A process for the preparation of ethyl 6,8-dichlorooctanoate

Abstract

This invention provides a method for preparing ethyl 6,8-dichlorooctanoate, belonging to the field of organic synthesis technology. The preparation method of this invention includes the following steps: (1) ethyl 8-chloro-6-oxooctanoate and ammonium formate are mixed in an organic solvent and subjected to catalytic transfer hydrogenation in the presence of a catalyst to selectively reduce the carbonyl functional group to a hydroxyl group, yielding ethyl 6-hydroxy-8-chlorooctanoate; (2) ethyl 6-hydroxy-8-chlorooctanoate is reacted with methanesulfonyl chloride to generate a methanesulfonate intermediate; the methanesulfonate intermediate undergoes a substitution reaction with lithium chloride in an organic solvent, converting the hydroxyl functional group to a chlorine group, to obtain ethyl 6,8-dichlorooctanoate. This invention provides a method for preparing ethyl 6,8-dichlorooctanoate, replacing the traditional carbonyl reduction and hydroxyl chlorination steps, improving reaction safety and environmental friendliness, and facilitating industrialization.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing ethyl 6,8-dichlorooctanoate. Background Technology

[0002] Ethyl 6,8-dichlorooctanoate is an essential intermediate in the synthesis of lipoic acid. Its structure contains both aliphatic chlorinated groups and ester functional groups, requiring highly selective and mild reaction conditions. This type of compound is typically prepared from adipic acid or its monoesters via a multi-step reaction involving acyl chloride, carbon skeleton construction, carbonyl reduction, and hydroxyl chlorination. The carbonyl reduction and hydroxyl chlorination steps are the core steps affecting product yield, safety, and industrial feasibility.

[0003] I. Existing technologies and shortcomings of carbonyl reduction processes In existing technologies, the methods for reducing ethyl 8-chloro-6-oxooctanoate to ethyl 6-hydroxy-8-chlorooctanoate mainly include the following categories: (1) Borohydride reduction route Chinese patent CN118666677A, entitled "A Method for Preparing Ethyl 6,8-Dichlorooctanoate," proposes a route that uses diethyl adipate as a starting material, constructs an intermediate, reduces it with potassium borohydride, and further completes subsequent conversions to prepare the target product. While this type of borohydride reduction system exhibits high reactivity, it typically carries safety risks due to strong exothermic reactions and stringent requirements for feed and temperature control. Furthermore, the reaction easily generates boron-containing wastewater, resulting in high post-treatment costs and hindering green and continuous production.

[0004] (2) MPV reduction route (hydrogen transfer) Chinese patent CN114149324A, entitled "A Method for Synthesizing Ethyl 6-hydroxy-8-chlorooctanoate, Ethyl 6,8-dichlorooctanoate, and Lipoic Acid," discloses a method for reducing the MPV of carbonyl compounds using a secondary alcohol as a hydrogen source and an inorganic salt system such as lithium salts / phosphates. While this type of method avoids borohydride reduction to some extent, its catalytic system is mostly a homogeneous inorganic salt system, making it difficult to recover the catalytic components after the reaction, resulting in a high salt load. Furthermore, the reaction time is often long, which is detrimental to equipment utilization, and the overall route still requires the use of a traditional hydroxyl chlorination system, failing to address safety and environmental concerns at the overall process level.

[0005] (3) Grignard / Reformatsky and chiral hydrogenation routes Chinese patent CN118598746A, entitled "A Method for the Synthesis and Application of Ethyl S-(-)-6,8-Dichlorooctanoate," discloses a route for constructing an intermediate via the Reformatsky reaction and then combining it with subsequent catalytic conversion to obtain a specific product. Such routes typically involve multiple steps, are sensitive to moisture / impurities, and may depend on specific catalytic systems or more complex reaction conditions, leading to increased process costs and difficulty in controlling scale-up stability, thus hindering widespread adoption in conventional fine chemical plants.

