阅读说明：本技术 一种8-氨基-1-{[2-(三甲基硅基)乙氧基]甲氧基}辛烷-3-酮的合成方法 (Synthesis method of 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-one ) 是由 吴磊 石晓青 赵雪锋 曾陵 于 2021-10-28 设计创作，主要内容包括：一种8-氨基-1-{[2-(三甲基硅基)乙氧基]甲氧基}辛烷-3-酮的合成方法,属于药物化学合成技术领域。步骤：先将二苯甲胺上N-Boc保护,再与氢化钠作用制得其钠盐中间体,其与1,5-二溴戊烷进行取代反应,得到中间体-1；将中间体-1制得锌溴化物中间体,接着与3-{[2-(三甲基硅基)乙氧基]甲氧基}丙酸甲酯反应,生成中间体-2,其通过催化氢化脱保护反应,得到硫辛酸中间体8-氨基-1-{[2-(三甲基硅基)乙氧基]甲氧基}辛烷-3-酮。本技术工艺条件温和,原料易得,各中间体的纯度高,有利于原料药生产的质量控制和提高,适合工业化生产。(A method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone, belonging to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: firstly, carrying out N-Boc protection on benzhydrylamine, then reacting with sodium hydride to prepare a sodium salt intermediate, and carrying out substitution reaction on the sodium salt intermediate and 1, 5-dibromopentane to obtain an intermediate-1; preparing the intermediate-1 into a zinc bromide intermediate, then reacting the zinc bromide intermediate with 3- { [2- (trimethylsilyl) ethoxy ] methoxy } methyl propionate to generate an intermediate-2, and carrying out deprotection reaction through catalytic hydrogenation to obtain a lipoic acid intermediate 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone. The method has the advantages of mild process conditions, easily obtained raw materials, high purity of each intermediate, contribution to quality control and improvement of raw material medicine production, and suitability for industrial production.)

1. A method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone is characterized by comprising the following steps:

A) synthesizing an intermediate-1, reacting benzhydrylamine with di-tert-butyl dicarbonate to carry out N-Boc protection, firstly carrying out N-H hydrogen-withdrawing reaction on the obtained N-Boc-benzhydrylamine and sodium hydride in a solvent to generate an amino sodium salt intermediate, controlling the reaction temperature and the reaction time of the N-H hydrogen-withdrawing reaction to generate the amino sodium salt intermediate, and then carrying out substitution reaction on the amino sodium salt intermediate and 1, 5-dibromopentane to obtain an intermediate-1;

B) synthesizing an intermediate-2, mixing the intermediate-1 obtained in the step A) with zinc powder, lithium chloride, trimethylchlorosilane, 1, 2-dibromoethane and tetrahydrofuran, reacting to generate a zinc bromide intermediate, controlling the reaction temperature and the reaction time of the reaction to generate the zinc bromide intermediate, then carrying out substitution reaction on methyl 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionate and the zinc bromide intermediate in a tetrakis (triphenylphosphine) palladium and tetrahydrofuran system, and carrying out acidolysis deprotection, water washing, post-treatment and purification to obtain an intermediate-2;

C) synthesizing a finished product, and carrying out catalytic hydrogenation deprotection reaction on the intermediate-2 obtained in the step B) to obtain a lipoic acid intermediate 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-one.

2. The method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octan-3-one according to claim 1, wherein the solvent in step a) is N, N-dimethylformamide or N, N-dimethylacetamide; the molar ratio of the benzhydrylamine to the sodium hydride to the 1, 5-dibromopentane is 1.0 to (1.5-2.0) to (1.3-1.5).

3. The method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octan-3-one according to claim 1, wherein in the step A), the reaction temperature and the reaction time for generating the sodium salt intermediate of the amino through the N-H hydrogen-withdrawing reaction are controlled to be 0-25 ℃ and 30 min-1H respectively.

4. The method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octan-3-one according to claim 1, wherein the temperature of the substitution reaction in the step A) is 20-35 ℃, and the reaction time is 6-12 h.

