A tetra-substituted furanone compound, a preparation method and application thereof

Abstract

The application discloses a tetra-substituted furanone compound and a preparation method and application thereof. The structural formula of the tetra-substituted furanone compound is shown in formula (III); wherein, R 1 is an aromatic group, a substituted aromatic group, an alkyl group or a substituted alkyl group; 2 R 3 is an aromatic group, a substituted aromatic group, an alkyl group, a substituted alkyl group or a heterocyclic group; R 4 is an aromatic group, a substituted aromatic group, an alkyl group, a substituted alkyl group or a heterocyclic group. The tetra-substituted furanone compound provided by the application is widely distributed in natural products and bioactive molecules, and can be used as a multi-purpose intermediate and precursor in organic synthesis. The tetra-substituted furanone compound is also a potential strong antiviral active molecule, and has a wide application prospect in the field of antiviral drug research and development.

Description

Technical Field

[0001] This invention relates to the field of chemical intermediate synthesis technology, and more specifically, to a tetrasubstituted furanone compound, its preparation method, and its application. Background Technology

[0002] Tetrasubstituted furanones are widely distributed in natural products and bioactive molecules. They possess a variety of biological activities, such as inhibiting coronaviruses, HCV proteases, and acting as T-cell proliferation inhibitors. In recent years, the demand for structurally diverse furan compounds has been increasing, particularly in the screening of bioactive molecules and the discovery of new drug lead compounds, requiring a continuously enriched library of compounds with diverse structures and functional groups. Therefore, developing a mild and widely applicable method for preparing tetrasubstituted furanones has significant research and application value. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings and deficiencies of existing technologies in the preparation of tetrasubstituted furanone compounds, which suffer from unfriendly and demanding reaction conditions. This invention provides a novel method for rapidly constructing structurally diverse tetrasubstituted furanone compounds. The tetrasubstituted furanone compounds provided by this invention are widely distributed in natural products and bioactive molecules, exhibiting excellent biological activity (such as inhibition of coronaviruses, HCV protease, and T-cell proliferation inhibitors). They can also serve as versatile intermediates and precursors in organic synthesis. These tetrasubstituted furanone compounds are also potential potent antiviral drugs, showing broad application prospects in the field of antiviral drug preparation.

[0004] Another object of the present invention is to provide a method for preparing the above-mentioned tetrasubstituted furanone compounds.

[0005] Another object of the present invention is to provide the application of the above-mentioned tetrasubstituted furanone compounds in inhibiting the activity of influenza viruses.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] A tetrasubstituted furanone compound, the structural formula of which is shown in formula (III):

[0008] ;

[0009] Among them, R 1 It is an aromatic group, a substituted aromatic group, an alkyl group, or a substituted alkyl group; R 2 It is an aromatic group, a substituted aromatic group, an alkyl group, a substituted alkyl group, or a heterocyclic group; R 3 It is an aromatic group, a substituted aromatic group, an alkyl group, a substituted alkyl group, or a heterocyclic group; R 4It can be an aromatic group, a substituted aromatic group, an alkyl group, a substituted alkyl group, or a heterocyclic group.

[0010] The tetrasubstituted furanone compounds provided by this invention are widely distributed in natural products and bioactive molecules, exhibiting excellent biological activity (such as inhibition of coronaviruses, HCV protease, and T-cell proliferation inhibitors), and can also serve as versatile intermediates and precursors in organic synthesis. These tetrasubstituted furanone compounds are also potential potent antiviral drugs, showing broad application prospects in the field of antiviral drug development.

[0011] Preferably, the R 1 For phenyl, substituted phenyl, C 1~8 Alkyl, C 3~6 Cyclic alkyl group, wherein the substituent on the phenyl group is halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl or nitro.

