Preparation method of isoquinoline quinazolinone compound

Abstract

The invention provides a preparation method of an isoquinoline quinazolinone compound, and belongs to the technical field of organic synthetic chemistry. Comprising the following steps: mixing a quinazolinone compound, a solvent, a catalyst, an oxidizing agent and alkali to prepare a reaction solution, and reacting to prepare the isoquinoline quinazolinone compound, the solvent comprises 1, 2-dichloroethane; the reaction formula is as follows: 1 is a quinazolinone compound, 2 is an isoquinoline quinazolinone compound, and R1 and R2 are independently selected from any one of F, Cl, Br, Me, OMe, tBu, CF3 and NO2, or are fused rings, thiophene, pyridine, quinoline and indole heterocyclic rings. The method provides a simple and effective method for synthesizing the isoquinoline quinazolinone derivative and realizing a new framework compound taking DCE as an acetylene source, and the method has the characteristics of simple operation, economical steps, strong functional group tolerance, good yield and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and in particular relates to a nitrogen-containing heterocyclic compound. Background Art

[0002] Quinazolin-4(3H)-one is a class of nitrogen-containing heterocyclic compounds widely found in natural alkaloids. In early studies, quinazolin-4(3H)-one and its derivatives showed various pharmacological activities such as antioxidant, antibacterial, and antitumor. It is the main active group in the structure of many drugs and is an extremely important class of natural alkaloid structures in the development of medicines. In addition to medicine, quinazolin-4(3H)-one and its derivatives have repeatedly shown good antibacterial and antiviral activities in the creation of pesticides, and have therefore attracted the attention of many scholars. Starting from natural products, it is an important strategy for the creation of green pesticides to find pesticide lead fragments that can solve drug resistance, are low in toxicity, and are easy to synthesize. Camelinine compounds and evodia rutaecarpine compounds are representative natural isoquinoline and quinazolinone alkaloids. Retrosynthetic analysis of the two types of natural product alkaloids was carried out to find suitable carbon-disynthetic sons. The reaction sites of 2-arylquinazolinone were connected by chemical means to construct a series of isoquinoline and quinazolinone derivative compounds. These compounds are widely present in a large number of biologically active natural products and drug molecules.

[0003] On the other hand, the existing method for synthesizing isoquinolinone and quinazolinone compounds mainly uses vinylene carbonate as a carbon-2 synthon to complete the synthesis of C5 and C6 positions. For example, patent publication number CN 112125900A discloses a method for synthesizing isoquinolinone and quinazolinone compounds, which realizes the first preparation of isoquinolinone and quinazolinone compounds without substitution groups at positions 5 and 6 by the reaction of 2-arylquinazolinone and vinylene carbonate catalyzed by rhodium salt; the present invention relates to a one-pot two-step reaction: in the first step, the raw material compound I and compound II undergo a CH activation reaction under the catalytic action of rhodium salt, followed by the removal of a molecule of CO2, followed by an intramolecular cyclization reaction to generate the final target product III. Vinylene carbonate belongs to Class A hazardous goods, has a phenol odor, is flammable at room temperature and has certain toxicity to the human body. There is a single problem in the method reports for synthesizing isoquinolinone and quinazolinone derivatives. In order to enrich the molecular library of such compounds, it is necessary to develop an efficient, economical and practical new method. In addition, some existing synthetic routes are lengthy and complex, with low atom economy, and a large amount of raw materials are converted into waste during the reaction, which not only wastes resources but also pollutes the environment, and does not conform to the current concept of green chemistry and sustainable development. With the growing demand for isoquinolinone and quinazolinone compounds in various fields, and the increasingly urgent requirements for green, efficient and low-cost synthetic methods, it is urgent to develop a new preparation method.

