NZ623022B2

NZ623022B2 - Method for producing pest controlling agent

Info

Publication number: NZ623022B2
Application number: NZ623022A
Authority: NZ
Inventors: Yoshimasa Fukuda; Shigeki Kitsuda; Nozomu Nakanishi; Ikuya Ohno
Original assignee: Meiji Seika Pharma Co Ltd
Priority date: 2011-08-26
Filing date: 2012-08-24
Publication date: 2015-11-03

Abstract

Disclosed is a method for producing a 2-aminopyridine compound of formula (I) by acylating a compound represented by Formula (A) by using an acylation agent, and further alkylating a 1-position nitrogen atom of the compound represented by Formula (B) in the absence of base. The compound is useful as a pest controlling agent. a pest controlling agent.

Description

TITLE OF THE INVENTION METHOD FOR PRODUCING PEST CONTROLLING AGENT BACKGROUND OF THE INVENTION Field of the Invention ? The present invention relates to a method for producing a novel pest l agent having a 2-acyliminopyridine structure.

Related Background Art Although many pest control agents have been developed so far, novel agents are still sought because of problems associated with decreased drug sensitivity, tence of the effects of agents, safety of agents in use, and the like.

In particular, as shown in Masaya Matsumura et al., Pest Management e, 2008, Vol. 64, No. 11, pp. 1115 to 1121 (Non-Patent Document 1), wet rice cultivation in East Asia and Southeast Asia obviously suffers damage due to planthoppers which have developed drug resistance to major pesticides including neonicotinoids represented by imidacloprid, phenylpyrazole-based agents represented by fipronil, and the like. Accordingly, specific agents against planthoppers which have developed resistance have been expected. In on, it is required that such novel agents be provided in amounts required as pest l agents stably and at low costs.

Methods described in PTION of European Patent IBPF12‘519 Application Publication No. 432600 (Patent Document 1), Japanese ined Patent Application Publication No.

Hei 05—78323 (Patent Document 2), DESCRIPTIONchEuropean Patent Application Publication No. 268915 (Patent Document 3), and Botho Kickhofen et al., Chemische Berichte, 1955, Vol. 88, pp. 1103 to 1108 (Non-Patent Document 2) are known as methods for producing a pest control agent having a 2—acyliminopyridine structure.

Patent Document 1 discloses a herbicide having the same ring ure as that of a compound represented by formula (I) described later. Patent Documents 2 and 3 disclose pesticides having the same ring ure as that of the nd represented by formula (I).

Non-Patent Document 2 discloses a compound having a ring structure similar to that of the compound represented by formula (I), as a synthetic intermediate.

However,theproductionnethodsdescribedinEQtent Documents 1, 2, and 3, and Non—Patent Document 2 are production s in which a compound ented by 2O formula (Ba) described later is used as an ediate, and fail to describe production in which a compound represented by formula (B) described later is used as an intermediate. Moreover, Patent Documents 1, 2, and 3, and Non—Patent Document 2 disclose productionlnethods in which a compound represented by formula (Ba) is used as an intermediate, but do not ically describe the IBPF12'519 production of a compound represented by formula (Ia) described later. Further, the ural a of N—[1—((6-chloropyridin—3—yl)methyl)pyridin~2(1H)—ylid ene]-2,2,2-trifluoroacetamide is disclosed, and a physical property value of the compound, i.e., a refractive index nD (25.5) of 1.4818 is described (CompoundNo.I3inTable1.0fPatentDocument2);however, this compound is not included in the list of compounds shown to have pest control activities (Tables 2 and 3 of Patent Document 2).

Moreover, Patent Document 3 discloses the structural formula of N—[1—((6—chloropyridin—3—y1)methyl)PYridin—Z(1H)—ylid ene]—2,2,2—trifluoroacetamide, anddescribes‘aphysical property value of the nd, i.e., a melting point of 60 to 62°C (Example No. 12 in Table 7 of Patent Document 3). However, this compound isruﬂ:listediJ1the examples of compounds which exhibited pest control activities in Examples. Neither Patent DocumentZ nor Patent Document 3 discloses a specific method for producing N—[1—((6—chloropyridin—3—yl)methyl)pyridin—Z(1H)-y1id ene]—2,2,2-trifluoroacetamide.

In addition, Wladysl, aw Pietrzycki, et al., Bulletin des Societes Chimiques Belges, 1993, Vol. 102, No. 11—12, pp. 709 to 717 atent nt 3) discloses N—(Pyridin—Z(1H)—ylidene]—acetamide as a 14: Vbr Interwoven\NRPortblOCC \RBR\80172831.docx-6/07/2015 tautomer of amide pyridine, but fails to describe a specific method for producing the tautomer, or a method for producing a yl derivative thereof.

SUMMARY OF THE INVENTION ? An aspect of the present invention is to provide a pest control agent having a 2-acyliminopyridine structure and being represented by formula (I) described later, in particular N-[1- ((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,2,2- trifluoroacetamide, in an amount required for a pest l agent stably and at a low cost.

Specifically, according to a first aspect of the invention, the present inventors have obtained a desired useful compound represented by the following formula (I) by using a nd represented by formula (A) as a starting nce, and a compound represented by formula (B) as an intermediate.

As a result, the present invention has been completed.

Provided is a method for producing a compound represented by the following formula (I): [Chem. 1] ( I ) IBPF12'519 [where Ar represents a phenyl group which may be substituted or a 5—to 6—membered heterocycle which may be substitutedd R1.represents a Cyﬁ alkyl group which may be substituted, and Y represents a hydrogen atom; a halogen atom; a hydroxyl group; a Cpﬁ alkyl group which may be substituted with a halogen atom; a CLﬁ alkyloxy group which may be substituted with a n atom; a cyano group; a formyl group; or a nitro group], the method comprising, as shown in the following reaction formula: [Chem. 2] n...Y Hﬂ-Y/, Ar /~ R4 Ar\/Q‘Y Y CORZ f —> NCOR NHZ NCOR1 1 (A) (B) (I) [where RlarKiY have the same meanings as those described above, R2 represents (1) a trifluoroacetoxy group, (2) a Cys alkyloxy group which may be substituted with a halogen atonlor a benzyloxy group whose phenyl group may be substituted with a n atom, a methyl group, a cyano group, a nitro group, or a methoxy group, (3) a Cyﬁ alkylcarbonyloxy group which may be substituted with a halogen atom (provided that a trifluoroacetoxy group is excluded)(n:aphenylcarbonyloxygroupwhosephenylgroup may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group,(4) a hydroxyl group, or (5) a halogen atom, and R4represents a halogen atom, a Cb6 alkylsulfoxy group which may be substitutedwithaahalogenatom,curaphenylsulfoxygroup which may be substituted with a halogen atom or a methyl group], the steps of: acylating an amino group at position 2 of a compound represented by formula (A) by use of an acylating agent represented by RJCORL to thereby produce a compound represented by a (B); [Chem. 3] (A) ; and further alkylating a nitrogen atom at position 1 of the compound represented by formula (B) by use of Ar-CHg—R4.

A second aspect of the present invention provides a useful intermediate represented by formula (B) (provided that compounds in which R1 is a methyl group or a phenyl group, and Y is a en atom are excluded), and a salt thereof.

A third aspect of the present invention provides a method for producing a compound represented by the following formula (Ia): [Chem. 4] IBPF12519 R%\-.><{1wa/ NCORm [whereR3representseahalogenatom,aicyanogroup,éanitro group, or a trifluoromethyl group, X represents a carbon atom or a nitrogen atom, and Rh represents a halogen—substituted Che alkyl group], the method being shown by the following reaction formula: [Chem. 5] ’5“> R iX'XI R /I R“ M &, wok»:/| F"'XI /| NH2 NH NCOR1a (Am (8% am [where R”, R4, R3 and X have the same meanings as those described above, Rm represents (1) a trifluoroacetoxy group, (2) a Cbﬁ alkyloxy group which may be substituted with a halogen atom or a benzyloxy group whose phenyl group may be tuted with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, &6alkylcarbonyloxygroupvﬂﬁchrmuzbesubstituted with a halogen atom (provided that a trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group whose phenyl group may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy nterwoven\NRPortbl\DCORBR\8017283_1.docs-0/07/2015 group, (4) a hydroxyl group, or (5) a halogen atom].

A fourth aspect of the present invention provides a compound represented by formula (I'), which is produced according to the following reaction formula: ? [Chem. 6] e-.--i- cly,„, ci.,,,,,,,, .. 1 i HN-rj? N ...? CI? N „,,,„,,,,,,NIr.I? I N,r= --30.? NH2 NCOCF3? NCOCF3 (v) (a)? ( I') [where the compound represented by formula (I') is N-[1-((6- chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,2,2- trifluoroacetamide which has the following physical ties (a) and/or (b): (a) diffraction angle peaks ined by powder X-ray diffraction being present at least at the following diffraction angles (28): 8.6±0.2°, 14.2±0.2°, 17.5±0.2°, 18.3±0.2°, 19.7±0.2°, 22.3±0.2°, 30.9±0.2°, and 35.3+0.2'; ? (b) a melting point determined by differential scanning calorimetry (DSC) of 155 to 158°C].

Another aspect of the present invention provides a method for producing a compound represented by the following formula (I): ? [Chem. 1] ( I ) [where Ar represents a phenyl group which may be substituted with halogen atoms,? alkyl groups which may be substituted with a halogen atom,? alkyloxy groups which may be substituted with IlArbrUnterwoven \NRPortblOCC \RBR \8017283_1.docx-6/07/2015 a halogen atom, a hydroxyl group, a cyano group, or a nitro group; or a 5-to ered heterocycle which may be tuted, with halogen atoms, C1_4 alkyl groups which may be substituted with a halogen atom, C1_4 alkyloxy groups which may be substituted with a halogen atom, a hydroxyl group, a cyano group, or a nitro group, R1 represents a 01-6 alkyl group which may be substituted with halogen atoms, C1_6 halogenated alkyloxy groups, a cyano group, a nitro group, or a hydroxyl group, and ? Y represents a hydrogen atom; a halogen atom; a yl group; a C1-6 alkyl group which may be substituted with a halogen atom; a C1-6 alkyloxy group which may be substituted with a halogen atom; a cyano group; a formyl group; or a nitro group], ? the method comprising, as shown in the following reaction formula: [Chem. 2] RiCOR2.

N CORI ? ? (A) B) (I) the steps of: ? ing an amino group at position 2 of a compound represented by formula (A) (Y has the same meaning as that described above) by use of an acylating agent represented by R1C0R2 (where R1 has the same meaning as that described above, and R2 represents (1) a trifluoroacetoxy group, (2) a C1-6 alkyloxy group which may be substituted with a halogen atom or a benzyloxy group whose phenyl group may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or a y group, (3) a C1-6 alkylcarbonyloxy group which may be substituted with a halogen atom (provided that a trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group whose phenyl group may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, (4) a hydroxyl group, or (5) a halogen atom) in the presence or in the absence of a condensation agent, phosphorus pentoxide, sulfuric acid, polyphosphoric acid, thionyl chloride, phosphorus oxychloride, or oxalyl dichloride, to thereby produce a compound represented by formula (B); and further alkylating a nitrogen atom at position 1 of the nd represented by formula (B) by use of Ar-CH2-R4 (where Ar has the same g as that described above, and R4 represents a n atom, a C1-6 alkylsulfoxy group which may be tuted with a halogen atom, or a phenylsulfoxy group which may be substituted with a halogen atom or a methyl group), wherein the acylation is carried out in the absence of a base.

HArbrUnterwovenWRPoriblOCC \RBR \8017283_1.docx-6/07/2015 Another aspect of the present invention provides a method for ing a compound represented by the following formula (Ia): [Chem. 3] NCORie a) [where R3 represents a halogen atom, a cyano group, a nitro group, or a trifluoromethyl group, X represents a carbon atom or a nitrogen atom, and Ria represents a halogen-substituted C1-6 alkyl , the method comprising, as shown in the ing reaction [Chem. 4] X R R3 Nrj.„? R4 ix (Ca) R1aCOR2a N r xI NH2 NH NcoRi a (Aa)? (Ba)? (Ia) the steps of: alkylating a nitrogen atom at position 1 of a compound represented by formula (Aa) by use of a compound represented by formula (Ca) (where R3 and X have the same meanings as those described above and R4 represents a halogen atom, a C1-6 alkylsulfoxy group which may be substituted with a halogen atom, or a phenylsulfoxy group which may be substituted with a halogen atom or a methyl group), to thereby produce a compound ented by formula (Ba); and acylating an imino group of the nd ented by formula (Ba) by use of an acylating agent represented by R1aCOR2a (where Ria has the same meaning as that described above, and R2a represents (1) a trifluoroacetoxy group, (2) a 01-6 alkyloxy group which may be substituted with a halogen atom or a benzyloxy group whose phenyl group may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, (3) a 01-6 alkylcarbonyloxy group which may be substituted with a n atom (provided that a trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group whose phenyl group may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, (4) a hydroxyl group, or (5) a halogen atom) in the presence or in the absence of a condensation agent, phosphorus pentoxide, sulfuric acid, polyphosphoric acid, l chloride, phosphorus oxychloride, or oxalyl dichloride ? wherein the acylation is carried out in the absence of a base.

Effects of the Invention According to the present invention, a iminopyridine derivative useful as a pest control agent can be produced HArbr\InterwovenWRPortblOCC \REM \8017283_1.docx-6/07/2015 efficiently in a good yield and, if ary, in a one-pot manner.

BRIEF DESCRIPTION OF THE DRAWINGS [Fig. 1] Fig. 1 is a graph showing results of powder -519 X—ray crystallography conducted on crystals of N—[1—((6—chloropyridin—3—yl)methyl)pyridin-Z(1H)~ylid ,2,2—trifluoroacetamide prepared by a first production method.

[Fig. 2] Fig. 2 is a graph showing results of differential scanning calorimetry conducted on crystals N—[l—((6-chloropyridin—3-yl)methyl)pYridin-Z(lH)—ylid ene]—2,2,2—trifluoroacetamide prepared by the first production method.

[Fig. 3] Fig. 3 is a graph showing results of powder X-ray crystallography conducted on crystals of N-[l—((6—chloropyridin—3-yl)methyl)pyridin—2(lH)-ylid ene]-2,2,2—trifluoroacetamide prepared by a second production method.

[Fig. 4] Fig. 4 is a graph g results of differential scanning calorimetry ted on crystals N-[1—((6—chloropyridin—3—yl)methyl)pyridin-2(1H)—ylid ene]—2,2,2—trifluoroacetamide prepared by the second production method.

[Fig. 5] Fig. 5 is a graph showing results of differential scanning calorimetry ted on crystals N—[1—((6—chloropyridin—3-yl)methyl)pyridin—2(1H)—ylid ene]-2,2,2—trifluoroacetamide prepared by a third IBPF12'519 production method.

[Fig. 6] Fig. 6 is a graph showing results of powder X—ray crystallography conducted on crystals of N—[1—((6—chloropyridin—3—yl)methyl)pyridin—2(1H)—ylid ene]-2,2,2-trifluoroacetamide prepared by a fourth production method.

[Fig. 7] Fig. 7 is a graph showing results of differential scanning metry conducted on crystals N-[l—((6—chloropyridin—3—yl)methyl)pyridin—Z(lH)~ylid ,2,2—trifluoroacetamide prepared by the fourth production method.

[Fig. 8] Fig. 8 is a graph g results of differential scanning calorimetry conducted on crystals of N—[1—((6—chloropyridin-3—yl)methyl)pyridin—Z(lH)-ylid ene]—2,2,2—trifluoroacetamide prepared by a fifth production method.

[Fig. 9] Fig. 9 is a graph showing results of powder X—ray crystallography conducted on crystals of N-[1—((6—chloropyridin-3—yl)methyl)pyridin—2(1H)-ylid ene]—2,2,2—trifluoroacetamide synthesized in Synthesis Example 4.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The "alkyl" used herein either as a substituent or a portion of a tuent means a , branched, or IBPF12619 cyclic alkyl, or an alkyl of a ation of any of these, unless otherwise defined.

The "halogen atom" used. herein means an atom selected from fluorine, ne, bromine, and iodine.

The term "equivalent" of the base used herein is, forexample,asfollows:when].molofpotassiumcarbonate is used for 1 mol of a compound ented by formula (A), the potassium carbonate is 2 equivalents; when lznol of sodium hydroxide or sodium hydrogen carbonate is used or, the sodium hydroxide or sodium hydrogen carbonate is 1 equivalent; and when 1 mol of an organic base is used therefor, the organic base is 1 equivalent.

The "salt" used herein refers to an inorganic acid salt such as a hydrochloride, a sulfuric acid salt, or a nitric acid salt; an c acid salt such as a trifluoroacetic acid salt, a difluoroacetic acid salt, a dichloroacetic acid salt; or the like.

The "reagent used simultaneouslyiuith an acylating agent R1COR2" used herein may be a hydrate thereof, when R2 represents a hydroxyl group.

The "condensation agent" used herein is a reagent for synthesis of carboxylic acid derivatives such as esters and amides, and examples of the "condensation agent" includes N,N'-dicyclohexylcarbodiimide, l-ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloride, l,l'—carbonyldiimidazole, dipyridyl IBPF12-519 ide, diimidazolyl ide, 1,3,5-trichlorobenzoyl chloride, 1,3,5—trichlorobenzoyl anhydride, PyBop (registered trademark, (benzotriazole—l—yloxy)tripyrrolidinophosphonium hexafluorophosphate), and.PyBrop (registered trademark, bromotri(pyrrolidino)phosphonium hexafluorophosphate), and the like.

The sign "Cmb" used herein and attached to a substituent means that the number of carbon atoms contained in the substituent is in the range from a to b. Moreover, for example, the "Cam" in a case of "Crb arbonyloxy" means that the number of carbon atoms in the alkyl moiety excluding the carbon atom in the carbonyloxy moiety is in the range from a to b.

Ar represents a phenyl group which may be substituted or a 5—to 6-membered heterocycle which may be substituted. Examples of the 5—to 6—membered heterocycle include pyridine, pyrimidine, thiazole, tetrahydrofuran, furan, and the like. Preferred examples of Ar e a 3-pyridyl group, a 5—pyrimidyl group, a zolyl group, a 5-thiazolyl group, and a 3—pyridyl group is more preferable. Examples of a substituent which may be introduced to the phenyl group or the heterocycle include halogen atoms, Chg alkyl groups which may be substituted with a halogen atom, C14 IBPF12-519 alkyloxy groups which may be substituted with a halogen atom, a yl group, a cyano group, and a nitro group.