[0012] Preferably, the R 2 For phenyl, substituted phenyl, C 1~4 straight-chain alkyl, C 3~6 The phenyl group contains cycloalkyl, S-containing heterocyclic, N-containing heterocyclic, or O-containing heterocyclic groups, wherein the heterocyclic group is a 3- to 8-membered heterocyclic group, and the substituent on the phenyl group is a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, a trifluoromethyl, or a nitro group.

[0013] R 3 For phenyl, substituted phenyl, C 1~4 straight-chain alkyl, C 3~6 The phenyl group contains cycloalkyl, S-containing heterocyclic, N-containing heterocyclic, or O-containing heterocyclic groups, wherein the heterocyclic group is a 3- to 8-membered heterocyclic group, and the substituent on the phenyl group is a halogen, a C1- to C6 alkyl, a C1- to C6 alkoxy, a trifluoromethyl, or a nitro group.

[0014] R 4 For phenyl, substituted phenyl, C 1~4 straight-chain alkyl, C 3~6 The phenyl group is a cycloalkyl group, an S-containing heterocyclic group, an N-containing heterocyclic group, or an O-containing heterocyclic group, wherein the heterocyclic group is a 3- to 8-membered heterocyclic group, and the substituent on the phenyl group is a halogen, a C1- to C6 alkyl group, a C1- to C6 alkoxy group, a trifluoromethyl group, or a nitro group.

[0015] This invention also protects the preparation method of the above-mentioned tetrasubstituted furanone compounds, which involves dissolving the compounds shown in formula (I) and formula (II) in an organic solvent, then adding a metal catalyst, an anionic salt, and a phosphine ligand, and reacting the mixture to obtain the compounds. The reaction formula is as follows:

[0016] .

[0017] The present invention provides a method for preparing tetrasubstituted furanone compounds. This method has the advantages of easy separation, readily available raw materials, high efficiency, mild reaction conditions, atom economy, and a wide substrate adaptability.

[0018] Preferably, the phosphine ligand is one or more of dcpf, dppf, dipf, dppp, or dppb.

[0019] Preferably, the metal catalyst M is one or more of [Rh(CO)2Cl]2, Pd(OAc)2, Rh2(OAc)4, Rh2(esp)2, Rh2(OPiv)4, Rh2(TFA)4, or FeTPPCl.

[0020] Preferably, the anionic salt is one or more of NaBArF, AgSbF6, and Ag(OTf)2.

[0021] Preferably, the organic solvent is one or more of chlorobenzene, toluene, tert-butyl methyl ether, dichloromethane, or ethyl acetate.

[0022] Preferably, the reaction molar ratio of the compound shown in formula (I) and the compound shown in formula (II) with the metal catalyst and the phosphine ligand and the anion is (1.5-3.0):(1.0-2.0):(0.02-0.01) (0.05-0.1):(0.05-0.1).

[0023] Preferably, the reaction temperature is 70 ℃~100 ℃ and the time is 3~24 h.

[0024] Preferably, the concentration of the compound shown in formula (II) in the organic solvent is (40.0-60.0) mol / L. Further, the concentration of the compound shown in formula (II) in the organic solvent is 50.0 mol / L.

[0025] Preferably, the reaction is followed by a separation and purification step.

[0026] More preferably, the separation and purification process is as follows: the solution after reaction is first concentrated under reduced pressure to remove the solvent, and then subjected to column chromatography with a mixed solution of ethyl acetate and petroleum ether to obtain tetrasubstituted furanone compounds.

[0027] Preferably, the volume ratio of ethyl acetate to petroleum ether is 1:20~40.

[0028] This invention also protects the use of the above-mentioned tetrasubstituted furanone compounds in the preparation of antiviral drugs or chemical products.

[0029] Preferably, the antiviral drug uses the tetrasubstituted furanone compound as the active ingredient.

[0030] More preferably, the antiviral drug is used to inhibit coronaviruses, HCV protease, and T-cell proliferation inhibitors.

