Preparation method of cannabinoid phenolic acid ester

Abstract

The invention relates to a method for preparing CBGA methyl ester, CBGA and CBG by taking methyl olive alcohol and geraniol as raw materials, and the method comprises the following steps: under the condition of a halogenated hydrocarbon organic solvent, taking geraniol and methyl olive alcohol as raw material medicines, and obtaining CBGA methyl ester under the catalysis of an acid catalyst; the method comprises the following steps: adding CBGA methyl ester into dimethyl sulfoxide and an alkaline reagent aqueous solution, and reacting to obtain CBGA or CBG.

Description

Technical Field

[0001] The present invention relates to a method for preparing CBGA methyl ester (cannabigerolic acid ester), and more particularly to a method for preparing CBGA methyl ester, CBGA and CBG by taking olive alcohol methyl ester and geraniol as raw materials. Background Art

[0002] CBGA methyl ester (cannabigerolic acid ester) has important application value in the fields of medicine, food, health products and cosmetics, and is also a precursor for the synthesis of CBGA. CBGA (CANNABIGEROLIC ACID) plays an important role in the biochemistry of cannabis plants and is a key precursor for the formation of cannabinoids such as tetrahydrocannabinolic acid A (THCA), cannabigerolic acid (CBDA), cannabigerolic acid (CBCA) and cannabigerol (CBG), all of which have extremely high medical value. CBG is a non-psychoactive cannabinoid that shows many potential health benefits, including the following: acting as a neuroprotectant; antioxidant properties; assisting skin diseases as an antibacterial and antifungal agent; appetizing; anti-inflammatory in the treatment of gastrointestinal diseases; and reducing intraocular pressure, which is beneficial for patients with glaucoma.

[0003] Patents WO2019033168A1, WO2019033164A1, and WO2020249184A1 have reported the catalytic synthesis of olive alcohol esters, geraniol, boron trifluoride ether, etc., with a yield of 6%-40%. The raw materials use acidic media such as Lewis acid or p-toluenesulfonic acid, which leads to the easy generation of THCA ester by-products during the reaction process, and the yield is low; Patents WO2015128200A1 and WO2021245672A1 use expensive CBGA to prepare CBGA methyl ester. The cost of CBGA is higher than that of CBGA methyl ester, and more impurities are produced. A small amount can be purified by column chromatography, but a large amount is difficult to separate and is not suitable for mass production; Patent CA3081858A1 uses olive alcohol, geraniol and a large amount of aluminum oxide to prepare CBG. A large amount of aluminum oxide not only acts as a catalyst but also forms an oil-water interface with the solvent to accelerate the reaction efficiency. However, this method has not proven that it can produce CBGA methyl ester with high yield and high purity.

[0004] The currently disclosed technologies all have many problems such as high impurities of CBGA methyl ester, high raw material cost, difficulty in separation, and difficulty in achieving industrial production. Summary of the invention

[0005] The present invention provides a method for preparing CBGA methyl ester with high purity, high yield, simple purification process and easy industrial production. The present invention also provides a method for preparing CBGA and CBG through CBGA methyl ester, which has high yield, high purity, low cost and is easy to industrialize.

[0006] The present invention solves the above technical problems through the following technical solutions:

[0007] The present invention provides a method for preparing CBGA methyl ester, which is characterized in that the preparation method is as follows:

[0008] Under the condition of halogenated hydrocarbon organic solvent, geraniol of formula I and olive alcohol methyl ester of formula II are used as raw materials, and CBGA methyl ester of formula III is obtained under the catalysis of an acidic catalyst, wherein the molar ratio of geraniol to olive alcohol methyl ester is 1.3-10:1

[0009]

[0010] In the present invention, the molar ratio of geraniol to olive alcohol methyl ester is 1.3-3:1; preferably 1.5-3:1; more preferably 1.5:1 or 2:1.

[0011] In the present invention, the acidic catalyst is selected from one or more of camphorsulfonic acid, p-toluenesulfonic acid and aluminum oxide, preferably aluminum oxide; the mass molar ratio of aluminum oxide to olive alcohol methyl ester is 1.5-10 g / mmol; preferably 1.5-3 g / mmol; more preferably 1.5 g / mmol, 2.4 g / mmol or 2.5 g / mmol.

[0012] The halogenated hydrocarbon organic solvent in the present invention is selected from one or more of chloroform, carbon tetrachloride, trichloroethane, dichloromethane, chlorobenzene and dichloroethane, preferably chlorobenzene and dichloroethane; the volume ratio of chlorobenzene to dichloroethane is 10:3.