Here, halogen atoms and C14 alkyl groups which may be substituted with a halogen atom are preferable, and a chlorine atom is particularly preferable. Specific examples of the phenyl group whicﬂlmay'be substituted and the 5—to 6—membered heterocycle whittlmay be substituted include a phenyl group, a 3-chlorophenyl group, a 4—chlorophenyl group, a ophenyl group, a ophenyl group, a ophenyl group, a 4—nitrophenyl group, a 3,5—dichlorophenyl group, a ylphenyl group, a 4—methoxyphenyl group, a 3,5—dibromophenyl group, a 2,4—dibromophenyl group, a 4-fluorophenyl group, a 4—bromophenyl group, a 3-nitrobromophenyl group, a 3,5—bis(trifluoromethyl)phenyl group, a 6—chloropyridylgroup,1a2—chloro—5—thiazolylgroup, a 6-chloro—5-fluoro—3—pyridyl group, a 6—bromo—3—pyridyl group, a 6—fluoro—3—pyridyl group, a 5,6—dichloro—3—pyridyl group, and a 6—trifluoromethyl—B-pyridyl group. Here, a 6-chloro—3—pyridyl group, a 6—fluoropyridyl group, a 6-chlorofluoro-3—pyridyl group, and a 6-bromo—3-pyridyl group are preferable, and a 6—chloro—3-pyridyl group is particularly preferable.

R1 represents a (h-a alkyl group which may be IBPF12‘519 substituted. Examples of a substituent which may be introduced to the Cbﬁ alkyl group include halogen atoms, Clﬁ nated alkyloxy groups, a cyano group, a nitro group, and a hydroxyl group. Specific examples of the Cyg alkyl group represented by R1 include a trifluoromethyl group, a difluorochloromethyl group, a trichloromethyl group, a pentafluoroethyl group, a difluoromethyl grOUp, a dichloromethyl grOUP, a dibromomethyl group, a chloromethyl group, a difluoroethyl grOUp, a dichloroethyl group, a 2,2,2—trifluoroethyl group, a<jifluorocyclopropyl group, a ifluoromethyl group, a trifluoromethoxymethyl group, and the like; preferred examples thereof include a trifluoromethyl group, a difluorochloromethyl group, a difluoromethyl group, a trichloromethyl group, and a pentafluoroethyl group; and a more preferred example is a trifluoromethyl group.

Rla represents a halogen—substituted C1% alkyl group. es thereof includeeatrifluoromethyl group, a trichloromethyl group, a difluorochloromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl grOUp, a chloromethyl grOUp, a difluoroethyl grOUp, a roethyl group, trifluoroethyl group, a pentafluoroethyl group, difluorocyclopropyl group, and the like. Here, trifluoromethyl group, a trichloromethyl grOUp, IBPF12'519 dichloromethyl group, a difluoromethyl group, a rochloromethyl group, a chloromethyl group, and a pentafluoroethylgrouparepreferable;atrifluoromethyl group, a difluoromethyl group, a difluorochloromethyl group,aichloromethylgroup,andaapentafluoroethylgroup are more preferable; and a trifluoromethyl group is particularly preferable.

Y represents a hydrogen atom; a n atom; a hydroxylgroup;a(hl6alkylgroupwhichmaybesubstituted with a halogen atom; a Chg alkyloxy group which may be substituted with a halogen atom; a cyano group; a formyl group; or a nitro group. Y preferably represents a hydrogen atom, a halogen atom, or a hydroxyl group, and more preferably represents a hydrogen atom.

Each of Rzand R%,represents H) a trifluoroacetoxy group, (2) a Cyﬁ alkyloxy group which may be substituted with a halogen atom or a benzyloxy group whose phenyl group may be tuted with a halogen atom, a methyl group, a cyano group, a nitro group, or axnethoxy group, (3) a C1_6 arbonyloxy group which may be substituted with a halogen atom (provided that a trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group whose phenyl group may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or‘a methoxy group, (4) a hydroxyl group, or (5) a halogen atom. esentseasubstituent substituted<m1a carbon IBPF12'519 atom of a pyridine ring or a pyrimidine ring, and it is evident that the number of R3 is O to 4 in the case of pyridine, and.0 to 3 in the case of the pyrimidine ring.

Each of the substituents represented by R3is a halogen atom, a cyano group, a nitro group, or a trifluoromethyl group, and the substituents may be the same orcjifferent.

R4 represents a halogen, a Clﬁ alkylsulfoxy group which may be substituted with a halogen atom, or a phenylsulfoxy group which may be substituted with a halogen atom or a methyl group.

Preferred examples of the compound represented by formula (I) or (Ia) include nd No. 1: N-[l-((6—chloropyridin-3—yl)methyl)pyridin—Z(1H)-ylid ene]—2,2,2—trifluoroacetamide, Compound No. 2: (6-chlorofluoropyridin-3—yl)methyl)pyridin-2 (lH)—ylidene]—2,2,2—trifluoroacetamide, nd No.

N-[l—((6—fluoropyridin—3—yl)methyl)pyridin—Z(lH)—ylid ene]—2,2,2—trifluoroacetamide, Compound No. 3: N—[l-((6—bromopyridin—3—yl)methyl)pyridin—2(lH)-ylide ne]—2,2,2—trifluoroacetamide, Compound No. 8: N—[l—((6—chloropyridin-3—yl)methyl)pyridin—2(lH)—ylid ene]-2,2—difluoroacetamide, Compound No. 4: 2-chloro—N—[l—((6-chloropyridin—3-yl)methyl)pyridin-2 (1H)—ylidene]~2,2—difluoroacetamide, Compound No. 7: N—[l—((6—chloropyridin—3-yl)methyl)pyridin—Z(lH)—ylid -519 ene]—2,2,3,3,3—pentafluoropropanamide, and Compound No.

N—[1-((2-Chloropyrimidin-5—yl)methyl)pyridin-2(1H)—yl idene]—2,2,2-trifluoroacetamide.

Of these compounds represented by formula (I) or formula (Ia), a particularly red example is a compound represented by formula (I'), i.e., N—[l-((6—chloropyridin—3—yl)methyl)pyridin—2(1H)-ylid ene]—2,2,2—trifluoroacetamide which has the following physical properties (a) and/or (b) (provided that the compound with nD(25.5)=1.4818 described in Patent Document 2 is excluded): (a) diffraction angle peaks determined by powder X-raydiffractionbeingpresentatleastem:thefollowing diffractionangles(29):8.6i0.2°,l4.2i0.2°,17.5i0.2°, 18.3i0.2°, 19.7:0.2°, 22.3i0.2°, 30.9i0.2°, and .3i0.2°; (b) a melting point determined by differential scanning calorimetry (DSC) of 155 to 158°C.

Preferred examples of the compound represented by formula (B) include 2,2,2—trifluoro—N-(pyridin—Z(1H)—ylidene)acetamide, ro-2,2—difluoro-N-(pyridin—2(lH)-ylidene)acetam ide, 2,2,3,3,3—pentafluoro—N—(pyridin—2(1H)-ylidene)propan amide, and IBPF12‘519 2,2-difluoro—N—(pYridin—Z(lH)-ylidene)acetamide; and a more preferred example is 2,2,2—trifluoro-N-(pyridin—Z(lH)—ylidene)acetamide represented by the following formula (Bl): [Chem. 7] (B1) Production Method The t invention.will be described in further detail according to the ing scheme.

[Chem. 8] av (5:4/ (1Y » R1COR2 HNY R4 ArVNm/ NHz NCOR1 N 0R1 (A) (B) (l) [in the above scheme, Ar, Y, R1,Ih, and R4have the same meanings as those described above].

In addition, the cOmpound represented by a (B) shown in the above scheme may be used for the subsequent step, without post treatment or isolation. 1—1: ProductiCWIOf Compound Represented by Formula (B) from Compound Represented by Formula (A) The compound represented by formula (A) can be obtained as a«:ommercially available compound, or can be IBPF12-519 obtained by the method described in Journal of labeled compounds &radiopharmaceuticals (l987),24(2), 119—123, for example.

A method for producing a compound represented by formula (B) from a compound represented by formula (A) is as follows. Specifically, the compound represented by formula (B) can be obtained by ng the compound represented by formula (A) with.an acylating agent R1COR2 (Rland thave the same meanings as those defined above) without a t or in a solvent which does not affect the reaction in the presence of or in the absence of a base.

Here, the numbers of equivalents of reagents are all the numbers of equivalents to the compound represented by a (A).

Examples of usable solvents include aromatic hydrocarbon—based solvents such as toluene, , and ethylbenzene; based solvents such as ethyl acetate and butyl acetate; ether—based solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aprotic polar c solvents such as N,N—dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, yl—2-pyrrolidinone, and acetonitrile; halogen-containing ts such as dichloromethane and chloroform; hydrocarbon—based solvent sucrlas cyclohexane; ketone—based solvents such IBPF12'519 as acetone and methyl ethyl ketone; water; and mixture solvents thereof.

Examples of usable bases e inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassiumhydrogencarbonate,sodium hydroxide, magnesium hydroxide, calcium hydroxide, m hydroxide, and barium hydroxide; organic bases such as 1,8—diazabicyclo[5.4.0]undec—7-ene, l,5—diazabicyclo[4.3.0]non—5—ene, triethylamine, diisopropylethylamine, pyridine, picoline, and dimethylaminopyridine; and alcoholates such as sodium ethoxide,sodiumnwthoxide,andpotassiumtert—butoxide.

The base does not arily need to be used; however, when the reaction is carried out in the presence of a base, the base can be used in an amount of 0.01 to 20.0 equivalents.

Examples of the acylating agent EhCORz include trifluoroacetic anhydride, trifluoroacetic acid, ethyl trifluoroacetate, oroacetyl chloride, and mixed acid anhydrides. In addition, these ing agents may be used alone or in combination of two or more. Of these acylating agents, trifluoroacetic anhydride, oroacetic acid, ethyl trifluoroacetate, or trifluoroacetyl chloride can be preferably used. In addition, when R2 represents a hydroxyl group, the reaction can be carried out by simultaneously using a IBPF12'519 condensation agent such as icyclohexylcarbodiimide, l—ethyl-3—(3—dimethylaminopropyl)carbodiimide hydrochloride, 1,1'—carbonyldiimidazole, dipyridyl disulfide, diimidazolyl disulfide, 1,3,5—trichlorobenzoyl chloride, 1,3,5—trichlorobenzoyl anhydride, PyBop (registered trademark, triazole—l—yloxy)tripyrrolidinophosphonium uorophosphate), or PyBrop(registered ark, bromotri(pyrrolidino) phosphonium hexafluorophosphate); or a reagent such as phosphorus pentoxide, sulfuric acid, polyphosphoric acid, thionyl chloride, phosphorus oxychloride, oxalyl dichloride, boron trifluoride, p—toluenesulfonic acid, or a halide, a sulfate,eanitrate, oran oxide<3firon, cobalt, copper, nickel, zinc, aluminum, lithium» or* magnesium. In addition, these reagents may be used alone or in combination of two or more. Preferred examples of the halide, the sulfate, the nitrate, or the oxide of iron, cobalt, copper, nickel, zinc, aluminum, lithium, or ium include zinc chloride, copper chloride, magnesium chloride, cobalt chloride, nickel de, ferric chloride, aluminum chloride, ferric sulfate, and aluminum sulfate. These nds of metals may be anhydrides or hydrates thereof. The amount of the IBPF12'519 acylating agent used is ably 0.5 to 10.0 equivalents, and.more preferably 1.0 to 5.0 equivalents.

The reaction temperature is preferably in a range from —80°C to 200°C. The reaction time is preferably in a range from 0.1 hours to 7 days.

Preferred modes are as follows: (1) When R2 represents a trifluoroacetoxy group, specifically, when trifluoroacetic ide is used as the ing agent, examples of preferred solvents include ester—based solvents such as ethyl acetate and butyl acetate; halogen-containing solvents such as dichloromethane and chloroform; and aromatic hydrocarbon—based solvents such as toluene, xylene, and ethylbenzene. Here, toluene is more preferable. The reaction is preferably d out in the absence of a base; however, when a base is used, preferred examples ofthebaseincludesodiumcarbonate,potassiumcarbonate, potassium hydrogen carbonate, triethylamine, pyridine, and the like. Here, potassium carbonate is more preferable. The amount of the acylating agent used is preferably 1.0 to 5.0 lents, and more preferably 1 . 0 to 1.5 equivalents. When the base is used, the amount of the base used is preferably 1.0 to 4.5 equivalents, andmorepreferablyl.01x>3.0equivalents. ction temperature is preferably in a range from —20°C to 50°C, andInoreIQreferablgrfron1—10°C1to 30°C. Thereactiontime '519 is preferably in a range from 0.1 hours to 7 days, and more preferably in a range from 0.5 hours to 4 hours.

Particularly preferred conditions are as follows: trifluoroaceticanhydrideisLnxxiastheacylatingagent; toluene is used as the solvent; the amount of the acylating agent used is 1.0 to 1.5 equivalents; the reaction temperature is —10°C to 30°C; and the on time is 0.5 to 4 hours. Regarding the base, no base is used, or wherla base is used, potassium.carbonate is used in an amount of 1.0 to 3.0 equivalents. (2) When R2 represents a Cyﬁ alkyloxy group which may be substituted with a halogen atom or a benzyloxy groupwhosephenylgroupnmykxasubstitutedwitheahalogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, specifically when ethyl trifluoroacetate, methyl trifluoroacetate, or propyl trifluoroacetate is used, particularly preferably when ethyl trifluoroacetate or the like is used, preferred examples of the solvent include aprotic polar organic solvents such as N,N—dimethylformamide, dimethyl sulfoxide, N,N—dimethylacetamide, N—methyl—Z—pyrrolidinone, and acetonitrile; ether—based solvents such as l ether, diisopropyl ether, ydrofuran, and dioxane; and mixture solvents of any of these solvents with an aromatic hydrocarbon~based solvent such as toluene, xylene, or IBPF12'519 ethylbenzene. Here, N,N—dimethylformamide or axnixture t of methylformamide with toluene is more preferable. The reaction is preferably carried out in the absence of a base; however, when a base is used, red examples of the base include potassium carbonate, ylamine, dimethylaminopyridine, and the like. Here, potassium carbonate and dimethylaminopyridine are more preferable. The amount of the acylating agent used is preferably 1.0 to 5.0 equivalents, andlnore preferably l.51x>5.0 equivalents.

When the base is used, the amount of the base used is preferably 0.01 to 3.0 equivalents, and more preferably 0.01 to 2.0 equivalents. The reaction temperature is preferably in a range from 20°C to 100°C, and more preferably from 40°C to 80°C. The reaction time is preferably in a range from 0.1 hours to 7 days, and more preferably in a range from 1 hour to 2 days.

Particularly preferred conditions are as follows: ethyl oroacetate is used as the acylating agent; N,N—dimethylformamide or a mixture solvent of N,N—dimethylformamide with toluene is used as the solvent; the amount of the acylating agent used is 1.5 to 5.0 equivalents; the reaction temperature is 40°C to 80°C; and the reaction time is 2 hours to 2 days.

Regarding the base, no base is used, or when a base is used, potassium carbonate or dimethylaminopyridine is IBPF12'519 used in an amount of 0.01 to 2.0 equivalents. (3)When Rzrepresents a(h_6alkylcarbonyloxygroup which may be substituted with a halogen atom (provided that a oroacetoxy group is excluded) or a phenylcarbonyloxy group whose phenyl group may be substituted with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, a specific example is a pivaloyl group. The reaction temperature is preferably in a range from —20°C to 50°C, and more preferably from -10°C to 30°C. The reaction time is preferably in a range from 0.1 hours to 7 days, and more preferably in a range from 0.5 hours to 4 hours. (4) When R2 ents a hydroxyl group, specific examples of the acylating agent include trifluoroacetic acid, difluorochloroacetic acid, trichloroacetic acid, difluoroacetic acid, dichloroacetic acid, dibromoacetic acid, chloroacetic acid, difluoropropionic acid, dichloropropionic acid, 2,2,2—trifluoropropionic acid, pentafluoropropionic acid, difluorocyclopropanecarboxylic acid, and the like.

Here, trifluoroacetic acid, oroacetic acid, dichloroacetic acid, difluoroacetic acid, difluorochloroacetic acid, chloroacetic acid, and pentafluoropropionic acid are preferable; trifluoroacetic acid, roacetic acid, difluorochloroacetic acid, and pentafluoropropionic IBPF12'519 acid are more preferable; and oroacetic acid is particularly able. When trifluoroacetic acid is used, preferred examples of the solvent include aromatic hydrocarbon—based solvents such as toluene, xylene, and ethylbenzene; amdaprotic polar organic solvents suchas N,N—dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methyl—2—pyrrolidinone, and acetonitrile. Here, toluene, xylene, N,N—dimethylformamide, N—methyl-Z-pyrrolidinone, N,N—dimethylacetamide,eamixturesolventcxftoluenewith N,N—dimethylformamide, a mixture solvent of xylene with N,N-dimethylformamide, a mixture solvent of xylene with N—methyl-2—pyrrolidinone, oreamixture solvent of xylene with N,N—dimethylacetamide is more preferable.

