Cannabinol derivative as well as preparation method and application thereof

Abstract

The invention discloses a cannabinol derivative as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. According to the present invention, citral (3, 7-dimethyl-2, 6-octadiene aldehyde) and a derivative thereof, and olive alcohol (1, 3-dihydroxy-5-amylbenzene) and a derivative thereof are adopted as starting materials, under the combined action of ethylenediamine and a photocatalyst, the one-pot efficient synthesis of the cannabinol derivative is achieved, the operation is simple and convenient, the steps are simple, and the yield is excellent. Besides, application potential of cannabinol and derivatives thereof in research and development of tumor stem cell drugs is further explored, and especially for glioblastoma stem cells, pancreatic cancer stem cells and liver cancer stem cells, the application potential of cannabinol and derivatives thereof as anti-tumor drugs specifically targeting tumor stem cells is shown.

Description

A cannabicycline derivative and its preparation method and application

[0001] This application claims priority to the Chinese patent application filed with the China Patent Office on April 30, 2024, with application number 202410540159.6 and invention name “A cannabicyclol derivative and its preparation method”, the entire contents of which are incorporated by reference into this application.

[0002] This application claims priority to the Chinese patent application filed with the China Patent Office on November 13, 2023, with application number 202311501773.3 and invention name “Application of cannabicyclol in the preparation of drugs for killing tumor stem cells or inhibiting tumor stem cell cloning”, the entire contents of which are incorporated by reference into this application. Technical Field

[0003] The present invention relates to the field of biomedicine technology, and in particular to a cannabicyclol derivative and a preparation method and application thereof. Background Art

[0004] Cancer poses a major threat to human health. Current mainstream treatments include surgery, radiotherapy, chemotherapy, immunotherapy, and targeted therapy. Although surgical treatment is effective, it is invasive, with prominent postoperative recovery issues, and most patients require supplemental drug therapy. Radiotherapy and chemotherapy are often accompanied by drug side effects and drug resistance. In comparison, although immunotherapy and targeted therapy reduce side effects, their high costs impose a heavy financial burden on patients. In addition, the efficacy of these therapies varies from individual to individual and is not universally applicable to all cancer types and patients. Therefore, the development of new anti-tumor drugs and therapies is crucial for tumor treatment.

[0005] Cancer stem cells (CSCs) possess the ability to self-renew and multidirectionally differentiate, capable of unlimited replication and differentiation into various tumor cells, and are key factors in the development and progression of tumors. However, there are currently very few specific targeted drugs for CSCs. For example, Vismodegib only targets a specific subpopulation of CSCs in basal cell carcinoma of the skin; LF3 inhibits the growth of colon cancer by inhibiting the Wnt signaling pathway; and while the JNK inhibitor AS602801 has shown inhibitory effects on CSCs both in vitro and in vivo, further research and development is still needed. Therefore, the development of new CSC-targeted therapeutic drugs is expected to bring revolutionary breakthroughs in tumor treatment.

[0006] Cannabicycline, as a non-psychoactive component of the cannabinoid class, has been relatively understudied, mainly because it is difficult to separate and extract from natural products, which limits its application in biological activity research. Chinese patent CN117379416A (publication number: CN202311501773.3) first proposed the use of cannabicycline in the preparation of drugs that kill or inhibit CSCs cloning, providing a new approach for the targeted treatment of CSCs. In order to overcome the difficulties in separating and extracting natural products, Chinese patent CN118530207A (publication number: CN202410540159.6) discloses a chemical synthesis method for cannabicycline, which breaks through the content limit and lays the foundation for in-depth research on its biological activity. Despite this, the development of a simpler and more efficient method for synthesizing cannabicycline remains a research hotspot.

[0007] Summary of the Invention

[0008] The object of the present invention is to provide a cannabicycline derivative and a preparation method and application thereof, so as to solve the above-mentioned technical problems.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] The present invention provides a cannabicycline derivative, which comprises the following general structural formula:

[0011] Among them, R 1 contains hydrogen, linear alkyl, branched alkyl, aryl or heteroaryl; R 2 and R 3 R independently comprises hydrogen, linear alkyl, branched alkyl, alkenyl, ester, heteroalkyl, aryl or heteroaryl; 4 and R 5 R independently comprises hydrogen, straight chain alkyl, branched chain alkyl, aryl or heteroaryl.

[0012] The present invention also provides a method for preparing a cannabicycline derivative.

[0013] (1) The preparation method of compounds 3a to 3z comprises the following steps:

[0014] The compound of formula I, the compound of formula II, and ethylenediamine are dissolved in toluene for reaction, and then a photocatalytic reaction is continued under a protective atmosphere and a photocatalyst to obtain a cannabicyclol derivative of formula III;

[0015] where R 1 contains hydrogen, linear alkyl, branched alkyl, aryl or heteroaryl; R 2 and R 3R independently comprises hydrogen, linear alkyl, branched alkyl, alkenyl, ester, heteroalkyl, aryl or heteroaryl; 4 and R 5 independently contain hydrogen, straight-chain alkyl, branched-chain alkyl, aryl, or heteroaryl;

[0016] (2) The preparation method of compound 5 comprises the following steps:

[0017] A cannabichromene derivative and 2,3-dichloro-5,6-dicyanobenzoquinone are reacted in the presence of indium trifluoromethanesulfonate to obtain a colorless oily liquid, namely compound 5;

[0018] The structural formula of the cannabinoid derivative is:

[0019] (3) The preparation method of compounds 7a to 7g comprises the following steps:

[0020] The cannabicycline derivative of formula III is mixed with a halogen-containing compound and reacted under the action of a base; the halogen-containing compound comprises a haloalkane, a haloester or a haloamine;

[0021] (4) The preparation method of compound 7h comprises the following steps:

[0022] Compound 7f, tryptamine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, and triethylamine are mixed and reacted to obtain a colorless oily liquid, namely compound 7h;

[0023] (5) The preparation method of compound 7i comprises the following steps:

[0024] Compound 7e, p-toluenesulfonyl azide, and cuprous thiophene-2-carboxylate are mixed and reacted to obtain a colorless oily liquid, namely compound 7i;

[0025] (6) The preparation method of compounds 9a to 9r comprises the following steps:

[0026] Compound 3a and an acid are reacted in the presence of a catalyst to obtain a colorless oily liquid;

[0027] The structural formula of the acid is: where R 7 Contains one of 2-methylpropyl, methyl, ethyl, n-nonyl, 2-naphthylmethyl, vinyl, 3-phenylvinyl, trans-4-methoxy-3-phenylvinyl, 4-pyridyl, furan, 4-morpholinomethyl, 4-morpholinoethyl, N,N-dimethylmethyl, 1-adamantyl and ferrocene;

[0028] (7) The preparation method of compounds 9s and 9t comprises the following steps:

[0029] Compound 3a and 5-bromovaleric acid are reacted in the presence of a catalyst to obtain an intermediate product, and the intermediate product is further reacted with a substituted compound to obtain a product; the substituted compound comprises triphenylphosphine or 4-hydroxycoumarin;

[0030] (8) The preparation method of compounds 13a to 13c comprises the following steps:

[0031] Compound 3a, trifluoromethanesulfonic anhydride and pyridine are mixed in a solvent to react to obtain an intermediate product, and the intermediate product is reacted with a substituted boronic acid in the presence of a catalyst;

[0032] The structural formula of the intermediate product is: The structural formula of the substituted boronic acid is: where R 8 is pyridine, phenyl or thiophene;

[0033] (9) The preparation method of compound 13d comprises the following steps:

[0034] Compound 3a, trifluoromethanesulfonic anhydride and pyridine are mixed in a solvent for reaction to obtain an intermediate product. The intermediate product, 1,1'-bis(diphenylphosphino)ferrocene, palladium acetate, formic acid and triethylamine are mixed in a solvent for reaction to obtain compound 13d.

[0035] The present invention also provides a use of a cannabicyclol derivative in the preparation of a drug for killing tumor stem cells or inhibiting the formation of tumor stem cells. The drug also contains pharmaceutically acceptable excipients, which include diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers or lubricants.

[0036] Beneficial effects of the present invention:

[0037] The present invention has discovered that cannabicycline and its derivatives have significant in vitro specificity for killing multiple types of tumor stem cells. Therefore, cannabicycline and its derivatives are expected to be developed into anti-tumor drugs that specifically target tumor stem cells. This invention can treat various cancers by killing multiple types of tumor stem cells. DETAILED DESCRIPTION

[0038] The present invention provides a cannabicycline derivative, which comprises the following general structural formula:

[0039] Among them, R 1 contains hydrogen, linear alkyl, branched alkyl, aryl or heteroaryl; R 2 and R 3 R independently comprises hydrogen, linear alkyl, branched alkyl, alkenyl, ester, heteroalkyl, aryl or heteroaryl;4 and R 5 R independently comprises hydrogen, straight chain alkyl, branched chain alkyl, aryl or heteroaryl.

[0040] In the present invention, the R 1 、R 2 、R 3 、R 4 and R 5 When there are substituents in the group, there are one or more substituents, and the substituents are independently selected from the following groups: C1 to C13 straight chain or branched alkyl, halogen atoms, C1 to C13 straight chain or branched alkoxy, cyano, amino, amine, hydroxyl, ester group, alkenyl, alkynyl, C3 to C10 cycloalkyl, C3 to C10 heterocycloalkyl, substituted or unsubstituted aryl and heteroaryl.

[0041] In the present invention, the R 1 、R 2 、R 3 、R 4 and R 5 Independently selected from one of the following structures:

[0042] In the present invention, the cannabicyclol derivative comprises the following structural formula:

[0043] In the present invention, the cannabicyclol derivatives comprise the following structural formulas: The structural formulas of compounds 3b, 3d, 3j, 3l to 3o, 3q to 3z are, in order:

[0044] The structural formula of compound 5 is:

[0045] The structural formulas of compounds 7a to 7i are:

[0046] The structural formulas of compounds 9a to 9t are:

[0047] The structural formulas of compounds 13a to 13d are:

[0048] The present invention also provides a method for preparing a cannabicycline derivative.

