CN1088921A

CN1088921A - Microbicide

Info

Publication number: CN1088921A
Application number: CN 93100011
Authority: CN
Inventors: A·休伯尔; B·霍斯泰特勒; M·萨特; U·马勒
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1993-01-01
Filing date: 1993-01-01
Publication date: 1994-07-06

Abstract

The benzoglyoxaline sulfonic acid of formula I.

R in the formula ₂For containing the unsaturated five-membered ring of no more than 2 heteroatoms N and/or S, or contain the unsaturated hexa-member heterocycle of no more than 2 N atoms, each heterocycle may be substituted, and X is oxygen or sulphur, R ₂, R ₃, R ₄Described as defined herein with n, this derivative is valuable microbicide, and composition state that can be suitable is used for crop protection, for example is used to control fungal disease.

Description

Microbicide

The present invention relates to the novel benzimidazole sulfonic acid of following formula I.And the preparation method who the present invention relates to this class material contains the pesticide composition that at least a this compounds is made effective constituent with relating to.Equally, the present invention relates to the preparation method of above-mentioned composition and relate to and use this effective constituents or this based composition to control or prevent the plant substance microorganism of causing a disease, particularly prevent the infringement of fungi plant.

According to this compounds of the present invention compound that is formula I

In the formula, with respect to substituent R ₁X-and R ₂, R ₄SO ₄Group occupies 1-or 3-position, forms the single isomer of position or isomer of hybrid position of planting, and each substituting group is defined as follows in the formula:

R ₁Be a kind of unsaturated five-membered ring that contains no more than 2 heteroatoms N and/or S, or a kind of unsaturated hexa-member heterocycle that contains no more than 2 N atoms, each heterocycle can not be substituted or replaced by at least 1 following substituting group: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkylhalide group, C ₁-C ₃The halogen alkoxyl group, COOC ₁-C ₃Alkyl, C ₃-C ₆Cycloalkyl, CN and nitro;

R ₂Group is identical or different following groups: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkylhalide group, C ₁-C ₃The halogen alkoxyl group, nitro;

R ₃Be cyano group ,-CS-NH ₂Or-C(SR ¹)=NH, wherein R ¹Be C ₁-C ₄Alkyl, C ₁-C ₄Alkylhalide group, perhaps unsubstituted or by halogen and/or CF ₃The benzyl that replaces;

R ₄Be C ₁-C ₄Alkyl, C ₃-C ₆Cycloalkyl ,-N(R ") (R

), R " and R wherein

Be identical or different C ₁-C ₃Alkyl;

X is oxygen or sulphur

N is integer 0,1 or 2.

Term " alkyl " itself or as another substituting group such as alkylhalide group, the part of alkoxyl group or halogen alkoxyl group, be interpreted as expression group for example following straight chain or side chain, be not all methyl, ethyl along with the carbonatoms of indication, propyl group, butyl and their isomer, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl.Halogen and halogen-be fluorine, chlorine, bromine or iodine.So the halogen alkoxyl group be one single to fully halogenated alkoxy grp, for example especially, OCH ₂F, OCHF ₂, OCHFCH ₃, OCH ₂CH ₂Br or OCF ₂CHFCl.

Term " cycloalkyl " representative ring propyl group, cyclobutyl, cyclopentyl or cyclohexyl.

The unsaturated five-membered ring of indication is interpreted as the expression pyrroles, thiophene, and pyrazoles, imidazoles, thiazole and isothiazole, corresponding hexa-member heterocycle is interpreted as the expression pyridine, pyrimidine, pyrazine and pyridazine.

The compound of formula I all is stable under the room temperature, famous oily matter or the solid with the microbicidel performance of preciousness.In agricultural sector and association area, this compounds can be used to protectiveness and therapeutic ground is controlled the plant harmful microorganism.Effective constituent according to formula I of the present invention is used under lower concentration, not only because of outstanding Microbicidal, fungicidal and famous especially, and because of good especially plant tolerance famous.

Important compound in formula I scope is R in the formula ₁Be the pyridine that does not replace or replace, pyrimidine, those compounds of pyrazine or pyridazine ring (subgroup I b), wherein, important compound is selected from the 6-membered heterocyclic compound that following substituting group replaces by 1 to 3: halogen, methyl, ethyl, sec.-propyl, methoxyl group, C ₁-C ₂Alkylhalide group (wherein halogen is F and/or Cl), CF ₃O, CHF ₂O or nitro (subgroup I c).

The material group of a particularly important is that those hexa-member heterocycles wherein are unsubstituted or single to three monobasic pyridines, each R in the subgroup I c scope ₂Group can be identical or different following groups: fluorine, chlorine, bromine, methyl, methoxyl group, CF ₃, CF ₃O or CHF ₂O, n=0 in the formula, the material of 1 or 2 (subgroup I d), particularly n=0 or 1 (subgroup I e).The material group of particularly important is those R wherein in the subgroup I d scope ₂Be halogen or C ₁-C ₂Alkylhalide group (subgroup I d ²), particularly in the formula pyridine ring by CF ₃Base replaces the compound of (subgroup I d ").

Another important material group is that those hexa-member heterocycles wherein are the pyrimidine that does not replace or halogen replaces or alkylhalide group replaces, R in the subgroup I c scope ₂Be fluorine, chlorine, bromine, methyl, methoxyl group or CF ₃, n is the compound of 0,1 or 2 (subgroup If).The material group of particularly important is those R wherein in the subgroup I f scope ₂Be fluorine, chlorine, bromine, methyl, methoxyl group or CF ₃, n=0 in the formula, 1 or 2 (subgroup I f ²) and formula in pyrimidine be connected the compound of 4-position (subgroup I f ").

R in the subgroup I d formula ₁For the preferred compound in the hexa-member heterocycle scope is those R wherein ₄Be methyl, dimethylamino, cyclopropyl, cyclopentyl or cyclohexyl (subgroup I g), particularly R in the formula ₄Be methyl (subgroup I g ²) or formula in R ₄Compound for dimethylamino (subgroup I g ").

