Cyclohexane-fused masked 2-pyridone compound as well as preparation method and application thereof

Abstract

The invention discloses a cyclohexane-fused masked 2-pyridone compound as well as a preparation method and application thereof, and relates to the technical field of organic synthesis. The preparation method of the compound comprises the following steps: taking simple and easily available substituted cyclohexane pentalenyl ester as a raw material, taking iodobenzene diacetic acid as an oxidant, taking ammonium carbamate as a nitrogen source, taking magnesium oxide and water as additives and taking chloroform and 2, 2, 2-trifluoroethanol as a mixed solvent; and reacting at room temperature to obtain the cyclohexane condensed and masked 2-pyridone compound. The method does not need to use a metal catalyst, does not need heating and does not need water-free and oxygen-free operation, and has the advantages of mild reaction conditions, simplicity in operation, high yield, wider reaction substrate range and the like; the prepared cyclohexane condensed and masked 2-pyridone compound has a good inhibition effect on phytopathogen, and can be used for preventing and treating botrytis cinerea, fusarium graminearum, sclerotinia rot of colza, phytophthora capsici and botryosphaeria dothidea.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a cyclohexane-fused masked 2-pyridone compound and a preparation method and application thereof. Background Art

[0002] 2-Pyridone compounds are widely present in natural products and drug molecules, showing a wide range of biological and drug activities, and have very important applications in the fields of medicine, pesticides, functional materials, etc. For example, Nepetalactam (J. Org. Chem. 1988, 53, 3968) is a 2-pyridone natural product isolated and purified from mint plants. Louisianin A and Louisianin B (J. Antibiot. 1995, 48, 874) are non-steroidal anti-androgen receptor inhibitors isolated from the culture fluid of Streptomyces WK-4028 extracted from soil samples in Louisiana. Pirfenidone (Nature Rev. Drug Discov. 2011, 10, 489) is a synthetic anti-inflammatory drug that shows good therapeutic effects on idiopathic pulmonary fibrosis that is poorly treated with corticosteroids. Milrinone (Bioorg.Med.Chem.2003,11,4749) is a second-generation phosphodiesterase inhibitor currently approved for intravenous administration for the treatment of decompensated congestive heart failure. Perampanel (J.Med.Chem.2012,55,10584) is an oral drug for the treatment of epilepsy that can significantly reduce the frequency of seizures in patients and has good tolerability.

[0003]

[0004] 2-Pyridone compounds are widely used in medicine, pesticides, materials and other fields. At the same time, 2-pyridone compounds can also be used as efficient ligands and organic synthesis intermediates in the field of organic synthesis (Nature 2017, 551, 489; Science 2021, 374, 1281).

[0005] At present, there are many methods for synthesizing 2-pyridone compounds, such as [4+2] cycloaddition, [3+3] cycloaddition, etc., but there is no literature report on the synthesis method of cyclohexane-fused masked 2-pyridone compounds through molecular editing via [5+1] cycloaddition. Masked 2-pyridone is also a very important organic synthesis intermediate (Org. Lett. 2023, 25, 1974), which can be deprotected under mild conditions to obtain 2-pyridone compounds. Therefore, it is of great significance to quickly and efficiently construct masked 2-pyridone compounds from simple and readily available raw materials. Summary of the invention

[0006] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0007] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0008] One of the objects of the present invention is to provide a cyclohexane-fused masked 2-pyridone compound, which has a good inhibitory effect on plant pathogens such as Botrytis cinerea, Fusarium graminearum, Sclerotinia sclerotiorum, Phytophthora capsici, and Botrytis cinerea, and can be potentially used in the prevention and treatment of plant pathogens.

[0009] In order to solve the above technical problems, the present invention provides the following technical solution: a cyclohexane-fused masked 2-pyridone compound, the compound structure is shown in formula (I):

[0010]

[0011] Among them, R 1 Selected from phenyl, C11 alkyl, adamantyl and one of the following structural formulas:

[0012]

[0013] R 2 One selected from cyclohexyl, tert-butyl, C5 alkyl, phenyl, naphthyl, and adamantyl;

[0014] R 3 is selected from hydrogen or methyl.

