Method for preparing 6, 8-dichlorocaprylic acid by pure water solvent system

Abstract

The invention provides a method for preparing 6, 8-dichlorocaprylic acid through a pure water solvent system, and belongs to the technical field of preparation of raw materials needed for preparing lipoic acid. The method comprises the following steps: diluting 6, 8-dichloro ethyl caprylate with water, adding a crown ether catalyst, dropwise adding a pyrophosphate aqueous solution under a heating condition for hydrolysis, acidifying, extracting with an organic solvent, and concentrating to obtain 6, 8-dichloro caprylic acid. The method has the advantages of mild reaction conditions, high hydrolysis rate and no need of an organic solvent to participate in the reaction.

Description

Technical Field

[0001] This invention belongs to the field of preparation technology of raw materials required for the preparation of thioctic acid, and specifically relates to a method for preparing 6,8-dichlorooctanoic acid using pure water as the sole solvent. Background Technology

[0002] 6,8-Dichlorooctanoic acid has the following chemical structural formula:

[0003] 6,8-Dichlorooctanoic acid is one of the important raw materials for the preparation of lipoic acid and optically active (R or S-type) lipoic acid. Lipoic acid is an essential factor for human cellular energy metabolism, and its derivatives have various uses in agriculture and industry, such as fungicides and growth promoters. It is also a B vitamin that can inhibit protein glycosylation, so lipoic acid can be used to treat sensory abnormalities caused by diabetic peripheral neuropathy. The synthesis of R-(+)-lipoic acid is mainly achieved through resolution. One method is the direct resolution of racemic lipoic acid, and the other is the resolution of 6,8-dichlorooctanoic acid. The former method results in high costs for recycling the remaining S-(-) lipoic acid, while the latter method can significantly reduce costs. This urgently requires an efficient method for the synthesis of 6,8-dichlorooctanoic acid, and subsequently, the preparation of lipoic acid.

[0004] The current method for preparing 6,8-dichlorooctanoic acid is as follows: One method involves acid hydrolysis of ethyl 6,8-dichlorooctanoate. However, this method yields a low content of 6,8-dichlorooctanoic acid, necessitating redistillation. Redistillation results in low yields, prolonged hydrolysis time, and the generation of large amounts of acid that pollute the environment. Furthermore, redistillation produces a significant amount of wastewater.

[0005] Another method involves hydrolyzing ethyl 6,8-dichlorooctanoate with alkaline solution, which requires heating and reflux with organic solvents, resulting in harsh conditions, high energy consumption, and complex operation. Summary of the Invention

[0006] The purpose of this invention is to address the bottlenecks in existing technologies by designing a method for preparing 6,8-dichlorooctanoic acid using a pure water solvent system.

[0007] Another objective of this invention is to accelerate the hydrolysis of ethyl 6,8-dichlorooctanoate with a small amount of crown ether catalyst and a certain amount of pyrophosphate, thereby efficiently preparing 6,8-dichlorooctanoic acid and reducing the occurrence of side reactions.

[0008] This invention provides a method for preparing 6,8-dichlorooctanoic acid using a pure aqueous solvent system. The reaction conditions are as follows: Commercially available ethyl 6,8-dichlorooctanoate is diluted with water, a crown ether catalyst is added, and the mixture is heated to 30-70°C under stirring. A pyrophosphate solution is then added dropwise to initiate the reaction. The reaction progress is monitored by thin-layer chromatography until the ethyl 6,8-dichlorooctanoate has essentially disappeared. The reaction solution is then allowed to stand at room temperature, filtered, and acidified with a 5-10% hydrochloric acid aqueous solution at a controlled temperature of 0-5°C. Extraction is then performed using an organic solvent. Finally, the organic phase is dried and concentrated to obtain 6,8-dichlorooctanoic acid.

[0009] The key points of this invention are mainly as follows: In this invention, the amount of pyrophosphate used is 1-2 equivalents (including any amount value of 1-2 equivalents), specifically any one of 1 equivalent, 1.2 equivalents, 1.5 equivalents, and 2.0 equivalents.

[0010] In this invention, the pyrophosphate is at least one of the third-generation or fourth-generation pyrophosphates of alkali metal or alkaline earth metal.

[0011] The pyrophosphate is M3HP2O7 or M4P2O7, wherein M is any one of Na, K, Mg, and Ca.

