CN100581362C - Bactericide composition and method for controlling plant disease - Google Patents

Bactericide composition and method for controlling plant disease Download PDF

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CN100581362C
CN100581362C CN200480032569A CN200480032569A CN100581362C CN 100581362 C CN100581362 C CN 100581362C CN 200480032569 A CN200480032569 A CN 200480032569A CN 200480032569 A CN200480032569 A CN 200480032569A CN 100581362 C CN100581362 C CN 100581362C
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trimethoxy
alkoxyl
alkyl
chloro
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CN1874680A (en
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西出久哉
西村重幸
三谷滋
南田幸二
金森文男
小川宗和
上林繁久
谷村丰史
樋口浩司
小南秀真
冈本智裕
西村昭广
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Ishihara Sangyo Kaisha Ltd
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Abstract

A bactericide composition which, when applied to crop plants infected with plant diseases, is stably and highly effective in controlling pests. The bactericide composition is characterized by containing, as active ingredients, (a) a benzoylpyridine derivative represented by the formula (I): (I) (wherein X is halogeno, nitro, an optionally substituted hydrocarbon group, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, hydroxy, optionally substituted alkylthio, cyano, optionally esterified or amidated carboxy, or optionally substituted amino; n is 1, 2, 3, or 4; R<1> is optionally substituted alkyl; R<2'> is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted cycloalkoxy, or hydroxy; p is 1, 2, or 3; and R<2'> is optionally substituted alkoxy or hydroxy; provided that at least two of the R<2'>s and R<2'> may form a fused ring containing oxygen) or a salt of the derivative and (b) at least one other bactericide.

Description

The method of control of microbicide compositions and plant disease
Technical field
The present invention relates to can be used as the microbicide compositions and the method for control that has used the plant disease of said composition of the agricultural or horticultural bactericide that significantly improves the effect that prevents and/or treats plant disease.
Background technology
In WO02/2527, the benzoyl pyridine derivative of having put down in writing as the active ingredient of microbicide compositions of the present invention is useful as bactericide, and put down in writing can be as required and mix to merge with other bactericide and use.But, and do not know that composition of the present invention has the bactericidal effect of significant excellence.
Patent documentation 1: international open communique WO02/2527
Summary of the invention
Benzoyl pyridine derivative shown in the aftermentioned formula (I) is aspect various plant disease control effects; effect to specific plant disease is insufficient; or lasting effect is shorter; or rain fastness is very weak; under some uses situation, aspect plant disease practical, only demonstrating inadequate preventive effect sometimes.
Present inventors further investigate in order to address the above problem; found that; use benzoyl pyridine derivative shown in the aftermentioned formula (I) and specific bactericide if mix; then compare with the situation of independent each compound of use; can obtain the bactericidal effect of beyond thought excellence, thereby finish the present invention.
That is, the present invention relates to a kind of microbicide compositions, it is characterized in that, contain (a) and (b) as active ingredient,
(a) be the benzoyl pyridine derivative shown in the formula (I) or its salt,
Figure C20048003256900061
[in the formula, X be halogen atom, nitro, can substituted alkyl, can substituted alkoxyl, can substituted aryloxy, can substituted cycloalkyloxy, hydroxyl, can substituted alkylthio group, cyano group, can esterified or amidated carboxyl or can substituted amino, n is 1,2,3 or 4; R 1For can substituted alkyl, R 2' being can substituted alkyl, can substituted alkoxyl, can substituted aryloxy, can substituted cycloalkyloxy or hydroxyl, p is 1,2 or 3, R 2" be can substituted alkoxyl or hydroxyl, or R 2' and R 2" at least 2 can form the condensed ring that contains oxygen atom],
(b) for being selected from least a kind of bactericide in the following substances, described material is imines bacterium (strobilurin) compounds, azole compounds, morpholine kind compound, pyrimidinamine compound, guanidine compound, the organochlorine compounds, glyoxaline compound, antibiotic, the pyridyl amine compound, quinoxaline compound, dithio amino formate compounds, the cyanoacetamide compounds, the phenyl amide compounds, the sulfenic acid compounds, copper compounds isoxazole compounds, organophosphorus compound, N-halo alkylthio compounds, two carbimide compounds, N-benzanilide compounds, piperazine compounds, pyridine compounds and their, the methyl alcohol compounds, piperidines, the organic tin compound, carbamide compounds, the cinnamic acid compound, the carbanilate compounds, cyanopyrrole compounds oxazolidone compounds, thiazole amide compound, the silicyl amides compound, the amino acid amide carbamate compound, the imidazolidine compounds, the hydroxyanilines compounds, oxime ether (oxime ether) compounds, the phenoxy group amides compound, benzophenone compound, Isoprothiolane (Isoprothiolane), pyroquilon (Pyroquilon), diclomezin (Diclomezine), quinoxyfen (Quinoxyfen), hundred dimension clever mono-hydrochloric salts (Propamocarb Hydrochloride), chloropicrin (Chloropicrin), dazomet (Dazomet), metham-sodium (Metam-sodium), Boscalid (Nicobifen), the two chlorine zarilamids (Diclocymet) and the third oxygen quinoline (Proquinazid).In addition, the present invention relates to a kind of the method for control of plant disease, it is characterized in that, above-mentioned microbicide compositions is applied to plant.
Halogen atom as in the formula (I) can use fluorine, chlorine, bromine or iodine, preferably uses for example fluorine, chlorine or bromine.
Hydrocarbyl portion as the be substituted alkyl in the formula (I) for example can list C 1-6Alkyl (for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group etc.), C 2-6Alkenyl (for example vinyl, pi-allyl, isopropenyl, 3-methyl-2-butene base etc.), C 2-6Alkynyl group (for example acetenyl, 1-propinyl, 2-propynyl etc.), C 3-6Cycloalkyl (for example cyclopropyl, cyclopenta, cyclohexyl), C 6-10Aryl etc.In addition, 2 substituting groups as can substituted alkyl for example can list, aryl, aryloxy, hydroxyl, nitro, nitroxyl, halogen (for example fluorine, chlorine, bromine, iodine etc.), halogenated alkoxy (CF for example 3O, HCF 2The C of O etc. 1-4Halogenated alkoxy), 1～5 the identical or different substituting group in cycloalkyl, amino, alkylthio group and the cyano group.In these can substituted alkyl, preferably can substituted alkyl, wherein special preferred alkyl.And then, in alkyl, C most preferably 1-4Alkyl.
As in the formula (I) can substituted alkyl, can substituted alkoxyl, moieties that can substituted alkylthio group, preferred C 1-6Alkyl (for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group etc.), wherein preferred C 1-4Alkyl.In addition, as these substituent 2 substituting groups, can list and be selected from aryl, aryloxy, hydroxyl, nitro, nitroxyl, halogen (for example fluorine, chlorine, bromine, iodine etc.), halogenated alkoxy (CF for example 3O, HCF 2The C of O etc. 1-4Halogenated alkoxy), 1～5 the identical or different substituting group in cycloalkyl, amino, alkylthio group and the cyano group.Have in the substituting group of moieties the preferred substituting group that does not have replacement, preferred especially C at these 1-4Alkyl.Wherein, most preferable.
As in the formula (I) can substituted aryloxy aryl moiety, except phenyl, can list the type that the condenses polycycle group that naphthyl is such, preferred phenyl.In addition, can substituted 2 substituting groups as these, can list halogen, alkyl, alkoxyl, hydroxyl etc.
As in the formula (I) can substituted cycloalkyloxy cycloalkyl moiety, be generally carbon number and be 3～10 cycloalkyl, for example, the monocyclic group of cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring octyl group etc., in addition, can also list and condense type polycycle group etc., preferred monocyclic group.In addition, as these can substituted group 2 substituting groups, can list halogen, alkyl, alkoxyl, hydroxyl etc.In cycloalkyloxy part, cyclohexyl oxygen base most preferably.
As in the formula (I) can esterified or amidated carboxyl, for example can list C 1-6Alkoxy carbonyl (for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl etc.), nitrooxy C 1-4Alkoxy amino carbonyl (for example 2-nitrooxy ethoxy carbonyl, 3-nitrooxy propoxycarbonyl etc.), phenyl C 1-4Alkoxy carbonyl (for example benzyl oxygen base carbonyl, phenethyl oxygen base carbonyl etc.) etc. can esterified carboxyl; Carbamoyl, C 1-6Alkyl monosubstituted amino carbonyl (for example methylamino carbonyl, ethylamino carbonyl, propyl group amino carbonyl, isopropyl amino carbonyl, butyl amino carbonyl, isobutylamino carbonyl, tert-butyl group amino carbonyl etc.), two C 1-6Alkyl amino-carbonyl (for example dimethylamino carbonyl, diethylamino carbonyl, dipropyl amino carbonyl, diisopropylaminoethyl carbonyl, dibutylamino carbonyl, different dibutylamino carbonyl etc.), nitrooxy C 1-4Alkyl amino-carbonyl (for example 2-nitrooxy ethylamino carbonyl, 3-nitrooxy propyl group amino carbonyl etc.), phenyl C 1-4Alkyl amino-carbonyl (for example benzylamino carbonyl, phenethyl amino carbonyl etc.) C 3-6Cycloalkyl amino carbonyl (for example cyclopropyl amino carbonyl etc.) C 3-6Cycloalkyl amino carbonyl (for example cyclopropyl amino carbonyl, cyclopenta amino carbonyl, cyclohexyl amino carbonyl etc.), cyclic aminocarbonyl (for example morpholino carbonyl, piperidino carbonyl, pyrrolidinyl carbonyl, thiomorpholine are for carbonyl etc.), amino carbonyl etc. can be by amidated carboxyl.
As in the formula (I) can substituted amino, for example can list amino; The alkyl amino of alkyl monosubstituted amino, dialkyl amido etc. etc.In addition, as the moieties of abovementioned alkyl amino, preferred C 1-4Alkyl.In addition, 2 substituting groups as can substituted amino can list, and are selected from aryl, aryloxy, hydroxyl, nitro, nitroxyl, halogen (for example fluorine, chlorine, bromine, iodine etc.), halogenated alkoxy (CF for example 3O, HCF 2The C of O etc. 1-4Halogenated alkoxy), 1～5 the identical or different substituting group in cycloalkyl, amino, alkylthio group and the cyano group.
In addition, the definition of aryl moiety, cycloalkyl moiety and moieties in substituent 2 substituting groups of above-mentioned each is according to each substituent definition.
Compound shown in the formula (I) can for example, can form the such inorganic acid salt of hydrochloride, hydrobromate, phosphate, sulphate or nitrate with the acidic materials salify; Acetate, benzoate, tosilate, mesylate or the such organic acid salt of propane sulfonic acid salt.
Compound shown in the formula (I) can obtain by disclosed manufacture method among the WO02/2527.In addition, also can be according to Journal of Organic Chemistry., 58,7832 (1993), European Journal of Organic Chemistry., 7, the method for 1371-1376 (2001) or each synthesis example described later is made.
As imines bacterium (strobilurin) compounds, for example can list, gram is received glad (Kresoxim-Methyl), nitrile Fluoxastrobin (Azoxystrobin), fork phenalgin acid amides (Metominofen), oxime bacterium ester (Trifloxystrobin), ZEN 90160 (Picoxystrobin), オ リ ザ ス ト ロ PVC Application (Oryzastrobin), ether bacterium amine (Dimoxystrobin) and fluoxastrobin (Fluoxastrobin).Wherein, preferred gram is received glad and nitrile Fluoxastrobin.
It is The Pesticide Manual (the 12nd edition that gram is received glad; BRITISH CROPPROTECTION COUNCIL) compound of the 568th～569 page of record.In addition, the nitrile Fluoxastrobin is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 54th～55 page of record.
As azole compounds, for example can list, according to general seat (Epoxiconazole), fluorine bacterium azoles (Triflumizole) Evil imidazoles fumarate (Oxpoconazole fumarate), Tebuconazole (Tebuconazole), acid amides azoles (Imibenconazole), fluorine ether azoles (Tetraconazole), triazolone (Triadimefon), Bitertanol (Bitertanol), etaconazole (Etaconazole), propiconazole (Propiconazole), penconazole (Penconazole), Flusilazole (Flusilazole), nitrile bacterium azoles (Myclobutanil), cyproconazole (Cyproconazole), azoles alcohol (Hexaconazole), furconazole_cis (Furconazole-Cis), prochloraz (Prochloraz), metconazole (Metconazole), シ プ コ Na ゾ one Le (Sipconazole), prothioconazoles (Prothioconazole), simeconazoles (Simeconazole), tricyclazole (Tricyclazole), probenazole (Probenazole), Fluquinconazole (Fluquinconazole) and triadimenol (Triadimenol).Wherein, preferably according to general seat, fluorine bacterium Zuo, Evil imidazoles fumarate, Tebuconazole, acid amides azoles, fluorine ether azoles, cyproconazole, metconazole, Fluquinconazole and triadimenol.
