A method for preparing cetyl ethylhexanoate and a product containing it

Abstract

The application belongs to the technical field of ester compound synthesis, and discloses a preparation method of cetostearyl ethylhexanoate and a product containing the same. The preparation method is as follows: cetostearyl alcohol and ethylhexanoic acid are mixed at a molar ratio of 1:(1.20-1.40), and then the mixture is heated to 140-160 DEG C under stirring, and then heated to 210-220 DEG C at a rate of 8-15 DEG C / h, and then reacted under normal pressure; the reaction is ended when the acid value of the reaction system is reduced to 40 mg KOH / g or less, and the crude cetostearyl ethylhexanoate is prepared; finally, the crude cetostearyl ethylhexanoate is subjected to three-stage molecular distillation. The cetostearyl ethylhexanoate prepared by the application does not introduce impurities such as foreign metal ions and acid anions, has strong stability, can play a more stable protective role on high-sensitivity active ingredients, and can better meet the application requirements of the medical field and high-end cosmetics.

Description

Technical Field

[0001] This invention belongs to the field of functional pharmaceutical excipient synthesis technology, specifically relating to a method for preparing cetyl ethylhexanoate and products containing it. Background Technology

[0002] Cetyl ethylhexanoate (also known as hexadecyl isooctanoate) is a branched saturated fatty acid higher fatty alcohol ester with high spreadability and low surface tension. Because it can form a breathable, soft, and water-repellent protective film on the skin or material surface, it is widely used in the preparation of transdermal drug delivery matrices, high-end cosmetics, and polymer plasticizers. In the pharmaceutical field, it is used as an ointment matrix to improve transdermal drug absorption efficiency; as a solvent / co-solvent for lipid-soluble drugs to improve the usability of topical drugs in the skin layer; and as a functional excipient to provide skin barrier protection, reduce irritation, and improve patient compliance in topical formulations. Furthermore, in cosmetics, it can be used as a substitute for natural squalane to provide a silky feel; and in plastics processing, it is used as an environmentally friendly plasticizer to improve the low-temperature flexibility of resins.

[0003] The industrial production methods of cetyl ethylhexanoate are mainly divided into bio-enzymatic catalysis and direct chemical esterification. Enzymatic methods typically use immobilized lipases as catalysts to carry out esterification reactions at relatively low temperatures, resulting in high product purity and eliminating the need for complex subsequent decolorization. However, enzymatic methods are extremely demanding in terms of reaction temperature, humidity, and solvent systems, leading to low production efficiency and the need for expensive bio-enzyme preparations, resulting in high production costs and making them unsuitable for large-scale continuous industrial production. Chemical synthesis utilizes the direct esterification and dehydration reaction of cetyl alcohol and 2-ethylhexanoic acid under the action of a catalyst. This method offers fast reaction speed, high yield, and relatively low cost, making it suitable for large-scale industrial production. However, traditional chemical methods are prone to side reactions such as etherification and oxidation during the reaction process, resulting in ester mixtures containing a large amount of unreacted raw materials, diesters, and polymers. The product purity is insufficient and the color is dark, affecting its application in high-end fields and posing significant challenges to subsequent separation and purification.

