Preparation method of natural product 27-Deoxywithaferin A

Abstract

The invention discloses a natural product 27-Deoxywithaferin A and a preparation method thereof, and belongs to the technical field of preparation of natural active ingredients in plants. The invention uses commercially available natural product withaferin A as a raw material, and realizes efficient semi-synthetic conversion of the natural product 27-Deoxywithaferin A through only three steps of reaction. Compared with the prior art, the synthetic route is greatly simplified, and the yield is significantly improved.

Description

Technical Field

[0001] The invention relates to the preparation of natural active ingredients in plants, and in particular to a natural product 27-Deoxywithaferin A and a preparation method thereof. Background Art

[0002] As part of traditional Chinese medicine, natural products are a traditional cultural treasure of the Chinese nation. In the practice of integrated Chinese and Western medicine treatment of tumors, it is found that many natural products play an important role in the prevention, treatment and rehabilitation of tumors. It is well known that natural products provide a plausible alternative to synthetic drugs due to their effectiveness, reliability and lower cost. In the past few decades, there have been more and more studies on natural medicinal plants and their bioactive components. Many of these components have shown different activities in inhibiting the occurrence and development of malignant tumors both in vitro and in vivo. There are many different targets in cancer cells. Nowadays, with the development of pharmacology, it has been found that many natural products can bind to biological macromolecular targets and interact with many specific targets in cells, especially proteins. Withanolides are one of the natural products that have been proven to be effective in treating malignant tumors. Withanolides are a naturally occurring C-28 steroidal lactone based on an ergoline skeleton, wherein C-22 and C-26, or C-26 and C-23 are properly oxidized to form a δ-lactone ring (Type A) or a γ-lactone ring (Type B), and the lactone ring often has an α,β-unsaturated lactone structure, as shown in the following Types A and Types B. In addition, C-1 is easily oxidized to form a 1-one ring. This basic structure is named "withanolide" and more than 90% of the compounds in the skeleton are 1-oxosteroids (Nat Prod Rep, 2011.28(4), 705-740.).

[0003]

[0004] Withaferin A (WA) is the first withanolide component extracted by Lavie from the Indian medicinal plant Withaniasomnifera in 1965 (Journal of Organic Chemistry, 1965, 30(6): 490-507), and is one of the main biologically active components of lactone compounds. In addition, 27-Deoxywithaferin A is also one of the natural components of withanolide. The structures of WA and 27-Deoxywithaferin A are shown in the following formula 1 and formula 5, respectively:

[0005]

[0006] At present, the research on WA and the natural product 27-deoxywithaferin A is mainly focused on their anticancer activity. For example, the Development Therapy Program of the National Cancer Institute of the United States tested 60 human cancer cell lines and found that the average growth inhibition concentration (IC) of WA on tumor cells was 50 ) is 620 nM; other studies have shown that WA has significant activity against human brain, 18 prostate cancers, 19 pancreatic cancers, 20 breast cancers and 21 mouse xenografts (Journal of Medicinal Chemistry, 2014.57(7), 2851-2863.). As for the natural product 27-Deoxywithaferin A, it has also been reported that it has significant antiproliferative activity against a variety of cancer cell lines (IC 50 :0.6~9μM), including leukemia, ovarian cancer, colorectal cancer, etc. Although the existing literature has conducted a lot of research on the potential anti-cancer properties of withaferin A, there are few reports on its structural modification. Among the synthetic methods of the natural product 27-Deoxywithaferin A, only Ikekawa et al. obtained 27-Deoxywithaferin A with extremely low total yield by starting from a high-level intermediate through more than 10 steps of chemical conversion (Tetrahedron Letters, 1982.23(45), 4725-4728.). However, the synthetic route in this report is complicated and the yield is too low. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a natural product 27-Deoxywithaferin A with a simple synthesis route and a high yield and a preparation method thereof.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] The natural product 27-Deoxywithaferin A of the present invention is a compound having a structure shown in the following formula 5, and its preparation method comprises the following steps:

