A method for synthesizing cetyl - PG - hydroxyethyl palmitamide

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing cetyl-PG hydroxyethyl palmitamide. The synthesis method of the present invention comprises the following steps: (1) preparing an SN1 intermediate, (2) preparing an SN2 secondary amine derivative, and (3) preparing cetyl-PG hydroxyethyl palmitamide. The synthetic process route provided by the present invention is simple, has a short production cycle, high economic benefits, uses easily available raw materials, low costs, and the yields of the prepared cetyl-PG hydroxyethyl palmitamide and the purity have been greatly improved. The total yield of the product can reach 77%, and the purity reaches 99.5%.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing cetyl-PG-hydroxyethyl palmitamide. Background Art

[0002] Cetyl-PG-hydroxyethyl palmitamide (abbreviated as "ceramide E") is a synthetic ceramide, which has a significant effect on repairing the barrier of sensitive skin, can improve the skin barrier; it can also enhance the cohesion of epidermal cells and promote the hydration of the epidermis, improving the water retention capacity of the skin, and is suitable for use in various skin care cosmetics.

[0003] Regarding the preparation of ceramide E, there have been some literature reports. CN112321446A discloses a method for synthesizing an amide derivative. It uses acetone glycerol ketal to prepare acetone glycerol ketal ether, which is then hydrolyzed and reacted with TsCl to obtain a tosylate derivative. The derivative is deprotected from p-toluenesulfonic acid to obtain glycidyl ether, and glycidyl ether is then reacted with ethanolamine to obtain a secondary amine derivative. The secondary amine derivative is then reacted with alkyl carboxylic acid methyl ester to produce the target product. However, the total yield of ceramide synthesized by this method is low, the purity is not high, the operation is cumbersome, and the overall cost is high; CN112441937A discloses a method that first reacts allyl bromide with cetyl alcohol to form allyl alkyl ether, then oxidizes it with m-chloroperoxybenzoic acid to obtain glycidyl ether, and then reacts it with ethanolamine and alkyl carboxylic acid methyl ester to obtain the product. However, this method uses reaction aids with high danger levels and strong corrosiveness such as sodium hydride and m-chloroperoxybenzoic acid during the reaction process. The reaction process is relatively dangerous, the operation difficulty is high, and there are many by-products. CN112321445A uses alkyl alcohol to react with epichlorohydrin to prepare glycidyl ether, then reacts it with ethanolamine to obtain a secondary amine derivative, and the secondary amine derivative reacts with alkyl carboxylic acid methyl ester to produce the target product; CN112441937A uses allyl bromide and alkyl alcohol to prepare glycidyl ether under the action of a strong base and a catalyst, and the glycidyl ether is then aminolyzed to obtain a secondary amine derivative, and then reacts with alkyl carboxylic acid methyl ester to obtain an amide derivative.

[0004] The above synthetic routes for ceramide E are all to first synthesize glycidyl ether, then glycidyl ether is condensed with ethanolamine to obtain a secondary amine derivative, and the secondary amine derivative is then reacted with alkyl carboxylic acid methyl ester to obtain the target product. However, the process for preparing glycidyl ether is relatively complex. The total yield of ceramide synthesized by this method is low, there are many by-products, the purity is low, and the cost is high, which is not suitable for industrial scale production.

[0005] Therefore, if a method for synthesizing ceramide E with simple synthesis method, high total yield of ceramide, high purity and low cost can be provided, it will be more suitable for industrial production, which will be a significant progress for this field. Summary of the Invention

[0006] To solve the above technical problems, the present invention provides a method for synthesizing cetyl-PG-hydroxyethyl palmitamide. The intermediate synthesized in the first step reacts directly with ethanolamine to obtain a secondary amine derivative, and the secondary amine derivative reacts with an acyl chloride compound to prepare the target product, avoiding the preparation of glycidyl ether. The total yield, purity and cost of the ceramide E synthesized by this method are high, and it is suitable for industrial scale production.

[0007] The technical solution of the present invention is as follows:

[0008] A method for synthesizing cetyl-PG-hydroxyethyl palmitamide, comprising the following steps:

[0009] (1) Preparation of SN1 intermediate: Dissolve cetyl alcohol and chloropropanediol in an organic solvent, add a protonic acid, and react to obtain the SN1 intermediate;

[0010] (2) Preparation of SN2 secondary amine derivative: React the SN1 intermediate with ethanolamine to obtain the SN2 secondary amine derivative;

[0011] (3) Preparation of cetyl-PG-hydroxyethyl palmitamide: React the SN2 secondary amine derivative with palmitoyl chloride to obtain cetyl-PG-hydroxyethyl palmitamide.

