Ethyl 6,8-dichlorooctanoate is a key intermediate for the preparation of lipoic acid starting from adipic acid. Ethyl 6,8-dichlorooctanoate is prepared by chlorination of ethyl 6-hydroxy-8-chlorooctanoate. Lipoic acid has a strong antioxidant capacity, mainly in the country for the treatment of diabetic peripheral neuropathy; in addition to drugs as a foreign country, but also as a dietary supplement and cosmetics raw materials widely used.

Synthesis from 6-hydroxy-Chloro-octanoic acid ethyl ester

6-Hydroxy-8-chlorooctanoate Ethyl chloride 6,8-dichlorooctanoate There are a variety of processes. As reported in the literature [Zhuranl Obshchei Khimii, 1964,34,3662], it was reported that 6-hydroxy-8-chlorooctanoic acid ethyl ester was reacted with thionyl chloride in benzene in refluxing for 1 hour in the presence of a catalytic amount of pyridine to prepare 6,8- Ethyl dichlorooctanoate, benzene as a solvent used strictly in the country, the above process does not have the possibility of commercial production. The more mature production process is ethyl 6-hydroxy-8-chloro-octanoate dissolved in DMF, ice bath, with stirring under the thionyl chloride solution of organic solvents, dropping slowly warming, the reaction for several hours, after neutralization. To give ethyl 6,8-dichlorooctanoate. Patent ZL200710156217.1 discloses a chemical synthesis of ethyl 6,8-dichlorooctanoate is prepared by dissolving 6-hydroxy-8-chlorooctanoic acid ethyl ester in DMF under ice-cooling with stirring. Bis (Trichloromethyl) carbonate in an organic solvent solution, dropping slowly warmed to 50 ° C ~ 90 ° C for 2 to 8 hours, the reaction was completed and the reaction solution was lye alkali ethyl 6,8-dichlorooctanoate.[1]

We hope that by looking for other ways to promote the progress of the reaction, in particular, to circumvent the pyridine, DMF, triethylamine catalyst to avoid the generation of refractory industrial wastewater containing the above components. Therefore, it is necessary to seek a new preparation method of ethyl 6,8-dichlorooctanoate to achieve the purpose of simplifying operation, reducing environmental pollution and reducing the production cost. It is necessary to promote the production of ethyl 6,8-dichlorooctanoate and even lipoic acid The economic and technological development has an important practical significance.

Under ice-water bath conditions, ethyl 6-hydroxy-8-chlorooctanoate was slowly added dropwise into an organic solvent dissolved in thionyl chloride or bis (trichloromethyl) carbonate while bubbling through the drying gas, 2 ~ 6 hours after the completion of the drop, and then warmed to 30 ~ 35 ℃, incubated for 1 to 2 hours, then warmed to 90 ~ 110 ℃, stop bubbling, incubated for 1 to 2 hours after the reaction was completed with alkaline solution to neutralization Sexually, the solvents were distilled off under atmospheric pressure and distilled in vacuo to give ethyl 6,8-dichlorooctanoate.

Synthesis from 7-hydroxyheptanal

Lipoic acid belongs to a class of compounds in the B vitamins. It acts as a coenzyme in the multi-enzyme system. It is a class of antioxidants. Its antioxidant effect is better than that of vitamins. It can eliminate free radicals that accelerate aging and disease; it can improve diabetics Insulin function and heart rate variability; treat hepatitis C; protect kidneys and pancreas; prevent cataracts; inhibit HIV proliferation. Ethyl 6,8-dichlorooctanoate is an important organic intermediate for the synthesis of lipoic acid. At present, the methods for synthesizing ethyl 6,8-dichlorooctanoate mainly include adipic acid route and cyclohexanone route. Xi Ruoming and others introduced the process of synthesizing methyl 6,8-dichlorooctanoate through methyl esterification, chlorination, ethylene addition, reductive chlorination and other steps of adipic acid (as shown in the following reaction formula). The reaction process will produce a lot of Solid waste and liquid waste are easy to generate polymers and are difficult to separate. Another route uses cyclohexanone and vinyl ethyl ether as raw materials. CN 107673972 discloses a method for synthesizing ethyl 6,8-dichlorooctanoate with cyclohexanone and vinyl ethyl ether as raw materials (as shown in the following reaction formula Show). The starting materials of this route are easy to obtain, and it is a synthetic route with industrialization potential, but there are relatively many by-products. [2]

The purpose of the present invention is to provide a method for preparing ethyl 6,8-dichlorooctanoate, which has the characteristics of easy availability of raw materials, simple process, high efficiency, and environmental protection. According to one aspect of the present invention, there is provided a method for preparing ethyl 6,8-dichlorooctanoate, the method comprising the following steps: As shown in the above reaction formula, compound 1 undergoes oxidative esterification to obtain compound 2, and then undergoes dehydration to produce compound 3, then undergoes Prins condensation reaction to obtain compound 4, then undergoes hydrolysis and hydrogenation to obtain compound 5, and finally undergoes chlorination to obtain 6,8 -Ethyl dichlorooctanoate.

Add 85ml of thionyl chloride in the flask, stir, slowly add 77g of compound 5 dropwise to it, and finish the dropwise addition in about 2 hours. Use alkali to absorb the gas generated during the dropping process. After the dripping was completed, it was heated to 80°C and refluxed for 2h, and 78g of ethyl 6,8-dichlorooctanoate (2mmHg, 124-127°C) was obtained by distillation. The molar yield was 87%.

Synthesis from 7-(2-hydroxyethyl)hex-2-lactone (II)

In order to overcome the defects of high raw material price, high production cost, three wastes, complicated operation and unsuitable for industrial production in the prior art method for preparing ethyl 6,8-dichlorooctanoate, the present invention provides a new synthetic method. The method for ethyl 6,8-dichlorooctanoate, which can obtain 6,8-dichlorooctanoate with cheap reaction raw materials, mild reaction conditions and high yield, and has industrial production feasibility and economy . Specifically, the present invention includes the following technical solutions. The invention provides a new chemical synthesis route of 6,8-dichlorooctanoate. In the method, the raw material cyclohexanone is cheap and easy to obtain, the reaction conditions are mild, the three wastes produced are less, the operation is simple, and the industrialization Mass production feasibility.[3]

5g of 7-(2-hydroxyethyl)hex-2-lactone (II) was added to 30mL of ethanol, cooled to 10°C, 11.2g of thionyl chloride was added dropwise, the temperature was raised to 50°C and the reaction was completed for 3 hours. , the system was concentrated to dryness, 50 mL of dichloromethane was added, washed once with 5% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain ethyl 6,8-dichlorooctanoate (I) 5.9 g, yield 78%.

References

[1]SUZHOU FUSHILAI PHARMACEUTICAL - CN105693510, 2016, A

[2]QINGDAO HUAHE PHARMACEUTICAL TECH - CN112479878, 2021, A

[3]FENGHUOLUN SHANGHAI BIOTECHNOLOGY - CN113773182, 2021, A