[0010] 1) placing a compound of the structure represented by the following formula 1 and a compound of the structure represented by the following formula 2 in an organic solvent, and reacting them in the presence of a basic catalyst to obtain a compound of the structure represented by the following formula 3;

[0011] 2) placing the compound of formula 3 in an organic solvent, adding a dehydroxylation agent to react, and obtaining a compound of formula 4;

[0012] 3) placing the compound of formula 4 in an organic solvent, adding an oxidant to react, and obtaining a crude target compound;

[0013]

[0014]

[0015] In the preparation method of the present invention, the organic solvent can be one or a combination of two or more selected from tetrahydrofuran, benzene, dichloromethane (DCM), toluene, acetonitrile, 1,2-dichloroethane (DCE), hexafluoroisopropanol, chloroform and chlorobenzene. The amount of the organic solvent can be determined as needed, preferably to fully dissolve the raw materials involved in the reaction.

[0016] In step 1) of the preparation method of the present invention, the molar ratio of the compound of the structure shown in Formula 1 and the compound of the structure shown in Formula 2 is a stoichiometric ratio. The selection and dosage of the alkaline catalyst are the same as those in the prior art. Specifically, the alkaline catalyst can be selected from one or more of triethylamine, potassium carbonate, DMAP, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, pyridine and N,N-diisopropylethylamine. Triethylamine is preferably used. For the amount of the alkaline catalyst, it is usually used in excess relative to the compound of the structure shown in Formula 1, preferably 1 to 2 times the molar amount of the compound of the structure shown in Formula 1. In this step, the reaction can be carried out at room temperature or under ice bath or heating conditions, preferably at room temperature, and the reaction is tracked and detected by thin layer chromatography to see if it is complete. When the reaction is carried out at room temperature, the reaction time is usually controlled to be 1 to 2 hours.

[0017] The crude product of the compound of structure shown in formula 3 is prepared by the above step 1). In order to improve its purity, it can be subjected to impurity removal and / or purification operations before being used for the preparation of the compound of structure shown in formula 4. It is preferred that the material obtained by the reaction is extracted first and then chromatographed on a silica gel column to reduce the burden on the silica gel column. Among them, the eluent used for elution during column chromatography is preferably a mixed solvent composed of petroleum ether (PE) and ethyl acetate (EtOAc) (or dichloromethane and ethyl acetate) in a volume ratio of 10:1 to 1:1. If extraction is involved, the extractant is the same as the organic solvent used in the reaction, and can also be a conventional extractant such as ethyl acetate.

[0018] In step 2) of the preparation method of the present invention, the selection and dosage of the dehydroxylation agent are the same as those in the prior art. Preferably, the dehydroxylation agent is a complex, such as n-Bu3SnH / AIBN (azobisisobutyronitrile), n-Bu3SnH / Et3B (triethylboron), diphenylsilane / peroxide, diphenylsilane / Et3B, trialkylsilane / peroxide / thiol, tris(trimethylsilyl)silane / AIBN, dibutylphosphine oxide / AIBN, dibutylphosphine oxide / Et3B, H3PO2 / Et3N / AIBN, tetraphenyldisilane / AIBN and Pd / C-H2; the total dosage of the dehydroxylation agent is usually 1.5 to 3 times the molar amount of the structural compound shown in Formula 3. It is further preferred that the dehydroxylation agent is n-Bu3SnH / AIBN, in which case the amount of n-Bu3SnH is preferably 1 to 2 times the molar amount of the structural compound shown in Formula 3, and the amount of AIBN is preferably 0.5 to 1 times the molar amount of the structural compound shown in Formula 3. In this step, the reaction needs to be carried out under anhydrous and oxygen-free conditions, so the reaction is designed to be carried out under the protection of an inert atmosphere (such as nitrogen, argon or helium, etc.). It is further preferred that the reaction is carried out under an inert atmosphere and heating conditions, and further, at 80°C or above and under strictly anhydrous and oxygen-free conditions. The reaction time is usually controlled at 20 to 30 hours.