[0006] In summary, existing carbonyl reduction routes generally suffer from the following problems: (1) It relies on strong reducing agents or homogeneous inorganic salt systems, which have a greater safety and environmental burden; (2) The system is complex, the salt load is high or there are many steps, and the stability for industrial scale-up is insufficient; (3) Even if a certain step is improved, it is still often necessary to combine it with the subsequent traditional chlorination system, making it difficult to achieve a green, safe and continuous process.

[0007] II. Existing technologies and shortcomings of hydroxyl chlorination processes In the process of converting ethyl 6-hydroxy-8-chlorooctanoate to ethyl 6,8-dichlorooctanoate, existing technologies mostly use chlorinating agents such as thionyl chloride, phosphorus oxychloride, or phosphoryl chloride to complete the hydroxyl chlorination. These reagents are highly reactive, but the reaction process is often accompanied by the generation of corrosive gases such as SO2 and HCl, which places higher demands on equipment corrosion protection, exhaust gas absorption, and safety management, and also results in higher treatment costs.

[0008] For example, routes such as CN118666677A and CN118598746A may still use traditional chlorinating agents in subsequent chlorination steps, inevitably leading to corrosive exhaust gases and safety and environmental pressures in the overall process. Although some patents have made improvements by optimizing temperature, additives, and feeding methods, they have failed to fundamentally eliminate the risks associated with traditional chlorinating agents in the chlorination system.

[0009] Therefore, there is a need for a method for preparing ethyl 6,8-dichlorooctanoate that differs from conventional high-risk reagent systems in both the carbonyl reduction and hydroxyl chlorination steps, while also considering safety, environmental friendliness, and industrial applicability, in order to solve the problems existing in the prior art. Summary of the Invention

[0010] In view of this, the present invention provides a method for preparing ethyl 6,8-dichlorooctanoate, which replaces the traditional carbonyl reduction and hydroxyl chlorination steps, improves reaction safety and environmental friendliness, and facilitates industrialization.

[0011] To achieve the above objectives, the present invention provides a method for preparing ethyl 6,8-dichlorooctanoate, comprising the following steps: (1) 8-chloro-6-oxooctanoic acid ethyl ester and ammonium formate are mixed in an organic solvent and subjected to catalytic transfer hydrogenation in the presence of a catalyst to selectively reduce the carbonyl functional group to a hydroxyl group to obtain 6-hydroxy-8-chlorooctanoic acid ethyl ester; (2) 6-hydroxy-8-chlorooctanoic acid ethyl ester is reacted with methanesulfonyl chloride to generate a methanesulfonate intermediate; the methanesulfonate intermediate is subjected to a substitution reaction with lithium chloride in an organic solvent to convert the hydroxyl functional group into a chlorine group, thereby obtaining 6,8-dichlorooctanoic acid ethyl ester.

[0012] The preparation method provided by this invention replaces the traditional borohydride, MPV or hydrosilylation reduction with catalytic transfer hydrogenation (CTH) mechanism, and replaces the traditional high-risk direct chlorination system with a two-step chlorination reaction of "sulfonate ester activation → chloride salt substitution", thereby improving reaction safety, reducing environmental burden and enhancing industrial applicability while ensuring high yield and high purity.

[0013] Optionally, the catalyst is a ruthenium-based catalyst, and the molar percentage of the ruthenium-based catalyst in ethyl 8-chloro-6-oxooctanoate is 0.01 to 2 mol%. Preferably, the molar percentage of the ruthenium-based catalyst in ethyl 8-chloro-6-oxooctanoate is 0.05 to 0.5 mol.

[0014] Optionally, the ruthenium-based catalyst is one or both of a complex-type ruthenium catalyst and a supported ruthenium catalyst.

[0015] Optionally, the amount of ammonium formate is 1 to 6 times the amount of ethyl 8-chloro-6-oxooctanoate. Preferably, the amount of ammonium formate is 2 to 4 times the amount of ethyl 8-chloro-6-oxooctanoate.

[0016] Optionally, the temperature of the catalytic transfer hydrogenation reaction is 20~90℃, and the time is 0.5~10h. Preferably, the temperature of the catalytic transfer hydrogenation reaction is 40~75℃, and the time is 1~6h.

