CN108069915B - Pyrazinamide compound, preparation method and application thereof, and bactericide - Google Patents

Pyrazinamide compound, preparation method and application thereof, and bactericide Download PDF

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CN108069915B
CN108069915B CN201611004241.9A CN201611004241A CN108069915B CN 108069915 B CN108069915 B CN 108069915B CN 201611004241 A CN201611004241 A CN 201611004241A CN 108069915 B CN108069915 B CN 108069915B
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CN108069915A (en
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杨光富
李华
熊力
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Central China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines

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Abstract

The invention relates to the field of pesticide bactericides and discloses a pyrazinamide compound, a preparation method and application thereof and a bactericide, wherein the pyrazinamide compound has a structure shown in a formula (I). According to the invention, a pyrazinamide compound with a brand new structure is designed by introducing a pyrazine ring segment and a diphenyl ether segment with wide biological activity into pyraziflumumid, and the pyrazinamide compound can be used as a brand new succinate dehydrogenase inhibitor or bactericide.

Description

Pyrazinamide compound, preparation method and application thereof, and bactericide
Technical Field
The invention relates to the field of pesticide bactericides, in particular to a pyrazinamide compound, a method for preparing the pyrazinamide compound, application of the pyrazinamide compound and the pyrazinamide compound prepared by the method as succinate dehydrogenase inhibitors, and a bactericide.
Background
Succinate dehydrogenase inhibitors (SDHIs) are bactericides which inhibit mitochondrial functions by acting on a complex II (also called succinate dehydrogenase or ubiquinone succinate reductase) on a mitochondrial respiratory electron transfer chain of pathogenic bacteria to interfere with succinate dehydrogenase on the respiratory electron transfer chain, prevent the mitochondrial functions from generating energy, inhibit the growth of the pathogenic bacteria and finally cause the death of the pathogenic bacteria so as to achieve the purpose of preventing and treating diseases.
The succinate dehydrogenase inhibitor bactericide has been the most promising bactericide in recent years due to high efficiency, broad-spectrum bactericidal activity and relatively low resistance risk, and is concerned by various pesticide companies in the world.
In 2014, two bactericides are newly disclosed, wherein one of the two bactericides is pyraziflumumid (test code NNF-0721) of succinate dehydrogenase inhibitor (SDHI) type which is developed by Nippon pesticide company, is mainly used for preventing and treating powdery mildew, scab, gray mold, sclerotinia sclerotiorum, ring spot, fruit spot, and leaf spot on rice, fruits and vegetables, and has the use dose of 100-2It is expected to be marketed in japan in 2018.
Disclosure of Invention
The invention aims to provide a pyrazinamide compound with broad-spectrum bacteriostatic and bactericidal activity.
The invention also aims to provide a pyrazinamide compound which can be used as a succinate dehydrogenase inhibitor.
The invention also aims to provide a pyrazinamide compound which can be used as a main active ingredient of a bactericide.
In order to achieve the above object, in a first aspect, the present invention provides a pyrazinamide-based compound having a structure represented by formula (I):
Figure BDA0001152927600000011
wherein R is11、R12、R13、R14And R15Each independently selected from H, amino, nitro, halogen, C1-8And C substituted by 1 to 4 halogens1-6And R is alkyl of11、R12、R13、R14And R15Not H at the same time;
R21selected from H, halogen, C1-6And C substituted by 1 to 4 halogens1-4Alkyl groups of (a);
R31、R32、R33and R34Each independently selected from H, amino, nitro, halogen, C1-8And C substituted by 1 to 4 halogens1-6Alkyl groups of (a); and
n is an integer of 0 to 6.
In a second aspect, the present invention provides a method for preparing a pyrazinamide-based compound having a structure represented by formula (I), the method comprising: contacting a compound represented by the formula (II-1) with a compound represented by the formula (II-2);
Figure BDA0001152927600000021
wherein R is11、R12、R13、R14、R15、R21、R31、R32、R33、R34And n is as defined above in the invention.
In a third aspect, the present invention provides pyrazinamide compounds prepared by the aforementioned method of the present invention.
In a fourth aspect, the invention provides the use of the pyrazinamide compound as a succinate dehydrogenase inhibitor.
In a fifth aspect, the invention provides a bactericide, which is composed of an active ingredient and an auxiliary material, wherein the active ingredient comprises at least one of the pyrazinamide compounds disclosed in the invention.
According to the invention, by introducing a pyrazine ring segment and a diphenyl ether segment with wide biological activity in NNF-0721, a pyrazinamide compound with a brand-new structure is designed, and the pyrazinamide compound can be used as a brand-new succinate dehydrogenase inhibitor or bactericide.
The pyrazinamide compound provided by the invention has obvious succinate dehydrogenase inhibition activity and certain inhibition activity on rice sheath blight disease, cucumber gray mold, cucumber downy mildew and cucumber powdery mildew, and has obvious broad spectrum advantage compared with the medicament in the prior art.
Meanwhile, the method for preparing the pyrazinamide compound has the advantages of cheap and easily-obtained raw materials, mild reaction conditions and simple post-treatment.
Moreover, the data in the specific examples prove that the pyrazinamide compound can be used as a good succinate dehydrogenase inhibitor and has good bactericidal activity.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
First aspectThe invention provides a pyrazinamide compound, which has a structure shown in a formula (I):
Figure BDA0001152927600000031
wherein R is11、R12、R13、R14And R15Each independently selected from H, amino, nitro, halogen, C1-8And C substituted by 1 to 4 halogens1-6And R is alkyl of11、R12、R13、R14And R15Not H at the same time;
R21selected from H, halogen, C1-6And C substituted by 1 to 4 halogens1-4Alkyl groups of (a);
R31、R32、R33and R34Each independently selected from H, amino, nitro, halogen, C1-8And C substituted by 1 to 4 halogens1-6Alkyl groups of (a); and
n is an integer of 0 to 6.
In the present invention, said R11、R12、R13、R14And R15May be the same or different. And R31、R32、R33And R34May be the same or different.
In the present invention, the halogen represents at least one element selected from the group consisting of fluorine, chlorine, bromine and iodine.
“C1-8Alkyl of (A) represents carbonThe alkyl group having 1 to 8 atoms may be, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclopentyl group, a methylcyclopentyl group, a cyclohexyl group, an n-heptyl group, or an n-octyl group.
"C substituted by 1-4 halogens1-6The "alkyl group of (1)" represents an alkyl group having 1 to 6 carbon atoms, and 1 to 4H's on the alkyl group are substituted with a halogen.
“C1-6The "alkyl group" in (1) represents an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclopentyl group, a methylcyclopentyl group, and a cyclohexyl group.
"C substituted by 1-4 halogens1-4The "alkyl group of (1)" represents an alkyl group having 1 to 4 carbon atoms, and 1 to 4H's on the alkyl group are substituted with a halogen.
Preferably, in formula (I), R11、R12、R13、R14And R15Each independently selected from H, amino, nitro, F, Cl, Br, I, C1-6And C substituted by 1 to 3 halogens selected from F, Cl, Br and I1-4Alkyl group of (1).
"C substituted by 1-3 halogens selected from F, Cl, Br and I1-4The "alkyl group of (1)" represents an alkyl group having 1 to 4 carbon atoms, and 1 to 3H's on the alkyl group are substituted with a halogen selected from F, Cl, Br and I.
Preferably, in formula (I), R21Selected from H, amino, nitro, F, Cl, Br, I, C1-4And C substituted by 1 to 3 halogens selected from F, Cl, Br and I1-3Alkyl group of (1).
"C substituted by 1-3 halogens selected from F, Cl, Br and I1-3The "alkyl group of (1)" represents an alkyl group having 1 to 3 carbon atoms, and 1 to 3H's on the alkyl group are substituted with a halogen selected from F, Cl, Br and I.
Preferably, in formula (I), R31、R32、R33And R34Each is independentThe three sites are selected from H, amino, nitro, F, Cl, Br, I and C1-6And C substituted by 1 to 3 halogens selected from F, Cl, Br and I1-4Alkyl group of (1).
Preferably, in formula (I), n is an integer of 0 to 4, more preferably n is 0,1, 2 or 3.
According to a preferred embodiment, in formula (I), R11、R12、R13、R14And R15Each independently selected from H, amino, nitro, F, Cl, Br, I, C1-6And C substituted by 1 to 3 halogens selected from F, Cl, Br and I1-4Alkyl groups of (a);
R21selected from H, F, Cl, Br, I, C1-4And C substituted by 1 to 3 halogens selected from F, Cl, Br and I1-3Alkyl groups of (a);
R31、R32、R33and R34Each independently selected from H, amino, nitro, F, Cl, Br, I, C1-6And C substituted by 1 to 3 halogens selected from F, Cl, Br and I1-4Alkyl groups of (a); and
n is an integer of 0 to 4.