Examples of the reagent used simultaneously include N,N'—dicyclohexylcarbodiimide, l—ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloride, phosphorus pentoxide, sulfuric acid, polyphosphoric acid, thionyl de, phOSphorus oxychloride, oxalyl dichloride, and the like. The reagent is preferably used in an amount of 0.2 to 5.0 equivalents. In addition, when zinc de, copper chloride, magnesium chloride, cobalt chloride, nickel de, ferric chloride, um de, ferric sulfate, aluminum sulfate, boron trifluoride, p—toluenesulfonicacid,orthelikeisusedasthereagent IBPF12‘519 used simultaneously, the reagent is preferably used in an amount of 0.0001 to 1.0 equivalents. The reaction is preferably d out in the absence of a base, when phosphoruspentoxide,sulfuricacid,polyphosphoricacid, thionyl chloride, phosphorus oxychloride, oxalyl dichloride, zinc chloride, copper chloride, magnesium chloride, cobalt chloride, nickel chloride, ferric chloride, aluminum chloride, ferric sulfate, aluminum sulfate,borontrifluoride,orpwtoluenesulfonicacidis used. Meanwhile, the on is preferably carried.out in the ce of a base, when N,N'~dicyclohexylcarbodiimide or 1—ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloride is used. When a base is used, preferred examples of the base include sodiunlcarbonate, potassium carbonate, potassiunlhydrogen carbonate, triethylamine, pyridine, dimethylaminopyridine, and the like. Here, triethylamine is more preferable. The amount of the acylatingagentusedisgneferablyl.01x35.0equivalents, andmorepreferablyl.0tx>3.0equivalents. ionyl chloride, phosphorus oxychloride, or oxalyl dichloride is used, the t is preferably used in an amount of 0.2 to 5.0 equivalents, and the reaction temperature is preferably in a range from —30°C to 80°C, and more ably from —10°C to 40°C. When phosphorus pentoxide,sulfuricacid,<n:polyphosphoricacidjisused, IBPF12-519 the reagent is preferably used_in an amount of 0.2 to 5.0 equivalents, and the reaction temperature is preferably in a range from —30°C to 200°C, andlnore preferably from —10°C to 160°C. When N,N'—dicyclohexylcarbodiimide or l—ethyl—3—(3-dimethylaminopropyl)carbodiimide hydrochloride is used, the following conditions are able: the reagent is used in an amount of 0.2 to .0 lents; the reaction ature is preferably in a range from —30°C to 80°C, and more preferably from —10°C to 40°C; and ylamine is used as the base in anamountof(%2 U35.0equivalents. Whenzincchloride, copper chloride, ium chloride, cobalt chloride, nickel chloride, ferric chloride, um chloride, ferric sulfate, aluminum sulfate, boron trifluoride, or p-toluenesulfonicacidjjsused,thefollowingconditions are19referable: the reagent iSllsedeIan amount of 0.0001 to 1.0 equivalents; the reaction temperature is preferably in a range from 20°C to 200°C, and more preferably from 80°C to 160°C. The reaction time is preferably in a range from 0.1 hours to 7 days, and more preferably in a range from 0.5 hours to 2 days.

Particularly preferred conditions are as follows: trifluoroacetic acid is used as the acylating agent; toluene, N,N—dimethylformamide, xylene, N—methyl—Z—pyrrolidinone, N,N—dimethylacetamide, a mixture solvent of N,N—dimethylformamide with toluene, IBPF12'519 a mixture solvent of xylene with N,N-dimethylformamide, a mixture solvent of xylene with N—methyl—2-pyrrolidinone, xture solvent ofxylene with N,N-dimethylacetamide is used as the solvent; and the amount of the acylating agent used is 1.0 to 3.0 equivalents. When thionyl de, phosphorus oxychloride, or oxalyl dichloride is used, particularly preferred conditions are as follows: the t is used in an amount of 0.3 to 3.0 equivalents; no base is used; the reaction temperature is —10°C to 40°C; and the reaction time is 0.5 hours to 1 day. When phosphorus pentoxide,sulfuricacid,<orpolyphosphoricacidijsused, particularly red conditions are as follows: the reagent is used in an amount of 0.2 to 2.0 lents; the reaction temperature is —10°C to 160°C; and the reaction time is 0.5 hours to 1 day. When N,N'—dicyclohexylcarbodiimide or l—ethyl—3—(3-dimethylaminopropyl)carbodiimide hydrochlorideijsused,particularlypreferredconditions are as follows: the reagent is used in an amount of 0.5 to 3 equivalents;, the reaction temperature is h10°C to 40°C; triethylamine is used as the base in an amount of 0.5 to 3.0 equivalents; and the reaction time is 0.5 to 1 day. When zinc chloride, copper chloride, magnesium chloride, cobalt chloride, nickel chloride, ferric de, aluminum chloride, ferric sulfate, aluminum IBPF12‘519 sulfate,borontrifluoride,orfrtoluenesulfonicacidis used, particularly preferred conditions are as follows: the reagent is used in an amount of 0.0001 to 0.5 equivalents; no base is used; the on temperature is 80°C to 160°C; and the reaction time is 2 hours to 2 days. (5) When Rgrepresents;a halogen.atom, specifically whentrifluoroacetylchlorideortnﬂfluoroacetylbromide isused,preferablywhentrifluoroacetylchlorideisused, preferred examples of the solvent include halogen-containing solvents such as chloroform and romethane; aromatic hydrocarbon—based solvents such as toluene, , and ethylbenzene; and aprotic polar organic solvents such as methylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N—methyl-Z-pyrrolidinone, and acetonitrile. Here, toluene, N,N—dimethylformamide, N—methyl—Z—pyrrolidinone, or aInixture solvent of any of these is more preferable. The reaction is preferably carried out in the absence of aloase; however, wherla base is used, preferred examples of the base include sodium carbonate, potassium carbonate, potassium hydrogen carbonate,triethylamine,pyridine,andthelike. Here, potassium carbonate is more preferable. The amount of the acylating agent used is ably 1.0 to 5.0 lents, andlnore preferably 1.0 to 3.0 equivalents.

IBPF12619 When the base is used, the amount of the base used is preferably 1.0 to 5.0 equivalents, and more preferably 1.0 to 3.0 equivalents. The reaction temperature is preferably in a range from —80°C to 40°C, and more preferably from —30°C to 30°C. The reaction time is preferably in a range from 0.1 hours to 7 days, and more preferably in a range from 0.5 hours to 8 hours. ile, when.R2.represents a chlorine atom, it is also possible to use R1COCl generated in advance by simultaneously using trifluoroacetic acid with thionyl chloride,phosphorusoxychloride,oxalicaciddichloride, or the like outside the on system in which the reaction of the compound represented by formula (A) is carried out. ularly preferred conditions are as follows: oroacetyl chlorideijsused asthe acylating agent; toluene, N,N—dimethylformamide, N—methyl—2—pyrrolidinone, or alnixture solvent of any of these is used as the solvent; the amount of the acylating agent used is 1.0 to 3.0 equivalents; the reaction temperature is —30°C to 30°C; and the reaction time is 0.5 hours to 8 hours. Regarding the base, particularly preferred conditions are as follows: no base is used; or when a base is used, potassium ate is used in an amount of 1.0 to 3.0 equivalents.

After the compound represented by formula (B) is IBPF12-519 synthesizedfromiﬂmacompoundrepresentedkn/formula(A), the compound represented by formula (B) may be neutralized by use of a base. es of usable bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, magnesium hydroxide, calciun1 hydroxide, m hydroxide, and barium hydroxide; c bases such as 1,8—diazabicyclo[5.4.0]undec-7—ene, l,5—diazabicyclo[4.3.0]non—5—ene, triethylamine, diisopropylethylamine, pyridine, picoline, and dimethylaminopyridine; and alcoholates such as sodium ethoxide,sodimnmethoxide,andpotassiumtert-butoxide.

Here, potassium carbonate, sodium ethoxide, or triethylamine is preferable. 1-2: Production of Compound Represented by Formula (I) or Formula (I') from Compound Represented by Formula (B) or Formula (8') A method for producing a compound represented by formula (I) or formula (I’) fron1a compound ented by formula (B) or formula (B') is as follows.

Specifically, the compound ented.by formula (I) or formula (I') can be obtained by reacting the compound represented by formula (B) or a (8') with Ar—CHg-R4 (Ar and R4have the same gs as those defined above) without a solvent or in a solvent which does not affect IBPF12'519 the reaction in the presence of a base.

Examples of usable ts e ether-based solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aprotic polar organic solvents such as N,N—dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, acetonitrile, N—methyl—2—pyrrolidinone, N—methyl—2—piperazinone, N,N—dimethyl-Z—imidazolidinone, and acetonitrile; halogen—containing solvents such as dichloromethane and chloroform; aromatic hydrocarbon-based ts such as e, xylene, and ethylbenzene; and mixture solvents thereof; and preferred examples thereof include aprotic polar organic ts. Here, N,N—dimethylformamide, N,N—dimethylacetamide, N—methyl—Z—pyrrolidinone, N,N—dimethyl—Z—imidazolidinone, acetonitrile, or a mixture solvent of N,N—dimethylformamide, N,N—dimethylacetamide, N—methyl—2—pyrrolidinone, N,N—dimethyl—2—imidazolidinone, oracetonitrileawithan aromatic hydrocarbon—based solvent is more preferable; and N,N—dimethylformamide or a e solvent of N,N—dimethylformamide with toluene is particularly preferable.

When the reaction is carried out in the presence of a base, examples of usable bases include nic bases such as sodium carbonate, potassium carbonate, sodiumhydrogencarbonate,potassiumhydrogencarbonate, IBPF12'519 sodiumhydroxide,magnesiumhydroxide,calciumhydroxide, lithium hydroxide, and barium hydroxide; and organic bases such as 1,8—diazabicyclo[5.4.0]undec—7—ene, l,5—diazabicyclo[4.3.0]non—5—ene, ylamine, diisopropylethylamine, pyridine, lutidine, collidine, N,N—dimethylaniline, and N,N-diethylaniline; preferred examples thereof include potassiunlcarbonate, potassium hydrogen carbonate, pyridine, triethylamine, and the like; and more preferred examples thereof e potassium carbonate and triethylamine.

The amount of Ar—CHz—R4 (Ar and R4 have the same meanings as those defined above) used is preferably 0.7 to 2.0 equivalents, and more ably 0.8 to 1.5 equivalents, to the compound represented by formula (B) or formula (B'). When the base is used, the amount of the base used is preferably 1.0 to 10.0 equivalents, and more preferably 1.0 to 5.0 equivalents, to the compound ented by formula (B) or formula (B').

The reaction temperature is preferably in a range 2O fron120°C to 100°C, andlnore preferably fron|40°C to 80°C.

The reaction time is preferably in a range from 0.1 hours to 3 days, and more ably in a range from 1 hour to 2 days.

Particularly preferred conditions are as follows: R4 is a chlorine atom; N,N—dimethylformamide, yl—Z—pyrrolidinone, N,N-dimethylacetamide, a IBPF12'519 mixture t of N,N-dimethylformamide with toluene, a mixture solvent of N,N—dimethylformamide with xylene, a mixture solvent of xylene with N~methyl—2—pyrrolidinone, xture solvent of xylene with N,N—dimethylacetamide is used as the solvent; the amount of Ar—CHz-unsed_is 0.8 to 1.5 equivalents to the compound represented by formula (B) or formula (B'); the reaction temperature is 40°C to 80°C; the reaction time is 1 hour to 2 days; and potassium carbonate or triethylamine is used as the base in an amount of 1.0 to .0 equivalents.

One—Pot Production for Obtaining Compound Represented by Formula (I) or Formula (I') from Compound ented by Ebrmula (A) or Ebrmula (A') through Compound Represented by Formula (B) or (B') When the compound represented by formula (I) or formula(I')issynthesizedfromthecompoundrepresented by formula (A) or formula (A'), the compound represented by formula (I) or formula (I') can be obtained by conducting the subsequent step, without isolation of the compound represented by formula (B) or a (B').

Specifically, the compound represented by formula (I) or formula (I ') can be ed by a reaction in which the reaction t represented by formula (B) or formula (B') is used as it is or after the excessive reagent is removed under d pressure; Ar—CHz—R4(Ar IBPFl2-519 and R4 have the same meanings as those described above) and the base are added thereto; and a reaction therebetween is d to proceed under the above—described ions.

Alpreferred example of the1nethod for ing the compound represented by formula (I) or formula (I') from the compound represented by formula (A) or formula (A') through the compound represented by formula (B) or formula (B') is a method in which a nd represented by a (A) or formula (A') is d with an acylating agent R1COR2 by use of an aromatic hydrocarbon—based solvent, an aprotic polar solvent, or a mixture solvent thereof in the absence of a base, to thereby obtain a compound represented by formula (B) or formula (B'); then Ar-CHz—R4, a base, and an aromatic hydrocarbon—based solvent, an aprotic polar organic solvent, or a mixture solvent thereof are added; and a reaction therebetween is allowed to proceed, as it is or while the ic arbon—based solvent is distilled off under reduced pressure, to thereby obtain a compound represented by formula (I) or formula (I').

Production of Compound Represented by Formula (B) or (B') from Compound Represented by Formula (A) or Formula (A') in One-Pot Production Here, the numbers of equivalents of reagents are all the numbers of equivalents to the compound IBPF12-519 represented by formula (A) or formula (A'). To obtain acompoundrepresentaﬂbyformula MD orformula(B')from a compound ented by formula (A) or formula (A'), it is particularly preferable to use R1COR2cn:CF§COR2in which Rzis a<3F3COO group, an OEt group, aliydroxyl group, or a chlorine atom.

When R2 is a CE3COO group (for example, trifluoroacetic anhydride), ularly preferred conditions areas follow:toluene isusedas thesolvent; the amount of the acylating agent used is 1.0 to 1.5 equivalents, the reaction temperature is ~10°C to 30°C; the reaction time is 0.5 to 4 hours; and regarding the base, no base is used, or when a base is used, ium ate is used in an amount of 1.0 to 3.0 equivalents.

When R2 is an OEt group (ethyl trifluoroacetate), particularly preferred conditions are as follows: N,N—dimethylformamide or a mixture solvent of N,N—dimethylformamide with toluene is used as the solvent; the amount of the acylating agent used is 1.5 to 5.0 equivalents; the reaction temperature is 40 to 80°C;thereactiontimeij52hourst022days;andregarding the base, no base is used, or when a base is used, potassium carbonate or dimethylaminopyridine is used in an amount of 0.01 to 2.0 equivalents.

When R2 is a hydroxyl group (for example, trifluoroacetic acid), ularly preferred IBPF12'519 conditions are as follows: toluene, N,N—dimethylformamide, , yl—Z—pyrrolidinone, N,N~dimethylacetamide, a mixture solvent of N,N—dimethylformamide with toluene, a mixture solvent of N,N-dimethylformamide with xylene, a mixture solvent of xylene with N—methyl—2-pyrrolidinone,orwanﬁxturesolvent<xfxylene with N,N-dimethylacetamide is used as the solvent; and the amount of the acylating agent used is 1.0 to 3.0 lents. When thionyl chloride, phosphorus oxychloride, or oxalyl ride is used, particularly preferred conditions are as follows: the reagent is used in an amount of 0.3 to 3.0 equivalents; no a base is used; the reaction temperature is —10°C to 40°C; and the reaction time is 0.5 hours to 1 day. When phosphorus pentoxide,sulfuricacid,(tholyphosphoricacid1hsused, particularly preferred conditions are as follows: the reagent is used in an amount of 0.5 to 2.0 equivalents; the reaction temperature is —10°C to 160°C; and the reaction time is 0.5 hours to 1 day. When N,N'-dicyclohexylcarbodiimide or 1—ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloridejjsused,particularlypreferredconditions are as follows: the t is used in an amount of 0.5 to 3.0 equivalents; the reaction temperature is —10°C to 40°C; triethylamine is used as the base in an amount of IBPF12'519 0.5 to 3.0 equivalents; and the reaction time is 0.5 to 1 day. When zinc chloride, copper chloride, magnesium chloride, cobalt chloride, nickel chloride, ferric de, aluminum chloride, ferric sulfate, aluminum sulfate, boron trifluoride, or p—toluenesulfonic acid is used, particularly preferred conditions are as follows: the reagent is used in an amount of 0.0001 to 0.5 equivalents; no base is used; the reaction temperature is 80°C to 160°C; and the reaction time is 2 hours to 2 days.

When R2 is a chlorine atom (for example, oroacetyl chloride), the conditions are as follows: toluene, N,N-dimethylformamide, N—methyl—Z-pyrrolidinone, or aInixture solvent of any of these is used as the solvent; the amount of the acylating agent used is 1.0 to 3.0 equivalents; the on ature is —30°C to 30°C; and the reaction time is 0.5 hours to 8 hours. Regarding the base, the following ions are particularly preferable: no base is used, 2O or when a base is used, potassium.carbonate is used in an amount of 1.0 to 3.0 equivalents.

Production of Compound Represented by Formula (I) or (I') from Compound Represented by Formula (B) or a (B') in One—Pot Production Conditions particularly preferable for obtaining acompoundrepresentadbyformula CH orformula(I')from IBPF12'519 a compound ented by formula (B) or formula (B') are asfollows:R4iseachlorineatom;N,N—dimethylformamide, N-methyl-Z—pyrrolidinone, N,N—dimethylacetamide, a mixture solvent of methylformamide with toluene, a mixture solvent of xylene with N,N-dimethylformamide, a mixture solvent of xylene with N—methyl—2—pyrrolidinone, oraimixture solventCfoylene with N,N—dimethylacetamid is used as the t; the amount of Ar—CHz—R4tised is 0.8 to 1.5 equivalents to the compound represented by formula (B) or formula (B'); the reaction temperature is 40°C to 80°C; the reaction time is 1 hour to 2 days; and regarding the base, potassium carbonate or ylamine is used in an amount of 1.0 to 5.0 equivalents.

Step of Producing Compound Represented by Formula (Ia) from Compound Represented by Formula (Ba) A method for obtaining a compound represented by formula (Ia) fronla compound represented by formula (Ba) is as follows. Specifically, the compound represented by formula (Ia) can be obtained reacting the compound ented by formula (Ba) with an acylating agent RNCORR Ghaandfhahavethesameneaningsasthosedefined above) without a solvent or in a solvent which does not affect the reaction in the presence of or in the absence of a base. Here, the numbers of equivalents of reagents herein are all the s of equivalents to the compound IBPF12'519 represented by formula (Ba).

Examples of usable solvents include aromatic hydrocarbon—based solvents such as toluene, xylene, and ethylbenzene;ester—basedsolventssucheusethylacetate and butyl acetate; ether—based ts such as l ether, diisopropyl ether, tetrahydrofuran, and dioxane; aprotic polar organic solvents such as N,N—dimethylformamide, dimethyl sulfoxide, N,N—dimethylacetamide, yl—2-pyrrolidinone, and acetonitrile; halogen-containing solvents such as dichloromethane and chloroform; hydrocarbon—based tssuch‘ascyclohexane;ketone—basedsolventssuch as acetone and methyl ethyl ketone; water; and mixture solvents thereof.

Examples of usable bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassiumhydrogencarbonate,sodium hydroxide, magnesium ide, calcium hydroxide, lithium hydroxide, and barium hydroxide; organic bases such as l,8—diazabicyclof5.4.0]undec—7—ene, 1,5—diazabicyclo[4.3.0]non—5—ene, triethylamine, diisopropylethylamine, pyridine, picoline, and dimethylaminopyridine; and alcoholates such as sodium ethoxide,sodiumnethoxide,andpotassiumtert—butoxide.

