Curcumin mannich hydrophilic derivative and preparation method thereof

Abstract

The invention belongs to the field of derivatization of natural products, and relates to a curcumin mannich hydrophilic derivative and a preparation method thereof. According to the method, dioxane / water is used as a reaction mixed solvent, amino acid is used as a hydrophilic structure to carry out hydrophilic modification of Mannich reaction on curcumin, and the purposes of improving the water solubility of curcumin, reducing the degradation degree and retaining an active structure are achieved. Dioxane can provide a mild Mannich reaction environment while serving as a good solvent to efficiently dissolve curcumin, so that the dual purposes of hydrophilic structure grafting and curcumin degradation degree reduction are achieved.

Description

Technical Field

[0001] This invention belongs to the field of natural product derivatization, and relates to a method for the derivatization preparation of curcumin, particularly a method for hydrophilic modification of curcumin by using dioxane / water as a reaction mixed solvent and amino acids as hydrophilic structures through the Mannich reaction. Background Technology

[0002] Curcumin, the main active ingredient extracted from the rhizomes of plants in the genus Curcuma such as Curcuma, Curcuma zedoaria, and Curcuma longa, is a natural polyphenol derivative. It is widely available, relatively inexpensive, and safe and non-toxic, primarily produced in Japan, the United States, Africa, and China. Due to its phenolic hydroxyl, phenolic methoxy, carbon-carbon double bond, and diketone structure, curcumin possesses excellent pharmacological activities, including anti-inflammatory, antioxidant, wound-healing, antibacterial, anticancer, anti-aging, anti-HIV, lipid-lowering, and anti-cell proliferation effects. It has certain preventive and therapeutic effects on cardiovascular diseases, neurological disorders, and pulmonary and liver fibrosis, with no significant toxicity or side effects, and shows broad clinical application prospects. However, curcumin is difficult to disperse in water, which severely limits its practical application. Therefore, improving the water solubility of curcumin is a key measure to realize its multiple applications.

[0003] Many scholars have used chemical modification methods to increase the hydrophilic structure of curcumin in order to improve its hydrophilicity. Ding et al. (Ding, X.; Cheng, D.; Zhao, L.; Luo, X.; Yue, L.; Zhang, Y.; Wang, Z. Carboxymethyl Chitosan Modified with Curcumin: A Photodynamic Antibacterial Agent with Good Solubility and Stability). Food Bioscience 2024, 57 (103525. https: / / doi.org / 10.1016 / j.fbio.2023.103525.) Coupling is used to chemically modify curcumin to improve its water solubility. However, the coupling reaction site is the phenolic hydroxyl group. This method of improving hydrophilicity at the expense of some curcumin activity (such as antioxidant and pharmacological activity) cannot meet practical application requirements.

[0004] Somparn (HORNIG, S.; HEINZE, T. Nanoscale Structures of DextranEsters. Carbohydrate Polymers 2007, 68(2), 280–286.) reported that hydrogenated derivatives of curcumin retained good free radical scavenging ability, antioxidant activity, and low cytotoxicity. CN101255119A disclosed the hydrophilic modification of tetrahydrocurcumin by using tetrahydrocurcumin as a raw material and carrying out the Mannich reaction in alkaline aqueous solution. However, the preparation of tetrahydrocurcumin by hydrogenation reaction has disadvantages such as harsh reaction conditions, complex steps, high risk, and high cost, resulting in low practical application significance. In addition, because curcumin is not hydrogenated for protection, its carbon-carbon double bond and diketone structure are easily destroyed in alkaline media, leading to curcumin degradation.

[0005] Therefore, hydrophilic modification of curcumin remains a significant technical challenge. Currently, the key issue in hydrophilic modification of curcumin using the Mannich reaction lies in selecting a suitable solvent to create a mild yet efficient reaction environment. Dioxane can efficiently dissolve curcumin while providing a mild Mannich reaction environment, thus achieving the dual objectives of hydrophilic structure grafting and reducing the degree of curcumin degradation. This invention employs the Mannich reaction, using dioxane / aqueous solution as the reaction solvent and amino acids as the hydrophilic structure, to hydrophilicize curcumin, thereby improving its hydrophilicity, reducing degradation, and preserving its active structure. Summary of the Invention

[0006] To address the issues of poor water solubility of curcumin and its easy degradation by the Mannich reaction, this invention aims to utilize a benign solvent to achieve, through simple operation, both improved water solubility of curcumin and reduced degradation by the alkali in the Mannich reaction. This achieves the goals of increasing water solubility, reducing degradation, and preserving the active structure of curcumin.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] This invention provides a method for preparing a curcumin Mannich hydrophilic derivative, comprising the following steps: Curcumin was dissolved in a dioxane solution, and amino acids were dissolved in a pre-adjusted acidic or alkaline solution. The two solutions were then completely mixed, heated to a specified temperature, and 37% formaldehyde solution was added dropwise. After reacting for a period of time, the curcumin Mannich hydrophilic derivative was obtained.