[0031] Compared with the prior art, the beneficial effects of the present invention are:

[0032] The tetrasubstituted furanone compounds provided by this invention are widely distributed in natural products and bioactive molecules. These compounds possess various biological activities, such as inhibiting coronaviruses, HCV proteases, and acting as T-cell proliferation inhibitors. They can also serve as versatile intermediates and precursors in organic synthesis. These tetrasubstituted furanone compounds are also potential potent antiviral molecules, showing broad application prospects in the field of antiviral drug development.

[0033] Furthermore, the method for preparing tetrasubstituted furanone compounds provided by this invention has the advantages of easy separation, readily available raw materials, high efficiency, mild reaction conditions, atom economy, and a wide substrate adaptability. The tetrasubstituted furanone compounds prepared by this method have high purity and bioactivity. Attached Figure Description

[0034] Figure 1 This is the H spectrum of product IV-a in Example 1 of the present invention;

[0035] Figure 2 This is the C spectrum of product IV-a in Example 1 of the present invention;

[0036] Figure 3 This is the H spectrum of product IV-b in Example 2 of the present invention;

[0037] Figure 4 This is the C spectrum of product IV-b in Example 2 of the present invention;

[0038] Figure 5 This is the F spectrum of product IV-b in Example 2 of the present invention;

[0039] Figure 6 This is the H spectrum of product IV-c in Example 3 of the present invention;

[0040] Figure 7 This is the C spectrum of product IV-c in Example 3 of the present invention;

[0041] Figure 8 This is the H spectrum of product IV-d in Example 4 of the present invention;

[0042] Figure 9 This is the C spectrum of product IV-d in Example 4 of the present invention;

[0043] Figure 10 This is the H spectrum of product IV-e in Example 5 of the present invention;

[0044] Figure 11 This is the C spectrum of product IV-e in Example 5 of the present invention;

[0045] Figure 12 This is the H spectrum of product IV-f in Example 6 of the present invention;

[0046] Figure 13 This is the C spectrum of product IV-f in Example 6 of the present invention;

[0047] Figure 14 This is the F spectrum of product IV-f in Example 6 of the present invention;

[0048] Figure 15 This is the H spectrum of product IV-g in Example 7 of the present invention;

[0049] Figure 16 This is the C spectrum of product IV-g in Example 7 of the present invention;

[0050] Figure 17 This is the H spectrum of product IV-h in Example 8 of the present invention;

[0051] Figure 18 This is the C spectrum of product IV-h in Example 8 of the present invention;

[0052] Figure 19 This is the H spectrum of product IV-i in Example 9 of the present invention;

[0053] Figure 20 This is the C spectrum of product IV-i in Example 9 of the present invention;

[0054] Figure 21 This is the H spectrum of product IV-j in Example 10 of the present invention;

[0055] Figure 22 This is the C spectrum of product IV-j in Example 10 of the present invention;

[0056] Figure 23 This is the H spectrum of product IV-k in Example 11 of the present invention;

[0057] Figure 24 This is the C spectrum of product IV-k in Example 11 of the present invention. Detailed Implementation

[0058] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0059] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0060] Example 1: Preparation of tetrasubstituted furanone compounds

[0061] The preparation of tetrasubstituted furanone compounds is carried out according to the following reaction formula:

[0062]

[0063] In the formula, R 1 It is ethyl; R 2 It can be phenyl, p-chlorophenyl, p-methyl, m-methyl, etc.; R 3 Phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl, p-trifluoromethylphenyl, thiophene, cyclopropyl, etc.

[0064] Example 1:

[0065] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 Benzene (0.1 mmol), dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube, and then 1 mL of anhydrous chlorobenzene was added to the reaction system. 3 The phenyl group was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 1–3 hours until the aldehyde was completely consumed. The reaction solution was then filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-a.

[0066] Example 2:

[0067] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 0.005 mmol of p-fluorophenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube, and then 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was then added. 3The phenyl group was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 5 hours until the aldehyde was completely consumed. The reaction solution was then filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-b.