[0004] Currently, there is a lot of research on chemical synthesis methods, such as using solid superacid S2O8. 2－The Ti-MCM-41 catalyst, used for the direct esterification of isooctanoic acid hexadecyl ester with an acid and alcohol, effectively avoids the drawbacks of traditional liquid acid catalysts. However, the self-made solid superacid catalyst is costly, and the synthesis of the mesoporous molecular sieve Ti-MCM-41 is cumbersome, requiring large amounts of template agents and highly oxidizing impregnation solutions, as well as extremely high calcination activation energy consumption. Moreover, the acid centers of the solid superacid are prone to hydration and deactivation when exposed to trace amounts of moisture, requiring the pre-reacting acid and alcohol raw materials to undergo strict deep dehydration treatment, significantly increasing the cost and complexity of the pretreatment process. Furthermore, in heterogeneous catalytic systems, reactants are difficult to diffuse into the internal pores of the molecular sieve, resulting in low utilization of active sites. This often requires extremely high reaction temperatures (e.g., 220℃) and long reaction times, easily triggering thermal oxidation side reactions of the product at high temperatures. Patent CN202510525303.3 discloses a method for preparing cetyl ethylhexanoate by catalyzing the esterification reaction of ethylhexanoic acid and cetyl alcohol under nitrogen protection using a titanium dioxide-supported stannous oxide composite material as a catalyst. This process, through the selection of a specific catalyst and the subsequent thin-film evaporation and nitrogen stripping processes, effectively reduces the occurrence of high-temperature side reactions and significantly improves the purity and yield of the product. However, this technology suffers from difficulties in catalyst separation and clogging. Due to the extremely large specific surface area of ​​nanoscale SnO / TiO2, it easily aggregates in viscous esterification products, making it difficult to completely retain using conventional filtration methods. Furthermore, this composite catalyst also poses a risk of residual metal ions: even trace amounts of tin (Sn) or titanium (Ti) ions remaining in the product can not only catalyze the hydrolysis of esters during storage but also become a fatal flaw that can trigger sensitization reactions when used as a carrier in high-end pharmaceuticals or in sensitive skin cosmetics.

[0005] Therefore, in order to address the problems of high catalyst cost, complex and cumbersome operation, numerous by-products, difficulty in separating products from catalysts, and difficulty in purification in existing chemical synthesis methods, there is an urgent need to provide an improved method for synthesizing cetyl ethylhexanoate to meet the needs of the pharmaceutical industry and high-end cosmetics. Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention proposes a method for preparing cetyl ethylhexanoate and a product containing it. The cetyl ethylhexanoate prepared by the present invention does not introduce impurities such as foreign metal ions and acid radical anions, exhibits strong stability, and can provide more stable protection for highly sensitive active ingredients, thus better meeting the application requirements of the pharmaceutical field and high-end cosmetics.

[0007] This invention provides a method for preparing cetyl ethylhexanoate.

[0008] Specifically, a method for preparing cetyl ethylhexanoate includes the following steps: (1) Cetyl alcohol and ethylhexanoic acid are mixed in a molar ratio of 1:(1.20-1.40). The mixture is heated to 140-160°C with stirring, and then heated to 210-220°C at a rate of 8-15°C / h. The mixture is then kept at room temperature. The reaction is stopped when the acid value of the reaction system drops to 40 mg KOH / g or below, and crude cetyl alcohol ethylhexanoate is obtained. (2) The crude cetyl ethylhexanoate prepared in step (1) is subjected to three-stage molecular distillation to obtain cetyl ethylhexanoate; the conditions for the three-stage molecular distillation are: the first stage molecular distillation is performed at 50-200 Pa and 100-160 °C, the second stage molecular distillation is performed at 10-100 Pa and 100-160 °C, and the third stage molecular distillation is performed at less than 10 Pa and 140-180 °C.

[0009] This invention, in a catalyst-free high-temperature esterification reaction system, precisely controls the ratio of cetyl alcohol to ethylhexanoic acid. The reactants are first heated to 140–160°C, then slowly heated to 210–220°C at a rate of 8–15°C / h for atmospheric pressure holding. This not only solves the problem of uneven heating of high-viscosity materials in the initial stage of the reaction, ensuring the uniformity of the temperature field within the reactor and preventing thermal decarboxylation or self-polymerization of free fatty acids due to excessively high local temperatures, but also, within the 150°C–220°C range, this heating rate and reactant ratio provide sufficient contact time between the alcohol and acid, promoting a positive equilibrium shift and improving the reaction rate and conversion rate of the catalyst-free reaction system. Combined with atmospheric pressure holding, this heating condition effectively suppresses the volatilization loss of low-boiling-point acids and avoids the formation of coking precursors due to local overheating, thus ensuring high conversion rates while achieving excellent product color. By employing a three-stage parameter gradient optimized molecular distillation process, residual raw materials (especially excess ethylhexanoic acid) and byproducts in the crude product can be efficiently separated under mild conditions. This avoids the introduction of additional impurities through high-temperature decolorization, resulting in a final product with an ester content greater than 99.5% and a color less than 10. Furthermore, because this method does not use catalysts and does not introduce any foreign metal ions, acid anions, or salts generated during neutralization, it exhibits strong stability and provides more stable protection for highly sensitive active ingredients (such as retinol), better meeting the application requirements of the pharmaceutical and high-end cosmetic fields.

