Trifluoromethyl-containing quinazolinone derivative as well as preparation method and application thereof

Abstract

The invention provides a trifluoromethyl-containing quinazolinone derivative as well as a preparation method and application thereof, and belongs to the technical field of organic synthetic chemistry. A quinazolinone compound 1 and a trifluoromethyl-containing alkynone compound 2 are taken as raw materials, a catalyst is added, synthesis of the novel trifluoromethyl quinazolinone compound is realized in a solvent in one step, and a series of trifluoromethyl-containing quinazolinone compounds with novel structures are synthesized. The reaction does not need inert gas protection, the operation is simple, the condition is mild, the functional group tolerance is strong, the atom utilization rate is 100%, only a catalytic amount of [Ru (p-cymene) Cl2] 2 needs to be added in the reaction, the used solvent is a green solvent, and the method has high step economy and atom economy. The obtained product has a wide industrial application prospect, and meanwhile, a new thought and a new method are provided for the field of synthesis of medicines and natural products.

Description

Technical Field

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

[0002] Take-all of wheat, also known as wheat sharp eyespot and black foot disease, was first discovered in Australia in 1852. Currently, this disease has been found in more than 40 countries. In 1931, take-all of wheat was first discovered in Zhejiang, China. Subsequently, it has been successively reported in 22 provinces in China, and the disease situation is most serious in large wheat-growing areas such as Henan and Shandong. The take-all pathogen of wheat is a soil-inhabiting bacterium. If not effectively controlled, it will continuously damage the subsequent crops. The take-all disease of wheat not only has a wide range of damage areas, fast transmission speed and is difficult to eradicate. Once wheat is infected, compared with normal plants, the thousand-grain weight is reduced by 15%, and the yield is reduced by 30 - 60%. In severely affected areas, there will be no harvest at all. Currently, for the control of take-all disease of wheat, chemical control is mainly used. However, chemical control mainly relies on agents such as silthiofam. Long-term use of one agent will lead to an increase in the drug resistance of the pathogenic bacteria in this area and a decrease in the drug efficacy. Therefore, the research and development of new fungicides are necessary.

[0003] C-H bond functionalization is one of the most convenient and powerful tools in organic synthesis methodology. This method has been widely used in the synthesis of various valuable chemicals, drugs, and complex natural products. The key to the potential application value of such reactions is to achieve the functional group transformation of C-H bonds with high regioselectivity. Since the C-H bond is directly used as the transformation center, substrate pre-functionalization is avoided, and the synthesis steps are shortened, which meets the requirements of green chemistry for the development of atom economy and step economy. How to achieve the functionalization of inert C-H bonds and selectively activate specific C-H bonds has always been a problem faced in this field. After decades of development, the transition metal-catalyzed C-H functionalization reaction assisted by a directing group has become an important means for high regioselective functionalization, and many innovative research results have been achieved. Among them, ruthenium catalysts are favored because of their low price and high reaction efficiency, and they show good potential in the activation of C-H bonds at the ortho position of aromatic hydrocarbons, providing more possibilities for the construction of complex molecules.

[0004] Quinazolinone, as an important nitrogen-containing heterocyclic compound, has been widely reported in the fields of medicinal chemistry and natural products. The pharmacological activities of quinazolinone compounds mainly include anti-tumor, anti-inflammatory, antibacterial, anti-malaria, blood pressure lowering, and sedative effects. Currently, more than 200 quinazolinone compounds have been isolated from natural products, and most of them have been proven to play important physiological roles in organisms. Therefore, the synthesis and application of quinazolinone compounds have become one of the research hotspots for organic synthetic chemists and medicinal chemists. However, the activation of carbon-hydrogen bonds in existing quinazolinone derivatives is mainly achieved through expensive metals such as rhodium and iridium, resulting in high economic costs. Moreover, the solvents used are organic solvents such as DCE and acetonitrile, which pose a great harm to the environment. In addition, the fungicidal performance of current quinazolinone derivatives is poor, and there is an urgent need to design a new compound with an economical and efficient preparation method and strong application potential. Summary of the Invention

[0005] In view of the above technical problems, the present invention provides a trifluoromethyl quinazolinone derivative, a preparation method thereof, and an application thereof, injecting fresh blood into organic synthesis and enriching the molecular library of such compounds. At the same time, a trifluoromethyl-containing alkynone is introduced into the quinazolinone derivative to prepare a novel trifluoromethyl isoindole[1,2-b]quinazolin-10(12H)-one skeleton with all quaternary carbons. This reaction does not require inert gas protection, has simple operation, mild conditions, strong functional group tolerance, an atom utilization rate of 100%, and only requires the addition of a catalytic amount of [Ru(p-cymene)Cl2]2. The solvent used is a green solvent, with high step economy and atom economy.

