Quinoid chalcone with isopentenyl in A ring and anti-diabetes application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses quinoid chalcones with an A ring having an isopentenyl group and an anti-diabetes application thereof. The compound provided by the invention has a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof, and the preparation method comprises the following steps: (1) synthesizing 3, 5-dihydroxy-2-acetyl-6, 6-diisopentenyl cyclohexane-2, 4-dienone, (2) synthesizing a quinone chalcone compound with an A ring having an isopentenyl group, and (3) synthesizing a quinoid chalcone compound with an A ring having an isopentenyl group. And (3) synthesizing a dimer compound with an A ring having isopentenyl and quinoid chalcone bridged by methylene. The compound provided by the invention is simple in preparation method and has a remarkable anti-diabetic effect. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and is a type of dimer compound of quinone chalcone with an isopentenyl group in the A ring connected by a methylene bridge, a preparation method, and a pharmaceutical composition containing the same and its application in anti-diabetic activity. Background Art

[0002] Protein tyrosine phosphatase 1B (PTP1B), a key member of the protein tyrosine phosphatase family, plays a crucial negative regulatory role in the insulin signaling pathway. Studies have demonstrated that the application of PTP1B inhibitors in insulin-sensitive cells increases the phosphorylation levels of the insulin receptor and its substrates, acting as insulin analogs and insulin sensitizers. Knocking out the PTP1B gene or inhibiting PTP1B protein and mRNA expression in vivo with antisense oligonucleotides (ASOs) not only significantly improves insulin sensitivity in mice but also significantly reduces the incidence of obesity. PTP1B is a novel target for the treatment of insulin resistance and related metabolic diseases.

[0003] α-glucosidase is widely distributed throughout the body and plays a crucial role in the body's metabolic processes. It degrades polysaccharides in food into monosaccharides, allowing them to be absorbed and utilized by the body during metabolism. α-glucosidase also participates in the biosynthesis and catabolism of glycolipids and glycoproteins in the body. Carbohydrates in food are broken down into oligosaccharides α-glucose and fructose by the action of amylase in saliva and pancreatic juice. These oligosaccharides are then broken down by glycosidases at the brush border of the small intestinal mucosal cells and absorbed into the bloodstream by the epithelial cells of the upper small intestine. α-glucosidase inhibitors can reduce the activity of α-glucosidase in the body, thereby effectively controlling the body's absorption of monosaccharides and lowering blood sugar levels.

[0004] Isopentenyl groups are a common and important group in medicinal chemistry. Literature research reveals the presence of numerous isopentenyl phloroglucinol compounds in natural products, which exhibit significant biological activity, making this class of compounds a hot topic in medicinal chemistry research. Previous research by our group synthesized a class of isopentenylquinone chalcone compounds that exhibited moderate activity. Furthermore, natural products such as quinone chalcone dimers and phloroglucinol dimers also exhibit a wide range of biological activities. To further identify promising lead compounds, we combined previous research with literature research and, inspired by this, designed and synthesized a class of dimers of quinone chalcone compounds with an isopentenyl group in the A ring, bridged by a methylene group. In vitro pharmacological experiments demonstrated that some of these compounds exhibited potent inhibitory activity against recombinant human PTP1B (protein tyrosine phosphatase 1B) and α-glucosidase. Summary of the Invention

[0005] The object of the present invention is to provide a class of dimer compounds of quinone chalcone with an isopentenyl group in the A ring connected by a methylene bridge or a pharmaceutically acceptable salt thereof.

[0006] Another object of the present invention is to provide a method for preparing the compound.

[0007] Another object of the present invention is to provide a pharmaceutical composition comprising an effective dose of a class of dimer compounds of quinone chalcone having an isopentenyl group in ring A linked by a methylene bridge and a pharmaceutically acceptable carrier and / or excipient.

[0008] Another object of the present invention is to provide a type of quinone chalcone dimer compound having an isopentenyl group in the A ring connected by a methylene bridge in the preparation of a medicine or health product for treating and / or preventing diabetes.

[0009] The present invention provides the following technical solutions:

[0010] The first aspect of the present invention provides a class of dimer compounds of quinone chalcone with an isopentenyl group in ring A bridged by methylene, characterized in that the compound has a structure represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0011]

[0012] Wherein, R is 1, 2, or 3 arbitrary monosubstituted, disubstituted, or polysubstituted groups on the benzene ring. When R is a monosubstituted group, its position is as shown in R1:

[0013]

[0014] When R is a disubstituted group, its position is as shown in R2 and R3:

[0015]

[0016] When R is a tri-substituent, its positions are as shown in R4, R5, and R6:

[0017]

[0018] wherein R1, R2, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, methoxymethoxy, bromine, and chlorine;

[0019] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the compound is selected from the following compounds:

[0020]

[0021]

[0022]

[0023] The second aspect of the present invention provides a method for preparing a compound having a structure of general formula (I), characterized in that it comprises the following steps:

[0024]

[0025] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0026] 2,4,6-trihydroxyacetophenone was added to an alkaline aqueous solution and stirred in an ice-water bath to dissolve. 2 times the molar amount of 2,4,6-trihydroxyacetophenone was added to the aqueous solution. After 60 minutes, the pH was adjusted to 3 with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic phase was washed and dried, and finally purified by normal phase silica gel column chromatography to obtain a yellow oily substance, 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone.

[0027] (2) Synthesis of a class of quinone chalcone compounds with an isopentenyl group in the A ring

[0028] An equal amount of potassium hydroxide and 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone was dissolved in aqueous ethanol. 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and substituted benzaldehyde were then added at a molar ratio of 1:1.5. The reaction was stirred at 55°C and monitored for completion by high-performance liquid chromatography. The mixture was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and purified by reverse-phase column chromatography to obtain a class of quinone chalcone compounds with an isopentenyl group in Ring A.

[0029] (3) Synthesis of a class of dimer compounds of quinone chalcone with isopentenyl group in ring A linked by methylene bridges

[0030] A quinone-type chalcone compound having an isopentenyl group in Ring A is dissolved in acetonitrile, followed by the addition of a catalytic amount of acetic acid and a 37% aqueous formaldehyde solution (2-20 times the molar amount of the isopentenyl quinone-type chalcone compound). The mixture is stirred at room temperature and monitored for completion by thin-layer chromatography. The mixture is quenched with water, extracted with ethyl acetate, and the organic layer is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the mixture is purified by normal-phase column chromatography to obtain a dimer of a quinone-type chalcone compound having an isopentenyl group in Ring A linked by a methylene bridge.

[0031] The third aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective dose of the compound as described in each case of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0032] The present invention also relates to pharmaceutical compositions comprising a compound of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants. Typically, the pharmaceutical compositions of the present invention contain 0.1-95% by weight of the compound of the present invention. The compound of the present invention is typically present in a unit dosage form in an amount of 0.1-100 mg, with preferred unit dosage forms containing 4-50 mg.

[0033] The pharmaceutical composition of the compounds of this invention can be prepared according to methods well known in the art. When used for this purpose, if necessary, the compounds of this invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to prepare suitable administration forms or dosage forms that can be used as human or veterinary medicines.

[0034] The compound of the present invention or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.

[0035] The compound of the present invention or the pharmaceutical composition containing the same can be administered by injection, including intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupuncture injection.

[0036] The dosage form can be a liquid or solid dosage form. For example, liquid dosage forms can be true solutions, colloids, microparticles, emulsions, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and freeze-dried powder injections.

[0037] The compound of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0038] For example, in order to prepare a unit dosage form into a tablet, a wide variety of carriers well known in the art can be used. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders such as water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia paste, gelatin paste, sodium carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants such as dry starch, alginate, agar powder, brown seaweed starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0039] For example, to prepare the dosing unit into a pill, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, glyceryl monostearate, kaolin, talc, etc.; binders, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.

[0040] For example, to prepare a dosing unit in the form of a capsule, the active ingredient compound of the present invention is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule. The active ingredient compound of the present invention can also be formulated into microcapsules and suspended in an aqueous medium to form a suspension, which can also be encapsulated in a hard capsule or formulated as an injection for use.

[0041] For example, the compounds of the present invention may be formulated into injectable formulations such as solutions, suspensions, emulsions, or freeze-dried powder injections. These formulations may be aqueous or non-aqueous and may contain one or more pharmacologically acceptable carriers, diluents, adhesives, lubricants, preservatives, surfactants, or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitol esters, fatty acid esters, and the like. In addition, to prepare isotonic injections, an appropriate amount of sodium chloride, glucose, or glycerol may be added to the injectable formulation. Conventional cosolvents, buffers, pH regulators, and the like may also be added. These adjuvants are commonly used in the art.

[0042] In addition, if necessary, colorants, preservatives, perfumes, flavorings, sweeteners or other materials may be added to the pharmaceutical preparations.

[0043] To achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known method of administration.

[0044] The dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of doses, and the therapeutic purpose. Therefore, the therapeutic dosage of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical ingredients of the present invention is well known to those skilled in the art. The dosage can be appropriately adjusted based on the actual amount of drug contained in the final formulation of the composition of the present invention to achieve the therapeutically effective amount required to achieve the preventive or therapeutic purpose of the present invention. The suitable daily dosage range of the compound of the present invention is: the amount of the compound of the present invention is 0.001-100 mg / kg body weight, preferably 0.1-60 mg / kg body weight, more preferably 1-30 mg / kg body weight, and most preferably 2-15 mg / kg body weight. The daily dosage of the compound of the present invention for adult patients is 10-500 mg, preferably 20-100 mg, which can be taken once or divided into 2-3 doses; the dosage for children is 5-30 mg per kg body weight, preferably 10-20 mg / kg body weight. The above dosage can be administered in a single dose or divided into several doses, such as two, three or four doses, depending on the clinical experience of the administering physician and the dosing regimen of the treatment. The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.

[0045] The fourth aspect of the present invention relates to the use of dimer compounds of quinone chalcone having an isopentenyl group on the A ring connected by a methylene bridge or pharmaceutically acceptable salts thereof in drugs for preventing and / or treating diabetes.

[0046] Experiments have shown that a class of dimer compounds of the present invention, which have a quinone chalcone with an isopentenyl group in the A ring and are bridged by a methylene group, show significant anti-diabetic activity in models for evaluating the efficacy of anti-diabetic drugs, a PTP1B (protein tyrosine phosphatase 1B) inhibition activity model, and an α-glucosidase inhibition activity model.

[0047] 1. The compound structure of the present invention is synthesized for the first time, and there are very few reports of similar structures in the literature. It has the potential to be further developed into a new drug for hypoglycemic effect.

[0048] 2. The compounds of the present invention have good hypoglycemic activity. In terms of the inhibitory activity against recombinant human PTP1B (protein tyrosine phosphatase 1B), the inhibition rate of some compounds at a concentration of 10 μM is 93.7% to 100.0%. 50 The inhibitory activity of some compounds against α-glucosidase was 79.4%, 69.9%, and 66.7% at a concentration of 10 μM, respectively. These rates were higher than the 65.1% inhibition rate of the active agent acarbose at a concentration of 20 μg / ml. Currently, there are no reports on the inhibitory activity of these compounds against recombinant human PTP1B (protein tyrosine phosphatase 1B) and α-glucosidase.