[0013] The reaction time in the present invention is 5-30h, preferably 16-24h.

[0014] The reaction temperature in the present invention is 80-100°C, preferably 92-95°C.

[0015] The present invention further provides a method for preparing CBGA, which is as follows: CBGA methyl ester is added to dimethyl sulfoxide and an alkaline reagent aqueous solution to react and obtain CBGA.

[0016] The alkaline reagent in the present invention is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide and sodium sulfide; preferably sodium sulfide and sodium hydroxide; the mass ratio of sodium sulfide to sodium hydroxide is 1:1.25.

[0017] The reaction time in the present invention is 40-80 hours, preferably 70-80 hours, and more preferably 72 hours.

[0018] The reaction temperature in the present invention is 10-40°C, preferably 30-35°C.

[0019] The present invention further provides a method for preparing CBG, which is as follows: adding CBGA methyl ester to dimethyl sulfoxide and an alkaline reagent aqueous solution to react and obtain CBG.

[0020] The alkaline reagent in the present invention is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide and sodium sulfide; preferably sodium sulfide; the mass ratio of sodium sulfide to CBGA methyl ester is 1.51:1.

[0021] The reaction time in the present invention is 1-10, preferably 4-5 hours.

[0022] The reaction temperature in the present invention is 80-100°C, preferably 100°C. Specific embodiments

[0023] Comparative Example 1

[0024] Add olivetol methyl ester (2.3 g, 9.7 mmol) and geraniol (1.0 g, 6.5 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (24.3 g, 2.5 g / mmol), add 20 mL of dichloroethane into the three-necked flask, ventilate with nitrogen three times, stir at 83 ° C for 8 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 189 mg of orange-yellow liquid with a yield of 8% and a purity of 100%.

[0025] Comparative Example 2

[0026] Add olivetol methyl ester (2.3 g, 9.7 mmol) and geraniol (1.0 g, 6.5 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (13.0 g, 1.3 g / mmol), add 15 mL of dichloroethane into the three-necked flask, ventilate with nitrogen three times, stir at 95 ° C for 16 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 361 mg of orange-yellow liquid with a yield of 15% and a purity of 100%.

[0027] Comparative Example 3

[0028] Olive alcohol methyl ester (1.2 g, 4.9 mmol) and geraniol (0.5 g, 3.3 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (8.1 g, 1.7 g / mmol) was added. 7.5 mL of dichloroethane was added to the three-necked flask, ventilated with nitrogen three times, stirred at 95 ° C for 16 hours, the reaction was stopped, and naturally cooled to room temperature, filtered, the filter cake was rinsed with a large amount of dichloromethane, the filtrate was combined, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (PE: EA = 30: 1) obtained 170 mg of orange-yellow oily liquid with a yield of 14% and a purity of 96.1%.

[0029] Example 1

[0030] Olive alcohol methyl ester (1.55 g, 6.5 mmol) and geraniol (1.0 g, 6.5 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (16.0 g, 2.5 g / mmol) was added. 20 mL of dichloroethane and 6 mL of chlorobenzene were added to the three-necked flask, ventilated with nitrogen three times, stirred at 95 ° C for 16 hours, the reaction was stopped, cooled naturally to room temperature, filtered, the filter cake was rinsed with a large amount of dichloromethane, the filtrate was combined, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (PE: EA = 30: 1) obtained 1.1 g of oily liquid with a yield of 45% and a purity of 95%.

[0031] Example 2

[0032] Olive alcohol methyl ester (1.0 g, 4.2 mmol) and geraniol (841 mg, 5.46 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (10.5 g, 2.5 g / mmol) was added. 11.2 mL of dichloroethane and 3.8 mL of chlorobenzene were added to the three-necked flask, ventilated with nitrogen three times, stirred at 95 ° C for 16 hours, the reaction was stopped, cooled naturally to room temperature, filtered, the filter cake was rinsed with a large amount of dichloromethane, the filtrate was combined, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (PE: EA = 100: 1) obtained 938 mg of orange-yellow liquid with a yield of 60% and a purity of 95.7%.