[0006] In order to achieve the above object, the technical solution of the present invention is realized as follows:

[0007] A trifluoromethyl quinazolinone derivative, and the preparation method is as follows:

[0008] A quinazolinone compound 1, a trifluoromethyl-containing alkynone compound 2, and a catalyst are added to a solvent for reaction to obtain a trifluoromethyl quinazolinone compound; the reaction formula is:

[0009]

[0010] In the formula, Ar 1 、Ar 2 、Ar 3 independently selected from a benzene ring or a heterocyclic ring substituted with an electron-donating group or an electron-withdrawing group; R is a polyfluoroalkyl group.

[0011] The Ar 1 、Ar2、Ar 3An independent benzene ring or heterocyclic ring substituted by an electron-donating group or an electron-withdrawing group selected from Me, OMe, F, Cl, Br, CF3, NO2 groups, and the heterocyclic ring is thiophene, pyridine or quinoline; the polyfluoroalkyl group is CF3, CHF2, C2F5, C3F7 or C4F9.

[0012] The temperature of the reaction is 60-130 °C and the time is 0.2-16 h.

[0013] The molar ratio of the quinazolinone compound 1, the trifluoromethyl ketone compound 2 and the catalyst is 1:(1-2):

[0014] (0.01-0.04).

[0015] The concentration of the quinazolinone compound 1 in the solvent is 0.05-2 M.

[0016] 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).

[0017] Preferably, the molar ratio of the ruthenium catalyst to the silver salt is 1:4.

[0018] The ruthenium catalyst is any one or more of dichloro(pentamethylcyclopentadienyl)rhodium dimer, pentamethylcyclopentadienylrhodium acetate, tris(acetonitrile)(pentamethylcyclopentadienyl)rhodium bis(hexafluoroantimonate), dichloro(p-methylcumylphenyl)ruthenium(II) dimer, pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride and (1,5-cyclooctadiene)ruthenium(II) dichloride; the silver salt is any one or more of silver tetrafluoroborate, silver bis(trifluoromethanesulfonyl)imide, silver trifluoromethanesulfonate, silver sulfate, silver acetate and silver trifluoroacetate.

[0019] The solvent is any one or more of diethyl carbonate, dichloroethane, propylene carbonate, γ-valerolactone and ethyl acetate.

[0020] An application of a trifluoromethyl quinazolinone derivative in the field of agricultural antibacterial and bactericidal.

[0021] Advantages of the present invention: According to the fact that fluorine atoms have a very high electron effect and can change the biological activity of compounds when combined with carbon atoms, and trifluoromethyl can promote the interaction of biomolecules with enzyme active sites, receptor recognition, migration mechanisms and other biological systems. Pioneeringly, quinazolinone compounds and trifluoromethyl alkynone compounds are selected as reactants, and under the action of a ruthenium metal catalyst, the construction of a novel quaternary carbon center skeleton is achieved in one step through a [4+1] tandem strategy, providing a simple and effective synthetic method for the construction of isoindolo[1,2-b]quinazolin-10(12H)-one. Moreover, this method has the characteristics of mild reaction conditions, simple operation, atom economy, step economy, strong functional group tolerance and excellent yield. The obtained products have broad industrial application prospects and also provide a new idea and method for the fields of medicine and natural product synthesis.

