Preparation method of cannabidiol

Abstract

The invention belongs to the technical field of carbocyclic compound synthesis, and is specifically related to a method for preparing cannabidiol, comprising the following steps: S1, 2,4-dihydroxy-6-pentyl benzoate and an amidating agent are subjected to an amidation reaction to obtain an intermediate I; S2, intermediate I and (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol, undergo a Friedel-Crafts alkylation reaction under acid catalysis to obtain an intermediate II; S3, under alkaline conditions, intermediate II is subjected to a decarboxylation reaction to obtain cannabidiol. The raw materials used in the present invention are simple and inexpensive, and the intermediates obtained in the preparation process can all be purified by recrystallization, and the operation is simple, and by increasing the purity of the intermediate, the purity of cannabidiol is finally improved, and the production cost of the cannabidiol of the present invention is relatively low, and the operation is more simple, and the processing of complex processes is reduced, and the application range is wide and it is easy to realize industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of carbocyclic compound synthesis, and specifically relates to a method for preparing cannabidiol. Background Art

[0002] Cannabidiol, referred to as CBD, is an important cannabinoid compound with a molecular formula of C 21 H 30 O 2 The Chinese chemical name is 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol, and the English chemical name is 2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol; CBD in plants is all levorotatory, and it was first isolated from cannabis plants in 1940.

[0003] Preclinical experiments have shown that CBD has significant anti-epileptic and anticonvulsant activity, and has fewer adverse reactions than existing anti-epileptic drugs, so it can be used as an alternative drug. The drug is used as an adjuvant treatment for rare epilepsy associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) in children over two years old. The anticonvulsant effect of CBD may be related to the stimulation of 5-HT1A receptors, inhibition of glutamate release, inhibition of norepinephrine, dopamine and adenosine reuptake, stimulation of glycine receptors, and stimulation and desensitization of transient receptor potential channels, so CBD needs to be prepared and studied in a more standardized manner.

[0004] The classic synthesis method of CBD is as follows: p-menth-2,8-dien-1-ol and 5-pentyl-1,3-benzenediol in BF 3 Cannabidiol is obtained by condensation reaction under catalysis. The reaction system is complex and many isomers are produced. The yield of (-)-CBD in the route disclosed in the literature is 41%. Its synthetic route is as follows:

[0005]

[0006] Patent US20090036523A1 discloses a cannabidiol prodrug, a method for preparing a cannabidiol prodrug, a preparation of a cannabidiol prodrug, and a method for using cannabinoids. Using p-toluenesulfonic acid as a catalyst, the yield of CBD obtained is 24%, and WO2006053766A1 uses zinc chloride as a catalyst, and the yield of CBD disclosed is 22%. When using this reaction system to synthesize CBD, due to the large number of isomers and dimers produced by Friedel-Crafts alkylation, the subsequent processing process is cumbersome, the yield of the target product is very low, and it is not suitable for industrial scale-up production.

[0007] Patents US20100298579A1, US20170349517A1 and WO2019033168A1 all use ethyl 2,4-dihydroxy-6-pentylbenzoate as a substrate and menth-2,8-diene-1-ol to carry out Friedel-Crafts alkylation reaction under the catalysis of acid. Due to the presence of ethyl ester group in the substrate, the number of isomers and dimers is significantly reduced compared with the classical synthesis method. However, due to the low melting point of intermediate I, it is difficult to precipitate solids, and it can only be purified by column chromatography, which cannot achieve the chemical purity of the key intermediate of the raw material drug.

[0008]

[0009] Chinese patent CN106810426A discloses a method for synthesizing cannabidiol, using methyl 2,4-dihydroxy-6-pentylbenzoate as a raw material, after ester exchange with N,N-dimethylethanolamine under potassium hydroxide catalysis, reacting with (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol under Lewis acid catalysis, obtaining a key intermediate product after acid-base extraction and recrystallization, and finally obtaining crude cannabidiol after hydrolysis and decarboxylation. The crude product obtained in this patent can obtain cannabidiol that meets the quality requirements of the raw material drug after one recrystallization, with a total yield of 35% to 40%, but a large amount of unreacted substrate will remain in the reaction solution after the production is completed, which is easy to increase the production cost.