[0015] As a preferred embodiment of the cyclohexane-fused masked 2-pyridone compound of the present invention, the compound is selected from one of the following compounds:

[0016]

[0017] Another object of the present invention is to provide a method for preparing the cyclohexane-fused masked 2-pyridone compound as described above, comprising: using the cyclohexane cyclopentadienyl ester compound represented by formula (II) as a raw material, reacting in a solvent at room temperature under the action of a trivalent iodine reagent, an ammonium reagent, magnesium oxide, and water;

[0018] The structural formula (II) is shown below;

[0019]

[0020] Among them, R in formula (II) 1 , R 2 , R 3 With R in formula (I) 1 , R 2 , R 3 The corresponding ones are consistent.

[0021] As a preferred embodiment of the method for preparing the cyclohexane-fused masked 2-pyridone compound of the present invention, the trivalent iodine reagent is selected from one of iodobenzene diacetic acid or bis(trifluoroacetoxy)iodobenzene; and the molar ratio of the trivalent iodine reagent to the compound represented by formula (II) is 2 to 3:1.

[0022] As a preferred embodiment of the method for preparing the cyclohexane-fused masked 2-pyridone compound of the present invention, the ammonium reagent is selected from ammonium carbamate, ammonium chloride and ammonium carbonate; the molar ratio of the ammonium reagent to the compound represented by formula (II) is 1.5 to 4:1.

[0023] As a preferred embodiment of the method for preparing the cyclohexane-fused masked 2-pyridone compound of the present invention, the molar ratio of the magnesium oxide to the compound represented by formula (II) is 3 to 10:1.

[0024] As a preferred embodiment of the method for preparing the cyclohexane-fused masked 2-pyridone compound of the present invention, the molar ratio of water to the compound represented by formula (II) is 1 to 5:1.

[0025] As a preferred embodiment of the method for preparing the cyclohexane-fused masked 2-pyridone compound of the present invention, the solvent is one of methanol, dichloroethane, chloroform, 2,2,2-trifluoroethanol, a mixed solvent of methanol and 2,2,2-trifluoroethanol, and a mixed solvent of chloroform and 2,2,2-trifluoroethanol, the concentration of the compound represented by formula (II) in the solvent is 0.1 mol / L, the reaction temperature is room temperature, and the reaction time is 10 to 30 minutes.

[0026] As a preferred embodiment of the method for preparing the cyclohexane-fused masked 2-pyridone compound of the present invention, the preferred solvent is a mixed solvent of chloroform and 2,2,2-trifluoroethanol, wherein the product ratio of chloroform to 2,2,2-trifluoroethanol is 1 to 19:1.

[0027] Another object of the present invention is to provide the use of the cyclohexane-fused masked 2-pyridone compound as described above in inhibiting plant pathogens or preparing a drug for inhibiting plant pathogens.

[0028] As a preferred embodiment of the application of the cyclohexane-fused masked 2-pyridone compound of the present invention, the plant pathogenic bacteria is one or more of Botrytis cinerea, Fusarium graminearum, Sclerotinia sclerotiorum, Phytophthora capsici, and Botrytis cinerea.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The cyclohexane-fused masked 2-pyridone compound of the present invention uses a simple and readily available cyclohexane cyclopentadienyl ester as a raw material, cheap and readily available iodophenyl diacetic acid as an oxidant, and ammonium carbamate as an ammonium reagent. The reaction does not require the use of any metal catalyst, and does not require heating or anhydrous and oxygen-free operation, thereby achieving efficient synthesis of the cyclohexane-fused masked 2-pyridone compound under mild reaction conditions. The method of the present invention has the advantages of readily available raw materials, mild conditions, high yield, wide substrate range, high atom economy, and the like.

[0031] The cyclohexane-fused masked 2-pyridone compound prepared by the present invention has a good inhibitory effect on plant pathogens such as Botrytis cinerea, Fusarium graminearum, Sclerotinia sclerotiorum, Phytophthora capsici, and Botrytis cinerea, and can be potentially used in the prevention and treatment of plant pathogens. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0033] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the target product 1a prepared in Example 1 of the present invention;

[0034] Figure 2 This is the carbon NMR spectrum of the target product 1a prepared in Example 1 of the present invention;

[0035] Figure 3 This is the single crystal diffraction pattern of the target product 1a prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0036] Now, various exemplary embodiments of the present invention are described in detail, and this detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the examples of the specification.