The base does not necessarily need to be used; r, when the reaction is carried out in the presence of a base, IBPF12'519 the base can be used in an amount of 0.01 to 20.0 equivalents.

Examples of the acylating agent R1COR2 include trifluoroacetic anhydride, trifluoroacetic acid, ethyl oroacetate, trifluoroacetyl chloride, and mixed acid anhydrides. In addition, these acylating agents may be used alone or in combination of two or more. Of these acylating agents, trifluoroacetic anhydride, trifluoroacetic acid, ethyl trifluoroacetate, or trifluoroacetyl chloride can be preferably used.

Moreover, when R2 represents a hydroxyl group, the reaction can be carried out by simultaneously using a reagent such as N,N'-dicyclohexylcarbodiimide, l-ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloride, l,l'-carbonyldiimidazole, dyl disulfide, diimidazolyl disulfide, trichlorobenzoyl chloride, 1,3,5-trichlorobenzoyl anhydride, PyBop (registered trademark), PyBrop (registered trademark), phosphorus ide, sulfuric acid, polyphosphoric acid, thionyl chloride, phosphorus oxychloride, oxalyl dichloride, zinc chloride, copper chloride, magnesium de, cobalt chloride, nickel chloride, ferric de, um chloride, ferric sulfate, aluminum sulfate, boron trifluoride, or p-toluenesulfonic acid. The amount of the acylating agent used is preferably 0.5 to IBPF12-519 .0 equivalents.

Preferred modes are as follows: (1) When R2 represents a oroacetoxy group, specifically when trifluoroacetic anhydride is used as the acylating agent, preferred examples of the solvent include ester-based solvents such as ethyl acetate and butyl acetate; halogen—containing solvents such as dichloromethane and form; and aromatic hydrocarbon—based solvents such as e, xylene, and ethylbenzene. Here, toluene is more preferable. The reaction is preferably carried out in the absence of a base; however, when a base is used, preferred examples ofthebaseincludesodiumcarbonate,potassiumcarbonate, potassium hydrogen ate, triethylamine, pyridine, and the like, and potassium carbonate is more preferable.

The amount of the acylating agent used is preferably 1.0 to 5.0 equivalents, and more ably 1.0 to 1.5 equivalents. When alaase is used, the amount of the base used is preferably 1.0 to 4.5 equivalents, and more preferably 1.0 to 3.0 equivalents. The reaction temperature is preferably in a range from —20°C to 50°C, epreferablyfrom~10°Cto30°C. Thereactiontime is preferably in a range from 0.1 hours to 7 days, and IBPF12'519 more preferably in a range from 0.5 hours to 4 hours. ularly preferred conditions are as follows: trifluoroaceticanhydrideisInxxiastheacylatingagent; toluene is used as the solvent; the amount of the acylating agent used is 1.0 to 1.5 equivalents; the reaction temperature is -lO°C to 30°C; and the reaction time is 0.5 to 4 hours. Regarding the base, no base is used, or when a base is used, ium.carbonate is used in an amount of 1.0 to 3.0 lents. (2) When R2 represents a Cyﬁ alkyloxy group which may be substituted with a halogen atom or a benzyloxy groupwhosephenylgroupnwykxasubstitutedwitheahalogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, specifically when ethyl trifluoroacetate, methyl oroacetate, or propyl trifluoroacetate is used, particularly preferably when ethyl trifluoroacetate or the like is used, preferred solvents include aprotic polar organic solvents such as N,N—dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methyl—Z—pyrrolidinone, and acetonitrile; ether—based solvents such.as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; and mixturesolvenUsofanyofthesesolventswithanaromatic hydrocarbon—based solvent such as toluene, , or ethylbenzene; and more preferred solvents include N,N—dimethylformamide, and a mixture solvent of IBPF12'519 N,N-dimethylformamide with toluene. The reaction is preferably carried<nﬂ1in the absence ofaibase; however, when a base is used, preferred examples of the base e potassium carbonate, triethylamine, dimethylaminopyridine, and the like, and more preferred examples thereof include potassium carbonate and dimethylaminopyridine. The amount of the acylating agent used isloreferably 1.0 to 5.0 equivalents, andtnore preferably 1.5 to 5.0 equivalents. Wherla base is used, the amount of the base used is preferably 0.01 to 3.0 equivalents,andmorepreferably0.01to2.0equivalents.

The reaction temperature is preferably in a range from 20W3t0100°C,andmorepreferablyfrom40°Cto80°C. The on time is preferably in a range from 0.1 hours to 7 days, and more preferably in a range from 1 hour to 2 days.

Particularly preferred conditions are as follows: ethyl trifluoroacetate is used as the acylating agent; N,N—dimethylformamide or a mixture solvent of N,N«dimethylformamide with toluene is used as the solvent; the amount of the ing agent used is 1.0 to 5.0 equivalents; the on temperature is 40°C to 80°C; and the reaction time is 2 hours to 2 days. ing the base, no base is used, or when a base is used, potassium carbonate or ylaminopyridine is used in an amount of 0.01 to 2.0 equivalents.

IBPF12'519 (3) When Rzrepresents a(h_6alkylcarbonyloxy'group which may be substituted with a halogen atom (provided that a trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group whose phenyl group may be substituted.with a halogen atom, a methyl group, a cyano group, a nitro group, or a methoxy group, a specific example thereof is a pivaloyl group. The reaction temperature is ably in a range from —20°C to 50°C, andmorepreferablyfrom-10°Ctxa30°C. Thereactiontime is preferably in a range from 0.1 hours to 7 days, and more preferably in a range from 0.5 hours to 4 hours. (4) When R2 represents a hydroxyl group, specific examples of the acylating agent include trifluoroacetic acid, difluorochloroacetic acid, trichloroacetic acid, difluoroacetic acid, dichloroacetic acid, dibromoacetic acid, chloroacetic acid, difluoropropionic acid, dichloropropionic acid, trifluoropropionic acid, luoropropionic acid, difluorocyclopropanecarboxylic acid, and the like.

Here, trifluoroacetic acid, oroacetic acid, dichloroacetic acid, difluoroacetic acid, difluorochloroacetic acid, chloroacetic acid, and luoropropionic acid are preferable; trifluoroacetic acid, difluoroacetic acid, difluorochloroacetic acid, and pentafluoropropionic acid are more preferable; and trifluoroacetic acid is IBPF12-519 particularly preferable. When trifluoroacetic acid is used, preferred examples of the solvent include aromatic hydrocarbon—based solvents such as toluene, xylene, and ethylbenzene; and aprotic polar organic solvents such as N,N—dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N—methyl—Z-pyrrolidinone, and itrile. Here, e, xylene, N,N—dimethylformamide, N-methyl—Z-pyrrolidinone, a mixture solvent of toluene with N,N—dimethylformamide, a mixture solvent of xylene with N,N-dimethylformamide, or a mixture solvent of xylene with N—methyl—Z—pyrrolidinone is more preferable. Examples of the reagent used simultaneously include N,N'—dicyclohexylcarbodiimide, l—3—(3—dimethylaminopropyl)carbodiimide hydrochloride, phosphorus ide, sulfuric acid, polyphosphoric acid, thionyl chloride, phosphorus oxychloride, oxalyl dichloride, and the like. The reagent is ably used in an amount of 0.2 to 5.0 equivalents. In addition, when zinc chloride, copper chloride, magnesium chloride, cobalt chloride, nickel de, ferric chloride, aluminum chloride, ferric sulfate, aluminum sulfate, boron oride, p—toluenesulfonicacid,orthelikeisusedasthereagent used simultaneously, the reagent is preferably used in an amount of 0.0001 to 1.0 equivalents. The reaction is IBPF12‘519 preferably d out in the absence of a base, when phosphoruspentoxide,sulfuricacid,polyphosphoricacid, thionyl chloride, phosphorus oxychloride, oxalyl dichloride, zinc chloride, copper chloride, magnesium de, cobalt chloride, nickel chloride, ferric chloride, um chloride, ferric sulfate, aluminum sulfate, boron trifluoride, orjo—toluenesulfonic acid is used. Meanwhile,Thereactionisgneferablycarriedout in the ce of a base, when N,N'—dicyclohexylcarbodiimide or l-ethyl—3—(3—dimethylaminopropyl)carbodiimide hydrochloride is used. When a base is used, preferred examples of the base include sodiunlcarbonate, potassium carbonate, potassiunlhydrogen carbonate, triethylamine, pyridine, dimethylaminopyridine, and the like. Here, triethylamine is more preferable. The amount of the acylatingagentusedijspreferably1.0tx>5.0equivalents, andmorepreferablyl.0tx>3.0equivalents. Whenthionyl de, phosphorus oxychloride, or oxalyl dichloride is Used, the reagent is preferably used in an amount of 0.2 to 5.0 equivalents, and the reaction temperature is preferably in a range from —30°C to 80°C, and more preferably —10°C to 40°C. When phOSphorus pentoxide, sulfuric acid, or osphoric acid is used, the reagent is preferably used in an amount of 0.2 to 5.0 equivalents, and the reaction temperature is preferably IBPF12'519 in a range from —30°C to 200°C, andlnore preferably from —10°C to 160°C. When N,N'-dicyclohexylcarbodiimide or 1—ethyl—3—(3—dimethylamin0propyl)carbodiimide hydrochloride is used, preferred conditions are as follows: the reagent is used in an amount of 0.2 to 5.0 equivalents; the reaction temperature is preferably in a range fron1-30°Cito 80°C, andlnore}areferably from —10°C to 40°C; and triethylamine is used as the base in an amount of 0.2 to 5.0 equivalents. When zinc chloride, copper chloride, magnesium chloride, cobalt chloride, nickel chloride, ferric chloride, aluminum chloride, ferric sulfate, aluminum sulfate, boron trifluoride, or p—toluenesulfonicacidijsused,thefollowingconditions arepreferable:thereagentistmedjx1anamountof0.0001 to 1.0 equivalents; the reaction temperature is ably in a range from 20°C to 200°C, and more preferably from 80°C to 160°C. The reaction time is ably in a range from 0.1 hours to 7 days, and more preferably in a range from 0.5 hours to 2 days. ularly preferred conditions are as follows: oroacetic acid is used as the acylating agent; toluene, N,N-dimethylformamide, xylene, y1—2—pyrrolidinone, N,N-dimethylacetamide, a mixture solvent of methylformamide with toluene, a mixture solvent of xylene with N,N—dimethylformamide, a mixture solvent of xylene with N—methyl—2-pyrrolidinone,or(amixturesolvent(ofxylene with N,N—dimethylacetamide is used as the solvent; and the amount of the acylating agent used is 1.0 to 3.0 equivalents. When thionyl chloride, phosphorus oxychloride, or oxalyl dichloride is used, particularly preferred conditions are as follows: the reagent is used in an amount of 0.3 to 3.0 equivalents; no base is used; the reaction temperature is —10°C to 40°C; and the reaction time is 0.5 hours to 1 day. When phosphorus pentoxide,sulfuricacid,(nrpolyphOSphoricacidijsused, particularly preferred conditions are as follows: the reagent is used in an amount of 0.2 to 2.0 equivalents; the reaction temperature is —10°C to 160°C; and the reaction time is 0.5 hours to 1 day. When N,N'—dicyclohexylcarbodiimide or l—ethyl—B—(3—dimethylamin0propyl)carbodiimide hydrochloridejxsused,particularlypreferredconditions are as follows: the t is used in an amount of 0.5 to 3.0 equivalents; the reaction temperature is —lO°C to 40°C; triethylamine is used aseabase in an amount of 0.5 to 3.0 equivalents; and the reaction time is 0.5 to 1cday.

When zinc chloride, c0pper chloride, magnesiunlchloride, cobalt de, nickel chloride, ferric chloride, aluminum chloride, ferric sulfate, aluminum e, boron trifluoride, or p—toluenesulfonic acid is used, particularly preferred conditions are as follows: the IBPF12'519 reagent isusedix1anemmnnﬁ;of0.0001to 0.5equivalents; no base is used; the reaction temperature is 80°C to 160°C; and the reaction time is 2 hours to 2 days. (5) When R2representsaahalogerlatom, specifically whentrifluoroacetylchlorideortrifluoroacetylbromide isused,preferablywhentrifluoroacetylchlorideisused, preferred es of the solvent include aromatic hydrocarbon—based solvents such as toluene, xylene, and ethylbenzene; halogen—containing solvents such as dichloromethane and chloroform; and c polar organicsolvents Suﬁ]asN,N-dimethylformamide,dimethyl sulfoxide, N,N—dimethylacetamide, N~methyl-2—pyrrolidinone, and acetonitrile. Here, toluene, N,N—dimethylformamide, N—methyl-Z—pyrrolidinone, or alnixture solvent of any<3f these is more preferable. The reaction is preferably d out in the e of ; however, wherla base is used, preferred examples of the base include sodium carbonate, potassium carbonate, potassium. hydrogen carbonate,triethylamine,pyridine,andthelike. Here, potassium carbonate is more preferable. The amount of the acylating agent used is preferably 1.0 to 5.0 equivalents, andlnore preferablyrl.0 to 3.0 equivalents.

When a base is used, the amount of the base used is preferably 1.0 to 5.0 lents, and more preferably 1.0 to 3.0 equivalents. The reaction temperature is IBPF12'519 preferably in a range from —80°C to 40°C, and more preferably from —30°C to 30°C. The on time is ably in a range from 0.1 hours to 7 days, and more preferably in a range from 0.5 hours to 8 hours.

Moreover, when R2 represents a chlorine atom, it is also possible to use R1COCl generated in advance by simultaneously using trifluoroacetic acid with thionyl Chloride,phosphorusoxychloride,oxalicaciddichloride, or the like outside the reaction system in which the reaction of the compound represented by a (Aa) is d out.

Particularly preferred conditions are as follows: trifluoroacetyl chloride is used as the acylating agent; toluene, N,N—dimethylformamide, N—methyl-2—pyrrolidinone, or a mixture solvent thereof is used as the solvent; the amount of the acylating agent used is 1.0 to 3.0 equivalents; the reaction temperature is —30°C to 30°C; and the reaction time is 0.5 hours to 8 hours. ing the base, particularly preferred conditions are as follows: no base is used, or when a base is used, potassium carbonate is used in an amount of 1.0 to 3.0 lents.

The compound represented by formula (Ba) can be obtained by the method described in Patent Document 3, or the like. Specifically, in a method for producing a compound represented by formula (Ba) from a compound '519 represented by formula (Aa), the compound represented by formula (Ba) can be ed by reacting a compound represented by formula (Aa) with a compound represented by formula (Ca) (X, R3, and R4 have the same meanings as those defined above) without a solvent or in a solvent which does not affect the reaction in the presence of or in the absence of a base.

[Chem. 9] f’ l (Ca) es of usable solvents include ether-based ts such as diethyl ether, diisopropyl ether, ydrofuran, and dioxane; aprotic polar organic solvents such as N,N—dimethylformamide, dimethyl sulfoxide, N,N—dimethylacetamide, acetonitrile, N-methyl-Z-pyrrolidinone, yl-Z-piperazinone, and N,N—dimethyl—2-imidazolidinone; halogen—containing solvents such as dichloromethane and chloroform; aromatic hydrocarbon—based solvents such as toluene, xylene, and ethylbenzene; and mixture solvents of any of these; and preferred examples thereof include aprotic polar organic solvents. Here, N,N-dimethylformamide, N,N—dimethylacetamide, or toluene is more able.

The reaction can be carried out even when no base is used; however, when a base is used, examples of usable bases include inorganic bases such as sodium carbonate, IBPF12'519 potassium carbonate, sodium hydrogen carbonate, potassium en carbonate, sodium hydroxide, ium hydroxide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, and barium hydroxide; and organic bases such as 1,8—diazabicyclo[5.4.0]undec—7—ene, 1,5-diazabicyclo[4.3.0]non-5—ene, triethylamine, diisopropylethylamine, ne, lutidine, N,N—dimethylaniline, N,N—diethylaniline, and dimethylaminopyridine; preferred examples thereof include potassium carbonate, triethylamine, pyridine, andthelike;andnwregmeferredexamplesthereofinclude triethylamine and potassium carbonate.

When a base is used, the amount of the base used ispreferablyl.01x>3.0equivalents,andnmrepreferably 1.1 to 2.5 equivalents, relative to the compound represented by a (Aa). The on temperature is preferably in a range from —20°C to 150°C, and more preferably from —10°C to 100°C.

The reaction time is preferably inearange from 0.1 hoursto'7days,andmorepreferablyfrom]_hourto22days.

[Chem. 10] *FKXI /| R3,,x / N\ N :11ij I ._..__> (lb) (Ba) IBPF12‘519 Another example of the method for obtaining the compound represented by formula (Ba) is aInethod in which a compound represented by formula (Ib) is hydrolyzed, to thereby produce a compound represented by formula (Ba) (in the formula, R1, R3, and X have the same gs as those defined above). es of usable solvents include ether—based solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aprotic polar organic solvents such as methylformamide, dimethyl sulfoxide, N,N—dimethylacetamide, acetonitrile, N—methyl—2—pyrrolidinone, Numethyl—Z—piperazinone, and N,N—dimethyl—Z-imidazolidinone; halogen—containing solvents such as dichloromethane and chloroform; aromatic hydrocarbon—based solvents such as toluene, xylene, andethylbenzene;alcohol—basedsolventssuchas methanol and ethanol; water; and.mixture ts of any of these; preferred es thereof include aromatic hydrocarbon—based solvents, aprotic polar organic solvents, and mixture solvents of water with an alcohol—based t. Here, aInixture solvent of water witl1N,N—dimethylformamide, methanol, or toluene iSInore preferable. As the acid, a mineral acid such as hydrochloric acid, sulfuric acid, oric acid, or nitric acid can be used. As the base, an nic base such as sodium carbonate, potassium carbonate, sodium IBPF12-519 hydrogencarbonate,potassiumhydrogencarbonate,sodium hydroxide, magnesium hydroxide, calcium hydroxide, m ide, or barium hydroxide can be used. The reaction temperature is preferably inaarange from -20°C to 150°C, and more preferably from 70°C to 100°C. The reaction time is preferably in a range from 0.1 hours to 7 days, and more preferably from 1 hour to 8 hours.

When a compound represented by formula (Ia) is synthesized from a compound represented by formula (Aa) through a compound represented by formula (Ba), the compound represented by formula (Ia) can be ed by ting the subsequent step, without isolation of the compound represented by formula (Ba).

