CN112645885B - Iminopyridazine derivative, preparation method and application thereof, and pesticide - Google Patents

Iminopyridazine derivative, preparation method and application thereof, and pesticide Download PDF

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CN112645885B
CN112645885B CN202110043090.2A CN202110043090A CN112645885B CN 112645885 B CN112645885 B CN 112645885B CN 202110043090 A CN202110043090 A CN 202110043090A CN 112645885 B CN112645885 B CN 112645885B
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iminopyridazine
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phenyl
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CN112645885A (en
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刘根炎
周聪伟
张志松
陈达
黄成�
吴风收
罗晓刚
巨修练
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Wuhan Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
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    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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Abstract

The invention belongs to the technical field of pesticide chemistry, and particularly relates to an iminopyridazine derivative, and a preparation method, application and pesticide thereof. The invention takes an iminopyridazine structure as a basis, introduces propionic acid or butyric acid side chains at the 1 site, and introduces aryl groups at the 3 site and the 5 site respectively or simultaneously to synthesize a polysubstituted iminopyridazine derivative, and the compound has obvious inhibition effect on GABA receptors of houseflies, which are public sanitary pests, and spodoptera litura, has better insecticidal activity on spodoptera litura, and has application prospect in preparing or developing insecticides.

Description

Iminopyridazine derivative, preparation method and application thereof, and pesticide
Technical Field
The invention belongs to the technical field of pesticide chemistry, and particularly relates to an iminopyridazine derivative, and a preparation method, application and pesticide thereof.
Background
In agricultural production, the use of pesticides is an indispensable link. The development of new efficient green insecticides is an urgent task to be accomplished because of the long-term use of some insecticides, to which the pests have developed resistance, and most of which have negative environmental impact.
Partial imino pyridazine derivatives show certain antagonistic action on insect GABA receptors, can be used as insect GABA receptor antagonists and can be used for preparing novel insecticides.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention belongs to the technical field of pesticide chemistry, and particularly relates to an iminopyridazine derivative, a preparation method and application thereof, and an insecticide.
The technical scheme provided by the invention is as follows:
an imino pyridazine derivative has a structure shown in the following general formula (I):
Figure BDA0002896653160000011
wherein:
R1selected from substituted or unsubstituted aryl, unsubstituted heteroaryl, the substituent is halogen, alkyl, alkoxy, halogenated alkoxy or dioxy alkylene;
R2selected from H, substituted or unsubstituted aryl, unsubstituted heteroaryl, the substituents being halogen, alkyl, alkoxy, haloalkoxy or dioxyalkylene;
n is 2 or 3;
R1and R2The same or different.
Specifically, the method comprises the following steps:
R1selected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4- (trifluoromethoxy) phenyl, 3,4- (methylenedioxy) phenyl, 4-biphenyl, 2-naphthyl, 3-furyl or 3-thienyl;
R2selected from H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4- (trifluoromethoxy) phenyl, 3,4- (methylenedioxy) phenyl, 4-biphenyl, 2-naphthyl, 3-furyl or 3-thienyl.
The iminopyridazine derivative is specifically selected from any one of the following compounds:
3- (6-imino-3-phenylpyridazin-1-yl) propionic acid;
3- [ 6-imino-3- (4-methylphenyl) pyridazin-1-yl ] propanoic acid;
3- [ 6-imino-3- (4-fluorophenyl) pyridazin-1-yl ] propionic acid;
3- [ 6-imino-3- (4-chlorophenyl) pyridazin-1-yl ] propanoic acid;
3- [ 6-imino-3- (4-methoxyphenyl) pyridazin-1-yl ] propionic acid;
3- [ 6-imino-3- (4-trifluoromethoxyphenyl) pyridazin-1-yl ] propionic acid;
3- [ 6-imino-3- (4-biphenyl) pyridazin-1-yl ] propanoic acid;
3- [ 6-imino-3- (2-naphthyl) pyridazin-1-yl ] propionic acid;
3- [ 6-imino-3- (3-furyl) pyridazin-1-yl ] propionic acid;
3- [ 6-imino-3- (3-thienyl) pyridazin-1-yl ] propanoic acid;
3- [ 6-imino-3- (3, 4-methylenedioxyphenyl) pyridazin-1-yl ] propanoic acid;
3- (6-imino-3, 5-diphenylpyridazin-1-yl) propionic acid;
3- [ 6-imino-3-phenyl-5- (4-methoxyphenyl) pyridazin-1-yl ] propionic acid;
3- [ 6-imino-3-phenyl-5- (4-biphenyl) pyridazin-1-yl ] propionic acid;
4- (6-imino-3, 5-diphenylpyridazin-1-yl) butanoic acid;
4- [ 6-imino-3, 5-bis (4-methoxyphenyl) pyridazin-1-yl ] butanoic acid;
[ 6-imino-3, 5-bis (4-methoxyphenyl) pyridazin-1-yl ] propionic acid;
4- [ 6-imino-3-phenyl-5- (4-methoxyphenyl) pyridazin-1-yl ] butanoic acid;
4- [ 6-imino-3- (3-furyl) -5- (4-methoxyphenyl) pyridazin-1-yl ] butanoic acid.
