A kind of atractylodes lactone derivative and its preparation method and use

Abstract

The present invention provides a series of atractylodes lactone derivatives, preparation methods, and uses thereof, relating to the field of natural medicinal chemistry. By utilizing the unique properties of the atractylodes lactone skeleton and modifying its chemical structure, the present invention provides a series of atractylodes lactone derivatives, the general structural formula of which is (I). The atractylodes lactone derivatives provided by the present invention have a significant inhibitory effect on Aβ aggregation and can significantly delay the onset of paralysis in CL4176 nematodes. They have the potential to be developed into drugs for treating Aβ-related diseases, such as Alzheimer's disease.

Description

Technical Field

[0001] The present invention relates to the field of natural medicinal chemistry, and in particular to an atractylodes lactone derivative, a preparation method and application thereof. Background Art

[0002] Alzheimer's disease (AD) is a common neurodegenerative disorder that primarily affects the elderly and is characterized by a gradual loss of cognitive function, including memory loss, language impairment, and behavioral changes. With the increasing aging of the global population, the incidence of AD continues to rise, becoming a major challenge to global public health. Although there are currently several drugs on the market to treat AD, such as acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, huperzine A, and galantamine) and the NMDA receptor antagonist memantine, these drugs can only alleviate AD-related symptoms and cannot prevent or reverse disease progression. Furthermore, the long-term efficacy and safety of newly approved antibody drugs, such as aducanumab and lencanumab, require further research and evaluation. Therefore, the development of anti-AD drugs with higher efficacy and improved safety has become a scientific issue that needs to be addressed urgently.

[0003] The pathological mechanism of AD is complex, involving multiple factors and pathways. Among them, the abnormal aggregation of β-amyloid protein (Aβ) is considered to be one of the core factors in the onset of AD. Aβ is a small peptide produced by the cleavage of amyloid precursor protein (APP) by β and γ secretases, which can be effectively cleared under normal circumstances. However, in AD patients, the production and clearance of Aβ are unbalanced, resulting in its abnormal aggregation in the brain and the formation of amyloid plaques. These plaques not only have a direct toxic effect on neurons, but also further aggravate neuronal damage and death by inducing inflammatory responses, oxidative stress and cell apoptosis. Therefore, inhibiting the aggregation of Aβ and clearing Aβ deposits in the brain are important strategies for the treatment of AD.

[0004] In recent years, the potential of traditional Chinese medicine and its active ingredients in the treatment of AD has attracted widespread attention. Traditional Chinese medicine has unique advantages in the treatment of complex diseases such as AD due to its advantages such as multiple targets, multiple pathways and diversity. As a traditional Chinese medicine, Atractylodes macrocephala has been favored by researchers because of its multiple pharmacological activities. Atractylodes lactone is one of the important active ingredients in Atractylodes macrocephala and has been shown to have certain neuroprotective effects. However, its anti-AD activity is limited and its drugability is poor, which limits its application in the development of Alzheimer's disease drugs. In order to overcome the above-mentioned shortcomings, the present invention chemically transforms Atractylodes lactone I in the hope of obtaining an anti-AD compound with a new structure, good activity and high stability. Summary of the Invention

[0005] (1) Technical problems solved

[0006] In view of the deficiencies of the prior art, the present invention provides a compound for treating or preventing Alzheimer's disease and a preparation method thereof.

[0007] (2) Technical solution

[0008] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0009] In one aspect, the present invention provides a derivative of Atractylodes lactone I, whose chemical structure is as shown in the general formula (I):

[0010]

[0011] Wherein, R' is hydrogen or alkyl; R is any one of hydrogen, hydroxyl, alkoxy, alkyl, halogen, and cyano.

[0012] Furthermore, the compound represented by formula (I) or its pharmaceutically acceptable salt or solvent compound.

[0013] On the other hand, the present invention provides the use of atractylodes lactone derivative represented by formula (I) in the preparation of a drug for inhibiting abnormal aggregation of β-amyloid protein.

[0014] On the other hand, the present invention provides the use of atractylodes lactone derivative represented by formula (I) in the preparation of a drug for treating or preventing Alzheimer's disease.

[0015] In another aspect, the present invention also provides a pharmaceutical composition comprising an effective amount of formula (I) and a pharmaceutically acceptable carrier.

