A process for the preparation of cetyl-pg hydroxyethyl palmitamide

Abstract

The application provides a preparation method of cetyl-PG hydroxyethyl palmitamide and belongs to the technical field of organic synthesis. The method comprises the following steps: (1) preparing an intermediate 1 by reacting cetyl alcohol and 1,3-dichloropropanol under the action of an acid binding agent; (2) preparing an intermediate 2 by reacting the intermediate 1 and ethanolamine under the action of an acid binding agent; and (3) preparing a product by reacting the intermediate 2 and palmitoyl chloride under the action of an acid binding agent and a catalyst. The preparation method of the cetyl-PG hydroxyethyl palmitamide has the advantages of high yield and selectivity, mild conditions, simple process route, short production period, easily obtained raw materials, low cost, high economic benefit, reduced three wastes, green environmental protection, continuous production and wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing cetyl-PG hydroxyethyl palmitamide. Background Technology

[0002] The stratum corneum of the skin is a thin film layer 20 μm thick. It is an important barrier to prevent harmful external stimuli such as various chemicals and microorganisms from penetrating the skin and causing damage to the human body. It also prevents the loss of moisture and nutrients. The intercellular lipids of the stratum corneum are composed of ceramides, cholesterol, cholesterol esters, fatty acids, etc., and form a lamellar structure containing water molecules (bound water), which has moisturizing and barrier functions.

[0003] Ceramides are a major component of the intercellular lipids in the stratum corneum, accounting for over 50%. Ceramides can penetrate the stratum corneum, replenishing the intercellular lipids, enhancing the skin barrier function, and reducing skin allergies. Ceramides can also significantly enhance the adhesion between keratinocytes, improve skin dryness, and reduce flaking. Furthermore, ceramides have a strong ability to associate water molecules, maintaining skin moisture by forming a network structure in the stratum corneum. Recent research has also found that ceramides are second messengers of cells, involved in cell recognition, growth, proliferation, and differentiation, and can delay skin aging. Pure natural ceramides extracted from plants and animals are low in content and expensive. While synthetic ceramides are relatively cheaper than natural products, the amount needed to achieve their full effect is still considerable, and ceramides have a high melting point, are poorly soluble in oil and water, and are difficult to apply in formulations. Therefore, we discovered a ceramide analogue with a similar structure to natural ceramides and the same barrier repair effects, and applied it as an active ingredient for the repairing effects of skincare products. This ceramide analogue, called Translucent Ceramide (INCI name: cetyl-PG hydroxyethyl palmitamide), has been shown by third-party efficacy evaluation to have significant effects on repairing the sensitive skin barrier. Compared to ceramide NG, Translucent Ceramide is easier to synthesize, has lower production costs, and a lower melting point, making it more convenient for formulation in skincare and cosmetic products.

[0004] Cetyl-PG hydroxyethyl palmitamide (referred to as "ceramide E") is a synthetic ceramide that has significant effects on repairing the skin barrier of sensitive skin. It can improve the skin barrier, enhance the cohesion of epidermal cells, promote epidermal hydration, and improve the skin's water retention capacity. It is suitable for use in various skin care and cosmetic products.

[0005] Regarding the preparation methods of ceramide E, some literature has been reported. CN112321446A discloses a method for synthesizing amide derivatives, which uses acetone glycerol to prepare acetone glycerol ether, followed by hydrolysis and reaction with p-toluenesulfonyl chloride to obtain p-toluenesulfonate derivative. The derivative is then desorbed to obtain glycidyl ether, which 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 generate the target product. However, this method produces ceramides with low overall yield and low purity, is cumbersome, and has high overall cost. CN112441937A discloses a method that uses allyl bromide to react with hexadecyl alcohol to generate allyl alkyl ether, which is then oxidized with m-chloroperoxybenzoic acid to obtain glycidyl ether, and then reacted with ethanolamine and alkyl carboxylic acid methyl ester to obtain the product. However, this method uses highly hazardous and corrosive reaction aids such as sodium hydride and m-chloroperoxybenzoic acid during the reaction process, making the reaction process dangerous, difficult to operate, and producing many byproducts. CN112321445A describes the preparation of glycidyl ether by reacting alkyl alcohol with epichlorohydrin, followed by reaction with ethanolamine to obtain a secondary amine derivative, which then reacts with methyl alkylcarboxylate to generate the target product. CN112441937A describes the preparation of glycidyl ether by reacting allyl bromide with alkyl alcohol under the action of a strong base and a catalyst, followed by aminolysis of the glycidyl ether to obtain a secondary amine derivative, which then reacts with methyl alkylcarboxylate to obtain an amide derivative.

[0006] Therefore, there is an urgent need in this field for a method to synthesize ceramide E that is high-yielding, easy and safe to operate, simple to implement, and low in cost. Summary of the Invention

[0007] The purpose of this invention is to propose a method for preparing cetyl-PG hydroxyethyl palmitamide, which overcomes the shortcomings of traditional preparation methods, such as harsh conditions, the need to heat hazardous chemicals (such as concentrated sulfuric acid), low yield, numerous side reactions, high cost, and difficulty in industrial application. This method has the advantages of significantly improved yield and selectivity, mild conditions, simple process route, short production cycle, readily available raw materials, low cost, high economic benefits, reduced waste, and greater environmental friendliness. It can achieve continuous production and has broad application prospects.

