AU2014201038B2 - Nitrogen-containing heterocyclic compound and method for producing same - Google Patents

Abstract

There are provided a nitrogen-containing heterocyclic compound such as a substituted amino-pyridine-N-oxide compound represented by formula (1), which is 5 useful as a synthetic intermediate for an agrochemical and the like; and a method for producing the nitrogen-containing heterocyclic compound. (In formula (1), R1 and R2 each represents a hydrogen atom or an unsubstituted or substituted alkyl group; R3 represents a hydrogen atom, an unsubstituted or substituted alkylcarbonyl group or the like; R! represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted 10 or substituted arylcarbonyl group or the like; A represents a hydroxyl group, a thiol group or the like; m represents any one of integers of 1 to 4; k represents any one of integers of 0 to 3; and k + m : 4.) Ak (NR3Rh4) m / (1)

Description

1 AUSTRALIA Patents Act 1990 NIPPON SODA CO., LTD. COMPLETE SPECIFICATION STANDARD PATENT Title: Nitrogen-containing heterocyclic compound and method for producing same The following statement is a full description of this invention including the best method of performing it known to us:- 1 A [DESCRIPTION] [TITLE OF INVENTION] NITROGEN-CONTAINING HETEROCYCLIC COMPOUND AND METHOD FOR 5 PRODUCING SAME [Technical Field] [0001] The present invention relates to a nitrogen-containing heterocyclic compound 10 and a method for producing the same. More specifically, the present invention relates to: (1) a substituted amino-pyridine-N-oxide derivative which is useful as a synthetic intermediate of agricultural chemicals or the like; (2) a method for producing a substituted amino-6-methylpyridine-N-oxide derivative; and (3) a method for producing a haloalkyl, nitrogen-containing heterocyclic derivative. 15 Priority is claimed on Japanese Patent Application No. 2010-087915, filed April 6, 2010, Japanese Patent Application No. 2010-087916, filed April 6, 2010, and Japanese Patent Application No. 2010-107195, filed May 7, 2010, the contents of which are incorporated herein by reference. 20 [Background Art] [0002] A 2-substituted amino-6-methylpyridine-N-oxide derivative is useful as an intermediate for the synthesis of chemical substances for pharmaceuticals and agrochemicals such as the tetrazolyloxime derivative disclosed in Patent Document 1 25 since the halogenation or the like of a methyl group at position 6 is easy.

2 In general, pyridine-N-oxide derivatives can be obtained by the oxidation of pyridine derivatives. For example, in Patent Document 2, a method for producing 2 chloro-pyridine-N-oxide by the oxidation of 2-chloro-pyridine using hydrogen peroxide in the presence of a catalyst represented by Y[PW 2 0 13 (OH)] (in which Y represents a 5 hydrogen atom, alkyl or ammonium) has been disclosed. [0003] In addition, with respect to the reaction of pyridine-N-oxide derivatives, as a method for introducing a halogen into the methyl group of 2-picoline derivatives, for example, it has been reported in Non-Patent Document 1 that 6-chloro-2-chloromethyl 10 pyridine can be produced by rearranging 6-chloro-2-methylpyridine-N-oxide with acetic anhydride to introduce oxygen to the methyl group, followed by the action of thionyl chloride thereon. In Non-Patent Document 2, a halogenation method by reacting triphosgene or diphosgene with 2-picoline-N-oxide in the presence of di-i-propylamine or triethylamine 15 has been reported. In addition, in Patent Document 3, a method to synthesize 2-chloro-5 methylpyridine from 3-methylpyridine-1-oxide has been shown. According to Patent Document 3, it has been reported that a desired product can be obtained by the method through a rearrangement reaction using trimethylamine and phosgene to convert the 2nd 20 position of the pyridine ring to trimethylammonium, followed by chlorination thereof. [Citation List] [Patent Document] [0004] 25 Patent Document 1: W02008/006873 Patnt ocuent2: KR-A- 10403->0025453 Patet Doumet 3:Jap nUexamined PatentApplication, First P1ublicatin No He 7-252226 Patnt )ocmen.4 Jpans Unexamined Paen App! ication, H] rt Publication IvNo Sho 62-142 136 [NnPtn Doun n u] [00051 Non-PtentDocumnt.1 Bane , H et Ab. Ttaern38 (22)77320 N a D n Na,r Rnd et A. Syntetc Conuniatins 34 10917.1103. 2004. ROW 5 A] . Throughout this spcifai thes a "copries"or "comprisig", wil be uderstood to, imly tit inclIusion, of"" a stted elment, integer or step or group of eemnts, integers or stpbut 'not the- exluio o any other elment, itger or step, or group of elements. intet r 1 steps. 20P [0005m..3 Any d.isuio of doICumnts acs maeilrdvcs particles or the l ike wih has been included in the preet pciiato is not to he, taken asanamisintht n or A of teemtrsform part of the prior rt base or. were como general knwledge in the iedreevn to the prsent disclsue as it exse eOretepirtydtwfec S claim of appli 3 A [Summnary of invnton] In one aspct the inveadon provides a method 'for producing a compound 5 presented by formua AS thew metodcopr mireci~acmoudersntdb onnula (7) wjth a haognate agea in a pesenc of a halogen ion soce t is soluble in an organic solvnt pN N tN R 0ach of R 1 and 1R2 independendy represents a hydrogen atn o an unsubshuted or sbstiutedalikyl grCoup.1 and- P and I may form a rMe tonffir: u an sutu o sub ed ar on group a sutued ao absti heteay gup, an usubstuted or substt u akoxycarbonyl group, an 15 usubtittedor substued alklsulfonyl grou, or an unisubsittd or subtiutd suSlfonyla group; 1C eprese n I1." sb ist t i susdu ed alkv Xycrbony group n ubstiuted or substtuted a y group unsubs utd substituted h eteroarycarbonyl group, an. unsubstud or subastitteda group, an 20 nasIed or suti groupanu aryiu Ifoyl group, arid R' and R<6 my be bonded to form a ring Arprsetsa. hydroxyl group, athiolgroup, ani-no group, anitro g ,roup, a hlgnatomn or! an organic g roup; I repreents any one of integers of f) o 3; where The halogen ion source that is soluble in an organic solvent is a halogenated anmnnium salt or a halogenated phosphonium salt. henavtors of the present invention have a preferred aini of providing method producing a substituted a ino-p d eNoxd dea veepresened byhe formnula Vin.priuaasbttt~ mn--lk pr in--xd derivnave, hc 1 ishighly111 secie.es o separae the catallyst and also useful as an h ~m Or the synheisofagrcutualchemicais and the Ile. In addition, another rferrd Am is to provide highly seeciv and Also high-,' yield met .hod thy producing a haloAkyl, n 1 hTerocyclic dervatve represent by the formua (5) wch useful as aiee ts } [Solution to Probienfj As a result of intense and extensive studies n order to achieve the above preferred aims, the inventors of e prest invention found that, among the .rnsto hosphori acaid salt presented byQ[PW theatre knows a catal for th epoxidaion reacion in Patent Document or the like, by using those hin wich Q represents a quaterna nitrogen cion as a catalyst, a subsituted amno4 mehylpyridine-oxide dedivai e can be obtaned with high selectivity through an oxidaton reaction of a substiuted amino6methylpyridine derivative with a peroxde, 10 and tdt he catalyst can be eaiy seprated aftr the conedon of hed reaction. addition the inventor of the present invention have und that a compound represented b fla (5) can be produced in highild and also with high sele ctivty by racng a compound represented by formula (4) with a haogenaigggent a uch as Il cltloride, bromide or sufu hloride j F rdher, e inventors of the 15 present Inention have also discoverd at a c pound re snted bforla 5 c be produced in high yield and ao Ith high select ity by reacting a compound represented by tbriula ( with genatinggentsuch as phosgene, Aphosgene tiphosgene or phosphorus oxychloride in the presence of sou cofhogen ons wh is slbein an ogncsolve:nt. 2 0 The present invention has been compiled by father studies based onhe fndinas. [0008] Disosed heeinis [1] A substituted amino pyridineJN-oxide compound represented by formula (I 25 fChendica~l Formula i] 5 (NRR)m R1) N 0~ R2 (in the formula (1), each of R' and R2 independently represents a hydrogen atom, or an unsubstituted or substituted alkyl group, and R 1 and R2 may form a ring together, R3 represents a hydrogen atom, an unsubstituted or substituted alkylcarbonyl 5 group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted alkoxycarbonyl group, R4 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an 10 unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, A represents a hydroxyl group, a thiol group, an amino group, a nitro group, a halogen atom or an organic group, m represents any one of integers of 1 to 4, and 15 k represents any one of integers of 0 to 3, wherein k + m < 4), with the proviso that 2-ethoxycarbonylamino-6-methylpyridine-N-oxide is excluded. [2] A method for producing a substituted amino-6-methylpyridine-N-oxide derivative 20 represented by formula (1-a) including oxidizing a substituted amino-6-methylpyridine derivative represented by formula (2) using a peroxide in the presence of a tungstophosphoric acid salt represented by formula (3): C~ Cl Formula2. Ak Ak (NRR)m 2) (NRaR (i--) 0 represens a hdoxy group a dil group an amin group, a nitro p gaoe atom or an organic group It represents any one of integers of 0 to 3, ? repreents a hydrogen atm, an unsubstAi d or substuted alky larbonv group an unsu tutedr substited aryiarbony grup an d ed or IC substtutd aloxycarbonv grup R- represents an unsubstitutd or subsmiuted akycarbonyl goup, an unsustitted r substitud aryle--arbonyl grua unsubs6titted or sbsitte heeroarylearbonyl group, an unsubstinned or substitutd alkoxycarbov group, anl unsubsitued or substited alkylsu ionyl group. or an unsubstied or subsuted I 5 aryl su fonv group $n epresents any Oo of integers of I to Z wherin k ± m 4 and c ppresents a u r nt d aon 2 0 [31 The m for poucing a subsitutd aWmiro nehvp inedaoxi ddiaiv accordig to the above pointi' -2j1, whren in formula. Q a) in ounria a104w hydrogen atom.