[0009] Furthermore, the acid solution includes, but is not limited to, hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, p-toluenesulfonic acid, and other inorganic or organic acids; the alkaline solution includes, but is not limited to, NaOH, KOH, triethylamine, DMAP, and other inorganic or organic bases.

[0010] Furthermore, the amino acid is selected from amino acids such as glycine and glutamic acid that have one or more carboxyl groups.

[0011] Furthermore, the molar ratio of curcumin to amino acids is 1:(0.5-8).

[0012] Furthermore, the molar ratio of curcumin to formaldehyde solution is 1:(0.5-8).

[0013] Furthermore, the pH value is adjusted to 3-12.

[0014] Furthermore, the reaction time is 0.5-48 hours.

[0015] Furthermore, the reaction temperature is 40-70℃.

[0016] A curcumin Mannich hydrophilic derivative was prepared by the above method.

[0017] Compared with existing technologies, the present invention has the following significant and superior effects: (1) The present invention uses the Mannich reaction, with dioxane / water solution as the reaction solvent (curcumin is first dissolved in dioxane solution, and then mixed with water containing amino acids, and finally a dioxane / water mixed solution is obtained, with a volume ratio of 1:1), to hydrophilically modify curcumin, completely dissolving curcumin while reducing its degradation.

[0018] (2) The curcumin derivative obtained by the method of the present invention has improved water solubility and retains its active structure, and can exert its good multiple pharmacological activities.

[0019] (3) The present invention achieves hydrophilic structure grafting under mild reaction conditions. The steps are simple, and it is environmentally friendly, non-toxic and harmless, with high practical application value. Attached Figure Description

[0020] Figure 1 This is a comparison chart of the water solubility of curcumin and the aqueous solution of Example 1.

[0021] Figure 2 This is a comparison curve of the antioxidant activity of unmodified curcumin and the curcumin Mannich hydrophilic derivative of Example 1, determined by DPPH.

[0022] Figure 3 This is a comparison curve of the antioxidant activity of unmodified curcumin and the curcumin Mannich hydrophilic derivative of Example 2, determined by DPPH.

[0023] Figure 4 This is a curve comparison of the antioxidant activity of unmodified curcumin and the curcumin Mannich hydrophilic derivative of Example 3, determined by ABTS.

[0024] Figure 5This is a curve comparison of the antioxidant activity of unmodified curcumin and the curcumin Mannich hydrophilic derivative of Example 4, determined by ABTS. Detailed Implementation

[0025] The present invention will now be described in further detail with reference to the accompanying drawings and embodiments, but the implementation and protection of the present invention are not limited thereto. It should be noted that any processes not specifically described in detail below are those that can be implemented or understood by those skilled in the art by referring to the prior art.

[0026] Examples and Comparative Examples The preparation method of a curcumin Mannich hydrophilic derivative of the present invention includes the following steps: Curcumin was dissolved in a dioxane solution, and amino acids were dissolved in an acidic or alkaline solution adjusted to pH. The two solutions were then mixed thoroughly. After stabilization, the mixture was heated to the reaction temperature, and 37% formaldehyde solution was added to allow the reaction to proceed for a period of time. The resulting curcumin Mannich hydrophilic derivative was then purified.

[0027] To make the present invention more fully disclosed, more specific embodiments are described below.

[0028] Example 1: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 0.49 mmol of glycine was completely dissolved in 25 mL of acetic acid solution at pH 3.5, and the two solutions were mixed thoroughly. The mixture was heated to 50 °C, and 0.49 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 4 hours to obtain the curcumin Mannich hydrophilic derivative.

[0029] Table 1 Comparison of various indicators between Example 1 and curcumin

[0030] Table 1 shows that the calculation results indicate that under the reaction conditions of 50℃ and a curcumin:glycine ratio of 1:1, the conversion rate of curcumin reached 91.69%, demonstrating the effectiveness of the modification method. Its water solubility was significantly improved from the unmodified insoluble state to 0.23 mg / mL. Combined with... Figure 1 As shown in the solubility diagram, the solubility of curcumin Mannich hydrophilic derivative in water is significantly improved, while unmodified curcumin is insoluble in water. Figure 2 For the comparison of the antioxidant properties of the curcumin Mannich hydrophilic derivative and unmodified curcumin in Example 1, the IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL. -1 and 27.36 μg·mL -1The IC-50 values ​​of curcumin Mannich's hydrophilic derivatives were 23.42 μg·mL. -1 and 28.14 μg·mL -1 The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0031] Example 2: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 0.98 mmol of glycine was completely dissolved in 25 mL of NaOH solution at pH 11, and the two were mixed thoroughly. The mixture was heated to 70 °C, and 0.98 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 5 hours to obtain the curcumin Mannich hydrophilic derivative.