[0012] In this invention, the concentration of pyrophosphate is 1-6 mol / L (inclusive of any concentration value or range within 1-6 mol / L), specifically any one of 1 mol / L, 2 mol / L, 4 mol / L, or 6 mol / L. In the hydrolysis reaction of ethyl 6,8-dichlorooctanoate, a low pyrophosphate concentration results in a slow hydrolysis rate. Within a certain range, the hydrolysis rate increases with increasing pyrophosphate concentration. However, when the pyrophosphate concentration is too high, side reactions occur. When the pyrophosphate concentration reaches 7 mol / L (see Comparative Example 2), the reaction yield and purity decrease. This may be because the high-concentration pyrophosphate solution is more alkaline under the action of the crown ether, leading to a substitution reaction with the chlorine atom on ethyl 6,8-dichlorooctanoate, thus reducing the reaction yield and purity.

[0013] In this invention, the hydrolysis temperature is 30-70℃ (inclusive of any temperature value or range within 30-70℃), specifically any one of 30℃, 40℃, 50℃, 60℃, and 70℃. In the hydrolysis reaction of ethyl 6,8-dichlorooctanoate, the hydrolysis rate increases with increasing reaction temperature within a certain range. However, when the reaction reaches a certain temperature, side reactions occur. When the reaction temperature reaches 80℃ (see Comparative Example 3), the reaction yield and purity decrease significantly. This may be because the hydrolysis of ethyl 6,8-dichlorooctanoate is constrained by the reactivity of the carbon at position 8; increasing the temperature can promote the substitution or elimination of the chlorine atom on the carbon at position 8, resulting in side reactions.

[0014] This invention uses crown ether catalysts, which can be any one of 12-crown-4, 15-crown-5, and 18-crown-6. In this invention, the hydrolysis of ethyl 6,8-dichlorooctanoate is a heterogeneous reaction with a slow hydrolysis rate; therefore, a crown ether catalyst is needed to promote the reaction.

[0015] In this invention, the mass ratio of ethyl 6,8-dichlorooctanoate to crown ether catalyst is 1:0.01-0.1 (i.e., 1wt%-10wt%), specifically any one of 1wt%, 3wt%, 5wt%, 7wt%, and 10wt%.

[0016] Compared with existing technologies, the present invention has milder reaction conditions, faster hydrolysis rate, and significantly shorter reaction time. It can use crown ether catalysts and pyrophosphates to replace organic solvents in the reaction, reducing side reactions generated under harsh conditions, and ultimately efficiently preparing 6,8-dichlorooctanoic acid. Detailed Implementation

[0017] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0018] Example 1 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 159.54 g (0.6 mol) of sodium pyrophosphate in 150 g of water (pyrophosphate concentration 4 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature was 50 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 83.53 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 98% and an HPLC purity of 99.6%.

[0019] Example 2 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 2.89 g of 15-crown-5. Dissolve 159.54 g (0.6 mol) of sodium pyrophosphate in 150 g of water (pyrophosphate concentration 4 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature was 50 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 80.98 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 95% and an HPLC purity of 98.3%.

[0020] Example 3 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 106.36 g (0.4 mol) of sodium pyrophosphate in 100 g of water (pyrophosphate concentration 4 mol / L), and slowly add this solution to the 500 mL reaction flask. The reaction temperature is 50 °C, and the mixture is stirred for 2 h. After the reaction is complete, allow it to stand at room temperature, filter, and acidify with 10% hydrochloric acid aqueous solution at 0-5 °C. Adjust the pH of the solution to 1-2. Extract the aqueous phase with 100 mL of ethyl acetate, repeating the extraction twice. Combine the organic phases, wash with 300 mL of pure water, and then rinse with 300 mL of pure water. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 77.57 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 91% and an HPLC purity of 92.5%.

[0021] Example 4 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 198.18 g (0.6 mol) of potassium pyrophosphate in 150 g of water (pyrophosphate concentration 4 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature is 50 °C, and the mixture is stirred for 2 h. After the reaction is complete, allow it to stand at room temperature, filter, and acidify with 10% hydrochloric acid aqueous solution at 0-5 °C. Adjust the pH of the solution to 1-2. Extract the aqueous phase with 100 mL of ethyl acetate, repeating the extraction twice. Combine the organic phases, wash with 300 mL of pure water, and then rinse with 300 mL of pure water. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 76.68 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 90% and an HPLC purity of 96.9%.

[0022] Example 5 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 159.54 g (0.6 mol) of sodium pyrophosphate in 300 g of water (pyrophosphate concentration 2 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature was 50 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 75.01 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 88% and an HPLC purity of 95.3%.

