Cannabidiol acetamide and its preparation method and application

Abstract

The present invention belongs to the technical field of cannabidiol derivatives, and discloses cannabidiol acetamide and a preparation method and application thereof, wherein the preparation method comprises: S1. substitution reaction: dissolving an amino compound mixture in dichloromethane, slowly adding bromoacetyl bromide dropwise under ice-water bath conditions, and stirring and reacting at room temperature for 4-5 hours; extracting the reaction solution with dichloromethane and water, retaining the organic phase, washing with clean water, drying and filtering, concentrating the filtrate under reduced pressure to a constant weight, and then separating and purifying it by silica gel column chromatography to obtain an intermediate; S2. acetylation reaction: under an inert atmosphere, stirring and mixing the intermediate with DMAP, K2CO3, and CH3CN, and then adding a mixed solution of cannabidiol and CH3CN, and stirring and reacting at 55°C for 12 hours; extracting the reaction solution cooled to room temperature with a mixed solvent of saturated NaHCO3 aqueous solution and dichloromethane, retaining the organic phase, drying and filtering, concentrating the filtrate under reduced pressure to a constant weight, and then separating and purifying it by silica gel column chromatography to obtain cannabidiol acetamide.

Description

Technical Field

[0001] The present invention belongs to the technical field of cannabidiol derivatives, and specifically relates to cannabidiol acetamide and a preparation method and application thereof. Background Art

[0002] Cannabidiol is a terpene secondary metabolite unique to cannabis. It has no addictive properties, can hinder the effects of tetrahydrocannabinol (THC) on the human nervous system, has no neuro-dependence, and has biological activities such as neuroprotection, anti-epileptic properties, and anti-cancer effects. In terms of external use on the skin, cannabidiol also has antioxidant, anti-aging, antibacterial and anti-inflammatory, acne-removing, and anti-allergic effects. Therefore, the development of cannabidiol lead drugs is one of the current research hotspots.

[0003] In existing research, due to the large steric hindrance of the cannabidiol structural skeleton, fewer active sites, and the difficulty in obtaining structurally diverse derivatives, the rational design and synthesis of cannabidiol acetamide derivatives based on the cannabidiol skeleton structure can be used as one of the effective ways to obtain compounds with both good stability and activity, which is of great significance for the research and development of new drugs and their application in cosmetics. Summary of the Invention

[0004] In view of this, in order to solve the problems raised in the above background technology, the purpose of the present invention is to provide cannabidiol acetamide and its preparation method and application.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A cannabidiol acetamide, the structural formula of which is:

[0007]

[0008] Wherein, R represents one of the following structural formulas

[0009]

[0010] As a general inventive concept, the present invention also provides the following technical solutions:

[0011] A method for preparing the cannabidiol acetamide as described above comprises the following steps:

[0012] First, an intermediate with an amide functional group is synthesized by using an amino compound as a raw material through a substitution reaction;

[0013] Then, the intermediate is acetylated with cannabidiol using a K2CO3 / DMAP / CH3CN catalytic system to synthesize cannabidiol acetamide.

[0014] Specifically:

[0015] S1. Substitution reaction: The amino compound mixture was dissolved in dichloromethane, and bromoacetyl bromide was slowly added dropwise under ice-water bath conditions. The reaction was stirred at room temperature for 4-5 hours. The reaction solution was extracted with dichloromethane and water. The organic phase was retained, washed with water, dried, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then purified by silica gel column chromatography to obtain the intermediate.

[0016] S2. Acetylation reaction: Under an inert atmosphere, the intermediate was stirred with DMAP, K2CO3, and CH3CN, and then a mixed solution of cannabidiol and CH3CN was added, and the mixture was stirred at 55°C for 12 hours. The reaction solution cooled to room temperature was extracted with a mixed solvent of saturated NaHCO3 aqueous solution and dichloromethane, and the organic phase was retained, dried, and filtered. The filtrate was concentrated under reduced pressure to a constant weight and then separated and purified by silica gel column chromatography to obtain cannabidiol acetamide.

