A method for preparing an amide compound

Abstract

The patent application discloses a preparation method of an amide compound, comprising the following steps: A, taking raw material secondary amine, palmitic acid and photocatalyst in turn into a non-polar solvent, adding into a reactor, controlling temperature at 0-35 DEG C, stirring for 0.5-1 h, dissolving the solution to be clear, then adding inorganic base to obtain a photo-reaction solution; B, adding the photo-reaction solution obtained in step A into a photo-reactor, starting stirring, and irradiating by photo-reaction equipment for 2-4 h; C, concentrating and removing the solvent of the reaction liquid obtained in step B under reduced pressure, stirring and filtering with water, recrystallizing with n-hexane / ethanol, filtering and drying to obtain product ceramide E. The preparation method is simple in operation, high in yield, sustainable, non-toxic and easy to handle.

Description

Technical Field

[0001] This invention relates to the field of fine chemical technology, specifically to a method for preparing ceramide E compounds. Background Technology

[0002] Ceramide E is a synthetic ceramide-like substance and a key component of the intercellular lipids of the stratum corneum. It plays an important role in maintaining the skin barrier function, locking in moisture, promoting skin self-repair, and inhibiting inflammatory responses, and is therefore widely used as an active ingredient in cosmetics.

[0003] Currently reported methods for synthesizing ceramide E are mainly traditional chemical synthesis methods. These methods typically involve multiple steps: first, a glycidyl ether intermediate is prepared; then, a secondary amine derivative is obtained through a ring-opening reaction with ethanolamine; finally, ceramide E is obtained through condensation with a long-chain fatty acid methyl ester (such as methyl palmitate) or an acyl chloride. Although these methods can produce ceramide E, most traditional synthetic methods suffer from low yields, high costs, slow reaction rates, and low purity, affecting the use of subsequent formulations.

[0004] Therefore, it is necessary to develop a new green synthesis process for ceramide E that is high in yield and purity, has mild reaction conditions, is safe and environmentally friendly, and has low cost. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides a method for preparing ceramide E, solving the problems of low yield, high cost, slow reaction rate, and low purity of existing ceramide E. This method has the advantages of no high temperature or high pressure, sustainability, non-toxicity, and ease of processing, effectively reducing side reactions and improving the purity of ceramide E to over 99%, making it suitable for large-scale industrial production.

[0006] The technical solution adopted in this invention is as follows:

[0007] A. Take the raw materials secondary amine, palmitic acid and photocatalyst and add them to a non-polar solvent in sequence. Add the solvent to the reactor, control the temperature at 0~35℃, stir for 0.5~1h, the solution dissolves and becomes clear, and then add an inorganic base to obtain the photoreaction solution.

[0008] B. Add the photoreaction solution obtained in step A to the photoreactor, start stirring, and irradiate the reaction with light using the photoreaction equipment for 2-4 hours. The reaction formula is as follows:

[0009] ;

[0010] C. The reaction solution obtained in step B is concentrated under reduced pressure to remove the solvent, water is added, the mixture is stirred and filtered, recrystallized with n-hexane / ethanol, filtered, and dried to obtain the product ceramide E.

[0011] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0012] 1. This invention employs a simple, efficient, and environmentally friendly carboxylic acid amidation synthesis method, and for the first time applies visible light photocatalysis technology to the synthesis of ceramide E. This method can achieve the target reaction simply by being carried out under visible light irradiation.

[0013] 2. This invention uses palmitic acid, which is cheaper and more readily available, as a raw material, replacing methyl palmitate or palmitoyl chloride used in traditional methods. It discovers new conditions for the preparation of ceramide E. Compared with existing technologies, the process capacity is improved by modifying the synthesis process conditions. At the same time, green light energy is used as a catalyst, and the reaction can be carried out at room temperature (0-35℃) and normal pressure, avoiding the risks of high-temperature heating and long-term reaction. This simplifies the process steps, saves process energy consumption, and the product yield can reach nearly 80% or more, greatly increasing the utilization rate of raw materials. After recrystallization, the product purity reaches more than 99%, the product quality is significantly improved, and the production cost is reduced.

[0014] 3. The photoreaction process of this invention can be carried out in a photoreactor, with stirring and light irradiation completed simultaneously. The light irradiation reaction time is 2-4 hours, eliminating the need for complex dropwise addition, stepwise feeding, or strict anhydrous and oxygen-free operations. The reaction speed is faster, significantly shortening the production cycle.

[0015] In a preferred embodiment of the present invention, in step A, the photocatalyst is a photo-oxidation-reduction catalyst, which is one or more of eosin Y, fluorescein, acid red 94, nilo red, rhodamine B, and rhodamine 6G.

[0016] In this invention, the inventors discovered through research that the catalysts described above have excellent light absorption performance and redox capabilities in the visible light region, and can efficiently catalyze the amidation reaction between palmitic acid and secondary amines under mild ambient light conditions.

[0017] In a preferred embodiment of the present invention, in step A, the nonpolar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, and n-heptane.