[0037] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0038] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0039] The raw material substituted cyclohexanedipaldienyl ester used in the examples was prepared according to the method reported in the reference (Org. Lett. 2020, 22, 6500-6504.).

[0040] Unless otherwise specified, other raw materials used in the examples were purchased commercially.

[0041] Example 1

[0042] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2a (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), and magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), and water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 50 to 3 / 50, V / V) to obtain the target product 1a (55.7 mg, white solid, yield 83%).

[0043] The reaction equation is as follows:

[0044]

[0045] The target product 1a was characterized by hydrogen nuclear magnetic resonance spectrum. Figure 1 As shown, the carbon NMR spectrum is Figure 2 As shown:

[0046] 1 H NMR (600MHz, CDCl3) δ8.20(d,J=7.4Hz,2H),7.58(t,J=7.4Hz,1H),7.45(t,J=7.7Hz,2H),6.84(s,1H ),2.90(t,J=5.2Hz,2H),2.77-2.66(m,3H),1.85-1.76(m,9H),1.43-1.36(m,4H),1.28-1.20(m,1H); 13 C NMR (150MHz, CDCl3) δ165.1,158.7,156.2,155.7,133.4,130.2,129.3,128.3,128.0,110.5,39.1,32.9,32.7,26.6,25.9,24.8,22.7,22.4.

[0047] The structure and relative configuration of the target product 1a were confirmed by single crystal diffraction, such as Figure 3 shown.

[0048] Example 2

[0049] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2b (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 50 to 4 / 50, V / V) to obtain the target product 1b (35.9 mg, colorless oil, yield 58%).

[0050] The reaction equation is as follows:

[0051]

[0052] The target product 1b was characterized as follows:

[0053] 1H NMR (600MHz, CDCl3) δ8.22-8.20(m,2H),7.61(t,J=7.4Hz,1H),7.48(t,J=7.8Hz,2H) ,6.95(s,1H),2.98-2.93(m,4H),1.89-1.84(m,2H),1.83-1.78(m,2H),1.41(s,9H); 13 C NMR (150MHz, CDCl3) δ165.2,160.8,157.2,155.7,133.5,130.3,130.3,129.4,128.4,111.1,36.2,33.1,30.2,28.3,22.8,22.2.

[0054] Example 3

[0055] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2c (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 50 to 3 / 50, V / V) to obtain the target product 1c (47.9 mg, yellow oil, yield 74%).

[0056] The reaction equation is as follows:

[0057]

[0058] The target product 1c was characterized as follows:

[0059] 1 H NMR (600MHz, CDCl3) δ8.20(d,J=7.8Hz,2H),7.59(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),6.79(s,1H),2.90(t,J=5.8Hz,2H), 2.67(t,J=5.7Hz,2H),2.55(t,J=7.8Hz,2H),1.87-1.80(m,4H),1.63-1.54(m,2H),1.39-1.32(m,4H),0.89(t,J=6.9Hz,3H); 13C NMR (150MHz, CDCl3) δ165.1,156.1,155.3,154.0,133.5,130.2,129.3,128.9,128.3,113.1,32.7,32.1,31.7,28.4,25.0,22.6,22.5,22.4,13.9.

[0060] Example 4

[0061] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2d (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-7 / 100, V / V) to obtain the target product 1d (31.0 mg, white solid, yield 40%).

[0062] The reaction equation is as follows:

[0063]

[0064] The target product 1d was characterized as follows:

[0065] 1 H NMR (600MHz, CDCl3) δ8.22-8.21(m,2H),7.61(t,J=7.4Hz,1H),7.48(t,J=7.8Hz,2H),6.92(s,1H),3 .05(t,J=6.1Hz,2H),2.96(t,J=6.8Hz,2H),2.11-2.07(m,9H),1.89-1.85(m,2H),1.82-1.76(m,8H); 13 C NMR (150MHz, CDCl3) δ165.3,160.2,157.5,156.0,133.5,130.7,130.3,129.5,128.4,111.2,40.5,38.5,36.6,33.0,28.8,28.5,22.6,22.0.

[0066] Example 5

[0067] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2e (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), after the reaction is completed, add 2 ml of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 50 to 3 / 50, V / V) to obtain the target product 1d (56.7 mg, white solid, yield 78%).

