A method for the asymmetric synthesis of ethyl R-6,8-dichlorooctanoate via catalytic hydrogenation using a composite catalyst

Abstract

This invention relates to the field of compound preparation technology and discloses a method for the asymmetric synthesis of R-6,8-dichlorooctanoate by hydrogenation catalyzed by a composite catalyst. The method includes the following steps: S1. Activation of the alumina support; S2. Preparation of the composite catalyst; S3. High-pressure hydrogenation; S4. Chlorination. The activated alumina support and ruthenium-palladium mixed catalyst of this invention exhibit high selectivity (over 99%) and optical purity (over 98%) in the hydrogenation reduction of 6-carbonyl-8-chlorooctanoate to R-6-hydroxy-8-chlorooctanoate under suitable temperature and pressure. The activated alumina support and ruthenium-palladium mixed catalyst also demonstrate high inhibition of dechlorination and ester reduction during carbonyl reduction under suitable temperature and pressure. The high-pressure hydrogenation process provides a novel process route for the carbonyl reduction of compounds. The use of the same solvent in both high-pressure hydrogenation and chlorination reduces the difficulty of subsequent post-processing and makes the method more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of compound preparation technology, specifically to a method for the asymmetric synthesis of R-6,8-dichlorooctanoate by hydrogenation catalyzed by a composite catalyst. Background Technology

[0002] Alpha-lipoic acid (ALA), chemically known as 1,2-dithiopentane-3-pentanoic acid, is a novel antioxidant and an important coenzyme in the body. It is soluble in both water and fats. In the tricarboxylic acid cycle, it acts as a coenzyme, particularly in the decarboxylation of pyruvate and other α-keto acids. Within the mitochondria, it catalyzes the conversion of anaerobic oxidation of carbohydrates, fats, and proteins into initiators for aerobic oxidation. Alpha-lipoic acid is a vitamin-like drug with antioxidant effects surpassing those of vitamins A, C, and E. In aqueous solution, it can directly eliminate harmful free radicals such as hydroxyl groups and reactive oxygen species. Clinically, it is mainly used to treat liver diseases, exhibiting antiviral activity with few side effects. Due to its important role, it has received widespread attention. Ethyl R-6,8-dichlorooctanoate, as an important intermediate for the R-configuration of alpha-lipoic acid, has a vast market value.

[0003] Currently, the main synthetic methods available on the market for R-6,8-dichlorooctanoate (α-lipoic acid) are as follows:

[0004] 1. Decomposition and Synthesis Method 1:

[0005] The chemical resolution method for racemic α-lipoic acid is currently widely used in industrial production. Ethyl 6-oxo-8-chlorooctanoate is reduced with sodium borohydride to ethyl 6-hydroxy-8-chlorooctanoate, which is then chlorinated to obtain racemic ethyl 6,8-dichlorooctanoate. Esterification, cyclization, and hydrolysis yield a racemic mixture of lipoic acids, which is then resolved to obtain α-lipoic acid. However, due to the unique disulfide five-membered ring structure of α-lipoic acid, polymerization easily occurs during the resolution process, leading to unstable yields and increased costs. Furthermore, the sodium borohydride reduction method suffers from difficulties in separating amphoteric borate compounds in the post-treatment stage, and the resulting mixed alcohol-water wastewater is difficult to treat, resulting in a large volume of waste (refer to existing technology CN105524040A, A method for preparing R-lipoic acid; Improved synthetic process of ethyl 6,8-dichlorooctanoate, Jiang Ling et al., Zhejiang University of Technology).

[0006] 2. Decomposition and Synthesis Method 2:

[0007] This method mainly uses a complexation reaction of 6,8-dichlorooctanoic acid and dehydroabimethionine to separate R-6,8-dichlorooctanoic acid, followed by esterification to prepare ethyl R-6,8-dichlorooctanoate. This method uses the expensive dehydroabimethionine, and the separation method wastes 50% of the S-configuration product, resulting in low yield and high production cost, making it unsuitable for industrial production (refer to the existing technology CN101880224A, a method for the separation of 6,8-dichlorooctanoic acid).

