A cannabidiol derivative and its preparation method and application

Abstract

The present invention belongs to the field of medical technology, and discloses a cannabidiol derivative and a preparation method and application thereof. The cannabidiol derivative of the present invention is a compound having a structure shown in Formula I, Formula II, Formula III or Formula IV, or a pharmaceutically acceptable salt of the compound; the structures shown in Formula I, Formula II, Formula III or Formula IV are respectively: #imgabs0##imgabs1# wherein: R 1 , R 2 , R 3 , R 4 Each is independently selected from a hydrocarbon group, an aryl group or a camphorsulfonyl group. The cannabidiol derivative of the present invention has a significant effect of binding to the capsaicin receptor TPRV1 to produce analgesic activity. The cannabidiol derivative has a better effect than cannabidiol and can be used to prepare analgesic drugs with a new mode of action, and has broad application prospects.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a cannabidiol derivative and a preparation method and application thereof. Background Art

[0002] Pain is a complex physiological and psychological activity and one of the common clinical symptoms. According to the Global Pain Index, physical pain is ubiquitous, but the duration and degree of relief provided by current pain treatments are still insufficient. Existing drugs for the treatment of pain include opioids, nonsteroidal anti-inflammatory drugs, selective COX2 inhibitors (Coxibs), antidepressants, anticonvulsants, and local anesthetics, etc. However, these drugs have great limitations, including constipation, tolerance, and dependence. Therefore, it is still very important to explore effective new analgesic mechanisms and drugs to treat severe pain.

[0003] The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated non-selective cation channel and a multimodal nociceptor. It is mainly expressed in the terminals of small and medium-sized sensory neurons in the central and peripheral regions, and is also found in different brain regions such as the cerebellum, hypothalamus, cerebral cortex, olfactory bulb, midbrain, and hippocampus. The capsaicin receptor TRPV1, like other members of the TRP ion channel subfamily, can be activated by protons, heat, and endogenous ligands. The difference is that only the TRPV1 subtype can be activated by vanillic acid compounds such as capsaicin (CAP) and resiniferatoxin (RTX). The activation of TRPV1 triggers the influx of calcium and sodium ions, thereby initiating a series of events related to pain transmission, including membrane depolarization, neuronal discharge, and the release of pain transmitters. The analgesic activity produced by capsaicin receptor agonists has attracted widespread attention because they do not act on opioid receptors and are not addictive. However, the currently known vanillic acid agonists usually have more serious irritant side effects.

[0004] Cannabidiol (CBD) is the most abundant non-psychoactive cannabinoid in cannabis. CBD has a low affinity for cannabinoid receptors, but may have a significant CB1 and CB2-independent mechanism of action, and has an antagonistic effect on CB1 receptors in the presence of tetrahydrocannabinol (THC). It is reported that CBD is an agonist of TRPV1 and 5-HT1A receptors, and can enhance adenosine receptor signals, which can produce a wide range of pharmacological activities, including analgesia, anticonvulsant, anti-inflammatory, antioxidant and antipsychotic effects. There are currently no reports on the structural modification of CBD against the capsaicin receptor TRPV1. Summary of the invention

[0005] The purpose of the present invention is to provide a cannabidiol derivative and a preparation method and application thereof, so as to solve the problem that there is a gap in the research of cannabidiol derivatives targeting capsaicin receptor TRPV1 in the prior art.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] The present invention provides a cannabidiol derivative, wherein the cannabidiol derivative is a compound or a pharmaceutically acceptable salt of the compound; the structural formula of the compound is Formula I, Formula II, Formula III or Formula IV;

[0008] The formula I is: The formula II is: The formula III is: The formula IV is:

[0009] Among them, R 1 , R 2 , R 3 , R 4 are independently preferably a hydrocarbon group, an aryl group or a camphor group; further, said R 1 , R 2 , R 3 R is independently preferably substituted aryl, quinoline, pyridine, imidazolyl, cyclohexyl, adamantyl, benzophenonyl or camphoryl, and more preferably 4-quinolyl, 4-benzoylphenyl, 2-(3-bromopyridyl), cyclohexyl, 4-bromophenyl, 3-(1-(4-methyltetrahydropyranyl)pyrazolyl), 5-(2H-pyran-2-onyl), 1-adamantyl, 2-(3-bromo-5-fluoropyridyl), 1-(4-bromophenyl)cyclobutanyl, α-cyclohexyl-4-methylphenylmethylene, 4-trifluoromethoxyphenyl, camphoryl, 5-dimethylaminonaphthyl, 3,5-difluorophenyl, biphenyl, 3,4-difluorophenyl, 3-trifluoromethyl-4-fluorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl or 2,5-difluorophenyl; 4 Preferably, it is one of C1 or C2 catechol and its methyl-protected compounds, wherein C1 or C2 refers to the number of carbon atoms between the catechol group and the nitrogen atom on the amide; the methyl-protected compound refers to the hydroxyl group on the catechol group being protected by a methyl group.

[0010] In the present invention, the cannabidiol derivative is preferably a compound selected from the following structure or a pharmaceutically acceptable salt of the compound:

[0011]

[0012]

[0013] In the present invention, the pharmaceutically acceptable refers to a substance that is suitable for use in humans without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, a substance with a reasonable benefit-risk ratio.

[0014] In the present invention, the pharmaceutically acceptable salt is a salt formed by the compound and a pharmaceutically acceptable inorganic acid or organic acid, wherein the inorganic acid can be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid or sulfuric acid; the organic acid can be selected from formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, succinic acid, methanesulfonic acid, 1,5-naphthalene disulfonic acid, suberic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, cinnamic acid, pyruvic acid, EDTA or amino acid.

[0015] The present invention also provides a method for preparing the above 1-A to 10-A, comprising the following steps:

[0016] (1) Compound 1 is reacted with a bromination reagent for 4 to 6 hours to obtain compound 2; (2) Compound 2 is reacted with a boronic acid reagent to obtain compound 3; (3) Compound 3 and R1-COOH are reacted with a condensation reagent, and then the methyl group is removed for 9 to 11 hours to obtain 1-A to 10-A.

[0017] In step (1) of the present invention, the structural formula of the compound 1 is preferably: The bromination reagent is preferably one or more of liquid bromine, bromine water, N-bromosuccinimide and pyridinium tribromide, and more preferably liquid bromine and / or bromine water; the mass volume ratio of the compound 1 to the bromination reagent is preferably 5-5.5 g: 2-2.3 mL, and more preferably 5.1-5.4 g: 2.1-2.2 mL;

[0018] In the present invention, the compound 1, the bromination reagent and the reaction solvent are mixed before reacting; the specific steps of the mixing are: mixing the compound 1 with the reaction solvent, and then dropping the bromination reagent; the mixing temperature is preferably -1 to 1°C, and more preferably 0°C; the reaction solvent is preferably one or more of tetrahydrofuran, dichloromethane, toluene and benzene, and more preferably tetrahydrofuran and / or dichloromethane; the mass volume ratio of the compound 1 to the reaction solvent is preferably 5 to 5.5 g: 300 to 350 mL, and more preferably 5.1 to 5.4 g: 310 to 340 mL; the dropping speed of the bromination reagent is preferably 0.5 to 2 mL / min, and more preferably 1 mL / min.

[0019] In step (2) of the present invention, compound 2 is refluxed with a boric acid reagent overnight to obtain compound 3;

[0020] The structural formula of the compound 2 is preferably: The boronic acid reagent is preferably pentylboronic acid and / or pentylboronic acid ester; the mass ratio of the compound 2 to the boronic acid reagent is preferably 1.2-1.8:1.1-1.2, and more preferably 1.3-1.5:1.15;

[0021] The compound 2 reacts with a boric acid reagent under the conditions of an alkaline reagent, a catalyst and a reaction solvent; the alkaline reagent is preferably one or more of cesium carbonate, potassium carbonate, potassium acetate, potassium phosphate, sodium carbonate and sodium acetate, the catalyst is preferably one or more of palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinodichloroferrocenepalladium) and bis(dibenzylideneacetonepalladium), the reaction solvent is preferably one or more of tetrahydrofuran, dioxane, toluene, benzene and dimethyl sulfoxide; the mass volume ratio of the compound 2 to the reaction solvent is preferably 1-2 g: 50-100 mL, more preferably 1.2-1.5 g: 60-70 mL; the mass ratio of the compound 2, the alkaline reagent and the catalyst is preferably 1-2: 4-5: 0.2-0.5, more preferably 1.2-1.5: 4.1-4.3: 0.3-0.45.