[0068] The reaction equation is as follows:

[0069]

[0070] The target product 1e was characterized as follows:

[0071] 1 H NMR (600MHz, CDCl3) δ8.20(dd,J=8.2,1.0Hz,2H),7.58(t,J=7.5Hz,1H),7.45(t,J=7.8Hz,2H),6.85(s,1H),2.93(t,J=6.7Hz,2 H),2.72-2.66(m,1H),2.48(s,2H),1.86-1.74(m,5H),1.63(t,J=6.8Hz,2H),1.41-1.33(m,4H),1.27-1.21(m,1H),1.02(s,6H); 13 C NMR (150MHz, CDCl3) δ165.0,159.0,155.7,155.1,133.4,130.2,129.3,128.3,127.0,110.5,39.1,38.7,35.0,32.7,29.8,29.2,28.1,26.6,26.0.

[0072] Example 6

[0073] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2f (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-4 / 100, V / V) to obtain the target product 1f (39.5 mg, yellow oil, yield 60%).

[0074] The reaction equation is as follows:

[0075]

[0076] The above target product 1f was characterized:

[0077] 1 H NMR (600MHz, CDCl3) δ8.23(dd,J=8.2,1.1Hz,2H),7.61(t,J=7.4Hz,1H),7.48(t,J=7.8Hz,2H),7.45-7.40(m,2H),7.40-7.3 6(m,1H),7.35-7.31(m,2H),6.89(s,1H),3.00(t,J=6.5Hz,2H),2.63(t,J=6.3Hz,2H),1.95-1.88(m,2H),1.78-1.72(m,2H); 13 CNMR (150MHz, CDCl3)165.1,157.0,155.3,153.4,138.6,133.6,130.3,129.2,128.6,128.4,128.4,128.3,128.0,114.2,32.7,27.1,22.8,22.7.

[0078] Example 7

[0079] Take a 10mL eggplant-shaped bottle, add 2g (0.2mmol) of substituted cyclopentadienyl ester, iodophenyl diacetic acid (0.6mmol), ammonium carbamate (0.3mmol), and magnesium oxide (1.0mmol) in sequence, add chloroform (1.8mL), 2,2,2-trifluoroethanol (0.2ml), and water (0.009ml) under atmospheric atmosphere, react at room temperature for 30 minutes (track the reaction by thin plate chromatography until the reaction is complete), after the reaction is completed, add 2ml of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-8 / 100, V / V) to obtain 1g (53.9mg, white solid, yield 71%) of the target product.

[0080] The reaction equation is as follows:

[0081]

[0082] The above target product 1g was characterized:

[0083] 1 H NMR (600MHz, CDCl3) δ8.25(d,J=7.5Hz,2H),7.92-7.85(m,3H),7.81(s,1H),7.62(t,J=7.4Hz,1H),7.55-7.52(m,2H),7.50(t,J=7 .7Hz,2H),7.46(d,J=8.4Hz,1H),6.99(s,1H),3.04(t,J=6.5Hz,2H),2.68(t,J=6.2Hz,2H),1.97-1.91(m,2H),1.78-1.72(m,2H); 13 C NMR (150MHz, CDCl3) δ165.2,157.0,155.3,153.4,136.1,133.6,133.0,132.7,130.3,129.2,1 28.8,128.4,128.1,127.9,127.7,127.6,126.5,126.5,126.3,114.4,32.7,27.2,22.8,22.7.

[0084] Example 8

[0085] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2h (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-6 / 100, V / V) to obtain the target product 1h (43.0 mg, yellow oil, yield 52%).

[0086] The reaction equation is as follows:

[0087]

[0088] The above target product 1h was characterized:

[0089] 1 H NMR (600MHz, CDCl3) δ6.70 (s, 1H), 2.85 (t, J = 5.4Hz, 2H), 2.72-2.62 (m, 3H), 2.55 (t,J=7.6Hz,2H),1.85-1.70(m,10H),1.39-1.24(m,22H),0.86(t,J=7.0Hz,3H); 13 CNMR (150MHz, CDCl3) δ172.2,158.5,156.0,155.5,127.8,110.3,39.1,34.3,32.9,32 .8,31.8,29.5,29.4,29.2,29.2,29.0,26.7,26.0,24.8,24.5,22.7,22.6,22.4,14.0.