[0019] The crude product of the structural compound shown in formula 4 is prepared by the above step 2). In order to improve its purity, it can be subjected to impurity removal and / or purification operations before being used for the preparation of the target compound. It is preferred that the material obtained by the reaction is extracted first and then chromatographed on a silica gel column to reduce the burden on the silica gel column. Among them, the eluent used for elution during column chromatography is preferably a mixed solvent composed of petroleum ether (PE) and ethyl acetate (EtOAc) (or dichloromethane and ethyl acetate) in a volume ratio of 10:1 to 1:1. If extraction is involved, the extractant is the same as the organic solvent used in the reaction, and can also be a conventional extractant such as ethyl acetate.

[0020] In step 1) of the preparation method of the present invention, the selection and dosage of the oxidant are the same as those in the prior art. Specifically, the oxidant can be one or a combination of two or more selected from hydrogen peroxide, sodium hypochlorite, hypochlorous acid, chromium trioxide and manganese dioxide. Hydrogen peroxide is preferably used. The dosage of the oxidant is usually used in excess relative to the compound of the structure shown in Formula 4, preferably 1.5 to 5 times the molar amount of the compound of the structure shown in Formula 1. In this step, the reaction is preferably carried out at room temperature, and the reaction is tracked and detected by thin layer chromatography to see if it is complete. When the reaction is carried out at room temperature, the reaction time is usually controlled to be 0.5 to 1h.

[0021] The above method prepares a crude target compound, so the method of the present invention also includes a step of purifying the crude target compound. Specifically, the conventional purification method can be used to purify the crude target compound to improve the purity of the target compound. Usually, silica gel column chromatography is used for purification, and the eluent used in the chromatography can be a mixed solvent composed of petroleum ether and ethyl acetate, or dichloromethane and ethyl acetate. In the mixed solvent, the volume ratio of petroleum ether and ethyl acetate, or dichloromethane and ethyl acetate is preferably 10:1 to 1:1.

[0022] On the other hand, the present invention also provides a compound having a structure shown in the following formula 3 or 4 or a pharmaceutically acceptable salt thereof:

[0023]

[0024] In another aspect, the present invention also provides a method for preparing the compound of the structure shown in the above formula 3 or 4, wherein:

[0025] The preparation method of the compound of the structure shown in Formula 3 is: taking the compound of the structure shown in Formula 1 and the compound of the structure shown in Formula 2 in an organic solvent, and reacting them in the presence of a basic catalyst to obtain the compound of the structure shown in Formula 3;

[0026] The preparation method of the compound of the structure shown in Formula 4 is as follows: taking the compound of the structure shown in Formula 3 and placing it in an organic solvent, adding a dehydroxylation agent to react, thereby obtaining the compound of the structure shown in Formula 4;

[0027]

[0028] In the preparation method of the structural compound represented by the above formula 3 or 4, the selection and dosage of the organic solvent, alkaline catalyst, dehydroxylation agent and reaction parameters are the same as those in the preparation method of the aforementioned natural product 27-Deoxywithaferin A, and will not be described in detail here.

[0029] The applicant's preliminary in vitro activity screening test results show that the structural compound represented by the above formula 3 or 4 has good anti-tumor activity. Therefore, the present invention further includes the use of the structural compound represented by the above formula 3 or 4 or its pharmaceutically acceptable salt in the preparation of anti-tumor drugs.

[0030] Furthermore, the present invention also includes a pharmaceutical composition, which includes a therapeutically effective dose of a compound having a structure shown in the above formula 3 or 4. The dosage form of the drug can be any pharmaceutically acceptable dosage form, such as conventional dosage forms such as granules, tablets, pills, capsules or injections.

[0031] The present invention uses commercially available natural product withaferin A as a raw material, and realizes the efficient semi-synthetic conversion of the natural product 27-Deoxywithaferin A through only three steps of reaction. Compared with the prior art, the synthetic route is greatly simplified, and the yield is significantly improved. In addition, the present invention also provides two novel withaferin A derivatives. The applicant's in vitro activity test shows that the compound shown in formula 3 has good anti-tumor activity, is expected to be used for the treatment of cancer, and has good potential medicinal value. DETAILED DESCRIPTION

[0032] In order to better explain the technical solution of the present invention, the present invention is further described in detail below in conjunction with embodiments, but the embodiments of the present invention are not limited thereto.