[0010] In some embodiments of the present invention, the molar ratio of cetyl alcohol to ethylhexanoic acid is 1:(1.22 to 1.35).

[0011] In some embodiments of the present invention, the stirring state in step (1) is to stir at a speed of 350 to 600 rpm.

[0012] In some embodiments of the present invention, in step (1), the temperature is raised to 145-155°C at a stirring speed of 350-500 rpm, and then raised to 210-220°C at a heating rate of 8-12°C / h for heat preservation reaction.

[0013] In some embodiments of the present invention, the heat preservation reaction time is 1 to 8 hours, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, etc. Preferably, the heat preservation reaction time is 2 to 5 hours. By controlling the heat preservation time, the esterification reaction can be ensured to proceed fully, avoiding insufficient reaction leading to low yield, and also avoiding excessive heat preservation causing oxidation side reactions that darken the product color.

[0014] It should be understood that the reaction process of cetyl alcohol and ethylhexanoic acid in step (1) includes a heating stage and a holding stage, both of which are carried out under atmospheric pressure and nitrogen protection. Reacting under atmospheric pressure and nitrogen protection can effectively prevent the raw materials and products in the reaction system from being oxidized by oxygen in the air, further reducing the occurrence of side reactions and improving the color and quality of the product.

[0015] In some embodiments of the present invention, the reaction is terminated in step (1) when the acid value of the reaction system drops to 25-40 mg KOH / g. At this time, the degree of esterification of the reaction is greater than 90%. Preferably, the reaction is terminated in step (1) when the acid value of the reaction system drops to 25-35 mg KOH / g.

[0016] In some embodiments of the present invention, the preparation method further includes: after the reaction is completed in step (1), cooling to 60-80°C, filtering the crude cetyl ethylhexanoate, and then subjecting the filtered crude product to the tertiary molecular distillation process in step (2). The filtration step can remove any solid impurities that may be present in the system in advance, preventing them from entering the subsequent distillation process and affecting the operation of the equipment.

[0017] In some embodiments of the present invention, the conditions for the first-stage molecular distillation are a pressure of 80–150 Pa, a temperature of 110–150 °C, and a scraper rotation speed of 100–300 rpm, mainly removing residual unreacted ethylhexanoic acid and a small amount of low-boiling-point impurities from the system. The conditions for the second-stage molecular distillation are a pressure of 20–80 Pa, a temperature of 110–150 °C, and a scraper rotation speed of 100–300 rpm, further removing residual unreacted ethylhexanoic acid, as well as cetyl alcohol and byproducts with small molecular weights from the system. The conditions for the third-stage molecular distillation are a pressure of 1–8 Pa, a temperature of 150–170 °C, and a scraper rotation speed of 100–300 rpm. Under these conditions, collecting the light components yields the qualified cetyl alcohol ethylhexanoate product.

[0018] The present invention also provides a product containing cetyl ethylhexanoate.

[0019] Specifically, a product containing cetyl ethylhexanoate includes cetyl ethylhexanoate prepared by the above preparation method, and at least one pharmaceutical / transdermal absorption ingredient or cosmetic active ingredient.

[0020] In some embodiments of the present invention, the pharmaceutical / transdermal absorption ingredients include nonsteroidal anti-inflammatory drugs (such as salicylic acid, ibuprofen), hormonal drugs (hydrocortisone, mometasone furoate), or antibiotics (ketoconazole, clindamycin); the cosmetic active ingredients include retinol (vitamin A) and its derivatives, vitamin E (tocopherol) and its derivatives, vitamin C and its derivatives, niacinamide, salicylic acid, or ceramides. The cetyl ethylhexanoate product of the present invention does not contain residual metal ions from catalysts, acid radical anions, or salts generated from neutralization reactions. It neither catalyzes ester bond hydrolysis nor triggers active ingredient degradation, and its stability protection effect on active ingredients is superior to that of cetyl ethylhexanoate synthesized by ordinary chemical methods. It is particularly suitable for adding easily deactivated sensitive active ingredients such as retinol. Simultaneously, this product itself possesses good transdermal absorption promoting effects and dissolving capabilities, thus better meeting the application needs of pharmaceutical preparations and high-end cosmetics.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The preparation method provided by this invention does not require the addition of an extra catalyst. By controlling the raw material ratio and the stepwise heating process, the esterification reaction can be effectively promoted to proceed smoothly. This not only avoids the problems of difficult catalyst separation and metal ion residue, but also eliminates the need for additional steps such as catalyst preparation and deep dehydration pretreatment of raw materials, greatly simplifying the production process and reducing production costs. More importantly, the purification by three-stage molecular distillation with gradient parameters can remove various impurities under mild conditions, resulting in a product with high purity, light color, and strong stability. It can provide more stable protection for highly sensitive active ingredients (such as retinol and peptides), meeting the application requirements of high-end fields.