Preferably, said R is1Wherein the substituted substituent is selected from H, halogen, methyl, methoxy, trifluoromethoxy, phenyl, or methylenedioxy.
Preferably, said R1The aryl is phenyl or naphthyl; heteroaryl is furyl or thienyl.
Preferably, said R is2Wherein the substituted substituent is selected from H, methoxy, or phenyl;
preferably, said R is2Wherein aryl is phenyl.
The invention also provides a preparation method of the iminopyridazine derivative, which comprises the following steps:
Figure BDA0002896653160000031
is alkylated with halogenated ester and then hydrolyzed to obtain the compound, wherein R1Selected from substituted or unsubstituted aryl, unsubstituted heteroaryl, R2Selected from the group consisting of H, substituted or unsubstituted aryl, the halogenated ester is 3-bromoethyl propionate or 4-bromoethyl butyrate;
or, will
Figure BDA0002896653160000032
Coupling with arylboronic acid Suzuki, alkylating with halogenated ester, and hydrolyzing to obtain the compound, wherein R is1、R2Is selected from substituted or unsubstituted aryl, and the halogenated ester is 3-bromoethyl propionate or 4-bromoethyl butyrate.
Wherein, will
Figure BDA0002896653160000041
And R1B(OH)2Coupling Suzuki, alkylating with halogenated ester, and hydrolyzing to obtain the final product, wherein R1Selected from substituted aryl, R2Selected from unsubstituted aryl or heteroaryl.
According to the scheme, the solvent used in the Suzuki coupling reaction is a mixed solvent of 1, 4-dioxane, tetrahydrofuran, N, N-dimethylformamide or 1, 4-dioxane and water.
According to the scheme, the catalyst used in the Suzuki coupling reaction is tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium dichloride, and the alkali is sodium carbonate, potassium carbonate or cesium carbonate.
According to the scheme, the mol ratio of reactants, boric acid, alkali and catalyst in the Suzuki coupling reaction is 1: (1.2-1.6): (1.2-1.6): (0.02-0.04), the reaction temperature is 85-105 ℃, and the reaction time is 6-10 hours.
According to the scheme, the solvent used in the alkylation reaction is N, N-dimethylformamide, and the halogenated ester is ethyl 3-bromopropionate or ethyl 4-bromobutyrate.
According to the scheme, the molar ratio of reactants to halogenated ester in the alkylation reaction is 1: (1.2-1.6), the reaction temperature is 75-90 ℃, and the reaction time is 7-10 hours.
According to the scheme, the solvent used in the hydrolysis reaction is water, and the alkali is sodium hydroxide or potassium hydroxide.
According to the scheme, the molar ratio of reactants to alkali in the hydrolysis reaction is 1: (3.0-5.0), the reaction temperature is 75-90 ℃, and the reaction time is 10-15 hours.
Based on the technical scheme, various substituted imino pyridazine derivatives can be simply and mildly obtained through the conventional reactions such as Suzuki coupling, alkylation, hydrolysis and the like. The invention also provides a salt of the iminopyridazine derivative, which is an acid salt of the iminopyridazine derivative.
Preferably, the hydrochloride of the iminopyridazine derivative is used.
The invention also provides a preparation method of the salt of the iminopyridazine derivative, which comprises the following steps:
1) The imino pyridazine derivative provided by the invention is adopted;
2) Acidifying the imino pyridazine derivative obtained in the step 1).
The invention also provides application of the iminopyridazine derivative in preparing insect GABA receptor inhibitors.
The invention also provides application of the salt of the iminopyridazine derivative in preparing insect GABA receptor inhibitors.
The present invention also provides a pesticide comprising: at least one of the above-mentioned iminopyridazine derivatives and/or at least one of the above-mentioned pharmaceutically acceptable salts of the iminopyridazine derivatives.
Preferably, the pharmaceutically acceptable salt of the iminopyridazine derivative is a hydrochloride of the iminopyridazine derivative.
The series of imino pyridazine derivatives synthesized by the invention have better control effect on agricultural pest Spodoptera litura (Spodoptera litura) and also have obvious inhibition effect on GABA receptors of houseflies (Musca domestica) and Spodoptera litura.
Detailed Description
The principles and features of the present invention are described below, and the examples are provided for illustration only and are not intended to limit the scope of the present invention.
The following examples are listed with respect to the following synthetic routes:
the synthetic route for 2a-k is as follows:
Figure BDA0002896653160000061
the synthetic route of 4a-c is as follows:
Figure BDA0002896653160000062
the synthetic routes of 6a-b, 7c are as follows:
Figure BDA0002896653160000063
the synthetic routes of 9a-b and 10a-b are as follows:
Figure BDA0002896653160000071
example 1
Synthesis of target Compound 3- (6-imino-3-arylpyridazin-1-yl) propionic acid (2 a-k)
Figure BDA0002896653160000072
In a 50mL single-necked flask, intermediates 1a to k (1.0 mmol), ethyl 3-bromopropionate (0.27g, 1.5 mmol) and DMF (0.5 mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.16g, 4.0 mmol) and water (10 mL) were added to the reaction mixture, and the mixture was further heated and stirred at 80 ℃ for 12 hours. After cooling, 20ml of ethyl acetate was added, followed by extraction with water (20 ml. Times.3). Adding 4mol/L hydrochloric acid into the water phase, stirring, and adjusting the pH value to 1-2. Then stirring for 30min under ice bath to precipitate solid. Recrystallizing the solid to obtain the 3- (6-imino-3-aryl pyridazine-1-yl) propionic acid (2 a-k).
