A method of preparing cannabidiol

Abstract

The application discloses a preparation method of cannabidiol. The method uses malonic acid ester compounds and hexanal as starting materials, and obtains compound (3) through a Knoevenagel condensation reaction under alkaline conditions; the obtained compound (3) and acetoacetic acid ester compounds are subjected to a Michael addition and intramolecular Aldol condensation reaction under alkaline conditions to obtain compound (5); compound (5) is subjected to oxidative aromatization to obtain compound (6); compound (6) and (+)-trans-p-mentha-2,8-diene-1-ol are subjected to a Friedel-Crafts alkylation reaction under acidic conditions to obtain compound (8); and finally, the obtained compound (8) is subjected to high-temperature hydrolysis decarboxylation under alkaline conditions to obtain the target compound cannabidiol (CBD). The preparation process of the CBD developed in the application has the advantages of low cost of raw materials, high reaction selectivity, no isomer generation, high total yield, few by-products, easy product purification, low process cost and easy industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and specifically to a method for preparing cannabidiol. Background Technology

[0002] Cannabidiol (CBD), Chinese chemical name: 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol, CAS registration number: 13956-29-1. Cannabidiol has a wide range of applications in the pharmaceutical field and can play an extremely effective role in the treatment of many diseases. Its main uses are as follows: (1) Cannabidiol has anti-tumor effects. Cannabidiol has played a role to varying degrees in the treatment of various cancers such as breast cancer, lung cancer, and colorectal cancer. It can also inhibit tumor migration, invasion, and angiogenesis, and affect the tumor microenvironment. (2) Cannabidiol has anti-anxiety and sedative effects. Studies on the treatment of COVID-19-related anxiety with cannabidiol have found that cannabidiol is a new pharmacological option for curing COVID-19-related anxiety. (3) Cannabidiol has antidepressant effects. (4) Cannabidiol has the effect of intervening in drug addiction. (5) Cannabidiol has the function of treating epilepsy. Cannabidiol can not only reduce the incidence and mortality of epilepsy, but also improve the physical and cognitive functions of epilepsy patients and improve their quality of life. (5) Cannabidiol also has the function of anti-rheumatoid arthritis. Studies have found that cannabidiol can increase the intracellular calcium level of synovial fibroblasts in rheumatoid arthritis, reduce cell viability and the production of synovial fibroblasts in rheumatoid arthritis, thereby playing a positive role in curing rheumatoid arthritis.

[0003] The classic one-step synthesis method for CBD is shown in the following formula: alkylation of menthol-2,8-dien-1-ol (A, menthol derivative) with 5-pentyl-1,3-benzenediol (B, oleuropein) under acid catalysis to obtain cannabidiol.

[0004]

[0005] Reference [Chem. Phys. Lipids, 2002, 121(1 / 2): 35-43.] reported a CBD yield of 41% using BF3 as a catalyst. US20090036523 reported a CBD yield of 24% using p-toluenesulfonic acid as a catalyst. WO2006053766 reported a CBD yield of 22% using zinc chloride as a catalyst.

[0006] The synthesis of CBD using this reaction system results in the formation of numerous isomers (the starting material oleyl alcohol (B) contains three reactive sites, leading to poor reaction selectivity) and dimers. The post-processing is complex, the yield of the target product is low, and the starting material oleyl alcohol (B) is expensive, resulting in high process costs. Therefore, this method is not suitable for the industrial-scale production of CBD.

[0007] US20100298579, US20170349517, WO2019033168, etc., used methyl 2,4-dihydroxy-6-pentylbenzoate (C) and a menthol derivative (A) as raw materials to first prepare an intermediate (D) under acid catalysis. This intermediate was then further decarboxylated to synthesize the target product CBD. The specific synthetic method is shown in the following formula:

[0008]

[0009] The synthesis of CBD using this reaction system yields a higher product yield than the one-step method, and produces fewer isomers (the oleyl alcohol derivative C contains two reactive sites) and dimers. However, the purity of the intermediate D is still low, and its melting point may be low (the melting point of this intermediate has not been reported in the literature), making it difficult to purify by recrystallization using conventional methods. This results in higher process costs and is not conducive to its industrial-scale production.