[0022] (2) The method provided by the present invention, since no exogenous catalyst is introduced, can eliminate the problems of product coloring and autocatalytic oxidation during storage caused by residual metal ions or acid groups from the source. This allows the final product to directly enter the short-path molecular distillation process without alkaline washing and neutralization. The preparation process is simple, the esterification rate is high, and the prepared product has strong stability, extremely low risk of autocatalytic oxidation degradation during storage, and high product quality stability. Attached Figure Description

[0023] Figure 1 This is a process flow diagram in Embodiment 1 of the present invention. Detailed Implementation

[0024] To enable those skilled in the art to more clearly understand the technical solutions described in this invention, the following embodiments are provided for illustration. It should be noted that the following embodiments do not constitute a limitation on the scope of protection claimed by this invention.

[0025] Unless otherwise specified, the raw materials, reagents or apparatus used in the following examples and comparative examples are available from conventional commercial sources or can be obtained by existing known methods.

[0026] The ester content, color (APHA), acid value, stability test, and protective effect against heat-sensitive active ingredients of cetyl ethylhexanoate in the following examples and comparative examples were determined according to the following methods: (1) The ester content of cetyl ethylhexanoate prepared in each example and comparative example was detected by gas chromatography. The acid value was in accordance with GB / T 14455.5-2008, the color was in accordance with GB / T 3143-1982, and the esterification rate was calculated based on the acid value.

[0027] (2) Stability test: Take the same amount of cetyl ethylhexanoate prepared in each example and comparative example, seal it in a transparent glass bottle, and place it in an oven at 60±2℃ in the dark for 8 weeks. Monitor the changes in ester content, color (APHA) and acid value.

[0028] (3) Protective effect on heat-sensitive active ingredients Vitamin A powder was dissolved in cetyl ethylhexanoate prepared in each example and comparative example under inert gas (nitrogen) protection to prepare 0.1% solutions. The solutions were sealed in 2 mL amber screw-top bottles (with PTFE gaskets) with headspace nitrogen protection during sealing. Accelerated destructive testing was then conducted at 40±2℃ under light-protected conditions (wrapped in black cloth). After 28 days, the vitamin A content was determined by liquid chromatography (LC) using a C18 column and a detection wavelength of 325 nm. The retention rate of vitamin A in each sample was calculated (retention rate = measured content / initial content × 100%).

[0029] Example 1 A method for preparing cetyl ethylhexanoate, such as... Figure 1 As shown, it includes the following steps: (1) Add 56.6g cetyl alcohol and 43.4g ethylhexanoic acid to a 200mL four-necked glass reaction flask and mix well. Under a nitrogen atmosphere, with a stirring speed of 400rpm, first rapidly heat to 150℃, then heat to 210℃ at a rate of 10℃ / h and keep the reaction at normal pressure. Stop the reaction when the acid value of the reaction system drops to 30mg KOH / g (keep the temperature for about 4h). After cooling to 70℃, filter the reaction product to remove solid impurities present in the system and obtain the filtered crude cetyl alcohol ethylhexanoate. (2) The crude cetyl ethylhexanoate prepared in step (1) is subjected to three-stage molecular distillation to obtain cetyl ethylhexanoate. The conditions for three-stage molecular distillation are as follows: the first stage of molecular distillation is performed at 120 Pa, 130 °C and a scraping speed of 200 rpm, mainly to remove unreacted ethylhexanoic acid and a small amount of low-boiling impurities in the system; the second stage of molecular distillation is performed at 60 Pa, 130 °C and a scraping speed of 200 rpm, to further remove unreacted ethylhexanoic acid, cetyl alcohol and byproducts with small molecular weight in the system; the third stage of molecular distillation is performed at 5 Pa, 160 °C and a scraping speed of 200 rpm. Under these conditions, the light components are collected to obtain the colorless, odorless and transparent liquid cetyl ethylhexanoate product.

