Preparation method of cannabidiol and derivatives thereof

Abstract

The invention discloses a preparation method of cannabidiol and derivatives thereof, and belongs to the technical field of organic synthesis. According to the method, an allyl alcohol compound and a resorcinol compound are taken as raw materials and subjected to a Friedel-Crafts reaction under the action of boron trifluoride diethyl etherate / organic acid magnesium, cannabidiol and derivatives thereof are generated in a high-selectivity manner, further cyclization of products is inhibited, and generation of a byproduct cannabinol is avoided. The reaction has high chemical selectivity and good yield, the reaction condition is mild, the operation is simple, and the pollution is less. Meanwhile, a new CBD derivative can be generated by the process and is used for providing activity research of prototype molecules.

Description

Technical Field

[0001] This invention relates to a method for preparing cannabidiol and its derivatives, belonging to the field of organic synthesis technology. Background Technology

[0002] Cannabidiol (CBD) is the main non-psychoactive component of the cannabis plant. Unlike tetrahydrocannabinol (THC), it is not addictive. CBD has various pharmacological effects, including anti-anxiety, antipsychotic, antiemetic, and anti-inflammatory properties. CBD can also resist tumor cell invasion through multiple pathways, effectively prolonging patient life. Although CBD has low affinity for the CB1 and CB2 receptors of cannabinoids, it is an effective GPR55 antagonist. Globally, significant progress has been made in drug development centered on CBD, with GW Pharmaceuticals being a prime example. This drug was approved by the US FDA in 2018, becoming the first plant-based CBD drug for the treatment of refractory epilepsy associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome, and tuberous sclerosis (TSC). In addition... In addition, other CBD drugs such as A CBD-containing mucosal spray has been approved in Europe for the treatment of neuropathic pain and spasms associated with multiple sclerosis, further expanding the clinical application of CBD. CBD is becoming a more attractive treatment option. Therefore, exploring the synthesis of synthetic CBD is essential.

[0003] Currently, the main methods for preparing cannabidiol (CBD) include plant extraction, bio-extraction, and chemical synthesis. Plant extraction presents significant challenges due to the high similarity in structure, physical, and chemical properties among cannabinoids, making separation and purification difficult. It also easily introduces harmful impurities such as heavy metals and various toxins absorbed by the plant from the environment, making it difficult to achieve pharmaceutical-grade purity. While bio-extraction is relatively environmentally friendly, its complex procedures and limited large-scale production capacity hinder market promotion and application. Existing chemical synthesis methods suffer from low yields and poor selectivity, often producing addictive impurities such as tetrahydrocannabinol (THC) during synthesis, further complicating subsequent purification.

[0004] Numerous synthetic routes for the chemical synthesis of cannabidiol (CBD) have been developed. The first route, reported by Petrzilka et al., used (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol and oleanol as starting materials, oxalic acid dihydrate as a catalyst, and benzene as a solvent, to yield cannabidiol in 23.5% yield and isocannabidiol in 34.5% under heating conditions. The reaction equation is as follows:

[0005]

[0006] Baek et al. reported that cannabidiol (CBD) was obtained in 56% yield and isocannabidiol (IBD) yield was 14% under heating conditions using (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol and oleyl alcohol as starting materials, boron trifluoride diethyl ether as catalyst, alumina as support, and dichloromethane as solvent. The reaction equation is as follows:

[0007]

[0008] In the above reactions, under acidic conditions, the CBD phenolic group undergoes an addition reaction with the isopropenyl group to form the tetrahydrocannabinol (THC) skeleton. THC is known to be addictive. Simultaneously, under acidic conditions, trans-cannabinol can undergo a reverse Friedel-Crafts reaction to reorganize and yield CBD. The reaction equations and mechanisms are as follows:

[0009] Summary of the Invention

[0010] To overcome the aforementioned shortcomings, this invention designs a magnesium / calcium-based catalyst-mediated Friedel-Crafts reaction. In an acidic environment with catalyst passivation, allyl alcohols are first converted into their corresponding carbocation active intermediates, thereby effectively initiating the electrophilic aromatic substitution process of the corresponding oleyl alcohol molecule. Through the binding of oleyl alcohol with the magnesium / calcium catalyst, this conversion reaction exhibits excellent stereoselectivity, with oleyl alcohol attacking the corresponding site of the isopropenyl group only in the trans configuration. The addition of the magnesium-based catalyst effectively promotes the attack of the aromatic site between the dihydroxyl groups on the corresponding site of the isopropenyl group in the trans configuration. It also inhibits the further cyclization of CBD under acidic conditions to yield the psychoactive tetrahydrocannabinol (THC) skeleton. This method has been used for the synthesis of cannabidiol and its derivatives.

[0011] The present invention discloses a method for preparing cannabidiol and its derivatives. The reaction principle is as follows: a carbocation-active intermediate is generated under the action of boron trifluoride ether, etc.; under the action of magnesium succinate, the aromatic site between the two hydroxyl groups is promoted to attack the corresponding site of the isopropenyl group in a trans configuration, and further cyclization of CBD under acidic conditions is inhibited to obtain the psychoactive tetrahydrocannabinol (THC) skeleton structure. The technical solution adopted is represented by the following reaction equation:

[0012]

[0013] The reaction includes the following steps: allyl alcohol compound 1 and dihydroxybenzene compound 2 are reacted in an organic solvent in the presence of a magnesium or calcium-based catalyst and an acid to obtain cannabidiol and its derivatives 3.

[0014] Wherein: R1 is selected from halogen, alkyl, three-membered ring, five-membered ring, six-membered ring or benzene ring; R2, R3 are selected from hydrogen, isopropenyl or alkyl; n = 1, 2, 3.

[0015] Furthermore, in the above technical solution, the acid is selected from BF3-Et2O, ZnCl2, p-TsOH, Sc(OTf)3, In(OTf)3, InBr3, SnCl4, H2SO4 or AlCl3.

[0016] Furthermore, in the above technical solution, the magnesium or calcium-based catalyst is selected from calcium alginate, calcium stearate, calcium disodium ethylenediaminetetraacetate, calcium pyruvate, calcium acetylpropionate, calcium dihydroxymalate, magnesium acetate, magnesium succinate, magnesium stearate, or magnesium citrate.

[0017] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate, etc.

[0018] Furthermore, in the above technical solution, the reaction temperature is 0-40℃, preferably 25℃.

[0019] Furthermore, in the above technical solution, the reaction is carried out under the protection of an inert gas.

[0020] Beneficial effects of the invention:

[0021] This invention utilizes a magnesium / calcium-based catalyst to improve the selectivity of the Friedel-Crafts reaction and inhibit the further addition reaction of CBD with isopropenyl groups under acidic conditions to form a psychoactive tetrahydrocannabinol (THC) skeleton. This effectively increases the yield of cannabidiol and its derivatives synthesized via the Friedel-Crafts reaction.

[0022] This invention has the advantages of simple synthesis process, mild conditions, easy operation, significantly improved synthesis yield, low environmental pollution, and green environmental protection. Detailed Implementation

[0023] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0024] Condition optimization experiment

[0025] 1. Screening of reaction acid conditions:

[0026]

[0027] Under argon protection, cyclohexenol A1 (30 mg, 0.2 mmol) was added to a dry reaction tube equipped with a magnetic stir bar and dissolved in dichloromethane (2 mL), followed by the addition of an acid catalyst (0.3 equivalents). After thorough mixing, a dichloromethane solution of oleuropein S1 (36 mg, 0.2 mmol) (0.5 mL) was slowly added dropwise using a syringe. The reaction system was stirred at room temperature for 20 minutes. Upon completion of the reaction, the reaction was quenched with water and extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. Finally, the crude product, cannabidiol, was obtained by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The screening results are as follows:

[0028] acid Yield % Boron trifluoride diethyl ether 54 Zinc chloride 8 p-Toluenesulfonic acid 35 Scandium trifluoromethanesulfonate 40 Indium trifluoromethanesulfonate 39 Indium tribromide 15 Tin tetrachloride 50 sulfuric acid 23 Aluminum trichloride 24

[0029] Various acid sources were used, including boron trifluoride diethyl ether, zinc chloride, p-toluenesulfonic acid, scandium trifluoromethanesulfonate, indium trifluoromethanesulfonate, indium tribromide, tin tetrachloride, sulfuric acid, and aluminum trichloride. Among these, boron trifluoride diethyl ether showed the best yield, reaching 54%.

[0030] 2. Screening of magnesium / calcium-based catalysts:

[0031]

[0032] Under argon protection, cyclohexenol A1 (30 mg, 0.2 mmol) was added to a dry reaction tube equipped with a magnetic stir bar and dissolved in dichloromethane (2 mL). A magnesium-based or calcium-based catalyst (5.0 equivalent) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially. After thorough mixing, a dichloromethane solution (0.5 mL) of oleanol S1 (36 mg, 0.2 mmol) was slowly added dropwise using a syringe. The reaction system was stirred at room temperature for 20 minutes. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. Finally, the crude product, cannabidiol, was obtained by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The screening results are as follows:

[0033]

[0034]

[0035] Various magnesium / calcium-based catalysts were employed, including calcium succinate, calcium acetate, calcium propionate, calcium alginate, calcium stearate, calcium disodium EDTA, calcium pyruvate, calcium levulinate, calcium malate dihydroxymethyl malate, magnesium succinate, magnesium stearate, magnesium citrate, and magnesium acetate. Among these, magnesium succinate showed the best yield, reaching 60%.

[0036] 3. Screening of reaction acid equivalent:

[0037]

[0038] Under argon protection, cyclohexenol A1 (30 mg, 0.2 mmol) was added to a dry reaction tube equipped with a magnetic stir bar and dissolved in dichloromethane (2 mL). Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (according to the stoichiometry) were then added sequentially. After thorough mixing, a dichloromethane solution of oleanol S1 (36 mg, 0.2 mmol) (0.5 mL) was slowly added dropwise using a syringe. The reaction system was stirred for 20 minutes at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. Finally, the crude product, cannabidiol, was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The screening results are as follows:

[0039] acid equivalent Yield % Boron trifluoride diethyl ether 0.3 50 Boron trifluoride diethyl ether 0.6 55 Boron trifluoride diethyl ether 1.0 60 Boron trifluoride diethyl ether 1.5 13 Boron trifluoride diethyl ether 2.0 0

[0040] Different amounts of reactant acid were used in the above reaction: 0.3 equivalents, 0.6 equivalents, 1.0 equivalents, 1.5 equivalents, and 2.0 equivalents of boron trifluoride diethyl ether. The 1.0 equivalent amount yielded the best result, reaching a yield of 60%.

[0041] 4. Screening of reaction time:

[0042]

[0043] Under argon protection, cyclohexenol A1 (30 mg, 0.2 mmol) was added to a dry reaction tube equipped with a magnetic stir bar and dissolved in dichloromethane (2 mL). Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride ether (28 mg, 0.2 mmol) were then added sequentially. After thorough mixing, a dichloromethane solution (0.5 mL) of oleanol S1 (36 mg, 0.2 mmol) was slowly added dropwise using a syringe. The reaction system was stirred at room temperature for the specified time. Upon completion of the reaction, water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. Finally, the crude product, cannabidiol, was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The screening results are as follows:

[0044] reaction time h Yield % 0.2 60 4 62 8 65 12 55

[0045] Different reaction times were used in the above reaction, namely 0.2 h, 4 h, 8 h, and 12 h. Among them, the 8 h reaction time was better, with a yield of 65%.

