CN101215260B

CN101215260B - Method for preparing benzoylpyridine derivatices and salt thereof

Info

Publication number: CN101215260B
Application number: CN200810001524.7A
Authority: CN
Inventors: 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
Original assignee: Ishihara Sangyo Kaisha Ltd
Current assignee: Ishihara Sangyo Kaisha Ltd
Priority date: 2003-10-31
Filing date: 2004-10-29
Publication date: 2014-07-09
Anticipated expiration: 2024-10-29
Also published as: CN101199274A; CN100581362C; CN101199274B; CN101215260A; CN1874680A

Abstract

The present invention provides a benzoylpyridine represented by the formula (I) or a method for preparing the salt thereof, wherein X is a halogen atom, a nitryl, a substitutable alkyl, a substitutable alkoxy group, a substitutable cyclolkoxy group, a hydroxyl group, a substitutable alkylthio, a cyano group, a carboxyl group which may be esterified or amidated, or a substitutable amino group, n is 1, 2, 3 or 4; R<1> is a substitutable alkyl, R<2'> is a substitutable alkyl, a substitutable alkoxyl, a substitutable aryloxy group, a substitutable cycloalkoxy group or a hydroxyl group, p is 1, 2 or 3, R<2''> is a substitutable alkoxyl group or hydroxyl group, or at least two condensation rings which can contain oxygen atom in R<2'> or R<2''>, and is the compound represented by the formula (XIII), in the formula, X and n are defined above, and reacts with the compound represented by the formula (XIV) when the lewis acid or anhydrating agent exists, in the formula, R<1>, R<2'>, R<2''> and p are defined above.

Description

The manufacture method of benzoyl pyridine derivative or its salt

The application is to be on October 29th, 2004 applying date, and application number is 200480032569.0, and denomination of invention is the divisional application of the Chinese patent application of " the method for control of Bactericide composition and Plant diseases ".

Technical field

The present invention relates to the Bactericide composition of the agricultural or horticultural bactericide that can be used as significantly improving the effect that prevents and/or treats Plant diseases and used the method for control of Plant diseases of said composition.

Background technology

In WO02/2527, having recorded as the benzoyl pyridine derivative of the effective constituent of Bactericide composition of the present invention is useful as sterilant, and has recorded can mix with other sterilant as required to merge and use.But, and do not know that composition of the present invention has the sterilization effect of significant excellence.

Patent documentation 1: International Publication communique WO02/2527

Summary of the invention

Benzoyl pyridine derivative shown in aftermentioned formula (I) is aspect various plant disease control effects; effect to specific Plant diseases is insufficient; or long-lasting is shorter; or rain fastness is very weak; under some uses situation, aspect Plant diseases practical, sometimes only demonstrating inadequate preventive effect.

The present inventors conduct in-depth research in order to address the above problem; found that; use the benzoyl pyridine derivative shown in aftermentioned formula (I) and specific sterilant if mixed; compare with the situation of the each compound of independent use; can obtain the sterilization effect of beyond thought excellence, thereby complete the present invention.

That is, the present invention relates to a kind of Bactericide composition, it is characterized in that, contain (a) and (b) as effective constituent,

(a) be the benzoyl pyridine derivative shown in formula (I) or its salt,

[in formula, X be halogen atom, nitro, can substituted alkyl, can substituted alkoxyl group, can substituted aryloxy, can substituted cycloalkyloxy, hydroxyl, can substituted alkylthio, cyano group, can be esterified or amidated carboxyl or can substituted amino, n is 1,2,3 or 4; R ¹for can substituted alkyl, R ^{2 '}for can substituted alkyl, can substituted alkoxyl group, can substituted aryloxy, can substituted cycloalkyloxy or hydroxyl, p is 1,2 or 3, R ^{2 "}can substituted alkoxyl group or hydroxyl, or R ^{2 '}and R ^{2 "}at least 2 can form the condensed ring that contains Sauerstoffatom],

(b) for being selected from least a kind of sterilant in following substances, described material is, imines bacterium (strobilurin) compounds, azole compounds, morpholine kind compound, pyrimidinamine compound, guanidine compound, organochlorine compounds, glyoxaline compound, microbiotic, pyridyl amine compound, quinoxaline compound, dithio amino formate compounds, malonamide nitrile compounds, phenylamide compound, sulfenic acid compounds, copper compounds, different azole compounds, organophosphorus compound, N-halo alkylthio compounds, two carbimide compounds, N-benzophenone aminated compounds, piperazine compounds, pyridine compounds and their, methyl alcohol compounds, piperidines, organic tin compound, carbamide compounds, cinnamic acid compound, phenylcarbamate compounds, cyanopyrrole compounds, oxazolidinones, thiazole amide compound, silyl amides, amino acid amide amino formate compounds, imidazolidine compounds, hydroxyanilines compounds, oxime ether (oxime ether) compounds, phenoxy group amides, benzophenone compound, isoprothiolane (Isoprothiolane), pyroquilon (Pyroquilon), diclomezin (Diclomezine), quinoxyfen (Quinoxyfen), the hundred clever mono-hydrochloric salts of dimension (Propamocarb Hydrochloride), trichloronitromethane (Chloropicrin), dazomet (Dazomet), metamsodium (Metam-sodium), boscalid amine (Nicobifen), 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 diseases, it is characterized in that, above-mentioned Bactericide composition is applied to plant.

As the halogen atom in formula (I), can use fluorine, chlorine, bromine or iodine, preferably use for example fluorine, chlorine or bromine.

As the hydrocarbyl portion of the be substituted alkyl in formula (I), for example can list C _1-6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl etc.), C _2-6alkenyl (such as vinyl, allyl group, pseudoallyl, 3-methyl-2-butene base etc.), C _2-6alkynyl group (such as ethynyl, 1-proyl, 2-propynyl etc.), C _3-6cycloalkyl (for example cyclopropyl, cyclopentyl, cyclohexyl), C _6-10aryl etc.In addition, as 2 substituting groups that can substituted alkyl, for example can list aryl, aryloxy, hydroxyl, nitro, nitroxyl, halogen (such as fluorine, chlorine, bromine, iodine etc.), halogenated alkoxy (for example CF ₃o, HCF ₂the C of O etc. _1-4halogenated alkoxy), 1～5 identical or different substituting group in cycloalkyl, amino, alkylthio and cyano group.In these can substituted alkyl, preferably can substituted alkyl, wherein alkyl particularly preferably.And then, in alkyl, most preferably C _1-4alkyl.

As in formula (I) can substituted alkyl, can substituted alkoxyl group, moieties that can substituted alkylthio, preferably C _1-6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl 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 (such as fluorine, chlorine, bromine, iodine etc.), halogenated alkoxy (for example CF ₃o, HCF ₂the C of O etc. _1-4halogenated alkoxy), 1～5 identical or different substituting group in cycloalkyl, amino, alkylthio and cyano group.Have in the substituting group of moieties at these, preferably without the substituting group replacing, particularly preferably C _1-4alkyl.Wherein, most preferable.

As in formula (I) can substituted aryloxy aryl moiety, except phenyl, can list, what naphthyl was such condenses type polycycle group, preferably phenyl.In addition, can substituted 2 substituting groups as these, can list halogen, alkyl, alkoxyl group, hydroxyl etc.

As in formula (I) can substituted cycloalkyloxy cycloalkyl moiety, be generally carbonatoms and be 3～10 cycloalkyl, for example, the monocyclic group of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ring octyl group etc., in addition, can also list and condense type polycycle group etc., preferably monocyclic group.In addition, 2 substituting groups that can substituted group as these, can list halogen, alkyl, alkoxyl group, hydroxyl etc.In cycloalkyloxy part, most preferably cyclohexyl oxygen base.

As in formula (I) can esterified or amidated carboxyl, for example can list C _1-6alkoxy carbonyl (such as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl etc.), nitrooxy C _1-4alkoxy amino carbonyl (such as 2-nitrooxy ethoxy carbonyl, 3-nitrooxy propoxycarbonyl etc.), phenyl C _1-4alkoxy carbonyl (such as benzyl oxygen base carbonyl, styroyl oxygen base carbonyl etc.) etc. can esterified carboxyl; Formamyl, C _1-6alkyl monosubstituted amino carbonyl (such as methylamino carbonyl, ethylamino carbonyl, propyl group aminocarboxyl, isopropylamino carbonyl, butyl aminocarboxyl, isobutylamino carbonyl, tertiary butyl aminocarboxyl etc.), two C _1-6alkyl amino-carbonyl (such as dimethylamino carbonyl, diethylamino carbonyl, dipropyl aminocarboxyl, diisopropylaminoethyl carbonyl, dibutylamino carbonyl, different dibutylamino carbonyl etc.), nitrooxy C _1-4alkyl amino-carbonyl (such as 2-nitrooxy ethylamino carbonyl, 3-nitrooxy propyl group aminocarboxyl etc.), phenyl C _1-4alkyl amino-carbonyl (such as benzylamino carbonyl, styroyl aminocarboxyl etc.) C _3-6cycloalkyl amino carbonyl (such as cyclopropylamino carbonyl etc.) C _3-6the carboxyl that can be amidated of cycloalkyl amino carbonyl (such as cyclopropylamino carbonyl, cyclopentyl aminocarboxyl, cyclohexyl aminocarboxyl etc.), cyclic aminocarbonyl (such as morpholino carbonyl, piperidino-(1-position only) carbonyl, pyrrolidyl carbonyl, thiomorpholine are for carbonyl etc.), aminocarboxyl etc.

As in formula (I) can substituted amino, for example can list amino; The alkylamino of alkyl monosubstituted amino, dialkyl amido etc. etc.In addition, as the moieties of abovementioned alkyl amino, preferably C _1-4alkyl.In addition, as 2 substituting groups that can substituted amino, can list, be selected from aryl, aryloxy, hydroxyl, nitro, nitroxyl, halogen (such as fluorine, chlorine, bromine, iodine etc.), halogenated alkoxy (for example CF ₃o, HCF ₂the C of O etc. _1-4halogenated alkoxy), 1～5 identical or different substituting group in cycloalkyl, amino, alkylthio and cyano group.

In addition, the definition of aryl moiety, cycloalkyl moiety and moieties in above-mentioned each substituent 2 substituting groups, according to each substituent definition.

Compound shown in formula (I), can be together with acidic substance salify, for example, can form the such inorganic acid salt of hydrochloride, hydrobromate, phosphoric acid salt, vitriol or nitrate; Acetate, benzoate, tosilate, mesylate or the such organic acid salt of propanesulfonic acid salt.

Compound shown in formula (I), can obtain by disclosed manufacture method in WO02/2527.In addition, also can be according to Journal of Organic Chemistry., 58,7832 (1993), European Journal of Organic Chemistry., the method of 7,1371-1376 (2001) or each synthesis example described later is manufactured.