When a compound represented by a (I) or formula (Ia) is synthesized from a compound represented by formula (A) or formula (Aa), the compound represented by formula (I) or formula (Ia) can be obtained by a reaction of the acylating agent, the solvent, Ar—CHz—Rm and the base at once.

When a compound represented by formula (I) or formula (Ia) is obtained from a compound represented by formula (A) or formula (Aa) by a reaction using the acylating agent, the solvent, Ar-CHz—Rm and the base at once, a preferred example is as follows. Specifically, a on of a compound ented by formula (A) or formula (Aa) is allowed to proceed at 20°C to 100°C for IBPF12'519 2 hours to 3 days by using an aromatic hydrocarbon—based solvent such as toluene, xylene, or ethylbenzene; an aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide, N,N—dimethylacetamide, acetonitrile, or N-methyl-Z—pyrrolidinone; or aInixture solvent thereof, an acylating agent in which R2 represents a CLB alkoxy group which may be substituted with a halogen atom and which is used in an amount of 1.0 to 5.0 lents to the compound represented by a (A) or (Aa), and a base in an amount of 1.0 to 10.0 lents to the compound represented by formula (A) or (Aa), and adding Ar—CHg—R4 in an amount of 0.8 to 1.5 equivalents to the compound ented by formula (A) or (Aa), to thereby obtain the compound represented by formula (I) or formula (Ia). Here, specific examples of the acylating agent include ethyl trifluoroacetate, methyl trifluoroacetate,propyltrifluoroacetate,andthelike.

Moreover, examples of the base used include inorganic bases such as sodium carbonate, potassium carbonate, sodiumhydrogencarbonate,potassiumhydrogencarbonate, sodiumhydroxide,magnesiumhydroxide,calciumhydroxide, lithium hydroxide, and barium hydroxide; organic bases such as 1,8- icyclo[5.4.0]undec—7-ene, azabicyclo[4.3.0]non—5—ene, triethylamine, diisopropylethylamine, pyridine, picoline, and dimethylaminopyridine; and alcoholates such as sodium IBPF12'519 ethoxide,sodiumnethoxide,andpotassiumtert—butoxide.

Particularly preferred conditions are as follows: toluene, N,N-dimethylformamide, or aInixture solvent of toluene with N,N—dimethylformamide is used as the t; ethyl trifluoroacetate isused astﬂmaacylating agent; R4 in Ar—CHz-R4 is a chlorine atom; potassium carbonate is used as the base; the amount of the acylating agent is preferably 1.0 to .0 equivalents, and more preferably 1.5 to 5.0 equivalents, the amount of Ar—Cerq is 0.8 to 1.5 equivalents, and the amount of the base is 1.0 to 5.0 equivalents, relative to the compound represented by formula (I) or formula (Ia); the reaction temperature is 40°C to 80°C; and the reaction time is 4 hours to 2 days.

Method for Purifying and ing Compound Represented by Formula (I) or Compound Represented by Formula (Ia) from Crude Product The compound represented by formula (I) and the compound represented by formula (Ia) can be purified and isolatedbyenu/oneof(Mfacombinatimiofcrystallization, t extraction, colunw1chromatography, and the like, which are ordinarily employed. The t used for the solvent tion is not particularly limited, as long as the solvent is immiscible with water, and ic examples thereof include ethyl acetate, butyl acetate, toluene,ethylbenzene,diethylether,diisopropylether, IBPF12'519 dichloromethane, chloroform, and the like. Examples of the solvent used for the crystallization include water, hexane, toluene, acetone, N,N—dimethylformamide, methanol, 2—propanol, dichloromethane, chloroform, ethyl acetate, diethyl ether, xylene, N—methyl—Z-pyrrolidinone, N,N-dimethylacetamide, and the like; as well as mixture solvents of any of these.

Alpreferredlnethod for purifying and isolating the compound represented by formula (I) and the compound represented by formula (Ia) is crystallization. Here, one of or a combination of acetone, toluene, water, N,N—dimethylformamide, methanol, xylene, yl—Z—pyrrolidinone, and N,N—dimethylacetamide is ably used as a crystallization solvent, and combinations of any of water, N,N~dimethylformamide, methanol, N~methyl-2—pyrrolidinone, and N,N—dimethylacetamide are more preferable.

Examples Specific examples of the present ion are shown below; however, the present invention is not limited thereto.

Synthesis Example 1: Synthesis of N-[1—((6-Chloropyridin—3-yl)methyl)pyridin—2(1H)~ylid ene]-2,2,2—trifluoroacetamide (Compound 1) (1} In 200 ml of ous dichloromethane, 25 g (270 mmol) of opyridine was dissolved, and 41 ml IBPF12-519 (30 g, 300 mmol) of triethylamine was added thereto, followed by g to 0°C. To this mixture, 38 ml (57 g, 270 mmol) of trifluoroacetic anhydride was added dropwise over 15 s, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction liquid was poured into approximately 100 ml of ice—water, followed by stirring for 10 ndnutes. The mixture was transferred to a separatory funnel, and phase separation was conducted.

The organic layer was washed twice with 150 ml of water, and twice with 150 ml of a 1% aqueous HCL solution, then driedoveranhydrousmagnesiumsulfate,andconcentrated under reduced pressure. Thus, 36 g of 2,2,2—trifluoro—N—(pyridin—Z(lH)—ylidene)acetamide was obtained (Percentage Yield: 71%). 1H—NMR , 5, ppm): 7.20 (1H, m), 7.83 (1H, m), 8.20 (1H, d), 8.35 (1H, d), .07 (1H, brs) 13C—NMR (CDCl3, 6, ppm): 115.3, 115.5 (q), 121.6, 139.1, 147.9, 149.5, 155.3 (g) MS: m/z=l91(M+H). (2) In 200 ml of anhydrous acetonitrile, g (126 mmol)(If2-chloro—5—chloromethylpyridinewascﬂssolved.

Then, 24 g (126 mmol) of the trifluoro—N—(pyridin—2(1H)—ylidene)acetamide obtainedbytheabove—describedmethodand21<3(151mmol) IBPF12'519 of potassium carbonate were added to the solution. The mixture was heated under reflux for 6 hours, followed by stirring at roonl temperature for 10 hours. After completion of the reaction, the reaction liquid was filtered,andthefiltratewasconcentratedunderreduced pressure. Diethyl ether was added to the residue for llization. The crystals formed were collected by filtration, and thoroughly washed with diethyl ether and water. The ed ls were dried under reduced re at 60°C for 1 hour. Thus, the target substance was obtained. Yield: 26 g (Percentage Yield: 66%). 1H—NMR (CDCl3, 6, ppm): .57 (2H, s), 6.92 (1H, td), 7.31 (1H, d), 7.80 (1H, td), 7.87 (1H, dd), 7.99 (1H, dd), 8.48 (2H, m) 13C-NMR (CDCl3, 5, ppm): 53.8, 115.5, 117.2 (q), 122.1, 124.7, 130.0, 139.2, 140.0, 142.5, 149.7, 151.8, 158.9, 163.5 (q) MS: m/z=3l6(M+H). (3) Powder X—ray crystallography Powder X—ray diffraction measurement was carried out under the following conditions; Apparatus name: RINT—2200 (Rigaku Corporation) X—ray: Cu—Kd (40 kV, 20 mA) Scan Range: 4 to 40°, Sampling width: 0.02°, Scan rate: l°/minute The results are as follows (Fig. 1).

IBPF12519 Diffractionangles(29):8.7°,14.2°,17.5°,l8.3°,19.8°, 22.4°, 30.9°, 35.3°. (4) Differential Scanning Calorimetry (DSC) Differential scanning calorimetry was carried out under the following conditions: Apparatus name: DSC—60 Sample cell: aluminum Temperature range: 50°C to 250°C (Temperature rise: °C/minute) Fig. 2 shows the results. (5) Moreover, crystals of the same quality were obtained by recrystallization according to the methods (second to fifth production methods) described in the following (i) to (iv). These kinds of crystals were subjected to powder X—ray crystallography and differential scanning metry under the same measurement conditions as described above. (i) Second Production Method To Compound 1 (700 mg), approximately 25 ml of hexane and approximately 25 ml of ethyl e were added, and Compound liuas completely dissolved n by being heated at 65°C in a hot—water bath. The solution was slowlyreturnaitoroomtemperature,andallowmﬂtostand ght. The crystals precipitated were ted by filtration, and washed with a small amount of a solution of hexanezethyl acetate=95:5. The crystals were dried '519 :UiadesiccatorunderreducedpressureferZZhours. Thus, 349 mg of white crystals were obtained.

Theresultscﬁfthepowderx~raycrystallographyare as follows (Fig. 3).

Diffractionangle(29):8.5°,14.0°,17.3°,18.l°,19.6% 22.2°, 30.8°, 35.2° Fig. 4 shows the results of the differential scanning calorimetry. (ii) Third Production Method ToCompound].(1.0g),28inlof2—propanolwasadded, and Compound 1 was completely dissolved by being heated at 65°C in a hot—water bath. The solution was slowly returned to room temperature, and allowed to stand overnight. The crystals precipitated were ted by filtration, then washed with a small amount of 2—propanol, and.then dried insidesiccator under reduced pressure for 2 hours. Thus, 695 mg of white crystals were ed.

Fig. 5 shows the results of the differential scanning calorimetry. (iii) Fourth Production Method To Compound 1 (700 mg), approximately 30 ml of e was added, and Compound 1 was completely dissolved by being heated at 65°C in a ter bath.

The mixture was slowly returned to room temperature, and allowed to stand overnight. The crystals precipitated were collected by filtration, washed witheasmall amount IBPF12-519 of toluene, and then dried in a desiccator under reduced reforiZhours. Thus,4401mgofwhitecrystalswere obtained.

The results oftﬂuepowder X—ray crystallography'are as s (Fig. 6).

Diffractionangle(29):8.6°,14.2°,17.5°,18.3°,19.7ﬂ 22.3°, 30.9°, 35.3° Fig. 7 shows the results of the differential scanning metry. (iv) Fifth Production Method To Compound 1 (50 mg), approximately 2 ml of methanol and imate1372 ml of water were added, and Compound 1 was dissolved by being heated at 65°C in a hot—water bath. This solution was returned to room temperature, and allowed to stand overnight. The crystals precipitated were collected by filtration.

Thus, 16 mg of white crystals ware obtained.

Fig. 8 shows the results of the differential ng calorimetry.

Table 1 shows specific examples of compounds which are pest control agents represented by formula (I), and were produced by methods similar to the method of Synthesis Example 1, and also shows physical properties of the compounds.

IBPF12-519 [Table 1] 21.: .:+=w A=+Hv 9+.” 31:... Ax+=w Az+zw A=+=v 37;: A I .12... u}. n u :3: a}. «an wnm amm mm.” WW”. nun MW“ N}: Own an “w.” N}. can .3. .2. .E .2: .32. .2... .2. .2... .Au .3 .3“. .3 .Au .3 S. .2“. Ii:is 23. .2. A... .2: .2: .5. .5. in. . .5. .5. .5. £3 .zuv .5; nn.rvww.h no.9 .5. .:H. 3.5-3.... an... .5. .5: £5 :1 3S an... no... mad 2.... 3.6 an... «m... 2.... an.h «a... .AE 3.... we.” .2. mm... on... .66 ma.» .2... .2. .3. .2. .2... . .3 .3. .2. .3... .AE .33 ..E .znv .3 .Au .3 .2. .A... .3... :9 .n 2. 3. A0 £1 Au .2: .21 .5. :53 .5. .23 :3. in. £5 .53 .5. .5. .2: .lﬁv £5 .2”. ww.h .5. .za. .XHV .5. 21a .5. .5. £3 .5. .5. o and pm... on... am... and 2.6 3..., 2.... m...” «min 3... on.» mm.u an... wo.m .Aua and nw.h a~..m and .3 2.6 am... 36 ES «a...

~ A! 205. .3 .25 .3 .2. .Au .3 Au .3 .2. .3. .3 .3 .2. .Au .9 3. .Au .xdv .3 .Au .AU .2. .5. .3 .:H .23. .1 .Am .25 .An in. .luv in. J3. .INV mh.h nu.» in. .ZH. ~=Hv in. an... :8. £3 :H. in. £1 .5. x. . hm.n .Al .el 3.... nu-h 9B.w 3.... .AI A! 32.9 2.. D 00 Q1 h r.

Ilia ('7 In “IIn In HAN HAH ON...” ONﬂﬂ .5 n n 1090 Iouo Hmuiaaanaoaedao AhawaHQIMIou d. d. 0| OI HNHINIHh‘HD-lakﬂﬂﬁﬂﬁhu gnu n u Hhawnahumuonedﬁulw HhuwuhmlnlauaHSOIo «huwuhaum10u0H£OIw HhﬂoﬂmaOHOH£UIw n1nlon0Hdorw ﬁhvﬁuhﬁlm IW .n cadulw .3. I9:0 E.m IBPF12'519 Synthesis Example 2: Synthesis of 2,2,2—trifluoro—N—(pyridin—Z(lH)—ylidene)acetamide In 10 ml of ethyl acetate, 1.0 g (10.6 mmol) of 2—aminopyridine was dissolved, and 1.78 ml (12.7 mmol) of triethylamine was added thereto. Then, under ice—cooling, 1.621nl(llﬂ7mmol)oftrifluoroaceticanhydridewasadded thereto. After that, the mixture was stirred at room temperature for 2 hours, and then 10 ml of ethyl acetate and 10 ml of water were added to this mixture. The resultant mixture was stirred, and then phase separation was ted. Theethyl acetate layerwas rwashed twice with 10 ml of water, then dried over anhydrous magnesium sulfate, and concentrated under reduced re. Thus, 1.56 g of 2,2,2—trifluoro-N-(pyridin-Z(lH)—ylidene)acetamide was obtained (77.2%).

Synthesis Example 3: Synthesis of Trifluoro—N—(pyridin—2(lH)—ylidene)acetamide In 25 ml of N,N—dimethylformamide, 4.7 g (50 mmol) of 2—aminopyridine was dissolved, and 35.5 g (250 mmol) of ethyl trifluoroacetate was added.thereto. After that, the mixture was stirred at 55 to 60°C for 15 hours, and then lOOnﬂ.of ethyl acetate and 100nﬂ.of water were added thereto. The ant mixture was stirred, and then phase separation was conducted. The ethyl acetate layer was further washed with 100 ml of water and with 100 mL IBPF12'519 of aqueous sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thus, 9.05 g of 2,2,2—trifluoro—N—(pyridin—Z(1H)—ylidene)acetamide was obtained (95.6%). lH-NMR (CDCl3, 5, ppm): 7.20 (1H, ddd), 7.83 (1H, td), 8.20 (1H, d), 8.35 (1H, d), .07 (1H, brs).

Synthesis Example 4: Synthesis of _————_——m N—[1—((6—chloropyridin—3—yl)methyl)pyridin—2(lH)-ylide ne]—2,2,2—trifluoroacetamide In 400 ml of toluene, 50.0 g (0.53 mol) of 2—aminopyridine was dissolved, and then 88.6nﬂ_(0.64 mol) of trifluoroacetic ide was added to the mixture se over 30 minutes under cooling to 5°C. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and 20 ml of toluene was distilled off under reduced pressure. To the reaction , 250 ml of dimethylformamide was added, and 88.2 g (0.64 mol) of potassium carbonate powder was lly added to the reaction liquid under ice—cooling. After that, 89.2 g (0.557 mol) of 2—chloro—5~chloromethylpyridinewasaddedtothereaction liquid. Under a reduced re (50 to 60 hPa) at 40 to 45°C, toluene was gradually distilledtoff, and thelnixture washeatedfor]_hour. Distillationbyheatingwasfurther IBPF12-519 conducted at 60 to 70°C and 35 hPa for 2.5 hours. Then, 5J3g(0.036mol)ofgxmassiumcarbonatepowderwasadded, and water was removed at 50 to 60°C and 35 hPa for further 1 hour. The reaction liquid was added to 2 L of water of 50°C, and after completion of the addition, the mixture was stirred for 30 minutes. After that, the mixture was filtered, and the crystals were subjected to slurry washing with 200 ml of water and subsequently with 500 ml of water. After the filtration, the ls were washed with 100 ml of toluene, while being pressed. Further, the ls were subjected to slurry washing with 400 ml of toluene. The obtained crystals were dried under reduced pressure at 60°C overnight with a vacuum pump. Thus, 147.78 g of the target compound N-[l-((6-chloropyridin—3—yl)methyl)pyridin—Z(1H)-ylide 2,2—trifluoroacetamideimasobtained(88.1%). Then, 8.21 g of the obtained title compound was sampled, and dissolved in 100 mL of acetone. To this solution, 300 mL of water was added, and the mixture was stirred at room 2O temperature. Thecrystalsprecipitatedwerecollectedby filtration, and the obtained crystals were dried under reduced pressure at 60°C overnight with a vacuum pump.

Thus, 7.28 g of crystals were ed. The results of powder X—ray crystallography conducted on the ed crystals are as follows (Fig. 9).

Diffractionangles(29):8.8°,14.3°,17.6°,18.3°,19.9% IBPF12'519 22.5°, 3l.O°, 35.4° Synthesis Example 5: Synthesis of N—[1—((6—Chloropyridin—3~yl)methyl)pyridin—Z(1H)—ylide ne]—2,2,2—trifluoroacetamide In 250 ml of toluene, 50.0 g (0.53 mol) of opyridinewascﬂssolved,andthen88.6nﬂ.(0.64mol) of trifluoroacetic anhydride was added dropwise over 30 minutes to the solution under cooling to 5°C. After the dropwise addition, the e was stirred at room temperature for 30 minutes, and 20 ml of toluene was distilled off under d pressure. To the reaction liquid, 250 ml of dimethylformamide was added, and then 88.2 g (0.64 mol) of potassium ate powder was added gradually to the reaction liquid under ice—cooling.

After that, 87.0 g (0.54 mol) of 2-chlorochloromethylpyridine was added, and toluene was gradually distilled off under a reduced pressure (50 to 60 hPa) at 50 to 60°C, followed by heating at 35 hPa.

One hour later, 5.0 g (0.036 mol) of potassium carbonate powder was added, and water was removed at 50 to 60°C and hPa. Four hours later, the reaction liquid was added to 1.1 L of water of 50°C. The reaction vessel was washed with 150 ml of methanol, and the washing liquid was also added water. Afterthe completion<3fthe addition, the mixture was heated at 50°C for 10 minutes, cooled gradually, and.stirred.atli3to 20°C for301ninutes. Then, IBPF12‘519 the crystalswere filtered,euuiwashedwith,150nd ofwater, and subsequently with 150 ml of toluene. The obtained crystals were dried under reduced pressure at 60°C for 11 hours with a vacuum pump. Thus, 147.32 g of the target compound (6—chloropyridin-3—yl)methyl)pyridin-2(1H)—y1ide he]—2,2,2-trifluoroacetamide was obtained (87.8%).

