WO2023071328A1

WO2023071328A1 - Method for synthesizing 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one

Info

Publication number: WO2023071328A1
Application number: PCT/CN2022/107743
Authority: WO
Inventors: 吴磊; 钱祥云; 张晓红; 曾陵
Original assignee: 苏州富士莱医药股份有限公司
Priority date: 2021-10-28
Filing date: 2022-07-26
Publication date: 2023-05-04
Also published as: CN113717210B; CN113717210A

Abstract

Disclosed is a method for synthesizing 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one, which belongs to the technical field of pharmaceutical chemical synthesis. The method comprises the steps of: firstly, protecting diphenylmethylamine with N-Boc, and then reacting the protected diphenylmethylamine with sodium hydride to prepare a sodium salt intermediate thereof, and subjecting the sodium salt intermediate and 1,5-dibromopentane to a substitution reaction to obtain intermediate-1; preparing the intermediate-1 into a zinc bromide intermediate, then reacting the zinc bromide intermediate with methyl 3-{[2-(trimethylsilyl)ethoxy]methoxy}propionate to produce intermediate-2, and subjecting the intermediate-2 to a catalytic hydrogenation deprotection reaction to obtain the lipoic acid intermediate 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one. The present technique has mild process conditions, the raw materials are easily available, the purity of each intermediate is high, the quality control and improvement of bulk drug production are facilitated and the method is suitable for industrial production.

Description

A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one

technical field

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

Background technique

α-lipoic acid is a vitamin-like compound that can eliminate free radicals that accelerate aging and cause disease. It is both water-soluble and fat-soluble. Universal antioxidant drug. α-lipoic acid has a certain effect on the treatment of many diseases such as liver disease, diabetes, HIV virus, tumor, nervous system degeneration, radiation injury, arsenic, mercury, cadmium and other heavy metal poisoning, for example, it can assist in the treatment of type II diabetes and improve Pancreatic islets function in glucose metabolism, protect nerve cells, prevent cataracts, prevent muscle damage and so on.

As shown in the following chemical structural formula, in the molecular structure of α-lipoic acid, there is a chiral carbon in position 3 of the dithiolane ring, which has optical activity and produces two corresponding right-handed (R) and left-handed (S) Enantiomers. Studies have shown that these two enantiomers of α-lipoic acid show different biological activities and pharmacological properties, among which the biological activity of the R-type is much higher than that of the S-type, and the S-type is basically inactive, but there is no Toxic and side effects, which may be due to the fact that during the metabolism of lipoic acid, a large amount of R-type lipoic acid can pass through the cell membrane and mitochondrial membrane into cells and mitochondria and be reduced to dihydrolipoic acid, while only a small amount of S-type lipoic acid enters Cells are restored. Dihydrolipoic acid has a stronger antioxidant capacity than lipoic acid, and the regeneration of endogenous antioxidants and the repair of oxidative damage must be achieved in the form of dihydrolipoic acid. R-lipoic acid is the natural form of lipoic acid in the human body. As a vitamin drug, its curative effect is better than that of racemic α-lipoic acid. It can promote skeletal muscle glucose uptake, reduce plasma insulin and free fatty acid levels, and improve blood sugar levels in the treatment of type II diabetes. R-lipoic acid is more active than racemic α-lipoic acid in the synthesis of glycogen under the action of insulin, the oxidation of glucose, and the increase of oxygen content in animal blood. It is more active in the prevention and treatment of heart disease, diabetes, liver disease and Alzheimer's disease and other diseases have broader prospects. R-lipoic acid has more and more replaced, and will eventually replace racemic α-lipoic acid, and has become a commonly used drug and nutritional supplement.

At present, there are many methods for preparing R-lipoic acid in the world, but there are three main types: one is the current industrialized method for preparing R-lipoic acid, which uses 6,8-dichlorooctanoic acid ethyl ester as the starting material, and undergoes thioxocyclization and cyclization. , hydrolysis to obtain racemic α-lipoic acid, and then use a resolving agent for multiple resolutions to obtain R-lipoic acid after refining. The yield of this step is not more than 50%. Although people have developed a racemization method for S-lipoic acid, the conversion of S-lipoic acid into cyclic lipoic acid is relatively harsh on actual production conditions, corrosive to equipment, and the yield is low, resulting in expensive production costs; The second is to use 6,8-dihydroxyoctanoic acid methyl ester or 6-hydroxy-8-chlorooctanoic acid methyl ester as the starting material to make mesylate, and then stereoselectively form R-lipoic acid. The process of this method is relatively complicated , especially not easy to obtain pure product; the third is to hydrolyze racemic 6,8-dichlorooctanoic acid ethyl ester into (±) dichlorooctanoic acid, and then use a resolving agent to split, rethio and cyclization, the method is basically The cost can be saved, but because about 50% of S-(-)-6,8-dichlorooctanoic acid is still unused, the cost is high.