[0068] Example 3:

[0069] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 0.005 mmol of p-chlorophenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube, and then 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was then added. 3 The phenyl group was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 5 hours until the aldehyde was completely consumed. The reaction solution was then filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-c.

[0070] Example 4:

[0071] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 0.005 mmol of p-bromophenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube. Then, 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added. 3 The phenyl group was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 2–4 hours until the aldehyde was completely consumed. The reaction solution was then concentrated, filtered, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-d.

[0072] Example 5:

[0073] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 The following substances were weighed into a test tube: p-nitrophenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol). Then, 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added. 3The phenyl group was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 2–4 hours until the aldehyde was completely consumed. The reaction solution was then filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-e.

[0074] Example 6:

[0075] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 The following substances were weighed into a test tube: p-trifluoromethylphenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol). Then, 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added. 3 The phenyl group was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 2–4 hours until the aldehyde was completely consumed. The reaction solution was then filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-f.

[0076] Example 7:

[0077] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 2-thienyl), dcpf (0.005 mmol), NaBArF (0.005 mmol) and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube, and then 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added. 3 The phenyl group was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 6 hours until the aldehyde was completely consumed. The reaction solution was filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-g.

[0078] Example 8:

[0079] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 The cyclopropyl group (0.005 mmol), dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube, and then 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added to the test tube. 3(The aldehyde is phenyl) is dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture is stirred at 100 °C for 2-4 hours until the aldehyde is completely consumed. The reaction solution is filtered and concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-h.

[0080] Example 9:

[0081] In the above reaction formula, the furanocyclobutanone (0.15 mmol, R) represented by formula (I) 1 It is ethyl; R 2 0.005 mmol of p-bromophenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube. Then, 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added. 3 (p-chlorophenyl) was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 7 hours until the aldehyde was completely consumed. The reaction solution was filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-i.

[0082] Example 10:

[0083] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 0.005 mmol of p-bromophenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube. Then, 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added. 3 (p-Toluyl) was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 8 hours until the aldehyde was completely consumed. The reaction solution was filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-j.

[0084] Example 11:

[0085] The furanocyclobutanone (0.15 mmol, R) shown in formula (I) above was reacted. 1 It is ethyl; R 2 0.005 mmol of p-bromophenyl, dcpf (0.005 mmol), NaBArF (0.005 mmol), and [Rh(CO)2Cl]2 (0.002 mmol) were weighed into a test tube. Then, 1 mL of anhydrous chlorobenzene was added to the reaction system. The aldehyde (0.1 mmol, R) shown in formula (II) was added. 3(m-Toluyl) was dissolved in 1 mL of anhydrous chlorobenzene and added. The mixture was stirred at 100 °C for 9 hours until the aldehyde was completely consumed. The reaction solution was filtered, concentrated, and purified by column chromatography to obtain the pure target product, namely the tetrasubstituted furanone compound IV-k.

[0086] The target products were identified as including 11 compounds. The specific spectral data of compounds IV-a to IV-k are as follows:

[0087] Spectral data of compound IV-a: 1 H NMR (400 MHz, CDCl3) (δ, ppm) δ 7.68 - 7.66(m, 2H), 7.56 - 7.54 (m, 2H), 7.47 - 7.43 (m, 1H), 7.36 - 7.29 (comp, 4H),7.25 - 7.21 (m, 1H), 7.16 - 7.14 (m, 2H), 7.09 - 7.05 (m, 2H), 7.03 - 6.98(m, 1H), 6.62 (d, J = 12.1 Hz, 1H), 6.59 (d, J = 12.1 Hz, 1H), 4.36 (q, J =7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) (δ, ppm)189.4, 160.3, 140.2, 138.7, 136.9, 133.6, 131.9, 130.5, 129.3, 128.7, 128.6,128.1, 127.6, 127.3, 127.2, 125.0, 120.5, 119.0, 102.3, 68.0, 14.9.

