阅读说明：本技术 一种硫辛酸衍生物8-（乙基二硫烷基）-6-（苯基二硫烷基）辛酸的制备方法 (Preparation method of lipoic acid derivative 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid ) 是由 莫国宁 钱祥云 于 2019-09-26 设计创作，主要内容包括：一种硫辛酸衍生物8-(乙基二硫烷基)-6-(苯基二硫烷基)辛酸的制备方法,属于药物化学合成技术领域。步骤：将6-巯基-8-(三苯甲硫基)辛酸与N-(苯硫基)邻苯二甲酰亚胺在溶剂体系中进行第一二硫醚化反应,得到6-(苯基二硫烷基)-8-(三苯甲硫基)辛酸；将6-(苯基二硫烷基)-8-(三苯甲硫基)辛酸在三乙基硅烷和酸的条件下进行脱保护反应,得到8-巯基-6-(苯基二硫烷基)辛酸；将8-巯基-6-(苯基二硫烷基)辛酸与乙硫醇在卤素和无机碱溶液体系中进行第二二硫醚化反应,得到成品。工艺操作简单,降低成本；工艺路线简洁,副反应可控,杂质较少,无污染物产生,体现绿色环保效果。(A preparation method of lipoic acid derivative 8- (ethyl disulfanyl) -6- (phenyl disulfanyl) octanoic acid, belonging to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: 6-mercapto-8- (tritylthio) octanoic acid and N- (phenylthio) phthalimide are subjected to a first disulfide etherification reaction in a solvent system to obtain 6- (phenyl disulfanyl) -8- (tritylthio) octanoic acid; carrying out deprotection reaction on 6- (phenyl disulfanyl) -8- (tritylthio) octanoic acid under the conditions of triethylsilane and acid to obtain 8-mercapto-6- (phenyl disulfanyl) octanoic acid; carrying out second disulfide reaction on 8-mercapto-6- (phenyl disulfanyl) octanoic acid and ethanethiol in a halogen and inorganic alkali solution system to obtain a finished product. The process is simple to operate, and the cost is reduced; the 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.)

1. A preparation method of lipoic acid derivative 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid is characterized by comprising the following steps:

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

6-mercapto-8- (tritylthio) octanoic acid and N- (phenylthio) phthalimide are subjected to a first thioetherification reaction in a solvent system to obtain 6- (phenyl disulfanyl) -8- (tritylthio) octanoic acid;

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

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

C) preparation of 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid:

carrying out a second disulfide reaction on the 8-mercapto-6- (phenyl disulfanyl) octanoic acid obtained in the step B) and ethanethiol in a halogen and inorganic alkali solution system to obtain the lipoic acid derivative 8- (ethyl disulfanyl) -6- (phenyl disulfanyl) octanoic acid.

2. The method of claim 1, wherein the solvent used in step a) is toluene, methyl tert-butyl ether, N-dimethylformamide, or N, N-dimethylacetamide.

3. The process of claim 1, wherein the molar ratio of 6-mercapto-8- (tritylthio) octanoic acid to N- (phenylthio) phthalimide in step A) is 1.0: 1.1 ~ 1.5.5.

4. The process for preparing lipoic acid derivative 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid in accordance with claim 1, wherein the temperature of the first disulfylation reaction in step A) is 50 ~ 80 ℃ and the reaction time is 20 ~ 36 h.

5. The method of claim 1, wherein the acid in step B) is acetic acid, trifluoroacetic acid, oxalic acid, formic acid, or propionic acid.

6. The method of claim 1, wherein the molar ratio of 6- (phenyldisulfanyl) -8- (tritylthio) octanoic acid to triethylsilane in step B) is 1.0: 2.0 ~ 2.5.5.

7. The method of claim 1, wherein the temperature of the deprotection reaction in step B) is 20 ~ 35 ℃ and the reaction time is 30 ~ 60 min.

8. The method of claim 1, wherein the molar ratio of 8-mercapto-6- (phenyldisulfanyl) octanoic acid, ethanethiol, halogen and inorganic base in step C) is 1.0: 1.5 ~ 2.0.0: 2.5 ~ 3.5.5: 3.5 ~ 4.5.5.

9. The method of claim 1 or 8, wherein the halogen is Br, for the preparation of lipoic acid derivative 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid₂Or I₂(ii) a The inorganic base is NaOH, KOH or K₂CO₃Or Na₂CO₃。

10. The process for the preparation of lipoic acid derivative 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid according to claim 1, characterised in that the second disulphide reaction in step C) is carried out at a temperature of 0 ~ 15 ℃ and for a time of 1 ~ 3 h.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of a lipoic acid derivative 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) 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 also shows some preparation methods for preparing thioctic acid derivatives of sulfide and disulfide structure series varieties, wherein the preparation of the disulfide structure needs to prepare a dipyridyl disulfide activating reagent (2, 2' -dipyridylidesulfuloside) in advance, the process is complicated, and the application and scale-up production are limited.

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 the preparation method of the lipoic acid derivative 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid comprises the following steps:

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

6-mercapto-8- (tritylthio) octanoic acid and N- (phenylthio) phthalimide are subjected to a first thioetherification reaction in a solvent system to obtain 6- (phenyl disulfanyl) -8- (tritylthio) octanoic acid;

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

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

C) preparation of 8- (ethyldisulfanyl) -6- (phenyldisulfanyl) octanoic acid:

carrying out a second disulfide reaction on the 8-mercapto-6- (phenyl disulfanyl) octanoic acid obtained in the step B) and ethanethiol in a halogen and inorganic alkali solution system to obtain the lipoic acid derivative 8- (ethyl disulfanyl) -6- (phenyl disulfanyl) octanoic acid.

In a particular embodiment of the invention, the solvent in step a) is toluene, methyl tert-butyl ether, N-dimethylformamide or N, N-dimethylacetamide.

In another specific embodiment of the present invention, the molar ratio of the 6-mercapto-8- (tritylthio) octanoic acid to the N- (phenylthio) phthalimide in step A) is 1.0: 1.1 to 1.5.

In another embodiment of the present invention, the temperature of the first thioetherification reaction in step a) is 50 to 80 ℃, and the reaction time is 20 to 36 hours.

In a further particular embodiment of the invention, the acid in step B) is acetic acid, trifluoroacetic acid, oxalic acid, formic acid or propionic acid.

In still another embodiment of the present invention, the molar ratio of 6- (phenyldisulfanyl) -8- (tritylthio) octanoic acid to triethylsilane in step B) is 1.0: 2.0 to 2.5.

In a more specific embodiment of the present invention, the temperature of the deprotection reaction in step B) is 20 to 35 ℃, and the reaction time is 30 to 60 min.

In a further specific embodiment of the present invention, the molar ratio of the 8-mercapto-6- (phenyldisulfanyl) octanoic acid, ethanethiol, halogen and inorganic base in step C) is 1.0: 1.5-2.0: 2.5-3.5: 3.5-4.5.

In yet a more particular embodiment of the invention, the halogen is Br₂Or I₂(ii) a The inorganic base is NaOH, KOH or K₂CO₃Or Na₂CO₃。

In yet another specific embodiment of the present invention, the temperature of the second disulfide reaction in step C) is 0 to 15 ℃ and the reaction time is 1 to 3 hours.

The technical scheme of the invention has the following beneficial effects:

(1) the two-time disulfide reaction is mild, the process operation is simple, the use of expensive raw materials is avoided, and the cost is reduced.

(2) 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.

(3) 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.