5. The method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-one according to claim 1, wherein the molar ratio of the intermediate methyl-1, 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionate, zinc powder, lithium chloride, trimethylchlorosilane and tetrakis (triphenylphosphine) palladium in the step B) is 1.0: 3.0-6.0: 1.5-2.5: 0.05-0.1.

6. The method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octan-3-one according to claim 1, wherein the reaction temperature and the reaction time for generating the zinc bromide intermediate in the step B) are controlled to be 40-60 ℃ and 1-3 h respectively.

7. The method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octan-3-one according to claim 1, wherein the temperature of the substitution reaction in the step B) is 20-35 ℃, and the reaction time is 2-6 h.

8. The method for synthesizing 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octan-3-one according to claim 1, wherein the acid hydrolysis deprotection in step B) is performed by using trifluoroacetic acid.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a synthesis method of 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-one.

Background

Alpha-lipoic acid is a compound which can eliminate free radicals which accelerate aging and cause diseases and is similar to vitamins, has the characteristics of water solubility and fat solubility, can assist coenzyme to carry out physiological metabolism which is beneficial to the immunity of an organism, and is a universal antioxidant medicine. Alpha-lipoic acid has certain effects on the treatment of liver diseases, diabetes, HIV virus, tumors, nervous system degeneration, radiation injury, heavy metal poisoning such as arsenic, mercury, cadmium and the like, and can be used for assisting in treating type II diabetes, improving islet function glucose metabolism, protecting nerve cells, preventing cataract, preventing muscle damage and the like.

As shown in the chemical structural formula, in the molecular structure of alpha-lipoic acid, a chiral carbon is arranged in the position 3 of dithiolane, so that the dithiolane has optical activity, and two corresponding dextrorotatory (R) enantiomers and levorotatory (S) enantiomers are generated. Research shows that the two enantiomers of alpha-lipoic acid show different biological activity and pharmacological properties, wherein the biological activity of the R-form is far higher than that of the S-form, the S-form is basically inactive, but has no toxic or side effect, which is probably because a large amount of the R-form lipoic acid can enter cells and mitochondria through cell membranes and mitochondrial membranes to be reduced into dihydrolipoic acid, and only a small amount of the S-form can enter the cells to be reduced in the metabolic process of the lipoic acid. The dihydrolipoic acid has stronger oxidation resistance than lipoic acid, and the regeneration of endogenous antioxidants and the repair of oxidative damage can be realized only by the form of the dihydrolipoic acid. R-lipoic acid is a natural form of lipoic acid in a human body, is used as a vitamin medicament, has a curative effect superior to that of racemic alpha-lipoic acid, has higher activity than that of racemic alpha-lipoic acid in the aspects of promoting skeletal muscle to take glucose, reducing the levels of plasma insulin and free fatty acid, improving glycogen synthesis and glucose oxidation under the action of insulin, increasing the blood oxygen content of animals and the like in the treatment of type II diabetes, has a wider prospect in the prevention and treatment of diseases such as heart disease, diabetes, liver disease, senile dementia and the like, and is increasingly replaced by the R-lipoic acid, and finally, the racemic alpha-lipoic acid is completely replaced, so that the R-lipoic acid becomes a commonly used medicament and a nutritional supplement.

There are many methods for preparing R-lipoic acid in the world, but there are three main types: the method is characterized in that 6, 8-dichloro ethyl caprylate is used as a starting material, raceme alpha-lipoic acid is obtained by means of thio-polymerization, cyclization and hydrolysis, the raceme alpha-lipoic acid is repeatedly split by a splitting agent, and the R-lipoic acid is obtained by refining, wherein the yield of the step is not more than 50%. Although the racemization method of S-lipoic acid has been developed, the conversion of S-lipoic acid into racemic lipoic acid is relatively harsh on actual production conditions, corrosive to equipment, and low in yield, resulting in expensive production cost; secondly, 6, 8-dihydroxy methyl caprylate or 6-hydroxy-8-chloro methyl caprylate is used as a starting material to prepare mesylate, and then R-lipoic acid is formed stereoselectively, so that the method has complex process and is not easy to obtain a pure product; thirdly, racemic ethyl 6, 8-dichlorooctanoate is hydrolyzed into (+/-) dichlorooctanoic acid, and then the (+/-) dichlorooctanoic acid is split, thionated and cyclized by a splitting agent in sequence, so that the method can basically save the cost, but the cost is higher because about 50 percent of S- (-) -6, 8-dichlorooctanoic acid is not utilized.