[4] The method for producing a substuted amino-6-moethypyridine-N-Oxide derivative according to the above point [2j mwheren the quaternary nitogen caon represented Q n formM (3s a quateiNary ammnin [5]he me hod for producing a substuted auino-6-nety iyri dine-oxide deative cordi o the above point wherein he tungstophosphori aci sa resented by formula (is obtained without an isolation operation after prepation. [6] A method for producing a compound represented by formula (5) inc uding reacting a compound represented by formula (4) with a halogenating agent: [Chemical Formula 3] SArl

A

1 AR an og ao 2 aor a sut unsubstituted or substiuted alkyl goup, and Rl a"nd R 2 mayfrmarngtgehr 1 5 A represents a hydroxyl group) a. tho group an' mino grout'. a. nItro gr'I oup a. S rpresets any on f nteger of L o 4, and apurit of A h ma lebonde-d to fbrm a ring "to~n n is 2 or more and C [0010] [73 The method r poduing a n e tag c compg.,ourn o 8 the above point [6], wherein all ofa 1 to a 4 in formula (4) and formula ) represent carbon atoml ai [8]The method for producing a nitroeivontaining heteroy ai copound according the above point [6] wein a eas one ofA in formula (4 and fornla (5)presents a 5 grouprepresented by fomula (6g tCheNical Formula 4] N / (6) (in thfrmiula (6)t niae a bniesite.

R

5 epesnt ahdoen atom, anluisubsted or substituted alkycroy uan substituted or substituted ary arbonyi group, an unsubsted or substtuted heteroarycarbonyl group, an unsubsitued or substuted alkoxyabonyl gnr, an unsubsituted or substited alkylsufAnyl grup or an nsubstued or substitted arvisulffonyl group, repesetsan unsubstitutd orsusiteakiaroIgopn 15 nsustutedor substituted aryiarbonyl grerup, an unsubstitutd or substiued hetemarylcarbon-y! group, an unsubstitued or substited a xcrony group. an unubsi ued or usituted ikyu group, an unsubstutd subNituted ay groupad and Rna be bonded to form a ing.) [9] Th method. for producing a itgecotiigeerycecmpudaodn to the above poit 6] where the compound presented by fMul (4) i s a compound presented by formula (7) and the compound repreented by irnula ( is a compound represented by formula (8): 9 [Chemical Formula 5] RU - R1 N N

R

6 R (7) (in the formula (7), A, R' and R2 are the same as defined above, 1 represents any one of integers of 0 to 3, 5 R5 represents a hydrogen atom, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, 10 R6 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, and R5 and R6 may be bonded to form a ring): 15 [Chemical Formula 6] A1 R 1 R N N R o R2(8 ) (in the formula (8), A, 1, R', R2, X, R and R6 are the same as defined above.) [0011] [10] The method for producing a nitrogen-containing heterocyclic compound according 10( to the above piynt [8b. wherein R5 represnts an unsubstited or sabsriuecl aikahoni group an uubsuted or ube a on group, an ".1 The metod Or producing a nro onta ining ereree cornpound according 5 o the above point [6], wherein the haonatn gn is aiot lethconeselee fo thaneW goup c S SO tho d c tin rd and sul uyl chloridet to the above-. poit [61, wherein the rean carre ouN the reasenc of a Aloeo sucthtisoulein anorgni solvosent.lhp-c ,ndoylo'd 10 [1] The mehodfo proucng a cnitogn-cnann ofeoyli opudcodn ] to nduci eda compod 9r nto y formulapound ipnluinted p n a ontcompound represeeded forf 15 formula ( 10), an d a step o F reacting thWe compoun" d re presented hb fomulIa (10i) witha haoentig agent to convert ino te compound ersetdb fornmula(1) [Chemial Formula 7j AAk A NNN N< 0 R0 R (in tfr aeh f g a' and 1ien t re- presents atom, oran 2 1 w nusiued or susiue lv ruadR n 2 myformrng oete represents anm tnsubstitued or substtuted alkvlarbonyl group, a unsubstauted Or subtitued arycarbon group an unsubsttedosubsuted heteroarvicarhonvi group, an unsubstitutd or substitued alkoxearbonyi group, an unsututed or substituted akylsuifong group or an unsubsthuted or situtd asu yI group. 5 ~R'represents an unsubstiued or substituted aikyecabony group 'an heteroarlcarbonyl grOUP. an unTsubsWiute or substiutd alkoxycarbuoyI group, an unsubstitud Or substiued aly u oyIgroup, or an unsubsduutd or substiuted1 ary].ulfo yn roup 1 0 A represnts ahvdroxyl group. aI rdol grou.'" anlmmo gru,-a-I ogrup nhaloge ao an org g p X epresents a halgen atomn I epreses any one of integers o to 4, and k represents any one of itegernof0 to 1 5 "wrei k + m S4A) too1'] 15] The method for producing a ntrogencontainina hetero c compound aecodin to the abov pon [1]werin a step of synhesing the compoundrepresened b formua ( 11) is cared out in the presence of a aoenion source t is soubinan oganc sovent 161 methodbr pducing a compound represened by form 3) including recnig a compounded by ul (9) with a halogenating e presence of a compound rened oan 2 [Chmical Formula 8] 12 Ak (NHR)m N R N U Re (9) [Chemical Formula 9] Ak (NR m-( X 1 (1 3)

(NR

8 / mR N R 2

R

8 X' (12) 5 (in the formula, each of R' and R 2 independently represents a hydrogen atom, or an unsubstituted or substituted alkyl group, and R' and R2 may form a ring together, R6 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an 10 unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, R8 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted alkoxycarbonyl group, 15 A represents a hydroxyl group, a thiol group, an amino group, a nitro group, a halogen atom or an organic group, m represents any one of integers of 1 to 4, k represents any one of integers of 0 to 3, 13 Orei k +n d r X reprsnt halge atm R ani 5 n CX rprset a lreao oraa bromned ao). egru ni [001 3] 5 17} The thod fo producing a nitrgen-conaiing heocyclic compound acring to Te above into [1 whercin the reaction is u ed out in tpreenc h ion sucthtis slbein anogai slen. [i1Sl The" producIttioni meIcthod according to the above Ponts [1-2], 1 or [1, whren h haognion sorcitat is sohlble in an organiS,kcnslven is a haoeaedamnun al 10 or a halogenaed phosphonium SaltX [19J The production mehod accordng to the above poins [ 12]t 15] or [17], wherein the halogen iOn source that is solduble in anrorganic solvnt is a tertiary or quaternary alkvi ammniu halide sal having an alkl roup of C 2 or more, or an alkv I phosphona ha.ide sal haing an alky-Nl gr'ou!-p o.'f (2 or" mo re. 15 201 Th production meho ccorin to an'ly one of th.e abocve pont [4] to 1] whina the halogenatig ageit is at leas one selectd frm te -group conisin.o Mhoyl chloride, tSronyl bromide, phosphorus owe hIorde, sulftrl chlorde, phosgene.. dhoene and triphNosgened es fects [0014] According to tie Production methd of the present iwnton, usiue derivaive, nj haloa dkL Vnirge-onannghteo emdrivativeQ catn be baie 2z wt high selectivity and also in high viUd 'The nir1emotiightrcci 14 compound obtained by the production method of the present invention is useful as an intermediate for the industrial production of agricultural chemicals or the like. [Description of Embodiments] 5 [0015] [1] Substituted amino-pyridine-N-oxide derivative which is useful as synthetic intermediate of agricultural chemicals or the like A substituted amino-pyridine-N-oxide derivative which is useful as a synthetic intermediate of agricultural chemicals or the like according to the present invention is a 10 compound represented by the formula (1). In the formula (1), each of R 1 and R 2 independently represents a hydrogen atom, or an unsubstituted or substituted alkyl group. R' and R2 may be bonded to form a ring. It should be noted that in the present invention, the term "unsubstituted" means that the corresponding group is composed only of a core group. 15 On the other hand, in the present invention, the term "substituted" means that any one of hydrogen atoms constituting the core group has been substituted with a group having a different structure from that of the core group. Accordingly, the term "substituent" refers to another group which substitutes the core group. The number of substituents may be one or two or more. If two or more substituents are present, the 20 substituents may be the same or may be different from each other. Examples of the group which may serve as a "substituent" include a nitro group; a halogen atom such as a chlorine atom, a fluorine atom and a bromine atom; a hydroxy group; an alkoxy group such as a methoxy group, an ethoxy group, an i-propoxy group, an n-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group and a t 25 butoxy group; an aryloxy group such as a phenoxy group and a 1-naphthyloxy group; a 15 haloalkoxy group such as a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-chloroethoxy group, a 2,2,2-trichloroethoxy group, a 1,1,1,3,3,3-hexafluoro-2-propoxy group; an alkylthio group such as a methylthio group and an ethylthio group; an arylthio group such as a phenylthio group and a 1 5 naphthylthio group; an alkyl group such as a methyl group and an ethyl group; an aryl group such as a phenyl group and a naphthyl group; a heteroaryl group such as a pyrrolyl group, a thiazolyl group and a pyrimidinyl group; an alkylcarbonyl group; an arylcarbonyl group; a heteroarylcarbonyl group; an alkoxycarbonyl group; an alkylsulfonyl group; and an arylsulfonyl group. 10 [0016] Specific examples of the unsubstituted alkyl group for R1 and R2 include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an s-butyl group, a t-butyl group and an n-pentyl group, and C 1

.

6 alkyl groups are preferred. 15 Examples of the substituted alkyl group for R' and R2 include a cyanoalkyl group such as a cyanomethyl group, a 1 -cyanoethyl group and a 2-cyanoethyl group (cyano C 1

.

6 alkyl groups are preferred); a nitroalkyl group such as a nitromethyl group (nitro C 1

.-

6 alkyl groups are preferred); a haloalkyl group such as a chloromethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl 20 group and a 2,2,2-trifluoroethyl group (halo C 1

.

6 alkyl groups are preferred); an alkoxyalkyl group such as a methoxymethyl group, an ethoxymethyl group, a 1 methoxyethyl group and a 2-methoxyethyl group (CI6 alkoxy C 1

.

6 alkyl groups are preferred); an arylalkyl group such as a phenylmethyl group and a 1 -naphthylethyl group

(C

6

.

10 aryl C 1

.

6 alkyl groups are preferred); and a heteroarylalkyl group such as 2 25 pyridylmethyl group (5-6 membered heteroaryl C 1

.

6 alkyl groups are preferred).

