Application of isoindolone compound

Abstract

The invention belongs to the field of organic synthesis and pesticide application, and particularly relates to application of a novel isoindolone substance, the structural formula is as follows: R1 is hydrogen, 3-methyl, 4-methyl, 4-methoxyl, 3-methoxyl or 2-methoxyl chloride; meanwhile, the N-methylbenzylamine can also be changed into N-methyl-N-(4-picolyl) amine (2) and N-methyl-2-thiophenemethylamine (3). Wherein R2 is selected from hydrogen, 3-methyl, 4-methyl, 5-methyl, 6-methyl, 3-methoxyl, 4-methoxyl, 5-methoxyl, 6-methoxyl, fluorine and chlorine; meanwhile, the 2-methoxy methyl benzoate can also be changed into the 2-methoxy methyl nicotinate pyridine (4). A biological activity determination result shows that the isoindolone compound containing the thiophene and methyl structure has medium to excellent inhibitory activity on phytophthora capsici, the activity of the compound A31 is the best, the inhibitory activity on the phytophthora capsici is 95 + / -3% and is equivalent to that of a control drug metalaxyl, and EC50 is equal to 1.3048 mu g / mL and is superior to that of the control drug metalaxyl.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical technology, in particular to four kinds of isoindolinone derivatives inhibiting oomycete growth substance, the preparation method of the compounds and the bioactivity test of the compounds on phytopathogenic oomycetes such as Phytophthora capsici, Pythium aphanidermatum, P. litchicola and P. spinosum BACKGROUND

[0002] Isoindolinone is the most common core structure in natural alkaloids, and is the basic skeleton of many natural active molecules. Many isoindolinone derivatives can be used to synthesize drug molecules with natural activity. Isoindolinone, as a nitrogen-containing heterocyclic ring containing alkaloids, can be used as a drug for treating mental diseases and anesthetics. With the in-depth research, isoindolinones and other derivatives show certain antibacterial and bactericidal effects. Therefore, the present application carries out in vitro antibacterial screening of a plurality of isoindolinone compounds on phytopathogenic oomycetes such as Phytophthora capsici, Pythium aphanidermatum, P. litchicola and P. spinosum, and carries out Ec50 test on isoindolinone compounds with an antibacterial rate of >90% at 100 μg / mL and controls with a positive control group of commercially available metalaxyl powder. SUMMARY

[0003] The present application aims to provide a preparation method of four kinds of isoindolinone derivatives with bactericidal activity.

[0004] Another object of the present application is to provide a novel compound with inhibitory effect on Phytophthora capsici, Pythium aphanidermatum, P. litchicola and P. spinosum.

[0005] The technical scheme of the present application: four kinds of isoindolinone derivatives, the general formula of the derivatives is as follows (I):

[0006]

[0007] wherein R 1 is selected from hydrogen, 3-methyl, 4-methyl, 4-methoxy, 3-methoxy, 2-methoxy, chlorine; wherein R 2 is selected from hydrogen, 3-methyl, 4-methyl, 5-methyl, 6-methyl, 3-methoxy, 4-methoxy, 5-methoxy, 6-methoxy, fluorine, chlorine.

[0008] The four kinds of isoindolinone derivatives with bactericidal activity are as follows:

[0009] Compound (A1): 2-methyl-3-phenylisoindolin-1-one

[0010] Compound (A2): 3-(4-methoxyphenyl)-2-methylisoindolin-1-one

[0011] Compound (A3): 2-methyl-3-(m-tolyl)isoindolin-l-one

[0012] Compound (A4): 2-methyl-3-(p-tolyl)isoindolin-l-one

[0013] Compound (A5): 3-(3-methoxyphenyl)-2-methylisoindolin-l-one

[0014] Compound (A6): 3-(2-methoxyphenyl)-2-methylisoindolin-l-one

[0015] Compound (A7): 3-(4-chlorophenyl)-2-methylisoindolin-l-one

[0016] Compound (A8): Methyl-3-(thiophen-2-yl)isoindolin-l-one

[0017] Compound (A9): 2-methyl-3-(pyridin-4-yl)isoindolin-l-one

[0018] Compound (A10): 5-methoxy-2-methyl-3-phenylisoindolin-l-one

[0019] Compound (A11): 2,7-dimethyl-3-phenylisoindolin-l-one

[0020] Compound (A12): 2,6-dimethyl-3-phenylisoindolin-l-one

[0021] Compound (A13): 2,4-dimethyl-3-phenylisoindolin-l-one

[0022] Compound (A14): 2,5-dimethyl-3-phenylisoindolin-l-one

[0023] Compound (A15): 2,4-methoxy-2-methyl-3-phenylisoindolin-l-one

[0024] Compound (A16): 7-methoxy-2-methyl-3-phenylisoindolin-l-one

[0025] Compound (A17): 6-methoxy-2-methyl-3-phenylisoindolin-l-one

[0026] Compound (A18): 4-fluoro-2-methyl-3-phenylisoindolin-l-one

[0027] Compound (A19): 4-chloro-2-methyl-3-phenylisoindolin-l-one

[0028] Compound (A20): 6-methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