As imines bacterium (strobilurin) compounds, for example can list gram receipts glad (Kresoxim-Methyl), nitrile Azoxystrobin (Azoxystrobin), fork phenalgin acid amides (Metominofen), oxime bacterium ester (Trifloxystrobin), ZEN 90160 (Picoxystrobin), ォリザストロ PVC Application (Oryzastrobin), dimoxystrobin (Dimoxystrobin) and fluoxastrobin (Fluoxastrobin).Wherein, receive glad and nitrile Azoxystrobin for preferred gram.

Gram receive glad be The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of 568th～569 pages of records.In addition, nitrile Azoxystrobin is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of 54th～55 pages of records.

As azole compounds, for example can list, according to general seat (Epoxiconazole), fluorine bacterium azoles (Triflumizole), imidazoles fumarate (Oxpoconazole fumarate), tebuconazole (Tebuconazole), acid amides azoles (Imibenconazole), fluorine ether azoles (Tetraconazole), triazolone (Triadimefon), Bitertanol (Bitertanol), etaconazole (Etaconazole), Wocosin 50TK (Propiconazole), Topaze (Penconazole), fluzilazol (Flusilazole), nitrile bacterium azoles (Myclobutanil), cyproconazole (Cyproconazole), own azoles alcohol (Hexaconazole), furconazole_cis (Furconazole-Cis), prochloraz (Prochloraz), metconazole (Metconazole), シプコ Na ゾ mono-Le (Sipconazole), prothioconazoles (Prothioconazole), simeconazoles (Simeconazole), tricyclazole (Tricyclazole), probenazole (Probenazole), fluquinconazole (Fluquinconazole) and Triabimeno I (Triadimenol).Wherein, preferably according to general seat, fluorine bacterium azoles, imidazoles fumarate, tebuconazole, acid amides azoles, fluorine ether azoles, cyproconazole, metconazole, fluquinconazole and Triabimeno I.

The Pesticide Manual (the 12nd edition according to general seat; BRITISH CROPPROTECTION COUNCIL) compound of 349th～350 pages of records.Fluorine bacterium azoles (Triflumizole) is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of 940th～941 pages of records. imidazoles fumarate (Oxpoconazole fhmarate) 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 864th～865 pages of records.Acid amides azoles (Imibenconazole) is The Pesticide Manual (the 12nd edition; BRITISHCROP PROTECTION COUNCIL) compound of 535th～536 pages of records.Fluorine ether azoles (Tetraconazole) is The Pesticide Manual (the 13rd edition; BRITISHCROP PROTECTION COUNCIL) compound of 945th～946 pages of records.Cyproconazole is The Pesticide Manual (the 13rd edition; BRITISH CROPPROTECTION COUNCIL) compound of 248th～249 pages of records.Metconazole is ThePesticide Manual (the 13rd edition; BRITISH CROP PROTECTIONCOUNCIL) compound of 643rd～644 pages of records.Fluquinconazole is The PesticideManual (the 13rd edition; BRITISH CROP PROTECTION COUNCIL) compound of 472nd～473 pages of records.Triabimeno I is The Pesticide Manual (the 13rd edition; BRITISH CROP PROTECTION COUNCIL) compound of 987th～989 pages of records.

As morpholine kind compound, for example can list fenpropimorph (Fenpropimorph) and spiral shell luxuriant amine (Spiroxamine).Fenpropimorph is The Pesticide Manual (the 12nd edition; BRITISH CROP PROTECTION COUNCIL) compound of 399th～400 pages of records.In addition, spiral shell luxuriant amine is The Pesticide Manual (the 12nd edition; BRITISH CROP PROTECTION COUNCIL) compound of 842nd～843 pages of records.

As pyrimidinamine compound, for example can list mepanipyrim (Mepanipyrim), pyrimethanil (Pyrimethanil) and ring the third pyrimidine (Cyprodinil).Wherein, preferred mepanipyrim.Mepanipyrim is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of 596th～597 pages of records.

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 539th～541 pages of records.

As organochlorine compounds, for example can list m-tetrachlorophthalodinitrile (Chlorothalonil), phthalide (Fthalide) and quintozene (Quintozene).Wherein, preferred m-tetrachlorophthalodinitrile.M-tetrachlorophthalodinitrile is The Pesticide Manual (the 12nd edition; BRITISH CROPPROTECTION COUNCIL) compound of 168th～169 pages of records.

As glyoxaline compound, can list cyazofamid (Cyazofamid), F-1991 (Benomyl), thiophanate methyl (Thiophanate-Methyl) and derosal (Carbendazim).Wherein, preferred cyazofamid.Cyazofamid is The Pesticide Manual (the 12nd edition; BRITISHCROP PROTECTION COUNCIL) compound of 523rd～524 pages of records.

As microbiotic, for example can list Polyoxin (Polyoxins).Polyoxin is The Pesticide Manual (the 12nd edition; BRITISH CROP PROTECTIONCOUNCIL) compound of 752nd～754 pages of records.

As pyridyl amine compound, for example can list fluazinam (Fluazinam).

As quinoxaline compound, for example can list quinomethionate (Quinomethionate).

As dithio amino formate compounds, for example can list maneb (Maneb), zineb (Zineb), zinc manganese ethylenebisdithiocarbamate (Mancozeb), polycarbamate (Polycarbamate), Carbatene (Metiram) and propineb (Propineb).

As malonamide nitrile compounds, for example can list cymoxanil (Cymoxanil).

As phenylamide compound, for example can list, metaxanin (Metalaxyl), Metalaxyl-M (Metalaxyl M), frost spirit (Oxadixyl), fenfuram (Ofurace), M 9834 (Benalaxyl), furalaxyl (Furalaxyl) and cyprofuram (Cyprofuram).

As sulfenic acid compounds, for example can list dichlofluanid (Dichlofluanid).

As copper compounds, for example can list copper hydroxide (Cupric hydroxide) and oxinecopper (Oxine Copper).

As different azole compounds, for example can list, hymexazol (Hymexazol).

As organophosphorus compound, for example can list, fosetyl (Fosetyl-Al), tolclofosmethyl (Tolcofos-Methyl), S-benzyl O, O-di-isopropyl thiophosphatephosphorothioate, O-ethyl S, S-Diphenyl disulfide substituted phosphate and ethyl halide are for phosphonic acids aluminium.

As N-halo alkylthio compounds, for example can list Vancide 89 (Captan), Difolatan (Captafol) and Phaltan (Folpet).

As two carbimide compounds, for example can list procymidone (Procymidone), isopropyl fixed (Iprodione) and vinclozolin (Vinclozolin).

As N-benzophenone aminated compounds, for example can list fultolanil (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 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 419th～420 pages of records.

As organic tin compound, for example can list fentin hydroxide (FentinHydroxide) and triphenyltin acetate (Fentin Acetate).

As carbamide compounds, for example can list pencycuron (Pencycuron).

As cinnamic acid compound, for example can list dimethomorph (Dimethomorph) and flumorph (Flumorph).

As phenylcarbamate compounds, for example can list the mould prestige of second (Diethofencarb).

As cyanopyrrole compounds, for example can list fluorine bacterium (Fludioxonil) and fenpiclonil (Fenpiclonil).

As oxazolidinones, for example can list, famoxadone (Famoxadone).

As thiazole amide compound, for example can list Guardian (Ethaboxam).

As silyl amides, for example can list Silthiopham (Silthiopham).

As amino acid amide amino formate compounds, for example can list zinc 1,2-propylene bisdithiocarbamate (Iprovalicarb) and ベ Application チァバリカ Le Block (benthiavalicarb).

As imidazolidine compounds, for example can list fenamidone (Fenamidone).

As 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 phenoxy group amides, 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), the clever mono-hydrochloric salts of hundred dimensions (Propamocarb Hydrochloride), trichloronitromethane (Chloropicrin), dazomet (Dazomet), metamsodium (Metam-sodium), boscalid amine (Nicobifen), two chlorine zarilamid (Diclocymet) and the third oxygen quinoline (Proquinazid).

As the sterilant of the effective constituent (b) of Bactericide composition of the present invention, can list above-mentioned illustrative material.Wherein, preferably use at least one being selected from imines azulenoid, azole compounds, morpholine kind compound, pyrimidinamine compound, guanidine compound, organochlorine compounds, glyoxaline compound, microbiotic, piperidines and benzophenone compound.Further preferably use and be selected from that gram receipts are glad, nitrile Azoxystrobin, comply with general seat, fluorine bacterium azoles, imidazoles fumarate, tebuconazole, acid amides azoles, fluorine ether azoles, cyproconazole, metconazole, fluquinconazole, Triabimeno I (triadimenol), fenpropimorph, spiral shell at least one in luxuriant amine, mepanipyrim, biguanide spicy acid salt, m-tetrachlorophthalodinitrile, cyazofamid, Polyoxin, fenpropidin and metrafenone.

Bactericide composition of the present invention, has stable high sterilization effect to the raise crop being infected by Plant diseases, uses said composition, can prevent and kill off Plant diseases.

Embodiment

In the time of the compound or its salt of manufacturing shown in above-mentioned formula (I), can list following preferred method.

(1) make the reacting metal salt of the substituted pyridine derivative shown in the substituted benzaldehyde shown in formula (VI-1) and formula (VII-1), phenylpyridyl methyl alcohol shown in manufacture formula (X), then by its oxidation, manufacture the method for the compound or its salt of above-mentioned formula (I)

formula (VI-1)

(in formula, R ¹, R ^{2 '}, R ^{2 "}described above with p),

formula (VII-1)

(in formula, X is described above, and Z is atoms metal or its composite salt),

formula (X)

(in formula, X, R ¹, R ^{2 '}, R ^{2 "}, n and p described above).

(2) make the pyridyl formaldehyde reaction of the replacement shown in metal-salt and the formula (VII-2) of the substituted benzene derivatives shown in formula (VI-2), phenylpyridyl methyl alcohol shown in manufacture formula (X), then by its oxidation, manufacture the method for the compound or its salt of above-mentioned formula (I)

formula (VI-2)

(in formula, R ¹, R ^{2 '}, R ^{2 "}described above with p, Z is atoms metal or its composite salt),

formula (VII-2)

(in formula, X and n are described above).

In above-mentioned method for making (1) and (2), the atoms metal representing as Z, can list the typical metal atom of lithium, magnesium, zinc, copper etc.; The transition metal atoms of palladium, ruthenium etc. etc.In addition, replace atoms metal, also can use composite salt (ate complex) such as diaryl copper lithium, the triaryl copper lithium etc. of atoms metal.

The compound of the compound of above-mentioned formula (VI-1) and formula (VII-2), can manufacture according to the method for known method, for example Journal of Organic Chemistry the 57th volume 6847-6852 page, record in 1992 conventionally.

Phenylpyridyl methyl alcohol shown in the formula (X) being produced by above-mentioned method for making (1) and (2), by known method, for example the metal onidiges by Manganse Dioxide, chromic acid etc., Swern oxidation style (dimethyl sulfone+oxalyl chloride), ruthenium oxidation style (tetrapropyl amine パ mono-Le テネ mono-ト+N-methylmorpholine-N-oxide compound) etc. are oxidized, and are transformed to the compound shown in formula (1).