[0017] Optionally, the organic solvent is one or a combination of two or more of acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane. Acetonitrile is preferred.

[0018] Optionally, an organic base is added when the ethyl 6-hydroxy-8-chlorooctanoate reacts with methanesulfonyl chloride.

[0019] Optionally, the organic base is one or both of triethylamine and diisopropylethylamine.

[0020] Optionally, the amount of methanesulfonyl chloride is 1.02 to 1.50 times the amount of ethyl 6-hydroxy-8-chlorooctanoate. Preferably, the amount of methanesulfonyl chloride is 1.05 to 1.20 times the amount of ethyl 6-hydroxy-8-chlorooctanoate.

[0021] Optionally, the amount of lithium chloride is 1.5 to 6 times the amount of the methanesulfonate intermediate. Preferably, the amount of lithium chloride is 2 to 4 times the amount of the methanesulfonate intermediate.

[0022] Optionally, the reaction temperature of ethyl 6-hydroxy-8-chlorooctanoate with methanesulfonyl chloride is -20 to 20°C. Preferably, the reaction temperature of ethyl 6-hydroxy-8-chlorooctanoate with methanesulfonyl chloride is -5 to 10°C.

[0023] Optionally, the temperature of the substitution reaction is 40~95℃. Preferably, the temperature of the substitution reaction is 60~85℃.

[0024] Optionally, the 6-hydroxy-8-chlorooctanoic acid ethyl ester obtained in step (1) is post-treated and then reacted with methanesulfonyl chloride to generate a methanesulfonate intermediate.

[0025] Optionally, the post-processing includes one or more of the following: filtration to remove solids, vacuum concentration, extraction, washing to neutral, drying, and concentration.

[0026] Optionally, steps (1) and / or (2) are carried out in a batch reactor or a continuous flow reactor.

[0027] To achieve the above objectives, the present invention also provides a method for preparing ethyl 6,8-dichlorooctanoate and its application in the synthesis of thioctic acid.

[0028] The above-described technical solution of the present invention has at least the following beneficial effects: (1) The reduction reaction of the present invention adopts the catalytic transfer hydrogenation mechanism of ammonium formate as hydrogen source, avoiding the use of strong reducing agents and hydrosilicification system. The reaction conditions are mild, which helps to reduce safety risks.

[0029] (2) The chlorination step of the present invention adopts the mechanism of “methanesulfonyl chloride activation → lithium chloride substitution”, avoiding the use of thionyl chloride / phosgene direct chlorination reagents, which helps to reduce corrosive tail gas and equipment corrosion protection pressure.

[0030] (3) The process route of the present invention is easy to achieve stable operation by controlling parameters such as temperature, feeding method and acid binding agent, and is suitable for industrial scale-up. Attached Figure Description

[0031] Figure 1This is a gas chromatogram of the product of Example 6 of the present invention; Figure 2 This is a gas chromatogram of the product of Comparative Example 1 of the present invention. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the following will be described in conjunction with the accompanying drawings of the embodiments of the present invention. Figures 1-2 The technical solutions of the embodiments of the present invention will be clearly and completely described herein. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0033] Schematic diagram of the catalytic transfer hydrogenation reaction of ethyl 6-carbonyl-8-chloro-octanoate in this invention:

[0034] Schematic diagram of the chlorination process of ethyl 6-hydroxy-8-chloro-octanoate in this invention:

[0035] Example 1 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of acetonitrile, and 0.2 g of Ru-TsDPEN catalyst was added. The temperature was raised to 60 °C. 45 g of ammonium formate was added to the system in three portions, and the reaction was stirred at 60 °C for 3 h. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl 6-hydroxy-8-chlorooctanoate intermediate. At 0–5 °C, the above intermediate was dissolved in 200 mL of dichloromethane, and 18 g of triethylamine was added. Then, 18 g of methanesulfonyl chloride was added dropwise under stirring, and the reaction was continued for 1 h after the addition was complete. The triethylamine salt was removed by filtration. 200 mL of acetonitrile and 12 g of lithium chloride were added to the filtrate, and the temperature was raised to 70 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 46.1 g of ethyl 6,8-dichlorooctanoate. Results: Yield 92.2%, GC purity 99.2%.