According to general seat is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 349th～350 page of record.Fluorine bacterium azoles (Triflumizole) is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 940th～941 page of record.Evil imidazoles fumarate (Oxpoconazole fumarate) is The Pesticide Manual (the 12nd edition; BRITISH CROP PROTECTION COUNCIL) compound of the 699th page of record.Tebuconazole (Tebuconazole) is The Pesticide Manual (the 12nd edition; BRITISHCROP PROTECTION COUNCIL) compound of the 864th～865 page of record.Acid amides azoles (Imibenconazole) is The Pesticide Manual (the 12nd edition; BRITISHCROP PROTECTION COUNCIL) compound of the 535th～536 page of record.Fluorine ether azoles (Tetraconazole) is The Pesticide Manual (the 13rd edition; BRITISHCROP PROTECTION COUNCIL) compound of the 945th～946 page of record.Cyproconazole is The Pesticide Manual (the 13rd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 248th～249 page of record.Metconazole is ThePesticide Manual (the 13rd edition; BRITISH CROP PROTECTIONCOUNCIL) compound of the 643rd～644 page of record.Fluquinconazole is The PesticideManual (the 13rd edition; BRITISH CROP PROTECTION COUNCIL) compound of the 472nd～473 page of record.Triadimenol is The Pesticide Manual (the 13rd edition; BRITISH CROP PROTECTION COUNCIL) compound of the 987th～989 page of record.
As morpholine kind compound, for example can list, (Fenpropimorph) is with the luxuriant amine of Luo Evil (Spiroxamine) for butadiene morpholine.Butadiene morpholine is The Pesticide ManuaI (the 12nd edition; BRITISH CROP PROTECTION COUNCIL) compound of the 399th～400 page of record.The luxuriant amine of ， Luo Evil is The Pesticide Manual (the 12nd edition in addition; BRITISH CROP PROTECTION COUNCIL) compound of the 842nd～843 page of record.
As pyrimidinamine compound, for example can list mepanipyrim (Mepanipyrim), pyrimethanil (Pyrimethanil) and ring third pyrimidine (Cyprodinil).Wherein, preferred mepanipyrim.Mepanipyrim is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 596th～597 page of record.
As guanidine compound, for example can list biguanide spicy acid salt (Iminoctadine).Biguanide spicy acid salt is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 539th～541 page of record.
As the organochlorine compounds, for example can list tpn (Chlorothalonil), Rabcide (Fthalide) and pcnb (Quintozene).Wherein, preferred tpn.Tpn is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 168th～169 page of record.
As glyoxaline compound, can list cyanogen frost azoles (Cyazofamid), benomyl (Benomyl), thiophanate methyl (Thiophanate-Methyl) and carbendazim (Carbendazim).Wherein, preferred cyanogen frost azoles.Cyanogen frost azoles is The Pesticide Manual (the 12nd edition; BRITISHCROP PROTECTION COUNCIL) compound of the 523rd～524 page of record.
As antibiotic, for example can list Polyoxin (Polyoxins).Polyoxin is The Pesticide Manual (the 12nd edition; BRITISH CROP PROTECTIONCOUNCIL) compound of the 752nd～754 page of record.
As the pyridyl amine compound, for example can list fluazinam (Fluazinam).
As quinoxaline compound, for example can list, mite manganese (Quinomethionate) goes out.
As dithio amino formate compounds, for example can list maneb (Maneb), zineb (Zineb), mancozeb (Mancozeb), Polycarbamate (Polycarbamate), Carbatene (Metiram) and propineb (Propineb).
As the cyanoacetamide compounds, for example can list cymoxanil (Cymoxanil).
As the phenyl amide compounds, for example can list metalaxyl (Metalaxyl), Metalaxyl-M (spirit of Metalaxyl M), Evil frost (Oxadixyl), fenfuram (Ofurace), M 9834 (Benalaxyl), furalaxyl (Furalaxyl) and cyprofuram (Cyprofuram).
As the sulfenic acid compounds, for example can list dichlofluanid (Dichlofluanid).
As the copper compounds, for example can list Kocide SD (Cupric hydroxide) and copper 8-hydroxyquinolinate (Oxine Copper).
As isoxazole compounds, for example can list hydroxyisoxazole (Hymexazol).
As organophosphorus compound, for example can list, fosetyl (Fosetyl-Al), tolelofos-methyl (Tolcofos-Methyl), S-benzyl O, O-diisopropyl thiophosphate, O-ethyl S, S-diphenyl phosphorodithioate and ethyl halide are for phosphonic acids aluminium.
As N-halo alkylthio compounds, for example can list captan (Captan), difoltan (Captafol) and folpet (Folpet).
As two carbimide compounds, for example can list procymidone (Procymidone), different third fixed (Iprodione) and the vinclozolin (Vinclozolin).
As N-benzanilide compounds, for example can list flutolanil (Flutolanil), the third oxygen mebenil (Mepronil), zoxamide (Zoxamid) and tiadinil (Tiadinil).
As piperazine compounds, for example can list triforine (Triforine).
As pyridine compounds and their, for example can list pyrifenox (Pyrifenox).
As the methyl alcohol compounds, for example can list fenarimol (Fenarimol) and Flutriafol (Flutriafol).
As piperidines, for example can list fenpropidin (Fenpropidine).Fenpropidin is The Pesticide Manual (the 13rd edition; BRITISH CROPPROTECTION COUNCIL) compound of the 419th～420 page of record.
As the organic tin compound, for example can list triphenyl tin hydroxide (FentinHydroxide) and triphenyltin acetate (Fentin Acetate).
As carbamide compounds, for example can list Pencycuron (Pencycuron).
As the cinnamic acid compound, for example can list dimethomorph (Dimethomorph) and flumorph (Flumorph).
As the carbanilate compounds, for example can list the mould prestige of second (Diethofencarb).
As the cyanopyrrole compounds, can list for example ， Fu Evil bacterium (Fludioxonil) and fenpiclonil (Fenpiclonil).
Zuo Wei oxazolidone compounds can list for example ， azolactone bacterium (Famoxadone).
As thiazole amide compound, for example can list Guardian (Ethaboxam).
As the silicyl amides compound, for example can list silicon metsulfovax (Silthiopham).
As the amino acid amide carbamate compound, for example can list Propineb (Iprovalicarb) and ベ Application チ ア バ リ カ Le Block (benthiavalicarb).
As the imidazolidine compounds, for example can list Fenamidone (Fenamidone).As the hydroxyanilines compounds, for example can list fenhexamid (Fenhexamid).
As benzenesulfonamides, for example can list flusulfamide (Flusulfamid).
As oxime ether (oxime ether) compounds, for example can list cyflufenamid (Cyflufenamid).
As the phenoxy group amides compound, for example can list zarilamid (Fenoxanil).
As benzophenone compound, for example can list metrafenone (Metrafenone).Metrafenone is AG CHEM NEW COMPOUND REVIEW, VOLUME21, the compound of 2003 the 17th pages of records.
As other compounds, for example can list Isoprothiolane (Isoprothiolane), pyroquilon (Pyroquilon), diclomezin (Diclomezine), quinoxyfen (Quinoxyfen), hundred dimension clever mono-hydrochloric salts (Propamocarb Hydrochloride), chloropicrin (Chloropicrin), dazomet (Dazomet), metham-sodium (Metam-sodium), Boscalid (Nicobifen), two chlorine zarilamid (Diclocymet) and the third oxygen quinoline (Proquinazid).
Bactericide as the active ingredient (b) of microbicide compositions of the present invention can list above-mentioned illustrative material.Wherein, the preferred use is selected from least a in imines azulenoid, azole compounds, morpholine kind compound, pyrimidinamine compound, guanidine compound, organochlorine compounds, glyoxaline compound, antibiotic, piperidines and the benzophenone compound.Further preferred the use is selected from gram and receives glad, nitrile Fluoxastrobin, at least a according in general seat, fluorine bacterium Zuo, Evil imidazoles fumarate, Tebuconazole, acid amides azoles, fluorine ether azoles, cyproconazole, metconazole, Fluquinconazole, triadimenol (triadimenol), the luxuriant amine of butadiene morpholine, Luo Evil, mepanipyrim, biguanide spicy acid salt, tpn, the white azoles of cyanogen, Polyoxin, fenpropidin and the metrafenone.
Microbicide compositions of the present invention has stable high bactericidal effect to the raise crop that is infected by plant disease, uses said composition, can prevent and kill off plant disease.
Embodiment
When the compound or its salt of making shown in the above-mentioned formula (I), can list following preferable methods.
(1) make the reacting metal salt of the substituted pyridine derivative shown in substituted benzaldehyde shown in the formula (VI-1) and the formula (VII-1), the phenylpyridyl methyl alcohol shown in the manufacturing formula (X) then with its oxidation, is made the method for the compound or its salt of above-mentioned formula (I),
Figure C20048003256900141
Formula (VI-1)
(in the formula, R 1, R 2', R 2" and p is as mentioned above),
Figure C20048003256900142
Formula (VII-1)
(in the formula, X as mentioned above, Z is metallic atom or its complex salt),
Formula (X)
(in the formula, X, R 1, R 2', R 2", n and p as mentioned above).
(2) make the slaine of the substituted benzene derivatives shown in the formula (VI-2) and the pyridine radicals formaldehyde reaction of the replacement shown in the formula (VII-2), phenylpyridyl methyl alcohol shown in the manufacturing formula (X), with its oxidation, make the method for the compound or its salt of above-mentioned formula (I) then
Figure C20048003256900144
Formula (VI-2)
(in the formula, R 1, R 2', R 2" and p is as mentioned above, Z is metallic atom or its complex salt),
Figure C20048003256900145
Formula (VII-2)
(in the formula, X and n are as mentioned above).
In above-mentioned method for making (1) and (2),, can list the typical metal atom of lithium, magnesium, zinc, copper etc. as the metallic atom that Z represents; The transition metal atoms of palladium, ruthenium etc. etc.In addition, replace metallic atom, the complex salt (ate complex) that also can use metallic atom is diaryl copper lithium, triaryl copper lithium etc. for example.
The compound of the compound of above-mentioned formula (VI-1) and formula (VII-2) can be made according to the method for known method, for example Journal of Organic Chemistry the 57th volume 6847-6852 page or leaf, record in 1992 usually.
Phenylpyridyl methyl alcohol shown in the formula (X) that produces by above-mentioned method for making (1) and (2), pass through known method, for example the burning agent by manganese dioxide, chromic acid etc., Swern oxidizing process (dimethyl sulfone+oxalyl chloride), ruthenium oxidizing process (tetrapropyl amine パ one Le テ ネ one ト+N-methylmorpholine-N-oxide) etc. are carried out oxidation, are transformed to the compound shown in the formula (1).
The compound of the formula (VII-1) in the method for making (1) can be by making formula (VIII)
[in the formula, X and n as mentioned above, Hal is a halogen atom] shown in compound and the compound shown in formula (IX): the Ar-Z (in the formula, Ar is an alkyl or aryl, and Z as mentioned above) react and obtain.This reaction is preferred in the presence of solvent, carry out under-100 ℃～120 ℃ reaction temperature.In addition,, for example can list isopropylmagnesium chloride, isopropyl bromination magnesium, lithium methide, butyl lithium, phenyl lithium, diisopropyl magnesium etc. as Ar-Z.Perhaps, also can use LDA, 2,2,6, the metalaxyl class of 6-tetramethyl piperamide lithium etc. obtains by hydrogen-metal exchange reaction.
(3) by with the compound of above-mentioned formula (VIII) and the compound shown in the formula (XI), in the presence of the transition-metal catalyst, under carbon monoxide atmosphere, react, make the method for the compound or its salt of above-mentioned formula (I) thus,
Formula (XI)
[in the formula, R 1, R 2', R 2" and p is as mentioned above, M is a metallic atom].
In above-mentioned method for making (3),, can list hydroxyl boron, boron alkyl, boron alkoxide, magnesium halide, zinc halide, tin alkyl, alkyl silane, alkoxyl alkane etc. as metallic atom.In addition, as transition-metal catalyst, can list palladium, rhodium, ruthenium etc.This reaction is preferably in the presence of single or the atent solvent that mixes, carry out under 0 ℃～200 ℃ reaction temperature.In addition, can under the carbon monoxide atmosphere of normal pressure, react, also can use pressure-resistant reaction device under the carbon monoxide pressurized state, to react.
(4) react by compound and the compound shown in the formula (XII) that makes above-mentioned formula (VII-1), make the method for the compound or its salt of above-mentioned formula (I),
Figure C20048003256900161
[in the formula, R 1, R 2', R 2" and p is as mentioned above, Y is a leaving group].
In above-mentioned method for making (4),, can list halogen, cyano group, alkoxyl etc. as the leaving group shown in the Y.The preferred aliphatic hydrocarbon of this reaction at hexane, cyclohexane, octane etc.; Under the existence of the ether solvent class of Di Iso Propyl Ether, oxolane, dimethoxy-ethane etc. single or the atent solvent that mixes, under-100 ℃～120 ℃ reaction temperature, carry out.In addition, transition metal complex that also can be by making nickel, palladium, iron etc. exists with the form of catalysis, further promotes reaction.
(5) make formula (XIII)
Figure C20048003256900162
Compound and formula (XIV) shown in [in the formula, X and n as mentioned above]
Figure C20048003256900163
[in the formula, R 1, R 2', R 2" and p as mentioned above] shown in compound, in the presence of lewis acid or dehydrating agent, react, make the method for the compound or its salt of above-mentioned formula (I).