[0033] Example 1: Preparation of the compound of formula 3 (hereinafter referred to as compound 3)

[0034]

[0035] To a DCM (25 mL) solution of a compound of formula 1 (hereinafter also referred to as compound 1) (6.0 mmol, 1.0 equivalent), a compound of formula 2 (hereinafter also referred to as compound 2) (4.0 mmol, 1.5 equivalent) was added, and then triethylamine (2.0 mmol, 5 equivalent) was added and stirred at room temperature for 8 hours. After the reaction was completed, the mixture was extracted with DCM (3×30 mL), then washed with H2O (40 mL), and the combined organic phase was washed with saturated brine (to better absorb the residual moisture in the organic phase and play a drying role), then dried with anhydrous Na2SO4, filtered and concentrated, and the resulting residue was purified by silica gel flash chromatography (eluent: PE / EtOAc, 10 / 1 to 1 / 1, volume ratio) to obtain compound 3, which is specifically characterized as follows:

[0036] Compound 3 (3-mercapto-4-(methylphenyl)withaferin A): yield 87.0%; light yellow solid, 1H NMR(600MHz,Chloroform-d)δ7.25-7.24(d,J=1.9Hz,2H),7.11-7.10(d,J=7.9Hz,2H),4.42–4.31(m,3 H),3.68-3.65(m,1H),3.43-3.43(d,J=2.7Hz,1H),3.27(s,1H),3.08-3.05(m,1H),2.52–2.45(m,2H),2 .31(s,3H),2.19-2.17(m,1H),2.03(s,3H),1.99–1.95(m,2H),1.92–1.89(m,1H),1.69–1.64(m,2H),1. 42–1.32(m,5H),1.29(s,3H),1.26–1.21(m,3H),1.15-1.08(m,3H),0.97(d,J=6.6Hz,3H),0.65(s,3H); 13 C NMR (151MHz, CDCl3) δ211.53,209.54,166.98,148.94,138.05,132.04,13 0.07,129.29,125.59,121.94,78.67,78.21,76.00,72.69,64.55,60.69,5 7.37,55.99,51.86,50.38,45.53,43.12,42.59,38.69,30.87,29.74,29.3 6,27.21,24.20,21.03,19.96,15.77,13.28,12.40,11.49.HRMS(ESI):m / z Calculate for C 35 H 47 O6S + [M+H] + :595.3088; found:595.3099.

[0037] Example 2: Preparation of the compound having the structure shown in Formula 3

[0038] Example 1 was repeated except that toluene was used instead of DCM and potassium carbonate was used instead of triethylamine.

[0039] Finally, a light yellow solid was obtained with a yield of 77%. The obtained light yellow solid was determined to be compound 3 through characterization.

[0040] Example 3: Preparation of the compound of formula 3

[0041] Example 1 was repeated except that acetonitrile was used instead of DCM and DMAP was used instead of triethylamine.

[0042] Finally, a light yellow solid was obtained with a yield of 80%. The obtained light yellow solid was determined to be compound 3 through characterization.

[0043] Example 4: Preparation of the compound of formula 4 (hereinafter referred to as compound 4)

[0044]

[0045] In a nitrogen-substituted dry flask, add p-Bu3SnH (2mmol, 2 equivalents) and AIBN (0.5mmol, 0.5 equivalents) to a toluene (5mL) solution of the compound of formula 3 (1.0mmol, 1.0 equivalents). The reaction device is equipped with a spherical condenser and placed in an oil bath and heated to reflux. After the reaction is completed, the temperature is restored to room temperature, saturated sodium bicarbonate solution (8mL) is added to the reaction mixture, extracted with EA (3×10mL), and then washed with H2O (20mL), and the combined organic phase is washed with saturated brine (to better absorb the residual moisture in the organic phase and play a drying role), and then dried with anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash chromatography (eluent: PE / EtOAc, 10 / 1~1 / 1, volume ratio) to obtain compound 4, which is characterized as follows:

[0046] Compound 4 (3-mercapto-benzyl-27-dehydroxy-withaferin A): yield 57%; white solid; 1HNMR(600MHz,Chloroform-d)δ7.28-7.27(d,J=8.1Hz,2H),7.13-7.12(d,J=7.8Hz,2H),4.37-4.34(dt,J=13.3,3.6Hz,1H),3.69-3.67(m,J=8.0, 5.5,2.7Hz,1H),3.45(d,J=2.7Hz,1H),3.29(s,J=2.3Hz,1H),3.11-3.06(dd,J=15.2,7.7,2.0Hz,1H),2.54-2.50(dd,J=15.2,5.5Hz,1H),2.46-2 .40(dd,J=17.3,13.4Hz,1H),2.33(s,3H),2.21-2.19(m,J=10.7,2.2Hz, 1H),2.04(s,1H),1.94(s,3H),1.87(s,3H),1.73-1.63(m,J=14.8,8.2,2 .8Hz,3H),1.44-1.34(m,4H),1.31(d,J=1.8Hz,3H),1.28-1.23(m,4H),1 .17–1.09(m,2H),0.98(d,J=6.7Hz,3H),0.89–0.82(m,1H),0.66(s,3H); 13 C NMR(151MHz, CDCl3)δ209.71,167.22,149.18,138.26,132.26(2C),130. 27(2C),129.52,122.14,78.42,76.25,64.75,60.92,56.23,52.15,50.5 9,45.74,43.35,42.78,39.24,38.97,38.58,31.10,29.74,29.56,27.41 ,24.42,21.82,21.25,20.68,15.99,13.55,12.62,11.69.HRMS(ESI):m / z calcd for C 35 H 47 O5S + [M+H] + :579.3139; found 579.3154.

[0047] Example 5: Preparation of the compound having the structure shown in Formula 4

[0048] Example 4 was repeated except that benzene was used instead of toluene, diphenylsilane was used instead of n-Bu3SnH, and Et3B was used instead of AIBN.

[0049] Finally, a white solid was obtained with a yield of 46%. The obtained white solid was determined to be compound 4 through characterization.

[0050] Example 6: Preparation of the compound having the structure shown in Formula 4

[0051] Example 4 was repeated except that hexafluoroisopropanol was used instead of toluene and dibutylphosphine oxide was used instead of n-Bu3SnH.

[0052] Finally, a white solid was obtained with a yield of 50%. The obtained white solid was determined to be compound 4 through characterization.

[0053] Example 7: Preparation of the compound having the structure shown in Formula 4

[0054] Example 4 was repeated except that chlorobenzene was used instead of toluene and tris(trimethylsilyl)silane was used instead of n-Bu3SnH.

[0055] Finally, a white solid was obtained with a yield of 43%. The obtained white solid was determined to be compound 4 through characterization.

[0056] Example 8: Preparation of the compound of formula 5 (hereinafter referred to as target compound or compound 5 or target compound 5)

[0057]

[0058] To the compound of the structure shown in Formula 4 (5.0 mmol, 1.0 equivalent) in THF (10 mL), 30 w / w% hydrogen peroxide (15.0 mmol, 3 equivalents) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was quenched with ice water, the mixture was extracted with DCM (3×15 mL), and then washed with H2O (25 mL), the combined organic phase was washed with saturated brine (to better absorb the residual moisture in the organic phase and play a drying role), and then dried with anhydrous Na2SO4, filtered and concentrated, and the obtained residue was purified by silica gel flash chromatography (eluent: PE / EtOAc, 10 / 1~1 / 1, volume ratio) to obtain the target compound 5, which is specifically characterized as follows:

[0059] Compound 5 (27-Deoxywithaferin A): yield 72%; white solid, 1H NMR(600MHz,Chloroform-d)δ6.95-6.92(m,1H),6.22-6.20(m,1H),4.37-4.34(m,1H),3.77(s,1H),3.24(s,1H),2.52(s,1H),2.52 -2.40(m,1H),2.17-2.14(m,1H),1.93(s,3H),1.88(s,3H),1.67-1.59(m,9H),1.41(s,3H),1.00(s,3H),0.86(m,5H),0.70(s,3H); 13 C NMR (151MHz, CDCl3) δ201.29,166.06,148.00,140.83,131.30,120.99,77.28,68.90,62.87,61.59,55.07,51.03,46.68, 43.12,41.54,38.33,37.83,30.15,28.76,28.68,26.24,23.26,21.14,19.51,16.41,12.36,11.46,10.59.HRMS(ESI):m / z calcd for C 28 H 39 O5 + [M+H] + :455.2792; found:455.2814.

