A method for preparing high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester

Abstract

This invention belongs to the field of organic chemistry and discloses a method for preparing high-purity bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester. The method includes: using 1,4-cyclohexanedicarboxylic acid and diethylene glycol monoethyl ether as main raw materials, an esterification reaction is carried out under the action of a catalyst; the reaction is accelerated by removing water, a byproduct of the reaction, at a reflux temperature of 70-80°C under reduced pressure using a water separator, and the reaction is carried out for 2.5-5 hours to obtain a reaction solution of bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester; the reaction solution is then subjected to hot filtration to remove impurities, and the filtrate is desolventized by vacuum distillation to obtain high-purity bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester. This preparation process has the advantages of short reaction time, low energy consumption, and simple post-processing. This invention provides a new, low-cost, efficient, and environmentally friendly industrial preparation method.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry technology and relates to a method for preparing high-purity bis-diethoxydiethylene cyclohexane 1,4-dicarboxylic acid ester. Specifically, it relates to a technical solution for the preparation, separation, and purification of cosmetic-grade high-purity bis-diethoxydiethylene cyclohexane 1,4-dicarboxylic acid ester suitable for industrial production. Background Technology

[0002] Bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester (trade name: Neosolue™-Aqulio) is a novel chemical penetration enhancer developed by Nippon Seika Co., Ltd. This novel chemical penetration enhancer exhibits amphiphilic solvent characteristics. Compared with traditional penetration enhancers, its structural properties demonstrate a series of significant technical features and advantages, mainly in the following aspects: 1. Highly efficient penetration enhancement: It shows significant penetration enhancement effects on various water-soluble and polar active ingredients, effectively improving their bioavailability; 2. Mild action and high safety: Its mechanism of action is to temporarily disturb the lipid spatial structure, rather than dissolving or permanently damaging the skin barrier. Transdermal water loss tests show that it does not damage the skin barrier function after use, has low irritation, and good safety. 3. Amphiphilic properties and broad compatibility: Its molecular structure possesses both hydrophilic and lipophilic components, enabling it to be well-compatible with various cosmetic ingredients. It is suitable for various dosage forms such as aqueous solutions, gels, lotions, and creams, without affecting formulation stability. 4. Synergistic potential: As mentioned earlier, it can produce significant synergistic effects when combined with other types of penetration enhancers (such as transdermal short peptide TD-1, ethoxydiethylene glycol, etc.), providing the possibility for developing highly efficient composite penetration enhancer systems. 5. Wide range of applications: It can be widely used in various skincare products, such as serums, toners, lotions, creams, and masks, helping whitening ingredients (such as tranexamic acid and vitamin C derivatives), anti-aging ingredients (such as peptides), moisturizing ingredients (such as hyaluronic acid), and soothing ingredients to better exert their effects. It is against this backdrop that a new type of penetration enhancer has attracted attention, aiming to overcome the shortcomings of existing technologies and improve the bioavailability of active ingredients. Diethoxydiethylene cyclohexane 1,4-dicarboxylic acid ester, as a novel penetration enhancer, is applied due to the urgent need in the cosmetics industry for safe and efficient transdermal absorption technology. It effectively enhances the penetration of active ingredients through a unique mechanism of action and possesses outstanding characteristics such as high efficiency, safety, broad compatibility, and synergistic effects. The recommended addition level is 0.1-2%.