[0049] (1) The preparation method of compounds 3a to 3z comprises the following steps:

[0050] The compound of formula I, the compound of formula II, and ethylenediamine are dissolved in toluene for reaction, and then a photocatalytic reaction is continued under a protective atmosphere and a photocatalyst to obtain a cannabicyclol derivative of formula III;

[0051] where R 1 contains hydrogen, linear alkyl, branched alkyl, aryl or heteroaryl; R 2 and R 3 R independently comprises hydrogen, linear alkyl, branched alkyl, alkenyl, ester, heteroalkyl, aryl or heteroaryl; 4 and R 5 independently contain hydrogen, straight-chain alkyl, branched-chain alkyl, aryl, or heteroaryl;

[0052] (2) The preparation method of compound 5 comprises the following steps:

[0053] A cannabichromene derivative and 2,3-dichloro-5,6-dicyanobenzoquinone are reacted in the presence of indium trifluoromethanesulfonate to obtain a colorless oily liquid, namely compound 5;

[0054] The structural formula of the cannabinoid derivative is:

[0055] (3) The preparation method of compounds 7a to 7g comprises the following steps:

[0056] The cannabicycline derivative of formula III is mixed with a halogen-containing compound and reacted under the action of a base; the halogen-containing compound comprises a haloalkane, a haloester or a haloamine;

[0057] (4) The preparation method of compound 7h comprises the following steps:

[0058] Compound 7f, tryptamine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, and triethylamine are mixed and reacted to obtain a colorless oily liquid, namely compound 7h;

[0059] (5) The preparation method of compound 7i comprises the following steps:

[0060] Compound 7e, p-toluenesulfonyl azide, and cuprous thiophene-2-carboxylate are mixed and reacted to obtain a colorless oily liquid, namely compound 7i;

[0061] (6) The preparation method of compounds 9a to 9r comprises the following steps:

[0062] Compound 3a and an acid are reacted in the presence of a catalyst to obtain a colorless oily liquid; the acid has the structural formula: where R 7Contains one of 2-methylpropyl, methyl, ethyl, n-nonyl, 2-naphthylmethyl, vinyl, 3-phenylvinyl, trans-4-methoxy-3-phenylvinyl, 4-pyridyl, furan, 4-morpholinomethyl, 4-morpholinoethyl, N,N-dimethylmethyl, 1-adamantyl and ferrocene;

[0063] (7) The preparation method of compounds 9s and 9t comprises the following steps:

[0064] Compound 3a and 5-bromovaleric acid are reacted in the presence of a catalyst to obtain an intermediate product, and the intermediate product is further reacted with a substituted compound to obtain a product; the substituted compound comprises triphenylphosphine or 4-hydroxycoumarin;

[0065] (8) The preparation method of compounds 13a to 13c comprises the following steps:

[0066] Compound 3a, trifluoromethanesulfonic anhydride and pyridine are mixed in a solvent to react to obtain an intermediate product, and the intermediate product is reacted with a substituted boronic acid in the presence of a catalyst;

[0067] The structural formula of the intermediate product is: The structural formula of the substituted boronic acid is: where R 8 is pyridine, phenyl or thiophene;

[0068] (9) The preparation method of compound 13d comprises the following steps:

[0069] Compound 3a, trifluoromethanesulfonic anhydride and pyridine are mixed in a solvent for reaction to obtain an intermediate product. The intermediate product, 1,1'-bis(diphenylphosphino)ferrocene, palladium acetate, formic acid and triethylamine are mixed in a solvent for reaction to obtain compound 13d.

[0070] In the present invention, the compound of formula I comprises the following structure:

[0071] In the present invention, the compound of formula II comprises citral,

[0072] In the present invention, the halogen-containing compound includes allyl bromide, methyl iodide, ethyl iodide, 1-iodopropane, 3-bromopropyne, ethyl bromoacetate, potassium iodide, and 2-(Boc-amino)ethyl bromide.

[0073] In the present invention, in (1), the photocatalyst comprises one or more of [Ir{dFCF3ppy}2(bpy)]PF6, [Ir{dFCF3ppy}2(dtbbpy)]PF6, [Ir(ppy)2(dtbbpy)]PF6, fac-Ir(ppy)3, [Ru(bpy)3]Cl2, [Ru(bpy)3](PF6)2 and Eosin Y, preferably [Ir{dFCF3ppy}2(bpy)]PF6; the illumination conditions are: wavelength 365-560nm, illumination time 30min-5h;

[0074] The molar ratio of the compound of formula I, the compound of formula II, ethylenediamine and the photocatalyst is 1:1:0.01-0.1:0.005-0.02, preferably 1:1:0.02-0.05:0.005-0.01.

[0075] In the present invention, in said (3), the molar ratio of the cannabicyclol derivative of formula III, the halogen-containing compound and the base is 1:2:1-5, preferably 1:2:2-4, and more preferably 1:2:3; the reaction temperature is 60-70°C, preferably 70°C; and the reaction time is 5-10h, preferably 8h.

[0076] In the present invention, in (6), the molar ratio of compound 3a, acid and catalyst is 1:1-2:1-3, preferably 1:2:2; the reaction temperature is 20-40°C, preferably 30°C; and the reaction time is 5-10h, preferably 5h.

[0077] The present invention also provides a use of a cannabicyclol derivative in the preparation of a drug for killing tumor stem cells or inhibiting the formation of tumor stem cells. The drug also contains pharmaceutically acceptable excipients, which include diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers or lubricants.

[0078] In the present invention, the tumor stem cells include glioblastoma stem cells, pancreatic cancer stem cells and liver cancer stem cells;

[0079] The glioblastoma stem cells include GSC3, GSC12 and GSC18;

[0080] The pancreatic cancer stem cells include PANC1-CSC, BXPC-3-CSC and ASPC1-CSC;

[0081] The liver cancer stem cells include HepG2-CSC, MHCC97H-CSC and SMMC7721-CSC.

[0082] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0083] The present invention adopts four approaches to synthesize olivetol analogs and citral analogs:

[0084] The above four approaches are all reported in literature or patents, and are specifically as follows:

[0085] Synthesis method (1): Compound Chinese patent number: CN112334466A;

[0086] Synthesis method (2): Synthesis, antiepileptic effects, and structure-activity relationships of α-asarone derivatives: In vitro and in vivo neuroprotective effect of selected derivatives. Bioorgan. Chem., 2021, 115, 105179;

[0087] Synthesis method (3): A Tandem Cross-Metathesis / Semipinacol Rearrangement Reaction. Org. Lett., 2012, 14, 2462;

[0088] Synthesis method (4): Enantioselective Tail-to-Head Cyclizations Catalyzed by Dual-Hydrogen-Bond Donors. J. Am. Chem. Soc. 2020, 142, 6951..

[0089] The present invention is specifically implemented as follows:

[0090] Example 1 Synthesis of Modified C-7 Cannabicycline Derivatives

[0091] The specific steps are as follows:

[0092] Take 3a as an example:

[0093] Under a nitrogen atmosphere, olivetol 1 (180 mg, 1 mmol, 1.0 eq.), citral 2 (152 mg, 1 mmol, 1.0 eq.), and ethylenediamine (7 μL, 10 mol%, 0.01 eq.) were added to 5 mL of toluene and heated under reflux for 3 hours. After completion of the reaction under nitrogen, as determined by thin-layer chromatography (TLC), the reaction mixture was stirred at room temperature. A photocatalyst, [Ir{dFCF3ppy}2(bpy)]PF6 (2 mg, 2 mol‰, 0.005 eq.), was added to the reaction solution and irradiated under a 405 nm LED light source for 3 hours (sunlight irradiation for 5 days was also used in this invention). After completion of the reaction, as determined by TLC, the organic phase was extracted with ethyl acetate (25 mL x 3 times) and collected. After rotary evaporation and purification by silica gel column chromatography, 62.2 mg of a colorless oily liquid (yield 39%, yield 30% under sunlight irradiation), compound 3a, was obtained. The NMR data are as follows:

[0094] 1 H NMR (600MHz, CDCl3) δ6.33(s,1H),6.18(s,1H),4.48(s,1H),3.06(d,J=9.6Hz,1H),2.57(m,,1H),2.50–2.42(m,2H),2.39(t,J=7.4Hz,1H) ,2.02–1.93(m,1H),1.71–1.65(m,1H),1.65–1.52(m,4H),1.38(s,3H ),1.37(s,3H),1.34–1.25(m,4H),0.88(t,J=6.8Hz,3H),0.80(s,3H).

[0095] Using the above method, a series of modified C-7 cannabicycline derivatives were synthesized. The specific products are as follows:

[0096] Compound 3b: (The raw materials used are: and citral (3a-3t all use citral)

[0097] 1 H NMR (500 MHz, CD3OD) δ 6.86 (t, J = 8.0 Hz, 1H), 6.32 (dd, J = 8.0, 1.1 Hz, 1H), 6.29 (dd, J = 8.1, 1.1 Hz, 1H), 3.13 (d, J = 9.6 Hz, 1H), 2.53 (d, J = 7.3 Hz, 1H), 2.38 (t, J = 7.5 Hz, 1H), 2.02–1.92 (m, 1H), 1.70–1.53 (m, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 0.76 (s, 3H). Yield: 37%.

[0098] Compound 3c: (The raw materials are: )

[0099] 1 H NMR (600 MHz, CD3OD) δ 6.11 (s, 1H), 6.07 (s, 1H), 3.02 (d, J = 9.6 Hz, 1H), 2.46 (t, J = 8.0 Hz, 1H), 2.30 (t, J = 7.5 Hz, 1H), 2.11 (s, 3H), 1.93–1.86 (m, 1H), 1.66–1.59 (m, 1H), 1.56–1.45 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H), 0.70 (s, 3H). Yield 44%.

[0100] Compound 3d: (Raw materials: The raw materials were synthesized by synthesis method (2)

[0101] 1 H NMR (600 MHz, CDCl3) δ 6.33 (s, 1H), 6.18 (s, 1H), 4.54 (s, 1H), 3.07 (d, J = 9.7 Hz, 1H), 2.57 (t, J = 7.9 Hz, 1H), 2.48–2.42 (m, 2H), 2.40 (t, J = 7.3 Hz, 1H), 2.02–1.95 (m, 1H), 1.71–1.67 (m, 1H), 1.63–1.56 (m, 4H), 1.38 (s, 3H), 1.38 (s, 3H), 0.91 (t, J = 7.4 Hz, 3H), 0.80 (s, 3H). The yield was 26%.

[0102] Compound 3e: (Raw materials: Synthesis method (2) Synthesis)

[0103] 1H NMR (600 MHz, CDCl3) δ 6.33 (s, 1H), 6.18 (s, 1H), 4.56 (s, 1H), 3.06 (d, J = 9.7 Hz, 1H), 2.57 (t, J = 7.9 Hz, 1H), 2.51–2.42 (m, 2H), 2.39 (t, J = 7.4 Hz, 1H), 2.02–1.94 (m, 1H), 1.72–1.65 (m, 1H), 1.65–1.51 (m, 4H), 1.38 (s, 3H), 1.38 (s, 3H), 1.32 (q, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H), 0.80 (s, 3H). The yield was 30%.

[0104] Compound 3f: (Raw materials: Synthesis method (2) Synthesis)

[0105] 1 H NMR (600 MHz, CDCl3) δ 6.33 (s, 1H), 6.18 (s, 1H), 4.66 (s, 1H), 3.07 (d, J = 9.6 Hz, 1H), 2.58 (t, J = 8.5 Hz, 1H), 2.49–2.42 (m, 2H), 2.40 (t, J = 7.4 Hz, 1H), 2.03–1.95 (m, 1H), 1.72–1.66 (m, 1H), 1.66–1.52 (m, 4H), 1.39 (s, 3H), 1.38 (s, 3H), 1.33–1.24 (m, 6H), 0.87 (t, J = 6.6 Hz, 3H), 0.80 (s, 3H). The yield was 29%.