[0008] The technical solution of this invention is implemented as follows:

[0009] This invention provides a method for preparing cetyl-PG hydroxyethyl palmitamide, comprising the following steps:

[0010] (1) Hexadecyl alcohol and 1,3-dichloropropanol were reacted in the presence of an acid-binding agent to prepare intermediate 1; the structure of intermediate 1 is as follows: ;

[0011] (2) Intermediate 1 and ethanolamine were reacted under the action of an acid-binding agent to prepare intermediate 2; the structure of intermediate 2 is as follows: ;

[0012] (3) The intermediate 2 and palmitoyl chloride were reacted under the action of an acid-binding agent and a catalyst to obtain the product;

[0013] The catalyst is prepared by coating magnetic SiO2 nanospheres with layered metal oxides, modifying the surface with silane coupling agents containing double bonds and amino groups, and then coupling with ionic liquids and lipases.

[0014] As a further improvement of the present invention, the molar ratio of hexadecyl alcohol, 1,3-dichloropropanol and acid-binding agent in step (1) is 1:1-1.5:3-5; the molar ratio of intermediate 1, ethanolamine and acid-binding agent in step (2) is 1:1.5-2:4-6; and the molar ratio of intermediate 2, palmitoyl chloride and acid-binding agent in step (3) is 1:1.2-1.5:3-5.

[0015] As a further improvement of the present invention, the acid-binding agent is selected from at least one of sodium bicarbonate, potassium bicarbonate, triethylamine, NaOH, and KOH.

[0016] As a further improvement of the present invention, the amount of catalyst added is 3-5 wt% of palmitoyl chloride, and the preparation method of the catalyst is as follows:

[0017] S1. Preparation of magnetic SiO2 nanospheres: Ammonia and NaOH solution were mixed to form an alkaline solution, and alkyl orthosilicate was added to obtain aqueous phase 1; ferric chloride and ferrous chloride were dissolved in water to obtain aqueous phase 2; cyclohexane, n-hexanol and surfactant were mixed evenly to obtain oil phase; under inert gas protection, aqueous phase 2 was added to aqueous phase 1, and then immediately added to oil phase; the mixture was heated and stirred to react; then isopropanol was added to demulsify; the mixture was centrifuged, washed, and dried to obtain magnetic SiO2 nanospheres;

[0018] S2. Coating of layered metal oxides: magnesium salt and aluminum salt are dissolved in water to obtain solution A. NaOH and sodium carbonate are dissolved in water to obtain solution B. Solution A is added dropwise to solution B and the reaction is stirred until the pH is neutral. Then magnetic SiO2 nanospheres are added, stirred for adsorption, separated by magnet, washed, dried, and calcined to obtain coated magnetic SiO2 nanospheres.

[0019] S3. Surface modification: Magnetic SiO2 nanospheres coated with ethanol were added, a composite silane coupling agent was added, the mixture was heated and stirred to react, separated by magnets, washed, and dried to obtain modified magnetic SiO2 nanospheres.

[0020] S4. Ionic liquid coupling: Modified coated magnetic SiO2 nanospheres were added to water, followed by an ionic liquid with double bonds. Under inert gas protection, an initiator was added, and the mixture was heated and stirred to react. The mixture was then separated by a magnet, washed, and dried to obtain ionic liquid-coupled modified coated magnetic SiO2 nanospheres.

[0021] S5. Lipase immobilization: Lipase was dissolved in water, N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, the mixture was stirred and activated, ionic liquid-coupled modified magnetic SiO2 nanospheres were added, the reaction was stirred, the mixture was separated by magnets, washed, and dried to obtain the catalyst.

[0022] As a further improvement of the present invention, in step S1, the concentration of ammonia water is 20-25 wt%, the concentration of NaOH solution is 1-2 mol / L, the volume ratio of ammonia water to NaOH solution is 5-10:4-8, the mass ratio of ferric chloride to ferrous chloride is 3.24:1.26, the volume ratio of cyclohexane to n-hexanol is 10-15:1-3, and the heating and stirring reaction temperature is 80-90℃ for 3-5 h.

[0023] As a further improvement of the present invention, the magnesium salt in step S2 is at least one of magnesium chloride, magnesium sulfate, and magnesium nitrate, the aluminum salt is aluminum nitrate, the molar ratio of the magnesium salt to the aluminum salt is 1-3:1, the mass ratio of NaOH to sodium carbonate is 2-4:0.5-0.7, the calcination temperature is 450-550℃, and the time is 1-3h.

[0024] As a further improvement of the present invention, the mass ratio of the coated magnetic SiO2 nanospheres and the composite silane coupling agent in step S3 is 10:3-4, the temperature of the heating and stirring reaction is 45-55℃, and the time is 2-4h. The composite silane coupling agent includes KH550 and KH570, with a mass ratio of 3-5:4-7.

[0025] As a further improvement of the present invention, the ionic liquid with double bonds in step S4 is 1-allyl-3-methylimidazolium chloride, the mass ratio of the modified coated magnetic SiO2 nanospheres, the ionic liquid with double bonds, and the initiator is 10-15:3-5:0.01-0.015, the initiator is selected from at least one of potassium persulfate, sodium persulfate, and ammonium persulfate, and the heating and stirring reaction temperature is 60-70°C, and the time is 3-5 hours.

[0026] As a further improvement of the present invention, the lipase in step S5 is Candida antarctica lipase B, and the mass ratio of the lipase, N-hydroxysuccinimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and ionic liquid-coupled modified magnetic SiO2 nanospheres is 3-6:1-3:1-3:10-12, and the stirring reaction time is 10-15 h.

[0027] The present invention further protects a moisturizing composition comprising cetyl-PG hydroxyethyl palmitamide and ceramide in a mass ratio of 7-10:1-3.