The prior art methods for preparing R-lipoic acid, including the above-mentioned three methods, have the disadvantages of high cost, low yield, large raw material consumption, incapability of meeting the requirements of industrial scale-up production, and non-compliance with the requirements of green and environment-friendly production due to high waste discharge.

In view of the shortcomings and drawbacks of the prior art, the applicant has already filed a patent application disclosing a method for synthesizing R-lipoic acid (application No. 202110776749.5), wherein the key intermediate involved is 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octan-3-one (formula 1), which has a simple process, safe and controllable operation and low cost, and is therefore suitable for industrial production, and the disclosed synthetic route is:

disclosure of Invention

The invention aims to provide a synthetic method of 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone. The chemical name of the lipoic acid intermediate is 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone, and the chemical structural formula is shown as a formula 1:

：

the task of the invention is accomplished by a synthetic method of lipoic acid intermediate 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone, which comprises the following steps:

A) synthesizing an intermediate-1, reacting benzhydrylamine with di-tert-butyl dicarbonate to carry out N-Boc protection, firstly carrying out N-H hydrogen-withdrawing reaction on the obtained N-Boc-benzhydrylamine and sodium hydride in a solvent to generate an amino sodium salt intermediate, controlling the reaction temperature and the reaction time of the N-H hydrogen-withdrawing reaction to generate the amino sodium salt intermediate, and then carrying out substitution reaction on the amino sodium salt intermediate and 1, 5-dibromopentane to obtain an intermediate-1 (formula INT-1), wherein the reaction formula is as follows:

；

B) synthesizing an intermediate-2, mixing the intermediate-1 obtained in the step A) with zinc powder, lithium chloride, trimethylchlorosilane, 1, 2-dibromoethane and tetrahydrofuran, reacting to generate a zinc bromide intermediate, controlling the reaction temperature and the reaction time of the reaction to generate the zinc bromide intermediate, then carrying out substitution reaction on methyl 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionate and the zinc bromide intermediate in a tetrakis (triphenylphosphine) palladium and tetrahydrofuran system, and carrying out acidolysis deprotection, water washing, post-treatment and purification to obtain an intermediate-2 (formula INT-2), wherein the reaction formula is as follows:

；

C) synthesizing a finished product, and carrying out catalytic hydrogenation deprotection reaction on the intermediate-2 obtained in the step B) to obtain a lipoic acid intermediate 8-amino-1- { [2- (trimethylsilyl) ethoxy]Methoxy octan-3-one (formula 1), reaction formula:；

in a further embodiment, the methods and conditions for N-Boc protection of benzhydrylamine and di-tert-butyl dicarbonate reaction described in step A) are conventional in the art for such reactions.

In a further embodiment, the solvent described in step a) is N, N-dimethylformamide or N, N-dimethylacetamide; the molar ratio of the benzhydrylamine to the sodium hydride to the 1, 5-dibromopentane is 1.0 to (1.5-2.0) to (1.3-1.5).

In a further embodiment, the reaction temperature and the reaction time for generating the sodium salt intermediate of the amino group by the N-H hydrogen-withdrawing reaction in the step A) are respectively controlled to be 0-25 ℃ and 30 min-1H.

In a further embodiment, the temperature of the substitution reaction in the step A) is 20-35 ℃, and the reaction time is 6-12 h.

