Isoquinolinone dihydropyridine-[1, 2-alpha] indole spiro compound as well as preparation method and application thereof

Abstract

The invention discloses an isoquinolinone dihydropyridine-[1, 2-alpha] indole spiro compound as well as a preparation method and application thereof, and belongs to the technical field of synthesis of organic compounds. An N-indole connected o-alkynyl nitrone compound is used as a raw material, a two-step one-pot method is adopted, and the isoquinolinone dihydropyridine-[1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, the invention relates to a novel method for synthesizing a spiro [1, 2-alpha] indole. The method disclosed by the invention has the advantages of simplicity in operation, low catalyst loading capacity, wide reaction substrate range, single stereoselectivity, high yield and the like. The isoquinolinone dihydropyridine-[1, 2-alpha] indole spiro compound prepared by the invention has a certain inhibition effect on phytopathogen, and can be potentially applied to prevention and treatment of tomato gray mold, wheat scab and rhizoctonia solani.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and specifically relates to an isoquinolinone dihydropyridine-[1,2-α]indole spiro compound and a preparation method and application thereof. Background Art

[0002] Isoquinolinone and pyridindolone are common structural units in natural products and drug molecules. Structural molecules with such skeletons have excellent biological and pharmaceutical activities and have important research value in the history of drug development and human disease treatment. Therefore, exploring and developing effective strategies for their efficient construction has always been a hot topic in the field of organic synthetic chemistry research.

[0003] Isoquinolinone alkaloids with an isoquinolinone core structure are of various types and widely found in nature, such as lotus leaves and purslane. These compounds have diverse biological activities (J. Med. Chem. 2004, 47, 561), such as analgesia and anti-inflammation (Tetrahedron Lett., 1998, 39, 3099), anti-tumor (J. Am. Chem. Soc. 2011, 133, 14952), anti-malarial, anti-depression, antibacterial, etc. Many polycyclic compounds containing pyridindolone units show unique and diverse biological activities (Org. Biomol. Chem. 2022, 20, 2086-2095). For example, Strychnine, isolated from the genus Strychnine, was used as a stimulant in medicine and as an insecticide to control rodents because of its strong neurotoxicity (Nature. 2022, 607, 617-622). (±)-Mersicarpine isolated from plants of the genus Kopsia is a strong biological and pharmacological activity against the human leukemia cell line HL60, reversibly blocking the cell cycle process in the S phase, and is a new translation inhibitor that induces apoptosis (Biosci. Biotechnol. Biochem. 2021, 85, 92-96). In addition to good biological activity, these natural products can also be used as important organic synthesis intermediates for the synthesis of complex natural products and bioactive molecules.

[0004] At present, there is no literature report on the method of synthesizing isoquinolinone and dihydropyridine-[1,2-α]indolone spiro compounds. Therefore, it is of great significance to quickly and efficiently construct isoquinolinone and dihydropyridine-[1,2-α]indolone spiro compounds from simple and readily available raw materials. Summary of the invention

[0005] Based on the above content, the present invention provides an isoquinolinone dihydropyridine-[1,2-α] indole spiro compound and its preparation method and application, which fills the technical gap in the synthesis of isoquinolinone dihydropyridine-[1,2-α] indole spiro compounds. The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract of the specification and the title of the invention of this application to avoid blurring the purpose of this section, the abstract of the specification and the title of the invention, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0006] In view of the above problems or problems existing in the prior art, the present invention is proposed.

[0007] One of the purposes of the present invention is to provide an isoquinolinone-dihydropyridine-[1,2-α]indole spiro compound, which has a certain inhibitory effect on plant pathogens and can be potentially used in the prevention and treatment of tomato gray mold, wheat fusarium rust and rice sheath blight.

[0008] In order to solve the above technical problems, the present invention provides the following technical solution: an isoquinolinone dihydropyridine-[1,2-α]indole spiro compound, the structural formula of which is shown in formula (I):

[0009]

[0010] Among them, R 1 is selected from one of hydrogen, halogen, methyl, ethyl, methoxy, methoxyester or cyano; R 2 is selected from one of hydrogen, methyl, CH2CH2OAc or CH2CH2NHBoc; R 3 One selected from hydrogen, methyl, halogen or trifluoromethyl.

[0011] Another object of the present invention is to provide a method for preparing an isoquinolinone-dihydropyridine-[1,2-α]indole spiro compound, which has the advantages of simple operation, low catalyst loading, wide substrate range, high yield, etc.

[0012] In order to solve the above technical problems, the present invention provides a method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound as described above, comprising the following steps: using an o-alkynyl nitrone compound represented by formula (II) as a raw material, heating the compound in a solvent A under the catalysis of a rhodium catalyst, filtering and concentrating the compound after the reaction, and reacting the compound in a solvent B under the promotion of cerium ammonium nitrate to obtain the compound;

[0013]

[0014] Among them, R 1 , R 2 , R3 With R in formula (I) 1 , R 2 , R 3 The corresponding ones are consistent.

