Pyridopyrimidone derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of pesticides, and discloses a compound with a structure as shown in a formula I. A preparation method of the compound comprises the following steps: sequentially carrying out hydrolysis, hydrazide and cyclization on methyl o-aminonicotinate to obtain the pyridopyrimidone derivative. The pyridopyrimidone derivative is a novel compound, has an inhibiting effect on gibberellic disease bacteria, rhizoctonia solani and botrytis cinerea, and can be used for preventing and treating plant diseases caused by fungi.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pesticides, and particularly relates to a pyridopyrimidinone derivative, a preparation method and application thereof. BACKGROUND

[0002] After the fungi infect crops, the normal physiological and biochemical functions of the host plants are affected, resulting in diseases, yellowing, wilting and death of the crops, and a serious decrease in the yield of the crops. Meanwhile, the parasitic pathogenic fungi can secrete certain mycotoxins in the agricultural crops infected thereby. In the past half century, fungicides have played an extremely important role in the prevention and treatment of plant fungal diseases. However, the wide use of the fungicides in agricultural production leads to the rapid generation of fungicide resistance, which greatly reduces the use effect of the existing fungicides, and indirectly causes the problems of pesticide residues and the re-outbreak of fungal diseases. Therefore, it is of far-reaching significance for the sustainable development of agriculture to develop a fungicide with novel structure, environmental friendliness and high economic benefit. SUMMARY

[0003] The first object of the present application is to provide a pyridopyrimidinone derivative; the second object of the present application is to provide a preparation method of the pyridopyrimidinone derivative; and the third object of the present application is to provide an application of the pyridopyrimidinone derivative in the prevention and treatment of plant pathogenic fungal diseases.

[0004] The pyridopyrimidinone derivative provided by the present application has the structural formula I:

[0005]

[0006] wherein, R 1 is selected from hydrogen, 2-chloro, 2-bromo, 2-methoxy, 2-trifluoromethyl, 3-chloro or 4-chloro; R 2 is selected from hydrogen or methyl; and X is selected from carbon or nitrogen.

[0007] The preparation method of the pyridopyrimidinone derivative provided by the present application comprises the following steps: subjecting methyl nicotinate to hydrolysis with a 5% sodium hydroxide solution, then subjecting the obtained product to reaction with a substituted aryl hydrazine in dichloromethane containing triethylamine and TBTU, and subjecting the obtained hydrazine molecule to cyclization reaction with triethyl ortho(meth)acetate in hot ethanol to obtain the pyridopyrimidinone derivative I, and the synthesis route is as follows:

[0008]

[0009] The pyridopyrimidinone derivative provided by the present application is used in the preparation of an anti-plant pathogenic fungal medicine.

[0010] The plant pathogenic fungi are Fusarium graminearum, Rhizoctonia solani or Botrytis cinerea.

[0011] Advantages: Compared with the prior art, the pyridopyrimidinone derivative has the following advantages (1) the pyridopyrimidinone derivative is a new type of compound, which has inhibitory effect on G. zeae, R. solani or B. cinerea; (2) the pyridopyrimidinone derivative has simple preparation method, raw materials are easy to obtain, and the reaction is novel and efficient; (3) the pyridopyrimidinone derivative can significantly inhibit R. solani, and the optimal inhibition rate thereof at a dose of 50 μg / mL is 98.8%, which has application prospect as a potential agricultural fungicide. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 NMR spectrum of the pyridopyrimidinone derivative prepared in Example 1;

[0013] Figure 2 NMR spectrum of the pyridopyrimidinone derivative prepared in Example 1;

[0014] Figure 3 High-resolution mass spectrum of the pyridopyrimidinone derivative prepared in Example 1;

[0015] Figure 4 Single crystal diffraction structure diagram of the pyridopyrimidinone derivative prepared in Example 1. DETAILED DESCRIPTION

[0016] The technical solutions of the present application are further described below in combination with examples.

