A kind of spiro[benzofuran-tetrahydropyrrole] compound, its preparation method and applications

Abstract

The present invention discloses a kind of spiro[benzofuran-tetrahydropyrrole] compounds, a preparation method and an application thereof. In the present invention, benzofuran aza-diene and β-sulfonamido-substituted enoate are used as reaction raw materials, and under the action of an organophosphorus catalyst, spiro[benzofuran-tetrahydropyrrole] compounds are efficiently obtained through a one-step reaction. The present invention has the following advantages: the organophosphorus catalyst is cheap and easily available, stable in air and has no pungent odor; there is no need to add transition metals as catalysts, oxidants or reductants, strong acids or strong bases; the present invention has a wide application range, is economical and practical, and is environmentally friendly; the reaction substrates are easy to prepare; the reaction is easy to scale up and has practical value. In addition, such compounds have a significant anti-proliferation effect on the tested human gastric cancer cells (HGC-27) and human liver cancer cells (HepG2), and have certain anti-cancer activities.

Description

Technical Field

[0001] The present invention mainly relates to an efficient and convenient synthesis method of spiro[benzofuran-tetrahydropyrrole] compounds and their applications in pharmaceuticals. Background Art

[0002] The benzofuran spiro five-membered ring skeleton has a special structure, and its core skeleton widely exists in natural compounds and drugs. For example, Ganoleucin D is a pharmacodynamic molecule with this core skeleton structure isolated from the natural product Ganoderma leucocontextum, and it has been proven to have significant inhibitory effects on Aldose reductase and HMG-CoA reductase and can be used to treat diabetes. Synerazol is isolated from soil samples and is a fungal metabolite with good antibacterial activity against fungi including Candida albicans. Armeniaspirol A is a novel natural product isolated from Streptomyces and has been identified as an antibacterial agent against Gram-positive pathogens. There are also studies showing its good antibacterial activity against Helicobacter pylori. Spiroapplantatumine K is a novel meroterpenoid compound isolated from plants of the genus Amygdalus, and it has a significant inhibitory effect on JAK3 and can be used to treat autoimmune-related diseases such as rheumatoid arthritis. In addition, a variety of natural compounds containing the benzofuran spiro five-membered ring skeleton have been found to have significant biological activities and new biological activities.

[0003]

[0004] Developing a simple synthetic strategy for this skeleton has always been a topic of great concern in the organic field. However, there are few reported catalytic synthesis methods for this skeleton. The goal of the present invention is to design a simple and practical catalytic method to construct this skeleton. Organophosphine catalysis is an excellent catalyst in cyclization reactions and is often used as an efficient catalyst for cyclization reactions. Therefore, the present invention splits this parent nucleus structure into benzofuran aza-diene and β-sulfonamido-substituted enoate, and efficiently constructs this parent nucleus structure through phosphine catalysis. Summary of the Invention

[0005] In view of the above technical problems, the present invention provides a spiro[benzofuran-tetrahydropyrrole] compound, its preparation method and its applications in pharmaceuticals. The inventors of the present invention have found through research that benzofuran aza-diene is a unique compound containing a benzofuran skeleton, which has characteristics such as stability and easy preparation. In view of this, the present invention designs a reaction method for preparing spiro[benzofuran-tetrahydropyrrole] compounds by reacting benzofuran aza-diene with β-sulfonamido-substituted enoate.

[0006] A method for synthesizing spiro[benzofuran-tetrahydropyrrole] compounds proposed by the present invention, under the catalysis of an organophosphorus catalyst, uses benzofuran azadiene and β-sulfonamide-substituted enoate as reaction raw materials, and reacts in a reaction solvent, effectively realizing the corresponding transformation, and preparing spiro[benzofuran-tetrahydropyrrole] compounds shown in formula (III). Among them, the reaction process is shown in the following reaction formula (a):

[0007]

[0008] In the above reaction formula, where R 1 is an alkyl group or an aryl-containing alkane.; R 2 is a benzene ring, a substituted benzene ring; R 1 is substituted by hydrogen or a halogen atom; preferably, R 1 is ethyl, isopropyl, tert-butyl, benzyl; R 2 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methoxyphenyl, 2-naphthyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl; R 3 is ethyl, isopropyl, tert-butyl, benzyl; R 3 is hydrogen, 5-fluorophenyl;

[0009] As shown in the above reaction formula (a), the present invention uses benzofuran azadiene shown in formula (I) and β-sulfonamide-substituted enoate as reaction raw materials, and reacts in a reaction solvent under the action of an organophosphorus catalyst to obtain spiro[benzofuran-tetrahydropyrrole] compounds shown in formula (III).