3- (6-imino-3-phenylpyridazin-1-yl) propionic acid (2 a):
white solid, yield 34.6%.1H NMR(400MHz,DMSO-d6)δ12.39(s,1H,COOH),8.05(d,J＝9.6Hz,1H,ArH),7.90(d,J＝7.3Hz,2H,ArH),7.54-7.42(m,3H,ArH),7.05(d,J＝9.7Hz,1H,ArH),4.34(t,J＝6.9Hz,2H,CH2),2.79(t,J＝6.9Hz,2H,CH2).HRMS(ESI):m/z calcd for C13H14ClN3O2(M-Cl)+,244.1086；found,244.1080.
3- [ 6-imino-3- (4-methylphenyl) pyridazin-1-yl ] propionic acid (2 b):
white solid, yield 42.5%.1H NMR(400MHz,DMSO-d6)δ12.37(s,1H,COOH),8.02(dd,J＝9.7,2.4Hz,1H,ArH),7.79(d,J＝7.7Hz,2H,ArH),7.30(d,J＝7.8Hz,2H,ArH),7.03(dd,J＝9.7,2.5Hz,1H,ArH),4.32(t,J＝7.3Hz,2H,CH2),2.84-2.70(m,2H,CH2),2.36(s,3H,ArCH3).MS(ESI):m/z calcd for C14H16ClN3O2(M-Cl+H)+,259.1；found,259.1.
3- [ 6-imino-3- (4-fluorophenyl) pyridazin-1-yl ] propionic acid (2 c):
yellow solid, yield 49.1%.1H NMR(400MHz,DMSO-d6)δ12.42(s,1H,COOH),8.06(d,J＝9.7Hz,1H,ArH),7.95(dd,J＝8.8,5.2Hz,2H,ArH),7.33(t,J＝8.7Hz,2H,ArH),7.06(d,J＝9.6Hz,1H,ArH),4.33(t,J＝7.0Hz,2H,CH2),2.79(t,J＝6.9Hz,2H,CH2).MS(ESI):m/z calcd for C13H13ClFN3O2(M-Cl+H)+,263.1；found,263.1.
3- [ 6-imino-3- (4-chlorophenyl) pyridazin-1-yl ] propanoic acid (2 d):
yellow solid, yield 28.7%.1H NMR(400MHz,DMSO-d6)δ12.41(s,1H,COOH),8.07(d,J＝9.7Hz,1H,ArH),7.92(d,J＝8.3Hz,2H,ArH),7.56(d,J＝8.2Hz,2H,ArH),7.07(d,J＝9.7Hz,1H,ArH),4.33(t,J＝6.9Hz,2H,CH2),2.79(t,J＝6.9Hz,2H,CH2).MS(ESI):m/z calcd for C13H13Cl2N3O2(M-Cl+H)+,279.1；found,279.1.
3- [ 6-imino-3- (4-methoxyphenyl) pyridazin-1-yl ] propionic acid (2 e):
yellow solid, yield 33.2%.1H NMR(400MHz,DMSO-d6)δ12.38(s,1H,COOH),8.00(d,J＝9.6Hz,1H,ArH),7.84(d,J＝7.7Hz,2H,ArH),7.02(t,J＝8.6Hz,3H,ArH),4.32(t,J＝6.8Hz,2H,CH2),3.82(s,3H,ArOCH3),2.78(t,J＝6.9Hz,2H,CH2).MS(ESI):m/z calcd for C14H16ClN3O3(M-Cl+H)+,275.1；found,275.1.
3- [ 6-imino-3- (4-trifluoromethoxyphenyl) pyridazin-1-yl ] propionic acid (2 f):
yellow solid, yield 25.7%.1H NMR(400MHz,DMSO-d6)δ12.69(s,1H,COOH),8.46(d,J＝9.6Hz,1H,ArH),8.17-8.06(m,2H,ArH),7.99(d,J＝9.6Hz,1H,ArH),7.58-7.45(m,2H,ArH),4.48(t,J＝6.5Hz,2H,CH2),2.97(t,J＝6.5Hz,2H,CH2).HRMS(ESI):m/z calcd for C14H13ClF3N3O3(M-Cl)+,328.0909；found,328.0892.
3- [ 6-imino-3- (4-biphenyl) pyridazin-1-yl ] propionic acid (2 g):
yellow solid, yield 36.4%.1H NMR(400MHz,DMSO-d6)δ12.44(s,1H,COOH),8.12(d,J＝9.8Hz,1H,ArH),8.00(d,J＝8.1Hz,2H,ArH),7.77(dd,J＝21.4,7.9Hz,4H,ArH),7.50(t,J＝7.6Hz,2H,ArH),7.41(t,J＝7.5Hz,1H,ArH),7.08(d,J＝9.6Hz,1H,ArH),4.35(t,J＝7.0Hz,2H,CH2),2.81(t,J＝7.0Hz,2H,CH2).HRMS(ESI):m/z calcd for C19H18ClN3O2(M-Cl)+,320.1399；found,320.1385.