[0090] Example 9

[0091] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2i (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-7 / 100, V / V) to obtain the target product 1i (54.3 mg, colorless oil, yield 69%).

[0092] The reaction equation is as follows:

[0093]

[0094] The target product 1i was characterized as follows:

[0095] 1 H NMR (600MHz, CDCl3) δ6.63 (s, 1H), 2.86 (t, J = 5.4Hz, 2H), 2.70-2.63 (m, 3H), 2.09-2.05 (m, 9H), 1.85-1.68 (m, 15H), 1.39-1.32 (m, 5H); 13 C NMR (150MHz, CDCl3) δ176.1,158.3,156.1,156.0,127.5,110.3,40.9,39.1,38.6,36.4,33.0,32.7,27.8,26.7,26.0,24.8,22.8,22.5.

[0096] Example 10

[0097] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2j (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), after the reaction is completed, add 2 ml of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-6 / 100, V / V) to obtain the target product 1j (49.7 mg, colorless oil, yield 61%).

[0098] The reaction equation is as follows:

[0099]

[0100] The above target product 1j was characterized:

[0101] 1 H NMR (600MHz, CDCl3) δ6.69 (s, 1H), 2.86 (t, J = 5.4Hz, 2H), 2.68-2.64 (m, 3H), 2.32 (s, 2H), 2.02-1.99 (m, 3H), 1.86-1.63 (m, 21H), 1.40-1.33 (m, 5H); 13 C NMR (150MHz, CDCl3) δ167.0,158.4,156.1,155.5,127.7,110.3,48.5,42.3,39.2,36.7,32.9,32.9,32.7,28.5,26.7,26.0,24.8,22.8,22.5.

[0102] Embodiment 11

[0103] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2k (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (trace the reaction by thin plate chromatography until the reaction is complete), add 2 ml of saturated sodium bicarbonate solution to quench after the reaction, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-9 / 100, V / V) to obtain the target product 1k (39.9 mg, light yellow oil, yield 43%).

[0104] The reaction equation is as follows:

[0105]

[0106] The above target product 1k was characterized:

[0107] 1 H NMR (600MHz, CDCl3) δ7.01(d,J=7.4Hz,1H),6.67(d,J=4.9Hz,2H),6.64(s,1H),3.99(t,J=5.6Hz,2H),2.89(t, J=5.6Hz,2H),2.73-2.66(m,3H),2.31(s,3H),2.19(s,3H),1.95-1.74(m,13H),1.41(s,6H),1.39-1.30(m,5H); 13 C NMR (150MHz, CDCl3) δ176.4,158.4,157.0,156.2,156.0,136.4,130.2,127.7,123.6,120.6,112. 0,110.2,67.9,42.3,39.2,37.0,33.0,32.8,26.7,26.0,25.1,25.0,24.9,22.8,22.5,21.4,15.8.

[0108] Example 12

[0109] Take a 10 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2l (0.2 mmol), iodophenyl diacetic acid (0.6 mmol), ammonium carbamate (0.3 mmol), and magnesium oxide (1.0 mmol) in sequence, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), and water (0.009 ml) under atmospheric atmosphere, react at room temperature for 30 minutes (track the reaction by thin plate chromatography until the reaction is complete), after the reaction is completed, add 2 ml of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent is ethyl acetate: petroleum ether = 1 / 100-10 / 100, V / V) to obtain the target product 1l (51.9 mg, light yellow oil, yield 56%).

[0110] The reaction equation is as follows:

[0111]

[0112] The target product 11 was characterized as follows:

[0113] 1 H NMR (600MHz, CDCl3) δ8.31(d,J=8.4Hz,2H),7.91(d,J=8.4Hz,2H),6.84(s,1H),3.11(t,J=7.6Hz 4H),2.89(t,J=5.7Hz,2H),2.77-2.69(m,3H),1.89-1.74(m,9H),1.55-1 .52(m,4H),1.41-1.34(m,4H),1.27-1.24(m,1H),0.85(t,J=7.4Hz,6H); 13 C NMR (150MHz, CDCl3) δ163.8,159.1,156.4,155.4,144.9,132.8,130.9,128.5, 126.9,110.3,49.6,39.2,32.9,32.8,26.7,26.0,24.9,22.7,22.4,21.7,11.1.