[0010] Besides the two chemical synthesis methods mentioned above, some literature reports other chemical synthesis methods to obtain cannabidiol, but these methods use expensive raw materials and have complicated synthesis steps, making it difficult to achieve industrial production.

[0011] In summary, all currently reported CBD synthesis methods have shortcomings and are difficult to meet the requirements of industrial production. Therefore, developing a high-efficiency, low-cost CBD synthesis method is of paramount importance. Summary of the Invention

[0012] The technical problem to be solved by this invention is: how to provide a CBD synthesis method with high product yield and purity, simple post-processing and low process cost.

[0013] To achieve the above technical objectives, the present invention adopts the following technical solution:

[0014] A method for preparing cannabidiol, the reaction formula of which is shown below.

[0015]

[0016] In the formula: R1 is CH3, CH3CH2; R2 is CH3, CH3CH2;

[0017] Includes the following steps:

[0018] A) Using malonate ester (1) and hexanal (2) as starting materials, the compounds were reacted with base in a solvent and then condensed by Knoevenagel to obtain compound (3);

[0019] B) Using the compound (3) obtained in step A) and the acetoacetate compound (4) as raw materials, react with a base in a solvent, and then undergo Michael addition reaction and intramolecular Aldol condensation reaction to obtain compound (5);

[0020] C) The compound (5) obtained from step B) is further oxidized and aromatized in a solvent by a dehydrogenating agent to obtain compound (6);

[0021] D) Using the compound (6) obtained in step C) and the cyclohexenol compound (7) as raw materials, react with acid in a solvent and undergo Friedel-Crafts alkylation reaction to obtain compound (8);

[0022] E) The compound (8) obtained from step D) is reacted with an alkali in a solvent and decarboxylated by high-temperature hydrolysis to obtain the target compound cannabidiol (CBD).

[0023] In step A), the solvent used in the reaction is: N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, ethylene glycol dimethyl ether, acetonitrile, preferably N,N-dimethylformamide or dimethyl sulfoxide; the base used in the reaction is: pyridine, hexahydropyridine, triethylamine, alkali metal salts of C1-C8 alcohols, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal carbonates. The reaction mixture consists of hydrogen salts, alkali metal or alkaline earth metal hydrides, or combinations of the above bases, preferably pyridine or triethylamine; the molar ratio of hexanal (2) to malonic acid ester (1) to base is 1.0:1.0-2.0:0.1-10.0, preferably 1.0:1.0-1.5:0.2-5.0; the reaction temperature is 0-120°C, preferably room temperature to 80°C; the reaction time is 1-72 hours, preferably 2-24 hours.

[0024] In step B), the solvent used in the reaction is: C 1-6 Fatty alcohols, N,N-dimethylformamide, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C 1-6 Fatty acids and C 1-6The preferred solvents for the reaction are: esters formed from fatty alcohols, dichloromethane, chloroform, 1,2-dichloroethane, dimethyl sulfoxide, C5-C8 alkanes, and aromatic hydrocarbons; methanol, ethanol, methyl tert-butyl ether, tetrahydrofuran, benzene, or toluene; and the base used in the reaction is: alkali metal salts of C1-C8 alcohols, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal bicarbonates, alkali metal or alkaline earth metal hydrides, or combinations of the above bases. The preferred bases are sodium methoxide, sodium ethoxide, potassium hydride, and sodium hydride; the molar ratio of acetoacetate compound (4) to compound (3) to base is 1.0:1.0~2.0:1.0~10.0, preferably 1.0:1.0~1.5:1.0~5.0; the reaction temperature is 0~150℃, preferably room temperature~100℃; the reaction time is 1~72 hours, preferably 2~24 hours.