[0015] The reaction equation is:

[0016]

[0017] As a preferred embodiment of the method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound of the present invention, the rhodium catalyst is one selected from (1,5-cyclooctadiene)rhodium chloride dimer, bis(1,5-cyclooctadiene)rhodium tetrafluoroborate and tetracarbonyl dirhodium dichloride; the molar ratio of the catalyst to the compound represented by formula (II) is 0.01 to 0.05:1.

[0018] As a preferred embodiment of the method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound of the present invention, wherein: the reaction is heated in solvent A under the catalysis of the rhodium catalyst, and a desiccant is added to the reaction system. The desiccant is Molecular sieve, the amount of the desiccant added is 100 mg of desiccant for every 0.1 mmol of the compound represented by formula (II).

[0019] As a preferred embodiment of the method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indole spiro compound of the present invention, the solvent A is toluene or dichloroethane, the concentration of the compound represented by formula (II) in the solvent A is 0.1 mol / L, the reaction temperature is 100° C., and the reaction time is 12 to 24 hours.

[0020] As a preferred embodiment of the method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indole spiro compound of the present invention, the molar ratio of the ammonium cerium nitrate to the compound represented by formula (II) is 4 to 6:1.

[0021] As a preferred embodiment of the method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indole spiro compound of the present invention, the reaction is promoted by ammonium cerium nitrate in solvent B, and solvent B is a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1 to 4:1; the concentration of the compound represented by formula (II) in solvent B is 0.1 mol / L, the reaction temperature is room temperature, and the reaction time is 5 to 30 minutes.

[0022] Another object of the present invention is to provide an application of an isoquinolinone dihydropyridine-[1,2-α]indole spiro compound in the preparation of a compound represented by formula (III), characterized in that the structural formula represented by formula (III) is:

[0023]

[0024] Another object of the present invention is to provide the use of the above-mentioned isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound or the above-mentioned compound represented by formula (III) in inhibiting tomato gray mold (Bc), and / or wheat fusarium (Gz), and / or rice sheath blight (Rs); or, in the preparation of a product for inhibiting tomato gray mold (Bc), and / or wheat fusarium (Gz), and / or rice sheath blight (Rs).

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound prepared by the invention has a certain inhibitory effect on plant pathogenic bacteria and can be potentially applied to the prevention and treatment of tomato gray mold, wheat fusarium head blight and rice sheath blight.

[0027] The invention uses indole, which is easily available, as a starting material, and conveniently synthesizes N-indole-linked ortho-alkynyl nitrone compounds as raw materials, and adopts a two-step one-pot method to provide a novel method for synthesizing isoquinolinone and dihydropyridine-[1,2-α] indole spirocyclic compounds that are difficult to prepare by conventional methods, based on a rhodium-catalyzed internal redox / dearomatization cycloaddition / cerium ammonium nitrate-promoted oxidative debenzylation / spirocyclization tandem reaction strategy. The method of the invention has the advantages of simple operation, low catalyst loading, wide reaction substrate range, single stereoselectivity, high yield, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] 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:

[0029] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the target product 1a prepared in Example 1 of the present invention;

[0030] Figure 2 This is the carbon NMR spectrum of the target product 1a prepared in Example 1 of the present invention;

[0031] Figure 3 The single crystal diffraction pattern of the target product 1a prepared in Example 1 of the present invention;

[0032] Figure 4 Schematic diagram of the reaction mechanism represented by raw material 2a in Example 1 of the present invention. DETAILED DESCRIPTION

[0033] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0034] 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.

[0035] 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.

[0036] The raw material N-indole-linked o-alkynyl nitrone compound used in the example, the method reported in the reference literature (Angew.Chem.Int.Ed.2008,47,7040-7043; Org.Chem.Fron.,2023,10,140-149; Org.Lett.2024,26,31,6631-6636.) starts from the simple and easily available indole, and the raw material can be obtained in a high yield in only three steps.

[0037] Example 1

[0038] Take a 10mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2a (0.2mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 4 / 1~2 / 1, V / V) to obtain the target product 1a.

[0039] (54.7 mg, yellow solid, yield 87%).

[0040] The reaction equation is:

[0041]

[0042] The target product 1a was characterized as follows: Figure 1 and 2 shown.

[0043] 1 H NMR (600MHz, CDCl3) δ8.67(s,1H),8.53(d,J=8.3Hz,1H),8.13(d,J=7.7Hz,1H),7.88(t, J=7.5Hz,1H),7.73(t,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.40(d,J=7.7Hz,1H),7.34(t ,J=7.5Hz,1H),7.23(t,J=7.5Hz,1H),6.15(s,1H),3.26(ddd,J=17.6,8.5,5.4Hz,1H),3 .09(ddd,J=17.7,7.3,5.2Hz,1H),2.60(ddd,J=13.6,8.5,5.2Hz,1H),2.39–2.33(m,1H); 13 C NMR (100MHz, CDCl3) δ198.3,168.4,157.2,137.1,136.2,135.0,132.9,130.4,1 28.9,128.3,127.9,126.2,125.2,124.0,120.5,116.6,106.1,66.5,31.7,29.8.