[0088] Spectral data of compound IV-b: 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.68 - 7.66 (m,2H), 7.56 - 7.52 (m, 2H), 7.37 - 7.33 (m, 2H), 7.24 - 7.22 (m, 1H), 7.13 -7.11 (m, 2H), 7.07 - 7.03 (m, 2H), 7.01 - 6.94 (comp, 3H), 6.62 (d, J = 12.0Hz, 1H), 6.58 (d, J = 12.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.29 (t, J =7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) (δ, ppm) 187.7, 165.2 (d, J = 252.2 Hz), 160.1, 140.5, 136.9, 134.8 (d, J = 2.9 Hz), 133.7, 132.0, 131.9, 130.4,.128.7 (d, J = 3.9 Hz), 128.1, 127.3, 125.1, 120.3, 118.9, 114.7 (d, J = 21.8Hz). 101.9, 68.0, 14.9; 19 F NMR (377 MHz, CDCl3) (δ, ppm) -107.43.

[0089] Spectral data of compound IV-c: 1 H NMR (400 MHz, CDCl3) (δ, ppm) 7.68 -7.65 (m,2H), 7.46 - 7.44 (m, 2H), 7.37 - 7.33 (m, 2H), 7.28 - 7.27 (m, 1H), 7.13 -7.00 (comp, 7H), 6.63 (d, J = 12.0 Hz, 1H), 6.57 (d, J = 12.0 Hz, 1H), 4.38(q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) (δ,ppm) 187.9, 160.3, 140.5, 138.1, 137.0, 136.9, 133.8, 130.8, 130.5, 130.4,128.71, 128.68, 128.22, 128.15, 127.9, 127.4, 125.1, 120.3, 118.9, 101.8,68.0, 14.9.

[0090] Spectral data of compound IV-d: 1 H NMR (400 MHz, CDCl3) (δ, ppm) 7.67 - 7.65 (m,2H), 7.44 - 7.42 (m, 2H), 7.39 - 7.33 (comp, 4H), 7.13 - 7.00 (comp, 6H),6.62 (d, J = 12.0 Hz, 1H), 6.57 (d, J = 12.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).; 13 C NMR (101 MHz, CDCl3) (δ, ppm) 188.0,160.3, 140.5, 137.4, 136.9, 133.8, 130.95, 130.85, 130.4, 128.7, 128.7,128.1, 127.4, 126.7, 125.1, 120.3, 118.4, 101.7, 68.0, 14.9.

[0091] Spectral data of compound IV-e: 1 H NMR (400 MHz, CDCl3) (δ, ppm) 8.13 - 8.15(m,2H), 7.68 - 7.66 (m, 2H), 7.59 - 7.57 (m, 2H), 7.39 - 7.35 (m, 2H), 7.28 -7.27 (m, 1H), 7.13 - 7.01 (comp, 5H), 6.64 (d, J = 12.0 Hz, 1H), 6.58 (d, J =12.0 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).; 13C NMR(101 MHz, CDCl3) (δ, ppm) 187.1, 161.1, 149.5, 144.1, 141.0, 136.9, 134.0,130.1, 130.0, 128.74, 128.71, 128.2, 127.6, 127.5, 125.2, 122.9, 120.0,118.5, 101.2, 68.0, 14.8.

[0092] Spectral data of compound IV-f: 1 H NMR (400 MHz, CDCl3) (δ, ppm) 7.68 - 7.65 (m,2H), 7.58 - 7.54 (comp, 4H), 7.37 - 7.33 (m, 2H), 7.27 - 7.25 (m, 1H), 7.14 -6.99 (comp, 5H), 6.63 (d, J = 12.0 Hz, 1H), 6.58 (d, J = 12.0 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) (δ,ppm) 188.0, 160.9, 141.9, 140.7, 136.9, 133.9, 133.1 (q, J = 32.0 Hz), 130.3,129.4, 128.7, 128.2, 128.1, 127.5, 127.4, 125.4, 124.6 (q, J = 3.6 Hz), 124.0 (q, J = 272.2 Hz), 120.2, 120.0, 118.7, 101.6, 68.0, 14.79; 19 F NMR (377 MHz, CDCl3) (δ, ppm) -62.82.