[0010] In the present invention, the catalyst is PhEt2P, Ph2EtP, (2-MeOC6H4)3P, (2-MeC6H4)3P.

[0011] In the present invention, the solvent is any one or any combination of chloroform, dichloromethane, acetonitrile, N,N-dimethylformamide. Preferably, the solvent is dichloromethane.

[0012] In the present invention, the dosage ratio of the starting material benzofuran azadiene shown in formula (I) and the raw material β-sulfonamide-substituted enoate shown in formula (II) is 1:1 - 2:1. Preferably, the dosage ratio of the two is 1.5:1.

[0013] In the present invention, the reaction temperature is 20 - 80 °C, preferably 40 - 50 °C.

[0014] The synthesis reaction of the present invention includes the following steps:

[0015] The reaction described by reaction formula (a) includes the following steps: Add benzofuran azadiene, β-sulfonamido-substituted enoate, and dichloromethane into a reaction vessel, and stir and react at 50 °C to obtain spiro[benzofuran-tetrahydropyrrole] compounds shown by formula (III).

[0016] In a specific example, as in reaction formula (a), in reaction flask A, add benzofuran azadiene (X mmol), β-sulfonamido-substituted enoate (Y mmol), and solvent (V mL), and stir the reaction system at 50 °C for 48 hours. After the reaction is completed, cool the reaction system to room temperature, concentrate it, and separate the target product by column chromatography.

[0017] The present invention also provides spiro[benzofuran-tetrahydropyrrole] compounds shown by formula (III) prepared according to the above synthesis method of the present invention,

[0018]

[0019] wherein, R 1 is an alkyl group or an aryl-containing alkane; R 2 is a benzene ring or a substituted benzene ring; R 3 is substituted by a hydrogen atom or a halogen atom.

[0020] The present invention also provides an application method of the above spiro[benzofuran-tetrahydropyrrole] compounds shown by formula (III) in synthesizing potential drugs containing a benzofuran spiro five-membered heterocyclic skeleton.

[0021] The present invention has the following advantages: (1) No transition metal is required as a catalyst, (2) No strong acid or strong base is required, (3) No oxidizing agent or reducing agent is required, (4) The organophosphine catalyst is cheap and readily available and stable in air, (5) The reaction substrates are easy to prepare, (6) The reaction is easy to operate, environmentally friendly, and has practical value.

[0022] The present invention uses easily prepared benzofuran azadiene compounds and β-sulfonamido-substituted enoate compounds as reaction raw materials, and reacts under the action of an organophosphine catalyst to obtain spiro[benzofuran-tetrahydropyrrole] compounds. The reaction operation is simple, the reaction conditions are relatively mild, and it is suitable for large-scale industrial production. Description of the Drawings

[0023] Figure 1 It is the hydrogen spectrum of compound 4.

[0024] Figure 2 It is the carbon spectrum of compound 4.

[0025] Figure 3 It is the hydrogen spectrum of compound 12.

[0026] Figure 4Carbon spectrum of Compound 12.

[0027] Figure 5 Hydrogen spectrum of Compound 16.

[0028] Figure 6 Carbon spectrum of Compound 16. Detailed implementation mode

[0029] Combined with the following specific examples, the present invention will be further described in detail. The protection scope of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be conceived by those skilled in the art are included in the present invention, and the appended claims are used as the protection scope. The processes, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the specifically mentioned content below, are all common knowledge and well-known common sense in the art, and the present invention has no special limiting content. The data given in the following examples include specific operations, reaction conditions and products. The product purity was identified by NMR.