[0030] Example 2 Example 2 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the material is heated to 150°C, and then heated to 210°C at a rate of 8°C / h and held at that temperature for 3 hours. The remaining raw material ratios and preparation process are the same as in Example 1.

[0031] Example 3 Example 3 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the material is heated to 150°C, and then heated to 210°C at a rate of 15°C / h and held at that temperature for 3 hours. The remaining raw material ratios and preparation process are the same as in Example 1.

[0032] Comparative Example 1 Comparative Example 1 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the material is heated to 150°C, and then heated to 210°C at a rate of 5°C / h and held at that temperature for 3h. The remaining raw material ratios and preparation process are the same as in Example 1.

[0033] Comparative Example 2 Comparative Example 2 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the material is heated to 150°C, and then heated to 210°C at a rate of 25°C / h and held at that temperature for 3h. The remaining raw material ratios and preparation process are the same as in Example 1.

[0034] The ester content, color (APHA), acid value, stability, and protective effect on heat-sensitive active ingredients of cetyl ethylhexanoate prepared in Examples 1-3 and Comparative Examples 1-2 were tested, and the test results are shown in Table 1.

[0035] Table 1

[0036] As shown in Table 1, the cetyl ethylhexanoate prepared in Examples 1-3 of this invention has an esterification rate higher than 90.0%, an ester content of not less than 99.75%, a color of less than 10, and an acid value of not more than 0.03 mg KOH / g. Furthermore, after being placed at 60°C for 8 weeks, the ester content is still greater than 99.70%, the color is not more than 12, and the acid value is less than 0.05 mg KOH / g. In the accelerated destructive test, the vitamin A alcohol retention rate is 97.0%. In Comparative Example 1, the heating rate was too slow, resulting in the material remaining in the acid-thermal unstable region (150-190°C) for too long, triggering acid decarboxylation, alcohol etherification, and thermal oxidation color development. Byproducts were difficult to remove by molecular distillation, leading to a darker color and decreased stability in the finished product. In contrast, the heating rate in Comparative Example 2 was too fast, causing heat transfer lag in the high-viscosity material, resulting in overheating and coking of the wall surface, uneven mixing, and residual coking products that significantly worsened the color of the finished product, increased the acid value, and caused a sharp drop in the vitamin A alcohol retention rate.

[0037] Example 4 Example 4 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the molar ratio of cetyl alcohol to ethylhexanoate is 1:1.2. The remaining raw material ratios and preparation process are the same as in Example 1.

[0038] Example 5 Example 5 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the molar ratio of cetyl alcohol to ethylhexanoate is 1:1.4. The remaining raw material ratios and preparation process are the same as in Example 1.

[0039] Comparative Example 3 Comparative Example 3 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the molar ratio of cetyl alcohol to ethylhexanoate is 1:1.1. The remaining raw material ratios and preparation process are the same as in Example 1.

[0040] Comparative Example 4 Comparative Example 4 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that the molar ratio of cetyl alcohol to ethylhexanoate is 1:1.5. The remaining raw material ratios and preparation process are the same as in Example 1.

[0041] The ester content, color (APHA), acid value, stability, and protective effect on heat-sensitive active ingredients of cetyl ethylhexanoate prepared in Examples 4-5 and Comparative Examples 3-4 were tested, and the test results are shown in Table 2.

[0042] Table 2

[0043] As shown in Table 2, the cetyl ethylhexanoate prepared in Example 1 of this invention exhibits significantly better color, stability, and protective effect against vitamin A than the comparative example. In Comparative Example 3, the amount of ethylhexanoic acid added was slightly less, resulting in a significantly lower esterification rate (90.8%) compared to the example (≥91.5%), and a slightly higher acid value and lower vitamin A retention rate. Although Comparative Example 4 had a slightly higher esterification rate than the example, the finished product had a darker color, a slightly higher acid value, and a lower vitamin A retention rate, indicating that its sensory and protective active ingredient properties as a cosmetic base oil were inferior to those of the example.