[0016] Furthermore, the pharmaceutical composition is in the form of capsules, tablets, injections, granules, pills or powders.

[0017] In another aspect, the present invention provides a method for preparing atractylodes lactone derivative represented by formula (I), comprising the following steps:

[0018] (1) Atractylodes lactone I and selenium dioxide are dissolved in anhydrous dioxane solvent, heated to 80-90°C under nitrogen protection, stirred and reacted for 2-3 hours, cooled to room temperature after the reaction, and dioxane is removed by distillation under reduced pressure. Ethyl acetate is then added, and the organic phase is washed 2-3 times with a saturated sodium thiosulfate solution and then washed 3-5 times with deionized water. The organic phase is then separated, concentrated and dried to obtain intermediate 1; the chemical structure of intermediate 1 is formula (II)

[0019]

[0020] (2) Dissolve the intermediate 1 and 2-iodobenzoic acid in acetonitrile, and then heat under reflux at 70-80°C for more than 24 hours. After the reaction, cool to room temperature, filter, and concentrate the filtrate to obtain the intermediate 2. The chemical structure of the intermediate 2 is formula (III):

[0021]

[0022] (3) The intermediate 2 is dissolved in dichloromethane, and then an indole derivative and stannous trifluoromethanesulfonate are added. The reaction is carried out under nitrogen protection for 36-48 hours. After the reaction is completed, the mixture is cooled to room temperature, a saturated sodium bicarbonate solution is added, and then the mixture is extracted with ethyl acetate as the organic phase. The extraction is repeated 3-5 times, and the organic phase is separated and collected. The organic phase is concentrated and dried to obtain the Atractylodes lactone derivative represented by formula (I).

[0023] Furthermore, the structural formula of the indole derivative in step (3) is as shown in formula (IV), wherein R' is hydrogen or alkyl; R is any one of hydrogen, hydroxyl, alkoxy, alkyl, halogen, and cyano;

[0024]

[0025] (3) Beneficial effects

[0026] Alzheimer's disease is a progressive neurodegenerative disease with an insidious onset. The clinical manifestations are irreversible deterioration of cognitive and memory functions, the main factor of which is the damage to neurons caused by excessive deposition of Aβ in the brain. The present invention utilizes the particularity of the atractylodes lactone skeleton and modifies its chemical structure to obtain a series of atractylodes lactone derivatives, the general structural formula of which is (I). The atractylodes lactone derivatives provided by the present invention have a significant inhibitory effect on Aβ aggregation and can significantly delay the paralysis of CL4176 nematodes, and have the application prospect of being developed into drugs for treating Aβ-related diseases such as Alzheimer's disease. DETAILED DESCRIPTION

[0027] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0028] The synthesis route of the Atractylodes macrocephala lactone derivative of the general formula (I) provided by the present invention is as follows:

[0029]

[0030] Example 1

[0031] Preparation of compound I-1

[0032]

[0033] (1) Atractylodes lactone I (115 mg, 0.5 mmol) and selenium dioxide (83 mg, 0.75 mmol) were added to a dry round-bottom flask, and then 3 mL of anhydrous dioxane was added to dissolve the mixture. The mixture was heated to 80°C and stirred for 2 h under nitrogen protection. After the reaction solution was cooled to room temperature, the dioxane was removed by distillation under reduced pressure, and then 5 mL of ethyl acetate was added. The organic phase was washed twice with a saturated sodium thiosulfate solution and then washed three times with water. The organic phase was dried and concentrated, and then purified by column chromatography (petroleum ether / ethyl acetate = 4:1-2:1) to obtain intermediate 1 (86 mg, yield 70%) as a light yellow oily liquid;

[0034] (2) Intermediate 1 (0.5 mmol) and 2-iodobenzoic acid (0.6 mmol) were dissolved in acetonitrile and then heated under reflux for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, namely, intermediate 2;

[0035] (3) Intermediate 2 was dissolved in dichloromethane, and an indole derivative (0.5 mmol) and stannous trifluoromethanesulfonate (0.05 mmol) were added, followed by stirring at room temperature overnight. After the reaction was completed, a saturated sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The organic solution was dried and concentrated, and then separated by column chromatography to obtain an off-white solid, i.e., the target product I-1.

