A method for preparing cannabinoids and cannabinoids

Abstract

The present invention discloses a method for preparing cannabidiol and its analogs, comprising the following cross-coupling reaction: wherein: R1 and R2 are both hydroxyl protecting groups, R3 is a C1-C9 alkyl group, X and Y are independently selected from any one of Cl, Br, I, MgCl, MgBr, and MgI, and n is any natural number of 1, 2, and 3; the catalyst is a catalyst for Kumada cross-coupling reaction. The present invention can not only effectively improve the selectivity of the reaction, so that the yield of compound 5 is as high as 92%, but also can achieve a high-yield reaction at room temperature, and the operation is simple, the reaction conditions are mild and controllable, and the catalyst used has the advantages of low toxicity, low price, easy availability, and environmental friendliness, which is very conducive to industrial amplification production, and can achieve the shortest synthetic route, high yield, and large-scale preparation of high-purity cannabidiol and its analogs with cheap and easily available olive alcohol as the starting material.

Description

Technical Field

[0001] The invention relates to a method for preparing cannabinoids and cannabinoids and their analogs, and belongs to the technical field of organic synthesis. Background Art

[0002] Cannabigerol (CBG) is a non-psychoactive cannabinoid with the following chemical structure:

[0003] Existing studies have shown that CBG not only has a wide range of antibacterial, antimicrobial and anti-inflammatory properties, but also has good pharmacological effects, such as antifungal, anti-inflammatory and analgesic, lowering intraocular pressure, neuroprotection, antidepression, stimulating appetite, enhancing cancer cell apoptosis, etc.; in addition, it has been reported that CBG has extremely strong antioxidant properties and can be used to treat neurodegenerative diseases, etc.; and cannabinoids are present in trace amounts in most cannabis plants, with the content in common strains being less than 1%. Therefore, how to achieve large-scale synthesis of cannabinoids and their analogs has attracted much attention in this research field.

[0004] After searching, it was found that the synthesis of CBG in the prior art mainly includes the following reports:

[0005] 1) CBG is directly synthesized using olive alcohol as a substrate under the action of different catalysts. The reagents catalyzing the reaction can be TsOH, CSA, MsOH, FeCl3, AcCl, BF3·OEt2 and acidic alumina, etc. The hydroxyl group in the raw material geraniol can also be a bromine atom. The reported yield is 39.9% to 62%, among which acidic alumina has the highest yield, such as: Tetrahedron Lett., 1968, 60, 5349-5352; WO20140134281A1; WO20160030828A1; US20170283837A1; US20200115306A1; J.Nat.Prod.2020, 83, 2587-2591 and other literature; the advantage of this method is that the route is short, but due to the presence of multiple reaction sites in the substrate, there are more by-products such as isomers and dimers with similar structures and difficult to separate, the post-processing steps are cumbersome, the yield of the target product is low, and it is difficult to achieve large-scale production to obtain high-purity CBG products;

[0006] 2) Using linalool and olive alcohol as raw materials, using fluid chemistry technology and using solid-supported p-toluenesulfonic acid as a catalyst to achieve the synthesis of CBG, but the yield is only 20%, and the ratio of CBG to by-products is 1:1, as reported in patent documents WO20170011210A1 and US20200325091A1;

[0007] 3) Patent document WO2020031179A1 reports the use of olive alcohol analog substrates to react with geraniol (bromogeraniol) or linalool to effectively block adverse reaction sites to improve the selectivity of the reaction, and patent document WO20200249184A1 reports another strategy for blocking adverse reaction sites in olive alcohol, namely: starting from olive alcohol, preparing a dibrominated compound, reacting with geraniol or linalool for electrophilic substitution, and then reducing and debrominating to generate CBG; although the above method can solve the problem of reaction selectivity to a certain extent, it adds additional reaction steps and preparation costs;

[0008] 4) In 2008, Tomohisa's group used NphB to catalyze the reaction of GPP and olivetol to produce CBG. NphB is a soluble prenyl transferase from Streptomyces (Bioorg. Med. Chem. 2008, 16, 8117–8126). The reaction scale of this method is relatively small at present, and there is no report that it can achieve large-scale synthesis;

[0009] 5) Patent documents US20200115306A1 and WO20210195751A1 respectively reported the Suzuki-Mayaura and Negishi coupling reaction strategies catalyzed by metal palladium. Starting from olive alcohol analogs, cross-coupling reactions were used to react with substituted geraniol to improve the selectivity of the reaction. This synthesis method still has the problems of many by-products and low yield, and also creates new problems, namely: heavy metal palladium is highly toxic, and heavy metal palladium residues are easily present in the reaction products, causing the heavy metal content of the raw materials to exceed the standard, or requiring additional expensive purification methods; at the same time, palladium catalysts are relatively expensive, which greatly increases the production cost of the reaction; in addition, the aryl boron reagent used in the reaction needs to be converted from the corresponding aryl halide via an aryl Grignard reagent or an aryl lithium reagent in two steps, which also significantly increases the difficulty and cost of industrialization.

[0010] From the above, it can be seen that there is currently no technology that can simultaneously achieve low cost, high yield, and large-scale preparation of high-purity cannabinoids. Summary of the invention

[0011] In view of the above-mentioned problems and needs in the prior art, the object of the present invention is to provide a method for preparing high-purity cannabinoids and their analogs at low cost, high yield and on a large scale.

[0012] In order to achieve the above-mentioned invention object, the technical solution adopted by the present invention is as follows:

[0013] A method for preparing cannabinoids and cannabinoids and their analogs, comprising the following cross-coupling reaction:

[0014]

[0015] Wherein: R1 and R2 are both hydroxyl protecting groups, R3 is a C1-C9 alkyl group, X and Y are independently selected from any one of Cl, Br, I, MgCl, MgBr, and MgI, and n is any natural number of 1, 2, and 3; and the catalyst is a catalyst for Kumada cross-coupling reaction.