The reaction of method for making (5) preferably in the presence of solvent, is carried out under 0 ℃～200 ℃ reaction temperature.As lewis acid or dehydrating agent, for example can list P 2O 5, phosphorous oxychloride, polyphosphoric acid, sulfuric acid, dicyclohexylcarbodiimide (DCC) etc.In addition,, can use any and the irrelevant solvent of reaction as solvent, for example, 1, the aromatic hydrocarbons of the halogenated hydrocarbon of 2-dichloroethane, carrene etc., benzene, chlorobenzene, dichloro-benzenes, nitrobenzene etc. etc. also can use the mixture of these solvents.
(6) manufacture method of the compound or its salt of a kind of above-mentioned formula (I) is the method that is made of following operation, and described operation is,
(a) the 1st operation, it is compound and the halogenating agent reaction that makes above-mentioned formula (XHI), the operation of coming the compound shown in the acquisition formula (XV)
Figure C20048003256900171
[in the formula, X and n as mentioned above, Hal is a halogen atom]; With
(b) the 2nd operation, it is the Friedel-Crafts reaction by the compound of the compound of the formula that obtains in the 1st operation (XV) and above-mentioned formula (XIV), obtains the operation of the compound of above-mentioned formula (I).
The reaction of the 1st operation of method for making (6) can be suitable for common carboxylic acid halides reaction.This reaction is preferably under the condition that has or do not exist atent solvent, carry out under 0～200 ℃ reaction temperature.Halogenating agent as using in this reaction can list fluorization agent, chlorinating agent, bromating agent etc., preferably uses chlorides such as thionyl chloride, phosphorous oxychloride, oxalyl chloride.The Friedel-Crafts reaction of the 2nd operation of method for making (6), can be in the presence of catalyzer, in solvent or under the solvent-free condition, under-78 ℃～200 ℃ reaction temperature, carry out, but preferably under 0 ℃～100 ℃ reaction temperature, carry out.As operable catalyzer in this reaction, can list FeCl 3, AlCl 3, SnCl 4, ZnCl 2, TiCl 4, SbCl 5, BF 3, BiCl 3Deng lewis acid catalyst, trifluoromethayl sulfonic acid, graphite.In addition,, can use the solvent of inertia under reaction condition, for example can list as solvent, 1,2-dichloroethane, carrene, chlorobenzene, dichloro-benzenes, nitrobenzene etc. still, also can use the mixture of these solvents.In addition, also can make by synthetic or derivatization with reference to Friedel-CraftsChemistry (Olah, G.A. work).
The compound of the above-mentioned formula of using as the production of raw material for use of method for making (5) and method for making (6) (XIII) can carry out oxidation and obtain by the compound with above-mentioned formula (VII-2).As oxidant, can use normally used inorganic or organic oxidizing agent.In addition, compound that can be by making above-mentioned formula (VII-1) directly with the dry ice reaction, perhaps react with the chlorine ethyl carbonate, hydrolysis obtains then.Perhaps, with the substituted pyridine-carboxylic acids or derivatives thereof, with the method for known document for example with reference to J.Heterocyclic.Chem., 36,653 (1999), make by synthetic or derivatization.In addition, can compile the 4th edition " experimental chemistry lecture 22, organic synthesis IV, 1992 ", make by synthetic or derivatization with reference to Japanization association.
In the benzoyl pyridine derivative shown in the formula (I), the compound shown in the preferred formula (I '),
[in the formula, be at A-situation of N=under, B is-CX 4=; At A be-situation of CH=under, B is-N=; X 1And X 2Represent halogen atom, alkoxyl, hydroxyl, alkyl, CF respectively independently 3Base or alkylthio group; X 3Be hydrogen atom, halogen atom, alkoxyl, alkyl, CF 3Base or alkylthio group; X 4Be hydrogen atom, halogen atom, alkoxyl, alkyl, CF 3Base or alkylthio group; R 1Be alkyl; R 2' be alkoxyl; P is 1,2 or 3; R 2" and R 2" ' be alkoxyl].
In the compound shown in the above-mentioned formula (I '), comprise A be-CH=, B for the compound under the situation of-N=be the compound shown in the formula (I '-1) and A for-N=, B be-CX 4=situation under compound be the compound shown in the formula (I '-2),
Formula (I '-1)
[X 1, X 2, X 3, R 1, R 2', R 2" and R 2" ' as mentioned above],
Figure C20048003256900183
Formula (I '-2)
[X 1, X 2, X 3, X 4, R 1, R 2', R 2" and R 2" ' as mentioned above].
In the compound shown in the above-mentioned formula (I '-1); further preferred the use is selected from least a in the following compound; described compound is: 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-4-bromo-5-chloro-2-methoxypyridine (compound N is o.1); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-5-chloro-4-ethyl-2-methoxypyridine (compound N is o.2); 3-(4; 5-dimethoxy-2-methyl benzoyl)-4; 5-two chloro-2-methoxypyridines (compound N o.3); 3-(5-ethyoxyl-4-methoxyl group-2-methyl benzoyl)-4; 5-two chloro-2-methoxypyridines (compound N o.4); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-4-bromo-5-chloro-2-ethoxy pyridine (compound N is o.5); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-5-chloro-2-ethyoxyl-4-picoline (compound N is o.6); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-5-bromo-4-chloro-2-ethoxy pyridine (compound N is o.7); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-4-chloro-5-iodo-2-methoxypyridine (compound N is o.8); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-5-iodo-2,4-dimethoxy-pyridine (compound N is o.9); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-methyl mercapto pyridine (compound N is o.10); 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2; 4-dimethoxy-pyridine (compound N o.11); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-4,5-two bromo-2-methoxypyridines (compound N is o.12); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-4-bromo-2-methoxyl group-5-picoline (compound N is o.13); 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-bromo-4-trifluoromethyl-2-methoxypyridine (compound N o.14); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-4,5-two chloro-2-methoxypyridines (compound N is o.15); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-2; 4-two chloro-5-picolines (compound N o.16); 3-(2,3,4-trimethoxy-6-methyl benzoyl)-2; 4-two chloro-5-iodine pyridines (compound N o.17); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-2-fluoro-4-iodo-5-picoline (compound N is o.18); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-2-fluoro-4; 5-lutidines (compound N o.19); 3-(2,3,4-trimethoxy-6-methyl benzoyl)-2-methoxyl group-4; 5-lutidines (compound N o.20); 3-(2-ethyoxyl-3; 4-dimethoxy-6-methyl benzoyl)-and 2-ethyoxyl-4,5-lutidines (compound N is o.21); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-4; 5-dimethyl-2-methyl mercapto pyridine (compound N o.22); 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-bromo-4-chloro-2-methoxypyridine (compound N o.23); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-4-chloro-2-methoxyl group-5-picoline (compound N is o.24); 3-(2,3,4-trimethoxy-6-methyl benzoyl)-2-chloro-5-trifluoromethyl-4-picoline (compound N o.25); 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-5-trifluoromethyl-2-methoxyl group-4-picoline (compound N is o.26); 3-(2,3,4-trimethoxy-6-methyl benzoyl)-2; 4-two chloro-5-5-flumethiazines (compound N o.27); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-4-chloro-5-trifluoromethyl-2-methoxypyridine (compound N is o.28); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-5-chloro-4-acetenyl-2-methoxypyridine (compound N is o.29); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-5-chloro-4-methyl fluoride-2-methoxypyridine (compound N is o.30); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-5-bromo-4-methyl fluoride-2-methoxypyridine (compound N is o.31); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-4-methyl fluoride-2-methoxyl group-5-picoline (compound N is o.32); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-5-chloro-4-difluoromethyl-2-methoxypyridine (compound N is o.33); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-5-ethyl-4-trifluoromethyl-2-methoxypyridine (compound N is o.34); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N is o.35); 3-(2; 3,4-trimethoxy-6-methyl benzoyl)-5-bromo-2-methoxyl group-4-picoline (compound N is o.36); 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-4-trifluoromethyl-2-methoxyl group-5-picoline (compound N is o.37) and 3-(4,5-dimethoxy-2-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N is o.38).
In the compound shown in the above-mentioned formula (I '-2); further preferred the use is selected from least a in the following compound; described compound is: 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-2; 5-two chloro-3-5-flumethiazines (compound N o.39); 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-2-chloro-3-trifluoromethyl-5-methoxypyridine (compound N is o.40); 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-2-bromo-3-trifluoromethyl-5-methoxypyridine (compound N is o.41); 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-2; 3; 5-trichloropyridine (compound N o.42); 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-3; 5-dichloropyridine (compound N o.43); 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-3-chloro-5-methoxypyridine (compound N is o.44); 4-(2,3,4-trimethoxy-6-methyl benzoyl)-2 bromo-3-chloro-5-methoxypyridine (compound N o.45) and 4-(2; 3,4-trimethoxy-6-methyl benzoyl)-3-bromo-5-picoline (compound N is o.46).
Microbicide compositions of the present invention is useful as agricultural or horticultural bactericide especially.As agricultural or horticultural bactericide, be effectively to preventing and kill off of for example following disease, described disease is: for example rice blast, gingili leaf rot, banded sclerotial blight; The powdery mildew of wheat class, head blight, mildew, snow mold, naked smut, eyeprint disease, leaf blight, glume blight; The black spot of oranges and tangerines, common shot hole; The blossom rot of apple, powdery mildew, spot defoliation, scab; The scab of pears, black spot; The grey scab of peach, scab, the rotten disease of plan stem dibbling; The anthrachose of grape of grape, late blight, powdery mildew, downy mildew; The anthracnose of persimmon, defoliation; Melon anthracnose, powdery mildew, climing rot, downy mildew; The ring spot of tomato, leaf mold, epidemic disease; The epidemic disease in summer of the black spot of brassicaceous vegetable, potato, epidemic disease; The powdery mildew of strawberry; The gray mold of various crops, stalk break etc.Particularly, show excellent preventive effect to powdery mildew and the rice blast of wheat class, greengrocery.In addition, also be effective to preventing and kill off of the microbial soil disease of pathogenic by sickle spore bacterium, pythium spp, rhizoctonia, verticillium sp, plasmodiophora brassicae etc.
Constitute a plurality of active ingredients of microbicide compositions of the present invention, same with existing pesticidal preparations, mix with various adjuvants, the preparation that forms the various forms of pulvis, granule, particle hydrating agents, hydrating agents, aqueous suspension agent, oiliness suspending agent, water-soluble preparation, emulsion, liquor, paste, aerosol, micro-spraying agent etc. uses.But,, then can be any preparation form of common this area use so long as be fit to purpose of the present invention.Adjuvant as the preparation use, can list the solid type carrier of the mixture of diatomite, calcium hydroxide, calcium carbonate, talcum, white carbon, kaolin, bentonite, kaolinite and sericite, clay, sodium carbonate, sodium bicarbonate, saltcake, zeolite, starch etc.; The solvent of water, toluene, dimethylbenzene, solvent naphtha, diox, acetone, isophorone, methyl iso-butyl ketone (MIBK), chlorobenzene, cyclohexane, dimethyl sulfoxide (DMSO), dimethyl formamide, dimethylacetylamide, N-N-methyl-2-2-pyrrolidone N-, alcohol etc.; Soap, benzoate, alkyl sulfo succinate, dialkyl sulfosuccinates, Merlon, alkyl sulfate salt, alkyl sulfate, alkyl aryl sulfate, alkyl biphenyl sulphate, the alcohol sulfuric acid, alkylsulfonate, alkylaryl sulfonates, arylsulphonate, ligninsulfonate, alkyl diphenyl base ether disulfonate, poly styrene sulfonate, alkyl phosphate salt, alkylaryl phosphate, the styryl aryl orthophosphate, the polyoxyethylene alkyl ether sulfuric acid, polyoxyethylene alkylaryl ether sulphate, the polyoxyethylene alkylaryl ether sulfuric acid, polyoxyethylene alkyl ether phosphate, polyxyethylated aryl phosphate ester salt, the surfactant of the anionic species that the salt of naphthalene sulfonic acid-formaldehyde condensation product is such, solvent; Sorbitan fatty ester, fatty acid glyceride, fatty acid polyglycerol ester, the fatty acid alcohol polyglycol ether, acetylenediol, acetylene alcohol, the oxyalkylene block polymer, polyoxyethylene alkyl ether, polyoxyethylene alkylaryl ether, polyoxyethylene styryl aryl ether, polyoxyethylene glycol alkyl ether, polyoxyethylene fatty acid ester, the polyoxyethylene sorbitan fatty acid ester, the polyoxyethylene fatty acid glyceride, polyoxyethylene hardened castor oil, the surfactant of the nonionic class that the polyoxypropylene fatty acid ester is such, solvent; Vegetable oil, the mineral wet goods of olive oil, melon kopok oil, castor oil, palm oil, camellia oil, cocoa butter, sesame oil, corn oil, rice bran oil, arachis oil, cottonseed oil, soybean oil, rapeseed oil, Linseed oil, tung oil, atoleine etc.These adjuvants in not departing from purpose scope of the present invention, can be selected from material well known in the art.In addition, also can use incremental agent, thickener, precipitation to prevent normally used various adjuvants such as agent, antifreezing agent, dispersion stabilizer, poisoning palliative, mould inhibitor.The ratio that cooperates of active ingredient compound and various adjuvants, be generally 0.005: 99.995～95: 5, be preferably 0.2: 99.8～90: 10.These preparations can directly use when reality is used, and thinner that also can water etc. is diluted to normal concentration, adds various solvents as required and uses.