[0029] Compound (A21): 3-(4-methoxyphenyl)-2,7-dimethylisoindolin-1-one

[0030] Compound (A22): 4-(4-methoxyphenyl)-2,4-dimethylisoindolin-1-one

[0031] Compound (A23): 2,6-dimethyl-3-(m-tolyl)isoindolin-1-one

[0032] Compound (A24): 2,4-dimethyl-3-(m-tolyl)isoindolin-1-one

[0033] Compound (A25): 5-methoxy-2-methyl-3-(p-tolyl)isoindolin-1-one

[0034] Compound (A26): 2,7-dimethyl-3-(p-tolyl)isoindolin-1-one

[0035] Compound (A27): 2,4-dimethyl-3-(p-tolyl)isoindolin-1-one

[0036] Compound (A28): 3-(3-methoxyphenyl)-2,7-dimethylisoindolin-1-one

[0037] Compound (A29): 3-(2-methoxyphenyl)-2,6-dimethylisoindolin-1-one

[0038] Compound (A30): 3-(4-chlorophenyl)-2,4-dimethylisoindolin-1-one

[0039] Compound (A31): 2,6-dimethyl-3-(thiophen-2-yl)isoindolin-1-one

[0040] Compound (A32): 2,4-dimethyl-3-(thiophen-2-yl)isoindolin-1-one

[0041] Compound (A33): 2,4-dimethyl-3-(pyridin-4-yl)isoindolin-1-one

[0042] A method for preparing a class of isoindolinone derivatives, comprising the steps of:

[0043] (1). In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine and its derivatives (0.1 mmol, 14 μL), methyl 2-methoxybenzoate and its derivatives (0.1 mmol, 14 μL), and methyl tert-butyl ether (0.6 mL). The mixture was heated at 110 °C for 12 h, then cooled to room temperature. A small amount of water was added to quench the reaction. The reaction was complete. The crude product was purified by flash chromatography on a silica gel column to give 27 products of A1-A7, A10-A19, A21-A30.

[0044]

[0045] (2). In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methyl-N-(4-pyridylmethyl)amine (0.1 mmol, 12 μL), and methyl 2-methoxybenzoate and its derivatives (0.1 mmol, 14 μL), and methyl tert-butyl ether (0.6 mL). The mixture was heated at 110 °C for 12 h, then cooled to room temperature. A small amount of water was added to quench the reaction. The reaction was complete. The crude product was purified by flash chromatography on a silica gel column to give 2 products of A9 and A33.

[0046]

[0047] (3). In a glove box under nitrogen, a dry microwave tube with a magnet was charged with LiN(SiMe3)2(50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine and its derivatives (0.1 mmol, 14 μL), and N-methyl-2- thienylmethylamine (0.1 mmol, 12 μL), and methyl tert-butyl ether (0.6 mL). The mixture was heated at 110 °C for 12 h, then cooled to room temperature. A small amount of water was added to quench the reaction. The reaction was complete. The crude product was purified by flash chromatography on a silica gel column to give 3 products of A8, A31 and A32.

[0048]

[0049] (4). In a dry microwave tube with a magnet, LiN(SiMe3)2(50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine and its derivatives (0.1 mmol, 14 μL), and 2-methoxybenzoic acid methyl ester pyridine (0.1 mmol, 15 μL) and methyl tert-butyl ether (0.6 mL) were sequentially added, and the reaction was carried out at 110 °C for 12 h, then cooled to room temperature, a small amount of water was added to quench the reaction, and the reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain one product of A20.

[0050]

[0051] The beneficial effects of the present application: The results of biological activity determination show that the four types of isoindolinone derivative compounds have moderate to excellent inhibitory activity against Phytophthora capsici, Pythium aphanidermatum, Pseudoperonospora cubensis, and Sclerotium rolfsii. Compound A31 has the best activity, with an inhibition activity of 95±3% against Phytophthora capsici, which is equivalent to the control drug metalaxyl, with an EC50 of 1.3048 μg / mL, which is better than the control drug metalaxyl. Specific embodiments

[0052] General examples

[0053] In a dry microwave tube with a magnet, LiN(SiMe3)2(50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine and its derivatives (0.1 mmol, 14 μL), and 2-methoxybenzoic acid methyl ester pyridine (0.1 mmol, 15 μL) and methyl tert-butyl ether (0.6 mL) were sequentially added, and the reaction was carried out at 110 °C for 12 h, then cooled to room temperature, a small amount of water was added to quench the reaction, and the reaction was completed. The crude product was purified by silica gel column flash chromatography to obtain one product of A20.