[0049] 3. The synthetic route of this type of compound is mature and simple to obtain.

[0050] Effective technical effects

[0051] 1. The present invention discloses a class of dimer compounds of quinone chalcone with an isopentenyl group in Ring A connected by a methylene bridge, which have novel structures and have not been reported in the literature. They have the potential to be further developed into new anti-diabetic drugs.

[0052] 2. The present invention provides a novel preparation method for a class of dimer compounds of quinone chalcone with an isopentenyl group in the A ring, which are bridged by methylene groups, and is easy to separate.

[0053] 3. The present invention's dimers of quinone chalcone with an isopentenyl group in Ring A, linked by a methylene bridge, exhibit promising antidiabetic activity, significantly inhibiting the activity of α-glucosidase and PTP1B, thereby lowering blood glucose levels by blocking sugar absorption and promoting sugar metabolism. The antidiabetic activity of these compounds has not been reported. DETAILED DESCRIPTION

[0054] Example 1

[0055] The synthesis method of compound 1 comprises the following steps:

[0056] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0057] 0.73 g of 2.2 eq of potassium hydroxide was added to 10 ml of water, and 1 g of 2,4,6-trihydroxyacetophenone was added and stirred to dissolve. 1.51 mL of 2.2 eq of bromoisoamylene was added to the aqueous solution, and the mixture was stirred at 0°C for 1 hour. The reaction was stopped, and the pH was adjusted to 3 with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and pure water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 603 mg of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone was separated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone with a yield of 33.3%. The following reactions occurred in this process:

[0058]

[0059] The structural characterization data of the product are: HRESIMS: (m / z 305.1745[M+H] + ,calcd,305.1747); 1 HNMR (DMSO-d6, 500MHz)δ H :1.52(6H,s,2×CH3),1.54(6H,s,2×CH3),2.44(2H,m,-CH2CH=,),2.45(3H,s,-CH3CO),2.53(2H,m,- CH2CH=),4.76(2H,t,J=7.5Hz,2×=CHCH2),5.53(1H,s,H-4),12.57(1H,s,5-OH),18.35(1H,s,3-OH).

[0060] (2) Synthesis of 2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0061] Dissolve 0.97g of potassium hydroxide in 2ml of water-3ml of ethanol solution, then add 0.97g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (1.7g) of 4-bromobenzaldehyde. Stir at 55°C for 11h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it is isolated and purified by reverse-phase flash preparative column chromatography (methanol:water = 80:20) to obtain 248mg of 2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 16.5%. The following reactions occur during this process:

[0062]

[0063] The structural characterization data of the product are: ESIMS (m / z 469.3[MH] - ); 1 H NMR (500 MHz, DMSO-d6) δ H :1.52(12H,s,4×CH3),2.48(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.61(1H,s,H-4),7.63(2H,d,J=8 .5Hz,H-3″,H-5″),7.67(2H,d,J=8.5Hz,H-2″,H-6″),7.77(1H,d,J=16.0Hz,H-2′),8.23(1H,d,J=16.0Hz,H-3′),18.86(1H,s,1′-OH).

[0064] (3) Synthesis of 4,4′-methylenebis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0065] 200 mg of 2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 15 mL of acetonitrile. 3-5 drops of acetic acid and 345 μL of 10 eq of 37% aqueous formaldehyde were then added. The mixture was stirred at room temperature for 1 hour and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 138 mg of 4,4′-methylenebis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 68.1%. The following reactions occurred during this process:

[0066]

[0067] The structural characterization data of the product are: HRESIMS (m / z 953.2244 [M+H] + ,calcd,953.2258); 1 H NMR (500 MHz, pyridine-d5) δ H:1.55(12H,s,4×CH3),1.73(12H,s,4×CH3),3.04(4H,m,2×-CH2CH=),3.15(4H,m,2×-CH2CH=),4.25(2H,s,-CH2-),5.46(4H,s,4×=CHCH2),7. 45(8H,m,H-2″,H-3″,H-5″,H-6″,H-2″″′,H-3″″′,H-5″″′,H-6″″′),7. 91(2H,d,J=16.0Hz,H-2′,H-2″″),8.92(2H,d,J=16.0Hz,H-3′,H-3″″).

[0068] 13 C NMR (125 MHz, DMSO-d6) δ C :16.1(-CH2-),18.0(4×CH3),25.8(4×CH3),37.6(4×-CH2CH=),60.8(C-6,C-6″′),106.4(C-2,C-2″′ ),106.8(C-4,C-4″′),121.4(C-2′,C-2″″),122.0(4×=CHCH2),129.2(C-2″,C-6″,C-2″″′,C-6″″’),1 30.2(C-3″,C-5″,C-3″″′,C-5″″′),130.7(C-4″,C-4″″′),131.8(4×-C=CH),133.4(C-1″,C-1″″′),13 6.2 (C-3′, C-3″″), 176.5 (C-5, C-5″′), 181.5 (C-1′, C-1″″), 193.5 (C-3, C-3″′), 198.5 (C-1, C-1″′).

[0069] Example 2

[0070] The synthesis method of compound 2 comprises the following steps:

[0071] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0072] The preparation method is the same as that of compound 1.

[0073] (2) Synthesis of 2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0074] Dissolve 0.8g of potassium hydroxide in 1.6ml of water-2.4ml of ethanol solution, then add 0.8g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.5eq (0.55g) of 4-chlorobenzaldehyde. Stir and react at 55°C for 13h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 309mg of 2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 80:20) to obtain 2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 27.6%. The following reactions occur during this process:

[0075]

[0076] The structural characterization data of the product are: ESIMS (m / z 427.3[M+H] + ); 1 H NMR (500 MHz, DMSO-d6) δ H :1.52(12H,s,4×CH3),2.48(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.62(1H,s,H-4),7.53(2H,d,J=8 .5Hz,H-3″,H-5″),7.70(2H,d,J=8.5Hz,H-2″,H-6″),7.79(1H,d,J=15.5Hz,H-2′),8.22(1H,d,J=15.5Hz,H-3′),18.89(1H,s,1′-OH).

[0077] (3) Synthesis of 4,4′-methylenebis[2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0078] 130 mg of 2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of methanol. 3-5 drops of acetic acid and 495 μL of 20 eq of 37% aqueous formaldehyde were added. The mixture was stirred at room temperature for 21 hours and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 160 mg of 4,4′-methylenebis[2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a 99% yield. The following reactions occurred during this process:

[0079] The structural characterization data of the product are: HRESIMS (m / z 865.3256[M+H] + ,calcd,865.3268); 1 H NMR (500 MHz, pyridine-d5) δ H :1.55(12H,s,4×CH3),1.73(12H,s,4×CH3),3.04(4H,m,2×-CH2CH=),3.15(4H, m,2×-CH2CH=),4.25(2H,s,-CH2-),5.46(4H,s,4×=CHCH2),7.29(4H,d,J=8.5H z,H-3″,H-5″,H-3″″′,H-5″″′),7.51(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″ ″′), 7.93 (2H, d, J = 16.0Hz, H-2′, H-2″″), 8.91 (2H, d, J = 16.0Hz, H-3′, H-3″″).

[0080] 13 C NMR (125 MHz, DMSO-d6) δ C:16.1(-CH2-),18.0(4×CH3),25.8(4×CH3),37.6(4×-CH2CH=),60.8(C-6,C-6″′),106.4(C-2,C-2″′ ),106.8(C-4,C-4″′),122.0(4×=CHCH2),122.0(C-2′,C-2″″),128.7(C-3″,C-5″,C-3″″′,C-5″″’),1 28.9(C-2″,C-6″,C-2″″′,C-6″″′),130.2(4×-C=CH),132.7(C-1″,C-1″″′),133.4(C-4″,C-4″″′),13 5.9 (C-3′, C-3″″), 176.6 (C-5, C-5″′), 181.5 (C-1′, C-1″″), 193.5 (C-3, C-3″′), 198.5 (C-1, C-1″′).

[0081] Example 3

[0082] The synthesis method of compound 3 comprises the following steps:

[0083] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0084] The preparation method is the same as that of compound 1.

[0085] (2) Synthesis of 2-(2,4-dichlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0086] Dissolve 1.1g of potassium hydroxide in 2.2ml of water-3.3ml of ethanol solution, then add 1.1g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (1.1g) of 2,4-dichlorobenzaldehyde. Stir and react at 55°C for 13h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 100mg of 2-(2,4-dichlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 90:10) to obtain 100mg of 2-(2,4-dichlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a 6% yield. The following reactions occur:

[0087]

[0088] The structural characterization data of the product are: ESIMS (m / z 459.4[MH] - );1 H NMR (500 MHz, DMSO-d6) δ H :1.53(6H,s,2×CH3),1.53(6H,s,2×CH3),2.48(2H,m,-CH2CH=),2.57(2H,m,- CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.61(1H,s,H-4),7.56(1H,dd,J=8 .5,2.5Hz,H-5″),7.76(1H,d,J=2.5Hz,H-3″),7.83(1H,d,J=8.5Hz,H-6″),7. 96(1H,d,J=16.0Hz,H-2′),8.23(1H,d,J=16.0Hz,H-3′),18.71(1H,s,1′-OH).

[0089] (3) Synthesis of 4,4′-methylenebis[2-(2,4-dichlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0090] 75 mg of 2-(2,4-dichlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of methanol. 3-5 drops of acetic acid and 20 eq (264 μL) of 37% formaldehyde solution were then added. The mixture was stirred at room temperature for 21 hours and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 60 mg of 4,4′-methylenebis[2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 60 mg of 4,4′-methylenebis[2-(4-chlorocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 78.8%. The following reactions occurred during this process:

[0091]

[0092] The structural characterization data of the product are: HRESIMS (m / z 931.2351[MH] - ,calcd,931.2344); 1 H NMR (500 MHz, pyridine-d5) δ H:1.58(12H,s,4×CH3),1.76(12H,s,4×CH3),3.06(4H,m,2×-CH2CH=),3.18(4H,m,2×- CH2CH=),4.32(2H,s,-CH2-),5.50(4H,t,J=8.5Hz,4×=CHCH2),7.21(2H,dd,J=2.0,8 .5Hz,H-5″,H-5″″′),7.39(2H,d,J=2.0Hz,H-3″,H-3″″′),7.79(2H,d,J=8.5Hz,H-6″ ,H-6″″′),8.30(2H,d,J=16.0Hz,H-2′,H-2″″),8.91(2H,d,J=16.0Hz,H-3′,H-3″″).