[0030] The synthesis reaction of the spiro[benzofuran-tetrahydropyrrole] compounds of the present invention includes the following steps: using benzofuran azadiene and β-sulfonamido-substituted enoate as reaction raw materials, under the catalysis of an organophosphorus catalyst, reacting in a reaction solvent to obtain spiro[benzofuran-tetrahydropyrrole] compounds; screening the catalyst and solvent conditions, specifically as follows:

[0031]

[0032]

[0033] Given the screening of the above conditions, the following examples use the catalyst (2-MeOC6H4)3P, the solvent is DCM, react at 50 °C for 48 h, and then concentrate and separate by column chromatography to obtain the target product. The spiro[benzofuran-tetrahydropyrrole] compounds shown in Table 1 are all products synthesized by the method of the present invention, and there are no published literatures revealing these compounds.

[0034] Table 1 New spiro[benzofuran-tetrahydropyrrole] compounds of the present invention

[0035]

[0036]

[0037] Example 1

[0038]

[0039] After adding benzofuran aza - diene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β - sulfonamido - substituted enoate (26.9 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2 - MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 1 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 70%, 10:1 d.r.; 1 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.50–7.39 (m, 3H), 7.19–7.07 (m, 5H), 7.01 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H), 4.98 (s, 1H), 4.26 - 4.22 (m, 1H), 3.62 (t, J = 11.6 Hz, 1H), 3.52 (s, 3H), 2.56 (s, 3H), 2.34 (s, 4H), 2.22 - 2.16 (m, 1H), 2.12 - 2.04 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ 176.9, 170.7, 169.6, 143.8, 143.7, 139.4, 138.3, 133.9, 133.7, 130.4, 129.6, 129.6, 128.0, 127.7, 127.6, 127.1, 127.0, 122.6, 118.1, 112.0, 98.3, 74.9, 53.4, 51.9, 44.0, 30.1, 21.7, 21.5. HRMS (ESI) m / z: calcd. for C 34 H 32 N2O7S2Na + (M + Na) + 667.1543, found 667.1536.

[0040] Example 2

[0041]

[0042] After adding benzofuran aza - diene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β - sulfonamido - substituted enoate (28.3 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2 - MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 2 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 78%, 20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.48–7.41 (m, 3H), 7.18–7.06 (m, 5H), 6.98 - 7.02 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H), 4.97 (s, 1H), 4.28 - 4.23 (m, 1H), 3.99 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 11.6 Hz, 1H), 2.56 (s, 3H), 2.34 (s, 4H), 2.21 - 2.15 (m, 1H), 2.09 - 2.04 (m, 1H), 1.10 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 177.0, 170.3, 169.6, 143.8, 143.7, 139.4, 138.3, 133.9, 133.6, 130.5, 129.6, 128.0, 127.73, 127.65, 127.2, 127.0, 122.6, 118.1, 112.0, 98.4, 74.8, 60.9, 53.4, 44.1, 30.3, 21.7, 21.6, 13.9. HRMS (ESI) m / z: calcd. for C 35 H 34 N2O7S2Na + (M + Na) + 681.1700, found 681.1719.

[0043] Example 3

[0044]

[0045] After adding benzofuran azadiene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (29.7 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 3 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 79%, 14:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.46 - 7.40 (m, 3H), 7.18–7.07 (m, 5H), 7.02 - 6.97 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H), 4.97 (s, 1H), 4.90 - 4.84 (m, 1H), 4.29 - 4.24 (m, 1H), 3.64 (t, J = 12.0 Hz, 1H), 2.56 (s, 3H), 2.34 (s, 4H), 2.19 - 2.13 (m, 1H), 2.04 - 1.99 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 176.9, 169.8, 169.6, 143.8, 143.6, 139.5, 138.3, 134.0, 133.5, 130.5, 129.6, 129.5, 128.0, 127.7, 127.6, 127.1, 127.0, 122.6, 118.0, 112.0, 98.5, 74.7, 68.4, 53.4, 44.0, 30.5, 21.7, 21.6, 21.5. HRMS (ESI) m / z: calcd. for C 31 H 29 NO6SNa + (M + Na) + 695.1856, found 695.1839.