The present invention also comprises a kind of the method for control of plant disease, it is characterized in that, microbicide compositions of the present invention is applied to agriculture and garden uses plant.The working concentration of microbicide compositions of the present invention, the difference along with the difference of object crop, using method, preparation form, amount of application etc., can not decide, but under the situation that cauline leaf is handled, unit active ingredient is generally 0.1～10000ppm, is preferably 1～2000ppm without exception.Under case of soil treatment, be generally 10～100000g/ha, be preferably 200～20000g/ha.
The various preparations of microbicide compositions of the present invention or using of its dilution can utilize general application process promptly to scatter (for example scatter, spraying, misting, atomizing, spread grain, used for ponds method etc.), soil application (sneak into, perfusion etc.), surface applied (coating, powder clothing, lining etc.) waits and carries out usually.In addition, also can utilize so-called ultrahigh concentration to scatter method (ultra lowvolume) on a small quantity uses.In the method, can contain 100% active component.
In microbicide compositions of the present invention; the suitable mixed weight ratio of the benzoyl pyridine derivative shown in the formula (I) or its salt and other bactericide, be generally 1: 10000～10000: 1, be preferably 1: 1000～1000: 1, more preferably 1: 200～200: 1.
Embodiment
Put down in writing relevant synthesis example of the present invention below, but the present invention is not limited.
Synthesis example 1
3-(2,3,4-trimethoxy-6-methyl benzoyl)-4,5-two chloro-2-methoxypyridines (compound N is o.15) synthetic
(a) in the 400ml oxolane, being dissolved with the solution that 34.2g (340mmol) diisopropylamine forms, drip 222ml n-BuLis (1.57mol/l hexane solution) at-20 ℃, stirred 1 hour.Solution is cooled to-78 ℃, is added on the solution that is dissolved with 32.0g (330mmol) 2-fluorine pyridine in the 50ml oxolane, stirred 4 hours, modulation 2-fluoro-3-pyridine radicals lithium.Then, in this solution, be added on the solution that is dissolved with 87.1g (341mmol) iodine in the 150ml oxolane, stirred 1 hour.In mixture, add 200ml water, stop reaction, under reduced pressure heat up in a steamer oxolane.After the ether extraction, organic layer is carried out drying with sodium sulphate, filter, under reduced pressure heat up in a steamer and desolvate, obtain the thick product 67.4g (thick yield 92%) of 2-fluoro-3-iodine pyridine.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝6.91-6.88(m，1H)，8.08-8.12(m，2H)
(b) in the solution that in the 380ml oxolane, is dissolved with 30.2g (302mmol) diisopropylamine, drip 189ml n-BuLi (1.57mol/l hexane solution) at-20 ℃, stirred 1 hour.Solution is cooled to-78 ℃, be added on the solution of the thick product that is dissolved with the 2-fluoro-3-iodine pyridine that obtains in 67.4g (302mmol) operation (a) in the 100ml oxolane, stirred 1 hour, the 2-fluoro-3-iodo-4-pyridine radicals lithium that the initial stage is generated is isomerizated into 2-fluoro-4-iodo-3-pyridine radicals lithium.In reactant mixture, add 300ml water, stop reaction, under reduced pressure heat up in a steamer oxolane.After the ether extraction, organic layer is carried out drying with sodium sulphate, filter, under reduced pressure heat up in a steamer and desolvate, obtain the thick product of 59.3g (thick yield 89%) 2-fluoro-4-iodine pyridine.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝7.33(d，1H，J＝2.8Hz)，7.51(d，1H，J＝5.2Hz)，7.88(dd，1H，J＝5.2Hz，2.8Hz)
Add 500ml methyl alcohol among the thick product 59.4g (253mmol) of the 2-fluoro-4-iodine pyridine that (c) in operation b, obtains, make its dissolving, add 21.5g (398mmol) sodium methoxide, added hot reflux 3 hours.Add 300ml water, stop reaction, under reduced pressure, heat up in a steamer methyl alcohol.After the ether extraction, organic layer is carried out drying with sodium sulphate, filter, under reduced pressure heat up in a steamer and desolvate, obtain the thick product 56.7g (thick yield 91%) of 4-iodo-2-methoxypyridine.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝3.86(s，3H)，7.12-7.16(m，2H)，7.79(d，1H，J＝5.6Hz)
(d) 50.6ml (2mol/l tetrahydrofuran solution) isopropylmagnesium chloride is carried out ice-cooled, be added on the solution that the 80ml oxolane is dissolved with the thick product of the 4-iodo-2-methoxypyridine that obtains in 19.8g (84.3mmol) operation (c), 0 ℃ stir 1 hour, at stirring at room 1 hour, modulation 2-methoxyl group-4-pyridine radicals magnesium chloride.Then, slowly add 16.9g (127mmol) N-chlorosuccinimide, stirring at room 1 hour.Add 100ml water, stop reaction, under reduced pressure heat up in a steamer oxolane.After the ether extraction, organic layer is carried out drying with sodium sulphate, filter, under reduced pressure heat up in a steamer and desolvate, obtain the thick product 11.0g (thick yield 91%) of 4-chloro-2-methoxypyridine.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝3.91(s，3H)，6.70(d，1H，J＝2.0Hz)，6.81(dd，1H，J＝6.0Hz，2.0Hz)，7.99(d，1H，J＝6.0Hz)
(e) the thick product 10.0g (69.9mmol) with the 4-chloro-2-methoxypyridine that obtains in the operation (d) was dissolved in the 100ml dimethyl formamide, adds 37.2g (279mmol) N-chloro-succinimide, stirring at room 12 hours.Add 400ml water, stop reaction, after the ether extraction,, use dried over sodium sulfate, filter, under reduced pressure heat up in a steamer and desolvate, obtain 4, the thick product 9.10g of 5-two chloro-2-methoxypyridines (thick yield 73%) organic layer saturated common salt water washing.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝3.90(s，3H)，6.85(s，1H)，8.14(s，1H)
(f) in the solution that in the 30ml oxolane, is dissolved with 2.40g (23.7mmol) diisopropylamine, drip 15.1ml n-BuLi (1.57mol/l hexane solution) at-20 ℃, stirred 1 hour.Solution is cooled to-78 ℃, is added on and is dissolved with 4 of the middle acquisition of 4.22g (23.6mmol) operation (e) in the 20ml oxolane, the solution of 5-two chloro-2-methoxypyridines stirred 2 hours, modulation 4,5-two chloro-2-methoxyl groups-3-pyridine radicals lithium.Then, be added in this solution and be dissolved with 5.00g (23.8mmol) 2,3 in the 20ml oxolane, the solution of 4-trimethoxy-6-tolyl aldehyde stirred 30 minutes.In mixture, add 50ml water, stop reaction, under reduced pressure heat up in a steamer oxolane.After the ether extraction, organic layer is carried out drying with sodium sulphate, filter, under reduced pressure heat up in a steamer and desolvate, utilize silica gel column chromatography to make with extra care, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (4,5-two chloro-2-methoxyl group-3-pyridine radicals) methyl alcohol 4.66g (yield 51%).
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝2.32(s，3H)，3.52(s，3H)，3.77(s，3H)，3.82(s，3H)，4.11(s，3H)，5.32(d，1H，J＝10.0Hz)，6.21(d，1H，J＝10.0Hz)，6，55(s，1H)，8.07(s，1H)
(g) in 30ml toluene, being dissolved with 4.66g (12.0mmol) operation (f), obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (4,5-two chloro-2-methoxyl group-3-pyridine radicals) methyl alcohol, add 13.8g (159mmol) manganese dioxide, carry out 2 hours the hot reflux that adds.After being cooled to room temperature, use sellaite to remove manganese dioxide after, under reduced pressure, heat up in a steamer toluene; utilize silica gel column chromatography to make with extra care, obtain 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-4,5-two chloro-2-methoxypyridine 2.98g (yield 65%).
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝2.46(s，3H)，3.45(s，3H)，3.74(s，3H)，3.90(s，3H)，4.00(s，3H)，6.55(s，1H)，8.13(s，1H)
Synthesis example 2
3-(2,3,4-trimethoxy-6-methyl benzoyl)-2-methoxyl group-4,5-lutidines (compound N is o.20) synthetic
(a) in the solution that in the 70ml oxolane, is dissolved with 4.02g (39.8mmol) diisopropylamine, drip 26.5ml n-BuLi (1.57mol/l hexane solution) at-78 ℃, stirred 30 minutes.In this solution, be added on the solution that is dissolved with 4.42g (39.8mmol) 2-fluoro-5-picoline in the 18ml oxolane, stirred 4 hours, modulation 2-fluoro-5-methyl-3-pyridine radicals lithium.Then, in this solution, be added on the solution that is dissolved with 10.1g (39.8mmol) iodine in the 27ml oxolane, stirred 2 hours.Add 16ml water, 120ml sodium thiosulfate solution, after the ether extraction, with magnesium sulfate organic layer is carried out drying, filtration, under reduced pressure heat up in a steamer and desolvate, the thick product that is obtained is made with extra care with silica gel column chromatography, obtain 2-fluoro-3-iodo-5-picoline 3.15g (yield 33%).
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝2.27(s，3H)，7.95(m，2H)
(b) in the solution that in the 27ml oxolane, is dissolved with 1.34g (13.3mmol) diisopropylamine, drip 8.90ml n-BuLi (1.57mol/l hexane solution) at-78 ℃, stirred 30 minutes.In this solution, be added on the solution of the 2-fluoro-3-iodo-5-picoline that obtains in the operation (a) that is dissolved with 3.15g (13.3mmol) in the 5ml oxolane, stirred then 1 hour, 2-fluoro-3-iodo-5-methyl-4-pyridine radicals lithium that the initial stage is generated is isomerizated into 2-fluoro-4-iodo-5-methyl-3-pyridine radicals lithium.Be added in reactant mixture and be dissolved with 2,3 of 2.79g (13.3mmol) in the 5ml oxolane, the solution of 4-trimethoxy-6-tolyl aldehyde stirred 2 hours.Be warming up to room temperature, add 50ml water then, after the ether extraction, with magnesium sulfate organic layer is carried out drying, filtration, under reduced pressure heating up in a steamer the thick product that desolvates, will obtain makes with extra care with silica gel column chromatography, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (2-fluoro-4-iodo-5-methyl-3-pyridine radicals) methyl alcohol of 4.45g (yield 75%).
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝2.21(s，3H)，2.42(s，3H)，3.72(s，3H)，3.79(s，3H)，3.81(s，3H)，4.97(d，1H，J＝10.0Hz)，6.08(d，1H，J＝10.0Hz)，.46(s，H)，.86(s，H)
(c) in 130ml toluene, being dissolved with 4.35g (9.70mmol) operation (b), obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (2-fluoro-4-iodo-5-methyl-3-pyridine radicals) methyl alcohol, adds 17.3g (0.18mol) manganese dioxide, added hot reflux 2 hours.Be cooled to room temperature, use sellaite then, remove manganese dioxide, under reduced pressure heat up in a steamer toluene then, make with extra care, obtain 2.80g (yield 65%) 3-(2 with silica gel column chromatography, 3,4-trimethoxy-6-methyl benzoyl)-(compound N is o.18 for 2-fluoro-4-iodo-5-picoline; Fusing point 140-141 ℃).
1H-NMR(CDCl 3，00MHz)：δ(ppm)＝2.41(s，H)，.50(s，H)，3.42(s，3H)，3.90(s，3H)，3.74(s，3H)，6.57(s，1H)，7.94(s，1H)
(d) mix the 3-(2 that obtains in 1.50g (3.37mmol) operation (c); 3; 4-trimethoxy-6-methyl benzoyl)-and 50% trimethylboroxin of 2-fluoro-4-iodo-5-picoline, 1.40g (10.1mmol) potash, 0.39g (0.34mmol) tetrakis triphenylphosphine palladium, 15ml diox, 0.42g (1.67mmol), heating 6 hours refluxes.After being cooled to room temperature; filter with sellaite; wash with ethyl acetate and oxolane; under reduced pressure heat up in a steamer and desolvate; the thick product that obtains is made with extra care with silica gel column chromatography, obtained the 3-(2,3 of 0.79g (yield 70%); 4-trimethoxy-6-methyl benzoyl)-and 2-fluoro-4,5-lutidines (compound N is o.19).