[0016] In one embodiment, the catalyst is selected from ferric fluoride (FeF3), ferric chloride (FeCl3), ferric bromide (FeBr3), ferric triacetyl acetonate (Fe(acac)3), ferric trifluoromethanesulfonate (Fe(OTf)3), ferrous fluoride (FeF2), ferrous chloride (FeCl2), ferrous bromide (FeBr2), ferrous trifluoromethanesulfonate (Fe(OTf)2), nickel chloride (NiCl2), nickel bromide (NiBr2), nickel iodide (NiI2), Ni(dme)Cl2, Ni(PPh3)2Cl2, ( MeNN2) at least one metal salt in NiCl and selected from N,N,N',N'-tetramethylethylenediamine (TMEDA), hexamethylenetetramine (HMTA), 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylpropyleneurea (DMPU), 1,1,3,3-tetramethylurea (TMU), N-methylpyrrolidone (NMP), N-methylcaprolactone (Me-CPL), N,N-bis(2-methoxyethyl)benzamide (Bis( OMeEt)-BA), 1-phenylpiperidine (Pip-BA), 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIPr·HCl), 1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride (SIMes·HCl), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr·HCl), 1,3-di-mesityl imidazolium-2-ylidene (IMes), 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIMes·HCl), 1,3-bis(diisopropylphenyl)-4,5-dihydroimidazole-2-ylidene (HIMes), 1,3-bis(diisopropylphenyl)-4,5-dihydroimidazole-2-ylidene (HIPr), 1,3-bis(diisopropyl)-4,5-dihydroimidazole-2-ylidene (HI2Pr), 1,2-bis(bis(3,5-di-tert-butylphenyl)phosphine A complex formed by at least one ligand selected from (FeCl3)2(TMEDA)3, FeCl2(SciOPP), [Fe(C2H4)4][Li(TMEDA)]2), and Fe(Bopa-tBu)Cl2.

[0017] In a preferred embodiment, the catalyst is a composite formed by ferric fluoride (FeF3) and 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIPr·HCl) ligand, or a composite formed by ferric chloride (FeCl3) and any one ligand selected from N,N,N',N'-tetramethylethylenediamine (TMEDA), 1,3-bis(diisopropylphenyl)-4,5-dihydroimidazole-2-ylidene (HIPr), or a composite formed by ferric triacetylacetonate (Fe(acac)3) and any one ligand selected from N,N,N',N'-tetramethylethylenediamine (TMEDA), 1,3 -dimethyl-2-imidazolidinone (DMI), 1,1,3,3-tetramethylurea (TMU), N-methylcaprolactone (Me-CPL), 1-phenylacylpiperidine (Pip-BA) formed by any one of the ligands, or a complex formed by ferrous chloride (FeCl2) and 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIPr·HCl) ligand, or a complex formed by nickel chloride (NiCl2) and Cp*CH2PPh2 (Cp*=1,2,3,4,5-pentamethyl-2,4-cyclopentadienyl) ligand, or a complex formed by ( Me A complex formed by NN2)NiCl and N,N,N',N'-tetramethylethylenediamine (TMEDA) ligand, or at least one complex selected from (FeCl3)2(TMEDA)3, FeCl2(SciOPP), and Fe(Bopa-tBu)Cl2.

[0018] In a preferred embodiment, in the composite, the molar ratio of the metal salt to the ligand is 1:(1-60).

[0019] In a further preferred embodiment, in the composite, the molar ratio of the metal salt to the ligand is 1:(2-40).

[0020] In one embodiment, the cross-coupling reaction comprises the following specific operations:

[0021] Compound 3 is reacted with compound 4 and a catalyst in an organic solvent at -20 to 80° C. under stirring. After the reaction is completed, the reaction is quenched with water or dilute hydrochloric acid, and then post-treated to obtain compound 5.

[0022] In a further embodiment, the post-treatment operation includes: extracting with dichloromethane or ethyl acetate, drying the organic phase collected by the extraction with anhydrous Na2SO4, and then distilling under reduced pressure, and then pulping and filtering to obtain compound 5.

[0023] In a preferred embodiment, the organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether (MTBE), and anhydrous ether.

[0024] In a preferred embodiment, the molar ratio of compound 3 to the catalyst and compound 4 is 1:(0.05-1):(1-3).

[0025] In a preferred embodiment, the temperature of the cross-coupling reaction is 0-50°C.

[0026] In a preferred embodiment, the pulping solvent is selected from at least one of methanol, ethanol, toluene and water.

[0027] In one embodiment, R1 and R2 are both selected from at least one of a C1-C5 alkyl group, a silane protecting group, an ester group, a (trimethylsilyl)ethoxymethyl group, an ether group, a benzyl group, a p-methoxybenzyl group, and an allyl group.

[0028] In a preferred embodiment, R1 and R2 are simultaneously selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, tert-butyldimethylsilyl, acetyl, (trimethylsilyl)ethoxymethyl, methoxymethyl ether, benzyl, p-methoxybenzyl, and allyl.

[0029] In one embodiment, R3 is selected from any one of methyl, ethyl, propyl, n-butyl, n-pentyl, n-heptyl, and dimethyl-n-heptyl.

[0030] In a preferred embodiment, R3 is selected from any one of methyl, n-pentyl and dimethyl-n-heptyl.

[0031] In one embodiment, when X is selected from any one of Cl, Br, and I, Y is selected from any one of MgCl, MgBr, and MgI; when X is selected from any one of MgCl, MgBr, and MgI, Y is selected from any one of Cl, Br, and I.

[0032] In a preferred embodiment, when X is Br or I, Y is MgBr; when X is MgBr, Y is Br or I.

[0033] In one embodiment, the preparation of compound 3 adopts the following reaction:

[0034]

[0035] Wherein: X is any one of Cl, Br, I, MgCl, MgBr, MgI, R1 and R2 are both hydroxyl protecting groups, and R3 is a C1-C9 alkyl group.

[0036] In one embodiment, the preparation of compound 2 adopts the following reaction:

[0037]

[0038] Wherein: X is any one of Cl, Br, I, MgCl, MgBr, and MgI; and R3 is a C1-C9 alkyl group.

[0039] In one embodiment, compound 5 is deprotected to obtain compound cannabinoids and their analogs, and the reaction formula is shown below:

[0040]

[0041] Wherein: R1 and R2 are both hydroxyl protecting groups, and R3 is a C1-C9 alkyl group.