[0106] Compound 3g: (Raw materials: Synthesis method (2) Synthesis)

[0107] 1 H NMR (600 MHz, CDCl3) δ 6.32 (s, 1H), 6.17 (s, 1H), 4.56 (s, 1H), 3.06 (d, J = 9.6 Hz, 1H), 2.57 (t, J = 7.7 Hz, 1H), 2.50–2.42 (m, 2H), 2.39 (t, J = 7.4 Hz, 1H), 2.01–1.94 (m, 1H), 1.72–1.67 (m, 1H), 1.65–1.52 (m, 4H), 1.38 (s, 3H), 1.38 (s, 3H), 1.31–1.24 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H), 0.80 (s, 3H). The yield was 22%.

[0108] Compound 3h: (Raw materials: Synthesis method (2) Synthesis)

[0109] 1 H NMR (600 MHz, CDCl3) δ 6.32 (s, 1H), 6.18 (s, 1H), 4.50 (s, 1H), 3.06 (d, J = 9.6 Hz, 1H), 2.57 (t, J = 8.4 Hz, 1H), 2.51–2.42 (m, 2H), 2.39 (t, J = 7.4 Hz, 1H), 2.01–1.94 (m, 1H), 1.70–1.66 (m, 1H), 1.65–1.53 (m, 4H), 1.38 (s, 3H), 1.37 (s, 3H), 1.30–1.22 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H), 0.80 (s, 3H). The yield was 27%.

[0110] Compound 3i: (Raw materials: Synthesis method (2) Synthesis)

[0111] 1 H NMR (600 MHz, CDCl3) δ 6.32 (s, 1H), 6.17 (s, 1H), 4.54 (s, 1H), 3.06 (d, J = 9.6 Hz, 1H), 2.57 (t, J = 8.4 Hz, 1H), 2.48–2.43 (m, 2H), 2.39 (t, J = 7.4 Hz, 1H), 2.01–1.94 (m, 1H), 1.71–1.67 (m, 1H), 1.64–1.52 (m, 4H), 1.38 (s, 3H), 1.38 (s, 3H), 1.30–1.23 (m, 20H), 0.88 (t, J = 6.9 Hz, 3H), 0.80 (s, 3H). The yield was 20%.

[0112] Compound 3j: (Raw materials: Synthesis method (1) Synthesis)

[0113] 1H NMR (600 MHz, CDCl3) δ 6.07 (s, 1H), 5.97 (s, 1H), 4.80 (s, 1H), 3.72 (s, 3H), 3.03 (d, J = 9.7 Hz, 1H), 2.57 (t, J = 8.2 Hz, 1H), 2.39 (t, J = 7.5 Hz, 1H), 2.01–1.94 (m, 1H), 1.71–1.54 (m, 3H), 1.38 (s, 3H), 1.36 (s, 3H), 0.78 (s, 3H). The yield was 28%.

[0114] Compound 3k: (Raw materials: Synthesis method (1) Synthesis)

[0115] 1 H NMR (600 MHz, CDCl3) δ 7.55 (d, J = 7.1 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 4.69 (s, 1H), 3.15 (d, J = 9.6 Hz, 1H), 2.63 (t, J = 8.3 Hz, 1H), 2.43 (t, J = 7.4 Hz, 1H), 2.07–2.00 (m, 1H), 1.75–1.56 (m, 3H), 1.42 (s, 3H), 1.41 (s, 3H), 0.85 (s, 3H). Yield 47%.

[0116] Compound 3l: (Raw materials: Synthesis method (1) Synthesis)

[0117] 1 H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 6.75 (s, 1H), 6.58 (s, 1H), 4.68 (s, 1H), 3.14 (d, J = 9.6 Hz, 1H), 2.62 (t, J = 8.4 Hz, 1H), 2.43 (t, J = 7.4 Hz, 1H), 2.37 (s, 3H), 2.08–1.99 (m, 1H), 1.74–1.57 (m, 3H), 1.42 (s, 3H), 1.41 (s, 3H), 0.85 (s, 3H). Yield: 35%.

[0118] Compound 3m: (Raw materials: Synthesis method (1) Synthesis)

[0119] 1 H NMR (600 MHz, CDCl3) δ 7.37 (s, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.29–7.25 (m, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.75 (s, 1H), 6.58 (s, 1H), 4.71 (s, 1H), 3.14 (d, J = 9.6 Hz, 1H), 2.62 (t, J = 8.1 Hz, 1H), 2.42 (t, J = 7.5 Hz, 1H), 2.38 (s, 3H), 2.04–1.98 (m, 1H), 1.74–1.57 (m, 3H), 1.41 (s, 3H), 1.40 (s, 3H), 0.84 (s, 3H). The yield was 35%.

[0120] Compound 3n: (Raw materials: Synthesis method (1) Synthesis)

[0121] 1 H NMR (600 MHz, CDCl3) δ 7.24–7.17 (m, 4H), 6.46 (s, 1H), 6.29 (s, 1H), 4.63 (s, 1H), 3.14 (d, J = 9.6 Hz, 1H), 2.62 (t, J = 8.0 Hz, 1H), 2.43 (t, J = 7.4 Hz, 1H), 2.29 (s, 3H), 2.07–2.00 (m, 1H), 1.77–1.69 (m, 1H), 1.67–1.59 (m, 2H), 1.41 (s, 6H), 0.86 (s, 3H). The yield was 24%.

[0122] Compound 3o: (Raw materials: Synthesis method (1) Synthesis)

[0123] 1 H NMR (600 MHz, CDCl3) δ 7.18 (s, 2H), 6.96 (s, 1H), 6.75 (s, 1H), 6.58 (s, 1H), 4.74 (s, 1H), 3.14 (d, J = 9.6 Hz, 1H), 2.62 (t, J = 8.2 Hz, 1H), 2.43 (t, J = 7.4 Hz, 1H), 2.35 (s, 6H), 2.05–1.98 (m, 1H), 1.75–1.57 (m, 3H), 1.42 (s, 3H), 1.41 (s, 3H), 0.84 (s, 3H). The yield was 36%.

[0124] Compound 3p: (Raw materials: Synthesis method (1) Synthesis)

[0125] 1 H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.42–7.37 (m, 2H), 6.62 (s, 1H), 6.58 (s, 1H), 3.16 (d, J = 9.6 Hz, 1H), 2.55 (t, J = 8.7 Hz, 1H), 2.38 (t, J = 7.4 Hz, 1H), 2.06–1.97 (m, 1H), 1.72–1.54 (m, 3H), 1.38 (s, 3H), 1.35 (s, 3H), 1.33 (d, J = 27.4 Hz, 9H), 0.81 (s, 3H). The yield was 23%.

[0126] Compound 3q: (Raw materials: Synthesis method (1) Synthesis)

[0127] 1 H NMR (600MHz, CDCl3) δ7.49(d,J=7.9Hz,2H),7.41(d,J=7.8Hz,2H),6.76(s,1H),6.58(s,1H),4.66(s,1H),3.14(d,J=9.5Hz,1H),2.62(t,J=8.6H z,1H),2.43(t,J=7.6Hz,1H),2.07–1.98(m,1H),1.75–1.69(m,1H),1.6 8-1.60 (m, 2H), 1.41 (d, J = 5.4Hz, 6H), 1.35 (s, 9H), 0.84 (s, 3H). The yield is 36%.

[0128] Compound 3r: (Raw materials: Synthesis method (1) Synthesis)

[0129] 1 H NMR (600MHz, CDCl3) δ7.49(t,J=7.0Hz,2H),7.07(t,J=8.6Hz,2H),6.70(d,J=1.7Hz,1H),6.53(d,J=1.6Hz,1H),4.73(d,J=4.5Hz,1H), 3.13(d,J=9.6Hz,1H),2.62(t,J=8.0Hz,1H),2.43(t,J=7.4Hz,1H),2.02(tt,J=11 .1, 6.3Hz, 1H), 1.74–1.57 (m, 3H), 1.42 (s, 3H), 1.41 (s, 3H), 0.84 (s, 3H). The yield is 43%.

[0130] Compound 3s: (Raw materials: Synthesis method (1) Synthesis)

[0131] 1 H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 10.1 Hz, 1H), 6.64 (s, 1H), 6.48 (s, 1H), 5.59 (d, J = 10.0 Hz, 1H), 5.17 (s, 1H), 5.10 (t, J = 7.4 Hz, 1H), 2.18–2.06 (m, 2H), 1.81–1.74 (m, 1H), 1.71–1.67 (m, 1H), 1.67 (s, 3H), 1.58 (s, 3H), 1.42 (s, 3H). The yield was 36%.

[0132] Compound 3t: (Raw materials: Synthesis method (1) Synthesis)

[0133] 1 H NMR (600 MHz, CDCl3) δ 7.38 (t, J = 2.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 2H), 6.76 (s, 1H), 6.60 (s, 1H), 4.66 (s, 1H), 3.12 (d, J = 9.6 Hz, 1H), 2.62 (t, J = 8.3 Hz, 1H), 2.43 (t, J = 7.5 Hz, 1H), 2.04–1.98 (m, 1H), 1.72–1.58 (m, 3H), 1.41 (s, 3H), 1.40 (s, 3H), 0.83 (s, 3H). The yield was 22%.

[0134] Example 2 Synthesis of Modified C-12 Cannabicycline Derivatives

[0135] The specific steps are as follows:

[0136] Taking compound 3u as an example: under a nitrogen atmosphere, olivetol 1a (36 mg, 0.2 mmol, 1.0 eq.), citral derivative 2 (R=H, 27.6 mg, 0.2 mmol, 1.0 eq.), and ethylenediamine (1 μL, 10 mol%, 0.01 eq.) were added to 2 mL of toluene and heated under reflux for 3 hours. After completion of the reaction as confirmed by thin-layer chromatography (TLC), the reaction mixture was stirred at room temperature. A photocatalyst, [Ir{dFCF3ppy}2(bpy)]PF6 (2 mg, 2 mol‰, 0.005 eq.), was added to the reaction mixture and irradiated under a 405 nm LED light source for 3 hours. After completion of the reaction as confirmed by TLC, the organic phase was extracted with ethyl acetate (3 times with 25 mL). After rotary evaporation and purification by silica gel column chromatography, 9.2 mg of a colorless oil (15% yield) was obtained, compound 3u. The NMR data are as follows:

[0137] Compound 3u: (Raw materials: 1a (3u-3z all use 1a) and Synthesis method (3) Synthesis)

[0138] 1 H NMR (600 MHz, CDCl3) δ 6.33 (s, 1H), 6.18 (s, 1H), 4.56 (s, 1H), 2.90 (t, J = 7.7 Hz, 1H), 2.51–2.40 (m, 3H), 2.32 (q, J = 6.2 Hz, 1H), 2.17–2.08 (m, 1H), 1.81 (q, J = 6.4 Hz, 1H), 1.72–1.60 (m, 2H), 1.56 (p, J = 7.5 Hz, 2H), 1.48 (dd, J = 12.8, 7.2 Hz, 1H), 1.38 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H), 1.33–1.25 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H). The yield was 13%.