The preparation methods of R-lipoic acid in the prior art, including the three methods mentioned above, all have high cost, low yield and large raw material consumption, which cannot meet the requirements of industrialized scale-up production, and because of high waste discharge It is a pity that it does not meet the requirements of green and environmental protection production.

In view of the deficiencies and defects in the prior art, the applicant has proposed a patent application, which discloses a synthetic method of R-lipoic acid (application number 202110776749.5), in which the key intermediate involved is 8- Amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one (Formula 1) is suitable for industrialization because of its simple process, safe and controllable operation, and low cost Production, the published synthetic route is:

Contents of the invention

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

Task of the present invention is accomplished like this, a kind of synthetic method of lipoic acid intermediate 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one , including the following steps:

A) Synthesis of intermediate-1, N-Boc protection on the reaction between benzhydrylamine and di-tert-butyl dicarbonate, and the obtained N-Boc-benzhydrylamine, first undergoes N-H hydrogen extraction reaction with sodium hydride in a solvent , generating the sodium salt intermediate of the amino group, and controlling the reaction temperature and the reaction time of the N-H hydrogen extraction reaction to generate the sodium salt intermediate of the amino group, and then carrying out the substitution reaction between the sodium salt intermediate of the amino group and 1,5-dibromopentane, Obtain intermediate-1 (formula INT-1), reaction formula is:

B) Synthesis of intermediate-2, the intermediate-1 obtained in step A) is mixed with zinc powder, lithium chloride, trimethylchlorosilane, 1,2-dibromoethane and tetrahydrofuran, and reacted to form a zinc bromide intermediate body, and control the reaction temperature and reaction time to generate the zinc bromide intermediate, then 3-{[2-(trimethylsilyl)ethoxy]methoxy}propionic acid methyl ester and the zinc The bromide intermediate is subjected to a substitution reaction in a tetrakis(triphenylphosphine) palladium and tetrahydrofuran system, and after acid deprotection, water washing, post-treatment and purification, intermediate-2 (formula INT-2) is obtained, and the reaction formula is:

C) to synthesize the finished product, the intermediate-2 obtained in step B) is subjected to a catalytic hydrogenation deprotection reaction to obtain the lipoic acid intermediate 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy Base} octane-3-one (formula 1), the reaction formula is:

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

In a further embodiment, the solvent described in step A) is N,N-dimethylformamide or N,N-dimethylacetamide; the diphenylmethylamine, sodium hydride, 1,5-di The molar ratio of bromopentane is 1.0:(1.5-2.0):(1.3-1.5).

In a further embodiment, the reaction temperature and reaction time of controlling the N-H hydrogen extraction reaction to form the sodium salt intermediate of the amino group in step A) are to control the reaction temperature and time to 0-25°C and 30min-1h, respectively.

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

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

In a further embodiment, the reaction temperature and reaction time for controlling the reaction to form the zinc bromide intermediate in step B) are to control the reaction temperature and time to 40-60° C. and 1-3 h, respectively.

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

In a further embodiment, the acid deprotection in step B) uses trifluoroacetic acid.

In a further embodiment, the method and conditions for the catalytic hydrogenation deprotection reaction in step C) are conventional methods and conditions for this type of reaction in the art.

The technical solution provided by the invention has the following technical effects: first, the process conditions are mild, and the purity of each intermediate is high, which is beneficial to the quality control and improvement of the raw material drug; Reasonable and environmentally friendly, it can be produced in large quantities to meet the needs of use, and is suitable for industrial production.

Detailed ways

The technical solution of the present invention will be described in further non-limiting detail below in conjunction with several preferred embodiments. The starting material 3-{[2-(trimethylsilyl)ethoxy]methoxy}propionate methyl ester can be obtained by Oxymethyl chloride can be obtained by ether synthesis.

