Synthesis method of cannabidiol without tetrahydrocannabinol impurity

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthetic method of cannabidiol without tetrahydrocannabinol impurities. The synthesis method comprises the following steps: (1) carrying out Friedel-Crafts alkylation reaction on ethyl 2, 4-dihydroxy-6-amyl benzoate, (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-alcohol, an acid-binding agent and Lewis acid in a solvent A, so as to obtain an intermediate; (2) in the presence of an alkaline regulator, carrying out a temperature-controlled decarboxylation reaction on the intermediate in a solvent B to obtain a reaction solution, adjusting the pH value of the reaction solution, and carrying out extraction and crystallization to obtain a crude cannabidiol product; and (3) dissolving the crude cannabidiol product in a solvent C, and carrying out crystallization treatment to obtain cannabidiol. The synthetic method is simple in condition, the prepared cannabidiol does not contain tetrahydrocannabinol impurities, and meanwhile, the synthetic method has the advantages of high cannabidiol purity, high yield and low preparation cost.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a method for synthesizing cannabidiol without tetrahydrocannabinol impurities. Background Art

[0002] Cannabidiol, abbreviated as CBD, is a non-psychoactive compound extracted from cannabis plants. It is often used for medical and cosmetic purposes. It has anti-inflammatory and analgesic, anti-epileptic, anti-depression, anxiety and neurodegenerative disease effects. It also has a certain inhibitory effect on cancers such as glioma.

[0003] There are many problems with the current methods of purifying cannabidiol from industrial hemp. For example, the current industrial hemp plants have a long planting cycle, the cannabidiol content is generally low, and the purification cost is high, which makes it difficult to meet potential demand; the purified cannabidiol often contains impurities such as chlorophyll, fatty acids or tetrahydrocannabinol, especially tetrahydrocannabinol. Unlike cannabidiol, tetrahydrocannabinol is a psychoactive substance that is addictive and dependent. Ingesting a large amount of it in a short period of time can cause irreversible damage to the human nervous system and respiratory system, and it is a controlled narcotic drug. Faced with the various problems existing in the current industrial hemp purification method, people hope to directly produce high-purity cannabidiol through artificial synthesis.

[0004] Compared with the industrial hemp purification method, the artificial synthesis of cannabidiol is a cheaper, simpler and more efficient method. At present, there are many reports on the artificial synthesis process of cannabidiol, but there are many impurities in the reaction process, crystallization is difficult, and the content of tetrahydrocannabinol is difficult to control. Therefore, it is of great significance to develop a cannabidiol synthesis process that avoids the production of tetrahydrocannabinol.

[0005] US Patent US20090036523A1 discloses that olivetol and (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol undergo Friedel-Crafts alkylation reaction in an argon atmosphere using p-toluenesulfonic acid as a catalyst to obtain the target product. The reaction process is as follows:

[0006] The reaction system is relatively complex: since olivetol has three reaction sites, the alkylation process is accompanied by many side reactions, producing more isomers and dimer impurities, which is troublesome to post-process and requires column chromatography purification. The yield is low, only 24%, and is not suitable for large-scale production.

[0007] U.S. Patent US20100298579A1 discloses that methyl 2,4-dihydroxy-6-pentylbenzoate and (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol are used as raw materials, and intermediate C is first prepared under Lewis acid catalysis, and then intermediate C is subjected to a one-step decarboxylation reaction to obtain the target product cannabidiol. The reaction process is as follows:

[0008] Among them, Δ9-THC refers to tetrahydrocannabinol; when the patent uses a boron trifluoride-ether complex as a catalyst, the intermediate cannabidiol acid methyl ester is prone to a ring closure side reaction, that is, it will further cyclize and decarboxylate to form a hallucinogenic Δ9-THC, and some Δ9-THC will even isomerize to form Δ8-THC, resulting in a decrease in the yield of CBD. The mechanism of action of this ring closure side reaction: Under the action of boron trifluoride-ether or protonic acid, the oxygen on the phenolic hydroxyl group in the intermediate will more easily attack the double bond of the propylene group, resulting in intramolecular cyclization. When other Lewis acids such as MgBr2 are used, due to their weak reaction activity, when the reaction scale is increased, a large amount of raw materials will remain, which is not conducive to industrialization.

[0009] Chinese patent CN113896616A discloses a method for preparing cannabidiol, which uses olive alcohol as a starting material, first converts olive alcohol into olive alcohol diester, then obtains cannabidiol diester through coupling reaction, and purifies and hydrolyzes the cannabidiol diester to obtain cannabidiol. The reaction process is as follows: In this patent, after the reaction, the steric hindrance effect of the phenolic hydroxyl group in olivetol increases, while the electron donating effect of the phenolic hydroxyl group is weakened, making the subsequent Friedel-Crafts alkylation difficult to carry out and the yield low, which is not conducive to industrial production.

[0010] It can be found that in the existing synthetic routes of cannabidiol, there are problems such as low cannabidiol yield and a large number of by-products such as tetrahydrocannabinol. Therefore, finding a low-cost synthetic route suitable for industrial production to produce high-purity cannabidiol and control the formation of psychoactive by-products such as tetrahydrocannabinol is of great significance for the application and promotion of cannabidiol. Summary of the invention

[0011] The object of the present invention is to provide a method for synthesizing cannabidiol without tetrahydrocannabinol impurities. The conditions of the synthesis method are simple, the cannabidiol prepared by the synthesis method does not contain tetrahydrocannabinol, and the cannabidiol has high purity, high yield and low preparation cost.

[0012] To achieve the above object, the technical solution adopted by the present invention is: The method for synthesizing cannabidiol without tetrahydrocannabinol described in the present invention comprises the following steps: (1) ethyl 2,4-dihydroxy-6-pentylbenzoate, (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol, an acid-binding agent and a Lewis acid are subjected to Friedel-Crafts alkylation reaction in solvent A to obtain an intermediate; (2) In the presence of an alkaline regulator, the intermediate is subjected to a temperature-controlled decarboxylation reaction in solvent B to obtain a reaction solution, the pH value of the reaction solution is adjusted, and the crude cannabidiol is obtained through extraction and crystallization; (3) Dissolving the crude cannabidiol in solvent C and subjecting it to crystallization treatment to obtain cannabidiol.

[0013] in: The acid binding agent is one of triethylamine, basic aluminum oxide or sodium bicarbonate.

[0014] The Lewis acid is one of scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate or indium trifluoromethanesulfonate.

[0015] The solvent A is one of dichloromethane, toluene or chloroform.

[0016] The molar ratio of 2,4-dihydroxy-6-pentylbenzoic acid ethyl ester, (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol, acid binding agent and Lewis acid is 1: (1.2-2.0): (0.05-0.3): (0.2-0.8).

[0017] The Friedel-Crafts alkylation reaction temperature is 15-30° C., and the Friedel-Crafts alkylation reaction time is 20-30 h.

[0018] The solvent B is one or more of water, ethanol or methanol; the alkaline regulator is sodium hydroxide.

[0019] The molar ratio of 2,4-dihydroxy-6-pentylbenzoic acid ethyl ester to the alkaline regulator is 1: (12-20); the temperature of the temperature-controlled decarboxylation reaction is 70-80° C., and the temperature-controlled decarboxylation reaction time is 3-5 hours.

[0020] The pH value of the reaction solution is adjusted to 5-6 by using an acidic reagent, wherein the acidic reagent is one of hydrochloric acid, citric acid or sulfuric acid; extraction is performed by using an extractant, wherein the extractant is one of ethyl acetate, n-heptane or petroleum ether; in step (2), the crystallization temperature is 5-15°C.

[0021] The solvent C is one of n-heptane, cyclohexane or n-pentane; in step (3), the dissolution temperature is 40-55°C, the crystallization temperature is -5-10°C, and the crystallization time is 2-3.5h.

[0022] The chemical reaction equation of the present invention is as follows: The beneficial effects of the present invention are as follows: (1) In the synthesis route of cannabidiol described in the present invention, ethyl 2,4-dihydroxy-6-pentylbenzoate and (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol are selected and subjected to Friedel-Crafts alkylation under the action of an acid-binding agent and a specific Lewis acid to obtain an acid ester intermediate; the intermediate is decarboxylated and refined under the action of an alkaline regulator to obtain high-purity cannabidiol that does not contain Δ9-THC / Δ8-THC.

[0023] The present invention selects a suitable synthesis route, and 2,4-dihydroxy-6-pentylbenzoic acid ethyl ester has only two alkylation reaction sites at positions 3 and 5. Affected by the steric hindrance of the pentyl group at position 6, the reaction activity at position 5 is greatly reduced, and the target obtained is mainly substituted at position 3, which reduces the generation of isomer side reactions and improves the yield and refining effect. Since Friedel-Crafts alkylation is carried out under the conditions of Lewis acid, the phenolic hydroxyl oxygen is more likely to nucleophilically attack the propylene double bond for the mechanism of tetrahydrocannabinol production to form a more stable six-membered ring structure. Therefore, by adding an appropriate acid binding agent to the system, the nucleophilic attack of oxygen can be weakened, and the generation of THC precursors can be reduced. Compared with Lewis acids such as p-toluenesulfonic acid, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate or indium trifluoromethanesulfonate have a lower degree of dissociation in a non-aqueous reaction system, reducing free hydrogen protons, and specific metal ions can be complexed with phenolic hydroxyl oxygen atoms, further weakening the nucleophilic attack ability. In addition, during decarboxylation, the present invention reduces the probability of ring closure side reactions by controlling the decarboxylation temperature.

[0024] (2) The process of synthesizing cannabidiol in the present invention is simple, the raw materials are easily available, and the final product does not contain structural analogs of cannabidiol, such as tetrahydrocannabinol, etc. Therefore, the impurity removal operation is simple, and there is no need to use impurity removal methods such as column chromatography, which are inefficient, costly, and only suitable for small batches. It is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the intermediate of Example 1; Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of cannabidiol in Example 1; Figure 3 This is the liquid chromatogram of cannabidiol in Example 1; Figure 4 This is the liquid chromatogram of cannabidiol in Example 3; Figure 5 This is the liquid chromatogram of cannabidiol in Example 5. DETAILED DESCRIPTION

[0026] The present invention is specifically described and illustrated below in conjunction with embodiments.

[0027] Example 1 35.0 g of ethyl 2,4-dihydroxy-6-pentylbenzoate, 25.2 g of zinc trifluoromethanesulfonate, 1.4 g of triethylamine and 300 ml of dichloromethane were added to a reaction flask, 33.8 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was diluted with 240 ml of dichloromethane and slowly added dropwise to the reaction flask, reacted at 15-20° C. for 20 h, filtered, and the filtrate was washed twice with purified water. The organic layer obtained after washing was concentrated under reduced pressure until no liquid flowed out, washed with 5 wt % sodium hydroxide aqueous solution, extracted with n-heptane, and the organic layer was concentrated under reduced pressure to obtain 59.2 g of an oily substance containing the intermediate. 1 HNMR (400 MHz, DMSO d 6): δ11.92 (s,1H), 9.87 (s,1H), 6.21 (s,1H), 5.10 (s,1H), 4.44(m,2H),4.29(q, J =7.1 Hz,2H),3.93 (d, J = 10.5 Hz,1H), 3.04(td, J = 11.2,3.0 Hz,1H),2.70 (t, J = 7.9 Hz,2H), 2.10 (d, J = 12.4 Hz,1H), 1.91 (d, J = 14.8 Hz,1H), 1.68 (td, J = 13.3,3.6 Hz,2H), 1.59 (s, 6H), 1.47 (t, J = 7.6 Hz,2H), 1.30 (m, 7H),0.85(m, 3H), such as Figure 1 shown.

[0028] Take 56.0g of oil, add 336ml of methanol; dissolve 69.5g of sodium hydroxide in 336ml of purified water, add dropwise to the oil, raise the temperature to 70-75°C, decarboxylate for 5h and then cool to room temperature, add 30wt% citric acid to adjust the pH to 5-6, add n-heptane for extraction to obtain an organic phase, wash the organic phase with water, dry it and concentrate it under reduced pressure until no liquid flows out, add 4 times the mass of n-heptane to the organic phase, cool it to 10°C, add seed crystals, stir overnight, filter and dry to obtain 24.2g of crude cannabidiol.

[0029] 60 ml of n-heptane was added to 20 g of crude cannabidiol and 1 g of activated carbon, heated to 45-50 °C, filtered, and the filtrate was slowly cooled to -5 °C within 120 min and kept warm for 90 min to obtain 16.88 g of cannabidiol. Cannabidiol was analyzed by nuclear magnetic resonance, such as Figure 2 As shown, the yield is 59.9%, the purity is 99.93%, and the liquid chromatogram is as follows Figure 3 As shown, THC was not detected.

[0030] Example 2 35.0 g of ethyl 2,4-dihydroxy-6-pentylbenzoate, 12.6 g of zinc trifluoromethanesulfonate, 1.2 g of sodium bicarbonate and 300 ml of dichloromethane were added to a reaction flask, 42.2 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was diluted with 240 ml of dichloromethane and slowly added dropwise to the reaction flask, reacted at 25-30° C. for 30 h, filtered, and the filtrate was washed twice with purified water. The organic layer obtained after washing was concentrated under reduced pressure until no liquid flowed out, and 5 wt% sodium hydroxide aqueous solution was added for washing, extracted with n-heptane, and the organic layer was concentrated under reduced pressure to obtain 62.3 g of an oily substance containing the intermediate.

[0031] Take 60.0g of oil, add 300ml of ethanol; dissolve 124.2g of sodium hydroxide in 300ml of purified water, add it dropwise to the oil, raise the temperature to 70-75°C, decarboxylate for 4h and then cool to room temperature, add 15wt% dilute hydrochloric acid to adjust the pH to 5-6, add ethyl acetate to extract, obtain an organic phase, wash the organic phase with water, dry it and concentrate it under reduced pressure until no liquid flows out, add 5 times the mass of n-heptane to the organic phase, cool it to 5°C, add seed crystals, stir overnight, filter and dry to obtain 25.7g of crude cannabidiol.

[0032] To 20 g of crude cannabidiol and 1 g of activated carbon, add 100 ml of n-pentane, heat to 50-55 °C, filter, slowly cool the filtrate to 10 °C within 120 min and keep warm for 90 min to obtain 16.26 g of cannabidiol with a yield of 63.9% and a purity of 99.90%. THC was not detected.

[0033] Example 3 35.0 g of ethyl 2,4-dihydroxy-6-pentylbenzoate, 12.6 g of zinc trifluoromethanesulfonate, 2.8 g of basic alumina and 300 ml of dichloromethane were added to a reaction flask, 25.4 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was diluted with 240 ml of dichloromethane and slowly added dropwise to the reaction flask, reacted at 20-25° C. for 24 h, filtered, and the filtrate was washed twice with purified water. The organic layer obtained after washing was concentrated under reduced pressure until no liquid flowed out, washed with 5 wt % sodium hydroxide aqueous solution, extracted with n-heptane, and the organic layer was concentrated under reduced pressure to obtain 59.5 g of an oily substance containing the intermediate.

[0034] Take 59.0g of oil, add 295ml of methanol; dissolve 91.6g of sodium hydroxide in 295ml of purified water, add dropwise to the oil, raise the temperature to 75-80°C, decarboxylate for 4h and then cool to room temperature, add 30wt% citric acid to adjust the pH to 5-6, add n-heptane for extraction to obtain an organic phase, wash the organic phase with water, dry it and concentrate it under reduced pressure until no liquid flows out, add 3 times the mass of n-heptane to the organic phase, cool it to 15°C, add seed crystals, stir overnight, filter and dry to obtain 25.2g of crude cannabidiol.

[0035] Add 80 ml of n-heptane to 20 g of crude cannabidiol and 1 g of activated carbon, heat to 40-45 ° C, filter, and slowly cool the filtrate to 5 ° C within 90 min and keep warm for 90 min to obtain 17.45 g of cannabidiol with a yield of 64.0% and a purity of 99.94%. The liquid chromatogram is as follows Figure 4 As shown, THC was not detected.

[0036] Example 4 35.0 g of ethyl 2,4-dihydroxy-6-pentylbenzoate, 17.1 g of scandium trifluoromethanesulfonate, 2.8 g of basic alumina and 300 ml of dichloromethane were added to a reaction flask, 33.8 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was diluted with 240 ml of dichloromethane and slowly added dropwise to the reaction flask, reacted at 25-30° C. for 24 h, filtered, and the filtrate was washed twice with purified water. The organic layer obtained after washing was concentrated under reduced pressure until no liquid flowed out, washed with 5 wt % sodium hydroxide aqueous solution, extracted with n-heptane, and the organic layer was concentrated under reduced pressure to obtain 58.4 g of an oily substance containing the intermediate.

[0037] Take 56.0g of oil, add 280ml of ethanol; dissolve 69.5g of sodium hydroxide in 280ml of purified water, add dropwise to the oil, raise the temperature to 75-80°C, decarboxylation reaction for 4h, then cool to room temperature, add 15wt% sulfuric acid to adjust the pH to 5-6, add ethyl acetate to extract, obtain an organic phase, wash the organic phase with water, dry and concentrate under reduced pressure until no liquid flows out, add 5 times the mass of n-heptane to the organic phase, cool to 5°C, add seed crystals, stir overnight, filter and dry to obtain 23.8g of crude cannabidiol.

[0038] Add 80 ml of cyclohexane to 20 g of crude cannabidiol and 1 g of activated carbon, heat to 50-55 ° C, filter, slowly cool the filtrate to 5 ° C within 90 minutes and keep warm for 90 minutes to obtain 16.80 g of cannabidiol with a yield of 56.9% and a purity of 99.93%. THC was not detected.

[0039] Example 5 35.0 g of ethyl 2,4-dihydroxy-6-pentylbenzoate, 15.6 g of indium trifluoromethanesulfonate, 3.5 g of sodium bicarbonate and 300 mL of dichloromethane were added to a reaction flask, 25.4 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was diluted with 240 ml of dichloromethane and slowly added dropwise to the reaction flask, reacted at 20-25° C. for 30 h, filtered, and the filtrate was washed twice with purified water. The organic layer obtained after washing was concentrated under reduced pressure until no liquid flowed out, washed with 5 wt % sodium hydroxide aqueous solution, extracted with n-heptane, and the organic layer was concentrated under reduced pressure to obtain 57.1 g of an oily substance containing the intermediate.

[0040] Take 56.0g of oil, add 280ml of methanol; dissolve 92.7g of sodium hydroxide in 280ml of purified water, add dropwise to the oil, raise the temperature to 75-80°C, decarboxylation reaction for 3h, then cool to room temperature, add 15wt% dilute hydrochloric acid to adjust the pH to 5-6, add ethyl acetate to extract, obtain an organic phase, wash the organic phase with water, dry and concentrate under reduced pressure until no liquid flows out, add 5 times the mass of n-heptane to the organic phase, cool to 5°C, add seed crystals, stir overnight, filter and dry to obtain 23.7g of crude cannabidiol.

[0041] Add 100 ml of cyclohexane to 20 g of crude cannabidiol and 1 g of activated carbon, heat to 45-50 ° C, filter, and slowly cool the filtrate to 0 ° C within 60 minutes and keep it warm for 120 minutes to obtain 16.70 g of cannabidiol with a yield of 54.8% and a purity of 99.90%. The liquid chromatogram is as follows: Figure 5 As shown, THC was not detected.

[0042] Example 6 35.0 g of ethyl 2,4-dihydroxy-6-pentylbenzoate, 40.3 g of zinc trifluoromethanesulfonate, 2.8 g of basic alumina and 300 ml of chloroform were added to a reaction flask, 29.6 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was diluted with 240 ml of chloroform and slowly added dropwise to the reaction flask, reacted at 15-20° C. for 30 h, filtered, and the filtrate was washed twice with purified water. The organic layer obtained after washing was concentrated under reduced pressure until no liquid flowed out, washed with 5 wt % sodium hydroxide aqueous solution, extracted with n-heptane, and the organic layer was concentrated under reduced pressure to obtain 62.3 g of an oily substance containing the intermediate.

[0043] Take 60.0g of oil, add 300ml of methanol; dissolve 74.5g of sodium hydroxide in 300ml of purified water, add dropwise to the oil, raise the temperature to 75-80°C, decarboxylation reaction for 3h and then cool to room temperature, add 30wt% citric acid to adjust the pH to 5-6, add ethyl acetate to extract, obtain an organic phase, wash the organic phase with water, dry and concentrate under reduced pressure until no liquid flows out, add 5 times the mass of n-heptane to the organic phase, cool to 5°C, add seed crystals, stir overnight, filter and dry to obtain 26.2g of crude cannabidiol.

[0044] To 20 g of crude cannabidiol and 1 g of activated carbon, add 100 ml of n-heptane, heat to 50-55 °C, filter, slowly cool the filtrate to 10 °C within 60 min and keep warm for 60 min to obtain 16.30 g of cannabidiol with a yield of 66.5% and a purity of 99.92%. THC was not detected.

[0045] Example 7 35.0 g of ethyl 2,4-dihydroxy-6-pentylbenzoate, 34.2 g of scandium trifluoromethanesulfonate, 0.7 g of triethylamine and 300 ml of toluene were added to a reaction flask, 33.8 g of (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol was diluted with 240 ml of toluene and slowly added dropwise to the reaction flask, reacted at 25-30° C. for 30 h, filtered, and the filtrate was washed twice with purified water. The organic layer obtained after washing was concentrated under reduced pressure until no liquid flowed out, washed with 5 wt % sodium hydroxide aqueous solution, extracted with n-heptane, and the organic layer was concentrated under reduced pressure to obtain 57.1 g of an oily substance containing the intermediate.

[0046] Take 56.0g of oil, add 336ml of ethanol; dissolve 92.7g of sodium hydroxide in 336ml of purified water, add dropwise to the oil, raise the temperature to 75-80°C, decarboxylation reaction for 4h, then cool to room temperature, add 15wt% sulfuric acid to adjust the pH to 5-6, add petroleum ether to extract, obtain an organic phase, wash the organic phase with water, dry it and concentrate it under reduced pressure until no liquid flows out, add 5 times the mass of petroleum ether to the organic phase, cool to 5°C, add seed crystals, stir overnight, filter and dry to obtain 25.7g of crude cannabidiol.

[0047] Add 80 ml of n-pentane to 20 g of crude cannabidiol and 1 g of activated carbon, heat to 45-50 ° C, filter, slowly cool the filtrate to 10 ° C within 60 min and keep warm for 60 min to obtain 16.70 g of cannabidiol with a yield of 64.5% and a purity of 99.90%. THC was not detected.

[0048] Comparative Example 1 Zinc trifluoromethanesulfonate was replaced by an equimolar amount of p-toluenesulfonic acid, and the remaining steps were the same as in Example 1, with a yield of 40.1% and a purity of 99.32%.

[0049] Comparative Example 2 Without adding the acid-binding agent alkaline alumina, the remaining steps were the same as those in Example 2, with a yield of 42.5% and a purity of 99.26%.

[0050] Comparative Example 3 The temperature was raised to 100-105° C. for temperature-controlled decarboxylation reaction, and the remaining steps were the same as those in Example 3, with a yield of 44.9% and a purity of 99.32%.

[0051] Comparative Example 4 The temperature was raised to 45-50° C. for temperature-controlled decarboxylation reaction, and the remaining steps were the same as those in Example 4, but the decarboxylation reaction was incomplete.

Claims

1. A method for synthesizing cannabidiol without tetrahydrocannabinol impurities, characterized in that: The following steps are involved: (1) ethyl 2,4-dihydroxy-6-pentylbenzoate, (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol, an acid-binding agent and a Lewis acid are subjected to Friedel-Crafts alkylation reaction in solvent A to obtain an intermediate; (2) In the presence of an alkaline regulator, the intermediate is subjected to a temperature-controlled decarboxylation reaction in solvent B at a temperature of 70 to 80° C. to obtain a reaction solution, the pH value of the reaction solution is adjusted, and the crude cannabidiol is obtained through extraction and crystallization; (3) The crude cannabidiol is dissolved in solvent C and subjected to crystallization treatment to obtain cannabidiol.

2. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: The acid binding agent is one of triethylamine, basic alumina or sodium bicarbonate.

3. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: The Lewis acid is one of scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate or indium trifluoromethanesulfonate.

4. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: Solvent A is one of dichloromethane, toluene or chloroform.

5. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: The molar ratio of ethyl 2,4-dihydroxy-6-pentylbenzoate, (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol, acid-binding agent and Lewis acid is 1:(1.2~2.0):(0.05~0.3):(0.2~0.8).

6. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: The reaction temperature of the Friedel-Crafts alkylation is 15-30°C, and the reaction time of the Friedel-Crafts alkylation is 20-30h.

7. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: Solvent B is one or more of water, ethanol or methanol; and the alkaline regulator is sodium hydroxide.

8. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: The molar ratio of ethyl 2,4-dihydroxy-6-pentylbenzoate to the alkaline regulator is 1:(12-20), and the temperature-controlled decarboxylation reaction time is 3-5 hours.

9. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: The pH value of the reaction solution is adjusted to 5-6 by using an acidic reagent, wherein the acidic reagent is one of hydrochloric acid, citric acid or sulfuric acid; extraction is performed by using an extractant, wherein the extractant is one of ethyl acetate, n-heptane or petroleum ether; in step (2), the crystallization temperature is 5-15°C.

10. The method for synthesizing cannabidiol without tetrahydrocannabinol impurities according to claim 1, characterized in that: Solvent C is one of n-heptane, cyclohexane or n-pentane; in step (3), the dissolution temperature is 40-55°C, the crystallization temperature is -5-10°C, and the crystallization time is 2-3.5h.

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