[0022] The present invention has carried out activity assays on 8 kinds of pathogenic bacteria common in agricultural production, namely Rhizoctonia solani, Phytophthora parasitica var. nicotianae, Fusarium graminearum, Fusarium oxysporum, Fusarium moniliforme, Sclerotium rolfsii, Gaeumannomyces graminis var. tritici and Rhizoctonia cerealis. The results show that the synthesized trifluoromethyl quinazolinone compound 3aa has good bactericidal activity against Gaeumannomyces graminis var. tritici, and the inhibition rate can reach 94%. Most of the 11 novel trifluoromethyl quinazolinone compounds have excellent inhibitory effects on Gaeumannomyces graminis var. tritici, with the inhibition rate above 90% and up to 97% at most, showing good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] 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, without creative efforts, other drawings can be obtained based on these drawings.

[0024] Figure 1 is the NMR 1 1H spectrum of compound 3aa; Figure 2 is the NMR 13 13C spectrum of compound 3aa.

[0025] Figure 3 is the NMR 19 19F spectrum of compound 3aa;

[0026] Figure 4 is the NMR 1 1H spectrum of compound 3ba; Figure 5 is the NMR 13 13C spectrum of compound 3ba.

[0027] Figure 6It is the NMR 19 F spectrum of compound 3ba;

[0028] Figure 7 It is the NMR 1 H spectrum of compound 3ca; Figure 8 It is the NMR 13 C spectrum of compound 3ca.

[0029] Figure 9 It is the NMR 19 F spectrum of compound 3ca;

[0030] Figure 10 It is the NMR 1 H spectrum of compound 3da; Figure 11 It is the NMR 13 C spectrum of compound 3da.

[0031] Figure 12 It is the NMR 19 F spectrum of compound 3da;

[0032] Figure 13 It is the NMR 1 H spectrum of compound 3ea; Figure 14 It is the NMR 13 C spectrum of compound 3ea.

[0033] Figure 15 It is the NMR 19 F spectrum of compound 3ea;

[0034] Figure 16 It is the NMR 1 H spectrum of compound 3fa; Figure 17 It is the NMR 13 C spectrum of compound 3fa.

[0035] Figure 18 It is the NMR 19 F spectrum of compound 3fa;

[0036] Figure 19 It is the NMR 1 H spectrum of compound 3ga; Figure 20 It is the NMR 13 C spectrum of compound 3ga.

[0037] Figure 21 It is the NMR 19 F spectrum of compound 3ga;

[0038] Figure 22 It is the NMR 1 H spectrum of compound 3ab; Figure 23 It is the NMR 13 C spectrum of compound 3ab.

[0039] Figure 24 is the 19F NMR spectrum of compound 3ab; 19 F spectrum;

[0040] Figure 25 is the 1H NMR spectrum of compound 3ac; 1 H spectrum; Figure 26 is the 13C NMR spectrum of compound 3ac; 13 C spectrum.

[0041] Figure 27 is the 19F NMR spectrum of compound 3ac; 19 F spectrum;

[0042] Figure 28 is the 1H NMR spectrum of compound 3ad; 1 H spectrum; Figure 29 is the 13C NMR spectrum of compound 3ad; 13 C spectrum.

[0043] Figure 30 is the 19F NMR spectrum of compound 3ad; 19 F spectrum;

[0044] Figure 31 is the 1H NMR spectrum of compound 3ae; 1 H spectrum; Figure 32 is the 13C NMR spectrum of compound 3ae; 13 C spectrum.

[0045] Figure 33 is the 19F NMR spectrum of compound 3ae; 19 F spectrum.

[0046] Figure 34 is the antibacterial rate of compound 3aa against different strains.

[0047] Figure 35 is the antibacterial rate of compound 3aa against Gaeumannomyces graminis at different concentrations.

[0048] Figure 36 is the antibacterial rate of the trifluoromethyl quinazolinone compounds prepared in Examples 1-11 against Gaeumannomyces graminis. Detailed implementation manners

[0049] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0050] Example 1

[0051]

[0052] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2a (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 8 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3aa was obtained by silica gel column separation. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: white solid, 94% yield. The NMR spectrum of the product is as shown in Figure 1 、 2 and Figure 3, 1 H NMR (400 MHz, CDCl3) δ 8.19 (t, J = 9.1 Hz, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.31 - 7.17 (m, 6H), 5.00 (d, J = 18.4 Hz, 1H), 4.22 (d, J = 18.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 186.92 (q, J = 36.4 Hz), 160.46, 154.77, 149.22, 146.90, 138.20, 134.73, 133.33, 131.90, 129.86, 129.19, 128.81, 127.69, 126.86, 126.42, 125.45, 123.87, 122.03, 121.45, 114.93 (q, J = 292.5 Hz), 70.28, 38.58. 19 F NMR (377 MHz, CDCl3) δ -79.54.