[0022] In step (3) of the present invention, the structural formula of the compound 3 is preferably: The R 1 R in -COOH 1 Selected from

[0023] The condensation reagent is preferably one or more of dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and Carter's condensation agent;

[0024] The compound 3 and R 1 The molar ratio of -COOH is preferably 0.4-0.7:0.6, and more preferably 0.5-0.6:0.6; the mass ratio of the compound 3 to the condensation agent is preferably 10-12:28-29, and more preferably 11:28.1-28.5.

[0025] In the present invention, compound 3, R 1The specific steps of reacting R1-COOH with a condensation reagent are as follows: reacting a solution of R1-COOH, a condensation reagent and an alkaline reagent for 20 to 40 minutes, and then adding compound 3 to react overnight; the alkaline reagent is preferably one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine and 1,8-diazabicycloundec-7-ene; the R 1 The solution of -COOH is R 1 -COOH in N,N-dimethylformamide solution, R 1 The molar volume ratio of -COOH to N,N-dimethylformamide is preferably 0.5 to 0.8 mmol:5 to 8 mL, and more preferably 0.6 to 0.7 mmol:6 to 7 mL.

[0026] The preparation routes of 1-A to 10-A of the present invention are:

[0027]

[0028] The present invention also provides a method for preparing 1-B, 2-B, 4-B or 8-B, comprising the following steps: reacting compound 3 with a reaction reagent for 3 to 12 hours, and then removing the methyl group for 9 to 11 hours to obtain 1-B, 2-B, 4-B or 8-B; the method for preparing compound 3 is the same as compound 3 in 1-A to 10-A;

[0029] In the present invention, the structural formula of the compound 3 is preferably: The reaction reagent is preferably R 2 -NHCOOPh, R 2 -N=C=O or R 2 -NH2; when the reaction reagent is R 2 -NHCOOPh or R 2 -N=C=O, the reaction is carried out under alkaline reagent conditions, and the alkaline reagent is preferably one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine and 1,8-diazabicycloundec-7-ene; when the reaction reagent is R 2 -NH2, the reaction is carried out under the conditions of a condensation reagent, and the condensation reagent is preferably one or more of dicyclohexylcarbodiimide, N,N'-disuccinimidyl carbonate, 1,1'-carbonyldiimidazole and 2-chloro-4,6-dimethoxytriazole; the reagent used for methyl removal is preferably one or more of aluminum trichloride, boron tribromide, boron trichloride and methylmagnesium iodide; the R 2 -NHCOOPh, R 2 -N=C=O or R 2 -R in NH2 2 Independently selected

[0030] The molar ratio of the compound 3 to the reaction reagent is preferably 0.1-1.5:0.3-1.1, and more preferably 0.5-1:0.5-1.

[0031] The preparation route of 1-B, 2-B, 4-B or 8-B of the present invention is:

[0032]

[0033] The present invention also provides a method for preparing the 9-SN to 20-SN, comprising the following steps: 3 -SO2Cl reacts with an alkaline reagent for 7 to 9 hours, and then removes the methyl group for 9 to 11 hours to obtain 9-SN to 20-SN; the preparation method of the compound 3 is the same as that of the compound 3 in 1-A to 10-A;

[0034] In the present invention, the structural formula of the compound 3 is preferably: The R 3 -R in SO2Cl 3 Selected from

[0035] The alkaline agent is preferably one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine and 1,8-diazabicycloundec-7-ene;

[0036] The compound 3, R 3 The molar ratio of -SO2Cl to the alkaline agent is preferably 0.2-0.3: 0.25-0.3: 0.6-0.7, and more preferably 0.21-0.28: 0.26-0.28: 0.61-0.68.

[0037] The preparation route of 9-SN to 20-SN of the present invention is:

[0038]

[0039] The present invention also provides a method for preparing the 13-SN-1 to 13-SN-4, comprising the following steps:

[0040] Compound 2, ethyl acrylate and a catalyst are subjected to coupling reaction at 70-90°C for 20-24h to obtain compound 10; compound 10 is subjected to hydrogenation reaction in a hydrogen atmosphere for 3-5h to obtain compound 11; compound 11, R 3-SO2Cl is reacted with an alkaline reagent for 7 to 9 hours to obtain compound 12; compound 12 is reacted with a hydrolysis reagent for 7 to 9 hours to obtain compound 13; compound 12 is subjected to methyl removal at 0 to 5°C for 9 to 11 hours to obtain 13-SN-1; compound 13 is subjected to methyl removal at 0 to 5°C for 9 to 11 hours to obtain 13-SN-2; compound 13 is subjected to condensation reaction with a condensation reagent for 11 to 13 hours and then subjected to methyl removal at 0 to 5°C for 9 to 11 hours to obtain 13-SN-3 or 13-SN-4; the preparation method of compound 2 is the same as compound 2 in 1-A to 10-A;

[0041] In the present invention, the structural formula of the compound 2 is preferably: The catalyst is preferably one or more of palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, bis(dibenzylideneacetonepalladium) and tris(dibenzylideneacetone)dipalladium; the coupling reaction is carried out under an alkaline reagent, and the alkaline reagent is preferably one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine and 1,8-diazabicycloundec-7-ene;

[0042] The mass volume ratio of the compound 2 to ethyl acrylate is preferably 1 g: 0.5-1 mL, and more preferably 1 g: 0.6-0.8 mL; the molar ratio of the compound 2 to the catalyst is preferably 4-4.5: 0.1-0.5, and more preferably 4.1-4.3: 0.2-0.4; the mass volume ratio of the compound 2 to the alkaline reagent is preferably 1 g: 2-3 mL, and more preferably 1 g: 2.2-2.7 mL.

[0043] In the present invention, the structural formula of the compound 10 is preferably The hydrogenation reaction is carried out under a catalyst, and the catalyst is preferably a Pd / C catalyst;

[0044] The mass ratio of the compound 10 to the catalyst is preferably 1-1.1:0.5, and more preferably 1.02-1.06:0.5.

[0045] In the present invention, the structural formula of the compound 11 is preferably The R 3 -R in SO2Cl 3 Selected from The alkaline agent is preferably one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine and 1,8-diazabicycloundec-7-ene;

[0046] The compound 11, R 3The molar ratio of -SO2Cl to the alkaline agent is preferably 1.1-1.2:1.7-1.8:3.5-4, and more preferably 1.15-1.18:1.72-1.78:3.6-3.9.

[0047] In the present invention, the structural formula of the compound 12 is preferably The hydrolysis agent is preferably one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and potassium tert-butoxide; the structural formula of the compound 13 is preferably

[0048] The molar ratio of the compound 12 to the hydrolysis agent is preferably 1.1-1.2:11-12, and more preferably 1.13-1.18:11.2-11.5.

[0049] In the present invention, the reagent used for removing methyl from the compound 12, the compound 13 and the product obtained by the condensation reaction is independently preferably one or more of aluminum trichloride, boron tribromide, boron trichloride and methylmagnesium iodide, and is further preferably aluminum trichloride, boron tribromide or boron trichloride;

[0050] In the present invention, the condensation reagent is preferably one or more of dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and Carter's condensation agent; the molar ratio of the compound 13 to the condensation reagent is preferably 1:2 to 2.5, and more preferably 1:2.2 to 2.4.

[0051] The present invention also provides a method for preparing the 13-SN-5 to 13-SN-7, comprising the following steps: reacting 13-SN-2, an amino compound and a condensation reagent for 11 to 13 hours to obtain 13-SN-5 to 13-SN-7; the 13-SN-2 is the 13-SN-2 obtained by the above-mentioned preparation method.

[0052] In the present invention, the amino compound is preferably dopamine hydrochloride, 3,4-dimethoxybenzylamine, 4-hydroxybenzylamine or 5-(aminomethyl)-2-methoxyphenol hydrochloride; the condensation reagent is preferably one or more of dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and Carter condensation agent;

[0053] The molar ratio of the 13-SN-2, amino compound and condensation reagent is preferably 1.5-2.5:1.5-3:3-6, and more preferably 1.8-2:2-2.5:4-5.