[0004] 1,2-Dichloroethane (DCE) is a bulk chemical industrial product with an annual global consumption of more than 50 million tons. It is mainly used in the production of vinyl chloride in industry, which has directly promoted the development of polyvinyl chloride in the field of new materials. As a common synthon and conventional solvent in organic synthesis, its availability and economy make it an ideal choice for the synthesis of complex molecules, especially transition metal-catalyzed functionalization reactions. Among them, the cyclization reaction of DCE as a vinyl equivalent has made important progress in recent years. In 2019, You Jinsong's research group reported a rhodium-catalyzed three-component cyclization reaction of simple pyridine, alkyne and DCE, realizing the synthesis of structurally diverse fused-ring pyridinium compounds, in which DCE played a triple role as a solvent, ethylene equivalent and in situ activation reagent (Angew. Chem. Int. Ed., 2019, 58, 254-258). Subsequently, the authors expanded alkynes to indoles, and adopted the same strategy to achieve the regioselective synthesis of more complex cationic azaspiralenes with the help of cheap copper catalysts (Angew.Chem.Int.Ed.,2020,59,23532-23536). Two years later, Yang Yudong's research group also used the in situ activation strategy to develop a copper-catalyzed oxidative CH cyclization reaction of quinoline and DCE, realizing the construction of a benzoquinolinium skeleton (Org.Lett.,2022,24,6256-6260). In the above work, DCE, as an electrophilic reagent, first undergoes nitrogen alkylation reaction, and then removes a molecule of hydrogen chloride under the action of a base to generate a key nitrogen vinyl intermediate, which is then cyclized with coupling fragments such as alkynes under the action of metals. However, there are no literature reports on the use of DCE as an acetylene equivalent. Summary of the invention

[0005] In view of the above technical problems, the present invention proposes a method for preparing an isoquinoline and quinazolinone compound, which solves the problem that DCE as an acetylene source requires high temperature and high pressure and the participation of precious metals. At the same time, in view of the problem that the existing method for synthesizing isoquinoline and quinazolinone derivatives is single, the method provides a simple and effective method for synthesizing isoquinoline and quinazolinone derivatives and realizing new framework compounds using DCE as an acetylene source, and the method has the characteristics of simple operation, economical steps, strong functional group tolerance and good yield.

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

[0007] A method for preparing an isoquinolinone quinazolinone compound comprises the following steps: mixing a quinazolinone compound, a solvent, a catalyst, an oxidant and a base to prepare a reaction solution, and reacting to obtain the isoquinolinone quinazolinone compound; the solvent comprises 1,2-dichloroethane; and the reaction formula is as follows:

[0008] Where R1 and R 2 F, Cl, Br, Me, OMe, t Any one of Bu, CF3, NO2, etc., or a condensed ring such as a naphthalene ring, and a heterocyclic ring such as thiophene, pyridine, quinoline, indole, etc.

[0009] The catalyst is a transition metal catalyst; the transition metal catalyst is a ruthenium or rhodium catalyst.

[0010] Using quinazolinone compound 1 and DCE as raw materials, a catalytic amount of ruthenium catalyst, silver salt, oxidant and base were added to achieve the efficient preparation of a series of isoquinoline and quinazolinone compounds in one step.

[0011] Under N2 atmosphere, quinazolinone compound 1, DCE, ruthenium catalyst, silver salt, oxidant and base are added into a 10mL reaction bottle equipped with a magnetic stirrer, the reaction temperature is 60-150 degrees, the reaction time is 0.5-16 hours, and after the reaction is completed, column chromatography or thin layer chromatography is used to separate and purify to obtain the corresponding isoquinoline and quinazolinone 2. The eluent used is petroleum ether and ethyl acetate prepared in a certain volume ratio, and the commonly used ratio is 15:1-10:1.