[0036] Example 2 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of acetonitrile, and 0.1 g of Ru-TsDPEN catalyst was added. The temperature was raised to 70 °C. 48 g of ammonium formate was added to the system in three portions, and the reaction was stirred at 70 °C for 4 h. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl 6-hydroxy-8-chlorooctanoate intermediate. At 0–5 °C, the above intermediate was dissolved in 200 mL of dichloromethane, and 18 g of triethylamine was added. Then, 18 g of methanesulfonyl chloride was added dropwise under stirring, and the reaction was continued for 1 h after the addition was complete. The triethylamine salt was removed by filtration. 200 mL of acetonitrile and 12 g of lithium chloride were added to the filtrate, and the temperature was raised to 70 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 45.3 g of ethyl 6,8-dichlorooctanoate. Results: Yield 90.5%, GC purity 99.0%.

[0037] Example 3 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of acetonitrile, and 0.2 g of Ru-TsDPEN catalyst was added. The temperature was raised to 60 °C. 45 g of ammonium formate was added to the system in three portions, and the reaction was stirred at 60 °C for 3 h. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl 6-hydroxy-8-chlorooctanoate intermediate. At 0–5 °C, the above intermediate was dissolved in 200 mL of dichloromethane, and 18 g of triethylamine was added. Then, 20 g of methanesulfonyl chloride was added dropwise under stirring, and the reaction was continued for 1 h after the addition was complete. The triethylamine salt was removed by filtration. 200 mL of acetonitrile and 15 g of lithium chloride were added to the filtrate, and the temperature was raised to 75 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 45.5 g of ethyl 6,8-dichlorooctanoate. Results: Yield 91.0%, GC purity 99.3%.

[0038] Example 4 Under nitrogen protection, 100.0 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of acetonitrile, and 0.2 g of Ru-TsDPEN catalyst was added. The temperature was raised to 60 °C. 45 g of ammonium formate was added to the system in three portions, and the reaction was stirred at 60 °C for 3 h. After the reaction was complete, the intermediate was not separated, and the acetonitrile was removed directly under reduced pressure. The resulting residue was dissolved in 200 mL of dichloromethane, and 18 g of triethylamine was added at 0–5 °C. Then, 18 g of methanesulfonyl chloride was added dropwise under stirring. After the addition was complete, the reaction was continued for 1 h. The triethylamine salt was removed by filtration, and 200 mL of acetonitrile and 12 g of lithium chloride were added to the filtrate. The temperature was raised to 70 °C and the reaction was carried out for 4 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 40.2 g of ethyl 6,8-dichlorooctanoate. Results: Overall yield 80.3%, GC purity 98.9%.

[0039] Example 5 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of 2-methyltetrahydrofuran, and 0.2 g of Ru-TsDPEN catalyst was added. The mixture was heated to 60 °C. 45 g of ammonium formate was added to the system in three portions, and the mixture was stirred at 60 °C for 3 h. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl 6-hydroxy-8-chlorooctanoate intermediate. At 0–5 °C, the above intermediate was dissolved in 200 mL of dichloromethane, and 18 g of triethylamine was added. Then, 18 g of methanesulfonyl chloride was added dropwise under stirring, and the reaction was continued for 1 h after the addition was complete. The triethylamine salt was removed by filtration. 200 mL of acetonitrile and 12 g of lithium chloride were added to the filtrate, and the mixture was heated to 70 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 44.6 g of ethyl 6,8-dichlorooctanoate. Results: Yield 89.1%, GC purity 98.9%.