[0025] In step C), the solvent used in the reaction is: C 1-6 Fatty alcohols, N,N-dimethylformamide, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C 1-6 Fatty acids and C 1-6 The preferred solvents are acetonitrile, N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, C5-C8 alkanes, acetonitrile, and aromatic hydrocarbons. The dehydrogenating agents used in the reaction are Br2, I2, N-chlorosuccinimide, N-bromosuccinimide, copper dihalide, a mixture of copper dihalide and alkali metal halides or alkaline earth metal halides, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, or Pd-C with a palladium content of 1%-30%. The preferred dehydrogenating agents are Br2, CuBr2, CuCl2, and C. The mixtures of uCl2 and MgCl2, CuCl2 and LiCl, and CuCl2 and NaCl; the molar ratio of compound (5) to dehydrogenating agent is 1.0:0.05 to 10.0, preferably 1.0:0.2 to 6.0; the molar ratio of copper dihalide to alkali metal halide or alkaline earth metal halide is 1.0:0.1 to 2.0, preferably 1.0:0.2 to 1.2; the reaction temperature is room temperature to 150°C, preferably room temperature to 120°C; the reaction time is 1 to 72 hours, preferably 2 to 24 hours.

[0026] In step D), the solvent used in the reaction is: C 1-6 Fatty alcohols, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C 1-6 Fatty acids and C 1-6The preferred solvents are: esters formed from fatty alcohols, dichloromethane, chloroform, 1,2-dichloroethane, C5-C8 alkanes, and aromatic hydrocarbons; the preferred solvents are: dichloromethane, chloroform, and 1,2-dichloroethane; the preferred acids used in the reaction are: phosphoric acid, sulfuric acid, aluminum trifluoride, zinc chloride, boron trifluoride-ethyl ether complex, p-toluenesulfonic acid, transition metal methanesulfonate, transition metal trifluoromethanesulfonate, or combinations of the above acids, with the preferred acids being: zinc chloride, boron trifluoride-ethyl ether complex, p-toluenesulfonic acid, and transition metal trifluoromethanesulfonate; the molar ratio of compound (6) to compound (7) to acid is 1.0:1.0-5.0:0.05-10.0, with the preferred molar ratio being 1.0:1.0-2.0:0.1-5.0; the reaction temperature is 0-100℃, with the preferred reaction temperature being 0-60℃; the reaction time is 1-72 hours, with the preferred reaction time being 2-24 hours.

[0027] In step E), the solvent used in the reaction is: C 1-6 Fatty alcohols, N,N-dimethylformamide, dimethyl sulfoxide, preferably methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide; the base used in the reaction is alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or alkaline earth metal bicarbonate, or a combination of the above bases, preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; the molar ratio of compound (8) to base is 1.0:2.0 to 50.0, preferably 1.0:5.0 to 25.0; the reaction temperature is 50 to 150°C, preferably 80 to 120°C; the reaction time is 1 to 72 hours, preferably 2 to 24 hours.

[0028] This invention discloses a method for preparing cannabidiol. The method uses malonic acid esters and hexanal as starting materials, and obtains 1,1-dialkoxycarbonyl-heptene (3) through a Knoevenagel condensation reaction under alkaline conditions; the obtained compound (3) is reacted with acetoacetate esters under alkaline conditions via Michael addition and intramolecular Aldol condensation to obtain 1-hydroxy-4,6-dialkoxycarbonyl-5-pentyl-cyclohexene-3-one compounds (5); compound (5) is then oxidatively aromatized to obtain 4,6-dialkoxycarbonyl-5-pentyl -1,3-benzenediol (6); compound (6) and (+)-trans-p-menth-2,8-dien-1-ol were subjected to Friedel-Crafts alkylation under acidic conditions to give 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-dialkoxycarbonyl-5-pentyl-1,3-benzenediol compound (8); finally, compound (8) was subjected to high-temperature hydrolysis and decarboxylation under alkaline conditions to give the target compound cannabidiol (CBD). The CBD preparation process developed in this invention uses inexpensive raw materials, has high reaction selectivity, does not generate isomers, has a high overall yield, few by-products, and the product is easy to purify. The process cost is low and it is easy to realize industrial production.

