A cyclohexane-fused masked 2-pyridinone compound, and a preparation method and application thereof

Abstract

The application discloses a cyclohexane-fused masked 2-pyridone compound and a preparation method and application thereof, and relates to the technical field of organic synthesis. The preparation method comprises the following steps: taking a simple and easily obtained substituted cyclohexane cyclopentadienyl ester as raw material, taking iodobenzene diacetic acid as an oxidant, taking ammonium carbamate as a nitrogen source, taking magnesium oxide and water as additives, taking chloroform and 2,2,2-trifluoroethanol as mixed solvents, and reacting at room temperature to obtain the cyclohexane-fused masked 2-pyridone compound. The application has the advantages of mild reaction condition, simple operation, high yield, wide reaction substrate range and the like, and does not need to use a metal catalyst, does not need to be heated and does not need to be operated in a water-free and oxygen-free manner. The cyclohexane-fused masked 2-pyridone compound prepared by the application has a good inhibiting effect on plant pathogenic fungi, and can be used for the prevention and treatment of tomato gray mold, cereal scab, rapeseed sclerotinia, pepper pythium blight and grape cavity disease.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic compound synthesis, and particularly relates to a cyclohexane-fused masked 2-pyridinone compound, a preparation method therefor and application thereof. BACKGROUND

[0002] 2-pyridinone compounds are widely present in natural products and drug molecules, and show diverse and extensive biological activity and drug activity, and have very important applications in the fields of medicine, pesticide, functional material and the like. For example, Nepetalactam (J. Org. Chem. 1988, 53, 3968) is a 2-pyridinone natural product isolated and purified from a mint plant. Louisianin A and Louisianin B (J. Antibiot. 1995, 48, 874) are non-steroidal anti-androgen receptor inhibitors isolated from the culture solution of Streptomyces WK-4028 extracted from a soil sample in Louisiana. Pirfenidone (Nature Rev. Drug Discov. 2011, 10, 489) is an artificially synthesized anti-inflammatory drug, and shows good therapeutic effect on idiopathic pulmonary fibrosis with poor therapeutic effect of corticosteroid treatment. Milrinone (Bioorg. Med. Chem. 2003, 11, 4749) is a second-generation phosphodiesterase inhibitor, and is currently approved for intravenous administration for the treatment of decompensated congestive heart failure. Perampanel (J. Med. Chem. 2012, 55, 10584) is an orally administered drug for treating epilepsy, which can significantly reduce the frequency of disease in patients, and has good tolerability.

[0003]

[0004] 2-pyridinone compounds are widely used in the fields of medicine, pesticide, material and the like, and at the same time, 2-pyridinone 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 and the like, but there is no literature report on the method for constructing cyclohexane-fused masked 2-pyridone compounds by [5+1] cycloaddition through molecular editing, and the masked 2-pyridone is also a very important organic synthesis intermediate (Org. Lett. 2023, 25, 1974), which can be removed under mild conditions to obtain 2-pyridone compounds, so it is of great significance to quickly and efficiently construct masked 2-pyridone compounds from simple and readily available raw materials. SUMMARY

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

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

[0008] One of the purposes of the present application is to provide a cyclohexane-fused masked 2-pyridone compound, which has good inhibitory effect on plant pathogenic fungi such as gray mold of eggplant, fusarium equiseti, sclerotinia sclerotiorum, phytophthora capsici, and botryosphaeria dothidea, and can be potentially applied to the prevention and control of plant pathogenic fungi.

[0009] To solve the above technical problems, the present application provides the following technical scheme: a cyclohexane-fused masked 2-pyridone compound, the compound structure formula is as shown in formula (I):

[0010]

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

[0012]

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

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

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

[0016]

[0017] Another object of the present application is to provide a preparation method of the cyclohexane-fused masked 2-pyridone compound as described above, which comprises, taking a cyclohexane and cyclopentadienyl ester compound shown in formula (II) as raw material, reacting in a solvent at room temperature under the joint action of a triiodine reagent, an ammonium reagent, magnesium oxide and water to obtain the product.

[0018] The structural formula of formula (II) is shown as follows:

[0019]

[0020] In formula (II), R 1 , R 2 , R 3 correspond to R 1 , R 2 , R 3 in formula (I) respectively.