[0017] Example 1

[0018] The pyridopyrimidinone derivative I1, R1 = 2-Cl, R2 = H, X = C, prepared in the present application is 3-((2-chlorophenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, and the chemical name is 3-((2-chlorophenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, and the structural formula is as follows:

[0019]

[0020] First step: synthesis of 2-aminonicotinic acid (intermediate A)

[0021]

[0022] In a 100 mL round bottom flask, methyl 2-aminonicotinate (13.15 mmol) and ethanol (30 mL) were added and stirred to dissolve the solid portion. After adding 5% NaOH solution dropwise, it was heated to 75-80 °C and refluxed for 2-4 hours. After the reaction was completed, the ethanol was removed by distillation under reduced pressure, and the residue was dissolved in water, and then acidified with 5% HCl solution to pH = 2-3. A solid was precipitated, filtered, and dried to obtain 2-aminonicotinic acid (intermediate A).

[0023] Second step: synthesis of 2-amino-N'-(2-chlorophenyl)nicotinohydrazide (intermediate Bl)

[0024]

[0025] In a dry 100 mL round bottom flask, 2-aminonicotinic acid (7.19 mmol), 2-chlorophenylhydrazine (7.01 mmol) and dichloromethane (40 mL) were added in sequence, stirred to dissolve, and then TBTU condensing agent (8 mmol) was added. After stirring at room temperature for about 30 min, triethylamine (3 mL) was added dropwise, and the reaction progress was monitored by TLC. After no obvious change, the excess dichloromethane was removed by distillation under reduced pressure to obtain 2-amino-N'-(2-chlorophenyl)nicotinohydrazide (intermediate Bl).

[0026] Third step: synthesis of 3-((2-chlorophenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one (target compound II)

[0027] 2-amino-N'-(2-chlorophenyl)nicotinohydrazide (2 mmol) and triethyl orthoformate (6 mmol) were dissolved in anhydrous ethanol (30 mL), and then heated to 75-80 °C for about 4-5 h. After the reaction was monitored by TLC and no obvious change was observed, the excess ethanol was removed by distillation under reduced pressure. After cooling to room temperature, a solid was precipitated. After filtration, the obtained filter cake was recrystallized with ethanol to obtain the target compound II.

[0028] The target compound II is a white solid; yield 63%; m.p. 192-194 °C; 1 H NMR (400 MHz, CDC13) 9.04 (dd, J = 4.5, 1.7 Hz, 1H), 8.59 (dd, J = 7.9, 1.9 Hz, 1H), 8.54 (s, 1H), 7.68 (s, 1H), 7.48 (dd, J = 7.9, 4.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.97 (dd, J = 11.1, 4.2 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDC13) δ 160.19, 157.72, 156.49, 151.77, 142.11, 136.62, 130.06, 127.96, 123.51, 122.92, 120.78, 117.99, 113.74.

[0029] Example 2

[0030] The pyridopyrimidinone derivative I2, R1= 2-Br, R2= H, X = C, chemical name 3-((2-bromophenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, structure as follows:

[0031]

[0032] First step: synthesis of 2-aminonicotinic acid (intermediate A)

[0033] As in example 1, first step.

[0034] Second step: synthesis of 2-amino-N'-(2-bromophenyl)nicotinohydrazide (intermediate B2)

[0035]

[0036] As in example 1, second step, except that 2-bromophenylhydrazine is used as reactant.

[0037] Third step: synthesis of 3-((2-bromophenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one (target compound I2) As in example 1, third step, except that 2-amino-N'-(2-bromophenyl)nicotinohydrazide is used as reactant.