1H-NMR(CDCl 3，00MHz)：δ(ppm)＝2.28(s，3H)，2.32(s，3H)，2.42(s，3H)，3.35(s，3H)，3.74(s，3H)，3.90(s，3H)，6.57(s，1H)，7.94(s，1H)
(e) 3-(2 that in the operation (d) that in 2.5ml methyl alcohol, is dissolved with 0.20g (0.60mmol), obtains; 3; 4-trimethoxy-6-methyl benzoyl)-2-fluoro-4; in the solution of 5-lutidines; dropping is dissolved with the solution of 60% sodium hydride of 0.06g (1.5mmol) in 1ml methyl alcohol, heating 16 hours refluxes.Behind the cool to room temperature; add 5ml water; carry out faintly acidization with watery hydrochloric acid, after the ether extraction, wash with saline solution; with magnesium sulfate organic layer is carried out drying, filtration; under reduced pressure heat up in a steamer the thick product that desolvates, will obtain and make with extra care, obtain the 3-(2,3 of 89.0mg (yield 43%) with silica gel column chromatography; 4-trimethoxy-6-methyl benzoyl)-and 2-methoxyl group-4, the 5-lutidines.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝2.19(s，3H)，2.21(s，3H)，2.39(s，3H)，3.24(s，3H)，3.70(s，3H)，3.74(s，3H)，3.87(s，3H)，6.53(s，1H)，7.87(s，1H)
Synthesis example 3
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-bromo-4-chloro-2-methoxypyridine (compound N o.23)
(a) 5.76g (40.1mmol) 4-chloro-2-methoxypyridine is dissolved in the 20ml dimethyl formamide, drips dimethyl formamide (20ml) solution 30 minutes of 8.01g (98% product, 44.1mmol) N-bromine succinimide.After at room temperature stirring 2 days because find unreacted raw material, so and then add N-bromine succinimide 2.85g (98% product, 16mmol), further stirred 3 days in room temperature.Inject reactant mixture to 250ml water, with ether (each 100ml) extraction 3 times.Water (100ml) washing organic layer with sodium thiosulfate solution (100ml) washing, then with saturated aqueous common salt (100ml) washing, carries out drying, filtration with magnesium sulfate, under reduced pressure heats up in a steamer and desolvates.The thick product that obtains is made with extra care with silica gel column chromatography, obtained 7.10g (yield 80%) 5-bromo-4-chloro-2-methoxypyridine.
1H-NMR(CDCl 3、400MHz)：δ(ppm)＝3.91(s，3H)、6.89(s，1H)、8.28(s，1H)
(b) in the 36ml oxolane, being dissolved with 2,2,6 of 3.84g (27mmol), in the solution of 6-tetramethyl pyridine, under argon gas stream, at 0 ℃ of dropping 18.3ml n-BuLi (1.57mol/l hexane solution, 27mmol), stirred 30 minutes at 0 ℃.The solution that is obtained is cooled to-78 ℃, is added on the solution of the 5-bromo-4-chloro-2-methoxypyridine that is dissolved with 6.10g (27mmol) in the 24ml oxolane, stirred 2 hours down, modulation 5-bromo-4-chloro-2-methoxyl group-3-pyridine radicals lithium synthermal.Then, be added on and be dissolved with 5.50g (26mmol) 2,3 in the 24ml oxolane, the solution of 4-trimethoxy-6-tolyl aldehyde stirred 1 hour down synthermal.In reactant mixture, add 37ml saturated aqueous ammonium chloride, then, add 150ml water, be warming up to room temperature after, with ethyl acetate (each 150ml) extraction 3 times.With saturated aqueous common salt (100ml) washing organic layer, carry out drying, filtration with magnesium sulfate, under reduced pressure heat up in a steamer and desolvate.The thick product that obtains is made with extra care with silica gel column chromatography, obtained 6.53g (yield 56%) (2,3,4-trimethoxy-6-aminomethyl phenyl) (5-bromo-4-chloro-2-methoxyl group-3-pyridine radicals) methyl alcohol.
1H-NMR(CDCl 3、400MHz)：δ(ppm)＝2.33(s，3H)、3.54(s，3H)、3.79(s，3H)、3.84(s，3H)、3.98(s，3H)、5.32(d，1H?J＝9.6Hz)、6.23(d，1HJ＝9.6Hz)、6.49(s，1H)、8.21(s，1H)
To in 70ml toluene, being dissolved with (2 of 2.21g (5.1mmol), 3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (5-bromo-4-chloro-2-methoxyl group-3-pyridine radicals) methyl alcohol, add 4.55g (88% product, 46mmol) manganese dioxide, heating 1 hour refluxes.And then, adding 4.55g (88% product, 46mmol) manganese dioxide, heating 1 hour refluxes.Reactant mixture is cooled to room temperature, uses sellaite to remove manganese dioxide then, under reduced pressure heat up in a steamer toluene.The thick product that obtains is made with extra care with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-bromo-4-chloro-2-methoxypyridine (84～87 ℃ of fusing points) of 1.90g (yield 87%).
1H-NMR(CDCl 3、400MHz)：δ(ppm)＝2.48(s，3H)、3.45(s，3H)、3.75(s，3H)、3.87(s，3H)、3.91(s，3H)、6.57(s，1H)、8.27(s，1H)
Synthesis example 4
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N o.35)
(a) to the 15ml N of 8.0g (65mmol) 2-methoxyl group-4-picoline, in dinethylformamide (DMF) solution, drop into N-chloro-succinimide 9.2g (69mmol), stirred 18 hours.In reaction solution, add entry, behind the extracted with diethyl ether water layer,, carry out drying, filter then, under reduced pressure heat up in a steamer and desolvate with anhydrous sodium sulfate with saturated common salt water washing organic layer.With the refining thick product of silica gel column chromatography, obtain 5-chloro-2-methoxyl group-4-picoline (32～33 ℃ of fusing points) of 8.5g (yield 82%). 1HNMR(CDCl 3，300MHz)：δ2.32(s，3H)，3.89(s，3H)，6.62(s，1H)，8.05(s，1H)
(b) to the 15ml N of 7.2g (46mmol) 5-chloro-2-methoxyl group-4-picoline, in dinethylformamide (DMF) solution, drop into 20.2g (114mmol) N-bromine succinimide, stirred 20 hours down at 50 ℃.In reaction solution, add rare sodium thiosulfate solution, use the extracted with diethyl ether water layer.With saturated common salt water washing organic layer, carry out drying with anhydrous sodium sulfate, filter with the silica gel filter cake then, under reduced pressure heat up in a steamer and desolvate, obtain 3-bromo-5-chloro-2-methoxyl group-4-picoline (44～45 ℃ of fusing points) of 10.6g (yield 97%).
1HNMR(CDCl 3，300MHz)：δ2.51(s，3H)，3.98(s，3H)，8.01(s，1H)
(c) in 2.2ml (4.4mmol) isopropylmagnesium chloride (2.0mol/l tetrahydrofuran solution), add 4ml oxolane, 0.62ml (4.4mmol) triethylamine, be cooled to 0 ℃, dropping is dissolved with the solution of 1.0g (4.2mmol) 3-bromo-5-chloro-2-methoxyl group-4-picoline in the 5ml oxolane, stirred modulation 5-chloro-2-methoxyl group-4-methyl-3-pyridine radicals magnesium chloride then 3 hours.To in the 5ml oxolane, be dissolved with 2,3 of 0.89g (4.2mmol), be added drop-wise in the reaction solution in the solution of 4-trimethoxy-6-tolyl aldehyde, stir after 1 hour, and be warming up to room temperature, and then stirred 1 hour.In reaction solution, add entry, stop reaction, extract out, use saturated common salt water washing organic layer then, carry out drying, filter then, under reduced pressure heat up in a steamer and desolvate with anhydrous magnesium sulfate with ethyl acetate.With the refining thick product of silica gel column chromatography, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (the 5-chloro-2-methoxyl group-4-methyl-3-pyridine radicals) methyl alcohol (faint yellow oily thing) of 1.1g (yield 70%).
1HNMR(CDCl 3，300MHz)：δ2.26(s，3H)，2.27(s，3H)，3.54(s，3H)，3.80(s，3H)，3.84(s，3H)，3.94(s，3H)，5.32(d，1H，J＝9.0Hz)，6.12(d，1H，J＝9.0Hz)，6.47(s，1H)，8.02(s，1H)
(d) in the 15ml toluene solution of 0.64g (1.7mmol) (2,3,4-trimethoxy-6-aminomethyl phenyl) (5-chloro-2-methoxyl group-4-methyl-3-pyridine radicals) methyl alcohol, add the 4g activated manganese dioxide, stirred 1 hour adding under the hot reflux.Use sellaite to come filtering reacting solution, under reduced pressure heat up in a steamer and desolvate, obtain 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (94.5～95.5 ℃ of fusing points) of 0.57g (yield 90%).
1HNMR(CDCl 3，00MHz)：δ2.31(s，3H)，2.40(s，3H)，3.30(s，3H)，3.73(s，3H)，3.74(s，3H)，3.88(s，3H)，6.54(s，1H)，8.06(s，1H)
Synthesis example 5
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-4-trifluoromethyl-2-methoxyl group-5-picoline (compound N o.37)
(a) will in 40ml methyl alcohol, be dissolved with the solution of 5.05g (27.8mmol) 2-chloro-4-5-flumethiazine, 3.59g (66.5mmol) sodium methoxide, stir 4 hours adding under the hot reflux.Add entry, stop reaction, extract, use the anhydrous sodium sulfate drying organic layer then, filter with the silica gel filter cake with ether.Under reduced pressure heat up in a steamer the 4-trifluoromethyl-2-methoxypyridine that desolvates, obtains 4.19g (yield 85%).
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝3.96(s，3H)，6.95(s，1H)，7.05(d，1H，J＝5.2Hz)，8.29(d，1H，J＝5.2Hz)
(b) in the solution of the 4-trifluoromethyl-2-methoxypyridine that in 15ml acetate, being dissolved with 8.21g (46.4mmol) operation (a), obtains, 7.98g (97.3mmol) sodium acetate, drip 4.00ml (78.1mmol) bromine, stirred 4 days.Add potassium hydroxide aqueous solution, stop reaction, after extracted with diethyl ether, use the anhydrous sodium sulfate drying organic layer, filter with the silica gel filter cake.Under reduced pressure heat up in a steamer and desolvate, obtain the mixture 5.81g (mol ratio 55: 45) of the 4-trifluoromethyl-2-methoxypyridine of 5-bromo-4-trifluoromethyl-2-methoxypyridine and raw material.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝3.94(s，3H)，7.03(s，1H)，8.37(s，1H)
(c) in the solution that in the 50ml oxolane, is dissolved with 3.80ml (27.1mmol) diisopropylamine, drip 17.1ml n-BuLi (1.57mol/l hexane solution) at 0 ℃, stirred 30 minutes.Solution is cooled to-78 ℃, be added on the mixture 5.81g(mol ratio 55: 45 that is dissolved with 5-bromo-4-trifluoromethyl-2-methoxypyridine of obtaining in the operation (c) and 4-trifluoromethyl-2-methoxypyridine among the oxolane 10mL) solution, stirred the mixture of modulation 5-bromo-4-trifluoromethyl-2-methoxyl group-3-pyridine radicals lithium and 4-trifluoromethyl-2-methoxyl group-3-pyridine radicals lithium 45 minutes.Be added on and be dissolved with 2,3 of 5.51g (26.2mmol) in the 15mL oxolane, the solution of 4-trimethoxy-6-tolyl aldehyde stirred 1 hour.In mixture, add entry, stop reaction, under reduced pressure heat up in a steamer oxolane.Behind ethyl acetate extraction, use the anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained (2,3,4-trimethoxy-6-aminomethyl phenyl) (5-bromo-4-trifluoromethyl-2-methoxyl group-3-pyridine radicals) methyl alcohol of 5.02g.
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝2.35(s，3H)，3.29(s，3H)，3.74(s，3H)，3.82(s，3H)，3.92(s，3H)，4.87(d，1H，J＝10.8Hz)，6.21(d，1H，J＝10.8Hz)，6.51(s，1H)，8.31(s，1H)
(d) in the operation (c) that in 110mL toluene, is dissolved with 4.80g (10.3mmol), obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (5-bromo-4-trifluoromethyl-2-methoxyl group-3-pyridine radicals) methyl alcohol, add 20.0g (230mmol) manganese dioxide, stirred 1 hour adding under the hot reflux.Be cooled to room temperature, then mixture filtered with sellaite, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-bromo-4-trifluoromethyl-2-methoxypyridine (compound N o.31) of 3.93g (yield 82%).
1H-NMR(CDCl 3，400MHz)：δ(ppm)＝2.57(s，3H)，3.36(s，3H)，3.75(s，3H)，3.86(s，3H)，3.93(s，3H)，6.59(s，1H)，8.38(s，1H)
(e) 3-(2 that in the 10ml oxolane, being dissolved with 0.60g (1.29mmol) operation (d), obtains; 3; 4-trimethoxy-6-methyl benzoyl)-solution of 5-bromo-4-trifluoromethyl-2-methoxypyridine, 0.10g (0.09mmol) tetrakis triphenylphosphine palladium in; drip 3.80ml (3.80mmol) zinc methide (1.0mol/l hexane solution) at 0 ℃; naturally after heating up, at room temperature stirred 8 days.Add entry, stop reaction, under reduced pressure heat up in a steamer oxolane.Behind ethyl acetate extraction, use the anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl)-4-trifluoromethyl-2-methoxyl group-5-picoline 0.50g (yield 96%).