Other important compound is that those X wherein are oxygen in the formula I scope, and X is sulphur and R in the formula ₁Be the pyrroles who does not replace or replace, thiophene, thiazole, isothiazole, the compound of imidazoles or pyrazoles ring (subgroup I i).

From these compounds, preferably 5 yuan of heterocycles are by halogen and/or methyl substituted compound (subgroup Ij) in the formula, and particularly preferred compound is each R in those its formulas ₂Can be identical or different following groups: halogen, methyl, methoxyl group, CF ₃, CF ₃O or CHF ₂O, n are 0,1 or 2 (subgroup I k).Important compound is for example, not have substituent R ₂The compound of (being n=0).

Important compound in the formula I scope is those R wherein ₃Be cyano group or C(S) NH ₂(subgroup I m), or XR in the formula ₁In the benzoglyoxaline ring, occupy the compound of 5/6-position (subgroup I n).

Important compound in the formula I scope is that X is an oxygen in those its formulas, comprises the compound of subgroup I b-I n.Preferred specific compound is in the subgroup I d scope, for example,

A) 1(3)-and (dimethylamino alkylsulfonyl)-2-cyano group-4-bromo-6-(3,5-dichloropyridine-2-base oxygen)-benzoglyoxaline (compound 1.23);

B) 1(3)-and methylsulfonyl-2-cyano group-6-(5-5-flumethiazine-2-base oxygen) benzoglyoxaline (compound 1.2);

C) 1(3)-and methylsulfonyl-2-cyano group-6-(3-chloro-5-5-flumethiazine-2-base oxygen) benzoglyoxaline (compound 1.66);

D) 1(3)-and ring third alkylsulfonyl-2-cyano group-6-(3-chloro-5-5-flumethiazine-2-base oxygen) benzoglyoxaline (compound 1.74).

The method for making of formula I compound is to make the compound of formula II and the compound reaction of formula III

R in the formula ₁, R ₂, R ₃, R ₄, the definition of X and n is described suc as formula I, and M is hydrogen or basic metal, preferred Na, K or Li, Q are halogen atom, preferred chlorine or bromine, or group O-SO ₂-R ₄, be reflected in the inert solvent, to carry out if be suitably under the situation of alkali, temperature of reaction is preferably-10 °-80 ℃ at-30 °-+180 ℃, and reaction pressure is a normal atmosphere, and decompression or supercharging are preferably barometric point.

Suitable solvent mainly is the polar reaction medium, such as independent with ketone (for example acetone, butanone, tertiary butyl ketone), or with ethers (such as ether ， diox, tetrahydrofuran (THF), 1,2-glycol dimethyl ether) mixture, or for example with the mixture of dimethyl formamide or methyl-sulphoxide.(such as KOH, reaction is favourable under situation NaOH) in that strong inorganic base is arranged to make the benzimidizole derivatives II.

Because thioamides base (R ₃=-CSNH ₂) or the different thioamides base (R that replaces ₃=-C(-SR)=NH) reactivity, operation steps are favourable by this way, and promptly the end reaction stage after sulfonylation is just introduced above-mentioned R ₃Base.Promptly so like this, sulfonylation 2-cyano-benzimidazole (formula I ')

Subsequently with H ₂S or with HS-R' reaction, the definition of R' is described suc as formula I.Produce thioamides (R ₃=-CSNH ₂) be reflected in the polar solvent (for example alcohols, such as ethanol) and carry out, but preferably carry out at dimethyl formamide (DMF) or in ethers (for example ether, tetrahydrofuran (THF)) or acetonitrile or pyridine, a kind of tertiary amine is used in reaction, such as trialkylamine.At-20 ℃-+80 ℃, particularly-10 ℃-+40 ℃ feed H down ₂S carries out.

Different thioamides base for the preparation replacement; operation steps is favourable in such a way; promptly in polar aprotic solvent (such as acetonitrile); at-20 ℃-+100 ℃; preferably-10-+40 ℃; have under the situation of weak base (such as alkaline carbonate), with mercaptan HS-R' handle sulfonylation 2-cyano-benzimidazole (formula I).

The 2-cyano-benzimidazole derivative of formula II can be prepared with original known method by O-phenylene diamine derivatives or its salt:

HY is a kind of acid, preferably haloid acid or sulfuric acid.But when step of reaction a) is carried out, also can use the O-phenylene diamine derivatives that is the free alkali state in Glacial acetic acid.Preferred solvent is a Glacial acetic acid; Ethers is such as ether ， diox, 1,2-glycol dimethyl ether; Ester class such as ethyl acetate or alcohols such as methyl alcohol and ethanol.

In the O-phenylene diamine derivatives that three halogen imidoethers (for example three chloro-or-chlorodifluoramethyl-imidoether) is added to dissolving or suspend under-20 ℃-+100 ℃ is favourable.At step of reaction b) in, the 2-trihalogenmethyl benzimidizole derivatives that obtains is added to (USP 3,576 818) are favourable in the concentrated liquor.

The also available corresponding ortho-nitrophenyl sulfonamide derivatives of the method for making of 2-cyano-benzimidazole derivative (formula II) replaces O-phenylene diamine derivatives, adds ZnCl in Glacial acetic acid ₂(or other Lewis acid) makes catalyzer, and it and formaldehyde and KCN are reacted, and obtains the compound of formula VII

(people such as K.Dimroth, Ber.98 3902(1965), uses K ₂CO ₃Make it cyclisation and obtain 1-hydroxyl-2-cyano-benzimidazole derivative (people such as B.Serafinatoa, Rocz.Chem.51,1783(1977)).And and PCl ₃Reaction obtains compound (the M=hydrogen of formula II; R ₃=CN).

R in the intermediate formula of formula II ₃=CN, M=hydrogen, this be novel cpd (compound ii ') ， And and be another object of the present invention.