[0032] Table 2 Comparison of various indicators between Example 2 and curcumin

[0033] Table 2 shows that the calculation results indicate that under the reaction conditions of 70℃ and curcumin:glycine = 1:2, the conversion rate of curcumin reached 97.04%, demonstrating the effectiveness of the modification method. Its water solubility was significantly improved from the unmodified insoluble state to 0.31 mg / mL. Figure 3 This example compares the antioxidant properties of the curcumin Mannich hydrophilic derivative and unmodified curcumin. The IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL⁻¹. -1 and 27.36 μg·mL -1 The IC-50 values ​​of curcumin Mannich's hydrophilic derivatives were 20.50 μg·mL. -1 and 29.32 μg·mL -1 The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0034] Example 3: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 0.49 mmol of glycine was completely dissolved in 25 mL of hydrochloric acid solution at pH 5, and the two solutions were mixed thoroughly. The mixture was heated to 40 °C, and 0.49 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 12 hours to obtain the curcumin Mannich hydrophilic derivative.

[0035] Table 3 Comparison of various indicators between Example 3 and curcumin

[0036] Table 3 shows that the calculation results indicate that under the reaction conditions of 40℃ and curcumin:glycine = 1:1, the conversion rate of curcumin reached 69.16%, demonstrating the effectiveness of the modification method. Its water solubility was significantly improved from the unmodified insoluble state to 0.21 mg / mL. Figure 4 This comparison examines the antioxidant properties of the curcumin Mannich hydrophilic derivative and unmodified curcumin in Example 3. The IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL⁻¹. -1 and 27.36 μg·mL -1 The IC-50 values ​​for curcumin Mannich's hydrophilic derivatives were 24.18 μg·mL. -1 and 28.82 μg·mL -1 The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0037] Example 4: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 0.98 mmol of glycine was completely dissolved in 25 mL of NaOH solution at pH 10, and the two solutions were mixed thoroughly. The mixture was heated to 60 °C, and 0.98 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 6 hours to obtain the curcumin Mannich hydrophilic derivative.

[0038] Table 4 Comparison of various indicators between Example 4 and curcumin

[0039] Table 4 shows that the calculation results indicate that under the reaction conditions of 60℃ and curcumin:glycine = 1:2, the conversion rate of curcumin reached 94.02%, demonstrating the effectiveness of the modification method. Its water solubility was significantly improved from the unmodified insoluble state to 0.33 mg / mL. Figure 5 This example compares the antioxidant properties of the curcumin Mannich hydrophilic derivative and unmodified curcumin in Example 4. The IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL. -1 and 27.36 μg·mL -1 The IC-50 of curcumin Mannich's hydrophilic derivatives was 21.46 μg·mL. -1 and 30.23 μg·mL -1The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0040] Example 5: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 0.98 mmol of glutamic acid was completely dissolved in 25 mL of KOH solution at pH 10, and the two were mixed thoroughly. The mixture was heated to 70 °C, and 0.98 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 24 hours to obtain the curcumin Mannich hydrophilic derivative.

[0041] Table 5 Comparison of various indicators between Example 5 and curcumin

[0042] Table 5 shows that, under the reaction conditions of 70℃ and a curcumin:glutamic acid ratio of 1:2, the conversion rate of curcumin reached 96.22%, indicating that the modification method was effective. Its water solubility was significantly improved from the unmodified insoluble state to 0.38 mg / mL. The IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL, respectively. -1 and 27.36 μg·mL -1 The IC-50 values ​​of the curcumin Mannich hydrophilic derivatives were 21.04 μg·mL. -1 and 30.42 μg·mL -1 The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0043] Example 6: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 1.47 mmol of glycine was completely dissolved in 25 mL of triethylamine solution at pH 9, and the two were mixed thoroughly. The mixture was heated to 50 °C, and 1.47 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 12 hours to obtain the curcumin Mannich hydrophilic derivative.