3- [ 6-imino-3- (2-naphthyl) pyridazin-1-yl ] propionic acid (2 h):
yellow solid, yield 22.6%.1H NMR(400MHz,DMSO-d6)δ12.50(s,1H,COOH),8.46(d,J＝1.8Hz,1H,ArH),8.22(d,J＝9.7Hz,1H,ArH),8.03-7.86(m,4H,ArH),7.57-7.49(m,2H,ArH),7.08(d,J＝9.7Hz,1H,ArH),4.35(t,J＝6.9Hz,2H,CH2),2.81(t,J＝6.9Hz,2H,CH2).HRMS(ESI):m/z calcd for C17H16ClN3O2(M-Cl)+,294.1243；found,294.1227.
3- [ 6-imino-3- (3-furyl) pyridazin-1-yl ] propionic acid (2 i):
yellow solid, yield 24.1%.1H NMR(400MHz,DMSO-d6)δ12.38(s,1H,COOH),8.35(s,1H,ArH),7.88-7.76(m,2H,ArH),7.02(d,J＝9.6Hz,1H,ArH),6.89(s,1H,ArH),4.27(t,J＝6.9Hz,2H,CH2),2.74(t,J＝7.0Hz,2H,CH2).MS(ESI):m/z calcd for C11H12ClN3O3(M-Cl+Na)+,257.1；found,257.1.
3- [ 6-imino-3- (3-thienyl) pyridazin-1-yl ] propanoic acid (2 j):
yellow solid, yield 19.5%.1H NMR(400MHz,DMSO-d6)δ12.40(s,1H,COOH),8.12(s,1H,ArH),8.01(d,J＝9.6Hz,1H,ArH),7.68(dd,J＝5.1,2.7Hz,1H,ArH),7.59(d,J＝5.0Hz,1H,ArH),7.04(d,J＝9.7Hz,1H,ArH),4.29(t,J＝6.9Hz,2H,CH2),2.77(t,J＝6.9Hz,2H,CH2).MS(ESI):m/z calcd for C11H12ClN3O2S(M-Cl+H)+,251.1；found,251.1.
3- [ 6-imino-3- (3, 4-methylenedioxyphenyl) pyridazin-1-yl ] propanoic acid (2 k):
yellow solid, yield 25.9%.1H NMR(400MHz,DMSO-d6)δ12.42(s,1H,COOH),8.00(d,J＝9.7Hz,1H,ArH),7.48-7.37(m,2H,ArH),7.01(dd,J＝9.2,3.4Hz,2H,ArH),6.10(s,2H,OCH2O),4.30(t,J＝6.9Hz,2H,CH2),2.77(t,J＝6.8Hz,2H,CH2).MS(ESI):m/z calcd for C14H14ClN3O4(M-Cl+H)+,289.1；found,289.1.
Example 2
Synthesis of target Compound 3- (6-imino-3, 5-diarylpyridazin-1-yl) propionic acid (4 a-c)
Figure BDA0002896653160000101
In a 50mL single-necked flask, 3-amino-4, 6-diarylpyridazine (3 a-c) (1.0 mmol), ethyl 3-bromopropionate (0.27g, 1.5 mmol) and DMF (0.5 mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.16g, 4.0 mmol) and water (10 mL) were added to the reaction solution, and the mixture was further heated and stirred at 80 ℃ for 12 hours. After cooling, 20mL of ethyl acetate was added, followed by extraction with water (20 mL. Times.3). Adding 4mol/L hydrochloric acid into the water phase, stirring, and adjusting the pH value to 1-2. Then stirring for 30min under ice bath to precipitate solid. Recrystallizing the solid to obtain the 3- (6-iminopyridazin-1-yl) propionic acid (4 a-c).
3- (6-imino-3, 5-diphenylpyridazin-1-yl) propionic acid (4 a):
white solid, yield 19.2%.1H NMR(400MHz,DMSO-d6)δ12.35(s,1H,COOH),8.14(s,1H,ArH),8.04-7.92(m,4H,ArH),7.54-7.44(m,6H,ArH),4.43(t,J＝7.1Hz,2H,CH2),2.84(t,J＝7.0Hz,2H,CH2).MS(ESI):m/z calcd for C19H18ClN3O2(M-Cl+H)+,321.1；found,321.1.
3- [ 6-imino-3-phenyl-5- (4-methoxyphenyl) pyridazin-1-yl ] propionic acid (4 b):
white solid, yield 23.7%.1H NMR(400MHz,DMSO-d6)δ12.37(s,1H,COOH),8.10(s,1H,ArH),8.05-7.97(m,4H,ArH),7.54-7.43(m,3H,ArH),7.04(d,J＝8.4Hz,2H,ArH),4.41(t,J＝6.9Hz,2H,CH2),3.83(s,3H,ArOCH3),2.83(t,J＝6.9Hz,2H,CH2).HRMS(ESI):m/z calcd for C20H20ClN3O3(M-Cl)+,350.1505；found,350.1491.