[0042] Compared with the prior art, the present invention has the following significant beneficial effects:

[0043] Experiments show that the present invention creatively adopts a Kumada cross-coupling reaction catalyst to catalyze the cross-coupling reaction of compound 3 and compound 4, which not only effectively improves the selectivity of the reaction and can make the yield of compound 5 as high as 92%, but also, compared with the existing palladium-catalyzed Suzuki-Mayaura coupling reaction conditions, the cross-coupling reaction of the present invention can not only achieve a high-yield reaction at room temperature, but also is simple to operate, and the reaction conditions are mild and controllable. In particular, the catalyst used has the advantages of low toxicity, low price, easy availability, and environmental friendliness, which is very conducive to industrial scale-up production; the key is that the present invention can use cheap and readily available olive alcohol as a starting material, and can prepare high-purity cannabinoid phenol in a shortest synthetic route, high yield, and large-scale, which has significant value for realizing the batch preparation of cannabinoid phenol and its analogs. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 HPLC analysis of the target product prepared in Example 1;

[0045] Figure 2 This is the HPLC analysis spectrum of CBG prepared in Example 35. DETAILED DESCRIPTION

[0046] A method for preparing cannabinoids can be prepared by the following synthetic route:

[0047]

[0048] in:

[0049] X can be Cl, Br, I or MgCl, MgBr, MgI, etc.;

[0050] Y can be Cl, Br, I or MgCl, MgBr, MgI, etc.;

[0051] R1 and R2 are both hydroxyl protecting groups, which can be independently selected from any one of C1-C5 alkyl groups, tert-butyldimethylsilyl (TBS) or other silicon protecting groups, acetyl (Ac) or other ester groups, (trimethylsilyl)ethoxymethyl (SEM), methoxymethyl ether (MOM) or other ether groups, benzyl (Bn), p-methoxybenzyl (PMB), and allyl groups, or a combination of at least two of them. The C1-C5 alkyl group is a straight or branched alkyl group having 1 to 5 carbon atoms (which can be 1, 2, 3, 4, or 5), and can be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, or n-pentyl, etc.

[0052] In the above route, the following reaction steps are specifically included:

[0053] (1) Olive alcohol is subjected to halogenation reaction to obtain compound 2, and the reaction formula is shown below:

[0054]

[0055] (2) Compound 2 is subjected to a protecting group reaction to obtain compound 3, and the reaction formula is as follows:

[0056]

[0057] (3) Compound 3 and compound 4 undergo a cross-coupling reaction to obtain compound 5. The reaction formula is as follows:

[0058]

[0059] (4) Compound 5 is subjected to a deprotection reaction to obtain the compound cannabidiol CBG, and the reaction formula is shown below:

[0060]

[0061] Among them, step 1, step 2 and step 4 can all be prepared using existing technologies, for example:

[0062] Step 1, the halogenation reaction is specifically as follows: firstly, olivetol 1 is subjected to a halogenation reaction with a halogenating agent in an organic solvent, and then reacted with a reducing agent in an organic solvent to obtain compound 2; the molar ratio of olivetol to the halogenating agent and the reducing agent can be 1:(1-5):(1-5); wherein the two "1-5" are independently 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, etc.; the halogenating agent can be a chlorinating agent, a brominating agent or an iodinating agent, and further preferably The reducing agent may be at least one of chlorine, liquid bromine, elemental iodine, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), dibromohydantoin, phosphorus trichloride, and phosphorus tribromide; the reducing agent may be thiosulfate, sulfite, sulfide, or hydrosulfide, and more preferably at least one of sodium thiosulfate, sodium sulfite, sodium sulfide, and sodium hydrosulfide; the organic solvent may be at least one of chloroform, dichloromethane, carbon tetrachloride, and tetrahydrofuran;

[0063] Step 2, the upper protecting group reaction is specifically: reacting compound 2 and an upper protecting group reagent in an organic solvent to obtain compound 3; the molar ratio of compound 2 to the upper protecting group reagent can be 1:(2-6); wherein "2-6" can be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.; the upper protecting group reagent can be an alkyl group reagent, an upper TBS protecting group reagent, an upper p-methoxybenzyl (PMB) protecting group reagent or an upper allyl protecting group reagent, and is further preferably at least one of dimethyl carbonate, dimethyl sulfate, iodomethane, tert-butyldimethylsilyl chloride (TBSCl), tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), 4-methoxybenzyl chloride (PMBCl), 4-methoxybenzyl bromide (PMBBr), allyl chloride, and allyl bromide; the organic solvent can be at least one of acetone, dichloromethane, N,N-dimethylformamide, and tetrahydrofuran;

[0064] Step 4, the deprotection reaction is specifically: reacting compound 5 with a deprotection reagent in an organic solvent to obtain the target product CBG; the molar ratio of compound 5 to the deprotection reagent can be 1: (2-6); wherein "2-6" can be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, etc.; the deprotection reagent can be a dealkylation reagent, a TBS deprotection reagent, a PMB deprotection reagent or a deallyl deprotection reagent, and is further preferably at least one of methyl magnesium iodide, boron tribromide, trimethylsilyl iodide, sodium ethanethiolate, tetrabutylammonium fluoride (TBAF), cesium fluoride (CsF), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), cerium ammonium nitrate (CAN), trifluoroacetic acid (TFA), palladium carbon, tetrakistriphenylphosphine palladium, etc.; the organic solvent can be at least one of anhydrous ether, methanol, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.

[0065] The main innovations of the present invention are:

[0066] Step 3, using a Kumada cross-coupling reaction catalyst to catalyze the following cross-coupling reaction:

[0067]

[0068] Wherein: R1 and R2 are both hydroxyl protecting groups, X and Y are independently selected from any one of Cl, Br, I, MgCl, MgBr, and MgI; in particular, when X is selected from any one of Cl, Br, and I, Y is selected from any one of MgCl, MgBr, and MgI; when X is selected from any one of MgCl, MgBr, and MgI, Y is selected from any one of Cl, Br, and I; as a preferred embodiment, when X is Br or I, Y is MgBr; when X is MgBr, Y is Br or I.

[0069] The cross-coupling reaction comprises the following specific operations:

[0070] Compound 3 is reacted with compound 4 and a catalyst in an organic solvent at -20 to 80° C. under stirring. After the reaction is completed, the reaction is quenched with water or dilute hydrochloric acid, and then post-treated to obtain compound 5;

[0071] The post-treatment operation includes: extracting with dichloromethane or ethyl acetate, drying the organic phase collected by the extraction with anhydrous Na2SO4, and then distilling under reduced pressure, and then beating and filtering to obtain compound 5.