[0017] Preferably, the mixing molar ratio of the amino compound to the bromoacetyl bromide is 1:1.

[0018] Preferably, the mixing molar ratio of the intermediate, DMAP and K2CO3 is 0.7-1:0.6:0.5, and the molar volume ratio of the intermediate to the CH3CN is 0.7-1:6.

[0019] Preferably, the amino compound is one of methylaniline, ethylaniline, diphenylamine, dimethylamine or diethylamine.

[0020] Preferably, the volume molar ratio of the dichloromethane to the methylaniline is 30:9-10.

[0021] Preferably, the volume molar ratio of the dichloromethane to the ethylaniline is 30:8-9.

[0022] Preferably, the mixing molar ratio of the dichloromethane to the diphenylamine is 80:17-18.

[0023] Preferably, the mixing molar ratio of the dichloromethane to the dimethylamine is 5:4.

[0024] Preferably, the mixing molar ratio of the dichloromethane to the diethylamine is 30:27-28.

[0025] In summary, the preparation method of the present invention uses an amino compound as a raw material and synthesizes an intermediate with an amide functional group through a substitution reaction, so that the intermediate has the advantage of being connected to an amide and a carbonyl group. The intermediate is then acetylated with cannabidiol to form a new cannabidiol acetamide with a tyrosinase activity inhibitory effect, which effectively increases the diversity of cannabidiol derivatives. The overall preparation method has the advantages of simple steps and easy operation.

[0026] In view of the fact that cannabidiol acetamide of the present invention can effectively inhibit tyrosinase activity, the present invention also provides the following technical solutions:

[0027] The use of the cannabidiol acetamide as described above or the cannabidiol acetamide prepared by the preparation method as described above in the preparation of drugs or reagents for inhibiting tyrosinase activity.

[0028] As a general inventive concept, the present invention also provides the following technical solutions:

[0029] The use of the cannabidiol acetamide as described above or the cannabidiol acetamide prepared by the preparation method as described above in the preparation of skin whitening products.

[0030] Specifically, the skin whitening product is a composition, and the composition is a cream, emulsion, spray, gel or patch. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The cannabidiol acetamide CA1 prepared in Example 1 1 H-NMR spectrum;

[0032] Figure 2 The cannabidiol acetamide CA1 prepared in Example 1 13 C-NMR spectrum;

[0033] Figure 3 This is a high-resolution mass spectrum of cannabidiol acetamide CA1 prepared in Example 1;

[0034] Figure 4 The cannabidiol acetamide CA2 prepared in Example 2 1 H-NMR spectrum;

[0035] Figure 5 The cannabidiol acetamide CA2 prepared in Example 2 13 C-NMR spectrum;

[0036] Figure 6 This is a high-resolution mass spectrum of cannabidiol acetamide CA2 prepared in Example 2;

[0037] Figure 7 The cannabidiol acetamide CA3 prepared in Example 3 1 H-NMR spectrum;

[0038] Figure 8 The cannabidiol acetamide CA3 prepared in Example 3 13 C-NMR spectrum;

[0039] Figure 9This is a high-resolution mass spectrum of cannabidiol acetamide CA3 prepared in Example 3;

[0040] Figure 10 The cannabidiol acetamide CA4 prepared in Example 4 1 H-NMR spectrum;

[0041] Figure 11 The cannabidiol acetamide CA4 prepared in Example 4 13 C-NMR spectrum;

[0042] Figure 12 This is a high-resolution mass spectrum of cannabidiol acetamide CA4 prepared in Example 4;

[0043] Figure 13 The cannabidiol acetamide CA5 prepared in Example 5 1 H-NMR spectrum;

[0044] Figure 14 The cannabidiol acetamide CA5 prepared in Example 5 13 C-NMR spectrum;

[0045] Figure 15 This is a high-resolution mass spectrum of cannabidiol acetamide CA5 prepared in Example 5;

[0046] Figure 16 This is a graph showing the changes in anti-tyrosinase activity of the five cannabidiol acetamides prepared in Examples 1, 2, 3, 4, and 5. DETAILED DESCRIPTION

[0047] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. 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 making creative efforts are within the scope of protection of the present invention.