[0028] The present invention has the following beneficial effects:

[0029] In the final step of this invention, an immobilized catalyst is used to lower the acylation reaction temperature, suppress side reactions, improve reaction activity, and greatly increase product yield. The catalyst uses silica microspheres encapsulating magnetic iron oxide as a carrier, which improves the catalyst's compressive strength and facilitates magnet separation, thereby enabling multiple separation and repeated catalysis of the catalyst. At the same time, the silica shell can also prevent the decomposition and dissolution of iron oxide.

[0030] Subsequently, a layered Mg-Al oxide (LDO) layer is coated on the surface of the microspheres. The high specific surface area increases the grafting sites for subsequent reactions and provides abundant active reaction sites for the catalytic reaction. Furthermore, the layered metal hydroxide can be rehydrated through the "memory effect," during which the OH groups adjacent to the original metal ions are rehydrated. - It is pulled back into the crystal lattice, manifesting as a reversible weak base site, and neutralizes the acyl chloride byproduct HCl, promoting the amide reaction while protecting the enzyme from acid poisoning.

[0031] The covalent "brush" formed by double bond free radical polymerization prevents the ionic liquid from falling off. The imidazole positive ion forms an ion pair with the negatively charged center in the enzyme, which improves the stability of the enzyme. The activation energy is reduced through ion pairing, thereby improving the catalytic activity. At the same time, it has a certain degree of solubility and reusability.

[0032] Lipases are not only fixed on the surface of the modified magnetic SiO2 nanospheres through chemical bonds formed by the coupling of carboxyl groups with amino groups on the surface of the ion pairs mentioned above, but also through the coupling of carboxyl groups with amino groups on the surface of the nanospheres. This achieves highly selective amidation, greatly improving the yield and selectivity of the reaction and reducing the occurrence of side reactions.

[0033] The preparation method of cetyl-PG hydroxyethyl palmitamide of this invention overcomes the shortcomings of traditional preparation methods, such as harsh conditions, need to heat hazardous chemicals (such as concentrated sulfuric acid), low yield, many side reactions, high cost, and difficulty in industrial application. It has the characteristics of significantly improved yield and selectivity, mild conditions, simple process route, short production cycle, readily available raw materials, low cost, high economic benefits, reduced waste, and greater green and environmental protection. It can realize continuous production and has broad application prospects. Attached Figure Description

[0034] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0035] Figure 1 This is a synthetic route diagram for the preparation method of cetyl-PG hydroxyethyl palmitamide of the present invention;

[0036] Figure 2 The hydrogen spectrum of cetyl-PG hydroxyethyl palmitamide of this invention is shown. Detailed Implementation

[0037] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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.

[0038] Lipase Candida antarctica lipase B, Novozymes.

[0039] Preparation Example 1: Catalyst

[0040] The preparation method is as follows:

[0041] S1. Preparation of magnetic SiO2 nanospheres: 50 mL of 20 wt% ammonia water and 40 mL of 1 mol / L NaOH solution were mixed to form an alkaline solution. 10 g of tetraethyl orthosilicate was added to obtain aqueous phase 1. 1.62 g of ferric chloride and 0.63 g of ferrous chloride were dissolved in 100 mL of water to obtain aqueous phase 2. 100 mL of cyclohexane, 10 mL of n-hexanol, 1 g of Span-85, and 1 g of Tween-85 were mixed evenly to obtain an oil phase. Under nitrogen protection, aqueous phase 2 was added to aqueous phase 1, and then immediately added to the oil phase. The mixture was heated to 90 °C and stirred for 3 h. Then, stirring was continued for 1 day. 150 mL of isopropanol was added to break the emulsion. The mixture was centrifuged, washed, and dried to obtain magnetic SiO2 nanospheres.

[0042] S2. Coating of layered metal oxides: Dissolve 0.1 mol magnesium chloride and 0.1 mol aluminum nitrate in 200 mL of water to obtain solution A. Dissolve 2 g NaOH and 0.5 g sodium carbonate in 100 mL of water to obtain solution B. Add solution A dropwise to 100 mL of solution B (solution A can be more than 200 mL at this time). Stir the reaction until the pH is neutral. Then add 1 g of magnetic SiO2 nanospheres and stir to adsorb for 24 h. Separate with a magnet, wash, dry, and calcine at 450 °C for 1 h to obtain coated magnetic SiO2 nanospheres.

[0043] S3. Surface modification: 10g of magnetic SiO2 nanospheres were added to 200mL of ethanol, 3g of composite silane coupling agent was added, the mixture was heated to 45℃, stirred and reacted for 2h, the magnets were separated, washed and dried to obtain modified magnetic SiO2 nanospheres.

[0044] The composite silane coupling agent includes KH550 and KH570 in a mass ratio of 3:4;

[0045] S4. Ionic liquid coupling: 10g of modified coated magnetic SiO2 nanospheres were added to 200mL of water, 3g of 1-allyl-3-methylimidazolium chloride was added, and 0.01g of sodium persulfate was added under nitrogen protection. The mixture was heated to 60℃ and stirred for 3h. The mixture was separated by magnets, washed, and dried to obtain ionic liquid-coupled modified coated magnetic SiO2 nanospheres.

[0046] S5. Lipase immobilization: Dissolve 3g of Candida antarctica lipase B in 300mL of water, add 1g of N-hydroxysuccinimide and 1g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stir and activate for 30min, add 10g of ionic liquid-coupled modified magnetic SiO2 nanospheres, stir and react for 10h, separate with magnets, wash, dry, and obtain the catalyst.