[0033] Example 3

[0034] Olive alcohol methyl ester (1.0 g, 4.2 mmol) and geraniol (970 mg, 6.3 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (10.5 g, 2.5 g / mmol) was added. 11.2 mL of dichloroethane and 3.8 mL of chlorobenzene were added to the three-necked flask, ventilated with nitrogen three times, stirred at 95 ° C for 16 hours, the reaction was stopped, cooled naturally to room temperature, filtered, the filter cake was rinsed with a large amount of dichloromethane, the filtrate was combined, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (PE: EA = 100: 1) obtained 986 mg of oily liquid with a yield of 63% and a purity of 95.2%.

[0035] Example 4

[0036] Add olivetol methyl ester (0.5 g, 2.1 mmol) and geraniol (970 mg, 6.3 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (5.3 g, 2.5 g / mmol), add 5.6 mL of dichloroethane and 1.9 mL of chlorobenzene into the three-necked flask, ventilate with nitrogen three times, stir at 95 ° C for 16 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 492 mg of colorless transparent liquid with a yield of 63% and a purity of 94%.

[0037] Example 5

[0038] Olive alcohol methyl ester (1.0 g, 4.2 mmol), geraniol (1.29 g, 8.4 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (1.0 g, 0.24 g / mmol) was added, and 11.2 mL of dichloroethane and 3.8 mL of chlorobenzene were added to the three-necked flask, nitrogen was ventilated three times, stirred at 95 ° C for 22 hours, the reaction was stopped, and naturally cooled to room temperature. The yield was less than 5%, and the product was too little and difficult to separate.

[0039] Example 6

[0040] Olive alcohol methyl ester (0.5 g, 2.1 mmol) and geraniol (647 mg, 4.2 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (2.1 g, 1.0 g / mmol) was added. 5.6 mL of dichloroethane and 1.9 mL of chlorobenzene were added to the three-necked flask, ventilated with nitrogen three times, stirred at 95 ° C for 22 hours, the reaction was stopped, cooled naturally to room temperature, filtered, the filter cake was rinsed with a large amount of dichloromethane, the filtrate was combined, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (PE: EA = 30: 1) obtained 275 mg of colorless transparent liquid with a yield of 35% and a purity of 97%.

[0041] Example 7

[0042] Add olivetol methyl ester (0.5 g, 2.1 mmol) and geraniol (647 mg, 4.2 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (2.5 g, 1.2 g / mmol), add 5.6 mL of dichloroethane and 1.9 mL of chlorobenzene into the three-necked flask, ventilate with nitrogen three times, stir at 95 ° C for 22 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 369 mg of colorless transparent liquid with a yield of 47% and a purity of 94%.

[0043] Example 8

[0044] Olive alcohol methyl ester (1.0 g, 4.2 mmol) and geraniol (1.26 g, 8.4 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (6.3 g, 1.5 g / mmol) was added. 20 mL of dichloroethane and 6 mL of chlorobenzene were added to the three-necked flask, ventilated with nitrogen three times, stirred at 95 ° C for 22 hours, the reaction was stopped, cooled naturally to room temperature, filtered, the filter cake was rinsed with a large amount of dichloromethane, the filtrate was combined, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (PE: EA = 100: 1) obtained 989 mg of oily liquid with a yield of 63% and a purity of 96%.

[0045] Example 9

[0046] Olive alcohol methyl ester (0.5 g, 2.1 mmol) and geraniol (647 mg, 4.2 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (6.3 g, 3 g / mmol) was added. 5.6 mL of dichloroethane and 1.9 mL of chlorobenzene were added to the three-necked flask, ventilated with nitrogen three times, stirred at 95 ° C for 22 hours, the reaction was stopped, and naturally cooled to room temperature, filtered, the filter cake was rinsed with a large amount of dichloromethane, the filtrate was combined, and the solvent was distilled off under reduced pressure. 488 mg of orange-yellow liquid was obtained by silica gel column chromatography (PE: EA = 30:1), with a yield of 62% and a purity of 94%.

[0047] Example 10

[0048] Add olivetol methyl ester (1.0 g, 4.2 mmol) and geraniol (1.29 g, 8.4 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (10.1 g, 2.4 g / mmol), add 15 mL of toluene into the three-necked flask, ventilate with nitrogen three times, stir at 93 ° C for 24 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 581 mg of oily liquid with a yield of 37% and a purity of 93.1%.

[0049] Embodiment 11

[0050] Add olivetol methyl ester (1.0 g, 4.2 mmol) and geraniol (1.29 g, 8.4 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (10.1 g, 2.4 g / mmol), add 15 mL of chlorobenzene into the three-necked flask, ventilate with nitrogen three times, stir at 93 ° C for 24 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 660 mg of oily liquid with a yield of 42% and a purity of 97.3%.