[0012] The reaction effect is better as described in the embodiment: under N2 atmosphere, compound 1 and ruthenium catalyst, silver salt, oxidant and base, solvent is DCE, concentration is 0.1M, reaction temperature is 130 degrees, reaction time is 10h, the effect is better. The reaction effect is best in nitrogen atmosphere, but not limited to this, other inert gas atmospheres and air atmospheres can also react; the best transition metal catalyst is dichloro (p-methyl isopropylphenyl) ruthenium (II) dimer described in the embodiment, the best silver salt is silver hexafluoroantimonate, and the molar ratio of dichloro (p-methyl isopropylphenyl) ruthenium (II) dimer to silver salt is 1:4, but not limited to this. Dichloro(pentamethylcyclopentadienyl)rhodium dimer, pentamethylcyclopentadienyl rhodium acetate, di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium, dichloro(p-methylisopropylphenyl)ruthenium(II) dimer, pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium chloride and (1,5-cyclooctadiene)dichlororuthenium(II), silver tetrafluoroborate, silver bistrifluoromethanesulfonyl imide, silver trifluoromethanesulfonate, silver sulfate, silver acetate and silver trifluoroacetate, any combination of transition metal catalyst and silver salt in a molar ratio of 1:4 can cause the reaction to occur; the best oxidant is the copper acetate described in the embodiment, but not limited to this, any oxidant among oxygen, benzoquinone and potassium thiosulfate can cause the reaction to occur; the best oxidant dosage is 3 equivalents, but not limited to this, and its dosage can also be adjusted, and the product can be obtained between 0.5-5 equivalents; the best base is The sodium tert-butoxide described in the embodiment has the best effect of 2 equivalents, but is not limited to this, and its dosage can also be adjusted, and the product can be obtained between 0.5-3 equivalents; the solvent is preferably dichloroethane (DCE) described in the embodiment, but is not limited to this, dichloroethane (DCE) and other solvents such as ethyl acetate (EA), ethylene glycol dimethyl ether (DME), 1,4-dioxane, N-dimethylformamide (DMF), N-dimethylacetamide, toluene, acetonitrile (ACN), chlorobenzene (PhCl) and dichloromethane (DCM) in a ratio of 1:4 can also cause the reaction to occur; the reaction concentration is preferably 0.1M described in the embodiment, but is not limited to this, and the concentration can be adjusted in the range of 0.05-0.2M; the reaction temperature is preferably 130 degrees described in the embodiment, but is not limited to this, and the reaction can also occur by lowering the temperature to 60 degrees or increasing it to 150 degrees. The reaction time is preferably 10h described in the embodiment, but is not limited to this, and the target product can still be obtained by shortening it to 0.5h or extending it to 18h.

[0013] Beneficial effects of the present invention: The present invention selects easily available 2-arylquinazolinone compounds and dichloroethane (DCE) as reactants, and under the action of a metal ruthenium catalyst, realizes the construction of an isoquinoline and quinazolinone skeleton in one step through a [4+2] cyclization strategy, provides a new idea of ​​using dichloroethane (DCE) as an acetylene source, and the method has the characteristics of simple reaction operation, atom economy, step economy, strong functional group tolerance and good yield. The obtained product has broad industrial application prospects, and at the same time provides a new idea and new method for the field of medicine and natural product synthesis. The 8 compounds prepared by the present invention all show certain fungicidal activity against 6 common pathogenic fungi in agriculture, such as Rhizoctonia solani, Fusarium graminearum, Fusarium moniliforme, Fusarium oxysporum, Nicotiana tabacum and wheat rust fungus. Among them, the fungicidal activity against wheat rust fungus is the highest, which can reach 75.92%, and has a good application prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. 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 paying creative work.

[0015] Figure 1 The NMR of compound 2a 1 H spectrum.

[0016] Figure 2 The NMR of compound 2a 13 C spectrum.

[0017] Figure 3 The NMR of compound 2b 1 H spectrum.

[0018] Figure 4 The NMR of compound 2b 13 C spectrum.

[0019] Figure 5 This is the NMR of compound 2c 1 H spectrum.

[0020] Figure 6 This is the NMR of compound 2c 13 C spectrum.

[0021] Figure 7 This is the NMR of compound 2c 19 F spectrum.

[0022] Figure 8 The NMR of compound 2d 1 H spectrum.

[0023] Fig. 9 The NMR of compound 2d 13 C spectrum.

[0024] Fig.10 The NMR of compound 2e 1 H spectrum.

[0025] Fig.11 The NMR of compound 2e 13 C spectrum.

[0026] Fig.12 The NMR of compound 2f 1 H spectrum.

[0027] Fig.13 The NMR of compound 2f 13 C spectrum.

[0028] Fig.14 This is the NMR of compound 2g 1 H spectrum.

[0029] Fig.15 This is the NMR of compound 2g 13 C spectrum.

[0030] Fig.16 This is the NMR of compound 2h 1 H spectrum.

[0031] Fig.17 This is the NMR of compound 2h 13 C spectrum.

[0032] Fig.18 is the inhibition rate of compound 2a against different bacterial species.

[0033] Fig.19 It is the inhibition rate of the isoquinoline and quinazolinone compounds prepared in Examples 1-8 against Pseudomonas aeruginosa. DETAILED DESCRIPTION

[0034] 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.