[0054] The preparation route of 13-SN-1 to 13-SN-4 of the present invention is:

[0055]

[0056] In the above steps of the present invention, the specific step of removing the methyl group is: mixing the reaction product with the reaction reagent and then dripping the reagent used for methyl removal; the reaction reagent is independently preferably one or more of tetrahydrofuran, dichloromethane, toluene and benzene; the reagent used for methyl removal is independently preferably one or more of aluminum chloride, boron tribromide, boron trichloride and methylmagnesium iodide, and is further preferably boron tribromide and / or boron trichloride; the concentration of the mixed solution obtained after the reaction product and the reaction reagent are mixed is independently preferably 0.01-0.2 mM, and is further preferably 0.15 mM; the amount of the reagent used for methyl removal is independently preferably 3-8 equivalents, and is further preferably 5 equivalents; the dripping speed of the reagent used for methyl removal is independently preferably 1-5 mL / min, and is further preferably 3 mL / min; the dripping temperature is independently preferably -80 to -75°C, and is further preferably -78 to -76°C.

[0057] In the preparation steps of 1-A to 10-A described in the present invention, in steps (1) and (2), the reaction product is post-treated after the reaction; the post-treatment in step (2) is specifically: the reaction product is filtered, rinsed, concentrated under reduced pressure and separated and purified in sequence, and the reagent used for rinsing is preferably ethyl acetate; in step (3), the reaction product is post-treated before the methyl group is removed; the product is post-treated after the methyl group is removed.

[0058] In the preparation steps of 1-B, 2-B, 4-B or 8-B of the present invention, the product obtained by the reaction is post-treated before the methyl group is removed; and the product obtained by the reaction is post-treated after the methyl group is removed.

[0059] In the preparation steps of 9-SN to 20-SN of the present invention, the product obtained by the reaction is post-treated after the coupling reaction, and the specific steps of the post-treatment are: the product obtained by suction filtration, elution, washing, drying, suction filtration, reduced pressure concentration and separation and purification are carried out in sequence, and the reagent used for the elution is preferably ethyl acetate; the product obtained by the reaction is post-treated after the hydrogenation reaction, and the specific steps of the post-treatment are: the product obtained by suction filtration, elution and reduced pressure concentration are carried out in sequence; the reagent used for the elution is preferably ethyl acetate; the product obtained by the reaction is post-treated after the condensation reaction; the product obtained by the reaction is post-treated after the hydrolysis reaction.

[0060] In the preparation steps of 13-SN-1 to 13-SN-4 of the present invention, the products obtained by removing the methyl groups are post-treated before obtaining 13-SN-1 to 13-SN-4.

[0061] In the preparation steps of 13-SN-5 to 13-SN-7 of the present invention, the reaction products are post-treated after the reaction.

[0062] In the above steps of the present invention, except for the preparation step (2) of 1-A to 10-A, the coupling reaction and the hydrogenation reaction in the preparation step of 1-B, 2-B, 4-B or 8-B, the specific steps of the post-treatment in the remaining steps are: quenching, washing, drying, filtering, concentrating under reduced pressure and separating and purifying the obtained product in sequence.

[0063] In the present invention, the reagent used for quenching is preferably a saturated NaHCO3 solution, a mixture of water and ethyl acetate or water; the reagent used for washing is preferably saturated NaCl and / or water, and the number of washings is preferably 2 to 4 times, more preferably 3 times; drying is preferably carried out using anhydrous sodium sulfate; the separation and purification is preferably silica gel column chromatography separation and purification;

[0064] In the present invention, the quenching or eluting is for separating the organic phase from the aqueous phase; the aqueous phase obtained by quenching or eluting is extracted to obtain an organic phase, which is combined with the organic phase obtained by quenching for washing; the extraction reagent is preferably dichloromethane.

[0065] The present invention also provides the use of the cannabidiol derivative or the cannabidiol derivative prepared by the preparation method of the cannabidiol derivative in the preparation of a drug that produces analgesic effect on capsaicin receptors.

[0066] In the present invention, the dosage form of the drug is not limited, as long as it is a dosage form that allows the active ingredients to effectively reach the body, and the dosage form of the drug can be selected from tablets, capsules, powders, granules, syrups, solutions, suspensions, injections, tinctures, oral liquids, aerosols, lozenges, granules, pills, powders or nano preparations.

[0067] In the present invention, in addition to the main active ingredients, the medicine may also contain a small amount of secondary ingredients that do not affect the active ingredients and / or pharmaceutically acceptable carriers; the medicine may contain sweeteners to improve the taste, antioxidants to prevent oxidation, and various auxiliary materials necessary for preparations.

[0068] In the present invention, the effective administration dose of the active ingredient of the drug may vary depending on the drug used, the mode of administration and the severity of the disease to be treated.

[0069] It can be seen from the above technical solution that compared with the prior art, the present invention has the following beneficial effects:

[0070] The cannabidiol derivatives described in the present invention have a significant effect on the analgesic activity of the capsaicin receptor (TRPV1), can be used to prepare analgesic drugs with a new mode of action, and have broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 The activity results of the cannabidiol derivatives obtained in Examples 1 to 26 on the TRPV1 receptor;

[0072] Figure 2 The activity results of the cannabidiol derivatives obtained in Examples 27 to 33 on the TRPV1 receptor;

[0073] Figure 3 The results are the screening results of analgesic activity of cannabidiol derivatives;

[0074] Figure 4 The results of the body temperature experiment on cannabidiol derivatives were verified. DETAILED DESCRIPTION

[0075] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0076] Example 1

[0077] 1.1: Preparation of compound 2:

[0078] At 0°C, liquid bromine (2.07 mL, 40.4 mmol) was added dropwise to a solution of compound 1 (5.17 g, 33.8 mmol) in anhydrous dichloromethane (330 mL) at a rate of 1 mL / min, and then the mixture was heated to room temperature for 5 h. Saturated NaHCO3 solution was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, the organic phases were washed 3 times with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound 2, with a mass of 5.02 g and a yield of 64%.

[0079] Compound 2 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 6.65 (s, 2H), 3.83 (s, 6H), 3.78 (s, 2H) ppm.

[0080] 1.2: Preparation of compound 3:

[0081] Potassium phosphate (4.12 g, 19.4 mmol) and bis(diphenylphosphino)ferrocenepalladium dichloride (473 mg, 0.646 mmol) were added to a toluene (67.2 mL) solution of compound 2 (1.5 g, 6.46 mmol) and n-pentylboronic acid (1.12 g, 9.7 mmol) at room temperature, and the mixture was refluxed overnight for 14 h. The product was cooled to room temperature, filtered, washed with ethyl acetate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound 3, with a mass of 1.33 g and a yield of 89%.

[0082] Compound 3 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 6.38 (s, 2H), 3.86 (s, 6H), 3.62 (s, 2H), 2.54 (t, J = 7.8Hz, 2H), 1.64-1.58 (m, 2H), 1.40-1.30 (m, 4H), 0.92 (t, J = 6.9Hz, 3H) ppm.

[0083] 1.3: Preparation of 1-A

[0084] To R 1 -COOH (0.6 mmol, R 1 for ) in N,N-dimethylformamide (5mL) solution, add O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (285mg, 0.75mmol) and N,N-diisopropylethylamine (0.26mL, 1.5mmol), react at room temperature for 30min, add compound 3 (111mg, 0.5mmol), react at room temperature overnight. Add water and ethyl acetate for separation, collect the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phases with water and saturated NaCl three times each, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the intermediate product. The intermediate product was dissolved in dichloromethane (maintaining the solution concentration at 0.1mM), and a dichloromethane solution of boron tribromide was added dropwise at a rate of 3mL / min at -78°C (maintaining the solution concentration at 1M, the amount of boron tribromide was 5eq.), and the temperature was raised to room temperature for reaction for 10h. Water was added to quench the reaction, the liquids were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed three times with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 1-A with a yield of 69%.

[0085] 1-A 1 H NMR is: 1H NMR (600MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.25 (s, 2H), 8.96 (dd, J = 4.1, 1.7Hz, 1 H),8.86(d,J=8.4Hz,1H),8.14(d,J=8.4Hz,1H),7.96(d,J=7.0Hz,1H),7.84 (dd,J=8.5,7.1Hz,1H),7.61(dd,J=8.6,4.1Hz,1H),6.25(s,2H),2.43(t,J= 7.6Hz,2H),1.57-1.51(m,2H),1.36-1.25(m,4H),0.88(t,J=7.1Hz,3H)ppm.

[0086] Example 2

[0087] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 2-A, and the yield is 50%. The other steps are the same as those in Example 1.