According to another preferred embodiment, the pyrazinamide-based compound is at least one of:
compound 1: r11Is F; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 2: r11Is Cl; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 3: r11Is Br; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 4: r11、R12、R14And R15Is H, R13Is F; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 5: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 6: r11Is Cl, R13Is CF3，R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 7: r11Is Cl, R13Is F, R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 8: r11And R12Is F, R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 9: r12、R13And R14Is F, R11、R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 10: r11Is F, R12、R13、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 11: r11Is Cl, R12、R13、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 12: r11Is Br, R12、R13、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 13: r13Is F, R11、R12、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 14: r11And R13Is Cl, R12、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 15: r11Is Cl, R13Is CF3，R12、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 16: r11Is Cl, R13Is F, R12、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 17: r11And R12Is F, R13、R14And R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 18: r12、R13And R14Is F, R11、R15Is H; r21Is Cl; r31、R32、R33And R34Are both H, and n is 0;
compound 19: r11Is Br; r12、R13、R14And R15Is H; r21Is CHF2；R31、R32、R33And R34Are both H, and n is 0;
compound 20: r11And R13Is Cl, R12、R14And R15Is H; r21Is CHF2；R31、R32、R33And R34Are both H, and n is 0;
compound 21: r11Is Cl, R13Is CF3，R12、R14And R15Is H; r21Is CHF2；R31、R32、R33And R34Are both H, and n is 0;
compound 22: r11Is Cl, R13Is F, R12、R14And R15Is H; r21Is CHF2；R31、R32、R33And R34Are both H, and n is 0;
compound 23: r12、R13And R14Is F, R11、R15Is H; r21Is CHF2；R31、R32、R33And R34Are both H, and n is 0;
compound 24: r11Is NO2，R13Is F, R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 25: r11Is Cl, R13Is NH2，R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 26: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R33Is CH3，R31、R32And R34Are both H, and n is 0;
compound 27: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R33is-CH (CH)3)2，R31、R32And R34Are both H, and n is 0;
compound 28: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R32Is CH3，R31、R33And R34Are both H, and n is 0;
compound 29: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R32And R33Is CH3，R31And R34Are both H, and n is 0;
compound 30: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R32Is Cl, R33Is CH3，R31And R34Are both H, and n is 0;
compound 31: r11Is F; r12、R13、R14And R15Is H; r21Is CF3；R33Is NO2，R31、R32And R34Are both H, and n is 0;
compound 32: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R33Is NH2，R31、R32And R34Are both H, and n is 0;
compound 33: r11Is F; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are all H, and n is 1;
compound 34: r11Is Br; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are all H, and n is 1;
compound 35: r11Is F; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are all H, and n is 1;
compound 36: r11Is F; r13Is F; r12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are all H, and n is 1;
compound 37: r11Is Cl; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 3.
Second aspect of the inventionThe invention provides a method for preparing a pyrazinamide compound, wherein the pyrazinamide compound has a structure shown in a formula (I), and the method comprises the following steps: contacting a compound represented by the formula (II-1) with a compound represented by the formula (II-2);
Figure BDA0001152927600000061
wherein R is11、R12、R13、R14、R15、R21、R31、R32、R33、R34And n is as defined above in the invention.
The substituents of the pyrazinamide compounds having the structure represented by formula (I) related in the second aspect and the following aspects of the present invention are the same as those of the pyrazinamide compounds described in the first aspect of the present invention, and in order to avoid repetition, specific types of pyrazinamide compounds are not described in detail in the present invention, and those skilled in the art should not be construed as limiting the present invention.
In the compound represented by the formula (II-1) and the compound represented by the formula (II-2) of the present invention, the substituents correspond to the same substituents in the pyrazinamide-based compound having the structure represented by the formula (I).
The method of the present invention is not particularly limited with respect to the source of the compound represented by the formula (II-1) and the compound represented by the formula (II-2), and the compounds may be obtained commercially, or the synthesis may be designed by selecting a synthetic method which is conventional in the art according to the difference of substituents.
Preferably, the method for preparing pyrazinamide compounds according to the present invention further comprises preparing a compound represented by formula (II-1) according to the following steps:
(1) in the presence of sodium azide and a palladium-carbon catalyst, carrying out first contact on a compound shown as a formula (II-3) and ethylenediamine hydrochloride to obtain a compound shown as a formula (II-4);
(2) carrying out second contact on the compound shown in the formula (II-4) and lithium hydroxide;
Figure BDA0001152927600000062
wherein R in the formula (II-3) and the formula (II-4)21As defined above in the present invention.
The "first contact" and the "second contact" are merely for distinguishing the contact process of different raw materials.
Preferably, the conditions of the first contacting include: the temperature is 0-120 ℃ and the time is 0.5-48 h.
Preferably, the first contacting is carried out in the presence of at least one solvent selected from the group consisting of ethyl acetate and water.
The molar ratio of the compound shown in the formula (II-3) to the ethylenediamine hydrochloride and the sodium azide can be 1: (0.8-2.4): (1-10).
The amount of the palladium on carbon catalyst is not particularly limited and may be a catalytic amount conventionally used in the art.
Preferably, the step of first contacting the compound represented by the formula (II-3) with ethylenediamine hydrochloride comprises: mixing sodium azide with water and ethylenediamine hydrochloride, adding an ethyl acetate solution in which a compound shown as a formula (II-3) is dissolved, adding a palladium carbon catalyst, stirring at 0-50 ℃ for 0.5-4h, heating to 5-50 ℃ for reaction for 0.5-4h, and finally reacting under a reflux condition for 0.2-40 h.
Preferably, the compound represented by the formula (II-4) obtained by first contacting the compound represented by the formula (II-3) with ethylenediamine hydrochloride is subjected to a post-treatment by a post-treatment means conventionally used in the art, and then introduced into the next step to react with lithium hydroxide.
According to a preferred embodiment, the compound of formula (II-1) is prepared by a process scheme according to formula 1, in particular: carrying out substitution reaction on the compound shown in the formula (II-5) to obtain a compound shown in a formula (II-3); further, in the presence of sodium azide and a palladium carbon catalyst, carrying out cyclization reaction on the compound shown in the formula (II-3) and ethylenediamine hydrochloride to obtain a compound shown in a formula (II-4); further, the compound represented by the formula (II-4) is subjected to hydrolysis to obtain a compound represented by the formula (II-1). Wherein, the substituents in the compounds of the formula (II-3), the formula (II-4) and the formula (II-5) are the same as the substituents in the compound of the formula (II-1).
Reaction formula 1:
Figure BDA0001152927600000071
preferably, the step of second contacting the compound represented by the formula (II-4) with lithium hydroxide comprises: and (2) carrying out second contact on the compound shown in the formula (II-4) and lithium hydroxide in the presence of tetrahydrofuran and water, wherein the conditions of the second contact comprise: the temperature is 0-50 ℃ and the time is 0.1-4 h. Preferably, the molar ratio of the compound shown in the formula (II-4) to the lithium hydroxide is 1: (1-8). The product obtained after the second contact of the compound of the formula (II-4) with lithium hydroxide is preferably adjusted to a pH of 1 to 6 with hydrochloric acid, then extracted and isolated to give the compound of the formula (II-1).
According to a preferred embodiment, when n is 0, the compound of formula (II-2) is prepared by the process scheme shown in scheme 2, in particular: contacting a compound represented by the formula (I-1) with a compound represented by the formula (I-2) to obtain a compound represented by the formula (I-3); further, the compound represented by the formula (I-3) is reduced to obtain a compound represented by the formula (II-2). Wherein, the substituents in the formula (I-1), the formula (I-2) and the formula (I-3) are the same as the substituents in the compound shown in the formula (II-2).
Reaction formula 2:
Figure BDA0001152927600000072
according to another preferred embodiment, when R11Is Cl, R13Is CF3，R12、R14And R15When n is 0, the compound represented by the formula (II-2) can be prepared by a process route shown in the reaction formula 3, specifically: contacting the compound represented by the formula (I-4) with the compound represented by the formula (I-5) to obtain the compound represented by the formula (II-2). Wherein R is31、R32、R33And R34The definitions of (A) are the same as above.
Reaction formula 3:
Figure BDA0001152927600000081
preferably, the conditions for contacting the compound represented by the formula (II-1) with the compound represented by the formula (II-2) include: the temperature is 0-60 ℃ and the time is 1-72 h.
More preferably, the step of contacting the compound represented by the formula (II-1) with the compound represented by the formula (II-2) comprises: reacting the compound represented by the formula (II-1) in N, N-Dimethylformamide (DMF) at 0-60 ℃ for 0.5-4h in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt), adding the compound represented by the formula (II-2) into the system, and continuing the reaction for 10-68 h.