[0046] 5. Screening of magnesium / calcium-based catalyst equivalents:

[0047]

[0048] Under argon protection, cyclohexenol A1 (30 mg, 0.2 mmol) was added to a dry reaction tube equipped with a magnetic stir bar and dissolved in dichloromethane (2 mL). Magnesium succinate (in appropriate amounts) and boron trifluoride diethyl ether were then added sequentially. After thorough mixing, a dichloromethane solution (0.5 mL) of oleuropein S1 (36 mg, 0.2 mmol) was slowly added dropwise using a syringe. The reaction system was stirred at room temperature for 8 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. Finally, the crude product, cannabidiol, was obtained by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The screening results are as follows:

[0049]

[0050]

[0051] Different amounts of magnesium / calcium-based catalysts were used in the above reaction, namely 1.0 equivalent, 2.0 equivalent, 3.0 equivalent, 4.0 equivalent, 5.0 equivalent, and 6.0 equivalent magnesium succinate. Among them, the 5.0 equivalent magnesium succinate catalyst showed the best yield, reaching 65%.

[0052] 6. Screening of reaction temperature:

[0053]

[0054] Under argon protection, in a dry reaction tube equipped with a magnetic stir bar, cyclohexenol A1 (30 mg, 0.2 mmol) was added and dissolved in dichloromethane (2 mL) at the corresponding temperature. Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially. After thorough mixing, a dichloromethane solution (0.5 mL) of oleanol S1 (36 mg, 0.2 mmol) was slowly added dropwise using a syringe. The reaction system was stirred for 8 hours at the corresponding temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. Finally, the crude product, cannabidiol, was obtained by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v). The screening results are as follows:

[0055] Temperature ℃ Yield % 0 58 25 65 40 60

[0056] Different reaction temperatures were used in the above reaction: 0℃, 25℃, and 40℃. The yield was best at 25℃, reaching 65%.

[0057] Example 1

[0058]

[0059] The reaction was carried out in a dry 5 mL reaction flask equipped with a stir bar. Under an argon atmosphere, Al (30 mg, 0.2 mmol) was first added and dissolved in 2 mL of dichloromethane. Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially, and after thorough mixing, a dichloromethane solution (0.5 mL) of S1 (36 mg, 0.2 mmol) was slowly added using a syringe. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to give the crude product. Finally, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give product 1, a pale yellow oil (40.9 mg, yield 65%). 1 H NMR (400MHz, CDCl3): 6.35–5.85(m,3H),5.57(s,1H),4.77–4.61(m,2H),4.56(s,1H),3.90–3.78(m,1H),2.48–2.35(m,3H),2.30–2.17 (m,1H),2.14–2.04(m,1H),1.87–1.71(m,5H),1.66(s,3H),1.56(dt,J=15.0,7.6Hz,2H),1.37–1.22(m,4H),0.88(t,J=7.0Hz,3H)ppm. 13 C NMR(101MHz, CDCl3):149.5,143.2,140.2,124.3,113.9,111.0,46.3,37.4 ,35.6,31.6,30.8,30.5,28.5,23.8,22.7,20.6,14.2ppm.HRMS(m / z):[M–H] – calcd for C 21 H 29 O2 – 313.2173, found 313.2176.

[0060] Example 2

[0061]

[0062] The reaction was carried out in a dry 5 mL reaction flask equipped with a stir bar. Under an argon atmosphere, A1 (30 mg, 0.2 mmol) was first added and dissolved in 2 mL of dichloromethane. Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially, and after thorough mixing, a dichloromethane solution (0.5 mL) of S2 (38 mg, 0.2 mmol) was slowly added using a syringe. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to obtain the crude product. Finally, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give product 2, a colorless oil (16.5 mg, yield 26%). 1 H NMR (400MHz, CDCl3): 6.49 (d, J=47.0Hz, 2H), 5.45 (s, 1H), 4.62–4.56 (m, 1H), 4.46 (s, 1H), 3.85–3.71 (m,1H),2.36–2.25(m,1H),2.23–2.10(m,1H),2.10–1.96(m,1H),1.82–1.65(m,5H),1.59(s,3H)ppm. 13 C NMR(101MHz, CDCl3):148.7,140.9,123.2,120.0,115.9,111.3,77.3,46.0,37.0,30.4,28.3,23.7,20.2ppm.HRMS(m / z):[M–H] – calcd for C 21 H 29 O2 – 313.2173, found 313.2176.