[0036] In step (3), the structural formula of the indole derivative is as shown in formula (IV), wherein R' is hydrogen or alkyl; R is any one of hydrogen, hydroxyl, alkoxy, alkyl, halogen, and cyano.

[0037] Spectral data of target product I-1: 1 H NMR(500MHz,Chloroform-d)δ8.03(s,1H),6.99(m,1H),6.91(m,2H),6.82(s,1H),6.51(m,1H),5.59(s,1H),3.26(m,2H ),3.18(m,1H),2.88(m,1H),2.35-2.54(m,3H),2.02(m,1H),1.94(m,1H),1.89(s,3H),1.83-1.76(m,1H),1.27(s,3H). 13C NMR(125MHz,Chloroform-d)δ212.50,171.24,150.34,148.70,146.92,138.15,122.82,122.37,121.11,117 .39,117.10,113.19,105.50,104.29,53.11,46.62,38.34,38.03,36.04,24.03,21.76,18.65,14.20,8.55.

[0038] Example 2

[0039] Preparation of compound I-2

[0040]

[0041] Compound I-2 was prepared according to the synthetic method for preparing compound I-1, and its spectral data is as follows: 1 H NMR(500MHz,Chloroform-d)δ7.58(M,1H),7.28(m,1H),7.20(M,1H),7.11(M,1H),6.87(m,1H),5.60(s,1H),3.71(s,3H),3 .21-3.01(m,3H),2.80-2.70(m,1H),2.54(m,1H),2.47-2.31(m,2H),1.93(m,1H),1.80(m,4H),1.61(br,1H),1.26(s,3H). 13 C NMR (126MHz, CDCl3) δ210.42,171.03,156.62,148.63,146.61,146.36,136.56,128.24,127.72,121.45,11 8.83,117.24,114.90,109.39,51.74,48.66,45.82,42.79,37.92,35.83,32.68,24.20,22.30,18.59,8.46.

[0042] Example 3

[0043] Preparation of compound I-3

[0044]

[0045] Compound I-3 was prepared according to the synthetic method for preparing compound I-1, and its spectral data is as follows: 1H NMR(500MHz,Chloroform-d)δ8.03(s,1H),6.99(m,1H),6.91(m,2H),6.82(s,1H),6.51(m,1H),5.59(s,1H),3.26(m,2H ),3.18(m,1H),2.88(m,1H),2.35-2.54(m,3H),2.02(m,1H),1.94(m,1H),1.89(s,3H),1.83-1.76(m,1H),1.27(s,3H). 13 C NMR(125MHz,Chloroform-d)δ212.50,171.24,150.34,148.70,146.92,138.15,122.82,122.37,121.11,117 .39,117.10,113.19,105.50,104.29,53.11,46.62,38.34,38.03,36.04,24.03,21.76,18.65,14.20,8.55.

[0046] Example 4

[0047] Preparation of compound I-4

[0048]

[0049] Compound I-4 was prepared according to the synthetic method for preparing compound I-1, and its spectral data is as follows: 1 H NMR(500MHz,Chloroform-d)δ8.01(s,1H),7.23(m,1H),7.05(m,1H),6.85(m,2H),5.61(m,1H),3.86(m,3H ),3.10(m,3H),2.76(m,1H),2.55–2.32(m,3H),2.00–1.89(m,1H),1.79(s,3H),1.74(m,1H),1.25(s,3H). 13 C NMR (126MHz, CDCl3) δ210.49,171.06,156.60,154.09,148.59,131.17,128.07,124.01,121.77,121.08 ,117.30,115.00,111.63,100.84,56.01,51.44,45.93,42.99,37.80,24.23,20.96,18.56,14.21,8.45.

[0050] Example 5

[0051] Preparation of compound I-5

[0052]

[0053] Compound I-5 was prepared according to the synthetic method for preparing compound I-1, and its spectral data is as follows: 1 H NMR(500MHz,Chloroform-d)δ7.98(s,1H),7.36(m,1H),7.22(m,1H),6.83–7.01(m,2H),5.60(s,1H),3.12–3.25(m,2H),3 .06(m,1H),2.70–2.80(m,1H),2.45(s,3H),2.31–2.39(m,1H),1.89–1.95(m,1H),1.80(s,3H),1.75(m,1H),1.26(s,3H). 13 C NMR (126MHz, CDCl3) δ210.45,200.05,171.06,156.59,149.13,146.71,134.19,128.63,123.59,121.01 ,117.84,114.99,112.56,111.01,51.63,45.86,37.80,35.80,24.25,22.34,21.08,18.56,14.21,8.41.