[0060] Example 9: Preparation of the compound having the structure shown in Formula 5

[0061] Example 8 was repeated except that dichloromethane was used instead of THF and manganese dioxide was used instead of hydrogen peroxide.

[0062] Finally, a white solid was obtained with a yield of 52%. After characterization, it was determined that the obtained white solid was the target compound 27-Deoxywithaferin A.

[0063] Example 10: Preparation of the compound having the structure shown in Formula 5

[0064] Example 8 was repeated except that toluene was used instead of THF and hypochlorous acid was used instead of hydrogen peroxide.

[0065] Finally, a white solid was obtained with a yield of 67%. After characterization, it was determined that the obtained white solid was the target compound 27-Deoxywithaferin A.

[0066] Experimental Example 1: Anti-cancer Activity Test of Compounds 1, 3, and 5

[0067] The anti-tumor activity of the compounds of the present invention was tested by MTT colorimetric method, and cisplatin (DDP) was selected as a positive control drug.

[0068] Instruments: clean bench (SW-CJ-1FD, AIRTECH, Sujing Antai), constant temperature CO2 incubator (3111, Thermo, USA), inverted biological microscope (IX71, OLYMPUS, Japan), enzyme-linked immunosorbent assay (Mode1680, BIO-RAD, USA), flat shaker (SWB-20L-1, MajorScience, USA), high pressure sterilizer (YX0.SG41.280, Shanghai Huaxian), high-speed low-temperature centrifuge (Micro CL17R, THERMOIEC, Germany).

[0069] Reagents: DMEM (GIBCO), fetal bovine serum (GIBCO), trypsin (SIGMA), DMSO (SIGMA).

[0070] Cell lines: Human colon cancer HCT-116 cells, human large cell lung cancer H460 cells, human osteosarcoma HOS cells, human nasopharyngeal carcinoma 5-8F cells, human breast cancer MCF-7 cells, and human triple-negative breast cancer M231 cells were purchased from the Stem Cell Bank of the Chinese Academy of Sciences.

[0071] Methods: The frozen cell lines were revived and cultured in a constant temperature 37℃ CO2 incubator. The medium was changed once a day. When the cells were in the exponential growth phase and in good condition, they could be plated. 1ml of 0.25% trypsin digestion solution was added and digested for 1-2min. The cell state was observed under a microscope. When the adherent cells became round and shrunk, the digestion solution was removed and 1-2ml of DMEM medium containing 10% fetal bovine serum was added to make a cell suspension. The cells were counted and the amount of cell suspension required was calculated according to the number of 5×104 cells per well and the total number of wells. The cell suspension was inoculated on a 96-well plate at 100μl / well, sealed with PBS liquid, and cultured in a constant temperature 37℃ CO2 incubator for 24h.

[0072] Use DMEM culture medium to prepare the test drug, positive control DDP, and blank control DMSO to a final concentration of 5 μM / well, with 3 replicates for each drug and culture for 48 hours. Add MTT reagent to a 96-well plate at 10 μl / well and continue incubation for 4 hours. Aspirate the culture medium in the plate, add 100 μl DMSO to each well, and shake on a plate shaker for 10 minutes to dissolve the crystals. Use an enzyme-linked immunosorbent assay to detect the absorbance of each well at a wavelength of 570 nm, and calculate the cell inhibition rate according to the following formula. The average value of the three preliminary screening results is the final inhibition rate. Compounds with a preliminary screening inhibition rate greater than 60% are subjected to concentration gradient screening (5-fold dilution) to prepare for the calculation of the IC of the test drug. 50The results of three repeated experiments are the final IC values ​​of the tested compounds. 50 The results are shown in Table 1 below.