[0051] Example 12

[0052] Add olivetol methyl ester (1.0 g, 4.2 mmol) and geraniol (1.29 g, 8.4 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (10.1 g, 2.4 g / mmol), add 15 mL of xylene into the three-necked flask, ventilate with nitrogen three times, stir at 93 ° C for 24 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 300 mg of oily liquid with a yield of 19% and a purity of 96.7%.

[0053] Example 13

[0054] Add olivetol methyl ester (1.0 g, 4.2 mmol) and geraniol (1.29 g, 8.4 mmol) into a 100 mL three-necked flask, then add acidic aluminum oxide (10.1 g, 2.4 g / mmol), add 15 mL of 1,4-dioxane into the three-necked flask, ventilate with nitrogen three times, stir at 93 ° C for 24 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 109 mg of oily liquid with a yield of 7% and a purity of 100%.

[0055] Embodiment 14

[0056] Olive alcohol methyl ester (1.0 g, 4.2 mmol), geraniol (1.29 g, 8.4 mmol) were added to a 100 mL three-necked flask, and then acidic aluminum oxide (10.1 g, 2.4 g / mmol) was added, and 15 mL of DMF was added to the three-necked flask, nitrogen was ventilated three times, stirred at 93 ° C for 24 hours, the reaction was stopped, and naturally cooled to room temperature. The yield was less than 5%, and the product was too little and difficult to separate.

[0057] Embodiment 15

[0058] Add olivetol methyl ester (5.0 g, 21.0 mmol) and geraniol (6.47 g, 42.0 mmol) into a 250 mL three-necked flask, then add acidic aluminum oxide (50.4 g, 2.4 g / mmol), add 50 mL of dichloroethane and 80 mL of chlorobenzene into the three-necked flask, ventilate with nitrogen three times, stir at 95 ° C for 12 hours, stop the reaction, cool naturally to room temperature, filter, rinse the filter cake with a large amount of dichloromethane, combine the filtrate, and distill under reduced pressure to remove the solvent. Silica gel column chromatography (PE: EA = 30: 1) obtains 5.0 g of oily liquid with a yield of 64% and a purity of 96%.

[0059] Example 16

[0060] Sodium sulfide (4.0 g, 51.0 mmol) and sodium hydroxide (8.0 g, 200.0 mmol) were added to a 500 mL three-necked flask, and then 20 mL of water was added to dissolve them, and then 100 mL of dimethyl sulfoxide was added, and then CBGA methyl ester (12.4 g, 33.0 mmol) was added to the three-necked flask. Under nitrogen, the reaction was stirred at room temperature for 72 h, and the reaction was stopped. 200 mL of water was added to the reaction solution, and then the pH value was adjusted to 3 with 1% citric acid, and extracted twice with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude CBGA product. Column chromatography (EA:PE=1%-20%) gave 7.40 g of a white solid with a yield of 62% and a purity of 98%.

[0061] Embodiment 17

[0062] Sodium sulfide (110 mg, 1.4 mmol) and potassium hydroxide (90 mg, 1.62 mmol) were added to a 100 mL three-necked flask, and then 60 mg of water was added, followed by 1.5 mL of dimethyl sulfoxide. CBGA methyl ester (100 mg, 0.27 mmol) was added to the three-necked flask. Under nitrogen, the reaction was stirred at 30 degrees for 72 hours. The reaction was stopped, 3 mL of water was added to the reaction solution, and then the pH value was adjusted to 3 with 1% citric acid. The mixture was extracted twice with 5 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude CBGA product. Column chromatography (EA:PE=1%-5%) gave 46 mg of an oily substance with a yield of 47% and a purity of 98%.

[0063] Embodiment 18

[0064] Sodium sulfide (500 mg, 6.4 mmol) and cesium carbonate (500 g, 1.53 mmol) were added to a 100 mL three-necked flask, and then 3 mL of water was added to dissolve it, and then 5 mL of dimethyl sulfoxide was added, and then CBGA methyl ester (557 mg, 1.5 mmol) was added to the three-necked flask. Under nitrogen conditions, the reaction was stirred at 35 degrees for 72 hours, and the reaction was stopped. 10 mL of water was added to the reaction solution, and then the pH value was adjusted to 3 with 1% citric acid, and extracted three times with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude CBGA product. Column chromatography (EA: PE = 1% -%) obtained 270 mg of an oily substance with a yield of 50% and a purity of 97%.