The compound of formula V can prepare by the compound that contains nitro of reduction-type VIII.The available reductive agent is some conventional reductive agent such as iron (Bechamps reduction), tin chloride (II), otherwise be the hydrogen that has catalyzer, for example Raney nickel or palladium/gac.Consistent (for example " Methoden der organischen Chemie " (the organic chemistry method) of Houben Weyl) mentioned in reaction conditions and the document.

Work as R ₁During for hexa-member heterocycle, the compound of formula VIII can make from the compound of formula IX.Method for making is to make it and suitable replacement 2-halogen pyridine, 2-halogen pyrazine, 3-halogen pyridazine, 2-halogen pyrimidine or 4-halogen pyrimidine (formula group X) reaction.Be reflected in the inert organic solvents and carry out, preferably polar solvent is such as DMF, DMSO, DMA, or ketone is such as acetone, butanone, alcohols be such as ethanol, propyl alcohol, butanols, or ethers such as ether or tetrahydrofuran (THF), being reflected under the situation of alkali and carrying out, preferably alkali-metal carbonic acid (hydrogen) salt or oxyhydroxide are such as Na ₂CO ₃, K ₂CO ₃, NaOH or KOH, or amine such as triethylamine or pyridine.Temperature of reaction is 0 ℃-+150 ℃, preferably 80-120 ℃.

Compound and the suitable replacement of the also available another kind of method of the compound of formula VIII by making the formula IX has the pyridine of a hydroxyl or sulfydryl, pyrimidine, pyridazine, or pyrazine (formula group XII) reaction and obtaining.Reaction is preferably under the above-mentioned same condition to be carried out.

The formula IX, X, known or available known method prepares in each compound of XI and XII or the document.

The formula II ' compound also can be synthetic by the compound of formula VIII.Method is to make it and 2-halogen pyridine, 2-halogen pyrazine, 3-halogen pyridazine, or 2-or 4-halogen pyrimidine (formula group X) reaction.Be reflected in the inert organic solvents and carry out, preferably polar solvent is such as DMF, and DMSO, DMA, or ketone is such as acetone, butanone, alcohols be such as ethanol, propyl alcohol, and butanols, or ethers such as ether or tetrahydrofuran (THF) carry out having under the situation of alkali.The example of preferred alkali is carbonate such as yellow soda ash or salt of wormwood, also has oxyhydroxide such as potassium hydroxide or sodium hydroxide, or amine such as triethylamine or pyridine.Temperature of reaction is 0 ℃-150 ℃, preferably 80 ℃-120 ℃.

The compound of formula VIII can be made as mentioned above by the compound of formula XIV.

The compound of formula XIV can make by the nitro in the compound of reduction-type IX.The example of available reductive agent is iron (Bechamps reduction), tin chloride (II), otherwise be the hydrogen that has under the catalyzer situation, for example Raney nickel or Pd/ gac.It is consistent that reaction conditions and document (for example Houben Weyl) are pointed out.

General reaction scheme 1

=replace or unsubstituted pyridone mercaptopyridine, hydroxy pyrimidine, mercaptopyrimidine, hydroxyl pyrazine, sulfydryl pyrazine, hydroxyl pyridazine, or sulfydryl pyridazine.

Z=leavings group (for example halogen), the position is with respect to NO ₂The ortho position or the contraposition of base,

=replace or unsubstituted 2-halogen pyridine 2-halogen pyrazine, 2-or 4-halogen pyrimidine, 3-halogen pyridazine.

Work as R ₂Be fluorine, during chlorine or bromine, corresponding compounds also can be by those R of halogenation ₂For the compound of hydrogen makes.This method use the formula II ', V, VII, VIII, IX, XI, the preparation of each compound of X III and X IV.

R ₁Be the compound of five-membered ring,, can prepare similarly according to their reactivity.

Work as R ₁When forming a thiazole ring, following reaction sequence is feasible:

General reaction scheme 2

The preparation of thiazolium compounds:

Or by forming thiazole ring: for example

When X=S, the compound of formula IX also can be the thiocyanic ester masked state and be used (US4076828).

Following formula: compound

When X=S, form that also can dipolymer becomes disulphide to exist.Can obtain sulfhydryl compound with reduction method thus, this reductive method is known in the document.

Beyond thoughtly be, have been found that now the compound of formula I has the Biocidal spectrum of the controlling plant of being used for pathogenic microorganism, particularly fungi, this meets practical requirement very much.The compound of formula I has the treatment and prevention performance that is of great value, and is used to protect a large amount of crops.The effective constituent of formula I makes various useful plant crops or its integral part (really, spending leaf, stem, stem tuber, root) go up the disease that exists and is suppressed or is eliminated, or even firm formation part (rice shoot) maintenance of plant is not subjected to the infringement of phytopathogenic fungi.

The fungal disease that " belongs to and planting " in the anti-following fungi " guiding principle " of the novel effective constituent of formula I is effective especially: imperfect fungi (for example tail spore bacterium), Basidiomycetes (for example handle rest fungus) and Ascomycetes (for example powdery mildew and black star bacterium), (for example single shaft is mould for particularly anti-Oomycete, downy mildew, rotten mould mould with epidemic disease) disease.Therefore, the compound of formula I is very valuable for the composition that replenishes controlling plant pathomycete in the Crop protection.As for actual application, the advantage of formula I compound is to have treatment and prevent performance And can be used for the protection of a large amount of crops.This effective constituents makes various useful plant crops or its integral part (really, flower, leaf, stem, stem tuber, root) go up the disease that exists and is suppressed or is eliminated, or even the firm formation part (rice shoot) of plant keeps not being subjected to the state of phytopathogenic fungi infringement.The compound of formula I can be used as seed dressing in addition and handles seed (fruit, stem tuber, seed) and rice shoot cutting, as a kind of antimycotic sfgd. that infects and resist soilborne phytopathogenic fungi.

The invention still further relates to and contain the composition of formula I compound as effective constituent, particularly crop production compositions ， And relates to their application in agricultural sector or association area.