[0054] Spectral data of the target compounds prepared according to the general examples

[0055]

[0056] 2-Methyl-3-phenylisoindolin-1-one (1A). 1 H NMR (400 MHz, CDCl3) δ 7.89-7.83 (m, 1H), 7.44-7.41 (m, 2H), 7.36-7.31 (m, 3H), 7.16-7.11 (m, 3H), 5.32 (s, 1H), 2.95 (s, 3H) ppm.13 C NMR (101 MHz, CDCI3) δ 168.8, 146.1, 137.03, 131.8, 131.7, 129.3, 128.8, 128.4, 127.5, 123.5, 123.1, 66.7, 27.6 ppm.

[0057]

[0058] 3-(4-Methoxyphenyl)-2-methylisoindolin-l-one (2A). 1 H NMR (400 MHz, CDCI3) δ 7.87-7.84 (m, 1 H), 7.45-7.41 (m, 2H), 7.25-7.13 (m, 1 H), 7.07-7.01 (m, 2H), 6.89-6.83 (m, 2H), 5.27 (s, 1 H), 3.78 (s, 3H), 2.93 (s, 3H) ppm. 13 C NMR (101 MHz, CDCI3) δ 168.7, 159.9, 146.4, 131.7, 128.8, 128.8, 128.3, 123.5, 123.0, 114.6, 66.2, 55.4, 27.5 ppm.

[0059]

[0060] 2-Methyl-3-(m-tolyl)isoindolin-1-one (3A). 1 H NMR (400 MHz, CDCI3) δ 7.96-7.91 (m, 1 H), 7.54-7.47 (m, 2H), 7.33-7.17 (m, 4H), 7.04-6.95 (m, 2H), 5.35 (s, 1 H), 3.02 (s, 3H), 2.37 (s, 3H) ppm. 13 C NMR (101 MHz, NONE) δ 169.0, 146.3, 139.2, 1367.0, 131.8, 131.7, 129.6, 129.2, 128.4, 128.0, 124.8, 123.6, 123.1, 66.8, 27.7, 21.6 ppm.

[0061]

[0062] Methyl-3-(p-tolyl)isoindolin-1-one (4A).1H NMR (400 MHz, CDC13) δ 7.90-7.86 (m, 1H), 7.46-7.41 (m, 2H), 7.26 (s, OH), 7.19-7.15 (m, 3H), 7.02 (d, J = 8.0 Hz, 2H), 5.30 (s, 1H), 2.96 (s, 3H), 2.35 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 169.2, 146.7, 139.0, 134.4, 132.2, 130.3, 128.7, 127.87, 123.9, 123.4, 66.9, 278.0, 21.7 ppm.

[0063]

[0064] 3-(3-Methoxyphenyl)-2-methylisoindolin-1-one (5A). 1 H NMR (400 MHz, CDC13) δ 8.26-8.19 (m, 1H), 7.82-7.78 (m, 2H), 7.66-7.61 (m, 1H), 7.56-7.52 (m, 1H), 7.22 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 7.12 (dt, J = 7.5, 1.3 Hz, 1H), 6.98 (t, J = 2.0 Hz, 1H), 5.66 (s, 1H), 4.10 (s, 3H), 3.34 (s, 3H) ppm. 13 C NMR (101 MHz, CDC13) δ 169.3, 160.7, 146.4, 139.0, 132.2, 132.0, 130.7, 128.8, 123.9, 123.4, 120.2, 114.4, 113.2, 67.0, 55.7, 28.0 ppm.

[0065]

[0066] 3-(2-Methoxyphenyl)-2-methylisoindolin-1-one (6A).1H NMR (400 MHz, CDC13) δ 7.87-7.85 (m, 1H), 7.42-7.40 (m, 2H), 7.31-7.28 (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.4 Hz, 1H), 6.75 (s, 1H), 6.04-5.99 (m, 1H), 3.96 (s, 3H), 2.99 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 169.8, 158.3, 147.2, 132.5, 132.1, 130.0, 128.6, 125.7, 124.0, 123.5, 121.8, 111.7, 59.9, 56.2, 28.3 ppm.