[0021] As a preferred scheme of the preparation method of the cyclohexane-fused masked 2-pyridone compound of the present application, the triiodine reagent is selected from one of iodobenzene diacetate or bis(trifluoroacetoxy)iodobenzene; the molar ratio of the triiodine reagent to the compound shown in formula (II) is 2-3:1.

[0022] As a preferred scheme of the preparation method of the cyclohexane-fused masked 2-pyridone compound of the present application, the ammonium reagent is selected from one of ammonium carbamate, ammonium chloride or ammonium carbonate; the molar ratio of the ammonium reagent to the compound shown in formula (II) is 1.5-4:1.

[0023] As a preferred scheme of the preparation method of the cyclohexane-fused masked 2-pyridone compound of the present application, the molar ratio of the magnesium oxide to the compound shown in formula (II) is 3-10:1.

[0024] As a preferred scheme of the preparation method of the cyclohexane-fused masked 2-pyridone compound of the present application, the molar ratio of the water to the compound shown in formula (II) is 1-5:1.

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

[0026] As a preferred scheme of the preparation method of the cyclohexane-fused masked 2-pyridone compound of the present application, preferably, the solvent is a mixed solvent of chloroform and 2,2,2-trifluoroethanol, wherein the ratio of chloroform to 2,2,2-trifluoroethanol is 1-19:1.

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

[0028] As a preferred scheme of the use of the cyclohexane-fused masked 2-pyridone compound of the present application, wherein: the plant pathogenic fungi is one or more of Botrytis cinerea, Fusarium equiseti, Sclerotinia sclerotiorum, Phytophthora capsici, and Botryosphaeria dothidea.

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

[0030] The cyclohexane-fused masked 2-pyridone compound of the present application uses a simple and readily available cyclohexane-cyclopentadienyl ester as a raw material, a cheap and readily available iodobenzene diacetic acid as an oxidizing agent, and ammonium carbamate as an ammonium reagent. The reaction does not require the use of any metal catalyst, does not require heating, and does not require anhydrous and anaerobic operation, thereby realizing the efficient synthesis of the cyclohexane-fused masked 2-pyridone compound under mild reaction conditions. The method of the present application has the advantages of readily available raw materials, mild conditions, high yield, wide substrate range, and high atomic economy.

[0031] The cyclohexane-fused masked 2-pyridone compound prepared by the present application has good inhibitory effect on plant pathogenic fungi such as Botrytis cinerea, Fusarium equiseti, Sclerotinia sclerotiorum, Phytophthora capsici, and Botryosphaeria dothidea, and can be potentially applied to the prevention and control of plant pathogenic fungi. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiment description will be briefly introduced as follows. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without any creative labor. Among them:

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

[0034] Figure 2 The nuclear magnetic resonance carbon spectrum of the target product 1a prepared in Example 1 of the present application;

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

[0036] The specific embodiments of the present application will now be described in detail with specific reference being made to the drawings. The following detailed description is made in connection with the preferred embodiments of the application, although it is to be understood that various modifications and changes can be made therein without departing from the scope of the present application.

[0037] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present application. It will be apparent, however, to one skilled in the art that the present application can be practiced without the specific details, or with an equivalent arrangement, and that the present application can include other implementations.

[0038] Second, the term "one embodiment" or "an embodiment" as used herein means that a particular implementation can include a particular feature, structure, or characteristic, but every embodiment can not necessarily include the particular feature, structure, or characteristic. Furthermore, the following claims can refer to "an" or "a" element or steps, however, this is merely for convenience and brevity and is used in the sense of one or more unless the context clearly indicates otherwise.

[0039] The starting substituted cyclohexane annulenes cyclopentadienyl 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 starting materials used in the examples were commercially available.