[0053] Example 2

[0054]

[0055] Under air conditions, quinazolinone 1b (0.20 mmol), alkynone compound 2a (0.26 mmol), [RhCp*Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DCE (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 100 °C for 12 h. After the reaction, the solvent was removed under reduced pressure, and the target product 3ba was obtained by silica gel column separation. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: white solid, 83% yield. The NMR spectrum of the product is as shown inFigure 4 , 5 As shown in and 6, 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.75 - 7.69 (t, J = 7.6 Hz, 1H), 7.39 (dd, J = 10.9, 4.1 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.4 Hz, 3H), 7.19 (dd, J = 6.5, 1.6 Hz, 2H), 7.00 (s, 1H), 4.99 (d, J = 18.4 Hz, 1H), 4.19 (d, J = 18.4 Hz, 1H), 2.35 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 185.70 (q, J = 36.1 Hz), 159.31, 153.76, 148.15, 146.08, 143.27, 137.25, 133.50, 129.83, 128.09, 128.01, 127.57, 126.38, 125.67, 125.46, 124.24, 122.45, 121.17, 120.15, 113.78 (q, J = 292.5 Hz)., 68.88, 37.46, 21.06. 19 F NMR (377 MHz, CDCl3) δ = -79.50.

[0056] Example 3

[0057]

[0058] Under air conditions, quinazolinone 1c (0.20 mmol), alkynone compound 2a (0.40 mmol), [Ru(p - cymene)Cl2]2 (3 mol%), AgSbF6 (12 mol%) and solvent EA (4.0 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 3ca 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, 86% yield. The NMR spectra of the product are as shown in Figure 7 , 8 and 9, 11H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.77 Hz, 1H), 7.42 (dt, J = 19.8, 7.7 Hz, 2H), 7.33 - 7.28 (m, 3H), 7.27 (d, J = 4.0 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.04 (d, J = 7.6 Hz, 1H), 5.05 (d, J = 18.3 Hz, 1H), 4.20 (d, J = 18.3 Hz, 1H), 3.02 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 185.82 (q, J = 36.0 Hz), 159.44, 154.49, 148.31, 146.18, 137.66, 137.52, 133.31, 131.21, 130.67, 128.00, 127.96, 127.46, 127.01, 125.53, 125.47, 124.22, 119.81, 118.03, 113.77 (d, J = 292.3 Hz), 68.22, 37.52, 18.09. 19 19F NMR (377 MHz, CDCl3) δ = -79.64.

[0059] Example 4

[0060]

[0061] Under air conditions, quinazolinone 1d (0.20 mmol), alkynone compound 2a (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgBF4 (8 mol%) and solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 8 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 and ethyl acetate in a ratio of 7:1. Product data characterization: white solid, 82% yield. The NMR spectra of the product are as shown in Figure 10 、 11 and Figure 12, 11H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.90 - 7.76 (m, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 6.8 Hz, 3H), 7.21 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 8.2 Hz, 1H), 5.03 (d, J = 18.6 Hz, 1H), 4.23 (d, J = 18.6 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 185.70 (d, J = 36.3 Hz), 159.07, 152.73, 147.92, 147.43, 136.43, 133.73, 132.25, 129.74, 129.06, 128.27, 127.94, 126.59, 125.96, 125.78, 124.27, 124.13, 124.03, 120.25, 113.77 (d, J = 292.2 Hz), 68.78, 37.49. 19 19F NMR (377 MHz, CDCl3) δ -79.47.