[0067]

[0068] (4-Chlorophenyl)-2-methylisoindolin-l-one (7A).1H NMR (400 MHz, CDC13) δ 7.91-7.86 (m, 1H), 7.49-7.45 (m, 2H), 7.36-7.33 (m, 3H), 7.18-7.14 (m, 1H), 7.11-7.07 (m, 2H), 5.32 (s, 1H), 2.97 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 169.6, 146.5, 136.45135.5, 132.7, 132.4, 130.3, 130.2, 129.7, 129.4, 124.5, 123.8, 66.8, 28.4 ppm.

[0069]

[0070] Methyl-3-(thiophen-2-yl)isoindolin-1-one (8A).1H NMR (400 MHz, CDC13) δ 7.89-7.86 (m, 1H), 7.49 (ddt, J = 7.4, 5.0, 1.4 Hz, 2H), 7.31-7.28 (m, 3H), 7.13 (dd, J = 3.5, 1.5 Hz, 1H), 7.03-7.00 (m, 1H), 5.66 (s, 1H), 3.02 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 169.8, 147.1, 142.0, 133.6, 1332, 130.5 129.1, 128.7, 128.3, 125.2, 124.8, 63.5, 29.2 ppm.

[0071]

[0072] 2-Methyl-3-(pyridin-4-yl)isoindolin-1-one (9A).1H NMR (400 MHz, CDC13) δ 8.65-8.59 (m, 1H), 7.91 (ddd, J = 5.7, 3.0, 0.8 Hz, 0H), 7.49 (dd, J = 5.6, 3.1 Hz, 1H), 7.20-7.11 (m, 1H), 5.34 (s, 0H), 3.01 (s, 1H) ppm.13C NMR (101 MHz, CDC13) δ 169.7, 151.4, 147.1, 145.1, 132.8, 132.4, 129.6, 124.6, 123.5, 122.9, 66.2, 28.4 ppm.

[0073]

[0074] 5-Methoxy-2-methyl-3-phenylisoindolin-l-one (10A).1H NMR (400 MHz, CDC13) δ 7.79 (d, J = 8.5 Hz, 1H), 7.38-7.35 (m, 2H), 7.16-7.14 (m, 1H), 6.96 (dd, J = 8.4, 2.2 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 5.27 (s, 1H), 3.77 (s, 3H), 2.94 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 170.3, 164.5, 149.9, 138.8, 130.8, 130.3, 129.1, 128.9, 126.4, 116.5, 109.5, 68.0, 57.2, 29.1 ppm.

[0075]

[0076] 2,7-Dimethyl-3-phenylisoindolin-l-one (11A).1H NMR (400 MHz, CDCI3) δ 7.16 - 7.06 (m, 1 H), 6.98 - 6.93 (m, 1 H), 6.76 (dd, J = 7.6, 1.1 Hz, 0 H), 5.07 (s, 0 H), 2.74 (s, 1 H), 2.58 (s, 1 H) ppm.13C NMR (101 MHz, CDCI3) δ 169.5, 146.5, 137.4, 137.2, 131.1, 130.1, 129.0, 128.5, 128.4, 127.3, 65.9, 27.2, 17.2 ppm.

[0077]

[0078] 2,6-Dimethyl-3-phenylisoindolin-1-one (12A).1H NMR (400 MHz, CDCI3) δ 7.55 - 7.54 (m, 1 H), 7.23 - 7.18 (m, 3 H), 7.14 - 7.11 (m, 1 H), 7.01 - 6.98 (m, 2 H), 6.91 (d, J = 7.7 Hz, 1 H), 5.15 (s, 1 H), 2.82 (s, 3 H), 2.29 (s, 3 H) ppm.13C NMR (101 MHz, CDCI3) δ 168.9, 143.4, 138.3, 137.2, 132.6, 131.7, 129.1, 128.6, 127.3, 125.97, 123.6, 122.6, 66.4, 27.5, 21.3 ppm.

[0079]

[0080] 2,4-Dimethyl-3-phenylisoindolin-l-one (13A). 1H NMR (400 MHz, CDC13) δ 7.68 (d, J = 7.5 Hz, 1H), 7.36 - 7.26 (m, 4H), 7.22 - 7.16 (m, 1H), 7.06 - 7.03 (m, 2H), 5.21 (s, 1H), 2.83 (s, 3H), 1.92 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 168.7, 143.9, 136.1, 133.2, 133.2, 132.2, 129.0, 128.8, 128.7, 128.3, 126.5, 121.0, 66.4, 27. 18.1 ppm.