[0046] Example 4

[0047]

[0048] After adding benzofuran aza - diene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β - sulfonamido - substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2 - MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 4 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 81%; 7:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.96–7.92 (m, 2H), 7.65–7.61 (m, 2H), 7.49–7.39 (m, 3H), 7.19–7.07 (m, 5H), 7.06–6.96 (m, 3H), 6.71 (d, J = 8.8 Hz, 1H), 4.96 (s, 1H), 4.22 - 4.27 (m, 1H), 3.63 (t, J = 11.6 Hz, 1H), 2.56 (s, 3H), 2.35 (s, 4H), 2.16–2.04 (m, 1H), 1.99 - 1.94 (m, 1H), 1.33 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 177.1, 169.6, 169.5, 143.7, 143.6, 139.4, 138.4, 134.0, 133.7, 130.5, 129.59, 129.57, 128.0, 127.7, 127.7, 127.14, 127.07, 122.6, 118.1, 112.0, 98.6, 81.2, 74.7, 53.4, 44.2, 31.6, 27.9, 21.7, 21.5. HRMS (ESI) m / z: calcd. for C 37 H 38 N2O7S2Na + (M + Na) + 709.2013, found 709.2022.

[0049] Example 5

[0050]

[0051] After adding benzofuran azadiene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 5 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 70%, 9:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.46 - 7.40 (m, 3H), 7.18–7.07 (m, 5H), 7.02 - 6.97 (m, 3H), 6.70 (d, J = 8.0 Hz, 1H), 4.96 (s, 1H), 4.28 - 4.24 (m, 1H), 3.99 - 3.88 (m, 2H), 3.63 (t, J = 11.6 Hz, 1H), 2.56 (s, 3H), 2.34 (s, 4H), 2.22 - 2.15 (m, 1H), 2.09 - 2.04 (m, 1H), 1.47 - 1.39 (m, 2H), 1.29 - 1.19 (m, 2H), 0.88 - 0.84 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 176.9, 170.4, 169.6, 143.7, 143.6, 139.4, 138.3, 133.9, 133.6, 130.4, 129.5, 128.0, 127.7, 127.6, 127.1, 127.0, 122.6, 118.1, 112.0, 98.4, 74.8, 64.8, 53.4, 44.0, 30.3, 30.2, 21.7, 21.5, 18.9, 13.6. HRMS (ESI) m / z: calcd. for C 37 H 38 N2O7S2Na + (M + Na) + 709.2013, found 709.2011.

[0052] Example 6

[0053]

[0054] After adding benzofuran azadiene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (34.5 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 6 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 83%, 10:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.50–7.40 (m, 3H), 7.36 - 7.32 (m, 3H), 7.08 - 7.22 (m, 7H), 6.99 - 6.95 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H), 5.09–4.93 (m, 3H), 4.29 - 4.24 (m, 1H), 3.66 (t, J = 11.6 Hz, 1H), 2.59 (s, 3H), 2.36 (s, 4H), 2.28 - 2.22 (m, 1H), 2.15 - 2.10 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 176.9, 170.1, 169.5, 143.8, 143.6, 139.4, 138.3, 135.2, 133.9, 133.5, 130.4, 129.6, 128.6, 128.4, 128.3, 128.0, 127.7, 127.6, 127.1, 127.0, 122.7, 118.1, 112.0, 98.4, 74.7, 66.8, 53.4, 44.0, 30.3, 21.7, 21.5. HRMS (ESI) m / z: calcd. for C 40 H 36 N2O7S2Na + (M + Na) + 743.1856, found 743.1865.

[0055] Example 7

[0056]

[0057] After adding benzofuran azadiene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (33.9 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 h. Then the solvent of the reaction solution was removed under reduced pressure, and the product 7 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 63%, 7:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.45 - 7.40 (m, 3H), 7.14 - 7.08 (m, 5H), 7.03 - 6.97 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H), 4.97 (s, 1H), 4.29 - 4.24 (m, 1H), 3.97 - 3.89 (m, 2H), 3.63 (t, J = 11.6 Hz, 1H), 2.55 (s, 3H), 2.34 (s, 4H), 2.22 - 2.16 (m, 1H), 2.10 - 2.05 (m, 1H), 1.46 - 1.42 (m, 2H), 1.27 - 1.21 (m, 6H), 0.87 (t, J = 6.8 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 176.9, 170.4, 169.6, 143.7, 143.6, 139.4, 138.4, 133.9, 133.7, 130.5, 129.6, 128.0, 127.7, 127.6, 127.1, 127.1, 122.6, 118.1, 112.0, 98.4, 74.8, 65.1, 53.4, 44.0, 31.3, 30.3, 28.3, 25.4, 22.4, 21.7, 21.5, 13.9. HRMS (ESI) m / z: calcd. for C 39 H 42 N2O7S2Na + (M + Na) + 737.2326, found 737.2329.