[0035] Example 1

[0036] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0037]

[0038] Specifically, the following steps are included: under nitrogen conditions, 2-phenyl-4-[3H]quinazolinone 1a (0.20 mmol), [Ru(p-cymene)Cl2]2 (10 mol%), AgSbF6 (40 mol%), copper acetate (3 equiv.), sodium tert-butoxide (2 equiv.) and DCE (2.0 mL) are added to a 10 mL sealed tube, and reacted in a reaction module at 130 degrees for 10 hours. After the reaction is completed, the solvent is removed under reduced pressure, and the target product 2a is separated by a silica gel column. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: white solid, 72% yield. The NMR spectrum of the product is as follows Figure 1 and 2 As shown, 1 H NMR (400MHz, Chloroform-d): δ9.09(d,J=8.0Hz,1H),8.66(d,J=7.8Hz,1H),8.47(d,J=8.0Hz,1H),7 .94-7.82(m,2H),7.74(t,J=7.5Hz,1H),7.71-7.62(m,2H),7.56-7.48(m,1H),7.05(d,J=7.8Hz,1H). 13 C NMR (100MHz, CDCl3): δ159.57,147.58,146.23,134.89,132.93,132.25,128. 56,127.56,127.50,127.33,127.27,126.53,125.83,121.96,117.79,113.26.

[0039] Example 2

[0040] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0041]

[0042] Specifically, the following steps are included: under nitrogen conditions, 2-(p-tolyl)quinazolin-4(3H)-one 1b (0.20 mmol), [Ru(p-cymene)Cl2]2 (10 mol%), AgSbF6 (40 mol%), copper acetate (2 equiv.), sodium tert-butoxide (2 equiv.) and DCE (2.0 mL) are added to a 10 mL sealed tube and reacted in a reaction module at 120 degrees for 14 hours. After the reaction is completed, the solvent is removed under reduced pressure and the target product 2b is obtained by separation with a silica gel column. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: light yellow solid, 72% yield. The NMR spectrum of the product is as follows Figure 3 and 4 As shown, 1 H NMR (400MHz, Chloroform-d): δ8.55(d,J=7.8Hz,1H),8.38(d,J=7.1Hz,1H),7.84-7.7 6(m,2H),7.52-7.44(m,2H),7.39(d,J=8.5Hz,2H),6.89(d,J=7.8Hz,1H),3.17(s,3H). 13 C NMR (100MHz, CDCl3): δ158.61,145.93,145.90,140.69,133.55,133.51,131.67, 130.09,126.73,126.01,124.85,124.80,124.03,120.56,116.25,113.02,26.12.

[0043] Example 3

[0044] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0045]

[0046] Specifically, the following steps are included: under argon conditions, 2-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one 1c (0.20mmol), [Ru(p-cymene)Cl2]2 (10mol%), AgSbF6 (40mol%), copper acetate (2equiv.), sodium tert-butoxide (2equiv.) and DCE (2.0mL) are added to a 10mL sealed tube and reacted in a reaction module at 100 degrees for 18h. After the reaction is completed, the solvent is removed under reduced pressure and the target product 2c is separated by a silica gel column. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 8:1. Product data characterization: white solid, 48% yield. The NMR spectrum of the product is as follows Figure 5-7 As shown, 1HNMR (400MHz, CDCl3): δ9.20(d,J=8.5Hz,1H),8.70(d,J=7.9Hz,1H),8.47(d, J=8.0Hz,1H),7.97-7.82(m,4H),7.56(t,J=7.4Hz,1H),7.05(d,J=7.9Hz,1H). 13 C NMR (100MHz, CDCl3): δ159.33, 147.30, 145.22, 135.28, 133.87 (q, J = 32.6Hz) 133.04, 130.16, 128 .32,127.88,127.51,126.65,124.69(q,J=3.4Hz),123.73(q,J=4.2Hz),123.53,118.17,112.40. 19 F NMR (376MHz,CDCl3)δ-79.54.