[0047] Preparation Example 2 Catalyst

[0048] The preparation method is as follows:

[0049] S1. Preparation of magnetic SiO2 nanospheres: 100 mL of 25 wt% ammonia water and 80 mL of 2 mol / L NaOH solution were mixed to form an alkaline solution. 10 g of tetraethyl orthosilicate was added to obtain aqueous phase 1. 1.62 g of ferric chloride and 0.63 g of ferrous chloride were dissolved in 100 mL of water to obtain aqueous phase 2. 150 mL of cyclohexane, 30 mL of n-hexanol, 2 g of Span-85, and 2 g of Tween-85 were mixed evenly to obtain an oil phase. Under nitrogen protection, aqueous phase 2 was added to aqueous phase 1, and then immediately added to the oil phase. The mixture was heated to 80 °C and stirred for 5 h. Stirring was continued for 2 days. Then, 150 mL of isopropanol was added to break the emulsion. The mixture was centrifuged, washed, and dried to obtain magnetic SiO2 nanospheres.

[0050] S2. Coating of layered metal oxides: Dissolve 0.3 mol magnesium sulfate and 0.1 mol aluminum nitrate in 200 mL of water to obtain solution A. Dissolve 4 g NaOH and 0.7 g sodium carbonate in 100 mL of water to obtain solution B. Add solution A dropwise to 100 mL of solution B (solution A can be more than 200 mL at this time). Stir the reaction until the pH is neutral. Then add 1 g of magnetic SiO2 nanospheres and stir to adsorb for 24 h. Separate with a magnet, wash, dry, and calcine at 550 °C for 3 h to obtain coated magnetic SiO2 nanospheres.

[0051] S3. Surface modification: 10g of magnetic SiO2 nanospheres were added to 200mL of ethanol, 4g of composite silane coupling agent was added, the mixture was heated to 55℃, stirred and reacted for 4h, the magnets were separated, washed and dried to obtain modified magnetic SiO2 nanospheres.

[0052] The composite silane coupling agent comprises KH550 and KH570 in a mass ratio of 5:7;

[0053] S4. Ionic liquid coupling: 15g of modified magnetic SiO2 nanospheres were added to 200mL of water, 5g of 1-allyl-3-methylimidazolium chloride was added, and 0.015g of potassium persulfate was added under nitrogen protection. The mixture was heated to 70℃ and stirred for 5h. The mixture was separated by magnets, washed, and dried to obtain ionic liquid-coupled modified magnetic SiO2 nanospheres.

[0054] S5. Lipase immobilization: 6g of lipase Candida antarctica lipase B was dissolved in 300mL of water, 3g of N-hydroxysuccinimide and 3g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred and activated for 30min. Then, 12g of ionic liquid-coupled modified magnetic SiO2 nanospheres were added, and the mixture was stirred and reacted for 15h. The mixture was separated by magnets, washed, and dried to obtain the catalyst.

[0055] Preparation Example 3 Catalyst

[0056] The preparation method is as follows:

[0057] S1. Preparation of magnetic SiO2 nanospheres: 70 mL of 22 wt% ammonia water and 60 mL of 1.5 mol / L NaOH solution were mixed to form an alkaline solution. 10 g of tetraethyl orthosilicate was added to obtain aqueous phase 1. 1.62 g of ferric chloride and 0.63 g of ferrous chloride were dissolved in 100 mL of water to obtain aqueous phase 2. 120 mL of cyclohexane, 20 mL of n-hexanol, 1.5 g of Span-85, and 1.5 g of Tween-85 were mixed evenly to obtain an oil phase. Under nitrogen protection, aqueous phase 2 was added to aqueous phase 1, and then immediately added to the oil phase. The mixture was heated to 85 °C and stirred for 4 h. Stirring was continued for 1.5 days. Then, 150 mL of isopropanol was added to break the emulsion. The mixture was centrifuged, washed, and dried to obtain magnetic SiO2 nanospheres.

[0058] S2. Coating of layered metal oxides: Dissolve 0.2 mol magnesium nitrate and 0.1 mol aluminum nitrate in 200 mL of water to obtain solution A. Dissolve 3 g NaOH and 0.6 g sodium carbonate in 100 mL of water to obtain solution B. Add solution A dropwise to 100 mL of solution B (solution A can be more than 200 mL at this time). Stir the reaction until the pH is neutral. Then add 1 g of magnetic SiO2 nanospheres and stir to adsorb for 24 h. Separate with a magnet, wash, dry, and calcine at 500 °C for 2 h to obtain coated magnetic SiO2 nanospheres.

[0059] S3. Surface modification: 10g of magnetic SiO2 nanospheres were added to 200mL of ethanol, 3.5g of composite silane coupling agent was added, the mixture was heated to 50℃, stirred and reacted for 3h, the magnets were separated, washed and dried to obtain modified magnetic SiO2 nanospheres.

[0060] The composite silane coupling agent comprises KH550 and KH570 in a mass ratio of 4:5;

[0061] S4. Ionic liquid coupling: 12g of modified coated magnetic SiO2 nanospheres were added to 200mL of water, 4g of 1-allyl-3-methylimidazolium chloride was added, and 0.012g of ammonium persulfate was added under nitrogen protection. The mixture was heated to 65℃ and stirred for 4h. The mixture was separated by magnets, washed, and dried to obtain ionic liquid-coupled modified coated magnetic SiO2 nanospheres.