1H-NMR(CDCl 3，00MHz)：δ(ppm)＝2.41(s，3H)，2.56(s，3H)，3.29(s，3H)，3.74(s，3H)，3.83(s，3H)，3.91(s，3H)，6.58(s，1H)，8.05(s，1H)
Synthesis example 6
4-(2,3,4-trimethoxy-6-methyl benzoyl)-2,5-two chloro-3-5-flumethiazines (compound N is o.39) synthetic
(a) in the solution that in the 60ml ether, is dissolved with 3.6ml (25mmol) diisopropylamine, drip 17ml (25mmol) n-BuLi (1.5mol/l hexane solution) at 0 ℃, stirred 45 minutes.Solution is cooled to-78 ℃, be added on and be dissolved with 2,3 of 6.0g (24mmol) in the 8ml ether, the solution of 6-three chloro-5-5-flumethiazines, stirred 25 minutes, modulation 2,3 is behind 6-three chloro-5-trifluoromethyls-4-pyridine radicals lithium, be added on and be dissolved with 2 of 5.0g (24mmol) in the 12ml toluene, 3, the solution of 4-trimethoxy-6-tolyl aldehyde stirred 1 hour.In mixture, add 30ml water, stop reaction, use the ethyl acetate extraction water layer, use the anhydrous sodium sulfate drying organic layer then, filter, under reduced pressure heat up in a steamer and desolvate, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (2,3,6-three chloro-5-trifluoromethyl-4-pyridine radicals) methyl alcohol (131～135 ℃ of fusing points).
(b) in 200ml methyl alcohol, being dissolved with operation (a), obtain 2,3,4-trimethoxy-6-aminomethyl phenyl) (2,3,6-three chloro-5-trifluoromethyl-4-pyridine radicals) in the solution of methyl alcohol, add the 5% palladium carbon of 2.7ml (19mmol) triethylamine, 0.9g, under nitrogen atmosphere, stirred 14 hours.Filtering mixt adds 30ml water, under reduced pressure heats up in a steamer methyl alcohol.Extract with ethyl acetate, use the anhydrous sodium sulfate drying organic layer then, filter, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained (2,3,4-trimethoxy-6-aminomethyl phenyl) (2,5-two chloro-3-trifluoromethyl-4-pyridine radicals) methyl alcohol (162～165 ℃ of fusing points) 2.38g (yield 24%).
(c) in 100ml toluene, being dissolved with 3.5g (8.2mmol) operation (b), obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (2,5-two chloro-3-trifluoromethyl-4-pyridine radicals) methyl alcohol, add 14g manganese dioxide, stirred 6 hours adding under the hot reflux.Cooling mixture filters then, under reduced pressure heats up in a steamer toluene.Thick product is made with extra care with silica gel column chromatography, obtained 4-(2,3,4-trimethoxy-6-methyl benzoyl)-2,5-two chloro-3-5-flumethiazines (106～109 ℃ of fusing points) 3.1g (yield 89%).
Synthesis example 7
Synthesizing of 4-(2,3,4-trimethoxy-6-methyl benzoyl)-2-chloro-3-trifluoromethyl-5-methoxypyridine (compound N o.40)
(a) in the solution of the 120ml ether of 15.0ml (107mmol) diisopropylamine, drip n-BuLi (1.5mol/l hexane solution) 70.0ml (106mmol) at 0 ℃, stirred 1 hour.With-78 ℃ of solution coolings, add 22.1g (102mmol) 2, the solution of the 10ml ether of 3-two chloro-5-5-flumethiazines, stirred modulation 2,3-two chloro-5-trifluoromethyls-4-pyridine radicals lithium 30 minutes, add 21.0g (100mmol) 2 then, 3, the solution of the 40ml toluene of 4-trimethoxy-6-tolyl aldehyde stirred 2 hours.In mixture, add 30ml water, stop reaction, use the ethyl acetate extraction water layer, use the anhydrous sodium sulfate drying organic layer then, filter, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained (2,3,4-trimethoxy-6-aminomethyl phenyl) (2,3-two chloro-5-trifluoromethyl-4-pyridine radicals) methyl alcohol (95～98 ℃ of fusing points) 24.8g (yield 58%).
(b) in operation (a), obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (2,3-two chloro-5-trifluoromethyl-4-pyridine radicals) in the methyl alcohol 200ml solution of methyl alcohol 24.8g (58.1mmol), triethylamine 9.50ml (68.2mmol), the 5% palladium carbon that adds 2.1g stirred 4 hours under nitrogen atmosphere.Filtering mixt adds 50ml water, under reduced pressure heats up in a steamer methyl alcohol.Use the ethyl acetate extraction water layer, use the anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained (2,3,4-trimethoxy-6-aminomethyl phenyl) (3-chloro-5-trifluoromethyl-4-pyridine radicals) methyl alcohol (102～105 ℃ of fusing points) 15.9g (yield 70%).
(c) (2,3,4-trimethoxy-6-aminomethyl phenyl) (3-chloro-5-trifluoromethyl-4-pyridine radicals) the methyl alcohol 15.9g that in operation (b), obtains (40, in toluene 220ml solution 6mmol), add 45g manganese dioxide, stirred 2 hours adding under the hot reflux.Filtering mixt under reduced pressure heats up in a steamer and desolvates, obtains 4-(2,3,4-trimethoxy-6-methyl benzoyl)-3-chloro-5-5-flumethiazine (75～77 ℃ of fusing points) 14.9g (yield 94%).
(d) 4-(2 that in operation (c), obtains; 3; 4-trimethoxy-6-methyl benzoyl)-the toluene 150ml solution of 3-chloro-5-5-flumethiazine 18.5g (47.5mmol), hexamethyl phosphoric triamide 16.6ml (95.4mmol) in; add sodium methoxide 16.4g (304mmol), stirred 30 minutes adding under the hot reflux.Add entry, stop reaction, use the ethyl acetate extraction water layer then, use the anhydrous sodium sulfate drying water layer, filter, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained 4-(2,3,4-trimethoxy-6-methyl benzoyl)-3-methoxyl group-5-5-flumethiazine (103～106 ℃ of fusing points) 11.7g (yield 64%).
(e) to 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-the chloroform 100ml solution of 3-methoxyl group-5-5-flumethiazine (compound N o.122) 5.6g (15mmol) in, add metachloroperbenzoic acid (m-CPBA) 6.1g (28mmol) at 0 ℃, then stirring at room 18 hours.Reaction solution is washed with sodium hydrate aqueous solution, under reduced pressure heat up in a steamer and desolvate, obtain 4-(2,3,4-trimethoxy-6-methyl benzoyl)-3-methoxyl group-5-5-flumethiazine-N-oxide (128～134 ℃ of fusing points) 5.8g (yield 99%).
(f) in 4ml toluene, 8ml dimethyl formamide, add 1.8ml (19mmol) phosphorous oxychloride at 0 ℃, stirred 10 minutes; add 4.0g (10mmol) 4-(2 then; 3,4-trimethoxy-6-methyl benzoyl)-3-methoxyl group-5-5-flumethiazine-N-oxide, stirred 20 minutes.Stirring at room 2 hours, then reaction solution is put in the frozen water, stop reaction.With the ethyl acetate extraction water layer, use the anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained 4-(2,3,4-trimethoxy-6-methyl benzoyl)-2-chloro-3-trifluoromethyl-5-methoxypyridine (117～119 ℃ of fusing points) 3.57g (yield 85%).
Synthesis example 8
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N o.35)
(a) with 45.6g (217mmol) 2,3,4-trimethoxy-6-tolyl aldehyde was dissolved in the 130ml dimethyl sulfoxide (DMSO), with 20 minutes dropping sodium dihydrogen phosphate 5.2g (44mmol) aqueous solution (50ml).Then, with 3 hours dropping sodium chlorite 28g (305mmol) aqueous solution (180ml), stirred 2 hours.Add saturated sodium bicarbonate aqueous solution until not foaming, stirred 1 hour, with 50ml ethyl acetate reaction solution is washed 2 times then, then, add concentrated hydrochloric acid, make water layer be acid, use ethyl acetate extraction.With organic layer saturated common salt water washing, use anhydrous sodium sulfate drying, filter, under reduced pressure heat up in a steamer and desolvate.With resulting crystallization hexane wash, obtain 2,3,4-trimethoxy-6-methyl benzoic acid (fusing point 95-97 ℃) 45.6g (yield 93%).
1HNMR：δ2.56(s，3H)，3.86(s，3H)，3.91(s，3H)，4.03(s，3H)，6.60(s，1H)
(b-1) 6.8ml (13.6mmol) isopropylmagnesium chloride (2M tetrahydrofuran solution) is cooled to 0 ℃, dropping is dissolved with the solution of 3-bromo-5-chloro-2-methoxyl group-4-picoline of 1.6g (6.6mmol) in the 5ml oxolane, stirred 3 hours modulation 5-chloro-2-methoxyl group-4-methyl-3-pyridine radicals magnesium chloride down synthermal.And then, reaction solution is cooled to-78 ℃, drip the solution that in the 15ml oxolane, is dissolved with 1.2g (13.3mmol) cuprous cyanide (I) and 1.15g (27.1mmol) lithium chloride, modulation 5-chloro-2-methoxyl group-4-methyl-3-pyridine radicals copper reactant.On the other hand, with 3.2g (14.3mmol) 2,3 synthetic in (a) operation, 4-trimethoxy-6-methyl benzoic acid, in the 7ml thionyl chloride, added hot reflux 3 hours, and under reduced pressure heated up in a steamer superfluous thionyl chloride, with modulate 2,3,4-trimethoxy-6-methyl benzoyl chloride is dissolved in the 7ml oxolane, is added in the pyridine radicals copper reactant that modulates in advance-78 ℃ of drips of solution that will obtain like this, stirs after 1 hour, be warming up to room temperature, and then stirred 2 hours.In reaction solution, add entry, ammoniacal liquor, stop reaction, use ethyl acetate extraction.With the organic layer anhydrous magnesium sulfate drying, filter then, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (85～88 ℃ of fusing points) 2.6g (yield 57%), use 1HNMR has identified compound.
(b-2) 11ml (11.0mmol) tetrahydrofuran solution of use 1M isopropylmagnesium chloride; 2.5g (10.6mmol) 3-bromo-5-chloro-2-methoxyl group-4-picoline; carry out and the same reaction of operation (b-1); replace cuprous cyanide (I); the lithium chloride tetrahydrofuran solution; and use 1.25g (1.1mmol) tetra-triphenylphosphine palladium; at 0 ℃; dripped by 2.4g (10.6mm0l) 2 with 2 hours; 3; 4-trimethoxy-6-methyl benzoic acid and 5ml thionyl chloride modulate 2; 3; 4-trimethoxy-6-methyl benzoyl chloride; stirred 15 hours down synthermal, obtain 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-and 5-chloro-2-methoxyl group-4-picoline 1.7g (yield 43%), use 1HNMR has identified compound.
(b-3) by with the same reaction of operation (b-2); replace the tetrahydrofuran solution of 1M isopropylmagnesium chloride and use the 0.5M isopropylmagnesium chloride 22ml (22.0mmol) tetrahydrofuran solution, replace tetra-triphenylphosphine palladium and use 1.14g (11.5mmol) copper chloride; obtain 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-and 5-chloro-2-methoxyl group-4-picoline 1.7g (yield 43%), use 1HNMR has identified compound.
Synthesis example 9
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N o.35)
(a) will 5.0g (19mmol) 2-bromo-3 be arranged at the 50ml ether dissolution, 4, the solution of 5-trimethoxytoluene is cooled to-78 ℃, drip 15ml (24mmol) n-BuLi (1.6M hexane solution), stirred 1.5 hours, and generated 2,3,4-trimethoxy-6-methyl-2-phenyl lithium drips 4.9ml (43mmol) trimethylborate then and then stirred 1 hour.Add dilute sulfuric acid, stop reaction, stir after 30 minutes, and then add entry.Use the ethyl acetate extraction water layer,,, under reduced pressure heat up in a steamer and desolvate, obtain 2,3,4-trimethoxy-6-aminomethyl phenyl boric acid (99～102 ℃ of fusing points) 3.26g (yield 75%) with anhydrous magnesium sulfate drying, filtration with saturated common salt water washing organic layer.
1HNMR：δ2.52(s，3H)，3.83(s，3H)，3.88(s，3H)，3.94(s，3H)，6.56(s，1H)
(b) in the 200ml autoclave, add 3-bromo-5-chloro-2-methoxyl group-4-picoline 1.0g (4.3mmol), 2,3,4-trimethoxy-6-aminomethyl phenyl boric acid 1.2g (5.4mmol), potash 1.8g (13mmol), palladium bichloride 46mg (0.26mmol), tricyclohexyl phosphine 147mg (0.52mmol), oxolane 40ml, enclose 10 atmospheric CO gas, stirred 20 hours at 120 ℃.Reaction solution is filtered with sellaite, add entry, under reduced pressure heat up in a steamer oxolane.Use the ethyl acetate extraction water layer,, filter then, under reduced pressure heat up in a steamer and desolvate the organic layer anhydrous magnesium sulfate drying.Thick product is made with extra care with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (92～94 ℃ of fusing points) 0.31g (yield 20%), use 1The HNMR authenticating compound.