[0093] 13 C NMR (125MHz, chloroform-d)δ C :18.1(-CH2-),18.0(2×CH3),18.1(2×CH3),26.0(2×CH3),26.0(2×CH3),36.9(2×-CH2CH=),37.8(2×-CH2CH=),55.1(C-6,C-6″ ′),110.4(C-2,C-2″′),115.4(C-4,C-4″′),117.4(2×=CHCH2),117.6(2×=CHCH2),126.2(C-2′,C-2″″),127.9(C-4″,C-4″″′), 129.1(C-5″,C-5″″′),130.2(C-3″,C-3″″′),132.0(C-6″,C-6″″′),135.7(C-1″,C-1″″′),136.0(C-2″,C-2″″′),136.3(2×-C= CH), 136.9 (2×-C=CH), 139.4 (C-3′, C-3″″), 172.1 (C-5, C-5″′), 186.8 (C-1′, C-1″″), 188.3 (C-3, C-3″′), 202.9 (C-1, C-1″′).

[0094] Example 4

[0095] The synthesis method of compound 4 comprises the following steps:

[0096] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0097] The preparation method is the same as that of compound 1.

[0098] (2) Synthesis of 2-cinnamoyl-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0099] Dissolve 0.8g of potassium hydroxide in 1.6ml of water-2.4ml of ethanol solution, then add 0.8g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.5eq (400μL) of benzaldehyde. Stir at 55°C for 13h. Completion of the reaction is monitored by HPLC. Quench with water, adjust the pH to neutral with dilute hydrochloric acid, and extract with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 337mg of 2-cinnamoyl-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 80:20) to obtain 32.7% yield of 2-cinnamoyl-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione. The following reactions occur:

[0100]

[0101] The structural characterization data of the product are: ESIMS (m / z 393.1 [M+H] + ); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.59(2H,m,-CH2CH=),4.80(2H,t,J=7.0Hz,2×=CHCH2),5.61(1H,s,H-4),7.47(3H ,m,H-3″,H-4″,H-5″),7.68(2H,m,H-2″,H-6″),7.81(1H,d,J=16.0Hz,H-2′),8.23(1H,d,J=16.0Hz,H-3′),18.90(1H,s,1′-OH).

[0102] (3) Synthesis of 4,4′-methylenebis(2-cinnamoyl-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione)

[0103] 265 mg of 2-cinnamoyl-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 3-5 drops of acetic acid and 548 μL of 10 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 5 hours and monitored for completion by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 210 mg of 4,4′-methylenebis(2-cinnamoyl-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione) in a yield of 79.5%. The following reactions occurred during this process:

[0104]

[0105] The structural characterization data of the product are: HRESIMS (m / z 797.4038[M+H] + ,calcd,797.4048); 1 H NMR (500 MHz, pyridine-d5) δ H :1.56(12H,s,4×CH3),1.73(12H,s,4×CH3),3.03(4H,m,2×-CH2CH=),3.15(4H,m,2×-CH 2CH=),4.19(2H,s,-CH2-),5.43(4H,t,J=8.0Hz,4×=CHCH2),7.28(2H,s,H-4″,H-4″″′), 7.29(4H,d,J=8.0Hz,H-3″,H-5″,H-3″″′,H-5″″′),7.64(4H,d,J=8.5Hz,H-2″,H-6″,H-2 ″″′,H-6″″′), 8.05(2H,d,J=16.0Hz,H-2′,H-2″″),8.97(2H,d,J=16.0Hz,H-3′,H-3″″).

[0106] 13 C NMR (125 MHz, DMSO-d6) δ C:16.2(-CH2-),18.0(2×CH3),18.1(2×CH3),25.8(2×CH3),25.9(2×CH3),37.6(4×-CH2CH=),60.7(C-6,C-6″ ′),106.3(C-2,C-2″′),106.7(C-4,C-4″′),122.1(4×=CHCH2),122.7(C-2′,C-2″″),127.3(C-4″,C-4″″′),1 28.6(C-2″,C-6″,C-2″″′,C-6″″′),128.9(C-3″,C-5″,C-3″″′,C-5″″′),130.0(4×-C=CH),134.6(C-1″,C-1″ ″′), 136.9 (C-3′, C-3″″), 176.5 (C-5, C-5″′), 181.8 (C-1′, C-1″″), 193.3 (C-3, C-3″′), 198.4 (C-1, C-1″′).

[0107] Example 5

[0108] The synthesis method of compound 5 comprises the following steps:

[0109] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0110] The preparation method is the same as that of compound 1.

[0111] (2) Synthesis of 2-(4-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0112] Dissolve 0.96g of potassium hydroxide in 2mL of water-3mL of ethanol solution, then add 0.96g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (1.15mL) of 4-methoxybenzaldehyde. Stir and react at 55°C for 13h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 312mg of 2-cinnamoyl-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 80:20) to obtain 23.4% yield. The following reactions occur during this process:

[0113]

[0114] The structural characterization data of the product are: ESIMS (m / z 423.1[M+H] + ); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.46(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.59(1H,s,H-4),7.04(2H,d,J=8 .5Hz,H-3″,H-5″),7.65(2H,d,J=8.5Hz,H-2″,H-6″),7.80(1H,d,J=16.0Hz,H-2′),8.13(1H,d,J=16.0Hz,H-3′),18.99(1H,s,1′-OH).

[0115] (3) Synthesis of 4,4′-methylenebis[2-(4-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0116] 200 mg of 2-(4-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of methanol. 10 drops of acetic acid and 768 μL of 20 eq of 37% formaldehyde solution were then added. The mixture was stirred at room temperature for 20 h, and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 140 mg of 4,4′-methylenebis[2-(4-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 69.0%. The following reactions occurred during this process:

[0117]

[0118] The structural characterization data of the product are: HRESIMS (m / z 857.4255[M+H] + ,calcd,857.4260); 1 H NMR (500 MHz, pyridine-d5) δ H:1.56(12H,s,4×CH3),1.72(12H,s,4×CH3),3.02(4H,m,2×-CH2CH=),3.11(4H,m,2× -CH2CH=),3.66(6H,s,2×OCH3),4.03(2H,s,-CH2-),5.34(4H,s,4×=CHCH2),6.93(4H ,d,J=8.5Hz,H-3″,H-5″,H-3″″′,H-5″″′),7.65(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′ ,H-6″″′),8.13(2H,d,J=16.0Hz,H-2′,H-2″″),8.85(2H,d,J=16.0Hz,H-3′,H-3″″).

[0119] 13 C NMR (125 MHz, DMSO-d6) δ C :16.1(-CH2-),18.0(4×CH3),25.8(4×CH3),37.7(4×-CH2CH=),55.3(2×OCH3),60.6(C-6,C-6″′),106.0( C-2,C-2″′),106.6(C-4,C-4″′),114.4(C-3″,C-5″,C-3″″′,C-5″″′),122.1(4×=CHCH2),127.4(C-2′,C- 2″″), 128.8(4×-C=CH), 129.5(C-1″,C-1″″′), 130.1(C-2″,C-6″,C-2″″′,C-6″″′), 134.8(C-3′,C-3″″), 159.7(C-4″,C-4″″′), 177.3(C-5,C-5″′), 182.4(C-1′,C-1″″), 193.5(C-3,C-3″′), 198.3(C-1,C-1″′).

[0120] Example 6

[0121] The synthesis method of compound 6 comprises the following steps:

[0122] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0123] The preparation method is the same as that of compound 1.

[0124] (2) Synthesis of 2-(2-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione: 1 g of potassium hydroxide was dissolved in 2 mL of water-3 mL of ethanol solution. 1 g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohex-2,4-dienone and 1.2 eq 537 mg (544 mg) of 2-methoxybenzaldehyde were added. The mixture was stirred at 55°C for 10 h and the reaction was monitored by HPLC for completion. The mixture was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, washed with pure water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the mixture was separated and purified by reverse phase flash preparative column chromatography (methanol: water = 80:20) to obtain 246 mg of 2-(2-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione with a yield of 17.7%. The following reaction occurred in this process:

[0125]

[0126] The structural characterization data of the product are: HRESIMS (m / z 423.2168 [M+H] + ,calcd,423.2166); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.46(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.88(3H,s,OCH 3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.59(1H,s,H-4),7.05(1H,t,J=8.0Hz,H-5″), 7.12(1H,d,J=8.0Hz,H-3″),7.45(1H,t,J=8.0Hz,H-4″),7.64(1H,d,J=8.0Hz,H-6″ ),8.07(1H,d,J=16.0Hz,H-2′),8.24(1H,d,J=16.0Hz,H-3′),18.93(1H,s,1′-OH).

[0127] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),55.7(OCH3),57.6(C-6),10 0.0(C-4),107.2(C-2),112.0(C-3″),118.3(2×=CHCH2),121.0(C-5″),123. 2(C-2′),123.6(C-4″),128.7(C-1″),131.8(C-6″),134.0(2×-C=CH),137.8 (C-3′),158.2(C-2″),179.9(C-5),185.7(C-1′),190.7(C-3),196.3(C-1).

[0128] (3) Synthesis of 4,4′-methylenebis[2-(2-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0129] 150 mg of 2-(2-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 6 drops of acetic acid and 576 μL of 20 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 18 hours and monitored for completion by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 112 mg of 4,4′-methylenebis[2-(2-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 73.6%. The following reactions occurred during this process:

[0130]

[0131] The structural characterization data of the product are: HRESIMS (m / z 857.4252 [M+H] + ,calcd,857.4260); 1 H NMR (500 MHz, pyridine-d5) δ H:1.55(12H,s,4×CH3),1.72(12H,s,4×CH3),3.01(4H,m,2×-CH2CH=),3.12(4H,m,2×-CH2CH=),3 .65(6H,s,2×OCH3),4.06(2H,s,-CH2-),5.36(4H,s,4×=CHCH2),6.87(2H,d,J=8.5Hz,H-3″,H-3 ″″′), 6.94(2H,t,J=8.5Hz,H-5″,H-5″″′),7.31(2H,t,J=8.5Hz,H-4″,H-4″″′),7.84(2H,d,J=8 .5Hz,H-6″,H-6″″′), 8.61(2H,d,J=16.0Hz,H-2′,H-2″″), 9.00(2H,d,J=16.0Hz,H-3′,H-3″″).

[0132] 13 C NMR (125 MHz, DMSO-d6) δ C :15.5(-CH2-),17.9(4×CH3),25.7(4×CH3),37.4(4×-CH2CH=),55.7(2×OCH3),59.1(C-6,C-6″′),106.6(C-2 ,C-2″′),108.7(C-4,C-4″′),111.9(C-3″,C-3″″′),119.7(4×=CHCH2),120.9(C-5″,C-5″″′),124.0(C-2′,C- 2″″),125.9(C-4″,C-4″″′),127.3(C-1″,C-1″″′),131.4(C-6″,C-6″″′),132.6(4×-C=CH),134.3(C-3′,C-3 ""), 157.8 (C-2", C-2""'), 184.5 (C-5, C-5"'), 186.1 (C-1', C-1""), 186.3 (C-3, C-3"'), 197.0 (C-1, C-1"').

[0133] Example 7

[0134] The synthesis method of compound 7 comprises the following steps:

[0135] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0136] The preparation method is the same as that of compound 1.