3- [ 6-imino-3-phenyl-5- (4-biphenyl) pyridazin-1-yl ] propionic acid (4 c):
white solid, yield 16.4%.1H NMR(400MHz,DMSO-d6)δ12.48(s,1H,COOH),8.21(s,1H,ArH),8.10-8.07(m,2H,ArH),8.03-7.98(m,2H,ArH),7.95-7.91(m,1H,ArH),7.58-7.36(m,9H,ArH),4.43(t,J＝6.9Hz,2H,CH2),2.84(t,J＝6.8Hz,2H,CH2).HRMS(ESI):m/z calcd for C25H22ClN3O2(M-Cl)+,396.1712；found,396.1695.
Example 3
Synthesis of intermediate 3-amino-4, 6-diarylpyridazine (6 a-b)
Figure BDA0002896653160000111
In a 50mL two-necked flask, 3-amino-4-bromo-6-chloropyridazine (5) (0.63g, 3.0 mmol), arylboronic acid (6.0 mmol), potassium carbonate (0.83g, 6.0 mmol), tetrakis (triphenylphosphine) palladium (0.21 g), 1, 4-dioxane (20 mL), and water (5 mL) were added, stirred well under argon, and heated to 100 ℃ and stirred under reflux for 8 hours. After the completion of the TLC monitoring reaction, the system was cooled to room temperature, 20mL of water was added, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The organic phase was washed with saturated brine (50 mL × 2), dried over a small amount of anhydrous sodium sulfate and rotary-distilled under reduced pressure, and the crude product was separated and purified by silica gel column chromatography [ V (ethyl acetate) = V (petroleum ether) =1 ] to obtain intermediates 6a and 6b.
3-amino-4, 6-diphenylpyridazine (6 a):
a reddish brown solid in 72.4% yield.1H NMR(400MHz,CDCl3)δ7.92(d,J＝7.5Hz,2H,ArH),7.62-7.29(m,9H,ArH),6.13(s,2H,ArNH2).MS(ESI):m/z 248.1(M+H)+.
3-amino-4, 6-bis (4-methoxyphenyl) pyridazine (6 b):
reddish brown solid, yield 77.6%.1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.7Hz,2H,ArH),7.48(d,J＝8.8Hz,3H,ArH),7.09-6.97(m,8.2Hz,4H,ArH),5.06(s,2H,ArNH2),3.87(d,J＝6.5Hz,6H,ArOCH3).MS(ESI):m/z 308.1(M+H)+.
Example 4
Synthesis of target Compound 4- (6-imino-3, 5-diarylpyridazin-1-yl) butanoic acid (7 a-b)
Figure BDA0002896653160000121
In a 50mL single-necked flask, 3-amino-4, 6-diarylpyridazine (6 a-b) (1.0 mmol), ethyl 4-bromobutyrate (0.29g, 1.5 mmol) and DMF (0.5 mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.160g, 4 mmol) and water (10 mL) were added to the reaction mixture, and the mixture was stirred at 80 ℃ for 12 hours. After cooling, 20mL of ethyl acetate was added, followed by extraction with water (20 mL. Times.3). Adding 4mol/L hydrochloric acid into the water phase, stirring, and adjusting the pH value to 1-2. Then stirring for 30min under ice bath to precipitate solid. Recrystallizing the solid to obtain the 4- (6-imino-3, 5-diaryl pyridazine-1-yl) butyric acid (7 a-b).
4- (6-imino-3, 5-diphenylpyridazin-1-yl) butanoic acid (7 a):
white solid, yield 20.7%.1H NMR(400MHz,DMSO-d6)δ12.12(s,1H,COOH),8.17-7.86(m,5H,ArH),7.58-7.37(m,6H,ArH),4.27(t,J＝6.9Hz,2H,CH2),2.36(t,J＝7.2Hz,2H,CH2),2.07(m,2H,CH2).MS(ESI):m/z calcd for C20H20ClN3O2(M-Cl+H)+,335.2；found,335.1.
4- [ 6-imino-3, 5-bis (4-methoxyphenyl) pyridazin-1-yl ] butanoic acid (7 b):
pale yellow solid, 18.6% yield.1H NMR(400MHz,DMSO-d6)δ12.13(s,1H,COOH),8.05-7.90(m,5H,ArH),7.04(dd,J＝8.8,4.9Hz,4H,ArH),4.23(t,J＝7.0Hz,2H,CH2),3.82(s,6H,ArOCH3),2.34(t,J＝7.3Hz,2H,CH2),2.04(m,2H,CH2).MS(ESI):m/z calcd for C22H24ClN3O4(M-Cl)+,394.2；found,394.2.
