Quinazolinone isoindole derivative as well as preparation method and application thereof

Abstract

The invention provides a quinazolinone isoindole derivative as well as a preparation method and application thereof, and belongs to the technical field of organic synthetic chemistry. The preparation method of the quinazolinone isoindole derivative comprises the following steps: adding a quinazolinone compound 1, an alkyne compound 2, an additive and a catalyst into a solvent, and reacting to obtain the quinazolinone isoindole derivative. The invention provides a simple and effective method for synthesizing a highly functionalized heterocyclic ring and realizing a new framework compound taking alkyne as a single carbon unit, and the method has the characteristics of mild reaction conditions, simple operation, economical steps, strong functional group tolerance, excellent yield and the like. The quinazolinone isoindole derivative has a good antibacterial effect on rhizoctonia solani, tobacco shin black fungus, fusarium graminearum, fusarium oxysporum, fusarium moniliforme, peanut sclerotium rolfsii, wheat take-all and wheat sheath blight. The sterilization rate of the compound 3al on rhizoctonia solani can reach 85.18%, and the compound 3al has a certain application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a quinazolinone-fused isoindole derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Since molecules containing nitrogen heterocycles and their analogues are widely present in pharmaceuticals, natural products, advanced materials, and crop protection agents, they are active structural motifs. Among the top 200 drugs sold globally, more than 70% of the drugs contain at least one heterocyclic nucleus as part of their entire skeleton (Current Topics in Medicinal Chemistry, 2022, 22, 1035 - 1044). Quinazolinone is one of the most special scaffolds found in numerous bioactive molecules, candidate drugs, pesticide molecules, and natural products, and has good pharmacological activities in medicine, such as anti-cancer, anti-malaria, antibacterial, anti-inflammatory, anti-diabetic, anti-convulsant, antihypertensive, diuretic, etc. For example, the antihypertensive drug prazosin and the diuretic metolazone. In addition, quinazolinone derivatives also have wide applications in agriculture and can be used as herbicides, fungicides, etc. For example, the acaricide Fenazaquin and the herbicide bentazone sulfur replace quinazolinone compounds. In the past few decades, due to the importance of the quinazolinone skeleton, its efficient synthesis has attracted extensive attention from synthetic chemists and medicinal chemists.

[0003] Isoindoline is a class of important nitrogen-containing heterocyclic compounds with special chemical properties and wide biological activities. Recent studies have found that isoindoline has a wide range of pharmacological activities, such as antiviral, antibacterial, anti-inflammatory, preventing cell senescence and apoptosis, inhibiting the growth of tumor cells. The isoindoline structure exists in the molecules of estrogen regulators and can be used as a molecular probe. Therefore, isoindoline and its derivatives are widely used in the fields of medicine, chemical industry, etc. For example, isoindoline derivatives are widely used in dyes.

[0004] Transition metals (Rh III 、Ru II 、Pd II and Co III)Catalytic aromatic C-H bond activation involves a directing group and coupling with alkynes and has been widely used in the preparation of various heterocycles. In these reported methods, alkynes usually act as a dicarbon synthon in the [n+2] cyclization process (Angew. Chem. Int. Ed. 2019, 58, 1700-1704). Although various examples of [n+1] cyclization with a single-carbon synthon have been reported in the cyclization reaction, where alkynes act as a single carbon atom, the examples are limited. In this context, alkynes as a single-carbon unit can contribute to the rapid formation of new compounds with a novel quinazolinone scaffold. It is highly necessary to develop an efficient and atom-economic protocol for the preparation and modification of fused heterocycles using heterocycles with an inherent directing group. Substrates containing a lactam moiety have been widely used in C-H activation reactions and bioactive compounds.

[0005] Existing methods for synthesizing quinazolinone-fused isoindole derivatives mainly rely on the cyclization of N-acylcyanamides, using tetrahydrofuran as the solvent, which is harmful to the human body (Angew. Chem. Int. Ed. 2007, 46, 576-5); moreover, the steps for synthesizing quinazolinone-fused isoindole derivatives by this method are complex and the atom economy is poor. There are problems such as being single and having poor atom economy in the reported methods for synthesizing quinazolinone-fused isoindole derivatives. To enrich the molecular library of such compounds, it is necessary to develop a new method that is efficient, economical, and practical. Summary of the Invention

[0006] In view of the above technical problems, the present invention provides a quinazolinone-fused isoindole derivative, its preparation method and application. This method provides a simple and effective way for synthesizing highly functionalized heterocycles and realizing new framework compounds with alkynes as a single-carbon unit, and has the characteristics of mild reaction conditions, simple operation, step economy, strong functional group tolerance, and excellent yield.