[0088] 2-A 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ=8.66(s,1H),8.02(d,J=8.3Hz,2H),7.90(d,J=8.3Hz,2H),7.82(d,J=7.0Hz,2H),7.64(t,J=7.4Hz,1H ),7.52(t,J=7.8Hz,2H),6.41(s,2H),2.45(t,J=7.8Hz,2H),1.58-1.51(m,2H),1.32-1.24(m,4H),0.87(t,J=7.0Hz,3H)ppm.

[0089] Example 3

[0090] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 3-A, and the yield is 46%. Other steps are the same as those in Example 1.

[0091] 3-A 1 H NMR is: 1H NMR (600MHz, methanol-d4) δ = 8.62 (dd, J = 4.5, 1.5 Hz, 1H), 8.18 ( dd, J = 8.2, 1.5 Hz, 1H), 7.44 ( dd, J = 8.2, 4.5 Hz,1H),6.29(s,2H),2.46(t,J=7.7Hz,2H),1.62-1.54(m,2H),1.39-1.24(m,4H),0.90(t,J=7.1Hz,3H)ppm.

[0092] Example 4

[0093] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 4-A, and the yield is 63%. Other steps are the same as those in Example 1.

[0094] 4-A 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 6.25 (s, 2H), 2.58-2.52 (m, 1H), 2.44 (t, J = 7.6Hz, 2H), 1.94 (dd, J = 13.8, 1.8Hz, 2H) ,1.83(dt,J=13.3,3.5Hz,2H),1.75-1.68(m,1H),1.59-1.49(m,4H),1.42-1.25(m,7H),0.90(t,J=7.1Hz,3H)ppm.

[0095] Example 5

[0096] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 5-A, and the yield is 68%.

[0097] 5-A 1 H NMR is: 1 H NMR (600MHz, acetone-d6) δ = 9.22-9.16 (m, 3H), 8.02 (d, J = 8.5Hz, 2H), 7.77 (d, J = 8.5Hz, 2H) ,6.37(s,2H),2.47(t,2H),1.61-1.55(m,2H),1.37-1.27(m,4H),0.88(t,J=7.0Hz,3H)ppm.

[0098] Example 6

[0099] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 6-A, and the yield is 56%.

[0100] 6-A 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 7.71 (d, J = 2.4Hz, 1H), 6.82 (d, J = 2.4Hz, 1H), 6.29 (s, 2H), 4.13 (d, J = 7.3Hz, 2H), 3.93 (dd, J = 11.6, 3.0Hz, 2H), 3.39 (td, J=11.8,2.3Hz,2H),2.46(t,J=7.7Hz,2H),2.25-2.16(m,1H),1.61-1.55(m ,2H),1.50(d,J=10.8Hz,2H),1.41-1.27(m,6H),0.91(t,J=7.1Hz,3H)ppm.

[0101] Example 7

[0102] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 7-A, and the yield is 58%.

[0103] 7-A 1 H NMR is: 1 H NMR(600MHz, methanol-d4)δ=8.99(s,1H),7.57(d,J=9.3Hz,1H),6.30(s,2H),5.63(d,J=9.2H z,1H),2.46(t,J=7.6Hz,2H),1.61-1.55(m,2H),1.38-1.28(m,4H),0.91(t,J=7.1Hz,3H)ppm.

[0104] Example 8

[0105] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 8-A, and the yield is 59%.

[0106] 8-A 1 H NMR is: 1H NMR (600MHz, methanol-d4) δ = 6.24 (s, 2H), 2.43 (t, J = 7.6Hz, 2H), 2.08 (s, 3H), 2.03-1.99 ( m,6H),1.84-1.76(m,6H),1.59-1.53(m,2H),1.36-1.27(m,4H),0.90(t,J=7.1Hz,3H)ppm.

[0107] Example 9

[0108] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 9-A, and the yield is 53%.

[0109] 9-A 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 10.25 (s, 1H), 8.48 (d, J = 2.5Hz, 1H), 7.87 (dd, J = 7.5, 2.5Hz, 1H), 7.63 (s, 2H) ,6.38(s,2H),2.47(t,J=7.7Hz,2H),1.61-1.53(m,2H),1.36-1.24(m,4H),0.88(t,J=6.9Hz,3H)ppm.

[0110] Example 10

[0111] The difference from Example 1 is: R 1 -COOH R 1 for The obtained product is recorded as 10-A, and the yield is 72%. Other steps are the same as those in Example 1.

[0112] 10-A 1 H NMR is: 1 HNMR(600MHz, methanol-d4)δ=7.53(d,J=8.5Hz,2H),7.39(d,J=8.5Hz,2H),6.19(s,2H),2.96-2.87(m,2H),2.60-2.52(m,2H) ,2.40(t,J=7.7Hz,2H),2.16-2.07(m,1H),1.97-1.88(m,1H),1.57-1.49(m,2H),1.35-1.23(m,4H),0.88(t,J=7.1Hz,3H)ppm.

[0113] Embodiment 11

[0114] Preparation of compound 5:

[0115] At 0°C, compound 4 (200 mg, 1.39 mmol, structural formula: ) in anhydrous tetrahydrofuran (14 mL) solution, phenyl chloroformate (0.26 mL, 2.08 mmol) and pyridine (0.36 mL, 4.16 mmol) were added in sequence, and the reaction was carried out at room temperature for 10 h. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, and the organic phases were washed with water and saturated NaCl three times each, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound 5, with a mass of 294 mg and a yield of 80%.

[0116] Preparation of compound 6:

[0117] Compound 3 (102 mg, 0.46 mmol) and compound 5 (100 mg, 0.38 mmol, structural formula: ) in acetonitrile (7.6 mL), 4-dimethylaminopyridine (70 mg, 0.57 mmol) was added, and the mixture was reacted at room temperature for 12 h. Ethyl acetate was added to quench the reaction, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 6, with a mass of 131 mg and a yield of 88%.

[0118] Compound 6 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 8.92 (s, 1H), 8.80 (s, 1H), 8.05 (s, 2H), 7.76 (s, 1H), 7.57 (s, 2H), 6.45 (s, 2H) ,3.86(s,6H),2.58(t,J=7.8Hz,2H),1.67–1.55(m,2H),1.41–1.29(m,4H),0.91(t,J=6.1Hz,3H)ppm.

[0119] Preparation of 1-B:

[0120] At -78°C, a dichloromethane solution of boron tribromide was added dropwise at a rate of 3 mL / min to a dichloromethane (12 mL) solution of compound 6 (125 mg, 0.32 mmol) (the volume of the solution was maintained at 0.96 mL and the concentration of the solution was 1 M), and the temperature was raised to room temperature for 10 h. Water was added to quench the reaction, the liquids were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated NaCl three times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 1-B, the mass of 1-B was 103 mg, and the yield was 88%.

[0121] 1-B 1H NMR is: 1 H NMR (600MHz, DMSO-d6) δ=9.75(s,2H),9.56(s,1H),8.93(dd,J=4.1,1.6Hz,1H),8.58(d,J=8.4Hz,1H),8.39(s,1H),8.00(dd,J=7.4,0.8Hz,1H),7 .79-7.70(m,2H),7.62(dd,J=8.6,4.1Hz,1H),6.23(s,2H),2.40(t,J=7. 6Hz,2H),1.54-1.48(m,2H),1.33-1.22(m,4H),0.87(t,J=7.1Hz,3H)ppm.

[0122] Example 12

[0123] Preparation of 2-B:

[0124] At room temperature, compound 7 (200 mg, 1.02 mmol, structural formula: ) and compound 3 (272 mg, 1.22 mmol) in acetonitrile (20 mL) were added with N, N'-disuccinimidyl carbonate (312 mg, 1.22 mmol), pyridine (0.16 mL, 2.03 mmol), N, N-diisopropylethylamine (0.52 mL, 3.04 mmol), and the mixture was reacted for 3 h. Water was added to quench the reaction, and ethyl acetate was extracted several times. The organic phases were combined, and the organic phases were washed with water and saturated NaCl three times each, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was separated and purified by silica gel column chromatography. The obtained product was dissolved in dichloromethane (maintaining the solution concentration at 0.1 mM), and a dichloromethane solution of boron tribromide was added dropwise at a rate of 3 mL / min at -78 ° C (maintaining the solution concentration at 1 M, and the amount of boron tribromide added was 5 eq.), and the reaction was carried out at room temperature for 10 h. Water was added to quench the reaction, the liquids were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed three times with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 2-B. The mass of 2-B was 77 mg, and the yield was 18%.