In addition, the present invention also comprises these preparation of compositions methods, and this method comprises effective constituent and one or more materials as herein described or one or more material group thorough mixing.Comprise that also the novel cpd or the novel compositions that it is characterized in that by using the formula I come methods for the treatment of plants.

The disclosed in this article example that is suitable for use as the plant variety of Crop protection target crop is, within the scope of the present invention, and cereal class (wheat, barley, rye, oat, rice, corn, Chinese sorghum and relevant kind); Beet (sugar beet and fodder beet); A kind of fruit, such as apple, pear, etc., drupe and berry (apple, pears, Lee, peach, apricot, cherry, strawberry, raspberry and immature fruit of Juteleaf Raspberry); Beans (Kidney bean, root of Szemao crotalaria, pea, soybean); Oil crops (Semen Brassicae campestris, leaf mustard, opium poppy, Fructus oleae europaeae, Sunflower Receptacle, coconut, castor-oil plant, cocoa, peanut); Dicotyledonous draft tendril section (summer squash, cucumber, watermelon); Textile plant (cotton, flax, hemp, jute); Citrus (orange, lemon, grape, red tangerine); Vegetables (spinach, lettuce, Caulis et Folium Brassicae capitatae, asparagus bean, Hu Luobu, onion, tomato, potato, big capsicums); Camphorwood section (avocado, Chinese cassia tree, camphor) or such as tobacco, nut, coffee, sugarcane, tea, pepper, grape, golden hop, bajiao banana and natural rubber latex plant, and ornamental flower.

The effective constituent of formula I is used ， And with the form of mixture usually and can or be administered to continuously on processed zone or the plant with other effective constituent while.Other effective constituent can be fertilizer, and micro-amboceptor or other are to the effective preparation of plant-growth.Yet also can use selective herbicide, and sterilant, fungicides, sterilant, nematocides, the mixture of invertebrate poison or many these preparations, as long as with conventional other carrier that uses in the compounding process, tensio-active agent or other are used enhancer additives and are matched altogether.

Suitable carriers and additive can be solid or liquid, favourable material in the compounding process, for example natural or regenerated mineral substance, solvent, dispersion agent, wetting agent, tackiness agent, thickening material, cementing agent or fertilizer.

The effective constituent of formula I or the preferred application process that contains the pesticide composition of at least a this effective constituent are that it is applied in (leaf dressing) on the leaf.The hazard level that the cause of disease considered of depending on the frequency of fertilising and consumption infects.The compound of formula I also can be applied in (coating) on the seed, perhaps with the liquid composition seed soaking of effective constituent, perhaps coats seed with solids composition.

The compound of formula I uses with the form of pure effective constituent, or preferably with compounding process in conventional auxiliary agent use together., they are processed into currently known methods for this reason, emulsifiable concentrates for example, the coating paste, direct sprayable property or dilutable solution, rare emulsion, wettable powder, soluble powder, pulvis, granula is wrapped with capsule, for example wraps in the polymer material.

The method of using atomizes such as spraying, and dusting is disseminated, and brushing or bold and vigorous watering are selected to adapt to predetermined target and popular environment according to the character of composition.

Suitable amount of application generally is per hectare (ha) 5g-2kg effective constituent (a.i.), better is 10g-1kga.i, and/ha is again best with 20g-600ga.i./ha.

Preparation promptly comprises the composition of formula I effective constituent or mixture (if needed, also contain solid or fluid additive) prepare with currently known methods, for example, effective constituent and extender thorough mixing and/or grinding, this extender is such as solvent, if solid carrier is and suitable tensio-active agent in addition.

What can be used as solvent is: aromatic hydrocarbons, preferred C ₈～C ₁₂Aromatic hydrocarbons, such as xylene mixture or replace naphthalene, phthalic ester such as dibutyl phthalate or dioctyl phthalate (DOP); Aliphatic hydrocrbon such as hexanaphthene or paraffinic hydrocarbons; Alcohols and glycols and their ether and ester, such as ethanol, ethylene glycol, ethylene glycol monomethyl ether or ethylene glycol monoethyl ether; Ketone is such as pimelinketone; Intensive polar solvent is such as the N-N-methyl-2-2-pyrrolidone N-, dimethyl sulfoxide (DMSO) or dimethyl formamide; With epoxidation or epoxidized vegetable oil not, such as epoxidation Oleum Cocois or soybean oil, and water.

Normally used solid carrier, but for example be used for pulvis and dispersion powder, be the levigated natural mineral such as calcite, talcum, kaolin, montmorillonite or attapulgite.In order to improve physicals, also can add the silicon-dioxide of high dispersing or the adsorbability polymer of high dispersing.The granular adsorption carrier that rational granula is used is the multi-hole type material, such as float stone, and brick slag, sepiolite or wilkinite, or non-sorptive carriers material, for example calcite or sand.In addition, the material of the granulation in advance of a large amount of inorganic or organic property also can use such as rhombspar or ground vegetable remains thing.

Suitable surface active cpd is to have well emulsify, the nonionic of dispersion and wettability, and positively charged ion and/or anion surfactant, it depends on the character of the formula I effective constituent of being prepared." tensio-active agent " also is understood that the mixture of presentation surface promoting agent.

Suitable anion surfactant both can be so-called water-soluble soap, also can be water-soluble synthetic surface active compound.

The example that nonionogenic tenside can be mentioned is the nonylphenol polyethoxyethanols, the Viscotrol C polyglycol ether, and polypropylene/polyethylene oxide adducts, the tributyl phenoxy group gathers ethylidene-ethanol, polyoxyethylene glycol and octylphenoxy polyethoxy ethanol.

Other suitable material is the fatty acid ester of polyoxyethylene sorbitol acid anhydride, such as polyoxyethylene sorbitan trioleate.

Cats product mainly is a quaternary ammonium salt, and this salt contains, as substituent at least one C of N- _8-22Alkyl and randomly by halogenated low alkyl group, benzyl or as other substituent rudimentary hydroxyalkyl.