[0007] To achieve the above object, the technical solution of the present invention is realized as follows:

[0008] A quinazolinone-fused isoindole derivative is prepared by adding a quinazolinone compound 1, an alkyne compound 2, an additive, and a catalyst to a solvent for reaction to obtain the quinazolinone-fused isoindole derivative; the reaction equation is:

[0009]

[0010] In the formula, R is any one of F, Cl, Br, Me, OMe, t Bu, CF3, and NO2; R 1 , R 2 , R 3 are independently selected from Me, OMe, tAny one of Bu, F, Cl, Br, CF3, NO2, Ph, or a fused ring, or a heterocyclic ring; the fused ring is a naphthalene ring; the heterocyclic ring is thiophene, pyridine, quinoline or indole.

[0011] The temperature of the reaction is 60 - 130 °C, and the time is 0.2 - 16 h.

[0012] The molar ratio of the quinazolinone compound 1, the trifluoromethyl propiolone compound 2, the catalyst and the additive is 1:(1 - 2):(0.01 - 0.04):(0.1 - 2.0).

[0013] The concentration of the quinazolinone compound 1 in the solvent is 0.05 - 2 M.

[0014] The catalyst is a transition metal catalyst; the transition metal catalyst is a ruthenium catalyst; a silver salt is further added to the ruthenium catalyst, and the molar ratio of the ruthenium catalyst to the silver salt is 1:(2 - 5).

[0015] Preferably, the molar ratio of the ruthenium catalyst to the silver salt is 1:4.

[0016] The ruthenium catalyst is any one or two or more of dichloro(pentamethylcyclopentadienyl)rhodium dimer, pentamethylcyclopentadienylrhodium acetate, tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium bis(hexafluoroantimonate), dichloro(p - cymene)ruthenium(II) dimer, pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride, and (1,5 - cyclooctadiene)ruthenium(II) dichloride; the silver salt is any one or two or more of silver tetrafluoroborate, silver bis(trifluoromethanesulfonyl)imide, silver trifluoromethanesulfonate, silver sulfate, silver acetate, and silver trifluoroacetate.

[0017] The solvent is any one or two or more of diethyl carbonate, dichloroethane, propylene carbonate, γ - valerolactone, and ethyl acetate.

[0018] The additive is any one of trifluoromethanesulfonic acid, formic acid, hydrochloric acid, 1 - adamantanecarboxylic acid, tartaric acid, trifluoroacetic acid, and its salicylic acid compounds.

[0019] The application of a quinazolinone - fused isoindole derivative in the field of agricultural antibacterial and bactericidal.

[0020] Advantages of the present invention: The present invention selects easily available quinazolinone compounds and alkyne compounds as reactants, and under the action of a ruthenium metal catalyst, the construction of a quinazolinone-fused isoindole skeleton is achieved in one step through a [4+1] tandem strategy, providing a simple and effective synthesis method. Moreover, this method has the characteristics of mild reaction conditions, simple operation, atom economy, step economy, strong functional group tolerance, and good yield. The obtained products have broad industrial application prospects, and at the same time provide a new idea and new method for the fields of medicine and natural product synthesis.

[0021] The present invention conducted a bactericidal activity assay on the synthesized novel quinazolinone-fused isoindole derivatives. The 15 compounds described in the examples all have good antibacterial effects against Rhizoctonia solani, Phytophthora parasitica var. nicotianae, Fusarium graminearum, Fusarium oxysporum, Fusarium moniliforme, Sclerotium rolfsii, Gaeumannomyces graminis var. tritici, and Rhizoctonia cerealis. Among them, the bactericidal rate of compound 3al against Rhizoctonia solani can reach 85.18%, showing certain application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0023] Figure 1 is the 1H NMR spectrum of compound 3aa; 1 H spectrum; Figure 2 is the 1H NMR spectrum of compound 3aa; 13 C spectrum.

[0024] Figure 3 is the 1H NMR spectrum of compound 3ba; 1 H spectrum; Figure 4 is the 1H NMR spectrum of compound 3ba; 13 C spectrum.

[0025] Figure 5 is the 1H NMR spectrum of compound 3ca; 1 H spectrum; Figure 6 is the 1H NMR spectrum of compound 3ca; 13 C spectrum.

[0026] Figure 7 is the 1H NMR spectrum of compound 3da; 1 H spectrum; Figure 8 is the 1H NMR spectrum of compound 3da; 13 C spectrum;

[0027] Figure 9 is the 1H NMR spectrum of compound 3da;19 F spectrum.

[0028] Figure 10 is the NMR 1 H spectrum of compound 3ea; Figure 11 is the NMR 13 C spectrum of compound 3ea.