[0029] Compared with previously reported synthesis methods, the present invention has the following advantages:

[0030] 1) The raw materials used are inexpensive;

[0031] 2) The process for preparing CBD described in this invention has high reaction selectivity and no isomers are generated (the prepared intermediate oleyl alcohol derivative 6 contains only one reactive site).

[0032] 3) High overall yield, few by-products, easy product purification, low process cost, and easy to achieve industrial production. Detailed Implementation

[0033] The specific embodiments of the present invention will be described in detail below. To avoid excessive and unnecessary detail, well-known structures or functions will not be described in detail in the following embodiments. The approximate language used in the following embodiments is for quantitative purposes, indicating that a certain degree of variation in quantity is permissible without changing the basic function. Unless otherwise defined, the technical and scientific terms used in the following embodiments have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0034] Example 1 Preparation of 1,1-dimethoxycarbonyl-heptene (3a)

[0035] 200 mL of dimethyl sulfoxide, 0.2 mol of hexanal, and pyridine (40 mmol, 20 mol%) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 30 minutes. Then, 0.2 mol of dimethyl malonate was added to the reaction mixture, and the reaction was stopped after 12 h at room temperature. After the reaction was stopped, the reaction mixture was transferred to a separatory funnel, and 1 L of water was added. The reaction mixture was extracted three times with 500 mL of ethyl acetate each time. The combined organic phases were desolventized to obtain a pale yellow liquid, which was then subjected to vacuum distillation to give a colorless oily liquid, 1,1-dimethoxycarbonyl-heptene, in approximately 88% yield. NMR analysis results: 1 H NMR(500MHz, CDCl3)δ / ppm 7.03 (t, J=7.9Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 2.30 (dt, J=7.7, 7.4Hz, 2H), 1.60-1.48 (m, 2H), 1.27-1.32 (m, 4H), 0.89 (t, J=6.2Hz, 3H); 13 CNMR (126MHz, CDCl3) δ / ppm 165.3, 164.5, 151.0, 128.2, 52.6, 51.5, 31.7, 30.1, 28.2, 22.5, 14.1.

[0036] Example 2 Preparation of 1,1-diethoxycarbonyl-heptene (3b)

[0037] The operation process is the same as in Example 1, except that dimethyl malonate is replaced with diethyl malonate and pyridine is replaced with triethylamine, to obtain a colorless oily liquid 1,1-diethoxycarbonyl-heptene with a yield of about 85%.

[0038] Example 3 Preparation of 1-hydroxy-4,6-dimethoxycarbonyl-5-pentyl-cyclohexene-3-one (5a)

[0039] Sodium methoxide (20 mmol), 20 mL methanol, and methyl acetoacetate (10 mmol) were added sequentially to a reaction flask. The reaction was activated at 60-70 °C for 0.5 h. Then, 1,1-dimethoxycarbonyl-heptene (15 mmol) was added dropwise to the reaction flask, and the reaction was stopped after 12 h at 60-70 °C. The reaction solution was transferred to a single-necked flask, and the methanol was evaporated to obtain a yellow viscous liquid. The solution was acidified with dilute hydrochloric acid until acidic, resulting in the precipitation of a large amount of white crystals. The resulting solid-liquid mixture was filtered, and the filter cake was washed with water until neutral and then dried under vacuum at room temperature for 24 h to obtain a white solid, 1-hydroxy-4,6-dimethoxycarbonyl-5-pentyl-cyclohexene-3-one, with a yield of approximately 80%. NMR analysis results: 1H NMR(500MHz, CDCl3)δ / ppm 10.06 (s, 1H), 5.97 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.18 ~ 3.14 (m, 2H), 2.21 ~ 2.14 (m, 1H), 1.39 ~ 1.24 (m, 8H), 0.87 (t, J = 0.4Hz, 3H); 13 C NMR (125MHz, CDCl3) δ / ppm 191.6, 185.9, 173.2, 171.4, 104.1, 56.9, 52.5, 36.3, 34.8, 33.8, 31.7, 31.4, 25.92, 22.5, 14.0.