[0125] 2-B 1 H NMR is: 1H NMR (600MHz, acetone-d6) δ = 9.31 (s, 2H), 9.23 (s, 1H), 7.96 (t, J = 1.6Hz, 1H), 7.86-7.79 (m, 4H), 7.65 (t, J = 7.4Hz, 1H), 7.55 (t, J = 7.7Hz, 2H), 7 .49(t,J=7.8Hz,1H),7.44(d,J=7.7Hz,1H),6.32(s,2H),2.43(t,J=7.7 Hz,2H),1.58-1.52(m,2H),1.34-1.25(m,4H),0.87(t,J=7.0Hz,3H)ppm.

[0126] Example 13

[0127] Preparation of 4-B:

[0128] Compound 3 (60 mg, 0.27 mmol) and compound 8 (69 μL, 0.54 mmol, structural formula: ) in tetrahydrofuran (1.4 mL), add triethylamine (0.11 mL, 0.81 mmol), and stir at room temperature for 12 h. Add water to quench the reaction, extract with ethyl acetate several times, combine the organic phases, wash the organic phases with water and saturated NaCl three times each, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained product is dissolved in dichloromethane (keeping the solution concentration at 0.1 mM), and a dichloromethane solution of boron tribromide is added dropwise at a rate of 3 mL / min at -78 ° C (keeping the solution concentration at 1 M, the amount of boron tribromide added is 5 eq.), and react at room temperature for 10 h. Add appropriate amount of water to quench the reaction, separate the liquids, collect the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phases with saturated NaCl three times, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel column chromatography to obtain 4-B, the mass of 4-B is 16 mg, and the yield is 18%.

[0129] 4-B 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 6.22 (s, 2H), 3.58-3.51 (m, 1H), 2.42 (t, J = 7.7Hz, 2H), 1.92 (dd, J = 12.9, 3.8Hz, 2H), 1.75 (dt,J=13.7,4.0Hz,2H),1.62(dt,J=13.2,4.0Hz,1H),1.59-1.52(m,2H),1.44-1.18(m,9H),0.90(t,J=7.2Hz,3H)ppm.

[0130] Embodiment 14

[0131] Preparation of 8-B:

[0132] To compound 9 (102 mg, 0.672 mmol, structural formula ) and compound 3 (100 mg, 0.448 mmol) in acetonitrile (10 mL) were added with N,N'-disuccinimidyl carbonate (230 mg, 0.896 mmol), pyridine (0.16 mL, 2.02 mmol) and N,N-diisopropylethylamine (0.33 mL, 2.016 mmol), and the mixture was reacted at room temperature for 3 h. Water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with water and saturated NaCl three times each, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography. The obtained product was dissolved in dichloromethane (maintaining the solution concentration at 0.1 mM), and a dichloromethane solution of boron tribromide was added dropwise at a rate of 3 mL / min at -78 ° C (maintaining the solution concentration at 1 M, the amount of boron tribromide added was 5 eq.), and the mixture was reacted at room temperature for 10 h. Water was added to quench the reaction, the liquids were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed three times with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 8-B. The mass of 8-B was 42 mg, and the yield was 25%.

[0133] 8-B 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 6.21 (s, 2H), 2.41 (t, J = 7.6Hz, 2H), 2.06 (s, 3H), 2.02 (d, J = 3.4H z,6H),1.72(t,J=3.2Hz,6H),1.59-1.51(m,2H),1.36-1.27(m,4H),0.90(t,J=7.2Hz,3H)ppm.

[0134] Embodiment 15

[0135] Preparation of 9-SN:

[0136] To compounds with sulfonyl chloride structure (0.27mmol, R 3 for ) and compound 3 (50mg, 0.22mmol) in dichloromethane (5mL) solution, add pyridine (54μL, 0.67mmol), and react at room temperature for 8h. Add water to quench the reaction, separate the liquids, collect the organic phase, extract the aqueous phase with ethyl acetate for multiple times, combine the organic phases, wash the organic phases with water and saturated NaCl three times each, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel column chromatography to obtain the intermediate product. The intermediate product was dissolved in dichloromethane (0.1mM), and a dichloromethane solution of boron tribromide was added dropwise at a rate of 3mL / min at -78°C (keeping the solution concentration at 1M, and the amount of boron tribromide added was 5eq.), and react at room temperature for 10h. Add water to quench the reaction, separate the liquids, collect the organic phase, extract the aqueous phase with ethyl acetate for multiple times, combine the organic phases, wash the organic phases with saturated NaCl three times, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and separate and purify by silica gel column chromatography to obtain 9-SN, with a yield of 28%.

[0137] 9-SN 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 7.77 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.40 (s, 1H), 6.24 (s, 2H), 6. 06(s,2H),2.41(t,J=7.8Hz,2H),1.57-1.45(m,2H),1.35-1.17(m,4H),0.87(t,J=7.2Hz,3H)ppm.

[0138] Example 16

[0139] Preparation of 10-SN:

[0140] The difference from Example 15 is: R 3 for The obtained product was recorded as 10-SN, and the yield was 46%.

[0141] 10-SN 1 H NMR is: 1H NMR (600MHz, CDCl3) δ = 6.96 (s, 1H), 6.37 (s, 2H), 3.66 (d, J = 15.3Hz, 1H), 3.09 (d, J = 15.3Hz, 1H), 2.47-2.41 (m, 3H), 2.20-2.12 (m, 2H), 2.06-1. 99(m,2H),1.97(d,J=18.8Hz,1H),1.59-1.52(m,2H),1.48-1.41(m,1H) ,1.36-1.24(m,4H),0.99(s,3H),0.91(s,3H),0.88(t,J=7.1Hz,3H)ppm.

[0142] Embodiment 17

[0143] Preparation of 11-SN:

[0144] The difference from Example 15 is: R 3 for The obtained product was recorded as 11-SN, and the yield was 28%.

[0145] 11-SN 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 6.96 (s, 1H), 6.37 (s, 2H), 3.66 (d, J = 15.3Hz, 1H), 3.09 (d, J = 15.3Hz, 1H), 2.48-2.40 (m, 3H), 2.21-2.12 (m, 2H), 2.07-1. 99(m,2H),1.97(d,J=18.9Hz,1H),1.59-1.52(m,2H),1.48-1.42(m,1H) ,1.34-1.26(m,4H),0.99(s,3H),0.91(s,3H),0.88(t,J=7.0Hz,3H)ppm.

[0146] Embodiment 18

[0147] Preparation of 12-SN:

[0148] The difference from Example 15 is: R 3 for The obtained product was recorded as 12-SN, and the yield was 19%.

[0149] 12-SN 1 H NMR is: 1H NMR (600MHz, CDCl3) δ = 8.52 (d, J = 8.5Hz, 1H), 8.37 (d, J = 8.6Hz, 1H), 8.09 (d, J = 7.4Hz, 1H), 7.52 (t, J = 6.0Hz, 1H), 7.39 (t, J = 6.0Hz, 1H), 7.17 (d, J = 7. 5Hz,1H),6.62(s,1H),6.11(s,2H),6.07(s,2H),2.87(s,6H),2.32(t,J=7 .8Hz,2H),1.47-1.41(m,2H),1.30-1.16(m,4H),0.85(t,J=7.2Hz,3H)ppm.

[0150] Embodiment 19

[0151] Preparation of 13-SN:

[0152] The difference from Example 15 is: R 3 for The obtained product was recorded as 13-SN, and the yield was 34%.

[0153] 13-SN 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 7.34-7.29 (m, 2H), 7.20 (tt, J = 8.9, 2.4Hz, 1H), 6.13 (s, 2H) ),2.40(t,J=7.6Hz,2H),1.57-1.51(m,2H),1.36-1.23(m,4H),0.89(t,J=7.2Hz,3H)ppm.

[0154] Embodiment 20

[0155] Preparation of 14-SN:

[0156] The difference from Example 15 is: R 3 for The obtained product was recorded as 14-SN, and the yield was 49%.

[0157] 14-SN 1 H NMR is: 1H NMR (600MHz, CDCl3) δ = 7.79 (d, J = 8.5Hz, 2H), 7.62 (d, J = 8.3Hz, 2H), 7.58 (d, J = 7.4Hz, 2H), 7.46 (t, J = 7.4Hz, 2H), 7.41 (t, J = 7.4Hz, 1H),6.30(s,1H),6.24(s,2H),6.01(s,2H),2.41(t,J=7.7Hz,2H),1.55-1.49(m,2H),1.33-1.21(m,4H),0.86(t,J=7.2Hz,3H)ppm.