Synthesis Example 6: Synthesis of N-[1—((6—Chloropyridin—3—yl)methyl)pyridin—2(1H)—ylide ne]—2,2,2—trifluoroacetamide In 10 ml of e, 1.0 g (10.6 mmol) of 2—aminopyridine was dissolved. After the solution was cooled to 5°C, 1.18 ml (15.9 mmol) of oroacetic acid and 0.99 ml (10.6 mmol) of phosphorus oxychloride were added thereto, followed by stirring at room ature for 6.5 hours. To the reaction liquid, 5.0 ml of dimethylformamide, 5.87 g (42.5 mmol) of potassium carbonate powder, and 1.72 g (10.6 mmol) of 2—chloro—5—chloromethylpyridine were added, and distillation was conducted under reduced pressure (60 to hPa) at 50 to 60°C. Two and a half hours later, the reaction liquid was added to 100 ml of water, and the crystals were filtered, and.washed with 30 ml of water and ml of toluene. The obtained crystals were dried under reduced pressure at 60°C. Thus, 2.09 g of the target compound IBPF12'519 N—[1—((6—chloropyridin—3—yl)methyl)pyridin—2(1H)—ylide ne]—2,2,2—trif1uoroacetamide was obtained (62.3%).

Synthesis Example 7: Synthesis of N—[l—((6-Chloropyridin—3—yl)methyl)pyridin-2(1H)—ylide ne]-2,2,2—trif1uoroacetamide In 100 ml of toluene, 10.0 g (0.106 mol) of 2-amin0pyridine was dissolved. After the solution was cooled to 5°C, 11.8 ml (0.159 mol) of oroacetic acid and9.9nﬂ.(0.106mol)ofphosphorusoxychloridewereadded, followed by stirring at room ature overnight. Then, ml of toluene was distilled off under dlpressure.

To the on liquid, 50 m1 of dimethylformamide, 35.28 g (0.256 mol) of potassium carbonate powder, and 17.22 g (0.106mol)of2—chloro—5—chloromethy1pyridinewereadded under ice-cooling. Then, distillation was conducted under d pressure (60 to 35 hPa) at 50 to 60°C. Two hours later, 25nﬂ.of dimethylformamide, 20nﬂ.of toluene, and 7.35 g (0.053 mol) of potassium carbonate powder were further added, and then distillation was conducted under reduced pressure (60 to 35 hPa) at 50 to 60°C for 2 hours.

To the reaction.1iquid, 60nﬂ_of1nethanol and 50nﬂ_of water were added, and the reaction liquid was added to 300 m1 ofwater,whilethevesselwasalsowashed. Thirtyminutes later, the crystals were filtered, and washed with 70 m1 of water and 40 m1 of toluene. The obtained crystals were dried under reduced pressure at 60°C. Thus, 25.75 g of IBPF12-519 the target compound was obtained (76.9%).

Synthesis Example 8: Synthesis of N—[1—((6—Chloropyridin—3—yl)methyl)pyridin—2(1H)-ylide ne]-2,2,2—trifluoroacetamide In 100 ml of toluene, 10.0 g (0.106 mol) of 2-aminopyridine was dissolved. After the solution was cooled to 5°C, 11.8 ml (0.159 mol) of trifluoroacetic acid and 7.7 ml (0.106 mol) of thionyl de were added thereto, followed by stirring at room temperature overnight. Then, 20 ml of toluene was distilled off under reduced pressure. To the reaction liquid, 50 ml of dimethylformamide, 35.28 g (0.256 Hml) of potassium carbonate , and 17.22 g (0.106 mol) of 2-chloro—5-chloromethylpyridine were added under ice-cooling. Then, distillation was conducted under reduced pressure (36 hPa) at 50 to 60°C for 1 hour. To the reaction liquid, 60 ml of ol and 50 ml of water were added, and the reaction liquid was added to 300 ml ofwater,whilethevesselwasalsowashed. Thirtyminutes later, the ls were filtered, and washed with 70 ml of water and 40 ml of toluene. The obtained crystals were dried under reduced re at 60°C. Thus, 22.31 g of the target compound was obtained (66.6%).

Synthesis Example 9: Synthesis of N—[1—((6—Chloropyridin—3—yl)methyl)pyridin—2(lH)—ylide ne]—2,2,2—trifluoroacetamide IBPF12'519 In 50 ml of toluene, 5.0 g (0.053 mol) of 2—aminopyridine was dissolved, and 8.86 ml (0.064 mol) of trifluoroacetic anhydride was added.dropwise theretc>over minutes under cooling to 5°C. After the dropwise addition, the mixture was stirred at room temperature for minutes, and 10 ml of toluene was distilled off under reduced pressure. To the reaction liquid, 25 ml of dimethylformamide was added, and then 8.82 g of potassium ate powder was gradually added thereto under ice-cooling. After that, 11.78 g (0.053 mol) of 2-chloro—5—methanesulfonyloxymethylpyridine was added, and toluene was gradually led off under reduced re (50 to 60 hPa) at 50 to 60°C, followed by heating at 35 hPa. Thirty minutes later, 30 ml of dimethylformamide, 30 ml of toluene, and 1.18 9 (0.0053 mol) of 2—chloro-5—methanesulfonyloxymethylpyridine were added, and d re distillation was conducted at 50 to 60°C and 55 hPa. Four hours later, the reaction liquid was added to 250 ml of water. Then, the reaction vessel was washed with 30 ml of methanol and 20 ml of water, and the washing liquids were also added to the water. After completion of the addition, the mixture was stirredaﬂ:roonltemperature foriﬂlminutes. Then,the crystals were filtered, and washed with 50 ml of water, and subsequently with 40 ml of toluene. The obtained crystals were dried under reduced pressure at 80°C for 11 IBPF12-519 hours with a vacuum pump. Thus, 11.63 g of the target compound N—[1—((6—chloropyridin-3—yl)methyl)pyridin-Z(1H)—ylide ne]—2,2,2-trifluoroacetamide was obtained (69.4%).

Synthesis Example 10: Synthesis of N—[1-((6-Chloropyridin-3—yl)methyl)pyridin-Z(1H)—ylide ne]-2,2,2—trif1uoroacetamide In 100 ml of toluene, 10.0 g (0.106 mol) of 2—aminopyridine was dissolved. After the solution was cooledtx>5°C, 11.84nﬂ.(0.159nml) oftrifluoroaceticacid and subsequently 5.94 ml (0.064 mol) of phosphorus oxychloride were added thereto, followed by stirring at room temperature overnight. Then, 20 ml of e was distilled off under reduced pressure. To the reaction liquid, 50 ml of dimethylformamide, 22.03 g (0.16 mol) of potassium carbonate , and 17.56 g (0.108 mol) of ro—5—chloromethylpyridine were added under ice-cooling. Then, lation was ted under reduced pressure (60 to 35 hPa) at 50 to 60°C. One hour later, 20 ml of dimethylformamide, 20 ml of toluene, and 4.41 g (0.032 mol) of potassium carbonate powder were further added thereto, and distillation was conducted under reduced pressure (60 to 35 hPa) and 50 to 60°C for 1.5 hours. The reaction liquid to which 30 ml of methanol was added was added to 250 ml of water of 50°C. Then, 50 ml of water was added thereto, while the vessel was also IBPF12-519 washed therewith. After being cooled to room temperature, the mixture was stirred for 301ninutes. The crystals were filtered,andwashedwithSOnﬂ.ofwaterand30nﬂ.oftoluene.

The obtained crystals were dried under reduced pressure at 60°C. Thus, 23.69qgof the target compountiwas obtained (70.6%).

Synthesis Example 11: sis of N—[l—((6—Chloropyridin—3—yl)methyl)pyridin-Z(1H)—ylide ne]—2,2,2—trifluoroacetamide In 100 ml of toluene, 10.0 g (0.106 mol) of 2—aminopyridine was dissolved. After the solution was cooled to 5°C, 11.8 ml (0.159 mol) of trifluoroacetic acid and subsequently 7.76 ml (0.106 mol) of thionyl chloride were added o portionwise, followed by stirring at room ature ght. Then, 50 ml of toluene was distilled off under reduced pressure. To the reaction liquid, 50 ml of e was added. Then, 50 ml of dimethylformamide, 22.03 g (0.16 mol) of potassium carbonate powder, and 17.56 g (0.108 mol) of ro—5—chloromethylpyridinewereaddedtheretounder ice—cooling. Then, distillation was conducted under reduced pressure (90 to 36 hPa) at 60°C for 1.5 hours. To the reaction liquid, 30 ml of methanol and 20 ml of water were added. The reaction liquid was added to 300 ml of water of 50°C, while the vessel was also washed. The mixture was stirred at room temperature for 30 minutes, IBPF12-519 and then the crystals were filtered, and washed with 50 ml of water and 30 ml of toluene. The obtained crystals were dried under reduced pressure at 60°C. Thus, 21.45 g of the target compound was ed (64.1%).

Synthesis Example 12: Synthesis of N—[l—((6-Chloropyridinyl)methyl)pyridin—Z(1H)—ylide ne]—2,2,2—trifluoroacetamide In 500 mL of dimethylformamide, 94 g (1 mol) of 2—aminopyridine was dissolved, and 284 g (2 mol) of ethyl oroacetate was added thereto, followed by stirring at 55 to 60°C for 24 hours. To the reaction , 82.8 g (0.6 mol) of potassium carbonate powder, l53.9 g (0.95 mol) of 2—chlorochloromethylpyridine, and 300 mL of toluene were added, ed by ng under reduced pressure (36 hPa) at 50 to 60°C for 3 hours. To the reaction liquid, 200 mL of methanol was added. Then, the reaction liquid was added to 2 L of hot water of 50°C.

After being cooled to room temperature, the mixture was stirred for 3 hours. The crystals were filtered, and washed with 400 mL of water and 450 mL of toluene. The obtained crystals were dried under reduced pressure at 45°C. Thus, 228.9 g of the target compound was obtained (Percentage Yield: 72.7%).

Synthesis Example 13: Synthesis of N—[l—((6-Chloropyridin—3-yl)methyl)pyridin—2(1H)—ylide ne]-2,2,2—trifluoroacetamide IBPF12'519 In a mixture solvent of 30 mL of dimethylformamide and 20 ml of toluene, 9.4 g (0.1 mol) of 2—amin0pyridine was dissolved, and 28.4 g (0.2 mol) of ethyl trifluoroacetate was added thereto, followed by ng at 60 to 65°C for 8 hours. To the reaction , 16.6 g (0.12 mol) of potassium carbonate powder and 16.2 g (0.1 mol) of 2—chloro-5—chloromethylpyridine were added, followed by stirring at 60 to 65°C for 15 hours. To the reaction , 15 mL of methanol was added, and then the reaction liquid was added to 120 mL of hot water of 50°C.

After being cooled to room ature, the mixture was stirred for 2 hours. The crystals were filtered, and washed with 50 mL of water and 100 mL of toluene. The obtained crystals were dried under reduced pressure at 45°C. Thus, 25.6 g of the target compound was obtained (Percentage Yield: 81.2%).

Synthesis Example 14: Synthesis of N—[l-((6—Chloropyridin—3—yl)methyl)pyridin—2(1H)—ylide ne]-2,2,2—trifluoroacetamide To 13.68 g (0.12 mol) of trifluoroacetic acid, 1.5 mL of dimethylformamide was added. Then, 14.28 g (0.12 mol) of thionyl chloride was added to the mixture, which was heated to 65°C. Trifluoroacetyl de generated therefrom was bubbled into a solution which was obtained by dissolving 9.4 g (0.1 mol) of 2—aminopyridine in 50 mL ofN—methylpyrrolidone,andwhichwascooledto—10°C,and IBPF12'519 thexnixture was stirred for] hour. To the reaction liquid, 100nﬂiof toluene, 48.3 g (0.351nol) assiun1carbonate powder, and 16.52 g (0.102 mol) of 2—ch1oro—5—chloromethylpyridine were added, and distillationwasconductedunderreducedpressure(36hPa) at 50 to 60°C for 3 hours. To the reaction liquid, 20 mL of methanol was added, and the mixture was added to 300 rm_ofwaterheatejt050°c,whilethevesselwasalsowashed.

Thelnixture wasstirreden:roonltemperature for1.5 hours.

Then, the crystals were filtered, and washed with 100 mL ofwaterandIBOIMJoftoluene. Theobtainedcrystalswere dried under reduced pressure at 45°C. Thus, 16.8 g of the target nd was obtained (Percentage Yield: 53.3%).

Synthesis Example 15: Synthesis of N-[l-((6-Chloropyridin-3—yl)methyl)pyridin—Z(1H)~ylide 2,2-trif1uoroacetamide To 18.24 g (0.16 mol) of trifluoroacetic acid, 8.76 g (0.12 mol) of dimethylformamide was added. While the mixture was heated to 65°C, 12.26 g (0.08 mol) of phosphorus oxychloride was added to this mixture.

Trifluoroacetyl chloride generated rom was d intoaasolutionvﬂﬂxﬁlwasobtainedkn/dissolving9.4 g(0.1 mol)of2—aminopyridinein80IMJofN-methylpyrrolidinone, and which was cooled to —15°C, and thexnixture was stirred for 2 hours. While being cooled to —10°C, the reaction liquid was neutralized by adding 14.9 g (0.22 mol) of IBPF12'519 sodium ethoxide powder thereto. To this reaction , 13.8 g (0.1 mol) of potassium carbonate powder and 16.2 g (0.1 mol) of 2—chloro-5—chloromethylpyridine were added, and distillation was conducted.under reduced pressure (36 hPa) at 50 to 60°C for 2 hours. To the reaction liquid, mL of methanol was added, and the mixture was added to 400 ml of water heated to 50°C, while the vessel was also washed. Afterthenﬁxturewasstirrejatroomtemperature for30nﬁnutes,thecrystalswerefiltered,andwashedwith 100rMJofwaterandSOrMJoftoluene. ainedcrystals were dried under reduced re at 45°C. Thus, 22.5 g of the target compound was obtained (Percentage Yield: 71.4%).

Synthesis Example 16: Synthesis of N—[l—((6-Chloropyridin-3—yl)methyl)pyridin—Z(1H)-ylide ne]—2,2,2—trifluoroacetamide In 20 ml of dimethylformamide, 3.00 g (18.6 mmol) of ro-5~chloromethylpyridine was dissolved, and 1.75 g (18.6 mmol) of 2—aminopyridine was added thereto, followed by stirring at 80°C for 8 hours, and at room temperature forIShours. After completion ofthe reaction, dimethylformamide was distilled off under reduced pressure,andacetonitrilewasadded. Aszaresult,asolid was precipitated. The soliciwas collected by filtration, thoroughly washed with acetonitrile, and then dried.

Thus, 2.07 g of 1—[(6—chloropyridin—3-yl)methyl] IBPF12'519 pyridine~2(1H)—imine hydrochloride was obtained (Percentage Yield: 44%). 1H—NMR (DMSO—d6, 6, ppm): .65 (2H, s), 6.96 (1H, t), 7.23 (1H, m), 7.57 (1H, d), 7.80 (1H, m), 7.91 (1H, m), 8.28 (1H, m), 8.49 (1H, d) In 5 ml of anhydrous dichloromethane, 50 mg (0.20 mmol) of 1—[(6—chloropyridin—3—yl)methyl] pyridine—2(1H)—imine hydrochloride obtained by the above—describedlnethod was suspended. Then, 122 mg (1.00 mmol) of dimethylaminopyridine and 50 mg (0.24 mmol) of trifluoroacetic anhydride were added.in this order to the sionunder ice-cooling, followedkn/stirringat room temperature for1.hour. After tiorlof the reaction, the reaction liquid was d with dichloromethane, washed with 1% hloric acid, and then dried over anhydrous magnesium sulfate. The dichloromethane was distilled off under reduced pressure. Thus, the target substance was obtained. Yield: 42 mg (Percentage Yield: Synthesis Example 17: Synthesis of N—[l-((6—Chloropyridin—3—yl)methyl)pYridin—Z(1H)—ylide ne]-2,2,2—trif1uoroacetamide In 15 mL of N,N—dimethylformamide, 4.6 g (0.02 mol) l—((6—chloropyridin—3—yl)methyl)pyridine—2(1H)—imine obtained by being synthesized according to the method of IBPF12'519 Synthesis Example 16, and then being lized was dissolved, and 5.7 g (0.04 mol) of ethyl trifluoroacetate was added thereto. After stirring at 56°C overnight, 60 mL of water was added to the mixture. The crystals precipitated were collected by filtration. The obtained crystalsweredriedunderreducedpressunsat45°C. Thus, .85 g of the target compound was obtained (Percentage Yield: 92.8%). sis Example 18: sis of N—[1—((6—Chloropyridin—3—yl)methyl)pyridin—2(1H)—ylide ne]—2,2,2—trifluoroacetamide In 6 mL of N,N—dimethylformamide, 2.2 g (0.01 mol) 1—((6—chloropyridin—3—yl)methyl)pyridine—2(1H)-imine obtained by being synthesized according to the method of Synthesis Example 16, and then being neutralized was dissolved. Then, 828 mg (0.006 mol) of potassium carbonate and 2.52 g (0.012 mol) of trifluoroacetic anhydride were added to the solution under ice—cooling.

After ng at room temperature for 1 hour, 30 mL of water‘wasadded133the1nixture. The crystalsprecipitated were collecteciby filtration. The obtained crystals were washed with 20 mL of water, and dried under reduced pressure at 45°C. Thus, 2.38 g of the target compound was obtained (Percentage Yield: .

Synthesis Example 19: Synthesis of IBPF12‘519 N—[1—((6—Chloropyridin—3—yl)methyl)pyridin—Z(1H)—ylide ne]—2,2,2—trifluoroacetamide To 4.56 g (0.04 mol) of trifluoroacetic acid, 3 mL of N,N—dimethylformamide was added. Then, 3.12 g (0.02 mol) of phosphorus oxychloride was added to the mixture, which was heated to 60°C. Trifluoroacetyl chloride generated therefrom was bubbled into a solution obtained by dissolving, in 25nﬂiof yl—2—pyrrolidinone, 4.38 g (0.02 mol) of l—((6—chloropyridin-3—yl)methyl)pyridine—2(lH)—imine, which was obtained by being synthesized according to the tafSynthesis Example 16,andtﬂuuibeingneutralized, and the reaction was allowed to d at —10°C for 45 minutes. Crystals precipitated by adding 125 mL of water were collected.by filtration. The obtained crystals were dried under reduced re at 45°C. Thus, 2.58 g of the target compound was obtained (Percentage Yield: 40.9%).

