Curcumin 4 ', 4'-dihydroxy diacylated derivative and preparation method thereof

Abstract

The invention discloses a curcumin 4 ', 4'-dihydroxy diacylated derivative and a preparation method thereof, and relates to the technical field of curcumin 4 ', 4'-dihydroxy diacylated derivative preparation, the curcumin 4 ', 4'-dihydroxy diacylated derivative has a chemical structural formula: # imgabs0 #, in which R groups represent common methyl, propyl, 2, 4-dihydroxy diacylated derivatives, and R groups represent common methyl, propyl, 2, 4-dihydroxy diacylated derivatives. R1 is one of 2, 2-dimethyl propyl and chloromethyl; according to the preparation method, curcumin and an acyl chloride compound are taken as raw materials, triethylamine is taken as alkali, anhydrous dichloromethane is taken as a solvent, a target compound curcumin 4 ', 4'-dihydroxy diacylated derivative is synthesized by adopting a one-pot method, and the preparation method of the curcumin 4 ', 4'-dihydroxy diacylated derivative has the advantages of being mild in reaction condition, excellent in functional group compatibility and high in yield. The yield is generally high; and the method is environment-friendly.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of curcumin 4',4'-dihydroxy diacylated derivatives, and in particular to a curcumin 4',4'-dihydroxy diacylated derivative and a preparation method thereof. Background Art

[0002] Curcumin is a natural polyphenol extracted from the root or stem of the genus Curcuma. It has multiple biological activities such as anti-tumor, antioxidant, anti-inflammatory, anti-atherosclerotic and hypolipidemic, and has low toxicity to normal cells. The molecular formula of curcumin is C 21 H 20 O6, the main chain is an unsaturated ester and an aromatic group. In its structural formula, the keto form and the enol form are in resonance with each other, and the enol form exists stably.

[0003] Curcumin itself has many disadvantages, such as poor stability (easy to decompose when exposed to light), poor water solubility, easy metabolic inactivation and low bioavailability, which limit the application of curcumin. Therefore, structural modification and synthesis of curcumin derivatives with various biological activities can improve its drug properties. The modifiable sites in the curcumin structure are mainly concentrated in 4'-hydroxyl, 3'-methoxy, carbonyl and 4-methylene, thus obtaining many derivatives with the characteristics of targeting, high activity and low toxicity.

[0004] The modification of the 4′-hydroxyl group on the benzene ring in the curcumin molecule can produce compounds with better biological activity. For example, dimethoxycurcumin synthesized by dimethylation of the two 4′-hydroxyl groups of curcumin can induce the death of breast cancer MCF-7 cells by blocking the cell cycle and inducing apoptosis; the two 4′-hydroxyl groups of curcumin are combined with nicotinic acid to synthesize a compound with enhanced solubility and stability, which exhibits strong antiproliferative activity in breast cancer cells and selectively induces G2 / M cell cycle arrest and tumor cell apoptosis; one of the 4′,4′-dihydroxyl groups of curcumin is monosubstituted into an ester to synthesize the succinate prodrug of curcumin, and the stability of the obtained derivative is significantly improved compared with curcumin, and the release of the compound in plasma is increased; the 3′-methoxyl group of curcumin is replaced by hydrogen, and the two 4′-hydroxyl groups are disaccharified, and the synthesized compound has improved water solubility compared with curcumin.

[0005] In summary, the 4′-substituent of curcumin has an important influence on the pharmacological activity of the compound. Curcumin derivatives synthesized by structural modification of the 4′-hydroxyl group show different degrees of antioxidant, antitumor, antibacterial and other biological activities, and at the same time, the physical and chemical properties such as drug stability and water solubility also have great changes. In recent years, with the vigorous development of my country's biological and pharmaceutical industries, in order to provide more material basis for biological activity screening, structural modification of active natural products is an effective means to obtain candidate compounds.

[0006] Therefore, this paper proposes a curcumin 4′,4′-dihydroxy diacylated derivative and a preparation method thereof. Summary of the invention

[0007] The purpose of the present invention is to design a curcumin 4',4'-dihydroxy diacylated derivative which has excellent functional group compatibility, generally high yield and is environmentally friendly.

[0008] In order to achieve the above technical effects, the present invention is implemented by the following technical scheme: a curcumin 4′,4′-dihydroxy diacylated derivative, characterized in that its chemical structure is: The R group represents one of the common methyl, propyl, 2,2-dimethylpropyl, and chloromethyl groups.

