Iminopyridazine derivative, preparation method and application thereof, and pesticide
阅读说明：本技术 亚氨基哒嗪类衍生物及其制备方法、应用和杀虫剂 (Iminopyridazine derivative, preparation method and application thereof, and pesticide ) 是由 刘根炎 周聪伟 张志松 陈达 黄成� 吴风收 罗晓刚 巨修练 于 2021-01-13 设计创作，主要内容包括：本发明属于农药化学技术领域,具体涉及亚氨基哒嗪类衍生物及其制备方法、应用和杀虫剂。本发明以亚氨基哒嗪结构为基础,在其1位引入丙酸或丁酸侧链,3位和5位分别或同时引入芳基,合成了一类多取代的亚氨基哒嗪衍生物,所述化合物对公共卫生害虫家蝇和农业害虫斜纹夜蛾的GABA受体具有明显的抑制作用,同时对斜纹夜蛾也具有较好的杀虫活性,具有制备或开发杀虫剂的应用前景。(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.)
1. An iminopyridazine derivative having a structure represented by the following general formula (I):
wherein:
R1selected from substituted or unsubstituted aryl, unsubstituted heteroaryl, the substituents being halogen, alkyl, alkoxy, haloalkoxy or dioxyalkylene;
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.
2. The iminopyridazine derivative according to claim 1, characterized in that:
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.
3. The iminopyridazine derivatives according to claim 1 or 2, characterized in that they are selected in particular 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 ] propionic 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.
4. A process for the preparation of the iminopyridazine derivatives according to any one of claims 1 to 3, characterized by comprising the following steps:
will be provided withIs hydrocarbonylated and hydrolyzed with halogenated ester to obtain the compound, wherein R1Selected from substituted or unsubstituted aryl, unsubstituted heteroaryl, R2Selected from H, the halogenated ester is 3-bromoethyl propionate or 4-bromoethyl butyrate;
or, willAre each independently of R1B(OH)2、R2B(OH)2Suzuki coupled and hydrocarbonized with haloestersObtaining (I), wherein R1Selected from substituted or unsubstituted aryl, unsubstituted heteroaryl, R2Is selected from substituted or unsubstituted aryl and unsubstituted heteroaryl, and the halogenated ester is ethyl 3-bromopropionate or ethyl 4-bromobutyrate.
5. A salt of an iminopyridazine derivative according to any one of claims 1 to 3, which is an acid salt of the iminopyridazine derivative.
6. A process for the preparation of the salts of iminopyridazine derivatives according to claim 5, characterized by comprising the following steps:
1) the iminopyridazine derivative according to any one of claims 1 to 3;
2) acidifying the imino pyridazine derivative obtained in the step 1).
7. Use of the iminopyridazine derivatives according to any one of claims 1 to 3, characterized in that: is used for preparing insect GABA receptor inhibitor.
8. Use of the salts of iminopyridazine derivatives according to claim 5, characterized in that: is used for preparing insect GABA receptor inhibitor.
9. An insecticide, comprising: at least one iminopyridazine derivative according to any one of claims 1 to 3 and/or at least one pharmaceutically acceptable salt of an iminopyridazine derivative according to any one of claims 1 to 3.
10. The insecticide according to claim 9, wherein: the pharmaceutically acceptable salt of the iminopyridazine derivative is an acid salt of the iminopyridazine derivative.
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):
wherein:
R1selected from substituted or unsubstituted aryl, unsubstituted heteroaryl, the substituents being halogen, alkyl, alkoxy, haloalkoxy or dioxyalkylene;
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 ] propionic 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 R is1The 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:
is alkylated with halogenated ester and then hydrolyzed to obtain the compound, wherein R1Selected from substituted or unsubstituted aryl, unsubstituted heteroaryl, R2Selected from H and substituted or unsubstituted aryl, the halogenated ester is 3-bromoethyl propionate or 4-bromoethyl butyrate;
or, willCoupling 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, willAnd R1B(OH)2Coupling Suzuki, alkylating with halogenated ester, and hydrolyzing to obtain the final product, wherein R1Selected from substituted aryl radicals, 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 mole 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) at 85-105 ℃ for 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 Musca domestica and Spodoptera litura.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
The following examples are listed with respect to the following synthetic routes:
the synthetic route for 2a-k is as follows:
the synthetic route of 4a-c is as follows:
the synthetic routes of 6a-b, 7c are as follows:
the synthetic routes of 9a-b and 10a-b are as follows:
example 1
Synthesis of target Compound 3- (6-imino-3-arylpyridazin-1-yl) propionic acid (2a-k)
Intermediate 1a-k (1.0mmol), ethyl 3-bromopropionate (0.27g, 1.5mmol), and DMF (0.5mL) were added to a 50mL single-neck flask and stirred at 80 ℃ for 8 h. Then, sodium hydroxide (0.16g, 4.0mmol) and water (10mL) 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-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 (4a-c)
In a 50mL single-necked flask, 3-amino-4, 6-diarylpyridazine (3a-c) (1.0mmol), ethyl 3-bromopropionate (0.27g, 1.5mmol) and DMF (0.5mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.16g, 4.0mmol) and water (10mL) 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 (6a-b)
In a 50mL two-necked flask, 3-amino-4-bromo-6-chloropyridazine (5) (0.63g, 3.0mmol), arylboronic acid (6.0mmol), potassium carbonate (0.83g, 6.0mmol), tetrakis (triphenylphosphine) palladium (0.21g), 1, 4-dioxane (20mL), and water (5mL) were added, stirred well under argon, and heated to 100 ℃ and stirred under reflux for 8 h. 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 (50mL × 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] to give intermediates 6a and 6 b.