[0072] The organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether (MTBE), and anhydrous ether;

[0073] The catalyst is selected from ferric fluoride (FeF3), ferric chloride (FeCl3), ferric bromide (FeBr3), ferric triacetyl acetonate (Fe(acac)3), ferric trifluoromethanesulfonate (Fe(OTf)3), ferrous fluoride (FeF2), ferrous chloride (FeCl2), ferrous bromide (FeBr2), ferrous trifluoromethanesulfonate (Fe(OTf)2), nickel chloride (NiCl2), nickel bromide (NiBr2), nickel iodide (NiI2), Ni(dme)Cl2, Ni(PPh3)2Cl2, ( MeNN2) at least one metal salt in NiCl and selected from N,N,N',N'-tetramethylethylenediamine (TMEDA), hexamethylenetetramine (HMTA), 1,3-dimethyl-2-imidazolidinone (DMI), N,N-dimethylpropyleneurea (DMPU), 1,1,3,3-tetramethylurea (TMU), N-methylpyrrolidone (NMP), N-methylcaprolactone (Me-CPL), N,N-bis(2-methoxyethyl)benzamide (Bis( OMeEt)-BA), 1-phenylpiperidine (Pip-BA), 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIPr·HCl), 1,3-bis(2,4,6-trimethylphenyl)imidazolium hydrochloride (SIMes·HCl), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr·HCl), 1,3-di-mesityl imidazolium-2-ylidene (IMes), 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIMes·HCl), 1,3-bis(diisopropylphenyl)-4,5-dihydroimidazole-2-ylidene (HIMes), 1,3-bis(diisopropylphenyl)-4,5-dihydroimidazole-2-ylidene (HIPr), 1,3-bis(diisopropyl)-4,5-dihydroimidazole-2-ylidene (HI2Pr), 1,2-bis(bis(3,5-di-tert-butylphenyl)phosphine A complex formed by at least one ligand selected from (FeCl3)2(TMEDA)3, FeCl2(SciOPP), [Fe(C2H4)4][Li(TMEDA)]2), and Fe(Bopa-tBu)Cl2;As a preferred embodiment, the catalyst is a composite of ferric fluoride (FeF3) and 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIPr·HCl) ligands, or a composite of ferric chloride (FeCl3) and any one of N,N,N',N'-tetramethylethylenediamine (TMEDA) and 1,3-bis(diisopropylphenyl)-4,5-dihydroimidazole-2-ylidene (HIPr), or a composite of ferric triacetylacetonate (Fe(acac)3) and any one of N,N,N',N'-tetramethylethylenediamine (TMEDA), 1,3- A complex formed by any one of the ligands selected from dimethyl-2-imidazolidinone (DMI), 1,1,3,3-tetramethylurea (TMU), N-methylcaprolactone (Me-CPL), and 1-phenylacylpiperidine (Pip-BA); or a complex formed by ferrous chloride (FeCl2) and 1,3-bis(2,6-diisopropylphenyl)imidazolium hydrochloride (SIPr·HCl) ligand; or a complex formed by nickel chloride (NiCl2) and Cp*CH2PPh2 (Cp*=1,2,3,4,5-pentamethyl-2,4-cyclopentadienyl) ligand; or (; Me NN2) A complex formed by NiCl and N,N,N',N'-tetramethylethylenediamine (TMEDA) ligand, or at least one complex selected from (FeCl3)2(TMEDA)3, FeCl2(SciOPP), and Fe(Bopa-tBu)Cl2; in the complex, the molar ratio of the metal salt to the ligand is 1:(1-60), preferably 1:(2-40);

[0074] The molar ratio between compound 3, catalyst and compound 4 is 1:(0.05-1):(1-3);

[0075] The cross-coupling reaction temperature is preferably 0 to 50°C, with room temperature being the best;

[0076] The pulping solvent may be selected from at least one of methanol, ethanol, toluene and water;

[0077] In one embodiment, R1 and R2 are both selected from at least one of a C1-C5 alkyl group, a silane protecting group, an ester group, a (trimethylsilyl)ethoxymethyl group, an ether group, a benzyl group, a p-methoxybenzyl group, and an allyl group.

[0078] In a preferred embodiment, R1 and R2 are simultaneously selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, tert-butyldimethylsilyl, acetyl, (trimethylsilyl)ethoxymethyl, methoxymethyl ether, benzyl, p-methoxybenzyl, and allyl.

[0079] The technical solution of the present invention is further described in detail and completely below in conjunction with specific embodiments.

[0080] Example 1

[0081] A method for preparing cannabinoids, comprising the following cross-coupling reaction:

[0082]

[0083] The specific operations are as follows:

[0084] Under N2 protection, compound 4-1 (434 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then the THF solution of compound 3-1 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When the reaction was completed by TLC monitoring (about 3 hours of reaction), water was added to quench the reaction, and then post-treatment was performed, namely: first extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, and the target product was obtained by vacuum distillation and pulping with a small amount of solvent: compound 5-1 (605 mg), with a yield of 88% and an HPLC purity of 97.2%. For detailed HPLC spectrum, please see Figure 1 shown.

[0085] The characterization data of the obtained compound 5-1 are as follows:

[0086] 1 H NMR (600MHz, CDCl3) δ6.37(s,2H),5.20–5.17(m,1H),5.08–5.04(m,1H),3.80(s,6H),3.31(d,J=7.2Hz,2H),2.56(t,J=7.8Hz,2H),2 .04(q,J=7.2Hz,2H),1.94(t,J=7.8Hz,2H),1.75(s,3H),1.66–1.58(m,5H),1.57(s,3H),1.36–1.31(m,4H),0.90(t,J=7.2Hz,3H).; 13 C NMR (151MHz, CDCl3) δ158.0,141.8,134.3,131.1,124.6,123.2,115.7,104 .2,55.8,39.9,36.6,31.7,31.3,26.8,25.7,22.6,22.0,17.7,16.0,14.1.

[0087] HPLC: AcCN:H2O=90:10, 254nm, 0.2ml / min.