[0038] Target compound I2 is a white solid; yield 63%; m.p. 169-171 °C; 1 H NMR (400 MHz, CDC13) δ 9.05 (dd, J = 4.6, 2.0 Hz, 1H), 8.60 (dd, J = 7.9, 2.0 Hz, 1H), 8.54 (s, 1H), 7.60-7.55 (m, 2H), 7.49 (dd, J = 7.9, 4.6 Hz, 1H), 7.16 (td, J = 7.8, 1.4 Hz, 1H), 6.91 (td, J = 7.7, 1.5 Hz, 1H), 6.49 (dd, J = 8.2, 1.4 Hz, 1H); 13C NMR (100 MHz, CDC13) δ 160.16, 157.73, 156.52, 151.69, 143.10, 136.63, 133.24, 128.65, 123.97, 122.94, 117.99, 113.76, 110.22.

[0039] Example 3

[0040] The pyridopyrimidinone derivative I3, R1= 2-OMe, R2= H, X = C, chemical name 3-((2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, structure formula as follows:

[0041]

[0042] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0043] As the first step of Example 1.

[0044] Second step: synthesis of 2-amino-N'-(2-methoxyphenyl)nicotinohydrazide (intermediate B3)

[0045]

[0046] As the second step of Example 1, except that 2-methoxyphenylhydrazine was used as the reactant.

[0047] Third step: synthesis of 3-((2-methoxyphenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one (target compound I3)

[0048] As the third step of Example 1, except that 2-amino-N'-(2-methoxyphenyl)nicotinohydrazide was used as the reactant.

[0049] Target compound I3 is a white solid; yield 66%; m.p. 164-166°C; 1 H NMR (400 MHz, CDC13) δ 9.04 (dt, J = 4.7, 1.6 Hz, 1H), 8.61-8.56 (m, 2H), 7.62 (s, 1H), 7.47 (ddd, J = 8.0, 4.6, 1.2 Hz, 1H), 7.02-6.90 (m, 2H), 6.81 (td, J = 7.6, 1.5 Hz, 1H), 6.52 (dd, J = 7.9, 1.5 Hz, 1H), 3.97 (d, J = 1.1 Hz, 3H); 13C NMR (100 MHz, CDC13) δ 160.35, 157.83, 156.31, 152.08, 147.99, 136.54, 135.25, 123.26, 122.70, 121.03, 118.03, 113.30, 110.93, 55.89.

[0050] Example 4

[0051] The pyridopyrimidinone derivative I4, R1= 2-CF3, R2= H, X = C, chemical name 3-((2-(trifluoromethyl)phenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, English name 3-((2-(trifluoromethyl)phenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, has the following structure:

[0052]

[0053] First step: synthesis of 2-aminonicotinic acid (intermediate A)

[0054] As in Example 1, first step.

[0055] Second step: synthesis of 2-amino-N'-(2-(trifluoromethyl)phenyl)nicotinohydrazide (intermediate B4)

[0056]

[0057] As in Example 1, second step, except that 2-(trifluoromethyl)phenylhydrazine is used as reactant.

[0058] Third step: synthesis of 3-((2-(trifluoromethyl)phenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one (target compound I4)

[0059] As in Example 1, third step, except that 2-amino-N'-(2-(trifluoromethyl)phenyl)nicotinohydrazide is used as reactant.

[0060] Target compound I4 is a white solid; yield 60%; m.p. 161-163°C; 1H NMR (400 MHz, CDC13) δ 9.03 (dd, J = 4.6, 1.9 Hz, 1H), 8.61 (dd, J = 8.0, 2.0 Hz, 1H), 8.47 (s, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.50 (dd, J = 8.0, 4.6 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H); 13 C NMR (100 MHz, CDC13) δ 160.25, 157.67, 156.55, 151.56, 143.67, 136.64, 133.41, 127.21, 127.16, 123.00, 122.36, 117.91, 116.35 (d, J = 31.2 Hz), 113.31.

[0061] Example 5

[0062] The pyridopyrimidinone derivative I5, R1= 3-Cl, R2= H, X = N, chemical name is 3-((3-chloropyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, English name is 3-((3-chloropyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, structural formula is as follows:

[0063]

[0064] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0065] As the first step of Example 1.

