A helix-2(3H)-furanone molecule and its preparation method and application

Abstract

The invention discloses a helix-2(3H)-furanone molecule and a preparation method and application thereof, and belongs to the field of pharmaceutical organic synthesis. Specifically, sulfur ylide is used as a raw material, and a target compound helix-2(3H)-furanone skeleton molecule is generated under the action of a catalyst and a Lewis base; the method has easy-to-obtain raw materials, simple preparation, mild conditions, high production safety, high yield, reduced reaction cost, and easy to scale up; the helix-2(3H)-furanone skeleton molecule also has certain anti-cancer cell proliferation activity.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical organic synthesis chemistry, and specifically relates to a helix-2(3H)-furanone molecule and a preparation method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to increase some understanding of the overall background of the invention, and should not be necessarily regarded as an admission or any form of suggestion that the information constitutes the prior art already known to ordinary technicians in this field.

[0003] Spirofuranone derivatives are widely present in natural drug active molecules. For example, pyrrolidine-spiro-butene lactone (I) has significant inhibitory activity against Shigella, Salmonella and Pseudomonas. Picealactones A can effectively inhibit the proliferation of breast cancer cell lines. The compound crotocaudin is extracted from the leaves and branches of swallowtail flower, which has an agonist effect on human pregnancy X receptor and is promising for the treatment of cholestasis. In the field of organic synthesis, the spiral-2(3H)-furanone molecular skeleton has attracted widespread attention due to its good biological activity and the rapid and efficient synthesis of the spiral-2(3H)-furanone molecular skeleton.

[0004] Catalytic cyclization reactions used to construct synthetically valuable ring frameworks are one of the most important categories of organic reactions. The skeletons of the constructed cyclized products exist in natural products, bioactive reagents, and drug molecules. Alkenyl oxiranes are one of the most common synthons for preparing oxygen-containing heterocycles and play a vital role. The reactions between alkenyl oxiranes and different reaction substrates can synthesize various types of heterocyclic compounds under the catalysis of Lewis acids and transition metals, such as seven-membered bridge rings, five-membered carbonates, furan rings, oxazolidinones, seven-membered and nine-membered heterocycles, etc.

[0005] The following are examples of existing domestic and international reports:

[0006] In 2012, Chiu's research group found that under the catalysis of Lewis acid TESOTf, silyl ether-substituted alkenyl oxirane can form an oxyallyl cationic intermediate, which can undergo a [4+3] cyclization reaction with furan and cyclopentadiene to prepare a 7-membered bridge ring. The synthetic route is as follows:

[0007]

[0008] Yamamoto, Jarvo, and Du Haifeng reported the preparation of oxazolidine derivatives by the [3 + 2] cycloaddition of vinyl oxirane with various imines in the presence of rhodium catalysts or in the presence of chiral palladium or nickel catalysts. The synthetic route is as follows:

[0009]

[0010] You Shuli combined the characteristics of his research group and realized the dearomatization / [3+2] cyclization reaction of alkenyl oxiranes with nitrobenzofuran, benzothiophene, and nitroindole under palladium catalysis to obtain furan heterocycles. The synthetic route is as follows:

[0011]

[0012] In 2021, Xia Jibao reported the Pd-catalyzed [3 + 1 + 1] cyclization of vinyl oxirane with azide and CO to synthesize oxazolidinone in 88% yield. Under mild additive-free and base-free conditions, the reaction provides an atomic- and step-level efficient strategy to produce oxazolidinones from readily available azide and carbon monoxide. This strategy provides a simple and efficient method to synthesize oxazolidinones from readily available compounds. The synthetic route is as follows:

[0013]

[0014] In 2017, Guo Hongchao's team described the palladium-catalyzed [5 + 2] cycloaddition reaction of 2-aryl-2-vinyl oxides with aminosulfonic acid-derived cyclic imines to obtain 1,3-oxazapine derivatives in 96% yield. In 2017, Guo Hongchao's team developed a method for the [5 + 3] cycloaddition reaction of zwitterionic allyl palladium intermediates generated in situ from vinyl oxides with azomethine under mild conditions to obtain 8-membered heterocycles in 51-85% yield.

[0015] In 2018, Zhao's team reported an efficient and enantioselective palladium-catalyzed reaction of olefinic oxiranes with α, β -Unsaturated imine undergoes [5+4] cyclization reaction to construct a nine-membered middle ring with a yield of 70-96%. The synthetic cyclization pathways developed by these methods reported at home and abroad can usually only construct single-ring cyclic compounds, or use special cyclic substrates, and need to construct additional cycles to achieve the spirocyclic synthesis goal. Due to the complicated route, low atom utilization and high production cost, the industrial application value of the spiral-2(3H)-furanone molecular skeleton is greatly limited; and due to the complex steps, the preparation time of the compound is long and the production efficiency is low. According to the existing information, there is no efficient and economical method for synthesizing the spiral-2(3H)-furanone skeleton that only needs one step to complete this cyclization process. Summary of the invention

[0016] In view of the deficiencies in the prior art, the present invention provides a novel method for synthesizing a class of helix-2(3H)-furanone molecules, which specifically uses sulfur ylide and ethylene oxide compounds as raw materials, and generates a target compound helix-2(3H)-furanone skeleton molecule under the action of a catalyst and a Lewis base; the method has easy-to-obtain raw materials, simple preparation, mild conditions, high production safety, high yield, reduced reaction cost, and easy to scale up; the helix-2(3H)-furanone skeleton molecule also has certain anti-cancer cell proliferation activity.

[0017] Vinyl oxirane is an important synthon and common cyclization intermediate for constructing oxygen-containing compounds. It often generates π-allyl intermediates under transition metal catalysis, and then undergoes cyclization reaction with electrophilic coupling reagents to synthesize monocyclic oxygen-containing compounds. However, the above intermediates are linear structures and often achieve the construction of monocyclic compounds. There is no report on the one-step synthesis of bicyclic or polycyclic compounds through cyclic intermediates. The inventors speculate that this type of electron-deficient alkenyl epoxyalkane can form a cyclic intermediate through lactonization under the catalysis of Lewis base, and then undergo cyclization again with electrophilic coupling reagents to construct multiple rings in one step.

[0018] The present invention can carry out two cycles simultaneously, and only one step is required to complete the ring formation process of the bicyclic or polycyclic structure in the helix-2(3H)-furanone molecular skeleton. The synthesis method of the present invention can be used to prepare a helix-2(3H)-furanone compound, and can also prepare a compound molecule having a helix-2(3H)-furanone skeleton. The helix-2(3H)-furanone compound mentioned in the present invention has the following structure:

[0019]

[0020] The technical solution adopted by the present invention is as follows:

[0021] The present invention specifically uses ethylene oxide compound III and sulfur ylide compound IV as raw materials, and under the action of a catalyst and a Lewis base, smoothly generates the target compound helix-2(3H)-furanone skeleton molecule in one step.