[0088] Example 2

[0089] A method for preparing cannabinoids, comprising the following cross-coupling reaction:

[0090]

[0091] The specific operations are as follows:

[0092] Under N2 protection, compound 4-1 (434 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then the THF solution of compound 3-2 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When TLC monitored the completion of the reaction (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was carried out, namely: first extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, distilled under reduced pressure, and slurried with a small amount of solvent to obtain the target product: compound 5-2 (467 mg), with a yield of 42%.

[0093] The characterization data of the obtained compound 5-2 are as follows:

[0094] 1 H NMR(600MHz, CDCl3) δ7.36(d,J=7.8Hz,4H),6.91(d,J=9.0Hz,4H),6.46(s,2 H),5.24(t,J=7.2Hz,1H),5.08(t,J=7.2Hz,1H),5.00(s,2H),3.83(s,6H),3. 40(d,J=6.6Hz,2H),2.55(t,J=7.8Hz,2H),2.03(m,2H),1.94(t,J=7.9Hz,2H ),1.65(s,3H),1.62–1.55(m,8H),1.37–1.27(m,4H),0.91(t,J=7.2Hz,3H).; 13 C NMR (151MHz, CDCl3) δ159.2,157.2,141.7,134.2,131.1,129.8,128.9,124.7,123.2,116.6 ,113.8,105.7,70.1,55.3,39.9,36.5,31.6,31.2,26.8,25.7,22.6,22.4,17.7,16.1,14.1.

[0095] Example 3

[0096] A method for preparing cannabinoids, comprising the following cross-coupling reaction:

[0097]

[0098] The specific operations are as follows:

[0099] Under N2 protection, compound 4-1 (434 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then the THF solution of compound 3-3 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When TLC monitored the completion of the reaction (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was carried out, namely: first extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, distilled under reduced pressure, and slurried with a small amount of solvent to obtain the target product: compound 5-3 (382 mg), with a yield of 35%.

[0100] The characterization data of the obtained compound 5-3 are as follows:

[0101] 1 H NMR (600MHz, CDCl3) δ6.27(s,2H),5.15(t,J=6.6Hz,1H),5.09(t,J=6.6Hz,1H),3.27(d,J=6.0Hz,2H),2.45(t,J=7.8Hz,2H),2.04(q,J=7.8Hz, 2H),1.94(t,J=7.8Hz,2H),1.68(s,3H),1.66(s,3H),1.60–1.52(m,5H) ,1.37–1.27(m,4H),0.99(s,18H),0.89(t,J=6.6Hz,3H),0.21(s,12H).; 13 C NMR (151MHz, CDCl3) δ154.4,140.8,133.8,131.1,124.6,124.3,120.8,112.1,39 .6,35.7,31.4,30.9,26.8,25.8,25.7,23.1,22.6,18.3,17.6,16.4,14.1,-4.0.

[0102] Example 4

[0103] A method for preparing cannabinoids, comprising the following cross-coupling reaction:

[0104]

[0105] The specific operations are as follows:

[0106] Under N2 protection, compound 4-1 (434 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then the THF solution of compound 3-4 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When TLC monitored the completion of the reaction (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was carried out, namely: first extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, distilled under reduced pressure, and slurried with a small amount of solvent to obtain the target product: compound 5-4 (459 mg), with a yield of 58%.

[0107] The characterization data of the obtained compound 5-4 are as follows:

[0108] 1 H NMR(600MHz, CDCl3)δ6.35(s,2H),6.05(m,2H),5.42–5.41(m,1H),5.40–5.38(m ,1H),5.28–5.21(m,5H),5.07(t,J=1.2Hz,1H),4.52(m,4H),3.38(d,J=6.6Hz,2 H),2.52(t,J=8.4Hz,2H),2.04(q,J=7.2Hz,2H),1.94(t,J=7.2Hz,2H),1.75(s, 3H),1.63(s,3H),1.60–1.53(m,5H),1.36–1.28(m,4H),0.89(t,J=6.6Hz,3H).; 13 C NMR (151MHz, CDCl3) δ157.0,141.6,134.1,133.9,131.1,124.6,123.2,116.7,116 .5,105.6,69.2,39.9,36.5,31.6,31.2,26.8,25.7,22.6,22.3,17.7,16.2,14.1.

[0109] Embodiments 5 to 9

[0110]

[0111] The cross-coupling reaction was carried out according to the operation described in Example 1 and the parameters in Table 1. The yields obtained are shown in Table 1.

[0112] Table 1

[0113]

[0114]

[0115] It can be seen from the results shown in Table 1 that when X in compound 3 is MgBr, Y in compound 4 can be Br or I, and the catalyst can be selected from any complex of (FeCl3)2(TMEDA)3, FeCl2(SciOPP), and Fe(Bopa-tBu)Cl2; but the results shown in Examples 1-4 show that when all other conditions are the same, the protecting groups selected by R1 and R2 have a significant effect on the selectivity of the reaction. When R1 and R2 are both methyl groups, only 3 hours of reaction at room temperature can achieve a yield of 88% (as in Example 1), while when R1 and R2 are both TBS, the yield can only reach 35% after 6 hours of reaction at room temperature, further illustrating that the result of the cross-coupling reaction described in the present invention is unpredictable.

[0116] Examples 10 to 19

[0117] The cross-coupling reaction described in Example 1 was investigated using different compounds under the same other conditions:

[0118] The specific operation is the same as described in Example 1, and the specific results are shown in Table 2.

[0119] Table 2

[0120]

[0121]

[0122] It can be seen from the results shown in Table 2 that the selectivity of the cross-coupling reaction is significantly affected by the catalyst, and different composites may produce significant differences. For example, the difference between Example 14 and Example 16 is that the composite metal salts are different, but Example 14 can achieve a yield of 86% when reacted at room temperature, while Example 16 has only a yield of 42% when reacted at 80°C; and it can be seen from the comparison between Example 17 and Example 18 that even if the other conditions are the same, only the selected ligands are different, which will produce significant differences in the results of the cross-coupling reaction, such as Example 17 cannot react at room temperature, while Example 18 can achieve a yield of 70% at room temperature; This shows that the metal salt and ligand constituting the catalyst will have a significant impact on the result of the cross-coupling reaction described in the present invention, and the yield of the reaction is unpredictable.