[0009] Another object of the present invention is to provide a method for preparing a 4′,4′-dihydroxy diacylated derivative of curcumin, characterized in that it comprises the following steps:

[0010] S1. Material preparation: Curcumin and anhydrous dichloromethane are taken at a molar volume ratio of curcumin: anhydrous dichloromethane = 3-6:20-40, and then curcumin and triethylamine are taken at a molar ratio of curcumin: triethylamine = 1-2:6-12, and then curcumin and an acyl chloride compound are taken at a molar ratio of curcumin: acyl chloride compound = 1-2:3-6;

[0011] S2. In an air atmosphere, first dissolve curcumin in anhydrous dichloromethane, then add triethylamine in an ice-water bath, and then add the acyl chloride compound after 4 to 6 minutes to obtain a reaction system;

[0012] S3, stirring the reaction system in S2 in an ice-water bath for 1 to 1.5 hours, and then stirring at room temperature for 1 hour to obtain an initial solution;

[0013] S4. After the reaction is completed, 1 mL of distilled water is added to the initial solution to quench the reaction, the sample is mixed with silica gel, and the solvent is removed by a rotary evaporator to obtain a crude product;

[0014] S5. Add the crude product obtained in S4 to a silica gel chromatography column, and separate and purify it using petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the target product, curcumin 4′,4′-dihydroxy diacylated derivative.

[0015] Furthermore, in S1, the acyl chloride compound is one of acetyl chloride, butyryl chloride, 3,3-dimethylbutyryl chloride, and 2-chloroacetyl chloride.

[0016] The beneficial effects of the present invention are:

[0017] The invention uses curcumin and an acyl chloride compound as raw materials, triethylamine as a base, and anhydrous dichloromethane as a solvent to synthesize a target compound curcumin 4′,4′-dihydroxy diacylated derivative by a one-pot method. The preparation method of the curcumin 4′,4′-dihydroxy diacylated derivative has the characteristics of mild reaction conditions, excellent functional group compatibility, generally high yield and environmental friendliness. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0019] Figure 1 The present invention provides a flow chart for preparing the curcumin 4′,4′-dihydroxy diacylated derivative. DETAILED DESCRIPTION

[0020] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] Example 1

[0022] This embodiment describes the synthesis method of 4',4'-bis(acetoxy)curcumin, and the specific steps are as follows:

[0023] (1) In an air atmosphere, curcumin is dissolved in anhydrous dichloromethane, triethylamine is added first under an ice-water bath, and acetyl chloride is added five minutes later to obtain a reaction system; wherein the molar ratio of curcumin to triethylamine is 1:6, the molar ratio of curcumin to acetyl chloride is 1:3, and the molar volume ratio of curcumin to anhydrous dichloromethane is 3:20;

[0024] (2) stirring the reaction system of step (1) in an ice-water bath for 1 hour, stirring the reaction at room temperature for 1 hour, adding distilled water to quench the reaction, diluting with ethyl acetate, adding silica gel, removing the solvent by vacuum distillation, and then separating and purifying with a silica gel chromatography column to obtain 4′,4′-bis(acetoxy)curcumin; wherein the separation and purification solvent is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:1;

[0025] The structural formula of 4',4'-bis(acetoxy)curcumin prepared in this embodiment is shown below:

[0026]

[0027] It is denoted as compound 1;

[0028] H NMR spectrum of 4′,4′-bis(acetoxy)curcumin:

[0029] 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=15.8Hz,2H),7.17–7.14(m,4H),7.06(d,J=8 .4Hz,2H),6.56(d,J=15.6Hz,2H),5.85(s,1H),3.87(s,6H),2.33(s,6H)ppm,onepeak of active hydrogen was not detected.

[0030] C NMR spectrum of 4′,4′-bis(acetoxy)curcumin:

[0031] 13 C NMR (100MHz, CDCl3)183.13,168.87,151.42,141.30,139.99,133.98,124.27,123.32,121.10,111.44,101.87,55.92,20.69ppm.

[0032] In this example, 4′,4′-bis(acetoxy)curcumin was a brown-yellow oily liquid with a yield of 82%. HRMScalc'd for C 25 H 25 O8 + 453.1544, found 453.1546[M+H] + .