[0054] Example 6: Preparation of Compound I-6

[0055]

[0056] Compound I-6 was prepared according to the synthetic method for preparing compound I-1, and its spectral data is as follows: 1 H NMR(500MHz,Chloroform-d)δ8.12(s,1H),7.50(m,1H),7.33(m,1H),7.08(m,1H),6.87(m,1H),5.62(m,1H),3.18(m,2H), 3.00(m,1H),2.80–2.69(m,1H),2.58–2.29(m,3H),1.95(m,2H),1.82(s,3H),1.81–1.74(m,1H),1.62(m,2H),1.26(s,3H). 13C NMR (126MHz, CDCl3) δ210.17,171.00,156.68,148.59,146.12,136.21,128.00,126.21,123.86,121.19, 120.13,119.15,117.23,113.38,111.27,51.42,45.98,42.95,37.78,35.84,24.21,20.65,18.54,8.51.

[0057] Example 7

[0058] Preparation of compound I-7

[0059]

[0060] Compound I-7 was prepared according to the synthetic method for preparing compound I-1, and its spectral data is as follows: 1 H NMR(500MHz,Chloroform-d)δ8.48(m,1H),7.59(m,1H),7.51(m,1H),7.37(m,1H),7.21(m,1H),7.15(m,1H),5.58(s,1H),3.59–3.37(m,1 H),3.24(m,1H),3.16–3.04(m,2H),2.98–2.82(m,1H),2.70–2.52(m,1H),2.40–2.33(m,1H),2.01–1.80(m,5H),1.60(m,2H),1.34(s,3H). 13 C NMR (126MHz, CDCl3) δ210.82,200.40,171.26,156.54,148.67,146.97,136.02,128.37,127.90,126.62,12 1.19,116.93,114.67,113.15,51.49,48.56,47.93,43.37,39.46,38.69,36.32,23.71,22.04,18.76,8.55.

[0061] Experimental Example 8

[0062] The atractylodes lactone derivatives provided by the present invention have a 2+ Induction of Aβ 25-35 Exploring the impact of aggregation

[0063] 1 Experimental Materials

[0064] Aβ 25-35purchased from Shanghai Qiangyao Biotechnology Co., Ltd.; thioflavin T (ThT) was purchased from Shanghai Yien Chemical Technology Co., Ltd.; curcumin was purchased from Shanghai Yien Chemical Technology Co., Ltd.; dimethyl sulfoxide (DMSO) was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) was purchased from Shanghai Yien Chemical Technology Co., Ltd.

[0065] 2 Experimental methods

[0066] 2.1 Solution preparation

[0067] HEPES buffer: Weigh an appropriate amount of HEPES and dissolve it in ultrapure water to prepare a 10 mM buffer solution (pH 7.2); Thioflavin T (ThT) solution: Weigh an appropriate amount of ThT and dissolve it in HEPES buffer to prepare an 80 μM solution;

[0068] Cu 2+ Solution: Weigh an appropriate amount of CuCl2 and dissolve it in HEPES buffer to prepare a 200 μM solution;

[0069] Aβ 25-35 Solution: Weigh an appropriate amount of Aβ 25-35 Dissolved in HEPES buffer (containing 37.5% DMSO) to prepare a 500 μM solution;

[0070] Curcumin solution: Weigh an appropriate amount of curcumin and dissolve it in DMSO to prepare a 200 μM solution;

[0071] Target compound solution: Weigh the target compound and dissolve it in DMSO to prepare a 200 μM solution.

[0072] 2.2 The cells were processed in the following groups, with 3 replicates per group:

[0073] Experimental group: 166 μL HEPES buffer, 10 μL Cu 2+ Solution, 4 μL Aβ 25-35 solution, 10 μL target compound solution.

[0074] Curcumin group (positive drug group): 166 μL HEPES buffer, 10 μL Cu 2+ Solution, 4 μL Aβ 25-35 solution, 10 μL curcumin solution.