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):
a reddish brown solid, 77.6% yield.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 (7a-b)
In a 50mL single-necked flask, 3-amino-4, 6-diarylpyridazine (6a-b) (1.0mmol), ethyl 4-bromobutyrate (0.29g, 1.5mmol) and DMF (0.5mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.160g, 4mmol) and water (10mL) 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, 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 (7c)
In a 50mL single-necked flask, 3-amino-4, 6-bis (4-methoxyphenyl) pyridazine (6b) (1.0mmol), ethyl 3-bromopropionate (0.27g, 1.5mmol) and DMF (0.5mL) were added, and the mixture was stirred at 80 ℃ for 8 hours. Then, sodium hydroxide (0.16g, 4.0mmol) and water (10mL) 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 [ 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 (9a-b)
A50 mL two-necked flask was charged with intermediate 8(0.71g, 3.0mmol), arylboronic acid (4.5mmol), potassium carbonate (0.622g, 4.5mmol), tetrakis (triphenylphosphine) palladium (0.105g), 1, 4-dioxane (20mL), and water (5mL), stirred well under argon, warmed to 100 ℃ and refluxed for 8 h. 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 (50mL × 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):
a reddish brown solid in 75.1% yield.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 (10a-b)
In a 50mL single-necked flask, 3-amino-4- (4-methoxyphenyl) -6-arylpyridazine (9a-b) (1.0mmol), ethyl 4-bromobutyrate (0.29g, 1.5mmol) and DMF (0.5mL) were added, and the mixture was stirred at 80 ℃ for 8 h. Then, sodium hydroxide (0.160g, 4mmol) and water (10mL) 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 solvent5And (3) adding 50 mu L of DMSO into 50 mu L of mother liquor of the mother liquor of mg/L, uniformly stirring to obtain 100 mu L of liquid medicine with the concentration of 50000mg/L, adding 500 mu L of DMSO into the liquid medicine, uniformly stirring, and then fully mixing with 10g of feed (fully mixing 10g of feed and 600 mu L of DMSO into a blank control group) to obtain the toxic feed with the 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 put into two six-hole plates, 0.5g of feed is added into each hole, and 10 prodenia litura larvae which grow healthily and have the same size are placed in each hole. And replacing newly prepared toxic feed every 24 h.
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: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.
Insecticidal Activity of 10 Compounds against Prodenia litura at concentration of 1100 mg/kg
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.
Insecticidal Activity of 10 Compounds against Prodenia litura at Table 2500 mg/kg concentration
Note: values represent mean ± SEM (n ═ 3)
As can be seen from the above table, compounds 2a, 2b, 2e, 2f, 2g, 2h and 2k had higher insecticidal activity against spodoptera 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 inhibitionPreparation of Activity (IC)50)
The antagonistic activity of the 18 iminopyridazine derivatives (10a 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 materials: 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
Using prodenia litura and housefly GABA receptor RDLbdAnd (3) taking cDNA of the subunits as a template, taking T7 polymerase as a promoter to perform in vitro transcription, and purifying to obtain cRNA of the spodoptera litura and the housefly GABA receptor subunits. The cRNA was injected into xenopus oocytes using a nanoliter microinjection system, 5ng per cell, and cultured for 48 h. 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
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 the 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 target compounds on GABA receptors of Spodoptera litura and Musca domestica50Value of
Note: values represent mean ± SEM (n ═ 3-4), and ND means no detection.
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 is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
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