[0081]

[0082] 2,5-Dimethyl-3-phenylisoindolin-l-one (14A). 1H NMR (400 MHz, CDC13) δ 7.76 (d, J = 7.8 Hz, 1H), 7138 - 7.34 (m, 2H), 7.27 - 7.23 (m, 2H), 7.17 - 7.13 (m, 2H), 6.96 (dt, J = 1.6, 0.8 Hz, 1H), 5.28 (s, 1H), 2.96 (s, 3H), 2.35 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 169.9, 147.5, 143.3, 138.3, 131.9, 130.3 (d, J = 19.3 Hz), 129.6, 128.5, 67.5, 28.5, 22.9 ppm.

[0083]

[0084] 2,4-Methoxy-2-methyl-3-phenylisoindolin-l-one (15A). 1H NMR (400 MHz, CDC13) δ 7.50 - 7.46 (m, 1H), 7.41 - 7.23 (m, 4H), 7.14 - 7.09 (m, 2H), 6.91 (dt, J = 8.0, 1.0 Hz, 1H), 5.32 (s, 1H), 3.63 (s, 2H), 2.88 (s, 2H) ppm.13C NMR (101 MHz, CDC13) δ 170.3, 156.3, 137.9, 131.9, 130.5, 130.3, 130.2, 130.0, 129.5, 117.3, 115.4, 66.6, 57.2, 29.1 ppm.

[0085]

[0086] 7-Methoxy-2-methyl-3-phenylisoindolin-1-one (16A).1H NMR (400 MHz, CDCI3) δ 7.39 - 7.26 (m, 1 H), 7.14 (dd, J = 7.7, 1.8 Hz, 0 H), 6.86 (d, J = 8.3 Hz, 0 H), 6.71 (dt, J = 7.6, 0.8 Hz, 0 H), 5.25 (s, 0 H), 3.97 (s, 1 H), 2.91 (s, 1 H) ppm.13C NMR (101 MHz, CDCI3) δ 167.67, 157.2, 148.9, 137.4, 133.4, 129.2, 128.7, 127.5, 118.9, 115.2, 110.5, 66.1, 56.0, 27.5 ppm.

[0087]

[0088] 6-Methoxy-2-methyl-3-phenylisoindolin-1-one (17A).1H NMR (400 MHz, CDCI3) δ 7.38 - 7.35 (m, 1 H), 7135 - 7.32 (m, 1 H), 7.14 - 7.11 (m, 1 H), 7.07 - 6.99 (m, 1 H), 5.28 (s, 1 H), 3.86 (s, 2 H), 2.96 (s, 2 H) ppm.13C NMR (101 MHz, CDCI3) δ 162.0, 153.4, 131.7, 130.4, 126.2, 122.4, 121.8, 120.6, 117.1, 113.2, 99.4, 59.5, 48.9, 20.9 ppm.

[0089]

[0090] 4-Fluoro-2-methyl-3-phenylisoindolin-l-one (18A). 1H NMR (400 MHz, CDC13) δ 7.50 - 7.47 (m, 1H), 7.44 - 7.38 (m, 1H), 7.32 - 7.17 (m, 2H), 7.13 - 6.90 (m, 2H), 5.33 (s, 1H), 3.65 (s, 3H), 2.89 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 117.2, 115.3, 66.6, 57.2, 29.0 ppm.19F NMR (376 MHz, CDC13) δ -118.2 ppm.

[0091]

[0092] 4-Chloro-2-methyl-3-phenylisoindolin-l-one (19A). 1H NMR (400 MHz, CDC13) δ 7.83 (dd, J = 6.6, 1.8 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.37 - 7.26 (m, 3H), 7.15 - 7.13 (m, 1H), 5.38 (s, 1H), 2.91 (s, 4H) ppm.13C NMR (101 MHz, CDC13) δ 168.9, 144.4, 136.4, 136.2, 134.0, 131.9, 131.4, 130.6, 130.5, 130.1, 123.7, 67.7, 29.0 ppm.

[0093]

[0094] Methyl-7-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (20A). 1H NMR (400 MHz, CDC13) δ 8.01 (d, J = 5.4 Hz, 1H), 7.38 (dt, J = 6.1, 0.9 Hz, 4H), 7.27 - 7.18 (m, 1H), 7.16 - 7.13 (m, 2H), 5.26 (s, 1H), 2.91 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 170.8, 158.5, 153.4, 131.2, 131.2, 130.9, 130.7, 129.5, 129.3, 127.8, 68.5, 29.1 ppm.

[0095]

[0096] 3-(4-Methoxypheny1)-2,7-dimethylisoindolin-1-one (21A).1H NMR (400 MHz, CDC13) δ 7.10-7.03 (m, 1H), 6.96-6.92 (m, 1H), 6.86-6.80 (m, 2H), 6.73 (dd, J = 7.4, 1.0 Hz, 1H), 6.67-6.63 (m, 2H), 5.00 (s, 1H), 3.57 (s, 2H), 2.70 (s, 2H), 2.55 (s, 2H) ppm.13C NMR (101 MHz, CDC13) δ 169.3, 159.6, 146.8, 137.1, 131.0, 130.0, 129.1, 128.6, 120.3, 114.3, 65.3, 55.2, 27.1, 17.2 ppm.