According to another preferred embodiment, when said n is 1, said compound of formula (II-2) is prepared by the process scheme shown in scheme 4, in particular: contacting a compound represented by the formula (I-6) with a compound represented by the formula (I-2) to obtain a compound represented by the formula (I-8); further, the compound represented by the formula (I-8) is reduced to obtain a compound represented by the formula (II-2). Wherein, the substituents in the formula (I-6), the formula (I-2) and the formula (I-8) are the same as the substituents in the compound shown in the formula (II-2).
Reaction formula 4:
Figure BDA0001152927600000082
according to another preferred embodiment, when n is a positive integer > 1, the compound of formula (II-2) is prepared by a process scheme shown in scheme 5, in particular: contacting a compound represented by the formula (I-9) with a compound represented by the formula (I-2) to obtain a compound represented by the formula (I-10); further, contacting the compound represented by the formula (I-10) with hydroxylamine hydrochloride to obtain a compound represented by the formula (I-11); then reacting the compound represented by the formula (I-11) in the presence of metallic zinc to produce a compound represented by the formula (II-2). Wherein the substituents in formula (I-9), formula (I-2), formula (I-10) and formula (I-11) are the same as the substituents in the compound represented by formula (II-2), and m ═ n-1.
Reaction formula 5:
Figure BDA0001152927600000091
third aspect of the inventionThe invention provides a pyrazinamide compound prepared by the method.
Fourth aspect of the inventionThe invention provides application of the pyrazinamide compound as a succinate dehydrogenase inhibitor.
Preferably, in the application of the invention, the pyrazinamide-based compound can be used for resisting plant fungal diseases.
Preferably, the plant fungal disease is at least one of rice sheath blight disease, cucumber gray mold, cucumber downy mildew and cucumber powdery mildew.
Fifth aspect of the inventionThe invention provides a bactericide which is composed of an active ingredient and an auxiliary material, wherein the active ingredient comprises at least one of the pyrazinamide compounds.
Preferably, in the bactericide, the active ingredient is contained in an amount of 1 to 99.9% by weight; more preferably 5 to 95 wt%.
Preferably, the dosage form of the bactericide is at least one selected from emulsifiable solution, suspending agent, wettable powder, granules, aqueous solution, poison bait, mother liquor and mother powder.
In the present invention, the adjuvant may be various adjuvants conventionally used in the art, and may be, for example, a surfactant, a solvent, etc.
The present invention will be described in detail below by way of examples.
In the following examples, the various starting materials used are commercially available in chemical purity, unless otherwise specified.
Preparation example 1: a compound represented by the formula (II-3) wherein R is prepared according to the reaction formula 121Is trifluoromethyl
Ethyl trifluoroacetoacetate (50mmol) is added into a 100mL round-bottom flask, sulfonyl chloride (55mmol) is slowly dropped at the temperature of 0 ℃, the reaction is stopped after stirring and reacting for 12h at the temperature of 25 ℃, 200mL ethyl acetate is added for extraction, an organic phase is washed by saturated saline, dried by anhydrous sodium sulfate, and a transparent liquid (the yield is 90 percent) is obtained after removing a solvent under reduced pressure and is directly put into the next reaction without further purification.
Preparation example 2: a compound represented by the formula (II-4) wherein R is prepared according to the reaction formula 121Is trifluoromethyl
4mL of water and 16.5mmol of ethylenediamine hydrochloride were added to a 100mL round-bottom flask, sodium azide (27.3mmol) was slowly added, 8mL of an ethyl acetate solution in which the intermediate (13.7mmol) obtained in preparation example 1 was dissolved was slowly added dropwise, 0.68g of a 10 wt% palladium-carbon catalyst and 2mL of ethyl acetate were added, the mixture was stirred at 25 ℃ for 2 hours, the mixture was heated to 35 ℃ for 1 hour, then the reaction was stopped after refluxing for 2 hours, celite was filtered, 50mL of ethyl acetate was added for extraction, the organic phase was washed with saturated brine, anhydrous sodium sulfate was dried, and the solvent was removed under reduced pressure to obtain a yellow solid (yield 60%), which was directly put into the next reaction without further purification.
Preparation example 3: a compound represented by the formula (II-1) wherein R is prepared according to the reaction formula 121Is trifluoromethyl
The intermediate (2mmol) prepared in preparation example 2 was added to a 100mL round bottom flask, lithium hydroxide monohydrate (4mmol) was added, 10mL tetrahydrofuran and 10mL water were added, the reaction was stopped after 0.5h at 25 ℃, pH was adjusted to 4 with 2M hydrochloric acid, 50mL ethyl acetate was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a yellow solid (yield 84%) which was directly put to the next reaction without further purification.
A compound represented by the formula (II-1) in the reaction scheme 1, wherein R is21Is difluoromethyl. The production method differs from the aforementioned production examples 1 to 3 in that the raw materials used in production example 1 are different. To obtain a compound represented by the formula (II-1), wherein R21Is difluoromethyl for use.
Preparation example 4: a compound represented by the formula (I-3) wherein the substituents are respectively as shown in Table 1 was prepared according to the reaction scheme 2
A50 mL round-bottom flask was charged with 7.1mmol of substituted 2-fluoronitrobenzene represented by the formula I-1 (specific substituents are shown in Table 1), 10.6mmol of substituted phenol represented by the formula I-2 (specific substituents are shown in Table 1) and 10.6mmol of potassium carbonate, and then 20mL of DMF was added and the temperature was raised to 100 ℃. TLC monitored that the reaction of the starting materials was complete and stopped, 50mL of diethyl ether was added, washed twice with 30mL of 2M NaOH and then with 50mL of saturated brine 1 time, and the solvent was removed under reduced pressure to give 2-nitrodiphenyl ether in the yields shown in Table 1.
TABLE 1
Figure BDA0001152927600000101
Wherein the structures of the different compounds represented by the different substituents with different numbers in table 1 are characterized as follows:
number 1:1H NMR(600MHz,CDCl3):δ7.98(dd,J＝8.4,1.8Hz,1H),7.54-7.44(m,1H),7.24-7.18(m,3H),7.19-7.11(m,2H),6.92(d,J＝8.4Hz,1H).
Figure BDA0001152927600000111
sequence number 2:1H NMR(600MHz,CDCl3):δ7.98(dd,J＝8.4,1.8Hz,1H),7.48(dd,J＝7.8,1.2Hz,2H),7.28(td,J＝7.8,1.8Hz,1H),7.23-7.14(m,1H),7.07(dd,J＝7.8,1.2Hz,1H),6.83(dd,J＝8.4,0.6Hz,1H).
Figure BDA0001152927600000112
sequence No. 3:1H NMR(600MHz,CDCl3):δ8.00(d,J＝8.4Hz,1H),7.67(d,J＝8.4Hz,1H),7.56-7.46(m,1H),7.36-7.31(m,1H),7.24-7.18(m,1H),7.12(td,J＝7.8,1.2Hz,1H),7.06(d,J＝7.8Hz,1H),6.85(d,J＝8.4Hz,1H).
Figure BDA0001152927600000113
number 4: mp is 32-34 deg.c,1H NMR(600MHz,CDCl3):δ7.95(d,J＝8.4Hz,1H),7.50(t,J＝8.4Hz,1H),7.20(t,J＝7.8Hz,1H),7.08(t,J＝7.8Hz,2H),7.05-7.00(m,2H),6.97(d,J＝8.4Hz,1H).
Figure BDA0001152927600000114
number 5: mp is 56-57 deg.C,1H NMR(600MHz,CDCl3):δ8.00(d,J＝7.8Hz,1H),7.64-7.39(m,2H),7.25(s,2H),7.00(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H).
Figure BDA0001152927600000115
number 6: mp is 40-42 ℃.1H NMR(600MHz,CDCl3):δ7.97(dd,J＝8.4,1.2Hz,1H),7.54-7.43(m,1H),7.24(dd,J＝7.8,3.0Hz,1H),7.22-7.17(m,1H),7.08(dd,J＝9.0,4.8Hz,1H),7.05-6.98(m,1H),6.79(dd,J＝8.4,0.6Hz,1H).
Figure BDA0001152927600000116
Number 7: mp is 59-61 deg.C,1H NMR(600MHz,CDCl3):δ8.00(d,J＝8.4Hz,1H),7.62-7.44(m,1H),7.30-7.23(m,1H),7.12-7.02(m,2H),7.00(d,J＝8.4Hz,1H),6.86(t,J＝7.2Hz,1H).GC-MS:m/z 251[M]+.
Figure BDA0001152927600000121
number 8:1H NMR(600MHz,CDCl3):δ8.02(dd,J＝8.4,1.2Hz,1H),7.72-7.56(m,1H),7.43-7.30(m,1H),7.14(d,J＝8.4Hz,1H),6.65(dd,J＝8.4,5.4Hz,2H).GC-MS:m/z 269[M]+.