The compound of the formula (VII-1) in method for making (1), can be by making formula (VIII)

Compound shown in compound shown in [in formula, X and n are described above, and Hal is halogen atom] and formula (IX): Ar-Z (in formula, Ar is alkyl or aryl, and Z is described above) reacts to obtain.This reaction preferably under the existence of solvent, carry out under the temperature of reaction of-100 DEG C～120 DEG C.In addition, as Ar-Z, for example can list isopropylmagnesium chloride, isopropyl magnesium bromide, lithium methide, butyllithium, phenyl lithium, di-isopropyl magnesium etc.Or, also can use LDA, 2,2,6, the metal amide class of 6-tetramethyl-piperamide lithium etc., obtains by hydrogen-metal exchange reaction.

(3) by by the compound of above-mentioned formula (VIII) with the compound shown in formula (XI), under the existence of transition-metal catalyst, react under carbon monoxide atmosphere, manufacture thus the method for the compound or its salt of above-mentioned formula (I)

formula (XI)

[in formula, R ¹, R ^{2 '}, R ^{2 "}described above with p, M is atoms metal].

In above-mentioned method for making (3), as atoms metal, can list hydroxyl boron, boron alkyl, boron alkoxide, magnesium halide, zinc halide, tin alkyl, alkyl silane, organoalkoxysilane etc.In addition, as transition-metal catalyst, can list palladium, rhodium, ruthenium etc.This reaction preferably under the existence of inert solvent single or that mix, carry out under the temperature of reaction of 0 DEG C～200 DEG C.In addition, can under the carbon monoxide atmosphere of normal pressure, react, also can use pressure-resistant reaction device to react under carbon monoxide pressurized state.

(4) react with the compound shown in formula (XII) by the compound that makes above-mentioned formula (VII-1), manufacture the method for the compound or its salt of above-mentioned formula (I),

[in formula, R ¹, R ^{2 '}, R ^{2 "}described above with p, Y is leavings group].

In above-mentioned method for making (4), as the leavings group shown in Y, can list halogen, cyano group, alkoxyl group etc.This reaction is preferably at the aliphatic hydrocarbon of hexane, hexanaphthene, octane etc.; Under the existence of the ether solvent class of Di Iso Propyl Ether, tetrahydrofuran (THF), glycol dimethyl ether etc. single or the inert solvent that mixes, carry out under the temperature of reaction of-100 DEG C～120 DEG C.In addition, also can exist with the form of catalysis by the transition metal complex that makes nickel, palladium, iron etc., further promote reaction.

(5) make formula (XIH)

[in formula, X and n described above] shown in compound and formula (XIV)

[in formula, R ¹, R ^{2 '}, R ^{2 "}described above with p] shown in compound, under the existence of Lewis acid or dewatering agent, react, manufacture the method for the compound or its salt of above-mentioned formula (I).

The reaction of method for making (5) preferably, under the existence of solvent, is carried out under the temperature of reaction of 0 DEG C～200 DEG C.As Lewis acid or dewatering agent, for example can list P ₂o ₅, phosphoryl chloride, Tripyrophosphoric acid, sulfuric acid, dicyclohexylcarbodiimide (DCC) etc.In addition, as solvent, can use any and react irrelevant solvent, for example, the aromatic hydrocarbons of the halon of 1,2-ethylene dichloride, methylene dichloride etc., benzene, chlorinated benzene, dichlorobenzene, oil of mirbane etc. etc., also can use the mixture of these solvents.

(6) manufacture method for the compound or its salt of above-mentioned formula (I), is the method being made up of following operation, and described operation is,

(a) the 1st operation, it is that the compound of above-mentioned formula (XIII) is reacted with halogenating agent, carrys out the operation of the compound shown in acquisition formula (XV)

[in formula, X and n are described above, and Hal is halogen atom]; With

(b) the 2nd operation, it is the Friedel-Crafts reaction of the compound of the formula (XV) by obtaining in the 1st operation and the compound of 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 acyl halogenating reaction.This reaction preferably exists or does not exist under the condition of inert solvent, under the temperature of reaction of 0～200 DEG C, carrying out.As the halogenating agent using in this reaction, can list fluorizating agent, chlorizating agent, bromizating agent etc., preferably use the muriates such as thionyl chloride, phosphoryl chloride, oxalyl chloride.The Friedel-Crafts reaction of the 2nd operation of method for making (6), can be under the existence of catalyzer, in solvent or under solvent-free condition, under the temperature of reaction of-78 DEG C～200 DEG C, carry out, but preferably under the temperature of reaction of 0 DEG C～100 DEG C, 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, as solvent, can use the solvent of inertia under reaction conditions, for example can list, 1,2-ethylene dichloride, methylene dichloride, chlorinated benzene, dichlorobenzene, oil of mirbane etc., still, also can use the mixture of these solvents.In addition, also can, with reference to Friedel-CraftsChemistry (Olah, G.A. work), manufacture by synthetic or derivatize.

The compound of the above-mentioned formula (XIII) using as the production of raw material for use of method for making (5) and method for making (6), can be by being oxidized the compound of above-mentioned formula (VII-2) to obtain.As oxygenant, can use normally used inorganic or organic oxidizing agent.In addition, can directly react with dry ice by the compound that makes above-mentioned formula (VII-1), or react with chlorine ethyl-carbonate, then hydrolysis obtains.Or, by substituted pyridine-carboxylic acids or derivatives thereof, by the method for known document for example with reference to J.Heterocyclic.Chem., 36,653 (1999), manufacture by synthetic or derivatize.In addition, can compile the 4th edition " experimental chemistry lecture 22, organic synthesis IV, 1992 " with reference to Japanization association, manufacture by synthetic or derivatize.

In the benzoyl pyridine derivative shown in formula (I), the compound shown in preferred formula (I '),

[in formula, at A be-N=in the situation that, B is-CX ⁴=; At A be-CH=in the situation that, B is-N=; X ¹and X ²represent independently respectively halogen atom, alkoxyl group, hydroxyl, alkyl, CF ₃base or alkylthio; X ³for hydrogen atom, halogen atom, alkoxyl group, alkyl, CF ₃base or alkylthio; X ⁴for hydrogen atom, halogen atom, alkoxyl group, alkyl, CF ₃base or alkylthio; R ¹for alkyl; R ^{2 '}for alkoxyl group; P is 1,2 or 3; R ^{2 "}and R ² for alkoxyl group].

In the compound shown in above-mentioned formula (I '), comprise A be-CH=, B be-compound in the situation of N=is the compound shown in formula (I '-1), and at A be-N=, B are-CX ⁴=situation under compound be the compound shown in formula (I '-2),

formula (I '-1)

[X ¹, X ², X ³, R ¹, R ^{2 '}, R ^{2 "}and R ² as mentioned above],

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 above-mentioned formula (I '-1), further preferably use at least one being selected from following compound, described compound is: 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxypyridine of the bromo-5-of-4-(compound N is o.1), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-4-ethyl-2-of-5-methoxypyridine (compound N is o.2), 3-(4, 5-dimethoxy-2-methyl benzoyl)-4, the chloro-2-methoxypyridine of 5-bis-(compound N o.3), 3-(5-oxyethyl group-4-methoxyl group-2-methyl benzoyl)-4, the chloro-2-methoxypyridine of 5-bis-(compound N o.4), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-5-chloro-2-ethoxy of-4-pyridine (compound N is o.5), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-5-chloro-2-ethoxy-4-picoline (compound N is o.6), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-4-chloro-2-ethoxy of-5-pyridine (compound N is o.7), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the iodo-2-methoxypyridine of the chloro-5-of-4-(compound N is o.8), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-5-iodo-2, 4-dimethoxy-pyridine (compound N o.9), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-methylthio group 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, the bromo-2-methoxypyridine of 5-bis-(compound N o.12), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-2-methoxyl group-5-of-4-picoline (compound N is o.13), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-4-trifluoromethyl-2-of-5-methoxypyridine (compound N is o.14), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-4, the chloro-2-methoxypyridine of 5-bis-(compound N o.15), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-2, 4-bis-chloro-5-methypyridines (compound N o.16), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-2, the chloro-5-iodine pyridine of 4-bis-(compound N o.17), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the iodo-5-picoline of the fluoro-4-of-2-(compound N is o.18), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-2-fluoro-4, 5-lutidine (compound N o.19), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-2-methoxyl group-4, 5-lutidine (compound N o.20), 3-(2-oxyethyl group-3, 4-dimethoxy-6-methyl benzoyl)-2-oxyethyl group-4, 5-lutidine (compound N o.21), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl)-4, 5-dimethyl-2-methylthio group pyridine (compound N o.22), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxypyridine of the bromo-4-of-5-(compound N is o.23), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-5-of-4-picoline (compound N is o.24), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-5-trifluoromethyl-4-of-2-picoline (compound N is 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-bis-chloro-5-trifluoromethylpyridines (compound N o.27), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-5-trifluoromethyl-2-of-4-methoxypyridine (compound N is o.28), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-4-ethynyl-2-of-5-methoxypyridine (compound N is o.29), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-4-methyl fluoride-2-of-5-methoxypyridine (compound N is o.30), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-4-methyl fluoride-2-of-5-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) the chloro-4-difluoromethyl-2-of-5-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) the chloro-2-methoxyl group-4-of-5-picoline (compound N is o.35), 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-2-methoxyl group-4-of-5-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) the chloro-2-methoxyl group-4-of-5-picoline (compound N is o.38).

In the compound shown in above-mentioned formula (I '-2), further preferably use at least one being selected from following compound, described compound is: 4-(2, 3, 4-trimethoxy-6-methyl benzoyl)-2, the chloro-3-5-flumethiazine of 5-bis-(compound N o.39), 4-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-3-trifluoromethyl-5-of-2-methoxypyridine (compound N is o.40), 4-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-3-trifluoromethyl-5-of-2-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-methoxyl pyridine (compound N is o.44), 4-(2, 3, 4-trimethoxy-6-methyl benzoyl)-2 bromo-3-chloro-5-methoxyl pyridine (compound N is o.45) and 4-(2, 3, 4-trimethoxy-6-methyl benzoyl) the bromo-5-picoline of-3-(compound N is o.46).

Bactericide composition of the present invention is useful as agricultural or horticultural bactericide especially.As agricultural or horticultural bactericide, be that effectively described disease is: for example rice blast, sesame leaf rot, banded sclerotial blight to preventing and kill off of for example following disease; 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, black spot; The black spot of pears, black spot; The grey scab of peach, black spot, plan stem dibbling maize ear rot; The anthrachose of grape of grape, late blight, Powdery Mildew, oidium; The anthrax of persimmon, defoliation; Melon anthrax, Powdery Mildew, climing rot, oidium; The ring spot of tomato, leaf mold, prevailing disease; The black spot of brassicaceous vegetable, the prevailing disease in summer of potato, prevailing disease; The Powdery Mildew of strawberry; Gray mold, the sclerotium disease etc. of various crops.The particularly Powdery Mildew to wheat class, greengrocery and rice blast, shows excellent preventive effect.In addition, to being also effective by the preventing and kill off of the microbial soil disease of pathogenic of Fusariumsp, pythium spp, rhizoctonia, verticillium sp, plasmodiophora brassicae etc.