[0093] Spectral data of compound IV-g: 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.73 - 7.72 (m,1H), 7.67 - 7.65 (m, 2H), 7.36 - 7.32 (m, 2H), 7.29 - 7.27 (m, 1H), 7.25 -7.21 (m, 1H), 7.15 - 7.12 (comp, 3H), 7.07 - 7.02 (m, 2H), 6.99 - 6.95 (m,1H), 6.65 (d, J = 12.0 Hz, 1H), 6.60 (d, J = 12.0 Hz, 1H), 4.39 (q, J = 7.1Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) (δ, ppm) 182.4,159.5, 142.3, 140.3, 136.9, 133.6, 132.8, 130.5, 128.7, 128.6, 128.0, 127.2,125.1, 124.5, 120.4, 118.9, 103.2, 68.2, 15.0.

[0094] Spectral data of compound IV-h: 1 H NMR (400 MHz, CDCl3) (δ, ppm) 7.56 - 7.54 (m,2H), 7.24 - 7.20 (m, 2H), 7.18 - 7.12 (comp, 3H), 7.10 - 7.02 (comp, 3H),6.68 (s, 2H), 4.60 (q, J = 7.1 Hz, 2H), 2.67 - 2.61 (m, 1H), 1.54 (t, J = 7.1Hz, 3H), 1.00 - 0.96 (m, 2H), 0.80 - 0.76 (m, 2H); 13 C NMR (101 MHz, CDCl3)(δ, ppm) 194.7, 161.7, 139.1, 137.3, 133.1, 130.4, 128.5, 128.4, 128.0,127.10, 127.06, 125.0, 121.4, 118.3, 103.7, 67.8, 19.0, 15.2, 10.6.

[0095] Spectral data of compound IV-i: 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.58 - 7.55 (m,2H), 7.46 - 7.39 (comp, 4H), 7.30 - 7.28 (m, 2H), 7.12 - 7.00 (comp, 5H),6.64 (d, J = 12.0 Hz, 1H), 6.54 (d, J = 12.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) (δ, ppm) 187.9, 160.4,139.4, 137.3, 136.7, 134.1, 133.0, 130.9, 128.9, 128.8, 128.6, 128.2, 127.1,126.9, 126.2, 120.0, 119.4, 101.9, 68.1, 14.9.

[0096] Spectral data of compound IV-j: 1 H NMR (400 MHz, CDCl3) (δ, ppm) 7.57 - 7.55 (m,2H), 7.43 - 7.41 (m, 2H), 7.38 - 7.35 (m, 2H), 7.17 - 7.11 (comp, 4H), 7.08 -6.98 (comp, 3H), 6.61 (d, J = 12.0 Hz, 1H), 6.55 (d, J = 12.0 Hz, 1H), 4.37(q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, CDCl3) (δ, ppm) 188.0, 160.2, 140.9, 137.4, 137.4, 137.0, 133.6, 131.0,130.8, 129.4, 128.7, 128.2, 127.6, 127.3, 126.7, 125.1, 120.4, 118.0, 101.7,68.0, 21.41, 14.92.

[0097] Spectral data of compound IV-k: 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.48 - 7.42(comp, 4H), 7.40 - 7.36 (m, 2H), 7.24 - 7.22 (m, 1H), 7.13 - 7.11 (m, 2H),7.08 - 6.98 (comp, 4H), 6.62 (d, J = 12.0 Hz, 1H), 6.56 (d, J = 12.0 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).; 13 C NMR(101 MHz, CDCl3) (δ, ppm) 188.0, 160.3, 140.7, 138.3, 137.4, 137.0, 133.6,131.0, 130.8, 130.3, 128.7, 128.6, 128.2, 128.1, 127.3, 126.7, 125.7, 122.4,120.4, 118.6, 101.7, 68.0, 21.7, 14.9.