[0063] Example 3

[0064]

[0065] The reaction was carried out in a dry 5 mL reaction flask equipped with a stir bar. Under an argon atmosphere, Al (30 mg, 0.2 mmol) was first added and dissolved in 2 mL of dichloromethane. Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially, and after thorough mixing, S3 (38 mg, 0.2 mmol) in dichloromethane solution (0.5 mL) was slowly added using a syringe. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to give the crude product. Finally, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give product 3, a pale yellow oil (45.7 mg, yield 70%). 1 H NMR(400MHz, CDCl3):6.39–5.80(m,2H),5.57(s,1H),4.67(s,1H),4.57(s,1H),3.90–3.77(m,1H),2.47– 2.15(m,3H),2.14–2.02(m,1H),1.88–1.75(m,9H),1.74–1.67(m,1H),1.65(s,3H),1.43–1.12(m,5H)ppm. 13 C NMR(101MHz, CDCl3):149.5,148.3,140.1,124.1,113.9,110.8,46.1,44.1 ,37.4,34.2,34.1,30.4,28.4,26.9,26.2,23.7,20.7ppm.HRMS(m / z):[M–H] – calcd for C 19 H 23 O2 – 325.2173, found 325.2165.

[0066] Example 4

[0067]

[0068] The reaction was carried out in a dry 5 mL reaction flask equipped with a stir bar. Under an argon atmosphere, Al (30 mg, 0.2 mmol) was first added and dissolved in 2 mL of dichloromethane. Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially, and after thorough mixing, S4 (37 mg, 0.2 mmol) in dichloromethane solution (0.5 mL) was slowly added using a syringe. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to give the crude product. Finally, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give product 4, a pale yellow oil (43.6 mg, yield 68%). 1 H NMR(400MHz, CDCl3):7.61–7.50(m,2H),7.44–7.36(m,2H),7.35–7.29(m,1 H),6.79–6.52(m,2H),5.66–5.56(m,1H),4.72–4.64(m,1H),4.63–4.57(m, 1H),3.94(ddp,J=10.7,4.5,2.4Hz,1H),2.46(td,J=10.9,3.6Hz,1H),2.33 –2.19(m,1H),2.18–2.08(m,1H),1.92–1.77(m,5H),1.73–1.66(m,3H)ppm. 13 C NMR(101MHz, CDCl3):149.18,140.85,140.45,140.34,128.63,127.35,126.78,123 .76,115.76,111.09,46.13,37.35,30.43,28.41,23.71,20.50ppm.HRMS(m / z):[MH] – calcd for C 22 H 23 O2 – 319.1704, found 319.1698.

[0069] Example 5

[0070]

[0071] The reaction was carried out in a dry 5 mL reaction flask equipped with a stir bar. Under an argon atmosphere, A2 (22 mg, 0.2 mmol) was added first, followed by 2 mL of dichloromethane for dissolution. Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially, and after thorough mixing, a dichloromethane solution (0.5 mL) of S1 (36 mg, 0.2 mmol) was slowly added using a syringe. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to give the crude product. Finally, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give product 5, a pale yellow oil (22.4 mg, yield 40%). 1 H NMR (400MHz, CDCl3): 6.22 (s, 2H), 5.64 (s, 1H), 3.89 (s, 1H), 2.44 (t, J = 7.8Hz, 2H), 2.20– 1.84(m,2H),1.79(s,3H),1.75–1.51(m,6H),1.42–1.20(m,4H),0.89(t,J=6.6Hz,3H)ppm. 13 CNMR(101MHz, CDCl3):142.9,141.0,123.7,114.4,108.5,35.5,32.2,31.6,30.7,30.0,28.3,24.1,22.5,14.0ppm.HRMS(m / z):[MH] – calcd for C 18 H 25 O2 – 273.1860, found 273.1855.