[0022] In the first aspect of the present invention, a spiro-2(3H)-furanone skeleton molecule is provided, the structure of which is shown in general formula Ⅰ or Ⅱ:

[0023]

[0024] Where R 1For: phenyl, benzyl, 2-Me-Ar, 3-Me-Ar, 4-Me-Ar, 2-Et-Ar, 3-Et-Ar, 4-Et-Ar, 2-t-Bu-Ar, 3-t -Bu-Ar, 4-t-Bu-Ar, 2-MeO-Ar, 3-MeO-Ar, 4-MeO-Ar, 2-EtO-Ar, 3-EtO-Ar, 4-EtO-A r, 2-t-BuO-Ar, 3-t-BuO-Ar, 4-t-BuO-Ar, 2-F-Ar, 3-F-Ar, 4-F-Ar, 2-Cl-Ar, 3-Cl-Ar, 4-Cl-Ar, 2-Br-Ar, 3-Br-Ar, 4-Br-Ar, 2-CF3-Ar, 3-CF3-Ar, 4-CF3-Ar, 2,3-2Cl- Ar, 3,4-2Cl-Ar, 2,4-2Cl-Ar, 2,3,4-3Cl-Ar, 2,3-2Br-Ar, 3,4-2Br-Ar, 2,4-2Br-Ar, 2,3,4-3Br-Ar, 2,3-2F-Ar, 3,4-2F-Ar, 2,4-2F-Ar, 2,3,4-3F-Ar, 2-NO2-Ar, 3-NO2-Ar, 4-NO2-Ar, 2-CN-Ar, 3-CN-Ar, 4-CN-Ar, 2-NH2-Ar, 3-NH2-Ar, 4-NH2-Ar, naphthalen-1-yl, naphthalen-2-yl, furan-1-yl, furan-2-yl, pyridin-4-yl, thiophen-1-yl, thiophen-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Ar represents phenyl (Ph);

[0025] R 2For: phenyl, benzyl, 2-Me-Ar, 3-Me-Ar, 4-Me-Ar, 2-Et-Ar, 3-Et-Ar, 4-Et-Ar, 2-t-Bu-Ar, 3-t-Bu-Ar, 4-t-Bu-Ar, 2-MeO-Ar, 3-MeO-Ar, 4-MeO-Ar, 2-EtO-Ar, 3-EtO-Ar, 4-EtO -Ar, 2-t-BuO-Ar, 3-t-BuO-Ar, 4-t-BuO-Ar, 2-F-Ar, 3-F-Ar, 4-F-Ar, 2-Cl-Ar, 3-Cl-Ar, 4-Cl-Ar, 2-Br-Ar, 3-Br-Ar, 4-Br-Ar, 2-CF3-Ar, 3-CF3-Ar, 4-CF3-Ar, 2,3 -2Cl-Ar, 3,4-2Cl-Ar, 2,4-2Cl-Ar, 2,3,4-3Cl-Ar, 2,3-2Br-Ar, 3,4-2Br-Ar, 2,4-2Br-Ar, 2,3,4-3Br-Ar, 2,3-2F-Ar, 3,4-2F-Ar, 2,4-2F-Ar, 2,3,4-3F-Ar, 2-NO2-Ar, 3-NO2-Ar, 4-NO2-Ar, 2-CN-Ar, 3-CN-Ar, 4-CN-Ar, 2-NH2-Ar, 3-NH2-Ar, 4-NH2-Ar, naphthalen-1-yl, naphthalen-2-yl, furan-1-yl, furan-2-yl, pyridin-4-yl, thiophen-1-yl, thiophen-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0026] In the second aspect of the present invention, a method for preparing the spiral-2(3H)-furanone skeleton molecule is provided, and the specific synthetic route is as follows:

[0027]

[0028] The method comprises the following steps:

[0029] Under an argon atmosphere, a set amount of a sulfur ylide compound, a catalyst and a base are mixed, and then an ethylene oxide compound and a solvent are added, and the reaction is carried out at a set temperature to obtain a reaction mixture, which is concentrated to dryness; and finally purified to obtain a cycloaddition product, the structure of which is shown in general formula I or II (ylide IV-1 can be synthesized into I, and ylide IV can be synthesized into II);

[0030] The structure of the ethylene oxide compound is shown in Formula III:

[0031]

[0032] In the formula, R 1For: phenyl, benzyl, 2-Me-Ar, 3-Me-Ar, 4-Me-Ar, 2-Et-Ar, 3-Et-Ar, 4-Et-Ar, 2-t-Bu-Ar, 3-t-Bu-Ar, 4-t-Bu-Ar, 2-MeO-Ar, 3-MeO-Ar, 4-MeO-Ar, 2-EtO-Ar, 3-EtO-Ar, 4-EtO -Ar, 2-t-BuO-Ar, 3-t-BuO-Ar, 4-t-BuO-Ar, 2-F-Ar, 3-F-Ar, 4-F-Ar, 2-Cl-Ar, 3-Cl-Ar, 4-Cl-Ar, 2-Br-Ar, 3-Br-Ar, 4-Br-Ar, 2-CF3-Ar, 3-CF3-Ar, 4-CF3-Ar, 2,3 -2Cl-Ar, 3,4-2Cl-Ar, 2,4-2Cl-Ar, 2,3,4-3Cl-Ar, 2,3-2Br-Ar, 3,4-2Br-Ar, 2,4-2Br-Ar, 2,3,4-3Br-Ar, 2,3-2F-Ar, 3,4-2F-Ar, 2,4-2F-Ar, 2,3,4-3F-Ar, 2-NO2-Ar, 3-NO2-Ar, 4-NO2-Ar, 2-CN-Ar, 3-CN-Ar, 4-CN-Ar, 2-NH2-Ar, 3-NH2-Ar, 4-NH2-Ar, naphthalen-1-yl, naphthalen-2-yl, furan-1-yl, furan-2-yl, pyridin-4-yl, thiophen-1-yl, thiophen-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0033] Where R 3 are: -CH3 (methyl), -CH2CH3 (ethyl), -C(CH3)3 (tert-butyl), C6H5CH2- (benzyl), 3,3-2CF3-Bn (3,3-2 trifluoromethyl-benzyl);

[0034] The structure of the sulfur ylide compound is shown in Formula IV-1 or IV:

[0035]

[0036] Except for IV-1, the structure is:

[0037]