In the following examples, the reference to Intermediate-1 is represented by Formula INT-1 and Intermediate-2 is represented by Formula INT-2.

Example 1:

A) Synthesis of Intermediate-1:

Diphenylmethylamine (5.0g, 27.3mmol) was dissolved in dichloromethane (80mL), triethylamine (6.0g, 59.3mmol) was added, cooled to 0°C, di-tert-butyl dicarbonate (6.0g, 27.5mmol) was added ), raised to 20°C and stirred for 12h, quenched with dropwise addition of water, added ethyl acetate (50mL), stirred for 5min, separated into layers, collected the organic phase, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, added N,N-di Methylformamide (50mL), cooled to 0°C, added 60% NaH (1.7g, 42.5mol), stirred at 0°C for 30min, added 1,5-dibromopentane (8.2g, 35.7mmol), reacted at 20°C 12h, add dropwise a mixture of ethyl acetate and saturated brine (50mL, 1:1) to quench, separate the layers, collect the organic phase, wash with brine, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, ethyl acetate-petroleum Recrystallization from an ether mixed solvent gave Intermediate-1, a white solid (10.4 g), with a yield of 88%. The reaction formula of this example (i.e. "this step", the same below) is as follows:

B) Synthesis of Intermediate-2:

In a 500mL reaction flask, add anhydrous tetrahydrofuran (40mL), under nitrogen protection and stirring at room temperature, add anhydrous lithium chloride (1.5g, 35.4mmol), zinc powder (4.6g, 70.3mmol), stir for 10min, add Add trimethylchlorosilane (0.13g, 1.2mmol) to a mixed solvent of 1,2-dibromoethane (4mL) and anhydrous tetrahydrofuran (20mL), heat up to 40°C and stir for 30min, cool down to room temperature, add the intermediate -1 (10.0g, 23.1mmol), the temperature of the reaction mixture was raised to 40°C for 3h, then cooled to room temperature, the insoluble matter was removed by suction filtration, the filtrate was collected, and tetrakis(triphenylphosphine)palladium (1.4g, 1.2mmol) was added, Stir at room temperature for 30min, add methyl 3-{[2-(trimethylsilyl)ethoxy]methoxy}propionate (5.4g, 23.0mmol) in anhydrous tetrahydrofuran solution (10mL), keep warm at 20°C for reaction 6h, add trifluoroacetic acid, stir for 30min, add dropwise 10% ammonium chloride aqueous solution, add dichloromethane for extraction, separate layers, collect the organic phase, wash with salt water, dry over anhydrous sodium sulfate, and rotary evaporate to dryness under reduced pressure, the crude product Purified by chromatographic column to obtain Intermediate-2 (9.5g) with a yield of 90%. The reaction formula of this embodiment is as follows:

C) The synthetic product is the lipoic acid intermediate 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one:

Intermediate-2 (9.1g, 20.0mmol) was dissolved in methanol (100mL), added with 10% palladium on carbon (0.10g, 0.9mmol), and reacted at 35°C for 8h under atmospheric pressure with hydrogen. The catalyst was removed by suction filtration through diatomaceous earth, and the filtrate was concentrated to dryness by rotary evaporation to obtain the finished product (5.1 g), with a yield of 88%. The reaction formula of this embodiment is as follows:

Example 2:

A) Synthesis of Intermediate-1:

Diphenylmethylamine (12.0g, 65.5mmol) was dissolved in dichloromethane (150mL), triethylamine (13.0g, 0.13mol) was added, cooled to 0°C, di-tert-butyl dicarbonate (15.0g, 68.7mmol) was added ), raised to 20°C and stirred for 12h, quenched with dropwise addition of water, added ethyl acetate (80mL), stirred for 5min, separated into layers, collected the organic phase, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, added N,N-di Methylformamide (100mL), cooled to 0°C, added 60% NaH (4.5g, 0.11mol), stirred at 10°C for 45min, added 1,5-dibromopentane (21.0g, 91.3mmol), reacted at 35°C 6h, add dropwise a mixture of ethyl acetate and saturated brine (100mL, 1:1) to quench, separate layers, collect the organic phase, wash with brine, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, ethyl acetate-petroleum Recrystallization from an ether mixed solvent gave Intermediate-1, a white solid (25.2 g), with a yield of 89%. The reaction formula of this step is the same as that of Example 1;