[0097]

[0098] 4-(4-methoxyphenyl)-2,4-dimethylisoindolin-1-one (22A).1H NMR (400 MHz, CDC13) δ 7.66 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.21-7.14 (m, 1H), 6.94 (d, J = 8.2 Hz, 2H), 6.80-6.74 (m, 2H), 5.16 (s, 1H), 3.73 (s, 3H), 2.81 (s, 3H), 1.91 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 168.5, 159.7, 144.1, 133.2, 132.2, 129.5, 128.7, 127.8, 121.0, 114.4, 113.6, 65.8, 27.1, 18.0 ppm.

[0099]

[0100] 2,6-Dimethyl-3-(m-tolyl)isoindolin-l-one (23A). ¾ NMR (400 MHz, CDC13) δ 7.54 (dt, J = 1.7, 0.8 Hz, 1H), 7.13 - 7.07 (m, 2H), 7.00 - 6.97 (m, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.81 (dt, J = 7.6, 1.5 Hz, 1H), 6.76 (d, J = 1.9 Hz, 1H), 5.11 (s, 1H), 2.81 (s, 3H), 2.28 - 2.28 (m, 4H), 2.17 - 2.16 (m, 3H) ppm.13C NMR (101 MHz, CDC13) δ 168.9, 143.4, 138.3, 137.2, 132.6, 131.7, 129.1, 128.6, 127.3, 126.0, 123.6, 122.6, 66.4, 27.5, 21.3 ppm.

[0101]

[0102] 2,4-Dimethyl-3-(m-tolyl)isoindolin-l-one (24A). ¾ NMR (400 MHz, CDC13) δ 7.56 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.07 - 7.01 (m, 2H), 6.94 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 5.04 (s, 1H), 2.69 (s, 3H), 2.11 (s, 3H), 1.80 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 168.5, 143.9, 138.7, 135.9, 133.0, 132.1, 129.3, 128.7, 128.6, 128.5, 125.5, 120.9, 66.2, 27.1, 21.3, 18.0 ppm.

[0103]

[0104] 5-Methoxy-2-methy-3-(p-tolyl)isoindolin-l-one (25A).1H NMR (400 MHz, CDCI3) δ 7.83 (d, J = 8.4 Hz, 1 H), 7.23 - 7.19 (m, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 7.00 (dd, J = 8.4, 2.3 Hz, 1 H), 6.69 - 6.66 (m, 1 H), 5.28 (s, 1 H), 3.81 (s, 2 H), 2.97 (s, 2 H), 2.39 (s, 3 H) ppm.13C NMR (101 MHz, CDCI3) δ 168.7, 163.0, 148.6, 138.6, 134.2, 130.0, 127.5, 124.9, 124.5, 114.9, 107.9, 66.3, 55.7, 27.6, 21.3 ppm.

[0105]

[0106] 2,7-Dimethyl-3-(p-tolyl)isoindolin-l-one (26A).1H NMR (400 MHz, CDCI3) δ 7.12 - 7.07 (m, 1 H), 6.98 - 6.95 (m, 2 H), 6.83 (d, J = 7.9 Hz, 2 H), 6.77 (dt, J = 7.5, 0.8 Hz, 1 H), 5.04 (s, 1 H), 2.74 (s, 1 H), 2.59 - 2.57 (m, 2 H), 2.15 (s, 2 H) ppm.13C NMR (101 MHz, CDCI3) δ 169.5, 146.7, 138.3, 137.2, 134.3, 131.0, 130.1, 129.7, 128.6, 127.3, 120.3, 65.6, 27.2, 21.1, 17.2 ppm.

[0107]

[0108] 2,4-Dimethyl-3-(p-tolyl)isoindolin-l-one (27A).1H NMR (400 MHz, CDCI3 ，CDCl3) δ 7.60-7.55 (m, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.12-7.05 (m, 2H), 7.01-6.95 (m, 2H), 6.82 (d, J = 7.7 Hz, 3H), 5.07 (s, 1H), 2.72 (s, 4H), 2.18 (s, 4H), 1.82 (s, 4H) ppm.13C NMR (101 MHz, CDC13) δ 168.5, 144.0, 138.4, 133.0, 132.2, 129.6, 129.0, 128.6, 128.1, 126.4, 120.9, 66.00, 27.1, 21.2, 18.0 ppm.