[0044] Table 6 Comparison of various indicators between Example 6 and curcumin

[0045] Table 6 shows that, under the reaction conditions of 50℃ and a curcumin:glycine ratio of 1:3, the conversion rate of curcumin reached 94.63%, indicating that the modification method was effective. Its water solubility was significantly improved from the unmodified insoluble state to 0.36 mg / mL. The IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL. -1 and 27.36 μg·mL -1 The IC-50 values ​​of curcumin Mannich's hydrophilic derivatives were 20.92 μg·mL. -1 and 30.86 μg·mL -1 The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0046] Example 7: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 1.96 mmol of glutamic acid was completely dissolved in 25 mL of oxalic acid solution at pH 5, and the two were mixed thoroughly. The mixture was heated to 60 °C, and 1.96 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 8 hours to obtain the curcumin Mannich hydrophilic derivative.

[0047] Table 7 Comparison of various indicators between Example 7 and curcumin

[0048] Table 7 shows that, under the reaction conditions of 60℃ and a curcumin:glutamic acid ratio of 1:4, the conversion rate of curcumin reached 94.34%, indicating that the modification method was effective. Its water solubility was significantly improved from the unmodified insoluble state to 0.27 mg / mL. The IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL. -1 and 27.36 μg·mL -1 The IC-50 values ​​for curcumin Mannich's hydrophilic derivatives were 23.69 μg·mL. -1 and 29.41 μg·mL -1 The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0049] Example 8: Preparation of curcumin Mannich hydrophilic derivatives 0.49 mmol of curcumin was completely dissolved in 25 mL of dioxane solution. 0.49 mmol of lysine was completely dissolved in 25 mL of DMAP solution at pH 9, and the two were mixed thoroughly. The mixture was heated to 70 °C, and 0.49 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 15 hours to obtain the curcumin Mannich hydrophilic derivative.

[0050] Table 8 Comparison of various indicators between Example 8 and curcumin

[0051] Table 8 shows that, under the reaction conditions of 70℃ and a curcumin:lysine ratio of 1:1, the conversion rate of curcumin reached 96.58%, indicating that the modification method was effective. Its water solubility was significantly improved from the unmodified insoluble state to 0.27 mg / mL. The IC-50 (DPPH) and IC-50 (ABTS) of unmodified curcumin were 16.73 μg·mL. -1 and 27.36 μg·mL -1 The IC-50 of curcumin Mannich's hydrophilic derivatives was 21.96 μg·mL. -1 and 30.75 μg·mL -1 The content of glycine grafted onto the active group is slightly higher than that of the grafted glycine. However, the grafted glycine still exhibits good free radical scavenging rate, indicating that the active structure is well protected.

[0052] Comparative Example 1: Preparation of hydrophilic derivatives of curcumin 0.49 mmol curcumin and 0.49 mmol glycine were dissolved separately in 25 mL of pH 11 NaOH solution and mixed thoroughly. The mixture was heated to 50 °C, and 0.49 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 5 hours to obtain a hydrophilic derivative of curcumin.

[0053] Table 9 Comparison of various indicators between Comparative Example 1 and curcumin

[0054] Direct modification of curcumin hydrophilic derivatives with alkali solution results in severe degradation. Although the water solubility is greatly improved, it has no practical application significance.

[0055] Comparative Example 2: Preparation of hydrophilic derivatives of curcumin 0.49 mmol curcumin and 0.98 mmol glutamic acid were dissolved separately in 25 mL of pH 9 KOH solution and mixed thoroughly. The mixture was heated to 60 °C, and 0.98 mmol of 37% formaldehyde solution was added dropwise. The mixture was stirred for 6 hours to obtain a hydrophilic derivative of curcumin.

[0056] Table 10 Comparison of various indicators between Comparative Example 2 and curcumin

[0057] Despite lowering the pH of the reaction environment, the hydrophilic curcumin derivatives modified directly with alkali solution still underwent severe degradation. Although water solubility was improved, the degradation of curcumin prevented the yield of an effective product.

[0058] Characterization part The curcumin Mannich hydrophilic derivative obtained by the method of this invention was determined and quantitatively analyzed by ultraviolet-visible spectrophotometry. The specific steps are as follows: Curcumin was prepared to a concentration of 7.2 μg / mL, and the ultraviolet-visible absorption spectrum in the range of 300-600 nm was obtained by scanning. The ultraviolet-visible absorption spectrum was analyzed by Gaussian peak fitting. The ultraviolet-visible absorption spectrum of the curcumin reaction solution was obtained under the same conditions, and Gaussian peak fitting was performed for analysis. The conversion rate was calculated based on the integral area of ​​the main absorption peak of the curcumin ultraviolet-visible spectrum and the second Gaussian peak (about 430 nm) of the curcumin Mannich hydrophilic derivative spectrum. The conversion rate formula is shown in equation (1): (1) Where A1 represents the integral area of ​​the main absorption peak of the 7.2 μg / mL curcumin solution; A2 represents the integral area of ​​the second Gaussian peak after the modified reaction solution is diluted to the same factor and subjected to Gaussian peaking.