[0048] Example 1

[0049] A method for preparing cannabidiol acetamide, the preparation chemical formula of which is as follows:

[0050]

[0051] In this embodiment, the specific preparation steps of cannabidiol acetamide CA1 include:

[0052] (1) Preparation of intermediate A by substitution reaction

[0053] Methylaniline (1.0 mL, 9.3 mmol) was dissolved in dichloromethane (30 mL), and bromoacetyl bromide (0.8 mL, 9.3 mmol) was slowly added dropwise in an ice-water bath, and the mixture was stirred at room temperature for 4 h. The reaction solution was extracted with 30 mL of dichloromethane and 30 mL of water, and the organic phase was retained. The organic phase was washed three times with 30 mL of clean water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1) to obtain intermediate A (1804.9 mg, yield 85.5%) as a yellow oil.

[0054] (2) Preparation of cannabidiol acetamide CA1 by acetylation reaction

[0055] Under an inert atmosphere, intermediate A (200.0 mg, 0.9 mmol) was mixed with DMAP (43.9 mg, 0.6 mmol), K2CO3 (69.1 mg, 0.5 mmol), and CH3CN (3.5 mL) and stirred for 10 min. A mixed solution of cannabidiol (283.0 mg, 0.9 mmol) and CH3CN (2.5 mL) was added, and the reaction was stirred at 55°C for 12 h. The reaction solution, which had been cooled to room temperature, was extracted with a mixed solvent of 20 mL of saturated NaHCO3 aqueous solution and 20 mL of dichloromethane. The organic phase was retained, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain cannabidiol acetamide CA1 (122.5 mg, 29.5% yield) as a yellow oil.

[0056] The cannabidiol acetamide CA1 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 1 shown 1 H-NMR spectrum. Figure 1 It can be seen that 1 The t peak at the chemical shift δ=7.43 in H-NMR spectrum is the meta-position on the benzene ring. H The d peak at δ = 7.37 is the para position of the benzene ring. H The d peak at δ = 7.22 is the ortho position of the benzene ring. H The single peak at δ = 4.27 is the bromoacetyl group CH2 COO, the single peak at δ = 3.28 is the methyl group connected to the N atom on aniline, which indicates the successful preparation of the target product cannabidiol acetamide CA1.

[0057] The cannabidiol acetamide CA1 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 1 shown 13 C-NMR diagram. Figure 2 It can be seen that13 The peaks at chemical shifts of δ = 129.90, 128.40, 128.10, and 124.63 in the C-NMR spectrum are those on the benzene ring, and δ = 168.34 is the peak of CH2 on the amide. C OO, δ = 67.76 is the amide C H2COO, thereby indicating the successful preparation of the target product cannabidiol acetamide CA1.

[0058] High-resolution mass spectrometry analysis of the cannabidiol acetamide CA1 prepared in this example showed that its structure was C 30 H 39 NO3, and obtain Figure 3 The high-resolution mass spectrum shown in Figure 2 is obtained from Figure 3 It can be seen that the measured molecular ion peak is 484.2831 ([M+Na] + ), while the theoretical molecular ion peak of cannabidiol acetamide CA1 is 484.2822 ([M+Na] + ), which further demonstrated that cannabidiol acetamide CA1 was successfully prepared.

[0059] In summary, this Example 1 can effectively prepare cannabidiol acetamide CA1 using methylaniline and cannabidiol as raw materials.

[0060] Example 2

[0061] A method for preparing cannabidiol acetamide, the preparation chemical formula of which is as follows:

[0062]

[0063] In this embodiment, the specific preparation steps of cannabidiol acetamide CA2 include:

[0064] (1) Preparation of intermediate B by substitution reaction

[0065] Ethylaniline (1.0 mL, 8.3 mmol) was mixed and dissolved in dichloromethane (30 mL). Bromoacetyl bromide (0.8 mL, 8.3 mmol) was slowly added dropwise in an ice-water bath, and the mixture was stirred at room temperature for 4 h. The reaction solution was extracted with 30 mL of dichloromethane and 30 mL of water. The organic phase was retained and washed three times with 30 mL of clean water, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1) to obtain intermediate B (1864.4 mg, yield 93.2%) as a yellow oil.