16 Examples of the ring to be formed by the bonding of R1 and R2 include a cycloalkyl group such as a cyclopropyl group and a cyclobutyl group (C 3 -8 cycloalkyl groups are preferred); a cycloalkenyl group such as a cyclohexenyl group (C 3

.

8 cycloalkenyl groups are preferred); and a saturated heterocyclic group such as a 5 morpholino group (3 to 8-membered saturated heterocyclic groups are preferred). [0017] In the formula (1), R 3 represents a hydrogen atom, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted alkoxycarbonyl group. 10 Examples of the unsubstituted alkylcarbonyl group for R3 include an acyl group and an ethylcarbonyl group, and C1.

6 alkylcarbonyl groups are preferred. Examples of the substituted alkylcarbonyl group for R3 include a cyano alkylcarbonyl group such as a cyano methylcarbonyl group (cyano C1.

3 alkyl carbonyl groups are preferred); a nitro alkyl carbonyl group such as a 1-nitro ethyl carbonyl group 15 (nitro C 1

-

6 alkyl carbonyl groups are preferred); a haloalkylcarbonyl group such as a chloromethyl carbonyl group, a difluoromethyl carbonyl group and a 2,2,2-trifluoroethyl carbonyl group (halo C,- 6 alkyl carbonyl groups are preferred); an alkoxy alkyl carbonyl group such as a methoxy acyl group and a 2-methoxyethyl carbonyl group (C 1

.

6 alkoxy

C

1

-

6 alkyl carbonyl groups are preferred); an aryl alkyl carbonyl group such as a phenyl 20 methyl carbonyl group and a 1 -naphthyl ethyl carbonyl group (C 6

.

1 0 aryl C 1 6 alkyl carbonyl groups are preferred); and a heteroaryl alkyl carbonyl group such as a 2-pyridyl methyl carbonyl group (5-6 membered heteroaryl C 1

.

6 alkyl carbonyl groups are preferred). [0018] 25 Examples of the unsubstituted arylcarbonyl group for R3 include a benzoyl 17 group and a 2-naphthyl carbonyl group, and C 6 -Io arylcarbonyl groups are preferred. Examples of the substituted arylcarbonyl group for R3 include an arylcarbonyl group substituted with a nitro group, such as a 4-nitro phenyl carbonyl group (C6.

1 0 arylcarbonyl groups substituted with a nitro group are preferred); an arylcarbonyl group 5 substituted with a cyano group such as a 2-cyanophenyl carbonyl group (C6-,o arylcarbonyl groups substituted with a cyano group are preferred); an arylcarbonyl group substituted with an alkyl group such as a 2-methyl phenyl carbonyl group and a 3,5 dimethylphenyl carbonyl group (C 6 .o arylcarbonyl groups substituted with a C 1

.

6 alkyl group are preferred); and an arylcarbonyl group substituted with a halogen atom such as 10 a 4-chlorophenyl carbonyl group and a 3,5-difluorophenyl carbonyl group (C6.io arylcarbonyl groups substituted with a halogen atom are preferred). Examples of the unsubstituted alkoxycarbonyl group for R3 include a methoxycarbonyl group and an ethoxycarbonyl group, and C 1

.

6 alkoxycarbonyl groups are preferred. 15 Examples of the substituted alkoxycarbonyl group for R? include a cyano alkoxycarbonyl group such as a cyano methoxycarbonyl group (cyano C 1

.

6 alkoxycarbonyl groups are preferred); a nitro alkoxycarbonyl group such as a 1 -nitro ethoxycarbonyl group (nitro C 1

.

6 alkoxycarbonyl groups are preferred); a haloalkoxycarbonyl group such as a chloromethoxy carbonyl group, a difluoromethoxy 20 carbonyl group and a 2,2,2-trifluoroethoxy carbonyl group (halo C 1

.

6 alkoxycarbonyl groups are preferred); an alkoxy alkoxycarbonyl group such as a methoxy methoxy carbonyl group and a 2-methoxyethoxy carbonyl group (C 1

-

6 alkoxy C 1

-

6 alkoxy carbonyl groups are preferred); an aryl alkoxycarbonyl group such as a phenyl methoxy carbonyl group and a 1 -naphthyl ethoxy carbonyl group (C6-10 aryl C .

6 alkoxycarbonyl groups are 25 preferred); and a heteroaryl alkoxy group such as a 2-pyridyl methoxy carbonyl group (5- 18 6 membered heteroaryl C 1 6 alkoxycarbonyl groups are preferred). [0019] In the formula (1), R 4 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted 5 heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group. Specific examples of the unsubstituted or substituted alkylcarbonyl group, the unsubstituted or substituted arylcarbonyl group, and the unsubstituted or substituted 10 alkoxycarbonyl group for R4 include the same as those described above as specific examples for R3. The heteroaryl carbonyl group for R 4 is one in which a monocyclic heteroaryl ring or fused heteroaryl ring containing at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom is bonded to a carbonyl 15 group, and a 5- to 6-membered heteroaryl carbonyl group is preferred. Examples of the unsubstituted heteroaryl carbonyl group for R4 include a pyrrolyl carbonyl group, a furyl carbonyl group, a thienyl carbonyl group, an imidazolyl carbonyl group, a pyrazolyl carbonyl group, a thiazolyl carbonyl group, an isothiazolyl carbonyl group, an oxazolyl carbonyl group, an isooxazolyl carbonyl group, a triazolyl 20 carbonyl group, a tetrazolyl carbonyl group, an oxadiazolyl carbonyl group, a 1,2,3 thiadiazolyl carbonyl group, a 1,2,4-thiadiazolyl carbonyl group, a 1,3,4-thiadiazolyl carbonyl group, a pyridyl carbonyl group, a pyrazinyl carboxy group, a pyrimidinyl carbonyl group, a pyridazinyl carboxyl group, a 1,2,4-triazinyl carbonyl group, a 1,3,5 triazinyl carbonyl group, an indolyl carbonyl group, a benzofuranylcarbonyl group, a 25 benzothienylcarbonyl group, a benzimidazolylcarbonyl group, a benzopyrazolylcarbonyl 19 group, a benzooxazolylcarbonyl group, a benzoisooxazolylcarbonyl group, a benzothiazolylcarbonyl group, a benzoisothiazolylcarbonyl group, an indazolylcarbonyl group, a purinylcarbonyl group, a quinolylcarbonyl group, an isoquinolylcarbonyl group, a phthalazinylcarbonyl group, a naphthyridinylcarbonyl group, a quinoxalinylcarbonyl 5 group, a quinazolinylcarbonyl group, a cinnolinylcarbonyl group, a pteridinylcarbonyl group and a pyrido [3,2-b] pyridylcarbonyl group. [0020] Examples of the substituted heteroaryl carbonyl group for R include a heteroaryl carbonyl group substituted with a cyano group such as a 3-cyano-2 10 pyridylcarbonyl group; a heteroaryl carbonyl group substituted with a nitro group such as a 4-nitro-2-pyridylcarbonyl group; a heteroaryl carbonyl group substituted with a halogen atom such as a 5-fluoro-2-pyridylcarbonyl group; a heteroaryl carbonyl group substituted with an alkyl group such as a 6-methyl-2-pyridylcarbonyl group (C 1 . alkyl 5-6 membered heteroaryl carbonyl groups are preferred); a heteroaryl carbonyl group 15 substituted with an alkoxy group such as a 2-methoxy-3-pyridylcarbonyl group (CI- 6 alkoxy 5-6 membered heteroaryl carbonyl groups are preferred); a heteroaryl carbonyl group substituted with an aryl group such as a 4-phenyl-3-pyridylcarbonyl group (C 6

.

10 aryl 5-6 membered heteroaryl carbonyl groups are preferred); and a heteroaryl carbonyl group substituted with a heteroaryl group such as a 5-(2-pyridyl)-3-pyridylcarbonyl 20 group (5-6 membered heteroaryl 5-6 membered heteroaryl carbonyl groups are preferred). [0021] Examples of the unsubstituted alkylsulfonyl group for R4 include a methylsulfonyl group and an ethylsulfonyl group, and C 1

.

6 alkylsulfonyl groups are preferred. 25 Examples of the substituted alkylsulfonyl group for R' include a cyano 20 alkylsulfonyl group such as a cyano methylsulfonyl group (cyano C 1

.

6 alkylsulfonyl groups are preferred); a nitro alkylsulfonyl group such as a 1-nitro ethylsulfonyl group (nitro CI.

6 alkylsulfonyl groups are preferred); a haloalkylsulfonyl group such as a chloromethyl sulfonyl group, a difluoromethyl sulfonyl group and a 2,2,2-trifluoroethyl 5 sulfonyl group (halo C 1

.

6 alkylsulfonyl groups are preferred); an alkoxy alkylsulfonyl group such as a methoxy methylsulfonyl group and a 2-methoxy ethylsulfonyl group (C 1 . 6 alkoxy C 1

.

6 alkylsulfonyl groups are preferred); an aryl alkylsulfonyl group such as a phenyl methylsulfonyl group and a 1-naphthyl ethyl sulfonyl group (C6.

1 0 aryl C 1

.

6 alkylsulfonyl groups are preferred); and a heteroaryl alkylsulfonyl group such as a 2 10 pyridyl methylsulfonyl group (5-6 membered heteroaryl C 1

.

6 alkylsulfonyl groups are preferred). [0022] Examples of the unsubstituted arylsulfonyl group for R4 include a phenylsulfonyl group and a 2-naphthylsulfonyl group, and C 6

.

1 0 arylsulfonyl groups are 15 preferred. Examples of the substituted arylsulfonyl group for R 4 include an arylsulfonyl group substituted with a cyano group such as a 2-cyano phenylsulfonyl group (C 6

.

10 arylsulfonyl groups substituted with a cyano group are preferred); an arylsulfonyl group substituted with a nitro group such as a 4-nitrophenylsulfonyl group (C 6

-

1 0 arylsulfonyl 20 groups substituted with a nitro group are preferred); an arylsulfonyl group substituted with a halogen atom such as a 4-chlorophenylsulfonyl group and a 3,5 difluorophenylsulfonyl group (C 6

.

10 arylsulfonyl groups substituted with a halogen atom are preferred); an arylsulfonyl group substituted with an alkyl group such as a 2 methylphenylsulfonyl group and a 3,5-dimethyl phenylsulfonyl group (C 6

.