Example 5
Synthesis of target Compound [ 6-imino-3, 5-bis (4-methoxyphenyl) pyridazin-1-yl ] propanoic acid (7 c)
Figure BDA0002896653160000131
In a 50mL single-necked flask, 3-amino-4, 6-bis (4-methoxyphenyl) pyridazine (6 b) (1.0 mmol), ethyl 3-bromopropionate (0.27g, 1.5 mmol) and DMF (0.5 mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.16g, 4.0 mmol) and water (10 mL) were added to the reaction mixture, and the mixture was further heated and stirred at 80 ℃ for 12 hours. After cooling, 20mL of ethyl acetate was added, followed by extraction with water (20 mL. Times.3). Adding 4mol/L hydrochloric acid into the water phase, stirring, and adjusting the pH value to 1-2. Then stirring for 30min under ice bath to precipitate solid. Recrystallizing the solid to obtain the [ 6-imino-3, 5-di (4-methoxyphenyl) pyridazin-1-yl ] propionic acid (7 c).
[ 6-imino-3, 5-bis (4-methoxyphenyl) pyridazin-1-yl ] propionic acid (7 c):
white solid, yield 22.3%.1H NMR(400MHz,DMSO-d6)δ12.38(s,1H,COOH),8.03(s,1H,ArH),8.00-7.89(m,4H,ArH),7.05-6.98(m,4H,ArH),4.37(t,J＝6.9Hz,2H,CH2),3.80(d,J＝2.0Hz,6H,ArOCH3),2.80(t,J＝6.9Hz,2H,CH2).MS(ESI):m/z calcd for C21H22ClN3O4(M-Cl+H)+,381.2；found,381.1.
Example 6
Synthesis of intermediate 3-amino-4- (4-methoxyphenyl) -6-arylpyridazine (9 a-b)
Figure BDA0002896653160000141
A50 mL two-neck flask was charged with intermediate 8 (0.71g, 3.0 mmol), arylboronic acid (4.5 mmol), potassium carbonate (0.622g, 4.5 mmol), tetrakis (triphenylphosphine) palladium (0.105 g), 1, 4-dioxane (20 mL), and water (5 mL), stirred well under argon, warmed to 100 ℃ and stirred under reflux for 8h. After the completion of the TLC monitoring reaction, the system was cooled to room temperature, 20mL of water was added, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The organic phase was washed with saturated brine (50 mL × 2), dried over a small amount of anhydrous sodium sulfate, rotary-distilled under reduced pressure, and the crude product was separated and purified by silica gel column chromatography [ V (ethyl acetate) = V (petroleum ether) =1:2] intermediates 9a and 9b are obtained.
3-amino-4- (4-methoxyphenyl) -6-phenylpyridazine (9 a):
reddish brown solid, yield 75.1%。1H NMR(400MHz,CDCl3)δ7.98(d,J＝7.7Hz,2H,ArH),7.53-7.37(m,6H,ArH),7.05(d,J＝8.2Hz,2H,ArH),5.13(s,2H,ArNH2),3.88(s,3H,ArOCH3).MS(ESI):m/z 278.1(M+H)+.
3-amino-4- (4-methoxyphenyl) -6- (3-furyl) pyridazine (9 b):
a reddish brown solid, 84.8% yield.1H NMR(400MHz,CDCl3)δ7.97(s,1H,ArH),7.52-7.41(m,3H,ArH),7.26(s,1H,ArH),7.08-6.94(m,3H,ArH),5.06(s,2H,ArNH2),3.87(s,3H,ArOCH3).MS(ESI):m/z 268.1(M+H)+.
Example 7
Synthesis of target Compound 4- [ 6-imino-3-aryl-5- (4-methoxyphenyl) pyridazin-1-yl ] butanoic acid (10 a-b)
Figure BDA0002896653160000151
In a 50mL single-necked flask, 3-amino-4- (4-methoxyphenyl) -6-arylpyridazine (9 a-b) (1.0 mmol), ethyl 4-bromobutyrate (0.29g, 1.5 mmol) and DMF (0.5 mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.160g, 4mmol) and water (10 mL) were added to the reaction solution, and the mixture was stirred at 80 ℃ for 12 hours. After cooling, 20mL of ethyl acetate was added, followed by extraction with water (20 mL. Times.3). Adding 4mol/L hydrochloric acid into the water phase, stirring, and adjusting the pH value to 1-2. Then stirring for 30min under ice bath to precipitate solid. Recrystallizing the solid to obtain the 4- [ 6-imino-3-aryl-5- (4-methoxyphenyl) pyridazin-1-yl ] butyric acid (10 a-b).
4- [ 6-imino-3-phenyl-5- (4-methoxyphenyl) pyridazin-1-yl ] butanoic acid (10 a):
pale yellow solid, yield 14.3%.1H NMR(400MHz,DMSO-d6)δ12.12(s,1H,COOH),8.11-7.94(m,5H,ArH),7.54-7.43(m,3H,ArH),7.04(d,J＝8.5Hz,2H,ArH),4.26(t,J＝7.0Hz,2H,CH2),3.83(s,3H,ArOCH3),2.35(t,J＝7.3Hz,2H,CH2),2.06(m,2H,CH2).MS(ESI):m/z calcd for C21H22ClN3O3(M-Cl)+,364.2；found,364.1.