[0029] Figure 12 is the NMR 1 H spectrum of compound 3fa; Figure 13 is the NMR 13 C spectrum of compound 3fa.

[0030] Figure 14 is the NMR 1 H spectrum of compound 3ga; Figure 15 is the NMR 13 C spectrum of compound 3ga;

[0031] Figure 16 is the NMR 19 F spectrum of compound 3ga.

[0032] Figure 17 is the NMR 1 H spectrum of compound 3ha; Figure 18 is the NMR 13 C spectrum of compound 3ha.

[0033] Figure 19 is the NMR 1 H spectrum of compound 3ab; Figure 20 is the NMR 13 C spectrum of compound 3ab;

[0034] Figure 21 is the NMR 19 F spectrum of compound 3ab.

[0035] Figure 22 is the NMR 1 H spectrum of compound 3ac; Figure 23 is the NMR 13 C spectrum of compound 3ac.

[0036] Figure 24 is the NMR 1 H spectrum of compound 3ad; Figure 25 is the NMR 13 C spectrum of compound 3ad.

[0037] Figure 26 is the NMR 1 H spectrum of compound 3ae; Figure 27 is the NMR 13 C spectrum of compound 3ae.

[0038] Figure 28 This is the NMR of compound 3af 1 H spectrum; Figure 29 This is the NMR of compound 3af 13 C spectrum.

[0039] Figure 30 This is the NMR of compound 3ag 1 H spectrum; Figure 31 This is the NMR of compound 3ag 13 C spectrum.

[0040] Figure 32 This is the NMR of compound 3ia 1 H spectrum; Figure 33 This is the NMR of compound 3ia 13 C spectrum.

[0041] Figure 34 is the inhibition rate of compound 3aa against different bacterial species.

[0042] Figure 35 The antibacterial rate of the quinazolinone and isoindole derivatives prepared in the examples against Triticum aestivum. DETAILED DESCRIPTION

[0043] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] Example 1

[0045]

[0046] Under air conditions, 2-phenyl-4-[3H]quinazolinone 1a (0.20mmol), 1,3-diphenylprop-2-ene-1-one 2a (0.24mmol), [Ru(p-cymene)Cl2]2 (2mol%), AgSbF6 (8mol%), salicylic acid (2equiv.) and solvent DEC (4.0mL) were added to a 10mL sealed tube and reacted in a reaction module at 120 degrees for 5h. After the reaction, the solvent was removed under reduced pressure and the target product 3aa was separated by a silica gel column. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: gray-brown solid, 88% yield. The NMR spectrum of the product is shown in Figure 1 and 2 As shown, 11H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.4 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.69 - 7.64 (m, 1H), 7.43 (q, J = 7.5 Hz, 2H), 7.34 (dt, J = 15.2, 8.1 Hz, 3H), 7.28 - 7.17 (m, 7H), 5.23 (d, J = 16.8 Hz, 1H), 4.39 (d, J = 16.8 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 195.66, 160.42, 155.38, 149.27, 148.47, 139.44, 137.04, 134.26, 133.23, 132.79, 131.85, 129.08, 128.94, 128.50, 128.30, 127.91, 127.49, 126.72, 126.35, 125.61, 123.44, 122.36, 121.64, 71.64, 40.59.

[0047] Example 2

[0048]

[0049] Under air conditions, 2-(p-tolyl)quinazolin-4(3H)-one 1b (0.20 mmol), 1,3-diphenylprop-2-en-1-one 2a (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgBF4 (8 mol%), salicylic acid (2 equiv.) and the solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 6 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ba was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: yellow solid, 30% yield. The NMR spectra of the product are as Figure 3 and 4 shown. 11H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.79 - 7.71 (m, 3H), 7.66 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.29 - 7.23 (m, 7H), 7.23 - 7.18 (m, 1H), 6.99 (s, 1H), 5.22 (d, J = 10.4 Hz, 1H), 4.36 (d, J = 16.7 Hz, 1H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 194.56, 159.34, 154.44, 148.25, 147.65, 142.64, 138.53, 135.98, 133.13, 132.11, 129.20, 128.12, 127.85, 127.38, 127.16, 126.85, 126.25, 125.61, 125.04, 124.48, 122.12, 121.66, 120.40, 70.30, 39.56, 20.78.