[0044] The structure and relative configuration of the target product 1a were confirmed by single crystal diffraction, such as Figure 3 shown.

[0045] Taking raw material 2a as a representative, the reaction mechanism of the present invention is as follows Figure 4 shown.

[0046] First, the carbon-carbon triple bond in 2a is complexed with the catalyst (1,5-cyclooctadiene) rhodium chloride dimer to obtain complex A. The nitrone attacks the metal-activated alkyne, and an intramolecular 6-exo-dig cyclization reaction occurs to produce intermediate B, which is then subjected to internal redox to obtain α-carbonyl carbene C. Subsequently, the imine attacks the rhodium carbene nucleophilically to obtain the cyclic imine ylide intermediate D. The highly active imine ylide undergoes an intramolecular dearomatization [3+2] cycloaddition with the side chain indole C(2)=C(3) bond to obtain E, and the Rh(I) salt is regenerated. Under the oxidation conditions mediated by ammonium cerium nitrate, E is first oxidized to secondary amine F, and benzaldehyde is generated as a byproduct. The single-electron oxidation of F by ammonium cerium nitrate produces a radical cation G, which undergoes homolytic cleavage of the carbon-carbon bond to form a new spirocyclic carbon radical H. Further oxidation by ammonium cerium nitrate resulted in deprotonation to give the carbon cation intermediate I, which was then further deprotonated to give the target product 1a.

[0047] Example 2

[0048] Take a 10mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2b (0.2mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 4 / 1~1 / 1, V / V) to obtain the target product 1b.

[0049] (41.6 mg, yellow solid, yield 52%).

[0050] The reaction equation is:

[0051]

[0052] 1H NMR (600MHz, CDCl3) δ8.75(s,1H),8.56(d,J=8.3Hz,1H),8.15(d,J=7.7Hz,1H),7.90(td,J=7.6,1.0Hz,1H),7.74(td ,J=7.6,0.9Hz,1H),7.65(d,J=7.6Hz,1H),7.54(d,J=7.7Hz,1H),7.39–7.35(m,1H),7.31–7.27(m,1H),4.12(ddd,J=1 0.8,8.2,5.9Hz,1H),4.05–3.99(m,1H),3.05(ddd,J=17.3,7.5,4.8Hz,1H),2.91(ddd,J=17.3,9.0,4.9Hz,1H),2.72 –2.66(m,1H),2.61(ddd,J=14.1,8.0,5.9Hz,1H),2.38(ddd,J=13.8,9.0,4.8Hz,1H),2.30–2.24(m,1H),1.85(s,3H); 13 C NMR (150MHz, CDCl3) δ198.6,170.7,168.0,157.1,136.3,134.8,133.6,133.0,130.2,130.0, 128.5,127.7,126.2,125.4,123.9,118.6,116.9,115.5,67.7,62.8,33.1,29.2,24.2,20.8;

[0053] Example 3

[0054] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2c (0.2 mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1c.

[0055] (54.9 mg, yellow solid, yield 60%).

[0056] The reaction equation is:

[0057]

[0058] 1 H NMR (600MHz, CDCl3) δ8.73 (s, 1H), 8.56 (d, J = 8.2Hz, 1H), 8.15 (d, J = 7.7Hz, 1H), 7.89 (t, J = 7.5Hz, 1H),7.74(t,J=7.6Hz,1H),7.63(d,J=7.6Hz,1H),7.52(d,J=7.4Hz,1H),7.37(t,J=7.7Hz,1H),7. 28(t,J=7.5Hz,1H),4.85(s,1H),3.30–3.13(m,2H),3.08–3.00(m,1H),2.94–2.85(m,1H),2.59–2 .50(m,1H),2.49–2.42(m,1H),2.37(ddd,J=13.5,8.8,4.8Hz,1H),2.31–2.24(m,1H),1.36(s,9H); 13 C NMR (150MHz, CDCl3) δ198.9,168.0,157.1,155.7,136.3,134.9,133.4,133.1,130.2,129.9,12 8.5,127.7,126.2,125.4,123.9,118.9,117.0,116.8,78.9,67.7,39.5,33.2,29.3,28.4,25.1.

[0059] Example 4

[0060] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2d (0.2 mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 4 / 1~1 / 1, V / V) to obtain the target product 1d

[0061] (51.8 mg, yellow solid, yield 78%).