[0040] Example 4 Preparation of 1-hydroxy-4,6-diethoxycarbonyl-5-pentyl-cyclohexene-3-one (5b)

[0041] The operation process is the same as in Example 3, except that 1,1-dimethoxycarbonyl-heptene is replaced with 1,1-diethoxycarbonyl-heptene, methanol is replaced with ethanol, and sodium methoxide is replaced with sodium ethoxide, to obtain a white solid 1-hydroxy-4,6-diethoxycarbonyl-5-pentyl-cyclohexene-3-one, with a yield of about 78%.

[0042] Example 5 Preparation of 4,6-dimethoxycarbonyl-5-pentyl-1,3-benzenediol (6a)

[0043] 1-Hydroxy-4,6-dimethoxycarbonyl-5-pentyl-cyclohexene-3-one (20 mmol), CuCl2 (40 mmol), MgCl2 (10 mmol), and 100 mL of acetonitrile were added sequentially to a reaction flask. The reaction was carried out at 80 °C for 12 h, and then the reaction solution was transferred to a single-necked flask. The acetonitrile in the reaction solution was evaporated to obtain a black solid. The obtained solid was acidified with a small amount of dilute hydrochloric acid and then transferred to a separatory funnel. 50 mL of water was added to the reaction mixture. The reaction mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined and the solvent was removed. The crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 v / v) to give a white solid, 4,6-dimethoxycarbonyl-5-pentyl-1,3-benzenediol, in approximately 78% yield. NMR analysis results: 1 HNMR(500MHz, CDCl3)δ / ppm 11.02 (s, 1H), 10.06 (s, 1H), 6.97 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 2.95 (t, J=0.8Hz, 2H), 1.34~1.53 (m, 6H), 0.92 (t, J=0.4Hz, 3H); 13C NMR (125MHz, CDCl3) δ / ppm 172.6, 160.1, 156.3, 151.4, 104.1, 52.4, 36.3, 32.1, 31.5, 22.6, 14.1.

[0044] Example 6 Preparation of 4,6-diethoxycarbonyl-5-pentyl-1,3-benzenediol (6b)

[0045] The procedure was the same as in Example 5, except that 1-hydroxy-4,6-dimethoxycarbonyl-5-pentyl-cyclohexene-3-one was replaced with 1-hydroxy-4,6-diethoxycarbonyl-5-pentyl-cyclohexene-3-one, and magnesium chloride was replaced with sodium chloride, to obtain a white solid 4,6-diethoxycarbonyl-5-pentyl-1,3-benzenediol with a yield of approximately 81%.

[0046] Example 7 Preparation of 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-dimethoxycarbonyl-5-pentyl-1,3-benzenediol (8a)