Figure BDA0001152927600000122
number 9:1H NMR(500MHz,DMSO)δ7.94(s,1H),7.80(s,1H),7.53(d,J＝8.3Hz,1H),7.44(d,J＝8.7Hz,1H),7.12(d,J＝8.7Hz,1H),7.05(d,J＝8.2Hz,1H),2.39(s,3H).GC-MZ:m/z 297[M+].
Figure BDA0001152927600000123
number 10:1H NMR(500MHz,DMSO):δ8.22(s,1H),7.74(s,1H),7.45(s,1H),7.23(m,2H),6.88(s,1H),2.87(m,1H),1.20(s,6H).
Figure BDA0001152927600000124
number 11:1H NMR(500MHz,DMSO):δ8.08(s,1H),7.45(s,1H),7.23-7.15(m,3H),6.88(dd,J＝7.8,1.2Hz,1H),2.28(s,3H).
Figure BDA0001152927600000125
number 12:1H NMR(500MHz,DMSO):δ8.01(dd,J＝8.4,1.8Hz,1H),7.45(s,1H),7.23(m,1H),7.10(dd,J＝7.8,1.2Hz,1H),6.88(s,1H),2.26(s,3H),2.17(s,3H).
Figure BDA0001152927600000126
number 13:1H NMR(500MHz,DMSO):δ8.01(dd,J＝8.4,1.8Hz,1H),7.55(s,1H),7.45(s,1H),7.23(dd,J＝7.8,1.2Hz,1H),6.88(s,1H),2.26(s,3H).
Figure BDA0001152927600000127
preparation example 5: a compound represented by the formula (II-2) was prepared according to reaction formula 2, wherein the substituents are respectively shown in Table 1, and n is 0
Respectively adding 3.2mmol of the intermediate prepared in preparation example 4 and ammonium chloride (3.2mmol) into a 100mL round-bottom flask, adding 50mL of ethanol and 6mL of water, heating to reflux, adding reduced iron powder (9.6mmol), stopping reaction after TLC (thin layer chromatography) monitoring that the raw materials react, filtering by using kieselguhr, concentrating the filtrate under reduced pressure, removing most of the solvent, adding 50mL of ethyl acetate for extraction, washing the organic phase by using saturated saline, adding anhydrous sodium sulfate for drying, and removing the solvent to obtain the product, wherein the structure of each product is characterized as follows.
Wherein the structures of the different compounds represented by the different substituents with different numbers in table 1 are characterized as follows:
number 1:1H NMR(600MHz,CDCl3):δ7.22-7.12(m,1H),7.05(dd,J＝6.0,3.0Hz,2H),7.00-6.93(m,2H),6.85(dd,J＝8.4,1.8Hz,1H),6.79(d,J＝7.8Hz,1H),6.75-6.67(m,1H),4.04(br,2H).
Figure BDA0001152927600000131
sequence number 2:1H NMR(600MHz,CDCl3)δ7.43(dd,J＝8.4,1.8Hz,1H),7.19-7.12(m,1H),7.02(td,J＝7.8,1.2Hz,1H),6.98(td,J＝7.8,1.2Hz,1H),6.88(dd,J＝8.4,1.2Hz,1H),6.85(dd,J＝7.8,1.2Hz,1H),6.79(dd,J＝7.8,1.2Hz,1H),6.74-6.68(m,1H),3.97(br,2H).
Figure BDA0001152927600000132
sequence No. 3:1H NMR(600MHz,CDCl3):δ7.61(dd,J＝7.8,1.8Hz,1H),7.25-7.16(m,1H),6.99(dd,J＝7.8,1.2Hz,1H),6.97(dd,J＝7.8,1.2Hz,1H),6.90-6.77(m,3H),6.72(td,J＝7.8,1.2Hz,1H),3.77(br,2H).
Figure BDA0001152927600000133
number 4:1H NMR(400MHz,CDCl3):δ7.11-6.96(m,3H),6.94-6.90(m,2H),6.83(dd,J＝12.8,8.0Hz,2H),6.72(t,J＝7.6Hz,1H),3.98(br,2H).
Figure BDA0001152927600000134
number 5:1H NMR(600MHz,CDCl3)δ7.45(s,1H),7.13(d,J＝9.0Hz,1H),7.00(t,J＝7.8Hz,1H),6.85(d,J＝7.8Hz,1H),6.80(t,J＝9.0Hz,1H),6.72(t,J＝7.8Hz,1H),3.93(br,2H).
Figure BDA0001152927600000135
number 6:1H NMR(600MHz,CDCl3):δ7.19(dd,J＝8.4,3.0Hz,1H),7.01-6.95(m,2H),6.95-6.88(m,2H),6.81-6.74(m,1H),6.69(d,J＝8.4Hz,1H),5.20(br,2H).GC-MS:m/z 237[M]+.
Figure BDA0001152927600000141
number 7:1H NMR(600MHz,CDCl3)δ7.00(td,J＝7.8,1.2Hz,1H),6.98-6.92(m,1H),6.91-6.86(m,1H),6.86-6.80(m,2H),6.72(td,J＝7.8,1.2Hz,1H),6.70-6.64(m,1H),3.92(br,2H).GC-MS:m/z 221[M]+.
Figure BDA0001152927600000142
number 8:1H NMR(600MHz,CDCl3):δ7.19-7.12(m,1H),7.09(td,J＝7.8,1.2Hz,1H),7.03-6.96(m,1H),6.90(dd,J＝8.4,1.2Hz,1H),6.64(dd,J＝8.4,6.0Hz,2H).GC-MS:m/z239[M]+.
Figure BDA0001152927600000143
number 9:1H NMR(500MHz,DMSO)δ7.66(s,1H),7.30(d,J＝8.7Hz,1H),6.70(d,J＝8.7Hz,1H),6.65(s,2H),6.37(d,J＝7.6Hz,1H),4.87(s,2H),2.19(s,3H).GC-MZ:m/z 268[M+].
Figure BDA0001152927600000144
number 10:1H NMR(500MHz,DMSO):δ7.45(s,1H),7.23(s,1H),6.99(s,1H),6.88-6.81(m,3H),5.27(s,2H),2.87(m,1H),1.20(s,6H).
Figure BDA0001152927600000145
number 11:1H NMR(500MHz,DMSO):δ7.45(s,1H),7.23(s,1H),6.88(dd,J＝7.8,1.2Hz,1H),6.76-6.72(s,3H)5.27(s,2H),2.28(s,3H).
Figure BDA0001152927600000146
number 12:1H NMR(500MHz,DMSO):δ7.45(s,1H),7.23(s,1H),6.88(m,1H),6.78(s,1H)6.69(s,1H),5.27(s,2H),2.21(s,3H),2.17(s,3H).
Figure BDA0001152927600000147
number 13:1H NMR(500MHz,DMSO):δ7.45(s,1H),7.23(s,1H),7.14(s,1H),6.88(dd,J＝7.8,1.2Hz,1H),6.77(s,1H),5.27(s,2H),2.26(s,3H).
Figure BDA0001152927600000151
preparation example 6: a compound represented by the formula (II-2) wherein n is 0 and R is prepared according to the reaction scheme 331、R32、R33And R34Are all H
Adding 3mmol of 1-chloro-4-trifluorotoluene, 3.3mmol of 2-aminophenol shown in formula I-4 and 3.6mmol of potassium carbonate into a 50mL round-bottom flask, adding 20mL of DMF, heating to 70 ℃, stopping the reaction after TLC monitors that the raw materials react completely, adding 50mL of ethyl acetate, washing with 50mL of saturated common salt water twice respectively, adding anhydrous sodium sulfate for drying, removing the solvent under reduced pressure, and performing column chromatography to obtain a compound shown in formula (II-2) in reaction formula 3 (yield 70%). The structure and structural characterization of the resulting compound are as follows:
1H NMR(600MHz,CDCl3)δ7.69(d,J＝1.2Hz,1H),7.33(d,J＝8.4Hz,1H),7.08-6.95(m,1H),6.85(dd,J＝8.4,0.6Hz,1H),6.82(d,J＝9.0Hz,1H),6.78(d,J＝7.8Hz,1H),6.74-6.67(m,1H),3.76(br,2H).GC-MS:m/z 287[M]+.
Figure BDA0001152927600000152
preparation example 7: the compound represented by the formula (I-8) was prepared according to reaction formula 4, and the substituents are respectively shown in Table 2
A100 mL round-bottom flask was charged with 4mmol of the substituted 2-fluorobenzaldehyde represented by the formula I-6, 6mmol of the substituted phenol represented by the formula I-2 and 8mmol of anhydrous potassium carbonate, and then 10mL of DMF was added and the temperature was raised to 100 ℃. TLC monitored that the reaction was complete, the reaction was stopped, 50mL of diethyl ether was added, washed twice with 30mL of 2M NaOH and then with 50mL of saturated brine 1 time, and the solvent was removed under reduced pressure to give the compound represented by formula I-8 in the yield shown in Table 2.