[0012] Preferably, the synthesis method specifically comprises the following steps:

[0013] (1) Preparation of SN1 intermediate: Dissolve cetyl alcohol and chloropropanediol in an organic solvent, add a protonic acid, and react to obtain the SN1 intermediate, as shown in the following reaction:

[0014]

[0015] (2) Preparation of SN2 secondary amine derivative: React the SN1 intermediate with ethanolamine to obtain the SN2 secondary amine derivative. The remaining ethanolamine in the product is removed by vacuum distillation from the SN2 secondary amine derivative to obtain the purified SN2 secondary amine derivative, as shown in the following reaction:

[0016]

[0017] (3) Preparation of cetyl-PG-hydroxyethyl palmitamide: Dissolve the purified SN2 secondary amine derivative, first add a small amount of acid-binding agent, then dropwise add palmitoyl chloride to react, and recrystallize the reaction product 2-3 times with an organic solvent to remove impurities, obtaining cetyl-PG-hydroxyethyl palmitamide, as shown in the following reaction:

[0018]

[0019] Preferably, the solvent in step (1) is one of petroleum ether, benzene, toluene, xylene, pyridine, etc., and the protonic acid is at least one of concentrated sulfuric acid, phosphoric acid, and nitric acid;

[0020] Preferably, in step (1), the dosage of the protonic acid is 0.3% - 2% of the molar amount of cetyl alcohol; the molar ratio of cetyl alcohol to chloropropylene glycol is 1:1 - 1:3;

[0021] Preferably, in step (1), the reaction temperature is 100 - 120°C, and the reaction time is 4 - 6 h;

[0022] Preferably, in step (2), the molar ratio of ethanolamine to the SN1 intermediate is 1:1 - 2:1;

[0023] Preferably, the reaction solvent in step (2) is one of ethanol, dichloromethane, dichloroethane, and petroleum ether;

[0024] Preferably, in step (2), the reaction temperature is 30 - 50°C, and the reaction time is 10 - 12 h;

[0025] Preferably, in step (3), the acid-binding agent is one of sodium bicarbonate, sodium carbonate, triethylamine, and pyridine; the solvent for dissolving the SN2 secondary amine derivative is one of ethyl acetate, dichloromethane, dichloroethane, and n-hexane; the organic solvent for recrystallization is one of ethyl acetate, ethanol, n-hexane, and methanol;

[0026] Preferably, in step (3), the molar ratio of palmitoyl chloride to the SN2 secondary amine derivative is 1:1 - 2:1; the molar ratio of the acid-binding agent to palmitoyl chloride is 0.5:1 - 1:1;

[0027] Preferably, in step (3), the reaction temperature is 10°C, and the reaction time is 1 - 2 h.

[0028] Since the present invention involves heating, therefore, in step (1) of the present invention, one of petroleum ether, benzene, toluene, xylene, pyridine, etc. with a relatively high boiling point is selected as the solvent. At the same time, solvents with a boiling point such as dichloromethane, methanol, and ethanol are not recommended. Ethanol, dichloromethane, dichloroethane, and petroleum ether have good solubility with ethanolamine and are easy to remove ethanolamine, reducing the content of ethanolamine. Therefore, in step (2), one of ethanol, dichloromethane, dichloroethane, and petroleum ether is selected as the solvent. In step (3), one of ethyl acetate, dichloromethane, dichloroethane, and n-hexane is selected as the solvent. These solvents have good solubility for the raw materials at low temperatures but poor solubility for the product, facilitating subsequent recrystallization.