[0047] Example 4

[0048] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0049]

[0050] Specifically, the following steps are included: under argon conditions, 2-(4-chlorophenyl)quinazolin-4(3H)-one 1d (0.20 mmol), [Ru(p-cymene)Cl2]2 (10 mol%), AgSbF6 (40 mol%), benzoquinone (2 equiv.), sodium tert-butoxide (2 equiv.) and DCE (2.0 mL) are added to a 10 mL sealed tube and reacted in a reaction module at 130 degrees for 12 hours. After the reaction is completed, the solvent is removed under reduced pressure and the target product 2d is obtained by separation with a silica gel column. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: white solid, 61% yield. The NMR spectrum of the product is as follows Figure 8 and 9 as shown. 1 HNMR (400MHz, CDCl3): δ9.24(d,J=2.1Hz,1H),8.65(d,J=7.8Hz,1H),8.46(d,J=6.8Hz,1H) ,7.94-7.86(m,2H),7.82(dd,J=8.4,2.1Hz,1H),7.57-7.49(m,2H),6.99(d,J=7.8Hz,1H). 13C NMR (100MHz, CDCl3): δ158.26,146.35,144.51,137.60,134.00,133.08,127. 87,126.48,126.32,125.01,124.83,124.78,122.23,116.71,116.26,110.95.

[0051] Example 5

[0052] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0053]

[0054] Specifically, the following steps are included: under nitrogen conditions, compound 2-phenylbenzo[h]quinazolin-4(3H)-one 1e (0.20mmol), [Ru(p-cymene)Cl2]2 (10mol%), AgSbF6 (40mol%), benzoquinone (3equiv.), sodium tert-butoxide (2equiv.) and DCE (2.0mL) are added to a 10mL sealed tube and reacted in a reaction module at 110 degrees for 12 hours. After the reaction is completed, the solvent is removed under reduced pressure and the target product 2e is separated by a silica gel column. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: white solid, 53% yield. The NMR spectrum of the product is as follows Fig.10 and 11 shown. 1 HNMR (400MHz, Chloroform-d): δ9.36(t,J=8.4Hz,2H),8.81(d,J=7.7Hz,1H),8.35(d,J=8.8Hz,1H),7.95(d d,J=6.1,3.3Hz,1H),7.84(t,J=8.8Hz,1H),7.80-7.73(m,4H),7.72(d,J=5.9Hz,1H),7.18(d,J=7.8Hz,1H). 13 C NMR (101MHz, CDCl3): δ159.32,146.56,146.20,136.51,133.15,132.34,130.23,129.61,128. 67,128.00,127.83,127.44,126.86,126.63,126.26,125.59,122.54,122.12,113.99,113.80.

[0055] Example 6

[0056] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0057]

[0058] Specifically, the following steps are included: under nitrogen conditions, 5-chloro-2-phenylquinazolin-4(3H)-one 1f (0.20 mmol), [Ru(p-cymene)Cl2]2 (10 mol%), AgSbF6 (40 mol%), copper acetate (3 equiv.), sodium tert-butoxide (2 equiv.) and DCE (2.0 mL) are added to a 10 mL sealed tube and reacted in a reaction module at 130 degrees for 12 hours. After the reaction is completed, the solvent is removed under reduced pressure and the target product 2f is separated by a silica gel column. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: white solid, 63% yield. The NMR spectrum of the product is as follows Fig.12 and 13 shown. 1 HNMR(400MHz,Chloroform-d): δ9.01(d,J=8.8Hz,1H),8.63(d,J=7.8Hz,1H),7. 81-7.71(m,2H),7.71-7.61(m,3H),7.49(d,J=7.7Hz,1H),7.05(d,J=7.9Hz,1H). 13 C NMR (100MHz, CDCl3): δ157.48,149.88,146.71,134.51,134.03,133.18,132. 60,128.62,128.31,127.24,127.06,126.90,126.52,121.77,114.93,113.52.