[0041] Example 1

[0042] Take 10 mL of a flask, add the substituted cyclopentadiene ester 2a (0.2 mmol), iodo benzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 50 ~ 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 by1H NMR as shown in Figure 1 Figure 2

[0046] 1 H NMR (600 MHz, CDC13) δ 8.20 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 6.84 (s, 1H), 2.90 (t, J = 5.2 Hz, 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 (150 MHz, CDC13) δ 165.1, 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 of the target product 1a and its relative configuration were confirmed by single crystal diffraction as shown in Figure 3

[0048] Example 2

[0049] Take 10 mL of ajar, add the substituted cyclopentadiene ester 2b (0.2 mmol), iodo benzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent ethyl acetate: petroleum ether = 1 / 50-4 / 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] 1 ​​​H NMR (600 MHz, CDC13) δ 8.22-8.20 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 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 (150 MHz, CDC13) δ 165.2, 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 10 mL of ajar, add the substituted cyclopentadiene ester 2c (0.2 mmol), iodo benzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 50-3 / 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 is characterized as follows:

[0059] 1 H NMR (600 MHz, CDC13) δ 8.22-8.20 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 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); 13C NMR (150 MHz, CDC13) δ 165.1, 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 10 mL of a flask, add the substituted cyclopentadiene ester 2d (0.2 mmol), iodo benzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporate to remove the solvent, and separate the crude product by silica gel column chromatography (eluent 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 is characterized as follows:

[0065] 1 H NMR (600 MHz, CDC13) δ 8.22-8.21 (m, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 6.92 (s, 1H), 3.05 (t, J = 6.1 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.11-2.07 (m, 9H), 1.89-1.85 (m, 2H), 1.82-1.76 (m, 8H); 13 C NMR (150 MHz, CDC13) δ 165.3, 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 10 mL of a flask, add the substituted cyclopentadiene ester 2e (0.2 mmol), iodo benzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent ethyl acetate: petroleum ether = 1 / 50 ~ 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 is characterized as follows:

[0071] 1 H NMR (600 MHz, CDCl3) δ 8.20 (dd, J = 8.2, 1.0 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 6.85 (s, 1H), 2.93 (t, J = 6.7 Hz, 2H), 2.72-2.66 (m, 1H), 2.48 (s, 2H), 1.86-1.74 (m, 5H), 1.63 (t, J = 6.8 Hz, 2H), 1.41-1.33 (m, 4H), 1.27-1.21 (m, 1H), 1.02 (s, 6H); 13 C NMR (150 MHz, CDCl3) δ 165.0, 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 10 mL of a flask, add the substituted cyclopentadiene ester 2f (0.2 mmol), iodobenzene diacetate (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporate to remove the solvent, and separate the crude product by silica gel column chromatography (eluent: 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 target product 1f is characterized as follows:

[0077] 1 H NMR (600 MHz, CDCI3) δ 8.23 (dd, J = 8.2, 1.1 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.45-7.40 (m, 2H), 7.40-7.36 (m, 1H), 7.35-7.31 (m, 2H), 6.89 (s, 1H), 3.00 (t, J = 6.5 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H), 1.95-1.88 (m, 2H), 1.78-1.72 (m, 2H); 13 CNMR (150 MHz, CDCI3) 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 10 mL of a gourd-shaped bottle, add the substituted cyclopentadiene ester 2g (0.2 mmol), iodobenzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100 ~ 8 / 100, V / V) to obtain the target product 1g (53.9 mg, white solid, yield 71%).

[0080] The reaction equation is as follows:

[0081]

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

[0083] 1 H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 7.5 Hz, 2H), 7.92-7.85 (m, 3H), 7.81 (s, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.55-7.52 (m, 2H), 7.50 (t, J = 7.7 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 3.04 (t, J = 6.5 Hz, 2H), 2.68 (t, J = 6.2 Hz, 2H), 1.97-1.91 (m, 2H), 1.78-1.72 (m, 2H); 13 C NMR (150 MHz, CDCl3) δ 165.2, 157.0, 155.3, 153.4, 136.1, 133.6, 133.0, 132.7, 130.3, 129.2, 128.8, 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 10 mL of a flask, add the substituted cyclopentadiene ester 2h (0.2 mmol), iodo benzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent: 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 target product 1h is characterized as follows:

[0089] 1 H NMR (600 MHz, CDCl3) δ 6.70 (s, 1H), 2.85 (t, J = 5.4 Hz, 2H), 2.72-2.62 (m, 3H), 2.55 (t, J = 7.6 Hz, 2H), 1.85-1.70 (m, 10H), 1.39-1.24 (m, 22H), 0.86 (t, J = 7.0 Hz, 3H); 13 CNMR (150 MHz, CDCl3) δ 172.2, 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 10 mL of a flask, add the substituted cyclopentadiene ester 2i (0.2 mmol), iodobenzene diacetate (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent: 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 is characterized as follows:

[0095] 1 H NMR (600 MHz, CDCl3) δ 6.63 (s, 1H), 2.86 (t, J = 5.4 Hz, 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 (150 MHz, CDCl3) δ 176.1, 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 10 mL of a flask, add the substituted cyclopentadiene ester 2j (0.2 mmol), iodobenzene diacetate (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent: 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 is characterized:

[0101] 1 H NMR (600 MHz, CDCl3) δ 6.69 (s, 1H), 2.86 (t, J = 5.4 Hz, 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 (150 MHz, CDCl3) δ 167.0, 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] Example 11

[0103] Take 10 mL of a flask, add the substituted cyclopentadiene ester 2k (0.2 mmol), iodo benzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and the crude product is separated by silica gel column chromatography (eluent: 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 target product 1k is characterized as follows:

[0107] 1 H NMR (600 MHz, CDCl3) δ 7.01 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 4.9 Hz, 2H), 6.64 (s, 1H), 3.99 (t, J = 5.6 Hz, 2H), 2.89 (t, J = 5.6 Hz, 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 (150 MHz, CDCl3) δ 176.4, 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 10 mL of a tomato-shaped bottle, add the substituted cyclopentadiene ester 2l (0.2 mmol), iodobenzene diacetic acid (0.6 mmol), carbamic acid ammonium (0.3 mmol), magnesium oxide (1.0 mmol) in turn, add chloroform (1.8 mL), 2,2,2-trifluoroethanol (0.2 ml), water (0.009 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), after the reaction is completed, add 2 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporate to remove the solvent, and separate the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100-10 / 100, V / V) to obtain the target product 1l (51.9 mg, yellowish oil, yield 56%).

[0110] The reaction equation is as follows:

[0111]

[0112] The target product 1l is characterized as follows:

[0113] 1 H NMR (600 MHz, CDCl3) δ 8.31 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 6.84 (s, 1H), 3.11 (t, J = 7.6 Hz 4H), 2.89 (t, J = 5.7 Hz, 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 = 7.4 Hz, 6H); 13 C NMR (150 MHz, CDCl3) δ 163.8, 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] Example 13

[0115] In order to verify the practicability of the present application, a gram-scale scale-up experiment was also carried out. When the substituted cyclopentadiene ester 2a was scaled up to 4 mmol (1.2898 g), the expected product was still obtained in a yield of 72%, fully demonstrating the practicability of the present application.

[0116] Take 50 mL of ajar, add the substituted cyclopentadiene ester 2a (4 mmol, 1.29 g), iodobenzene diacetate (12 mmol), carbamide (6 mmol), magnesium oxide (20 mmol) in turn, add chloroform (36 mL), 2,2,2-trifluoroethanol (4 ml), water (0.18 ml) under atmospheric conditions, react at room temperature for 30 minutes (thin plate chromatography to track the reaction until the reaction is complete), filter to remove the magnesium oxide after the reaction is completed, add 40 milliliters of saturated sodium bicarbonate solution to quench, extract twice with dichloromethane, combine the organic phase, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, filter, rotary evaporation to remove the solvent, and separate the crude product by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 50 ~ 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] Example 14

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

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

[0122] The reaction equation is as follows:

[0123]

[0124] The target product 3 is characterized as follows:

[0125] 1 H NMR (600 MHz, CDCl3) δ 12.99 (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 (150 MHz, CDCl3) δ 165.0, 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] Example 15

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

[0128]

[0129] Table 1

[0130]

[0131] As can be seen from Table 1, the yield using mixed solvent is higher than that of single solvent; decomposition is used when using bis(trifluoroacetoxy)iodobenzene as an oxidant; the yield is general when using ammonium carbonate and ammonium chloride; the best effect is achieved when using iodobenzene diacetate as an oxidant, ammonium carbamate as an ammonia source, water and magnesium oxide as additives, and trichloromethane and 2,2,2-trifluoroethanol as mixed solvents.

[0132] Therefore, the present application provides a high-efficiency method for synthesizing a masked 2-pyridone compound, which does not require a metal catalyst and has the advantages of simple operation, wide substrate range, and high yield.