[0008] 3. Bioenzymatic method:

[0009] A reductase catalyst is introduced into a system consisting of ethyl 6-carbonyl-8-chlorooctanoate, glucose dehydrogenase, glucose, nicotinamide adenine dinucleotide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and water, and a chiral reduction reaction is carried out under controlled temperature and pH conditions to obtain ethyl (S)-6-hydroxy-8-chlorooctanoate. This is then chlorinated with di(trichloromethyl) carbonate to obtain ethyl R-6,8-dichlorooctanoate. This method requires a very clean operating environment to ensure the effectiveness of the enzyme (refer to prior art CN105087681A, Preparation method and application of ethyl A(S)-6-hydroxy-8-chlorooctanoate). Summary of the Invention

[0010] To address the aforementioned technical problems, the present invention aims to provide a method for the asymmetric synthesis of R-6,8-dichlorooctanoate via catalytic hydrogenation using a composite catalyst, which has low production costs and high product purity.

[0011] To achieve the above objectives, the present invention provides the following technical solution: The method includes the following steps:

[0012] S1. Activation of aluminum oxide carrier: Add solvent I, deionized water and alkaline solution to a flask, add aluminum oxide powder while stirring, stir evenly, filter and dry;

[0013] S2. Preparation of composite catalyst: A mixed aqueous solution of ruthenium trichloride trihydrate and palladium chloride dihydrate was prepared in a flask, and the aluminum oxide treated in S1 was added with stirring. After adsorption, it was reduced with 85% hydrazine hydrate, filtered and dried to obtain the composite catalyst.

[0014] S3. High-pressure hydrogenation: In a high-pressure reactor, solvent 2, ethyl 6-carbonyl-8-chlorooctanoate, and a composite catalyst are added. The temperature is controlled at 80-85℃ and the hydrogen pressure is 3.0-3.5MPa to prepare ethyl R-6-hydroxy-8-chlorooctanoate.

[0015] S4. Chlorination: The reaction solution of S3 is heated to 40-50℃, and chlorination reagent is added dropwise. After the reaction, solvent II is recovered under reduced pressure, and then distilled to obtain ethyl R-6,8-dichlorooctanoate.

[0016] Preferably, the solvent in S1 is ethanol or methanol.

[0017] Preferably, the alkaline solution in S1 is one of sodium ethoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide.

[0018] Preferably, in S1, the mass ratio of solvent one to aluminum oxide powder is between 1:1 and 1:5; the mass ratio of deionized water to aluminum oxide powder is between 1:1 and 1:10; and the mass ratio of alkaline solution to aluminum oxide powder is between 1:100 and 1:10.

[0019] Preferably, in S2, the molar ratio of metallic ruthenium to palladium in ruthenium trichloride trihydrate and palladium chloride dihydrate is between 1:1 and 5:1.

[0020] Preferably, the solvent two in S2 is one of DMF, DMSO, tetrahydrofuran, and dioxane, and the mass ratio of solvent two to ethyl 6-carbonyl-8-chlorooctanoate is in the range of 2:1 to 10:1.

[0021] Preferably, the mass ratio of the composite catalyst in S3 to ethyl 6-carbonyl-8-chlorooctanoate is between 1:200 and 1:10.

[0022] Preferably, the hydrogen pressure range for high-pressure hydrogenation in S3 is 2.0-5.0 MPa.

[0023] Preferably, the chlorinating agent in S4 is one of di(trichloromethyl) carbonate, thionyl chloride, and trichloroisocyanuric acid, and the molar ratio of the chlorinating agent to ethyl 6-carbonyl-8-chlorooctanoate is in the range of 1.5:1 to 1:1.

[0024] Preferably, the chlorination time in S4 is between 2 and 12 hours.

[0025] Compared with the prior art, the beneficial effects of the present invention are:

[0026] 1. The present invention provides a highly selective method for the hydrogenation reduction of 6-carbonyl-8-chlorooctanoate to R-6-hydroxy-8-chlorooctanoate using an activated alumina support and a ruthenium-palladium mixed catalyst under suitable temperature and pressure, with a selectivity of over 99% and an optical purity of over 98%.

[0027] 2. This invention uses activated alumina support and a ruthenium and palladium mixed catalyst to exhibit high inhibition of dechlorination and ester reduction during carbonyl reduction under appropriate temperature and pressure.

[0028] 3. High-pressure hydrogenation process, applied to the novel process route for carbonyl reduction of the compounds of this invention;

[0029] 4. High-pressure hydrogenation and chlorination use the same solvent, reducing the difficulty of subsequent post-processing and making it more suitable for industrial production. Attached Figure Description

[0030] Figure 1 This is the synthetic route of the present invention.

[0031] Figure 2 The image shows the 1H NMR spectrum of ethyl R-6,8-dichlorooctanoate of this invention.