[0123] Embodiments 20 to 26

[0124] The cross-coupling reaction described in Example 1 was investigated with different solvents and reaction temperatures under the same other conditions:

[0125] The specific operation is the same as described in Example 1, and the specific results are shown in Table 3.

[0126] Table 3

[0127]

[0128] From the results shown in Table 3, it can be seen that the selectivity of the cross-coupling reaction is less affected by the solvent and temperature. The reaction solvent can be any one of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), toluene, methyl tert-butyl ether (MTBE), and anhydrous ether (Et2O). A high yield can be achieved at 0 to 50°C.

[0129] Embodiment 27

[0130] A method for preparing cannabinoids, comprising the following cross-coupling reaction:

[0131]

[0132] The specific operations are as follows:

[0133] Under N2 protection, compound 3-6 (125 mg, 0.25 mmol) and FeCl3 (0.05 mmol) were first dissolved in 1 mL THF, and then the ligand HIPr (0.1 mmol) was added, and then the THF solution of compound 4-3 (0.27 mL, 1.0 M, 0.27 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When TLC monitored the completion of the reaction (about 3 hours of reaction), dilute hydrochloric acid was added to quench the reaction, and then post-treatment was performed, namely: first extracted three times with ethyl acetate, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, distilled under reduced pressure, and slurried with a small amount of solvent to obtain the target product: compound 5-6 (53 mg), with a yield of 38%.

[0134] Embodiment 28

[0135] A method for preparing cannabinoids, comprising the following cross-coupling reaction:

[0136]

[0137] The specific operations are as follows:

[0138] Under N2 protection, compound 3-7 (84 mg, 0.25 mmol) and Fe(acac)3 (0.05 mmol) were first dissolved in 1 mL THF, and then the ligand TMEDA (6 mg, 0.05 mmol) was added, and then the THF solution of compound 4-3 (0.27 mL, 1.0 M, 0.27 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When TLC monitored the completion of the reaction (about 3 hours of reaction), dilute hydrochloric acid was added to quench the reaction, and then post-treatment was performed, namely: first extracted three times with ethyl acetate, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, distilled under reduced pressure, and slurried with a small amount of solvent to obtain the target product: compound 5-7 (45 mg), with a yield of 52%.

[0139] Examples 29 to 32

[0140]

[0141] The above cross-coupling reaction was carried out with reference to the operation described in Example 27 and the parameters in Table 4. The yields obtained are shown in Table 4.

[0142] Table 4

[0143] Example X <![CDATA[R1 / R2]]> Metal Salts Ligand Reaction temperature Yield 27 Br PMB / PMB <![CDATA[FeCl3]]> HIPr r.t. 38％ 28 I Me / Me <![CDATA[Fe(acac)3]]> TMEDA r.t. 52％ 29 Br Me / Me <![CDATA[FeCl3]]> HIPr r.t. 75％ 30 Br TBS / TBS <![CDATA[FeCl3]]> HIPr r.t. 33％ 31 Br allyl / allyl <![CDATA[FeCl3]]> HIPr r.t. 23％ 32 I Me / Me <![CDATA[NiCl2]]> <![CDATA[Cp*CH2PPh2]]> 25℃ 73％

[0144] It can be seen from the results shown in Table 4 that when Y in compound 4 is MgBr, X in compound 3 can be Br or I; and the results shown in Examples 27, 29 to 31 show that when all other conditions are the same, the protecting groups selected by R1 and R2 have a significant effect on the selectivity of the reaction. When R1 and R2 are both methyl, the yield can reach 75% (such as Example 29) at room temperature, while when R1 and R2 are allyl, the yield is only 23% (such as Example 31); and the results shown in Examples 28 and 32 show that when all other conditions are the same, the catalytic effects of different compounds are significantly different, further illustrating that the results of the cross-coupling reaction described in the present invention are unpredictable.

[0145] Embodiment 33

[0146] The preparation of compound 3 in the present invention can be carried out by the following reaction formula:

[0147]

[0148] The specific reaction conditions can be seen in Table 5:

[0149] Table 5

[0150]

[0151]

[0152] The specific operations are as follows:

[0153] Compound 2 is dissolved in acetone or anhydrous DMF, and then a protecting group reagent and a base are added. The reaction is stirred in the range of room temperature to 120°C. After the reaction is completed, water or a 2M dilute hydrochloric acid solution is added to quench the reaction. The mixture is then extracted three times with ether or ethyl acetate. The organic phase collected by the extraction is washed with saturated brine and dried over anhydrous Na2SO4. Finally, the solvent is concentrated to obtain the target product: Compound 3.

[0154] Embodiment 34

[0155] The preparation of compound 2 in the present invention can be carried out using the following reaction formula:

[0156]

[0157] The specific reaction conditions can be seen in Table 6:

[0158] Table 6

[0159] Serial number Halogenation reagents reducing agent Solvents Reaction temperature Reaction time Yield 1 <![CDATA[Cl2]]> <![CDATA[Na2S2O3]]> <![CDATA[CHCl3]]> reflux 24h 78％ 2 <![CDATA[Br2]]> <![CDATA[Na2S2O3]]> <![CDATA[CHCl3]]> reflux 2h 90％ 3 NCS <![CDATA[Na2S2O3]]> <![CDATA[CCl4]]> reflux 16h 12％ 4 NBS <![CDATA[Na2S2O3]]> <![CDATA[CCl4]]> reflux 16h 65％ 5 NIS <![CDATA[Na2S2O3]]> <![CDATA[CCl4]]> reflux 16h 40％ 6 Dibromohydantoin <![CDATA[Na2S2O3]]> THF reflux 16h 67％ 7 <![CDATA[Br2]]> <![CDATA[Na2SO3]]> <![CDATA[CHCl3]]> reflux 1h 90％ 8 <![CDATA[Br2]]> <![CDATA[Na2SO3]]> <![CDATA[CHCl3]]> r.t. 24h 45％ 9 NIS <![CDATA[Na2S]]> <![CDATA[CCl4]]> r.t. 16h 40％ 10 NBS NaHS DCM reflux 24h 20％

[0160] The specific operations are as follows:

[0161] Olive alcohol (21.6 g, 120 mmol) was dissolved in 204 mL of solvent, and a halogenating agent (396 mmol, 3.3 eq) was added dropwise. The mixture was reacted at room temperature or under heating reflux until the raw material disappeared. The solvent was then dried by rotary evaporation. 60 mL of methanol, 200 mL of water and 300 mL of an aqueous solution containing 30.2 g of Na2SO3 (2 eq) and 9.6 g of NaOH (2 eq) were added, stirred, and then diluted HCl was added for acidification. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, the solvent was concentrated, and recrystallized (n-heptane). The obtained light yellow solid was the target compound: Compound 2.