[0062] The reaction equation is:

[0063]

[0064] 1 H NMR (600MHz, CDCl3) δ8.73(s,1H),8.29(d,J=8.3Hz,1H),8.13(d,J=7.7Hz,1H),7.88( t,J=7.4Hz,1H),7.74(t,J=7.6Hz,1H),7.64(d,J=7.5Hz,1H),7.29–7.23(m,1H),6.91( t,J=8.9Hz,1H),6.28(s,1H),3.23(ddd,J=17.7,7.7,5.5Hz,1H),3.10(ddd,J=17.8,7 .7,5.3Hz,1H),2.56(ddd,J=13.3,7.8,5.3Hz,1H),2.40(ddd,J=13.4,7.6,5.6Hz,1H); 13 C NMR (150MHz, CDCl3) δ197.6,168.4,158.0,155.5(d,J=248.3Hz),137.0(d,J=9.0Hz),136.9,136.4,133.4,130.1,128.7, 127.7, 126.3, 126.1 (d, J = 7.2Hz), 117.7 (d, J = 21.7Hz), 112.7 (d, J = 3.7Hz), 109.4 (d, J = 18.5Hz), 101.7, 66.4, 31.6, 29.6; 19 FNMR (565MHz, CDCl3) δ-122.19 (dd, J = 9.5, 5.4Hz).

[0065] Example 5

[0066] Take a 10mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2e (0.2mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 4 / 1~1 / 1, V / V) to obtain the target product 1e.

[0067] (62.9 mg, yellow solid, yield 80%).

[0068] The reaction equation is:

[0069]

[0070] 1 H NMR (600MHz, CDCl3) δ8.71(s,1H),8.46(d,J=8.2Hz,1H),8.12(d,J=7.7Hz,1H ),7.86(t,J=7.5Hz,1H),7.72(t,J=7.6Hz,1H),7.61(d,J=7.5Hz,1H),7.38(d ,J=7.8Hz,1H),7.18(t,J=8.0Hz,1H),6.24(s,1H),3.20(dt,J=17.5,6.3Hz,1 H),3.08(ddd,J=13.2,7.1,5.7Hz,1H),2.54–2.47(m,1H),2.43–2.36(m,1H); 13 C NMR (150MHz, CDCl3) δ197.7,168.3,157.8,137.8,136.3,135.3,133.2,130.1,1 29.6,128.6,127.6,126.9,126.3,126.1,115.6,114.3,105.9,66.5,31.7,29.6.

[0071] Example 6

[0072] Take a 10mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2f (0.2mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 4 / 1~1 / 1, V / V) to obtain the target product 1f.

[0073] (40.6 mg, brown solid, yield 59%).

[0074] The reaction equation is:

[0075]

[0076] 1 H NMR (600MHz, CDCl3) δ8.66(s,1H),8.40(d,J=9.0Hz,1H),8.12(d,J=7.7Hz,1H),7.87(td,J =7.6,1.2Hz,1H),7.72(td,J=7.6,1.1Hz,1H),7.60(d,J=7.4Hz,1H),6.93(dd,J=9.0,2.5H z,1H),6.86(d,J=2.5Hz,1H),6.08(s,1H),3.79(s,3H),3.22(ddd,J=17.6,8.5,5.4Hz,1H) ,3.05(ddd,J=17.7,7.4,5.2Hz,1H),2.58(ddd,J=13.6,8.5,5.2Hz,1H),2.38–2.31(m,1H); 13 C NMR (150MHz, CDCl3) δ198.3,168.0,157.2,156.7,137.7,136.2,132.9,130.4,129. 9,129.8,128.3,127.9,126.2,117.4,113.4,105.9,103.4,66.5,55.6,31.8,29.6.

[0077] Example 7

[0078] Take a 10mL round-bottom flask and add 2g (0.2mmol) of N-indole-linked o-alkynyl nitrone, Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under an argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 4 / 1~1 / 1, V / V) to obtain 1g of the target product.

[0079] (48.8 mg, yellow solid, yield 70%).

[0080] The reaction equation is:

[0081]

[0082] 1 H NMR (600MHz, CDCl3) δ8.69(s,1H),8.38(d,J=8.8Hz,1H),8.07(d,J=7.6Hz,1H),7.82(t, J=7.2Hz,1H),7.68(t,J=7.5Hz,1H),7.58(d,J=7.5Hz,1H),7.32(d,J=1.9Hz,1H),7.22(d d,J=8.8,2.0Hz,1H),6.10(s,1H),3.17(ddd,J=17.7,7.6,5.5Hz,1H),3.03(ddd,J=17.8 ,7.8,5.3Hz,1H),2.49(ddd,J=13.2,7.6,5.3Hz,1H),2.37(ddd,J=13.5,7.8,5.5Hz,1H); 13 C NMR (150MHz, CDCl3) δ197.5,168.0,157.9,138.2,136.2,133.2,130.1,129. 9,129.3,128.6,127.5,126.1,125.1,120.0,117.4,105.3,66.3,31.5,29.4.