[0032] Figure 3 This is the GC chromatogram of the chiral purity of ethyl R-6,8-dichlorooctanoate according to the present invention. Detailed Implementation

[0033] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0034] Example 1: S1. Activation of the carrier aluminum oxide: In a 500ml three-necked flask, add 100g of methanol and 100g of deionized water, mix well, then add 1g of 28% sodium methoxide methanol solution, stir well again, then add 50g of aluminum oxide powder that has been calcined at 400℃, stir for 1 hour, filter out the solid aluminum oxide, and wash with water until the washing solution reaches a pH of about 7. Dry the carrier aluminum oxide at 120℃ to constant weight, and set aside for use.

[0035] S2. Preparation of the composite catalyst: 1.31 g of ruthenium trichloride trihydrate and 0.53 g of palladium chloride dihydrate were dissolved in 400 ml of deionized water. 50 g of the pre-treated aluminum oxide was added between 25-35℃, and the mixture was stirred intermittently. After standing for 2 hours, 0.1 g of 85% hydrazine hydrate was added dropwise, and the mixture was stirred for 0.5 hours. The solid was filtered off, and the eluent was washed with water until the pH of the eluent was approximately 7-7.5. The prepared wet catalyst was then ready for use.

[0036] Before hydrogenation in this project, the above catalyst is washed with DMF at a mass ratio of 2 and then filtered before use.

[0037] Example 2: S3. High-pressure hydrogenation: In a 500ml stainless steel high-pressure reactor, add 200g of DMF solvent, 50g of ethyl 6-carbonyl-8-chlorooctanoate, and 0.5g of composite catalyst (dry weight). Seal the high-pressure reactor and purge twice with nitrogen at 0.4-0.5MPa positive pressure. Then, turn on the stir and purge once more with nitrogen at 0.4-0.5MPa positive pressure. Pressurize with hydrogen to 1.5MPa, adjust the reactor speed to 500-600r / min, slowly raise the temperature to 80-85℃, and pressurize with hydrogen to 3.0-3.5MPa. Maintain the pressure at 3.0-3.5MPa for about 6 hours until the pressure remains essentially constant. Maintain the temperature at 80-85℃ and hold the pressure for 1 hour. Cool to 20-30℃, filter to recover the catalyst, and set the reaction solution aside for later use.

[0038] S4. Chlorination: The reaction solution from the previous step was added to a 500ml four-necked reaction flask. Under a micro-nitrogen gas flow, the temperature was slowly raised to 40-50℃. A pre-prepared di(trichloromethyl) carbonate solution (23.6g dissolved in 75g DMF) was added dropwise over approximately 2 hours. After the addition was complete, the mixture was kept at 45-50℃ for 3-4 hours. The concentration of intermediate R-6-hydroxy-8-chlorooctanoate ethyl ester was determined to be ≤0.5%. The pressure was then reduced to -0.095MPa, and DMF was recovered below 100℃. Distillation continued, maintaining a vacuum of -0.097-0.098MPa. The fraction collected at 125-130℃ was a colorless, transparent liquid, approximately 51.3g, of R-6,8-dichlorooctanoate ethyl ester, yielding 94% (two steps). GC purity was 99.5%, and optical purity was 98.7%. 1H—NMR (300 MHz, DMSO): 4.15 (2H, -OCH2CH3), 4.10 (1H, -CHCl), 3.75 (2H, -CH2Cl), 2.32 (2H, -CH2-), 2.10 (2H, -CH2-), 1.75 (2H, -CH2-), 1.60 (2H,-CH2-), 1.49(2H,-CH2-), 1.26(3H,-OCH2CH3), such as Figure 2 As shown.

[0039] Example 3: S3. High-pressure hydrogenation: In a 500ml stainless steel high-pressure reactor, add 300g of DMF solvent, 75g of ethyl 6-carbonyl-8-chlorooctanoate, and 0.75g of mixed catalyst (dry weight). Seal the high-pressure reactor and purge twice with nitrogen at 0.4-0.5MPa positive pressure. Then, open the stirrer and purge once more with nitrogen at 0.4-0.5MPa positive pressure. Pressurize with hydrogen to 1.5MPa, adjust the reactor speed to 500-600r / min, slowly raise the temperature to 80-85℃, and pressurize with hydrogen to 3.0-3.5MPa. Maintain the pressure at 3.0-3.5MPa for about 6 hours until the pressure remains essentially constant. Maintain the temperature at 80-85℃ and hold the pressure for 1 hour. Cool to 20-30℃, filter to recover the catalyst, and set the reaction solution aside for later use.