[0010] In addition to the above chemical synthesis methods, some literature also discloses the use of other chemical synthesis methods to obtain cannabidiol. However, these methods have limitations in industrial production due to expensive raw materials, complicated synthesis steps, or low overall yield. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a method for preparing cannabidiol, which has a high yield of cannabidiol, a simple process and is easy to operate.

[0012] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0013] The method for preparing cannabidiol of the present invention comprises the following steps:

[0014] S1, 2,4-dihydroxy-6-pentylbenzoate and an amidation reagent are subjected to an amidation reaction to obtain an intermediate I;

[0015] S2, intermediate I and (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol undergo Friedel-Crafts alkylation reaction under acid catalysis to obtain intermediate II;

[0016] S3. Under alkaline conditions, intermediate II undergoes a decarboxylation reaction to obtain cannabidiol;

[0017] The reaction formula is as follows:

[0018]

[0019] R is methyl or ethyl; n = 1, 2 or 3.

[0020] in:

[0021] In the step S1, the amidation reagent is one of N,N-dimethyl-1,2-ethylenediamine, N,N-dimethyl-1,3-propylenediamine or N,N-dimethyl-1,4-butanediamine, and the mass ratio of 2,4-dihydroxy-6-pentylbenzoate to the amidation reagent is 1:0.87-1.22.

[0022] In the step S1, the amidation reaction temperature is 90-120° C., and the amidation reaction time is 6-12 hours.

[0023] The amidation reaction in step S1 is carried out in the presence of a base, the base is one of sodium tert-butoxide, potassium tert-butoxide or sodium ethoxide, and the mass ratio of 2,4-dihydroxy-6-pentyl benzoate to the base is 1:0.31-0.49; after the amidation reaction in step S1 is completed, intermediate I is obtained by recrystallization.

[0024] The solvent used for recrystallization in step S1 is one of petroleum ether, cyclohexane or n-heptane.

[0025] In step S2, the Friedel-Crafts alkylation reaction temperature is -5 to 40°C, and the Friedel-Crafts alkylation reaction time is 12 to 24 hours.

[0026] In the step S2, the acid is one of p-toluenesulfonic acid, camphorsulfonic acid or zinc trifluoromethanesulfonate, and the mass ratio of intermediate I to the acid is 1:0.28-0.62; after the Friedel-Crafts alkylation reaction is completed, the intermediate II is obtained by acid treatment, alkali treatment and cooling crystallization.

[0027] The solvent used for the Friedel-Crafts alkylation reaction in step S2 is one of dichloromethane, chloroform and 1,2-dichloroethane; hydrochloric acid is used for acid treatment and sodium carbonate is used for alkali treatment; and the solvent used for cooling crystallization is one of petroleum ether, n-heptane or cyclohexane.

[0028] The temperature of the decarboxylation reaction in step S3 is 80-120° C., and the time of the decarboxylation reaction is 4-8 hours. The solvent used in the decarboxylation reaction is one of purified water, methanol, ethanol or ethylene glycol. The decarboxylation reaction is carried out in the presence of a base, which is one of sodium hydroxide, lithium hydroxide or potassium hydroxide. After the decarboxylation reaction is completed, acid treatment and recrystallization are performed to obtain cannabidiol.

[0029] The acid treatment in step S3 uses one of oxalic acid, citric acid or hydrochloric acid to adjust the pH value to 5-6; the solvent for recrystallization is one of petroleum ether, n-heptane or cyclohexane.

[0030] The method for preparing cannabidiol of the present invention further comprises the following steps:

[0031] A1, using 2,4-dihydroxy-6-pentylbenzoate as a raw material, carrying out an amidation reaction with an amidation reagent in an alkaline environment under a nitrogen atmosphere, and then extracting, washing, and recrystallizing to obtain an intermediate I;

[0032] A2, dissolving intermediate I together with an acidic substance in an organic solvent, and subjecting it to Friedel-Crafts alkylation reaction with (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol under acid catalysis, followed by acid treatment, alkali treatment, drying, and cooling crystallization to obtain intermediate II;

[0033] A3. Dissolve the intermediate II in a solvent and carry out a high-temperature decarboxylation reaction under alkaline conditions, and then adjust the pH value, extract, wash, and recrystallize to obtain the target compound cannabidiol.