[0058] Example 8

[0059]

[0060] After adding benzofuran azadiene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (33.7 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 8 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 60%, 10:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.45 - 7.40 (m, 3H), 7.15 - 7.08 (m, 5H), 7.03 - 6.97 (m, 3H), 6.70 (d, J = 8.4 Hz, 1H), 4.97 (s, 1H), 4.66 - 4.61 (m, 1H), 4.30 - 4.25 (m, 1H), 3.64 (t, J = 12.0 Hz, 1H), 2.55 (s, 3H), 2.34 (s, 4H), 2.21 - 2.14 (m, 1H), 2.05 - 2.00 (m, 1H), 1.76 - 1.66 (m, 3H), 1.53 - 1.50 (m, 1H), 1.33 - 1.20f (m, 6H). 13 C NMR (100 MHz, CDCl3) δ 176.9, 169.7, 169.6, 143.7, 143.6, 139.4, 138.3, 134.0, 133.7, 130.5, 129.6, 129.5, 128.0, 127.7, 127.6, 127.1, 127.0, 122.6, 118.1, 112.0, 98.6, 74.7, 73.4, 53.4, 44.1, 31.5, 31.4, 30.6, 25.2, 23.6, 23.6, 21.7, 21.5. HRMS (ESI) m / z: calcd. for C 39 H 40 N2O7S2Na + (M + Na) + 735.2169, found 735.2174.

[0061] Example 9

[0062]

[0063] After adding 2-fluorobenzofuran azadiene (59.0 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 10 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 64%, >20:1 d.r.; 1 H NMR(400MHz,CDCl3)δ8.49(d,J=8.0Hz,1H),7.94(d,J=8.4Hz,2H),7.65(d,J=7.6Hz,3H),7.47–7.43(m,3H),7.15–6.99(m,3H),6.94(d,J=8.0Hz,2H),6.81–6.73(m,2H),5.33(s,1H),4.25-4.20(m,1H),3.63(t,J=12.0Hz,1H),2.56(s,3H),2.31(s,3H),2.24–2.13(m,1H),2.13–2.03(m,1H),1.96-1.91(m,1H),1.34(s,9H). 13 C NMR(100MHz,CDCl3)δ176.3,169.4,169.1,143.6(d,J=19Hz),139.2,138.5,133.2(d,J=278Hz),130.8,129.5(d,J=24Hz),127.7,127.2,123.6(d,J=3Hz),122.8,122.0(d,J=13Hz),117.8,114.7(d,J=21Hz),111.4,98.1,81.2,67.2,53.3,44.9,31.3,27.9,21.7,21.5. 19 F NMR(377MHz,CDCl3)δ-117.1.HRMS(ESI)m / z:calcd.for C 37 H 38 N2O7S2 + (M+H) + 705.2099,found 705.2102.

[0064] Example 10

[0065]

[0066] After adding 4-fluorobenzofuran azadiene (59.0 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 11 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 58%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.49–7.42 (m, 3H), 7.17–7.09 (m, 2H), 7.08–6.99 (m, 3H), 6.82–6.72 (m, 3H), 4.91 (s, 1H), 4.22 - 4.27 (m, 1H), 3.62 (t, J = 11.6 Hz, 1H), 2.55 (s, 3H), 2.35 (s, 4H), 2.18 - 2.14 (m, 1H), 2.00 - 1.95 (m, 1H), 1.33 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 176.7, 169.5, 169.4, 162.3 (d, J = 246 Hz), 143.8 (d, J = 5 Hz), 139.6, 138.3, 133.6, 130.6, 129.8 (d, J = 3 Hz), 129.6 (d, J = 6 Hz), 128.9 (d, J = 8 Hz), 127.6, 127.1, 122.7, 118.0, 114.7 (d, J = 21 Hz), 112.0, 98.5, 81.3, 74.1, 53.4, 44.0, 31.6, 27.9, 21.7, 21.5. 19 F NMR (377 MHz, CDCl3) δ -113.9. HRMS (ESI) m / z: calcd. for C 37 H 38 F N2O7S2 + (M + H) + 705.2099, found 705.2087.