TABLE 2
Figure BDA0001152927600000153
Wherein, the structures of different compounds represented by different substituents with different numbers in table 2 are characterized as follows:
number 1:1H NMR(600MHz,DMSO)δ10.48(s,1H),7.86(d,J＝7.7Hz,1H),7.68–7.63(m,1H),7.46(t,J＝8.8Hz,1H),7.36–7.27(m,4H),6.87(d,J＝8.3Hz,1H).GC-MZ:m/z 216[M+].
Figure BDA0001152927600000154
sequence number 2:1H NMR(600MHz,DMSO)δ10.48(s,1H),7.87(d,J＝7.7Hz,1H),7.81(d,J＝8.0Hz,1H),7.65(t,J＝7.8Hz,1H),7.48(t,J＝7.7Hz,1H),7.32–7.23(m,3H),6.78(d,J＝8.4Hz,1H).GC-MZ:m/z 276[M+].
Figure BDA0001152927600000161
sequence No. 3:1H NMR(600MHz,DMSO)δ10.41(s,1H),7.85(d,J＝7.7Hz,1H),7.66(t,J＝7.7Hz,1H),7.30(t,J＝8.5Hz,3H),7.22(d,J＝4.4Hz,2H),6.91(d,J＝8.4Hz,1H).GC-MZ:m/z 216[M+].
Figure BDA0001152927600000162
number 4:1H NMR(600MHz,DMSO)δ10.48(s,1H),7.86(d,J＝6.9Hz,1H),7.72–7.67(m,1H),7.64(t,J＝7.3Hz,1H),7.41(dd,J＝8.8,5.3Hz,1H),7.34(dd,J＝11.4,5.5Hz,1H),7.28(t,J＝7.5Hz,1H),6.77(d,J＝8.3Hz,1H).GC-MZ:m/z 250[M+].
Figure BDA0001152927600000163
preparation example 8: a compound represented by the formula (II-2) wherein the substituents are respectively as shown in Table 2 and n is 1 was prepared according to reaction formula 4
Adding 2mmol of the compound shown in the formula I-8 and hydroxylamine hydrochloride (3mmol) into a 100mL round-bottom flask, adding 10mL of ethanol, heating to reflux, reacting for 0.5h, cooling to 25 ℃, adding zinc powder (5mmol), slowly dropwise adding concentrated hydrochloric acid (0.67mL), stopping the reaction after the raw material reaction is monitored by TLC, filtering by using kieselguhr, concentrating the filtrate under reduced pressure, removing most of the solvent, adding 50mL of ethyl acetate for extraction, washing the organic phase by using saturated saline solution, adding anhydrous sodium sulfate for drying, removing the solvent, and performing column chromatography to obtain the product, wherein the structure of each product is characterized as follows.
Wherein, the structures of different compounds represented by different substituents with different numbers in table 2 are characterized as follows:
number 1:1H NMR(500MHz,DMSO)δ7.54(d,J＝6.9Hz,1H),7.37(d,J＝8.9Hz,1H),7.23–7.11(m,4H),7.01(s,1H),6.74(d,J＝7.7Hz,1H),3.77(s,2H).GC-MZ:m/z 216[M+].
Figure BDA0001152927600000164
sequence number 2:1H NMR(500MHz,DMSO)δ7.55(d,J＝5.0Hz,1H),7.35(t,J＝6.8Hz,2H),7.23(d,J＝6.8Hz,1H),7.17(d,J＝6.9Hz,1H),7.09(d,J＝6.1Hz,1H),6.91(d,J＝7.2Hz,1H),6.86(d,J＝8.9Hz,1H),3.69(s,2H).GC-MZ:m/z 278[M+].
Figure BDA0001152927600000165
sequence No. 3:1H NMR(500MHz,DMSO)δ7.53(d,J＝7.1Hz,1H),7.20(dt,J＝18.3,7.8Hz,4H),7.00–6.94(m,2H),6.82(d,J＝7.8Hz,1H),3.71(s,2H).GC-MZ:m/z 216[M+].
Figure BDA0001152927600000171
number 4:1H NMR(500MHz,DMSO)δ7.60(d,J＝8.2Hz,1H),7.54(d,J＝6.9Hz,1H),7.26–7.17(m,2H),7.15(d,J＝6.9Hz,1H),7.08–7.00(m,1H),6.67(d,J＝7.8Hz,1H),3.76(s,2H).GC-MZ:m/z250[M+].
Figure BDA0001152927600000172
preparation example 9: a compound of the following structure was prepared according to equation 5:1H NMR(500MHz,DMSO):δ7.35-7.16(m,5H),6.99-6.06(m,3H),2.68-2.63(m,4H),2.09(m,2H),1.50(s,2H).
Figure BDA0001152927600000173
preparation example 10: preparation of a Compound of formula (I)
A100 mL round-bottomed flask was charged with the compound represented by the formula (II-1) (2mmol), EDCI (2.4mmol), HOBt (2.4mmol) and 10mL of DMF, and reacted at 25 ℃ for 1 hour. Then adding the compound (2.4mmol) shown in the formula (II-2) into the solution, reacting at 25 ℃ for 24h, removing the solvent, and carrying out column chromatography to obtain the target product.
Specifically, the structures and characterization data for compound 1-compound 37 are as follows:
compound 1: the yield is 50%, mp is 128-.1H NMR(500MHz,CDCl3) δ 10.15(s,1H),8.84(s,1H),8.78(s,1H),8.65(d, J ═ 8.0Hz,1H), 7.24-7.11 (m,5H),7.06(t, J ═ 7.7Hz,1H),6.80(d, J ═ 8.1Hz,1H), hrms (maldi) calculated value C18H11F4N3O2[M+H]+378.08602, found: 378.08420.
Figure BDA0001152927600000174
compound 2: the yield is 48%, mp ═ 126-.1H NMR(500MHz,CDCl3) δ 10.15(s,1H),8.85(s,1H),8.79(s,1H),8.66(d, J ═ 7.6Hz,1H), 7.23-7.12 (m,5H),7.08(d, J ═ 7.2Hz,1H),6.81(d, J ═ 8.0Hz,1H), hrms (maldi) calcd C18H11ClF3N3O2[M+Na]+416.03841, found:416.04089.
Figure BDA0001152927600000181
compound 3: the yield is 32%, mp is 108-.1H NMR(500MHz,CDCl3) δ 10.20(s,1H),8.86(s,1H),8.81(s,1H),8.69(d, J ═ 7.7Hz,1H),7.68(d, J ═ 7.2Hz,1H),7.32(t, J ═ 7.2Hz,1H),7.22(t, J ═ 7.2Hz,1H), 7.15-7.04 (m,3H),6.84(d, J ═ 7.6Hz,1H), hrms (maldi) calculated value: c18H11BrF3N3O2[M+H]+438.00595, found: 438.00332.
Figure BDA0001152927600000182
compound 4: the yield was 39%, mp is 85-86.1H NMR(500MHz,CDCl3) δ 10.05(s,1H),8.84(s,1H),8.76(s,1H),8.64(d, J ═ 8.0Hz,1H),7.16(t, J ═ 7.5Hz,1H), 7.11-7.04 (m,5H),6.83(d, J ═ 8.1Hz,1H), hrms (maldi) calculated value C18H11F4N3O2[M+Na]+400.06796, found: 400.06666.
Figure BDA0001152927600000183
compound 5: the yield is 40%, mp is 103 and 104.1H NMR(500MHz,CDCl3) δ 10.11(s,1H),8.85(s,1H),8.78(s,1H),8.65(d, J ═ 8.0Hz,1H),7.50(s,1H),7.21(t, J ═ 8.8Hz,2H),7.10(t, J ═ 7.5Hz,1H),7.00(d, J ═ 8.6Hz,1H),6.81(d, J ═ 8.0Hz,1H), hrms (maldi) calculated values: c18H10Cl2F3N3O2[M+H]+428.01749, found: 428.01690.
Figure BDA0001152927600000184
compound 6: the yield thereof was found to be 39%, and mp was 88-89.1H NMR(500MHz,CDCl3)δ10.10(s,1H),8.87(s,1H),8.78(s,1H),8.69(d,J ═ 7.5Hz,1H),7.79(s,1H),7.50(d, J ═ 8.1Hz,1H),7.30(s,1H),7.18(s,1H),7.09(d, J ═ 8.3Hz,1H),6.97(d, J ═ 7.5Hz,1H), hrms (maldi) calcd for C19H10ClF6N3O2[M+H]+462.04385, found 462.04126.