[0034] The present invention uses 2,4-dihydroxy-6-pentylbenzoate as a starting material, and then obtains an intermediate I through amidation. Since the nitrogen atom and the carbon atom in the amide group are connected by a single bond, while the carbon atom and the oxygen atom in the ester group are connected by a double bond, the bond energy required is greater, so the amide group is easier to obtain than the ester group, so that the reaction conversion rate is higher than the exchange yield of the ester group generated before; since the amide group of the intermediate I is more stable than the ester group, the lone pair of electrons on the nitrogen atom in the amide bond can form an intramolecular hydrogen bond, so that the amide bond needs a larger bond energy to break, and there is a greater steric hindrance between the amide bond and the group with a larger molecular weight, so the intermediate I with the amide bond has a more stable structure.

[0035] After intermediate I is purified by recrystallization, it undergoes Friedel-Crafts alkylation with (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol under the catalysis of proton acid or Lewis acid such as p-toluenesulfonic acid, camphorsulfonic acid or zinc trifluoromethanesulfonate. (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol is rearranged under the action of acid to form a carbon cation, which then attacks the benzene ring of 2,4-dihydroxy-6-pentyl benzoate to prepare intermediate II. Since the hydroxyl group on the benzene ring affects the activity of the ortho and para carbons, the two meta carbons are The hydroxyl group will also affect the activity of the adjacent carbon, making it more active and easier to react. When the carbon cation attacks the benzene ring, it preferentially combines with the more active carbon. In addition, due to the presence of an amide group in intermediate I, the lone pair of electrons in the amide group will reduce the electron cloud density at the meta position of the benzene ring, making it easier to react with the carbon cation. The amide group, hydroxyl group and sulfonic acid group work together to make (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol replace to a specific position, which is not prone to side reactions. Compared with the addition of an ester group, the structure of intermediate II is more stable. The present invention can effectively reduce the generation of isomers. Compared with the direct reaction of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol with 5-pentyl-1,3-benzenediol, the method of the present invention can effectively avoid the generation of complex isomers, and the product yield is significantly improved. The intermediate II is decarboxylated at high temperature in an alkali solution to obtain cannabidiol with a purity of more than 99.95%, and the total reaction yield can reach more than 60%.

[0036] The beneficial effects of the present invention are as follows:

[0037] The present invention uses 2,4-dihydroxy-6-pentyl benzoate and an amidation agent to carry out an amidation reaction, so that the ester group of 2,4-dihydroxy-6-pentyl benzoate is changed into an amide group, thereby introducing a new basic group so that the intermediate I can be precipitated by crystallization, and the intermediate I with high purity and high yield is obtained, and the generation of impurities in the reaction process can be effectively reduced. The intermediate II is prepared by an alkylation reaction to reduce the generation of complex isomers, and the purity and yield of cannabidiol are improved; the raw materials used in the present invention are low in price, and the intermediates obtained in the preparation process can be purified by recrystallization, the operation is simple, and the purity of cannabidiol is finally improved by improving the purity of the intermediates. The production cost of the cannabidiol of the present invention is low, the operation is simpler, the processing of complex processes is reduced, the total yield of the whole process is high, the by-products are small, the product purity is high, the application range is wide, and it is easy to realize industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the H NMR spectrum of the intermediate I of Example 1;

[0039] Figure 2 is the H NMR spectrum of the intermediate II of Example 1;

[0040] Figure 3 This is the H NMR spectrum of cannabidiol in Example 1. DETAILED DESCRIPTION

[0041] Example 1

[0042] S1. Preparation of intermediate I:

[0043] 101 g of ethyl 2, 4-dihydroxy-6-pentylbenzoate and 88 g of N,N-dimethyl-1,2-ethylenediamine were added to a 250 mL reaction bottle, and 42.2 g of sodium tert-butoxide was added. The mixture was stirred at 100 °C under nitrogen protection and kept warm for 6 h. After the reaction, the pH was adjusted to 3-4 with 1N HCl, and 150 mL of ethyl acetate was used for extraction twice. The organic phase was then adjusted to pH 10 with a saturated sodium carbonate solution, and then washed twice with 150 mL of purified water. The ethyl acetate was evaporated to dryness under reduced pressure, 3 v / m of petroleum ether was added, and the temperature was raised to dissolve, and the mixture was cooled to 0 °C for recrystallization. After filtration and drying, 100.3 g of white intermediate I was obtained, with a yield of 85% and a HPLC purity of 99.50%.

[0044] S2. Preparation of intermediate II:

[0045] 88.3 g of intermediate I was weighed and added to a 500 mL reaction bottle, 54.5 g of zinc trifluoromethanesulfonate was added and dissolved in 200 mL of dichloromethane, the reaction bottle was transferred to 15 ° C and stirred for 10 minutes, then 59.3 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was weighed and dissolved in 100 mL of dichloromethane and then slowly added dropwise to the reaction system, and the reaction was kept warm for 24 h. After the reaction, the mixture was transferred to a separatory funnel and washed twice with 250 mL of purified water. The organic phase was evaporated to dryness under reduced pressure and then 200 mL of n-heptane was added to dissolve it. The pH was adjusted to 3 with 1N HCl aqueous solution, and the organic phase was separated. The pH was adjusted to 10 with saturated sodium carbonate aqueous solution, and then the organic phase was separated and washed once with 150 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure, 4 v / m of n-heptane was added and the temperature was raised to 50 ° C to dissolve it, and the temperature was lowered to 5 ° C to recrystallize it. After filtration and drying, 96.5 g of a white intermediate II solid was obtained with a yield of 75% and an HPLC purity of 99.21%.

[0046] S3. Preparation of cannabidiol:

[0047] 85.6 g of intermediate II was added to a 500 mL reaction bottle, 150 mL of methanol was added to dissolve, and then 150 mL of 30% NaOH solution was added, and the temperature was raised to 80°C for reaction for 8 hours. After the reaction, the mixture was cooled to room temperature and 30% citric acid solution was added to adjust the pH to 5-6, and 150 mL of n-heptane was added for extraction twice. After the organic phases were combined, the mixture was washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and then 4 v / m of n-heptane was added to dissolve the mixture and then cooled to -20°C for recrystallization to obtain 59.1 g of cannabidiol, with a yield of 94% and a HPLC purity of 99.95%.

[0048] The NMR spectra of the prepared intermediate I, intermediate II and cannabidiol are as follows: Figure 1-3 shown.

[0049] Example 2

[0050] S1. Preparation of intermediate I:

[0051] 101 g of ethyl 2, 4-dihydroxy-6-pentylbenzoate and 102 g of N,N-dimethyl-1,3-propylenediamine were added to a 250 mL reaction bottle, and 49.4 g of potassium tert-butoxide was added. The mixture was stirred at 90°C under nitrogen protection and kept warm for 9 h. After the reaction, the pH was adjusted to 3-4 with 1N HCl, and extracted twice with 150 mL of methyl tert-butyl ether. The organic phase was then adjusted to pH 10 with a saturated sodium carbonate solution, and then washed twice with 150 mL of purified water. The methyl tert-butyl ether was evaporated to dryness under reduced pressure, 3 v / m of cyclohexane was added, and the mixture was heated to dissolve, and then cooled to 0°C for recrystallization. After filtration and drying, 102.5 g of white intermediate I was obtained, with a yield of 83% and a HPLC purity of 99.33%.

[0052] S2. Preparation of intermediate II:

[0053] 92.4 g of intermediate I was weighed and added to a 500 mL reaction bottle, 25.8 g of p-toluenesulfonic acid was added and 200 mL of chloroform was added to dissolve, the reaction bottle was transferred to -5 °C and stirred for 10 minutes, then 59.3 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was weighed and dissolved in 100 mL of chloroform and then slowly added dropwise to the reaction system, and the reaction was kept warm for 12 h. After the reaction, the mixture was transferred to a separatory funnel and washed twice with 250 mL of purified water. The organic phase was evaporated to dryness under reduced pressure and then 200 mL of n-heptane was added to dissolve it. The pH was adjusted to 3 with 1N HCl aqueous solution, and the organic phase was separated. The pH was adjusted to 10 with saturated sodium carbonate aqueous solution, and then the organic phase was separated and washed once with 150 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure, 4 v / m of petroleum ether was added and the temperature was raised to 55 ° C to dissolve it, and the temperature was lowered to 0 ° C for recrystallization. After filtration and drying, 103.6 g of a white intermediate II solid was obtained with a yield of 78% and an HPLC purity of 99.41%.