[0040] Example 6 Under nitrogen protection, 100.0 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of acetonitrile. 0.2 g of a catalytic system formed in situ from [RuCl2(p-cymene)]2 and TsDPEN was added, and the mixture was heated to 60 °C. 45 g of ammonium formate was added to the system in three portions, and the mixture was stirred at 60 °C for 3 h. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the intermediate ethyl 6-hydroxy-8-chlorooctanoate. The intermediate was dissolved in 200 mL of dichloromethane at 0–5 °C, and 18 g of triethylamine was added. Then, 18 g of methanesulfonyl chloride was added dropwise under stirring, and the reaction was continued for 1 h after the addition was complete. The triethylamine salt was removed by filtration. 200 mL of acetonitrile and 12 g of lithium chloride were added to the filtrate, and the mixture was heated to 70 °C for 4 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 44.2 g of ethyl 6,8-dichlorooctanoate. Results: Yield 88.4%, gas chromatogram shown below. Figure 1 This indicates that the GC purity is 98.7%.

[0041] Comparative Example 1 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of anhydrous methanol and cooled to 0–5 °C. 25 g of sodium borohydride was added in portions, controlling the system temperature to not exceed 5 °C, and the reaction continued for 1.5 h after the addition was complete. After the reaction was complete, deionized water was slowly added to quench the reaction. The mixture was then extracted, washed, dried, and concentrated under reduced pressure to obtain the intermediate ethyl 6-hydroxy-8-chlorooctanoate. The intermediate was dissolved in 200 mL of dichloromethane at 0–5 °C, and 18 g of triethylamine was added. Then, 18 g of methanesulfonyl chloride was added dropwise under stirring, and the reaction continued for 1 h after the addition was complete. The triethylamine salt was removed by filtration. 200 mL of acetonitrile and 12 g of lithium chloride were added to the filtrate, and the mixture was heated to 70 °C and reacted for 4 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 38.1 g of ethyl 6,8-dichlorooctanoate. Results: Overall yield 76.2%; gas chromatogram shown in [insert gas chromatogram here]. Figure 2 This indicates that the GC purity is 96.6%.

[0042] Comparative Example 2 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 400 mL of isopropanol, and 9.5 g of lithium chloride and 9.6 g of potassium phosphate were added. The mixture was heated to 85 °C and stirred for 8 h. After the reaction was complete, the inorganic salt was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl 6-hydroxy-8-chlorooctanoate intermediate. At 0–5 °C, the above intermediate was dissolved in 200 mL of dichloromethane, and 18 g of triethylamine was added. Then, 18 g of methanesulfonyl chloride was added dropwise under stirring, and the reaction was continued for 1 h after the addition was complete. The triethylamine salt was removed by filtration. 200 mL of acetonitrile and 12 g of lithium chloride were added to the filtrate, and the mixture was heated to 70 °C and reacted for 4 h. After the reaction was complete, the mixture was cooled to room temperature, washed with water, dried, and distilled under reduced pressure to obtain 39.1 g of ethyl 6,8-dichlorooctanoate. Results: Overall yield 78.1%, GC purity 97.8%.

[0043] Comparative Example 3 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of acetonitrile, and 0.2 g of Ru-TsDPEN catalyst was added. The temperature was raised to 60 °C. 45 g of ammonium formate was added to the system in three portions, and the reaction was stirred at 60 °C for 3 h. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl 6-hydroxy-8-chlorooctanoate intermediate. The intermediate was dissolved in 200 mL of dichloromethane, cooled to 0 °C, and 26 g of thionyl chloride was slowly added dropwise. After the addition was complete, the temperature was raised to 50 °C and the reaction was continued for 2 h. After the reaction was complete, the solvent and excess reagent were removed under reduced pressure, and 43.0 g of ethyl 6,8-dichlorooctanoate was obtained after post-treatment. Results: Yield 86.0%, GC purity 98.8%. Significant gas was emitted during the reaction.