[0047] 4,6-Dimethoxycarbonyl-5-pentyl-1,3-benzenediol (30 mmol), anhydrous magnesium sulfate (10 mmol), scandium trifluoromethanesulfonate (2 mmol), (+)-trans-p-menth-2,8-dien-1-ol (40 mmol), and 60 mL of dichloromethane were added sequentially to the reaction flask. The reaction was carried out at room temperature for 12 hours under argon protection. Then, sodium carbonate (4 mmol) was added and the reaction was continued at room temperature for another 2 hours to terminate the reaction. The solid-liquid mixture obtained from the reaction was filtered. After removing the solvent from the filtrate, 100 mL of n-hexane was added to dissolve the obtained solid. The n-hexane solution was then washed with 100 mL of 20% sodium hydroxide solution. The aqueous phase was extracted twice with 100 mL of n-hexane each time. The organic phases were combined and the solvent was removed to obtain a pale yellow solid, 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-dimethoxycarbonyl-5-pentyl-1,3-benzenediol, in approximately 91% yield. The crude product was directly used for the next reaction without further purification. NMR analysis results: 1 H NMR(500MHz, CDCl3)δ / ppm 12.02(s, 1H), 6.53(s, 1H), 5.58(s, 1H), 4.54(s, 1H), 4.41(s, 1H),, 4.05(s, 3H), 3.97(s, 3H), 2.96 (t, J=0.8Hz, 2H), 2.52-2.49 (m, 1H), 2.38-2.35 (m, 1H), 1.84~1.34 (m, 16H), 0.92 (t, J=0.4Hz, 3H); 13C NMR(125MHz, CDCl3)δ / ppm 173.1, 163.1, 160.2, 156.3, 151.4, 147.2, 124.1, 114.3, 104.1, 52.4, 46.7, 36.8, 36.4, 32.1, 31.4, 30.2, 27.8, 23.7, 22.5, 18.8, 14.1.

[0048] Example 8 Preparation of 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-diethoxycarbonyl-5-pentyl-1,3-benzenediol (8b)

[0049] The procedure was the same as in Example 7, except that 4,6-dimethoxycarbonyl-5-pentyl-1,3-benzenediol was replaced with 4,6-diethoxycarbonyl-5-pentyl-1,3-benzenediol, yielding a pale yellow solid 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-diethoxycarbonyl-5-pentyl-1,3-benzenediol with a yield of approximately 93%.

[0050] Example 9 Preparation of 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (CBD)

[0051] 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-dimethoxycarbonyl-5-pentyl-1,3-benzenediol (30 mmol), sodium hydroxide (0.6 mol), 100 mL methanol, and 100 mL water were added sequentially to a reaction flask. The reaction mixture was reacted at 100 °C for 12 hours under argon protection, and then cooled to room temperature to terminate the reaction. The reaction mixture was neutralized to neutral by adding citric acid aqueous solution and then transferred to a separatory funnel. The reaction mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and the solvent was removed. The crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 15:1 v / v) to give a white solid 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol, with a yield of approximately 87%. NMR analysis results: 1H NMR(500MHz, CDCl3)δ / ppm 6.26-6.21(m, 2H), 6.03(s, 1H), 5.60(s, 1H), 4.92(s, 1H), 4.68(s, 1H), 4.58(s, 1H), 3.91-3.89(m, 1H), 2.47-2.43(m , 3H), 2.30-2.14(m, 2H), 1.90~1.77(m, 5H), 1.70(s, 3H), 1.61~1.55(m, 2H), 1.37~1.29(m, 4H), 0.92(t, J=0.4Hz, 3H); 13 C NMR (125MHz, CDCl3) δ / ppm149.2, 143.0, 140.0, 124.2, 113.8, 110.9, 46.2, 37.2, 35.5, 31.5, 30.4, 28.4, 22.7, 22.5, 20.5, 14.0.

[0052] Example 10 Preparation of 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol (CBD)

[0053] The procedure was the same as in Example 9, except that 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-dimethoxycarbonyl-5-pentyl-1,3-benzenediol was replaced with 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-4,6-diethoxycarbonyl-5-pentyl-1,3-benzenediol, and sodium hydroxide was replaced with potassium hydroxide, yielding a white solid 2-[(1R,6R)-3-methyl-6-(1-methylvinyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol with a yield of approximately 91%.