[0062] S5. Lipase immobilization: 4.5g of lipase Candida antarctica lipase B was dissolved in 300mL of water, 2g of N-hydroxysuccinimide and 2g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred and activated for 30min. Then, 11g of ionic liquid-coupled modified magnetic SiO2 nanospheres were added, and the mixture was stirred and reacted for 12h. The mixture was separated by magnets, washed, and dried to obtain the catalyst.

[0063] Comparative Preparation Example 1

[0064] The difference from preparation example 3 is that no silica shell was coated in step S1.

[0065] The preparation method is as follows:

[0066] S1. Preparation of magnetic particles: 1.62 g of ferric chloride and 0.63 g of ferrous chloride were dissolved in 100 mL of water. Under nitrogen protection, ammonia was added dropwise to adjust the pH of the solution to 10. The solution was heated to 85 °C and stirred for 4 h. The mixture was then filtered, washed, and dried to obtain magnetic particles.

[0067] S2. Coating of layered metal oxides: Dissolve 0.2 mol magnesium nitrate and 0.1 mol aluminum nitrate in 200 mL of water to obtain solution A. Dissolve 3 g NaOH and 0.6 g sodium carbonate in 100 mL of water to obtain solution B. Add solution A dropwise to 100 mL of solution B (solution A can be more than 200 mL at this time). Stir the reaction until the pH is neutral. Then add 1 g of magnetic particles and stir to adsorb for 24 h. Separate the magnetic particles with magnets, wash, dry, and calcine at 500℃ for 2 h to obtain coated magnetic particles.

[0068] S3. Surface modification: 10g of coated magnetic particles were added to 200mL of ethanol, 3.5g of composite silane coupling agent was added, heated to 50℃, stirred and reacted for 3h, the magnets were separated, washed and dried to obtain modified coated magnetic particles.

[0069] The composite silane coupling agent comprises KH550 and KH570 in a mass ratio of 4:5;

[0070] S4. Ionic liquid coupling: 12g of modified coated magnetic particles were added to 200mL of water, 4g of 1-allyl-3-methylimidazolium chloride was added, and 0.012g of ammonium persulfate was added under nitrogen protection. The mixture was heated to 65℃ and stirred for 4h. The magnets were separated, washed, and dried to obtain ionic liquid-coupled modified coated magnetic particles.

[0071] S5. Lipase immobilization: 4.5g of lipase Candida antarctica lipase B was dissolved in 300mL of water, 2g of N-hydroxysuccinimide and 2g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred and activated for 30min. Then, 11g of ionic liquid-coupled modified magnetic particles were added, and the mixture was stirred and reacted for 12h. The particles were separated by magnets, washed, and dried to obtain the catalyst.

[0072] Comparative Preparation Example 2

[0073] The difference from preparation example 3 is that step S2 was not performed.

[0074] The preparation method is as follows:

[0075] S1. Preparation of magnetic SiO2 nanospheres: 70 mL of 22 wt% ammonia water and 60 mL of 1.5 mol / L NaOH solution were mixed to form an alkaline solution. 10 g of tetraethyl orthosilicate was added to obtain aqueous phase 1. 1.62 g of ferric chloride and 0.63 g of ferrous chloride were dissolved in 100 mL of water to obtain aqueous phase 2. 120 mL of cyclohexane, 20 mL of n-hexanol, 1.5 g of Span-85, and 1.5 g of Tween-85 were mixed evenly to obtain an oil phase. Under nitrogen protection, aqueous phase 2 was added to aqueous phase 1, and then immediately added to the oil phase. The mixture was heated to 85 °C and stirred for 4 h. Stirring was continued for 1.5 days. Then, 150 mL of isopropanol was added to break the emulsion. The mixture was centrifuged, washed, and dried to obtain magnetic SiO2 nanospheres.

[0076] S2. Surface modification: 10g of magnetic SiO2 nanospheres were added to 200mL of ethanol, 3.5g of composite silane coupling agent was added, heated to 50℃, stirred and reacted for 3h, the magnets were separated, washed and dried to obtain modified magnetic SiO2 nanospheres.

[0077] The composite silane coupling agent comprises KH550 and KH570 in a mass ratio of 4:5;

[0078] S3. Ionic liquid coupling: 12g of modified magnetic SiO2 nanospheres were added to 200mL of water, 4g of 1-allyl-3-methylimidazolium chloride was added, and 0.012g of ammonium persulfate was added under nitrogen protection. The mixture was heated to 65℃ and stirred for 4h. The mixture was separated by magnets, washed, and dried to obtain ionic liquid-coupled modified magnetic SiO2 nanospheres.

[0079] S4. Lipase immobilization: 4.5g of lipase Candida antarctica lipase B was dissolved in 300mL of water, 2g of N-hydroxysuccinimide and 2g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred and activated for 30min. Then, 11g of ionic liquid-coupled modified magnetic SiO2 nanospheres were added, and the mixture was stirred and reacted for 12h. The mixture was separated by magnets, washed, and dried to obtain the catalyst.

[0080] Comparative preparation example 3

[0081] The difference compared to preparation example 3 is that step S4 was not performed.

[0082] The preparation method is as follows:

[0083] S1. Preparation of magnetic SiO2 nanospheres: 70 mL of 22 wt% ammonia water and 60 mL of 1.5 mol / L NaOH solution were mixed to form an alkaline solution. 10 g of tetraethyl orthosilicate was added to obtain aqueous phase 1. 1.62 g of ferric chloride and 0.63 g of ferrous chloride were dissolved in 100 mL of water to obtain aqueous phase 2. 120 mL of cyclohexane, 20 mL of n-hexanol, 1.5 g of Span-85, and 1.5 g of Tween-85 were mixed evenly to obtain an oil phase. Under nitrogen protection, aqueous phase 2 was added to aqueous phase 1, and then immediately added to the oil phase. The mixture was heated to 85 °C and stirred for 4 h. Stirring was continued for 1.5 days. Then, 150 mL of isopropanol was added to break the emulsion. The mixture was centrifuged, washed, and dried to obtain magnetic SiO2 nanospheres.