[0066] Second step: synthesis of 2-amino-N'-(3-chloropyridin-2-yl)nicotinohydrazide (intermediate B5)

[0067]

[0068] As the second step of Example 1, except that 3-chloro-2-hydrazinopyridine is used as the reactant.

[0069] Third step: synthesis of 3-((3-chloropyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one (target compound I5)

[0070] As the third step of Example 1, except that 2-amino-N'-(3-chloropyridin-2-yl)nicotinohydrazide is used as the reactant.

[0071] The target compound I5 is a white solid; yield 55%; m.p. 228-230°C; 1 H NMR (400 MHz, CDC13) δ 9.06 (dd, J = 4.6, 2.0 Hz, 1H), 8.62 (dd, J = 7.9, 2.0 Hz, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 8.02 (dd, J = 4.8, 1.5 Hz, 1H), 7.69 (dd, J = 7.9, 1.5 Hz, 1H), 7.49 (dd, J = 7.9, 4.6 Hz, 1H), 6.94 (dd, J = 7.8, 4.8 Hz, 1H); 13 C NMR (100 MHz, CDC13) δ 160.30, 157.90, 156.28, 152.46, 151.96, 146.14, 137.75, 136.59, 122.59, 119.20, 117.87, 116.87.

[0072] Example 6

[0073] The pyridopyrimidinone derivative I6, R1= 2-C1, R2= CH3, X = C, according to the present application, is 3-((2-chlorophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, and its chemical name is 3-((2-chlorophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, and its structural formula is as follows:

[0074]

[0075] First step: synthesis of 2-aminonicotinic acid (intermediate A)

[0076] As the first step of Example 1.

[0077] Second step: synthesis of 2-amino-N'-(2-chlorophenyl)nicotinohydrazide (intermediate Bl)

[0078] As the second step of Example 1.

[0079] Third step: synthesis of 3-((2-chlorophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one (target compound I6)

[0080] As the third step of Example 1, except that triethyl orthoacetate is used as the reactant.

[0081] The target compound I6 is a white solid; yield 57%; m.p. 166-168°C; 1HNMR (400 MHz, CDC13) δ 9.01 (dd, J = 4.7, 2.0 Hz, IH), 8.50 (dt, J = 8.0, 2.0 Hz, IH), 7.50 (d, J = 4.9 Hz, IH), 7.44-7.38 (m, 2H), 7.11 (td, J = 7.8, 1.4 Hz, IH), 6.95 (td, J = 7.7, 1.5 Hz, IH), 6.40 (dd, J = 8.1, 1.4 Hz, IH), 2.76 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 160.90, 160.77, 156.89, 156.63, 141.61, 136.48, 130.13, 128.00, 123.15, 122.15, 120.81, 116.21, 112.71, 22.05.

[0082] Example 7

[0083] The pyridopyrimidinone derivative I7, R1= 2-Br, R2= CH3, X = C, chemical name 3-((2-bromophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, English name 3-((2-bromophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, has the following structure:

[0084]

[0085] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0086] As in the first step of Example 1.

[0087] Second step: synthesis of 2-amino-N'-(2-bromophenyl)nicotinohydrazide (intermediate B2)

[0088] As in the second step of Example 2.

[0089] Third step: synthesis of 3-((2-bromophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one (target compound I7)

[0090] As in the third step of Example 2, except that triethyl orthoacetate is the reactant.

[0091] Target compound I7 is a white solid; yield 52%; m.p. 162-164°C; 1HNMR (400 MHz, CDC13) δ 9.01 (dd, J = 4.6, 2.0 Hz, IH), 8.51 (dd, J = 7.9, 2.0 Hz, IH), 7.58 (dd, J = 8.0, 1.4 Hz, IH), 7.45-7.39 (m, 2H), 7.16 (td, J = 7.8, 1.4 Hz, IH), 6.89 (td, J = 7.7, 1.4 Hz, IH), 6.38 (dd, J = 8.1, 1.4 Hz, IH), 2.75 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 160.81, 160.78, 156.90, 156.65, 142.56, 136.50, 133.32, 128.69, 123.67, 122.17, 116.21, 112.84, 110.30, 22.06.