[0038] In other IV structures, R 2For: phenyl, benzyl, 2-Me-Ar, 3-Me-Ar, 4-Me-Ar, 2-Et-Ar, 3-Et-Ar, 4-Et-Ar, 2-t-Bu-Ar, 3-t-Bu-Ar, 4-t-Bu-Ar, 2-MeO-Ar, 3-MeO-Ar, 4-MeO-Ar, 2-EtO-Ar, 3-EtO-Ar, 4-EtO -Ar, 2-t-BuO-Ar, 3-t-BuO-Ar, 4-t-BuO-Ar, 2-F-Ar, 3-F-Ar, 4-F-Ar, 2-Cl-Ar, 3-Cl-Ar, 4-Cl-Ar, 2-Br-Ar, 3-Br-Ar, 4-Br-Ar, 2-CF3-Ar, 3-CF3-Ar, 4-CF3-Ar, 2,3 -2Cl-Ar, 3,4-2Cl-Ar, 2,4-2Cl-Ar, 2,3,4-3Cl-Ar, 2,3-2Br-Ar, 3,4-2Br-Ar, 2,4-2Br-Ar, 2,3,4-3Br-Ar, 2,3-2F-Ar, 3,4-2F-Ar, 2,4-2F-Ar, 2,3,4-3F-Ar, 2-NO2-Ar, 3-NO2-Ar, 4-NO2-Ar, 2-CN-Ar, 3-CN-Ar, 4-CN-Ar, 2-NH2-Ar, 3-NH2-Ar, 4-NH2-Ar, naphthalen-1-yl, naphthalen-2-yl, furan-1-yl, furan-2-yl, pyridin-4-yl, thiophen-1-yl, thiophen-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0039] Furthermore, the molar ratio of the ethylene oxide compound to the sulfur ylide compound is 1-10:1, preferably 1-3:1, and more preferably 2:1.

[0040] Further, the catalyst is at least one of triphenylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, PCY3 (tricyclohexylphosphine), tri(p-tolyl)phosphine, tri(m-tolyl)phosphine, tri(o-tolyl)phosphine, tri(3-chlorophenylphosphine), tri(2,4,6-trimethoxyphenylphosphine), tri(2-furanphenylphosphine), DPPF (1,1'-bis(diphenylphosphino)ferrocene), DPPB (1,4-bis(diphenylphosphino)butane), DPPP (1,3-bis(diphenylphosphino)propane), DPPE (1,2-bis(diphenylphosphino)ethane), BINAP (1,1'-binaphthyl-2,2'-bisdiphenylphosphine), and Xanthpos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). Preferably, tri(p-tolyl)phosphine is used.

[0041] Furthermore, the molar ratio of the catalyst to the sulfur ylide compound is 0.001-0.5:1, preferably 0.2:1.

[0042] Furthermore, the solvent is at least one of water, DCM (dichloromethane), DMF (N,N-dimethylformamide), THF (tetrahydrofuran), DCE (dichloroethane), acetone, toluene, acetonitrile, ether, EA (ethyl acetate), n-hexane, cyclohexane, chloroform, and carbon tetrachloride, preferably chloroform.

[0043] Further, the reaction temperature is -20 to 200°C, preferably -20 to 100°C, more preferably -20 to 50°C, and most preferably 0°C. The reaction time is 1 to 72 h, preferably 24 to 72 h, and more preferably 48 h.

[0044] Furthermore, the base is at least one of K2CO3, KHCO3, KOH, t-BuOK, Na2CO3, NaHCO3, sodium acetate, NaOH, sodium ethoxide, NaH, Cs2CO3, CsF, triethylamine, and LiOH·H2O, preferably CsF.

[0045] Furthermore, the molar ratio of the base to the sulfur ylide compound is 1-10:1, preferably 2:1.

[0046] Furthermore, the purification method comprises: using a mobile phase eluent consisting of ethyl acetate and petroleum ether for rapid column chromatography.

[0047] In the third aspect of the present invention, human breast cancer cells MCF-7 were selected to study the cytotoxicity of the synthesized compounds (100 nmol / mL) in inhibiting the proliferation of cancer cells.

[0048] In order to study the activity of the compounds at the cellular level, human breast cancer cells MCF-7 were selected to study the cytotoxicity of the synthesized compounds (100 nmol / mL) in inhibiting the proliferation of cancer cells. It was finally found that compound I had a strong inhibitory effect on human breast cancer cells MCF-7 at 100 nmol / mL.

[0049] Next, a gradient anticancer activity experiment was conducted to test the IC values ​​of the compounds against human breast cancer cells MCF-7. 50 The results showed that compound I had a certain inhibitory ability on human breast cancer cell MCF-7.

[0050] Compared with the related art known to the inventor, one of the technical solutions of the present invention has the following beneficial effects:

[0051] (1) The reagents and catalysts used are cheap and readily available, and the synthesis is simple.

[0052] (2) The preparation process has high reaction activity and high yield, is simple and efficient, has mild reaction conditions, and has fewer reaction steps, making it more economical and environmentally friendly.

[0053] (3) The compound has a novel structure, can be derived into many compounds, and has certain anti-human breast cancer cell MCF-7 activity.

[0054] (4) Compared with traditional methods, this method greatly reduces the reaction cost, reduces the reaction steps, shortens the reaction time, and improves the preparation efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0056] Figure 1-1 Hydrogen spectrum of compound I-1 in Example 1.

[0057] Figure 1-2 This is the carbon spectrum of compound I-1 in Example 1.

[0058] Figure 2-1 This is the hydrogen spectrum of compound II-1 in Example 13.

[0059] Figure 2-2 This is the carbon spectrum of compound II-1 in Example 13.

[0060] Figure 3-1 It is the hydrogen spectrum of compound I-2 in Example 14.

[0061] Figure 3-2 This is the carbon spectrum of compound I-2 in Example 14.

[0062] Figure 4-1 It is the hydrogen spectrum of compound I-3 in Example 15.

[0063] Figure 4-2 This is the carbon spectrum of compound I-3 in Example 15.

[0064] Figure 5-1 It is the hydrogen spectrum of compound I-4 in Example 16.

[0065] Figure 5-2 This is the carbon spectrum of compound I-4 in Example 16.

[0066] Figure 5-3 It is the fluorine spectrum of compound I-4 in Example 16.

[0067] Figure 6-1 It is the hydrogen spectrum of compound I-5 in Example 17.

[0068] Figure 6-2 This is the carbon spectrum of compound I-5 in Example 17.

[0069] Figure 6-3It is the fluorine spectrum of compound I-5 in Example 17.

[0070] Figure 7-1 It is the hydrogen spectrum of compound I-6 in Example 18.

[0071] Figure 7-2 This is the carbon spectrum of compound I-6 in Example 18.

[0072] Figure 8-1 It is the hydrogen spectrum of compound I-7 in Example 19.