Be usually used in other tensio-active agent in the compounding process and be that the people of the industry knows or can in technical literature, find.

In general, pesticide preparation comprises 0.1-99%(weight), 0.1-95%(weight particularly) formula I effective constituent, contain 99.9-1%(weight), 99.8-5%(weight particularly) solid or fluid additive, and 0-25%(weight), tensio-active agent 0.1-25%(weight particularly).

Although concentrate composition often is preferably the commercial goods, the ultimate consumer generally uses diluted composition.

Composition also can contain other additive such as stablizer, defoamer, and viscosity modifier, cementing agent or tackiness agent, and fertilizer or other reach the effective constituent of specific function.

The following example specifies above-mentioned invention and not to scope of the present invention any restriction in addition.Each temperature value is degree centigrade.

Preparation embodiment

H-1.1(3)-and methylsulfonyl-2-cyano group-6-(3-chloro-5-5-flumethiazine-2-base oxygen) preparation (compound 1.66) of benzoglyoxaline

A) preparation of benzoglyoxaline intermediate 2-cyano group-5-(3-chloro-5-5-flumethiazine-2-base oxygen)

With 4.55g(15mmol) 1,2-diamino-4-(3-chloro-5-5-flumethiazine-2-base oxygen) benzene is dissolved in the 35ml Glacial acetic acid, dropwise adds 3.95g(22mmol under stirring at room) 2,2,2-trichloro-ethylideneimide acid methyl esters.Continue to stir 14 hours, mixture impouring 150ml Shui Zhong And is used the 40ml extracted with diethyl ether three times at every turn, the extraction liquid with dried over sodium sulfate merges boils off solvent.No longer purify, gained dun buttery 2-trichloromethyl-5-(3-chloro-5-5-flumethiazine-2-base oxygen) benzoglyoxaline, be dissolved in the 30ml tetrahydrofuran (THF), under stirring at room, during 1 hour, add 25% ammoniacal liquor 70ml, stir and continued again 1 hour.After the tetrahydrofuran (THF) vacuum steamed, the pH of mixture is transferred to 5 with concentrated hydrochloric acid.Leach the silicagel column that the solid ， And that is precipitated out makes elutriant with ethyl acetate/hexane (1: 1) with suction filtration and carry out stratography.After steaming elutriant, dissolve this crystalline precipitate, Guo Lv And drying with the 15ml hexane.This cream-coloured xln is＞270 ℃ of following fusions.

B) preparation of the finished product

With 1.02g(15.5mmol) 85%KOH once adds 4.14g(12mmol to) 2-cyano group-5-(3-chloro-5-5-flumethiazine-2-base oxygen) and benzoglyoxaline in the solution of 65ml acetone, mixture was stirred 1 hour.At room temperature during 1 hour, dropwise add 3.2g(28mmol to this mixture) methylsulfonyl chloride, continue to stir 16 hours under 20 ℃ again.For finishing this reaction, add other 0.5g(7.6mmol) 85%KOH, add 1.6g(14mmol after half an hour) methylsulfonyl chloride ， And continue to stir 4 hours in room temperature.Subsequently reaction mixture impouring 200ml water Zhong ， And is used the 30ml ethyl acetate extraction three times at every turn, use the saturated Na of 20ml at every turn ₂CO ₃The organic phase twice that solution washing merges with the 20ml water washing once, is filtered with sodium sulfate Gan Zao And.Boil off solvent then.With the most of crystal of 20ml ether dissolution, Guo Lv And drying.This light gray crystal is 196-206 ℃ of following fusion.

H-2.1-N, N-two methylsulfonyls-2-cyano group-4-bromo-6-(6-chloro-pyridazine-3-base sulphur) preparation (compound 1.304) of benzoglyoxaline

A) preparation of aniline intermediate 2-nitro-4-(6-chloro-pyridazine-3-base sulphur)

78.1g2-nitro-4-thiocyano aniline is dissolved in And continuation 15.2g sodium borohydride processing Zhong the 900ml diglyme under 30 ℃.Stirring is after 1 hour down at 60 ℃ for mixture, and cool to room temperature adds 26.4g powdery KOH and 61.4g3, the 6-dichloro-pyridazine.Mixture is after stirring 1 hour under 60 ℃, in the impouring ice, the suspension filtered of gained.With toluene Chong Jie Jing And ether dissolution, obtain the 39.4g product a), fusing point＞230 ℃.

B) intermediate 2-bromo-4-(6-chloro-pyridazine-3-base sulphur)-preparation of 6-N-methyl-p-nitroaniline

With the 10.0g compound a) and the 2.9g sodium acetate be dissolved in the 130ml Glacial acetic acid.Slowly drip the 7.5g bromine, gained suspension stirred 30 minutes down at 55 ℃.Mixture impouring Bing Zhong And is filtered, wash gained solid and dry with water.Use ethyl acetate: hexane=do elutriant on silicagel column stratography at 1: 1 obtains the 6.4g compound b), fusing point＞250 ℃.

C) intermediate 1,2-diamino-3-bromo-5-(6-chloro-pyridazine-3-base sulphur) preparation of benzene

With the 6.4g compound b) be dissolved in the 200ml tetrahydrofuran (THF), add the 1.2g Raney nickel, mixture stirred 51 hours in the room temperature nitrogen atmosphere.Total amount 3.6g Raney nickel adds in two batches.Then leach Cuiization Ji And and steam solvent.Obtain the 4.3g compound c), fusing point 160-161 ℃.