[0067] Example 11

[0068]

[0069] After adding 2-chlorobenzofuran azadiene (61.5 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 12 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 80%, 7:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.70 - 7.64 (m, 3H), 7.43 - 7.41 (m, 3H), 7.21 - 7.17 (m, 1H), 7.08–6.96 (m, 5H), 6.70 (d, J = 8.4 Hz, 1H), 5.56 (s, 1H), 4.26 - 4.21 (m, 1H), 3.65 (t, J = 12.0 Hz, 1H), 2.55 (s, 3H), 2.32 (s, 4H), 2.14 - 2.07 (m, 1H), 1.98 - 1.93 (m, 1H), 1.34 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 176.5, 169.4, 168.9, 143.7, 143.6, 139.2, 138.4, 133.5, 133.1, 132.4, 131.2, 130.8, 129.6, 129.5, 129.1, 128.8, 127.7, 127.2, 126.0, 122.8, 118.0, 111.9, 98.1, 81.2, 69.8, 53.2, 45.3, 31.3, 27.9, 21.7, 21.5. HRMS (ESI) m / z: calcd. For C 37 H 37 ClN2O7S2Na + (M + Na) + 743.1623, found 743.1623.

[0070] Example 12

[0071]

[0072] After adding 4-chlorobenzofuran azadiene (56.3 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 13 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 79%, 10:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.51–7.42 (m, 3H), 7.12–7.00 (m, 7H), 6.75 (d, J = 8.4 Hz, 1H), 4.91 (s, 1H), 4.27 - 4.22 (m, 1H), 3.61 (t, J = 11.8 Hz, 1H), 2.56 (s, 3H), 2.35 (s, 4H), 2.13 - 2.07 (m, 1H), 1.99 - 1.94 (m, 1H), 1.33 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 176.6, 169.5, 169.4, 143.8, 143.8, 139.7, 138.3, 133.8, 133.6, 132.7, 130.6, 129.65, 129.59, 128.5, 128.0, 127.6, 127.1, 122.9, 118.0, 112.1, 98.4, 81.3, 74.0, 53.4, 44.2, 31.5, 27.9, 21.7, 21.5. HRMS (ESI) m / z: calcd. for C 37 H 37 ClN2O7S2Na + (M + Na) + 743.1623, found 743.1634.

[0073] Example 13

[0074]

[0075] After adding 2-bromobenzofuran azadiene (68.2 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 14 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 63%, 10:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.64–7.59 (m, 1H), 7.44 - 7.40 (m, 3H), 7.24 - 7.21 (m, 2H), 7.04 - 6.95 (m, 4H), 6.69 (d, J = 8.4 Hz, 1H), 5.57 (s, 1H), 4.25 - 4.20 (m, 1H), 3.65 (t, J = 12.0 Hz, 1H), 2.54 (s, 3H), 2.33 (s, 4H), 2.15 - 2.08 (m, 1H), 1.99 - 1.94 (m, 1H), 1.34 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 176.6, 169.5, 168.8, 143.6, 143.5, 139.2, 138.4, 134.9, 133.7, 132.1, 131.6, 130.8, 129.6, 129.4, 129.3, 127.8, 127.2, 127.1, 126.5, 122.8, 122.6, 118.2, 111.9, 98.1, 81.2, 71.8, 53.1, 45.4, 31.3, 27.9, 21.7, 21.5. HRMS (ESI) m / z: calcd. for C 37 H 37 BrN2O7S2Na + (M + Na) + 787.1118, found 787.1128.

[0076] Example 14

[0077]

[0078] After adding 4-nitrobenzofuran azadiene (63.1 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 15 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 78%, 7:1 d.r.; 1 H NMR(400MHz,CDCl3)δ8.48(d,J=8.0Hz,1H),7.98(d,J=9.2Hz,2H),7.93(d,J=8.4Hz,2H),7.63(d,J=8.4Hz,2H),7.49–7.43(m,3H),7.41–7.32(m,2H),7.09–7.01(m,3H),6.72(d,J=8.4Hz,1H),5.02(s,1H),4.27-4.22(m,1H),3.65(t,J=12.0Hz,1H),2.56(s,3H),2.35(s,4H),2.14-2.07(m,1H),1.99-1.94(m,1H),1.32(s,9H). 13 C NMR(100MHz,CDCl3)δ176.0,169.19,169.17,147.5,144.2,144.0,141.8,139.9,138.1,133.1,130.7,129.8,129.6,128.0,127.6,127.2,123.2,123.0,117.8,112.0,98.3,81.4,73.8,53.5,44.4,31.3,27.9,21.7,21.5.HRMS(ESI)m / z:calcd.for C 37 H 38 BrN3O9S2 + (M+H) + 732.2044,found 732.2060.

