阅读说明：本技术 一种硫辛酸衍生物6-(苄基硫基)-8-[(羟基苯基甲基)硫基]辛酸的制备方法 (Preparation method of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid ) 是由 吴磊 赵雪锋 石晓青 曾陵 于 2021-10-28 设计创作，主要内容包括：本发明公开了一种硫辛酸衍生物6-(苄基硫基)-8-[(羟基苯基甲基)硫基]辛酸的制备方法,将6-巯基-8-(三苯甲硫基)辛酸与氯化苄反应,得到6-(苄基硫基)-8-(三苯甲硫基)辛酸；将6-(苄基硫基)-8-(三苯甲硫基)辛酸反应,得到8-巯基-6-(苄基硫基)辛酸；将8-巯基-6-(苄基硫基)辛酸与三甲基氯硅烷反应,得到6-(苄基硫基)-8-[(三甲基硅基)硫基]辛酸；将6-(苄基硫基)-8-[(三甲基硅基)硫基]辛酸与苯甲醛在溶剂体系中反应,得到的中间体最后得到成品。操作简单,工艺路线简洁,副反应可控,杂质较少,无污染物产生。(The invention discloses a preparation method of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] caprylic acid, which comprises the steps of reacting 6-mercapto-8- (triphenylmethylthio) caprylic acid with benzyl chloride to obtain 6- (benzylthio) -8- (triphenylmethylthio) caprylic acid; reacting 6- (benzylthio) -8- (triphenylmethylthio) octanoic acid to obtain 8-mercapto-6- (benzylthio) octanoic acid; reacting 8-mercapto-6- (benzylthio) octanoic acid with trimethylchlorosilane to obtain 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid; 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid and benzaldehyde react in a solvent system to obtain an intermediate, and a finished product is finally obtained. Simple operation, simple process route, controllable side reaction, less impurities and no pollutant generation.)

1. A preparation method of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid is characterized by comprising the following steps:

A) preparation of 6- (benzylthio) -8- (tritylthio) octanoic acid:

carrying out thioetherification reaction on 6-mercapto-8- (tritylthio) octanoic acid and benzyl chloride in a system of alkali and a solvent to obtain 6- (benzylthio) -8- (tritylthio) octanoic acid;

B) preparation of 8-mercapto-6- (benzylthio) octanoic acid:

carrying out deprotection reaction on the 6- (benzylthio) -8- (triphenylmethylthio) octanoic acid obtained in the step A) under the conditions of triethylsilane and acid to obtain 8-mercapto-6- (benzylthio) octanoic acid;

C) preparation of 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid:

carrying out silanization reaction on the 8-mercapto-6- (benzylthio) caprylic acid obtained in the step B) and trimethylchlorosilane in an acid-binding agent alkali and solvent system to obtain 6- (benzylthio) -8- [ (trimethylsilyl) thio ] caprylic acid;

D) preparation of 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid:

performing addition reaction on the 6- (benzylthio) -8- [ (trimethylsilyl) thio ] caprylic acid obtained in the step C) and benzaldehyde in a solvent system, and then performing acidolysis deprotection on an obtained adduct intermediate to obtain the 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] caprylic acid.

2. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterized by the fact that: the alkali in the step A) is sodium methoxide, sodium ethoxide or sodium isopropoxide; the solvent is methanol, ethanol or isopropanol;

the molar ratio of the 6-mercapto-8- (tritylthio) octanoic acid to the benzyl chloride to the alkali is 1.0: 1.1-1.3: 1.5-2.0.

3. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterized by the fact that: the temperature of the thioetherification reaction in the step A) is 25-80 ℃, and the reaction time is 6-12 h.

4. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterized by the fact that: the acid in the step B) is acetic acid, trifluoroacetic acid, oxalic acid, formic acid or propionic acid; the molar ratio of the 6- (benzylthio) -8- (triphenylmethylthio) octanoic acid to the triethylsilane is 1.0: 2.0-2.5.

5. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterised in that; the temperature of the deprotection reaction in the step B) is 20-35 ℃, and the reaction time is 30-60 min.

6. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterised in that; the acid-binding agent base in the step C) is triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine or 2, 6-dimethylpyridine; the solvent is dichloromethane, chloroform or 1, 2-dichloroethane;

the molar ratio of the 8-mercapto-6- (benzylthio) octanoic acid to the trimethylchlorosilane to the acid-binding agent alkali is 1.0 to 1.5 to 1.4 to 2.0.

7. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterized by the fact that: the temperature of the silanization reaction in the step C) is 20-35 ℃, and the reaction time is 2-6 h.

8. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterized by the fact that:

the solvent in the step D) is methanol, ethanol, isopropanol, dichloromethane, 1, 2-dichloroethane, chloroform or toluene; the molar ratio of the 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid to the benzaldehyde is 1.0: 1.5-2.0.

9. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterized by the fact that:

the temperature of the addition reaction in the step D) is 30-60 ℃, and the reaction time is 6-12 h.

10. The process for the preparation of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid, according to claim 1, characterized by the fact that: and D), carrying out acidolysis deprotection, acidifying with a 6N hydrochloric acid solution at 20-30 ℃ to reach pH =2, and stirring for 1 h.

Technical Field

The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] caprylic acid.

Background

Lipoic acid (α -Lipoic acid) is a natural product with biological activity and was first isolated from pig liver by Reed in 1951. Lipoic acid is widely used in the fields of clinical medicine in Europe and America, such as treatment of liver diseases, Alzheimer's disease, diabetes, cancer, cataract, heart diseases, Parkinson's disease, AIDS, psoriasis, eczema, rheumatism, heart diseases, neurological diseases, subacute necrotic encephalopathy, radiation injury, heavy metal poisoning and the like, and is known as an 'universal antioxidant'. With the intensive research and development of the pharmacology and pharmacodynamics of the lipoic acid, researchers in the medical field apply and develop various lipoic acid derivatives and salts thereof, and the adaptation disease range and the treatment effect of lipoic acid series products are greatly enriched and expanded so as to meet the requirements of medical clinics and markets.

Patent WO2008131117a1 discloses lipoic acid derivatives and salts thereof, including ring-opened thioether and disulfide structures (formula II, III), which can be used as composition components of pharmaceutical preparations for treating various diseases related to the above, such as diabetes, alzheimer's disease, cancer, etc. Lipoic acid and its derivatives maintain the availability of the redox transition from SH to S-S due to their redox potential characteristics to have the desired antioxidant effect.

In the formula R₁、R₂Various substituents, which may be the same or different, or one of which is a substituent and the other is unsubstituted. The patent does not disclose specific examples of the preparation method or process for a plurality of thioctic acid derivative thioether and disulfide structure series varieties.

Disclosure of Invention

Aiming at the defects and limitations in the prior art, the invention aims to provide a novel preparation method of lipoic acid derivatives, which has the advantages of simple process, mild preparation conditions, cheap and easily available raw materials, capability of meeting the requirements of the enlarged production of the lipoic acid derivatives and capability of reflecting excellent green and environment-friendly effects.

The invention aims to achieve the aim that a preparation method of lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid comprises the following steps:

A) preparation of 6- (benzylthio) -8- (tritylthio) octanoic acid:

carrying out thioetherification reaction on 6-mercapto-8- (tritylthio) octanoic acid and benzyl chloride in an alkali and solvent system to obtain 6- (benzylthio) -8- (tritylthio) octanoic acid;

B) preparation of 8-mercapto-6- (benzylthio) octanoic acid:

carrying out deprotection reaction on the 6- (benzylthio) -8- (triphenylmethylthio) octanoic acid obtained in the step A) under the conditions of triethylsilane and acid to obtain 8-mercapto-6- (benzylthio) octanoic acid;

C) preparation of 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid:

carrying out silanization reaction on the 8-mercapto-6- (benzylthio) caprylic acid obtained in the step B) and trimethylchlorosilane in an acid-binding agent alkali and solvent system to obtain 6- (benzylthio) -8- [ (trimethylsilyl) thio ] caprylic acid;

D) preparation of 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid:

performing addition reaction on the 6- (benzylthio) -8- [ (trimethylsilyl) thio ] caprylic acid obtained in the step C) and benzaldehyde in a solvent system, and then performing acidolysis deprotection on an obtained adduct intermediate to obtain the 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] caprylic acid.