[0003] Currently, the synthesis method for bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester is a "one-step method," which uses 1,4-cyclohexanedicarboxylic acid and diethylene glycol monoethyl ether as main raw materials. An esterification reaction occurs under heating conditions to generate a reaction solution of bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester. The reaction solution is then separated and purified to obtain a pale yellow to colorless liquid, bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester. The original Japanese patent JP2009035497 relates to a penetration enhancer for dicarboxylic acid diesters containing polyoxyethylene monoalkyl ether and a method for producing cosmetics or topical formulations containing them. This patented technology uses one equivalent amount of 1,4-cyclohexanedicarboxylic acid and three equivalent amounts of diethylene glycol monoethyl ether as raw materials, heated to 150–230°C under nitrogen protection, and the reaction is carried out for 33 hours after water removal by distillation. Unreacted diethylene glycol monoethyl ether was then removed by distillation under reduced pressure, ultimately yielding the target product, bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester, with a yield of 96%. The final product was a colorless to pale yellow liquid. The invention involves adding three times the amount of diethylene glycol monoethyl ether to ensure complete reaction, heating to 150–230°C, and removing the water generated during the reaction by distillation. The reaction takes 33 hours. This preparation process significantly increases raw material costs and presents challenges in post-processing separation, along with other disadvantages such as high reaction temperature, long reaction time, high energy consumption, and low production efficiency. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides a synthetic method for preparing high-purity bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester for skin care, suitable for industrial production. This invention uses 1,4-cyclohexanedicarboxylic acid and diethylene glycol monoethyl ether in a specific ratio as main raw materials. An esterification reaction occurs under the action of an appropriate catalyst. The reaction is accelerated by removing water, a byproduct generated during the reaction, at a reduced pressure and a reflux temperature of 70-110°C using a water separator. This shortens the reaction time to 2.5-5 hours. By lowering the reaction temperature and reducing the reaction time, the problems of increased byproducts and darkening of the product color caused by prolonged high temperatures are solved, rapidly converting the product into a bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester reaction solution. The reaction solution is then subjected to hot filtration to remove impurities, and the filtrate is distilled under reduced pressure to remove the solvent, yielding high-purity bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester. This preparation process features short reaction time, low energy consumption, and simple post-processing, achieving high yield and high purity in the preparation of the target product, bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester. This invention provides an industrial preparation method with low production cost, high efficiency, environmental friendliness, and stable process parameter control.

[0005] The entire preparation process consists of two stages: a reaction stage (S1) and a post-treatment stage (S2). The reaction stage (S1) involves mixing 1,4-cyclohexanedicarboxylic acid and diethylene glycol monoethyl ether (DED ether) in a reactor equipped with reflux and water separation devices, along with a suitable amount of catalyst, in a uniform stirring motion. Under reduced pressure, the mixture is heated to the target temperature required by the process and refluxed to remove the water generated during the reaction. The reaction lasts for 2.5-5 hours. After the reaction is completed, a bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester reaction solution is obtained. The post-treatment stage (S2) involves filtering the bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester reaction solution at room temperature to remove insoluble matter, washing with water, and then concentrating the organic phase under reduced pressure to remove the solvent, yielding the high-purity target product, bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester. The reaction equation is as follows:

[0006]

[0007] In this preparation process, the main raw materials mentioned in the reaction stage (S1) are 1,4-cyclohexanedicarboxylic acid and diethylene glycol monoethyl ether. The catalyst includes one or more of the following: concentrated sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid hydrate, cation exchange resin, and H2SO4-SiO2 solid acid, preferably H2SO4-SiO2 solid acid. The organic solvent used is one or more of toluene, xylene, isobutanol, and isoamyl alcohol, preferably toluene. The molar ratio of 1,4-cyclohexanedicarboxylic acid to diethylene glycol monoethyl ether is 1:1.9-3. The amount of catalyst added is 1-10% of the mass of 1,4-cyclohexanedicarboxylic acid. The reaction temperature is 70-110℃, preferably 80℃. The general method for the post-treatment stage (S2) is to cool the reaction solution to room temperature, filter, wash with water, and then heat the organic phase to a specified temperature under reduced pressure to remove the solvent. The organic solvent is one or more of ethyl acetate, toluene, xylene, isobutanol, and isoamyl alcohol, preferably toluene. Attached Figure Description

[0008] Figure 1 This is the 1H NMR spectrum of the high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester prepared in Example 1. Detailed Implementation

[0009] A method for preparing high-purity bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester. The entire process includes an esterification reaction stage and a post-treatment stage. The esterification reaction stage is carried out in a reactor equipped with a water separation reflux device, using 1,4-cyclohexanedicarboxylic acid and diethylene glycol monoethyl ether as the reaction system, with or without the addition of organic solvent. The esterification reaction occurs under the action of a catalyst at atmospheric or reduced pressure, at a reaction temperature of 70-110℃, for 2.5-5 hours, to generate a bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester reaction solution. After the post-treatment stage, high-purity bis-diethoxydiethylenecyclohexane 1,4-dicarboxylic acid ester is obtained.

[0010] The organic solvent is one or more of toluene, xylene, isobutanol, and isoamyl alcohol.