[0079] Example 15

[0080]

[0081] After adding 4-(trifluoromethyl)benzofuranodiazaallene (66.5 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the solvent was removed under reduced pressure from the reaction solution, and the product 16 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 90%, 10:1 d.r.; 1 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.48–7.43 (m, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 7.06–7.00 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H), 5.00 (s, 1H), 4.29 - 4.24 (m, 1H), 3.64 (t, J = 12.0 Hz, 1H), 2.56 (s, 3H), 2.34 (s, 4H), 2.14 - 2.07 (m, 1H), 1.99 - 1.94 (m, 1H), 1.33 (s, 9H). 13 13C NMR (100 MHz, CDCl3) δ 176.4, 169.3, 169.3, 143.9 (d, J = 4 Hz), 139.7, 138.2 (d, J = 8 Hz), 133.4, 130.6, 130.1 (d, J = 32 Hz), 129.6 (d, J = 8 Hz), 127.9, 127.6, 127.5, 127.1, 124.7 (d, J = 4 Hz), 123.8 (d, J = 270 Hz), 122.9, 117.9, 112.0, 98.4, 81.4, 74.1, 53.4, 44.3, 31.3, 27.9, 21.7, 21.5. 19 19F NMR (100 MHz, CDCl3) δ -62.7. HRMS (ESI) m / z: calcd. for C 38 H 37 F3N2O7S2Na + (M + Na) + 777.1886, found 777.1891.

[0082] Example 16

[0083]

[0084] After adding benzofuran azadiene (59.0 mg, 0.15 mmol, 1.5 equiv.) and the reaction solvent dichloromethane (0.1 mL) into the reaction tube, β-sulfonamido-substituted enoate (31.1 mg, 0.10 mmol, 1.0 equiv.) was added, and then the organophosphorus catalyst (2-MeOC6H4)3P (7.0 mg, 20 mol%) was added. The mixture was stirred at 50 °C for 48 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 17 was obtained by column chromatography (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 80%, 8:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 6.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.19–7.08 (m, 6H), 7.04 (d, J = 8.4 Hz, 2H), 6.67 (dd, J = 9.2, 4.0 Hz, 1H), 4.92 (s, 1H), 4.27-4.22 (m, 1H), 3.61 (t, J = 12.0 Hz, 1H), 2.56 (s, 3H), 2.35 (s, 4H), 2.14-2.07 (m, 1H), 2.00-1.95 (m, 1H), 1.34 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 176.63, 176.60, 169.35, 165.89, 157.2 (d, J = 242 Hz), 144.01, 143.68, 137.91, 133.7 (d, J = 18 Hz), 129.6 (d, J = 1 Hz), 128.14, 127.7 (d, J = 13 Hz), 127.51, 127.25, 127.19, 127.05, 118.3 (d, J = 10 Hz), 115.5 (d, J = 25 Hz), 113.0 (d, J = 8 Hz), 99.6, 81.3, 74.9, 53.4, 44.2, 31.6, 27.9, 21.7, 21.5. 19 F NMR (377 MHz, CDCl3) δ -118.5. HRMS (ESI) m / z: calcd. for C 37 H 37 FN2O7S2Na + (M+Na) + 727.1918, found 727.1910.