[0029] The present invention explores the reaction time and temperature of each step and finds that: in step (1), when the reaction temperature is greater than 120 °C, the content of reaction by-products increases; when the temperature is less than 100 °C, the raw materials are not completely reacted; when the reaction time is less than 4 h, there is raw material residue, and when the reaction time is greater than 6 h, side reactions increase. In step (2), when the reaction temperature is less than 30 °C, the raw materials cannot be completely reacted; when the reaction temperature is greater than 50 °C, side reactions will occur, resulting in an increase in the content of by-products; when the reaction time is less than 10 h, the amount of raw material residue is large, and when the reaction time is greater than 12 h, the content of by-products increases. In step (3), when the reaction temperature is less than 10 °C, the reaction rate is slow and the raw materials are not completely reacted; when the reaction temperature is greater than 10 °C, multiple side reactions occur and the by-products increase; when the reaction time is less than 1 h, the raw materials are not completely reacted yet, and when the reaction time is greater than 2 h, the by-products generated by the reaction increase and the content of by-products increases. Therefore, it is preferred that the reaction temperature in step (1) is 100-120 °C and the reaction time is 4-6 h; the reaction temperature in step (2) is 30-50 °C and the reaction time is 10-12 h; the reaction temperature in step (3) is 10 °C and the reaction time is 1-2 h. At this time, the total yield and purity of the obtained ceramide E are the highest and the impurities are the least.

[0030] The present invention further explores the amounts used in each step and finds that: in step (1), when the molar ratio of cetyl alcohol to chloropropanediol is greater than 1:3, the types and content of by-products increase; when the molar ratio is less than 1:1, the raw materials are not completely reacted. In step (2), when the molar ratio of ethanolamine to SN1 intermediate is less than 1:1, it is not completely reacted; when the molar ratio is greater than 2:1, other impurities will be generated, affecting the subsequent reaction. In step (3), when the molar ratio of palmitoyl chloride to SN2 secondary amine derivative is greater than 2:1, the residual acyl chloride will cause the product to turn yellow and become viscous, and by-products will be generated during the reaction, affecting the reaction result; when the molar ratio is less than 1:1, the product yield is low. Therefore, it is preferred that the molar ratio of cetyl alcohol to chloropropanediol in step (1) is 1:1-1:3; the molar ratio of ethanolamine to SN1 intermediate in step (2) is 1:1-2:1; the molar ratio of palmitoyl chloride to SN2 secondary amine derivative in step (3) is 1:1-2:1. At this time, the total yield and purity of the obtained ceramide E are the highest and the impurities are the least.

[0031] The beneficial effects of the present invention are as follows:

[0032] (1) Compared with the existing synthesis process of ceramide E (cetyl-PG-hydroxyethyl palmitamide), the yield and yield of ceramide E (cetyl-PG-hydroxyethyl palmitamide) prepared by using the synthesis method of the present invention have been greatly improved. The total product yield is above 75%, and the purity reaches 99.5%.

[0033] (2) The synthetic process route of the present invention is simple, with a short production cycle. Moreover, the raw materials are easily obtainable, the cost is low, the economic benefit is high, and the content of by-products in each step of the reaction is relatively low, making it more suitable for industrial production.

[0034] (3) There are no high pressures and high temperatures in the entire synthetic process of the present invention. During the process, the catalyst and solvent are conventional reagents, with strong safety and high operability. The reaction can be carried out in a conventional reaction kettle. Description of the Drawings

[0035] Figure 1 It is the liquid chromatogram of the target product after purification in Example 1;

[0036] Figure 2 It is the liquid chromatogram of the target product after purification in Comparative Example 4;

[0037] Figure 3 It is the liquid chromatogram of the target product after purification in Comparative Example 5;

[0038] Figure 4 It is the liquid chromatogram of the target product produced according to the traditional process in Comparative Example 11. Detailed Embodiments

[0039] In order to enable those skilled in the art to better understand the present invention, the present invention will be further elaborated below in conjunction with specific embodiments.

[0040] Example 1

[0041] A synthesis method of cetyl-PG hydroxyethyl palmitamide, comprising the following steps:

[0042] (1) Add 0.1 mol (24.24 g) of cetyl alcohol, 50 mL of petroleum ether, and 0.001 mol (0.13 g) of concentrated sulfuric acid to a 500 mL three-necked flask. Stir and heat to 100 °C. When all the materials are dissolved and the solution is colorless and transparent, slowly add dropwise 0.2 mol (22.00 g) of chloropropanediol. After reacting for 5.5 h, detect by TLC. When there is no image of cetyl alcohol, stop the reaction and rotary evaporate to remove the petroleum ether to obtain the SN1 intermediate (1-chloro-3-(pentadecyloxy)-2-propanol), and the content of the intermediate is about 95% or more.

[0043] (2) Add 0.095 mol (25.12 g) of the SN1 intermediate to a 500 mL three-necked flask, add 50 mL of dichloroethane, stir and heat to 45 °C, and start to add dropwise 0.2 mol (12.21 g) of ethanolamine. After the addition is complete, react for 11 h, and evaporate to dryness under reduced pressure to obtain a white solid to obtain the SN2 secondary amine derivative, with a content of 90% or more and an ethanolamine content of 3% or less.