[0158] Embodiment 21

[0159] Preparation of FJ-15-SN:

[0160] The difference from Example 15 is: R 3 for The obtained product was recorded as 15-SN, and the yield was 70%.

[0161] 15-SN 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 9.10 (d, J = 2.7Hz, 1H), 8.45 (d, J = 5.9Hz, 1H), 8.36 (d, J = 6.9Hz, 1H), 8.10 (d, J = 6.8Hz, 1H), 7. 65-7.58(m,2H),6.25(s,2H),2.36(t,J=7.8Hz,2H),1.51-1.44(m,2H),1.29-1.21(m,4H),0.84(t,J=7.1Hz,3H)ppm.

[0162] Embodiment 22

[0163] Preparation of FJ-16-SN:

[0164] The difference from Example 15 is: R 3 for The obtained product was recorded as 16-SN, and the yield was 35%.

[0165] 16-SN 1 H NMR is: 1H NMR(600MHz, CDCl3)δ=7.61-7.56(m,1H),7.52-7.48(m,1H),6.32(s,1H),6.25(s,2H),5.94( s,2H),2.42(t,J=7.7Hz,2H),1.55-1.49(m,2H),1.34-1.20(m,4H),0.87(t,J=7.2Hz,3H)ppm.

[0166] Embodiment 23

[0167] Preparation of FJ-17-SN:

[0168] The difference from Example 15 is: R 3 for The obtained product was recorded as 17-SN, and the yield was 22%.

[0169] 17-SN 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 8.00 (dd, J = 6.5, 2.5Hz, 1H), 7.93-7.90 (m, 1H), 7.23 (t, J = 9.1Hz, 1H), 6.33 (s, 1H), 6.2 4(s,2H),5.92(s,2H),2.42(t,J=7.7Hz,2H),1.55-1.48(m,2H),1.34-1.21(m,4H),0.87(t,J=7.2Hz,3H)ppm.

[0170] Embodiment 24

[0171] Preparation of FJ-18-SN:

[0172] The difference from Example 15 is: R 3 for The obtained product was recorded as 18-SN, and the yield was 49%.

[0173] 18-SN 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 7.54 (d, J = 7.8Hz, 1H), 7.48-7.42 (m, 2H), 7.32 (td, J = 8.4, 2.7Hz, 1H), 6.12(s,2H),2.39(t,J=7.6Hz,2H),1.56-1.50(m,2H),1.36-1.23(m,4H),0.89(t,J=7.2Hz,3H)ppm.

[0174] Embodiment 25

[0175] Preparation of FJ-19-SN:

[0176] The difference from Example 15 is: R 3 for The obtained product was recorded as 19-SN, and the yield was 46%.

[0177] 19-SN 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 7.98 (s, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.81 (d, J = 7.9Hz, 1H), 7.55 (t, J = 7.9Hz, 1H), 6.33 (s, 1H ),6.23(s,2H),5.89(s,2H),2.41(t,J=7.7Hz,2H),1.54-1.47(m,2H),1.33-1.20(m,4H),0.87(t,J=7.2Hz,3H)ppm.

[0178] Embodiment 26

[0179] Preparation of FJ-20-SN:

[0180] The difference from Example 15 is: R 3 for The obtained product was recorded as 20-SN, and the yield was 40%.

[0181] 20-SN 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 7.45-7.39 (m, 1H), 7.28-7.22 (m, 1H), 7.16 (td, J = 9.0, 3.9Hz, 1H), 6.62 (s, 1H), 6. 24(s,2H),5.98(s,2H),2.40(t,J=7.8Hz,2H),1.50(m,2H),1.33-1.20(m,4H),0.86(t,J=7.1Hz,3H)ppm.

[0182] Embodiment 27

[0183] Preparation of compound 10:

[0184] Tris(dibenzylideneacetone)dipalladium (197 mg, 0.22 mmol), tris(2-methylphenyl)phosphine (131 mg, 0.43 mmol) and N,N-diisopropylethylamine (2.9 mL) were added to a solution of compound 2 (1 g, 4.31 mmol) and ethyl acrylate (0.7 mL, 6.44 mmol) in N,N-dimethylformamide (2.9 mL), and the mixture was refluxed at 80°C for 20 h. The mixture was cooled to room temperature, filtered, rinsed with ethyl acetate, and the organic phases were combined. The organic phases were washed with water and saturated NaCl three times each, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound 10, with a mass of 1.06 g and a yield of 98%.

[0185] Compound 10 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 7.59 (d, J = 15.8Hz, 1H), 6.72 (s, 2H), 6.25 (d, J = 15.8Hz, 1H), 4.24 (q, J = 7.1Hz, 2H), 3.87 (s, 6H), 1.33 (t, J = 7.1Hz, 3H) ppm.

[0186] Preparation of compound 11:

[0187] A 10% Pd / C catalyst (500 mg) was added to a solution of compound 10 (1.06 g, 4.22 mmol) in anhydrous methanol (42 mL), and the mixture was reacted at room temperature for 4 h in a hydrogen atmosphere. The reaction solution was filtered, washed with ethyl acetate, and concentrated under reduced pressure to obtain compound 11.

[0188] Compound 11 1 H NMR is: 1 H NMR (600MHz, acetone-d6) δ = 6.46 (s, 2H), 4.08 (q, J = 7.1Hz, 2H), 3.88 (s, 2H), 3.8 0(s,6H),2.81(t,J=7.8Hz,2H),2.56(t,J=7.8Hz,2H),1.20(t,J=7.1Hz,3H)ppm.

[0189] Preparation of compound 12:

[0190] Pyridine (0.29 mL, 3.59 mmol) was added to a solution of 3,5-difluorobenzenesulfonyl chloride (378 mg, 1.78 mmol) and compound 11 (300 mg, 1.18 mmol) in dichloromethane (12 mL), and the mixture was reacted at room temperature for 8 h. Water was added to quench the reaction, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate for several times, the organic phases were combined, the organic phases were washed with water and saturated NaCl for three times each, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound 12, the mass of compound 12 was 481 mg, and the yield was 95%.

[0191] Compound 12 1 H NMR is: 1 H NMR (600MHz, CDCl3) δ = 7.40-7.33 (m, 2H), 6.98 (tt, J = 8.5, 2.3Hz, 1H), 6.37 (s, 1H), 6.35 (s, 2H), 4.11 (q,J=7.1Hz,2H),3.61(s,6H),2.88(t,J=7.7Hz,2H),2.59(t,J=7.8Hz,2H),1.23(t,J=7.1Hz,3H)ppm.

[0192] Preparation of compound 13:

[0193] To a solution of compound 12 (483 mg, 1.12 mmol) in tetrahydrofuran (7.5 mL) was added a solution of lithium hydroxide (269 mg, 11.2 mmol) in water (7.5 mL), and the mixture was reacted at room temperature for 3 h. The pH was adjusted to 2 with 1 M dilute hydrochloric acid, extracted with ethyl acetate, washed three times with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 13.

[0194] Compound 13 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 7.36-7.31 (m, 2H), 7.23 (tt, J = 8.9, 2.3Hz, 1H), 6.48 (s, 2H), 3.58 (s, 6H), 2.87 (t, J = 7.6Hz, 2H), 2.60 (t, J = 7.6Hz, 2H) ppm.

[0195] Preparation of 13-SN-1:

[0196] To a solution of compound 12 (30 mg, 0.07 mmol) in anhydrous dichloromethane (0.7 mL) was added a dichloromethane solution of boron tribromide at a rate of 3 mL / min (the concentration of the solution was kept at 1 M, and the amount of boron tribromide was 5 eq.) at -78°C, and the temperature was raised to 0°C for reaction for 10 h. An appropriate amount of saturated sodium bicarbonate aqueous solution was added to quench the reaction, the liquids were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed three times with saturated NaCl, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 13-SN-1, the mass of 13-SN-1 was 17 mg, and the yield was 61%.

[0197] 13-SN-1 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 7.35-7.30 (m, 2H), 7.21 (tt, J = 8.9, 2.4Hz, 1H), 6.16 (s, 2H), 4 .09(q,J=7.1Hz,2H),2.72(t,J=7.6Hz,2H),2.54(t,J=7.5Hz,2H),1.20(t,J=7.1Hz,3H)ppm.