[0066] (2) Preparation of cannabidiol acetamide CA2 by acetylation reaction

[0067] Under an inert atmosphere, intermediate B (200.0 mg, 0.8 mmol) was mixed with DMAP (43.9 mg, 0.6 mmol), K2CO3 (69.1 mg, 0.5 mmol), and CH3CN (3.5 mL) and stirred for 10 min. A mixed solution of cannabidiol (251.6 mg, 0.8 mmol) and CH3CN (2.5 mL) was added, and the reaction was stirred at 55°C for 12 h. The reaction solution, which had been cooled to room temperature, was extracted with a mixed solvent of 20 mL of saturated NaHCO3 aqueous solution and 20 mL of dichloromethane. The organic phase was retained, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to give cannabidiol acetamide CA2 (135.7 mg, 35.7% yield) as a yellow oil.

[0068] The cannabidiol acetamide CA2 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 4 shown 1 H-NMR spectrum. Figure 4 It can be seen that 1 The t peak at the chemical shift δ=7.44 in H-NMR spectrum is the meta-position on the benzene ring. H The d peak at δ = 7.38 is the para position of the benzene ring. H The d peak at δ = 7.19 is the ortho position of the benzene ring. H The single peak at δ = 4.24 is the bromoacetyl group CH2 COO, the single peak at δ = 3.79 is N- CH2 CH3, the single peak at δ = 1.56 is N-CH2 CH3 , which indicates the successful preparation of the target product cannabidiol acetamide CA2.

[0069] The cannabidiol acetamide CA2 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 5 shown 13 C-NMR diagram. Figure 5 It can be seen that 13 The peaks at chemical shifts of δ = 129.90, 128.40, 128.10, and 124.63 in the C-NMR spectrum are those on the benzene ring, and δ = 167.36 is the peak of CH2 on the amide. C OO, δ = 67.60 is on the amide C H2COO, thereby indicating the successful preparation of the target product cannabidiol acetamide CA2.

[0070] High-resolution mass spectrometry analysis of the cannabidiol acetamide CA2 prepared in this example showed that its structure was C 31 H 41 NO3, and obtain Figure 6 The high-resolution mass spectrum shown in Figure 2 is obtained from Figure 6 It can be seen that the measured molecular ion peak is 448.2830 ([M+Na] + ), while the theoretical molecular ion peak of cannabidiol acetamide CA2 is 448.2822 ([M+Na] + ), which further demonstrated that cannabidiol acetamide CA2 was successfully prepared.

[0071] In summary, Example 2 can effectively prepare cannabidiol acetamide CA2 using methylaniline and cannabidiol as raw materials.

[0072] Example 3

[0073] A method for preparing cannabidiol acetamide, the preparation chemical formula of which is as follows:

[0074]

[0075] In this embodiment, the specific preparation steps of cannabidiol acetamide CA3 include:

[0076] (1) Preparation of intermediate C by substitution reaction

[0077] Diphenylamine (3.0 g, 17.7 mmol) was mixed and dissolved in dichloromethane (80 mL). Bromoacetyl bromide (1.6 mL, 17.7 mmol) was slowly added dropwise in an ice-water bath, and the mixture was stirred at room temperature for 4 h. The reaction solution was extracted with 60 mL of dichloromethane and 60 mL of water. The organic phase was retained and washed three times with 60 mL of clean water, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 8 / 2) to obtain intermediate C (4634.6 mg, yield 90.6%) as a yellow oil.