[0054] The embodiments of the present invention have been described in detail above, but the content described is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the scope of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing cannabidiol, characterized in that... Includes the following steps: A) Using malonate ester (1) and hexanal (2) as starting materials, the compounds were reacted with base in a solvent and then condensed by Knoevenagel to obtain compound (3); B) Using the compound (3) obtained in step A) and the acetoacetate compound (4) as raw materials, react with a base in a solvent, and undergo Michael addition reaction and intramolecular Aldol condensation reaction to obtain compound (5); C) The compound (5) obtained from step B) is further oxidized and aromatized in a solvent by a dehydrogenating agent to obtain compound (6); D) Using the compound (6) obtained in step C) and the cyclohexenol compound (7) as raw materials, react with acid in a solvent and undergo Friedel-Crafts alkylation reaction to obtain compound (8); E) The compound (8) obtained from step D) is reacted with an alkali in a solvent and decarboxylated by high-temperature hydrolysis to obtain the target compound cannabidiol; ； In the formula, R1 is CH3, CH3CH2; R2 is CH3, CH3CH2; In step B), the solvent used in the reaction is selected from one or more of the following components: C 1-6 Fatty alcohols, N,N-dimethylformamide, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C 1-6 Fatty acids and C 1-6 Esters formed from fatty alcohols, dichloromethane, chloroform, 1,2-dichloroethane, dimethyl sulfoxide, C5~C8 alkanes, aromatic hydrocarbons; The base used in the reaction is selected from one or more of the following components: alkali metal salts, alkali metal or alkaline earth metal hydroxides of C1~C8 alcohols: acetoacetate esters (4): Compound (3): The molar ratio of base is 1.0:1.0~2.0:1.0~10.0; the reaction temperature is 0~150℃; the reaction time is 1~72 hours; In step C), the solvent used in the reaction is selected from one or more of the following components: C 1-6 Fatty alcohols, N,N-dimethylformamide, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C 1-6 Fatty acids and C 1-6 The reaction mixture consists of esters formed from fatty alcohols, dichloromethane, chloroform, 1,2-dichloroethane, dimethyl sulfoxide, C5-C8 alkanes, acetonitrile, and aromatic hydrocarbons. The dehydrogenating agent used in the reaction is selected from one of the following components: a mixture of copper dihalide and alkali metal halides or alkaline earth metal halides; Compound (5): The molar ratio of the dehydrogenating agent is 1.0:0.05~10.0; the molar ratio of copper dihalide to alkali metal halides or alkaline earth metal halides is 1.0:0.1~2.0; the reaction temperature is room temperature~150℃; the reaction time is 1~72 hours. In step D), the solvent used in the reaction is selected from one or more of the following components: C1-6 fatty alcohols, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, C 1-6 Fatty acids and C 1-6 The reaction mixture consists of esters formed from fatty alcohols, dichloromethane, chloroform, 1,2-dichloroethane, C5-C8 alkanes, and aromatic hydrocarbons; the acid used in the reaction is scandium trifluoromethanesulfonate; the molar ratio of compound (6): compound (7): acid is 1.0:1.0~5.0:0.05~10.0; the reaction temperature is 0~100℃; and the reaction time is 1~72 hours.

2. The method for preparing cannabidiol according to claim 1, characterized in that, In step A), the solvent used in the reaction is selected from one or more of the following components: N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, ethylene glycol dimethyl ether, acetonitrile; the base used in the reaction is selected from one or more of the following components: pyridine, hexahydropyridine, triethylamine, alkali metal salts of C1~C8 alcohols, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal bicarbonates, alkali metal or alkaline earth metal hydrides; the molar ratio of hexanal (2): malonate compound (1): base is 1.0:1.0~2.0:0.1~10.0; the reaction temperature is 0~120℃; the reaction time is 1~72 hours.

3. The method for preparing cannabidiol according to claim 1, characterized in that, In step E), the solvent used in the reaction is selected from one or more of the following components: C 1-6 Fatty alcohol, N,N-dimethylformamide, dimethyl sulfoxide; the base used in the reaction is selected from one or more of the following components: alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, alkali metal or alkaline earth metal bicarbonate; compound (8): the molar ratio of base is 1.0:2.0~50.0; the reaction temperature is 50~150℃; the reaction time is 1~72 hours.

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