In further embodiments, the base in step a) is sodium methoxide, sodium ethoxide, or sodium isopropoxide; the solvent is methanol, ethanol or isopropanol; the molar ratio of the 6-mercapto-8- (tritylthio) octanoic acid to the benzyl chloride to the alkali is 1.0: 1.1-1.3: 1.5-2.0.

In a further embodiment, the temperature of the thioetherification reaction in the step A) is 25-80 ℃, and the reaction time is 6-12 hours.

In further embodiments, the acid described in step B) is acetic acid, trifluoroacetic acid, oxalic acid, formic acid, or propionic acid; the molar ratio of the 6- (benzylthio) -8- (triphenylmethylthio) octanoic acid to the triethylsilane is 1.0: 2.0-2.5.

In a further embodiment, the temperature of the deprotection reaction in the step B) is 20-35 ℃, and the reaction time is 30-60 min.

In a further embodiment, the acid-binding agent base in step C) is triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine or 2, 6-lutidine; the solvent is dichloromethane, chloroform or 1, 2-dichloroethane; the molar ratio of the 8-mercapto-6- (benzylthio) octanoic acid to the trimethylchlorosilane to the acid-binding agent alkali is 1.0 to 1.5 to 1.4 to 2.0.

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

In further embodiments, the solvent described in step D) is methanol, ethanol, isopropanol, dichloromethane, 1, 2-dichloroethane, chloroform or toluene; the molar ratio of the 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid to the benzaldehyde is 1.0: 1.5-2.0.

In a further embodiment, the temperature of the addition reaction in the step D) is 30-60 ℃, and the reaction time is 6-12 h.

In a further embodiment, the acidolysis deprotection described in step D) is acidified with 6N hydrochloric acid solution at 20-30 ℃ to pH =2 and stirred for 1 h.

Has the advantages that: (1) the thioetherification reaction is mild, the process operation is simple, the use of expensive raw materials is avoided, and the cost is reduced.

(2) The two deprotection reactions have simple process and lower cost.

(3) The whole process route is simple, the side reaction is controllable, the impurities are less, no pollutant is generated, and the green and environment-friendly effect is embodied.

(4) The initial raw materials and the used reagents are easy to obtain, can be produced in large scale to meet the use requirements of the raw material medicaments, 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.

Example 1

A) Preparation of 6- (benzylthio) -8- (tritylthio) octanoic acid:

dissolving 6-mercapto-8- (tritylthio) octanoic acid (20.0 g, 44.4 mmol) and benzyl chloride (6.2 g, 48.8 mmol) in methanol (200 mL), dropwise adding a methanol solution of sodium methoxide (66.6 mmol, 40 mL), reacting at 25 ℃ for 1h, then heating to 60 ℃ for 12h, after the reaction is finished, carrying out reduced pressure rotary evaporation to dryness, extracting dichloromethane, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent to obtain 6- (benzylthio) -8- (tritylthio) octanoic acid as a white solid (20.5 g), wherein the yield is 85%, and the thioetherification reaction in the step has the following reaction formula:

。

B) preparation of 8-mercapto-6- (benzylthio) octanoic acid:

dissolving 6- (benzylthio) -8- (triphenylmethylthio) octanoic acid (20.0 g, 37.0 mmol) in acetic acid (200 mL), slowly adding triethylsilane (8.6 g, 74.0 mmol), keeping the temperature at 20 ℃ for reaction for 1h, after the reaction is finished, removing insoluble matters by suction filtration, collecting filtrate, carrying out reduced pressure rotary evaporation to dryness, and recrystallizing a crude product by using an ethyl acetate-petroleum ether mixed solvent to obtain 8-mercapto-6- (benzylthio) octanoic acid as an off-white solid (9.5 g), wherein the yield is 86%, and the deprotection reaction formula in the step is as follows:

。

C) preparation of 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid:

dissolving 8-mercapto-6- (benzylthio) octanoic acid (9.0 g, 30.2 mmol) and triethylamine (4.3 g, 42.2 mol) in dichloromethane (100 mL), cooling to 10 ℃, dropwise adding a dichloromethane (10 mL) solution of trimethylchlorosilane (3.3 g, 30.2 mol), keeping the temperature for reaction at 20 ℃ for 6h, dropwise adding water to quench the reaction solution after the reaction is finished, decompressing and concentrating to remove the organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, decompressing and rotary-steaming to dryness, recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent, and drying in vacuum to obtain 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid (10.0 g), wherein the yield is 90%, and the reaction formula of the silylation reaction in the step is as follows:

。

D) preparation of 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid:

dissolving 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid (10.0 g, 27.0 mmol) and benzaldehyde (4.3 g, 40.5 mol) in ethanol (100 mL), keeping the temperature at 30 ℃ for 12h, acidifying with 6N hydrochloric acid solution at 20 ℃ to pH =2, stirring for 1h, extracting with dichloromethane, layering, washing an organic phase with brine, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, and recrystallizing a crude product with an ethyl acetate-petroleum ether mixed solvent to obtain 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid as a white solid (9.4 g) with 86% yield, wherein the reaction formula of the addition reaction and the acidolysis deprotection reaction in the step is as follows:

wherein I is the lipoic acid derivative 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid.

Example 2

A) Preparation of 6- (benzylthio) -8- (tritylthio) octanoic acid:

6-mercapto-8- (tritylthio) octanoic acid (45.0 g, 0.10 mol) and benzyl chloride (15.0 g, 0.12 mol) are dissolved in ethanol (500 mL), an ethanol solution of sodium ethoxide (0.18 mol, 50 mL) is added dropwise to react for 1h at 25 ℃, then the temperature is increased to 75 ℃ to react for 9h, after the reaction is finished, reduced pressure rotary evaporation is carried out to dryness, dichloromethane is used for extraction, salt water is used for washing, anhydrous sodium sulfate is used for drying, reduced pressure rotary evaporation is carried out to dryness, and the crude product is recrystallized by an ethyl acetate-petroleum ether mixed solvent to obtain 6- (benzylthio) -8- (tritylthio) octanoic acid as a white solid (47.5 g) with the yield of 88%.

B) Preparation of 8-mercapto-6- (benzylthio) octanoic acid:

6- (benzylthio) -8- (tritylthio) octanoic acid (47.0 g, 86.9 mmol) was dissolved in trifluoroacetic acid (500 mL), triethylsilane (22.0 g, 0.19 mol) was slowly added thereto, the reaction was carried out at 25 ℃ for 40min, after the completion of the reaction, insoluble matter was removed by suction filtration, the filtrate was collected, evaporated to dryness under reduced pressure, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 8-mercapto-6- (benzylthio) octanoic acid as an off-white solid (23.0 g) in 89% yield.

C) Preparation of 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid:

dissolving 8-mercapto-6- (benzylthio) octanoic acid (23.0 g, 77.1 mmol) and pyridine (10.0 g, 0.13 mol) in chloroform (300 mL), cooling to 10 ℃, dropwise adding a chloroform (300 mL) solution of trimethylchlorosilane (10.0 g, 92.0 mmol), keeping the temperature at 30 ℃ for reaction for 4 hours, dropwise adding water to quench the reaction solution after the reaction is finished, decompressing and concentrating to remove an organic solvent, adding dichloromethane for extraction, washing with salt water, drying with anhydrous sodium sulfate, decompressing and rotary-steaming to dryness, recrystallizing a crude product with an ethyl acetate-petroleum ether mixed solvent, and drying in vacuum to obtain 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid (26.0 g) with the yield of 91%.