[0054] S3. Preparation of cannabidiol:

[0055] 88.5 g of intermediate II was added to a 500 mL reaction bottle, 150 mL of ethanol was added to dissolve, and then 150 mL of 30% KOH solution was added, and the temperature was raised to 90°C for reaction for 6 hours. After the reaction, the mixture was cooled to room temperature and 12% hydrochloric acid solution was added to adjust the pH to 5-6, and 150 mL of petroleum ether was added for extraction twice. After the organic phases were combined, they were washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and then 4 v / m of petroleum ether was added for recrystallization at 5°C to obtain 57.8 g of cannabidiol, with a yield of 92% and a HPLC purity of 99.97%.

[0056] Example 3

[0057] S1. Preparation of intermediate I:

[0058] 95.3 g of methyl 2, 4-dihydroxy-6-pentylbenzoate and 116 g of N,N-dimethyl-1,4-butanediamine were added to a 250 mL reaction bottle, and 30 g of sodium ethoxide was added. The mixture was stirred at 120 °C under nitrogen protection and kept warm for 12 h. After the reaction, the pH was adjusted to 3-4 using 1N HCl, and extracted twice with 150 mL of dichloromethane. The organic phase was then adjusted to pH 10 using a saturated sodium carbonate solution, and then washed twice with 150 mL of purified water. The dichloromethane was evaporated to dryness under reduced pressure, 3 v / m of n-heptane was added and heated to dissolve, and then the temperature was lowered to 0 °C for recrystallization. After filtration and drying, 112.2 g of white intermediate I was obtained, with a yield of 87% and an HPLC purity of 99.88%.

[0059] S2. Preparation of intermediate II:

[0060] 96.7 g of intermediate I was weighed and added to a 500 mL reaction bottle, 34.8 g of camphorsulfonic acid was added and 200 mL of 1,2-dichloroethane was added to dissolve, the reaction bottle was transferred to 40 ° C and stirred for 10 minutes, then 59.3 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was weighed and dissolved in 100 mL of 1,2-dichloroethane and then slowly added dropwise to the reaction system, and the reaction was kept warm for 16 h. After the reaction, the mixture was transferred to a separatory funnel and washed twice with 250 mL of purified water. The organic phase was evaporated to dryness under reduced pressure and then 200 mL of cyclohexane was added to dissolve it. The pH was adjusted to 3 with 1N HCl aqueous solution, and the organic phase was separated. The pH was adjusted to 10 with saturated sodium carbonate aqueous solution, and then the organic phase was separated and washed once with 150 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure, 4 v / m of cyclohexane was added and the temperature was raised to 45 ° C to dissolve it. The temperature was lowered to 0 ° C for recrystallization, and 109.6 g of a white intermediate II solid was obtained after filtration and drying. The yield was 80% and the HPLC purity was 99.89%.

[0061] S3. Preparation of cannabidiol:

[0062] 91.3 g of intermediate II was added to a 500 mL reaction bottle, 150 mL of ethylene glycol was added to dissolve, and then 150 mL of 35% LiOH solution was added, and the temperature was raised to 120°C for 4 hours. After the reaction, the mixture was cooled to room temperature and 35% oxalic acid solution was added to adjust the pH to 5-6, and 150 mL of cyclohexane was added for extraction twice. After the organic phases were combined, they were washed once with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and then 4 v / m of cyclohexane was added to dissolve the mixture and the temperature was lowered to 15°C for recrystallization to obtain 58.5 g of cannabidiol, with a yield of 93% and a HPLC purity of 99.96%.

[0063] Comparative Example 1

[0064] According to Example 1, step S1 is not performed, and only steps S2 and S3 are performed; in step S2, 88.3 g of methyl 2, 4-dihydroxy-6-pentylbenzoate is weighed and added to a 500 mL reaction bottle, and the remaining steps are the same as steps S2 and S3 of Example 1; the final cannabidiol yield is 26%, and the HPLC purity is 99.21%.

[0065] Comparative Example 2

[0066] According to Example 1, in step S2, zinc trifluoromethanesulfonate is not added, and the remaining steps are the same as step S1, step S2 and step S3 of Example 1; the final cannabidiol yield is 35% and the HPLC purity is 99.17%.

[0067] Comparative Example 3

[0068] According to Example 1, step S1 is not performed, and only steps S2 and S3 are performed; in step S2, 88.3 g of methyl 2, 4-dihydroxy-6-pentylbenzoate is weighed and added to a 500 mL reaction bottle, and zinc trifluoromethanesulfonate is not added, and the remaining steps are the same as steps S2 and S3 of Example 1; the final cannabidiol yield is 21%, and the HPLC purity is 99.12%.