[0059] Example 7

[0060] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0061]

[0062] Specifically, the following steps are included: under nitrogen conditions, 1 g (0.20 mmol) of 6-methoxy-2-phenylquinazoline-4 (3H) -one, [Ru (p-cymene) Cl2] 2 (10 mol%), AgSbF6 (40 mol%), copper acetate (3 equiv.), sodium tert-butoxide (2 equiv.) and DCE (2.0 mL) are added to a 10 mL sealed tube and reacted in a reaction module at 130 degrees for 12 hours. After the reaction is completed, the solvent is removed under reduced pressure and separated with a silica gel column to obtain 2 g of the target product. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 5:1. Product data characterization: white solid, 74% yield. The NMR spectrum of the product is as follows Fig.14 and 15 shown. 1 HNMR (400MHz, Chloroform-d): δ8.98(d,J=8.0Hz,1H),8.59(d,J=7.9Hz,1H),7.72(d,J= 2.9Hz,1H),7.69-7.54(m,4H),7.42(d,J=9.1Hz,1H),6.97(d,J=7.8Hz,1H),3.91(s,3H). 13 C NMR (100MHz, CDCl3): δ159.32,157.82,144.41,142.55,132.47,131.84,129.29, 128.55,127.71,126.91,126.52,126.14,121.97,118.41,113.41,105.69,55.94.

[0063] Example 8

[0064] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0065]

[0066] Specifically, the following steps are included: under nitrogen conditions, 7-chloro-2-phenylquinazoline-4(3H)-one 1h (0.20mmol), [Ru(p-cymene)Cl2]2 (10mol%), AgSbF6 (40mol%), copper acetate (3equiv.), sodium tert-butoxide (2equiv.) and DCE (2.0mL) are added to a 10mL sealed tube and reacted in a reaction module at 130 degrees for 12h. After the reaction, the solvent is removed under reduced pressure and the target product 2h is separated by a silica gel column. All eluents are prepared from petroleum ether and ethyl acetate in a ratio of 10:1. Product data characterization: white solid, 67% yield. The NMR spectrum of the product is as follows Fig.16 and 17 shown.1 HNMR(400MHz,Chloroform-d): δ9.05(d,J=8.0Hz,1H),8.63(d,J=7.9Hz,1H),8.58(d,J=2.3Hz ,1H),7.91(dd,J=8.8,2.3Hz,1H),7.80-7.73(m,2H),7.72-7.62(m,2H),7.07(d,J=7.8Hz,1H). 13 C NMR (100MHz, CDCl3): δ157.42,145.45,145.32,136.98,131.90,131.46,1 28.60,128.35,127.69,126.25,125.57,120.78,117.97,117.94,112.70.

[0067] Example 9

[0068] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0069]

[0070] Specifically, the method comprises the following steps: under nitrogen conditions, 7-chloro-2-phenylquinazoline-4(3H)-one 1h (0.50mmol), di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium (1mol%), silver sulfate (5mol%), benzoquinone (0.5equiv.), sodium tert-butoxide (3equiv.), DCE (2.0mL) and EA (8.0mL) are added into a 20mL sealed tube and reacted in a reaction module at 150 degrees for 0.5h. After the reaction is completed, the solvent is removed under reduced pressure, and the target product 2h is separated by a silica gel column, and all eluents are prepared by petroleum ether and ethyl acetate in a ratio of 10:1.

[0071] Example 10

[0072] A method for preparing an isoquinoline-quinazolinone compound, the reaction formula is as follows:

[0073]

[0074] Specifically, the method comprises the following steps: under nitrogen conditions, 7-chloro-2-phenylquinazolin-4(3H)-one 1h (0.80mmol), (1,5-cyclooctadiene) dichlororuthenium (II) (20mol%), silver bis(trifluoromethanesulfonyl)imide (40mol%), potassium thiosulfate (5equiv.), sodium tert-butoxide (0.5equiv.), DCE (2.0mL) and DMF (2.0mL) are added into a 10mL sealed tube and reacted in a reaction module at 60 degrees for 18h. After the reaction is completed, the solvent is removed under reduced pressure, and the target product 2h is separated by a silica gel column. All eluents are prepared by mixing petroleum ether and ethyl acetate in a ratio of 10:1.

[0075] Bactericidal activity test:

[0076] Take 6.6 mg of the above-synthesized drug and dissolve it in 0.33 mL DMSO, then add an aqueous solution containing 1% Tween 80 to make a 2 mg / mL original drug. Pipette an appropriate amount of the test drug into a conical flask under sterile conditions, shake it thoroughly, and then pour it into three culture dishes with a diameter of 9 cm to make a 200 μg / mL drug-containing plate. The above experiment sets the treatment without drug as a blank control, and each treatment is repeated three times. Cut the bacterial cake along the edge of the colony with a 5 mm diameter puncher under sterile conditions, inoculate the bacterial cake in the center of the drug-containing plate with an inoculator, with the mycelium facing up, cover the dish, and place the culture dish in a constant temperature incubator at 25 degrees Celsius for cultivation. When the diameter of the control colony expands to more than 6 cm, measure the colony diameter using the cross method and take the average value; calculate the antibacterial rate after the cultivation.