Form multiple effective constituents of Bactericide composition of the present invention, same with existing pesticide preparation, mix with various auxiliarys, the preparation that forms the various forms of pulvis, granule, particle hydrating agents, hydrating agents, aqueous suspension agent, oiliness suspension agent, water-soluble preparation, emulsion, liquor, paste, aerosol, micro-spraying agent etc. uses.But, as long as being applicable to object of the present invention, can be any preparation form that common this area is used.The auxiliary using as preparation, can list the solid type carrier of the mixture of diatomite, slaked lime, calcium carbonate, talcum, white carbon(ink), kaolin, wilkinite, kaolinite and sericite, clay, sodium carbonate, sodium bicarbonate, saltcake, zeolite, starch etc., water, toluene, dimethylbenzene, solvent naphtha, two the solvent of alkane, acetone, isophorone, methyl iso-butyl ketone (MIBK), chlorobenzene, hexanaphthene, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, METHYLPYRROLIDONE, alcohol etc., soap, benzoate, alkyl sulfo succinate, dialkyl sulfosuccinates, polycarbonate, alkyl sulfuric ester salt, alkyl-sulphate, alkyl aryl sulfate, alkyl biphenyl sulphate, alcohol sulfuric acid, alkylsulfonate, alkylaryl sulphonate, arylsulphonate, ligninsulfonate, alkyl diphenyl base ether stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate, poly styrene sulfonate, alkyl phosphate salt, alkylaryl phosphoric acid salt, styryl aryl orthophosphate, Voranol EP 2001 sulfuric acid, polyoxyethylene alkylaryl ether vitriol, polyoxyethylene alkylaryl ether sulfuric acid, Voranol EP 2001 phosphoric acid salt, polyxyethylated aryl phosphate ester salt, the tensio-active agent of the such anionic species of the salt of naphthalene sulfonic acidformaldehyde condensation product, developping agent, sorbitan fatty(acid)ester, glycerol fatty acid ester, fatty acid polyglycerol ester, fatty acid alcohol polyglycol ether, acetylenediol, acetylene alcohol, oxyalkylene block polymer, Voranol EP 2001, polyoxyethylene alkylaryl ether, polyoxyethylene styryl aryl ethers, polyoxyethylene glycol alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerol fatty acid ester, polyoxyethylene hardened castor oil, the tensio-active agent of the such nonionic class of polyoxypropylene fatty acid ester, developping agent, vegetables oil, the mineral wet goods of sweet oil, melon baobab oil, Viscotrol C, plam oil, Camellia oil, Oleum Cocois, sesame oil, Semen Maydis oil, Rice pollard oil, Peanut oil, Oleum Gossypii semen, soybean oil, rapeseed oil, Toenol 1140, tung oil, whiteruss etc.These auxiliarys, are not departing within the scope of object of the present invention, can from material well known in the art, select.In addition, also can use the normally used various auxiliarys such as extender, thickening material, precipitation preventing agent, frostproofer, dispersion stabilizer, poisoning light-weight additive, mould inhibitor.The mixing ratio of effective constituent compound and various auxiliarys, is generally 0.005: 99.995～95: 5, is preferably 0.2: 99.8～90: 10.These preparations, in the time that reality is used, can directly use, and thinner that also can water etc. is diluted to normality, adds as required various developping agents and uses.

The present invention also comprises a kind of the method for control of Plant diseases, it is characterized in that, Bactericide composition of the present invention is applied to agriculture and garden and uses plant.The working concentration of Bactericide composition of the present invention, the difference along with the difference of object crop, using method, preparation form, amount of application etc., can not determine, but the in the situation that of cauline leaf processing, unit effective constituent is generally 0.1～10000ppm, is preferably 1～2000ppm without exception.The in the situation that of soil treatment, be generally 10～100000g/ha, be preferably 200～20000g/ha.

The various preparations of Bactericide composition of the present invention or using of its dilution, conventionally can utilize general application process to scatter (for example scatter, spraying, misting, atomizing, spread grain, method used for ponds etc.), soil application (sneak into, perfusion etc.), surface applied (coating, powder clothing, coating etc.) etc. and carry out.In addition, also can utilize so-called ultrahigh concentration to scatter on a small quantity method (ultra lowvolume) uses.In the method, can contain 100% activeconstituents.

In Bactericide composition of the present invention; the suitable mixed weight ratio of the benzoyl pyridine derivative shown in formula (I) or its salt and other sterilant, is generally 1: 10000～10000: 1, is preferably 1: 1000～1000: 1, more preferably 1: 200～200: 1.

Embodiment

Record 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, the chloro-2-methoxypyridine of 5-bis-(compound N is o.15) synthetic

(a) to being dissolved with in the solution that 34.2g (340mmol) diisopropylamine forms, drip 222ml n-Butyl Lithiums (1.57mol/l hexane solution) at-20 DEG C in 400ml tetrahydrofuran (THF), stir 1 hour.Solution is cooled to-78 DEG C, is added on the solution that is dissolved with 32.0g (330mmol) 2-fluorine pyridine in 50ml tetrahydrofuran (THF), stir 4 hours, modulation 2-fluoro-3-pyridine base lithium.Then, in this solution, be added on the solution that is dissolved with 87.1g (341mmol) iodine in 150ml tetrahydrofuran (THF), stir 1 hour.In mixture, add 200ml water, stopped reaction, under reduced pressure heats up in a steamer tetrahydrofuran (THF).With after ether extraction, organic layer is dried with sodium sulfate, filter, under reduced pressure heat up in a steamer desolventizing, obtain the thick resultant 67.4g (thick yield 92%) of the fluoro-3-iodine pyridine of 2-.

¹H-NMR(CDCl ₃，400MHz)：δ(ppm)＝6.91-6.88(m，1H)，8.08-8.12(m，2H)

(b) to being dissolved with in 380ml tetrahydrofuran (THF) in the solution of 30.2g (302mmol) diisopropylamine, drip 189ml n-Butyl Lithium (1.57mol/l hexane solution) at-20 DEG C, stir 1 hour.Solution is cooled to-78 DEG C, be added on the solution that is dissolved with the thick resultant of the fluoro-3-iodine pyridine of 2-obtaining in 67.4g (302mmol) operation (a) in 100ml tetrahydrofuran (THF), stir 1 hour, make the iodo-4-pyridyl of the fluoro-3-of the 2-lithium that the initial stage generates be isomerizated into the iodo-3-pyridyl of the fluoro-4-of 2-lithium.In reaction mixture, add 300ml water, stopped reaction, under reduced pressure heats up in a steamer tetrahydrofuran (THF).With after ether extraction, organic layer is dried with sodium sulfate, filter, under reduced pressure heat up in a steamer desolventizing, obtain the thick resultant of 59.3g (thick yield 89%) the fluoro-4-iodine pyridine of 2-.

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)

(c) in the thick resultant 59.4g (253mmol) of the fluoro-4-iodine pyridine of 2-obtaining in operation b, add 500ml methyl alcohol, it is dissolved, add 21.5g (398mmol) sodium methylate, reflux 3 hours.Add 300ml water, stopped reaction, under reduced pressure, heats up in a steamer methyl alcohol.With after ether extraction, organic layer is dried with sodium sulfate, filter, under reduced pressure heat up in a steamer desolventizing, obtain the thick resultant 56.7g (thick yield 91%) of the iodo-2-methoxypyridine of 4-.

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 to solution ice-cooled, that be added on 80ml tetrahydrofuran (THF) and be dissolved with the thick resultant of the iodo-2-methoxypyridine of 4-obtaining in 19.8g (84.3mmol) operation (c), 0 DEG C stir 1 hour, stirring at room temperature 1 hour, modulation 2-methoxyl group-4-pyridyl magnesium chloride.Then, slowly add 16.9g (127mmol) N-chlorosuccinimide, stirring at room temperature 1 hour.Add 100ml water, stopped reaction, under reduced pressure heats up in a steamer tetrahydrofuran (THF).With after ether extraction, organic layer is dried with sodium sulfate, filter, under reduced pressure heat up in a steamer desolventizing, obtain the thick resultant 11.0g (thick yield 91%) of the chloro-2-methoxypyridine of 4-.

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 resultant 10.0g (69.9mmol) of the chloro-2-methoxypyridine of 4-obtaining in operation (d) is dissolved in 100ml dimethyl formamide, add 37.2g (279mmol) N-chloro-succinimide, stirring at room temperature 12 hours.Add 400ml water, stopped reaction, with after ether extraction, by organic layer saturated common salt water washing, by dried over sodium sulfate, filters, and under reduced pressure heats up in a steamer desolventizing, obtains the thick resultant 9.10g (thick yield 73%) of the chloro-2-methoxypyridine of 4,5-bis-.

¹H-NMR(CDCl ₃，400MHz)：δ(ppm)＝3.90(s，3H)，6.85(s，1H)，8.14(s，1H)

(f) to being dissolved with in 30ml tetrahydrofuran (THF) in the solution of 2.40g (23.7mmol) diisopropylamine, drip 15.1ml n-Butyl Lithium (1.57mol/l hexane solution) at-20 DEG C, stir 1 hour.Solution is cooled to-78 DEG C, be added in 20ml tetrahydrofuran (THF) and be dissolved with 4 of the middle acquisition of 4.22g (23.6mmol) operation (e), the solution of the chloro-2-methoxypyridine of 5-bis-, stirs 2 hours, the chloro-2-methoxyl group-3-of modulation 4,5-bis-pyridyl lithium.Then, be dissolved with 5.00g (23.8mmol) 2,3 to being added in 20ml tetrahydrofuran (THF) in this solution, the solution of 4-trimethoxy-6-tolyl aldehyde, stirs 30 minutes.In mixture, add 50ml water, stopped reaction, under reduced pressure heats up in a steamer tetrahydrofuran (THF).With after ether extraction, organic layer is dried with sodium sulfate, filter, under reduced pressure heat up in a steamer desolventizing, utilize silica gel column chromatography to refine, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-2-methoxyl group-3-of 4,5-bis-pyridyl) 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) to be dissolved with (2 of the middle acquisition of 4.66g (12.0mmol) operation (f) in 30ml toluene, 3,4-trimethoxy-6-aminomethyl phenyl) (4, the chloro-2-methoxyl group-3-of 5-bis-pyridyl) in the solution of methyl alcohol, add 13.8g (159mmol) Manganse Dioxide, carry out the reflux of 2 hours.Be cooled to after room temperature, remove after Manganse Dioxide with sellaite, under reduced pressure, heat up in a steamer toluene; utilize silica gel column chromatography to refine, obtain 3-(2,3; 4-trimethoxy-6-methyl benzoyl)-4, the chloro-2-methoxypyridine of 5-bis-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-lutidine (compound N is o.20) synthetic

(a) to being dissolved with in 70ml tetrahydrofuran (THF) in the solution of 4.02g (39.8mmol) diisopropylamine, drip 26.5ml n-Butyl Lithium (1.57mol/l hexane solution) at-78 DEG C, stir 30 minutes.In this solution, be added on the solution that is dissolved with the fluoro-5-picoline of 4.42g (39.8mmol) 2-in 18ml tetrahydrofuran (THF), stir 4 hours, the fluoro-5-methyl-3-of modulation 2-pyridyl lithium.Then, in this solution, be added on the solution that is dissolved with 10.1g (39.8mmol) iodine in 27ml tetrahydrofuran (THF), stir 2 hours.Add 16ml water, 120ml sodium thiosulfate solution, with after ether extraction, organic layer is dried, is filtered with magnesium sulfate, under reduced pressure heat up in a steamer desolventizing, obtained thick resultant silica gel column chromatography is refined, obtain the fluoro-3-of 2-iodo-5-picoline 3.15g (yield 33%).