[0137] (2) Synthesis of 2-(3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione: 1 g of potassium hydroxide was dissolved in 2 mL of water-3 mL of ethanol solution, and then 1 g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.2 eq 481 mL of 2-methoxybenzaldehyde were added. The mixture was stirred at 55°C for 10 h and the reaction was monitored by high performance liquid chromatography. The mixture was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, washed with pure water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the mixture was separated and purified by reverse phase flash preparative column chromatography (methanol: water = 90:10) to obtain 233 mg of 2-(2-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione with a yield of 16.8%. The following reaction occurred in this process:

[0138]

[0139] The structural characterization data of the product are: HRESIMS (m / z 423.2169[M+H] + ,calcd,423.2166); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.59(2H,m,-CH2CH=),3.80(3H,s,O CH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.62(1H,s,H-4),7.04(1H,d,J=8.0Hz,H- 4″),7.20(1H,s,H-2″),7.28(1H,d,J=8.0Hz,H-6″),7.39(1H,t,J=8.0Hz,H-5″), 7.78(1H,d,J=16.0Hz,H-2′),8.19(1H,d,J=16.0Hz,H-3′),18.90(1H,s,1′-OH).

[0140] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),55.2(OCH3),57.6(C-6),9 9.9(C-4),107.3(C-2),113.9(C-2″),116.3(C-4″),118.2(2×=CHCH2),120. 4(C-2′),123.8(C-6″),130.3(C-1″),134.1(2×-C=CH),136.3(C-5″),143.1 (C-3′),159.7(C-2″),180.0(C-5),185.6(C-1′),190.7(C-3),196.4(C-1).

[0141] (3) Synthesis of 4,4′-methylenebis[2-(3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0142] 150 mg of 2-(3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 8 drops of acetic acid and 576 μL of 20 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 18 hours and monitored for completion by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 150 mg of 4,4′-methylenebis[2-(3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 98.6%. The following reactions occurred during this process:

[0143]

[0144] The structural characterization data of the product are: HRESIMS (m / z 857.4248[M+H] + ,calcd,857.4260); 1 H NMR (500 MHz, pyridine-d5) δ H:1.55(12H,s,4×CH3),1.73(12H,s,4×CH3),3.03(4H,m,2×-CH2CH=),3.15(4H,m,2×-CH2CH=), 3.63(6H,s,2×OCH3),4.21(2H,s,-CH2-),5.43(4H,s,4×=CHCH2),6.94(2H,dd,J=2.5,8.5Hz,H -4″,H-4″″′),7.23(2H,s,H-2″,H-2″″′),7.25(2H,d,J=8.5Hz,H-5″,H-5″″′),7.32(2H,d,J=8 .5Hz, H-6″, H-6″″′), 8.05 (2H, d, J = 16.0Hz, H-2′, H-2″″), 8.97 (2H, d, J = 16.0Hz, H-3′, H-3″″).

[0145] 13 C NMR (125 MHz, DMSO-d6) δ C :15.5(-CH2-),17.9(4×CH3),25.7(4×CH3),37.5(4×-CH2CH=),55.2(2×OCH3),59.2(C-6,C-6″′),106.7(C-2 ,C-2″′),108.6(C-4,C-4″′),113.4(C-2″,C-2″″′),115.5(C-4″,C-4″″′),119.6(4×=CHCH2),120.0(C-6″,C- 6″″′),126.3(C-2′,C-2″″),130.1(C-5″,C-5″″′),132.6(4×-C=CH),137.1(C-3′,C-3″″),139.7(C-1″,C-1″ ″′),159.7(C-3″,C-3″″′),184.3(C-5,C-5″′),186.1(C-1′,C-1″″),186.4(C-3,C-3″′),197.1(C-1,C-1″′).

[0146] Example 8

[0147] The synthesis method of compound 8 comprises the following steps:

[0148] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0149] The preparation method is the same as that of compound 1.

[0150] (2) Synthesis of 2-(3,4-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0151] Dissolve 1g of potassium hydroxide in 2mL of water-3mL of ethanol solution, then add 1g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.2eq (656mg) of 3,4-dimethoxybenzaldehyde. Stir at 55°C for 10h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 449mg of 2-(3,4-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 90:10) to obtain 40.2% yield of 2-(3,4-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione. The following reaction occurs:

[0152]

[0153] The structural characterization data of the product are: ESIMS (m / z 453.2 [M+H] + ); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.82(6H, s,2×OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.60(1H,s,H-4),7.06(1H,d,J=8 .5Hz,H-5″),7.23(1H,d,J=2.0Hz,H-2″),7.30(1H,dd,J=2.0,8.5Hz,H-6″),7. 80(1H,d,J=15.5Hz,H-2′), 8.11(1H,d,J=15.5Hz,H-3′), 19.00(1H,s,1′-OH).

[0154] (3) Synthesis of 4,4′-methylenebis[2-(3,4-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0155] 150 mg of 2-(3,4-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 200 μL of acetic acid and 538 μL of 20 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 29 hours and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 124 mg of 4,4′-methylenebis[2-(3,4-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in an 81.6% yield. The following reactions occurred during this process:

[0156]

[0157] The structural characterization data of the product are: HRESIMS (m / z 917.4463[M+H] + ,calcd,917.4470); 1 H NMR (500 MHz, pyridine-d5) δ H :1.56(12H,s,4×CH3),1.72(12H,s,4×CH3),3.02(4H,m,2×-CH2CH=),3.12(4H,m,2×-CH2 CH=),3.72(6H,s,2×OCH3),3.73(6H,s,2×OCH3),4.07(2H,s,-CH2-),5.36(4H,s,4×=CHCH 2),6.87(2H,d,J=9.0Hz,H-5″,H-5″″′),7.31(2H,d,J=9.0Hz,H-6″,H-6″″′),7.31(2H,s, H-2″,H-2″″′),8.16(2H,d,J=15.5Hz,H-2′,H-2″″),8.89(2H,d,J=15.5Hz,H-3′,H-3″″).

[0158] 13 C NMR (125MHz, chloroform-d)δ C:18.0(2×CH3),18.1(2×CH3),18.4(-CH2-),26.0(2×CH3),26.0(2×CH3),37.0(2×-CH2CH=),37.8(2×-CH2CH=),55.0(C-6,C-6″′),56. 1(2×OCH3),56.2(2×OCH3),109.9(C-2,C-2″′),110.8(C-4,C-4″′),111.2(C-2″,C-2″″′),115.6(C-5″,C-5″″′),117.6(2×=CHCH2),11 7.8(2×=CHCH2),121.1(C-2′,C-2″″),123.9(C-6″,C-6″″′),128.4(C-1″,C-1″″′),135.4(2×-C=CH),135.7(2×-C=CH),146.0(C-3′,C -3″″), 149.3(C-4″,C-4″″′), 151.9(C-3″,C-3″″′), 171.6(C-5,C-5″′), 187.0(C-1′,C-1″″), 188.4(C-3,C-3″′), 202.8(C-1,C-1″′).

[0159] Example 9

[0160] The synthesis method of compound 9 comprises the following steps:

[0161] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0162] The preparation method is the same as that of compound 1.

[0163] (2) Synthesis of 2-(3,5-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0164] Dissolve 1g of potassium hydroxide in 2mL of water-3mL of ethanol solution, then add 1g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.2eq (656mg) of 3,5-dimethoxybenzaldehyde. Stir at 55°C for 10h. Completion of the reaction is monitored by HPLC. Quench with water, adjust the pH to neutral with dilute hydrochloric acid, and extract with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 212mg of 2-(3,5-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 90:10) to obtain 212mg of 2-(3,5-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 14.2%. The following reactions occur:

[0165]

[0166] The structural characterization data of the product are: HRESIMS (m / z 453.2274 [M+H] + ,calcd,453.2272); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.59(2H,m,-CH2CH=),3.79(6H,s,2×OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.61(1H,s,H-4),6 .61(1H,t,J=2.0Hz,H-4″),6.82(2H,d,J=2.0Hz,H-2″,H-6″),7.73(1H,d,J=16.0Hz,H-2′),8.13(1H,d,J=16.0Hz,H-3′),18.86(1H,s,1′-OH).

[0167] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),55.4(2×OCH3),57.6(C-6),99.9(C-4),102.6(C-4″),106.2(C-2″,C-6″),107.3(C-2),118.2(2 ×=CHCH2),124.1(C-2′),134.1(2×-C=CH),136.8(C-1″),143.1(C-3′),1 60.8(C-3″,C-5″),180.2(C-5),185.5(C-1′),190.7(C-3),196.4(C-1).

[0168] (3) Synthesis of 4,4′-methylenebis[2-(3,5-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0169] 150 mg of 2-(3,5-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 200 μL of acetic acid and 538 μL of 20 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 29 hours and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 100 mg of 4,4′-methylenebis[2-(3,5-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 65.8%. The following reactions occurred during this process:

[0170]

[0171] The structural characterization data of the product are: HRESIMS (m / z 917.4470[M+H] + ,calcd,917.4470); 1 H NMR (500 MHz, pyridine-d5) δ H:1.55(12H,s,4×CH3),1.73(12H,s,4×CH3),3.04(4H,m,2×-CH2CH=),3.15( 4H,m,2×-CH2CH=),3.65(12H,s,4×OCH3),4.24(2H,s,-CH2-),5.44(4H,s,4× =CHCH2),6.66(2H,s,H-4″,H-4″″′),6.97(4H,s,H-2″,H-6″,H-2″″′,H-6″″′ ), 8.05 (2H, d, J = 15.5Hz, H-2′, H-2″″), 8.99 (2H, d, J = 15.5Hz, H-3′, H-3″″).

[0172] 13 C NMR (125MHz, chloroform-d)δ C :18.0(2×CH3),18.1(2×CH3),18.4(-CH2-),26.0(2×CH3),26.0(2×CH3),37.0(2×-CH2CH=),37.8(2×-CH2CH=),55.1(C-6,C-6 ″′),55.6(4×OCH3),103.2(C-4″,C-4″″′),106.9(C-2,C-2″′),110.2(C-4,C-4″′),115.5(C-2″,C-6″,C-2″″′,C-6″″’),117.5 (2×=CHCH2),117.7(2×=CHCH2),124.0(C-2′,C-2″″),135.5(2×-C=CH),135.9(2×-C=CH),137.2(C-1″,C-1″″′),145.6(C-3′,C -3″″),161.1(C-3″,C-5″,C-3″″′,C-5″″′),171.8(C-5,C-5″′),187.2(C-1′,C-1″″),188.2(C-3,C-3″′),202.8(C-1,C-1″′).

[0173] Example 10

[0174] The synthesis method of compound 10 comprises the following steps:

[0175] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0176] The preparation method is the same as that of compound 1.