[0040] S4. Chlorination: Transfer the reaction solution from the previous step to a 500ml four-necked flask. Under a micro-nitrogen gas flow, slowly heat to 40-50℃, and add dropwise a pre-prepared di(trichloromethyl) carbonate solution (35.4g dissolved in 106g DMF). The addition is completed in about 2 hours. After the addition is complete, maintain the temperature at 45-50℃ for 3-4 hours. The concentration of intermediate R-6-hydroxy-8-chlorooctanoate ethyl ester is ≤0.5%. Begin vacuum distillation at -0.095MPa, recover DMF below 100℃, and continue distillation under vacuum of -0.097-0.098MPa. Collect the fraction at 125-130℃, yielding approximately 76.9g of colorless, transparent liquid R-6,8-dichlorooctanoate ethyl ester, with a yield of 94.1%. GC purity 99.4%, optical purity 98.5%.

[0041] Example 4: S3. High-pressure hydrogenation: In a 500ml stainless steel high-pressure reactor, add 400g of DMF solvent, 100g of ethyl 6-carbonyl-8-chlorooctanoate, and 1.0g of mixed catalyst (dry weight). Seal the high-pressure reactor and purge twice with nitrogen at 0.4-0.5MPa positive pressure. Then, turn on the stir and purge once more with nitrogen at 0.4-0.5MPa positive pressure. Pressurize with hydrogen to 1.5MPa, adjust the reactor speed to 500-600r / min, slowly raise the temperature to 80-85℃, and pressurize with hydrogen to 3.0-3.5MPa. Maintain the pressure at 3.0-3.5MPa for about 6 hours until the pressure remains essentially constant. Maintain the temperature at 80-85℃ and hold the pressure for 1 hour. Cool to 20-30℃, filter to recover the catalyst, and set the reaction solution aside for later use.

[0042] S4. Chlorination: Transfer the reaction solution from the previous step to a 1000ml four-necked flask. Under a micro-nitrogen gas flow, slowly heat to 40-50℃, and add dropwise a pre-prepared di(trichloromethyl) carbonate solution (47.2g dissolved in 141.6g DMF). The addition is completed in about 2 hours. After the addition is complete, maintain the temperature at 45-50℃ for 3-4 hours. The concentration of intermediate R-6-hydroxy-8-chlorooctanoate ethyl ester is ≤0.5%. Begin vacuum distillation at -0.095MPa, recover DMF below 100℃, and continue distillation under vacuum of -0.097-0.098MPa. Collect the fraction at 125-130℃, yielding approximately 103.6g of colorless, transparent liquid R-6,8-dichlorooctanoate ethyl ester, with a yield of 95.0%. GC purity 99.7%, optical purity 98.7%.

[0043] Example 5: S3. High-pressure hydrogenation: In a 1000ml stainless steel high-pressure reactor, add 600g of DMF solvent, 150g of ethyl 6-carbonyl-8-chlorooctanoate, and 1.5g of mixed catalyst (dry weight). Seal the high-pressure reactor and purge twice with nitrogen at 0.4-0.5MPa positive pressure. Then, open the stirrer and purge once more with nitrogen at 0.4-0.5MPa positive pressure. Pressurize with hydrogen to 1.5MPa, adjust the reactor speed to 500-600r / min, slowly raise the temperature to 80-85℃, and pressurize with hydrogen to 3.0-3.5MPa. Maintain the pressure at 3.0-3.5MPa for about 6 hours until the pressure remains essentially constant. Maintain the temperature at 80-85℃ and hold the pressure for 1 hour. Cool to 20-30℃, filter to recover the catalyst, and set the reaction solution aside for later use.

[0044] S4. Chlorination: Transfer the reaction solution from the previous step to a 1000ml four-necked flask. Under a micro-nitrogen gas flow, slowly heat to 40-50℃, and add dropwise a pre-prepared di(trichloromethyl) carbonate solution (70.8g dissolved in 212.4g DMF). The addition is completed in about 2 hours. After the addition is complete, maintain the temperature at 45-50℃ for 3-4 hours. The concentration of intermediate R-6-hydroxy-8-chlorooctanoate ethyl ester is ≤0.5%. Begin vacuum distillation at -0.095MPa, recover DMF below 100℃, and continue distillation under vacuum of -0.097-0.098MPa. Collect the fraction at 125-130℃, yielding approximately 156.3g of colorless, transparent liquid R-6,8-dichlorooctanoate ethyl ester, with a yield of 95.5%. GC purity 99.6%, optical purity 98.8%.