[0078] (2) Preparation of cannabidiol acetamide CA3 by acetylation reaction

[0079] Under an inert atmosphere, intermediate C (200.0 mg, 0.7 mmol) was mixed with DMAP (43.9 mg, 0.6 mmol), K2CO3 (69.1 mg, 0.5 mmol), and CH3CN (3.5 mL) and stirred for 10 min. A mixed solution of cannabidiol (220.1 mg, 0.7 mmol) and CH3CN (2.5 mL) was added, and the reaction was stirred at 55°C for 12 h. The reaction solution, which had been cooled to room temperature, was extracted with a mixed solvent of 20 mL of saturated NaHCO3 aqueous solution and 20 mL of dichloromethane. The organic phase was retained, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain cannabidiol acetamide CA3 (119.8 mg, 32.7% yield) as a yellow oil.

[0080] The cannabidiol acetamide CA3 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 7 shown 1 H-NMR spectrum. Figure 7 It can be seen that 1 The single peaks at δ=7.38 and δ=7.28 in the H-NMR spectrum are the meta-positions on the benzene ring. H , the single peak at δ = 4.40 is the bromoacetyl group CH2 COO, thereby indicating the successful preparation of the target product cannabidiol acetamide CA3.

[0081] The cannabidiol acetamide CA3 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 8 shown 13 C-NMR diagram. Figure 8 It can be seen that 13 The peaks at chemical shifts of δ = 130.90, 129.36, 128.56, 126.63, 124.86, 124.55, and 124.32 in the C-NMR spectrum are on the benzene ring, and the peak at chemical shift of δ = 168.36 is on the CH2 C OO, chemical shift is δ=68.47 for amide C H2COO, thereby indicating the successful preparation of the target product cannabidiol acetamide CA3.

[0082] High-resolution mass spectrometry analysis of the cannabidiol acetamide CA3 prepared in this example showed that its structure was C 31 H 41 NO3, and obtain Figure 9 The high-resolution mass spectrum shown in Figure 2 is obtained from Figure 9 It can be seen that the measured molecular ion peak is 546.2988 ([M+Na] +), while the theoretical molecular ion peak of cannabidiol acetamide CA3 is 546.2979 ([M+Na] + ), which further demonstrated that cannabidiol acetamide CA3 was successfully prepared.

[0083] In summary, this Example 3 can effectively prepare cannabidiol acetamide CA3 using methylaniline and cannabidiol as raw materials.

[0084] Example 4

[0085] A method for preparing cannabidiol acetamide, the preparation chemical formula of which is as follows:

[0086]

[0087] In this embodiment, the specific preparation steps of cannabidiol acetamide CA4 include:

[0088] (1) Preparation of intermediate D by substitution reaction

[0089] Dimethylamine (0.1 mL, 4.0 mmol) in a tetrahydrofuran solution was dissolved in dichloromethane (5 mL). Bromoacetyl bromide (0.3 mL, 4.0 mmol) was slowly added dropwise in an ice-water bath, and the mixture was stirred at room temperature for 5 h. The reaction solution was extracted with 10 mL of dichloromethane and 10 mL of water. The organic phase was retained and washed three times with 10 mL of clean water, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1) to obtain intermediate D (116.1 mg, yield 17.6%) as a yellow oil.

[0090] (2) Preparation of cannabidiol acetamide CA4 by acetylation reaction

[0091] Under an inert atmosphere, intermediate D (110.0 mg, 0.7 mmol) was mixed with DMAP (43.9 mg, 0.6 mmol), K2CO3 (69.1 mg, 0.5 mmol), and CH3CN (3.5 mL) and stirred for 10 min. A mixed solution of cannabidiol (220.1 mg, 0.7 mmol) and CH3CN (2.5 mL) was added, and the reaction was stirred at 55°C for 12 h. The reaction solution, which had been cooled to room temperature, was extracted with a mixed solvent of 20 mL of saturated NaHCO3 aqueous solution and 20 mL of dichloromethane. The organic phase was retained, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain cannabidiol acetamide CA4 (29.9 mg, 10.7% yield) as a yellow oil.

[0092] The cannabidiol acetamide CA4 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 10 shown 1 H-NMR spectrum. Figure 10 It can be seen that 1 The singlet peak at δ=4.54 in the H-NMR spectrum is due to the bromoacetyl group. CH2 COO, the single peaks at δ = 3.06 and 2.98 are peaks connected by N atoms, which indicates the successful preparation of the target product cannabidiol acetamide CA4.