4- [ 6-imino-3- (3-furyl) -5- (4-methoxyphenyl) pyridazin-1-yl ] butanoic acid (10 b):
pale yellow solid, yield 11.6%.1H NMR(400MHz,DMSO-d6)δ12.13(s,1H,COOH),8.46(s,1H,ArH),7.98-7.92(m,3H,ArH),7.80(s,1H,ArH),7.04(d,J＝8.9Hz,2H,ArH),6.93(s,1H,ArH),4.19(t,J＝7.0Hz,2H,CH2),3.83(s,3H,ArOCH3),2.32(t,J＝7.3Hz,2H,CH2),2.01(m,2H,CH2).MS(ESI):m/z calcd for C19H20ClN3O4(M-Cl+Na)+,377.1；found,377.1.
Example 8
Insecticidal Activity test
The toxicity of 10 compounds on the spodoptera litura larvae at the concentrations of 100mg/kg and 500mg/kg is determined by adopting an artificial feed mixing method.
Reagents and materials:
raw materials: 2a, 2b, 2e, 2f, 2g, 2h, 2k, 7a, 7b, 10a
Solvent: DMSO (analytical reagent)
Biological material: prodenia litura, artificial feed
2. Experimental methods
2.1 preparing 100mg/kg toxic feed
Preparing the target compound into 1 × 10 by taking DMSO as a solvent5And (3) taking 10 mu L of mother liquor, adding 90 mu L of DMSO into 10 mu L of mother liquor, uniformly stirring to obtain 100 mu L of liquid medicine with the concentration of 10000mg/L, adding 500 mu L of DMSO into the liquid medicine, uniformly stirring, and then fully mixing with 10g of feed (10 g of feed is added into a blank control group and 600 mu L of DMSO is fully mixed) to obtain toxic feed with the concentration of 100 mg/kg. The newly prepared toxic feed is put into a culture dish and put in a fume hood for ventilation, and the solvent DMSO is completely volatilized as far as possible.
2.2 preparing 500mg/kg toxic fodder
Preparing the target compound into 1 × 10 by taking DMSO as a solvent5Adding 50 μ L DMSO into 50 μ L of mother liquor, stirring to obtain 100 μ L medicinal liquid with concentration of 50000mg/L, adding 500 μ L DMSO,stirring well, and mixing with 10g feed (adding 10g feed into blank control group and mixing with 600 μ L DMSO well) to obtain toxic feed with concentration of 500 mg/kg. The new toxic feed is poured into a petri dish and placed in a fume hood for ventilation, and the solvent DMSO is completely volatilized as much as possible.
2.3 mixing and inoculating insects
Two batches of feeds with the concentration of 100mg/kg and 500mg/kg are respectively placed in the two six-hole plates, 0.5g of feed is added into each hole, and 10 prodenia litura larvae which are healthy and consistent in size are placed in each hole. And replacing newly prepared toxic feed every 24 hours.
2.4 inspection and data processing
After 48h, the number of deaths of spodoptera litura larvae was counted (larvae were touched and were counted as dead if there was no response). The experiment was repeated three times for each compound, and the mortality was counted, calculated and corrected.
Mortality correction:
Figure BDA0002896653160000171
wherein, PtIndicating the mortality, P, of the experimental groups0Indicating mortality in the control group, P1Indicating corrected mortality.
3. Results of the experiment
The test results are shown in tables 1 and 2, respectively, wherein the samples are the iminopyridazine derivatives prepared in the examples, and the sample numbers correspond to the specific numbers of the compounds in the examples.
TABLE 1 insecticidal Activity of 10 Compounds at a concentration of 100mg/kg on Prodenia litura
Figure BDA0002896653160000172
Figure BDA0002896653160000181
Note: values represent mean ± SEM (n = 3)
As can be seen from the above table, compounds 2a, 2b, 2e, 2f, 2g, 2h and 2k have certain insecticidal activity against spodoptera litura larvae at a concentration of 100mg/kg, with compound 2k having the best killing effect against spodoptera litura larvae.
TABLE 2 insecticidal Activity of 10 Compounds at 500mg/kg concentration on Spodoptera litura
Figure BDA0002896653160000182
Note: values represent mean ± SEM (n = 3)
As can be seen from the above table, compounds 2a, 2b, 2e, 2f, 2g, 2h and 2k have higher insecticidal activity against Heliothis litura larvae at a concentration of 500 mg/kg. Wherein, the compound 2f has the best killing effect on the spodoptera litura larvae, and the killing effect is 2k times
Example 9
Insect GABA receptor inhibitory Activity (IC)50)
The antagonistic activity of the 18 iminopyridazine derivatives (10 a is not contained) on prodenia litura and housefly GABA receptors is tested by adopting a double-electrode voltage-clamp electrophysiology method.
1. Reagents and materials:
raw medicines: 18 target compounds
Solvent: DMSO (analytical reagent)
Biological material: xenopus laevis oocytes, sterile standard oocyte culture fluid, ca-free2+Oocyte culture solution
1. Experimental methods
RDL (receptor-directed fragment of spodoptera litura) and housefly GABA (gamma-aminobutyric acid) receptorbdThe cDNA of the subunit is taken as a template, T7 polymerase is taken as a promoter to carry out transcription in vitro, and the cRNA of the spodoptera litura and the housefly GABA receptor subunit is obtained after purification. The cRNA was injected into xenopus oocytes using a nanoliter microinjection system, 5ng per cell, and cultured for 48h. After the corresponding receptor is expressed, a double-electrode voltage clamp system is used for testing the inhibition rate of the compound on the GABA receptor of prodenia litura and houseflies.