[0098] Test Example 4: Inhibitory activity of substituted furanone derivatives against influenza virus:

[0099] 1. The influenza virus used for the assay was the recombinant GFP-H1N1 strain, and the host cell was the human non-small cell lung cancer cell line A549 (both the influenza virus and cell line used in this study were provided by Guangzhou Medical University).

[0100] 2. The inhibitory effect of tetrasubstituted furanone derivatives on influenza virus H1N1 was determined using a dual-fluorescence method. The specific determination procedure is as follows:

[0101] (1) Cell plating: A549 human non-small cell lung cancer cell line was prepared into a single-cell suspension, and 100 µL was seeded into 96-well plates. The concentration of the single-cell suspension was 2.5-3.0 × 10⁻⁶. 4 Cells per well were collected and then placed in a CO2 incubator (37°C, 5% CO2, 95% air) for overnight incubation. The next day, the drug was added and the cell density was approximately 90%.

[0102] (2) Drug treatment: Tetrasubstituted furanone derivatives (compounds IV-a to IV-k) were dissolved in DMSO to prepare a 10.00 mM stock solution, which was then diluted sequentially with blank medium to concentrations of 10.00 µM, 5.00 µM, 2.50 µM, 1.25 µM, 625.00 nM, 312.50 nM, 156.25 nM, 78.12 nM, and 39.06 nM. The original medium was discarded, and 50 µL of the drug solution prepared in the concentration gradient was added to each well of the cells to make the final concentrations of 5.00 µM, 2.50 µM, 1.25 µM, 625.00 nM, 312.50 nM, 156.25 nM, 78.12 nM, 39.06 nM, and 19.53 nM, respectively. 50 µL of blank medium was added to the control group.

[0103] (3) Viral infection: Subsequently, 50 µL of virus solution prepared with empty culture medium (virus titer of 2×10⁻⁶) was added to each well of the cells in the original drug solution. 7 FFU / ml, MOI=0.2). The control group received only empty culture medium, 50 μl per well. Incubation continued for 24 hours in a CO2 incubator.

[0104] (4) Fixation and staining of nuclei: 100 µL of 4% paraformaldehyde was added to each well of the plate that had been treated with the virus for 24 hours to fix the nuclei at room temperature, and then the liquid was discarded; finally, the nucleus staining solution was added to stain the nuclei.

[0105] (5) Results processing: Fluorescence values ​​were read and photographed using a fluorescence microplate reader, and the inhibition rate was calculated using GraphPadPrism 10.1.2. The results are shown in Table 1.

[0106] As shown in Table 2, the tetrasubstituted furanone derivatives (compounds IV-a to IV-k) of the present invention exhibit good inhibitory effects on influenza virus H1N1 strain, with an inhibition rate of up to 99.59%, which can inhibit the infection of influenza virus H1N1. This indicates that the tetrasubstituted furanone derivatives of the present invention have the potential to be prepared into anti-influenza virus drugs for application.

[0107] Table 1. Structure and inhibition rate of compound IV-a-IV-k

[0108]

[0109]

[0110] In summary, the tetrasubstituted furanone compounds provided by this invention are widely distributed in natural products and bioactive molecules, exhibiting a variety of biological activities, such as inhibiting coronaviruses, HCV proteases, and acting as T-cell proliferation inhibitors. They can also serve as versatile intermediates and precursors in organic synthesis. These tetrasubstituted furanone compounds also possess potential for potent antiviral activity and have broad application prospects in the field of antiviral drug development.

[0111] Furthermore, the method for preparing tetrasubstituted furanone compounds provided by this invention has the advantages of easy separation, readily available raw materials, high efficiency, mild reaction conditions, atom economy, and a wide substrate adaptability. This method uses oxygen as an oxidant, making it a novel and green preparation method. The tetrasubstituted furanone compounds obtained by this method exhibit high purity and bioactivity.