[0093] The cannabidiol acetamide CA4 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 11 shown 13 C-NMR diagram. Figure 11 It can be seen that 13 The C-NMR nuclear magnetic spectrum shows an amide peak at a chemical shift of δ=168.3 and an amide peak at a chemical shift of δ=68.6. C H2COO, thereby indicating the successful preparation of the target product cannabidiol acetamide CA4.

[0094] High-resolution mass spectrometry analysis of the cannabidiol acetamide CA4 prepared in this example showed that its structure was C 25 H 37 NO3, and obtain Figure 12 The high-resolution mass spectrum shown in Figure 2 is obtained from Figure 12 It can be seen that the measured molecular ion peak is 422.2672 ([M+Na] + ), while the theoretical molecular ion peak of cannabidiol acetamide CA4 is 422.2672 ([M+Na] + ), which further demonstrated that cannabidiol acetamide CA4 was successfully prepared.

[0095] In summary, Example 4 can effectively prepare cannabidiol acetamide CA4 using methylaniline and cannabidiol as raw materials.

[0096] Example 5

[0097] A method for preparing cannabidiol acetamide, the preparation chemical formula of which is as follows:

[0098]

[0099] In this embodiment, the specific preparation steps of cannabidiol acetamide CA5 include:

[0100] (1) Preparation of intermediate E by substitution reaction

[0101] Diethylamine (2.8 mL, 27.4 mmol) was mixed and dissolved in dichloromethane (30 mL), and bromoacetyl bromide (2.4 mL, 27.4 mmol) was slowly added dropwise in an ice-water bath, and the reaction was stirred at room temperature for 4 h; the reaction solution was extracted with 50 mL of dichloromethane and 50 mL of water, and the organic phase was retained. The organic phase was washed three times with 50 mL of clean water, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 8 / 2) to obtain intermediate E (4648.6 mg, yield 87.9%) as a yellow oil;

[0102] (2) Preparation of cannabidiol acetamide CA5 by acetylation reaction

[0103] Under an inert atmosphere, intermediate E (200.0 mg, 1.0 mmol) was mixed with DMAP (43.9 mg, 0.6 mmol), K2CO3 (69.1 mg, 0.5 mmol), and CH3CN (3.5 mL) and stirred for 10 min. A mixed solution of cannabidiol (314.5 mg, 1.0 mmol) and CH3CN (2.5 mL) was added, and the reaction was stirred at 55°C for 12 h. The reaction solution, which had been cooled to room temperature, was extracted with a mixed solvent of 20 mL of saturated NaHCO3 aqueous solution and 20 mL of dichloromethane. The organic phase was retained, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to give cannabidiol acetamide CA5 (152.5 mg, 35.7% yield) as a yellow oil.

[0104] The cannabidiol acetamide CA5 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 13 shown 1 H-NMR spectrum. Figure 13 It can be seen that 1 The single peak at chemical shift δ = 4.51 in H-NMR spectrum is the bromoacetyl group. CH2 COO, the m peak at δ = 3.41 is the peak connected by N atoms, and the single peak at δ = 1.78 is the methyl peak of two ethyl groups connected by N, which indicates the successful preparation of the target product cannabidiol acetamide CA5.

[0105] The cannabidiol acetamide CA5 prepared in this example was subjected to nuclear magnetic resonance analysis and the following was obtained: Figure 14 shown 13 C-NMR diagram. Figure 14 It can be seen that 13 The C-NMR spectrum shows an amide peak at a chemical shift of δ=167.2 and an amide peak at a chemical shift of δ=68.4. CH2COO, thereby indicating the successful preparation of the target product cannabidiol acetamide CA5.

[0106] High-resolution mass spectrometry analysis of the cannabidiol acetamide CA5 prepared in this example showed that its structure was C 25 H 37 NO3, and obtain Figure 15 The high-resolution mass spectrum shown in Figure 2 is obtained from Figure 15 It can be seen that the measured molecular ion peak is 450.2974 ([M+Na] + ), while the theoretical molecular ion peak of cannabidiol acetamide CA5 is 450.2979 ([M+Na] + ), which further demonstrated that cannabidiol acetamide CA5 was successfully prepared.