[0018] In this scheme, the solvent has a strong ability to dissolve palmitic acid and secondary amine derivatives, which can ensure that the reactants are fully dispersed and form a homogeneous solution before light exposure, thereby improving the reaction efficiency.

[0019] In a preferred embodiment of the present invention, in step A, the inorganic base is one or more of potassium carbonate, sodium carbonate, and sodium bicarbonate.

[0020] In this scheme, the aforementioned inorganic base is weakly alkaline, which can neutralize the protons of palmitic acid during the reaction to form carboxylate. The carboxylate forms free radicals under the action of a photocatalyst, which then undergo free radical coupling reaction with secondary amines to construct amide bonds, thereby promoting a more efficient reaction and improving the conversion rate and yield of the reaction process.

[0021] In a preferred embodiment of the present invention, in step A, the mass-to-volume ratio of secondary amine, palmitic acid, and nonpolar solvent is 1:(0.72-1.44):(5-10).

[0022] In this scheme, the above ratio allows the secondary amine and palmitic acid to fully dissolve in a nonpolar solvent to form a clear and homogeneous photoreaction solution. The palmitic acid is in appropriate excess relative to the secondary amine to promote a more complete reaction and improve the conversion rate of the secondary amine.

[0023] In a preferred embodiment of the present invention, in step A, the molar ratio of secondary amine to photocatalyst is 1:(0.01 to 0.03).

[0024] In this invention, the inventors discovered that adding the photocatalyst in the above ratio can provide sufficient catalytic active sites to excite photo-oxidation-reduction cycles under visible light, promote the rapid amidation reaction of palmitic acid and secondary amines, and reduce side reactions by a smaller amount of photocatalyst, ensuring the purity of subsequent products while effectively controlling raw material costs.

[0025] In a preferred embodiment of the present invention, in step B, the visible light wavelength range required for the photocatalytic reaction is 450–560 nm.

[0026] In this invention, the inventors discovered that using visible light within the aforementioned wavelength range can effectively excite the catalyst's reactivity, resulting in high light energy utilization efficiency and a fast amidation reaction rate. Furthermore, the 450–560 nm visible light range is a mild blue-green light band, which can reduce side reactions and ensure the purity and yield of subsequent products.

[0027] In a preferred embodiment of the present invention, in step C, the drying is vacuum drying, with the drying temperature controlled at 35-50°C, the drying time at 4-6 hours, and the vacuum degree at 0.095-0.08 MPa.

[0028] In this scheme, the above-mentioned relatively mild conditions can effectively remove the residual organic solvent after recrystallization, avoid product melting, agglomeration or thermal oxidative degradation, and the use of vacuum drying can significantly reduce the boiling point of the solvent, accelerate volatilization, and improve the purity of the product. Attached Figure Description

[0029] Figure 1 This is the 1H NMR spectrum of ceramide E prepared in Example 1 of this invention.

[0030] Figure 2This is the carbon NMR spectrum of ceramide E prepared in Example 1 of this invention.

[0031] Figure 3 This is the liquid phase spectrum of ceramide E prepared in Example 1 of this invention. Detailed Implementation

[0032] Typical embodiments embodying the features and advantages of the present invention will be specifically described in the following description. It should be understood that the present invention can have various variations in different embodiments without departing from the scope of the present invention, and the descriptions and illustrations herein are for illustrative purposes only and not intended to limit the present invention.

[0033] In this invention, the "mass-volume ratio of the secondary amine, palmitic acid and nonpolar solvent" and the "molar ratio of the photocatalyst and secondary amine" are described as follows: secondary amine and palmitic acid are in mass, nonpolar solvent is in volume, and photocatalyst is in amount of substance.

[0034] Example 1

[0035] This embodiment discloses a method for preparing amide compounds, comprising the following steps:

[0036] A. Take 3.6g of secondary amine, 3.2g of palmitic acid and 0.13g of eosin Y and add them to 28ml of nonpolar solvent dichloromethane. Add the solution to the reactor, control the temperature at 25℃, stir for 0.1h, the solution dissolves and becomes clear, add 1.38g of potassium carbonate to obtain the photoreaction solution.

[0037] B. Add the photoreaction solution obtained in step A to the photoreactor. The visible light wavelength is 540nm. Start stirring and irradiate the reaction with light using the photoreaction device for 3 hours. The reaction formula is as follows:

[0038] ;

[0039] C. The reaction solution obtained in step B was concentrated under reduced pressure to remove the solvent, water was added and stirred, filtered, recrystallized with n-hexane / ethanol, filtered, dried under reduced pressure, and the drying temperature was controlled at 35-50℃, the drying time was 4-6h, and the vacuum degree was 0.095-0.08MPa to obtain 5.12g of product ceramide E, with a yield of 85.62% and a purity of 99.805%.

[0040] Figure 1 This is the 1H NMR spectrum of ceramide E prepared in Example 1 of this invention.

[0041] Figure 2 This is the carbon NMR spectrum of ceramide E prepared in Example 1 of this invention.