[0177] (2) Synthesis of 2-(3,5-dimethoxy-4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0178] Dissolve 1.56g of potassium hydroxide in 3mL of water-4.5mL of ethanol solution, then add 1.56g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1eq (1.16g) of 3,5-dimethoxy-4-methoxymethoxybenzaldehyde. Stir and react at 55°C for 10h. Completion of the reaction is monitored by HPLC. Quench with water, adjust the pH to neutral with dilute hydrochloric acid, and extract with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 2-(3,5-dimethoxy-4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione (305mg, 11.6% yield) is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 90:10). The following reactions occur:

[0179] The structural characterization data of the product are: HRESIMS (m / z 513.2490 [M+H] + ,calcd,513.2483); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.48(2H,m,-CH2CH=),2.59(2H,m,-CH2CH=),3.46(3H,s,OCH3),3.84(6H,s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5. 04(2H,s,-OCH2O),5.61(1H,s,H-4),7.01(2H,s,H-2″,H-6″),7.78(1H, d,J=15.5Hz,H-2′),8.11(1H,d,J=15.5Hz,H-3′),18.94(1H,s,1′-OH).

[0180] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),56.0(2×OCH3),56.5(OCH3),57 .5(C-6),97.4(-OCH2O),100.0(C-4),105.7(C-2″,C-6″),107.2(C-2),118.3(2 ×=CHCH2),122.6(C-2′),130.8(C-1″),134.1(2×-C=CH),136.4(C-3″,C-5″),14 3.7(C-3′),153.3(C-4″),179.9(C-5),185.5(C-1′),190.8(C-3),196.4(C-1).

[0181] (3) Synthesis of 2-(3,5-dimethoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0182] 200 mg of 2-(3,5-dimethoxy-4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was added to 75 mg of 1 eq of p-toluenesulfonic acid hydrate and dissolved in 5 mL of methanol. The mixture was stirred at room temperature for 2 days and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 136 mg of 2-(3,5-dimethoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 70:30) with a yield of 74.4%. The following reactions occurred during the reaction:

[0183]

[0184] The structural characterization data of the product are: HRESIMS (m / z 469.2225[M+H] + ,calcd,469.2221); 1 H NMR (500 MHz, DMSO-d6) δ H:1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.57(2H,m,-CH2CH=),3.82(6H,s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5 .57(1H,s,H-4),6.97(2H,s,H-2″,H-6″),7.78(1H,d,J=15.5Hz,H-2′),8.07(1H,d,J=15.5Hz,H-3′),18.99(1H,s,1′-OH).

[0185] 13 C NMR (125 MHz, DMSO-d6) δ C :17.8(2×CH3),25.7(2×CH3),37.1(2×-CH2CH=),56.1(2×OCH3),57.5(C-6),100.1(C-4),106.4(C-2″,C-6″),106.9(C-2),118.4(2×=CHCH2),120 .1(C-2′),125.3(C-1″),133.9(2×-C=CH),139.1(C-4″),144.7(C-3′),1 48.2(C-3″,C-5″),179.7(C-5),185.3(C-1′),190.7(C-3),196.4(C-1).

[0186] (4) Synthesis of 4,4′-methylenebis[2-(3,5-dimethoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0187] 106 mg of 2-(3,5-dimethoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 7 mL of acetonitrile, followed by the addition of 300 μL of acetic acid and 20 eq (367 μL) of 37% formaldehyde solution. The reaction was stirred at room temperature for 2.5 days and monitored for completion by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 100 mg of 4,4′-methylenebis[2-(3,5-dimethoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 93.1%. The following reactions occurred during this process:

[0188]

[0189] The structural characterization data of the product are: HRESIMS (m / z 949.4364[M+H] + ,calcd,949.4369); 1 H NMR (500 MHz, pyridine-d5) δ H :1.56(12H,s,4×CH3),1.73(12H,s,4×CH3),3.02(4H,m,2×-CH2CH=),3.10(4H,m,2×-CH2CH=),3.79(12H,s,4×OCH3),4.01(2H,s,-CH2-),5 ...

[0190] 13 C NMR (125MHz, chloroform-d)δ C :18.1(4×CH3),26.0(4×CH3),29.8(-CH2-),37.0(2×-CH2CH=),37.8(2×-CH2CH=),55.0(C-6,C-6″′),56.5(4×OCH3),1 06.2(C-2″,C-6″,C-2″″′,C-6″″′),109.9(C-2,C-2″′),115.6(C-4,C-4″′),117.6(2×=CHCH2),117.8(2×=CHCH2),121. 1(C-2′,C-2″″),127.0(C-1″,C-1″″′),135.4(2×-C=CH),135.8(2×-C=CH),138.1(C-4″,C-4″″′),146.3(C-3′,C-3″″), 147.4(C-3″,C-5″,C-3″″′,C-5″″′), 171.6(C-5,C-5″′), 186.8(C-1′,C-1″″), 188.3(C-3,C-3″′), 202.8(C-1,C-1″′).

[0191] Example 11

[0192] The synthesis method of compound 11 comprises the following steps:

[0193] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0194] The preparation method is the same as that of compound 1.

[0195] (2) Synthesis of 2-(3,4-dimethoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0196] Dissolve 1.4g of potassium hydroxide in 3mL of water-4.5mL of ethanol solution, then add 1.4g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1eq (1.04g) of 3,4-dimethoxymethoxybenzaldehyde. Stir and react at 55°C for 10h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it is isolated and purified by reverse-phase flash preparative column chromatography (methanol:water = 90:10) to obtain 429mg of 2-(3,4-dimethoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in an 18.2% yield. The following reactions occur:

[0197]

[0198] The structural characterization data of the product are: HRESIMS (m / z 513.2487 [M+H] + ,calcd,513.2483); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.40(3H,s,OCH3),3.43( 3H,s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.25(2H,s,-OCH2O),5.27(2H,s,-OCH2O),5.6 0(1H,s,H-4),7.19(1H,d,J=8.5Hz,H-5″),7.32(1H,dd,J=2.0,8.5Hz,H-6″),7.41(1H,d,J=2 .0Hz,H-2″),7.75(1H,d,J=16.0Hz,H-2′),8.08(1H,d,J=16.0Hz,H-3′),18.96(1H,s,1′-OH).

[0199] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),55.9(OCH3),55.9(OCH3),57.5(C-6), 94.4(-OCH2O),94.9(-OCH2O),100.0(C-4),107.1(C-2),116.5(C-2″),116.6(C-5″),1 18.3(2×=CHCH2),121.6(C-2′),123.8(C-6″),128.9(C-1″),134.1(2×-C=CH),143.3(C -3′),147.0(C-3″),149.4(C-4″),179.6(C-5),185.4(C-1′),190.8(C-3),196.3(C-1).

[0200] (3) Synthesis of 2-(3,4-dihydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0201] 300 mg of 2-(3,4-dimethoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was added to 223 mg of 2 eq of p-toluenesulfonic acid hydrate and dissolved in 5 mL of methanol. The mixture was stirred at room temperature for 2 days and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 253 mg of 2-(3,4-dihydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 70:30) with a yield of 99%. The following reactions occurred during this process:

[0202] The structural characterization data of the product are: HRESIMS (m / z 425.1962[M+H] + ,calcd,469.1959); 1 H NMR (500 MHz, DMSO-d6) δ H:1.52(12H,s,4×CH3),2.45(2H,m,-CH2CH=),2.55(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.50(1H,s,H-4),6.79(1H,d,J=8.5Hz,H-5″ ),6.97(1H,dd,J=2.5,8.5Hz,H-6″),7.15(1H,d,J=2.5Hz,H-2″),7.65(1 H,d,J=15.5Hz,H-2′),8.06(1H,d,J=15.5Hz,H-3′),18.90(1H,s,1′-OH).

[0203] 13 C NMR (125 MHz, DMSO-d6) δ C :17.8(2×CH3),25.7(2×CH3),37.1(2×-CH2CH=),57.7(C-6),99.8(C-4),106.7(C-2),113.8(C-2″),116.0(C-5″),118.6(2×=CHCH2),119.8(C-2′ ),122.9(C-6″),126.6(C-1″),133.8(2×-C=CH),144.0(C-3′),145.9(C- 3″),149.1(C-4″),180.5(C-5),185.2(C-1′),190.3(C-3),196.6(C-1).

[0204] (4) Synthesis of 4,4′-methylenebis[2-(3,4-dihydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0205] 199 mg of 2-(3,4-dihydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 7 mL of acetonitrile, followed by the addition of 320 μL of acetic acid and 761 μL of 20 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 2 days and monitored for completion by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 89 mg of 4,4′-methylenebis[2-(3,4-dihydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 44.1%. The following reactions occurred during this process:

[0206]

[0207] The structural characterization data of the product are: HRESIMS (861.3835 [M + H] + ,calcd,861.3844); 1 H NMR (500 MHz, pyridine-d5) δ H :1.54(12H,s,4×CH3),1.70(12H,s,4×CH3),2.97(4H,m,2×-CH2CH=),3.06(4H ,m,2×-CH2CH=),3.90(2H,s,-CH2-),5.27(4H,s,4×=CHCH2),7.21(2H,d,J=8.5 Hz,H-6″,H-6″″′),7.28(2H,d,J=8.5Hz,H-5″,H-5″″′),7.78(2H,s,H-2″,H-2″ ″′), 8.24 (2H, d, J = 15.5Hz, H-2′, H-2″″), 8.85 (2H, d, J = 15.5Hz, H-3′, H-3″″).

[0208] 13 C NMR (125 MHz, DMSO-d6) δ C :17.7(2×CH3),17.8(2×CH3),19.5(-CH2-),25.5(2×CH3),25.6(2×CH3),36.9(2×-CH2CH=),37.3(2×-CH2CH=),54.5(C-6,C-6″ ′),108.9(C-2,C-2″′),114.4(C-4,C-4″′),115.3(C-2″,C-2″″′),116.0(C-5″,C-5″″′),117.3(2×=CHCH2),117.7(2×=CHCH2) ,124.1(C-2′,C-2″″),126.2(C-6″,C-6″″′),128.7(C-1″,C-1″″′),131.7(2×-C=CH),135.0(2×-C=CH),146.1(C-3′,C-3″″),1 48.0(C-3″,C-3″″′), 150.4(C-4″,C-4″″′), 170.6(C-5,C-5″′), 185.9(C-1′,C-1″″), 187.5(C-3,C-3″′), 202.5(C-1,C-1″′).

[0209] Example 12

[0210] The synthesis method of compound 12 comprises the following steps:

[0211] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0212] The preparation method is the same as that of compound 1.

[0213] (2) Synthesis of 2-(2-methoxymethoxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0214] 3.3g of potassium hydroxide was dissolved in 7mL of water-10.5mL of ethanol solution. 3.3g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.25eq (2.65g) of 2-methoxymethoxy-3-methoxybenzaldehyde were then added. The mixture was stirred at 55°C for 10h and the reaction was monitored for completion by HPLC. The mixture was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 1.2g of 2-(2-methoxymethoxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 85:15) to obtain 2-(2-methoxymethoxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 22.9%. The following reactions occurred:

[0215]

[0216] The structural characterization data of the product are: HRESIMS (m / z 483.2383 [M+H] + ,calcd,483.2377); 1 H NMR (500 MHz, DMSO-d6) δ H :1.52(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.47(3H,s,OCH3),3. 82(3H,s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.10(2H,s,-OCH2O),5.60(1H,s,H-4), 7.16(1H,dd,J=2.0,8.5Hz,H-4″),7.19(1H,t,J=8.5Hz,H-5″),7.28(1H,dd,J=2.0,8.5Hz ,H-6″),8.16(1H,d,J=16.0Hz,H-2′),8.20(1H,d,J=16.0Hz,H-3′),18.89(1H,s,1′-OH).