[0045] Example 6: S3. High-pressure hydrogenation: In a 1000ml stainless steel high-pressure reactor, add 600g of solvent DMF, 150g of ethyl 6-carbonyl-8-chlorooctanoate, and 1.5g of mixed catalyst (dry weight). Seal the high-pressure reactor and purge twice with nitrogen at 0.4-0.5MPa positive pressure. Then, open the stirrer and purge once more with nitrogen at 0.4-0.5MPa positive pressure. Pressurize with hydrogen to 1.5MPa, adjust the reactor speed to 500-600r / min, slowly raise the temperature to 80-85℃, and pressurize with hydrogen to 3.0-3.5MPa. Maintain the pressure at 3.0-3.5MPa for about 6 hours until the pressure remains essentially constant. Maintain the temperature at 80-85℃ and hold the pressure for 1 hour. Cool to 20-30℃, filter to recover the catalyst, and set the reaction solution aside for later use.

[0046] S4. Chlorination: Transfer the reaction solution from the previous step to a 1000ml four-necked flask. Under a micro-nitrogen gas flow, slowly heat to 40-50℃, and add dropwise a pre-prepared di(trichloromethyl) carbonate solution (70.8g dissolved in 212.4g DMF). The addition is completed in about 2 hours. After the addition is complete, maintain the temperature at 45-50℃ for 3-4 hours. The concentration of intermediate R-6-hydroxy-8-chlorooctanoate ethyl ester is ≤0.5%. Begin vacuum distillation at -0.095MPa, recover DMF below 100℃, and continue distillation under vacuum of -0.097-0.098MPa. Collect the fraction at 125-130℃, yielding approximately 156.8g of colorless, transparent liquid R-6,8-dichlorooctanoate ethyl ester, with a yield of 95.8%. GC purity 99.8%, optical purity 98.9%.

[0047] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for the asymmetric synthesis of ethyl R-6,8-dichlorooctanoate via catalytic hydrogenation using a composite catalyst, characterized in that: The method includes the following steps: S1. Activation of aluminum oxide carrier: Add solvent I, deionized water and alkaline solution to a flask, add aluminum oxide powder while stirring, stir evenly, filter and dry; S2. Preparation of composite catalyst: A mixed aqueous solution of ruthenium trichloride trihydrate and palladium chloride dihydrate was prepared in a flask, and the aluminum oxide treated in S1 was added with stirring. After adsorption, it was reduced with 85% hydrazine hydrate, filtered and dried to obtain the composite catalyst. S3. High-pressure hydrogenation: In a high-pressure reactor, solvent 2, ethyl 6-carbonyl-8-chlorooctanoate, and a composite catalyst are added. The temperature is controlled at 80-85℃ and the hydrogen pressure is 3.0-3.5MPa to prepare ethyl R-6-hydroxy-8-chlorooctanoate. S4. Chlorination: The reaction solution of S3 is heated to 40-50℃, and chlorination reagent is added dropwise. After the reaction, solvent II is recovered under reduced pressure, and then distilled to obtain ethyl R-6,8-dichlorooctanoate.

2. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: The solvent mentioned in S1 is ethanol or methanol.

3. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: The alkaline solution mentioned in S1 is one of sodium ethoxide, sodium methoxide, sodium hydroxide, and potassium hydroxide.

4. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: The mass ratio of solvent 1 to aluminum oxide powder in S1 is between 1:1 and 1:5; the mass ratio of deionized water to aluminum oxide powder is between 1:1 and 1:10; and the mass ratio of alkaline solution to aluminum oxide powder is between 1:100 and 1:

10.

5. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: In S2, the molar ratio of metallic ruthenium to palladium in ruthenium trichloride trihydrate and palladium chloride dihydrate ranges from 1:1 to 5:

1.

6. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: Solvent 2 in S2 is one of DMF, DMSO, tetrahydrofuran, and dioxane, and the mass ratio of solvent 2 to ethyl 6-carbonyl-8-chlorooctanoate is in the range of 2:1 to 10:

1.

7. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: The mass ratio of the composite catalyst described in S3 to ethyl 6-carbonyl-8-chlorooctanoate ranges from 1:200 to 1:

10.

8. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: The S3 medium-high pressure hydrogen addition hydrogen pressure range is 2.0-5.0 MPa.

9. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: The chlorinating agent mentioned in S4 is one of di(trichloromethyl) carbonate, thionyl chloride, and trichloroisocyanuric acid, and the molar ratio of the chlorinating agent to ethyl 6-carbonyl-8-chlorooctanoate is in the range of 1.5:1 to 1:

1.

10. The method for asymmetric synthesis of ethyl R-6,8-dichlorooctanoate by catalytic hydrogenation using a composite catalyst according to claim 1, characterized in that: The chlorination time in S4 ranges from 2 to 12 hours.

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