[0162] Example 35: Preparation of CBG

[0163]

[0164] Under N2 protection, the raw material (364 mg, 1.05 mmol) was added to the reaction tube, and MeMgI (1.41 mL, 4.23 mmol) was added dropwise under ice bath. After vacuuming, the mixture was stirred at 160°C until the raw material disappeared. Then, ether was added to dissolve the reaction system, and 30 mL of saturated NH4Cl was added to quench the reaction. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product CBG (214 mg) with a yield of 64% and an HPLC purity of 98.4%. For detailed HPLC spectrum, please see Figure 2 shown.

[0165] The characterization data of the obtained compound CBG are as follows:

[0166] 1 H NMR (600MHz, CDCl3) δ6.25(s,2H),5.28(t,J=7.2Hz,1H),5.06(t,J=6.6Hz,1H),5.00(s,2H),3.40(d,J=6.6Hz,2H),2.46(t,J=7.8Hz,2H ),2.11(q,J=7.2Hz,2H),2.06(t,J=7.2Hz,2H),1.82(s,3H),1.68(s,3H),1.60–1.52(m,5H),1.35–1.28(m,4H),0.89(t,J=6.6Hz,3H).; 13 C NMR (151MHz, CDCl3) δ154.8,142.8,139.0,132.1,123.8,121.7,110.6,108.4,39.7,35.5,31.5,30.8,26.4,25.7,22.6,22.3,17.7,16.2,14.0.

[0167] HPLC: AcCN:H2O=70:30, 220nm, 1ml / min.

[0168] Example 36: Preparation of CBG

[0169]

[0170] Under N2 protection, the raw material (11 mg, 0.02 mmol) was dissolved in anhydrous DMF, TBAF (16 mg, 0.06 mmol) was added dropwise, and the mixture was stirred at room temperature until the raw material disappeared. Then, saturated brine was added for washing, and the mixture was extracted three times with DCM, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product CBG.

[0171] Example 37: Preparation of CBG

[0172]

[0173] Under N2 protection, the raw material (15 mg, 0.036 mmol) and DDQ (20 mg, 0.09 mmol) were dissolved in MeCN and stirred at room temperature until the raw material disappeared, then extracted three times with EtOAc, dried over anhydrous Na2SO4, concentrated the solvent and recrystallized (n-heptane) to obtain the target product CBG.

[0174] Example 38: Preparation of CBG

[0175]

[0176] Under N2 protection, the raw material (15 mg, 0.036 mmol) and Pd(Ph3P)4 (4 mg, 10%) were dissolved in MeOH, K2CO3 (30 mg, 0.21 mmol) was added, and the reaction was stirred at 60°C until the raw material disappeared, then 2.8 mL of 2M HCl was added to quench the reaction, and the mixture was extracted three times with EtOAc, dried over anhydrous Na2SO4, and the solvent was concentrated and recrystallized (n-heptane) to obtain the target product CBG.

[0177] Example 39: Preparation of CBG Analog 1

[0178]

[0179] The specific operations are as follows:

[0180] Under N2 protection, compound 4-1 (434 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then a THF solution of compound 3-8 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When the reaction was completed by TLC monitoring (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was performed, namely: first extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, and the crude product was obtained by spin drying;

[0181] Under N2 protection, the crude product was added to a reaction tube, and MeMgI (2.67 mL, 8 mmol) was added dropwise in an ice bath. After evacuation, the mixture was stirred at 160°C until the raw material disappeared. Ether was then added to dissolve the reaction system, and 56 mL of saturated NH4Cl was added to quench the reaction. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product: CBG analog 1 (284 mg) with a yield of 54%.

[0182] The characterization data of the obtained CBG analog 1 are as follows:

[0183] 1 H NMR(600MHz, CDCl3)δ6.25(s,2H),5.29–5.24(m,1H),5.10–5.00(m,3H),3.39(d,J=7.2Hz,2H ),2.22(s,3H),2.13–2.09(m,2H),2.08–2.04(m,2H),1.81(s,3H),1.68(s,3H),1.59(s,3H).

[0184] Example 40: Preparation of CBG Analog 2

[0185]

[0186] The specific operations are as follows:

[0187] Under N2 protection, compound 4-4 (298 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then a THF solution of compound 3-1 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When the reaction was completed by TLC monitoring (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was performed, namely: firstly extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, and the crude product was obtained by spin drying;

[0188] Under N2 protection, the crude product was added to a reaction tube, and MeMgI (2.67 mL, 8 mmol) was added dropwise in an ice bath. After evacuation, the mixture was stirred at 160°C until the raw material disappeared. Ether was then added to dissolve the reaction system, and 56 mL of saturated NH4Cl was added to quench the reaction. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product: CBG analogue 2 (312 mg) with a yield of 63%.

[0189] The characterization data of the obtained CBG analog 2 are as follows:

[0190] 1 H NMR (600MHz, CDCl3) δ6.27(s,2H),5.39(s,2H),5.31–5.26(m,1H),3.41(d,J=7.2Hz,2H),2.49– 2.43(m,2H),1.84(s,3H),1.77(s,3H),1.62–1.50(m,2H),1.41–1.23(m,4H),0.98–0.80(m,3H).

[0191] Example 41: Preparation of CBG Analog 3

[0192]

[0193] The specific operations are as follows:

[0194] Under N2 protection, compound 4-5 (570 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then a THF solution of compound 3-1 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was complete, the reaction was stirred at room temperature. When the reaction was completed by TLC monitoring (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was performed, namely: first extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, and the crude product was obtained by spin drying;

[0195] Under N2 protection, the crude product was added to a reaction tube, and MeMgI (2.67 mL, 8 mmol) was added dropwise in an ice bath. After evacuation, the mixture was stirred at 160°C until the raw material disappeared. Ether was then added to dissolve the reaction system, and 56 mL of saturated NH4Cl was added to quench the reaction. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product: CBG analog 3 (437 mg) with a yield of 57%.