[0073] Figure 8-2 This is the carbon spectrum of compound I-7 in Example 19.

[0074] Figure 9-1 It is the hydrogen spectrum of compound I-8 in Example 20.

[0075] Figure 9-2 It is the carbon spectrum of compound I-8 in Example 20.

[0076] Figure 9-3 It is the fluorine spectrum of compound I-8 in Example 20.

[0077] Figure 10-1 It is the hydrogen spectrum of compound I-9 in Example 21.

[0078] Figure 10-2 This is the carbon spectrum of compound I-9 in Example 21.

[0079] Figure 11-1 This is the hydrogen spectrum of compound II-2 in Example 22.

[0080] Figure 11-2 This is the carbon spectrum of compound II-2 in Example 22.

[0081] Figure 12-1 This is the hydrogen spectrum of compound II-3 in Example 23.

[0082] Figure 12-2 This is the carbon spectrum of compound II-3 in Example 23.

[0083] Figure 13-1 This is the hydrogen spectrum of compound II-4 in Example 24.

[0084] Figure 13-2 This is the carbon spectrum of compound II-4 in Example 24.

[0085] Figure 14-1 This is the hydrogen spectrum of compound II-5 in Example 25.

[0086] Figure 14-2 This is the carbon spectrum of compound II-5 in Example 25. DETAILED DESCRIPTION

[0087] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0088] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations and / or combinations thereof.

[0089] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0090] All reactions were carried out in oven-dried glassware with magnetic stirring under argon atmosphere. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. All solvents were used after purification and drying according to standard methods. Organic solutions were concentrated under reduced pressure on a rotary evaporator or oil pump. The reactions were monitored by thin layer chromatography (TLC) on silica gel coated glass plates. Chromatograms were observed by fluorescence quenching with UV light at 254 nm. Flash column chromatography was performed using Qingdao Marine Column Chromatography Silica Gel (200-300 mesh). Deuterated chloroform (400 or 800 MHz NMR instrument, internal reference Me4Si) was used for recording 1 H NMR spectroscopy. 1 H NMR data are given below: chemical shift (ppm), multiplicity (s = singlet; d = doublet; q = quartet; m = multiplet; br = broad), coupling constant (Hz), and integration. 13 The data of C NMR spectroscopy are reported as chemical shifts. HRMS measurements were performed using a QTOF as the mass analyzer.

[0091] Example 1

[0092]

[0093] Under argon atmosphere, a mixture of sulfur ylide IV-1 (27.3 mg, 0.1 mmol, 1.0 equivalent), tri(p-tolyl)phosphine (6.1 mg, 0.02 mmol, 0.2 equivalent), and CsF (30.4 mg, 0.2 mmol, 2.0 equivalent) was added to a Shrek tube, and ethylene oxide compound III-1 (40.8 mg, 0.2 mmol, 2 equivalent) and 1 mL of solvent chloroform were added. The mixture was stirred at 0 °C for 48 hours, and the reaction was detected by TLC to obtain a reaction mixture, which was then concentrated to dryness under reduced pressure. The cycloaddition product I-1 (26.9 mg) was purified by rapid silica gel column chromatography using a mobile phase eluent consisting of 10% EA / PE with a yield of 89%. The product was a white powder. (mp) melting point = 115 -117 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.50 (dd, J = 7.9, 6.1 Hz, 2H), 7.41 – 7.37 (m, 1H), 7.33 (dd, J = 4.9,1.9 Hz, 3H), 7.25 (t, J = 7.5 Hz, 1H), 7.14 (dd, J = 6.6, 2.9 Hz, 2H), 6.84(s, 1H), 3.52 (d, J = 18.6 Hz, 1H), 3.28 (d, J = 18.6 Hz, 1H), 2.71 (d, J =5.0 Hz, 1H), 2.16 (d, J = 5.0 Hz, 1H); 13 C NMR (201 MHz, CDCl3) δ 197.1,174.8, 150.8, 139.0, 135.6, 133.6, 131.5, 127.1, 126.8, 126.7, 126.5, 125.0,122.8, 122.3, 44.1, 39.4, 31.7, 24.4; HRMS (ESI) calculate for C 20 H 14 O3Na + [M+Na] + 325.0841, found 325.0845, Figure 1-1 and Figure 1-2 .

[0094] Example 2

[0095] The catalyst, base, solvent and temperature in Example 1 were replaced with triphenylphosphine (5.2 mg, 0.02 mmol, 0.2 equivalent), potassium carbonate (27.6 mg, 0.2 mmol, 2.0 equivalent), dichloromethane 1 mL, 25 ° C. The remaining process and conditions were the same as in Example 1. The purified cycloaddition product I-1 (19.0 mg) had a yield of 63% and the product was a white powder.

[0096] Example 3

[0097] The catalyst, base and temperature in Example 1 were replaced with triphenylphosphine (5.2 mg, 0.02 mmol, 0.2 equivalent), potassium carbonate (27.6 mg, 0.2 mmol, 2.0 equivalent) and 25 °C. The remaining process and conditions were the same as in Example 1. The purified cycloaddition product I-1 (20.9 mg) had a yield of 69% and the product was a white powder.

[0098] Example 4

[0099] The catalyst and temperature in Example 1 were replaced with triphenylphosphine (5.2 mg, 0.02 mmol, 0.2 equivalent) and 25°C. The remaining processes and conditions were the same as in Example 1. The purified cycloaddition product I-1 (22.4 mg) had a yield of 74% and was a white powder.

[0100] Example 5

[0101] The temperature in Example 1 was changed to 25°C, and the remaining processes and conditions were the same as in Example 1. The cycloaddition product I-1 (25.7 mg) obtained by purification had a yield of 85%, and the product was a white powder.

[0102] Example 6

[0103] The temperature in Example 1 was changed to -20°C, and the remaining processes and conditions were the same as in Example 1. The cycloaddition product I-1 (22.1 mg) obtained by purification had a yield of 73% and the product was a white powder.

[0104] Example 7

[0105] The base in Example 1 was replaced with CsF (15.2 mg, 0.1 mmol, 1.0 equivalent), and the remaining processes and conditions were the same as in Example 1. The purified cycloaddition product I-1 (18.1 mg) had a yield of 60% and was a white powder.

[0106] Example 8

[0107] The base in Example 1 was replaced with CsF (45.6 mg, 0.3 mmol, 3.0 equivalents), and the remaining processes and conditions were the same as in Example 1. The cycloaddition product I-1 (23.3 mg) obtained by purification had a yield of 77% and the product was a white powder.

[0108] Example 9

[0109] The ethylene oxide compound in Example 1 was replaced with III-1 (20.4 mg, 0.1 mmol, 1 equivalent), and the remaining processes and conditions were the same as in Example 1. The purified cycloaddition product I-1 (16.0 mg) had a yield of 53% and was a white powder.