[0059] The water solubility of the curcumin Mannich hydrophilic derivative obtained by the method of this invention was evaluated by weighing. Specifically, an excess of the curcumin Mannich hydrophilic derivative was dissolved in a deionized aqueous solution, shaken thoroughly for 24-72 hours, filtered to obtain a saturated supernatant, dried to obtain an absolutely dry curcumin Mannich hydrophilic derivative, and its water solubility (mg / mL) was recorded by weighing.

[0060] For the curcumin Mannich hydrophilic derivatives obtained by the method of this invention, their antioxidant activity (represented as "IC-50 (DPPH)" in the table) was evaluated by measuring the ability of curcumin and its derivatives to scavenge DPPH free radicals (nitrogen free radicals and hydroxyl free radicals). The specific method is as follows: Curcumin and its derivatives were dissolved in 50% ethanol solution to prepare a series of solutions of different concentrations. The curcumin solution and DPPH solution were mixed and stored at room temperature in the dark for 30 min. The absorbance (A2) of the curcumin solution in the visible region of 517 nm was measured using a UV-Vis spectrophotometer. At the same time, the blank group (A0) was DPPH solution and the control group (A1) was curcumin solution. The free radical scavenging activity test of the curcumin Mannich hydrophilic derivatives was performed in the same way. The free radical scavenging activity (RSA1) of the sample was calculated according to formula (2): (2) Wherein, RSA1 (%) represents free radical scavenging activity; A2 represents the absorbance of curcumin (or its derivative) / DPPH solution at 517 nm; A1 represents the absorbance of curcumin (or its derivative) solution at 517 nm; and A0 represents the absorbance of DPPH solution at 517 nm.

[0061] For the curcumin Mannich hydrophilic derivatives obtained by the method of this invention, their antioxidant activity was evaluated by measuring the ability of curcumin and its derivatives to scavenge ABTS free radicals (represented as "IC-50 (ABTS)" in the table). The specific method was as follows: 88 μL of potassium persulfate (37.8 g / L) was mixed with 0.3 mM ABTS solution (3.8 g / L), and allowed to stand at room temperature in the dark for 12-16 h to prepare an ABTS stock solution. Before use, the ABTS solution was diluted with 50% ethanol until an absorbance value of approximately 0.70 ± 0.05 was read at 734 nm. A series of solutions of different concentrations were prepared by dissolving curcumin and its derivatives in 50% ethanol solution. The curcumin solution and ABTS solution were mixed thoroughly and reacted completely at room temperature in the dark for 6 min. The absorbance (A2) of the solution at 734 nm in the visible region was measured using a UV-Vis spectrophotometer. Meanwhile, the blank group (A0) was ABTS solution, and the control group (A1) was curcumin solution. The curcumin Mannich hydrophilic derivative free radical scavenging activity test was performed using the same method. The ABTS free radical scavenging activity (RSA2) of the samples was calculated according to formula (3): (3) Wherein, RSA2 (%) represents free radical scavenging activity; A2 represents the absorbance of curcumin (or its derivative) / ABTS solution at 734 nm; A1 represents the absorbance of curcumin (or its derivative) solution at 734 nm; and A0 represents the absorbance of ABTS solution at 734 nm.

Claims

1. A method for preparing a curcumin Mannich hydrophilic derivative, characterized in that, Includes the following steps: Curcumin was dissolved in a dioxane solution, and amino acids were dissolved in a pre-adjusted acidic or alkaline solution. The two solutions were then completely mixed, heated, and formaldehyde solution was added dropwise to carry out the Mannich reaction, yielding curcumin Mannich hydrophilic derivatives.

2. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that, The acid solution includes hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, p-toluenesulfonic acid (an inorganic or organic acid).

3. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that, The alkaline solution includes NaOH, KOH, triethylamine, DMAP (an inorganic or organic base).

4. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that, The amino acid selected is an amino acid having one or more carboxyl groups.

5. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that, The molar ratio of curcumin to amino acids is 1:(0.5-8).

6. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that, The molar ratio of curcumin to formaldehyde solution is 1:(0.5-8).

7. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that, The pH value is adjusted to 3-12.

8. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that: The reaction temperature is 40-70℃.

9. The method for preparing the curcumin Mannich hydrophilic derivative according to claim 1, characterized in that, The reaction time is 0.5-48 hours.

10. The curcumin Mannich hydrophilic derivative obtained by the preparation method according to any one of claims 1-9.

Images