[0062] Example 5

[0063]

[0064] Under air conditions, quinazolinone 1e (0.20 mmol), alkynone compound 2a (0.20 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 8 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 and ethyl acetate in a ratio of 5:1. Product data characterization: Pale yellow solid, 75% yield. The NMR spectrum of the product is as shown in Figure 13 、 14As shown in Figures 14 and 15, 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.27 (d, J = 6.6 Hz, 3H), 7.22 (d, J = 5.6 Hz, 1H), 7.17 (d, J = 6.9 Hz, 2H), 4.97 (d, J = 18.4 Hz, 1H), 4.19 (d, J = 18.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 186.81 (q, J = 36.3 Hz), 159.30, 154.86, 147.68, 146.74, 137.77, 134.95, 133.43, 132.52, 131.55, 129.86, 129.14, 128.84, 126.23, 125.33, 123.80, 122.39, 121.95, 114.79 (q, J = 292.3 Hz), 70.33, 38.40. 19F NMR (377 MHz, CDCl3) δ = -79.57.

[0065] Example 6

[0066]

[0067] Under air conditions, quinazolinone 1f (0.20 mmol), alkynone compound 2a (0.24 mmol), [Ru(p - cymene)Cl2]2 (4 mol%), Ag2SO4 (16 mol%) and solvent DEC (4.0 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 3fa 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, 84% yield. The NMR spectra of the product are as shown in Figure 16 and 17 Figures 14 and 18. 1 1H NMR (400 MHz, CDCl3) δ 8.20 - 8.08 (m, 1H), 7.97 (dd, J = 5.1, 3.2 Hz, 2H), 7.49 (ddd, J = 14.4, 7.8, 2.7 Hz, 3H), 7.25 (q, J = 5.4 Hz, 3H), 7.19 (t, J = 4.2 Hz, 1H), 7.14 (dd, J = 7.7, 1.7 Hz, 2H), 4.93 (d, J = 18.4 Hz, 1H), 4.17 (d, J = 18.4 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 185.73 (q, J = 36.3 Hz), 158.80, 154.66, 149.14, 145.83, 136.69, 132.51, 130.43, 129.25, 128.96, 128.82, 128.29, 128.08, 127.78, 127.10, 124.26, 122.90, 120.87, 119.09, 113.72 (q, J = 292.3 Hz), 69.27, 37.31. 19 19F NMR (377 MHz, CDCl3) δ -79.58.

[0068] Example 7

[0069]

[0070] Under air conditions, 1 g (0.20 mmol) of quinazolinone, 2a (0.24 mmol) of alkynone compound, [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DCE (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 8 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, 68% yield. The NMR spectra of the product are as shown in Figure 19 、 20 and 21, 1 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.7 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.52 (d, J = 8.9 Hz, 1H), 7.39 (td, J = 8.0, 4.7 Hz, 1H), 7.35 - 7.29 (m, 3H), 7.26 (s, 1H), 7.24 - 7.20 (m, 2H), 5.02 (d, J = 18.4 Hz, 1H), 4.26 (d, J = 18.4 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 185.69 (q, J = 36.3 Hz), 156.28 (d, J = 245.4), 145.78, 137.63, 137.57 (d, J = 12.0 Hz), 132.51, 130.48, 128.79, 128.09, 127.79, 125.65 (d, J = 7.8 Hz), 124.31, 123.22, 122.21, 121.25, 121.21, 120.81, 119.23, 119.04, 113.74 (q, J = 292.1 Hz), 69.33, 37.30. 19 19F NMR (377 MHz, CDCl3) δ = -79.58, -124.71.

[0071] Example 8

[0072]

[0073] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2b (0.26 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgOAc (8 mol%) and solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 8 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: white solid, 78% yield. The NMR spectra of the product are as shown in Figure 22 、 23 and 24, 1 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.7 Hz, 2H), 7.89 - 7.76 (m, 3H), 7.57 (dt, J = 18.1, 7.3 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 4.71 (d, J = 17.0 Hz, 1H), 4.32 (d, J = 17.0 Hz, 1H). 1313C NMR (101 MHz, CDCl3) δ 186.33 (q, J = 36.2 Hz), 160.32, 155.31, 149.13, 144.02, 134.61, 134.16, 133.67, 132.87, 132.75, 132.33, 130.29, 129.98, 128.56, 127.69, 127.29, 126.76, 126.70, 123.27, 122.06, 121.04, 114.68 (d, J = 292.2 Hz), 69.43, 39.92. 19 19F NMR (377 MHz, CDCl3) δ -79.71.