¹H-NMR(CDCl ₃，400MHz)：δ(ppm)＝2.27(s，3H)，7.95(m，2H)

(b) to being dissolved with in 27ml tetrahydrofuran (THF) in the solution of 1.34g (13.3mmol) diisopropylamine, drip 8.90ml n-Butyl Lithium (1.57mol/l hexane solution) at-78 DEG C, stir 30 minutes.To the solution that is added on the iodo-5-picoline of the fluoro-3-of 2-obtaining in the operation (a) that is dissolved with 3.15g (13.3mmol) in 5ml tetrahydrofuran (THF) in this solution, then stir 1 hour, make the iodo-5-methyl-4-of the fluoro-3-of the 2-pyridyl lithium that the initial stage generates be isomerizated into the iodo-5-methyl-3-of the fluoro-4-of 2-pyridyl lithium.Be dissolved with 2,3 of 2.79g (13.3mmol) to being added in 5ml tetrahydrofuran (THF) in reaction mixture, the solution of 4-trimethoxy-6-tolyl aldehyde, stirs 2 hours.Be warming up to room temperature, then add 50ml water, with after ether extraction, organic layer is dried, is filtered with magnesium sulfate, under reduced pressure heat up in a steamer desolventizing, the thick resultant silica gel column chromatography obtaining is refined, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (the iodo-5-methyl-3-of the fluoro-4-of 2-pyridyl) 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) to be dissolved with (2 of the middle acquisition of 4.35g (9.70mmol) operation (b) in 130ml toluene, 3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (the iodo-5-methyl-3-of the fluoro-4-of 2-pyridyl) methyl alcohol, add 17.3g (0.18mol) Manganse Dioxide, reflux 2 hours.Be cooled to room temperature, then use sellaite, remove Manganse Dioxide, then under reduced pressure heat up in a steamer toluene, refine with silica gel column chromatography, (compound N o.18 for the iodo-5-picoline of the fluoro-4-of-2-to obtain 2.80g (yield 65%) 3-(2,3,4-trimethoxy-6-methyl benzoyl); Fusing point 140-141 DEG C).

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 obtaining in 1.50g (3.37mmol) operation (c); 3,4-trimethoxy-6-methyl benzoyl) the iodo-5-picoline of the fluoro-4-of-2-, 1.40g (10.1mmol) salt of wormwood, 0.39g (0.34mmol) tetrakis triphenylphosphine palladium, 15ml bis- 50% trimethylboroxin of alkane, 0.42g (1.67mmol), reflux 6 hours.Be cooled to after room temperature; filter with sellaite; wash with ethyl acetate and tetrahydrofuran (THF); under reduced pressure heat up in a steamer desolventizing; the thick resultant silica gel column chromatography obtaining is refined, obtained the 3-(2,3 of 0.79g (yield 70%); 4-trimethoxy-6-methyl benzoyl)-2-is fluoro-4,5-lutidine (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) to be dissolved with the 3-(2 obtaining in the operation (d) of 0.20g (0.60mmol) in 2.5ml methyl alcohol; 3; 4-trimethoxy-6-methyl benzoyl)-2-fluoro-4; in the solution of 5-lutidine; drip the solution of 60% sodium hydride that is dissolved with 0.06g (1.5mmol) in 1ml methyl alcohol, reflux 16 hours.After cool to room temperature; add 5ml water; carry out slightly acidic with dilute hydrochloric acid, with after ether extraction, wash with salt solution; organic layer is dried, is filtered with magnesium sulfate; under reduced pressure heat up in a steamer desolventizing, the thick resultant silica gel column chromatography obtaining is refined, obtain the 3-(2,3 of 89.0mg (yield 43%); 4-trimethoxy-6-methyl benzoyl)-2-methoxyl group-4,5-lutidine.

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) the chloro-2-methoxypyridine of the bromo-4-of-5-(compound N o.23)

(a) the chloro-2-methoxypyridine of 5.76g (40.1mmol) 4-is dissolved in 20ml dimethyl formamide, drips dimethyl formamide (20ml) solution 30 minutes of 8.01g (98% product, 44.1mmol) N-bromine succinimide.At room temperature stir after 2 days because find unreacted raw material, so and then add N-bromine succinimide 2.85g (98% product, 16mmol), further stir 3 days in room temperature.Inject reaction 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, is dried, filters with magnesium sulfate, under reduced pressure heats up in a steamer desolventizing.The thick resultant silica gel column chromatography obtaining is refined, obtained the chloro-2-methoxypyridine of 7.10g (yield 80%) the bromo-4-of 5-.

¹H-NMR(CDCl ₃、400MHz)：δ(ppm)＝3.91(s，3H)、6.89(s，1H)、8.28(s，1H)

(b) to be dissolved with 2 of 3.84g (27mmol) in 36ml tetrahydrofuran (THF), in the solution of 2,6,6-tetramethyl pyridine, under argon gas stream, at 0 DEG C of dropping 18.3ml n-Butyl Lithium (1.57mol/l hexane solution, 27mmol), stir 30 minutes at 0 DEG C.Obtained solution is cooled to-78 DEG C, be added on the solution of the chloro-2-methoxypyridine of the bromo-4-of 5-that is dissolved with 6.10g (27mmol) in 24ml tetrahydrofuran (THF), synthermal lower stirring 2 hours, the chloro-2-methoxyl group-3-of the modulation bromo-4-of 5-pyridyl lithium.Then, be added in 24ml tetrahydrofuran (THF) and be dissolved with 5.50g (26mmol) 2,3, the solution of 4-trimethoxy-6-tolyl aldehyde, synthermal lower stirring 1 hour.To adding 37ml saturated aqueous ammonium chloride, then in reaction mixture, add 150ml water, be warming up to after room temperature, with ethyl acetate (each 150ml) extraction 3 times.With saturated aqueous common salt (100ml) washing organic layer, be dried, filter with magnesium sulfate, under reduced pressure heat up in a steamer desolventizing.The thick resultant silica gel column chromatography obtaining is refined, obtained 6.53g (yield 56%) (2,3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-2-methoxyl group-3-of the bromo-4-of 5-pyridyl) 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 be dissolved with (2 of 2.21g (5.1mmol) in 70ml toluene, 3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (the chloro-2-methoxyl group-3-of the bromo-4-of 5-pyridyl) methyl alcohol, add 4.55g (88% product, 46mmol) Manganse Dioxide, reflux 1 hour.And then, add 4.55g (88% product, 46mmol) Manganse Dioxide, reflux 1 hour.Reaction mixture is cooled to room temperature, then removes Manganse Dioxide with sellaite, under reduced pressure heat up in a steamer toluene.The thick resultant silica gel column chromatography obtaining is refined, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxypyridine of the bromo-4-of-5-(84～87 DEG C 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) the chloro-2-methoxyl group-4-of-5-picoline (compound N o.35)

(a) in 15ml DMF (DMF) solution of 8.0g (65mmol) 2-methoxyl group-4-picoline, drop into N-chloro-succinimide 9.2g (69mmol), stir 18 hours.In reaction soln, add water, with after extracted with diethyl ether water layer, with saturated common salt water washing organic layer, be dried by anhydrous sodium sulphate, then filter, under reduced pressure heat up in a steamer desolventizing.With silica gel column chromatography refining crude resultant, obtain the chloro-2-methoxyl group-4-of the 5-picoline (32～33 DEG C 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 the chloro-2-methoxyl group-4-of 7.2g (46mmol) 5-picoline, in dinethylformamide (DMF) solution, drop into 20.2g (114mmol) N-bromine succinimide, at 50 DEG C, stir 20 hours.In reaction soln, add rare sodium thiosulfate solution, use extracted with diethyl ether water layer.With saturated common salt water washing organic layer, be dried by anhydrous sodium sulphate, then filter with silica gel filter cake, under reduced pressure heat up in a steamer desolventizing, obtain the chloro-2-methoxyl group-4-of the bromo-5-of the 3-picoline (44～45 DEG C 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 tetrahydrofuran (THF), 0.62ml (4.4mmol) triethylamine, be cooled to 0 DEG C, drip the solution that is dissolved with the chloro-2-methoxyl group-4-of the bromo-5-of 1.0g (4.2mmol) 3-picoline in 5ml tetrahydrofuran (THF), then stir the chloro-2-methoxyl group-4-of modulation 5-methyl-3-pyridyl magnesium chloride 3 hours.To in 5ml tetrahydrofuran (THF), be dissolved with 2,3 of 0.89g (4.2mmol), in the solution of 4-trimethoxy-6-tolyl aldehyde, be added drop-wise in reaction soln, stir after 1 hour, be warming up to room temperature, and then stir 1 hour.In reaction soln, add water, stopped reaction, extracts out by ethyl acetate, then uses saturated common salt water washing organic layer, is dried with anhydrous magnesium sulfate, then filters, and under reduced pressure heats up in a steamer desolventizing.With silica gel column chromatography refining crude resultant, obtain (2 of 1.1g (yield 70%), 3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-2-methoxyl group-4-of 5-methyl-3-pyridyl) methyl alcohol (faint yellow oily matter).

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) to 0.64g (1.7mmol) (2,3,4-trimethoxy-6-aminomethyl phenyl) in the 15ml toluene solution of (the chloro-2-methoxyl group-4-of 5-methyl-3-pyridyl) methyl alcohol, add 4g activated manganese dioxide, under reflux, stir 1 hour.Carry out filtering reacting solution with sellaite; under reduced pressure heat up in a steamer desolventizing; obtain 3-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-picoline (94.5～95.5 DEG C 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 the chloro-4-5-flumethiazine of 5.05g (27.8mmol) 2-, 3.59g (66.5mmol) sodium methylate, under reflux, stir 4 hours.Add water, stopped reaction, extracts with ether, then uses anhydrous sodium sulfate drying organic layer, filters with silica gel filter cake.Under reduced pressure heat up in a steamer 4-trifluoromethyl-2-methoxypyridine of desolventizing, acquisition 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) to being dissolved with in 15ml acetic acid in the solution of the middle 4-trifluoromethyl-2-methoxypyridine obtaining of 8.21g (46.4mmol) operation (a), 7.98g (97.3mmol) sodium acetate, drip 4.00ml (78.1mmol) bromine, stir 4 days.Add potassium hydroxide aqueous solution, stopped reaction, with after extracted with diethyl ether, uses anhydrous sodium sulfate drying organic layer, filters with silica gel filter cake.Under reduced pressure heat up in a steamer desolventizing, obtain the mixture 5.81g (mol ratio 55: 45) of 4-trifluoromethyl-2-methoxypyridine of the bromo-4-trifluoromethyl-2-methoxypyridine of 5-and raw material.