[0139] Using the above method, a series of C-12 cannabicycline derivatives were synthesized. The specific products are as follows:

[0140] Compound 3v: (Raw materials: Synthesis method (3) Synthesis)

[0141] 1H NMR (600 MHz, CDCl3) δ 6.33 (s, 1H), 6.19 (s, 1H), 4.51 (s, 1H), 2.95 (t, J = 7.7 Hz, 1H), 2.47–2.43 (m, 3H), 2.39 (q, J = 6.5 Hz, 1H), 2.18–2.11 (m, 1H), 1.99–1.90 (m, 1H), 1.78–1.69 (m, 1H), 1.67–1.62 (m, 2H), 1.63–1.52 (m, 3H), 1.49–1.41 (m, 1H), 1.38 (s, 3H), 1.34–1.24 (m, 4H), 0.87 (t, J = 7.1 Hz, 6H). The yield was 11%.

[0142] Compound 3w: (Raw materials: Synthesis method (3) Synthesis)

[0143] 1 H NMR (600MHz, CDCl3) δ6.35 (s, 1H), 6.19 (s, 1H), 4.57 (s, 1H), 3.15 (t, J = 8.0Hz, 1H), 2.50–2.43(m,3H),2.39(t,J=8.4Hz,1H),2.22–2.15(m,1H),1.94–1.87(m,1H),1.8 6–1.80(m,1H),1.69–1.62(m,2H),1.56(t,J=7.5Hz,2H),1.51–1.45(m,1H),1.31(s,3H),1.33–1.27(m,4H),0.97(d,J=6.7Hz,3H),0.88(dd,J=6.8,3.6Hz,6H). The yield was 14%.

[0144] Compound 3x: (Raw materials: Synthesis method (3) Synthesis)

[0145] 1HNMR(600MHz, CDCl3)δ7.41(d,J=7.5Hz,2H),7.36(t,J=7.5Hz,2H),7.24(d,J=7.1Hz,1H), 6.35(s,1H),6.20(s,1H),4.06(s,1H),3.37(t,J=7.7Hz,1H),2.91–2.85(m,2H),2.69–2.6 5(m,1H),2.47–2.43(m,2H),2.31–2.24(m,1H),1.82–1.70(m,2H),1.64(dd,J=12.7,7.1Hz,1H),1.55(p,J=7.6Hz,2H),1.44(s,3H),1.33–1.25(m,4H),0.86(t,J=6.8Hz,3H). The yield was 15%.

[0146] Compound 3y: (Raw materials: Synthesis method (3) Synthesis)

[0147] 1 HNMR(600MHz, CDCl3)δ6.32(s,1H),6.29(s,1H),4.86(s,1H),3.11–3.06(m,1H),2.5 9–2.55(m,1H),2.50–2.44(m,3H),2.10–2.02(m,1H),1.76–1.68(m,1H),1.66–1.62( m, 1H), 1.57 (p, J = 7.6 Hz, 2H), 1.43–1.40 (m, 1H), 1.39 (s, 3H), 1.33–1.27 (m, 4H), 1.15–1.13 (m, 2H), 0.88 (t, J = 6.8 Hz, 3H), 0.67–0.53 (m, 2H), 0.24–0.13 (m, 2H). The yield was 12%.

[0148] Compound 3z: (Raw materials: Synthesis method (4) Synthesis)

[0149] 1H NMR (600MHz, CDCl3) δ7.50(d,J=7.7Hz,2H),7.37(t,J=7.6Hz,2H),7.28(d,J=7.4Hz,1H),6.5 0(s,1H),6.23(s,1H),4.60(s,1H),3.28(d,J=9.8Hz,1H),3.20(t,J=8.9Hz,1H),2.63(t,J=7. 8Hz, 1H), 2.51(t, J=7.8Hz, 2H), 2.41–2.35(m, 1H), 2.02–1.96(m, 1H), 1.88–1.77(m, 2H), 1.62(p, J=7.5Hz, 2H), 1.47(s, 3H), 1.40–1.29(m, 4H), 0.92(t, J=6.9Hz, 3H), 0.85(s, 3H). The yield was 24%.

[0150] Example 3 Synthesis of Polysubstituted Modified Cannabicycline Derivatives

[0151] The specific steps are as follows:

[0152] Under a nitrogen atmosphere, a cannabichromene derivative 4 (35 mg, 0.1 mmol, 1.0 eq.), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 2.6 mg, 10 mol%), and indium trifluoromethanesulfonate (In(OTf)3, 5.7 mg, 10 mol%) were added to 1 mL of toluene. After completion of the reaction as confirmed by thin-layer chromatography (TLC), the product was filtered through a short column, concentrated by rotary evaporation, and purified by silica gel column chromatography to yield 12 mg of a colorless oily liquid (34% yield), compound 5. The NMR data are as follows:

[0153] Compound 5: 1 H NMR(600MHz, CDCl3)δ6.19(s,1H),5.94–5.85(m,1H),4.99–4.88(m,2H),4.35 (s,1H),3.43–3.23(m,2H),3.07(d,J=9.6Hz,1H),2.59–2.51(m,2H),2.50–2.4 1(m,1H),2.37(t,J=7.4Hz,1H),1.96–1.88(m,1H),1.69–1.63(m,1H),1.60–1. 49(m,4H),1.37(s,6H),1.35–1.32(m,4H),0.89(t,J=6.8Hz,3H),0.77(s,3H).

[0154] Example 4 Synthesis of 5-OH Modified Cannabicycline Derivatives

[0155] Taking 7a as an example: After cannabicycline was synthesized according to the method of Example 2, 3a (31.4 mg, 0.1 mmol, 1.0 eq.), allyl bromide 6 (24.2 mg, 0.2 mmol, 2.0 eq.) and potassium carbonate (27.6 mg, 0.2 mmol, 2.0 eq.) were added to 2 mL of acetone under a nitrogen atmosphere and reacted at 70°C. After the reaction was confirmed to be complete by thin-layer chromatography, the product was filtered through a short column, concentrated by rotary evaporation, and purified and separated by silica gel column chromatography. 25.3 mg of a colorless oily liquid (yield 71%) was obtained, namely compound 7a. The NMR data are as follows:

[0156] Compound 7a:

[0157] 1 H NMR(600MHz, CDCl3)δ6.35(d,J=16.7Hz,1H),6.22(s,1H),6.14–6.01(m,1H),5.38(d, J=17.2Hz,1H),5.26(d,J=10.4Hz,1H),4.51–4.42(m,2H),3.10(d,J=9.6Hz,1H),2.56– 2.45(m,3H),2.36(t,J=7.4Hz,1H),2.00–1.91(m,1H),1.70–1.63(m,1H),1.62–1.53(m ,4H),1.37(s,3H),1.34(s,3H),1.32–1.28(m,4H),0.88(t,J=6.7Hz,3H),0.73(s,3H).

[0158] The above method was used to synthesize 5-OH substituted cannabicycline derivatives. The specific products are as follows:

[0159] Compound 7b: (The raw materials are: 3a and iodomethane, the method of Example 4)

[0160] 1 H NMR (600MHz, CDCl3) δ6.35(s,1H),6.24(s,1H),3.75(s,3H),3.06(d,J=9.6Hz,1H),2.56–2.47(m,3H),2.36(t,J=7.4Hz,1H),2.00–1.92 (m,1H),1.68–1.64(m,1H),1.62–1.54(m,4H),1.38(s,3H),1.34(s,3H),1.34–1.28(m,4H),0.89(t,J=6.8Hz,3H),0.71(s,3H). The yield is 73%.

[0161] Compound 7c: (The raw materials are: 3a and iodoethane, the method of Example 4)

[0162] 1 H NMR(600MHz, CDCl3)δ6.33(s,1H),6.21(s,1H),3.99–3.92(m,2H),3.07(d, J=9.6Hz,1H),2.57–2.45(m,3H),2.36(t,J=7.3Hz,1H),2.02–1.92(m,1H), 1.69–1.63(m,1H),1.62–1.55(m,4H),1.40(t,J=7.0Hz,3H),1.38(s,3H),1 .35 (s, 3H), 1.33–1.28 (m, 4H), 0.88 (t, J = 6.7Hz, 3H), 0.74 (s, 3H). The yield is 57%.

[0163] Compound 7d: (The raw materials are: 3a and 1-iodopropane, the method of Example 4)

[0164] 1 H NMR(600MHz, CDCl3)δ6.34(s,1H),6.22(s,1H),3.93–3.87(m,1H),3.82–3.78(m,1H) ,3.09(d,J=9.6Hz,1H),2.55–2.47(m,3H),2.36(t,J=7.3Hz,1H),2.01–1.94(m,1H), 1.86–1.76 (m, 2H), 1.69–1.64 (m, 1H), 1.63–1.56 (m, 4H), 1.38 (s, 3H), 1.35 (s, 3H), 1.33–1.30 (m, 4H), 1.05 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 6.7 Hz, 3H), 0.74 (s, 3H). The yield was 48%.

[0165] Compound 7e: (The raw materials are: 3a and 3-bromopropyne, the method of Example 4)

[0166] 1H NMR(600MHz, CDCl3)δ6.38(s,1H),6.28(s,1H),4.66–4.58(m,2H),3.09(d,J=9.6Hz,1H),2.57–2.47(m,4H),2.37(t,J=7.3Hz,1H),2.00–1 .91(m,1H),1.69–1.64(m,1H),1.61–1.55(m,4H),1.38(s,3H),1.37(s,3H),1.34–1.29(m,4H),0.88(t,J=6.7Hz,3H),0.74(s,3H). The yield is 20%.