[0065] Embodiment 19

[0066] Sodium sulfide (7.5 g, 96.1 mmol) was dissolved in 60 ml of water, and then added to a reaction bottle containing 75 ml of dimethyl sulfoxide, and then CBGA methyl ester (5.1 g, 13.7 mmol) was added, and nitrogen was replaced 3 times, and the reaction was stirred at 100 degrees for 5 hours to stop the reaction. 100 ml of water was added to the reaction solution, and the pH value was adjusted to 3 with 1% citric acid, and 70 ml of ethyl acetate was extracted twice, and the organic layer was separated, dried over anhydrous sodium sulfate, and the extract was concentrated to obtain 4.53 g of CBG oily crude product with a purity of 92%. The obtained crude product was dissolved in 18 ml of n-hexane, placed at -40 ° C for crystallization, and then waited until no solid was precipitated, and filtered to obtain 3.63 g of white solid, with a yield of 84% and a purity of 96.7%.

Claims

1. A method for preparing CBGA methyl ester, characterized in that The preparation method is as follows: Under the condition of halogenated hydrocarbon organic solvent, geraniol of formula I and olive alcohol methyl ester of formula II are used as raw materials, and CBGA methyl ester of formula III is obtained under the catalysis of an acidic catalyst, wherein the molar ratio of geraniol to olive alcohol methyl ester is 1-3:1; and the mass molar ratio of the acidic catalyst to olive alcohol methyl ester is 1.5-10 g / mmol.

2. The preparation method according to claim 1, characterized in that The molar ratio of geraniol to olive alcohol methyl ester is 1.3-3:1; preferably 1.5-3:1; more preferably 1.5:1 or 2:

1.

3. The preparation method according to claim 1, characterized in that The acidic catalyst is selected from one or more of camphorsulfonic acid, p-toluenesulfonic acid, and aluminum oxide, preferably aluminum oxide; the mass molar ratio of aluminum oxide to olive alcohol methyl ester is 1.5-3 g / mmol; more preferably 1.5 g / mmol, 2.4 g / mmol or 2.5 g / mmol.

4. The preparation method according to claim 1, characterized in that The halogenated hydrocarbon organic solvent is selected from one or more of chloroform, carbon tetrachloride, trichloroethane, dichloromethane, chlorobenzene and dichloroethane, preferably chlorobenzene and dichloroethane.

5. The preparation method according to claim 4, characterized in that The volume ratio of the chlorobenzene to the ethylene dichloride is 10:

3.

6. The preparation method according to claim 1, characterized in that The reaction time is 5-30h, preferably 16-24h.

7. The preparation method according to claim 1, characterized in that The reaction temperature is 80-100°C, preferably 92-95°C.

8. A method for preparing CBGA, characterized in that The preparation method is as follows: 1) preparing CBGA methyl ester according to the preparation method according to any one of claims 1 to 6; 2) Add CBGA methyl ester to dimethyl sulfoxide and an alkaline reagent aqueous solution to react and obtain CBGA.

9. The preparation method according to claim 8, characterized in that The alkaline reagent is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide, and sodium sulfide; preferably sodium sulfide and sodium hydroxide; the mass ratio of sodium sulfide to sodium hydroxide is 1:1.

25.

10. The preparation method according to claim 8, characterized in that The reaction time of step 2) is 40-80 hours, preferably 70-80 hours, more preferably 72 hours.

11. The preparation method according to claim 8, characterized in that The reaction temperature of step 2) is 10-40°C, preferably 30-35°C.

12. A method for preparing CBG, characterized in that The preparation method is as follows: 1) preparing CBGA methyl ester according to the preparation method according to any one of claims 1 to 6; 2) Add CBGA methyl ester to dimethyl sulfoxide and alkaline reagent aqueous solution to react and obtain CBG.

13. The preparation method according to claim 12, characterized in that The alkaline reagent is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide, and sodium sulfide; preferably sodium sulfide; the mass ratio of sodium sulfide to CBGA methyl ester is 1.51:

1.

14. The preparation method according to claim 12, characterized in that The reaction time of step 2) is 1-10 hours, preferably 4-5 hours.

15. The preparation method according to claim 12, characterized in that The reaction temperature of step 2) is 80-100°C, preferably 100°C.

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