[0033] Example 2

[0034] This embodiment describes the synthesis method of 4',4'-bis(butyryloxy)curcumin, and the specific steps are as follows:

[0035] (1) In an air atmosphere, curcumin is dissolved in anhydrous dichloromethane, triethylamine is added first under an ice-water bath, and then butyryl chloride is added five minutes later to obtain a reaction system; wherein the molar ratio of curcumin to triethylamine is 1:6, the molar ratio of curcumin to butyryl chloride is 1:3, and the molar volume ratio of curcumin to anhydrous dichloromethane is 3:20;

[0036] (2) stirring the reaction system of step (1) in an ice-water bath for 1 hour, stirring the reaction at room temperature for 1 hour, adding distilled water to quench the reaction, diluting with ethyl acetate, adding silica gel, removing the solvent by vacuum distillation, and then separating and purifying with a silica gel chromatography column to obtain 4′,4′-bis(butyryloxy)curcumin; wherein the separation and purification solvent is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:1;

[0037] The structural formula of 4',4'-bis(butyryloxy)curcumin prepared in this example is shown below:

[0038]

[0039] It is denoted as compound 2;

[0040] H NMR spectrum of 4′,4′-bis(butyryloxy)curcumin:

[0041] 1 H NMR(400MHz,Chloroform-d)δ7.58–7.52(m,2H),7.11–7.06(m,3H),7.01(d,J=8.8Hz,2H),6.87(d,J=8.0Hz,1H),6.48(d, J=3.6Hz,2H),6.14(s,1H),5.79(s,1H),3.83(s,6H),2.56(t,J=7.4Hz,4H),1.84–1.74(m,4H),1.04(t,J=7.4Hz,6H)ppm.

[0042] C NMR spectrum of 4′,4′-bis(butyryloxy)curcumin:

[0043] 13 C NMR (100MHz, CDCl3) δ184.48,181.79,171.56,151.32,148.04,146.85,141.23,141.11,139.37,133.88,127. 41,124.04,123.19,122.96,121.60,120.90,114.87,111.35,109.69,101.55,55.79,35.81,18.47,13.52ppm.

[0044] In this example, 4′,4′-bis(butyryloxy)curcumin was a brown-yellow oily liquid with a yield of 85%. HRMScalc'd for C 29 H 33 O8 + 509.2170, found 509.2176[M+H] + .

[0045] Example 3

[0046] This example describes the synthesis method of 4',4'-bis(3,3-dimethylbutyryloxy)curcumin, and the specific steps are as follows:

[0047] (1) In an air atmosphere, curcumin is dissolved in anhydrous dichloromethane, triethylamine is added first under an ice-water bath, and then 3,3-dimethylbutyryl chloride is added five minutes later to obtain a reaction system; wherein the molar ratio of curcumin to triethylamine is 1:6, the molar ratio of curcumin to 3,3-dimethylbutyryl chloride is 1:3, and the molar volume ratio of curcumin to anhydrous dichloromethane is 3:20;

[0048] (2) stirring the reaction system of step (1) in an ice-water bath for 1 hour, stirring the reaction at room temperature for 1 hour, adding distilled water to quench the reaction, diluting with ethyl acetate, adding silica gel, removing the solvent by vacuum distillation, and then separating and purifying with a silica gel chromatography column to obtain 4′,4′-bis(3,3-dimethylbutyryloxy)curcumin; wherein the separation and purification solvent is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:1;

[0049] The structural formula of 4',4'-bis(3,3-dimethylbutyryloxy)curcumin prepared in this example is shown below:

[0050]

[0051] It is denoted as compound 3;

[0052] H NMR spectrum of 4′,4′-bis(3,3-dimethylbutyryloxy)curcumin:

[0053] 1 H NMR(400MHz,Chloroform-d)δ7.62–7.57(m,2H),7.14–7.10(m,3H),7.05–7.03(m,2H),6.92(d,J=8 .0Hz,1H),6.56–6.51(m,2H),5.97(s,1H),5.82(s,1H),3.86(s,6H),2.47(s,4H),1.15(s,18H)ppm.

[0054] C NMR spectrum of 4′,4′-bis(3,3-dimethylbutyryloxy)curcumin:

[0055] 13 C NMR (100MHz, CDCl3) δ184.58,183.26,182.02,170.18,151.57,148.12,146.94,141.24,139.62,134.06,127. 66,124.25,123.49,123.16,121.87,121.09,114.99,111.52,109.78,101.67,55.88,47.71,31.21,29.72ppm.

[0056] In this example, 4′,4′-bis(3,3-dimethylbutyryloxy)curcumin was a brown-yellow oily liquid with a yield of 78%. HRMS calculated for C 33 H 41 O8 + 565.2796,found565.2798[M+H] + .