[0084] S2. Coating of layered metal oxides: Dissolve 0.2 mol magnesium nitrate and 0.1 mol aluminum nitrate in 200 mL of water to obtain solution A. Dissolve 3 g NaOH and 0.6 g sodium carbonate in 100 mL of water to obtain solution B. Add solution A dropwise to 100 mL of solution B (solution A can be more than 200 mL at this time). Stir the reaction until the pH is neutral. Then add 1 g of magnetic SiO2 nanospheres and stir to adsorb for 24 h. Separate with a magnet, wash, dry, and calcine at 500 °C for 2 h to obtain coated magnetic SiO2 nanospheres.

[0085] S3. Surface modification: 10g of magnetic SiO2 nanospheres were added to 200mL of ethanol, 3.5g of composite silane coupling agent was added, the mixture was heated to 50℃, stirred and reacted for 3h, the magnets were separated, washed and dried to obtain modified magnetic SiO2 nanospheres.

[0086] The composite silane coupling agent comprises KH550 and KH570 in a mass ratio of 4:5;

[0087] S4. Lipase immobilization: 4.5g of lipase Candida antarctica lipase B was dissolved in 300mL of water, 2g of N-hydroxysuccinimide and 2g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred and activated for 30min. Then, 11g of modified coated magnetic SiO2 nanospheres were added, and the mixture was stirred and reacted for 12h. The mixture was separated by magnets, washed, and dried to obtain the catalyst.

[0088] Comparative preparation example 4

[0089] The difference from preparation example 3 is that step S5 was not performed.

[0090] The preparation method is as follows:

[0091] S1. Preparation of magnetic SiO2 nanospheres: 70 mL of 22 wt% ammonia water and 60 mL of 1.5 mol / L NaOH solution were mixed to form an alkaline solution. 10 g of tetraethyl orthosilicate was added to obtain aqueous phase 1. 1.62 g of ferric chloride and 0.63 g of ferrous chloride were dissolved in 100 mL of water to obtain aqueous phase 2. 120 mL of cyclohexane, 20 mL of n-hexanol, 1.5 g of Span-85, and 1.5 g of Tween-85 were mixed evenly to obtain an oil phase. Under nitrogen protection, aqueous phase 2 was added to aqueous phase 1, and then immediately added to the oil phase. The mixture was heated to 85 °C and stirred for 4 h. Stirring was continued for 1.5 days. Then, 150 mL of isopropanol was added to break the emulsion. The mixture was centrifuged, washed, and dried to obtain magnetic SiO2 nanospheres.

[0092] S2. Coating of layered metal oxides: Dissolve 0.2 mol magnesium nitrate and 0.1 mol aluminum nitrate in 200 mL of water to obtain solution A. Dissolve 3 g NaOH and 0.6 g sodium carbonate in 100 mL of water to obtain solution B. Add solution A dropwise to 100 mL of solution B (solution A can be more than 200 mL at this time). Stir the reaction until the pH is neutral. Then add 1 g of magnetic SiO2 nanospheres and stir to adsorb for 24 h. Separate with a magnet, wash, dry, and calcine at 500 °C for 2 h to obtain coated magnetic SiO2 nanospheres.

[0093] S3. Surface modification: 10g of magnetic SiO2 nanospheres were added to 200mL of ethanol, 3.5g of composite silane coupling agent was added, the mixture was heated to 50℃, stirred and reacted for 3h, the magnets were separated, washed and dried to obtain modified magnetic SiO2 nanospheres.

[0094] The composite silane coupling agent comprises KH550 and KH570 in a mass ratio of 4:5;

[0095] S4. Ionic liquid coupling: 12g of modified coated magnetic SiO2 nanospheres were added to 200mL of water, 4g of 1-allyl-3-methylimidazolium chloride was added, and 0.012g of ammonium persulfate was added under nitrogen protection. The mixture was heated to 65℃ and stirred for 4h. The mixture was separated by magnets, washed, and dried to obtain ionic liquid-coupled modified coated magnetic SiO2 nanospheres, which are used as catalysts.

[0096] Test Example 1

[0097] The specific surface area of ​​the catalysts prepared in Preparation Examples 1-3 and Comparative Preparation Examples 1-4 was determined using a 3-FLEX 3500 multi-station high-throughput gas adsorption analyzer. Compressive strength was tested using an LJ 5000 compression testing machine with a range of 0-5000 N.

[0098] The results are shown in Table 1.

[0099] Table 1

[0100]

[0101] As can be seen from the table above, the catalysts prepared in Examples 1-3 of the present invention have a large specific surface area and compressive strength.

[0102] Example 1: As Figure 1 This embodiment provides a method for preparing cetyl-PG hydroxyethyl palmitamide, comprising the following steps:

[0103] 0.1 mol of cetyl alcohol and 0.1 mol of 1,3-dichloropropanol were mixed and added to 200 mL of acetonitrile. 0.3 mol of triethylamine was then added, and the mixture was heated to reflux with stirring for 4 h. TLC analysis showed no cetyl alcohol formation. The reaction was stopped, the mixture was filtered, and the solvent and excess triethylamine were removed under reduced pressure to obtain intermediate 1. ESI-MS calculated value: C 19 H 38 O2(M+H) + 298.50, measured value: 298.5.