[0112] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A tetrasubstituted furanone compound, characterized in that, The structural formula of the tetrasubstituted furanone compound is shown in formula (III): ； Among them, R 1 It is an aromatic group, a substituted aromatic group, an alkyl group, or a substituted alkyl group; R 2 It is an aromatic group, a substituted aromatic group, an alkyl group, a substituted alkyl group, or a heterocyclic group; R 3 Aromatic groups, substituted aromatic groups, alkyl groups, substituted alkyl groups, or heterocyclic groups; R 4 Aromatic groups, substituted aromatic groups, alkyl groups, substituted alkyl groups, or heterocyclic groups.

2. The tetrasubstituted furanone compound according to claim 1, characterized in that, The R 1 For phenyl, substituted phenyl, C 1~8 Alkyl, C 3~6 Cyclic alkyl group, wherein the substituent on the phenyl group is halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl or nitro.

3. The tetrasubstituted furanone compound according to claim 1, characterized in that, The R 2 For phenyl, substituted phenyl, C 1~4 straight-chain alkyl, C 3~6 The phenyl group contains cycloalkyl, S-containing heterocyclic, N-containing heterocyclic, or O-containing heterocyclic groups, wherein the heterocyclic group is a 3- to 8-membered heterocyclic group, and the substituent on the phenyl group is a halogen, a C1- to C6 alkyl, a C1- to C6 alkoxy, a trifluoromethyl, or a nitro group. R 3 For phenyl, substituted phenyl, C 1~4 straight-chain alkyl, C 3~6 The phenyl group contains cycloalkyl, S-containing heterocyclic, N-containing heterocyclic, or O-containing heterocyclic groups, wherein the heterocyclic group is a 3- to 8-membered heterocyclic group, and the substituent on the phenyl group is a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, a trifluoromethyl, or a nitro group. R 4 For phenyl, substituted phenyl, C 1~4 straight-chain alkyl, C 3~6 The phenyl group is a cycloalkyl group, an S-containing heterocyclic group, an N-containing heterocyclic group, or an O-containing heterocyclic group, wherein the heterocyclic group is a 3- to 8-membered heterocyclic group, and the substituent on the phenyl group is a halogen, a C1- to C6 alkyl group, a C1- to C6 alkoxy group, a trifluoromethyl group, or a nitro group.

4. A method for preparing a tetrasubstituted furanone compound as described in any one of claims 1 to 3, characterized in that, The compounds shown in formulas (I) and (II) are mixed in an organic solvent, and then a metal catalyst, an anionic salt, and a phosphine ligand are added. After reaction, the following reaction formula is obtained: 。 5. The preparation method according to claim 4, characterized in that, The phosphine ligand is one or more of dcpf, dppf, dppp, dppb or dipf; The metal catalyst is one or more of [Rh(CO)2Cl]2, Pd(OAc)2, Rh2(OAc)4, Rh2(esp)2, Rh2(OPiv)4, Rh2(TFA)4, or FeTPPCl.

6. The preparation method according to claim 4, characterized in that, The anionic salt is one or more of NaBArF, AgSbF6, and Ag(OTf)2.

7. The preparation method according to claim 4, characterized in that, The organic solvent is one or more of chlorobenzene, toluene, tert-butyl methyl ether, dichloromethane, or ethyl acetate.

8. The preparation method according to claim 4, characterized in that, The molar ratio of the compound shown in formula (I) and the compound shown in formula (II) to the metal catalyst and the phosphine ligand and anion is (1.5-3.0):(1.0-2.0):(0.02-0.01)(0.05-0.1):(0.05-0.1).

9. The use of a tetrasubstituted furanone compound as described in any one of claims 1 to 3 in the preparation of antiviral drugs or chemical products.

10. The use of the tetrasubstituted furanone compound according to claim 9 in the preparation of antiviral drugs or chemical products, characterized in that, The structures of the tetrasubstituted furanone compounds are as follows: 。

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