D) Preparation of 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid:

6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid (26.0 g, 70.1 mmol), benzaldehyde (13.0 g, 0.12 mol) were dissolved in 1, 2-dichloroethane (400 mL), reacted at 50 ℃ for 8 hours, acidified to pH =2 with 6N hydrochloric acid solution at 25 ℃, stirred for 1 hour, extracted with dichloromethane, separated into layers, the organic phase was washed with brine, dried over anhydrous sodium sulfate, rotary evaporated to dryness under reduced pressure, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid as a white solid (25.0 g) in 88% yield.

What is not mentioned in this example is the same as that described in example 1.

Example 3

A) Preparation of 6- (benzylthio) -8- (tritylthio) octanoic acid:

6-mercapto-8- (tritylthio) octanoic acid (55.0 g, 0.12 mol), benzyl chloride (20.0 g, 0.16 mol) are dissolved in isopropanol (600 mL), isopropanol solution of sodium isopropoxide (0.24 mol, 50 mL) is added dropwise to react for 1h at 25 ℃, then the temperature is increased to 80 ℃ to react for 6h, after the reaction is finished, reduced pressure rotary evaporation is carried out till dryness, dichloromethane is extracted, salt water is washed, anhydrous sodium sulfate is dried, reduced pressure rotary evaporation is carried out till dryness, and the crude product is recrystallized by an ethyl acetate-petroleum ether mixed solvent to obtain 6- (benzylthio) -8- (tritylthio) octanoic acid as a white solid (60.0 g) with the yield of 91%.

B) Preparation of 8-mercapto-6- (benzylthio) octanoic acid:

dissolving 6- (benzylthio) -8- (triphenylmethylthio) octanoic acid (60.0 g, 0.11 mol) in oxalic acid (600 mL), slowly adding triethylsilane (32.0 g, 0.28 mol), keeping the temperature at 35 ℃ for reaction for 30min, after the reaction is finished, removing insoluble substances by suction filtration, collecting filtrate, decompressing and rotary-steaming to dryness, and recrystallizing a crude product by using an ethyl acetate-petroleum ether mixed solvent to obtain 8-mercapto-6- (benzylthio) octanoic acid as an off-white solid (30.0 g), wherein the yield is 91%.

C) Preparation of 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid:

dissolving 8-mercapto-6- (benzylthio) octanoic acid (30.0 g, 0.10 mol) and N, N-diisopropylethylamine (26.0 g, 0.20 mol) in 1, 2-dichloroethane (500 mL), cooling to 10 ℃, dropwise adding a1, 2-dichloroethane (50 mL) solution of trimethylchlorosilane (16.0 g, 0.15 mol), keeping the temperature at 35 ℃ for reaction for 2 hours, dropwise adding water to quench the reaction solution after the reaction is finished, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane for extraction, washing with common salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing the crude product with an ethyl acetate-petroleum ether mixed solvent, and carrying out vacuum drying to obtain 6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid (35.0 g) with the yield of 94%.

D) Preparation of 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid:

6- (benzylthio) -8- [ (trimethylsilyl) thio ] octanoic acid (35.0 g, 94.4 mmol), benzaldehyde (20.0 g, 0.19 mmol) were dissolved in toluene (500 mL), reacted at 60 ℃ for 6 hours, acidified with 6N hydrochloric acid solution at 30 ℃ to pH =2, stirred for 1 hour, extracted with dichloromethane, separated, the organic phase was washed with brine, dried over anhydrous sodium sulfate, rotary evaporated to dryness under reduced pressure, and the crude product was recrystallized from an ethyl acetate-petroleum ether mixed solvent to give 6- (benzylthio) -8- [ (hydroxyphenylmethyl) thio ] octanoic acid as a white solid (34.8 g) in 91% yield.

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.