[0109]

[0110] 3-(3-Methoxyphenyl)-2,7-dimethylisoindolin-l-one (28A).1H NMR (400 MHz, CDC13) δ 7.75-7.67 (m, 1H), 7.61-7.57 (m, 0H), 7.41 (d, J = 7.5 Hz, 0H), 7.30-7.25 (m, 0H), 7.19 (dt, J = 7.5, 1.2 Hz, 0H), 7.07-7.05 (m, 0H), 5.66 (s, 0H), 4.18 (s, 1H), 3.38 (s, 1H), 3.19 (s, 1H) ppm.13C NMR (101 MHz, CDC13) δ 170.2, 160.7, 146.9, 139.6, 137.8, 131.6, 130.8, 130.6, 129.0, 120.9, 120.2, 114.3, 113.2, 66.4, 55.8, 27.9, 17.8 ppm.

[0111]

[0112] 3-(2-Methoxyphenyl)-2,6-dimethylisoindolin-l-one (29A). 1H NMR (400 MHz, CDC13) δ 7.67-7.66 (m, 1H), 7.30-7.27 (m, 1H), 7.26-7.22 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 5.95 (s, 1H), 2.98 (s, 3H), 2.41 (s, 2H) ppm.13C NMR (101 MHz, CDC13) δ 170.1, 158.3, 144.7, 138.7, 133.3, 132.8, 130.1, 126.1, 124.4, 122.0, 111.8, 56.4, 28.4, 22.1 ppm.

[0113]

[0114] 3-(4-Chlorophenyl)-2,4-dimethylisoindolin-l-one (30A). 1H NMR (400 MHz, CDC13) δ 7.75 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.29-7.24 (m, 1H), 7.06 (d, J = 8.1 Hz, 2H), 5.26 (s, 1H), 2.89 (s, 3H), 1.99 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 169.2, 144.1, 135.4, 135.2, 134.0, 133.7, 132.7, 130.3, 130.0, 129.6, 121.8, 66.2, 27.8, 18.7 ppm.

[0115]

[0116] 2,6-Dimethyl-3-(thiophen-2-yl)isoindolin-l-one (31A). ¾ NMR (400 MHz, CDC13) δ 8.26-8.26 (m, 1H), 7.91-7.85 (m, 2H), 7.76 (d, J = 7.7 Hz, 1H), 7.70 (dd, J = 3.5, 1.2 Hz, 1H), 7.59 (dd, J = 5.1, 3.5 Hz, 1H), 6.20 (s, 1H), 3.60 (s, 3H), 3.02 (s, 2H) ppm.13C NMR (101 MHz, CDC13) δ 168.9, 143.4, 141.3, 139.3, 133.5, 132.2, 127.9, 127.6, 127.2, 124.4, 123.5, 62.3, 28.1, 22.1 ppm.

[0117]

[0118] 2,4-Dimethyl-3-(thiophen-2-yl)isoindolin-l-one (32A). ¾ NMR (400 MHz, CDC13) δ 7.73 (dd, J = 7.5, 0.7 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.31-7.27 (m, 2H), 7.14 (dd, J = 3.4, 1.3 Hz, 1H), 7.00 (dd, J = 5.1, 3.4 Hz, 1H), 5.61 (s, 1H), 2.96 (s, 3H), 2.08 (s, 4H) ppm.13C NMR (101 MHz, CDC13) δ 169.8, 145.0, 141.4, 135.2, 135.1, 133.5, 130.8, 130.6, 130.0, 128.5, 122.8, 62.8, 28.1, 19.5 ppm.

[0119]

[0120] 2,4-Dimethyl-3-(pyridin-4-yl)isoindolin-l-one (33A). 1H NMR (400 MHz, CDC13) δ 8.20 (d, J = 5.3 Hz, 1H), 7.37 (d, J = 1.7 Hz, 2H), 7.27 (d, J = 0.7 Hz, 1H), 7.16 - 7.12 (m, 1H), 5.29 (s, 1H), 4.13 (s, 3H), 2.93 (s, 3H) ppm.13C NMR (101 MHz, CDC13) δ 168.2, 162.1, 160.3, 151.8, 137.2, 131.1, 130.8, 130.6, 129.1, 127.7, 115.4, 113.5, 67.7, 55.9, 29.2 ppm.