[0104] 0.1 mol of intermediate 1 and 0.15 mol of ethanolamine were mixed and added to 200 mL of acetonitrile. 0.4 mol of triethylamine was added, and the mixture was heated to reflux and stirred for 5 h. TLC detection showed no sign of intermediate 1, so the reaction was stopped. The mixture was filtered, and the solvent and excess triethylamine were removed under reduced pressure. The mixture was then purified by column chromatography to obtain intermediate 2. ESI-MS calculated value: C 21 H 46 NO3(M+H) + 360.59, measured value: 360.6.

[0105] (3) 0.1 mol of intermediate 2 and 0.12 mol of palmitoyl chloride were mixed and added to 200 mL of dichloromethane. The catalyst prepared in Preparation Example 1 was added at 3 wt% of palmitoyl chloride. 0.3 mol of triethylamine was added, and the mixture was heated under reflux and stirred for 3 h. The catalyst was separated by magnetism and recycled. The reaction system was filtered, and the solvent and excess triethylamine were removed under reduced pressure. The mixture was purified by column chromatography to obtain cetyl-PG hydroxyethyl palmitamide. ESI-MS calculated value: C 37 H 76 NO4(M+H) + 599.00, measured value: 599.0. For example... Figure 2 The figure shows the proton NMR spectrum of the prepared cetyl-PG hydroxyethyl palmitamide. As can be seen from the figure, the cetyl-PG hydroxyethyl palmitamide was successfully synthesized.

[0106] Example 2: As Figure 1 This embodiment provides a method for preparing cetyl-PG hydroxyethyl palmitamide, comprising the following steps:

[0107] 0.1 mol hexadecyl alcohol and 0.15 mol 1,3-dichloropropanol were mixed and added to 200 mL acetonitrile. 0.5 mol triethylamine was added, and the mixture was heated under reflux and stirred for 4 h. TLC detection showed no hexadecyl alcohol. The reaction was stopped, filtered, and the solvent and excess triethylamine were removed under reduced pressure to obtain intermediate 1.

[0108] (2) Mix 0.1 mol of intermediate 1 and 0.2 mol of ethanolamine and add them to 200 mL of acetonitrile. Add 0.6 mol of triethylamine, heat and reflux and stir for 5 h. Detect by TLC. No intermediate 1 is visible. Stop the reaction, filter, remove solvent and excess triethylamine under reduced pressure, and separate and purify by column chromatography to obtain intermediate 2.

[0109] (3) 0.1 mol intermediate 2 and 0.15 mol palmitoyl chloride were mixed and added to 200 mL of dichloromethane. The catalyst prepared in Preparation Example 2 was added at 5 wt% of palmitoyl chloride. 0.5 mol of triethylamine was added. The mixture was heated and stirred under reflux for 3 h. The catalyst was separated by a magnet and recycled. The reaction system was filtered, and the solvent and excess triethylamine were removed under reduced pressure. The mixture was purified by column chromatography to obtain cetyl-PG hydroxyethyl palmitamide.

[0110] Example 3: As Figure 1 This embodiment provides a method for preparing cetyl-PG hydroxyethyl palmitamide, comprising the following steps:

[0111] 0.1 mol hexadecyl alcohol and 0.12 mol 1,3-dichloropropanol were mixed and added to 200 mL acetonitrile. 0.4 mol triethylamine was added, and the mixture was heated under reflux and stirred for 4 h. TLC detection showed no hexadecyl alcohol. The reaction was stopped, filtered, and the solvent and excess triethylamine were removed under reduced pressure to obtain intermediate 1.

[0112] (2) Mix 0.1 mol of intermediate 1 and 0.17 mol of ethanolamine and add them to 200 mL of acetonitrile. Add 0.5 mol of triethylamine, heat and reflux and stir for 5 h. Detect by TLC. No intermediate 1 is visible. Stop the reaction, filter, remove solvent and excess triethylamine under reduced pressure, and separate and purify by column chromatography to obtain intermediate 2.

[0113] (3) 0.1 mol intermediate 2 and 0.13 mol palmitoyl chloride were mixed and added to 200 mL of dichloromethane. The catalyst prepared in Preparation Example 3 was added at an amount of 4 wt% of palmitoyl chloride. 0.4 mol of triethylamine was added. The mixture was heated under reflux and stirred for 3 h. The catalyst was separated by a magnet and recycled. The reaction system was filtered, and the solvent and excess triethylamine were removed under reduced pressure. The mixture was purified by column chromatography to obtain cetyl-PG hydroxyethyl palmitamide.

[0114] Comparative Example 1

[0115] The difference from Example 3 is that the catalyst was prepared by Comparative Preparation Example 1.

[0116] Comparative Example 2

[0117] The difference from Example 3 is that the catalyst was prepared by Comparative Preparation Example 2.

[0118] Comparative Example 3

[0119] The difference from Example 3 is that the catalyst was prepared by Comparative Preparation Example 3.

[0120] Comparative Example 4

[0121] The difference from Example 3 is that the catalyst was prepared by Comparative Preparation Example 4.

[0122] Test Example 2

[0123] The reactions in Examples 1-3 and Comparative Examples 1-4 were evaluated, and the results are shown in Table 2.

[0124] Table 2

[0125]

[0126] As can be seen from the table above, the cetyl-PG hydroxyethyl palmitamide prepared by the reactions in Examples 1-3 of this invention has high yield and high purity.

[0127] Test Example 3

[0128] The catalyst in Example 3 was separated, and the reaction in Example 3 was repeated 5 times. The reaction was evaluated, and the results are shown in Table 3.