[0167] Synthesis of Compound 7f: After cannabicycline was synthesized according to the method of Example 2, 3a (94.2 mg, 0.3 mmol, 1.0 eq.), ethyl bromoacetate (50.1 mg, 0.3 mmol, 1.0 eq.), potassium iodide (50 mg, 0.3 mmol, 1.0 eq.), and potassium carbonate (82.9 mg, 0.6 mmol, 2.0 eq.) were added to 10 mL of acetone under a nitrogen atmosphere and heated at 70°C for 6 hours. After completion of the reaction as confirmed by thin-layer chromatography (TLC), the product was filtered through a short column, concentrated by rotary evaporation, and purified and isolated by silica gel column chromatography. The purified compound (84.2 mg, 0.2 mmol, 1.0 eq.) and potassium carbonate (82.8 mg, 0.6 mmol, 3.0 eq.) were added to 5 mL of methanol. After confirming the completion of the reaction by TLC, the product was filtered through a short column, concentrated by rotary evaporation, and purified by silica gel column chromatography to obtain 25 mg of a colorless oily liquid (total yield 23%), namely compound 7f. The NMR data are as follows:

[0168] Compound 7f:

[0169] 1 HNMR (600MHz, CDCl3) δ6.42 (s, 1H), 6.12 (s, 1H), 4.62 (d, J = 4.3Hz, 2H), 3.1 5(d,J=9.6Hz,1H),2.55(t,J=8.3Hz,1H),2.50(q,J=7.5Hz,2H),2.38(t,J= 7.3Hz,1H),2.00–1.94(m,1H),1.70–1.64(m,1H),1.61–1.54(m,4H),1.39( s,3H),1.38(s,3H),1.33–1.27(m,4H),0.88(t,J=6.8Hz,3H),0.75(s,3H).

[0170] Compound 7g was synthesized as follows: After cannabicycline was synthesized according to the method of Example 2, 3a (94.2 mg, 0.3 mmol, 1.0 eq.), 2-(Boc-amino)ethyl bromide (67.2 mg, 0.3 mmol, 1.0 eq.), potassium iodide (50 mg, 0.3 mmol, 1.0 eq.), potassium carbonate (82.9 mg, 0.6 mmol, 2.0 eq.), and acetone (10 mL) were heated and stirred at 70°C under a nitrogen atmosphere. After completion of the reaction as confirmed by thin-layer chromatography (TLC), the product was filtered through a short column, concentrated by rotary evaporation, and purified by silica gel column chromatography. The purified compound (92 mg, 0.2 mmol, 1.0 eq.) and trifluoroacetic acid (3.42 mg, 15 mol%, 0.03 eq.) were added to 5 mL of dichloromethane. After the reaction was confirmed to be complete by thin-layer chromatography, 2M NaOH solution was added to adjust the pH to 8-9, and the organic phase was extracted with ethyl acetate (25 mL x 3 times). After rotary evaporation and purification by silica gel column chromatography, 48 mg of a light yellow oily liquid (total yield 67%), compound 7g, was obtained. The NMR data are as follows:

[0171] Compound 7g:

[0172] 1 H NMR (600MHz, CDCl3) δ6.36(s,1H),6.21(s,1H),4.02–3.94(m,2H),3.64(s,2H),3.17–3.07(m,3H),2.55–2.44(m,3H),2.35(t,J=7.3Hz,1H) ,1.99–1.91(m,1H),1.67–1.61(m,1H),1.61–1.53(m,4H),1.36(s,3H ),1.33(s,3H),1.32–1.28(m,4H),0.87(t,J=6.8Hz,3H),0.71(s,3H).

[0173] Compound 7h was synthesized as follows: Under a nitrogen atmosphere, 7f (380.5 mg, 1 mmol, 1.0 eq.), tryptamine (160 mg, 1 mmol, 1.0 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, 229 mg, 1.2 mmol, 1.2 eq.), 1-hydroxybenzotriazole (HOBT, 148 mg, 1.1 mmol, 1.1 eq.), and triethylamine (350 μL) were added to 5 mL of dichloromethane. Completion of the reaction was confirmed by thin-layer chromatography (TLC). The product was then filtered through a short column, concentrated by rotary evaporation, and purified by silica gel column chromatography to yield 200 mg of a colorless oily liquid (39% yield), compound 7h.

[0174] Compound 7h:

[0175] 1 H NMR (600MHz, CDCl3) δ7.99(s,1H),7.56(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.19(t,J=7.6Hz,1H),7.09(t,J=7.5Hz,1H),6.64( s,1H),6.49(t,J=6.0Hz,1H),6.44(s,1H),6.19(s,1H),4.52(d,J=15.4Hz,1H),4.42(d,J=15.3Hz,1H),3.86–3.78(m,1H),3.56–3. 49(m,1H),3.04–2.97(m,1H),2.92–2.85(m,1H),2.71(d,J=9.5Hz,1H),2.52–2.48(m,2H),2.45(t,J=8.0Hz,1H),2.27(t,J=7.4Hz,1H),1.94–1.86(m,1H),1.64–1.53(m,5H),1.40(s,3H),1.34–1.27(m,4H),1.06(s,3H),0.88(t,J=6.2Hz,3H),0.54(s,3H). The yield was 39%.

[0176] Compound 7i was synthesized as follows: Under a nitrogen atmosphere, 7e (70.4 mg, 0.2 mmol, 1.0 eq.), p-toluenesulfonyl azide (59.1 mg, 0.3 mmol, 1.5 eq.), and cuprous thiophene-2-carboxylate (3.8 mg, 10 mol%, 0.1 eq.) were added to 5 mL of toluene. Completion of the reaction was confirmed by thin-layer chromatography (TLC). The product was then filtered through a short column, concentrated by rotary evaporation, and purified by silica gel column chromatography to yield 61.3 mg (56% yield) of compound 7i as a colorless oil.

[0177] Compound 7i:

[0178] 1H NMR (600MHz, CDCl3) δ8.16(s,1H),7.98(d,J=8.2Hz,2H),7.38(d,J=8.1Hz,2H),6.39(s ,1H),6.28(s,1H),5.16–5.09(m,2H),3.02(d,J=9.6Hz,1H),2.55–2.47(m,3H),2.45(s ,3H),2.32(t,J=7.4Hz,1H),2.00–1.89(m,1H),1.66–1.60(m,1H),1.59–1.52(m,4H),1.37(s,3H),1.34–1.26(m,4H),1.07(s,3H),0.88(t,J=6.8Hz,3H),0.64(s,3H). The yield was 39%.

[0179] Example 5 Esterification reaction of modified 5-OH

[0180] Taking 9a as an example: After synthesizing cannabicycline according to the method of Example 2, 3a (62.8 mg, 0.2 mmol, 1.0 eq.), 2-methylbutanoic acid 8 (30.6 mg, 0.3 mmol, 1.5 eq.), 4-dimethylaminopyridine (DMAP, 5 mg, 20 mol%, 0.02 eq.), and N,N'-dicyclohexylcarbodiimide (DCC, 50 mg, 0.24 mmol, 1.2 eq.) were added to 2 mL of dichloromethane under a nitrogen atmosphere. After the reaction was confirmed to be complete by thin-layer chromatography, the organic phase was extracted with ethyl acetate (25 mL x 3 times) and collected. After rotary evaporation and concentration, it was purified and separated by silica gel column chromatography. 37 mg of a colorless oily liquid (yield 46%) was obtained, namely compound 9a. The NMR data are as follows:

[0181] Compound 9a:

[0182] 1H NMR (600MHz, CDCl3) δ6.60 (s, 1H), 6.45 (d, J = 10.1Hz, 1H), 2.99 (dd, J = 15.2, 9.6Hz, 1H), 2.64–2.57(m,1H),2.56–2.48(m,3H),2.39(t,J=7.1Hz,1H),2.02–1.93(m,1H),1.88–1.8 1(m,1H),1.73–1.67(m,1H),1.65–1.55(m,5H),1.34(d,J=3.8Hz,3H),1.33–1.29(m,8H) ,1.27(d,J=6.9Hz,2H),1.06–1.00(m,3H),0.88(t,J=6.7Hz,3H),0.72(d,J=11.4Hz,3H).

[0183] Compound 9b: (The raw materials are: 3a and acetic anhydride, the method of Example 5)

[0184] 1 HNMR(600MHz, CDCl3)δ6.60(s,1H),6.48(s,1H),2.97(d,J=9.6Hz,1H),2.56–2.48(m,3H),2.38(t,J=7.5Hz,1H),2.29(s,3H),2.00–1.9 1(m,1H),1.72–1.67(m,1H),1.65–1.55(m,4H),1.36(s,3H),1.32(s,3H),1.31–1.27(m,4H),0.88(t,J=6.7Hz,3H),0.75(s,3H). The yield is 10%.

[0185] Compound 9c: (The raw materials are: 3a and propionyl chloride, the method of Example 5)

[0186] 1 HNMR (600 MHz, CDCl3) δ 6.60 (s, 1H), 6.48 (s, 1H), 2.97 (d, J = 9.6 Hz, 1H), 2.60–2.55 (m, 2H), 2.54–2.48 (m, 3H), 2.38 (t, J = 7.1 Hz, 1H), 1.99–1.91 (m, 1H), 1.72–1.67 (m, 1H), 1.65–1.55 (m, 4H), 1.35 (s, 3H), 1.31 (s, 3H), 1.30–1.28 (m, 4H), 1.26 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.73 (s, 3H). The yield was 31%.

[0187] Compound 9d: (Raw materials: 3a and n-decanoic acid, method of Example 5)

[0188] 1 HNMR (600 MHz, CDCl3) δ 6.59 (s, 1H), 6.47 (s, 1H), 2.97 (d, J = 9.6 Hz, 1H), 2.58–2.48 (m, 5H), 2.38 (t, J = 7.5 Hz, 1H), 1.99–1.93 (m, 1H), 1.74 (p, J = 7.5 Hz, 2H), 1.72–1.67 (m, 1H), 1.64–1.55 (m, 4H), 1.43–1.37 (m, 2H), 1.35 (s, 3H), 1.31 (s, 3H), 1.31–1.25 (m, 14H), 0.90–0.86 (m, 6H), 0.74 (s, 3H). The yield was 32%.

[0189] Compound 9e: (The raw materials are: 3a and 2-naphthylacetic acid, the method of Example 5)

[0190] 1 H NMR(600MHz, CDCl3)δ7.91–7.80(m,4H),7.54–7.47(m,3H),6.60(s,1H),6.45(s,1H),4 .03(d,J=3.6Hz,2H),3.00(d,J=9.6Hz,1H),2.53(t,J=8.5Hz,1H),2.49(td,J=7.5,2.8H z, 2H), 2.37 (t, J = 7.2 Hz, 1H), 2.00–1.91 (m, 1H), 1.73–1.66 (m, 1H), 1.64–1.52 (m, 4H), 1.35 (s, 3H), 1.31–1.28 (m, 4H), 1.27 (s, 3H), 0.87 (t, J = 6.8 Hz, 3H), 0.74 (s, 3H). The yield was 31%.