Figure BDA0001152927600000185
Compound 7: the yield thereof was found to be 56%, mp being 107-.1H NMR(500MHz,CDCl3) δ 10.14(s,1H),8.86(s,1H),8.80(s,1H),8.66(d, J ═ 7.9Hz,1H),7.26(s,1H),7.18(t, J ═ 7.1Hz,1H),7.08(d, J ═ 5.9Hz,2H),7.00(t, J ═ 7.9Hz,1H),6.73(d, J ═ 7.9Hz,1H), hrms (maldi) calculated values: c18H10ClF4N3O2[M+H]+412.04704, found: 412.04542.
Figure BDA0001152927600000191
compound 8: the yield was 38%, mp 105-.1H NMR(500MHz,CDCl3) δ 10.07(s,1H),8.83(s,1H),8.77(s,1H),8.62(d, J ═ 7.9Hz,1H),7.18(d, J ═ 7.5Hz,1H),7.09(t, J ═ 7.5Hz,1H),7.00(dd, J ═ 15.0,6.5Hz,2H),6.87(d, J ═ 7.5Hz,2H), hrms (maldi) calcd C calcd for C18H10F5N3O2[M+H]+396.07659, found 396.07590.
Figure BDA0001152927600000192
Compound 9: the yield is 40%, mp is 145-.1H NMR(500MHz,CDCl3) δ 9.91(s,1H),8.86(s,1H),8.76(s,1H),8.65(d, J ═ 7.9Hz,1H),7.27(s,1H),7.17(d, J ═ 7.4Hz,1H),6.98(d, J ═ 7.8Hz,1H),6.71(s,2H) hrms (maldi) calcd C18H9F6N3O2[M+H]+414.06717, found 414.06562.
Figure BDA0001152927600000193
Compound 10: yield 51%, mp 123-.1H NMR(500MHz,CDCl3) δ 10.27(s,1H),8.66(d, J ═ 8.0Hz,1H),8.55(d, J ═ 10.0Hz,1H),8.52(s,1H),7.17(ddd, J ═ 15.0,12.8,5.5Hz,5H),7.05(t, J ═ 7.7Hz,1H),6.80(d, J ═ 8.0Hz,1H), hrms (hrmaldi) calculated value C17H11ClFN3O2[M+H]+344.05966, found 344.05887.
Figure BDA0001152927600000194
Compound 11: the yield was 47%, mp ═ 122-.1H NMR(500MHz,CDCl3) δ 10.27(s,1H),8.65(t, J ═ 11.2Hz,1H),8.56(s,1H),8.53(s,1H), 7.24-7.10 (m,5H),7.05(t, J ═ 7.7Hz,1H),6.80(d, J ═ 8.0Hz,1H), hrms (maldi) calcd for C17H11Cl2N3O2[M+Na]+382.01205, found 382.01484.
Figure BDA0001152927600000201
Compound 12: yield 62%, mp ═ 145-.1H NMR(500MHz,CDCl3) δ 10.29(s,1H),8.66(d, J ═ 7.9Hz,1H),8.55(s,1H),8.52(d, J ═ 1.3Hz,1H),7.64(d, J ═ 7.8Hz,1H), 7.31-7.26 (m,1H),7.19(t, J ═ 7.4Hz,1H), 7.10-7.00 (m,3H),6.82(d, J ═ 7.9Hz,1H), hrms maldi) calculated value C, m,1H17H11BrClN3O2[M+H]+403.97959, found 403.97728.
Figure BDA0001152927600000202
Compound 13: the yield was 41%, mp ═ 142-.1H NMR(500MHz,CDCl3) δ 10.18(s,1H),8.65(d, J ═ 8.0Hz,1H),8.56(s,1H),8.50(s,1H),7.16(t, J ═ 7.6Hz,1H), 7.09-7.02 (m,5H),6.83(d, J ═ 8.0Hz,1H), hrms (maldi) calcd for C17H11ClFN3O2[M+H]+344.05966, found 344.05836
Figure BDA0001152927600000203
Compound 14: the yield is 56%, mp is 133-.1H NMR(500MHz,CDCl3) δ 10.23(s,1H),8.66(d, J ═ 7.8Hz,1H),8.57(s,1H),8.52(s,1H),7.49(s,1H),7.22(d, J ═ 7.3Hz,2H),7.09(t, J ═ 7.3Hz,1H),6.98(d, J ═ 8.5Hz,1H),6.81(d, J ═ 7.8Hz,1H), hrms (maldi) calculated value C17H10Cl3N3O2[M+H]+393.99114, found 393.98919.
Figure BDA0001152927600000204
Compound 15: the yield was 65%, mp is 159-.1H NMR(500MHz,CDCl3) δ 10.20(s,1H),8.67(d, J ═ 8.0Hz,1H),8.57(s,1H),8.50(s,1H),7.76(s,1H),7.47(d, J ═ 8.4Hz,1H),7.29(d, J ═ 7.3Hz,1H),7.15(t, J ═ 7.4Hz,1H),7.05(d, J ═ 8.4Hz,1H),6.95(d, J ═ 7.9Hz,1H), hrms (maldi) calcd C (calculated value of d, J ═ 7.9Hz,1H)18H10Cl2F3N3O2[M+H]+428.01749, found 428.01427.
Figure BDA0001152927600000205
Compound 16: the yield is 39%, mp ═ 117-.1H NMR(500MHz,CDCl3) δ 10.27(s,1H),8.66(d, J ═ 7.9Hz,1H),8.57(s,1H),8.54(s,1H),7.26 to 7.22(m,1H),7.18(t, J ═ 7.5Hz,1H),7.06(d, J ═ 4.8Hz,2H),7.00(d, J ═ 8.0Hz,1H),6.73(d, J ═ 7.9Hz,1H), hrms (maldi) calculated value C17H10Cl2FN3O2[M+H]+378.02069, found 378.01909.
Figure BDA0001152927600000211
Compound 17: the yield was 41%, mp is 143-.1H NMR(500MHz,CDCl3) δ 10.22(s,1H),8.65(d, J ═ 8.0Hz,1H),8.58(s,1H),8.53(s,1H),7.21(t, J ═ 7.3Hz,1H),7.09(t, J ═ 7.4Hz,1H), 7.06-6.96 (m,2H), 6.91-6.82 (m,2H), hrms (maldi) calcd for C17H10ClF2N3O2[M+H]+362.05024, found 362.04896.
Figure BDA0001152927600000212
Compound 18: the yield was 37%, mp 173 ═ 175.1H NMR(500MHz,CDCl3) δ 10.05(s,1H),8.66(d, J ═ 8.1Hz,1H),8.58(s,1H),8.50(s,1H),7.28(d, J ═ 9.4Hz,1H),7.15(t, J ═ 7.5Hz,1H),6.98(d, J ═ 7.8Hz,1H),6.70(s,2H), hrms (maldi) calcd C17H9ClF3N3O2[M+H]+380.04082, found 380.03889.
Figure BDA0001152927600000213
Compound 19: the yield was 39%, mp being 91-93.1H NMR(500MHz,CDCl3) δ 10.58(s,1H),8.91(s,1H),8.72(s,1H),8.62(d, J ═ 8.0Hz,1H),8.04(t, J ═ 54.2Hz,1H),7.67(d, J ═ 7.7Hz,1H),7.30(t, J ═ 7.4Hz,1H),7.21(t, J ═ 7.4Hz,1H),7.08(dt, J ═ 17.8,7.9Hz,3H),6.83(d, J ═ 7.9Hz,1H), hrms (maldi) C calculated value C (dt, J ═ 17.8,7.9Hz,3H),6.83(d, J ═ 7.9Hz,1H)18H12BrF2N3O2[M+H]+420.01537, found 420.01481.
Figure BDA0001152927600000214
Compound 20: the yield was 33%, mp ═ 129-.1H NMR(500MHz,CDCl3) δ 10.52(s,1H),8.91(s,1H),8.72(s,1H),8.61(d, J ═ 8.1Hz,1H),8.02(t, J ═ 54.1Hz,1H),7.50(s,1H),7.22(dd, J ═ 12.2,5.7Hz,2H),7.10(t, J ═ 7.7Hz,1H),7.00(d, J ═ 8.6Hz,1H),6.81(d, J ═ 8.1Hz,1H), hrms (maldi) calculated value C18H11Cl2F2N3O2[M+H]+:410.02691Found 410.02564.