D) preparation of benzoglyoxaline intermediate 2-cyano group-4-bromo-6-(6-pyridazine-3-base sulphur)

With the 4.3g compound c) be suspended in the 30ml Glacial acetic acid, dropwise add 3.55g2,2,2-trichloro-ethylideneimide acid methyl esters, mixture stir at room temperature after 1 hour that And uses the 20ml extracted with diethyl ether three times at every turn in the impouring frozen water.Use the dried over sodium sulfate organic phase, Guo Lv And concentrates.Resistates is dissolved in the 30ml tetrahydrofuran (THF).Gained solution at room temperature is added drop-wise in the 60ml strong aqua.After 1 hour, reaction mixture is concentrated Yong Shui Xi Shi And concentrated hydrochloric acid acidifying.The suspension filtered that generates, Shui Xi And drying.Obtain the 4.6g compound d), fusing point＞250 ℃.

E) preparation of the finished product

With the 2.3g compound d) be dissolved in the 10mlN-N-methyl-2-2-pyrrolidone N-, add the 0.28g60% sodium hydride.When gas stops to emit, under 40 ℃, continue again to stir 10 minutes, mixture is cooled to 15 ℃.Add 0.876mlN, N-dimethylamino SULPHURYL CHLORIDE.Dun suspension was stirred respectively 60 minutes and 30 minutes under room temperature and 35 ℃.The mixture impouring is iced-Shui Zhong And and is used the 20ml ethyl acetate extraction three times at every turn.Dried over sodium sulfate is used in organic phase water and salt water washing, crosses filter And and concentrates.The resistates ethyl acetate: hexane=make elutriant at 1: 1, stratography on silicagel column obtains the 1.17g title compound, fusing point 169-170 ℃.

H-3.1(3)-and methylsulfonyl-2-thioamides base-6-(3-chloro-5-5-flumethiazine-2-base oxygen) preparation (compound 3.34) of benzoglyoxaline

1.12g compound 1.66 is dissolved in 12ml diox and the 4ml tetrahydrofuran (THF).Add 0.43ml triethylamine ， And and fed hydrogen sulfide 30 minutes in room temperature.Solution concentration in 1/2 Ti Ji And impouring ice-water.Use the ethyl acetate extraction mixture.Dried over sodium sulfate is used in organic phase salt water washing, crosses filter And and concentrates.The crystal ether dissolution that forms.Obtain 0.47g compound 3.34, fusing point 181-182 ℃.

H-4.1(3)-and N, N-dimethylamino alkylsulfonyl-2-cyano group-6-(4-trifluoromethyl-2-oxygen-thiazolyl) preparation (compound 1.250) of benzoglyoxaline

This product with described method under the H-2 item by following intermediate manufacturing:

The preparation of intermediate

The 50.0g4-amino-3-nitro phenol is dissolved in the 40ml acetone, then adds the 34.4g cyanogen bromide.During 45 minutes, dropwise adding the 32.9g triethylamine under 0-5 ℃.To adding the last of triethylamine, add other 100ml acetone.Then continue again to stir 15 minutes.Reaction mixture filters through Hyflo, concentrates then with washing with acetone.Obtain the orange-yellow powder of 64.7g, can be directly in next step application.

Product is dissolved in the 500ml tetrahydrofuran (THF), and gained solution filters once more to remove trace of triethylamine salt.Then during 3 hours, feeding 12.0g hydrogen sulfide under 25-30 ℃, continuing again to stir 1 hour.In order to quicken (work-up), with reaction mixture under agitation in the impouring ice-water, Guo Lv And washing.Moist solid is dissolved in the ethyl acetate, removes water in the mixture with sal epsom, mixture Jing Guo Lv And concentrates.Obtain the orange powdered thiocarbamate of 56.0g 4-amino-3-nitro phenyl ester.

The amino nitro phenyl ester of this thiocarbamate of 1.0g is dissolved in 10ml diox/toluene (1: 1), dropwise adds 1.2g bromine trifluoroacetone.Reaction mixture stirred 1 hour down at 35 ℃, filtered then, with hexane and ether Xi Di And drying.To anhydrate in order removing, to make this powder suspension in ethylene dichloride, And and 2.5 gram thionyl chloride refluxed 1 hour together.Reaction mixture is through concentrating, and resistates is dissolved in the ethyl acetate, mixture 10%K ₂CO ₃Solution and salt water washing, the organic phase dried over mgso concentrates then.Obtain the orange oily 1-amino of 0.35g-2-nitro-4-(4-trifluoromethyl-2-oxygen-thiazolyl) benzene, according to ¹It is purified that H NMR spectrum is measured product, this thing is directly processed obtained the finished product.

The reaction scheme of this intermediate preparation:

Energy prepares according to this mode or is as follows according to some examples of the above-mentioned wherein compound of another method preparation.

* with respect to-SO ₂R ₄Isomery object mixture or pure isomer A or B 1 or 3.

* with respect to-SO ₂R ₄At 1 or 3 s' isomer mixture, or pure isomer A or B.

The formulation Example of formula I effective constituent (percentage ratio that %=calculates by weight)

2.1. wettable powder

a)??b)??c)

Effective constituent 25% 50% 75% in the table

Sodium lignosulfonate 5% 5%-

Sodium lauryl sulphate 3%-5%

Diisobutyl sodium naphthalene sulfonate-6% 10%

Octylphenol polyethylene glycol ether-2%-

(7-8mol oxyethane)

High dispersive silicon-dioxide 5% 10% 10%

Kaolin 62% 27%-

Effective constituent and additive thorough mixing ， And are fully ground in suitable grinding machine.The wettable powder that provides like this can be diluted with water to any suspension that needs concentration.

2.2. emulsion enriched material

Effective constituent 10% in the table

Octylphenol polyethylene glycol ether 3%

(4-5mol oxyethane)

Calcium dodecylbenzene sulphonate 3%

Viscotrol C polyglycol ether 4%

(35mol oxyethane)

Pimelinketone 34%

Xylene mixture 50%

Anyly require dilution emulsion to prepare by this enriched material dilute with water.

2.3. pulvis

a)??b)

Effective constituent 5% 8% in the table

Talcum 95%-

Kaolin-92%

The method for making of ready-to-use pulvis is to make effective constituent and carrier Hun He And grinding mixture in suitable grinding machine.