[0198] Embodiment 28

[0199] Preparation of 13-SN-2:

[0200] The difference from Example 27 is that the reactant is a solution of compound 13 (100 mg, 0.25 mmol) in anhydrous dichloromethane (2.5 mL); the reagent used to quench the reaction is water; the rest is the same as Example 27. 13-SN-2 is obtained, the mass of 13-SN-2 is 62 mg, and the yield is 67%.

[0201] 13-SN-2 1 H NMR is: 1 H NMR (600MHz, acetone-d6) δ = 7.38-7.29 (m, 3H), 6.29 (s, 2H), 2.72 (t, J = 7.7Hz, 2H), 2.53 (t, J = 7.6Hz, 2H) ppm.

[0202] Embodiment 29

[0203] Preparation of 13-SN-3:

[0204] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.18 mmol), 1-hydroxybenzotriazole (22 mg, 0.16 mmol) and N,N-diisopropylethylamine (31 μL, 0.18 mmol) were added to a solution of compound 13 (60 mg, 0.15 mmol) and 4-hydroxybenzylamine (22 mg, 0.18 mmol) in N,N-dimethylformamide (1.5 mL), and the mixture was reacted at room temperature for 12 h. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated NaCl three times each, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain the intermediate product. The intermediate product was dissolved in anhydrous dichloromethane (maintaining the solution concentration at 0.1 mM), and a dichloromethane solution of boron tribromide (maintaining the solution concentration at 1 M, the amount of boron tribromide was 5 eq.) was added dropwise at -78°C at a rate of 3 mL / min, and the temperature was raised to 0°C for reaction for 10 h. Water was added to quench the reaction, the liquids were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated NaCl three times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 13-SN-3, with a mass of 44 mg and a yield of 62%.

[0205] 13-SN-3 1 H NMR is: 1 H NMR (600MHz, methanol-d4) δ = 7.36-7.30 (m, 2H), 7.20 (tt, J = 8.9, 2.4Hz, 1H), 7.01 (d, J = 8.5Hz, 2H) ,6.71(d,J=8.5Hz,2H),6.18(s,2H),4.21(s,2H),2.73(t,J=7.6Hz,2H),2.44(t,J=7.6Hz,2H)ppm.

[0206] Embodiment 30

[0207] Preparation of 13-SN-4:

[0208] The difference from Example 29 is that 4-hydroxybenzylamine (22 mg, 0.18 mmol) is replaced by ethanolamine (11 μL, 0.18 mmol); the addition of N,N-diisopropylethylamine (31 μL, 0.18 mmol) is omitted; the rest is the same as Example 29. 13-SN-4 is obtained, the mass of 13-SN-4 is 31 mg, and the yield is 50%.

[0209] 13-SN-4 1 H NMR is: 1HNMR (600MHz, methanol-d4) δ = 7.37-7.30 (m, 2H), 7.22 (tt, J = 8.9, 2.4Hz, 1H), 6.16 (s, 2H), 3 .54(t,J=5.9Hz,2H),3.26(t,J=5.9Hz,2H),2.71(t,J=6.0Hz,2H),2.41(t,J=7.8Hz,2H)ppm.

[0210] Embodiment 31

[0211] Preparation of 13-SN-5:

[0212] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg, 0.18 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol) and N,N-diisopropylethylamine (32 μL, 0.18 mmol) were added to a solution of compound 13-SN-2 (57 mg, 0.16 mmol) and dopamine hydrochloride (35 mg, 0.18 mmol) in N,N-dimethylformamide (1.5 mL), and the mixture was reacted at room temperature for 12 h. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated NaCl three times each, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 13-SN-5, with a mass of 21 mg and a yield of 26%.

[0213] 13-SN-5 1 H NMR is: 1 H NMR (600MHz, methanol-d 4) δ=7.34-7.30(m,2H),7.19(tt,J=8.9,2.4Hz,1H),6.67(d,J=8.0Hz,1H),6.61(d,J=2.2Hz,1H),6.47(dd,J=8.0,2 .2Hz,1H),6.16(s,2H),3.28(t,J=6.0,2H),2.69(t,J=7.7Hz,2H),2.56(t,J=7.5Hz,2H),2.36(t,J=7.7Hz,2H)ppm.

[0214] Embodiment 32

[0215] Preparation of 13-SN-6:

[0216] The difference from Example 31 is that dopamine hydrochloride (35 mg, 0.18 mmol) is replaced by 3,4-dimethoxybenzylamine (45 mg, 0.27 mmol); 13-SN-2 is (90 mg, 0.24 mmol); N,N-dimethylformamide is (2.4 mL); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is (55 mg, 0.29 mmol); 1-hydroxybenzotriazole is (27 mg, 0.20 mmol); N,N-diisopropylethylamine is (50 μL, 0.29 mmol); the rest is the same as Example 31. 13-SN-6 is obtained, with a mass of 48 mg and a yield of 38%.

[0217] 13-SN-6 1 H NMR is: 1 H NMR (600MHz, methanol-d 4) δ=7.35–7.29(m,2H),7.20(tt,J=8.9,2.4Hz,1H),6.87(d,J=8.3Hz,1H),6.82(d,J=2.2Hz,1H),6.71(dd,J=8.2, 2.0Hz,1H),6.17(s,2H),4.25(s,2H),3.80(s,3H),3.79(s,3H),2.74(t,J=7.6Hz,2H),,2.45(t,J=7.6Hz,2H)ppm.

[0218] Embodiment 33

[0219] Preparation of 13-SN-7:

[0220] The difference from Example 32 is that 3,4-dimethoxybenzylamine (44 mg, 0.27 mmol) is replaced by 5-(aminomethyl)-2-methoxyphenol hydrochloride (50 mg, 0.265 mmol); the rest is the same as Example 32. 13-SN-7 is obtained, the mass of 13-SN-7 is 85 mg, and the yield is 70%.

[0221] 13-SN-7 1 H NMR is: 1HNMR (600MHz, methanol-d4) δ = 7.35-7.30 (m, 2H), 7.21 (tt, J = 8.9, 2.4Hz, 1H), 6.80 (d, J = 2.1Hz, 1H), 6.72 (d, J = 8.0Hz, 1 H),6.63(dd,J=8.1,2.1Hz,1H),6.18(s,2H),4.23(s,2H),3.81(s,3H),2.74(t,J=7.7Hz,2H),2.45(t,J=7.7Hz,2H)ppm.

[0222] Application Example 1

[0223] The compounds obtained in Examples 1 to 33 were subjected to preliminary drug screening to determine the effects of the target compounds on activating TRPV1 to promote calcium influx. The results obtained are as follows: Figure 1 and 2 shown.

[0224] Transient receptor potential vanilloid 1 (TRPV1) ion channels are widely distributed in the central and peripheral nervous systems and are related to the perception of temperature, toxic substances, and pain. TRPV1 is a non-selective cation channel that is sensitive to Ca 2+ It is highly permeable. After TRPV1 is activated, intracellular Ca 2+ The concentration increases, thereby promoting the ablation of nerve endings, and can block the transmission of nerve impulse signals to achieve analgesic effects. Therefore, the present invention establishes a HEK293 cell model that highly expresses TRPV1 receptors, and determines the effect of the target compound on activating TRPV1 to promote calcium ion influx for preliminary drug screening.

[0225] from Figure 1 and 2 It can be seen that some compounds in the cannabidiol derivatives described in the present invention can significantly activate TRPV1 channel receptors and promote Ca 2+ The fluorescence intensity increased significantly.

[0226] Application Example 2

[0227] The analgesic activity of 7-A, 1-B, 13-SN, 14-SN, 15-SN, 19-SN, 13-SN-6, and 13-SN-7 was tested, and the results were as follows: Figure 3 shown.

[0228] The analgesic activity of the above compounds was evaluated by the hot plate test, and qualified mice (pain threshold <30s) were screened out. The pain threshold of each group of mice before administration was measured using an intelligent hot plate instrument (temperature set to 55°C) (two measurements were taken as the average value, and the interval between the two measurements was >15min). The qualified mice were randomly divided into a control group and a drug group, and the pain threshold was tested at 0.5, 1, and 2h after administration.

[0229] Depend on Figure 3 It can be seen that the above compounds can increase the pain threshold, indicating that they have analgesic activity.