[0085] Example 17

[0086] In vitro Antitumor Activity Experiment of Spiro[benzofuran-tetrahydropyrrole] Compounds

[0087] In this invention, the MTT method was used to evaluate the inhibitory effect of spiro[benzofuran-tetrahydropyrrole] compounds on the proliferation of human gastric cancer cells (HGC-27) and human liver cancer cells (HepG2). RPMI1640 containing 100 U / mL penicillin-streptomycin and 10% fetal bovine serum was used as the cell culture medium, and the cells were cultured in a cell incubator at 37 °C and 5% CO2. When subculturing the cells, the cell density was adjusted to 5×10 4 ~1×10 5 cells / well and inoculated into a 96-well plate, and then cultured in an incubator at 37 °C and 5% CO2. After 24 hours, different concentrations of the drug were added, and a blank control group (culture medium), a normal control group (cells + culture medium), and a positive control group were set up, and the treatment was carried out for 48 hours. After the experiment was terminated, 20 μL of MTT (5 mg / ml) was added to each well and incubated at 37 °C for 4 hours. Then the supernatant was aspirated, 150 μL of DMSO was added to each well, and it was shaken well. The absorbance (OD) at a wavelength of 492 nm was measured. After MTT is taken up by living cells and metabolized by mitochondria to generate formazan, the more vigorous the mitochondrial activity, the more formazan is generated, and the higher the absorbance, which reflects the cell survival situation. The cell inhibition rate was calculated to determine whether the drug had an inhibitory effect on cell proliferation. The half-maximal inhibitory concentration (IC 50 ), which is often used as a quantitative index to reflect the drug effect and is widely used in various drug screenings. Therefore, the statistical software SPSS13.0 was used to calculate and compare the IC 50 of the drug acting on different cells to reflect the drug effect. Cell inhibition rate (%) = (average OD value of the experimental group - average OD value of the blank group) / (average OD value of the blank group) * 100%.

[0088]

[0089] The results of the MTT experiment showed that Compounds 4, 12, and 16 all showed moderate anti-gastric cancer (IC 50 values were 8.9 - 26.1 μM) and anti-liver cancer (IC 50Activity at a value of 16.5 - 42.8 μM), among which Compound 4 has the best anti - proliferative effect, and the compound concentrations are 8.9 μg / mL and 16.5 μg / mL when the cell survival rates of human gastric cancer cells HGC - 27 and human liver cancer cells HepG2 are 50%. Compounds 12 and 16 also have certain anti - proliferative effects. In the above - mentioned embodiments of this application, Compounds 1, 2, 3, 5, 6, 7, 8 have structural similarities with Compound 4; Compounds 9, 11, 13, 14, 15 have structural similarities with Compound 12; Therefore, for those skilled in the art, it can also be predicted that compounds with structures similar to 4, 12, 16 have certain anti - proliferative effects on human gastric cancer cells HGC - 27 and human liver cancer cells HepG2.

Claims

1. A method for synthesizing a spiro[benzofuran-tetrahydropyrrole] compound, characterized in that, Using benzofuran azadiene and β-sulfonamido-substituted enoate as reaction raw materials, under the catalysis of an organophosphorus catalyst, reacting in a reaction solvent to obtain a spiro[benzofuran-tetrahydropyrrole] compound shown in formula (Ⅲ); the reaction process is shown in reaction formula (a); R 1 is isopropyl, R 2 is phenyl, R 3 is hydrogen; or R 1 is isopropyl, R 2 is 4-chlorophenyl, R 3 is hydrogen; or R 1 is methyl, R 2 is phenyl, R 3 is hydrogen, and the catalyst is selected from PhEt2P, Ph2EtP or (2-MeOC6H4)3P; The reaction solvent is selected from any one or a combination of chloroform, dichloromethane, acetonitrile, or N,N-dimethylformamide.

2. The synthesis method according to claim 1, characterized in that, In the reaction, the dosage ratio of the raw material benzofuran azadiene to β-sulfonamido-substituted enoate is 1:1 - 2:

1.

3. The synthesis method according to claim 1, characterized in that, The reaction temperature is 20 - 80 °C.

4. A spiro[benzofuran-tetrahydropyrrole] compound prepared by the synthesis method according to any one of claims 1-3, characterized in that, Its structure is shown in formula (Ⅲ): Formula (III); R 1 is isopropyl, R 2 is phenyl, R 3 is hydrogen; or R 1 is isopropyl, R 2 is 4-chlorophenyl, R 3 is hydrogen; or R 1 is methyl, R 2 is phenyl, R 3 is hydrogen.

5. Use of the spiro[benzofuran-tetrahydropyrrole] compound according to claim 4 in the preparation of a drug for treating gastric cancer and liver cancer, wherein the human gastric cancer cells are selected from HGC-27 and the human liver cancer cells are selected from HepG2.

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