[0114] Embodiment 13

[0115] In order to verify the practicability of the present invention, the present invention also carried out a gram-scale expansion experiment. When the substituted cyclopentadienyl ester 2a was enlarged to 4 mmol (1.2898 g), the expected product was still obtained with a yield of 72%, which fully demonstrated the practicability of the present invention.

[0116] Take a 50 mL eggplant-shaped bottle, add substituted cyclopentadienyl ester 2a (4 mmol, 1.29 g), iodophenyl diacetic acid (12 mmol), ammonium carbamate (6 mmol), and magnesium oxide (20 mmol) in sequence, add chloroform (36 mL), 2,2,2-trifluoroethanol (4 ml), and water (0.18 ml) under atmospheric atmosphere, react for 30 minutes at room temperature (track the reaction by thin plate chromatography until the reaction is complete), filter and remove magnesium oxide after the reaction, add 40 ml of saturated sodium bicarbonate solution to the filtrate to quench, extract twice with dichloromethane, combine the organic phases, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, and concentrate by rotary evaporation to remove the solvent. The crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 50 to 3 / 50, V / V) to obtain the target product 1a (0.966 g, white solid, yield 72%).

[0117] The reaction equation is as follows:

[0118]

[0119] Embodiment 14

[0120] In order to verify the practicability of the present invention, the present invention also carried out a protecting group removal conversion reaction, and the masked 2-pyridone compound 1a was reacted under mild conditions to remove the benzoyl protecting group to obtain the 2-pyridone compound 3 with a yield of 92%, which fully demonstrated the practicability of the present invention.

[0121] Take a 10 mL eggplant-shaped bottle, add the masked 2-pyridone compound 1a (0.2 mmol) and potassium carbonate (0.04 mmol) in sequence, add methanol (2 mL) under atmospheric atmosphere, and react at room temperature for 30 minutes (track the reaction by thin plate chromatography until the reaction is complete). After the reaction, the solvent is removed by rotary evaporation, and the crude product is separated by silica gel column chromatography (eluent is ethyl acetate: methanol = 50 / 1 ~ 25 / 1, V / V) to separate the target product 3 (42.6 mg, white solid, yield 92%).

[0122] The reaction equation is as follows:

[0123]

[0124] The above target product 3 was characterized:

[0125] 1 H NMR (600MHz, CDCl3) δ12.99(s,1H),6.30(s,1H),2.70(s,2H),2.47-2.44(m,3H),1.83-1.75(m,8H),1.36-1.22(m,6H); 13C NMR (150MHz, CDCl3) δ165.0,162.1,142.6,113.5,112.7,39.5,32.9,27.4,26.8,26.1,23.2,22.8,21.5.

[0126] Embodiment 15

[0127] On the basis of Example 1, the reaction conditions such as trivalent iodine reagent, ammonium reagent, additive A, additive B, and solvent were optimized. The specific optimization results are shown in Table 1 below:

[0128]

[0129] Table 1

[0130]

[0131] It can be seen from Table 1 that the yield of using a mixed solvent is higher than that of a single solvent; decomposition occurs when bis(trifluoroacetoxy)iodobenzene is used as an oxidant; the yield is average when ammonium carbonate and ammonium chloride are used; the best effect is achieved when iodobenzene diacetic acid is used as an oxidant, ammonium carbamate is used as an ammonia source, water and magnesium oxide are used as additives, and chloroform and 2,2,2-trifluoroethanol are used as a mixed solvent.

[0132] It can be seen that the present invention provides an efficient method for synthesizing masked 2-pyridone compounds, which does not require a metal catalyst and has the advantages of simple operation, a wide substrate range, and a high yield.

[0133] Example 16

[0134] Tomato gray mold (Bc), also known as Botrytis cinerea, is a broad-host pathogen that can cause sudden wilting, leaf fall, blossom end rot, fruit rot and cellar rot in seedlings, fruits and storage organs of many plants. When it is humid, a large amount of gray mold (conidiophores and conidia) is produced on the surface of the diseased part, which is called gray mold. Its fast reproduction rate, large genetic variation and high adaptability have a great impact on its prevention and control.