[0217] 13C NMR (125 MHz, DMSO-d6) δ C :17.8(2×CH3),25.7(2×CH3),37.1(2×-CH2CH=),55.9(OCH3),57.3(OCH3),57.7(C -6),94.3(-OCH2O),99.9(C-4),107.2(C-2),114.9(C-4″),118.2(C-6″),118.3(2× =CHCH2),124.3(C-2′),124.9(C-5″),129.2(C-1″),134.1(2×-C=CH),137.7(C-3′) ,145.0(C-3″),152.4(C-2″),180.3(C-5),185.5(C-1′),190.7(C-3),196.5(C-1).

[0218] (3) Synthesis of 2-(2-hydroxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0219] 1g of 2-(2-methoxymethoxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was added to 395mg of 1eq of p-toluenesulfonic acid hydrate and dissolved in 25mL of methanol. The mixture was stirred at room temperature for 1.5 days, and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 640mg of 2-(2-hydroxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 84:16) with a yield of 70.4%. The following reactions occurred during the reaction:

[0220]

[0221] The structural characterization data of the product are: HRESIMS (m / z 439.2118[M+H] + ,calcd,439.2115); 1 H NMR (500 MHz, DMSO-d6) δ H:1.52(12H,s,4×CH3),2.46(2H,m,-CH2CH=),2.57(2H,m,-CH2CH=),3.82(3H ,s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.57(1H,s,H-4),6.85(1H,t,J= 8.0Hz,H-5″),7.03(1H,d,J=8.0Hz,H-4″),7.15(1H,d,J=8.0Hz,H-6″),8.12 (1H,d,J=16.0Hz,H-2′),8.24(1H,d,J=16.0Hz,H-3′),18.95(1H,s,1′-OH).

[0222] 13 C NMR (125 MHz, DMSO-d6) δ C :17.8(2×CH3),25.7(2×CH3),37.1(2×-CH2CH=),56.0(OCH3),57.6(C-6),10 0.0(C-4),107.1(C-2),113.6(C-4″),118.4(2×=CHCH2),119.3(C-5″),119. 4(C-6″),122.0(C-2′),122.7(C-1″),134.0(2×-C=CH),138.5(C-3′),146.6 (C-3″),148.2(C-2″),180.1(C-5),185.7(C-1′),190.7(C-3),196.4(C-1).

[0223] (4) Synthesis of 4,4′-methylenebis[2-(2-hydroxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0224] 204 mg of 2-(2-hydroxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile and 1 mL of methanol. Acetic acid (200 μL) and 755 μL of 20 eq of 37% aqueous formaldehyde were then added. The mixture was stirred at room temperature for 1.5 days and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 150 mg of 4,4′-methylenebis[2-(2-hydroxy-3-methoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 72.5%. The following reactions occurred during this process:

[0225]

[0226] The structural characterization data of the product are: HRESIMS (m / z 889.4154[M+H] + ,calcd,889.4158); 1 H NMR (500 MHz, pyridine-d5) δ H :1.54(12H,s,4×CH3),1.70(12H,s,4×CH3),2.98(4H,m,2×-CH2CH=),3.08(4H,m,2×-C H2CH=),3.67(6H,s,2×OCH3),3.94(2H,s,-CH2-),5.30(4H,s,4×=CHCH2),6.84(2H,t, J=8.0Hz,H-5″,H-5″″′),6.92(2H,d,J=8.0Hz,H-4″,H-4″″′),7.53(2H,d,J=8.0Hz,H- 6″,H-6″″′), 9.00(2H,d,J=16.0Hz,H-2′,H-2″″),9.15(2H,d,J=16.0Hz,H-3′,H-3″″).

[0227] 13 C NMR (125 MHz, DMSO-d6) δ C :14.1(-CH2-),17.8(4×CH3),25.5(4×CH3),36.8(2×-CH2CH=),37.1(2×-CH2CH=),54.5(C-6,C-6″′),56.0(2×OCH 3),109.3(C-2,C-2″′),114.5(C-2′,C-2″″),115.3(C-4,C-4″′),117.2(C-4″,C-4″″′),119.4(4×=CHCH2),121.2( C-6″,C-6″″′),121.5(C-5″,C-5″″′),135.0(4×-C=CH),141.6(C-3′,C-3″″),147.3(C-3″,C-3″″′),148.2(C-2″, C-2″″′), 119.5(C-1″,C-1″″′), 170.7(C-5,C-5″′), 186.4(C-1′,C-1″″), 187.4(C-3,C-3″′), 202.5(C-1,C-1″′).

[0228] Example 13

[0229] The synthesis method of compound 13 comprises the following steps:

[0230] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0231] The preparation method is the same as that of compound 1.

[0232] (2) Synthesis of 2-(4-methylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0233] Dissolve 1.5g of potassium hydroxide in 3mL of water-4.5mL of ethanol solution, then add 1.5g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 710μL of 1.22eq of 4-methylbenzaldehyde. Stir and react at 55°C for 10h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 2-(4-methylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 85:15) to obtain 837mg of 2-(4-methylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 41.8%. The following reactions occur:

[0234]

[0235] The structural characterization data of the product are: HRESIMS (m / z 407.2223 [M+H] + ,calcd,407.2117); 1 H NMR (500 MHz, DMSO-d6) δ H :1.52(12H,s,4×CH3),2.34(3H,s,CH3),2.47(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.58(1H,s,H-4),7.28( 2H,d,J=8.0Hz,H-3″,H-5″),7.57(2H,d,J=8.0Hz,H-2″,H-6″),7.77(1H ,d,J=16.0Hz,H-2′),8.20(1H,d,J=16.0Hz,H-3′),18.91(1H,s,1′-OH). 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),21.1(CH3),25.7(2×CH3),37.1(2×-CH2CH=),57.7(C-6),99.9(C-4),107.1(C-2),118.4(2×=CHCH2),122.5(C-2′),128.5(C-2″ ,C-6″),129.8(C-3″,C-5″),132.2(C-1″),134.0(2×-C=CH),140.8(C-4 ″),143.2(C-3′),180.3(C-5),185.5(C-1′),190.6(C-3),196.5(C-1).

[0236] (3) Synthesis of 4,4′-methylenebis[2-(4-methylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0237] 450 mg of 2-(4-methylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile. Then, 200 μL of acetic acid and 10 eq (1.2 mL) of 37% aqueous formaldehyde were added. The mixture was stirred at room temperature for 2 h and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 248 mg of 4,4′-methylenebis[2-(4-methylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 54.3%. The following reactions occurred during this process:

[0238]

[0239] The structural characterization data of the product are: HRESIMS (m / z 825.4352[M+H] + ,calcd,825.4361); 1 H NMR (500 MHz, pyridine-d5) δ H:1.47(24H,s,8×CH3),2.26(4H,m,2×-CH2CH=),2.30(6H,s,2×CH3),2.37(4H,m, 2×-CH2CH=), 3.20(2H,s,-CH2-), 4.89(4H,t,J=7.0Hz, 4×=CHCH2), 7.18(4H,d,J= 8.5Hz,H-3″,H-5″,H-3″″′,H-5″″′),7.27(2H,d,J=16.0Hz,H-2′,H-2″″),7.40(4 H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″″′),8.04(2H,d,J=16.0Hz,H-3′,H-3″″).

[0240] 13 C NMR (125 MHz, DMSO-d6) δ C :16.1(-CH2-),18.0(4×CH3),21.1(2×CH3),25.8(4×CH3),37.7(4×-CH2CH=),60.7(C-6,C-6″′),106.2( C-2, C-2″′), 106.4 (C-4, C-4″′), 122.1 (4×=CHCH2), 127.3 (C-2″, C-6″, C-2″″′, C-6″″′), 128.8 (C-2′, C- 2″″),129.5(C-3″,C-5″,C-3″″′,C-5″″′),130.2(4×-C=CH),134.1(C-1″,C-1″″′),134.9(C-3′,C-3″″), 138.1 (C-4″, C-4″″′), 177.1 (C-5, C-5″′), 182.2 (C-1′, C-1″″), 193.5 (C-3, C-3″′), 198.4 (C-1, C-1″′).

[0241] Example 14

[0242] The synthesis method of compound 14 comprises the following steps:

[0243] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0244] The preparation method is the same as that of compound 1.

[0245] (2) Synthesis of 2-(3-methoxy-4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0246] Dissolve 1.55g of potassium hydroxide in 3mL of water-4.5mL of ethanol solution, then add 1.55g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.2eq of 2-methoxymethoxy-3-methoxybenzaldehyde. Stir and react at 55°C for 10h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 580g of 2-(3-methoxy-4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 85:15) to obtain 2-(3-methoxy-4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 23.6%. The following reactions occur during this process:

[0247]

[0248] The structural characterization data of the product are: HRESIMS (m / z 483.2372 [M+H] + ,calcd,483.2377); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.39(3H,s,OCH 3),3.89(3H,s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.24(2H,s,-OCH2O),5.60(1 H,s,H-4),7.15(1H,d,J=8.0Hz,H-5″),7.26(1H,d,J=8.0Hz,H-6″),7.27(1H,s,H-2 ″),7.79(1H,d,J=15.5Hz,H-2′),8.12(1H,d,J=15.5Hz,H-3′),18.98(1H,s,1′-OH).

[0249] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),55.6(OCH3),55.9(OCH3),57.5(C- 6),94.5(-OCH2O),100.1(C-4),107.1(C-2),112.0(C-5″),116.2(C-2″),118.3(2× =CHCH2),121.5(C-2′),121.9(C-6″),129.1(C-1″),134.0(2×-C=CH),143.7(C-3′) ,148.4(C-3″),149.8(C-4″),179.6(C-5),185.5(C-1′),190.9(C-3),196.4(C-1).

[0250] (3) Synthesis of 2-(3-methoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0251] 740 mg of 2-(3-methoxy-4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was added to 292 mg of 1 eq of p-toluenesulfonic acid hydrate and dissolved in 15 mL of methanol. The mixture was stirred at room temperature for 1 day, and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 380 mg of 2-(3-methoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 80:20) with a yield of 56.5%. The following reactions occurred during this process:

[0252]

[0253] The structural characterization data of the product are: ESIMS (m / z 439.2[M+H] + ); 1 H NMR (500 MHz, DMSO-d6) δ H:1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.57(2H,m,-CH2CH=),3.83(3H, s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.58(1H,s,H-4),6.87(1H,d,J=8. 0Hz,H-5″),7.18(1H,dd,J=2.0,8.0Hz,H-6″),7.21(1H,d,J=2.0Hz,H-2″),7. 77(1H,d,J=15.5Hz,H-2′),8.08(1H,d,J=15.5Hz,H-3′),19.00(1H,s,1′-OH).