[0057] Example 4

[0058] This embodiment describes the synthesis method of 4',4'-bis(chloroacetoxy)curcumin, and the specific steps are as follows:

[0059] (1) In an air atmosphere, curcumin is dissolved in anhydrous dichloromethane, triethylamine is added first under an ice-water bath, and 2-chloroacetyl chloride is added five minutes later to obtain a reaction system; wherein the molar ratio of curcumin to triethylamine is 1:6, the molar ratio of curcumin to 2-chloroacetyl chloride is 1:3, and the molar volume ratio of curcumin to anhydrous dichloromethane is 3:20;

[0060] (2) stirring the reaction system of step (1) in an ice-water bath for 1 hour, stirring the reaction at room temperature for 1 hour, adding distilled water to quench the reaction, diluting with ethyl acetate, adding silica gel, removing the solvent by vacuum distillation, and then separating and purifying with a silica gel chromatography column to obtain 4′,4′-bis(chloroacetoxy)curcumin; wherein the separation and purification solvent is petroleum ether-ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 1:1;

[0061] The structural formula of 4',4'-bis(chloroacetyloxy)curcumin prepared in this embodiment is shown below:

[0062]

[0063] It is denoted as compound 4;

[0064] H NMR spectrum of 4′,4′-bis(chloroacetoxy)curcumin:

[0065] 1 H NMR(400MHz,Chloroform-d)δ7.58(d,J=16.0Hz,2H),7.15–7.05(m,6H),6.55(d,J=16.0Hz,2H),5.84(s,1H),4.35(s,4H),3.85(s,6H)ppm, one peak of activehydrogen was not detected.

[0066] C NMR spectrum of 4′,4′-bis(chloroacetoxy)curcumin:

[0067] 13 C NMR (100MHz, CDCl3) δ183.11,165.36,151.17,140.74,139.81,134.52,124.61,122.96,121.08,111.64,102.07,56.03,40.69ppm.

[0068] In this example, 4′,4′-bis(chloroacetoxy)curcumin was a brown-yellow oily liquid with a yield of 88%. HRMScalc'd for C 25 H 23 Cl2O8 + 521.0764, found 521.0768[M+H] + .

[0069] In summary, the present invention uses curcumin and acyl chloride compounds as raw materials to synthesize curcumin 4′,4′-dihydroxy diacylated derivatives in one pot under mild conditions. Examples 1 to 4 show that the two 4′-hydroxyl groups in the curcumin structure are respectively acylated by acetyl chloride, butyryl chloride, 3,3-dimethylbutyryl chloride, and 2-chloroacetyl chloride to obtain 4′,4′-bis(acetoxy)curcumin derivatives with a yield of 82%, 4′,4′-bis(butyryloxy)curcumin with a yield of 85%, 4′,4′-bis(3,3-dimethylbutyryloxy)curcumin with a yield of 78%, and 4′,4′-bis(chloroacetoxy)curcumin with a yield of 88%.

Claims

1. A 4′,4′-dihydroxy diacylated derivative of curcumin, characterized in that: Its chemical structure is: The R group represents one of the common methyl, propyl, 2,2-dimethylpropyl, and chloromethyl groups.

2. A method for preparing a 4′,4′-dihydroxy diacylated derivative of curcumin, characterized in that: The following steps are involved: S1. Material preparation: Curcumin and anhydrous dichloromethane are taken at a molar volume ratio of curcumin: anhydrous dichloromethane = 3-6:20-40, and then curcumin and triethylamine are taken at a molar ratio of curcumin: triethylamine = 1-2:6-12, and then curcumin and an acyl chloride compound are taken at a molar ratio of curcumin: acyl chloride compound = 1-2:3-6; S2. In an air atmosphere, first dissolve curcumin in anhydrous dichloromethane, then add triethylamine in an ice-water bath, and then add the acyl chloride compound after 4 to 6 minutes to obtain a reaction system; S3, stirring the reaction system in S2 in an ice-water bath for 1 to 1.5 hours, and then stirring at room temperature for 1 hour to obtain an initial solution; S4. After the reaction is completed, 1 mL of distilled water is added to the initial solution to quench the reaction, the sample is mixed with silica gel, and then the solvent is removed by a rotary evaporator to obtain a crude product; S5. Add the crude product obtained in S4 to a silica gel chromatography column, and separate and purify it using petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the target product, curcumin 4′,4′-dihydroxy diacylated derivative.

3. The method for preparing a curcumin 4′,4′-dihydroxy diacylated derivative according to claim 2, characterized in that: In S1, the acyl chloride compound is one of acetyl chloride, butyryl chloride, 3,3-dimethylbutyryl chloride and 2-chloroacetyl chloride.

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