[0092] Example 8

[0093] The pyridopyrimidinone derivative I8, R1= 2-OMe, R2= CH3, X = C, chemical name 3-((2-methoxyphenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, English name 3-((2-methoxyphenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, has the following structure:

[0094]

[0095] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0096] As the first step of Example 1.

[0097] Second step: synthesis of 2-amino-N'-(2-methoxyphenyl) nicotinohydrazide (intermediate B3)

[0098] As the second step of Example 3.

[0099] Third step: synthesis of 3-((2-methoxyphenyl)amino)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one (target compound I8)

[0100] As the third step of Example 3, except that triethyl orthoacetate is used as the reactant.

[0101] The target compound I8 is a white solid; yield 70%; m.p. 163-165°C; 1H NMR (400 MHz, CDC13) δ 8.99 (dd, J = 4.6, 2.0 Hz, 1H), 8.49 (dd, J = 7.9, 2.0 Hz, 1H), 7.54 (s, 1H), 7.39 (dd, J = 7.9, 4.6 Hz, 1H), 6.99 - 6.91 (m, 2H), 6.82 - 6.77 (m, 1H), 6.35 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 2.79 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 161.29, 160.92, 156.99, 156.45, 147.82, 136.41, 134.88, 122.58, 121.94, 121.06, 116.30, 111.66, 110.78, 55.86, 22.16.

[0102] Example 9

[0103] The pyridopyrimidinone derivative I9, R1= 2-CF3, R2= CH3, X = C, chemical name is 2-methyl-3-((2-(trifluoromethyl)phenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, English name is 2-methyl-3-((2-(trifluoromethyl)phenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one, structural formula is as follows:

[0104]

[0105] First step: synthesis of 2-aminonicotinic acid (intermediate A)

[0106] As the first step of Example 1.

[0107] Second step: synthesis of 2-amino-N'-(2-(trifluoromethyl)phenyl)hydrazide nicotinic acid (intermediate B4)

[0108] As the second step of Example 4.

[0109] Third step: synthesis of 2-methyl-3-((2-(trifluoromethyl)phenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one (target compound I9)

[0110] As the third step of Example 4, except that the original acetic acid triethyl ester is used as the reactant.

[0111] The target compound I9 is a white solid; yield 55%; m.p. 151-153°C; 1HNMR (400 MHz, CDC13) δ 9.04 (dd, J = 4.6, 2.0 Hz, IH), 8.57 (dd, J = 7.9, 2.0 Hz, IH), 7.70-7.65 (m, IH), 7.55 (s, IH), 7.46 (dd, J = 7.9, 4.6 Hz, IH), 7.42-7.36 (m, IH), 7.12 (t, J = 7.6 Hz, IH), 6.47 (d, J = 8.2 Hz, IH), 2.69 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 160.90, 160.48, 156.88, 156.74, 142.98, 136.56, 133.47, 127.34, 127.29, 122.37, 122.28, 116.81, 116.04, 112.84, 21.77.

[0112] Example 10

[0113] The pyridopyrimidinone derivative I according to the present application 10 , R1= 2-Cl, R2= CH3, X = N, chemical name 3-((3-chloropyridin-2-yl)amino)-2- methylpyrido[2,3-d]pyrimidin-4(3H)-one, English name 3-((3-chloropyridin-2-yl)amino)- 2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, structural formula as follows:

[0114]

[0115] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0116] As the first step of Example 1.

[0117] Second step: synthesis of 2-amino-N'-(3-chloropyridin-2-yl)nicotinohydrazide (intermediate B5)

[0118] As the second step of Example 5.