[0075] Blank group: 170 μL HEPES buffer, 10 μL Cu 2+ solution, 10 μL target compound solution.

[0076] Control group: 166 μL HEPES buffer, 10 μL Cu 2+ Solution, 4 μL Aβ 25-35solution, 10 μL DMSO solution.

[0077] Solvent group: 170 μL HEPES buffer, 10 μL Cu 2+ solution, 10 μL DMSO solution.

[0078] Add them to black 96-well plates and incubate them at 37°C for 24 hours. After incubation, add 10 μL of ThT solution to each group and incubate them at 37°C for 3 hours. Use a multifunctional microplate reader to measure the fluorescence value at an excitation wavelength of 440 nm and an emission wavelength of 480 nm. 2+ Induction of Aβ 25-35 The aggregation inhibition percentage is calculated as follows: inhibition percentage = 100-(IF i -IF0) / (IF c -IF r )×100. Where IFi: fluorescence value of the experimental group, IF0: fluorescence value of the blank group, IF c : Fluorescence value of the control group, IF r : Fluorescence value of the solvent group.

[0079] The results are shown in Table 1. The series of Atractylodes lactone derivatives prepared by the present invention have an effect on Cu 2+ Induction of Aβ 25-35 Compounds Ⅰ-1, Ⅰ-3, Ⅰ-4, Ⅰ-5 and Ⅰ-7 have significant inhibitory effects on Cu aggregation. 2+ Induction of Aβ 25-35 The inhibitory effect of compound I-2 and compound I-6 on Cu aggregation was significantly higher than that of curcumin, with significant difference (P<0.01). 2+ Induction of Aβ 25-35 The inhibitory effect on aggregation is comparable to that of curcumin. The above results show that the atractylodes lactone derivatives provided by the present invention have a significant inhibitory effect on Aβ aggregation.

[0080] Table 1 Compounds of formula (I) for Cu 2+ Induction of Aβ 25-35 The impact of aggregation

[0081] Group Inhibition percentage (%) Curcumin group 43.6±1.79 Group Ⅰ-1 54.3±1.34** Group I-2 47.8±2.26 Group I-3 66.8±2.62** Group I-4 61.5±1.38** Group I-5 55.1±2.47** Group I-6 41.3±1.43 Group I-7 64.1±1.33**

[0082] Note: Compared with the curcumin group, *P<0.05, **P<0.01.

[0083] Experimental Example 9

[0084] Study on the effect of the atractylodes lactone derivatives provided by the present invention on the CL4176 nematode paralysis model

[0085] 1 Experimental Materials

[0086] MgSO4 was purchased from Shanghai MacLean Biochemical Technology Co., Ltd., agar powder, yeast powder, cholesterol, tryptone, NaCl, and CaCl2 were all purchased from Beijing Solebeau Technology Co., Ltd., Na2HPO4·12H2O and KH2PO4 were purchased from Sinopharm Chemical Reagent Co., Ltd., and the transgenic AD model Caenorhabditis elegans strains CL802 (smg-1(cc546)I;109rol-6(su1006)II), CL4176[dvIs27[myo-3p::A-Beta(1-42)::let-8513'UTR)+rol-6(su1006)]X] and uracil-deficient Escherichia coli OP50 were purchased from the Caenorhabditis elegans Genetics Center in the United States.

[0087] 2. Solution Preparation

[0088] 2.1M9 buffer preparation

[0089] Weigh 0.6 g of sodium hydrogen phosphate, 0.3 g of potassium dihydrogen phosphate, 0.5 g of sodium chloride, and 0.025 g of magnesium sulfate (dehydrated), dissolve them in 100 mL of deionized water, and sterilize them at high temperature before use.

[0090] 2.2 Preparation of NGM culture plates

[0091] Weigh 3.0g sodium chloride, 2.5g tryptone, and 17g agar into a conical flask. Add 975mL of deionized water and autoclave. When the sterilization solution temperature drops to approximately 55°C, add 0.5mL of 1M calcium chloride solution, 1mL of 5mg / mL cholesterol solution, 1mL of 1M magnesium sulfate solution, and 25mL of potassium phosphate buffer. Use a pipette to add the prepared culture medium to the corresponding petri dishes or well plates and cool overnight to solidify.