B) Synthesis of Intermediate-2:

In a 2L reaction flask, add anhydrous tetrahydrofuran (30mL), under nitrogen protection and stirring at room temperature, add anhydrous lithium chloride (6.0g, 0.14mol), zinc powder (22.0g, 0.34mol), stir for 10min, add Add trimethylchlorosilane (0.6g, 5.5mmol) to a mixed solvent of 1,2-dibromoethane (3mL) and anhydrous tetrahydrofuran (30mL), heat up to 60°C and stir for 30min, cool down to room temperature, add the intermediate -1 (25.0g, 57.8mmol), the temperature of the reaction mixture was raised to 60°C for 1h, then cooled to room temperature, the insolubles were removed by suction filtration, the filtrate was collected, tetrakis(triphenylphosphine)palladium (6.5g, 5.6mmol) was added, Stir at room temperature for 30min, add methyl 3-{[2-(trimethylsilyl)ethoxy]methoxy}propionate (13.6g, 58.0mmol) in anhydrous tetrahydrofuran solution (40mL), keep warm at 35°C for reaction 2h, add trifluoroacetic acid, stir for 30min, add dropwise 10% ammonium chloride aqueous solution, add dichloromethane for extraction, separate layers, collect the organic phase, wash with salt water, dry over anhydrous sodium sulfate, and rotary evaporate to dryness under reduced pressure, the crude product Purified by chromatographic column to obtain Intermediate-2 (23.8g), the yield is 90%, and the reaction formula is the same as that of Example 1;

Intermediate-2 (23.5g, 51.6mmol) was dissolved in isopropanol (300mL), added with 10% palladium on carbon (0.3g, 2.8mmol), and reacted at 35°C under normal pressure with hydrogen for 8h. The catalyst was removed by suction filtration through diatomaceous earth, and the filtrate was concentrated to dryness by rotary evaporation to obtain the finished product (14.0 g), with a yield of 94%, and the reaction formula was the same as in Example 1.

Example 3:

A) Synthesis of Intermediate-1:

Diphenylmethylamine (16.6g, 90.6mmol) was dissolved in dichloromethane (200mL), triethylamine (18.0g, 0.18mol) was added, cooled to 0°C, di-tert-butyl dicarbonate (20.0g, 91.6mmol) was added ), raised to 20°C and stirred for 12h, quenched with dropwise addition of water, added ethyl acetate (100mL), stirred for 5min, separated into layers, collected the organic phase, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, added N,N-di Methylacetamide (200mL), cooled to 0°C, added 60% NaH (7.0g, 0.18mol), stirred at 15°C for 1h, added 1,5-dibromopentane (29.0g, 0.13mol), reacted at 30°C 9h, add dropwise a mixture of ethyl acetate and saturated brine (500mL, 1:1) to quench, separate layers, collect the organic phase, wash with brine, dry over anhydrous sodium sulfate, concentrate to dryness under reduced pressure, ethyl acetate-petroleum Recrystallization from an ether mixed solvent gave Intermediate-1, a white solid (34.5 g), with a yield of 88%, and the reaction formula was the same as in Example 1;

B) Synthesis of Intermediate-2:

In a 2L reaction flask, add anhydrous tetrahydrofuran (100mL), under nitrogen protection and stirring at room temperature, add anhydrous lithium chloride (6.5g, 0.15mol), zinc powder (23.0g, 0.35mol), stir for 10min, add Add trimethylchlorosilane (0.6g, 5.5mmol) to a mixed solvent of 1,2-dibromoethane (3mL) and anhydrous tetrahydrofuran (30mL), heat up to 50°C and stir for 30min, cool down to room temperature, add the intermediate -1 (34.0g, 78.6mmol), the reaction mixture was warmed up to 50°C for 2h, cooled to room temperature, insolubles were removed by suction filtration, the filtrate was collected, tetrakis(triphenylphosphine)palladium (7.0g, 6.1mmol) was added, Stir at room temperature for 30min, add methyl 3-{[2-(trimethylsilyl)ethoxy]methoxy}propanoate (18.4g, 78.5mmol) in anhydrous tetrahydrofuran solution (80mL), keep warm at 30°C for reaction 4h, add trifluoroacetic acid, stir for 30min, add dropwise 10% ammonium chloride aqueous solution, add dichloromethane for extraction, separate layers, collect the organic phase, wash with salt water, dry over anhydrous sodium sulfate, and rotary evaporate to dryness under reduced pressure, the crude product Purified by column chromatography to obtain Intermediate-2 (32.0 g), with a yield of 89%, and the reaction formula is the same as that of Example 1;