Figure BDA0001152927600000221
Compound 21: the yield thereof was found to be 43%, mp ═ 113-.1H NMR(500MHz,CDCl3) δ 10.47(s,1H),8.92(s,1H),8.70(s,1H),8.63(d, J ═ 8.0Hz,1H),8.01(t, J ═ 54.0Hz,1H),7.78(s,1H),7.48(d, J ═ 8.4Hz,1H),7.29(t, J ═ 7.4Hz,1H),7.17(t, J ═ 7.5Hz,1H),7.07(d, J ═ 8.3Hz,1H),6.95(d, J ═ 7.9Hz,1H), ms (maldi) calculated value C hrc (hrmaldi)19H11ClF5N3O2[M+H]+444.05327, found 444.05641.
Figure BDA0001152927600000222
Compound 22: the yield thereof was 33%, mp ═ 134 and 135.1H NMR(500MHz,CDCl3) δ 10.57(s,1H),8.92(s,1H),8.73(s,1H),8.61(d, J ═ 7.8Hz,1H),8.04(t, J ═ 54.1Hz,1H),7.27(s,1H),7.19(t, J ═ 7.3Hz,1H),7.08(t, J ═ 6.8Hz,2H),7.01(t, J ═ 8.1Hz,1H),6.73(d, J ═ 7.7Hz,1H), hrms (maldi) calculated C18H11ClF3N3O2[M+Na]+416.03841, found 416.03654.
Figure BDA0001152927600000223
Compound 23: the yield is 31 percent, and mp is 146-.1H NMR(500MHz,CDCl3) δ 10.32(s,1H),8.92(s,1H),8.70(s,1H),8.61(d, J ═ 8.0Hz,1H),8.00(t, J ═ 54.1Hz,1H), 7.32-7.27 (m,1H),7.18(t, J ═ 7.5Hz,1H),7.00(d, J ═ 7.8Hz,1H),6.72(s,2H) hrms (maldi) calcd C18H10F5N3O2[M+H]+396.07659, found 396.07665.
Figure BDA0001152927600000224
Compound 24: the yield thereof was found to be 55%.1H NMR(500MHz,DMSO)δ10.81(s,1H),8.85(s,1H),8.64(s,1H),8.34(d,J＝8.0Hz,1H),8.02(t,1H),7.78-7.81(m,3H),7.10-7.19(m,3H).
Figure BDA0001152927600000225
Compound 25: the yield thereof was found to be 56%.1H NMR(500MHz,DMSO)δ10.81(s,1H),8.85(s,1H),8.74(s,1H),7.81(d,J＝8.0Hz,1H),7.14–7.10(m,3H),6.97(d,J＝8.0Hz,1H),6.76(d,J＝8.1Hz,1H),6.61(d,J＝8.0Hz,1H),5.32(s,2H).
Figure BDA0001152927600000231
Compound 26: the yield thereof was found to be 60%, mp being 156.1-157.9 ℃.1H NMR (500MHz, DMSO) δ 10.45(s,1H),9.03(s,1H),8.99(s,1H),8.00(s,1H),7.74(s,1H),7.42(d, J ═ 8.7Hz,1H),7.05(d, J ═ 8.7Hz,1H),7.01(d, J ═ 8.1Hz,1H),6.75(d, J ═ 8.1Hz,1H),2.34(s,3H) · hrms (maldi) calculated value C19H12Cl2F3N3O2[M+H]+442.03313, found 442.03231.
Figure BDA0001152927600000232
Compound 27: the yield thereof was found to be 57%.1H NMR(500MHz,DMSO)δ10.80(s,1H),8.85(s,1H),8.64(s,1H),7.84(s,1H),7.45(s,1H),7.23-7.19(m,2H),7.10(d,J＝8.1Hz,1H).6.88(d,J＝8.1Hz,1H),2.87(m,1H),1.20(d,J＝8.1Hz,6H).
Figure BDA0001152927600000233
Compound 28: the yield thereof was found to be 51%.1H NMR(500MHz,DMSO)δ10.81(s,1H),8.84(s,1H),8.68(s,1H),7.65(d,J＝8.0Hz,1H),7.45(d,J＝8.1Hz,1H)，7.21–6.99(m,3H),6.88(d,J＝8.0Hz,1H),2.28(s,3H).
Figure BDA0001152927600000234
Compound 29: the yield thereof was found to be 60%.1H NMR(500MHz,DMSO)δ10.85(s,1H),8.84(s,1H),8.78(s,1H),7.45(s,1H),7.39–6.88(m,4H),2.16-2.17(s,6H).
Figure BDA0001152927600000235
Compound 30: the yield thereof was found to be 55%.1H NMR(500MHz,DMSO)δ10.85(s,1H),8.84(s,1H),8.78(s,1H),7.62(s 1H),7.45–7.39(m,2H),7.23(d,J＝7.7Hz,1H),6.88(d,J＝8.1Hz,1H),2.26(s,3H).
Figure BDA0001152927600000241
Compound 31: the yield thereof was found to be 55%.1H NMR(500MHz,DMSO)δ10.81(s,1H),8.84(s,1H),8.78(s,1H),8.55(s,1H),8.09(d,J＝8.1Hz,1H),7.33(m,2H),7.12-7.16(m,2H),6.80(d,J＝8.1Hz,1H).
Figure BDA0001152927600000242
Compound 32: the yield thereof was found to be 55%.1H NMR(500MHz,DMSO)δ10.81(s,1H),8.84(s,1H),8.78(s,1H),7.45(s,1H),7.23–6.88(m,4H),6.57(d,J＝8.0Hz,1H),5.28(d,J＝8.1Hz,2H).
Figure BDA0001152927600000243
Compound 33: the yield was 65%, mp is 89.3-92.1 ℃.1H NMR (500MHz, DMSO) δ 9.31(s,1H),9.04(s,1H),8.98(s,1H),7.46(d, J ═ 7.2Hz,1H),7.40(s,1H),7.26(dd, J ═ 19.4,11.3Hz,3H), 7.19-7.11 (m,2H),6.76(d, J ═ 7.9Hz,1H),4.61(d, J ═ 5.3Hz,2H), hrms (maldi) calculated value C19H13F4N3O2[M+H]+392.10167, found 392.10179.
Figure BDA0001152927600000244
Compound 34: the yield thereof was found to be 63%, mp being 52.6-54.3 ℃.1H NMR (500MHz, DMSO) δ 9.29(d, J ═ 16.4Hz,1H),8.98(s,1H),7.47(d, J ═ 7.2Hz,1H),7.40(t, J ═ 7.1Hz,2H),7.30(dd, J ═ 16.5,8.4Hz,1H),7.17(dt, J ═ 14.9,7.2Hz,2H),7.02(t, J ═ 8.1Hz,1H),6.89(d, J ═ 7.9Hz,1H),4.57(dd, J ═ 31.9,5.2Hz,2H), hrms (maldi) · calculated value C19H13BrF3N3O2[M+Na]+452.02160, found 452.02181.
Figure BDA0001152927600000251
Compound 35: the yield thereof was found to be 45%, mp ═ 61.1 to 62.0 ℃.1H NMR (500MHz, DMSO) δ 9.28(s,1H),9.04(s,1H),8.98(s,1H),7.47(d, J ═ 7.2Hz,1H),7.30(t, J ═ 7.4Hz,1H),7.24(t, J ═ 7.7Hz,2H),7.17(t, J ═ 7.0Hz,1H),7.08(s,2H),6.85(d, J ═ 7.9Hz,1H),4.55(d, J ═ 4.1Hz,2H), hrms (maldi) C calculated value19H13F4N3O2[M+H+]392.10167 found 392.10191.
Figure BDA0001152927600000252
Compound 36: the yield was 60%, mp ═ 107.6 to 108.7 ℃.1H NMR (500MHz, DMSO) δ 9.30(s,1H),9.04(s,1H),8.98(s,1H), 7.65-7.58 (m,1H),7.46(d, J ═ 7.2Hz,1H),7.27(s,2H), 7.22-7.12 (m,2H),6.68(d, J ═ 7.9Hz,1H),4.61(s,2H). hrms (maldi) calcd C19H12ClF4N3O2[M+Na]+448.04464, found 448.04592.
Figure BDA0001152927600000253
Compound 37: the yield thereof was found to be 55%.1H NMR(500MHz,DMSO)δ8.98(s,1H),8.78(s,1H),8.65(d,J＝8.0Hz,1H),7.38–7.16(m,5H),6.99-6.90(m,3H),3.18(t,J＝7.7Hz,2H)2.63(t,J＝7.7Hz,2H)2.09(m,2H).
Figure BDA0001152927600000254
Test example 1: the method is used for measuring the inhibitory activity of a control medicament and a target compound on succinate dehydrogenase.
The enzyme used in this test example was succinate dehydrogenase, which was isolated from porcine hearts.