Synthesis Example 20: Synthesis of N-[l-((6—Chloropyridin—3—yl)methyl)pyridin—Z(lH)—ylide 2O ne]—2,2,2—trifluoroacetamide In 3 mL of N,N—dimethylformamide, 4.38 g (0.02 mol) l—((6—chloropyridin-3—yl)methyl)pyridine—2(1H)—imine, which was obtained by being synthesized ing to the method of Synthesis Example 16, and then neutralized, was dissolved. To this solution, 2.7 g (0.024 mol) of IBPF12‘519 trifluoroacetic acid and 2.8 g (0.02 mol) of phosphorus pentoxide were added. The mixture was stirred at 120°C for 3 hours, and then ed to room temperature.

Crystals precipitated by adding 50 mL of water were collected by filtration. The obtained crystals were dried under reduced re at 45°C. Thus, 2.12 g of the target compound was obtained (Percentage Yield: 33.7%).

Synthesis Example 21: Synthesis of N—[l—((6—Chloropyridin—3—yl)methyl)pyridin—Z(1H)—ylide he]—2,2,2—trifluoroacetamide In 50 mL of dimethylformamide, 9.4 g (0.1 mol) of 2—aminopyridine was dissolved. To this solution, 28.8 g (0.2 mol) of ethyl trifluoroacetate, 16.2 g (0.1 mol) of ro-5—chloromethylpyridine, and 13.8 g (0.1 mol) of potassium carbonate were added, followed by stirring at 55 to 60°C for 20 hours. To the reaction , 1.38 g (0.1 mol) of potassium carbonate powder, 3.24(0.02 mol) of 2—chloro-5—chloromethylpyridine, and 5.689 (0.04 mol) of ethyl trifluoroacetate were further added, followed by stirringat.55tx>60°Cfor 6hours. 'Lathereactionliquid, 40 mL of ol was added, and then the on liquid was added to 300 mL of hot water of 50°C. After being cooled to room temperature, the mixture was stirred for 1 hour. The crystals were filtered, and washed with 100 mL of water and 75 mL of toluene. The obtained crystals were dried under reduced pressure at 45°C. Thus, 24.0 g IBPFl2-519 of the target compound was obtained (Percentage Yield: Synthesis Example 22: sis of N—[l—((6—Chloropyridin—3—yl)methyl)pyridin-2(lH)—ylide ne]—2,2,2—trifluoroacetamide In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g (0.1 mol) of 2-aminopyridine was dissolved. To this solution, 28.8 g (0.2 mol) of ethyl trifluoroacetate, 16.2 g (0.1 mol) of 2—chloro—5—chloromethylpyridine, and 16.6 g (0.12 mol) of potassium carbonate were added, followed by stirring at 60 to 65°C for 18 hours. To the reaction liquid, 15 mL of methanol was added, and then the reaction liquid was added to 120 mL of hot water of 50°C. After being cooled to room ature, the mixture was stirred for 1 hour. Crystals were filtered, and washed with 50 mL of water and 100 mL of toluene. The obtained crystals were dried under reduced pressure at 45°C. Thus, 23.9 g of the target compound was ed (Percentage Yield: 75.9%).

Synthesis Example 23: Synthesis of N-[1—((6—Chloropyridin-3—yl)methyl)pyridin—Z(1H)—ylide ne]—2,2,2—trifluoroacetamide In a mixture t of 25 mL of N,N—dimethylformamide and 10 ml of toluene, 4.7 g (0.05 mol) of 2—aminopyridine was dissolved. To the on, .5 g (0.25 mol) of ethyl trifluoroacetate, 9.72 g (0.06 IBPF12'519 mol) loro—5—chloromethylpyridine, and8.28 g(0.06 mol) of potassium carbonate powder were added, followed by stirring at 65°C for 18 hours. To the reaction liquid, mL of methanol was added, and then the reaction liquid was added to 150 mL of hot water of 50°C. After being cooled to room temperature, the e was stirred for 1 hour. Crystals were filtered, and washed with 50 mL of water and 50 mL of toluene. The obtained crystals were dried under reduced pressure at 45°C. Thus, 13.78 g of the target compound was obtained (Percentage Yield: 87.5%).

Synthesis e 24: Synthesis of N—[1-((6—Chloropyridin-3—yl)methyl)pyridin—Z(1H)—ylide ne]—2,2,2—trifluoroacetamide In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g (0.1 mol) of 2—aminopyridine was<dissolved. To this solution, 14.2 g (0.1 mol) of ethyl trifluoroacetate was added, ed by stirring at 60 to 65°C for 7 hours.

Subsequently, 16.2 g (0.1 mol) of 2—chloro—5—chloromethylpyridine and 16.6 g (0.12 mol) of potassium ate were added thereto, followed by stirringat(ﬂ)to65°CforZH3hours. Tothereactionliquid, mL of methanol was added. Then the reaction liquid was added to 150 mL of hot water of 50°C, and the mixture was cooled to room temperature. Crystals were filtered, and washed with 50 mL of water and 75 mL of toluene. The IBPF12'519 obtained crystals were dried under reduced pressure at 60°C. Thus, 20.6 g of the target compound was ed ntage Yield: 65.4%).

Synthesis Example 25: Synthesis of N-[l-((6—Chloropyridin—3—yl)methyl)pyridin—Z(1H)—ylide ne]—2,2,2—trifluoroacetamide In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g (0.1 mol) of opyridine was dissolved. To the solution, 7.1 g (0.05 mol) of ethyl trifluoroacetate was added, followed by stirring at 60 to 65°C for 7.5 hours. oncentrationunderreducedpressure(90hPa,40°C), the residue was cooled on ice, and 20 mL of toluene and .5 g (0.05 mol) of trifluoroacetic anhydride were added to the residue, followed by stirring at room temperature for 1 hour. Subsequently, 16.2 g (0.1 mol) of 2—chloro-5—chloromethylpyridine, 20 mL of dimethylformamide, and 16.6 g (0.12 mol) of potassium carbonate were added, followeciby stirring undereareduced pressure of 110 hPa at 60 to 65°C for 4 hours. After concentration under d pressure (90 hPa, 50°C), 25 mL of methanol was added to the reaction liquid, and this mixture was added to 250 mL of hot water of 50°C. The mixture was cooled to room temperature with stirring.

Crystals were filtered, and washed.with 90nﬂiof water and 90 mL of toluene. The obtained crystals were dried under reduced pressure at 60°C. Thus, 19.8 g of the target -519 compound was obtained (Percentage Yield: 62.9%).

Synthesis Example 26: Synthesis of N-[1—((6—Chloropyridin—3-yl)methyl)pyridin—Z(1H)—ylide 2,2—trif1uoroacetamide In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g (0.1 mol) of 2-aminopyridine was dissolved. To the solution, 21.3 g (0.15 mol) of ethyl trifluoroacetate was added, ed by ng at 60 to 65°C for 7.5 hours.

Afterconcentrationunderreducedpressure(90hPa,40°C), the residue was cooled on ice, and 20 mL of toluene and .5 g (0.05 mol) of trifluoroacetic anhydride were added to the residue, followed by stirring at room temperature for 1 hour. Subsequently, 16.2 g (0.1 mol) of 2—chloro—5—chloromethylpyridine, 20 mL of dimethylformamide, and 16.6 g (0.12 mol) of potassium carbonate were added , followed by stirring under a reduced pressure of 110 hPa at 60 to 65°C for 4 hours. After concentration under reduced pressure (90 hPa, 50°C), 25 mL of methanol was added to the reaction liquid, and the mixture was added to 250 mL of hot water of 50°C. Then, the mixture was cooled.to room temperature with stirring.

Crystals were filtered, and washed.with f water and 90 mL of toluene. The obtained crystals were dried under reduced pressure at 60°C. Thus, 22.68 g of the target nd was obtained (Percentage Yield: 72.0%).

Synthesis Example 27: Synthesis of IBPF12'519 N—[1—((6—Chloropyridin-3—yl)methyl)pyridin—2(1H)-ylide ne]—2,2,2—trifluoroacetamide In 40 ml of xylene, 2.35 g (0.025 mol) of 2—aminopyridine was suspended. To this mixture, 2.85 g (0.025 mmol) of trifluoroacetic acid and 135 mg of ferric chloridehexahydratewereadded,andattachedeiDean-Stark trap. The mixture was stirred at 150°C for 16 hours, removing the resulting water by the Dean—Stark trap.

After the solution was cooled to 60°C, 4.05 g (0.025 mol) of 2—chloro-5—chloromethylpyridine, 16 mL of ylformamide, and 2.42 g (0.0175 mol) of potassium carbonate were added, followeclby stirring undereareduced pressure of 60—110 hPa at 60 to 65°C for 3 hours. Then, mL of methanol was added to the reaction mixture, and this e was added to 80 mL of hot water of 50°C. The mixture was cooled to room ature with stirring.

Crystals were filtered, and washed with 20 mL of water and mL of toluene. The obtained crystals were dried under reduced pressure at 60°C. Thus, 6.32 g of the target compound was obtained (Percentage Yield: 80.3%).

Synthesis Example 28: Synthesis of N—[1—((6—Chloro—5—fluoropyridin—3—yl)methyl)pyridin~2( 1H)—ylidene]-2,2,2—trifluoroacetamide (Compound 2) In 80 m1 of carbon tetrachloride, 4.00 g (27.6 mmol) of 2—chloro—3—fluoro—5-methylpyridine ssolved. To this solution, 7.37 g (41.4 mmol) of N—bromosuccinimide IBPF12'519 and 20 mg of benzoyl peroxide were added, and the mixture was heated under reflux overnight. After completion of the on, the reaction liquid was returned to room temperature, and concentrated under reduced pressure.

Then, the residue was purified by silica gel column chromatography (hexanezethyl acetate=l9:l). Thus, 3.06 g of 5—(bromomethyl)-2—chloro—3—fluoropyridine was ed ntage Yield: 51%). lH—NMR (CDCl3, 6, ppm): 4.45 (2H, s), 7.54 (1H, dd), 8.23 (1H, s) Ir15 ml of anhydrous acetonitrile, 50 mg (0.22 mmol) of 5—(bromomethyl)-2—chloro-3—fluoropyridine obtained by the above—described method was dissolved. To this solution, 42 mg (0.22 mmol) of 2,2,2—trifluoro—N—(pyridin—2(lH)—ylidene)acetamide obtained by the above—described method and 36 mg (0.26 mmol) of potassium carbonate were added in this order, followed by heating under reflux for 7 hours. After completion of the reaction, the reaction liquid was returned to room temperature. The insolublelnatters were filtered, and the filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added. As a result, a solid. was precipitated. The solid was ted by filtration, washed with diethyl ether, and dried in a ator under reduced pressure. Thus, the target substance was obtained. Yield: 29 mg (Percentage -519 Yield: 40%). lH—NMR (CDClB, 5, ppm): 5.54 (2H, s), 6.89 (1H, td), 7.76 (1H, dd), 7.80 (1H, td), 7.85 (1H, d), 8.29 (1H, d), 8.57 (1H, d) MS: m/z = 334 (M+H) Synthesis Example 29: Synthesis of N-[l-((6—Bromopyridin—3—yl)methyl)pyridin-2(1H)—yliden ,2—trifluoroacetamide (Compound 3) In 15 ml of carbon tetrachloride, 500 mg (2.92 mmol) of 2—bromo-5—methylpyridine was dissolved. To this solution, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added, followed by heating under reflux for 19 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure.

The e was purified by silica gel column chromatography (hexanezethyl acetate=19:1). Thus, 143 mg of 2-bromo—5—bromomethylpyridine was obtained (Percentage Yield: 20%). lH—NMR (CDCl3, 6, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d) In 10nﬂ_of anhydrous acetonitrile, 70ng (0.28 mmol) of 2-bromo—5-bromomethylpyridine obtained by the above—described.method was dissolved. To this solution, 54 mg (0.28 mmol) of 2,2,2—trifluoro—N—(pyridin-2(lH)—ylidene)acetamide IBPF12519 synthesized by the above—described method and 46 mg (0.34 mmol) of potassium carbonate were added in this order, followed by heating under reflux for 6 hours. After completion of the reaction, the reaction liquid was returned. to room temperature. Then, the insoluble matters were filtered, and the filtrate was concentrated under reducecipressure. To the e, diethyl ether was added. As a result, a solid was itated. The solid was collected by filtration, washed with diethyl ether, and then dried in a desiccator under reduced pressure.

Thus, the target nce was obtained. Yield: 81 mg ntage Yield: 82%). 1H-NMR (CDC13, 5, ppm): 5.52 (2H, s), 6.88 (1H, t), 7.48 (1H, d), 7.78 (2H, m), 7.84 (1H, d), 8.44 (1H, d), 8.53 (1H, d) MS: m/z = 360 (M+H) sis Example 30: Synthesis of 2—chloro—N~[1—((6—Chloropyridin—3—yl)methyl)pyridin—2( 1H)—ylidene}—2,2—difluoroacetamide (Compound 4) In 5 ml of dichloromethane, 200 mg (2.13 mmol) of 2-aminopyridine was dissolved. To this solution, 491 mg (2.55 mmol) of EDC—HCl, 311 mg (2.55 mmol) of dimethylaminopyridine, and 187 pl (2.23 mmol, 290 mg) of chlorodifluoroacetic acid were added in this order, followed by stirring overnight. After completion of the reaction, the reaction liquid was diluted with IBPF12619 dichloromethane, washed with water and with 1% hydrochloricacid,andthendriedoveranhydrousmagnesium sulfate. Thus, 105 mg of 2—chloro—2,2-difluoro—N-(pyridin—Z(1H)—ylidene)acetami de was obtained (Percentage Yield: 24%). 1H-NMR (CDC13, 6, ppm): 7.19 (1H, dd), 7.82 (1H, m), 8.18 (1H, d), 8.36 (1H, d), 9.35 (1H, br 8) To 68 mg (0.33 mmol) of 2—chloro—2, 2—difluoro—N—(pyridin—2(1H)-ylidene)acetamide synthesized by the above-described method, 53 mg (0.33 mmol) of 2—chlorochloromethy1pyridine dissolved in 6 m1 of ous acetonitrile was added. Subsequently, 50 mg (0.36 mmol) of potassium carbonate was added to the mixture, followed by heating under reflux for 1 hour.

After completion of the reaction, the reaction liquid was returned.to room temperature, and then concentrated under reduceclpressure. Diethyl ether was addedtx>the residue.

As a result, a solid was precipitated. The solid was collected by tion, and dried. Thus, the target substance was obtained. Yield: 49 mg (Percentage Yield: 45 o\° ). 1H—NMR , 5, ppm): 5.56 (2H, s), 6.92 (1H, t), 7.33 (1H, d), 7.82 (1H, m), 7.91 (1H, dd), 8.02 (1H, d), 8.45 (1H, d), 8.48 (1H, d) 13C—NMR (CDCl3, 5, ppm): 53.8, 115.2, 120.1 (t), 122.1, 124.8, 139.0, 140.0, 142.3, 150.0, 151.9, 159.1, 159.1, IBPF12‘519 165.8 (t) MS: m/z = 332 (M+H) Synthesis Example 31: Synthesis of 2,2,2—Trichloro—N—[1—((6—chloropyridin—3—yl)methyl)pyr (1H)—y1idene]acetamide und 5) In 4 ml of anhydrous dichloromethane, 70 mg (0.27 mmol) of l—[(6—chloropyridin—3-yl)methyl] pyridine—2(1H)—iminehydrochlorideobtainedbythenwthod of Synthesis Example1i3was suspended. To this suspension, 94 ul (0.68 mmol, 68 mg) of triethylamine and 33 pg (0.27 mmol,49rmﬂ oftrichloroacetylchloridewereaddedeIthis order,followedknlstirringém;roomtemperaturefor].hour.

After completion of the on, the reaction was quenched. by adding water, and phase separation was conducted by using dichloromethane and water. The organic layer was washed once with water, and twice with 1% hydrochloric acid, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

Diethyl ether was added to the residue. As a result, a solid was precipitated. The solid was collected by filtration, and dried. Thus, the target substance was obtained. Yield: 61 mg (Percentage Yield: 62%). lH-NMR (CDCl3, 5, ppm): 5.59 (2H, s), 6.86 (1H, t), 7.32 (1H, d), 7.78 (1H, td), 7.91 (2H, m), 8.43 (1H, d), 8.50 (1H, d) MS: m/z = 364 (M+H) IBPF12'519 Synthesis Example 32: Synthesis of N—[1—((2-Chloropyrimidin—5—yl)methyl)pyridin-2(1H)-yli dene]~2,2,2—trifluoroacetamide (Compound 6) In 30 ml of carbon tetrachloride, 1.04 g (8.13 mmol) of 2-chloro—5-methylpyrimidine was dissolved. To this on, 1.73 g (9.75 mmol) of N—bromosuccinimide and 20 mg of l peroxide were added, followed by heating underrefluxforfihours. Aftercompletionofthereaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexanezethyl acetate=3:1). Thus, 641 mg of -bromomethy1chloropyrimidine was obtained (Percentage Yield: 38%). lH—NMR (CDC13, 5, ppm): 4.42 (2H, s), 8.66 (2H, s) In 6nﬂ_of anhydrous itrile, 104 mg (0.50 mmol) of 5—bromomethyl—2—chloropyrimidine obtained by the above—described method was dissolved. To this on, 96 mg (0.50 mmol) of 2,2,2—trifluoro—N—(pyridin-2(lH)-ylidene)acetamide obtained by the above—described method and 76 mg (0.55 mmol) of potassium carbonate were added, followed by heating under reflux for 1 hour. After completion of the reaction, the on liquid. was returned to room temperature. The insoluble matters were removed by filtration, and the filtrate was concentrated under IBPF12-519 reducedpressure. Diethyletherwasaddedtotheresidue.