[0050] Example 3

[0051]

[0052] Under air conditions, 2-(4-methoxyphenyl)quinazolin-4(3H)-one 1c (0.20 mmol), 1,3-diphenylprop-2-en-1-one 2a (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), Ag2SO4 (8 mol%), 1-adamantanecarboxylic acid (2 equiv.) and the solvent DEC (2.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ca was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 4:1. Product data characterization: yellow solid, 27% yield. The NMR spectrum of the product is as Figure 5 and 6 shown 11H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.3 Hz, 2H), 7.73 (t, J = 8.0 Hz, 3H), 7.65 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.28 - 7.23 (m, 6H), 7.24 - 7.18 (m, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.68 (s, 1H), 5.19 (d, J = 16.7 Hz, 1H), 4.37 (d, J = 16.7 Hz, 1H), 3.71 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 194.57, 162.59, 159.33, 154.14, 149.60, 148.32, 138.32, 135.98, 133.14, 132.15, 127.84, 127.42, 127.24, 126.86, 126.02, 125.60, 124.82, 124.58, 123.84, 123.12, 120.08, 114.59, 106.41, 70.27, 54.63, 39.64.

[0053] Example 4

[0054]

[0055] Under air conditions, 2-(4-fluorophenyl)quinazolin-4(3H)-one 1d (0.20 mmol), 1,3-diphenylprop-2-en-1-one 2a (0.20 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%), salicylic acid (2 equiv.) and the solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 10 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3da was separated by silica gel column chromatography. All eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 5:1:1. Product data characterization: white solid, 53% yield. The NMR spectrum of the product is as Figures 7 - 9 shown. 11H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 8.2, 4.9 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.9 Hz, 3H), 7.74 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 7.4 Hz, 3H), 7.31 (t, J = 6.9 Hz, 4H), 7.21 (t, J = 8.8 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 5.30 (d, J = 17.0 Hz, 1H), 4.43 (d, J = 17.0 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 194.30, 165.87 (d, J = 254.0 Hz), 159.21, 153.33, 149.93, 149.84, 148.09, 137.74, 135.72, 133.30, 132.37, 128.02, 127.52, 127.49, 126.88, 126.78, 126.33, 125.66, 125.35, 124.50, 124.42, 120.24, 116.14 (d, J = 23.7 Hz), 108.94 (d, J = 24.8 Hz), 70.30, 39.53. 19 19F NMR (377 MHz, CDCl3) δ -113.59.

[0056] Example 5

[0057]

[0058] Under air conditions, 2-(2-methoxyphenyl)quinazolin-4(3H)-one 1e (0.20 mmol), 1,3-diphenylprop-2-en-1-one 2a (0.24 mmol), [Ru(p-cymene)Cl2]2 (4 mol%), AgSbF6 (16 mol%), tartaric acid (2 equiv.) and solvent DEC (2.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 16 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ea was separated by silica gel column chromatography. All eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 3:1:1. Product data characterization: yellow solid, 67% yield. The NMR spectra of the product are as shown in Figure 10 and 11 shown. 1H NMR (400MHz, CDCl3) δ8.07(d,J=7.9Hz,1H),7.84(d,J=8.2Hz,1H),7.74(d,J =7.9Hz,2H),7.66(t,J=7.7Hz,1H),7.37(t,J=7.9Hz,2H),7.32(t,J=7.6Hz, 1H),7.26(d,J=3.2Hz,5H),7.24-7.20(m,2H),6.91(d,J=8.3Hz,1H),6.79(d ,J=7.6Hz,1H),5.26(d,J=16.3Hz,1H),4.30(d,J=16.4Hz,1H),4.07(s,3H). 13 C NMR (100MHz, CDCl3) δ194.44,159.26,156.23,153.86,149.80,148.35,138.60,136.03,133.19,132.89,132.07,127 .85,127.38,127.14,127.01,126.88,125.29,125.20,124.38,119.87,117.95,113.24,109.83,69.86,55.34,39.54.

[0059] Example 6

[0060]

[0061] Under air conditions, 5-bromo-2-phenylquinazoline-4(3H)-one 1f (0.20mmol), 1,3-diphenylprop-2-ene-1-one 2a (0.20mmol), [Ru(p-cymene)Cl2]2 (2mol%), AgSbF6 (8mol%), trifluoroacetic acid (2equiv.) and solvent DEC (4.0mL) were added to a 10mL sealed tube and reacted in a reaction module at 120 degrees for 12h. After the reaction, the solvent was removed under reduced pressure and the target product 3fa was separated by a silica gel column. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: gray-brown solid, 43% yield. The NMR spectrum of the product is shown in Figure 12 and 13 shown. 11H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 7.4 Hz, 3H), 7.57 (d, J = 7.7 Hz, 1H), 7.46 (dd, J = 5.4, 2.9 Hz, 2H), 7.40 (dd, J = 14.1, 7.5 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.28 - 7.22 (m, 4H), 7.21 - 7.17 (m, 2H), 5.28 (d, J = 16.7 Hz, 1H), 4.34 (d, J = 16.6 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 194.75, 157.34, 154.63, 150.50, 147.75, 137.96, 135.96, 132.76, 132.19, 132.07, 130.19, 128.91, 128.06, 127.94, 127.45, 127.22, 126.85, 126.51, 124.47, 122.48, 121.21, 120.42, 118.43, 71.17, 39.22.