[0110] Example 10

[0111] The sulfur ylide in Example 1 was replaced by IV-1 (54.6 mg, 0.2 mmol, 2.0 equivalents), and the ethylene oxide compound was replaced by III-1 (20.4 mg, 0.1 mmol, 1 equivalent). The remaining processes and conditions were the same as in Example 1. The purified cycloaddition product I-1 (23.3 mg) had a yield of 77% and the product was a white powder.

[0112] Embodiment 11

[0113] The reaction time in Example 1 was changed to 36 hours, and the remaining processes and conditions were the same as in Example 1. The cycloaddition product I-1 (20.6 mg) obtained by purification had a yield of 68%, and the product was a white powder.

[0114] Example 12

[0115] The reaction time in Example 1 was changed to 72 hours, and the remaining processes and conditions were the same as in Example 1. The cycloaddition product I-1 (27.2 mg) obtained by purification had a yield of 90%, and the product was a white powder.

[0116] Example 13

[0117]

[0118] The sulfur ylide in Example 1 was replaced with IV-2 (26.31 mg, 0.1 mmol, 1.0 equivalent), and the remaining process and conditions were the same as in Example 1. The cycloaddition product II-1 (26.1 mg) was purified with a yield of 80%, and the product was a white powder. (mp) melting point = 115 -117 °C; 1 H NMR (400 MHz, Chloroform- d) δ 7.61 – 7.53 (m, 2H), 7.52– 7.45 (m, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.21 – 7.15 (m, 1H), 7.14 – 7.05(m, 2H), 6.86 (s, 1H), 6.75 – 6.66 (m, 2H), 3.28 (dd, J = 8.5, 7.6 Hz, 1H),2.61 (dd, J = 7.6, 4.9 Hz, 1H), 2.03 (dd, J = 8.5, 4.9 Hz, 1H); 13 C NMR (101MHz, CDCl3) δ 190.8, 177.2, 139.5, 136.6, 133.6, 129.5, 128.7, 128.5, 128.22,128.21,128.16, 122.74, 37.0, 34.6, 18.0; HRMS (ESI) calcd for C 19 H 14 O3Na + [M+Na] + 313.0841, found 313.0846, as Figure 2-1 and Figure 2-2 .

[0119] Embodiment 14

[0120] The ethylene oxide compound in Example 1 is replaced by R 1 is 4-Me-Ar (phenyl), R 3 The oxirane compound III-2 (43.6 mg, 0.2 mmol, 2 equivalents) containing -CH3 (methyl) was purified with the same process and conditions as in Example 1. The yield of the cycloaddition product I-2 obtained was 82% (25.9 mg), and the product was a white powder. (mp) melting point = 116 -119 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.53 – 7.47 (m, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.25(t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.03 (d,J = 7.6 Hz, 2H), 6.80(d, J = 1.7 Hz, 1H), 3.51 (d, J = 18.6 Hz, 1H), 3.28 (d, J = 18.6 Hz, 1H),2.71 (d, J = 4.8 Hz, 1H), 2.33 (s, 3H), 2.14 (d, J = 4.9 Hz, 1H); 13 C NMR (101MHz, CDCl3) δ 198.2, 175.9, 151.8, 139.9, 137.5, 136.7, 134.7, 129.6, 128.9,127.5, 126.1, 123.8, 123.2, 45.1, 40.5, 32.8, 25.4, 21.4; HRMS (ESI)calculate for C 21 H 16 O3Na + [M+Na] + 339.0997, found 339.0987, Figure 3-1 and Figure 3-2 .

[0121] Embodiment 15

[0122] The ethylene oxide compound in Example 1 is replaced by R 1 3-MeO-Ar (phenyl), R 3 The oxirane compound III-3 (46.8 mg, 0.2 mmol, 2 equivalents) containing -CH3 (methyl) was used. The remaining process and conditions were the same as those in Example 1. The yield of the purified cycloaddition product I-3 was 80% (26.6 mg), and the product was a colorless oil. 1 H NMR (800 MHz, Chloroform- d )δ 7.54 – 7.48 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.25 (td, J = 7.9, 2.6 Hz,2H), 6.88 – 6.82 (m, 2H), 6.74 (dt, J = 7.5, 1.2 Hz, 1H), 6.65 (dd, J= 2.5,1.5 Hz, 1H), 3.76 (s, 3H), 3.51 (d, J = 18.6 Hz, 1H), 3.28 (d, J = 18.7 Hz,1H), 2.72 (d, J = 4.9 Hz, 1H), 2.15 (d, J = 4.9 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 197.0, 174.7, 158.2, 150.7, 139.1, 135.6, 133.6, 132.8, 128.0,126.5, 125.0, 122.8, 122.1, 119.3, 112.9, 111.7, 54.2, 44.1, 39.4, 31.7,24.3; HRMS (ESI) calculate for C 21 H 16 O4Na + [M+Na] + 355.0947, found 355.0951, as Figure 4-1 and Figure 4-2 .

[0123] Example 16

[0124] The ethylene oxide compound in Example 1 is replaced by R 1 is 3-F-Ar (phenyl), R 3 The -CH3(methyl)oxirane compound III-4 (44.4 mg, 0.2 mmol, 2 equivalents) was prepared. The remaining processes and conditions were the same as those in Example 1. The yield of the purified cycloaddition product I-4 was 80% (25.6 mg), and the product was a colorless oil. 1 H NMR (800 MHz, Chloroform- d ) δ7.51 (ddd, J = 7.1, 6.1, 1.5 Hz, 2H), 7.41 – 7.38 (m, 1H), 7.31 – 7.24 (m,2H), 7.01 (tdd, J = 8.5, 2.6, 0.9 Hz, 1H), 6.92 (dt, J = 7.6, 1.3 Hz, 1H), 6.86 (s, 1H), 6.85 – 6.82 (m, 1H), 3.50 (d,J = 18.6 Hz, 1H), 3.29 (d, J =18.6 Hz, 1H), 2.69 (d, J = 5.0 Hz, 1H), 2.17 (d, J = 5.0 Hz, 1H); 13 C NMR (101MHz, CDCl3) δ 197.2, 174.4, 161.4 (d, J = 245.6 Hz), 150.8, 139.5, 135.5,133.8, 128.6 (d, J = 8.7 Hz), 126.6, 125.1, 122.8, 122.4 (d, J = 2.9 Hz),121.3 (d, J = 2.2 Hz), 113.8 (d, J = 8.2 Hz), 113.6 (d, J = 6.7 Hz), 44.2,39.3, 31.7, 24.4; 19 F NMR (377 MHz, CDCl3) δ -113.09; HRMS (ESI) calculate forC 20 H 13 FO3Na + [M+Na] + 343.0747, found 343.0745, as Figure 5-1 , Figure 5-2 and Figure 5-3 .