¹H-NMR(CDCl ₃，400MHz)：δ(ppm)＝3.94(s，3H)，7.03(s，1H)，8.37(s，1H)

(c) to being dissolved with in 50ml tetrahydrofuran (THF) in the solution of 3.80ml (27.1mmol) diisopropylamine, drip 17.1ml n-Butyl Lithium (1.57mol/l hexane solution) at 0 DEG C, stir 30 minutes.Solution is cooled to-78 DEG C, be added on the solution that is dissolved with the mixture 5.81g (mol ratio 55: 45) of the middle bromo-4-trifluoromethyl-2-methoxypyridine of 5-obtaining of operation (c) and 4-trifluoromethyl-2-methoxypyridine in tetrahydrofuran (THF) 10mL, stir the mixture of modulation 5-bromo-4-trifluoromethyl-2-methoxyl group-3-pyridyl lithium and 4-trifluoromethyl-2-methoxyl group-3-pyridyl lithium 45 minutes.Be added in 15mL tetrahydrofuran (THF) and be dissolved with 2,3 of 5.51g (26.2mmol), the solution of 4-trimethoxy-6-tolyl aldehyde, stirs 1 hour.In mixture, add water, stopped reaction, under reduced pressure heats up in a steamer tetrahydrofuran (THF).After being extracted with ethyl acetate, use anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtained (2,3,4-trimethoxy-6-aminomethyl phenyl) (the bromo-4-trifluoromethyl-2-of 5-methoxyl group-3-pyridyl) 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 110mL toluene, be dissolved with in the operation (c) of 4.80g (10.3mmol), obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) in the solution of (the bromo-4-trifluoromethyl-2-of 5-methoxyl group-3-pyridyl) methyl alcohol, add 20.0g (230mmol) Manganse Dioxide, under reflux, stir 1 hour.Be cooled to room temperature, then mixture filtered with sellaite, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl) the bromo-4-trifluoromethyl-2-of-5-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) to be dissolved with the 3-(2 obtaining in 0.60g (1.29mmol) operation (d) in 10ml tetrahydrofuran (THF); 3; 4-trimethoxy-6-methyl benzoyl) in the solution of the bromo-4-trifluoromethyl-2-of-5-methoxypyridine, 0.10g (0.09mmol) tetrakis triphenylphosphine palladium; drip 3.80ml (3.80mmol) zinc methide (1.0mol/l hexane solution) at 0 DEG C; naturally, after heating up, at room temperature stir 8 days.Add water, stopped reaction, under reduced pressure heats up in a steamer tetrahydrofuran (THF).After being extracted with ethyl acetate, use anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined 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, the chloro-3-5-flumethiazine of 5-bis-(compound N is o.39) synthetic

(a) to being dissolved with in 60ml ether in the solution of 3.6ml (25mmol) diisopropylamine, drip 17ml (25mmol) n-Butyl Lithium (1.5mol/l hexane solution) at 0 DEG C, stir 45 minutes.Solution is cooled to-78 DEG C, be added on and in 8ml ether, be dissolved with 2,3 of 6.0g (24mmol), the solution of 6-tri-chloro-5-trifluoromethylpyridines, stir 25 minutes, after the chloro-5-trifluoromethyl-4-of modulation 2,3,6-tri-pyridyl lithium, be added on and in 12ml toluene, be dissolved with 2 of 5.0g (24mmol), the solution of 3,4-trimethoxy-6-tolyl aldehyde, stirs 1 hour.In mixture, add 30ml water, stopped reaction, be extracted with ethyl acetate water layer, then use anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer desolventizing, acquisition (2,3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-5-trifluoromethyl-4-of 2,3,6-tri-pyridyl) methyl alcohol (131～135 DEG C of fusing points).

(b) to be dissolved with 2 of the middle acquisition of operation (a) in 200ml methyl alcohol, 3,4-trimethoxy-6-aminomethyl phenyl) (2,3, the chloro-5-trifluoromethyl-4-of 6-tri-pyridyl) in the solution of methyl alcohol, the 5% palladium carbon that adds 2.7ml (19mmol) triethylamine, 0.9g stirs 14 hours under nitrogen atmosphere.Filtering mixt, adds 30ml water, under reduced pressure heats up in a steamer methyl alcohol.Extract by ethyl acetate, then use anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-3-trifluoromethyl-4-of 2,5-bis-pyridyl) methyl alcohol (162～165 DEG C of fusing points) 2.38g (yield 24%).

(c) to be dissolved with (2 of the middle acquisition of 3.5g (8.2mmol) operation (b) in 100ml toluene, 3,4-trimethoxy-6-aminomethyl phenyl) (2, the chloro-3-trifluoromethyl-4-of 5-bis-pyridyl) in the solution of methyl alcohol, add 14g Manganse Dioxide, under reflux, stir 6 hours.Cooling mixture, then filters, and under reduced pressure heats up in a steamer toluene.Thick resultant is refined with silica gel column chromatography, obtained 4-(2,3,4-trimethoxy-6-methyl benzoyl)-2, the chloro-3-5-flumethiazine of 5-bis-(106～109 DEG C of fusing points) 3.1g (yield 89%).

Synthesis example 7

Synthesizing of 4-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-3-trifluoromethyl-5-of-2-methoxypyridine (compound N o.40)

(a) in the solution of the 120ml ether of 15.0ml (107mmol) diisopropylamine, drip n-Butyl Lithium (1.5mol/l hexane solution) 70.0ml (106mmol) at 0 DEG C, stir 1 hour.By cooling solution-78 DEG C, add 22.1g (102mmol) 2, the solution of the 10ml ether of 3-bis-chloro-5-trifluoromethylpyridines, stir the chloro-5-trifluoromethyl-4-of modulation 2,3-bis-pyridyl lithium 30 minutes, then add 21.0g (100mmol) 2, the solution of the 40ml toluene of 3,4-trimethoxy-6-tolyl aldehyde, stirs 2 hours.In mixture, add 30ml water, stopped reaction, is extracted with ethyl acetate water layer, then uses anhydrous sodium sulfate drying organic layer, filters, and under reduced pressure heats up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-5-trifluoromethyl-4-of 2,3-bis-pyridyl) methyl alcohol (95～98 DEG C of fusing points) 24.8g (yield 58%).

(b) to (2 of the middle acquisition of operation (a), 3,4-trimethoxy-6-aminomethyl phenyl) (2, the chloro-5-trifluoromethyl-4-of 3-bis-pyridyl) 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 stirs 4 hours under nitrogen atmosphere.Filtering mixt, adds 50ml water, under reduced pressure heats up in a steamer methyl alcohol.Be extracted with ethyl acetate water layer, use anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtain (2,3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-5-trifluoromethyl-4-of 3-pyridyl) methyl alcohol (102～105 DEG C of fusing points) 15.9g (yield 70%).

(c) to (2 of the middle acquisition of operation (b), 3,4-trimethoxy-6-aminomethyl phenyl) (the chloro-5-trifluoromethyl-4-of 3-pyridyl) methyl alcohol 15.9g (40, in toluene 220ml solution 6mmol), add 45g Manganse Dioxide, under reflux, stir 2 hours.Filtering mixt, under reduced pressure heats up in a steamer desolventizing, obtains 4-(2,3,4-trimethoxy-6-methyl benzoyl)-3-chloro-5-trifluoromethylpyridine (75～77 DEG C of fusing points) 14.9g (yield 94%).

(d) to the middle 4-(2 obtaining of operation (c); 3; 4-trimethoxy-6-methyl benzoyl) in the toluene 150ml solution of-3-chloro-5-trifluoromethylpyridine 18.5g (47.5mmol), hexamethyl phosphoric triamide 16.6ml (95.4mmol); add sodium methylate 16.4g (304mmol), under reflux, stir 30 minutes.Add water, stopped reaction, is then extracted with ethyl acetate water layer, uses anhydrous sodium sulfate drying water layer, filters, and under reduced pressure heats up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtained 4-(2,3,4-trimethoxy-6-methyl benzoyl)-3-methoxyl group-5-5-flumethiazine (103～106 DEG C of fusing points) 11.7g (yield 64%).

(e) to 4-(2; 3; 4-trimethoxy-6-methyl benzoyl) in the chloroform 100ml solution of-3-methoxyl group-5-5-flumethiazine (compound N is o.122) 5.6g (15mmol); add metachloroperbenzoic acid (m-CPBA) 6.1g (28mmol) at 0 DEG C, then stirring at room temperature 18 hours.Reaction soln is washed with aqueous sodium hydroxide solution; under reduced pressure heat up in a steamer desolventizing; obtain 4-(2; 3,4-trimethoxy-6-methyl benzoyl)-3-methoxyl group-5-5-flumethiazine-N-oxide compound (128～134 DEG C of fusing points) 5.8g (yield 99%).

(f) in 4ml toluene, 8ml dimethyl formamide; add 1.8ml (19mmol) phosphoryl chloride at 0 DEG C; stir 10 minutes; then add 4.0g (10mmol) 4-(2; 3; 4-trimethoxy-6-methyl benzoyl)-3-methoxyl group-5-5-flumethiazine-N-oxide compound, stirs 20 minutes.Stirring at room temperature 2 hours, then reaction soln is put in frozen water to stopped reaction.Be extracted with ethyl acetate water layer, use anhydrous sodium sulfate drying organic layer, filter, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtained 4-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-3-trifluoromethyl-5-of-2-methoxypyridine (117～119 DEG C of fusing points) 3.57g (yield 85%).