[0023] Example 6 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 159.54 g (0.6 mol) of sodium pyrophosphate in 100 g of water (pyrophosphate concentration 6 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature was 50 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 73.27 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 86% and an HPLC purity of 80.4%.

[0024] Example 7 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 175.35 g (0.6 mol) of tripotassium pyrophosphate in 150 g of water (pyrophosphate concentration 4 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature was 30 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 74.16 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 87% and an HPLC purity of 84.7%.

[0025] Example 8 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 146.34 g (0.6 mol) of trisodium pyrophosphate in 150 g of water (pyrophosphate concentration 4 mol / L), and slowly add this solution to the 500 mL reaction flask. The reaction temperature was 70 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 75.85 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 89% and an HPLC purity of 80.5%.

[0026] Comparative Example 1 96.46 g (0.4 mol, purity 98%) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate was added to a 500 mL reaction flask, along with 50 g of pure water. 159.54 g (0.6 mol) of sodium pyrophosphate was dissolved in 150 g of water (pyrophosphate concentration 4 mol / L), and this solution was slowly added to the 500 mL reaction flask. The reaction was carried out at 50 °C and stirred for 2 h. After the reaction was complete, the solution was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, then washed with 300 mL of saturated brine, and finally dried over anhydrous sodium sulfate. The solution was then distilled under reduced pressure and frozen to obtain 66.49 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 78% and an HPLC purity of 85%.

[0027] Comparative Example 2 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 159.54 g (0.6 mol) of sodium pyrophosphate in 86 g of water (pyrophosphate concentration 7 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature was 50 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 69.90 g of white solid 6,8-dichlorooctanoic acid, with a yield of 82% and an HPLC purity of 65%.

[0028] Comparative Example 3 Add 96.46 g (0.4 mol, 98% purity) of commercially available industrial-grade ethyl 6,8-dichlorooctanoate to a 500 mL reaction flask, along with 50 g of pure water and 4.82 g of 15-crown-5. Dissolve 159.54 g (0.6 mol) of sodium pyrophosphate in 150 g of water (pyrophosphate concentration 4 mol / L), and slowly add the solution to the 500 mL reaction flask. The reaction temperature was 80 °C, and the mixture was stirred for 2 h. After the reaction was complete, the mixture was allowed to stand at room temperature, filtered, and acidified with 10% hydrochloric acid aqueous solution at 0-5 °C. The pH of the solution was adjusted to 1-2. The aqueous phase was extracted with 100 mL of ethyl acetate, and the extraction was repeated twice. The organic phases were combined, washed with 300 mL of pure water, and then rinsed with 300 mL of ethyl acetate. The sample was washed with mL of saturated saline solution, dried with anhydrous sodium sulfate, distilled under reduced pressure, and frozen to obtain 71.60 g of 6,8-dichlorooctanoic acid as a white solid, with a yield of 84% and an HPLC purity of 55%.

Claims

1. A process for the preparation of 6,8-dichlorooctanoic acid from a pure aqueous solvent system, characterized in that, The method comprises the following steps: diluting ethyl 6,8-dichlorooctanoate with water, adding a crown ether catalyst, adding dropwise an aqueous pyrophosphate solution under heating, hydrolyzing, acidifying with an aqueous hydrochloric acid solution at a certain temperature, and finally extracting with an organic solvent and concentrating to obtain 6,8-dichlorooctanoic acid.

2. The method of claim 1, wherein: The crown ether catalyst is at least one of 12-crown-4, 15-crown-5 and 18-crown-6.

3. The method according to claim 1 or 2, characterized in that: The mass ratio of ethyl 6,8-dichlorooctanoate to the crown ether catalyst is 1:0.01-0.

1.

4. The method of claim 1, wherein: The hydrolysis temperature is 30-70 DEG C.

5. The method of claim 1, wherein: The pyrophosphate is at least one of a tripyrophosphate and a tetrapyrophosphate of an alkali metal or an alkaline earth metal.

6. The method of claim 5, wherein: The pyrophosphate is M3HP2O7 or M4P2O7, wherein M is any one of Na, K, Mg and Ca.

7. The method of claim 1, wherein: The pyrophosphate is used in an amount of 1-2 equivalents.

8. The method of claim 1, wherein: The pyrophosphate has a concentration of 1-6 mol / L.

9. The method of claim 1, wherein: The organic solvent comprises ethyl acetate.

10. The method of claim 1, wherein: The acidifying solvent is an aqueous hydrochloric acid solution with a concentration of 5-10%, and the acidifying temperature is controlled to be 0-5 DEG C.

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