2. Results of the experiment
The results of the activity test of 18 compounds of interest at 30 μ M concentration on prodenia litura and housefly GABA receptors are shown in Table 3.
TABLE 3 inhibition Activity of target Compounds on the GABA receptors of Spodoptera litura and Musca domestica
Figure BDA0002896653160000191
Figure BDA0002896653160000201
Note: values represent mean ± SEM (n = 3-4)
The above table can show that some synthesized target compounds show certain inhibition effect on prodenia litura and housefly GABA receptors at 30 μ M. The inhibition rate of the compounds 2b, 2e and 2f on the GABA receptors of the prodenia litura is higher than that of the GABA receptors of the houseflies, and the inhibition rate of the compounds 2g, 2j, 2k, 4b, 4c, 7b, 7c and 10b on the GABA receptors of the houseflies is obviously higher than that of the prodenia litura, so that the compounds possibly have certain selectivity on the prodenia litura and the GABA receptors of the houseflies. The inhibition rate of the compounds 2h and 2k on GABA receptors of prodenia litura and houseflies at 30 mu M is higher than 80%.
IC was determined for compound steps with over 50% inhibition in prodenia litura and housefly GABA receptors50The values and measurement results are shown in Table 4.
TABLE 4 IC of some target compounds on the GABA receptors of spodoptera litura and houseflies50Value of
Figure BDA0002896653160000202
Note: values represent mean ± SEM (n = 3-4), ND means not detected.
Test results show that the 6 target compounds show better antagonism in prodenia litura and housefly GABA receptors, and the IC of the 6 target compounds50Values range from 2.2 to 24.8. Mu.M at low micromolar levels. Among them, the compound has the highest activity for 2h, 2k times.
Finally, the imino pyridazine derivative provided by the invention shows an inhibiting effect on prodenia litura and housefly GABA receptors, and has insecticidal activity on target insects, thereby expanding the substrate and possibility for the development of novel insecticides.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.

Claims (8)

1. An iminopyridazine derivative having a structure represented by the following general formula (I):
Figure 715535DEST_PATH_IMAGE001
（Ⅰ）；
wherein:
n is 2;
R1selected from 4- (trifluoromethoxy) phenyl, 3,4- (methylenedioxy) phenyl, 4-biphenyl, 2-naphthyl, R2Is selected from H;
or, R1Selected from 4-methoxyphenyl, R2Is selected from 4-methoxyphenyl.
2. A process for the preparation of the iminopyridazine derivatives according to claim 1, characterized by comprising the following steps:
will be provided with
Figure 48428DEST_PATH_IMAGE002
Hydrocarbonylation with halogenated ester to obtain the halogenated ester, wherein the halogenated ester is 3-bromoethyl propionate;
or, will
Figure 800483DEST_PATH_IMAGE003
Are each independently of R1B(OH)2、R2B(OH)2Coupling Suzuki, and hydrocarbonylating with halogenated esterWherein the halogenated ester is ethyl 3-bromopropionate.
3. A pharmaceutically acceptable salt of an iminopyridazine derivative according to claim 1, which is an acid salt of the iminopyridazine derivative.
4. A process for the preparation of a salt of an iminopyridazine derivative according to claim 3, characterized by comprising the following steps:
1) Using the iminopyridazine derivative according to claim 1;
2) Acidifying the imino pyridazine derivative obtained in the step 1).
5. Use of the iminopyridazine derivatives according to claim 1, characterized in that:
used for preparing prodenia litura GABA receptor inhibitor R1Selected from 4- (trifluoromethoxy) phenyl, 2-naphthyl or 3,4- (methylenedioxy) phenyl, R2Is selected from H;
alternatively, for the preparation of Musca domestica GABA receptor inhibitors, R1Selected from 4- (trifluoromethoxy) phenyl, 3,4- (methylenedioxy) phenyl, 4-biphenyl, 2-naphthyl, R2Is selected from H; or, R1Selected from 4-methoxyphenyl, R2Is selected from 4-methoxyphenyl.
6. Use of the salts of iminopyridazine derivatives according to claim 3, characterized in that:
used for preparing prodenia litura GABA receptor inhibitor R1Selected from 4- (trifluoromethoxy) phenyl, 2-naphthyl or 3,4- (methylenedioxy) phenyl, R2Is selected from H;
alternatively, for the preparation of Musca domestica GABA receptor inhibitors, R1Selected from 4- (trifluoromethoxy) phenyl, 3,4- (methylenedioxy) phenyl, 4-biphenyl, 2-naphthyl, R2Is selected from H; or, R1Selected from 4-methoxyphenyl, R2Selected from 4-methoxyphenyl。
7. A spodoptera litura or housefly insecticide comprising: at least one iminopyridazine derivative of claim 1 and/or at least one pharmaceutically acceptable salt of an iminopyridazine derivative of claim 3.
8. The insecticide according to claim 7, wherein: the pharmaceutically acceptable salt of the iminopyridazine derivative is an acid salt of the iminopyridazine derivative.
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