[0044] (3) Add 0.09 mol (32.31 g) of SN2 secondary amine derivative into a 500 mL three-necked flask, add 100 ml of dichloroethane and 0.09 mol (9.09 g) of triethylamine, stir and cool down to 10 °C. After the sample is dissolved, add dropwise 0.09 mol (24.74 g) of palmitoyl chloride. White solid appears in the solution. Filter by suction after reacting for 2 h. Recrystallize the solid with methanol to obtain ceramide E, with an overall yield of 77% and a purity of 99.5%.

[0045] Example 2

[0046] The differences from Example 1 are as follows: In step (1), xylene is used as the organic solvent; in step (2), dichloromethane is used as the reaction solvent.

[0047] Step (3) is as follows: Add 0.09 mol (32.21 g) of SN2 secondary amine derivative into a 500 mL three-necked flask, add 50 ml of dichloromethane, stir and cool down to 10 °C. After the sample is dissolved, add dropwise 0.09 mol (24.74 g) of palmitoyl chloride. After reacting for 1 h, add dropwise 0.09 mol (9.09 g) of triethylamine. White solid appears in the solution. Filter by suction after reacting for 1 h. Recrystallize the solid with methanol to obtain ceramide E, with an overall yield of 75% and a purity of 99.2%.

[0048] Example 3

[0049] The differences from Example 1 are as follows: In step (1), the protonic acid is concentrated nitric acid and the reaction time is 6 h; in step (2), the reaction time is 10 h.

[0050] Step (3) is as follows: Add 0.09 mol (32.21 g) of SN2 secondary amine derivative into a 500 mL three-necked flask, add 50 ml of dichloromethane, stir and cool down to 10 °C. After the sample is dissolved, add dropwise 0.09 mol (24.74 g) of palmitoyl chloride. After reacting for 1 h, add dropwise 0.09 mol (7.56 g) of sodium bicarbonate. White solid appears in the solution. Filter by suction after reacting for 1 h. Recrystallize the solid with methanol to obtain ceramide E, with an overall yield of 57% and a purity of 98.5%.

[0051] Example 4

[0052] The difference from Example 1 is that in step (1), the reaction temperature is 110 °C.

[0053] The overall yield of ceramide E is 60% and the purity is 99.1%.

[0054] Example 5

[0055] The difference from Example 1 is that in step (1), the reaction temperature is 120 °C.

[0056] The total yield of ceramide E is 59%, and the purity is 99.1%.

[0057] Example 6

[0058] It is different from Example 1 in that: in step (1), the reaction time is 4 h.

[0059] The total yield of ceramide E is 65%, and the purity is 99.0%.

[0060] Example 7

[0061] It is different from Example 1 in that: in step (1), the molar ratio of cetyl alcohol to chloropropanediol is 1:1.

[0062] The total yield of ceramide E is 61%, and the purity is 98.5%.

[0063] Example 8

[0064] It is different from Example 1 in that: in step (2), the molar ratio of ethanolamine to SN1 intermediate is 1:1.

[0065] The total yield of ceramide E is 59%, and the purity is 99.3%.

[0066] Example 9

[0067] It is different from Example 1 in that: in step (2), the reaction time is 10 h.

[0068] The total yield of ceramide E is 65%, and the purity is 99.3%.

[0069] Example 10

[0070] It is different from Example 1 in that: in step (3), the molar ratio of palmitoyl chloride to SN2 secondary amine derivative is 1.5:1.

[0071] The total yield of ceramide E is 67%, and the purity is 98.5%.

[0072] Comparative Example 1

[0073] The synthesis method is the same as that of Example 1, except that the reaction time of step (1) is 2 h. The total yield of ceramide E is 55%, and the purity is 99.5%.

[0074] Comparative Example 2

[0075] The synthesis method is the same as that of Example 1, except that the reaction time of step (1) is 7 h. The total yield of ceramide E is 53%, and the purity is 99.5%.

[0076] Comparative Example 3

[0077] The synthesis method is the same as that of Example 1, except that in step (1), the molar ratio of cetyl alcohol to chloropropanediol is 1:2.5. The total yield of ceramide E is 51%, and the purity is 99.2%.