[0254] (4) Synthesis of 4,4′-methylenebis[2-(3-methoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0255] 220 mg of 2-(3-methoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 150 μL of acetic acid and 814 μL of 20 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 1.5 days and monitored for completion by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 84:16) to obtain 120 mg of 4,4′-methylenebis[2-(3-methoxy-4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 53.8%. The following reactions occurred during this process:

[0256]

[0257] The structural characterization data of the product are: HRESIMS (m / z 889.4152[M+H] + ,calcd,889.4158); 1 H NMR (500 MHz, pyridine-d5) δ H:1.56(12H,s,4×CH3),1.72(12H,s,4×CH3),3.01(4H,m,2×-CH2CH=),3.10(4H,m,2×- CH2CH=),3.74(6H,s,2×OCH3),3.99(2H,s,-CH2-),5.32(4H,s,4×=CHCH2),7.18(2H,d d,J=2.5,8.0Hz,H-6″,H-6″″′),7.36(2H,s,H-2″,H-2″″′),7.40(2H,d,J=8.0Hz,H-5 ″,H-5″″′), 8.23(2H,d,J=16.0Hz,H-2′,H-2″″),8.87(2H,d,J=16.0Hz,H-3′,H-3″″).

[0258] 13 C NMR (125 MHz, DMSO-d6) δ C :17.7(4×CH3),25.5(4×CH3),36.8(-CH2-),37.2(4×-CH2CH=),54.4(C-6,C-6″′),55.6(2×OCH3),109.1(C-2 ,C-2″′),113.0(C-4,C-4″′),115.4(C-2″,C-2″″′),116.1(C-5″,C-5″″′),117.3(4×=CHCH2),118.4(C-2′,C- 2″″),123.6(C-6″,C-6″″′),126.1(C-1″,C-1″″′),134.9(4×-C=CH),147.5(C-3′,C-3″″),148.0(C-4″,C-4″ ″′), 150.9 (C-3″, C-3″″′), 170.4 (C-5, C-5″′), 186.0 (C-1′, C-1″″), 187.3 (C-3, C-3″′), 202.3 (C-1, C-1″′).

[0259] Example 15

[0260] The synthesis method of compound 15 comprises the following steps:

[0261] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0262] The preparation method is the same as that of compound 1.

[0263] (2) Synthesis of 2-(2,6-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0264] 300 mg of potassium hydroxide was dissolved in 0.6 mL of water-0.9 mL of ethanol solution. 300 mg of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3 eq (492 mg) of 2,6-dimethoxybenzaldehyde were then added. The mixture was stirred at 55°C for 19 h, and the reaction was monitored for completion by HPLC. The mixture was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 126 mg of 2-(2,6-dimethoxycinnamyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 84:16) to obtain 2-(2,6-dimethoxycinnamyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 28.2%. The following reactions occurred during this process:

[0265]

[0266] The structural characterization data of the product are: HRESIMS (m / z 453.2270[M+H] + ,calcd,453.2272); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.42(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.87(6H,s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.56(1H,s,H-4),6. 73(2H,d,J=8.5Hz,H-3″,H-5″), 7.37(1H,t,J=8.5Hz,H-4″), 8.14(1H,d,J=16.0Hz,H-2′), 8.53(1H,d,J=16.0Hz,H-3′), 18.99(1H,s,1′-OH).

[0267] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),56.0(2×OCH3),57.5(C- 6),100.1(C-4),104.2(C-3″,C-5″),107.3(C-2),112.1(C-1″),118.5(C -2′),118.5(2×=CHCH2),126.0(C-4″),132.3(C-3′),133.9(2×-C=CH),1 59.8(C-2″,C-6″),179.6(C-5),186.5(C-1′),190.7(C-3),195.9(C-1).

[0268] (3) Synthesis of 4,4′-methylenebis[2-(2,6-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0269] 60 mg of 2-(2,6-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 50 μL of acetic acid and 20 eq (215 μL) of 37% formaldehyde solution. The reaction was stirred at room temperature for 1 day, and completion was monitored by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal-phase flash preparative column chromatography (petroleum ether:ethyl acetate = 84:16) to obtain 47 mg of 4,4′-methylenebis[2-(2,6-dimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 77.3%. The following reactions occurred during this process:

[0270]

[0271] The structural characterization data of the product are: HRESIMS (m / z 917.4465 [M+H] + ,calcd,917.4470); 1 H NMR (500 MHz, pyridine-d5) δ H:1.54(12H,s,4×CH3),1.69(12H,s,4×CH3),2.97(4H,m,2×-CH2CH=),3.05( 4H,m,2×-CH2CH=),3.77(2H,s,-CH2-),3.82(12H,s,4×OCH3),5.20(4H,s,4× =CHCH2),6.61(4H,s,H-3″,H-5″,H-3″″′,H-5″″′),7.32(2H,s,H-4″,H-4″″′ ), 8.92 (2H, d, J = 16.5Hz, H-2′, H-2″″), 9.46 (2H, d, J = 16.5Hz, H-3′, H-3″″).

[0272] 13 C NMR (125MHz, chloroform-d)δ C :17.9(2×CH3),18.0(2×CH3),18.6(-CH2-),26.0(2×CH3),26.0(2×CH3),37.0(2×-CH2CH=),37.8(2×-CH2CH=),55.0(C-6,C-6 ″′),56.0(4×OCH3),103.7(C-3″,C-5″,C-3″″′,C-5″″′),110.1(C-2,C-2″′),111.3(C-4,C-4″′),115.7(C-1″,C-1″″’),117.6 (2×=CHCH2),118.0(2×=CHCH2),125.4(C-2′,C-2″″),132.4(C-4″,C-4″″′),135.3(2×-C=CH),135.5(2×-C=CH),136.9(C-3′,C -3″″),160.8(C-2″,C-6″,C-2″″′,C-6″″′),171.3(C-5,C-5″′),188.4(C-1′,C-1″″),188.4(C-3,C-3″′),202.8(C-1,C-1″′).

[0273] Example 16

[0274] The synthesis method of compound 16 comprises the following steps:

[0275] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0276] The preparation method is the same as that of compound 1.

[0277] (2) Synthesis of 2-(4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0278] Take 1g of potassium hydroxide and dissolve it in 2ml of water-3ml of ethanol solution. Then add 1g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.2eq (655mg) of 4-methoxymethoxybenzaldehyde. Stir and react at 55°C for 10h. The reaction is monitored by high performance liquid chromatography. Quench with water, adjust the pH to neutral with dilute hydrochloric acid, and then extract with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and pure water, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and finally purified by normal phase flash preparative column chromatography (petroleum ether: ethyl acetate = 91:

[0279] 9) 637 mg of 2-(4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified with a yield of 42.8%. The following reaction occurred during this process:

[0280]

[0281] The structural characterization data of the product are: HRESIMS (m / z 453.2269[M+H] + ,calcd,453.2272); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.39(3H, s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.26(2H,s,-OCH2O),5.60(1H,s,H -4),7.11(2H,d,J=8.5Hz,H-3″,H-5″),7.64(2H,d,J=8.5Hz,H-2″,H-6″),7.8 0(1H,d,J=16.0Hz,H-2′),8.14(1H,d,J=16.0Hz,H-3′),18.99(1H,s,1′-OH).

[0282] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),55.8(OCH3),57.5(C-4),9 3.7(-OCH2O),100.1(C-6),107.0(C-2),116.6(C-3″,C-5″),118.3(2×=CHCH 2),121.2(C-2′),128.4(C-1″),130.3(C-2″,C-6″),134.1(2×-C=CH),143.3 (C-3′),158.9(C-4″),179.5(C-5),185.5(C-1′),190.9(C-1),196.3(C-3).

[0283] (3) Synthesis of 2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0284] 637 mg of 2-(4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was added to 268 mg of 1 eq of p-toluenesulfonic acid hydrate and dissolved in 15 mL of methanol. The mixture was stirred at room temperature for 1 day, and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 330 mg of 2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 75:25) with a yield of 57.4%. The following reactions occurred during this process:

[0285]

[0286] The structural characterization data of the product are: HRESIMS (m / z 409.2001[M+H] + ,calcd,409.2010); 1 H NMR (500 MHz, DMSO-d6) δ H:1.52(12H,s,4×CH3),2.46(2H,m,-CH2CH=),2.56(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.55(1H,s,H-4),6.85(2H,d,J=8 .5Hz,H-3″,H-5″),7.54(2H,d,J=8.5Hz,H-2″,H-6″),7.75(1H,d,J=16.0Hz,H-2′),8.10(1H,d,J=16.0Hz,H-3′),18.97(1H,s,1′-OH).

[0287] (4) Synthesis of 4,4′-methylenebis[2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0288] 392 mg of 2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 20 mL of acetonitrile. 3-5 drops of acetic acid and 156 μL of 2 eq of 37% formaldehyde solution were then added. The reaction was stirred at room temperature for 1 hour and monitored for completion by thin-layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 330 mg of 4,4′-methylenebis[2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in an 83.0% yield. The following reactions occurred during this process:

[0289]

[0290] The structural characterization data of the product are: HRESIMS (m / z 829.3942[M+H] + ,calcd,829.3946); 1 H NMR (500 MHz, pyridine-d5) δ H:1.56(12H,s,4×CH3),1.71(12H,s,4×CH3),3.00(4H,m,2×-CH2CH=),3.08(4H, m,2×-CH2CH=),3.95(2H,s,-CH2-),5.30(4H,s,4×=CHCH2),7.12(4H,d,J=8.5H z,H-3″,H-5″,H-3″″′,H-5″″′),7.70(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″ ″′), 8.21 (2H, d, J = 16.0Hz, H-2′, H-2″″), 8.85 (2H, d, J = 16.0Hz, H-3′, H-3″″).

[0291] 13 C NMR (125 MHz, DMSO-d6) δ C :17.7(4×CH3),25.5(4×CH3),36.8(-CH2-),37.2(4×-CH2CH=),54.4(C-6,C-6″′),109.0(C-2,C-2″′ ),115.3(C-4,C-4″′),116.4(C-2′,C-2″″),117.3(C-3″,C-5″,C-3″″′,C-5″″′),118.1(4×=CHCH2),1 25.7(C-1″,C-1″″′),131.6(C-2″,C-6″,C-2″″′,C-6″″′),134.9(4×-C=CH),147.3(C-3′,C-3″″),161 .4(C-4″,C-4″″′),170.6(C-5,C-5″′),186.1(C-1′,C-1″″),187.4(C-3,C-3″′),202.4(C-1,C-1″′).

[0292] Example 17

[0293] The synthesis method of compound 17 comprises the following steps:

[0294] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0295] The preparation method is the same as that of compound 1.