1 0 arylsulfonyl 25 groups substituted with a C 1

.

6 alkyl group are preferred); and an arylsulfonyl group 21 substituted with an alkoxy group such as a 4-methoxyphenylsulfonyl group (C 6 10 arylsulfonyl groups substituted with a C 1

.

6 alkoxy group are preferred). [0023] In the formula (1), A represents a hydroxyl group, a thiol group, an amino group, 5 a nitro group, a halogen atom or an organic group. Examples of the halogen atom for A include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The organic group for A is a general description that represents all groups containing a carbon atom within a substituent, and examples thereof include a cyano 10 group, an amino group having a substituent (amino groups substituted with a C 1

.

6 alkyl group or a C 6

-

10 aryl group are preferred); an unsubstituted or substituted alkyl group (Cj. 6 alkyl groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkoxy group or a C 6 . 10 aryl group are preferred), an unsubstituted or substituted alkenyl group (C 2

-

6 alkenyl groups substituted with a nitro group, a halogen atom, a C .

6 alkoxy group or a C 6

..

1 0 aryl 15 group are preferred), an unsubstituted or substituted alkynyl group (C 2

.

6 alkynyl groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkoxy group or a C 6

-

1 0 aryl group are preferred), an unsubstituted or substituted aryl group (C 6

.

10 aryl groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkyl group or a halo C 1

-

6 alkyl group are preferred), an unsubstituted or substituted heteroaryl group (5-6 membered heteroaryl 20 groups substituted with a nitro group, a halogen atom, a C 1

..

6 alkyl group or a halo C 1

.

6 alkyl group are preferred), an unsubstituted or substituted alkoxy group (C 1

.

6 alkoxy groups substituted with a nitro group, a halogen atom, a C1-6 alkoxy group or a C 6

-

10 aryl group are preferred), an unsubstituted or substituted alkenyloxy group (C 2

-

6 alkenyloxy groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkoxy group or a C 6

.

1 0 aryl 25 group are preferred), an unsubstituted or substituted alkynyloxy group (C 2

-

6 alkynyloxy 22 groups substituted with a nitro group, a halogen atom, a C 16 alkoxy group or a C 6

.

1 0 aryl group are preferred), an unsubstituted or substituted aryloxy group (C 6 .1 0 aryloxy groups substituted with a nitro group, a halogen atom, a C 1 6 alkyl group or a halo C 1

-

6 alkyl group are preferred), an unsubstituted or substituted heteroaryloxy group (5-6 membered 5 heteroaryloxy groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkyl group or a halo C 1

.

6 alkyl group are preferred), a formyl group, an unsubstituted or substituted alkylcarbonyl group (C 6 alkylcarbonyl groups substituted with a nitro group, a halogen atom, a C 1

-

6 alkoxy group or a C 6

.

1 0 aryl group are preferred), an unsubstituted or substituted alkenylcarbonyl group (C 2

.

6 alkenylcarbonyl groups substituted with a nitro 10 group, a halogen atom, a C 1

.

6 alkoxy group or a C 6 o 10 aryl group are preferred), an unsubstituted or substituted alkynylcarbonyl group (C 2

.

6 alkynylcarbonyl groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkoxy group or a C 6

.

10 aryl group are preferred), an unsubstituted or substituted arylcarbonyl group (C 6 .10 arylcarbonyl groups substituted with a nitro group, a halogen atom, a C 1 6 alkyl group or a halo C 1

.

6 15 alkyl group are preferred), an unsubstituted or substituted heteroarylcarbonyl group (5-6 membered heteroarylcarbonyl groups substituted with a nitro group, a halogen atom, a C1.

6 alkyl group or a halo CI- 6 alkyl group are preferred), an unsubstituted or substituted alkylthio group (C 1

.

6 alkylthio groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkoxy group or a C 6

.

1 0 aryl group are preferred), an unsubstituted or substituted 20 alkenylthio group (C 2

-

6 alkenylthio groups substituted with a nitro group, a halogen atom, a C 1

..

6 alkoxy group or a C 6

.

1 0 aryl group are preferred), an unsubstituted or substituted alkynylthio group (C 2

-

6 alkynylthio groups substituted with a nitro group, a halogen atom, a C .

6 alkoxy group or a C 6

.

1 0 aryl group are preferred), an unsubstituted or substituted arylthio group (C 6

.

10 arylthio groups substituted with a nitro group, a halogen atom, a C 1

.-

6 25 alkyl group or a halo C 1

.

6 alkyl group are preferred), an unsubstituted or substituted 23 heteroarylthio group (5-6 membered heteroarylthio groups substituted with a nitro group, a halogen atom, a C 1

-

6 alkyl group or a halo C 1

.-

6 alkyl group are preferred), an unsubstituted or substituted alkylsulfinyl group (Cl.

6 alkylsulfinyl groups substituted with a nitro group, a halogen atom, a CI.

6 alkoxy group or a C6.10 aryl group are 5 preferred), an unsubstituted or substituted alkenylsulfinyl group (C 2

.

6 alkenylsulfinyl groups substituted with a nitro group, a halogen atom, a C 1

-

6 alkoxy group or a C 6

-

10 aryl group are preferred), an unsubstituted or substituted alkynylsulfinyl group (C 2 -6 alkynylsulfinyl groups substituted with a nitro group, a halogen atom, a C 1

..

6 alkoxy group or a C 6

.

1 0 aryl group are preferred), an unsubstituted or substituted arylsulfinyl 10 group (C 6

..

1 0 arylsulfinyl groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkyl group or a halo C 1

-

6 alkyl group are preferred), an unsubstituted or substituted heteroarylsulfinyl group (5-6 membered heteroarylsulfinyl groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkyl group or a halo C,1.

6 alkyl group are preferred), an unsubstituted or substituted alkylsulfonyl group (C 1

.

6 alkylsulfonyl groups substituted 15 with a nitro group, a halogen atom, a C 1

.

6 alkoxy group or a C 6

.

1 0 aryl group are preferred), an unsubstituted or substituted alkenylsulfonyl group (C 2

.

6 alkenylsulfonyl groups substituted with a nitro group, a halogen atom, a C .

6 alkoxy group or a C 6

.

10 aryl group are preferred), an unsubstituted or substituted alkynylsulfonyl group (C 2

-

6 alkynylsulfonyl groups substituted with a nitro group, a halogen atom, a C 1

-

6 alkoxy 20 group or a C 6 .o 1 0 aryl group are preferred), an unsubstituted or substituted arylsulfonyl group (C 6

-

10 arylsulfonyl groups substituted with a nitro group, a halogen atom, a C.

6 alkyl group or a halo C1.

6 alkyl group are preferred), and an unsubstituted or substituted heteroarylsulfonyl group (5-6 membered heteroarylsulfonyl groups substituted with a nitro group, a halogen atom, a C 1

.

6 alkyl group or a halo C.

6 alkyl group are preferred). 25 [0024] 24 In the formula (1), m represents any one of integers of 1 to 4, and is preferably 1. In the formula (1), k represents any one of integers of 0 to 3. In addition, k + m:5 4, with the proviso that 2-ethoxycarbonylamino-6 methylpyridine-N-oxide is excluded in the formula (1). 5 [0025] [2] Method for producing substituted amino-6-methylpyridine-N-oxide derivative The production method of the present invention includes oxidation of a substituted amino-6-methylpyridine derivative represented by formula (2) using a peroxide in the presence of a tungstophosphoric acid salt represented by formula (3). 10 By the production method of the present invention, it is possible to obtain a substituted amino-6-methylpyridine-N-oxide derivative represented by formula (1-a). The substituted amino-6-methylpyridine derivative used in the production method of the present invention is a compound represented by formula (2). Specific examples of A, R3 and R 4 in formula (2) or formula (1-a) include the 15 same as those described above as specific examples in the aforementioned formula (1). m and k in formula (2) or formula (1-a) are the same as defined above as m and k in the aforementioned formula (1). Among these, R3 is preferably an unsubstituted or substituted alkoxycarbonyl group, more preferably an unsubstituted or substituted C 1

-

6 alkoxycarbonyl group, and 20 still more preferably a t-butoxy group. Among these, R is preferably a hydrogen atom, or an unsubstituted or substituted arylcarbonyl group, more preferably a hydrogen atom or a benzoyl group, and still more preferably a hydrogen atom. As a substitution position for NR 3

R

4 , the 2nd position of pyridine is preferred. 25 [0026] 25 The substituted amino-6-methylpyridine derivative represented by the formula (2) can be obtained, for example, by reacting an acid chloride or acid anhydride with commercially available 2-amino-6-methylpyridine in the presence of a base such as pyridine or triethylamine. More specifically, it is possible to obtain 2-[(t 5 butoxycarbonyl)amino]-6-methyl pyridine by using di-t-butyl dicarbonate in the reaction as the acid anhydride. [0027] The tungstophosphoric acid salt used in the production method of the present invention is a compound represented by formula (3). 10 [PW 4 0 24 ] in formula (3) is a peroxotungsten heteropolyanion. The anion may also be represented by the formula {PO4{W(O)(0 2

)

2

]

4 }. Q in the formula (3) represents a quaternary nitrogen cation. [0028] As a quaternary nitrogen cation, there are quaternary ammonium, iminium, 15 diazonium, cations of non-cyclic nitrogen skeletons, cations of nitrogen-containing cyclic skeletons, and the like. Examples of the quaternary ammonium include tetramethylammonium, tetraethylammonium, tetra-(n-butyl)ammonium, tetraphenylammonium, tetrabenzylammonium, N,NN-trimethylbenzylammonium, N,NN-tri(n 20 butyl)benzylammonium, hexadecyltrimethylammonium, dihexadecyl dimethylammonium, trioctadecylmethylammonium, dioctadecyldimethylammonium, trioctylmethylammonium, N,N,N-trimethylanilinium and N,N,NN',N',N' hexamethylethane-1,2-diaminium. Examples of the iminium include benzylidene-t-butylmethylammonium and 25 dibenzhydrylidene ammonium.