[0011] The catalyst is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid hydrate, cation exchange resin, and H2SO4-SiO2 solid acid.

[0012] The molar ratio of 1,4-cyclohexanedicarboxylic acid to diethylene glycol monoethyl ether is 1:1.9-3; the amount of catalyst added is 1-10% of the mass of 1,4-cyclohexanedicarboxylic acid.

[0013] The reaction temperature is 70-80℃.

[0014] The post-processing stage includes one or more of the following: adding organic solvent, washing with water, extraction, filtration, drying, and desolventizing by vacuum distillation.

[0015] Example 1

[0016] In a 1000 ml round-bottom flask, a rotor was added, and 100 g (0.58 mol) of 1,4-cyclohexanedicarboxylic acid, 234 g (1.75 mol) of diethylene glycol monoethyl ether, and 3 g (3 wt%) of p-toluenesulfonic acid monohydrate were weighed out. The mixture was stirred and, under normal pressure, slowly heated to 100 °C and reacted for 5 hours. The reaction was then checked for completeness. The reaction solution was cooled to room temperature, and 500 ml of ethyl acetate was added. The solution was washed once with 250 ml of 5% sodium bicarbonate aqueous solution and extracted twice with 200 ml of water. The pH of the aqueous phase was checked until neutral. The organic phase was dried over a small amount of anhydrous sodium sulfate. The filtrate was recovered under reduced pressure until no liquid flowed out, then heated to 80 °C and removed under reduced pressure (-0.098 MPa) to remove residual ethyl acetate. 200 g of a pale yellow liquid was obtained, with a yield of 85.2% and a purity of 95.2%. 1 NMR: δH (600MHz, d 6-DMSO) 4.08-4.12 (m, 4H), 3.55-3.58 (m, 4H), 3.49-3.51 (m, 4H), 3.41-3.47 (m, 6H), 3.36-3.39 (d, 2H), 1.79-1.89 (d, 2H), 1.57-1.73 (m, 6H), 1.33-1.37 (t, 2H), 1.04-1.15 (m, 6H) ¹H NMR spectrum as shown Figure 1 As shown; GC-MS: M=404.5.

[0017] Example 2

[0018] In a 1000ml round-bottom flask, a rotor was added, and 100g (0.58mol) of 1,4-cyclohexanedicarboxylic acid and 194.8g (1.45mol) of diethylene glycol monoethyl ether were weighed out. 6g (6% wt) of p-toluenesulfonic acid monohydrate was added. The mixture was stirred and, under normal pressure, slowly heated to 110℃ and reacted for 3 hours. The reaction was then checked for completeness. The reaction solution was cooled to room temperature, and 500ml of ethyl acetate was added. The solution was washed once with 250ml of 5% sodium bicarbonate aqueous solution and extracted twice with 200ml of water. The pH of the aqueous phase was checked until neutral. The solution was filtered with organic solvent, and the filtrate was recovered under reduced pressure until no liquid flowed out. The solution was then heated to 80℃ and subjected to reduced pressure of -0.098 MPa to remove residual ethyl acetate, yielding 216.4g of a colorless to pale yellow liquid, with a yield of 92.0% and a purity of 96.4%.

[0019] Example 3

[0020] In a 1000ml round-bottom flask equipped with a water separator and reflux device, a rotor was added, and 100g (0.58mol) of 1,4-cyclohexanedicarboxylic acid, 147.7g (1.10mol) of diethylene glycol monoethyl ether, 3g (3wt%) of p-toluenesulfonic acid monohydrate, and 100ml of toluene were added. The mixture was stirred and heated to 110℃ under normal pressure for 2.5 hours. The reaction was then checked for completeness. The reaction solution was cooled to room temperature, and 50ml of toluene was added. The solution was washed once with 250ml of sodium bicarbonate aqueous solution (5%), and extracted twice with 100ml of water. The pH of the aqueous phase was checked until neutral. The solution was filtered with organic solvent, and the filtrate was recovered under reduced pressure until no liquid flowed out. The solution was then heated to 100℃ and the residual toluene was removed under reduced pressure of -0.098MPa, yielding 220g of a colorless to pale yellow liquid, with a yield of 90.0% and a purity of 98.2%.