[0073] Note: IC 50 Statistical analysis was performed using GraphPad Prism version 9.0 (GraphPad Software, San Diego, CA). Data are expressed as mean ± SD, and P < 0.05 was considered to indicate a significant difference.

[0074] Cell inhibition rate % = [(blank control OD value - drug group OD value) / blank control group OD value] × 100%

[0075] Table 1. Inhibitory activity of test compounds 1, 3 and 5 against various cancer cell lines

[0076]

[0077] Note: a IC 50 Values ​​represent three determinations, (mean±SD).

[0078] b Data are expressed as IC 50 , that is, the concentration of compound that inhibits 50% of cancer cell survival (mean±SD).

Claims

1. A method for preparing a natural product 27-Deoxywithaferin A having a structure shown in the following formula 5, comprising the following steps: 1) placing a compound of the structure shown in the following formula 1 and a compound of the structure shown in the following formula 2 in an organic solvent, and reacting them in the presence of a basic catalyst to obtain a compound of the structure shown in the following formula 3; the basic catalyst is selected from triethylamine, potassium carbonate, DMAP, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, pyridine and N , N - one or a combination of two or more of diisopropylethylamine; 2) placing the compound of the structure shown in Formula 3 in an organic solvent, adding a dehydroxylation agent for reaction, and obtaining a compound of the structure shown in Formula 4; the dehydroxylation agent is selected from one of n-Bu3SnH / AIBN, n-Bu3SnH / Et3B, diphenylsilane / Et3B, tris(trimethylsilyl)silane / AIBN, dibutylphosphine oxide / AIBN, dibutylphosphine oxide / Et3B, H3PO2 / Et3N / AIBN and tetraphenyldisilane / AIBN; 3) placing the compound of formula 4 in an organic solvent, adding an oxidant to react, and obtaining a crude target compound; the oxidant is one or a combination of two or more selected from hydrogen peroxide, sodium hypochlorite, hypochlorous acid, chromium trioxide and manganese dioxide; 。 2. The preparation method according to claim 1, characterized in that: The organic solvent is one or a combination of two or more selected from tetrahydrofuran, benzene, dichloromethane, toluene, acetonitrile, 1,2-dichloroethane, hexafluoroisopropanol, chloroform and chlorobenzene.

3. The preparation method according to claim 1, characterized in that: In step 2), the reaction is carried out under inert atmosphere protection conditions.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The method also includes a step of purifying the obtained crude target compound.

5. A compound having a structure represented by the following formula 3 or 4 or a pharmaceutically acceptable salt thereof: 。 6. The method for preparing the compound of formula 3 or 4 according to claim 5, characterized in that: The compound represented by the following formula 1 and the compound represented by the following formula 2 are placed in an organic solvent and reacted in the presence of a basic catalyst to obtain a compound represented by the following formula 3; The compound of the structure shown in Formula 3 is placed in an organic solvent, and a dehydroxylation agent is added to react to obtain a compound of the structure shown in Formula 4; In the above method, The alkaline catalyst is selected from triethylamine, potassium carbonate, DMAP, cesium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, pyridine and N , N - one or a combination of two or more of diisopropylethylamine; The dehydroxylation agent is selected from one of n-Bu3SnH / AIBN, n-Bu3SnH / Et3B, diphenylsilane / Et3B, tris(trimethylsilyl)silane / AIBN, dibutylphosphine oxide / AIBN, dibutylphosphine oxide / Et3B, H3PO2 / Et3N / AIBN and tetraphenyldisilane / AIBN; The organic solvent is one or a combination of two or more selected from tetrahydrofuran, benzene, dichloromethane, toluene, acetonitrile, 1,2-dichloroethane, hexafluoroisopropanol, chloroform and chlorobenzene; 。 7. Use of the compound of formula 3 or a pharmaceutically acceptable salt thereof as claimed in claim 5 in the preparation of an anti-tumor drug, wherein: The tumor is colon cancer, lung cancer, osteosarcoma, nasopharyngeal carcinoma or breast cancer.

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