26 Examples of the diazonium include benzene diazonium, naphthalene-2 diazonium and benzene-1,4-bis(diazonium). [0029] Examples of the cations of non-cyclic nitrogen skeletons include 1,1-dimethyl 5 1-phenyldiazan-1-ium, hexamethyldiazan-1,2-dium, 2,2-dimethyltriazan-2-ium, 1,2 dimethyltriazan-1-ium, 1,1,1,3-tetramethyltriaza-2-en-1-ium and 1H-4X 5 -pyrido[1,2,3 de]quinoxalin-4-ylium. Examples of the cations of nitrogen-containing cyclic skeletons include 2,2 diethyl-2,5-diazabicyclo[4.2.2]decan-2-ium, 1,3-dimethylpyridin-1-ium, 3,7-dibromo-5 10 methylphenazin-5-ium, 1,3-dimethyl-1H-benzimidazol-3-ium, 1,1,4,4 tetramethylpiperazin- 1,4-dium and cetyl pyridinium. Among these, from the viewpoints of selectivity and reactivity, Q is preferably a quaternary ammonium, more preferably tetra-(n-butyl) ammonium or benzyltri(n butyl)ammonium, and particularly preferably tetra-(n-butyl) ammonium. 15 [0030] The tungstophosphoric acid salt represented by the formula (3) can be obtained by the method described in Patent Document 4 or the like. For example, by dissolving sodium tungstate (VI) in distilled water, adding an aqueous solution of phosphoric acid to the obtained solution, and then adding 20 concentrated sulfuric acid to adjust the pH to an acidic range, followed by addition of hydrogen peroxide, stirring at room temperature, and then, adding a halogenated quaternary ammonium such as tetra-(n-butyl)ammonium chloride, it is possible to obtain the tungstophosphoric acid salt represented by the formula (3) such as tri[tetra-(n butyl)ammonium]tetra(diperoxotungsto)phosphoric acid salt. 25 [0031] 27 The tungstophosphoric acid salt represented by the formula (3) which is used in the production method of the present invention can be isolated and purified after preparation to be subjected to an oxidation reaction, although it can also be subjected to an oxidation reaction continuously without carrying out an isolation operation. From 5 the viewpoint of ease of operation, the prepared tungstophosphoric acid salt which is represented by the formula (3) is preferably subjected to an oxidation reaction continuously without carrying out an isolation operation. It should be noted that the isolation operation includes filtration, washing, and the like. [0032] 10 The used amount of tungstophosphoric acid salt represented by the formula (3) is not particularly limited, although it is preferably 0.001 mol% to 1,000 mol%, more preferably 0.01 mol% to 100 mol%, and particularly preferably 0.1 mol% to 10 mol%, relative to the substituted amino-6-methylpyridine derivative represented by the formula (2). 15 [0033] The peroxide used in the oxidation reaction in the production method of the present invention is not particularly limited. Examples thereof include organic peroxides such as dicumyl peroxide, 1,1-di-t-butylperoxy-3,3,5-trimethylcyclohexane, 1,1-di-t-butyl peroxycyclohexane, 2,2-di-t-butyl peroxybutane, n-butyl 4,4-t-butyl 20 peroxyvalerate, 2,2-bis(4,4-di-t-butylperoxycyclohexane)propane, 2,2,4-trimethylpentyl peroxyneodecanoate, a-cumyl peroxyneodecanoate, t-butyl peroxyneohexanoate, t-butyl peroxyacetate, t-butyl peroxylaurate, t-butyl peroxybenzoate, t-butyl peroxyisophthalate, peracetic acid and performic acid; and inorganic peroxides such as hydrogen peroxide and sodium peroxide. 25 Of these, hydrogen peroxide is preferred from the viewpoints of safety, economy 28 and selectivity. [0034] The used amount of peroxide is not particularly limited, although it is preferably 100 mol% to 2,000 mol%, more preferably 100 mol% to 1,000 mol%, and particularly 5 preferably 100 mol% to 200 mol%, relative to the substituted amino-6-methylpyridine derivative represented by the formula (2). In addition, an aqueous hydrogen peroxide solution may be used as the peroxide. The concentration of the aqueous hydrogen peroxide solution is not particularly limited, although it is preferably 0.1 to 70% by weight, more preferably 5 to 40% by weight, and 10 particularly preferably 30 to 35% by weight. [0035] In the production method of the present invention, the reaction may be carried out in the presence of an organic solvent. The organic solvent is not particularly limited as long as it is an organic solvent capable of dissolving the substituted amino-6 15 methylpyridine derivative represented by the formula (2) without being oxidized. Examples thereof include acetonitrile, benzene, acetone, methylene chloride, chloroform and dioxane. For example, when using hydrogen peroxide as the peroxide, as a solvent, methylene chloride or chloroform is preferred, and chloroform is particularly preferred. [0036] 20 The temperature from the start of the oxidation reaction until the end of the oxidation reaction is not particularly limited, although the temperature is preferably from -78 0 C to 200*C, more preferably from -20*C to 120'C, and particularly preferably from 1 0 0 C to 100*C. When the temperature is too high, side reactions tend to proceed. When the temperature is too low, the reactions tend to proceed poorly. The time for the 25 oxidation reaction may be appropriately selected depending on the scale of the reaction.

29 The progress of the reaction may be observed, for example, by general analysis, such as gas chromatography, high-performance liquid chromatography, thin layer chromatography, NMR or IR. [0037] 5 By the oxidation reaction as described above, it is possible to obtain a substituted amino-6-methylpyridine-N-oxide derivative represented by formula (1-a). After completion of the oxidation reaction, the substituted amino-6-methylpyridine-N oxide derivative represented by formula (1-a) which has been generated may be isolated. The isolation method may be appropriately selected in accordance with the type of 10 peroxide used in the oxidation reaction or the nature of the target product. For example, when hydrogen peroxide is used as the peroxide, after the completion of the oxidation reaction or after decomposing the remaining hydrogen peroxide with a reducing agent such as sodium sulfite, water and an organic solvent, if necessary, are added to the reaction solution, followed by performing an extraction and liquid separation operation, 15 and then concentrating the separated organic layer to isolate a desired product. [0038] In addition, an aqueous layer obtained by the liquid separation operation contains a tungstophosphoric acid salt represented by formula (3), and therefore the aqueous layer may be reused as it is or after conducting a concentration treatment or the 20 like as needed for the oxidation reaction in the production method of the present invention. [0039] The production method of the present invention is economical because the removal of tungstophosphoric acid salt represented by the formula (3) after the reaction is 25 easy, and the reuse thereof is also possible.

30 In addition, the substituted amino-6-methylpyridine-N-oxide derivative represented by formula (1-a) which is obtained by the production method of the present invention is useful as an intermediate in the manufacture of agricultural chemicals or the like. 5 [3] Method for producing haloalkyl-nitrogen-containing heterocyclic derivative [3-1] First embodiment The method for producing a haloalkyl nitrogen-containing heterocyclic compound according to the present invention includes a step of reacting a compound represented by formula (4) with a halogenating agent to synthesize a compound 10 represented by formula (5). [0040] The raw material used in the production method of the present invention is a compound represented by formula (4). In the formula (4), each of a', a 2 , a 3 and a 4 independently represents a carbon 15 atom, a nitrogen atom, an oxygen atom or a sulfur atom. Of the possibilities, it is preferable that all of a 1 , a2, a3 and a 4 represent a carbon atom. Specific examples of R, R 2 and A in formula (4) include the same as those described above as specific examples in the aforementioned formula (1). n indicates the number of substitutents of A, and is any one of integers of 0 to 4. 20 When n is 2 or more, each A may be the same or may be different from each other. In addition, more than one A may be bonded with each other to form a ring, such as a quinoline ring, an isoquinoline ring, a 2,6-naphthyridine ring, a 1,8-naphthyridine ring, a phthalazine ring, a quinoxaline ring, a quinazoline ring, a pteridine ring, or a purine ring. 25 [0041] 31 In the present invention, at least one of A is preferably a group represented by formula (6). In the formula (6), * indicates a binding site. In the formula (6), R 5 represents a hydrogen atom, an unsubstituted or 5 substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, and specific examples thereof include the same as those described above as specific examples for R 4 in the aforementioned formula 10 (1). Of these, an unsubstituted or substituted alkylcarbonyl group (more preferably, an unsubstituted or substituted C 1

.

6 alkylcarbonyl group), an unsubstituted or substituted arylcarbonyl group (more preferably, an unsubstituted or substituted C 6

-

10 arylcarbonyl group), or an unsubstituted or substituted alkoxycarbonyl group (more preferably, an unsubstituted or substituted Cr- alkoxycarbonyl group) is preferable. 15 In the formula (6), Ri represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylearbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, and specific examples thereof include the same as those described 20 above as specific examples for R 4 in the aforementioned formula (1). R and R may be bonded to form a ring. [0042] In the production method of the present invention, among the compounds represented by formula (4) that are raw materials, a compound represented by formula 25 (7) is preferably used.