[0044] Example 6 A method for preparing cetyl ethylhexanoate includes the following steps: (1) Add 56.6g cetyl alcohol and 43.4g ethylhexanoic acid to a 200mL four-necked glass reaction flask and mix well. Under a nitrogen atmosphere, with a stirring speed of 450rpm, first rapidly heat to 155℃, then heat to 220℃ at a rate of 12℃ / h and maintain the temperature at normal pressure; stop the reaction when the acid value of the reaction system drops to 28mg KOH / g (maintain the temperature for about 4.2h), and after cooling to 70℃, filter the reaction product to remove the solid impurities present in the system, and obtain the filtered crude cetyl alcohol ethylhexanoate; (2) The crude cetyl ethylhexanoate prepared in step (1) is subjected to three-stage molecular distillation to obtain cetyl ethylhexanoate. The conditions for three-stage molecular distillation are as follows: the first stage of molecular distillation is performed at 100 Pa, 120 °C and 180 rpm to remove unreacted ethylhexanoic acid and a small amount of low-boiling impurities in the system; the second stage of molecular distillation is performed at 50 Pa, 120 °C and 180 rpm to further remove unreacted ethylhexanoic acid, cetyl alcohol and byproducts with small molecular weight in the system; the third stage of molecular distillation is performed at 3 Pa, 150 °C and 180 rpm. Under these conditions, the light components are collected to obtain the colorless, odorless and transparent liquid cetyl ethylhexanoate product.

[0045] Comparative Example 5 Comparative Example 5 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that it only involves two-stage molecular distillation. The conditions for the first-stage molecular distillation are as follows: the first-stage molecular distillation is performed at 100 Pa and 120 °C, mainly to remove unreacted ethylhexanoic acid and a small amount of low-boiling-point impurities from the system; the second-stage molecular distillation is performed at 3 Pa and 150 °C, under which the light fraction is collected to obtain the finished cetyl ethylhexanoate product. The remaining raw material ratios and preparation process are the same as in Example 1.

[0046] Comparative Example 6 Comparative Example 6 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that in step (1), the temperature is first raised to 120°C under stirring, and then raised to 200°C at a rate of 10°C / h and held at that temperature. The reaction is terminated when the acid value of the reaction system drops to 30 mg KOH / g. The proportions of other raw materials and the preparation process are the same as in Example 1.

[0047] Comparative Example 7 Comparative Example 7 provides a method for preparing cetyl ethylhexanoate, which differs from Example 1 in that in step (1), the temperature is first raised to 180°C under stirring, and then raised to 220°C at a rate of 10°C / h and held at that temperature. The reaction is terminated when the acid value of the reaction system drops to 30 mg KOH / g. The proportions of other raw materials and the preparation process are the same as in Example 1.

[0048] The ester content, color (APHA), acid value, stability, and protective effect on heat-sensitive active ingredients of cetyl ethylhexanoate prepared in Examples 6 and Comparative Examples 5-7 were tested, and the test results are shown in Table 3.

[0049] Table 3

[0050] As shown in Table 3, Comparative Example 5 only underwent two-stage molecular distillation, resulting in less effective removal of impurities such as small-molecule alcohols and acids compared to the Examples 1. This led to a significantly lower ester content and a significantly higher acid value compared to Example 1. Furthermore, its stability testing showed that its ability to store stably was also inferior to Example 1, and its protective effect on retinol was less effective due to interference from impurities. Comparative Example 6 began with a slow heating process at a relatively low temperature, and the final holding temperature was also low, failing to effectively promote the esterification reaction and resulting in a significant decrease in its esterification rate. Comparative Example 7 first heated to a high temperature (180°C) and then slowly increased the temperature. The high-viscosity material experienced thermal hysteresis and micro-charring on the wall surface, leading to a darker product color and the appearance of more byproducts. This resulted in a significant decrease in ester content and a marked impact on the protective effect on retinol.