[0125] Embodiment 17

[0126] The ethylene oxide compound in Example 1 is replaced by R 1 is 4-F-Ar (phenyl), R 3 The -CH3 (methyl) oxirane compound III-5 (44.4 mg, 0.2 mmol, 2 equivalents) was purified under the same conditions as in Example 1. The yield of the cycloaddition product I-5 obtained was 81% (25.9 mg). The product was a white powder. (mp) melting point = 117 -119 °C; 1 H NMR (400 MHz, Chloroform- d) δ 7.62 – 7.55 (m, 2H), 7.50 – 7.43 (m, 1H), 7.33 (td, J = 7.5, 1.0 Hz, 1H), 7.17 (ddt, J = 8.2, 5.2, 2.5 Hz, 2H), 7.12 – 7.04 (m,2H), 6.89 (s, 1H), 3.59 (d, J = 18.8 Hz, 1H), 3.36 (d, J = 18.8 Hz, 1H), 2.73(d, J = 4.8 Hz, 1H), 2.22 (d, J = 4.8 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ198.3, 175.6, 163.7, 161.2, 151.9, 140.2, 136.6, 134.8, 129.5, 129.4, 128.51,128.48, 127.6, 126.1, 123.8, 122.4, 115.3, 115.1, 45.1, 40.4, 32.7, 25.4; 19 FNMR (377 MHz, CDCl3) δ -113.79; HRMS (ESI) calculate for C 20 H 13 FO3Na + [M+Na] + 343.0747, found 343.0753, as Figure 6-1 , Figure 6-2 and Figure 6-3 .

[0127] Embodiment 18

[0128] The ethylene oxide compound in Example 1 is replaced by R 1 is 3-Br-Ar (phenyl), R 3 The -CH3(methyl)oxirane compound III-6 (56.6 mg, 0.2 mmol, 2 equivalents) was prepared. The remaining processes and conditions were the same as those in Example 1. The yield of the purified cycloaddition product I-6 was 78% (29.7 mg), and the product was a colorless oil. 1 H NMR (800 MHz, Chloroform- d)δ 7.54 – 7.49 (m, 2H), 7.44 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.40 (dt, J =7.7, 1.0 Hz, 1H), 7.29 – 7.25 (m, 2H), 7.21 (t, J = 7.8 Hz, 1H), 7.09 (ddd, J = 7.7, 1.6, 1.1 Hz, 1H), 6.86 (s, 1H), 3.50 (d, J = 18.5 Hz, 1H), 3.29 (d, J = 18.6 Hz, 1H), 2.68 (d, J = 5.0 Hz, 1H), 2.17 (d, J = 5.0 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 197.2, 174.4, 150.8, 139.7, 135.5, 133.8, 133.5, 129.8,129.5, 128.6, 126.6, 125.4, 125.1, 122.8, 121.1, 121.0, 44.2, 39.2, 31.7,24.5; HRMS (ESI) calculate for C 20 H 13 BrO3Na + [M+Na] + 402.9946, found 402.9939, such as Figure 7-1 and Figure 7-2 .

[0129] Embodiment 19

[0130] The ethylene oxide compound in Example 1 is replaced by R 1 4-Br-Ar, R 3 The -CH3 (methyl) oxirane compound III-7 (47.6 mg, 0.2 mmol, 2 equivalents) was purified under the same conditions as in Example 1. The yield of the cycloaddition product I-7 obtained was 82% (31.3 mg). The product was a white powder. (mp) melting point = 122 -124 °C; 1 H NMR (800MHz, Chloroform- d ) δ 7.52 (ddd,J = 7.1, 6.3, 1.5 Hz, 2H), 7.47 – 7.43 (m,2H), 7.42 – 7.39 (m, 1H), 7.29 – 7.25 (m, 1H), 7.04 – 7.00 (m, 2H), 6.84 (s,1H), 3.51 (d, J = 18.6 Hz, 1H), 3.29 (d, J = 18.6 Hz, 1H), 2.67 (d, J = 5.0Hz, 1H), 2.17 (d, J = 5.0 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 197.3, 174.5,150.8, 139.4, 135.5, 133.8, 130.5, 130.3, 128.2, 126.6, 125.1, 122.8, 121.3,120.9, 44.2, 39.3, 31.7, 24.4; HRMS (ESI) calculate for C 20 H 13 BrO3Na + [M+Na] + 402.9946, found 402.9936, such as Figure 8-1 and Figure 8-2 .

[0131] Embodiment 20

[0132] The ethylene oxide compound in Example 1 is replaced by R 1 4-CF3-Ar, R 3 The -CH3 (methyl) oxirane compound III-8 (54.4 mg, 0.2 mmol, 2 equivalents) was prepared. The remaining processes and conditions were the same as those in Example 1. The yield of the purified cycloaddition product I-8 was 75% (27.8 mg). The product was a white powder. (mp) melting point = 103 -106 °C; 1 H NMR (400MHz, Chloroform- d ) δ 7.65 (d, J = 8.1 Hz, 2H), 7.59 (ddd, J = 10.1, 7.5, 2.0Hz, 2H), 7.48 (d, J = 7.7 Hz, 1H), 7.34 (dd,J = 7.8, 5.3 Hz, 3H), 6.96 (s,1H), 3.58 (d, J = 18.8 Hz, 1H), 3.37 (d, J = 18.8 Hz, 1H), 2.77 (d, J = 4.9Hz, 1H), 2.28 (d, J = 4.9 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 198.5, 175.3,152.0, 141.1, 136.45, 136.41, 135.0, δ 129.7 (q, J = 32.4 Hz), 127.8, 127.7,126.2, 125.2 (q, J = 3.7 Hz),δ 124.2 (d, J = 271.9 Hz), 123.8, 122.2, 45.3,40.3, 32.8, 25.6; 19 F NMR (377 MHz, CDCl3) δ -62.36; HRMS (ESI) calculate forC 21 H 13 F3O3Na + [M+Na] + 393.0715, found 393.0706, Figure 9-1 , Figure 9-2 and Figure 9-3 .