[0092] 3 Experimental methods

[0093] 3.1 Evenly spread 200 μL of compound solution onto a freshly prepared NGM plate and allow to dry naturally at room temperature. Add 50 μL of OP50 bacterial solution to the center of the plate and allow to dry overnight. Synchronized C. elegans of the relevant strain was inoculated onto the drug-containing plate. 200 μL of donepezil hydrochloride solution was used as the positive drug group. For the control group, 0.1% DMSO-M9 solution was used.

[0094] 3.2 The synchronized CL4176 strain of Caenorhabditis elegans was cultured at 16°C for 48 hours, ie, when the Caenorhabditis elegans reached the L3 stage, the culture plate was transferred to 25°C to induce transcriptional expression of the Aβ gene.

[0095] 3.3 The culture plate was transferred to 25℃ and the number of paralyzed C. elegans was recorded after 36 hours. The paralyzed C. elegans showed partial rigidity of the trunk, leading to movement disorder or even loss of movement function, and the head could twist.

[0096] 4 Detection indicators

[0097] For paralysis rate testing, each group should have at least 30 nematodes. Paralysis rate within 36 hours (%) = paralyzed nematode count / total nematode count × 100%. Each experiment was repeated three times.

[0098] 5 Results

[0099] The results are shown in Table 2. The paralysis rate of nematodes within 36 hours in the Atractylodes lactone derivatives I-3 group was significantly lower than that in the control group (P<0.05). The Atractylodes lactone derivatives provided by the present invention can significantly delay the paralysis time of CL4176 nematodes.

[0100] Table 2 Effects of the Atractylodes macrocephala lactone derivative I-3 provided by the present invention on the paralysis rate of nematodes

[0101] Group Paralysis rate (%) control group 90.6±4.99 Group I-3 72.1±5.30*

[0102] Note: Compared with the control group, *P<0.05, **P<0.01.

[0103] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A derivative of Atractylodes macrocephala lactone, characterized in that The chemical structural formula of the atractylodes lactone derivative is (I) Wherein, R' is hydrogen or alkyl; R is any one of hydrogen, hydroxyl, alkoxy, alkyl, halogen, and cyano.

2. Use of the atractylodes lactone derivative according to claim 1 in the preparation of a drug for inhibiting abnormal aggregation of β-amyloid protein.

3. Use of the atractylodes lactone derivative according to claim 1 in the preparation of a drug for treating and / or preventing Alzheimer's disease.

4. A pharmaceutical composition, characterized in that The pharmaceutical combination comprises an effective amount of the compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition is in the form of capsules, tablets, injections, granules, pills or powders.

6. The method for preparing the atractylodes lactone derivative according to claim 1, wherein: The atractylodes lactone derivative represented by formula (I) is prepared according to the following steps: (1) Atractylodes lactone I and selenium dioxide are dissolved in anhydrous dioxane solvent, heated to 80-90°C under nitrogen protection, stirred and reacted for 2-3 hours, cooled to room temperature after the reaction, and dioxane is removed by vacuum distillation. Ethyl acetate is then added, and the organic phase is washed 2-3 times with a saturated sodium thiosulfate solution and then washed 3-5 times with deionized water. The organic phase is then separated, and the organic phase is concentrated and dried to obtain intermediate 1; the chemical structure of intermediate 1 is formula (II), (2) Dissolve the intermediate 1 and 2-iodobenzoic acid in acetonitrile, and then heat under reflux at 70-80°C for more than 24 hours; after the reaction is completed, cool to room temperature, filter, and concentrate the filtrate to obtain the intermediate 2; the chemical structure of the intermediate 2 is formula (III), (3) The intermediate 2 is dissolved in dichloromethane, and then an indole derivative and stannous trifluoromethanesulfonate are added. The reaction is carried out under nitrogen protection for 36-48 hours. After the reaction is completed, the mixture is cooled to room temperature, a saturated sodium bicarbonate solution is added, and then the mixture is extracted with ethyl acetate as the organic phase. The extraction is repeated 3-5 times, and the organic phase is separated and collected. The organic phase is concentrated and dried to obtain the Atractylodes lactone derivative represented by formula (I).

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