[0119] Third step: synthesis of 3-((3-chloropyridin-2-yl)amino)-2-methylpyrido[2,3-d]pyrimidin- 4(3H)-one (target compound I 10 )

[0120] As the third step of Example 5, except that the original acetic acid triethyl ester is used as the reactant.

[0121] Target compound I 10 is a white solid; yield 58%; m.p. 217-219°C; 1H NMR (400 MHz, CDC13) δ 8.99 (dd, J = 4.6, 2.0 Hz, 1H), 8.50 (dd, J = 7.9, 2.0 Hz, 1H), 8.00 (dd, J = 4.9, 1.5 Hz, 1H), 7.91 (s, 1H), 7.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.39 (dd, J = 7.9, 4.6 Hz, 1H), 6.91 (dd, J = 7.8, 4.8 Hz, 1H), 2.72 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 161.26, 160.96, 157.14, 156.39, 152.23, 146.21, 137.68, 136.45, 121.82, 118.93, 117.11, 116.06, 22.19.

[0122] Example 11

[0123] The pyridopyrimidinone derivative I according to the present application 11 , R1= 3-Cl, R2= H, X = C, chemical name 3-((3-chlorophenyl)amino)pyrido[2,3- d]pyrimidin-4(3H)-one, English name 3-((3-chlorophenyl)amino)pyrido[2,3- d]pyrimidin-4(3H)-one, structural formula as follows:

[0124]

[0125] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0126] As the first step of Example 1.

[0127] Second step: synthesis of 2-amino-N'-(3-chlorophenyl)nicotinohydrazide (intermediate B6)

[0128]

[0129] As the second step of Example 1, except that 3-chlorophenylhydrazine is used as the reactant.

[0130] Third step: synthesis of 3-((3-chlorophenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)- one (target compound I 11 ) As the third step of Example 1, except that 2-amino-N'-(3-chlorophenyl)nicotinohydrazide is used as the reactant.

[0131] Target compound I 11 is a white solid; yield 50%; m.p. 215-217°C; 1HNMR (400 MHz, CDC13) δ 9.08 (s, IH), 8.63 (d, J = 6.9 Hz, IH), 8.51 (s, IH), 7.52 (s, IH), 7.29 (s, IH), 7.23-7.15 (m, IH), 7.01 (d, J = 6.3 Hz, IH), 6.79 (s, IH), 6.70 (d, J = 7.0 Hz, IH); 13 C NMR (100 MHz, CDC13) δ 160.52, 157.73, 156.60, 151.22, 147.18, 136.67, 135.50, 130.69, 123.50, 123.00, 117.92, 114.76, 112.71.

[0132] Example 12

[0133] The pyridopyrimidinone derivative I according to the present application 12 , R1= 3-Cl, R2= CH3, X = C, chemical name 3-((3-chlorophenyl)amino)-2- methylpyrido[2,3-d]pyrimidin-4(3H)-one, English name 3-((3-chlorophenyl)amino)- 2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, structural formula as follows:

[0134]

[0135] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0136] As in the first step of Example 1.

[0137] Second step: synthesis of 2-amino-N'-(3-chlorophenyl)nicotinohydrazide (intermediate B6)

[0138] As in the second step of Example 11.

[0139] Third step: synthesis of 3-((3-chlorophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin- 4(3H)-one (target compound I 12 )

[0140] As in the third step of Example 11, except that triethyl orthoacetate is used as the reactant.

[0141] Target compound I 12 is a white solid; yield 57%; m.p. 251-253°C; 1H NMR (400 MHz, CDC13) δ 9.03 (d, J = 2.5 Hz, IH), 8.55 (d, J = 6.6 Hz, IH), 7.44 (dd, J = 7.6, 4.6 Hz, IH), 7.19 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 7.5 Hz, IH), 6.72 (s, IH), 6.63 (d, J = 7.1 Hz, IH), 2.73 (s, 3H); 13 CNMR (100 MHz, CDC13) δ 161.16, 160.40, 156.90, 156.72, 146.72, 136.55, 135.60, 130.76, 123.16, 122.21, 116.12, 114.13, 112.10, 21.98.