32 In the formula (7), A, R1, R2, R5 and R6 are the same as A, R', R2, R and R6 defined above in formula (4) and formula (6). In the formula (7), 1 indicates the number of substituents of A, and is any one of integers from 0 to 3. When 1 is 2 or more, each A may be the same or may be different 5 from each other, and may also be bonded with each other to form a ring. [0043] The compounds represented by the formula (4) or formula (7) may be obtained by oxidizing the corresponding 2-picoline derivative using a known method, for example, an oxidation method using meta-chloroperbenzoic acid, an oxidation method using 10 hydrogen peroxide in the presence of tungstic acid (refer to U.S. Patent No. 3,047,579), or the like. [0044] (Halogenating agent) The halogenating agent used in the present invention is not particularly limited 15 as long as it is an agent used for halogenation in a known synthesis reaction. Examples of the halogenating agent include thionyl chloride, thionyl bromide, sulfuryl chloride, phosgene, diphosgene, triphosgene and phosphorus oxychloride. Among these, thionyl chloride, thionyl bromide or sulfuryl chloride is capable of suppressing the generation of byproducts and increasing the selectivity and yield for the 20 synthesis reaction of the compound represented by formula (4), even without the presence of a halogen ion source described later. In addition, phosgene, diphosgene, triphosgene or phosphorus oxychloride allows the reaction to proceed under mild conditions and also increases the selectivity and yield for the synthesis reaction of the compound represented by formula (4). 25 Phosgene, diphosgene, triphosgene or phosphorus oxychloride may be suitably used 33 when R 5 in the formula (6) represents a hydrogen atom. The amount of the halogenating agent used is not particularly limited, although it is preferably from 0.8 to 10 equivalent, and more preferably from 1.5 to 2.5 equivalents, relative to the compound represented by formula (4). However, for diphosgene and 5 triphosgene, it is preferable to convert each of the equivalent values described above for phosgene for use. [0045] (Halogen ion source) The halogen ion source soluble in organic solvents which is used in the present 10 invention is a salt containing a halogen anion which is soluble in organic solvents. Examples of the halogen ion source include an ammonium halide salt, preferably a tertiary or quaternary alkyl ammonium halide salt, and more preferably a triethylamine hydrohalide salt or a di-i-propylethylamine hydrohalide salt. In addition, examples of other halogen ion sources that are soluble in organic 15 solvents include a phosphonium halide salt, preferably an alkyl phosphonium halide salt having an alkyl group of C 2 or more. [0046] By making a halogen ion source which is soluble in an organic solvent to be present in the reaction system, it is possible to suppress the generation of byproducts, and 20 to increase the selectivity and yield for the synthesis reaction of the compound represented by formula (4). The halogen ion source exhibits more significant effects when phosgene, diphosgene, triphosgene or phosphorus oxychloride is used as a halogenating agent. [0047] 25 The used amount of the halogen ion source which is soluble in organic solvents 34 is not particularly limited, although it is preferably 0.8 times or more the molar amount of the halogen atom, and more preferably 1 to 6 times the molar amount of the halogen atom, relative to the compound represented by formula (4). [0048] 5 (Organic solvent) In the production method of the present invention, it is possible to use an organic solvent. Usable organic solvents are not particularly limited, although haloalkanes are preferred, and methylene chloride or chloroform is more preferred. [0049] 10 (Other reaction sub-materials) In the production method of the present invention, it is preferable that a deoxidizing agent be present, in addition to the halogen ion source. An amine soluble in organic solvents is desirable as the deoxidizing agent, and tertiary alkyl amines having an alkyl group of C 2 or more are more preferred, and triethylamine or di-i-propylethyl 15 amine is particularly preferred. The amount of the deoxidizing agent used is preferably at least an amount that may almost completely capture the hydrogen halide generated as a result of the reaction, and more specifically, at least one time the molar amount of hydrogen halide generated. The upper limit of the amount used is preferably six times the molar amount of hydrogen 20 halide generated. In the present invention, the coexistence of a halogen ion source and a deoxidizing agent is preferred. [0050] (Reaction between compound represented by formula (4) and halogenating agent) The reaction between the compound represented by the formula (4) and the 25 halogenating agent is not particularly limited in terms of the technique employed. For 35 example, the reaction may be carried out by dissolving a halogen ion source and a deoxidizing agent that are used as necessary in an organic solvent, adding the compound represented by formula (4) to the solution, followed by the addition of a halogenating agent thereto. In the present invention, in order to achieve especially high yield, it is 5 preferable to dissolve the halogen ion source and the deoxidizing agent that are used as necessary in an organic solvent, followed by adding the compound represented by formula (4) and the halogenating agent almost simultaneously to the solution. The addition of the halogenating agent may be carried out by dropwise addition of an organic solvent solution of the halogenating agent or by blowing in a gaseous halogenating agent. 10 Moreover, addition of the compound represented by formula (4) may be carried out by the dropwise addition of the liquid. The temperature from the start of the reaction until the end of the reaction is not particularly limited, although in view of enhancing the selectivity, the temperature is preferably not more than 40 *C, and more preferably within the range from -40*C to 15 20 0 C. [0051] By the production method of the present invention, it is possible to obtain a compound represented by formula (5). A, a 1 , a 2 , a 3 , a4, R', R 2 and n in formula (5) are the same as defined above for A, a', a2, a?, a4, R', R2 and n in formula (4). X represents 20 a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. It should be noted that in the cases where the compound represented by formula (4) serving as a raw material is a compound represented by formula (7), it is possible to obtain a compound represented by formula (8). In the formula (8), A, 1, R', R2, Ri and R6 are the same as defined above for A, 1, R 1 , R2, R and RW in formula (7), and X 25 represents a halogen atom.

36 [3-2] Second embodiment The method for producing a nitrogen-containing heterocyclic compound according to the present invention includes a step of converting a compound represented by formula (9) into a compound represented by formula (10), and a step of reacting the 5 compound represented by the formula (10) with a halogenating agent to synthesize a compound represented by formula (11). [0052] The raw material used in the production method of the present invention is a compound represented by formula (9). The compound corresponds to a compound 10 represented by the formula (4) in which all of a', a 2 , a 3 and a 4 represent carbon atoms and also at least one of A is a group represented by formula (6a). It should be noted that * indicates a binding site in the formula (6a). [0053] [Chemical Formula 10] H /N 15 R6 (6 a) [0054] Specific examples of A, R' and R2 in formula (9) include the same as those described above as specific examples in the aforementioned formulae (4) and (5). In addition, k and m in formula (9), formula (10) and formula (11) are the same as defined 20 above for k and m in the formula (1). In the formula (9) or formula (6a), R6 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl 37 group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, and specific examples thereof include the same as those described above as specific examples for R3 and R4. Of these, an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an 5 unsubstituted or substituted heteroarylcarbonyl group, or an unsubstituted or substituted alkoxycarbonyl group is preferred, an unsubstituted or substituted alkoxycarbonyl group is more preferred, and an unsubstituted or substituted C 3 8 alkoxycarbonyl group is particularly preferred. [0055] 10 The compounds represented by formula (9) (except for 2-ethoxycarbonyl amino 6-methyl pyridine-N-oxide) are novel substances. The compound may be obtained by a method in which the corresponding 2-picoline derivative is oxidized with meta chloroperbenzoic acid, a method in which the corresponding 2-picoline derivative is oxidized with hydrogen peroxide in the presence of tungstic acid (refer to U.S. Patent No. 15 3,047,579), or the like. [0056] (Step of converting compound represented by formula (9) into compound represented by formula (10)) Examples of the method to convert a compound represented by formula (9) into 20 a compound represented by formula (10) include a method in which a compound represented by R 7 X is reacted with the compound represented by formula (9). Here, R 7 is the same as R7 in the formula (10) described later, and X' represents a chlorine atom or a bromine atom. By going through the conversion step, it is possible to obtain a compound 25 represented by formula (10).

38 A, k, R 1 , R2, R 6 and m in formula (10) are the same as defined above for A, k, R', R2, R6 and m in formula (9). In the formula (10), R 7 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, an unsubstituted or substituted 5 heteroarylcarbonyl group, an unsubstituted or substituted alkoxycarbonyl group, an unsubstituted or substituted alkylsulfonyl group, or an unsubstituted or substituted arylsulfonyl group, and specific examples thereof include the same as those described above as specific examples for R 3 and R4. When m is 2 or more, each R7 may be the same or may be different from each other. 10 [0057] (Reaction between compound represented by formula (10) and halogenating agent) For the reaction between a compound represented by formula (10) and a halogenating agent, the same technique as that used in the reaction between a compound represented by formula (4) and a halogenating agent in the first embodiment may be 15 employed. In addition, examples of the halogenating agents, halogen ion sources, organic solvents and other reaction auxiliary materials that may be used in the second embodiment include the same as those that may be used in the first embodiment. [0058] By the production method according to the second embodiment of the present 20 invention, it is possible to obtain a compound represented by formula (11). In the formula (11), A, k, R 1 , R2, R6, RW and m are the same as defined above for A, k, R', R2, 6 , R 7 and m in the aforementioned formula (9) and formula (10). In the formula (11), X represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. 25 [0059] 39 [3-3] Third embodiment The method for producing a nitrogen-containing heterocyclic compound according to the present invention includes a step of reacting the compound represented by formula (9) with a halogenating agent in the presence of a compound represented by 5 formula (12) to synthesize a compound represented by formula (13). For the method for reacting the compound represented by formula (9) with a halogenating agent in the presence of a compound represented by formula (12), the same technique as that used in the method to react the compound represented by formula (4) with a halogenating agent in the first embodiment may be employed, with the exception 10 that the compound represented by formula (12) is present in the reaction system. In addition, examples of the halogenating agents, halogen ion sources, organic solvents and other reaction auxiliary materials that may be used in the third embodiment include the same as those that may be used in the first embodiment. [0060] 15 By the production method according to the third embodiment of the present invention, it is possible to obtain a compound represented by formula (13). In the formula (12), R 8 represents an unsubstituted or substituted alkylcarbonyl group, an unsubstituted or substituted arylcarbonyl group, or an unsubstituted or substituted alkoxycarbonyl group, and specific examples thereof include the same as 20 those described above as specific examples for R 3 . In addition, X' in the formula (12) represents a chlorine atom or a bromine atom. In the formula (13), specific examples of A, R', 2W, R6 and RW include the same as those described above as specific examples for A, R', R 2 , R6 and R8 in the aforementioned formula (9) and formula (12). In the formula (13), k and m are the 25 same as defined above for k and m in the aforementioned formula (9) and formula (12).