[0296] (2) Synthesis of 2-(3,4-dimethylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0297] Dissolve 1g of potassium hydroxide in 2mL of water-3mL of ethanol solution, then add 1g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 530μL of 1.2eq of 3,4-dimethylbenzaldehyde. Stir and react at 55°C for 10h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 494mg of 2-(3,4-dimethylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 80:20) to obtain 2-(3,4-dimethylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 35.7%. The following reactions occur:

[0298]

[0299] The structural characterization data of the product are: HRESIMS (m / z 421.2374[M+H] + ,calcd,421.2373); 1 H NMR (500 MHz, DMSO-d6) δ H :1.52(12H,s,4×CH3),2.26(6H,s,2×CH3),2.48(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.60(1H,s,H-4),7.24(1H ,d,J=8.0Hz,H-5″),7.40(1H,d,J=8.0Hz,H-6″),7.44(1H,s,H-2″),7.76( 1H,d,J=15.5Hz,H-2′),8.18(1H,d,J=15.5Hz,H-3′),18.97(1H,s,1′-OH).

[0300] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),19.4(CH3),19.6(CH3),25.7(2×CH3),37.0(2×-CH2CH=),57.5( C-6),100.0(C-4),107.1(C-2),118.3(2×=CHCH2),122.1(C-2′),126.3(C-6″) ,129.4(C-1″),130.3(C-2″),132.5(C-5″),134.1(2×-C=CH),137.2(C-3″),13 9.9(C-4″),143.7(C-3′),179.7(C-5),185.6(C-1′),190.9(C-3),196.4(C-1).

[0301] (3) Synthesis of 4,4′-methylenebis[2-(3,4-dimethylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0302] 150 mg of 2-(3,4-dimethylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of methanol. 3-5 drops of acetic acid and 15 eq (435 μL) of 37% aqueous formaldehyde were added. The mixture was stirred at room temperature for 1 day and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was separated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 75 mg of 4,4′-methylenebis[2-(3,4-dimethylcinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 49.3%. The following reactions occurred during this process:

[0303]

[0304] The structural characterization data of the product are: HRESIMS (m / z 853.4656[M+H] + ,calcd,853.4674); 1 H NMR (500 MHz, pyridine-d5) δ H:1.56(12H,s,4×CH3),1.73(12H,s,4×CH3),2.04(6H,s,2×CH3),2.07(6H,s,2×CH3),3.0 3(4H,m,2×-CH2CH=),3.13(4H,m,2×-CH2CH=),4.13(2H,s,-CH2-),5.40(4H,s,4×=CHCH2 ),7.07(2H,d,J=7.5Hz,H-5″,H-5″″′),7.42(2H,s,H-2″,H-2″″′),7.46(4H,d,J=8.5Hz, H-6″, H-6″″′), 8.10 (2H, d, J = 15.5Hz, H-2′, H-2″″), 8.96 (2H, d, J = 15.5Hz, H-3′, H-3″″).

[0305] 13 C NMR (125 MHz, DMSO-d6) δ C :16.1(-CH2-),18.0(4×CH3),19.4(2×CH3),19.6(2×CH3),25.8(4×CH3),37.7(4×-CH2CH=),60.7(C-6,C-6″′),1 06.2(C-2,C-2″′),106.7(C-4,C-4″′),122.1(4×=CHCH2),125.1(C-2′,C-2″″),128.3(C-6″,C-6″″′),128.5(C- 1″,C-1″″′),130.0(C-2″,C-2″″′),130.1(4×-C=CH),134.5(C-5″,C-5″″′),135.1(C-4″,C-4″″′),136.6(C-3″, C-3″″), 137.0 (C-3′, C-3″″), 177.0 (C-5, C-5″′), 182.3 (C-1′, C-1″″), 193.4 (C-3, C-3″′), 198.4 (C-1, C-1″′).

[0306] Example 18

[0307] The synthesis method of compound 18 comprises the following steps:

[0308] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0309] The preparation method is the same as that of compound 1.

[0310] (2) Synthesis of 2-(3,4,5-trimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0311] Dissolve 1g of potassium hydroxide in 2mL of water-3mL of ethanol solution, then add 1g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.2eq (774mg, 780mg) of 3,4,5-trimethoxybenzaldehyde. Stir at 55°C for 10h. Completion of the reaction is monitored by HPLC. Quench with water, adjust the pH to neutral with dilute hydrochloric acid, and extract with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 283mg of 2-(3,4,5-trimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using reverse-phase flash preparative column chromatography (methanol:water = 80:20) to obtain 283mg of 2-(3,4,5-trimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione in a yield of 17.8%. The following reactions occur:

[0312]

[0313] The structural characterization data of the product are: ESIMS (m / z 483.1 [M+H] + ); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.57(2H,m,-CH2CH=),3.72(3H,s,OCH3),3.84(6H,s,2×OCH3),4.80(2H,t,J=7.5Hz,2× =CHCH2),5.57(1H,s,H-4),6.99(2H,s,H-2″,H-6″),7.77(1H,d,J=16.0Hz,H-2′),8.10(1H,d,J=16.0Hz,H-3′),18.88(1H,s,1′-OH).

[0314] (3) Synthesis of 4,4′-methylenebis[2-(3,4,5-trimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0315] 150 mg of 2-(3,4,5-trimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 10 mL of acetonitrile, followed by the addition of 200 μL of acetic acid and 505 μL of 20 eq of 37% formaldehyde solution. The reaction was stirred at room temperature for 29 hours and monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 103 mg of 4,4′-methylenebis[2-(3,4,5-trimethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 67.8%. The following reactions occurred during this process:

[0316]

[0317] The structural characterization data of the product are: HRESIMS (m / z 977.4681[M+H] + ,calcd,977.4682); 1 H NMR (500 MHz, pyridine-d5) δ H :1.56(12H,s,4×CH3),1.74(12H,s,4×CH3),3.05(4H,m,2×-CH2CH=),3.15 (4H,m,2×-CH2CH=),3.71(12H,s,4×OCH3),3.88(6H,s,2×OCH3),4.24(2H,s ,-CH2-),5.45(4H,s,4×=CHCH2),7.02(4H,s,H-2″,H-6″,H-2″″′,H-6″″′) ,8.10(2H,d,J=15.5Hz,H-2′,H-2″″),8.96(2H,d,J=15.5Hz,H-3′,H-3″″).

[0318] 13 C NMR (125MHz, chloroform-d)δ C:17.7(-CH2-),18.1(4×CH3),26.0(4×CH3),37.0(2×-CH2CH=),37.9(2×-CH2CH=),55.0(C-6,C-6″′),56.3(4×OCH3),61.2 (2×OCH3),106.2(C-2,C-2″′),106.2(C-2″,6″,C-2″″′,C-6″″′),110.0(C-4,C-4″′),117.3(2×=CHCH2),117.6(2×=CHCH2) ,121.2(C-2′,C-2″″),130.7(C-1″,C-1″″′),135.7(2×-C=CH),135.8(2×-C=CH),140.8(C-4″,C-4″″′),145.4(C-3′,C-3″ ″), 153.6 (C-3″, C-5″, C-3″″′, C-5″″′), 171.2 (C-5, C-5″′), 187.2 (C-1′, C-1″″), 188.4 (C-3, C-3″′), 202.7 (C-1, C-1″′).

[0319] Pharmacological experiments

[0320] Experimental Example 1 In vitro screening model: protein tyrosine phosphatase 1B (PTP1B) inhibitory activity screening

[0321] Insulin exerts its biological effects through the insulin signaling system. Within this system, many important cytokines, such as IRS-1, are activated through acidification by tyrosine phosphatases and subsequently inactivated by dephosphorylation by protein tyrosine phosphatase 1B (PTP1B). Therefore, PTP1B inhibitors can enhance the effects of insulin by prolonging the insulin signaling pathway. Currently, PTP1B has become a key target for insulin sensitizers.

[0322] 1 Method

[0323] Using molecular biology methods, human PTP1B protein was overexpressed in recombinant hGST-PTP1B-BL21 E. coli strains induced by IPTG. hGST-PTP1B protease was purified using a GST affinity chromatography column. Protein content was determined using Bio-Rad protein assay reagents. In vitro enzymatic analysis using the peptide para-NitroPhenyl Phosphate as a substrate was used to investigate the effects of drugs on hGST-PTP1B protease activity.

[0324] 2 Results

[0325] In vitro pharmacological experiments showed that the inhibition rates of compounds 1, 2, 3, 4, 5, and 16 on recombinant human PTP1B (protein tyrosine phosphatase 1B) at a concentration of 10 μM were 97.7%, 99.0%, 100.0%, 99.5%, 93.7%, and 84.5%, respectively. 50 They are 5.02μM, 9.72μM, 12.00μM, 2.42μM, 0.54μM and 0.68μM respectively.

[0326] Experimental Example 2 In vitro screening model: α-glucosidase inhibitory activity screening

[0327] α-glucosidase is located within the brush border of the small intestine. Its primary function is to promote the breakdown and absorption of starch dextrins, polysaccharides, sucrose, and maltose in the intestine, and to break down other oligosaccharides into dextrose, galactose, and dextrose fructose. α-glucosidase inhibitors reversibly inhibit brush border α-glucosidases (including amylase, maltase, sucrase, and isomaltase), delaying the conversion of polysaccharides and disaccharides into absorbable monosaccharides and mitigating postprandial blood sugar increases.

[0328] 1 Method

[0329] 0.1M PBS buffer (50 μL) and blank buffer (80 μL) were added to the experimental and blank groups, respectively. 10 μL of sample and 30 μL of alpha-glucosidase were added to each group. The mixture was reacted in a 37°C water bath for 5 minutes, followed by centrifugation at 90 rpm. PNPG (1 mM) (20 μL) was then added to each group. The mixture was reacted in a 37°C water bath for 15 minutes, followed by centrifugation at 90 rpm. The reaction was terminated with 50 μL of 0.4M Na₂CO₃. OD values ​​were measured at 400 nm on a spectrophotometer.

[0330] 2 Results

[0331] In vitro pharmacological experiments showed that the inhibition rates of compounds 11, 12, and 14 on α-glucosidase at a concentration of 10 μM were 79.4%, 69.9%, and 66.7%, respectively, which were all higher than the inhibition rate of the positive drug acarbose at a concentration of 20 μg / ml on α-glucosidase of 65.1%.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, characterized in that: Wherein, R is 1, 2, or 3 arbitrary monosubstituted, disubstituted, or polysubstituted groups on the benzene ring. When R is a single substituent, its position is as shown in R1: When R is a disubstituted group, its position is as shown in R2 and R3: When R is a tri-substituent, its positions are as shown in R4, R5, and R6: Wherein R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, methoxymethoxy, bromine and chlorine.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from the following compounds:

3. A pharmaceutical composition, characterized in that Contains an effective dose of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that The dosage form of the composition is selected from tablets, capsules, pills, granules, oral solutions and suspensions.

5. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing diabetes.

Images