Intermediate-2 (32.0g, 70.2mmol) was dissolved in ethanol (400mL), added with 10% palladium carbon (0.4g, 3.8mmol), and reacted at 35°C for 8h under normal pressure with hydrogen. The catalyst was removed by suction filtration through diatomaceous earth, and the filtrate was concentrated to dryness by rotary evaporation to obtain the finished product (19.0 g) with a yield of 93%. The reaction formula was the same as in Example 1.

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various equivalent transformations can be carried out to the technical solutions of the present invention. These equivalent transformations All belong to the protection scope of the present invention.

Claims

A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one is characterized in that comprising the steps:

A) Synthesis of intermediate-1, N-Boc protection on the reaction between benzhydrylamine and di-tert-butyl dicarbonate, and the obtained N-Boc-benzhydrylamine, first undergoes N-H hydrogen extraction reaction with sodium hydride in a solvent , generating the sodium salt intermediate of the amino group, and controlling the reaction temperature and the reaction time of the N-H hydrogen extraction reaction to generate the sodium salt intermediate of the amino group, and then carrying out the substitution reaction between the sodium salt intermediate of the amino group and 1,5-dibromopentane, Obtain intermediate-1, intermediate-1 is shown in the following formula:

B) Synthesis of intermediate-2, the intermediate-1 obtained in step A) is mixed with zinc powder, lithium chloride, trimethylchlorosilane, 1,2-dibromoethane and tetrahydrofuran, and reacted to form a zinc bromide intermediate body, and control the reaction temperature and reaction time to generate the zinc bromide intermediate, then 3-{[2-(trimethylsilyl)ethoxy]methoxy}propionic acid methyl ester and the zinc The bromide intermediate is subjected to a substitution reaction in a tetrakis(triphenylphosphine) palladium and tetrahydrofuran system, and after acid deprotection, water washing, post-treatment and purification, intermediate-2 is obtained, and intermediate-2 is shown in the following formula:

C) to synthesize the finished product, the intermediate-2 obtained in step B) is subjected to a catalytic hydrogenation deprotection reaction to obtain the lipoic acid intermediate 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy Base} octane-3-one.
A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one according to claim 1, characterized in that, step A ) is N,N-dimethylformamide or N,N-dimethylacetamide; the molar ratio of benzhydrylamine, sodium hydride, and 1,5-dibromopentane is 1.0: (1.5-2.0): (1.3-1.5).
A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one according to claim 1, characterized in that, step A ) is N,N-dimethylformamide or N,N-dimethylacetamide; the molar ratio of benzhydrylamine, sodium hydride, and 1,5-dibromopentane is 1.0: (1.5-2.0): (1.3-1.5).
A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one according to claim 1, characterized in that, step A ) said substitution reaction temperature is 20-35 ° C, the reaction time is 6-12h.
A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one according to claim 1, characterized in that step B ) in intermediate-1, 3-{[2-(trimethylsilyl)ethoxy]methoxy}methyl propionate, zinc powder, lithium chloride, trimethylchlorosilane, tetrakis( The molar ratio of triphenylphosphine) palladium is 1.0: 1.0: (3.0-6.0): (1.5-2.5): (0.05-0.1): (0.05-0.1).
A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one according to claim 1, characterized in that step B ) to control the reaction temperature and reaction time to generate the zinc bromide intermediate is to control the reaction temperature and time to 40-60° C. and 1-3 h, respectively.
A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one according to claim 1, characterized in that step B ) said substitution reaction temperature is 20-35 ° C, the reaction time is 2-6h.
A kind of synthetic method of 8-amino-1-{[2-(trimethylsilyl)ethoxy]methoxy}octane-3-one according to claim 1, characterized in that step B ) described in acid deprotection is the use of trifluoroacetic acid.