Synthesis example 8

(a) by 45.6g (217mmol) 2,3,4-trimethoxy-6-tolyl aldehyde was dissolved in 130ml dimethyl sulfoxide (DMSO), with 20 minutes dropping SODIUM PHOSPHATE, MONOBASIC 5.2g (44mmol) aqueous solution (50ml).Then,, with 3 hours dropping Textone 28g (305mmol) aqueous solution (180ml), stir 2 hours.Add saturated sodium bicarbonate aqueous solution until do not foam, stir 1 hour, then by 50ml ethyl acetate, reaction soln is washed 2 times, then, add concentrated hydrochloric acid, make water layer be acid, be extracted with ethyl acetate.By organic layer saturated common salt water washing, with anhydrous sodium sulfate drying, filter, under reduced pressure heat up in a steamer desolventizing.Obtained crystallization is washed with hexane, obtain 2,3,4-trimethoxy-6-tolyl acid (fusing point 95-97 DEG C) 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 DEG C, drip the solution of the chloro-2-methoxyl group-4-of the bromo-5-of the 3-picoline that is dissolved with 1.6g (6.6mmol) in 5ml tetrahydrofuran (THF), synthermal lower stirring 3 hours, the chloro-2-methoxyl group-4-of modulation 5-methyl-3-pyridyl magnesium chloride.And then, reaction soln is cooled to-78 DEG C, drip the solution that is dissolved with 1.2g (13.3mmol) cuprous cyanide (I) and 1.15g (27.1mmol) lithium chloride in 15ml tetrahydrofuran (THF), the chloro-2-methoxyl group-4-of modulation 5-methyl-3-pyridyl copper reagent.On the other hand, by 3.2g (14.3mmol) 2,3 synthetic in (a) operation, 4-trimethoxy-6-tolyl acid, in 7ml thionyl chloride, reflux 3 hours, under reduced pressure heats up in a steamer superfluous thionyl chloride, by modulate 2,3,4-trimethoxy-6-methyl benzoyl chloride is dissolved in 7ml tetrahydrofuran (THF), at-78 DEG C, the solution obtaining is like this added drop-wise in the pyridyl copper reagent modulating in advance, stirs after 1 hour, be warming up to room temperature, and then stir 2 hours.In reaction soln, add water, ammoniacal liquor, stopped reaction, is extracted with ethyl acetate.By organic layer anhydrous magnesium sulfate drying, then filter, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-picoline (85～88 DEG C of fusing points) 2.6g (yield 57%), use ¹hNMR has identified compound.

(b-2) 11ml (11.0mmol) tetrahydrofuran solution of use 1M isopropylmagnesium chloride, the chloro-2-methoxyl group-4-of the bromo-5-of 2.5g (10.6mmol) 3-picoline, carry out the reaction same with operation (b-1), replace cuprous cyanide (I), lithium chloride tetrahydrofuran solution, and use 1.25g (1.1mmol) tetra-triphenylphosphine palladium, at 0 DEG C, with 2 hours drip by 2.4g (10.6mmol) 2, 3, 4-trimethoxy-6-tolyl acid and 5ml thionyl chloride modulate 2, 3, 4-trimethoxy-6-methyl benzoyl chloride, synthermal lower stirring 15 hours, obtain 3-(2, 3, 4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-picoline 1.7g (yield 43%), with ¹hNMR has identified compound.

(b-3) by the reaction same with operation (b-2); replace the tetrahydrofuran solution of 1M isopropylmagnesium chloride and use 0.5M isopropylmagnesium chloride 22ml (22.0mmol) tetrahydrofuran solution, replace tetra-triphenylphosphine palladium and use 1.14g (11.5mmol) cupric chloride; obtain 3-(2; 3; 4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-picoline 1.7g (yield 43%), uses ¹hNMR has identified compound.

Synthesis example 9

(a) will there is 5.0g (19mmol) 2-bromo-3 at 50ml ether dissolution, 4, the solution of 5-trimethoxytoluene is cooled to-78 DEG C, drip 15ml (24mmol) n-Butyl Lithium (1.6M hexane solution), stir 1.5 hours, generate 2,3,4-trimethoxy-6-methyl-2-phenyl lithium, then drips 4.9ml (43mmol) trimethyl borate and then stirs 1 hour.Add dilute sulphuric acid, stopped reaction, stirs after 30 minutes, and then adds water.Be extracted with ethyl acetate water layer, with saturated common salt water washing organic layer, with anhydrous magnesium sulfate drying, filtration, under reduced pressure heat up in a steamer desolventizing, obtain 2,3,4-trimethoxy-6-aminomethyl phenyl boric acid (99～102 DEG C of fusing points) 3.26g (yield 75%).

¹HNMR：δ2.52(s，3H)，3.83(s，3H)，3.88(s，3H)，3.94(s，3H)，6.56(s，1H)

(b) in 200ml autoclave, add the bromo-5-of 3-chloro-2-methoxyl group-4-picoline 1.0g (4.3mmol), 2,3,4-trimethoxy-6-aminomethyl phenyl boric acid 1.2g (5.4mmol), salt of wormwood 1.8g (13mmol), Palladous chloride 46mg (0.26mmol), tricyclohexyl phosphine 147mg (0.52mmol), tetrahydrofuran (THF) 40ml, enclose 10 atmospheric CO (carbon monoxide converter) gas, stir 20 hours at 120 DEG C.Reaction soln is filtered with sellaite, add water, under reduced pressure heat up in a steamer tetrahydrofuran (THF).Be extracted with ethyl acetate water layer, by organic layer anhydrous magnesium sulfate drying, then filter, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtained 3-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-picoline (92～94 DEG C of fusing points) 0.31g (yield 20%), use ¹hNMR authenticating compound.

Synthesis example 10

(a) to possessing in the 500ml four-hole boiling flask of stirrer, water cooler, thermometer and nitrogen balloon, add 5.4g (222mmol) magnesium and 95ml tetrahydrofuran (THF), temperature in system is remained on to 40 DEG C on one side, drip isopropyl chloride 17.3g (220mmol) on one side, stir a night.Then, temperature in system is remained on to 0 DEG C or below it, drip the solution of the 95ml tetrahydrofuran (THF) of the chloro-2-methoxyl group-4-of the bromo-5-of 47.3g (200mmol) 3-picoline simultaneously, stir 3 hours, then to dropwise reaction liquid in dry ice.

In 300ml water, drop into reaction solution, after separatory, carry out acidification to dripping hydrochloric acid water in water layer, extract with ether.Under reduced pressure heat up in a steamer desolventizing, obtain 5-chloro-2-methoxyl group-4-methylnicotinic acid (127～129 DEG C of fusing points) 26g (yield 65%).

(b) to possessing in the 50ml four-hole boiling flask of stirrer, water 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-ethylene dichloride 20ml and Vanadium Pentoxide in FLAKES 7.1g (50.0mmol) stir 1 hour under refluxing.

In 50ml water, drop into reaction solution, add aqueous sodium hydroxide solution, make its alkalization, after separatory, under reduced pressure heat up in a steamer desolventizing.In obtained resistates, add 5ml hexane, the crystallization of separating out is filtered, obtain target compound 0.4g (yield 22%).

Synthesis example 11

To possessing in the 20ml eggplant-shape bottle of reflux cooler, add 5-chloro-2-methoxyl group-4-methylnicotinic acid 1.0g (5.0mmol), 1,2-ethylene dichloride 10g and oxalyl chloride 0.62g (5.0mmol), stir 20 minutes at 25 DEG C, then 60 DEG C～65 DEG C heating 2 hours.25 DEG C cooling, then in reaction mixture, add 3,4,5-trimethoxytoluene 0.80g (4.4mmol), Aluminum chloride anhydrous 0.70g (5.2mmol), 25 DEG C stir 3 hours.

In reaction mixture, add water and ethyl acetate, after extraction, separatory, by organic layer dried over sodium sulfate, under reduced pressure heat up in a steamer desolventizing.In the solid of separating out, add normal hexane, filter, dry, obtain target compound 0.66g (yield 36.1%).

Synthesis example 12

(a) to 6.0g (26.6mmol) 2,3, in 4-trimethoxy-6-tolyl acid, add 10ml thionyl chloride, under reflux, stir 4 hours, then under reduced pressure heat up in a steamer superfluous thionyl chloride.Add wherein toluene 20ml, acetonitrile 8ml, cupric cyanide (I) 3.1g (34.5mmol), under reflux, stir 16 hours.Be cooled to after room temperature, use sellaite filtering reacting solution, under reduced pressure heat up in a steamer desolventizing.Thick resultant is refined 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 in 20ml tetrahydrofuran (THF), be dissolved with 1.9g (8.0mmol) 2; 3; the solution of 4-trimethoxy-6-toluyl nitrile is cooled to-10 DEG C, adds 0.32g (0.91mmol) Acetyl Acetone acid iron (III) salt, stirs 20 minutes.In other reaction vessels, in the tetrahydrofuran solution 4.1ml (8.2mmol) of 2M isopropylmagnesium chloride, add tetrahydrofuran (THF) 4ml, be cooled to 0 DEG C, drip the solution that is dissolved with the chloro-2-methoxyl group-4-of the bromo-5-of 1.0g (4.2mmol) 3-picoline in 5ml tetrahydrofuran (THF), then stir 3 hours, generate the chloro-2-methoxyl group-4-of 5-methyl-3-pyridyl magnesium chloride.To just modulated 2,3, in 4-trimethoxy-6-toluyl nitrile-iron mixing solutions, drip the pyridyl magnesium chloride solution that modulates, stir 3 hours.In reaction soln, add 10% aqueous ammonium chloride solution, stopped reaction, after being extracted with ethyl acetate, with saturated common salt water washing organic layer, is dried with anhydrous magnesium sulfate, then filters, and under reduced pressure heats up in a steamer desolventizing.Thick resultant is refined with silica gel column chromatography, obtained target compound 1.7g (yield 58%).

Intermediate synthesis example 1

(a) to possessing in the 2L four-hole boiling flask of stirrer, thermometer and gas duct (importing), add 324g (3.00mol) 2-AMINO-4-PICOLINE and 485g methyl alcohol, mixed dissolution, then temperature in system is remained on to 10～30 DEG C, simultaneously with 1 hour 30 minutes importing 361.4g (9.90mol) hydrogen chloride gas.

Then, to possessing stirrer, thermometer, dropping funnel and connecting in the 2L four-hole boiling flask of the conduit with bubble counter (derivation) of gas generating unit and diazotization reaction device, mix Sodium Nitrite 414g (6.00mol), methyl alcohol 211g (6.60mol) and water 454g, temperature in system is remained on to 20～30 DEG C, simultaneously with 5 hours dropping 38% aqueous sulfuric acid 812.4g (3.15mol).

In methyl nitrite generating unit, in dripping 38% aqueous sulfuric acid, produce corresponding methyl nitrite gas, import in diazotization reaction device by bubble counter.

On the other hand, in diazotization reaction, carry out water cooling so that the interior temperature of system can maintain 20～30 DEG C.

Import after methyl nitrite gas, under equality of temperature, stir 13 hours, finish reaction.

Heat up in a steamer after methyl alcohol in decompression, drop into water 648g, and then at 30 DEG C or below it, drip 40% aqueous sodium hydroxide solution 518g, the pH in regulation system is 12.

Generation oil is extracted with the ether of 910g, after separatory, under reduced pressure heat up in a steamer desolventizing, obtain 375.3g oil.In addition, this oil (thick resultant) consist of the chloro-4-picoline 70.7% of 2-(yield 69.5%), 2-methoxyl group-4-picoline 26.6% (yield 27.2%), 2-AMINO-4-PICOLINE 2.6%.