40 In addition, X in the formula (13) represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. [0061] The compounds represented by the formula (5), (8), (11) or (13) that are 5 obtained by the production method of the present invention are useful as intermediates for the synthesis of agricultural chemicals, pharmaceutical products, or the like. [Examples] [0062] 10 The present invention will be described in more detail below using a series of examples and comparative examples. However, the technical scope of the present invention is in no way limited by these examples. [0063] Example A1 15 1.65 g (5 mmol) of sodium tungstate (VI) dihydrate (Na 2 WO4-2H 2 0) was dissolved in 20ml of distilled water. 6 ml of 10% phosphoric acid (H 3 PO4) was added to the obtained solution, and concentrated sulfuric acid was then added thereto to adjust the pH to 2.0. 8 ml of a 25% aqueous hydrogen peroxide solution was added to the solution, 20 and the resulting mixture was stirred at room temperature for 20 minutes. An aqueous solution of tetra(n-butyl) ammonium chloride (4 mol) was slowly added dropwise to the reaction mixture which had been stirred vigorously. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 50 minutes. The obtained reaction solution was filtered, and the residue was washed with 25 water. The obtained residue was dissolved in chloroform and was then dehydrated and 41 dried with anhydrous sodium sulfate, and the obtained solution was filtered. Then, the solvent was removed from the filtrate by distillation, thereby yielding colorless crystals ([(n-C 4 H9) 4 N]3 [PW 4 024]). [0064] 5 0.5 67 g of a 30% aqueous hydrogen peroxide solution was charged into a reaction vessel. 0.093 g of the tungstophosphoric acid salt obtained above was added thereto. Subsequently, 1.25 ml of a methylene chloride solution of 2-[(t butoxycarbonyl)arnino]-6-methyl pyridine having a concentration of 2 mol/L was added 10 thereto, and the resulting mixture was stirred at room temperature for 20 minutes. Then, the mixture was stirred for 1 hour while refluxing. 2 ml of water and 3 ml of methylene chloride were added to the reaction solution, followed by extraction and liquid separation. The resulting aqueous layer was extracted twice with 3 ml of methylene chloride, and all of the obtained organic layers 15 were brought together. The resulting organic layer was analyzed by HPLC. As a result, it was shown that 2-[(t-butoxycarbonyl)amino]-6-methyl pyridine-N-oxide was obtained with a yield of 97.6%. The measurement results of 'H-NMR spectrum of the obtained 2-[(t butoxycarbonyl)amino]-6-methyl pyridine-N-oxide were as follows. 20 'H-NMR (CDCl 3 , 6ppm): 1.53 (9H, s), 2.55 (3H, s), 6.87 (1H, d, J = 7.6 Hz), 7.19 (1H, t, J = 8.2 Hz), 8.01 (1H, d, J = 8.8 Hz), 9.43 (1H, brs). [0065] Example A2 0.2 g of a 10% aqueous phosphoric acid solution (H 3

PO

4 ) was added to a 25 reaction vessel charged with 0.041 g of sodium tungstate (VI) dihydrate (Na 2 W0 4 '2H 2 0), 42 and 0.567 g of a 30% aqueous hydrogen peroxide solution was then added thereto. Subsequently, 0.031 g of benzyltri(n-butyl)ammonium chloride was added thereto, and the resulting mixture was stirred at room temperature for 10 minutes. White crystals precipitated in the reaction solution. 5 Subsequently, 1.25 ml of a methylene chloride solution of 2-[(t butoxycarbonyl)amino]-6-methyl pyridine having a concentration of 2 mol/l was added thereto, and the resulting mixture was stirred at room temperature for 5 minutes. Then, the mixture was stirred for 2 hours while refluxing. 5 ml of water was added to the obtained reaction solution for extraction and 10 liquid separation, and the resulting aqueous layer was extracted twice with 3 ml of methylene chloride. All of the obtained organic layers were brought together. The resulting organic layer was analyzed by HPLC. As a result, it was shown that 2-[(t butoxycarbonyl)amino]-6-methyl pyridine-N-oxide was obtained with a yield of 97.1%. [0066] 15 Example A3 1.63 g of a 10% aqueous phosphoric acid solution (H 3 PO4) was added to a reaction vessel charged with 0.274 g of sodium tungstate (VI) dihydrate (Na 2

WO

4 -2H 2 0), and 2.45 g of a 30% aqueous hydrogen peroxide solution was then added thereto. Subsequently, 0.207 g of benzyltri(n-butyl)ammrnonium chloride was added 20 thereto, and the resulting mixture was stirred at room temperature for 10 minutes. White crystals precipitated in the reaction solution. Subsequently, 8.3 ml of a chloroform solution of 2-[(t-butoxycarbonyl)amino] 6-methyl pyridine having a concentration of 2 mol/l was added thereto, and the resulting mixture was stirred at room temperature for 5 minutes. Then, the mixture was stirred 25 for 2 hours while refluxing.

43 10 ml of water was added to the obtained reaction solution for extraction and liquid separation, and the resulting aqueous layer was extracted twice with 5 ml of chloroform. All of the obtained organic layers were brought together. The resulting organic layer was analyzed by HPLC. As a result, it was shown that 2-[(t 5 butoxycarbonyl)amino]-6-methyl pyridine-N-oxide was obtained with a yield of almost 100%. [0067] From the results shown above, it is clear that a substituted amino-6 methylpyridine-N-oxide derivative can be obtained with high selectivity by oxidizing a 10 substituted amino-6-methylpyridine derivative using a peroxide, such as hydrogen peroxide, in the presence of a tungstophosphoric acid salt, such as [(n

C

4

H

9

)

4 N]3[PW 4 0 24 ] or [(C 6

H

5

CH

2 )(n-C 4 H9) 3

N]

3

[PW

4 0 24 ]. In addition, from a comparison between Example Al and Example A2, it is apparent that the selectivity of the oxidation reaction of a substituted amino-6-methylpyridine derivative does not 15 decline, even when a tungstophosphoric acid salt is used as it is in the oxidation reaction without isolation after the preparation thereof. From a comparison between Example A2 and Example A3, it is evident that a target product can be obtained with a high yield with a smaller amount of catalyst and oxidizing agent when chloroform is used as a reaction solvent. 20 [0068] Example B1 7 ml of a methylene chloride solution containing 0.54 g (2.4 mmol) of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide was cooled to -17'C. 0.63 g (5.3 mmol) of thionyl chloride was added thereto, and 3 ml of a methylene chloride solution 25 containing 1.02 g (8.6 mmol) of triethylamine was then added dropwise thereto. The 44 reaction was allowed to proceed for 3 hours at -15*C. Then, 20 ml of water was added thereto at -104C. Then, the pH was adjusted to 11 with caustic soda. 2-t butoxycarbonyl amino-6-chloromethyl pyridine which was the target product was obtained with a yield of 60% in the organic layer obtained by liquid separation. 5 [0069] Example B2 A solution A was prepared by dissolving 1.35 g (6.0 mmol) of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide in 18 ml of methylene chloride and was cooled to -15 C. 10 A solution B was prepared by dissolving 1.57 g (13.2 mmol) of thionyl chloride in 18 ml of methylene chloride. A solution C was prepared by dissolving 2.43 g (24.0 mmol) of triethylamine in 18 ml of methylene chloride. The solution B was added dropwise to the solution A. When 5 minutes had 15 elapsed from the start of the dropwise addition, the dropwise addition of solution C was started. The solution B was added dropwise over 70 minutes and the solution C was added dropwise over 105 minutes, so that each of the solutions was added entirely. When one hour had elapsed after the completion of the dropwise addition, 100 ml of water was added thereto. Then, the pH was adjusted to 3.7 by adding saturated sodium 20 bicarbonate water thereto. 2-t-butoxycarbonyl amino-6-chloromethyl pyridine which was the target product was obtained with a yield of 62% in the organic layer obtained by liquid separation. [0070] Example B3 25 0.3 g (3.0 mmol) of triethylamine and 2.48 g (18.0 mmol) of triethylamine 45 hydrochloride were dissolved in 18 ml of methylene chloride. The solution was cooled to -144C, and 18 ml of a methylene chloride solution containing 1.34 g (6.0 mmol) of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide and 2.13 g (21.1 mmol) of triethylamine and 18 ml of a methylene chloride solution containing 1.57 g (13.2 mmol) 5 of thionyl chloride were added dropwise at the same time. The reaction was allowed to proceed for 2 hours at -I 5C. Then, 15 ml of water was added thereto. Then, the pH was adjusted to 13 with caustic soda. After liquid separation, the organic layer was washed with dilute hydrochloric acid. 2-t-butoxycarbonyl amino-6-chloromethyl pyridine which was the target product was obtained with a yield of 55% in the resulting 10 organic layer. [0071] Example B4 0.31 g (3.1 mmol) of triethylamine and 2.57 g (18.7 mmol) of triethylamine hydrochloride were dissolved in 18 ml of chloroform. The solution was cooled to 15 14*C, and 18 ml of a chloroform solution containing 1.34 g (6.0 mmol) of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide and 2.20 g (21.8 mmol) of triethylamine and 18 ml of a methylene chloride solution containing 1.63 g (13.7 mmol) of thionyl chloride were added dropwise at the same time over 105 minutes. The reaction was allowed to proceed for 2 hours at -15*C. Then, 30 ml of water was added 20 thereto. Then, the pH was adjusted to 5 with saturated sodium bicarbonate water. 2-t butoxycarbonyl amino-6-chloromethyl pyridine which was the target product was obtained with a yield of 77% in the organic layer obtained by liquid separation. [0072] Example B5 25 0.224 g (1.0 mmol) of 2-t-butoxycarbonyl amino-6-chloromethyl pyridine-N- 46 oxide was dissolved in 2 ml of chloroform. While ice-cooling the resultant with stirring, 0.139 ml (1.0 mmol) of triethylamine, 0.174 ml (1.5 mmol) of benzoyl chloride, 0.088 ml (1.2 mmol) of thionyl chloride and 0.14 g (1.0 mmol) of triethylamine hydrochloride were sequentially added thereto. After completion of the addition, 0.418 ml (3.0 mmol) 5 of triethylamine which was dissolved in 2 ml of chloroform was added dropwise over 15 minutes. After the completion of the dropwise addition, the resulting mixture was stirred under ice cooling for 5 minutes, and then at room temperature for 30 minutes. Then, the resultant was quantitatively analyzed by HPLC. 2-benzoyl-t-butoxycarbonyl amino-6-chloromethyl pyridine which was the target product was obtained with a yield 10 of 72%. [0073] Example B6 1 ml of a chloroform solution containing 0.22 g (1.0 mmol) of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide was added dropwise to 5 mL of a 15 chloroform solution containing 2.0 mmol of para-nitrobenzoyl chloride over 10 minutes at room temperature. After 20 minutes had elapsed therefrom, the reaction mixture was cooled to -15 0 C, and 0.30 g (3.0 mmol) of triethylamine was added dropwise thereto over 5 minutes. After 5 minutes had elapsed therefrom, 1 ml of a chloroform solution containing 0.20 g (0.67 mmol) of triphosgene was added dropwise thereto over a period 20 of 5 minutes. After 20 minutes had elapsed therefrom, 0.20 g (2.0 mmol) of triethylamine was added dropwise thereto over 5 minutes, and the resulting mixture was then stirred for 30 minutes. The resulting reaction solution was poured into saturated sodium bicarbonate water, and was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated. The resulting crude product 25 was purified by column chromatography (hexane/ ethyl acetate) to obtain 2-t- 47 butoxycarbonyl-2-para-nitrobenzoyl amino-6-chloromethyl pyridine which was the target product with a yield of 64% (as measured by HPLC). [0074] Example B7 5 A solution C was obtained by dissolving 0.27 g (2.5 mmol) of triethylamine and 2.07 g (15 mmol) of triethylamine hydrochloride in 15 mL of chloroform. A solution A was prepared by adding chloroform to 1.14 g (5.07 mmol) of 2-t butoxycarbonyl amino-6-chloromethyl pyridine-N-oxide and 1.77 g (17.5 mmol) of triethylamine up to a total volume of 10 mL. 10 1.16 g (11.77 mmol) of phosgene was dissolved in chloroform and brought up to a total volume of 10 mL, thereby preparing a solution B. The solution C was cooled to around -15 0 C. The solution A and solution B were added dropwise thereto at the same time over 40 minutes. After the completion of the dropwise addition, the reaction mixture was stirred for 30 minutes at -15*C. 10 mL 15 of water was added to the aforementioned reaction mixture maintained at 0*C or below. The pH was adjusted to 11 or more by adding an aqueous solution of caustic soda having a concentration of 28%. Following liquid separation, the resulting aqueous layer was extracted with chloroform. When the organic layer was quantitatively analyzed by HPLC, it was shown that 2-t-butoxycarbonyl amino-6-chloromethyl pyridine which was 20 the target product was obtained with a yield of 69%. 1% of byproducts (in terms of HPLC relative area percentage) was included therein. [0075] Example B8 The reaction was carried out in the same manner as in Example B7 with the 25 exception that triethylamine was replaced with di-i-propyl ethyl amine and triethylamine 48 hydrochloride was replaced with di-i-propyl ethyl amine hydrochloride, respectively. The organic layer obtained by chloroform extraction was analyzed by HPLC. As a result, the byproduct content was 1% (HPLC relative area percentage). The organic layer was concentrated, and the resulting crude product was purified by silica gel column 5 chromatography (hexane/ ethyl acetate) to obtain 0.67 g of 2-t-butoxycarbonyl amino-6 chloromethyl pyridine (yield: 55%) which was the target product. [0076] Example B9 20.37 g (92.2 mmol) of 2-t-butoxycarbonyl amino-6-methyl pyridine was 10 dissolved in 100 mL of chloroform, and the resulting solution was cooled with ice water. 25 g (101.4 mmol) of a 70% by weight product of meta-chloroperbenzoic acid was added thereto. After confirming that there is no large heat generation, the temperature was raised to room temperature. After 2 hours had elapsed, 20 mL of water was added thereto. Then, the pH was adjusted to 14 by adding an aqueous solution of caustic soda 15 having a concentration of 28%. Following liquid separation, the resulting aqueous layer was extracted with chloroform. The chloroform layer was washed with a 28% aqueous solution of caustic soda and then with water, and then dried with magnesium sulfate. Chloroform was removed by distillation under reduced pressure to obtain 21.30 g of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide (yield: 99.6%) in a light orange oily 20 form. The NMR spectrum and MS spectrum of the obtained 2-t-butoxycarbonyl amino-6-methyl pyridine-N-oxide were measured, and the following results were obtained. 1 H NMR: 1.53 (9H, s), 2.55 (3H, s), 6.87 (IH, d, J = 7.6 Hz), 7.19 (1H, t, J = 8.2 25 Hz), 8.01 (1H, d, J= 8.8 Hz), 9.43 (1H, brs).