In a further embodiment, the feeding molar ratio of the intermediate methyl-1, methyl-3- { [2- (trimethylsilyl) ethoxy ] methoxy } propionate, zinc powder, lithium chloride, trimethylchlorosilane and tetrakis (triphenylphosphine) palladium in the step B) is 1.0: 3.0-6.0: 1.5-2.5: 0.05-0.1.

In a further embodiment, the reaction temperature and the reaction time for generating the zinc bromide intermediate in the step B) are controlled to be 40-60 ℃ and 1-3 hours respectively.

In a further embodiment, the temperature of the substitution reaction in the step B) is 20-35 ℃, and the reaction time is 2-6 h.

In a further embodiment, the acidolytic deprotection in step B) is using trifluoroacetic acid.

In further embodiments, the methods and conditions of the catalytic hydrogenation deprotection reaction described in step C) are conventional in the art for such reactions.

The technical scheme provided by the invention has the following technical effects: firstly, the process conditions are mild, the purity of each intermediate is high, and the quality control and improvement of the raw material medicines are facilitated; secondly, the reagent raw materials used in the process route of the invention are easy to obtain, the technical scheme is reasonable and environment-friendly, and the method can be used for mass production to meet the use requirements and is suitable for industrial production.

Detailed Description

The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments. Starting material methyl 3- { [2- (trimethylsilyl) ethoxy ] methoxy } propanoate, was obtained by ether synthesis from methyl 3-hydroxypropionate with 2- (trimethylsilyl) ethoxymethyl chloride.

In the examples below, reference to intermediate-1 is simultaneously illustrated by the formula INT-1 and intermediate-2 is simultaneously illustrated by the formula INT-2.

Example 1:

A) synthesis of intermediate-1:

benzhydrylamine (5.0 g, 27.3 mmol) is dissolved in dichloromethane (80 mL), triethylamine (6.0 g, 59.3 mmol) is added, the mixture is cooled to 0 ℃, di-tert-butyl dicarbonate (6.0 g, 27.5 mmol) is added, the mixture is heated to 20 ℃ and stirred for 12h, water is added for quenching, ethyl acetate (50 mL) is added, stirring is carried out for 5min, layering is carried out, an organic phase is collected, anhydrous sodium sulfate is dried, decompression concentration is carried out until dryness, N-dimethylformamide (50 mL) is added, cooling is carried out to 0 ℃, 60% NaH (1.7 g, 42.5 mol) is added, stirring is carried out for 30min at 0 ℃, 1, 5-dibromopentane (8.2 g, 35.7 mmol) is added, the mixture is reacted for 12h at 20 ℃, a mixture of ethyl acetate and saturated saline water (50 mL, 1: 1) is added for quenching, layering is collected, an organic phase is washed with saline water, anhydrous sodium sulfate is dried, decompression concentration is carried out until dryness, ethyl acetate-petroleum ether mixed solvent is recrystallized, intermediate-1 was obtained as a white solid (10.4 g) in 88% yield, and the reaction formula of this example (i.e., "this step", the same applies below) was as follows:

；

B) synthesis of intermediate-2:

adding anhydrous tetrahydrofuran (40 mL) into a 500mL reaction bottle, adding anhydrous lithium chloride (1.5 g, 35.4 mmol) and zinc powder (4.6 g, 70.3 mmol) under the protection of nitrogen and stirring at normal temperature, stirring for 10min, adding a mixed solvent of 1, 2-dibromoethane (4 mL) and anhydrous tetrahydrofuran (20 mL), adding trimethylchlorosilane (0.13 g, 1.2 mmol), heating to 40 ℃, stirring for 30min, cooling to normal temperature, adding intermediate-1 (10.0 g, 23.1 mmol), heating the reaction mixture to 40 ℃, reacting for 3h, cooling to normal temperature, filtering to remove insoluble substances, collecting filtrate, adding tetrakis (triphenylphosphine) palladium (1.4 g, 1.2 mmol), stirring at normal temperature for 30min, adding an anhydrous tetrahydrofuran solution (10 mL) of 3- { [2- (trimethylsilyl) ethoxy ] methoxy } methyl propionate (5.4 g, 23.0 mmol), keeping the temperature for reaction for 6h at 20 ℃, adding trifluoroacetic acid, stirring for 30min, dropwise adding a 10% ammonium chloride aqueous solution, adding dichloromethane for extraction, carrying out layering, collecting an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying a crude product by a chromatographic column to obtain an intermediate-2 (9.5 g), wherein the yield is 90%, and the reaction formula of the embodiment is as follows:

；

C) synthesizing a finished product, namely a lipoic acid intermediate 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone:

intermediate-2 (9.1 g, 20.0 mmol) was dissolved in methanol (100 mL), 10% palladium on charcoal (0.10 g, 0.9 mmol) was added, and the reaction was carried out under hydrogen at atmospheric pressure at 35 ℃ for 8 hours. The catalyst was removed by suction filtration through celite and the filtrate was concentrated to dryness by rotary evaporation to give the final product (5.1 g) in 88% yield, the reaction of this example is as follows:

。

example 2:

A) synthesis of intermediate-1:

benzhydrylamine (12.0 g, 65.5 mmol) is dissolved in dichloromethane (150 mL), triethylamine (13.0 g, 0.13 mol) is added, the mixture is cooled to 0 ℃, di-tert-butyl dicarbonate (15.0 g, 68.7 mmol) is added, the mixture is heated to 20 ℃ and stirred for 12h, water is added for quenching, ethyl acetate (80 mL) is added, stirring is carried out for 5min, layering is carried out, an organic phase is collected, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out until dry, N-dimethylformamide (100 mL) is added, cooling is carried out to 0 ℃, 60% NaH (4.5 g, 0.11 mol) is added, stirring is carried out for 45min at 10 ℃, 1, 5-dibromopentane (21.0 g, 91.3 mmol) is added, the mixture is reacted for 6h at 35 ℃, a mixed solution of ethyl acetate and saturated saline (100 mL, 1: 1) is added for quenching, layering is collected, an organic phase is washed with saline, dried by anhydrous sodium sulfate, reduced pressure concentration is carried out until dry, an ethyl acetate-petroleum ether mixed solution is recrystallized, intermediate-1 was obtained as a white solid (25.2 g) in 89% yield, according to the same reaction scheme as in example 1;

B) synthesis of intermediate-2:

adding anhydrous tetrahydrofuran (30 mL) into a 2L reaction bottle, adding anhydrous lithium chloride (6.0 g, 0.14 mol) and zinc powder (22.0 g, 0.34 mol) under the protection of nitrogen and stirring at normal temperature, stirring for 10min, adding a mixed solvent of 1, 2-dibromoethane (3 mL) and anhydrous tetrahydrofuran (30 mL), adding trimethylchlorosilane (0.6 g, 5.5 mmol), heating to 60 ℃, stirring for 30min, cooling to normal temperature, adding intermediate-1 (25.0 g, 57.8 mmol), heating the reaction mixture to 60 ℃, reacting for 1h, cooling to normal temperature, filtering to remove insoluble substances, collecting filtrate, adding tetrakis (triphenylphosphine) palladium (6.5 g, 5.6 mmol), stirring at normal temperature for 30min, adding an anhydrous tetrahydrofuran solution (40 mL) of 3- { [2- (trimethylsilyl) ethoxy ] methoxy } methyl propionate (13.6 g, 58.0 mmol), keeping the temperature and reacting for 2h at 35 ℃, adding trifluoroacetic acid, stirring for 30min, dropwise adding 10% ammonium chloride aqueous solution, adding dichloromethane for extraction, carrying out layering, collecting an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying a crude product by a chromatographic column to obtain an intermediate-2 (23.8 g), wherein the yield is 90%, and the reaction formula is the same as that in example 1;

C) synthesizing a finished product, namely a lipoic acid intermediate 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone:

intermediate-2 (23.5 g, 51.6 mmol) was dissolved in isopropanol (300 mL), 10% palladium on charcoal (0.3 g, 2.8 mmol) was added, and the reaction was allowed to proceed under hydrogen at atmospheric pressure at 35 ℃ for 8 h. The catalyst was removed by suction filtration through celite and the filtrate was concentrated to dryness by rotary evaporation to give the final product (14.0 g) in 94% yield according to the same reaction scheme as example 1.