[0062] Example 7

[0063]

[0064] Under air conditions, 1 g (0.20 mmol) of 6-fluoro-2-phenylquinazolin-4(3H)-one, 2a (0.24 mmol) of 1,3-diphenylprop-2-en-1-one, [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%), salicylic acid (3 equiv.) and the solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ga was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: white solid, 56% yield. The NMR spectrum of the product is as Figures 14 - 16 shown. 1 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 6.9 Hz, 1H), 7.80 (dd, J = 9.0, 4.8 Hz, 1H), 7.73 (dd, J = 8.3, 3.1 Hz, 3H), 7.48 - 7.42 (m, 2H), 7.42 - 7.36 (m, 2H), 7.29 (s, 1H), 7.26 (t, J = 3.6 Hz, 5H), 7.24 - 7.18 (m, 2H), 5.22 (d, J = 16.8 Hz, 1H), 4.39 (d, J = 16.8

[0065] Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 194.52, 159.67 (d, J = 240.6 Hz), 153.89, 147.1

[0066] 9, 144.49, 137.98, 135.83, 132.26, 131.90, 130.35, 128.46, 128.38, 128.14, 127.91, 127.46, 127.37, 126.81, 124.50, 122.42, 121.81, (d, J = 23.1 Hz), 121.24, 110.79 (d, J = 23.3 Hz), 70.67, 39.31. 19 F NMR (377 MHz, CDCl3) δ -113.26.

[0067] Example 8

[0068]

[0069] Under air conditions, 6-fluoro-2-phenylquinazolin-4(3H)-one 1h (0.20 mmol), 1,3-diphenylprop-2-en-1-one 2a (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%), trifluoroacetic acid (2 equiv.) and the solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 15 h. After the reaction was completed, the solvent was removed under reduced pressure, and the target product 3ha was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: A grayish-brown solid with a yield of 35%. The NMR spectrum of the product is as Figure 17 and 18 shown. 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 6.8 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.78 - 7.69 (m, 3H), 7.61 (dd, J = 8.7, 2.4 Hz, 1H), 7.50 - 7.37 (m, 3H), 7.31 - 7.25 (m, 6H), 7.24 - 7.19 (m, 2H), 5.21 (d, J = 16.9 Hz, 1H), 4.39 (d, J = 16.8 Hz, 1H). 1313C NMR (100 MHz, CDCl3) δ 194.49, 158.24, 154.58, 147.38, 146.57, 137.97, 135.84, 133.56, 132.28, 132.00, 131.04, 130.41, 128.14, 127.93, 127.88, 127.48, 127.38, 126.82, 125.11, 124.47, 122.51, 121.54, 121.24, 70.76, 39.37.

[0070] Example 9

[0071]

[0072] Under air conditions, 2-phenylquinazolin-4(3H)-one 1a (0.20 mmol), 3-(3-fluorophenyl)-1-phenylprop-2-yn-1-one 2b (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%), salicylic acid (2 equiv.) and solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 10 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ab was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: yellow solid, 45% yield. The NMR spectrum of the product is as Figures 19 - 21 shown. 1 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.1 Hz, 1H), 8.09 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.70 (dd, J = 13.8, 7.1 Hz, 3H), 7.45 (dt, J = 14.9, 7.4 Hz, 2H), 7.40 - 7.32 (m, 2H), 7.23 (dt, J = 13.5, 7.8 Hz, 4H), 7.03 (d, J = 8.0 Hz, 1H), 6.98 - 6.88 (m, 2H), 5.17 (d, J = 16.8 Hz, 1H), 4.33 (s, 1H). 1313C NMR (100 MHz, CDCl3) δ 194.12, 163.10 (d, J = 247.0 Hz), 159.20, 154.13, 146.80, 140.93 (d, J = 6.8 Hz), 135.72, 133.42, 132.31, 131.95, 130.51, 129.48 (d, J = 8.4 Hz), 128.32, 127.48, 126.82, 126.28, 125.64, 125.53, 122.69, 121.18, 120.32, 120.21, 120.18, 114.42 (d, J = 21.1 Hz), 112.14 (d, J = 23.4 Hz), 70.11, 39.38. 19 19F NMR (377 MHz, CDCl3) δ -111.36.