[0078] Comparative Example 4

[0079] The synthesis method is the same as that of Example 1, except that in step (1), the reaction temperature is 130 °C. The total yield of ceramide E is 45%, and the purity is 98.9%.

[0080] Comparative Example 5

[0081] The synthesis method is the same as that of Example 1, except that in step (2), the reaction time is 14 h. The total yield of ceramide E is 46%, and the purity is 98.6%.

[0082] Comparative Example 6

[0083] The synthesis method is the same as that of Example 1, except that in step (2), the molar ratio of ethanolamine to SN1 intermediate is 3:1. The total yield of ceramide E is 50%, and the purity is 99.0%.

[0084] Comparative Example 7

[0085] The synthesis method is the same as that of Example 1, except that in step (2), the reaction temperature is 55 °C. The total yield of ceramide E is 52%, and the purity is 99.0%.

[0086] Comparative Example 8

[0087] The synthesis method is the same as that of Example 1, except that in step (3), the molar ratio of palmitoyl chloride to SN2 secondary amine derivative is 1:2. The total yield of ceramide E is 47%, and the purity is 98.5%.

[0088] Comparative Example 9

[0089] The synthesis method is the same as that of Example 1, except that in step (3), the molar ratio of palmitoyl chloride to SN2 secondary amine derivative is 3:1. The total yield of ceramide E is 40%, and the purity is 99.1%.

[0090] Comparative Example 10

[0091] The synthesis method is the same as that of Example 1, except that in step (3), the reaction time is 3 h. The total yield of ceramide E is 47%, and the purity is 98.5%.

[0092] Comparative Example 11

[0093] According to the traditional method, glycidyl ether is first prepared, and then cetyl-PG-hydroxyethyl palmitamide is further prepared. The specific synthesis method is as follows:

[0094] Step 1: Add 0.1 mol (24.2 g) of cetyl alcohol and 120 mL of petroleum ether into a three-necked flask, heat up to 35 °C, and stir to dissolve. Then add 0.0005 mol (0.16 g) of tetrabutylammonium bromide and 0.2 mol (8.000 g) of NaOH; stir for a while, and dropwise add 0.15 mol (13.8 g) of epichlorohydrin. After dropping, continue the reaction for about 8 hours until the reaction ends. Filter, wash the filter cake with a small amount of petroleum ether, combine the filtrates, and evaporate to dryness under reduced pressure to obtain a pale yellow oily crude product. This glycidyl ether can be directly used for the next step without purification.

[0095] Step 2: Take all of the above glycidyl ether crude product, add 300 mL of ethanol and 0.2 mol (18.32 g) of ethanolamine, stir at room temperature, and react completely in about 14 hours. Evaporate to dryness under reduced pressure to obtain a white solid. Recrystallize with petroleum ether to obtain a crude product of the secondary amine derivative, which can be directly used for the next step without further purification. Step 3: Take all of the above crude product of the secondary amine derivative, add 0.01 mol (0.561 g) of KOH into a round-bottom flask, then add 100 mL of ethanol, heat up to 80 °C and stir to dissolve; subsequently, evaporate ethanol under reduced pressure. Heat up to 80 °C again, and slowly dropwise add 0.12 mol (32.400 g) of methyl palmitate under reduced pressure, and finish dropping in about 3 hours; continue the reaction for 4 hours and then stop the reaction. Recrystallize with n-hexane / ethanol to obtain ceramide E with a total yield of 40% and a purity of 98%.

[0096] The total yields and purities of ceramide E prepared in Examples 1-10 and Comparative Examples 1-11 are shown in Table 1.

[0097] Table 1 Total yields and purities of ceramide E under different conditions

[0098]

[0099]