[0142] Example 13

[0143] The pyridopyrimidinone derivative I according to the present application 13 , R1= 4-Cl, R2= H, X = = C, chemical name 3-((4-chlorophenyl)amino)pyrido[2,3- d]pyrimidin-4(3H)-one, English name 3-((4-chlorophenyl)amino)pyrido[2,3- d]pyrimidin-4(3H)-one, structural formula as follows:

[0144]

[0145] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0146] As the first step of Example 1.

[0147] Second step: synthesis of 2-amino-N'-(4-chlorophenyl)nicotinohydrazide (intermediate B7)

[0148]

[0149] As the second step of Example 1, except that 4-chlorophenylhydrazine is used as the reactant.

[0150] Third step: synthesis of 3-((4-chlorophenyl)amino)pyrido[2,3-d]pyrimidin-4(3H)-one (target compound I 13 ) As the third step of Example 1, except that 2-amino-N'-(4-chlorophenyl)nicotinohydrazide is used as the reactant.

[0151] Target compound I 13 is a white solid; yield 57%; m.p. 193-195°C; 1H NMR (400 MHz, CDC13) δ 9.06 (dd, J = 4.5, 1.9 Hz, 1H), 8.61 (dd, J = 7.9, 1.9 Hz, 1H), 8.53 (s, 1H), 7.50 (dd, J = 7.9, 4.6 Hz, 1H), 7.40 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H); 13 C NMR (100 MHz, CDC13) δ 160.60, 157.73, 156.55, 151.36, 144.56, 136.62, 129.58, 128.47, 122.96, 117.90. 116.03.

[0152] Example 14

[0153] The pyridopyrimidinone derivative I according to the present application 14 , R1= 4-Cl, R2= CH3, X = C, chemical name 3-((4-chlorophenyl)amino)-2- methylpyrido[2,3-d]pyrimidin-4(3H)-one, English name 3-((4-chlorophenyl)amino)- 2-methylpyrido[2,3-d]pyrimidin-4(3H)-one, structural formula as follows:

[0154]

[0155] First step: synthesis of 2-amino-nicotinic acid (intermediate A)

[0156] As the first step of Example 1.

[0157] Second step: synthesis of 2-amino-N'-(4-chlorophenyl)nicotinohydrazide (intermediate B7)

[0158] As the second step of Example 13.

[0159] Third step: synthesis of 3-((4-chlorophenyl)amino)-2-methylpyrido[2,3-d]pyrimidin- 4(3H)-one (target compound I 14 )

[0160] As the third step of Example 13, except that triethyl orthoacetate is used as the reactant.

[0161] Target compound I 14 is a white solid; yield 57%; m.p. 115-117°C; 1H NMR (400 MHz, CDC13) δ 9.01 (dd, J = 4.6, 2.0 Hz, 1H), 8.53 (dd, J = 7.9, 2.0 Hz, 1H), 7.43 (dd, J = 7.9, 4.6 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 2.72 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 161.25, 160.73, 156.85, 156.61, 144.09, 136.50, 129.60, 127.81, 122.16, 116.12, 115.11, 22.00.

[0162] Application performance test

[0163] Test method for inhibiting plant pathogenic fungi activity:

[0164] The inhibitory effect of the target molecule on Fusarium graminearum, Rhizoctonia solanis and Botrytis cinerea was determined by mycelial growth rate method at a pesticide mass concentration of 50 μg / mL. 200 g of potato slices were added to 800 mL of boiling double distilled water, and boiling was continued until it could be easily broken with a glass rod. It was filtered with gauze, and the filtrate was prepared. Another 200 mL of double distilled water was measured, 20 g of agar powder was added, and it was stirred uniformly. Then the filtrate obtained in the previous step was added, and double distilled water was added to 1 L. After boiling, 20 g of glucose was added, and it was stirred uniformly. Then it was divided into conical bottles to obtain PDA culture medium. The freshly prepared PDA culture medium was sterilized at 121°C for 20 min, and then 100 μL of drug-containing DMSO was measured with a 200 μL pipette gun and added to 45 mL of sterilized and not yet cooled PDA culture medium. After shaking, the drug-containing medium was uniformly transferred to three disposable petri dishes, and then it was naturally cooled under ultraviolet light. After cooling, a 5 mm diameter fungus cake was inoculated at the center of the disposable petri dish, and then it was transferred to a 25°C constant temperature incubator for inverted culture in the dark. When the diameter (C) of the blank control colony reached 70-80 mm, the diameter (T) of each treatment group was measured by cross method. Then the inhibition rate (I) of the plant pathogenic fungi of the corresponding treatment group was calculated according to the colony diameters of the blank group and the drug-treated group. The calculation formula is as follows:

[0165]

[0166] Using the agricultural fungicide hymexazol as a positive control, the mycelial growth rate method was used to determine the inhibitory effect of target molecules I1-I 14The inhibitory activities of the medicament with a concentration of 50 μg / mL on plant pathogenic fungi Gibberella zeae, Rhizoctonia solani and Botrytis cinerea were tested, and the results are shown in Table 1.

[0167] Table 1 Compound I 1～ I 14 Inhibitory activities (%) on plant pathogenic fungi at a concentration of 50 μg / mL

[0168]

[0169]

[0170] As shown in Table 1, some of the target molecules showed significant inhibitory activities on Gibberella zeae, Rhizoctonia solani and Botrytis cinerea at a concentration of 50 μg / mL. Among them, target molecules I1, I2, I3, I6, I7, I8 and I 13 could significantly inhibit the growth of Gibberella zeae mycelium at 50 μg / mL, with inhibition rates of 61.9%, 63.1%, 67.4%, 54.8%, 53.1%, 68.2% and 62.0%, respectively, which were better than the inhibition rate of hymexazol on Gibberella zeae at this concentration (49.7%). At the same time, target molecules I1, I2, I4, I6, I 11 , I 12 , I 13 and I 14 also showed significant inhibitory activities on Rhizoctonia solani at 50 μg / mL, with inhibition rates of 98.8%, 98.7%, 84.6%, 84.6%, 82.0%, 55.3%, 71.6% and 66.8%, respectively, which were better than the inhibition rate of hymexazol on Rhizoctonia solani at this concentration (37.9%). In addition, target molecules I2 and I 13 also showed significant inhibitory activities on Botrytis cinerea at 50 μg / mL, with inhibition rates of 67.5% and 65.2%, respectively, which were better than the inhibition rate of hymexazol on Botrytis cinerea at this concentration (63.1%). It is worth noting that the inhibition rates of compounds I1 and I2 on Rhizoctonia solani at 50 μg / mL both exceeded 95%, which had the potential to be developed as potential agricultural fungicides.

Claims

1. A pyridopyrimidine ketone derivative, characterized in that, The structural formula is shown as I: wherein R 1 is selected from hydrogen, 2-chloro, 2-bromo, 2-methoxy, 2-trifluoromethyl, 3-chloro, or 4-chloro; R 2 is selected from hydrogen or methyl; and X is selected from carbon or nitrogen.

2. A process for the preparation of a pyridopyrimidinone derivative according to claim 1, characterized in that, The pyridopyrimidinone derivatives I are synthesized by the following route: methylethanolamine is reacted with substituted aryl isocyanate to obtain substituted aryl urea, which is hydrolyzed by 5% sodium hydroxide solution, and then reacted with substituted aryl hydrazine in dichloromethane containing triethylamine and TBTU, and the obtained hydrazine molecule is cyclized with triethyl ortho(methyl)acetate in hot ethanol.

3. The pyridopyrimidinone derivative of claim 1 is used in the prevention and treatment of wheat scab, rice sheath blight or tomato gray mold.

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