[0133] Example 16

[0134] Botrytis cinerea (B.c), also known as gray mold, is a broad-host plant that can cause the collapse of various plant seedlings, fruit and storage organs, defoliation, flower rot, rotten fruit and rotten cellar. A large number of gray mold layers (conidiophores and conidia) are produced on the surface of the diseased part in wet conditions, which is called gray mold. The characteristics of fast reproduction rate, large genetic variation and high adaptability have brought great influence on its control.

[0135] Fusarium graminearum (F.g), also known as Fusarium graminearum, can cause diseases of field crops of the Gramineae family. For example, the sexual state causes wheat scab. In stored grain diseases, the fungus can cause heat and mold of wheat, corn and other grain crops. The fungus is an aerobic mesophilic bacterium, and the optimum temperature for growth and reproduction is 20-40℃.

[0136] Sclerotinia sclerotiorum (S.s), also known as sclerotinia stem rot, is one of the important diseases of oilseed rape in China, which is caused by Sclerotinia sclerotiorum. The disease mainly harms the stems, leaves, flowers, silique and seeds of oilseed rape. The pathogen has a wide host range and can infect many plants, in addition to many cruciferous plants, it can also infect lettuce, sunflower, carrot, soybean, broad bean and pea.

[0137] Pestalotiopsis funerea (P.c), also 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 the infection and spread are fast, which can cause an outbreak of the disease in a short period. The disease is caused by the infection of P. funerea and occurs on peppers. It can occur in the seedling and adult stages of peppers, with the adult stage being the main occurrence. The pathogen can infect roots, stems, leaves and fruits, and can cause complete loss of yield when the disease is severe. The host range of P. funerea is wide, in addition to peppers, it can also harm tomatoes, eggplants and melon crops.

[0138] Botryosphaeria dothidea (B.d) belongs to the genus Botryosphaeria, which is a worldwide distributed fungus with a very wide host range. It can cause branch dieback, canker, gum flow and fruit rot of various forest trees and fruit trees, and can also cause root rot leading to the death of the whole tree. The diseases caused by Botryosphaeria dothidea on forest trees and fruit trees degrade the quality of timber, reduce the yield of economic forests, and cause serious damage and economic losses due to fruit rot and deterioration.

[0139] The compounds 1a-1l prepared in Examples 1-13 were subjected to inhibition test experiments of tomato gray mold, wheat scab, oilseed rape sclerotinia, pepper pestalotiopsis and grape botryosphaeria, and the specific process was as follows:

[0140] The plant fungi used in this experiment were tomato gray mold, wheat scab, oilseed rape sclerotinia, pepper pestalotiopsis and grape botryosphaeria strains stored at 4°C in the laboratory. The culture medium used was potato agar glucose medium (PDA for short). The PDA medium formula: potato (peeled) 200 g, glucose 20 g, agar 15 g, distilled water 1000 mL, preparation method: wash and peel the potato, weigh 200 g and cut into small pieces, cook until soft (boil for 20-30 minutes, until it can be poked with a glass rod), filter in a beaker with eight layers of gauze, add 15-20 g of agar according to the experimental needs, add 20 g of glucose, stir evenly, dissolve thoroughly, cool slightly, make up the water to 1000 mL, sterilize at 121°C for 30 minutes after dispensing, cool and reserve.

[0141] Experimental method: growth rate method.

[0142] (1) First, two kinds of plant fungi were cultured on PDA plates at 25°C for 3-6 days for use; (2) The compounds 1a-1l prepared in Examples 1-13 were dissolved in DMSO to prepare a compound solution, and then diluted with sterile water to prepare a compound solution with a concentration of 0.5 mg / mL;

[0143] (2) The PDA medium was heated to dissolve, and cooled to 45-50°C. The test compound was added to the medium to make a 50 mg / L solution, and the solution was poured into Petri dishes and cooled. Chlorothalonil and tetramethylthiuram disulfide were used as positive controls.

[0144] (3) The mycelium of each strain was punched with a puncher to make a round cake (0.50 cm in diameter) at the edge of the mycelium after 6 days of culture, and the cake was picked up with a needle and placed in the center of the Petri dish. The Petri dish was then inverted and placed in an incubator (28°C) for culture.

[0145] (4) The growth of the mycelium was observed at different times after treatment, and the diameter was measured using a cross method and the data was processed to calculate the inhibition rate.