49 "C NMR: 18.09, 28.01, 81.76, 110.23, 117.65, 126.68, 144.31, 146.85, 151.37. MS m/z: 224 (Me), 168, 151, 124, 107. [0077] Example B 10 5 4 mL of a chloroform solution containing 0.45 g (2 mmol) of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide and 0.26 g (2 mmol) of diisopropylethylamine was prepared, and was adjusted to 10'C. 0.29 g (2 mmol) of benzoyl chloride was added dropwise to the solution over 10 minutes at 1OC. After stirring further for 40 minutes at 10*C, 5 mL of water was added thereto, followed by 10 liquid separation. The chloroform layer obtained by liquid separation was washed twice with 5 mL of water, and then dried with magnesium sulfate, followed by filtration. The resulting solution was concentrated under reduced pressure and dried to obtain 0.64 g of 2-t-butoxycarbonyl-2-benzoyl amino-6-methyl pyridine-N-oxide (yield: 97%) in the form of yellow-brown amorphous which was the target product. 15 The NMR spectrum of the obtained 2-t-butoxycarbonyl-2-benzoyl amino-6 methyl pyridine-N-oxide was measured, and the following results were obtained. 'H-NMR: 1.23 (9H, s), 2.54 (3H, s), 7.20 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 5.4 Hz, 1H), 7.35 (dd, J = 7.6, 2.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.53 (tt, J = 7.4, 1.2 Hz, 1H), 7.92 (dd, J = 6.8, 1.2 Hz, 2H). 20 C-NMR: 18.2, 27.5, 84.3, 123.4, 124.5, 124.8, 128.0, 128.7, 131.9, 135.6, 144.7, 149.2, 151.0, 170.9. [0078] Example B11 2 mL of a chloroform solution containing 0.24 g (1 mmol) of 2-t 25 butoxycarbonyl amino-6-methyl pyridine and 0.26 g (2 mmol) of diisopropylethylamine 50 was prepared, and was cooled in ice water. The above mixed solution was added dropwise at 0*C to 0.3 mL of a chloroform solution containing 0.11 g (1.2 mmol) of methyl chloroformate. After stirring further for 20 minutes, the temperature was raised to room temperature. After stirring further for 5 hours at room temperature, 5 mL of 5 water and 1 mL of 3N hydrochloric acid were added thereto, followed by liquid separation. The organic layer obtained by liquid separation was dried with magnesium sulfate, followed by filtration, and the resulting solution was concentrated under reduced pressure to obtain 0.27 g of 2-t-butoxycarbonyl-methoxycarbonyl amino-6-methyl pyridine-N-oxide (yield: 96%) as a pale yellow oily liquid which was the target product. 10 The NMR spectrum of the obtained 2-t-butoxycarbonyl-methoxycarbonyl amino-6-methyl pyridine-N-oxide was measured, and the following results were obtained. 1 H-NMR: 1.44 (9H, s), 2.54 (3H, s), 3.79 (3H, s), 7.13-7.26 (m, 3H). [0079] Comparative Example B 1 15 1 Oml of a methylene chloride solution containing 1.99 g (6.7 mmol) of triphosgene was cooled to 0*C. 5 ml of a methylene chloride solution containing 1.12 g (5 mmol) of 2-t-butoxycarbonyl amino-6-methyl pyridine-N-oxide and 5 ml of a methylene chloride solution containing 1.01 g (10 mmol) of di-i-propylamine were each added dropwise thereto at the same time. After the completion of the dropwise addition, 20 the liquid temperature was adjusted to room temperature, and the resulting mixture was then stirred for 1 hour. The reaction solution was poured into saturated sodium bicarbonate water, and was then extracted with methylene chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated. The resulting crude product was purified by column chromatography (hexane/ ethyl acetate). Only 73 mg 25 of 2-t-butoxycarbonyl amino-6-chloromethyl pyridine which was the target product was 51 obtained (yield: 3%). On the other hand, 503 mg (67%) of byproducts in the form of a white solid were produced. [0080] Comparative Example B2 5 1.03 g (8 mmol) of di-i-propylethyl amine and 0.67 g (3 mmol) of 2-t butoxycarbonyl amino-6-methyl pyridine-N-oxide were dissolved in 10 ml of methylene chloride, and the resulting solution was then cooled to -15*C. 20 mL of a methylene chloride solution containing 0.60 g (2 mmol) of triphosgene was added dropwise thereto over a period of 2 hours while maintaining the inner temperature at -15'C. After the 10 completion of the dropwise addition, the resulting liquid was stirred for 1 hour at -I5'C. 20 mL of water was added to the aforementioned reaction mixture maintained at 0*C or below. The pH was adjusted to 11 or more by adding an aqueous solution of caustic soda having a concentration of 28%. Following liquid separation, the resulting aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, dried 15 with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ ethyl acetate). 0.18 g of 2-t-butoxycarbonyl amino-6-chloromethyl pyridine which was the target product was obtained (yield: 25%). 4% of byproducts (in terms of HPLC relative area percentage) was produced. 20 [0081] Comparative Example B3 The reaction was carried out in the same manner as in Example B8 with the exception that no di-i-propyl ethyl amine hydrochloride was added. The yield of 2-t butoxycarbonyl amino-6-chloromethyl pyridine after purification by silica gel column 25 chromatography was 32%. 13% of byproducts (in terms of HPLC relative area 52 percentage) was produced. [Industrial Applicability] [0082] 5 According to the production method of the present invention, nitrogen containing heterocyclic compounds such as a substituted amino-6-methylpyridine-N oxide derivative, and a haloalkyl, nitrogen-containing heterocyclic derivative can be obtained with high selectivity and also in high yield. The nitrogen-containing heterocyclic compound obtained by the production method of the present invention is 10 useful as an intermediate for the industrial production of agricultural chemicals or the like.

Claims (2)

1. 2. The method according to Claim 1, wherein R' represents an unsubstituted or substituted aikylcarbonyl group, an unsubstituted or substituted ary Icarbonyl group. or an unsubstitted or substituted alkoxycarbonyl group. 3, The method according to Claim I or Claim 2, wherein the halogenating agent is at least one selected from the group consisting of thionyl chloride, thionyl bromide, phosphorus oxychl oride, sulfuryl chloride, phosgene, diphosgene and tri ph osgene.
2. 4. The method according to any one of Claims 1 to 3. wherein the haogenating agent is at least one selected fromn the group consisting of thionyli chloride, thionyl bromnid~e and sulIfuryi chloride, 5, The method acorimg to any one oftCaims I to 3. w herein the halogenating agent is at least one selected from the goup consisting of phosgene, diphosgene, triphosgene and phosphorus oxychioride 10 6, The method according to any one of Claims 1 to 5, wherein the halogen ion source that is soluble in an organic solvent is a tertiary or quatermary alkyl amnonium halide salt havin an alkyl group of C2 or more, or an alkyl phosphoniun bai de salt having an alkyl group of C2 or more.