[0135] Fusarium graminearum (Fg), also known as Fusarium graminearum, can cause diseases in field gramineous crops. For example, it can cause wheat fusarium head blight. Among the stored grain diseases, the fungus can cause wheat, corn and other grain crops to heat up and mold. The fungus is an aerobic mesophilic fungus, and the optimal temperature for growth, development and reproduction is 20-40℃.

[0136] Sclerotinia sclerotiorum (Ss), also known as sclerotium stem rot, occurs in all rapeseed producing areas in my country. It is one of the important rapeseed diseases. It is caused by Sclerotinia sclerotiorum and occurs in crops such as rapeseed. The disease mainly harms the stems, leaves, flowers, siliques and seeds of rapeseed. The host range of the pathogen is very wide and can infect a variety of plants. In addition to a variety of cruciferous plants, common hosts include lettuce, sunflower, carrot, soybean, broad bean and pea.

[0137] Pepper Phytophthora (Pc), commonly known as black rod, is one of the world's diseases that harm pepper production. The disease is mainly spread by soil or rainwater, and it infects and spreads quickly, causing an outbreak in a short period of time. The disease is caused by infection with pepper Phytophthora, and occurs on peppers. Pepper blight can occur in both the seedling stage and the adult stage, with the adult stage being the main stage. The pathogen can infect roots, stems, leaves, and fruits, and often causes a total crop failure when it is severe. The host range of the genus Phytophthora is wide. In addition to peppers, it can also harm crops such as tomatoes, eggplants, and melons.

[0138] Botrytis cinerea (Bd) belongs to the genus Botrytis cinerea, which is a type of fungus distributed worldwide with a wide host range. It can damage the branches and fruits of many forest trees and fruit trees, causing branch dieback, canker, gum flow and fruit rot, and can also cause root rot and lead to the death of the entire tree. The diseases of forest trees and fruit trees caused by Botrytis cinerea degrade the quality of timber forests, reduce the yield of economic forests, and cause fruit rot and deterioration, causing serious damage and economic losses.

[0139] The compounds 1a-11 prepared in Examples 1-13 were subjected to inhibition tests on Botrytis cinerea, Fusarium graminearum, Sclerotinia sclerotiorum, Phytophthora capsici and Botrytis cinerea. The specific process is as follows:

[0140] The plant fungi used in this experiment are tomato gray mold, graminearum fusarium, rapeseed sclerotinia, pepper phytophthora and Botrytis cinerea species stored at 4°C in the laboratory. The culture medium used is potato agar glucose medium (PDA for short). PDA medium formula: 200g potato (peeled), 20g glucose, 15g agar, 1000mL distilled water, preparation method: wash and peel the potato, weigh 200g and cut into small pieces, add water and boil (boil for 20-30 minutes, can be pierced by a glass rod), filter into a beaker with eight layers of gauze, add 15-20g agar according to the experimental needs, add 20g glucose, stir evenly, cool slightly after fully dissolved, add water to 1000mL, sterilize at 121°C for 30 minutes after packaging, and set aside after cooling.

[0141] Experimental method: Growth rate method was used.

[0142] (1) First, culture the two plant fungi on a PDA plate at 25°C for about 3 to 6 days for later use;

[0143] (2) Heat and melt the PDA culture medium, cool it to 45-50°C, add 50 mg / L of the test compound to prepare a culture medium containing 50 mg / L of the drug solution, and pour it into culture dishes to cool. Chlorothalonil and Tetramethylthiuram Disulfide are used as positive controls;

[0144] (3) Using aseptic operation procedures, use a cork puncher to punch a round bacterial cake (0.50 cm in diameter) at the edge of the hyphae of each strain after 6 days of culture (the growth conditions should be as consistent as possible), then use an inoculation needle to pick it to the center of the drug-containing plate, and then place the culture dish upside down in an incubator (28°C) for culture;

[0145] (4) Observe and measure the growth of mycelium at different times after treatment, measure the diameter using the cross method, process the data, and calculate the inhibition rate;

[0146] (5) Inhibition rate (%) = (control mycelium diameter - treated mycelium diameter) / (control mycelium diameter - 0.5) × 100;

[0147] (6) Each treatment was repeated 3 times.

[0148] The test results are shown in Table 2.