Example 3:

A) synthesis of intermediate-1:

benzhydrylamine (16.6 g, 90.6 mmol) is dissolved in dichloromethane (200 mL), triethylamine (18.0 g, 0.18 mol) is added, the mixture is cooled to 0 ℃, di-tert-butyl dicarbonate (20.0 g, 91.6 mmol) is added, the mixture is heated to 20 ℃ and stirred for 12h, water is added for quenching, ethyl acetate (100 mL) is added, stirring is carried out for 5min, layering is carried out, an organic phase is collected, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out until the organic phase is dry, N-dimethylacetamide (200 mL) is added, cooling is carried out to 0 ℃, 60% NaH (7.0 g, 0.18 mol) is added, stirring is carried out for 1h at 15 ℃, 1, 5-dibromopentane (29.0 g, 0.13 mol) is added, reaction is carried out for 9h at 30 ℃, a mixed solution of ethyl acetate and saturated saline (500 mL, 1: 1) is added for quenching, layering is collected, an organic phase is washed with saline, dried by anhydrous sodium sulfate, reduced pressure concentration is carried out until the organic phase is dry, recrystallization is carried out, intermediate-1 was obtained as a white solid (34.5 g) in 88% yield according to the same reaction scheme as in example 1;

B) synthesis of intermediate-2:

adding anhydrous tetrahydrofuran (100 mL) into a 2L reaction bottle, adding anhydrous lithium chloride (6.5 g, 0.15 mol) and zinc powder (23.0 g, 0.35 mol) under the protection of nitrogen and stirring at normal temperature, stirring for 10min, adding a mixed solvent of 1, 2-dibromoethane (3 mL) and anhydrous tetrahydrofuran (30 mL), adding trimethylchlorosilane (0.6 g, 5.5 mmol), heating to 50 ℃, stirring for 30min, cooling to normal temperature, adding intermediate-1 (34.0 g, 78.6 mmol), heating the reaction mixture to 50 ℃, reacting for 2h, cooling to normal temperature, filtering to remove insoluble substances, collecting filtrate, adding tetrakis (triphenylphosphine) palladium (7.0 g, 6.1 mmol), stirring at normal temperature for 30min, adding an anhydrous tetrahydrofuran solution (80 mL) of 3- { [2- (trimethylsilyl) ethoxy ] methoxy } methyl propionate (18.4 g, 78.5 mmol), keeping the temperature for reaction at 30 ℃ for 4h, adding trifluoroacetic acid, stirring for 30min, dropwise adding 10% ammonium chloride aqueous solution, adding dichloromethane for extraction, carrying out layering, collecting an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and purifying a crude product by a chromatographic column to obtain an intermediate-2 (32.0 g), wherein the yield is 89%, and the reaction formula is the same as that in example 1;

C) synthesizing a finished product, namely a lipoic acid intermediate 8-amino-1- { [2- (trimethylsilyl) ethoxy ] methoxy } octane-3-ketone:

intermediate-2 (32.0 g, 70.2 mmol) was dissolved in ethanol (400 mL), 10% palladium on charcoal (0.4 g, 3.8 mmol) was added, and the reaction was carried out under hydrogen at normal pressure and 35 ℃ for 8 hours. The catalyst was removed by suction filtration through celite and the filtrate was concentrated to dryness by rotary evaporation to give the final product (19.0 g) in 93% yield according to the same reaction scheme as example 1.

Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention.