embodiments, the acidic solution in step c) is one of nitric acid, sulfuric acid or hydrochloric acid.

[0048] In some embodiments, the extraction in step d) is performed twice.

[0049] The following examples are obtained under the same conditions with different metal reducing agents.

[0050] Example 1

[0051] In a 250 ml single-necked flask, add 100 g of methanol, followed by 22.7 g of methyl 6,8-dichlorooctanoate, 36.4 g of sodium sulfide nonahydrate, and 4.2 g of sulfur. Reflux at high temperature for 3 hours. Cool and filter, then add the filtrate to a 500 ml three-necked flask. Add 80 ml of water and 10 g of magnesium powder, and reflux under nitrogen for 8 hours. Cool to room temperature, acidify with 10% hydrochloric acid to a pH of 1.5, and recover the methanol by vacuum distillation. The mother liquor is extracted twice with isopropyl acetate, the recovered solvents are combined, and vacuum distillation is performed. The fractions at 195-205°C / 1.5 mmHg are collected to yield 19.8 g of product.

[0052] Example 2

[0053] In a 250 ml single-necked flask, add 100 g of methanol, followed by 22.7 g of methyl 6,8-dichlorooctanoate, 36.4 g of sodium sulfide nonahydrate, and 4.2 g of sulfur. Reflux at elevated temperature for 3 hours. Cool and filter, then add the filtrate to a 500 ml three-necked flask. Add 80 ml of water and 11 g of aluminum powder, and reflux under nitrogen for 8 hours. Cool to room temperature, acidify with 10% hydrochloric acid to a pH of 1.5, and distill under reduced pressure to recover methanol. The mother liquor is extracted twice with isopropyl acetate, the recovered solvents are combined, and then distilled under reduced pressure. The fractions at 195-205°C / 1.5 mmHg are collected to yield 18.5 g of product.

[0054] Example 3

[0055] In a 250 ml single-necked flask, add 100 g of methanol, followed by 22.7 g of methyl 6,8-dichlorooctanoate, 36.4 g of sodium sulfide nonahydrate, and 4.2 g of sulfur. Reflux at elevated temperature for 3 hours. Cool and filter, then add the filtrate to a 500 ml three-necked flask. Add 80 ml of water, 15 g of zinc powder, and 10 g of ammonium chloride. Reflux under nitrogen for 8 hours. Cool to room temperature, acidify with 10% hydrochloric acid to a pH of 1.5, and distill under reduced pressure to recover methanol. The mother liquor is extracted twice with isopropyl acetate, combined, and the recovered solvent is then distilled under reduced pressure. The fractions at 195-205°C / 1.5 mmHg are collected to yield 17.1 g of product.

[0056] Example 4

[0057] In a 250 ml single-necked flask, add 100 g of methanol, followed by 22.7 g of methyl 6,8-dichlorooctanoate, 36.4 g of sodium sulfide nonahydrate, and 4.2 g of sulfur. Reflux at elevated temperature for 3 hours. Cool and filter, then add the filtrate to a 500 ml three-necked flask. Add 80 ml of water, 18 g of iron powder, and 10 g of ammonium chloride. Reflux under nitrogen for 8 hours. Cool to room temperature, acidify with 10% hydrochloric acid to a pH of 1.5, and distill under reduced pressure to recover methanol. The mother liquor is extracted twice with isopropyl acetate, combined, and the recovered solvent is then distilled under reduced pressure. The fractions at 195-205°C / 1.5 mmHg are collected to yield 17.6 g of product.

[0058] In combination with the contents in the above embodiments, it can be seen that when metallic magnesium is selected as the metal reducing agent, the content of dihydrolipoic acid extracted is the highest.

[0059] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present application. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application is not limited to the embodiments shown herein, but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing dihydrolipoic acid, characterized in that: include: 6,8-dichlorooctanoic acid methyl ester, sodium sulfide nonahydrate and sulfur are sequentially added to an alcohol reaction solvent, first heated to reflux, then filtered and cooled to obtain a filtrate; Water and a metal reducing agent are sequentially added to the filtrate, and the mixture is heated to reflux under nitrogen protection, and then cooled to room temperature to obtain a reducing solution; Adding an acidic solution to the reducing solution to lower the pH until 1 < pH < 7, and recovering the alcohol reaction solvent under reduced pressure to obtain a mother liquor; The mother liquor was extracted with isopropyl acetate, combined and the solvent was recovered under reduced pressure and then distilled under reduced pressure to obtain dihydrolipoic acid: That is, the above formula (I); Metal reducing agents include Class I metal reducing agents and Class II metal reducing agents, among which: When a type of metal reducing agent is selected, a promoter needs to be added, and the type of metal reducing agent is zinc and iron; When the second type of metal reducing agent is selected, no promoter is needed, and the second type of metal reducing agent is magnesium and aluminum; The accelerator is ammonium chloride; The alcohol reaction solvent is a mixed solution of methanol, ethanol or propanol and water; The acidic solution is one of nitric acid, sulfuric acid or hydrochloric acid.

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