[0100] As can be seen from Table 1, the total yield and purity of ceramide E prepared in Example 1 are the highest. Compared with the total yield of ceramide E prepared by the traditional method, its yield is nearly twice that of the traditional method, and its purity is also improved compared with that of ceramide E obtained by the traditional method; the molar ratio between the solvents and raw materials used, as well as the temperature and time of the reaction, will all have a greater impact on the final total yield. When the reaction temperature increases above the highest temperature limited by the present invention, the content of reaction by-products increases and its total yield decreases. When the reaction temperature decreases below the lowest temperature limited by the present invention, it will cause incomplete reaction of the raw materials and thus the total yield also decreases accordingly; when the reaction time increases above the highest time limited by the present invention, the content of by-products will increase correspondingly. When the reaction time is shortened below the lowest time limited by the present invention, the residual amount of raw materials is large and the total yield decreases accordingly; when the molar ratio of hexadecanol to chloropropanediol is greater than 1:3, the types and content of by-products increase. When the molar ratio is less than 1:1, the raw materials are not completely reacted; when the molar ratio of ethanolamine to SN1 intermediate is less than 1:1, the reaction is incomplete. When the molar ratio is greater than 2:1, other impurities will be generated, affecting the subsequent reaction; when the molar ratio of palmitoyl chloride to SN2 secondary amine derivative is greater than 2:1, the residual acyl chloride will cause the product to turn yellow and become viscous, and by-products will be generated during the reaction, affecting the reaction result. When the molar ratio is less than 1:1, the product yield is low. That is, within the limited ranges of temperature, time, and molar ratio of the present invention, the highest total yield and purity of ceramide E can be obtained.

[0101] Test Example

[0102] The target products of Example 1, Comparative Example 4, Comparative Example 5, and Comparative Example 11 were measured using liquid chromatography, and their chromatograms of the target products are respectively as Figures 1 - 4 shown, Figure 1 That is, there are only two peaks in Example 1. The first peak is a by-product with a content of 0.5%, and the second peak is the target product, namely ceramide E, with a content of 99.5%. It can be seen that the by-products are very few; Figure 2 That is, there are three peaks in Comparative Example 4. The first and second peaks are by-products with contents of 0.5% and 0.8% respectively, and the third peak is the target product, namely ceramide E, with a content of 98.6%. It can be seen that the increase in reaction temperature will lead to an increase in by-products and a decrease in the total yield of ceramide E; Figure 3 That is, there are three peaks in Comparative Example 5. The first and second peaks are by-products with contents of 0.5% and 0.6% respectively, and the third peak is the target product, namely ceramide E, with a content of 98.9%. It can be seen that the prolongation of the reaction time will also lead to an increase in by-products and a decrease in the total yield of ceramide E; Figure 4That is, Comparative Example 11 has four peaks. The first, second, and third peaks are by-products, and their contents are 0.2%, 1.5%, and 0.3% respectively. The third peak is the target product, namely ceramide E, and its content is 98%. It can be seen that there are more by-products when preparing ceramide E using the traditional method, which affects the overall yield and purity, and the total yield is relatively low.

Claims

1. A method for synthesizing cetyl - PG - hydroxyethyl palmitamide, characterized in that, It includes the following steps: (1) Prepare the SN1 intermediate: Dissolve cetyl alcohol and chloropropylene glycol in an organic solvent, add a protonic acid, and react to obtain the SN1 intermediate; wherein, the organic solvent is any one of petroleum ether and xylene, the protonic acid is at least one of concentrated sulfuric acid and concentrated nitric acid, the dosage of the protonic acid is 0.3% - 2% of the molar amount of cetyl alcohol, the molar ratio of cetyl alcohol to chloropropylene glycol is 1:1 - 1:3, the reaction temperature is 100 - 120 °C, and the reaction time is 4 - 6 h; The reaction equation for this step is as follows: (2) Prepare the SN2 secondary amine derivative: React the SN1 intermediate prepared in (1) with ethanolamine to obtain the SN2 secondary amine derivative; wherein, the molar ratio of ethanolamine to the SN1 intermediate is 1:1 - 2:1, the reaction solvent is one of dichloromethane and dichloroethane, the reaction temperature is 30 - 50 °C, and the reaction time is 10 - 12 h; The reaction equation for this step is as follows: (3) Prepare cetyl-PG hydroxyethyl palmitamide: Dissolve the purified SN2 secondary amine derivative, first add a small amount of acid-binding agent, then dropwise add palmitoyl chloride for reaction, recrystallize the reaction product 2 - 3 times with an organic solvent to remove impurities, and obtain cetyl-PG hydroxyethyl palmitamide, wherein, the acid-binding agent is one of sodium bicarbonate and triethylamine; the solvent for dissolving the SN2 secondary amine derivative is one of dichloromethane and dichloroethane; the organic solvent for recrystallization is methanol, the molar ratio of palmitoyl chloride to the SN2 secondary amine derivative is 1:1 - 2:1; the molar ratio of the acid-binding agent to palmitoyl chloride is 0.5:1 - 1:1, the reaction temperature is 10 °C, and the reaction time is 1 - 2 h; The reaction equation for this step is as follows:

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