[0196] The characterization data of the obtained CBG analog 3 are as follows:

[0197] 1 H NMR(600MHz, CDCl3)δ6.25(s,2H),5.32–5.25(m,1H),5.13–5.05(m,4H),3.40(d,J=7.2Hz,2H),2.47–2.43(m,2H),2.15–2.10(m,2H),2.10–2.04( m,4H),2.00–1.95(m,2H),1.84–1.80(m,3H),1.68(s,3H),1.61(s,3H),1 .60(s,3H),1.58–1.54(m,2H),1.36–1.27(m,4H),0.90(t,J=7.0Hz,3H).

[0198] Example 42: Preparation of CBG Analog 4

[0199]

[0200] The specific operations are as follows:

[0201] Under N2 protection, compound 4-4 (298 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then a THF solution of compound 3-9 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When the reaction was completed by TLC monitoring (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was performed, namely: firstly extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, and the crude product was obtained by spin drying;

[0202] Under N2 protection, the crude product was added to a reaction tube, and MeMgI (2.67 mL, 8 mmol) was added dropwise in an ice bath. After evacuation, the mixture was stirred at 160°C until the raw material disappeared. Ether was then added to dissolve the reaction system, and 56 mL of saturated NH4Cl was added to quench the reaction. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product: CBG analogue 4 (304 mg) with a yield of 50%.

[0203] The characterization data of the obtained CBG analog 4 are as follows:

[0204] 1 H NMR (600MHz, CDCl3) δ6.39 (s, 2H), 5.39–5.23 (m, 3H), 3.41 (d, J = 7.1Hz, 2H), 1.83 (s, 3H), 1. 77(s,3H),1.53–1.48(m,2H),1.23-1.18(s,12H),1.10–1.05(m,2H),0.87(t,J=7.1Hz,3H).

[0205] Example 43: Preparation of CBG Analog 5

[0206]

[0207] The specific operations are as follows:

[0208] Under N2 protection, compound 4-1 (434 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then a THF solution of compound 3-9 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction was stirred at room temperature. When the reaction was completed by TLC monitoring (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was performed, namely: first extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, and the crude product was obtained by spin drying;

[0209] Under N2 protection, the crude product was added to a reaction tube, and MeMgI (2.67 mL, 8 mmol) was added dropwise in an ice bath. After evacuation, the mixture was stirred at 160°C until the raw material disappeared. Ether was then added to dissolve the reaction system, and 56 mL of saturated NH4Cl was added to quench the reaction. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product: CBG analog 5 (498 mg) with a yield of 67%.

[0210] The characterization data of the obtained CBG analog 5 are as follows:

[0211] 1 H NMR(600MHz, CDCl3)δ6.40(s,2H),5.36–5.20(m,3H),5.12–5.05(m,1H),3.43(d,J=7.1Hz,2H),2.16–2.11(m,2H),2.11–2.06 (m,2H),1.83(s,3H),1.70(s,3H),1.61(s,3H),1.55–1.50(m,2H),1.29–1.18(m,12H),1.11–1.05(m,2H),0.90–0.85(m,3H).

[0212] Example 44: Preparation of CBG Analog 6

[0213]

[0214] The specific operations are as follows:

[0215] Under N2 protection, compound 4-5 (570 mg, 2 mmol) and catalyst (FeCl3)2(TMEDA)3 (20 mg, 0.03 mmol) were first dissolved in tetrahydrofuran THF (1.5 mL), and then a THF solution of compound 3-9 (2.6 mL, 1.0 M, 2.6 mmol) was added dropwise to the reaction system. After the addition was complete, the reaction was stirred at room temperature. When the reaction was completed by TLC monitoring (about 3.5 hours of reaction), water was added to quench the reaction, and then post-treatment was performed, namely: firstly extracted three times with dichloromethane DCM, and then the organic phase collected by the extraction was dried with anhydrous Na2SO4, and the crude product was obtained by spin drying;

[0216] Under N2 protection, the crude product was added to a reaction tube, and MeMgI (2.67 mL, 8 mmol) was added dropwise in an ice bath. After evacuation, the mixture was stirred at 160°C until the raw material disappeared. Ether was then added to dissolve the reaction system, and 56 mL of saturated NH4Cl was added to quench the reaction. The mixture was extracted with ether three times, dried over anhydrous Na2SO4, and the solvent was concentrated to dryness and then recrystallized (n-heptane) to obtain the target product: CBG analog 6 (542 mg) with a yield of 62%.

[0217] The characterization data of the obtained CBG analog 6 are as follows:

[0218] 1 H NMR(600MHz, CDCl3)δ6.38(s,2H),5.33–5.30(m,1H),5.17–5.14(m,2H),5.1 2–5.08(m,2H),3.42(d,J=7.2Hz,2H),2.16–2.11(m,2H),2.11–2.05(m,4H), 2.02–1.97(m,2H),1.83(s,3H),1.69(s,3H),1.62(s,3H),1.60(s,3H),1.53 –1.49(m,2H),1.23–1.18(m,12H),1.10–1.04(m,2H),0.86(t,J=7.1Hz,3H).

[0219] Finally, it should be pointed out that the above are only some preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above contents of the present invention all fall within the scope of protection of the present invention.

Claims

1. A method for preparing cannabinoids, comprising the following cross-coupling reaction: in: R1 and R2 are both methyl or methoxymethyl ether; Y is selected from Br or I, and the catalyst is (FeCl3)2(TMEDA)3; the cross-coupling reaction includes the following specific operations: Compound 3 is reacted with compound 4 and a catalyst in an organic solvent at room temperature under stirring. After the reaction is completed, the reaction is quenched with water or dilute hydrochloric acid, and then post-treated to obtain compound 5; the organic solvent is tetrahydrofuran; and the molar ratio of compound 3 to the catalyst and compound 4 is 1:(0.05-1):(1-3).

2. The method according to claim 1, characterized in that The post-treatment operation includes: extracting with dichloromethane or ethyl acetate, drying the organic phase collected by the extraction with anhydrous Na2SO4, and then distilling under reduced pressure, and then beating and filtering to obtain compound 5.

3. The method according to claim 2, characterized in that: The pulping solvent is selected from at least one of methanol, ethanol, toluene and water.

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