[0133] Embodiment 21

[0134] The ethylene oxide compound in Example 1 is replaced by R 1 3-NO2-Ar, R 3 The -CH3(methyl)oxirane compound III-9 (49.8 mg, 0.2 mmol, 2 equivalents) was prepared. The remaining processes and conditions were the same as those in Example 1. The yield of the purified cycloaddition product I-9 was 78% (27.1 mg), and the product was a yellow oil. 1 H NMR (800 MHz, Chloroform- d ) δ8.17 (ddd, J = 8.0, 2.3, 1.3 Hz, 1H), 8.01 (t, J= 1.9 Hz, 1H), 7.55 – 7.44(m, 4H), 7.41 (d, J = 7.7 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.96 (s, 1H), 3.51 (d, J = 18.6 Hz, 1H), 3.31 (d, J = 18.7 Hz, 1H), 2.69 (d, J = 5.2 Hz,1H), 2.23 (d, J = 5.2 Hz, 1H); 13 C NMR (101 MHz, CDCl3) δ 197.6, 174.0, 151.0,147.0, 140.4, 135.3, 134.1, 133.3, 132.6, 128.0, 126.7, 125.1, 122.8, 121.7,121.5, 120.3, 44.3, 39.2, 31.6, 24.7; HRMS (ESI) calculate for C 20 H 13 NO5Na + [M+Na] + 370.0691, found 370.0682, Figure 10-1 and Figure 10-2 .

[0135] Embodiment 22

[0136] The sulfur ylide in Example 13 was replaced by R 2 The sulfur ylide IV-3 (27.5 mg, 0.1 mmol, 1.0 equivalent) of 4-Me-Ar was purified with the same process and conditions as in Example 1. The cycloaddition product II-2 was purified with a yield of 77% (23.4 mg) and the product was a white powder. (mp) melting point = 107 -109 °C; 1 H NMR (800 MHz, Chloroform- d ) δ7.48 – 7.45 (m, 2H), 7.21 – 7.18 (m, 1H), 7.14 – 7.07 (m, 4H), 6.84 (s, 1H), 6.73 – 6.69 (m, 2H), 3.25 (dd, J = 8.6, 7.6 Hz, 1H), 2.58 (dd,J = 7.6, 5.0Hz, 1H), 2.33 (s, 3H), 1.99 (dd, J = 8.5, 5.0 Hz, 1H); 13 C NMR (201 MHz, CDCl3) δ 189.3, 176.3, 143.6, 138.4, 133.2, 128.5, 128.3, 127.4, 127.3,127.2, 127.1, 121.8, 36.0, 33.5, 20.7, 16.9; HRMS (ESI) calcd for C 20 H 16 O3Na + [M+Na] + 327.0997, found 327.1000, Figure 11-1 and Figure 11-2 .

[0137] Embodiment 23

[0138] The sulfur ylide in Example 13 was replaced by R 2 The sulfur ylide IV-4 (29.1 mg, 0.1 mmol, 1.0 equiv.) of 4-OMe-Ar was used, and the remaining process and conditions were the same as in Example 1. The yield of the purified cycloaddition product II-3 was 78% (25.0 mg), and the product was a colorless oil. 1 H NMR (400 MHz, Chloroform- d ) δ 7.58 – 7.51 (m, 2H), 7.19(tt, J = 7.0, 1.3 Hz, 1H), 7.14 – 7.05 (m, 2H), 6.85 (s, 1H), 6.83 – 6.77 (m,2H), 6.75 – 6.68 (m, 2H), 3.80 (s, 3H), 3.23 (dd, J = 8.6, 7.6 Hz, 1H), 2.58(dd, J = 7.6, 4.9 Hz, 1H), 1.99 (dd, J = 8.6, 4.9 Hz, 1H); 13C NMR (201 MHz, CDCl3) δ 188.0, 176.4, 162.9, 138.2, 129.5, 128.8, 128.5, 127.4, 127.2,127.1, 121.9, 112.8, 54.5, 35.9, 33.4, 16.9; HRMS (ESI) calcd for C 20 H 16 O4Na + [M+Na] + 343.0947, found 343.0951, as Figure 12-1 and Figure 12-2 .

[0139] Embodiment 24

[0140] The sulfur ylide in Example 13 was replaced by R 2 The sulfur ylide IV-5 (34.0 mg, 0.1 mmol, 1.0 equivalent) of 4-Br-Ar was purified with the same process and conditions as in Example 1. The cycloaddition product II-4 was purified with a yield of 65% (24.0 mg) and the product was a white powder. (mp) melting point = 128 -131 °C; 1 H NMR (800 MHz, Chloroform- d ) δ7.51 – 7.46 (m, 2H), 7.44 – 7.40 (m, 2H), 7.23 – 7.19 (m, 1H), 7.12 (dd, J =8.5, 7.0 Hz, 2H), 6.87 (s, 1H), 6.74 – 6.70 (m, 2H), 3.22 (dd, J = 8.5, 7.5Hz, 1H), 2.61 (dd, J = 7.5, 5.1 Hz, 1H), 2.03 (dd, J = 8.5, 5.1 Hz, 1H); 13 CNMR (201 MHz, CDCl3) δ 188.9, 176.0, 138.6, 134.2, 131.0, 128.6, 128.4,128.0, 127.6, 127.2, 127.1, 121.5, 35.6, 33.6, 16.9; HRMS (ESI) calcd forC 19 H 13 BrO3Na +[M+Na] + 390.9946, found 390.9937, Figure 13-1 and Figure 13-2 .

[0141] Embodiment 25

[0142] The sulfur ylide in Example 13 was replaced by R 2 The naphthalene-2-yl sulfur ylide IV-6 (31.1 mg, 0.1 mmol, 1.0 equivalent) was used. The remaining process and conditions were the same as in Example 1. The cycloaddition product II-5 obtained by purification had a yield of 65% (22.1 mg) and the product was a white powder. (mp) melting point = 118 -121 °C; 1 H NMR (800 MHz, Chloroform- d ) δ8.11 (d, J = 1.9 Hz, 1H), 7.87 – 7.83 (m, 1H), 7.80 – 7.75 (m, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.57 – 7.51 (m, 2H), 7.48 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H),7.20 – 7.15 (m, 1H), 7.09 – 7.04 (m, 2H), 6.82 (s, 1H), 6.71 – 6.65 (m, 2H),3.42 (dd, J = 8.5, 7.5 Hz, 1H), 2.65 (dd, J = 7.6, 5.1 Hz, 1H), 2.05 (dd, J =8.5, 5.1 Hz, 1H); 13 C NMR (201 MHz, CDCl3) δ 189.6, 176.3, 138.4, 134.7,133.0, 131.3, 129.1, 128.7, 128.5, 127.9, 127.5, 127.4, 127.2, 127.1, 126.8,126.0, 122.5, 121.7, 36.0, 33.7, 17.0; HRMS (ESI) calcd for C 23 H 16 O3Na + [M+Na] +363.0997, found 363.1004, as Figure 14-1 and Figure 14-2 .

[0143] Usage test data:

[0144] Instruments and reagents

[0145] Instruments: benchtop centrifuge, cell counter, CO2 incubator, inverted microscope, microplate reader (450 nm filter), 10 uL, 100 - 200 uL multichannel pipette, etc.