[0077] The calculation formula is: Inhibition rate I = (D0-D t ) / D0×100%

[0078] D0 is the average diameter of mycelium in the control disk, D t is the average diameter of mycelium in the sample disk.

[0079] The antibacterial activity of six common pathogenic fungi in agricultural production was determined, namely, Rhizoctonia solani, Fusarium graminearum, Fusarium moniliforme, Fusarium oxysporum, Phytophthora nicotianae, and Psoralea corylifolia. Fig.18 As shown in the figure, the results showed that the synthesized isoquinoline and quinazolinone compound 2a had certain bactericidal activity against several pathogens, among which the bactericidal activity against wheat take-all pathogen was the highest, with an inhibition rate of 75.92%. On this basis, the antibacterial activity of 8 functionalized isoquinoline and quinazolinone compounds against wheat take-all pathogen was investigated. Fig.19 As shown, the results showed that the eight isoquinoline and quinazolinone compounds all had certain fungicidal activity against wheat take-all pathogen and had good application prospects.

[0080] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing an isoquinolinone compound, characterized in that: The following steps are involved: A quinazolinone compound, a solvent, a catalyst, an oxidant and a base are mixed to prepare a reaction solution, and an isoquinolinoquinazolinone compound is obtained by reaction; the solvent includes 1,2-dichloroethane; the reaction formula is as follows: In the formula, 1 is a quinazolinone compound, 2 is an isoquinolinone quinazolinone compound, and R 1 and R 2 independently selected from F, Cl, Br, Me, OMe, t Any one of Bu, CF3, NO2, or a condensed ring, as well as thiophene, pyridine, quinoline, indole heterocycle.

2. The method for preparing the isoquinolinone compound according to claim 1, characterized in that: The solvent also includes other solvents, and the other solvents are any one of ethyl acetate, ethylene glycol dimethyl ether, 1,4-dioxane, NN dimethylformamide, NN dimethylacetamide, acetonitrile, toluene, chlorobenzene and dichloromethane; the volume ratio of 1,2-dichloroethane to other solvents is 1:(1-5).

3. The method for preparing the isoquinolinone compound according to claim 2, characterized in that: The catalyst is a transition metal catalyst; the transition metal catalyst is a ruthenium or rhodium catalyst; silver salt is also added to the catalyst, and the molar ratio of the catalyst to the silver salt is 1:(2-5).

4. The method for preparing the isoquinolinoquinazolinone compound according to claim 3, characterized in that: The amount of the transition metal catalyst used is 1-20 mol% of the quinazolinone compound.

5. The method for preparing the isoquinolinone compound according to claim 4, characterized in that: The transition metal catalyst is any one or more of dichloro(pentamethylcyclopentadienyl)rhodium dimer, pentamethylcyclopentadienyl rhodium acetate, bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium, dichloro(p-methylisopropylphenyl)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 bistrifluoromethanesulfonyl imide, silver trifluoromethanesulfonate, silver sulfate, silver acetate and silver trifluoroacetate.

6. The method for preparing the isoquinolinoquinazolinone compound according to claim 5, characterized in that: The oxidant is any one or more of oxygen, copper acetate, benzoquinone and potassium persulfate.

7. The method for preparing the isoquinolinoquinazolinone compound according to claim 6, characterized in that: The base is sodium tert-butoxide.

8. The method for preparing the isoquinolinoquinazolinone compound according to claim 7, characterized in that: The amount of the oxidant used is 0.5-5 equivalents of the quinazolinone compound; the amount of the base used is 0.5-3 equivalents of the quinazolinone compound.

9. The method for preparing the isoquinolinoquinazolinone compound according to claim 8, characterized in that: The concentration of the oxazolinone compound in the reaction solution is 0.05-0.2M.

10. The method for preparing the isoquinolinoquinazolinone compound according to any one of claims 1 to 9, characterized in that: The reaction temperature is 60-150° C. and the reaction time is 0.5-16 h.

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