[0121] 3. Antimicrobial activity data of the target compounds

[0122] The inhibitory activity of the target compounds against P. capsici, P. aphanidermatum, P. litchii and P. helicoides was determined by using the cross method. Pure ethanol (DMSO) was used as the negative control, and the agricultural fungicide metalaxyl was used as the positive control. The compounds were tested at a concentration of 100 μg / mL. The preparation of V8 medium: the carbon source was V8 Vegetable Juice imported from the United States (original flavor); the oomycete culture medium additive was calcium carbonate; the brand of oomycete culture medium agar powder was Solabio; the oomycete culture medium water was sterile pure water, and the ratio was carbon source: additive: agar powder: water = 100 mL: 10 mg: 10 g: 900 mL. After the medium was prepared, 300 μL of isatinone derivative mother liquor prepared in advance at 5 μg / mL was added, and the inhibition rate was calculated according to the following formula:

[0123] I = (Ctur-Ttur) / Ctur x 100%

[0124] Wherein, Ctur is the blank control group, Ttur is the drug treatment group, and Itur is the inhibition rate.

[0125] The codes and names of common plant pathogenic oomycetes are as follows: P. capsici: Phytophthora capsici, P. aphanidermatum: Pythium aphanidermatum, P. litchii: Postharvest litchi downy blight, P. helicoides: Phytopythium helicoides.

[0126] Table 1 Bacteriostatic activity of the isatinones of the present application (inhibition / % at 100 μg / mL)

[0127]

[0128]

[0129] As can be seen from Table 1, the four types of isatinone derivatives synthesized in the present application all have different degrees of bactericidal activity at 100 μg / mL, and most of the isatinone compounds of the present application have good bactericidal activity. Among them, 7A, 13A, 21A, 22A, 23A, 26A, 30A and 31A have a pepper Phytophthora inhibition rate of >90%, 7A, 11A, 21A, 24 and 30A have a melon fruit Phytophthora inhibition rate of >90%, 7A, 13A, 21A, 24A, 27A, 30A and 31A have a litchi downy mildew inhibition rate of >90%, all of which are close to the positive control group metalaxyl.

[0130] Table 2 Ec50 values of the isatinones of the present application

[0131]

[0132]

[0133] The results of the bacterial Ec50 determination are shown in Table 2, which shows that compounds 22A and 31A have good effects on pepper Phytophthora, with Ec50 values of 1.7583 and 1.3048 μg / mL, respectively, which are better than the positive control group metalaxyl 1.8830 μg / mL.

Claims

1. An application of an isoindole ketone compound, characterized in that, The structural formula of the novel isoindolone is as follows: Where R 1 It is any one of hydrogen, 3-methyl, 4-methyl, 4-methoxy, 3-methoxy, 2-methoxy, and chlorine; wherein R 2 It is selected from any one of hydrogen, 3-methyl, 4-methyl, 5-methyl, 6-methyl, 3-methoxy, 4-methoxy, 5-methoxy, 6-methoxy, fluorine, and chlorine.

2. The method for preparing the four types of isoindole ketone derivatives that inhibit the growth of oomycetes according to claim 1, characterized in that, The reaction formula is as follows:

3. The method for preparing the four types of isoindole ketone derivatives that inhibit the growth of oomycetes according to claim 2, characterized in that, The process includes the following steps: Under a nitrogen atmosphere, reacting an N-methylbenzylamine derivative and a methyl 2-methoxybenzoate derivative as shown in Formula 2 with an organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride to synthesize isoindolone as shown in Formula 1; and under a nitrogen atmosphere, reacting an N-methyl-N-(4-pyridinylmethyl)amine derivative and a methyl 2-methoxybenzoate derivative with an organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride to synthesize... The isoindolone shown in Formula 2 was synthesized by reacting N-methyl-2-thiophene methylamine and methyl 2-methoxybenzoate derivatives with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride under a nitrogen atmosphere; the isoindolone shown in Formula 4 was synthesized by reacting N-methylbenzylamine derivatives and methyl 2-methoxynicotinate pyridine with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride under a nitrogen atmosphere.

4. The test for the four types of isoindole ketone derivatives inhibiting oomycete growth according to claims 1 and 2, characterized in that, The codes and names of common plant pathogenic oomycetes are as follows: P. capsici: Phytophthora capsici, P. aphandrmatum: Pythium aphandrmatum, P. litchii: Postharvest litchi downyblight, P. helicoides: Phytopytopythium helicoides. The inhibitory activity against oomycetes was tested by adding four types of isoindoleone derivatives to V8 medium.

5. The V8 culture medium according to claim 4, characterized in that, The carbon source is imported American V8 VegetableJuice mixed vegetable juice (original flavor); the Oomycetes culture medium additive is calcium carbonate; the Oomycetes culture medium agar powder is Solarbio; the Oomycetes culture medium water is sterile pure water; the ratio is carbon source: additive: agar powder: water = 100mL: 10mg: 10g: 900mL.

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