[0146] (5) Inhibition rate (%) = (diameter of control mycelium - diameter of treated mycelium) / (diameter of control mycelium - 0.5) x 100.

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

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

[0149] Table 2

[0150]

[0151]

[0152] As shown in Table 2, the compounds had certain inhibitory activity against the plant pathogenic fungi B. d, F. g, S. s, P. c, and B. d. Compound 1d had better inhibitory effect than chlorothalonil and worse inhibitory effect than tetramethylthiuram disulfide against B. d. Compound 1b had significantly better inhibitory effect than chlorothalonil and tetramethylthiuram disulfide against F. g. Compound 1k had better inhibitory effect than tetramethylthiuram disulfide against S. s. Compounds 1a, 1b, and 1f had inhibitory effect close to that of tetramethylthiuram disulfide against P. c. Compounds 1b, 1d, 1h, 1i, and 1k had good inhibitory effect against B. d, and compound 1k had better inhibitory effect than chlorothalonil and tetramethylthiuram disulfide.

[0153] It should be noted that the above examples are only used to illustrate the technical solutions of the present application but not limit the present application. Although the present application is described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or equivalently replaced, without departing from the spirit and scope of the technical solutions of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. A cyclohexane-fused masked 2-pyridinone compound characterized by: The compound has a structure shown in formula (I): wherein R 1 is selected from phenyl, C11alkyl, adamantyl, and one of the following structural formulae: R 2 one selected from cyclohexyl, t-butyl, C5alkyl, phenyl, naphthyl, and adamantyl; R 3 is selected from hydrogen or methyl.

2. The cyclohexane-fused masked 2-pyrone compound according to claim 1, wherein: The compound is selected from one of the following compounds:

3. The process for the preparation of a cyclohexane-fused masked 2-pyridinone compound according to claim 1 or 2, characterized in that: The method comprises the steps of, The cyclopentadienyl cyclohexane ester compound shown in formula (II) is used as raw material, and a trivalent iodine reagent, an ammonium reagent, magnesium oxide, and water are used together in a solvent at room temperature to obtain the compound shown in formula (I). wherein R 1 , R 2 , R 3 in formula (II) correspond to R 1 , R 2 , R 3 in formula (I).

4. A process for the preparation of a cyclohexane-fused masked 2-pyridinone compound as claimed in claim 3, characterized in that: The trivalent iodine reagent is selected from iodobenzene diacetate or bis(trifluoroacetoxy)iodobenzene, and the molar ratio of the trivalent iodine reagent to the compound shown in formula (II) is 2-3:

1.

5. A process for the preparation of a cyclohexane-fused masked 2-pyridinone compound according to claim 3 or 4, characterized in that: The ammonium reagent is selected from one of ammonium carbamate, ammonium chloride, and ammonium carbonate, and the molar ratio of the ammonium reagent to the compound shown in formula (II) is 1.5-4:

1.

6. A process for the preparation of a cyclohexane-fused masked 2-pyridinone compound as claimed in claim 5, characterized in that: The molar ratio of the magnesium oxide to the compound shown in formula (II) is 3-10:

1.

7. A process for the preparation of a cyclohexane-fused masked 2-pyridinone compound as claimed in any one of claims 3, 4, 6, characterized in that: The molar ratio of the water to the compound shown in formula (II) is 1-5:

1.

8. A process for the preparation of a cyclohexane-fused masked 2-pyridinone compound as claimed in 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 shown in formula (II) in the solvent is 0.1 mol / L, the reaction temperature is room temperature, and the reaction time is 10-30 minutes.

9. A process for the preparation of a cyclohexane-fused masked 2-pyridinone compound as claimed in claim 8, characterized in that: The solvent is a mixed solvent of chloroform and 2,2,2-trifluoroethanol, and the ratio of chloroform to 2,2,2-trifluoroethanol is 1-19:

1.

10. Use of the cyclohexane-fused masked 2-pyridinone compounds according to claim 1 or 2 for inhibiting phytopathogenic fungi or for the manufacture of a pharmaceutical for inhibiting phytopathogenic fungi, characterized in that: The plant pathogenic fungi are one or more of Botrytis cinerea, Fusarium equiseti, Sclerotinia sclerotiorum, Phytophthora capsici, and Botryosphaeria dothidea.

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