[0083] Example 8

[0084] Take a 10mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2h (0.2mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 4 / 1~1 / 1, V / V) to obtain the target product 1h

[0085] (55.1 mg, yellow solid, yield 74%).

[0086] The reaction equation is:

[0087]

[0088] 1H NMR (600MHz, CDCl3) δ8.71(s,1H),8.56(d,J=8.7Hz,1H),8.13(d,J=7.2Hz,2H),8.03(d,J=8.7Hz,1H),7.90(t,J=7.3Hz,1H),7.74(t,J= 7.5Hz,1H),7.63(d,J=7.4Hz,1H),6.24(s,1H),3.91(s,3H),3.29–3.20(m,1H),3.14–3.05(m,1H),2.59–2.52(m,1H),2.44–2.36(m,1H); 13 C NMR (150MHz, CDCl3) δ197.9,168.4,167.3,157.8,138.5,137.7,136.4,133.2,130.3,1 28.8,128.5,127.8,126.5,126.3,125.9,122.7,116.3,106.4,66.5,52.0,31.7,29.7.

[0089] Example 9

[0090] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2i (0.2 mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 4 / 1 to 1 / 1, V / V) to obtain the target product 1i.

[0091] (44 mg, yellow solid, yield 67%).

[0092] The reaction equation is:

[0093]

[0094] 1H NMR (600MHz, CDCl3) δ8.66 (s, 1H), 8.36 (s, 1H), 8.12 (d, J = 7.7Hz, 1H), 7.87 (td, J = 7.6, 1.1Hz,1H),7.72(td,J=7.6,0.9Hz,1H),7.60(d,J=7.6Hz,1H),7.27(d,J=7.3Hz,1H),7 .05(d,J=7.9Hz,1H),6.09(s,1H),3.23(ddd,J=17.6,8.4,5.4Hz,1H),3.08(ddd,J=17. 7,7.4,5.2Hz,1H),2.58(ddd,J=13.6,8.4,5.2Hz,1H),2.47(s,3H),2.37–2.31(m,1H); 13 C NMR (150MHz, CDCl3) δ198.3,168.5,157.2,136.3,136.1,135.4,135.4,132.9,130. 4,128.3,128.0,126.6,126.2,125.4,120.0,116.9,106.0,66.5,31.6,29.8,21.9.

[0095] Example 10

[0096] Take a 10 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2j (0.2 mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 4 / 1~1 / 1, V / V) to obtain the target product 1j.

[0097] (40.1 mg, yellow solid, yield 61%).

[0098] The reaction equation is:

[0099]

[0100] 1H NMR (600MHz, CDCl3) δ8.66(s,1H),8.11(d,J=7.7Hz,1H),7.85(td,J=7.6,0.9Hz,1H),7.71(t,J=7.6Hz,1H),7.58(d,J=7.6Hz,1H),7.20(dd,J=6.8Hz,1 .8Hz,1H),7.16–7.11(m,2H),6.14(s,1H),3.26(ddd,J=17.3,8.7,5.7Hz,1H ),3.10(ddd,J=17.3,6.8,5.6Hz,1H),2.69–2.62(m,4H),2.38–2.32(m,1H); 13 C NMR (150MHz, CDCl3) δ198.3,167.7,157.1,138.6,136.1,134.9,132.9,130.7,130. 4,128.5,128.3,127.9,127.1,126.2,124.5,118.1,106.9,67.0,31.6,30.5,23.0.

[0101] Embodiment 11

[0102] Take a 10mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2k (0.2mmol), Molecular sieves (200 mg) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.002 mmol), toluene (2 mL) was added under argon atmosphere, and the reaction was carried out at 100 ° C for 12 hours. After cooling to room temperature, the molecular sieves were filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (0.1 mmol), acetonitrile (1.6 mL) and water (0.4 mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation after filtration. The crude product was separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 5 / 1~3 / 1, V / V) to obtain the target product 1k

[0103] (55.8 mg, yellow solid, yield 73%).

[0104] The reaction equation is:

[0105]

[0106] 1H NMR(600MHz, CDCl3)δ8.72(s,1H),8.51(d,J=8.3Hz,1H),8.24(d,J=8.0Hz,1H), 7.96(d,J=8.0Hz,1H),7.88(s,1H),7.40(d,J=7.7Hz,1H),7.34(t,J=7.8Hz,1H), 7.23(t,J=7.5Hz,1H),6.13(s,1H),3.26(ddd,J=17.7,8.4,5.4Hz,1H),3.08(ddd ,J=17.7,7.2,5.3Hz,1H),2.60(ddd,J=13.6,8.4,5.2Hz,1H),2.42–2.35(m,1H); 13 C NMR (150MHz, CDCl3) δ197.3,168.1,155.8,137.4(d,J=33.4Hz),136.3,135.0,130.6,130.1,129.4(dd,J= 7.0, 3.5Hz), 128.7, 127.1, 125.4, 125.3 (dd, J = 7.3, 3.6Hz), 124.1, 120.5, 116.6, 106.2, 66.8, 31.6, 29.7; 19 F NMR(377MHz, CDCl3)δ-63.35(s).