2.4. extrude particle

Effective constituent 10% in the table

Sodium lignosulfonate 2%

Carboxymethyl cellulose 1%

Kaolin 87%

Effective constituent is mixed with additive, and mixture is through grinding mill And water-wet.Then dry in airflow mixture Ji Chu And.

2.5. coating particle

Effective constituent 3% in the table

Polyoxyethylene glycol (MW200) 3%

Kaolin 94%

(MW=molecular weight)

In mixing tank, finely disintegrated effective constituent evenly is coated on the kaolin, kaolin has used polyoxyethylene glycol wetting.What obtain according to the method, is dustless coating particle.

2.6. suspension concentrate

Effective constituent 40% in the table

Ethylene glycol 10%

Nonoxynol-9 6%

(15mol oxyethane)

Sodium lignosulfonate 10%

Carboxymethyl cellulose 1%

37% formalin 0.2%

Silicone oil (being 75%) 0.8%

The water miscible liquid state

Water 32%

Finely disintegrated effective constituent is closely mixed with additive.Obtain a kind of suspension-concentrates like this, the suspension of the concentration of any requirement can both be prepared by this enriched material dilute with water.

3. biological Examples

Embodiment 3.1: the effect of anti-vine shoot Pseudoperonospora cubensis

A) residual provide protection

The spray mixing thing that the vine shoot rice shoot of 4-5 leaf phase is made with the effective constituent wettable powder (0.02% effective constituent) spraying.After 24 hours, the rice shoot of having handled is infected with the sporangia suspension of fungi.After cultivating 6 days under 20 ℃ of relative atmospheric moistures with 95-100%, fungi spreads in evaluation.

B) residual therapeutic action

The vine shoot rice shoot in 4-5 leaf stage makes it to infect with the sporangia suspension of a kind of fungi.Under 20 ℃ of relative atmospheric moistures, cultivate after 24 hours spray mixing thing (0.02% effective constituent) spraying that the dry ， And of the rice shoot that has infected is made with the effective constituent wettable powder in the dampening chamber with 95-100%.Spray-painting on the rice shoot of having handled is dried, rice shoot is sent add the dampening chamber.Infect after 6 days, fungi spreads in evaluation.

The anti-vine shoot Pseudoperonospora cubensis of compound is active fine in the table, and particularly effective constituent numbering 1.2,1.24,1.66,1.250,1.276,1.303,1.322,1.346,3.79 and other spread fungi and be subjected to complete inhibition (the residual 0-5% of spreading).It is 100% that the Pseudoperonospora cubensis of the contrast rice shoot that, is untreated but has infected spreads.

Embodiment 3.2: the effect of anti-tomato rice shoot eqpidemic disease

Residual provide protection

Spray mixing thing (0.02% effective constituent) spraying that the tomato rice shoot in three weeks of having grown is made with the effective constituent wettable powder.After 24 hours, the rice shoot of having handled is infected with the sporangia suspension of fungi.Infecting the rice shoot cultivation under 20 ℃ of relative atmospheric moistures with 90-100% after 5 days, fungi spreads in evaluation.

Compound exhibits goes out continual activity (fungi spread＜20%), compound number 1.2,1.12 in the table, 1.23,1.24,1.26,1.54,1.66,1.146,1.177,1.199,1.221,1.230,1.275,1.308,3.50,3.79 and other in fact prevent something from spreading fully (0-5% spreads).It is 100% that the eqpidemic disease of the contrast rice shoot that, is untreated but has infected spreads.

Embodiment 3.3: the effect of anti-potato rice shoot eqpidemic disease

Residual provide protection

In potato rice shoot (Cultivar Bintje) three weeks of growth in age in 2-3 week, the spray mixing thing made from the effective constituent wettable powder (0.02% effective constituent) is sprayed then.After 24 hours, the rice shoot of having handled is infected with the sporangia suspension of fungi.Infecting the rice shoot cultivation under 20 ℃ of relative atmospheric moistures with 90-100% after 5 days, fungi spreads in evaluation.

Compound exhibits goes out continual activity (fungi spread＜20%) in the table.Compound number 1.23,1.24,1.66,1.146 and other in fact prevent something from spreading fully (0-5% spreads).It is 100% that the eqpidemic disease of the contrast rice shoot that is untreated but has infected spreads.

Embodiment 3.4: the effect of anti-sugar beet (Beta vulgaris) pythium debaryanum

A) effect after soil wets thoroughly

Cultivating fungi ， And on aseptic oat grain adds fungi in the mixture of soil and sand to.The soil that infects is like this filled flowerpot ， And sowing sugar beet seed.After planting immediately being poured on the whole soil with aqueous suspensions (20ppm effective constituent is according to the soil volume calculation) by the test preparation of prescription as wettable powder.So flowerpot is placed on 2-3 week in the 20-24 ℃ of greenhouse.Slowly spray by water with keeping and to keep soil evenly moistening.In the evaluation of test, measure emerging and the quantity of healthy and ill rice shoot of sugar beet.

B) effect after seed dressing is used

Cultivating fungi ， And on aseptic oat grain adds fungi in the mixture of soil and sand to.The soil that infects is like this filled flowerpot ， And sowing sugar beet seed, and this seed is with handling as the test preparation (1000ppm effective constituent is calculated according to seed weight) of seed dressing pulvis by prescription.So, the flowerpot of having sowed is placed on 2-3 week in the 20-24 ℃ of greenhouse.Slowly spray by water with keeping and to keep soil evenly moistening.In the evaluation of test, measure emerging and the quantity of healthy and ill rice shoot of sugar beet.

Handling back＞80% rice shoot with the effective constituent of table 1 and 3 Chinese style I all emerges and outward appearance health.Contrast have only in the flowerpot minority rice shoot emerge and outward appearance unhealthy.

Embodiment 3.5: the direct effect of anti-tobacco downy mildew

By the effective constituent that prescription is made, concentration range 10,1 0.1ppm), is mixed with the agar of water system, and agar mixture is poured in the petri diss.After the cooling, with 100 μ l sporangia suspensions (10 ⁶Spore/ml) streak culture on the culture plate of plane.Culture plate was cultivated 16 hours down at 18 ℃.

There is not the sprouting of the compound inhibition tobacco downy mildew of table of discovery 1 and 3.

Claims

1, the benzoglyoxaline sulfonic acid of formula I

R ₃Be cyano group ,-CS-NH ₂Or-C (SR ')=NH, wherein R ' is C ₁-C ₄Alkyl, C ₁-C ₄Alkylhalide group, perhaps unsubstituted or by halogen and/or CF ₃The benzyl that replaces;

R ₄Be C ₁-C ₄Alkyl, C ₃-C ₆Cycloalkyl ,-N (R ") (R ' "),

Wherein R " and R ' " is identical or different C ₁-C ₃Alkyl;

X is oxygen or sulphur

N is integer 0,1 or 2.

2, according to the benzoglyoxaline sulfonic acid of the formula I of claim 1, R wherein ₄SO ₂Be in respect to substituent R ₁X-and R ₂1-or 3-position, and form pure positional isomers and hybrid position isomer, each substituting group is defined as follows in the formula:

R ₁For containing the unsaturated five-membered ring of no more than 2 sub-N of heterocycle and/or S, or contain the unsaturated hexa-member heterocycle of no more than 2 N atoms, each heterocycle can be unsubstituted or be replaced by at least 1 following substituting group: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkylhalide group, C ₁-C ₃Halogen alkoxyl group, and nitro;

R ₂Group is identical with different following groups: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkylhalide group, C ₁-C ₃The halogen alkoxyl group, nitro;

R ₃Be cyano group ,-CS-NH ₂Or-C(SR ')=NH, wherein R ' is C ₁-C ₄Alkyl, C ₁-C ₄Alkylhalide group, perhaps unsubstituted or by halogen and/or CF ₃The benzyl that replaces;

R ₄Be C ₁-C ₄Alkyl, C ₃-C ₆Cycloalkyl ,-N(R ") (R ), R " and R wherein

Be identical or different C ₁-C ₃Alkyl;

X is oxygen or sulphur

N is integer 0,1 or 2.

3, according to the derivative of claim 2, R wherein ₁Be pyridine, pyrimidine, pyrazine or pyridazine ring unsubstituted or that replace.

4, according to the derivative of claim 3, wherein hexa-member heterocycle is replaced by 1 to 3 substituting group, and this substituting group is selected from halogen, methyl, ethyl, sec.-propyl, methoxyl group, C ₁-C ₂Alkylhalide group wherein this halogen is F and/or Cl, CF ₃O, CHF ₂O or nitro.

5, according to the derivative of claim 4, wherein hexa-member heterocycle is unsubstituted or singly substitutes onto trisubstituted pyridine, each R ₂Group is identical or different following groups: fluorine, chlorine, bromine, methyl, methoxyl group, CF ₃, CF ₃O, or CHF ₂O, n=0,1 or 2.

6, according to the derivative of claim 5, R wherein ₂Be halogen or C ₁-C ₂Alkylhalide group.

7, according to the derivative of claim 6, wherein pyridine ring is by CF ₃Replace.

8, according to the derivative of claim 4, wherein this hexa-member heterocycle is a pyrimidine, and this pyrimidine is not substituted or is replaced by following groups: halogen, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, or C ₁-C ₂Alkylhalide group, R ₂Be fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl or trifluoromethoxy, n are 0,1 or 2.

9, according to the derivative of claim 8, wherein this hexa-member heterocycle is unsubstituted or by halogen-or pyrimidine of replacing of alkylhalide group, R ₂Be fluorine, chlorine, bromine, methyl, methoxyl group or CF ₃, n is 0,1 or 2.

10, according to the derivative of claim 9, wherein pyrimidine ring is connected the 4-position.

11, according to the derivative of claim 4, R wherein ₄Be methyl, dimethylamino, cyclopropyl, cyclopentyl or cyclohexyl.

12, according to the derivative of claim 11, R wherein ₄Be methyl.

13, according to the derivative of claim 11, R wherein ₄Be N, the N-dimethylamino.

14, according to the derivative of claim 2, R wherein ₃Be cyano group or C(S) NH ₂

15, according to the derivative of claim 2, XR wherein ₁Be in the 5/6-position.

16, according to the derivative of claim 2, R wherein ₁Be pyrroles unsubstituted or that replace, thiophene, thiazole, isothiazole, imidazoles or pyrazoles ring.

17, according to the derivative of claim 16, wherein this five-membered ring is by halogen and/or methyl substituted.

18, according to the derivative of claim 16, each R wherein ₂Group is identical or different halogen, methyl, methoxyl group, CF ₃, CF ₃O or CHF ₂O, n are 0,1 or 2.

19, according to the derivative of claim 2, wherein X is an oxygen.

20, according to the derivative of claim 2, wherein X is a sulphur.

21, a kind of II ' compound

R in the formula ₁, R ₂, X and n definition is as described in the claim 2.

22, the method for formula I compound of preparation claim 2, this method be by making formula II compound in-30 ℃-+180 ℃ inert solvent, reacts with formula III compound being with or without under the situation of alkali

R in the formula ₁, R ₂, R ₃, X and n definition are described suc as formula I, and M is hydrogen or basic metal, and Q is halogen atom or O-SO ₂-R ₄Base.

23, control and prevent that plant is subjected to the composition of microorganism encroach, said composition comprises the formula I compound of claim 2 as effective constituent and suitable carriers material.

24, according to the composition of claim 23, said composition comprises the compound of claim 3 as effective constituent.

25, according to claim 23 composition, said composition comprises among the claim 4-19 each compound as effective constituent.

26, control and prevent that plant is subjected to the method for microorganism encroach, this method comprises that to plant integral part of plant or the matrix of plant are used the compound of formula I.

27, the compound with claim 2 is used as microbicide.