[0044] Comparative Example 3 Under nitrogen protection, 100 g of ethyl 8-chloro-6-oxooctanoate was dissolved in 300 mL of acetonitrile, and 0.2 g of Ru-TsDPEN catalyst was added. The mixture was heated to 60 °C. 45 g of ammonium formate was added to the system in three portions, and the mixture was stirred at 60 °C for 3 h. After the reaction was complete, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain ethyl 6-hydroxy-8-chlorooctanoate intermediate. This intermediate was dissolved in 200 mL of dichloromethane, and an appropriate amount of triethylamine was added. The mixture was cooled to 0–5 °C, and bis(trichloromethyl) carbonate was added in portions. The reaction was carried out at 0–25 °C until the substrate was substantially converted. After the reaction was complete, the mixture was washed with water, dried, concentrated under reduced pressure, and purified to obtain 44.0 g of ethyl 6,8-dichlorooctanoate. Results: Yield 88.0%, GC purity 98.9%.

[0045] The yields and purities of the products from the above examples and comparative examples were statistically analyzed, and Table 1 is obtained. In Table 1, yield = actual product mass / theoretical product mass; GC purity was calculated using the area normalization method.

[0046] The gas chromatography analysis conditions were as follows: the detector was a flame ionization detector (FID), the column was an HP-5 (30m×0.32mm×0.25μm), the carrier gas was high-purity nitrogen, and the column temperature program was an initial temperature of 80℃ held for 2 min, then increased to 220℃ at a rate of 10℃ / min and held for 5 min.

[0047] Table 1. Product yield and purity results for the examples and comparative examples.

[0048] As shown in Table 1, the purity of the embodiments in this invention is higher than that of the comparative example. The highest yield of the embodiments can reach 92.2%, while the highest yield of the comparative example is only 86%. Furthermore, considering both the yield and purity, the embodiments outperform the comparative example.

[0049] On the other hand, the technical solution provided by the present invention replaces the hydrogenation and chlorination steps in the prior art, and adopts a catalytic transfer hydrogenation mechanism with ammonium formate as the hydrogen source and a methanesulfonyl chloride activation → lithium chloride substitution mechanism. The reaction is safe, environmentally friendly, and the reaction conditions are easy to control, which is conducive to industrial production.

[0050] The above are preferred embodiments of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the preparation of ethyl 6,8-dichlorooctanoate, characterized in that, Includes the following steps: (1) 8-chloro-6-oxooctanoic acid ethyl ester and ammonium formate are mixed in an organic solvent and subjected to catalytic transfer hydrogenation in the presence of a catalyst to selectively reduce the carbonyl functional group to a hydroxyl group to obtain 6-hydroxy-8-chlorooctanoic acid ethyl ester; (2) 6-hydroxy-8-chlorooctanoic acid ethyl ester is reacted with methanesulfonyl chloride to generate a methanesulfonate intermediate; the methanesulfonate intermediate is subjected to a substitution reaction with lithium chloride in an organic solvent to convert the hydroxyl functional group into a chlorine group, thereby obtaining 6,8-dichlorooctanoic acid ethyl ester.

2. The process for the preparation of ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, The catalyst is a ruthenium-based catalyst, and the molar percentage of the ruthenium-based catalyst relative to the molar percentage of ethyl 8-chloro-6-oxooctanoate is 0.01–2 mol.

3. The process for the preparation of ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, The amount of ammonium formate is 1 to 6 times the amount of ethyl 8-chloro-6-oxooctanoate.

4. The process for the preparation of ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, The catalytic transfer hydrogenation reaction is carried out at a temperature of 20~90℃ for a time of 0.5~10h.

5. The method for preparing ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, An organic base is added when ethyl 6-hydroxy-8-chlorooctanoate reacts with methanesulfonyl chloride.

6. The method for preparing ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, The amount of methanesulfonyl chloride is 1.02 to 1.50 times the amount of ethyl 6-hydroxy-8-chlorooctanoate.

7. The method for preparing ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, The amount of lithium chloride is 1.5 to 6 times the amount of the methanesulfonate intermediate.

8. The method for preparing ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, The reaction temperature of ethyl 6-hydroxy-8-chlorooctanoate with methanesulfonyl chloride is -20~20℃.

9. The method for preparing ethyl 6,8-dichlorooctanoate according to claim 1, characterized in that, The temperature for the substitution reaction is 40~95℃.

10. The use of ethyl 6,8-dichlorooctanoate prepared by the method of any one of claims 1-9 in the synthesis of thioctic acid.

Images