[0042] Figure 1 and Figure 2The nuclear magnetic resonance spectrum characteristics are completely consistent with the target structure of ceramide E, and no obvious impurity peaks or characteristic signals of unreacted starting materials are seen in the spectrum, which fully proves that the photocatalytic amidation synthesis route adopted in this invention has successfully constructed amide bonds, and the product yield is high and the purity is good, reaching a purity level of over 99%.

[0043] like Figure 3 The liquid phase spectrum of ceramide E prepared in this embodiment is shown. The ceramide E prepared in this embodiment exhibits a single main peak with a peak area ratio as high as 99.805%. It can be seen that the purity of ceramide E in the product obtained by the photocatalytic amidation synthesis route of this invention is very high, reaching more than 99%, which meets the requirements of high purity and high safety of raw materials in the cosmetics and pharmaceutical fields.

[0044] Example 2

[0045] The steps of Example 1 were repeated, except that the wavelength of the light was selected. The selected wavelengths and experimental results are shown in Table 1 below.

[0046] Table 1

[0047]

[0048] In this invention, the visible light wavelength range required for the photocatalytic reaction is 450–560 nm. Different wavelengths of light are used in the irradiation equipment to prepare ceramide E. The results show that the yield and purity are optimal under the wavelength of 540 nm.

[0049] Example 3

[0050] This embodiment discloses a method for preparing amide compounds, comprising the following steps:

[0051] A. Take 3.6g of secondary amine, 3.2g of palmitic acid and 0.067g of photocatalyst fluorescein and add them to 32ml of nonpolar solvent toluene. Add the solution to the reactor, control the temperature at 25~35℃, stir for 1h, the solution dissolves and becomes clear, add 1.38g of potassium carbonate to obtain the photoreaction solution.

[0052] B. Add the photoreaction solution obtained in step A to the photoreactor. The visible light wavelength range is 540nm. Start stirring and irradiate the reaction with light using the photoreaction device for 3 hours. The reaction formula is as follows:

[0053] ;

[0054] C. The reaction solution obtained in step B was concentrated under reduced pressure to remove the solvent, water was added and stirred, filtered, recrystallized with n-hexane / ethanol, filtered, dried under reduced pressure, and the drying temperature was controlled at 35-50℃, the drying time was 4-6h, and the vacuum degree was 0.095-0.08MPa to obtain 4.78g of product ceramide E, with a yield of 80.00% and a purity of 99.6%.

[0055] Example 4

[0056] The steps of Example 1 were repeated, except that the types of photocatalysts were screened. The selected catalysts and experimental results are shown in Table 2 below.

[0057] Table 2

[0058]

[0059] In this invention, the photocatalyst can be one of eosin Y, fluorescein, Acid Red 94, Nile Red, Rhodamine B, and Rhodamine 6G. Ceramide E was prepared using various photocatalysts. The results showed that eosin Y had the best yield and purity.

[0060] The above embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-substantial changes and substitutions made by those skilled in the art based on the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing an amide compound, characterized in that, Includes the following steps: A. Take the raw materials secondary amine, palmitic acid and photocatalyst and add them to a non-polar solvent in sequence. Add the solvent to the reactor, control the temperature at 0~35℃, stir for 0.5~1h, the solution dissolves and becomes clear, and then add an inorganic base to obtain the photoreaction solution. B. Add the photoreaction solution obtained in step A to the photoreactor, start stirring, and irradiate the reaction with light using the photoreaction equipment for 2-4 hours. The reaction formula is as follows: ； C. The reaction solution obtained in step B is concentrated under reduced pressure to remove the solvent, water is added, the mixture is stirred and filtered, recrystallized with n-hexane / ethanol, filtered, and dried to obtain the product ceramide E.

2. The method for preparing amide compounds according to claim 1, characterized in that: In step A, the photocatalyst is a photo-oxidation-reduction catalyst, which is one or more of eosin Y, fluorescein, acid red 94, nilo red, rhodamine B, and rhodamine 6G.

3. The method for preparing amide compounds according to claim 1, characterized in that: In step A, the nonpolar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, and n-heptane.

4. The method for preparing amide compounds according to claim 1, characterized in that: In step A, the inorganic base is one or more of potassium carbonate, sodium carbonate, and sodium bicarbonate.

5. The method for preparing amide compounds according to claim 1, characterized in that: In step A, the mass-volume ratio of secondary amine, palmitic acid, and nonpolar solvent is 1:(0.72-1.44):(5-10).

6. The method for preparing amide compounds according to claim 1, characterized in that: In step A, the molar ratio of secondary amine to photocatalyst is 1:(0.01~0.03).

7. The method for preparing amide compounds according to claim 1, characterized in that: In step B, the visible light wavelength range required for the photocatalytic reaction is 450–560 nm.

8. The method for preparing amide compounds according to claim 1, characterized in that: In step C, the drying is vacuum drying, with the drying temperature controlled at 35-50℃, the drying time at 4-6 hours, and the vacuum degree at 0.095-0.08MPa.

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