The test method comprises the following steps: the total volume is 1.8mL, and the system contains 100mM Na2HPO4-NaH2PO4Buffer (pH 7.4), 0.3mM EDTA, 20mM sodium succinate, 53. mu.M DCIP (2, 6-dichloroindophenol sodium), 2nM succinate dehydrogenase. Constant temperature water bath at 23 ℃ and magnetic stirring at 600 rpm. The decrease in the light absorption of the substrate DCIP was monitored at a wavelength of 600nm and the experimental points in the linear range, i.e.the experimental points where the substrate consumption was controlled not to exceed 5%, were collected. The molar extinction coefficient of DCIP was 21mM-1cm-1. Calculating the reduction yield of DCIP in the reaction time, fitting a linear slope, deducting a baseline slope to obtain the initial reaction speed, and fitting (by Sigma Plot software9.0) to obtain IC50. Table 3 shows the results of the enzyme inhibitory activity tests of the compounds obtained in the preceding preparation examples and of the control drug NNF-0721.
TABLE 3
Compound (I) IC50(μM) Compound (I) IC50(μM)
1 1.51±0.11 20 1.54±0.23
2 1.81±0.13 21 0.504±0.015
3 0.660±0.016 22 1.70±0.15
4 1.67±0.11 23 1.71±0.11
5 0.497±0.010 24 1.45±0.12
6 0.863±0.011 25 1.42±0.15
7 1.02±0.14 26 0.143±0.015
8 1.61±0.12 27 1.02±0.11
9 1.47±0.13 28 1.04±0.04
10 1.61±0.13 29 0.96±0.16
11 1.62±0.10 30 0.69±0.13
12 1.05±0.13 31 1.11±0.12
13 1.63±0.11 32 0.89±0.16
14 0.485±0.011 33 1.79±0.12
15 0.333±0.012 34 1.04±0.12
16 1.52±0.13 35 1.40±0.12
17 1.60±0.12 36 1.67±0.11
18 1.73±0.12 37 1.12±0.13
19 1.62±0.16 NNF-0721 1.52±0.11
As can be seen from the results of enzyme inhibitory activity tests, the pyrazinamide compounds of the invention all show good inhibitory activity against SQR derived from pig hearts, and the effect of most compounds is better than that of a commercial control medicament NNF-0721.
Test example 2: bactericidal activity screening results
The test method comprises the following steps: each compound in table 4 was formulated into a 5 wt% emulsifiable concentrate. The tests all adopt living potted plants, and the effective concentration of the compound is 200 mg/L.
Pseudoperonospora cubensis (Pseudoperonospora cubensis)
Selecting two potted cucumber seedlings with the same growth vigor in the true leaf period (the growing points are removed), spraying, naturally airing, inoculating for 24 hours, taking fresh cucumber downy mildew diseased leaves, dipping the diseased leaves with distilled water at about 10 ℃ by using a brush pen, washing the sporocysts on the back of the diseased leaves, and preparing a sporocysts suspension (2-3 multiplied by 105/mL). Uniformly spraying and inoculating on cucumber seedlings by using an inoculation sprayer (the pressure is 0.1MPa), transferring inoculated test materials to a phytotron, keeping the relative humidity at 100%, the temperature at 20 ℃, keeping the temperature at 20 ℃ after 24h, keeping the relative humidity at about 90%, inducing by moisture retention, and carrying out grading investigation according to blank control disease occurrence after 5d, wherein the control effect is calculated according to disease indexes.
Cucumber powdery mildew (Sphaerotheca uliginea)
Selecting a cucumber seedling with consistent true leaf stage and growth vigor, and drying in the shade for 24h after spray treatment. Washing fresh spores on the leaves of the cucumber full of powdery mildew, filtering the fresh spores by using double-layer gauze to prepare suspension with the spore concentration of about 10 ten thousand/mL, and spraying for inoculation. And (3) naturally drying the inoculated test material, then moving the test material to a thermostatic chamber under light (21-23 ℃), and carrying out grading investigation according to the disease incidence condition of blank control after 8d, wherein the control effect% is calculated according to disease indexes.
Cucumber gray mold (Botrytis cinerea)
The method adopts a leaf inoculation method. Two potted cucumber seedlings with the same growth vigor of the true leaf period are selected, and after the agent is sprayed and dried, a fungus cake is inoculated on the leaves. And (4) after the dark light moisture preservation is carried out for 24 hours at the temperature of 22-26 ℃, the natural light culture is recovered for 4 days. After full disease control, the diameter of the lesion of each inoculation point is measured by a caliper, and the control effect percent is calculated.
Rice sheath blight disease (Rhizoctonia solani)
Selecting potted rice seedlings with two or three leaves and one heart and consistent growth, spraying for 24 hr, and clamping bacterial rhizoctonia solani in the center of the base of each pot of rice seedlings sprayed with the pesticide, with the attention paid to the fact that the bacterial blocks do not contact with pot soil and water layer. And (3) transferring the inoculated test material into a moisture preservation box (RH 100%) for culturing for 24h, then transferring to the temperature of 28 ℃, restoring natural illumination culture at the humidity of 90%, and investigating the control effect after 7 days when the disease is fully developed according to blank control.
The investigation method comprises the following steps: the grading standard adopts 'pesticide field efficacy test criteria' and the prevention and treatment effect is calculated by disease index.
Disease index ∑ (number of diseased leaves at each stage × number of relative stages) × 100/(total number of leaves × 9);
control effect (%) (control disease index-treatment disease index) × 100/control disease index;
the test results are shown in table 4.
TABLE 4
Figure BDA0001152927600000271
According to the activity test results, the pyrazinamide compound shows certain inhibitory activity on rhizoctonia solani, cucumber powdery mildew, cucumber gray mold and cucumber downy mildew at the concentration of 200mg/L, and especially shows good control effect on cucumber powdery mildew.
Test example 3: double sieve test
The test method comprises the following steps: part of the compounds of the present invention (specifically, as shown in table 5) were selected and sieved again, and each compound in table 5 was formulated into a 5 wt% emulsifiable concentrate. The tests all used in vivo potting and the effective concentrations of the compounds are shown in Table 5.
In particular, the same treatment as in test example 2 for cucumber powdery mildew was used for rescreening. The results are shown in Table 5.
TABLE 5
Figure BDA0001152927600000281
Figure BDA0001152927600000291
From the above results, it can be seen that the compounds of the present invention all showed excellent control effect on cucumber powdery mildew, and in particular, the compounds 5, 6, 26, 35 and 36 of the present invention showed more than 80% activity on cucumber powdery mildew at a concentration of 50mg/L, and were superior to the commercial control agent thifluzamide at each tested concentration.
From the above results, it can be seen that the compounds provided by the present invention have a significant broad spectrum of antibacterial benefits.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.

Claims (8)

1. A pyrazinamide compound having a structure represented by formula (I):
Figure 182842DEST_PATH_IMAGE001
the pyrazinamide compound is at least one of the following compounds:
compound 1: r11Is F; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 3: r11Is Br; r12、R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 5: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 6: r11Is Cl, R13Is CF3，R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are all made ofH, and n is 0;
compound 7: r11Is Cl, R13Is F, R12、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 8: r11And R12Is F, R13、R14And R15Is H; r21Is CF3；R31、R32、R33And R34Are both H, and n is 0;
compound 26: r11And R13Is Cl, R12、R14And R15Is H; r21Is CF3；R33Is CH3，R31、R32And R34Are both H, and n is 0.
2. A process for producing a pyrazinamide compound according to claim 1, which comprises: contacting a compound represented by the formula (II-1) with a compound represented by the formula (II-2);
Figure 449745DEST_PATH_IMAGE002
wherein R is11、R12、R13、R14、R15、R21、R31、R32、R33、R34And n is as defined in claim 1.
3. The method of claim 2, wherein the method further comprises preparing the compound of formula (II-1) according to the following steps:
(1) in the presence of sodium azide and a palladium-carbon catalyst, carrying out first contact on a compound shown as a formula (II-3) and ethylenediamine hydrochloride to obtain a compound shown as a formula (II-4);
(2) carrying out second contact on the compound shown in the formula (II-4) and lithium hydroxide;
Figure 741049DEST_PATH_IMAGE003
wherein R in the formula (II-3) and the formula (II-4)21Is defined as in claim 2.
4. The method according to claim 2 or 3, wherein the conditions for contacting the compound represented by the formula (II-1) with the compound represented by the formula (II-2) comprise: the temperature is 0-60 ℃ and the time is 1-72 h.
5. The use of pyrazinamide compounds according to claim 1 as inhibitors of succinate dehydrogenase.
6. A bactericide which is composed of an active ingredient and an auxiliary material, wherein the active ingredient comprises at least one of the pyrazinamide compounds according to claim 1.
7. The bactericide as claimed in claim 6, wherein the content of said active ingredient is 1 to 99.9% by weight.
8. The bactericide according to claim 6, wherein the bactericide is in a form selected from at least one of emulsifiable concentrate, suspension, wettable powder, dust, granule, aqueous solution, poison bait, mother liquor and mother powder.
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