[0072] Example 6

[0073]

[0074] The reaction was carried out in a dry 5 mL reaction flask equipped with a stir bar. Under an argon atmosphere, A3 (31 mg, 0.2 mmol) was added first, followed by 2 mL of dichloromethane for dissolution. Magnesium succinate (144 mg, 1.0 mmol) and boron trifluoride diethyl ether (28 mg, 0.2 mmol) were added sequentially, and after thorough mixing, a dichloromethane solution (0.5 mL) of S1 (36 mg, 0.2 mmol) was slowly added using a syringe. The mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted with dichloromethane (3 × 2.0 mL). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to give the crude product. Finally, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to give product 6, a yellow oil (15.7 mg, yield 22%). 1 H NMR(400MHz, CDCl3):6.25(s,2H),5.33–5.22(m,1H),5.12–4.98(m,1H),3.46–3.35(m,2H),2.52–2.39(m,2H),2.1 5–2.01(m,4H),1.85–1.79(m,3H),1.70–1.64(m,3H),1.62–1.52(m,5H),1.42–1.22(m,4H),0.95–0.82(m,3H)ppm. 13 C NMR (101MHz, CDCl3):154.8,142.8,139.0,132.1,123.8,121.7,110.6,108.3,39.7,35.5,31.5,30.8,26.4,22.6,22.3,17.7,16.2,14.0ppm HRMS(m / z):[MH] – calcd for C 21 H 31 O2 – 315.2330, found 315.2324.

[0075] Example 7

[0076] Following the procedures in Examples 1-6, only the reaction substrate was changed to obtain a series of cannabidiol derivatives.

[0077]

[0078]

[0079] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing cannabidiol and its derivatives, characterized in that, The reaction includes the following steps: allyl alcohol compound 1 and dihydroxybenzene compound 2 react in an organic solvent in the presence of an organic acid, magnesium or calcium-based catalyst, to give cannabidiol and its derivatives 3; the reaction equation is shown below: Wherein: R1 is selected from halogen, alkyl, three-membered ring, five-membered ring, six-membered ring or benzene ring; R2, R3 are selected from hydrogen, isopropenyl or alkyl; n = 1, 2, 3.

2. The method for preparing cannabidiol and its derivatives according to claim 1, characterized in that: The acid is selected from BF3-Et2O, ZnCl2, p-TsOH, Sc(OTf)3, In(OTf)3, InBr3, SnCl4, H2SO4 or AlCl3.

3. The method for preparing cannabidiol and its derivatives according to claim 1, characterized in that: The magnesium or calcium-based catalyst is selected from calcium alginate, calcium stearate, calcium disodium ethylenediaminetetraacetate, calcium pyruvate, calcium acetopropionate, calcium dihydroxymalate, magnesium acetate, magnesium succinate, magnesium stearate, or magnesium citrate.

4. The method for preparing cannabidiol and its derivatives according to claim 1, characterized in that: The organic solvent is selected from dichloromethane, chloroform, tetrahydrofuran, toluene, and ethyl acetate.

5. The method for preparing cannabidiol and its derivatives according to claim 1, characterized in that: The reaction temperature is 0-40℃.

6. The method for preparing cannabidiol and its derivatives according to claim 5, characterized in that: The reaction temperature is 25℃.

7. The method for preparing cannabidiol and its derivatives according to any one of claims 1-6, characterized in that: The reaction is carried out under the protection of an inert gas.

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