[0073] Example 10

[0074]

[0075] Under air conditions, 2-phenylquinazolin-4(3H)-one 1a (0.20 mmol), 3-(3-chlorophenyl)-1-phenylprop-2-yn-1-one 2c (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgOAc (8 mol%), tartaric acid (2 equiv.) and solvent EA (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 10 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ac was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: pale yellow solid, 52% yield. The NMR spectra of the product are as shown in Figure 22 and 23 shown. 1 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 - 7.66 (m, 3H), 7.50 - 7.41 (m, 2H), 7.41 - 7.32 (m, 2H), 7.26 (dd, J = 11.1, 4.4 Hz, 3H), 7.22 - 7.16 (m, 3H), 7.12 (dq, J = 5.9, 2.9 Hz, 1H), 5.16 (d, J = 16.7 Hz, 1H), 4.35 (d, J = 16.8 Hz, 1H). 1313C NMR (100 MHz, CDCl3) δ 194.13, 159.20, 154.07, 146.72, 140.45, 135.74, 133.83, 133.40, 132.30, 131.95, 130.63, 129.10, 128.34, 127.52, 127.47, 126.83, 126.35, 125.65, 125.50, 124.90, 122.84, 122.62, 121.23, 120.36, 70.04, 39.27.

[0076] Example 11

[0077]

[0078] Under air conditions, 2-phenylquinazolin-4(3H)-one 1a (0.20 mmol), 3-(3-bromophenyl)-1-phenylprop-2-yn-1-one 2d (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%), salicylic acid (2 equiv.) and the solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ad was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: pale yellow solid, 51% yield. The NMR spectrum of the product is as Figure 24 and 25 shown. 1 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.1 Hz, 1H), 8.10 (d, J = 7.4 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.70 (dd, J = 13.2, 7.2 Hz, 3H), 7.47 (dd, J = 14.8, 7.3 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.35 (dd, J = 8.1, 5.1 Hz, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.20 (d, J = 9.1 Hz, 1H), 7.17 - 7.09 (m, 2H), 5.15 (d, J = 16.7 Hz, 1H), 4.34 (d, J = 16.7 Hz, 1H). 1313C NMR (100 MHz, CDCl3) δ 194.15, 159.24, 154.02, 148.05, 146.68, 140.72, 135.78, 133.36, 132.28, 131.90, 130.72, 130.45, 129.35, 128.33, 127.73, 127.47, 126.83, 126.44, 125.65, 125.47, 123.35, 122.54, 122.02, 121.26, 120.40, 69.95, 39.28.

[0079] Example 12

[0080]

[0081] Under air conditions, 2-phenylquinazolin-4(3H)-one 1a (0.20 mmol), 3-(4-tert-butylphenyl)-1-phenylprop-2-yn-1-one 2e (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%), 1-adamantanecarboxylic acid (2 equiv.) and the solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ae was separated by silica gel column chromatography. All eluents were prepared from petroleum ether, ethyl acetate and dichloromethane in a ratio of 5:1:1. Product data characterization: yellow solid, 62% yield. The NMR spectrum of the product is as Figure 26 and 27 shown. 1 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.4 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.78 - 7.67 (m, 3H), 7.50 - 7.40 (m, 3H), 7.37 (dd, J = 13.2, 6.8 Hz, 2H), 7.30 - 7.27 (m, 3H), 7.24 - 7.19 (m, 2H), 6.92 (dd, J = 30.9, 7.9 Hz, 1H), 5.31 (d, J = 17.0 Hz, 1H), 4.40 (d, J = 17.0 Hz, 1H), 1.20 (s, 9H). 13C NMR (100MHz, CDCl3) δ195.84,160.55,155.81,151.20,148.79,137.05,136.07,134.51,133.33,133.02,131.51,129.17,128 .59,127.98,127.10,126.85,126.59,125.96,125.39,123.70,122.41,121.55,119.31,117.67,71.87,40.77,34.58,31.29.