[0107] Example 12

[0108] In order to verify the application value of the present invention, the present invention also carried out a millimole-scale amplification experiment. When the raw material N-indole-linked o-alkynyl nitrone 2a was amplified to 1 mmol (406.5 mg), and the loading amount of the catalyst (1,5-cyclooctadiene) rhodium chloride dimer was further reduced to 0.5 mol%, the reaction was still able to obtain the expected product with a yield of 87%, which fully demonstrated the potential application value of the present invention.

[0109] Take a 100 mL round-bottom flask and add N-indole-linked o-alkynyl nitrone 2a (1 mmol, 406.5 mg), Molecular sieve (1g) and (1,5-cyclooctadiene) rhodium chloride dimer catalyst (0.5mmol), toluene (10mL) was added under argon atmosphere, and the reaction was carried out at 100°C for 12 hours. After cooling to room temperature, the molecular sieve was filtered, and the filtrate was concentrated by rotary evaporation. Then, ammonium cerium nitrate (5mmol), acetonitrile (8mL) and water (2mL) were added to the reaction system for further reaction for 30 minutes. After the reaction was completed, water and ethyl acetate were added to extract twice, the organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated by rotary evaporation. The crude product was separated by silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 4 / 1~2 / 1, V / V) to obtain the target product 1a (273.5mg, yellow solid, yield 87%)

[0110] The reaction equation is:

[0111]

[0112] 1 H NMR (600MHz, CDCl3) δ8.67(s,1H),8.53(d,J=8.3Hz,1H),8.13(d,J=7.7Hz,1H),7.88(t, J=7.5Hz,1H),7.73(t,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.40(d,J=7.7Hz,1H),7.34(t ,J=7.5Hz,1H),7.23(t,J=7.5Hz,1H),6.15(s,1H),3.26(ddd,J=17.6,8.5,5.4Hz,1H),3 .09(ddd,J=17.7,7.3,5.2Hz,1H),2.60(ddd,J=13.6,8.5,5.2Hz,1H),2.39–2.33(m,1H); 13 C NMR (100MHz, CDCl3) δ198.3,168.4,157.2,137.1,136.2,135.0,132.9,130.4,1 28.9,128.3,127.9,126.2,125.2,124.0,120.5,116.6,106.1,66.5,31.7,29.8.

[0113] Embodiment 13

[0114] The isoquinolinone-dihydropyridine-[1,2-α]indole spiro compounds prepared in Examples 1 to 12 are an important class of organic synthesis intermediates that can be further structurally modified and chemically transformed into various compounds.

[0115] Taking the isoquinolinone-dihydropyridine-[1,2-α]indole spirocyclic compound 1a prepared in Example 12 as an example, under the action of sodium cyanoborohydride, the carbon-nitrogen double bond can be selectively reduced to obtain compound 3a. The reaction equation is as follows:

[0116]

[0117] Take a 10mL round-bottom flask, add isoquinolinone and dihydropyridine-[1,2-α] indole spiro compound 1a (0.2mmol), then add sodium cyanoborohydride (0.6mmol) and methanol (2mL), and react at room temperature for 3 hours (TLC tracking reaction until the reaction is complete). After the reaction is completed, add ammonium chloride to quench, extract twice with ethyl acetate, combine the organic phases, dry over anhydrous magnesium sulfate, filter and concentrate the filtrate by rotary evaporation. The crude product is separated by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 6 / 1~2 / 1, V / V) to obtain the target product 3a (50mg, brown-yellow solid, yield 79%).

[0118] 1 H NMR (600MHz, CDCl3) δ8.50(d,J=8.3Hz,1H),8.16(d,J=7.8Hz,1H),7.59(t,J=7.5Hz,1H),7.45(t,J=7.6Hz,1H),7.39(d,J=7.7Hz,1H),7.33(t,J=7.7 Hz,1H),7.23(t,J=7.5Hz,2H),6.18(s,1H),4.18(d,J=17.4Hz,1H),4.09( d,J=17.4Hz,1H),3.21–3.12(m,1H),2.94–2.83(m,2H),2.11–2.06(m,1H); 13 C NMR (150MHz, CDCl3) δ194.3,168.5,143.5,135.6,135.1,134.1,130.3,128.6,1 28.1,127.6,125.9,125.3,124.0,120.5,116.6,107.1,59.6,42.9,29.7,29.2.