[0107] In summary, this Example 5 can effectively prepare cannabidiol acetamide CA5 using methylaniline and cannabidiol as raw materials.

[0108] In addition, the present invention also studied the anti-tyrosinase activity of five cannabidiol acetamides, CA1, CA2, CA3, CA4 and CA5, prepared in Examples 1, 2, 3, 4 and 5, and obtained the following results: Figure 16 The change of anti-tyrosinase activity is shown in the graph. Figure 16 It can be seen that when the sample concentration is 10umoL~500umoL, the inhibition rate of the sample on tyrosinase shows a slowly increasing trend, and the IC50 of the five cannabidiol acetamides CA1, CA2, CA3, CA4 and CA5 on tyrosinase inhibitory activity are 0.197, 0.134, 0.307, 0.456 and 0.417 respectively. This proves that the five cannabidiol acetamides CA1, CA2, CA3, CA4 and CA5 have a strong inhibitory effect on tyrosinase activity.

[0109] Based on the characteristics of cannabidiol acetamide of the present invention that can effectively inhibit tyrosinase activity, the present invention also provides the following applications:

[0110] Application 1:

[0111] Application of cannabidiol acetamide in the preparation of drugs or reagents for inhibiting tyrosinase activity.

[0112] Application 1:

[0113] Application of cannabidiol acetamide in the preparation of skin whitening products.

[0114] Specifically, the skin whitening product is a composition, and the composition is a cream, emulsion, spray, gel or patch.

[0115] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A cannabidiol acetamide, characterized in that The cannabidiol acetamide is one of the following structural formulas CA1, CA2, CA3, CA4, and CA5: 、 、 、 、 。 2. The method for preparing cannabidiol acetamide according to claim 1, wherein: S1. The amino compound mixture was dissolved in dichloromethane, bromoacetyl bromide was slowly added dropwise under ice-water bath conditions, and the reaction was stirred at room temperature for 4 to 5 hours; the reaction solution was extracted with dichloromethane and water, the organic phase was retained, washed with water, dried, filtered, and the filtrate was concentrated under reduced pressure to constant weight and then purified by silica gel column chromatography to obtain the intermediate; S2. Under an inert atmosphere, the intermediate was stirred with DMAP, K2CO3, and CH3CN, and then a mixed solution of cannabidiol and CH3CN was added, and the reaction was stirred at 55°C for 12 hours; the reaction solution cooled to room temperature was extracted with a mixed solvent of saturated NaHCO3 aqueous solution and dichloromethane, and the organic phase was retained, dried, and filtered. The filtrate was concentrated under reduced pressure to constant weight and then separated and purified by silica gel column chromatography to obtain cannabidiol acetamide.

3. The preparation method according to claim 2, wherein: The mixing molar ratio of the amino compound to the bromoacetyl bromide is 1:

1.

4. The preparation method according to claim 2 or 3, characterized in that: The mixing molar ratio of the intermediate, DMAP and K2CO3 is 0.7-1:0.6:0.5, and the molar volume ratio of the intermediate and CH3CN is 0.7-1:

6.

5. The preparation method according to claim 2 or 3, characterized in that: The amino compound is one of methylaniline, ethylaniline, diphenylamine, dimethylamine or diethylamine.

6. The preparation method according to claim 5, characterized in that: The volume molar ratio of the dichloromethane to the methylaniline is 30:9-10; The volume molar ratio of the dichloromethane to the ethylaniline is 30:8-9; The mixing molar ratio of the dichloromethane to the diphenylamine is 80:17-18; The mixing molar ratio of the dichloromethane to the dimethylamine is 5:4; The mixing molar ratio of the dichloromethane to the diethylamine is 30:27-28.

7. Use of the cannabidiol acetamide according to claim 1 or the cannabidiol acetamide prepared by the preparation method according to any one of claims 2 to 6 in the preparation of drugs or reagents for inhibiting tyrosinase activity.

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