[0129] Table 3

[0130]

[0131] As can be seen from the table above, the catalyst used in Example 3 of the present invention still maintains high catalytic activity in repeated catalysis.

[0132] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of cetyl-PG hydroxyethyl palmitamide, characterized in that, Comprising the following steps: (1) The intermediate 1 is prepared by reacting hexadecanol and 1,3-dichloropropanol under the action of an acid-binding agent; the structure of the intermediate 1 is as follows: ; (2) the intermediate 1 and ethanolamine are reacted in the presence of an acid binding agent to obtain the intermediate 2; the structure of the intermediate 2 is as follows: ; (3) reacting intermediate 2 and palmitoyl chloride in the presence of an acid-binding agent and a catalyst to obtain a product; The catalyst is prepared by coating magnetic SiO2 nanospheres with layered metal oxides, modifying the surface of the coated magnetic SiO2 nanospheres with a silane coupling agent containing a double bond and an amino group, and coupling an ionic liquid and a lipase. The preparation method of the catalyst is as follows: S1. Preparation of magnetic SiO2 nanospheres: mix ammonia water and NaOH solution to form an alkaline solution, add alkyl silicate to obtain water phase 1; dissolve ferric chloride and ferrous chloride in water to obtain water phase 2; mix cyclohexane, n-hexanol and a surfactant uniformly to obtain an oil phase; under the protection of inert gas, add water phase 2 to water phase 1, then immediately add the oil phase, heat and stir to react, then add isopropanol to break the emulsion, centrifuge, wash, dry, and obtain magnetic SiO2 nanospheres; S2. Coating with layered metal oxides: dissolve magnesium salt and aluminum salt in water to obtain solution A, dissolve NaOH and sodium carbonate in water to obtain solution B, add solution A dropwise to solution B, stir to react until the pH is neutral, then add magnetic SiO2 nanospheres, stir to adsorb, separate with a magnet, wash, dry, calcine, and obtain coated magnetic SiO2 nanospheres; S3. Surface modification: add the coated magnetic SiO2 nanospheres to ethanol, add a composite silane coupling agent, heat and stir to react, separate with a magnet, wash, dry, and obtain modified coated magnetic SiO2 nanospheres; S4. Ionic liquid coupling: add the modified coated magnetic SiO2 nanospheres to water, add an ionic liquid containing a double bond, add an initiator under the protection of inert gas, heat and stir to react, separate with a magnet, wash, dry, and obtain ionic liquid-coupled modified coated magnetic SiO2 nanospheres, wherein the ionic liquid containing a double bond is 1-allyl-3-methyl imidazole chloride; S5. Lipase immobilization: dissolve lipase in water, add N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, stir to activate, add ionic liquid-coupled modified coated magnetic SiO2 nanospheres, stir to react, separate with a magnet, wash, dry, and obtain a catalyst, wherein the lipase is Candida antarctica lipase B.

2. The production method according to claim 1, characterized by, In step (1), the molar ratio of the cetyl alcohol, 1,3-dichloropropanol and acid-binding agent is 1:1-1.5:3-5; in step (2), the molar ratio of the intermediate 1, ethanolamine and acid-binding agent is 1:1.5-2:4-6; in step (3), the molar ratio of the intermediate 2, palmitoyl chloride and acid-binding agent is 1:1.2-1.5:3-5.

3. The preparation method according to claim 1, characterized in that, The acid-binding agent is at least one selected from sodium bicarbonate, potassium bicarbonate, triethylamine, NaOH and KOH.

4. The method of claim 1, wherein, The addition amount of the catalyst is 3-5 wt% of the mass of palmitoyl chloride.

5. The preparation method according to claim 1, characterized in that, The concentration of the ammonia water in step S1 is 20-25wt%, the concentration of the NaOH solution is 1-2mol / L, the volume ratio of the ammonia water and NaOH solution is 5-10:4-8, the mass ratio of the ferric chloride and ferrous chloride is 3.24:1.26, the volume ratio of the cyclohexane and n-hexanol is 10-15:1-3, the temperature of the heating and stirring reaction is 80-90℃, and the time is 3-5h.

6. The method of claim 1, wherein, The magnesium salt in step S2 is at least one of magnesium chloride, magnesium sulfate and magnesium nitrate, the aluminum salt is aluminum nitrate, the molar ratio of the magnesium salt and aluminum salt is 1-3:1, the mass ratio of the NaOH and sodium carbonate is 2-4:0.5-0.7, the calcination temperature is 450-550℃, and the time is 1-3h.

7. The preparation method according to claim 1, characterized in that, The mass ratio of the coated magnetic SiO2 nanoballs and the composite silane coupling agent in step S3 is 10:3-4, the temperature of the heating and stirring reaction is 45-55℃, the time is 2-4h, the composite silane coupling agent includes KH550 and KH570, and the mass ratio is 3-5:4-7.

8. The method of claim 1, wherein, The mass ratio of the modified coated magnetic SiO2 nanoballs, the ionic liquid with double bonds and the initiator in step S4 is 10-15:3-5:0.01-0.015, the initiator is at least one of potassium persulfate, sodium persulfate and ammonium persulfate, the temperature of the heating and stirring reaction is 60-70℃, and the time is 3-5h.

9. The method of claim 1, wherein, The mass ratio of the lipase, N-hydroxysuccinimide, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, the ionic liquid coupling modified coated magnetic SiO2 nanoballs in step S5 is 3-6:1-3:1-3:10-12, and the stirring reaction time is 10-15h.

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