[0119] Embodiment 14

[0120] On the basis of Example 1, the reaction conditions such as the type of catalyst and its loading amount, the type of reaction solvent, the reaction time, the loading amount of ammonium cerium nitrate, the ratio of acetonitrile and water, etc. were optimized. The specific optimization results are shown in Table 1 below:

[0121] Table 1

[0122]

[0123]

[0124] It can be seen from the data in Table 1 that under the same reaction conditions, the product yield is the highest when (1,5-cyclooctadiene) rhodium chloride dimer is used as a catalyst. When other catalysts are used, such as gold tribromide, platinum dibromide, platinum tetraiodide, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate, tetracarbonyl dirhodium dichloride, etc., the product yield decreases to varying degrees.

[0125] When (1,5-cyclooctadiene)rhodium chloride dimer was used as the catalyst, the yield was slightly reduced when solvent A was replaced with dichloroethane.

[0126] When (1,5-cyclooctadiene)rhodium chloride dimer was used as catalyst and toluene was used as solvent, the yield decreased when the loading amount of ammonium cerium nitrate was increased or decreased.

[0127] When (1,5-cyclooctadiene)rhodium chloride dimer is used as catalyst, toluene is used as solvent, and the loading amount of cerium ammonium nitrate is 5 equivalents, the yield is greatly reduced when the ratio of acetonitrile and water in solvent B is changed from 4:1 to 1:1.

[0128] When (1,5-cyclooctadiene)rhodium chloride dimer is used as catalyst, toluene is used as solvent, the loading amount of ammonium cerium nitrate is 5 equivalents, the ratio of acetonitrile to water is 4:1, and the loading amount of the catalyst (1,5-cyclooctadiene)rhodium chloride dimer is reduced to 1 mol%, the yield does not change substantially.

[0129] Furthermore, the optimal reaction conditions obtained are: using 1 mol% (1,5-cyclooctadiene) rhodium chloride dimer as a catalyst, solvent A is toluene, cerium ammonium nitrate is 5 equivalents, and the volume ratio of acetonitrile: water is 4:1.

[0130] Embodiment 15

[0131] 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 tomatoes become infected, they cause a large number of rotten fruits in early spring, generally reducing production by 20-30%, and even up to 50% in severe plots. When the stem is infected, it starts as a small water-soaked spot, which then expands into an oblong or irregular shape, light brown. When the humidity is high, a gray mold layer (conidia and conidiophores of the pathogen) grows on the surface of the lesion. In severe cases, the stems and leaves above the diseased part die, leading to wilt.

[0132] Wheat fusarium head blight (Gz) Wheat fusarium head blight is one of the main fungal diseases of wheat crops. It is widespread throughout the country and has always been one of the most serious diseases in the wheat-growing areas south of the Huaihe River and the middle and lower reaches of the Yangtze River. Wheat can be affected by the disease from the seedling stage to the ear stage, and it can cause various hazards such as seedling blight, base rot, stalk rot and ear rot. After wheat is infected with fusarium head blight, the thousand-grain weight is reduced, the germination rate is reduced, the germination potential is weakened, the flour yield is low, the flour quality is poor, and the color is dark. Not only does it cause a reduction in wheat yield, but also because the metabolites of the pathogen contain toxins such as vomiting toxins and estrogen-like toxins, it can cause acute poisoning after being eaten by humans and animals.

[0133] Rice Sheath Blight (Rs) Rice sheath blight is a disease of rice caused by infection with Rhizoctonia solani. The disease mainly occurs on leaf sheaths and leaves. In the early stage of the disease, oval dark green water-soaked spots first appear on the leaf sheaths near the water surface, and then gradually expand into cloud-like spots, with grayish white in the middle and grayish green when wet. The disease is a high temperature and high humidity disease. Within the suitable range, the higher the humidity, the more serious the disease.

[0134] Furthermore, effective prevention and treatment of these diseases is of great significance.

[0135] Furthermore, on the basis of Examples 1 to 12, the mycelium growth rate inhibition method was used to determine the antibacterial activity. Weigh different compounds and dissolve them in dimethyl sulfoxide (DMSO) and dissolve them completely by ultrasound to prepare a 10 mg / mL drug solution, filter through a 0.22 μm sterile filter membrane, and add it to a sterilized PDA medium under aseptic conditions to prepare a drug-containing medium with a concentration of 50 mg / L. Take a 5 mm diameter bacterial cake from the edge of the test colony that has been cultured for 5 days, inoculate it in the center of a PDA plate containing different drug solutions, and use a PDA plate without drug solution as a control. Three replicates are set for each treatment. The mycelium face is facing down and cultured at 28°C. After 5 days, the colony diameter is determined by the cross method, and the mycelium growth inhibition rate is calculated. Three replicates are set for each treatment. The calculation formula is as follows:

[0136]

[0137] Furthermore, the mycelium growth rate inhibition method was used to determine the antibacterial activity of different compounds against tomato gray mold (Bc), wheat fusarium rust (Gz) and rice sheath blight (Rs), and Tetramethylthiuram Disulfide (Thiram) and Chlorothalonil (Chlorothalonil) were used as positive controls to calculate the mycelium growth inhibition rate. The results are shown in Table 2.