[0069] It can be seen from Example 1 and Comparative Examples 1-3 that the present invention can effectively avoid the generation of isomers and improve the yield of cannabidiol. Compared with Example 1, Comparative Example 1 performs an alkylation reaction without performing an amidation reaction, and the yield and purity of cannabidiol are lower. Compared with Example 1, Comparative Example 2 does not use zinc triflate, and the yield and purity of cannabidiol finally obtained are lower. Compared with Example 1, Comparative Example 3 neither performs an amidation reaction nor uses zinc triflate, which has the greatest impact on the purity and yield of cannabidiol.

Claims

1. A method for preparing cannabidiol, characterized in that: The following steps are involved: S1, 2,4-dihydroxy-6-pentylbenzoate and an amidation reagent are subjected to an amidation reaction to obtain an intermediate I; S2, intermediate I and (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol undergo Friedel-Crafts alkylation reaction under acid catalysis to obtain intermediate II; S3. Under alkaline conditions, intermediate II undergoes a decarboxylation reaction to obtain cannabidiol; The reaction formula is as follows: R is methyl or ethyl; n = 1, 2 or 3.

2. The method for preparing cannabidiol according to claim 1, characterized in that: In step S1, the amidating agent is one of N,N-dimethyl-1,2-ethylenediamine, N,N-dimethyl-1,3-propylenediamine or N,N-dimethyl-1,4-butanediamine, and the mass ratio of 2,4-dihydroxy-6-pentylbenzoate to the amidating agent is 1:0.87-1.

22.

3. The method for preparing cannabidiol according to claim 1, characterized in that: In step S1, the amidation reaction temperature is 90-120° C., and the amidation reaction time is 6-12 h.

4. The method for preparing cannabidiol according to claim 1, characterized in that: The amidation reaction in step S1 is carried out in the presence of a base, the base is one of sodium tert-butoxide, potassium tert-butoxide or sodium ethoxide, and the mass ratio of 2,4-dihydroxy-6-pentylbenzoate to the base is 1:0.31-0.49; after the amidation reaction in step S1 is completed, intermediate I is obtained by recrystallization.

5. The method for preparing cannabidiol according to claim 4, characterized in that: The solvent used for recrystallization in step S1 is one of petroleum ether, cyclohexane or n-heptane.

6. The method for preparing cannabidiol according to claim 1, characterized in that: In step S2, the Friedel-Crafts alkylation reaction temperature is -5 to 40°C, and the Friedel-Crafts alkylation reaction time is 12 to 24 hours.

7. The method for preparing cannabidiol according to claim 1, characterized in that: In step S2, the acid is one of p-toluenesulfonic acid, camphorsulfonic acid or zinc trifluoromethanesulfonate, and the mass ratio of intermediate I to the acid is 1:0.28-0.62; after the Friedel-Crafts alkylation reaction is completed, the intermediate II is obtained by acid treatment, alkali treatment and cooling crystallization.

8. The method for preparing cannabidiol according to claim 7, characterized in that: The solvent used for the Friedel-Crafts alkylation reaction in step S2 is one of dichloromethane, chloroform and 1,2-dichloroethane; hydrochloric acid is used for the acid treatment and sodium carbonate is used for the alkali treatment; the solvent used for the cooling crystallization is one of petroleum ether, n-heptane or cyclohexane.

9. The method for preparing cannabidiol according to claim 1, characterized in that: The temperature of the decarboxylation reaction in step S3 is 80-120° C., and the time of the decarboxylation reaction is 4-8 hours; the solvent used in the decarboxylation reaction is one of purified water, methanol, ethanol or ethylene glycol; the decarboxylation reaction is carried out in the presence of a base, and the base is one of sodium hydroxide, lithium hydroxide or potassium hydroxide; after the decarboxylation reaction is completed, acid treatment and recrystallization are carried out to obtain cannabidiol.

10. The method for preparing cannabidiol according to claim 9, characterized in that: The acid treatment in step S3 uses one of oxalic acid, citric acid or hydrochloric acid to adjust the pH value to 5-6; the solvent for recrystallization is one of petroleum ether, n-heptane or cyclohexane.

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