[0191] Compound 9f: (Raw materials: 3a and acryloyl chloride, method of Example 5)

[0192] 1H NMR (600MHz, CDCl3) δ6.63–6.57(m,2H),6.52(s,1H),6.32(dd,J=17.3,10.5Hz, 1H),6.01(d,J=10.5Hz,1H),2.99(d,J=9.6Hz,1H),2.56–2.49(m,3H),2.37(t,J =7.5Hz,1H),2.00–1.93(m,1H),1.72–1.67(m,1H),1.64–1.56(m,4H),1.36(s,3 H), 1.31 (t, J=6.6Hz, 4H), 1.26 (s, 3H), 0.91–0.86 (m, 3H), 0.75 (s, 3H). The yield is 46%.

[0193] Compound 9g: (Raw materials: 3a and cinnamic acid, method of Example 5)

[0194] 1 H NMR(600MHz, CDCl3)δ7.88(d,J=16.0Hz,1H),7.62–7.57(m,2H),7.46–7.42(m,3H),6 .66–6.62(m,2H),6.57(s,1H),3.06(d,J=9.6Hz,1H),2.58–2.51(m,3H),2.38(t,J=7 .5Hz,1H),2.06–1.94(m,1H),1.73–1.68(m,1H),1.62(hept,J=7.2,6.1Hz,4H),1.38(s,3H),1.35–1.30(m,4H),1.29(s,3H),0.89(t,J=6.3Hz,3H),0.81(s,3H). The yield was 38%.

[0195] Compound 9h: (The raw materials are: 3a and trans-4-methoxycinnamic acid, the method of Example 5)

[0196] 1HNMR (600MHz, CDCl3) δ7.82(d,J=15.9Hz,1H),7.55(d,J=8.4Hz,2H),6.94(d,J=8.3Hz,2H) ,6.62(s,1H),6.55(s,1H),6.49(d,J=15.9Hz,1H),3.86(s,3H),3.05(d,J=9.6Hz,1H),2.57 –2.50(m,3H),2.37(t,J=7.5Hz,1H),2.04–1.95(m,1H),1.72–1.68(m,1H),1.65–1.56(m,4H),1.37(s,3H),1.33–1.29(m,4H),1.28(s,3H),0.88(t,J=6.3Hz,3H),0.80(s,3H). The yield was 57%.

[0197] Compound 9i: (The raw materials are: 3a and isonicotinic acid, the method of Example 5)

[0198] 1 H NMR(600MHz, CDCl3) δ8.88(d,J=4.9Hz,2H),8.00(d,J=5.1Hz,2H),6.69(s, 1H),6.56(s,1H),3.01(d,J=9.6Hz,1H),2.58–2.53(m,3H),2.35(t,J=7.6Hz ,1H),2.06–1.95(m,1H),1.74–1.68(m,1H),1.67–1.57(m,4H),1.37(s,3H), 1.35–1.29 (m, 4H), 1.06 (s, 3H), 0.89 (t, J = 6.7Hz, 3H), 0.79 (s, 3H). The yield is 51%.

[0199] Compound 9j: (Raw materials: 3a and 2-furoic acid, method of Example 5)

[0200] 1H NMR (600MHz, CDCl3) δ7.67(d,J=1.7Hz,1H),7.36(d,J=3.5Hz,1H),6.64(s,1H),6. 59(dd,J=3.5,1.7Hz,1H),6.57(s,1H),3.05(d,J=9.6Hz,1H),2.57–2.49(m,3H),2. 35(t, J=7.5Hz,1H),2.02–1.94(m,1H),1.72–1.67(m,1H),1.64–1.55(m,4H),1.37(s,3H),1.34–1.29(m,4H),1.16(s,3H),0.88(t, J=6.7Hz,3H),0.80(s,3H). The yield was 37%.

[0201] Compound 9k: (The raw materials are: 3a and 4-morpholineacetic acid, the method of Example 5)

[0202] 1 H NMR (600MHz, CDCl3) δ6.53 (s, 1H), 6.42 (s, 1H), 3.71 (t, J = 4.7Hz, 4H), 3.43–3.3 4(m,2H),2.89(d,J=9.7Hz,1H),2.61(t,J=4.8Hz,4H),2.48–2.40(m,3H),2.31(t ,J=7.6Hz,1H),1.92–1.84(m,1H),1.65–1.59(m,1H),1.58–1.47(m,4H),1.28(s, 3H), 1.25 (s, 3H), 1.24–1.20 (m, 4H), 0.80 (t, J = 6.7Hz, 3H), 0.66 (s, 3H). The yield is 45%.

[0203] Compound 91: (The starting materials are: 3a and 3-(4-morpholinyl)propionic acid, the method of Example 5)

[0204] 1H NMR (600MHz, CDCl3) δ6.60(s,1H),6.49(s,1H),3.73(t,J=4.6Hz,4H),2.97(d,J=9 .6Hz,1H),2.80(t,J=7.2Hz,2H),2.73(q,J=7.9,7.2Hz,2H),2.54–2.49(m,7H),2.3 8(t, J=7.6Hz,1H),2.01–1.91(m,1H),1.77–1.66(m,1H),1.65–1.54(m,4H),1.35(s,3H),1.31(s,3H),1.32–1.28(m,4H),0.87(t, J=6.7Hz,3H),0.73(s,3H). The yield was 57%.

[0205] Compound 9m: (The raw materials are: 3a and N,N-dimethylglycine, the method of Example 5)

[0206] 1 H NMR (600MHz, CDCl3) δ6.59(s,1H),6.49(s,1H),3.47–3.37(m,2H),2.97(d,J=9.6Hz,1H),2.57–2.48(m,3H),2.44(s,6H),2.38(t,J=7.5Hz,1H),1 .99–1.91(m,1H),1.72–1.65(m,1H),1.64–1.53(m,4H),1.34(s,3H),1.3 1 (s, 3H), 1.31–1.27 (m, 4H), 0.87 (t, J = 6.7Hz, 3H), 0.72 (s, 3H). The yield is 34%.

[0207] Compound 9n: (The raw materials are: 3a and 3-(dimethylamino)propionic acid, the method of Example 5)

[0208] 1 HNMR(600MHz, CDCl3)δ6.59(s,1H),6.48(s,1H),2.97(d,J=9.6Hz,1H),2.75–2.69(m,4H),2.57–2.47(m,3H),2.38(t,J=7.6Hz,1H),2.30(s,6H), 2.00–1.90(m,1H),1.73–1.66(m,1H),1.65–1.54(m,4H),1.35(s,3H),1. 31 (s, 3H), 1.31–1.28 (m, 4H), 0.87 (t, J = 6.7Hz, 3H), 0.73 (s, 3H). The yield is 15%.

[0209] Compound 9o: (The raw materials are: 3a and 1-adamantanecarboxylic acid, the method of Example 5)

[0210] 1 H NMR (600MHz, CDCl3) δ6.61–6.59(m,1H),6.35–6.32(m,1H),3.02(d,J=9.5Hz,1H) ,2.51(dt,J=11.6,8.5Hz,3H),2.40(t,J=8.7Hz,1H),2.10–2.05(m,8H),2.01(dt ,J=13.2,6.6Hz,1H),1.81–1.70(m,6H),1.68–1.60(m,2H),1.59–1.55(m,4H),1. 31 (s, 3H), 1.31 (s, 4H), 1.29 (s, 3H), 0.88 (t, J = 6.7Hz, 3H), 0.66 (s, 3H). The yield is 15%.

[0211] Compound 9p: (The raw materials are: 3a and ferrocenecarboxylic acid, the method of Example 5)

[0212] 1 H NMR (600 MHz, CDCl3) δ 6.63 (s, 1H), 6.56 (s, 1H), 4.94 (s, 2H), 4.50 (s, 2H), 4.32 (s, 5H), 3.03 (d, J = 9.6 Hz, 1H), 2.60–2.51 (m, 3H), 2.35 (t, J = 7.5 Hz, 1H), 2.02–1.95 (m, 1H), 1.72–1.66 (m, 1H), 1.63–1.56 (m, 4H), 1.36 (s, 3H), 1.35–1.32 (m, 4H), 1.22 (s, 3H), 0.89 (t, J = 6.6 Hz, 3H), 0.77 (s, 3H). The yield was 72%.

[0213] Compound 9q: (Raw materials: 3h and propionic anhydride, method of Example 5)

[0214] 1H NMR (600 MHz, CDCl3) δ 6.59 (s, 1H), 6.48 (s, 1H), 2.97 (d, J = 9.6 Hz, 1H), 2.60–2.55 (m, 2H), 2.54–2.49 (m, 3H), 2.38 (t, J = 7.5 Hz, 1H), 2.00–1.92 (m, 1H), 1.72–1.67 (m, 1H), 1.64–1.55 (m, 4H), 1.35 (s, 3H), 1.31 (s, 3H), 1.26 (h, J = 6.7 Hz, 13H), 0.87 (t, J = 6.9 Hz, 3H), 0.73 (s, 3H). The yield was 47%.

[0215] Compound 9r: (Raw materials: 3e and propionic anhydride, method of Example 5)

[0216] 1 HNMR (600 MHz, CDCl3) δ 6.59 (s, 1H), 6.48 (s, 1H), 2.97 (d, J = 9.6 Hz, 1H), 2.61–2.54 (m, 2H), 2.54–2.50 (m, 3H), 2.38 (t, J = 7.5 Hz, 1H), 2.01–1.92 (m, 1H), 1.72–1.67 (m, 1H), 1.64–1.54 (m, 4H), 1.35 (s, 3H), 1.34–1.32 (m, 2H), 1.31 (s, 3H), 1.26 (t, J = 7.5 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H), 0.73 (s, 3H). The yield was 49%.

[0217] Compound 9s was synthesized as follows: After cannabicycline was synthesized according to the method of Example 2, 3a (157 mg, 0.5 mmol, 1.0 eq.), 5-bromovaleric acid (108.6 mg, 0.6 mmol, 1.2 eq.), 4-dimethylaminopyridine (DMAP, 12.2 mg, 20 mol%, 0.02 eq.), and N,N'-dicyclohexylcarbodiimide (DCC, 124 mg, 0.6 mmol, 1.2 eq.) were added to 2 mL of dichloromethane under a nitrogen atmosphere. After completion of the reaction as confirmed by thin-layer chromatography (TLC), the mixture was filtered through a short column, concentrated by rotary evaporation, and purified by silica gel column chromatography. The purified product (160 mg, 0.3 mmol, 1.0 eq.) and triphenylphosphine (157.2 mg, 0.6 mmol, 2.0 eq.) were added to 5 mL of toluene and stirred at 110°C for 3 hours. After confirming the completion of the reaction by TLC, the product was concentrated by rotary evaporation and purified by silica gel column chromatography to obtain 61 mg of a colorless oily liquid (yield 28%), namely compound 9s. The NMR data are as follows:

[0218] Compound 9s:

[0219] 1 H NMR (600MHz, CDCl3) δ7.84 (dd, J=12.8, 7.8Hz, 6H), 7.76 (t, J=7.7Hz, 3H), 7.70–7.63 (m, 6H), 6.56 (s,1H),6.31(s,1H),4.04–3.90(m,2H),2.83(d,J=9.6Hz,1H),2.71–2.55(m,2H),2.51–2.42(m,3H ),2.32(t,J=7.6Hz,1H),2.17–2.09(m,2H),1.94–1.87(m,1H),1.85–1.78(m,2H),1.68–1.62(m,1H ),1.61–1.50(m,4H),1.32(s,3H),1.30–1.26(m,4H),1.19(s,3H),0.88–0.85(m,3H),0.64(s,3H).