[0138] Table 2 Inhibition rate of compounds on plant pathogens

[0139]

[0140] The results showed that for Botrytis cinerea (Bc), compounds 1a, 1c-1d, 1f, 1h-1j, and 3a all had certain inhibitory activity against the plant pathogenic fungus Botrytis cinerea, and the inhibitory effect was significantly better than the positive control thiram; for Gibberella fusca (Gz), compounds 1a, 1d-1e, 1g, 1j, and 3a all had certain inhibitory activity against the plant pathogenic fungus Gibberella fusca, and the inhibitory effect was better than the positive control thiram, among which 1d and 1j had significantly better inhibitory effects than chlorothalonil. For Rhizoctonia solani (Rs), compounds 1a-1k and 3a all had certain inhibitory activity against the plant pathogenic fungus Rhizoctonia solani, and the inhibitory effect was significantly better than the positive control thiram, and 1a and 1c-1d had significantly better inhibitory effects than chlorothalonil.

[0141] The invention uses indole, which is easily available, as a starting material, and conveniently synthesizes N-indole-linked ortho-alkynyl nitrone compounds as raw materials, and adopts a two-step one-pot method to provide a novel method for synthesizing isoquinolinone and dihydropyridine-[1,2-α] indole spirocyclic compounds that are difficult to prepare by conventional methods, based on a rhodium-catalyzed internal redox / dearomatization [3+2] cycloaddition and a cerium ammonium nitrate-promoted oxidative debenzylation / spirocyclization tandem reaction strategy. The method of the invention has the advantages of simple operation, low catalyst loading, wide reaction substrate range, single stereoselectivity, high yield, etc.

[0142] 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 can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. An isoquinolinone-dihydropyridine-[1,2-α]indole spiro compound, characterized in that: The structural formula is shown in formula (I): Among them, R 1 is selected from one of hydrogen, halogen, methyl, ethyl, methoxy, methoxyester or cyano; R 2 is selected from one of hydrogen, methyl, CH2CH2OAc or CH2CH2NHBoc; R 3 One selected from hydrogen, methyl, halogen or trifluoromethyl.

2. The method for preparing the isoquinolinone-dihydropyridine-[1,2-α]indole spiro compound according to claim 1, characterized in that: The method comprises: using an o-alkynyl nitrone compound represented by formula (II) as a raw material, heating the compound in solvent A under the catalysis of a rhodium catalyst, filtering and concentrating the compound after the reaction, and reacting the compound in solvent B under the promotion of ammonium cerium nitrate to obtain the obtained compound; Among them, R 1 , R 2 , R 3 With R in formula (I) 1 , R 2 , R 3 The corresponding ones are consistent.

3. The method for preparing the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound according to claim 2, characterized in that: The rhodium catalyst is selected from one of (1,5-cyclooctadiene) rhodium chloride dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate or tetracarbonyl dirhodium dichloride; The molar ratio of the rhodium catalyst to the compound represented by formula (II) is 0.01-0.05:

1.

4. The method for preparing the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound according to claim 2 or 3, characterized in that: The heating reaction is carried out in solvent A under the catalysis of rhodium catalyst, and a desiccant is added to the reaction system. The desiccant is Molecular sieve, the amount of the desiccant added is 100 mg of desiccant for every 0.1 mmol of the compound represented by formula (II).

5. The method for preparing the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound according to claim 4, characterized in that: The solvent A is toluene or dichloroethane, the concentration of the compound represented by formula (II) in the solvent A is 0.1 mol / L, the reaction temperature is 100° C., and the reaction time is 12 to 24 hours.

6. The method for preparing the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound according to any one of claims 2, 3 and 5, characterized in that: The molar ratio of the ammonium cerium nitrate to the compound represented by formula (II) is 4 to 6:

1.

7. The method for preparing the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound according to claim 6, characterized in that: The solvent B is a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1 to 4:

1.

8. The method for preparing the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound according to any one of claims 2, 3, 5 and 7, characterized in that: The concentration of the compound represented by formula (II) in the solvent B is 0.1 mol / L, the reaction temperature is room temperature, and the reaction time is 5 to 30 minutes.

9. Use of the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound as claimed in claim 1 in the preparation of a compound represented by formula (III), characterized in that: The structural formula shown in formula (III) is:

10. Use of the isoquinolinone dihydropyridine-[1,2-α]indole spiro compound according to claim 1 or the compound represented by formula (III) according to claim 9 in inhibiting Botrytis cinerea, and / or Gibberella fusca, and / or Sheath blight of rice; or, use ... in inhibiting Botrytis cinerea, and / or Gibberella fusca, and / or Sheath blight of rice.

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