[0082] Example 13

[0083]

[0084] Under air conditions, 2-phenylquinazolin-4(3H)-one 1a (0.20mmol), 3-(4-bromophenyl)-1-phenylprop-2-yn-1-one 2f (0.24mmol), [Ru(p-cymene)Cl2]2 (2mol%), AgSbF6 (8mol%), salicylic acid (2equiv.) and solvent DEC (4.0mL) were added to a 10mL sealed tube and reacted in a reaction module at 120 degrees for 12h. After the reaction, the solvent was removed under reduced pressure and the target product 3af was separated by a silica gel column. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: gray-brown solid, 72% yield. The NMR spectrum of the product is shown in Figure 28 and 29 shown. 1 H NMR (400MHz, CDCl3) δ8.09(d,J=7.5Hz,1H),8.03(d,J=7.9Hz,1H),7.70(d,J=8.2Hz,1H),7.63(dd,J=13.1,7.1Hz,3H),7.43-7.35(m,2H), 7.30(p,J=6.8Hz,4H),7.19(t,J=7.7Hz,2H),7.14(d,J=6.9Hz,1H),7.06(d,J=8.8Hz,2H),5.04(d,J=16.7Hz,1H),4.31(d,J=16.8Hz,1H). 1313C NMR (100 MHz, CDCl3) δ 194.26, 159.32, 153.93, 148.10, 146.77, 137.40, 135.80, 133.35, 132.29, 131.86, 130.93, 130.80, 128.29, 127.47, 126.82, 126.55, 126.45, 125.60, 125.46, 122.48, 121.46, 121.38, 120.43, 70.14, 39.36.

[0085] Example 14

[0086]

[0087] Under air conditions, 2-phenylquinazolin-4(3H)-one 1a (0.20 mmol), 3-(2-naphthyl)-1-phenylprop-2-yn-1-one 2g (0.40 mmol), [Ru(p-cymene)Cl2]2 (1 mol%), AgSbF6 (5 mol%), salicylic acid (2 equiv.) and the solvent DEC (0.2 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 60 °C for 16 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ag was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 8:1. Product data characterization: yellow solid, 62% yield. The NMR spectrum of the product is as Figure 30 and 31 shown. 1 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 7.5 Hz, 1H), 8.08 (t, J = 9.4 Hz, 1H), 7.98 (s, 1H), 7.83 - 7.73 (m, 4H), 7.66 (dd, J = 19.4, 8.6 Hz, 3H), 7.44 (dd, J = 12.8, 5.5 Hz, 2H), 7.38 (dd, J = 12.8, 7.1 Hz, 3H), 7.31 (t, J = 7.1 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.06 (dd, J = 8.7, 2.1 Hz, 1H), 5.38 (d, J = 16.6 Hz, 1H), 4.53 (d, J = 16.7 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 195.75, 160.50, 155.62, 148.47, 137.13, 136.79, 134.45, 133.38, 133.25, 133.02, 131.97, 129.32, 129.06, 128.62, 128.50, 128.04, 127.69, 127.50, 126.83, 126.79, 126.69, 126.53, 124.99, 123.65, 123.21, 122.56, 121.67, 71.78, 40.57.

[0088] Example 15

[0089]

[0090] Under air conditions, 2-(1-naphthyl)quinazolin-4(3H)-one 1i (0.20 mmol), 1,3-diphenylprop-2-en-1-one 2a (0.20 mmol), [Ru(p-cymene)Cl2]2 (4 mol%), AgSbF6 (8 mol%), salicylic acid (2 equiv.) and the solvent DEC (1.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 130 °C for 0.2 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ia was separated by silica gel column chromatography. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: yellow solid, 45% yield. The NMR spectrum of the product is as Figure 32 and 33 shown. 1 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 6.9 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.41 (dd, J = 14.7, 7.1 Hz, 2H), 7.32 (dt, J = 15.3, 7.7 Hz, 3H), 7.23 (d, J = 3.0 Hz, 6H), 7.21 - 7.15 (m, 3H), 5.21 (d, J = 16.8 Hz, 1H), 4.38 (d, J = 16.8 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 194.56, 159.32, 154.31, 148.13, 147.36, 138.31, 135.89, 133.19, 132.15, 131.72, 130.71, 128.00, 127.85, 127.41, 127.22, 126.81, 126.36, 125.62, 125.27, 124.49, 122.36, 121.25, 120.51, 70.53, 39.48.

[0091] Bactericidal activity test:

[0092] Take 6.6 mg of the above synthesized drug and dissolve it in 0.33 mL of DMSO, then add an aqueous solution containing 1% Tween 80 to prepare a stock solution of 2 mg / mL. Appropriately pipette the test agent under sterile conditions into a conical flask, shake well, and then pour an equal amount into three petri dishes with a diameter of 9 cm to prepare drug-containing plates of 200 μg / mL. The above experiment was set with a treatment without the agent as a blank control, and each treatment was repeated three times. For the cultured pathogenic bacteria, under sterile conditions, use a punch with a diameter of 5 mm to cut out a mycelial disc along the edge of the colony, and use an inoculator to inoculate the mycelial disc in the center of the drug-containing plate, with the mycelial surface facing up, cover the petri dish lid, and place the petri dish in an incubator at a constant temperature of 25 °C. When the diameter of the control colony expands to more than 6 cm, measure the diameter of the colony by the cross method and take the average value; calculate the inhibition rate at the end of the culture.