[0074] Example 9

[0075]

[0076] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2c (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 0.2 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: white solid, 90% yield. The NMR spectra of the product are as shown in Figure 25 、 26 and Figure 27, 1 1H NMR (400 MHz, CDCl3) δ 8.28 - 8.16 (m, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.50 - 7.41 (m, 2H), 7.35 (s, 1H), 7.26 - 7.23 (m, 1H), 7.22 - 7.14 (m, 2H), 4.98 (d, J = 18.3 Hz, 1H), 4.21 (d, J = 18.4, 9.3 Hz, 1H). 1313C NMR (100 MHz, CDCl3) δ 186.46 (q, J = 36.3 Hz), 160.28, 154.37, 149.06, 146.08, 140.45, 134.80, 133.39, 131.96, 131.78, 130.57, 130.08, 128.56, 127.66, 126.95, 126.78, 124.15, 123.93, 123.26, 121.89, 121.20, 114.76 (q, J = 292.2 Hz), 69.51, 38.26. 19 19F NMR (377 MHz, CDCl3) δ = -79.54.

[0077] Example 10

[0078]

[0079] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2d (0.24 mmol), [Ru(p-cymene)Cl2]2 (3 mol%), AgSbF6 (12 mol%) and 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: white solid, 81% yield. The NMR spectra of the product are as shown in Figure 28 、 29 and 30, 1 1H NMR (400 MHz, CDCl3) δ 8.28 - 8.17 (m, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.02 (d, J = 18.4 Hz, 1H), 4.22 (d, J = 18.4 Hz, 1H), 3.74 (s, 3H). 13 13C NMR (100

[0080] MHz, CDCl3) δ 185.80 (q, J = 36.1 Hz), 159.35, 158.55, 153.47, 148.04, 145.91, 133.50,

[0081] 132.15, 130.80, 128.76, 128.65, 126.47, 125.99, 125.67, 125.65, 122.64, 120.92, 120.35, 113.76 (q, J = 292.4 Hz), 113.21, 68.95, 54.22, 37.51. 19 19F NMR (377 MHz, CDCl3) δ -79.60.

[0082] Example 11

[0083]

[0084] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2e (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DEC (4.0 mL) were added to a 10 mL sealed tube and reacted in a reaction module at 120 °C for 3 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 and ethyl acetate in a ratio of 5:1. Product data characterization: white solid, 79% yield. The NMR spectrum of the product is as shown in Figure 31 、 32 and 33, 1 1H NMR (400 MHz, CDCl3) δ 8.20 - 8.11 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.52 - 7.44 (m, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.26 - 7.15 (m, 6H), 5.38 (t, J = 53.8 Hz, 1H), 4.84 (d, J = 18.1 Hz, 1H), 4.16 (d, J = 18.1 Hz, 1H). 13 13C NMR (100 MHz, CDCl3) δ 193.88 (t, J = 26.5 Hz), 159.30, 153.82, 148.00, 146.31, 137.37, 133.50, 132.10, 130.56, 128.49, 127.98, 127.51, 126.42, 125.69, 125.62, 124.27, 122.64, 120.97, 120.31, 108.25 (t, J = 253.7 Hz), 69.38, 37.19. 19 19F NMR (377 MHz, CDCl3) δ -127.05.

[0085] Example 12

[0086]

[0087] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2f (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DEC (2.0 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 3af was obtained by silica gel column separation. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: white solid, 82% yield.

[0088] Example 13

[0089]

[0090] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2g (0.24 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and solvent DEC (1.0 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 3ag was obtained by silica gel column separation. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: white solid, 98% yield.

[0091] Example 14

[0092]

[0093] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2h (0.20 mmol), [Ru(p-cymene)Cl2]2 (2 mol%), AgSbF6 (8 mol%) and 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 3ah was obtained by silica gel column separation. All eluents were prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: light yellow solid, 74% yield.