[0146] Reagents: CCK-8 detection kit, DMEM medium, double antibody, FBS, PBS, DMSO.

[0147] Cell line: Human breast cancer cells (Michigan Cancer Foundation-7, MCF-7)

[0148] The items required should be disinfected and sterilized under ultraviolet light for at least 30 minutes.

[0149] After the required cells are revived and subcultured, observe the cell growth status under a microscope to see if they are in good condition, and select cells with good condition and cell density of 80%-90% for plate seeding. Digest the cells cultured the day before, centrifuge, count the cells, dilute to 50,000-70,000 / mL in the sample tank, add 100 μL of culture medium per well to the middle 60 wells of the 96-well plate, wait for the cells to sink to the bottom, then put them into the incubator, and culture them at 37°C, 5% CO2, 90% humidity for 24 hours to allow the cells to reach the appropriate density.

[0150] First, the compound to be tested was dissolved in DMSO at a concentration of 100 μmol / mL to prepare a stock solution, and then 1 μL of the stock solution was mixed with 1 mL of complete culture medium, diluted one thousand times, and 0.033% Tween was added to assist dissolution. A blank group and a control group were set up, and 100 μL of the drug-added culture medium was added to each well. The culture plate was incubated for 24 hours at 37 °C, 5% CO2, and 90% humidity. The complete culture medium and CCK-8 reagent were thawed in advance, prepared in a ratio of 9:1, and 100 μL was added to each well. The 96-well plate was placed in an incubator for one hour, and the 96-well plate was taken out from the light, and the absorbance at 450 nm was measured with an enzyme reader. The results were processed and analyzed using Excel and Graphpad Prism.

[0151] Set up the experimental wells (culture medium containing cells, CCK-8, and test substances)

[0152] Negative control wells (containing cell culture medium, CCK-8, and no test substance)

[0153] Positive control wells (culture medium containing cells, CCK-8, positive control sample)

[0154] Blank wells (medium without cells and test substances, CCK-8)

[0155] Experimental result calculation formula:

[0156] Cell survival rate = [(experimental well - blank well) / (negative control well - blank well)] x 100%

[0157] Inhibition rate = [(negative control well - experimental well) / (negative control well - blank well)] x 100%

[0158] In order to study the activity of the compounds at the cellular level, human breast cancer cells MCF-7 were selected to study the cytotoxicity of the synthesized compounds (100 nmol / mL) in inhibiting the proliferation of cancer cells. It was finally found that compound I had a strong inhibitory effect on human breast cancer cells MCF-7 at 100 nmol / mL.

[0159] Compound No. Inhibitory rate of MCF-7 cells I-1 96.35% I-2 97.27% I-3 97.15% I-4 96.69% I-5 97.13% I-6 7.52% I-7 90.03% I-8 89.61% I-9 95.03%

[0160] Next, a gradient anticancer activity experiment was conducted to test the IC values ​​of the compounds against human breast cancer cells MCF-7. 50 The results showed that compound I had a certain inhibitory ability on human breast cancer cell MCF-7.

[0161] Compound <![CDATA[IC value for human breast cancer cell MCF-7 (μmol / L)]]> 50 ​ I-1 42.61 I-2 41.02 I-3 40.96 I-4 42.76 I-5 43.96 I-7 48.82 I-8 47.43 I-9 45.03

[0162] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A helical-2(3H)-furanone skeleton molecule, characterized in that: The structure is shown in general formula Ⅰ: Where R 1 They are: phenyl, 4-Me-Ph, 3-MeO-Ph, 3-F-Ph, 4-F-Ph, 4-Br-Ph, 4-CF3-Ph, 3-NO2-Ph.

2. A method for preparing the helix-2(3H)-furanone skeleton molecule as claimed in claim 1, characterized in that: The method comprises the following steps: In an argon atmosphere, a set amount of a sulfur ylide compound, a catalyst and a base are mixed, and then an ethylene oxide compound and a solvent are added to react at a set temperature to obtain a reaction mixture, which is concentrated to dryness; and finally purified to obtain a cycloaddition product, the structure of which is shown in general formula I; The structure of the ethylene oxide compound is shown in Formula III: In the formula, R 1 Are: phenyl, 4-Me-Ph, 3-MeO-Ph, 3-F-Ph, 4-F-Ph, 4-Br-Ph, 4-CF3-Ph, 3-NO2-Ph; Where R 3 For: -CH3; The structure of the sulfur ylide compound is shown in Formula IV-1: 。 3. The method for preparing the helix-2(3H)-furanone skeleton molecule according to claim 2, characterized in that: The molar ratio of the ethylene oxide compound to the sulfur ylide compound is 1-10:

1.

4. The method for preparing the helix-2(3H)-furanone skeleton molecule according to claim 2, characterized in that: The catalyst is at least one of triphenylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, tricyclohexylphosphine, tri(p-tolyl)phosphine, tri(m-tolyl)phosphine, tri(o-tolyl)phosphine, tri(3-chlorophenylphosphine), tri(2,4,6-trimethoxyphenylphosphine), tri(2-furanphenylphosphine), 1,1'-bis(diphenylphosphino)ferrocene, 1,4-bis(diphenylphosphino)butane, 1,3-bis(diphenylphosphino)propane, 1,2-bis(diphenylphosphino)ethane, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

5. The method for preparing the helix-2(3H)-furanone skeleton molecule according to claim 2, characterized in that: The molar ratio of the catalyst to the sulfur ylide compound is 0.1-0.2:

1.

6. The method for preparing the helix-2(3H)-furanone skeleton molecule according to claim 2, characterized in that: The solvent is at least one of water, dichloromethane, N,N-dimethylformamide, tetrahydrofuran, dichloroethane, acetone, toluene, acetonitrile, ether, ethyl acetate, n-hexane, cyclohexane, chloroform and carbon tetrachloride.

7. The method for preparing the helix-2(3H)-furanone skeleton molecule according to claim 2, characterized in that: The reaction temperature is -20~200 ℃; the reaction time is 1~72 h.

8. The method for preparing the helix-2(3H)-furanone skeleton molecule according to claim 2, characterized in that: The base is at least one of K2CO3, KHCO3, KOH, t-BuOK, Na2CO3, NaHCO3, sodium acetate, NaOH, sodium ethoxide, NaH, Cs2CO3, CsF, triethylamine, and LiOH·H2O.

9. The method for preparing the helix-2(3H)-furanone skeleton molecule according to claim 2, characterized in that: The molar ratio of the base to the sulfur ylide compound is 1-3:

1.

10. Use of the helix-2(3H)-furanone skeleton molecule according to claim 1 in the preparation of anti-breast cancer drugs.

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