(b) to possessing in the 2L four-hole boiling flask of stirrer, thermometer, cooling tube and dropping funnel, add 356g methyl alcohol, under agitation remain 50 DEG C or below it, drop into sodium methylate 237.6g (4.4mol) simultaneously, then temperature in system is remained on to 60～70 DEG C, simultaneously with the thick resultant 375.3g (70.7% product, 2.2mol) that drips the chloro-4-picoline of the 2-obtaining in above-mentioned operation for 3 hours.

Drip after end, heat up in a steamer methyl alcohol, simultaneously reflux 3 hours (amount of heating up in a steamer of methyl alcohol is during this period 120g).

Reaction finishes afterwards, the remaining methyl alcohol in system is heated up in a steamer in decompression, then drops into 750g water, dissolve inorganic salts.

Extracted with diethyl ether by the oil generating with 1050g, after separatory, under reduced pressure heats up in a steamer desolventizing, obtains 370g oil (thick resultant).The purity of the 2-methoxyl group-4-picoline obtaining in addition, is 95% (the 2 stage yields that start from 2-AMINO-4-PICOLINE are 95%).

Intermediate synthesis example 2

Synthesizing of the chloro-4-methyl-2-of 5-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-divinyl synthetic

In the solution of the 100ml toluene of 3.15g (37mmol) pyridine; add 2.28g (37mmol) acetic acid; at room temperature stir 1 hour, then add the solution of the 20ml toluene of 49.3g (373mmol) ethanoyl acetaldehyde dimethyl-acetal.And then, with the solution that slowly adds the 30ml toluene of 24.65g (373mmol) propane dinitrile for 20 minutes, at room temperature stir 5 days.With 50ml water washing reaction mixture, be then dried with magnesium sulfate, under reduced pressure heat up in a steamer desolventizing, 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-divinyl.

(b) 3-cyano group-4-methylpyridone is synthetic

By 4 of acquisition in (a), 4-dicyano-3-methyl-3-crotonaldehyde-dimethyl-acetal, 1,1-dicyano-4-methoxyl group-2-methyl isophthalic acid, the mixture 69.35g of 3-divinyl is to be no more than 30 DEG C like that, be slowly added drop-wise in vitriol oil 113g with 3 hours.At room temperature stir 20 minutes, be then warming up to 50 DEG C, synthermal lower stirring 2 hours.After letting cool, reaction mixture is slowly injected in frozen water (500ml), the crystallization that leaching obtains, with 100ml water washing crystallization.By air-dry crystallization 1 week, and then be under reduced pressure dried 8 hours at 70 DEG C, obtain the coarse crystallization of 3-cyano group-4-methylpyridone 34.2g (2 stage yield 68%). 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) the chloro-3-cyano group-4-of 2-picoline is synthetic

In the mixture of phosphorus pentachloride 6.52g (31.3mmol), phosphoryl chloride 30ml (48g, 313mmol), slowly add 3-cyano group-4-methylpyridone 14g (104mmol), at room temperature stir 70 minutes, then under reflux, stir 2 hours.After letting cool, in frozen water (400ml), inject reaction mixture, after superfluous reagent is decomposed, use 100ml dichloromethane extraction 3 times.With 100ml saturated common salt water washing dichloromethane solution, be dried, under reduced pressure heat up in a steamer desolventizing with magnesium sulfate, obtain the coarse crystallization 15.1g of the chloro-3-cyano group-4-of 2-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 chloro-3-cyano group-4-of the 2-picoline obtaining in 15.1g (c) is dissolved in 150ml anhydrous methanol, adds the methanol solution 24.9g (129mmol) of 28% sodium methylate, at room temperature stir 2 days.Reaction mixture is injected in 200ml saturated aqueous common salt, with 100ml ethyl acetate extraction 3 times.By dried over mgso for ethyl acetate solution, filter by sellaite-silicagel column, fully wash pillar by ethyl acetate.Merging filtrate, washings, the coarse crystallization of under reduced pressure heating up in a steamer 3-cyano group-4-methyl-2-methoxypyridine of desolventizing, acquisition 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) the chloro-3-cyano group-4-of 5-methyl-2-methoxypyridine is synthetic

By 14.04g (95mmol) (d) in obtain 3-cyano group-4-methyl-2-methoxypyridine be dissolved in 100ml dimethyl formamide, add 25.4g (190mmol) N-chloro-succinimide, at room temperature stir 3 days.With thin-layer chromatography confirm reaction carry out situation time, in order to confirm the remaining situation of raw material, 50 DEG C stir 22 hours, then 60 DEG C stir 22 hours.After letting cool, reaction mixture is injected in water 300ml, with 100ml ethyl acetate extraction 3 times.Ethyl acetate solution is used to 150ml water washing 2 times successively, then with the water washing of 100ml saturated common salt, be dried with magnesium sulfate, under reduced pressure heat up in a steamer desolventizing.The residuum of acquisition is refined 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) the chloro-3-formyl radical-4-of 5-methyl-2-methoxypyridine is synthetic

The chloro-3-cyano group-4-of 2.47g (13.5mmol) 5-methyl-2-methoxypyridine is dissolved in 50ml anhydrous methylene chloride, is cooled to-78 DEG C, then slowly drip the toluene solution 20.3ml (20.3mmol) of 1M diisobutyl aluminium hydride.At-78 DEG C, stir 2 hours, be then slowly warming up to room temperature, synthermal stirring 3 days.Obtained solution is carried out cooling at ice bath, slowly add 30ml water, finish reaction.Reaction mixture is injected in the 1N hydrochloric acid of 150ml, uses 100ml dichloromethane extraction 2 times.By 100ml saturated common salt water washing for dichloromethane solution, be dried, under reduced pressure heat up in a steamer desolventizing with magnesium sulfate, obtain the chloro-3-formyl radical-4-of thick 5-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) the chloro-4-methyl-2-of 5-methoxyl group-nicotinic acid is synthetic

The chloro-3-formyl radical-4-of the thick 5-methyl-2-methoxypyridine obtaining in (f) is dissolved in 14ml dimethyl sulfoxide (DMSO); add the aqueous solution 5.7ml of 0.33g (2.7mmol) SODIUM PHOSPHATE, MONOBASIC, and then with within 3 hours, slowly dripping Textone 2.16g (79% product, 18.9mmol) aqueous solution 20ml.Obtained mixture is at room temperature stirred 5 days, add saturated sodium bicarbonate water 50ml, stir a night.By ethyl acetate 50ml washing 2 times for obtained solution, then by concentrated hydrochloric acid furnishing acidity for water layer, with 70ml ethyl acetate extraction 3 times.By 50ml saturated common salt water washing for ethyl acetate solution, be dried, under reduced pressure heat up in a steamer desolventizing with magnesium sulfate, obtain coarse crystallization.Again coarse crystallization is dissolved in 50ml ethyl acetate, with the saturated sodium bicarbonate water of 50ml carry out stripping for 2 times, by water layer concentrated hydrochloric acid furnishing acidity, with 70ml ethyl acetate extraction 3 times.Be dried, under reduced pressure heat up in a steamer desolventizing by 50ml saturated common salt water washing for ethyl acetate solution, with magnesium sulfate, obtain white crystallization.With after 50ml hexane wash crystallization, air-dry, the chloro-4-methyl-2-of acquisition 0.55g (2 stage yield 20%) 5-methoxyl group-nicotinic acid. ¹H-NMR(400MHz、CDCl ₃)：δ(ppm)2.46(s，3H)、3.99(s，3H)、8.16(s，1H)、

Record the test example the present invention relates to, but the present invention is not limited only to this below.

Test example 1

Wheat powdery mildew experiment of preventive effects

Cultivated wheat in the polyethylene alms bowl of diameter 7.5cm (kind: No. 61, agricultural), in the time reaching 1.5 leaf age, is adjusted to by each test compound the admixing medical solutions that normality forms with spray tank and scatters in the mode that is equivalent to 200L/ha.After liquid is dry, spread the mitogenetic sporozoite of lower Powdery Mildew and inoculate, remain in the thermostatic chamber of 20 DEG C.After inoculation 6～8 days, investigate sporozoite and form area, obtain sickness rate according to following calculating formula, the results are shown in table 1～table 53.In addition, scatter water with spray tank except replacing liquid, the average lesion area in non-processor district is obtained in operation same with treatment zone.

Sickness rate=(a/b) × 100

A: the average lesion area for the treatment of zone

B: the average lesion area in non-processor district

The formula of utilizing Corby, calculates theoretical value.When trial value is during lower than theoretical value, Bactericide composition of the present invention, in wheat powdery mildew experiment of preventive effects, has synergy.The theoretical value that the formula by Corby in such situation is obtained is shown in () of table 1～table 53 in the lump.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Test example 2 powdery mildew of cucumber experiment of preventive effects

With the polyethylene alms bowl cultivated cucumber (kind: four leaves) of diameter 7.5cm, in the time reaching 1.5 leaf age, scatter the compounds of this invention with spray tank and be adjusted to the admixing medical solutions 10mL that normality forms.After liquid is dry, the mitogenetic sporozoite suspension of spray inoculation Powdery Mildew, remains in the thermostatic chamber of 20 DEG C.After inoculation 6～11 days, research sporozoite forms area, and obtain sickness rate same with test example 3, the results are shown in table 54～table 96.Replace liquid and scatter water with spray tank, in addition, the operate average lesion area of obtaining non-processor district same with treatment zone.

The theoretical value of being tried to achieve by the formula of Corby in addition, is as shown in () of table 54～table 96.

Table 54

Table 55

Table 56

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

Table 67

Table 68

Table 69

Table 70

Table 71

Table 72

Table 73

Table 74

Table 75

Table 76

Table 77

Table 78

Table 79

Table 80

Table 81

Table 82

Table 83

Table 84

Table 85

Table 86

Table 87

Table 88

Table 89

Table 90

Table 91

Table 92

Table 93

Table 94

Table 95

Table 96

, record formulation example of the present invention below, but amount of formulation, formulation etc. in the present invention are not limited only to record example.

Formulation example 1

By the compound of the mixture of above-mentioned each composition and formula (I) and according to general seat, mix with the part by weight of 8: 1: 1, obtain hydrating agents.

Formulation example 2

In above-mentioned each composition, add the needed water of appropriate granulation, mix, granulate, obtain granule.

Formulation example 3

By above-mentioned each composition mixing homogeneous, obtain pulvis.

Claims

The manufacture method of 1.3-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-picoline,

Be the method being made up of following operation, described operation is,

(a) the 1st operation, it is in 1,2-ethylene dichloride, to make the chloro-2-methoxyl group-4-methylnicotinic acid of 5-and chlorination reaction, obtains the operation of the chloro-2-methoxyl group-4-of 5-methylnicotinic acid acyl chlorides; With

(b) the 2nd operation; it is the 5-chloro-2-methoxyl group-4-methylnicotinic acid acyl chlorides and 3 by obtaining in the 1st operation; 4; the Friedel-Crafts reaction of 5-trimethoxytoluene; obtain the operation of 3-(2,3,4-trimethoxy-6-methyl benzoyl) the chloro-2-methoxyl group-4-of-5-picoline; described Friedel-Crafts reaction carries out in 1,2-ethylene dichloride.