[0093] The calculation formula is: Inhibition rate I = (D0 - D t ) / D0 × 100%

[0094] D0 is the average diameter of the mycelium on the control plate, and D t is the average diameter of the mycelium on the sample plate.

[0095] The compound 3aa prepared in Example 1 was selected to carry out activity determination on 8 common pathogenic bacteria in agriculture, namely Rhizoctonia solani, Phytophthora parasitica var. nicotianae, Fusarium graminearum, Fusarium oxysporum, Fusarium moniliforme, Sclerotium rolfsii, Gaeumannomyces graminis var. tritici, and Rhizoctonia cerealis. The inhibition effects are shown in Figure 34 , and the results show that 3aa showed certain bactericidal activity against the common bacteria in agricultural pests and diseases. Among them, the bactericidal rate of compound 3aa against Gaeumannomyces graminis var. tritici can reach 69%. Then, the activity tests of 14 compounds, namely 3ba, 3ca, 3da, 3ea, 3fa, 3ga, 3ha, 3ia, 3ab, 3ac, 3ad, 3ae, 3af, and 3ag, synthesized in Examples 2 - 15 against Gaeumannomyces graminis var. tritici were carried out. The inhibition effects are shown in Figure 35, wherein the bactericidal rate of compound 3al against Rhizoctonia solani can reach 85.18%, showing certain application prospects.

[0096] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing a quinazolinone-fused isoindole derivative, characterized in that, The quinazolinone compound 1, alkyne compound 2, additive and catalyst are added to a solvent for reaction to obtain a quinazolinone-fused isoindole derivative; the reaction equation is as follows: Wherein, R is any one of F, Cl, Br, Me, OMe, t Bu, CF3 and NO2; R 1 , R 2 , R 3 are independently selected from any one of Me, OMe, t Bu, F, Cl, Br, CF3, NO2, Ph, or is a fused ring, or is a heterocycle; the fused ring is a naphthalene ring; the heterocycle is thiophene, pyridine, quinoline or indole.

2. The preparation method of the quinazolinone-fused isoindole derivative according to claim 1, characterized in that, The temperature of the reaction is 60 - 130 °C, and the time is 0.2 - 16 h.

3. The preparation method of the quinazolinone-fused isoindole derivative according to claim 2, characterized in that, The molar ratio of the quinazolinone compound 1, trifluoromethyl-containing alkynone compound 2, catalyst and additive is 1:(1 - 2):(0.01 - 0.04):(0.1 - 2.0).

4. The method for preparing the quinazolinone-fused isoindole derivative according to claim 3, characterized in that, The concentration of the quinazolinone compound 1 in the solvent is 0.05 - 2 M.

5. The preparation method of the quinazolinone-fused isoindole derivative according to claim 4, characterized in that, The catalyst is a transition metal catalyst; the transition metal catalyst is a ruthenium catalyst; a silver salt is further added to the ruthenium catalyst, and the molar ratio of the ruthenium catalyst to the silver salt is 1:(2 - 5).

6. The preparation method of the quinazolinone-fused isoindole derivative according to claim 5, characterized in that, The ruthenium catalyst is any one or two or more of dichloro(pentamethylcyclopentadienyl)rhodium dimer, pentamethylcyclopentadienylrhodium acetate, tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium bis(hexafluorantimonate), dichloro(p - cymene)ruthenium(II) dimer, pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride, and (1,5 - cyclooctadiene)ruthenium(II) dichloride; the silver salt is any one or two or more of silver tetrafluoroborate, silver bis(trifluoromethanesulfonyl)imide, silver trifluoromethanesulfonate, silver sulfate, silver acetate, and silver trifluoroacetate.

7. The preparation method of the quinazolinone-fused isoindole derivative according to claim 6, characterized in that, The solvent is any one or two or more of diethyl carbonate, dichloroethane, propylene carbonate, γ - valerolactone, and ethyl acetate.

8. The preparation method of the quinazolinone-fused isoindole derivative according to claim 7, characterized in that, The additive is any one of trifluoromethanesulfonic acid, formic acid, hydrochloric acid, 1 - adamantanecarboxylic acid, tartaric acid, trifluoroacetic acid, and its salicylic acid compounds.

9. A quinazolinone-fused isoindole derivative prepared by the method according to any one of claims 1 - 8.

10. Use of the quinazolinone-fused isoindole derivative according to claim 9 in the field of agricultural antibacterial and bactericidal.

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