[0051] Comparative Example 8 Cetyl ethylhexanoate was prepared according to the preparation method of Example 1 in patent CN 120535409 A.

[0052] The ester content, color (APHA), acid value, stability, and protective effect on heat-sensitive active ingredients of cetyl ethylhexanoate prepared in Comparative Example 8 were tested, and the test results are shown in Table 4.

[0053] Table 4

[0054] As shown in Table 4, the cetyl ethylhexanoate prepared in Example 1 of this invention has a high esterification rate and ester content, low acid value, and light color. Furthermore, after 8 weeks of accelerated heat storage at 60°C, the color (APHA) only increased from 8 to 10, and the acid value remained at or below 0.05 mg KOH / g, significantly superior to existing methods (color increased to above 25, acid value increased to above 0.15). This is because this invention does not use a metal catalyst, eliminating the catalytic effect of metal ions on thermal oxidation, thus maintaining extremely high chemical inertness of the product under extreme conditions. The study also found that after 28 days of accelerated storage, the retinol retention rate in the oil sample of this invention was above 98%; while the retinol retention rate in the oil sample of Comparative Example 8 was only 86%.

[0055] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing cetyl ethylhexanoate, characterized in that, Includes the following steps: (1) Cetyl alcohol and ethylhexanoic acid are mixed in a molar ratio of 1:(1.20-1.40). The mixture is heated to 140-160°C with stirring, and then heated to 210-220°C at a rate of 8-15°C / h. The mixture is then kept at room temperature. The reaction is stopped when the acid value of the reaction system drops to 40 mg KOH / g or below, and crude cetyl alcohol ethylhexanoate is obtained. (2) The crude cetyl ethylhexanoate prepared in step (1) is subjected to three-stage molecular distillation to obtain cetyl ethylhexanoate; the conditions for the three-stage molecular distillation are: the first stage molecular distillation is performed at 50-200 Pa and 100-160 °C, the second stage molecular distillation is performed at 10-100 Pa and 100-160 °C, and the third stage molecular distillation is performed at less than 10 Pa and 140-180 °C.

2. The preparation method according to claim 1, characterized in that, The molar ratio of cetyl alcohol to ethylhexanoic acid is 1:(1.22~1.35).

3. The preparation method according to claim 1 or 2, characterized in that, The stirring state in step (1) is to stir at a speed of 350 to 600 rpm.

4. The preparation method according to claim 3, characterized in that, In step (1), under stirring, the temperature is first raised to 145-155℃, and then raised to 210-220℃ at a heating rate of 8-12℃ / h, and the reaction is maintained at this temperature for 1-8h.

5. The preparation method according to claim 4, characterized in that, In step (1), the reaction is terminated when the acid value of the reaction system drops to 25-40 mg KOH / g.

6. The preparation method according to any one of claims 1, 2, 4, and 5, characterized in that, The preparation method further includes: after the reaction is completed in step (1), the temperature is lowered to 60-80°C, the crude cetyl ethylhexanoate is filtered, and the filtered crude product is then subjected to the tertiary molecular distillation treatment in step (2).

7. The preparation method according to claim 6, characterized in that, The conditions for the first-stage molecular distillation treatment are 80–150 Pa and 110–150 °C; the conditions for the second-stage molecular distillation treatment are 20–80 Pa and 110–150 °C; and the conditions for the third-stage molecular distillation treatment are 1–8 Pa and 150–170 °C.

8. A product containing cetyl ethylhexanoate, characterized in that, It includes cetyl ethylhexanoate prepared by any one of claims 1 to 7, and at least one cosmetic active ingredient or pharmaceutical / transdermal absorption ingredient.

9. The product according to claim 8, characterized in that, The pharmaceutical / transdermal absorption ingredient includes at least one of nonsteroidal anti-inflammatory drugs, hormonal drugs, or antibiotics.

10. The product according to claim 8, characterized in that, The cosmetic active ingredients include retinol and its derivatives, vitamin E and its derivatives, vitamin C and its derivatives, niacinamide, salicylic acid or ceramide; the pharmaceutical / transdermal absorption ingredients include nonsteroidal anti-inflammatory drugs, hormonal drugs or antibiotics.

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