[0021] Example 4

[0022] In a 500ml round-bottom flask equipped with a water separator and reflux device, a rotor was added, and 100g (0.58mol) of 1,4-cyclohexanedicarboxylic acid, 147.7g (1.10mol) of diethylene glycol monoethyl ether, 3g (3%wt) of H2SO4-SiO2 solid acid, and 100ml of toluene were added. The mixture was stirred and heated to 110℃ under normal pressure for 4.5 hours. The reaction was then checked for completeness. The reaction solution was cooled to room temperature, filtered to recover the catalyst, and the filtrate was washed with 50ml of water until neutral. The organic phase was recovered under reduced pressure until no liquid flowed out. The temperature was then raised to 100℃, and residual toluene was removed under reduced pressure of -0.098MPa, yielding 221g of a pale yellow liquid, with a yield of 92.1% and a purity of 94.5%.

[0023] Example 5

[0024] In a 500ml round flask equipped with a water separator and reflux device, a rotor was added, and 100g (0.58mol) of 1,4-cyclohexanedicarboxylic acid and 163.6g (1.22mol) of diethylene glycol monoethyl ether were weighed out. 5g (5% wt) of H₂SO₄-SiO₂ solid acid was added, along with 100ml of toluene. The mixture was stirred, and under a vacuum ≥0.085, the temperature was raised to 80℃ and refluxed for 2.5 hours. The reaction was then checked for completeness. The mixture was cooled to room temperature, filtered, and the filtrate was recovered under reduced pressure until no solvent flowed out. The temperature was then raised to 100℃ and the solution was recovered under reduced pressure for 2 hours until no liquid flowed out. The solution was cooled to obtain 226g of a colorless liquid, with a yield of 96.5% and a purity of 98.2%.

[0025] Example 6

[0026] In a 100-liter glass reactor equipped with a water separator and reflux device, 10 liters of toluene were added, along with 10 kg (58 mol) of 1,4-cyclohexanedicarboxylic acid, 16.36 kg (121.8 mol) of diethylene glycol monoethyl ether, and 600 g (6% wt) of H₂SO₄-SiO₂ solid acid. The mixture was stirred, and under vacuum ≥0.085 MPa, the temperature was raised to 80°C and refluxed for 3 hours. The reaction was then checked for completeness. The mixture was cooled to room temperature, filtered, and the filtrate was recovered under reduced pressure until no solvent flowed out. The temperature was then raised to 100°C and the solution was recovered under reduced pressure for 2 hours until no liquid flowed out. The solution was cooled to obtain 23.0 kg of a colorless liquid, with a yield of 98.0% and a purity of 98.9%.

Claims

1. A method for preparing high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester, the entire process comprising: The esterification reaction stage and the post-treatment stage are characterized in that the esterification reaction stage is carried out in a reactor equipped with a water separation and reflux device, with 1,4-cyclohexanedicarboxylic acid and diethylene glycol monoethyl ether as the reaction system, with or without the addition of organic solvent, under the action of a catalyst, the esterification reaction occurs, and the reaction is carried out under reduced pressure at a reaction temperature of 70-110°C for 2.5-5 hours to generate a bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester reaction solution. After the post-treatment stage, high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester is obtained.

2. The method for preparing high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester according to claim 1, characterized in that: The organic solvent is one or more of toluene, xylene, isobutanol, and isoamyl alcohol.

3. The method for preparing high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester according to claim 1, characterized in that: The catalyst is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid hydrate, cation exchange resin, and H2SO4-SiO2 solid acid.

4. The method for preparing high-purity bis-diethoxydiethylene cyclohexane 1,4-dicarboxylic acid ester according to claim 1, characterized in that: The molar ratio of 1,4-cyclohexanedicarboxylic acid to diethylene glycol monoethyl ether is 1:1.9-3; the amount of catalyst added is 1-10% of the mass of 1,4-cyclohexanedicarboxylic acid.

5. The method for preparing high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester according to claim 1, characterized in that: The reaction temperature is 70-80℃.

6. The method for preparing high-purity bis-diethoxydiethylene glycol cyclohexane 1,4-dicarboxylic acid ester according to claim 1, characterized in that: The post-processing stage includes one or more of the following: adding organic solvent, washing with water, extraction, filtration, drying, and desolventizing by vacuum distillation.

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