[0094] Example 15

[0095]

[0096] Under air conditions, quinazolinone 1a (0.20 mmol), alkynone compound 2i (0.4 mmol), [Ru(p-cymene)Cl2]2 (1 mol%), AgSbF6 (5 mol%) and 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 3ai 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, 88% yield. Bactericidal activity test:

[0097] Take 6.6 mg of the synthesized drug above 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. Appropriate amounts of the test agent were pipetted into conical flasks under sterile conditions, shaken well, and then poured equally 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. The cultured pathogenic bacteria were cut into disks with a diameter of 5 mm along the edge of the colony under sterile conditions using a puncher, and the disks were inoculated in the center of the drug-containing plate with the mycelial side facing up, covered with the petri dish lid, and the petri dishes were placed in an incubator at a constant temperature of 25 °C. When the diameter of the control colony expanded to more than 6 cm, the diameter of the colony was measured by the cross method, and the average value was taken; the inhibition rate was calculated at the end of the culture.

[0098] The calculation formula is: inhibition rate I = (D0 - D t ) / D0 × 100%

[0099] D0 is the average diameter of the mycelium of the control plate, D t is the average diameter of the mycelium of the sample plate.

[0100] The present invention determined the activities of 8 kinds of pathogenic bacteria common in agricultural production, namely Rhizoctonia solani, Phytophthora parasitica var. nicotianae, Fusarium graminearum, Fusarium oxysporum, Fusarium moniliforme, Sclerotium rolfsii, Gaeumannomyces graminis var. tritici and Rhizoctonia cerealis. The results showed that the synthesized trifluoromethyl quinazolinone compound 3aa had good bactericidal activity against Gaeumannomyces graminis var. tritici, and the inhibition rate could reach 94%, as Figure 34 shown. On this basis, the inhibitory activities of trifluoromethyl quinazolinone compounds against Gaeumannomyces graminis var. tritici at different concentrations were investigated, and it was found that the inhibitory effect was the best at a concentration of 200 ppm against Gaeumannomyces graminis var. tritici, as Figure 35 shown. Therefore, the inhibitory activities of 11 novel trifluoromethyl quinazolinone compounds against Gaeumannomyces graminis var. tritici were tested at a concentration of 200 ppm. As Figure 36As shown, the results indicate that most of the 11 novel trifluoromethyl quinazolinone compounds have excellent inhibitory effects on the pathogen of wheat take-all, with the inhibition rate above 90%, and the highest reaching 97%, showing good application prospects.

[0101] 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 principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of a trifluoromethyl quinazolinone derivative, characterized in that, The quinazolinone compound 1, the trifluoromethyl-containing alkynone compound 2, and a catalyst are added to a solvent for reaction to obtain a trifluoromethyl-containing quinazolinone compound; the reaction equation is as follows: In the formula, Ar 1 ,Ar 2 ,Ar 3 Independently selected from benzene rings or heterocyclic rings substituted with electron donating or electron withdrawing groups; R is a polyfluoroalkyl group.

2. The preparation method of the trifluoromethyl quinazolinone derivative according to claim 1, characterized in that, The Ar 1 , Ar2, Ar 3 is independently a benzene ring or a heterocyclic ring substituted with an electron-donating group or an electron-withdrawing group selected from Me, OMe, F, Cl, Br, CF3, NO2 groups, and the heterocyclic ring is thiophene, pyridine or quinoline; the polyfluoroalkyl group is CF3, CHF2, C2F5, C3F7 or C4F9.

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

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

5. The preparation method of the trifluoromethyl quinazolinone derivative according to claim 4, characterized in that, The concentration of the quinazolinone compound 1 in the solvent is 0.05 - 2 M.

6. The preparation method of the trifluoromethyl quinazolinone derivative according to claim 5, 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).

7. The preparation method of the trifluoromethyl quinazolinone derivative according to claim 6, characterized in that, The ruthenium catalyst is any one 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 more of silver tetrafluoroborate, silver bis(trifluoromethanesulfonyl)imide, silver trifluoromethanesulfonate, silver sulfate, silver acetate, and silver trifluoroacetate.

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

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

10. Use of the trifluoromethyl-containing quinazolinone derivative according to claim 9 in the field of agricultural antibacterial and bactericidal applications.

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