[0220] Compound 9t was synthesized as follows: After cannabicycline was synthesized according to the method of Example 2, 3a (157 mg, 0.5 mmol, 1.0 eq.), 5-bromovaleric acid (108.6 mg, 0.6 mmol, 1.2 eq.), 4-dimethylaminopyridine (DMAP, 12.2 mg, 20 mol%, 0.02 eq.), and N,N'-dicyclohexylcarbodiimide (DCC, 124 mg, 0.6 mmol, 1.2 eq.) were added to 2 mL of dichloromethane under a nitrogen atmosphere. Completion of the reaction was confirmed by thin-layer chromatography (TLC), followed by filtration through a short column, concentration by rotary evaporation, and purification and isolation by silica gel column chromatography. Under a nitrogen atmosphere, the purified product (95.4 mg, 0.2 mmol, 1.0 eq.), 4-hydroxycoumarin (81 mg, 0.5 mmol, 2.5 eq.), and potassium carbonate (82.8 mg, 0.6, 3.0 eq.) were added to 10 mL of acetone and stirred at 70°C. After completion of the reaction as confirmed by thin-layer chromatography (TLC), the organic phase was extracted with ethyl acetate (25 mL x 3 times) and collected. After rotary evaporation and purification by silica gel column chromatography, 20 mg of a colorless oil (18% yield) was obtained, compound 9t. The NMR data are as follows:

[0221] Compound 9t:

[0222] 1H NMR (600MHz, CDCl3) δ7.83(d,J=7.8Hz,1H),7.55(t,J=7.9Hz,1H),7.32(d,J=8.3Hz,1H),7.26(t,J =7.2Hz,1H),6.61(s,1H),6.48(s,1H),5.68(s,1H),4.19(t,J=5.8Hz,2H),2.96(d,J=9.6Hz,1H),2 .73–2.63(m,2H),2.59–2.45(m,3H),2.38(t,J=7.5Hz,1H),2.08–1.93(m,5H),1.71–1.67(m,1H),1 .65–1.54(m,4H),1.35(s,3H),1.30(s,3H),1.30–1.27(m,4H),0.87(t,J=6.7Hz,3H),0.73(s,3H).

[0223] Example 6 Synthesis of Other Types of Cannabicycline Derivatives

[0224] Taking 13a as an example: After synthesizing cannabicycline according to the method of Example 2, 3a (314 mg, 1 mmol, 1.0 eq.), trifluoromethanesulfonic anhydride 10 (423 mg, 1.5 mmol, 1.5 eq.), and pyridine (173 μL, 1.2 mmol, 1.2 eq.) were added to 2 mL of dichloromethane at 0°C under a nitrogen atmosphere. After completion of the reaction as determined by thin-layer chromatography (TLC), the organic phase was extracted with ethyl acetate (25 mL x 3 times) and collected. After rotary evaporation and concentration, the product was purified and isolated by silica gel column chromatography. 420 mg of a colorless oily liquid (94% yield) was obtained, namely, compound 11.

[0225] Under a nitrogen atmosphere, 11 (89.2 mg, 0.2 mmol, 1.0 eq.), 4-pyridineboronic acid 12 (110.7 mg, 0.5 mmol, 2.5 eq.), potassium carbonate (55.2 mg, 0.4 mmol, 2.0 eq.), and bis(triphenylphosphine)palladium dichloride (7 mg, 5 mol%) were added to a 1,4-dioxane:water mixture (8 mL, V:V = 3:1). After completion of the reaction as determined by thin-layer chromatography (TLC), the organic phase was extracted with ethyl acetate (25 mL x 3 times) and collected. After rotary evaporation and concentration, the product was purified and isolated by silica gel column chromatography. 67 mg of a colorless oily liquid (89% yield) was obtained, namely compound 13a. The NMR data are as follows:

[0226] Compound 13a:

[0227] 1H NMR (600MHz, CDCl3) δ8.60(s,2H),7.21(s,2H),6.78(s,1H),6.59(s,1H),3.22(d,J=9.6Hz,1H),2.56–2.47(m,3H),2.31(t,J=8.3Hz,1H), 2.02–1.94(m,1H),1.76–1.67(m,1H),1.65–1.55(m,4H),1.33–1.30(m,4H),1.29(s,3H),0.87(t,J=5.8Hz,3H),0.83(s,3H),0.52(s,3H).

[0228] Using the above method, C-5 coupled cannabicycline derivatives were synthesized, and the specific products are as follows:

[0229] Compound 13b: (The raw materials are: 11 and phenylboronic acid, the method of Example 6)

[0230] 1 H NMR (600MHz, CDCl3) δ7.36(t,J=7.5Hz,2H),7.30(t,J=7.4Hz,1H),7.25(d,J=3.9Hz,2H ),6.73(s,1H),6.67(s,1H),3.25(d,J=9.8Hz,1H),2.60(t,J=8.5Hz,1H),2.53–2.50(m ,2H),2.42(t,J=7.7Hz,1H),2.04–1.96(m,1H),1.74–1.67(m,1H),1.59–1.55(m,4H),1.40(s,3H),1.32–1.30(m,4H),1.29(s,3H),0.88(t,J=7.1Hz,3H),0.71(s,3H). The yield was 13%.

[0231] Compound 13c: (The raw materials are: 1,1 and 3-thiophene boronic acid, the method of Example 5)

[0232] 1H NMR (600MHz, CDCl3) δ7.33–7.30(m,1H),7.12(s,1H),7.07(d,J=4.9Hz,1H),6.72(s,1H),6.69(s,1H),3.36(d,J=9.7Hz,1H),2.55–2.50(m ,3H), 2.31(t,J=6.9Hz,1H),2.03–1.94(m,1H),1.74–1.66(m,1H),1.65–1.56(m,4H),1.31(s,6H),0.90–0.85(m,7H),0.52(s,3H). The yield is 82%.

[0233] Synthesis of Compound 13d: Under a nitrogen atmosphere, 11 (89.2 mg, 0.2 mmol, 1.0 eq.), 1,1'-bis(diphenylphosphino)ferrocene (7.3 mg, 5 mol%, 0.05 eq.), palladium acetate (11.2 mg, 5 mol%, 0.05 eq.), triethylamine (300 μL), and formic acid (80 μL) were added to 2 mL of tetrahydrofuran and stirred at 60°C for 4 hours. Completion of the reaction was confirmed by thin-layer chromatography (TLC). The organic phase was extracted with ethyl acetate (3 times with 25 mL). After rotary evaporation and subsequent purification by silica gel column chromatography, 67 mg of a colorless oil (89% yield) was obtained, namely, Compound 13d.

[0234] Compound 13d:

[0235] 1 H NMR (600MHz, CDCl3) δ6.79(d,J=7.6Hz,1H),6.70(s,1H),6.68(s,1H),3.02(d,J=9.6Hz,1H),2.62(t,J=8.6Hz,1H),2.53(t,J=7.9Hz,2H),2.39(t,J= 7.6Hz,1H),1.98–1.89(m,1H),1.73–1.66(m,1H),1.65–1.54(m,4H),1.38( s,3H),1.35(s,3H),1.33–1.30(m,4H),0.89(t,J=6.7Hz,3H),0.72(s,3H).

[0236] Examples 7-9: One-pot synthesis of cannabicycline using different photocatalysts

[0237] The preparation method and raw materials of this embodiment are the same as those of Example 1, except that different catalysts are used, as shown in Table 1.

[0238] Table 1. Effect of different photocatalysts on the yield of one-pot synthesis products

[0239] Application Example 1 Activity Screening of Cannabicycline and Its Derivatives

[0240] The purpose of this application example is to explore the killing effect of cannabicyclol and its derivatives on various cancer stem cells (CSCs).

[0241] Test samples: cannabicycline and its derivatives 3a to 13d obtained in Examples 1 to 6, 1 H-NMR (600 MHz, CDCl3) and 13 C-NMR (151 MHz, CDCl3) showed that the structure was correct and further experiments could be performed.

[0242] Primary activity screening: ① Dissolve the above-mentioned synthetic compounds in DMSO to prepare a 40 μg / mL solution of cannabicyclol and its derivatives.

[0243] ② Set up a control group: 200 μL DMSO solvent.

[0244] ③ The dilution was performed in a two-fold gradient from 3a to 13d to obtain solutions of cannabicyclol and its derivatives with concentrations of 40, 20, 10, 5, 2.5, 1.25, 0.625 and 0.3125 μg / mL, respectively.

[0245] ④1) Three glioblastoma stem cells (GSC-3, GSC-12 and GSC-18), three pancreatic cancer cell line-derived stem cells (PANC-1-CSC, BXPC-3-CSC and ASPC1-CSC), three liver cancer cell line-derived stem cells (HepG2-CSC, MHCC97H-CSC and SMMC7721-CSC), HEK-293T, 16 tumor cell lines (U251, U87, T98G, PANC1, BXPC3, ASPC1, HepG2, MHCC97H, SMMC7721, PC3, SKOV3, MDA-MB231, A549, HCT116, HEC-1B, MKN28 and GSC-3diff and GSC-12diff cells differentiated from glioma stem cells GSC-3 and GSC-12 (all cells were provided by the Tumor Animal Model Preparation and Application Laboratory of West China Hospital, Sichuan University) were cultured at a rate of 2 × 10 4 The cells were inoculated into a 96-well plate at a concentration of 100 μL / well, and 100 μL of culture medium was added to each well.

[0246] 2) HEK-293T, GSC-3diff, GSC-12diff, and 16 tumor cell lines were added to DMEM+10% FBS+1% double-antibody culture medium, and CSCs were added to serum-free stem cell culture medium consisting of DMEM / F12+EGF (20 ng / mL)+bFGF (20 ng / mL)+B-27 (1×)+1% double-antibody culture medium.

[0247] ⑥ Place the inoculated cells in a cell culture incubator and culture for 24 hours. When the cells are well attached, discard the culture medium in the 96-well plate.

[0248] ⑦Add 200 μL of cannabicyclol and its derivative solutions of different concentrations to the cultured cells.

[0249] ⑧The experiment was repeated 3 times.

[0250] ⑨ Place the 96-well plate in a cell culture incubator and continue culturing at 37°C, 5% CO2 for 72 hours. Discard 100 μL of cannabicycline and its derivative solution (discard 100 μL of DMSO solvent in the control group) from each well, add 20 μL of MTS (CellTiter AQueous Non-Radioactive Cell Proliferation Assay, #G3581), mix well, and continue incubating in the cell culture incubator for 2 hours.