[0230] Application Example 3

[0231] The effects of 1-B, 13-SN-6, 13-SN-7, and commercially available cannabidiol on body temperature were determined. The results are as follows: Figure 4 shown.

[0232] TRPV1 receptors are associated with temperature perception, and TRPV1 agonists can cause a significant drop in body temperature after acute administration. In order to verify whether CBD derivatives can cause a drop in body temperature, the present invention measured the body temperature of mice after administration (0h, 0.25h, 1h, 2h, 4h).

[0233] Depend on Figure 4 It can be seen that 1-B and 13-SN-6 caused the body temperature of mice to drop rapidly after administration, reaching the lowest value at 0.25h and gradually returning to normal level after 1h. Consistent with the cell results, 1-B and 13-SN-6 are TRPV1 agonists, and the body temperature drop caused by 1-B and 13-SN-6 is reversible.

[0234] The above is only a preferred embodiment of the present invention. Without departing from the principle of the present invention, several improvements and modifications may be made, and these improvements and modifications should also be regarded as within the protection scope of the present invention.

Claims

1. A cannabidiol derivative, characterized in that: The cannabidiol derivative is selected from the following compounds or pharmaceutically acceptable salts of the compounds: 。 2. The method for preparing the cannabidiol derivative according to claim 1, characterized in that: The preparation of 2-A, 4-A to 10-A comprises the following steps: Compound 3, R 1 -COOH reacts with a condensation reagent, followed by methyl removal for 9 to 11 hours to obtain 2-A, 4-A to 10-A; The R 1 R in -COOH 1 Selected from The condensation reagent is one or more of dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and Carter condensation agent; the methyl removal reagent is one or more of aluminum chloride, boron tribromide and boron trichloride; The compound 3 and R 1 The molar ratio of -COOH is 0.4-0.7:0.6; the mass ratio of the compound 3 to the condensation reagent is 10-12:28-29; The structural formula of the compound 3 is: ; The preparation of compound 3 comprises the following steps: reacting compound 1 with a bromination reagent for 4 to 6 hours to obtain compound 2; reacting compound 2 with a boronic acid reagent to obtain compound 3; the boronic acid reagent is pentyl boronic acid and / or pentyl boric acid ester; The structural formula of the compound 1 is: , the structural formula of the compound 2 is .

3. The method for preparing the cannabidiol derivative according to claim 1, characterized in that: The preparation of 1-B, 2-B, 4-B or 8-B comprises the following steps: reacting compound 3 with a reaction reagent for 3 to 12 hours, and then removing the methyl group for 9 to 11 hours to obtain 1-B, 2-B, 4-B or 8-B; The reaction reagent is R 2 -NHCOOPh, R 2 -N=C=O or R 2 -NH2; when the reaction reagent is R 2 -NHCOOPh or R 2 -N=C=O, the reaction is carried out under alkaline reagent conditions, and the alkaline reagent is one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-lutidine and 1,8-diazabicycloundec-7-ene; when the reaction reagent is R 2 -NH2, the reaction is carried out under the conditions of a condensation reagent, and the condensation reagent is one or more of dicyclohexylcarbodiimide, N,N'-disuccinimidyl carbonate, 1,1'-carbonyldiimidazole and 2-chloro-4,6-dimethoxytriazole; The reagent used for methyl removal is one or more of aluminum chloride, boron tribromide and boron trichloride; The R 2 -NHCOOPh, R 2 -N=C=O or R 2 -R in NH2 2 Independently selected , ; The structural formula of the compound 3 is: , The preparation of compound 3 comprises the following steps: reacting compound 1 with a bromination reagent for 4 to 6 hours to obtain compound 2; reacting compound 2 with a boronic acid reagent to obtain compound 3; the boronic acid reagent is pentyl boronic acid and / or pentyl boric acid ester; The structural formula of the compound 1 is: , the structural formula of the compound 2 is ; The molar ratio of the compound 3 to the reaction reagent is 0.1-1.5:0.3-1.

1.

4. The method for preparing the cannabidiol derivative according to claim 1, characterized in that: The preparation of 9-SN~20-SN comprises the following steps: 3 -SO2Cl reacts with alkaline reagent for 7~9h, and then removes methyl group for 9~11h to obtain 9-SN~20-SN; The R 3 -R in SO2Cl 3 Selected from ; The alkaline reagent is one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine and 1,8-diazabicycloundec-7-ene; The reagent used for methyl removal is one or more of aluminum chloride, boron tribromide and boron trichloride; The compound 3, R 3 -The molar ratio of SO2Cl to alkaline reagent is 0.2~0.3:0.25~0.3:0.6~0.7; The structural formula of the compound 3 is: ; The preparation of compound 3 comprises the following steps: reacting compound 1 with a bromination reagent for 4 to 6 hours to obtain compound 2; reacting compound 2 with a boronic acid reagent to obtain compound 3; the boronic acid reagent is pentyl boronic acid and / or pentyl boric acid ester; The structural formula of the compound 1 is: , the structural formula of the compound 2 is .

5. The method for preparing the cannabidiol derivative according to any one of claims 2 to 4, characterized in that: In the preparation of the compound 3; The bromination reagent is one or more of liquid bromine, bromine water, N-bromosuccinimide and pyridinium tribromide; The mass volume ratio of the compound 1 to the bromination reagent is 5-5.5 g: 2-2.3 mL; the mass volume ratio of the compound 2 to the boric acid reagent is 1.2-1.8: 1.1-1.

2.

6. The method for preparing the cannabidiol derivative according to claim 1, characterized in that: The preparation of 13-SN-6 and 13-SN-7 comprises the following steps: Compound 1 is reacted with a bromination reagent for 4 to 6 hours to obtain compound 2; Compound 2, ethyl acrylate and a catalyst are subjected to coupling reaction at 70-90°C for 20-24h to obtain compound 10; Compound 10 was subjected to hydrogenation reaction in a hydrogen atmosphere for 3-5 hours to obtain compound 11; Compound 11, R 3 -SO2Cl and alkaline reagent were subjected to condensation reaction for 7-9h to obtain compound 12; Compound 12 and a hydrolysis agent were reacted for 7 to 9 hours to obtain compound 13; Compound 13 was subjected to demethylation at 0-5°C for 9-11h to obtain 13-SN-2; Reacting 13-SN-2, an amino compound and a condensation reagent for 11 to 13 hours to obtain 13-SN-6 to 13-SN-7; The R 3 -R in SO2Cl 3 Selected from ; The bromination reagent is one or more of liquid bromine, bromine water, N-bromosuccinimide and pyridinium tribromide; The catalyst is one or more of palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(diphenylphosphinoferrocene)palladium dichloride, bis(dibenzylideneacetone)palladium and tris(dibenzylideneacetone)dipalladium; The alkaline reagent is one or more of potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine, pyridine and 1,8-diazabicycloundec-7-ene; The hydrolysis agent is one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and potassium tert-butoxide; The reagent used for methyl removal is independently one or more of aluminum trichloride, boron tribromide and boron trichloride; the condensation reagent is one or more of dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, O-(7-nitrobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate and Carter condensation agent; The amino compound is 3,4-dimethoxybenzylamine or 5-(aminomethyl)-2-methoxyphenol hydrochloride; The mass volume ratio of the compound 1 to the bromination reagent is 5-5.5 g: 2-2.3 mL; the mass volume ratio of the compound 2 to ethyl acrylate is 1 g: 0.5-1 mL; the molar ratio of the compound 2 to the catalyst is 4-4.5: 0.1-0.5; the compound 11, R 3 -The molar ratio of SO2Cl to the alkaline reagent is 1.1~1.2:1.7~1.8:3.5~4; the molar ratio of the compound 12 to the hydrolysis reagent is 1.1~1.2:11~12; The structural formula of the compound 1 is: , the structural formula of the compound 2 is ; The structural formula of the compound 10 is: ; The structural formula of the compound 11 is: ; The structural formula of the compound 12 is: ; The structural formula of the compound 13 is: The structural formula of the compound 13-SN-2 is: .

7. The method for preparing the cannabidiol derivative according to claim 6, characterized in that: The condensation reagent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; The molar ratio of the 13-SN-2, the amino compound and the condensation reagent is 1.5-2.5:1.5-3:3-6.

8. Use of the cannabidiol derivatives prepared by the cannabidiol derivatives according to claim 1 or the method for preparing the cannabidiol derivatives according to any one of claims 2 to 7 in the preparation of drugs that produce analgesic effects on capsaicin receptors.

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