Synthesis example 10
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N o.35)
(a) in the 500ml four-hole boiling flask that possesses agitator, cooler, thermometer and nitrogen balloon, add 5.4g (222mmol) magnesium and 95ml oxolane, temperature in the system is remained on 40 ℃ on one side,, stir a night Yi Bian drip isopropyl chloride 17.3g (220mmol).Then, temperature in the system is remained on 0 ℃ or below it, drip the solution of the 95ml oxolane of 47.3g (200mmol) 3-bromo-5-chloro-2-methoxyl group-4-picoline simultaneously, stirred 3 hours, then dropwise reaction liquid in dry ice.
Drop into reactant liquor in 300ml water, behind the separatory, dripping hydrochloric acid water carries out acidification in water layer, extracts with ether.Under reduced pressure heat up in a steamer and desolvate, obtain 5-chloro-2-methoxyl group-4-methylnicotinic acid (127～129 ℃ of fusing points) 26g (yield 65%).
(b) in the 50ml four-hole boiling flask that possesses agitator, cooler, thermometer and nitrogen balloon, add 5-chloro-2-methoxyl group-4-methylnicotinic acid 1.0g (4.96mmol), 3,4,5-trimethoxytoluene 0.9g (4.94mmol), 1,2-dichloroethane 20ml and phosphorus pentoxide 7.1g (50.0mmol) stirred 1 hour under refluxing.
In 50ml water, drop into reactant liquor, add sodium hydrate aqueous solution, make its alkalization, behind the separatory, under reduced pressure heat up in a steamer and desolvate.In the residue that is obtained, add the 5ml hexane, the crystallization of separating out is filtered, obtain object 0.4g (yield 22%).
Synthesis example 11
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N o.35)
In the 20ml eggplant-shape bottle that possesses reflux cooler, add 5-chloro-2-methoxyl group-4-methylnicotinic acid 1.0g (5.0mmol), 1,2-dichloroethane 10g and oxalyl chloride 0.62g (5.0mmol) stirred 20 minutes at 25 ℃, then 60 ℃～65 ℃ heating 2 hours.25 ℃ of coolings, in reactant mixture, add 3,4 then, 5-trimethoxytoluene 0.80g (4.4mmol), anhydrous Aluminum chloride 0.70g (5.2mmol) stirred 3 hours at 25 ℃.
In reactant mixture, add entry and ethyl acetate, behind extraction, the separatory, with the organic layer dried over sodium sulfate, under reduced pressure heat up in a steamer and desolvate.Add n-hexane in the solid of separating out, filter, drying obtains object 0.66g (yield 36.1%).
Synthesis example 12
Synthesizing of 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline (compound N o.35)
(a) to 6.0g (26.6mmol) 2,3, add the 10ml thionyl chloride in 4-trimethoxy-6-methyl benzoic acid, stirred 4 hours adding under the hot reflux, under reduced pressure heat up in a steamer superfluous thionyl chloride then.To wherein adding toluene 20ml, acetonitrile 8ml, copper cyanider (I) 3.1g (34.5mmol), stirred 16 hours adding under the hot reflux.After being cooled to room temperature, use the sellaite filtering reacting solution, under reduced pressure heat up in a steamer and desolvate.Thick product is made with extra care with silica gel column chromatography, obtained 2,3,4-trimethoxy-6-toluyl nitrile 2.8g (yield 45%).
1HNMR：δ2.44(s，3H)，3.85(s，3H)，3.95(s，3H)，4.14(s，3H)，6.53(s，1H)
(b) will be dissolved with 1.9g (8.0mmol) 2,3 in the 20ml oxolane, the solution of 4-trimethoxy-6-toluyl nitrile is cooled to-10 ℃, adds 0.32g (0.91mmol) pentanedione acid iron (III) salt, stirs 20 minutes.In other reaction vessels, in the tetrahydrofuran solution 4.1ml of 2M isopropylmagnesium chloride (8.2mmol), add oxolane 4ml, be cooled to 0 ℃, dropping is dissolved with the solution of 1.0g (4.2mmol) 3-bromo-5-chloro-2-methoxyl group-4-picoline in the 5ml oxolane, stirred then 3 hours, and generated 5-chloro-2-methoxyl group-4-methyl-3-pyridine radicals magnesium chloride.To just modulated 2,3, in 4-trimethoxy-6-toluyl nitrile-iron mixed solution, drip the pyridine radicals magnesium chloride solution modulate, stirred 3 hours.In reaction solution, add 10% aqueous ammonium chloride solution, stop reaction, behind ethyl acetate extraction,, carry out drying, filter then, under reduced pressure heat up in a steamer and desolvate with anhydrous magnesium sulfate with saturated common salt water washing organic layer.Thick product is made with extra care with silica gel column chromatography, obtained object 1.7g (yield 58%).
Intermediate synthesis example 1
(a) in the 2L four-hole boiling flask that possesses agitator, thermometer and gas conduit (importing), add 324g (3.00mol) 2-amino-4-picoline and 485g methyl alcohol, mixed dissolution, then temperature in the system is remained on 10～30 ℃, simultaneously with 1 hour 30 minutes importing 361.4g (9.90mol) hydrogen chloride gas.
Then, to possessing agitator, thermometer, dropping funel, reaching in the 2L four-hole boiling flask of the conduit that has bubble counter (derivation) that connects gas generating unit and diazo-reaction device, mix natrium nitrosum 414g (6.00mol), methyl alcohol 211g (6.60mol) and water 454g, temperature in the system is remained on 20～30 ℃, simultaneously with 5 hours dropping 38% aqueous sulfuric acid 812.4g (3.15mol).
In the methyl nitrite generating means, when dripping 38% aqueous sulfuric acid, produce corresponding methyl nitrite gas, import in the diazo-reaction device by bubble counter.
On the other hand, in diazo-reaction, carry out water cooling so that the interior temperature of system can maintain 20～30 ℃.
After importing methyl nitrite gas, under equality of temperature, stirred 13 hours, finish reaction.
After methyl alcohol is heated up in a steamer in decompression, drop into water 648g, and then, drip 40% sodium hydrate aqueous solution 518g at 30 ℃ or below it, the pH in the regulation system is 12.
To generate oil with the ether of 910g and extract, and behind the separatory, under reduced pressure heat up in a steamer and desolvate, obtain 375.3g oil.In addition, this oil (thick product) consists of 2-chloro-4-picoline 70.7% (yield 69.5%), 2-methoxyl group-4-picoline 26.6% (yield 27.2%), 2-amino-4-picoline 2.6%.
(b) in the 2L four-hole boiling flask that possesses agitator, thermometer, cooling tube and dropping funel, add 356g methyl alcohol, under agitation remain 50 ℃ or below it, drop into sodium methoxide 237.6g (4.4mol) simultaneously, then temperature in the system is remained on 60～70 ℃, simultaneously with the thick product 375.3g (70.7% product, 2.2mol) that dripped the 2-chloro-4-picoline that obtains in the above-mentioned operation in 3 hours.
Drip after the end, heat up in a steamer methyl alcohol, added hot reflux simultaneously 3 hours (amount of heating up in a steamer of methyl alcohol during this period is 120g).
Reaction finishes the back, the remaining methyl alcohol in the system is heated up in a steamer in decompression, drops into 750g water then, dissolve inorganic salts.
With the oil that generates extracted with diethyl ether with 1050g, behind the separatory, under reduced pressure heat up in a steamer and desolvate, obtain 370g oil (thick product).The purity of the 2-methoxyl group-4-picoline that is obtained in addition, is 95% (the 2 stage yields that begin from 2-amino-4-picoline are 95%).
Intermediate synthesis example 2
Synthesizing of 5-chloro-4-methyl-2-methoxyl group-nicotinic acid
(a) 4,4-dicyano-3-methyl-3-crotonaldehyde-dimethyl-acetal, 1,1-dicyano-4-methoxyl group-2-methyl isophthalic acid, the mixture of 3-butadiene synthetic
In the solution of the 100ml toluene of 3.15g (37mmol) pyridine, add 2.28g (37mmol) acetate, at room temperature stirred 1 hour, add the solution of the 20ml toluene of 49.3g (373mmol) acetyl group acetaldehyde dimethyl-acetal then.And then the solution with slowly adding the 30ml toluene of 24.65g (373mmol) malononitrile in 20 minutes at room temperature stirred 5 days.With 50ml water washing reactant mixture, carry out drying with magnesium sulfate then, under reduced pressure heat up in a steamer and desolvate, obtain 4,4-dicyano-3-methyl-3-crotonaldehyde-dimethyl-acetal, 1,1-dicyano-4-methoxyl group-2-methyl isophthalic acid, the mixture 69.35g of 3-butadiene.
(b) 3-cyano group-4-methylpyridone is synthetic
With obtain in (a) 4,4-dicyano-3-methyl-3-crotonaldehyde-dimethyl-acetal, 1,1-dicyano-4-methoxyl group-2-methyl isophthalic acid, the mixture 69.35g of 3-butadiene is to be no more than 30 ℃ like that, slowly be added drop-wise among the concentrated sulfuric acid 113g with 3 hours.At room temperature stirred 20 minutes, and be warming up to 50 ℃ then, stirred 2 hours down synthermal.Put cold after, reactant mixture slowly is injected in the frozen water (500ml), the crystallization that leaching obtained is with 100ml water washing crystallization.With air-dry 1 week of crystallization, and then, obtain the coarse crystallization of 3-cyano group-4-methylpyridone 34.2g (2 stage yield 68%) under reduced pressure 70 ℃ of dryings 8 hours. 1H-NMR(400MHz、DMSO-d6)：δ(ppm)2.35(s，3H)、6.29(d，J＝6.4Hz，1H)、7.64(d，J＝6.4Hz，1H)
(c) 2-chloro-3-cyano group-4-picoline is synthetic
In the mixture of phosphorus pentachloride 6.52g (31.3mmol), phosphorous oxychloride 30ml (48g, 313mmol), slowly add 3-cyano group-4-methylpyridone 14g (104mmol), at room temperature stirred 70 minutes, stirred 2 hours adding under the hot reflux then.Put cold after, in frozen water (400ml), inject reactant mixture, superfluous reactant is decomposed after, with 100ml dichloromethane extraction 3 times.With 100ml saturated common salt water washing dichloromethane solution, carry out drying, under reduced pressure heat up in a steamer and desolvate with magnesium sulfate, obtain the coarse crystallization 15.1g of 2-chloro-3-cyano group-4-picoline. 1H-NMR(400MHz、DMSO-d6)：δ(ppm)2.86(s，3H)、7.89(d，J＝5.6Hz，1H)、8.86(d，J＝5.6Hz，1H)
(d) 3-cyano group-4-methyl-2-methoxypyridine is synthetic
The coarse crystallization of the 2-chloro-3-cyano group-4-picoline of acquisition among the 15.1g (c) is dissolved in the 150ml absolute methanol, adds the methanol solution 24.9g (129mmol) of 28% sodium methoxide, at room temperature stirred 2 days.Reactant mixture is injected in the 200ml saturated aqueous common salt, uses 100ml ethyl acetate extraction 3 times.Ethyl acetate solution with dried over mgso, filter by sellaite-silicagel column, is fully washed pillar with ethyl acetate.Merging filtrate, cleaning solution, the coarse crystallization of under reduced pressure heating up in a steamer the 3-cyano group-4-methyl-2-methoxypyridine that desolvates, obtains 14.04g. 1H-NMR(400MHz、CDCl 3)：δ(ppm)2.51(s，3H)、4.03(s，3H)、6.84(d，J＝5.2Hz，1H)、8.18(d，J＝5.2Hz，1H)
(e) 5-chloro-3-cyano group-4-methyl-2-methoxypyridine is synthetic
3-cyano group-4-methyl-2-methoxypyridine that 14.04g (95mmol) is obtained in (d) is dissolved in the 100ml dimethyl formamide, adds 25.4g (190mmol) N-chloro-succinimide, at room temperature stirs 3 days.Confirm with thin layer chromatography reaction carry out situation the time, in order to confirm the remaining situation of raw material, 50 ℃ stir 22 hours, stirred 22 hours at 60 ℃ then.Put cold after, reactant mixture is injected among the water 300ml, with 100ml ethyl acetate extraction 3 times.Ethyl acetate solution is used the 150ml water washing 2 times successively,, under reduced pressure heat up in a steamer and desolvate then with the water washing of 100ml saturated common salt, carry out drying with magnesium sulfate.The residue that obtains is made with extra care with silicagel column, obtained 5-chloro-3-cyano group-4-methyl-2-methoxypyridine 13.68g (3 stage yield 79%).