[0251] ⑩Measure the absorbance at 490 nm on a microplate reader and calculate the IC 50 value.

[0252] The above method was used to conduct a preliminary screening of cannabicyclol and its derivatives, and the preliminary screening activity data were summarized in Table 2.

[0253] Table 2. Preliminary screening activity of some cannabicycline derivatives against 3#-GSC, U251, and 293T

[0254] Initial screening of cannabicycline and its derivatives against 3#-GSC, 293T, and U251 revealed that, among derivatives 3a to 3i with different alkyl chain lengths, the compound with zero length (3b) exhibited selective anti-glioma stem cell activity; those substituted with pentyl (3a) or hexyl (3f) exhibited some selective anti-glioma stem cell activity. Among derivatives 3k to 3t with aryl, substituted aryl, or heteroaryl groups, with the exception of m-methylphenyl (3m), p-tert-butylphenyl (3p), and heteroaromatic ring (3t), which exhibited weak selective anti-glioma stem cell activity, the aryl-substituted products showed no significant selective anti-glioma stem cell activity. Activity data for derivatives with different substituents introduced into the C-12 position of cannabicycline revealed that 3u to 3z exhibited some selective anti-glioma stem cell activity. Initial screening of derivatives at the 5-OH position of cannabicycline showed that the anti-glioma stem cell activity of etherified products 7a~7i disappeared, while the activity and selectivity were significantly weakened when the 5-OH hydroxyl group of cannabicycline was coupled to a phenyl group (13b); the anti-glioma stem cell activity of esterified products 9a~9t showed that when an acetyl group (9b) or a propionyl group (9c) was introduced, the activity and selectivity were maintained, and when certain water-soluble alkylamines (9k~9n) were introduced, the anti-glioma stem cell activity and selectivity were maintained and improved.

[0255] Application Example 2

[0256] Using the scheme in Application Example 1, the IC values ​​of cannabicycline (compound 3a) on 9 types of tumor stem cells were measured. 50 The values ​​are shown in Table 3. The IC values ​​of cannabicycline against the remaining tumor cells (HEK-293T, GSC-3diff, GSC-12diff and 16 tumor cell lines) 50 The values ​​are shown in Table 4.

[0257] Table 3. IC values ​​of cannabicycline against different cancer stem cells 50 value

[0258] The data in Table 3 show that cannabicyclol has significant inhibitory activity against nine different cancer stem cell lines.

[0259] Table 4. IC values ​​of cannabicycline against HEK-293T, GSC-3diff, GSC-12diff, and 16 tumor cell lines 50 value

[0260] The data in Table 4 show that cannabicycline has no obvious inhibitory effect on HEK-293T, GSC-3diff, GSC-12diff and 16 tumor cell lines.

[0261] Through the above data analysis, cannabicyclol can specifically kill tumor stem cell lines without affecting ordinary tumor cell lines, and has the characteristics of specifically killing tumor stem cells.

[0262] Application Example 3: Preferred cannabicycline derivatives specifically kill tumor stem cells

[0263] Using the scheme in Application Example 1, compounds 3t, 9a, 9c, 9k, 9l, 9m, 9n, 13b and other cannabicycline derivatives were selected, and the IC values ​​of the selected compounds were determined. 50 The results are summarized in Table 5. As can be seen from Table 5, the IC values ​​of the preferred cannabicycline derivatives specific for 3#-GSC glioma stem cells are 50 The values ​​ranged from 2.901 to 9.325 μg / mL, and the IC values ​​for normal cells (293T) were 50 The values ​​were greater than 16.39 μg / mL, and most compounds were greater than 40 μg / mL. The IC 50 The values ​​were greater than 13.97 μg / mL, and some compounds were greater than 40 μg / mL. The results showed that some cannabicyclol derivatives have the ability to selectively kill tumor stem cells.

[0264] Table 5. IC values ​​of preferred compounds for cancer stem cells, tumor cells and normal cells 50 value

[0265] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A cannabicycline derivative, characterized in that The cannabicycline derivatives comprise the following general structural formula: Among them, R 1 R comprises hydrogen, linear alkyl, branched alkyl, aryl or heteroaryl; 2 and R 3 R independently comprises hydrogen, straight chain alkyl, branched chain alkyl, alkenyl, ester, heteroalkyl, aryl or heteroaryl; 4 and R 5 R independently comprises hydrogen, straight chain alkyl, branched chain alkyl, aryl or heteroaryl.

2. The cannabicycline derivative according to claim 1, characterized in that The R 1 , R 2 , R 3 , R 4 and R 5 When there are substituents in the group, there are one or more substituents, and the substituents are independently selected from the following groups: C1 to C13 straight chain or branched alkyl, halogen atoms, C1 to C13 straight chain or branched alkoxy, cyano, amino, amine, hydroxyl, ester, alkenyl, alkynyl, C3 to C10 cycloalkyl, C3 to C10 heterocycloalkyl, substituted or unsubstituted aryl and heteroaryl.

3. The cannabicycline derivative according to claim 2, characterized in that The R 1 , R 2 , R 3 , R 4 and R 5 Independently selected from one of the following structures:

4. The cannabicycline derivative according to claim 1, characterized in that The cannabicycline derivative comprises the following structural formula:

5. The cannabicycline derivative according to claim 1, characterized in that The cannabicycline derivative comprises the following structural formula: The structural formulas of compounds 3b, 3d, 3j, 3l-3o, 3q to 3z are as follows: The structural formula of compound 5 is: The structural formulas of compounds 7a to 7i are: The structural formulas of compounds 9a to 9t are: The structural formulas of compounds 13a to 13d are:

6. The method for preparing the cannabicycline derivative according to claim 4 or 5, characterized in that: (1) The preparation method of compounds 3a to 3z comprises the following steps: The compound of formula I, the compound of formula II and ethylenediamine are dissolved in toluene for reaction, and then a photocatalytic reaction is continued under the action of a protective atmosphere and a photocatalyst to obtain a cannabicyclol derivative of formula III; Where R 1 R comprises hydrogen, linear alkyl, branched alkyl, aryl or heteroaryl; 2 and R 3 R independently comprises hydrogen, straight chain alkyl, branched chain alkyl, alkenyl, ester, heteroalkyl, aryl or heteroaryl; 4 and R 5 independently contain hydrogen, straight chain alkyl, branched chain alkyl, aryl or heteroaryl; (2) The preparation method of compound 5 comprises the following steps: The cannabichromene derivative and 2,3-dichloro-5,6-dicyanobenzoquinone are reacted under the action of indium trifluoromethanesulfonate to obtain a colorless oily liquid, namely compound 5; The structural formula of the cannabinoid derivative is: (3) The preparation method of compounds 7a to 7g comprises the following steps: The cannabicycline derivative of formula III is mixed with a halogen-containing compound and reacted under the action of a base; the halogen-containing compound comprises a halogenated alkyl, a halogenated ester or a halogenated amine; (4) The preparation method of compound 7h comprises the following steps: Compound 7f, tryptamine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and triethylamine are mixed and reacted to obtain a colorless oily liquid, namely compound 7h; (5) The preparation method of compound 7i comprises the following steps: Compound 7e, p-toluenesulfonyl azide and cuprous thiophene-2-carboxylate are mixed and reacted to obtain a colorless oily liquid, namely compound 7i; (6) The preparation method of compounds 9a to 9r comprises the following steps: Compound 3a and an acid are reacted in the presence of a catalyst to obtain a colorless oily liquid; the acid has the structural formula: Where R 7 It comprises one of 2-methylbutyl, ethyl, propyl, n-decyl, 2-naphthylethyl, propenyl, 3-phenylpropenyl, trans-4-methoxy-3-phenylpropenyl, 4-pyridylmethyl, furan, 4-morpholinoethyl, 4-morpholinopropyl, N,N-dimethylethyl, 1-adamantylmethyl and ferrocenylmethyl; (7) The preparation method of compounds 9s and 9t comprises the following steps: Compound 3a and 5-bromovaleric acid are reacted in the presence of a catalyst to obtain an intermediate product, and the intermediate product is further reacted with a substituted compound to obtain a product; the substituted compound comprises triphenylphosphine or 4-hydroxycoumarin; (8) The preparation method of compounds 13a to 13c comprises the following steps: Compound 3a, trifluoromethanesulfonic anhydride and pyridine are mixed in a solvent for reaction to obtain an intermediate product, and the intermediate product is reacted with a substituted boronic acid in the presence of a catalyst; The structural formula of the intermediate product is: The structural formula of the substituted boronic acid is: Where R 8 is pyridine, phenyl or thiophene; (9) The preparation method of compound 13d comprises the following steps: Compound 3a, trifluoromethanesulfonic anhydride and pyridine are mixed in a solvent for reaction to obtain an intermediate product, and the intermediate product, 1,1'-bis(diphenylphosphino)ferrocene, palladium acetate, formic acid and triethylamine are mixed in a solvent for reaction to obtain compound 13d.

7. The preparation method according to claim 6, characterized in that: In (1), the photocatalyst comprises one or more of [Ir{dFCF3ppy}2(bpy)]PF6, [Ir{dFCF3ppy}2(dtbbpy)]PF6, [Ir(ppy)2(dtbbpy)]PF6, fac-Ir(ppy)3, [Ru(bpy)3]Cl2, [Ru(bpy)3](PF6)2 and Eosin Y, and the illumination conditions are: wavelength 365-560nm, illumination time 30min-5h; The molar ratio of the compound of formula I, the compound of formula II, ethylenediamine and the photocatalyst is 1:1:0.01-0.1:0.005-0.

02.

8. The preparation method according to claim 6, characterized in that: In said (3), the molar ratio of the cannabicyclophenol derivative of formula III, the halogen-containing compound and the base is 1:2:1-5, the reaction temperature is 60-70°C, and the reaction time is 5-10 hours.

9. The preparation method according to claim 6, characterized in that: In the above (6), the molar ratio of compound 3a, acid and catalyst is 1:1-2:1-3, the reaction temperature is 20-40°C, and the reaction time is 5-10 hours.

10. Use of the cannabicycline derivative according to any one of claims 1 to 5 in the preparation of a drug for killing tumor stem cells or inhibiting the formation of tumor stem cells, characterized in that: The medicine further comprises pharmaceutically acceptable excipients, which include diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.

11. The use according to claim 10, characterized in that: The tumor stem cells include glioblastoma stem cells, pancreatic cancer stem cells and liver cancer stem cells; The glioblastoma stem cells include GSC3, GSC12 and GSC18; The pancreatic cancer stem cells include PANC-1-CSC, BXPC-3-CSC and ASPC-1-CSC; The liver cancer stem cells include HepG2-CSC, MHCC97H-CSC and SMMC7721-CSC.