[0149] Table 2

[0150]

[0151]

[0152] From the data in Table 2, it can be concluded that the compounds have certain inhibitory activity against plant pathogenic fungi such as Botrytis cinerea, Fusarium graminearum, Sclerotinia sclerotiorum, Phytophthora capsici and Botrytis cinerea. Compound 1d has a better inhibitory effect on Botrytis cinerea (Bd) than the positive drug thiophanate-methyl but inferior to thiram; while for Fusarium graminearum (Fg), the inhibitory effect of compound 1b is significantly better than the positive drugs thiophanate-methyl and thiram; for Sclerotinia sclerotiorum (Ss), the inhibitory effect of compound 1k is better than the positive drug thiram; for Phytophthora capsici (Pc), the inhibitory effects of compounds 1a, 1b and 1f are close to the positive drug thiram; for Botrytis cinerea (Bd), compounds 1b, 1d, 1h, 1i and 1k all have good inhibitory effects, among which the inhibitory effect of compound 1k is better than the positive drugs thiophanate-methyl and thiram.

[0153] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A cyclohexane-fused masked 2-pyridone compound, characterized in that: The structural formula of the compound is shown in formula (I): Among them, R 1 Selected from phenyl, C11 alkyl, adamantyl and one of the following structural formulas: R 2 One selected from cyclohexyl, tert-butyl, C5 alkyl, phenyl, naphthyl, and adamantyl; R 3 is selected from hydrogen or methyl.

2. The cyclohexane-fused masked 2-pyridone compound according to claim 1, characterized in that: The compound is selected from one of the following compounds:

3. The method for preparing the cyclohexane-fused masked 2-pyridone compound according to claim 1 or 2, characterized in that: include, The cyclohexane cyclopentadienyl ester compound represented by formula (II) is used as a raw material, and reacts in a solvent at room temperature under the action of a trivalent iodine reagent, an ammonium reagent, magnesium oxide, and water to obtain a compound represented by formula (I); Among them, R in formula (II) 1 , R 2 , R 3 With R in formula (I) 1 , R 2 , R 3 The corresponding ones are consistent.

4. The method for preparing a cyclohexane-fused masked 2-pyridone compound according to claim 3, characterized in that: The trivalent iodine reagent is selected from iodobenzene diacetic acid or bis(trifluoroacetyloxy)iodobenzene; the molar ratio of the trivalent iodine reagent to the compound represented by formula (II) is 2 to 3:

1.

5. A method for preparing a cyclohexane-fused masked 2-pyridone compound as claimed in claim 3 or 4, characterized in that: The ammonium reagent is selected from one of ammonium carbamate, ammonium chloride and ammonium carbonate; the molar ratio of the ammonium reagent to the compound represented by formula (II) is 1.5 to 4:

1.

6. The method for preparing a cyclohexane-fused masked 2-pyridone compound according to claim 5, characterized in that: The molar ratio of the magnesium oxide to the compound represented by formula (II) is 3 to 10:

1.

7. A method for preparing a cyclohexane-fused masked 2-pyridone compound as claimed in any one of claims 3, 4 and 6, characterized in that: The molar ratio of water to the compound represented by formula (II) is 1 to 5:

1.

8. The method for preparing a cyclohexane-fused masked 2-pyridone compound according to claim 7, characterized in that: The solvent is one of methanol, dichloroethane, chloroform, 2,2,2-trifluoroethanol, a mixed solvent of methanol and 2,2,2-trifluoroethanol, and a mixed solvent of chloroform and 2,2,2-trifluoroethanol; The concentration of the compound represented by formula (II) in the solvent is 0.1 mol / L, the reaction temperature is room temperature, and the reaction time is 10 to 30 minutes.

9. The method for preparing a cyclohexane-fused masked 2-pyridone compound according to claim 8, characterized in that: The solvent is a mixed solvent of chloroform and 2,2,2-trifluoroethanol, wherein the product ratio of chloroform to 2,2,2-trifluoroethanol is 1 to 19:

1.

10. Use of the cyclohexane-fused masked 2-pyridone compound according to claim 1 or 2 in inhibiting plant pathogens or preparing a drug for inhibiting plant pathogens, characterized in that: The plant pathogenic bacteria are one or more of Botrytis cinerea, Fusarium graminearum, Sclerotinia sclerotiorum, Phytophthora capsici, and Botrytis cinerea.

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