1H-NMR(400MHz、CDCl 3)：δ(ppm)2.56(s，3H)、4.03(s，3H)、8.23(s，1H)
(f) 5-chloro-3-formoxyl-4-methyl-2-methoxypyridine is synthetic
2.47g (13.5mmol) 5-chloro-3-cyano group-4-methyl-2-methoxypyridine is dissolved in the 50ml anhydrous methylene chloride, is cooled to-78 ℃, slowly drip the toluene solution 20.3ml (20.3mmol) of 1M diisobutyl aluminium hydride then.Stirred 2 hours down at-78 ℃, slowly be warming up to room temperature then, synthermal stirring 3 days.The solution that is obtained is cooled off at ice bath, slowly add 30ml water, finish reaction.Reactant mixture is injected in the 1N hydrochloric acid of 150ml, uses 100ml dichloromethane extraction 2 times.Dichloromethane solution with the water washing of 100ml saturated common salt, is carried out drying, under reduced pressure heats up in a steamer and desolvate with magnesium sulfate, obtain thick 5-chloro-3-formoxyl-4-methyl-2-methoxypyridine.
1H-NMR(400MHz、CDCl 3)：δ(ppm)2.65(s，3H)、4.03(s，3H)、8.25(s，1H)、10.48(s，1H)
(g) 5-chloro-4-methyl-2-methoxyl group-nicotinic acid is synthetic
The thick 5-chloro-3-formoxyl-4-methyl-2-methoxypyridine that obtains in (f) is dissolved in the 14ml dimethyl sulfoxide (DMSO); the aqueous solution 5.7ml that adds 0.33g (2.7mmol) sodium dihydrogen phosphate, and then with 3 hours slow dropping sodium chlorite 2.16g (79% product, 18.9mmol) aqueous solution 20ml.The mixture that is obtained was at room temperature stirred 5 days, add saturated sodium bicarbonate water 50ml, stir a night.The solution that is obtained is washed 2 times with ethyl acetate 50ml, then water layer is used concentrated hydrochloric acid furnishing acidity, use 70ml ethyl acetate extraction 3 times.Ethyl acetate solution with the water washing of 50ml saturated common salt, is carried out drying, under reduced pressure heats up in a steamer and desolvate with magnesium sulfate, obtain coarse crystallization.Once more coarse crystallization is dissolved in the 50ml ethyl acetate, with the saturated sodium bicarbonate water of 50ml carry out stripping for 2 times, with water layer with concentrated hydrochloric acid furnishing acidity, with 70ml ethyl acetate extraction 3 times.Ethyl acetate solution with the water washing of 50ml saturated common salt, carry out drying, under reduced pressure heat up in a steamer and desolvate with magnesium sulfate, is obtained the crystallization of white.After the crystallization of 50ml hexane wash, air-dry, acquisition 0.55g (2 stage yield 20%) 5-chloro-4-methyl-2-methoxyl group-nicotinic acid. 1H-NMR(400MHz、CDCl 3)：δ(ppm)2.46(s，3H)、3.99(s，3H)、8.16(s，1H)、
Below, the test example that record the present invention relates to, but the present invention is not limited only to this.
Test example 1
The test of wheat powdery mildew preventive effect
(the kind: No. 61, agricultural), when reaching 1.5 leaf ages, with aerosol can each test compound is adjusted to the admixing medical solutions that normal concentration forms and scatters of cultivated wheat in the polyethylene alms bowl of diameter 7.5cm in the mode that is equivalent to 200L/ha.After the soup drying, spread down the mitogenetic sporozoite of white powder germ and inoculate, remain in 20 ℃ the thermostatic chamber.After inoculation 6～8 days, investigate sporozoite and form area, obtain the incidence of disease according to following calculating formula, it the results are shown in table 1～table 53.In addition, with the aerosol can distribution water, operate the average lesion area of obtaining the non-processor district equally except replacing soup with treatment region.
The incidence of disease=(a/b) * 100
A: the average lesion area of treatment region
B: the average lesion area in non-processor district
Utilize the formula of Corby, calculate theoretical value.When test value was lower than theoretical value, microbicide compositions of the present invention had synergy in the test of wheat powdery mildew preventive effect.The theoretical value that the formula by Corby under such situation is obtained is shown in () of table 1～table 53 in the lump.
Table 1
Figure C20048003256900421
Table 2
Figure C20048003256900422
Table 3
Figure C20048003256900431
Table 4
Table 5
Figure C20048003256900433
Table 6
Figure C20048003256900434
Table 7
Figure C20048003256900435
Table 8
Figure C20048003256900441
Table 9
Figure C20048003256900442
Table 10
Figure C20048003256900443
Table 11
Figure C20048003256900444
Table 12
Table 13
Figure C20048003256900452
Table 14
Figure C20048003256900453
Table 15
Figure C20048003256900454
Table 16
Figure C20048003256900461
Table 17
Figure C20048003256900462
Table 18
Figure C20048003256900463
Table 19
Figure C20048003256900464
Table 20
Figure C20048003256900471
Table 21
Figure C20048003256900472
Table 22
Figure C20048003256900473
Table 23
Figure C20048003256900474
Table 24
Table 25
Table 26
Figure C20048003256900483
Table 27
Figure C20048003256900484
Table 28
Figure C20048003256900491
Table 29
Figure C20048003256900492
Table 30
Figure C20048003256900493
Table 31
Table 32
Figure C20048003256900495
Table 33
Table 34
Figure C20048003256900502
Table 35
Figure C20048003256900503
Table 36
Figure C20048003256900504
Table 37
Figure C20048003256900511
Table 38
Table 39
Figure C20048003256900513
Table 40
Figure C20048003256900514
Table 41
Figure C20048003256900515
Table 42
Figure C20048003256900521
Table 43
Figure C20048003256900522
Table 44
Figure C20048003256900523
Table 45
Figure C20048003256900524
Table 46
Figure C20048003256900531
Table 47
Figure C20048003256900532
Table 48
Figure C20048003256900533
Table 49
Figure C20048003256900534
Table 50
Table 51
Table 52
Table 53
The test of test example 2 powdery mildew of cucumber preventive effects
Polyethylene pot culture training cucumber (kind: four leaves), when reaching 1.5 leaf ages, scatter The compounds of this invention with aerosol can and be adjusted to the admixing medical solutions 10mL that normal concentration forms with diameter 7.5cm.After the soup drying, the mitogenetic sporozoite suspension of spray inoculation white powder germ remains in 20 ℃ the thermostatic chamber.After inoculation 6～11 days, the research sporozoite forms area, obtains the incidence of disease equally with test example 3, and it the results are shown in table 54～table 96.Replace soup and scatter water with aerosol can, in addition, with the same average lesion area of obtaining the non-processor district of operating of treatment region.
In addition, the theoretical value of being tried to achieve by the formula of Corby is as shown in () of table 54～table 96.
Table 54
Figure C20048003256900551
Table 55
Figure C20048003256900552
Table 56
Figure C20048003256900553
Table 57
Figure C20048003256900554
Table 58
Table 59
Figure C20048003256900561
Table 60
Figure C20048003256900562
Table 61
Figure C20048003256900563
Table 62
Figure C20048003256900564
Table 63
Figure C20048003256900565
Table 64
Figure C20048003256900571
Table 65
Figure C20048003256900572
Table 66
Table 67
Figure C20048003256900574
Table 68
Figure C20048003256900575
Table 69
Figure C20048003256900581
Table 70
Figure C20048003256900582
Table 71
Figure C20048003256900583
Table 72
Figure C20048003256900584
Table 73
Table 74
Figure C20048003256900591
Table 75
Figure C20048003256900592
Table 76
Figure C20048003256900593
Table 77
Figure C20048003256900594
Table 78
Figure C20048003256900601
Table 79
Figure C20048003256900602
Table 80
Figure C20048003256900603
Table 81
Figure C20048003256900604
Table 82
Figure C20048003256900605
Table 83
Figure C20048003256900611
Table 84
Table 85
Figure C20048003256900613
Table 86
Figure C20048003256900614
Table 87
Figure C20048003256900615
Table 88
Figure C20048003256900621
Table 89
Figure C20048003256900622
Table 90
Figure C20048003256900623
Table 91
Figure C20048003256900624
Table 92
Figure C20048003256900625
Table 93
Figure C20048003256900631
Table 94
Table 95
Figure C20048003256900633
Table 96
Figure C20048003256900634
Below, put down in writing formulation example of the present invention, but the amount of formulation among the present invention, formulation etc. are not limited only to the record example.
Formulation example 1
(a) kaolin 78 weight portions
(b) sodium formaldehyde condensation products 2 weight portions
(c) polyxyethylated aryl-sulfate 5 weight portions
(d) moisture amorphous silicas 15 weight portions
With the compound of above-mentioned each mixture of ingredients and formula (I) and according to general seat, mix with 8: 1: 1 part by weight, obtain hydrating agents.
Formulation example 2
(a) compound 0.5 weight portion of formula (I)
(b) according to general seat 0.5 weight portion
(c) bentonite 20 weight portions
(d) kaolin 74 weight portions
(e) wooden sodium sulfonate's 5 weight portions
In above-mentioned each composition, add an amount of needed water of granulation, mix, granulate, obtain granule.
Formulation example 3
(a) The compounds of this invention 2 weight portions
(b) according to general seat 3 weight portions
(c) talcum 95 weight portions
With above-mentioned each composition mixing homogeneous, obtain pulvis.

Claims (8)

1. a microbicide compositions is characterized in that, contain (a) and (b),
(a) be the benzoyl pyridine derivative shown in the formula (I) or its salt,
Figure C2004800325690002C1
In the formula, X is halogen atom, C 1-6Alkoxyl, C 1-6Alkyl or CF 3Base, n are 1,2,3 or 4; R 1Be C 1-6Alkyl, R 2' be C 1-6Alkoxyl, p are 1,2 or 3, R 2" be C 1-6Alkoxyl,
(b) for being selected from a kind bactericide in the following azole compounds: according to general seat, fluorine bacterium Zuo, Evil imidazoles fumarate, Tebuconazole, acid amides azoles, fluorine ether azoles, triazolone, Bitertanol, etaconazole, propiconazole, penconazole, Flusilazole, nitrile bacterium azoles, cyproconazole, own azoles alcohol, furconazole_cis, Prochloraz, metconazole, Sipconazole, prothioconazoles, simeconazoles, tricyclazole, probenazole, Fluquinconazole and triadimenol
(a) benzoyl pyridine derivative or its salt, with (b) the mixed weight ratio of bactericide be 1: 10000～10000: 1.
2. microbicide compositions as claimed in claim 1, (b) bactericide is to be selected from a kind of in the following substances: according to general seat, fluorine bacterium Zuo, Evil imidazoles fumarate, Tebuconazole, acid amides azoles, fluorine ether azoles, cyproconazole, metconazole, Fluquinconazole and triadimenol.
3. microbicide compositions as claimed in claim 1, benzoyl pyridine derivative are the compound shown in the formula (I '),
In the formula, be under the situation of N at A, B is CX 4At A is under the situation of CH, and B is N; X 1And X 2Represent halogen atom, C respectively independently 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; X 3Be hydrogen atom, halogen atom, C 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; X 4Be hydrogen atom, halogen atom, C 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; R 1Be C 1-6Alkyl; R 2' be C 1-6Alkoxyl; P is 1,2 or 3; R 2" and R 2" ' be C 1-6Alkoxyl.
4. microbicide compositions as claimed in claim 3, benzoyl pyridine derivative are the compound shown in the formula (I '-1),
Figure C2004800325690003C1
In the formula, X 1And X 2Represent halogen atom, C respectively independently 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; X 3Be hydrogen atom, halogen atom, C 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; R 1Be C 1-6Alkyl; R 2' be C 1-6Alkoxyl; P is 1,2 or 3; R 2" and R 2" ' be C 1-6Alkoxyl.
5. microbicide compositions as claimed in claim 4; the benzoyl pyridine derivative is be selected from following substances at least a; described material is; 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-4,5-two chloro-2-methoxypyridines; 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-2-methoxyl group-4; the 5-lutidines; 3-(2,3,4-trimethoxy-6-methyl benzoyl)-5-bromo-4-chloro-2-methoxypyridine; 3-(2; 3; 4-trimethoxy-6-methyl benzoyl)-5-chloro-2-methoxyl group-4-picoline and 3-(2,3,4-trimethoxy-6-methyl benzoyl)-4-trifluoromethyl-2-methoxyl group-5-picoline.
6. microbicide compositions as claimed in claim 3, benzoyl pyridine derivative are the compound shown in the formula (I '-2),
Figure C2004800325690003C2
In the formula, X 1And X 2Represent halogen atom, C respectively independently 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; X 3Be hydrogen atom, halogen atom, C 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; X 4Be hydrogen atom, halogen atom, C 1-6Alkoxyl, C 1-6Alkyl or CF 3Base; R 1Be C 1-6Alkyl; R 2' be C 1-6Alkoxyl; P is 1,2 or 3; R 2" and R 2" ' be C 1-6Alkoxyl.
7. microbicide compositions as claimed in claim 6; the benzoyl pyridine derivative is to be selected from least a in the following compound; described compound is: 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-2; 5-two chloro-3-5-flumethiazines and 4-(2,3,4-trimethoxy-6-methyl benzoyl)-2-chloro-3-trifluoromethyl-5-methoxypyridine.
8. the method for control of a plant disease is characterized in that, each described microbicide compositions of claim 1～7 is applied to plant.
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