As a result, a solid was precipitated. The solid was collected by tion, washed with diethyl ether, and then dried in a desiccator under d pressure. Thus, the target substance was obtained. Yield: 92 mg (Percentage Yield: 58%). 1H-NMR (CDCl3, 5, ppm): 5.54 (2H, s), 6.98 (1H, m), 7.87 (1H, m), 8.18 (1H, m), 8.48 (1H, m), 8.83 (2H, m) 13C—NMR (CDC13, 6, ppm): 60.0, 115.6, 117.1 (q), 122.1, 127.5, 139.2, 142.9, 158.8, 160.3 (2C), 161.4, 163.8 (g) MS: m/z = 317 (M+H) Synthesis Example 33: Synthesis of N—[1—((6—Chloropyridin—3—y1)methyl)pyridin—2(1H)—y1ide ne]—2,2,3,3,3-pentafluoropropanamide (Compound 7) In 15 ml of anhydrous dichloromethane, 300 mg (3.19 mmol) of 2—aminopyridine was dissolved. To this solution, 919 mg (4.78 mmol) of EDC—HCl, 583 mg (4.78 mmol) of DMAP, and397}ﬂ_(628mg,3.83mmol)ofpentafluoropropionicacid were added in this order, followed by stirring at room temperature overnight. After completiorlof the reaction, the reaction liquid was diluted with dichloromethane, oncewithwater,andtwicewith1%}umupchloricacid, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thus, 85 mg of 2,2,3,3,3—pentafluoro—N—(pyridin—Z(1H)—ylidene)propana mide was obtained (Percentage Yield: 11%).

IBPFl2-519 To 77 mg (0.32 mmol) of 2,2,3,3,3—pentafluoro—N—(pyridin—2(1H)-ylidene)propana mide obtained by the above—described , 52 mg (0.32 mmol) of 2-chloro—5—chloromethylpyridine dissolved in 8 ml of anhydrous acetonitrile and 49 mg (0.35 mmol) of potassium carbonate were added, followeciby g under reflux for 11 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and the insoluble s were filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanezethyl acetate=1:3). Thus, the target substance was obtained. Yield: 12 mg (Percentage Yield: 10%). lH—NMR (CDCl3, 5, ppm): 5.56 (2H, s), 6.90 (1H, td), 7.32 (1H, d), 7.79 (2H, m), 7.84 (1H, d), 8.43 (1H, d), 8.56 (1H, d) MS: m/z = 366 (M+H) Synthesis e 34: Synthesis of N—[l-((6—Chloropyridin—3—y1)methyl)pyridin-Z(1H)~y1ide ne]—2,2—difluoroacetamide (Compound 8) In 10 ml of anhydrous dichloromethane, 400 mg (4.26 mmol) of 2—aminopyridine was dissolved. To this solution, 322 pl (490 mg, 5.11 mmol) of difluoroacetic acid, 982 mg (5.10 mmol) of EDC-HCl, and 622 mg (5.11 mmol) of DMAP were added, followed by ng at room temperature for 61 hours. After completion of the reaction, the reaction IBPF12'519 liquid was diluted with dichloromethane, and washed once with water, and twice with 1% HCl aq., then dried over anhydrous magnesium sulfate, and trated under reduced pressure. Thus, 102 mg of 2,2—difluoro—N—(pyridin—Z(1H)—ylidene)acetamide was obtained (Percentage Yield: 14%). 1H—NMR (CDCl3, 6, ppm): 6.03 (1H, t), 7.15 (1H, m), 7.78 (1H, td), 8.20 (1H, d), 8.34 (1H, dd), 8.72 (1H, br s) In 10 ml of anhydrous acetonitrile, 100 mg (0.58 mmol) of 2,2—difluoro—N—(pyridin—Z(lH)—ylidene)acetamide obtained by the above—described method was dissolved. To this on, 94 mg (0.58 mmol) of 2-chloro—5—chloromethylpyridine dissolved in 5 Inl of anhydrous acetonitrile was added, and uently 84 mg (0.63 mmol) of potassium carbonate was added thereto, ed by heating under reflux for 140 minutes. After completion of the reaction, the reaction liquid was returned to room temperature, and the insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue. As a result, a solid was precipitated. The solid was collected by filtration, and dried well. Thus, the target substance was obtained. Yield: 63 mg (Percentage Yield: 37%). lH—NMR moon, 5, ppm): 5.52 (2H, s), 5.90 (1H, t), 6.79 IBPF12-519 (1H, td), 7.33 (1H, d), 7.71 (1H, m), 7.77 (1H, dd), 7.85 (1H, dd), 8.45 (1H, d), 8.50 (1H, d) R (DMSO—d6, 5, ppm): 53.0, 111.0 (t), 115.2, 120.7, 124.7, 131.7, 140.6, 141.6, 143.2, 150.4, 150.9, 158.3, 169.4 (t) MS: m/z = 298 (M+H) Test Example 1 Test for l of Diamondback Moth (Plutella xylostella) A leaf disk having a diameter of 5.0 cm was cut out fromcabbagegrownineapot. Then,aliquidagentprepared to be 50% acetone-water (to which 0.05% Tween20 was added) and to n 500 ppm of a compound represented by formula (I) was spread over the leaf disk. After the leaf disk was air dried, second instar larvae were released on the leaf disk. After that, the leaf disk.was allowed to stand in a thermostatic chamber at 25°C (16—hour light period and 8—hour dark ). Three days after the release, the insects were observed for their mortality, and the mortality rate was calculated in accordance with the following formula. The test was duplicated.

Mortality rate (%) = [Number of dead insects/(Number of survived insects + Number of dead insects)] X 100 Test Example 2 Test for Control of Cotton Aphid (Aphis gossypii) A leaf disk having a diameter of 2.0 cm was cut out IBPF12-519 from cucumber (Cucumis sativus L.) grown in a pot. Then, a liquid agent prepared to be 50% acetone—water (to which 0.05%\ Tween20 was added) and to contain 500 ppm of a compound represented by a (I) was spread over the leaf disk. After the leaf as ied, first instar larvae were released on the leaf disk. After that, the leaf disk was allowed to stand in a thermostatic chamber at 25°C (16-hour light period and 8-hour dark ).

Three days after the release, the insects were observed for theirlnortality, and thelnortality ratezwas calculated in ance with the following formula. The test was duplicated.

Mortality rate (%) = r of dead insects/(Number of survived insects + Number of dead insects)] X 100 Test Example 3 Test for Control of Laodelphax striatellus Roots of wheat seedlings 48 hours after seeding were each treated with 200 uL of a liquid agent prepared to be %\ acetone—water, and to contain 100 ppm of a compound represented by formula (I). The agent was absorbed through the roots for 72 hours, and then 10 second instar larvae of Laodelphax striatellus were released on each wheat seedling. After that, the wheat seedlings were allowedtuostandjxlathermostaticchamberat 25°C(l6—hour light period.and 8—hour dark period). Four days after the release, the insects were observed for their mortality, -519 and the mortality rate was calculated in accordance with the following formula. The test was duplicated. ity rate (%) = [Number of dead insects/(Number of survived insects + Number of dead insects)] x 100 Table 2 shows the results of Test Examples 1 to 3, i.e., specific bioactivities (mortality rates (%)) of pest control agents represented by formula (I).

IBPF12'519 {Table 2] nmﬂﬂmwﬁOmn mﬁﬂnwumw Hﬂwuﬂmm MwonOHhk IIHIIEHE: H H ‘79"? m U) m‘bm Inn—I— unnum- l-mnI_ unsun- Inn-.— Inn-I. -nu-.MI Inna- Inn-I—aI.

H%wﬂuhnumponoasulm ahaonmaﬂnlmlouoanulu 4%vﬁuhAIMIouo«£UIw d%vauhAIMIou0H£UIw “haonaﬂnpumrouoaxunm ahaouwﬁ#DIMrou0d£0IN avﬂwwnlmnonoasulm a%vﬂ»%almlonoasulm HwﬁmSRIONOHSUI¢ auvﬂuha-m a%uauhanmuonoa£u-m H%Uﬂuhﬁlm10uoHSU|m Ah.au%ﬁlwaouo«£U| wkﬁaukgumnonoa£UIo nnmnouoa£0rm a%vﬁu>nnmpo»oaauum savﬂauuh.nmlonoa£u:m QIMIOMOHSU1w wugwnﬂwﬂﬁ IBPF12'519 <Effect against insecticide resistant pests> Reference Example Test for Control of Nilaparvata lugens Rice plant seedlings grown in a pot were treated by soil drench with a liquid agent ed to be 10% acetone-water, and to contain a predetermined concentration of a nd of the t invention.

Three days after the treatment, 10 sensitive or resistant strain of second instar larvae of Nilaparvata lugens were released on each of the rice plant seedlings. After that, the rice plant seedlings were allowed to stand in a thermostatic chamber at 25°C (16-hour light period and 8-hour dark ). Three days after the release, the insects were observed for their mortality, and the mortality rate was calculated in accordance with the following formula. The test was duplicated.

Mortality rate (%) = [Number of dead insects/(Number of survived insects + Number of dead insects)] x 100 Note that the pests tested were as follows: Insects bred for generations in a room for a long period (sensitive strain), (I) s collected in Kumamoto ture in 2007, and bred for generations in a room —collected strain: resistant strain), or (II) Insects collected in Fukuoka Prefecture in 2005, and bred for generations in a room (field~collected strain).

As a result, treatments with Compound 1 at 0.05 IBPF12'519 mg/seedling achieved mortality rates of 100% for all the strains, and treatments with Compound 1 at 0.005 mg/seedling achieved mortality rates of 90% or higher for all the strains. In addition, treatments with Compound 2 at 0.01 mg/seedling achieved mortality rates of 72% for the sensitive strain and 70% for the strain (II).

Treatments with Compound 19 at 0.01 dling achieved mortality rates of 100% for the sensitive strain and 93% for the strain (II). On the other hand, treatments with imidacloprid at 0.051ng/seedling achievedlnortality rates of 100% for the sensitive strain, 40% for the strain (I), and 60% for the strain (II).

These results indicate that Compound 1 has a high icidal activity against Nilaparvata lugens resistant to imidacloprid.

Reference Example Test for Control of Laodelphax striatellus Rice plant seedlings grown in a pot were treated by soil drench with a liquid agent prepared to be 10% acetone—water, and to n a predetermined concentration of a compound of the present invention.

Three days after the treatment, 10 sensitive or resistant strain of second instar larvae of Laodelphax ellus were ed on each of the rice plant ngs. After that the rice plant seedlings were allowed to stand in a thermostatic chamber at 25°C (16-hour light period and IBPFlZﬁlQ 8—hour dark period). Three days after the release, the insects were ed for their mortality, and the mortality rate was calculated in accordance with the following formula. The test was duplicated.

Mortality rate (%) = [Number of dead insects/(Number of survived insects + Number of dead insects)] x 100 Note that the pests tested were insects bred for generationsi11aroomforealongperiod(sensitivestrain), and insects collected in Kumamoto Prefecture in 2006, and bred for generations in a room (field—collected strain: resistant strain).

As a result, treatments with Compound 1 at 0.01 mg/seedling achieved mortality rates of 100% for all the strains, ents with Compound.1 at 0.005 mg/seedling achieved mortality rates of 90% or higher for all the s. Meanwhile, treatments with Compound 3 at 0.01 mg/seedling achieved mortality rates of 100% for the sensitive strain and 90% for the field-collected strain.

On the other hand, ents with imidacloprid at 0.01 mg/seedling achieved ity rates of 100% for the sensitive strain and 50% for the field—collected strain.

In addition, treatments with il at 0.01 mg/seedling achieved mortality rates of 100% for the sensitive strain and 70% for the field—collected strain.

These results indicate that Compounds 1 and 3 have high inseciticidal activities against Laodelphax IBPF12'519 striatellus resistant to imidacloprid and fipronil.

Reference Example In Vitro Metabolism Test of Compound]_and Imidacloprid Using Crude Enzyme Extraction higuid of Housefly (Musca ica) As described in Pest Management Science (2003), 59(3), 347-352, and Journal of Pesticide Science (2004), 29(2), 110—116, imidacloprid is known to be inactivated by oxidative metabolism, which is thought to be one of the mechanisms for the acquisition of the resistance. To investigate effects on insects acquiring such ance, the following experiment was carried out.

To adult housefly (Musca domestica) (0.645 g), 10 ml of a potassium ate buffer (pH 7.4, containing 1 mM EDTA) was added, and the adult housefly was sufficiently ground with Physcotron (Nichion Irika Kikai Seisakusho).

After that, the ground material was fuged under conditions of 10,000 g and 15 minutes. The ed supernatant was r centrifuged under ions of 100,000 g and 60 minutes. Thus, precipitates were obtained. The precipitates were dissolved in 1 ml of a potassium phosphate buffer, and this solution was used as a crude enzyme solution. The enzyme extraction operations were all conducted on ice or under a condition of 4°C.

Reagents were mixed with each other at the following ratio in a tube having a capacity of 1.5 mL, and allowed IBPF12'519 to react with each other at 25°C for 40 hours. After the reaction, 1 mL of acetone was added to the mixture, followed by ng. Then, the formed precipitates were removed.by centrifugation at 12000 rpm for 51ninutes. The acetone in the supernatant was distilled off, and the residue was injected into a LC/MS for analysis.

The described crude enzyme extraction liquid: 300 Solution of Compound 1 in DMSO: 5 uL Glucose 6-phosphate solution: 5 uL NADP+ solution: 5 uL Glucose 6—phosphate dehydrogenase solution: 5 uL Potassiun1phosphate buffer (pH 7.4, containing1.mM EDTA): 180 uL <Ana1ysis Conditions> Column: CAPCELL PAK C18 MG Mobile phase ition: 0 to 3 minutes: 85% water, 5 o\0 acetonitrile, 10% aqueous formic acid solution (0.1 v/v%) 3 to 30 minutes: 85q25% water, 5a65% acetonitrile, 10% aqueous formic acid solution (0.1 v/v%) .1 to 36 s: 90% acetonitrile, 10% aqueous formic acid solution (0.1 v/v%) Column temperature: 40°C, Flow rate: 0.35 ute, Injection amount: 100 uL UV wavelength: 325 nm for Compound. 1, 300 nm for IBPF12'519 imidacloprid.

Asearesult, thetotal.areapercentage«ofmetabolites was 0.08 for Compound 1. In contrast, the total area percentage oflnetabolites was 2.55 for imidacloprid. The amount.of metabolites of Compound]_was smaller than that of imidacloprid. These results indicate that Compound 1 usedeffectivelyforpestcontrolofresistantpests which inactivate imidacloprid by metabolism. <Controlling Effect on Animal-Parasitic Pests> Reference Example Test for Control of Haemaphysalis longicornis Into a glass Vial having a capacity of 4 mL, 30 uL of an acetone solution containing 200 ppm or 10 ppm of a nd of the t invention was introduced. The vial was placed on a shaker, and air dried, while being d. Thus, a dry film of the compound was formed on the inner wall of the Vial. After the vial was dried for 24 hourscnrlonger,10 larvaeof'Haemaphysalislongicornis were released in the vial, and then the vial was .

The vial was allowed to stand in a thermostatic chamber under conditions of 25°C, a humidity of 85%, and total darkness. One day after the release, the larvae were observed for their mortality, and the mortality rate was calculated in accordance with the following formula. The test was duplicated.

Mortality rate (%) = [Number of dead insects/(Number of IBPF12'519 ed insects + Number of dead insects)] x 100 As a result, Compound 1 and Compound 9 in treatment amounts of 200 ppm showed tickcidal effects withlnortality rates of 80% or higher.

Compound 1 and Compound 9 in treatment amounts of ppm showed acaricidal s with mortality rates of 80%\ or higher.

Diasimilartest,imidaclopridjjxatreatmentamount of 10 ppm ed a mortality rate of 4%.

Reference Example Effect of Controlling Haemaphysalis longicornis on Body Surface of Mouse Hair on the back of a mouse (ICR, male, 5-weeks old) in a region having a diameter of approximately 2 cm was shaved, and a 15—mL polystyrene l tube cut to have a height of approximately 1.5 cm was bonded to this region with an instant adhesive.

Then, 20 uL of a lOOO—fold diluted liquid of a pest l agent prepared according to the following formulation was added dropwise onto the body surface of theInousexNithin,the bonded tube. After sufficient drying, or more larvae of Haemaphysalis longicornis were released into the tube, and the tube was capped. Three days after the release, the larvae of Haemaphysalis longicornis were observed for their mortality, and the blood-sucking inhibition rate was calculated in accordance with the following formula.

Formulation [Drop Preparation] Compound 1? 48% by weight Ethanol? 52% by weight The components were uniformly mixed with each other, and a drop preparation was obtained. blood-sucking inhibition rate (%) = 100 - [Number of allodermanyssus /(Number of survived ticks + Number of dead ticks)] x 100 As a result, Compound 1 showed an effect of lling Haemaphysalis longicornis with a blood-sucking tion rate of 91%.

[Industrial Applicability] As described above, according to the present invention, it is possible to e 2-acyliminopyridine derivative represented by formula (I), which is useful as a pest control agent, in a good yield and, if necessary, effectively in a onepot manner, and in turn to provide the 2-acyliminopyridine derivative in an amount ed as a tick control agent stably and at a low cost. Accordingly, the present invention greatly contributes to the field of pest control.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior ation (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification s.

Throughout this specification and the claims which , unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. liArbrUnterwoven\NRPortbRDCMBR\8017283_1.docx-6/07/2015 THE

Claims

CLAIMS DEFINING THE INVENTION ARE AS S:

1.? A method for producing a compound represented by the following formula (I): [Chem. 1] 5 (I) [where Ar represents a phenyl group which may be substituted with halogen atoms, C1_9 alkyl groups which may be substituted with a halogen atom, C1-4 alkyloxy groups which may be substituted with 10 a halogen atom, a hydroxyl group, a cyano group, or a nitro group; or a 5-to 6-membered heterocycle which may be tuted, with halogen atoms, C1-4 alkyl groups which may be substituted with a halogen atom, C1_.4 alkyloxy groups which may be tuted with a halogen atom, a hydroxyl group, a cyano 15 group, or a nitro group, R1 represents a C1-6 alkyl group which may be substituted with halogen atoms, 01-6 halogenated alkyloxy groups, a cyano group, a nitro group, or a hydroxyl group, and Y represents a hydrogen atom; a halogen atom; a hydroxyl 20 group; a 01-6 alkyl group which may be substituted with a n atom; a C1-6 alkyloxy group which may be substituted with a halogen atom; a cyano group; a formyl group; or a nitro group], HArbrUnterwoven \NRPortbl \DCC\RBR\8017283_1.docs-