CA2194080C - Novel process for preparing 2,6-di(4,6-dimethoxypyrimidin-2-yl) oxybenzoic acid oxime ester derivatives - Google Patents

Abstract

A process for preparing a 2,6-di(4,6-dimethoxy-pyrimidin-2-yl)oxybenzoic acid oxime ester derivative, having a herbicidal activity and the following formula (I), (see fig. I) (I) in which R1 represents hydrogen halogen, cyano, nitro, alkyl, cycloalkyl, alkoxy, alkenyloxy, alkylthio, amino which can be substituted with alkyl, aryl, aryloxy, acyl or acyloxy, n denotes an integer of 1 to 5, and R2 represents hydrogen, halogen, cyano, nitro, alkyl, alkoxy, alkylthio, alkoxycarbonyl, alkenyloxycarbonyl, arylmethoxycarbonyl, heteroarylmethoxy carbonyl, alkylaminocarbonyl, di (alkyl) aminocarbonyl, arylmethylaminocarbonyl, heteroarylmethylaminocarbonyl, or phenyl which can be substituted with R1. The process comprise reacting a compound having the following formula (V), (see fig II) (V) in which R represents hydrogen or alkali metal cation, with a pyrimidine derivative having the following formula (VI), (see fig. III) (VI) in which Z represents halogen, alkylsulfonyl or aryl-sulfonyl.

Description

2,6-DI(4,6-DlMETHOXYl'YRlMIDIN-2-YL)OXYBENZOIC ACID OXIME
ESTER DERIVATIVES

TECHNICAL FIELD

The present invention relates to a novel process for preparing a pyrimidyloxyb~n~~ic acid oxime ester derivative havin~ a herbicidal activiLy. More specifically, tlle present invention relates to a novel process for preparing a 2,6-di(4,6-~limethoxypyrimidin-2-yl)oxybenzoic acid oxime ester derivative represented by the following formula (1):

CH O~N'lOJ~OJ~ocl~3 O~O--N =~
~3~(Rl)n in which ~I represents hydro~en, halogen, cyano, nitro,. Cl-C4 alkyl, C3_CG
cycloalkyl, Cl-C.I alkoxy, C2-C4 all;cnyloxy, Cl-C4 alkylLIliO, amino which can be substituted with Cl-C4 alkyl, aryl, aryloxy, Cl-C4 acyl or Cl-C4 acyloxy, n denotes an integer of 1 to 5, R2 represents hydrogen, halogen, cyano, nitro, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylLhio, Cl-C.I alkoxycarbonyl, C2-C4 alkenyloxycarbonyl, arylmellloxycarbonyl, heLeroarylmethoxy carbonyl, Cl-C4 alkylaminocarbonyl, di(CI-C4 alkyl)~minoc?--bo-nyl, arylmethylarninocarbonyl, heteroarylmetllylaminocarbonyl, Qr 2194~80 phenyl which can be substituled with Rl.

In Ihe definitions for tlle substituents of the compound of formula (I), the term "alkyl" whicll is used alone or in the form of a composite term such as "alkyllhio" or "alkylaminocarbonyl" means a straight or branched salurated hydrocarbon radical, for Px~mple methyl, ethyl, n-propyl, isopropyl, various isomers of butyl, etc.; the term "alkoxy"
means methoxy, eLhoxy, n-propoxy, isopropoxy, or valious isomers of butoxy, etc.; the terrn "alkenyl" which is used alone or in the forrn of a composite terrn SUCll as "alkenyloxy" means a straight or br~nrhe-l 10 ~Ikene~ for examplc, vinyl, l-prol~enyl, 2-propenyl, various isomers of buLenyl, etc.; and the telm "halogen" means fluorine, chlorine, bromine or iodine, etc.

The presenl; invention also relates to a new interm~ te which can be used in the process for preparation of the compound of formula (Ij and to processes for prel)aring tlle same.

13ACKGROUND A~T

2 0 The compound of formula (I) as mentioned above exhibits an excellent herbicidal aclivity over a wide spectrum of grasses, broadleaved weeds, annu~l wee~ls or perennial weeds. Specific~lly, it has a superior effect on a direct seeded rice for preventing annual and perennial weeds in question including a barnyard grass. Therefore, it has already been applicated as a novel compound with the process for its preparation by the uresent inventors (see, European Patent Application No. 658549) According~ lo the patent applicalion as mentioned above, the desired componn~l of formula (I) can be prepared by carrying out an estelification reaction of a 2,6-disubstituted benzoic acid derivative of the , following formula (Il) with an arylketone oxime compound of the following formula (III) as represenled in the following reacLion scheme A.

Rez~tion SçhPmP A:

C1130 NJ~O~O ~OCH3 + HO-N (I
0 S :=~(Rl)n ¢~N

(111) (Il) in which, 1~1, R2 and n are defined as previously describcd.

Howcvcr, since Ihe carboxyl group in tlle benzoic acid delivative of formula (Il) is sterically hindered severely, it cannot react actively 2 ~ with the bulky aryll;etone oxime in the esterification reaction under a convention~l reaclion condilion. Thel efore, the above reaction has a problem that it should be carried out under a special and uneconomic reacl;ion condition in order to raise lhe reaction yield.
.

DISCLOSURE OF INVENTION

Thus, tl-e present inventors have extensively studied to develol~ a process which is more efficient as well as direct than the prior method having the problem as mentioned above. According to this, we have identified that the desired compound of formula (I) can be prepared in a high yield without any special reaction conditions by using a compound represented by the following fonnula (V) as a starting substance, and _ 3 --2i s4~ao then Coml!lpte~l the present invention:

~=~, (Rl )n CH30 ~

~ N ~ R2 (V
CH30 ~OR

~0 in which, Rl, R2 and n are defined as above, and R represents hydrogen or alkali metal cation.

Thus, it is an object of the present invention to provide a novel process for preparing the desired compound of formula (I), as defined above.

2 0 It is anotller object of the present invention to provide a novel interme~ te which can be used for the preparation of the compound of formula (I) and processes for preparing the interme~ te.

DESCRIPTION OF THE PR~~ KI~L EMBODIMENTS

In one aspect, the present invention relates to an improved process for preparing the compound of formula (I) using the compound of formula (V) as a starting material. The process for preparation according to the present invention can be represente-l bliefly by the following reaction s-~hpmp B.

Reac~ion Scheme B:

~(RI)n ~ ~o~O-N~ + z~ ~

(V) (Vl) OCHl OCH3 CIIJO N OJ~O ~OC113 O-N=~
,~9C~(Rl)n (I) ~

20 in the reaction scl-P-ne I3, Rl represents hydl o~en, halogen, cyano, nilro, Cl-C4 alkyl, C3-C~
cycloalkyl, Cl-C4 allcoxy, C2-C4 alkenyloxy, Cl-C4 alkylthio, amino wllicll can be substituted with Cl-C4 allsyl, aryl, aryloxy, Cl-C4 acyl or Cl-C~ acyloxy, n dcnotes an inleger of 1 to 5, represents hydrogen, halogen, cyano, nitro, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylthio, Cl-C4 alkOXyCal'bOllylj C2-C4 3 ~ alkenyloxycarbonyl, arylmel-hoxycarbonyl, heteroarylmethoxy carbonyl, Cl-C4 alkylarninocarbonyl, di(CI-C4 alkyl)aminocarbo-nyl, arylmetllylaminocarbonyl, heteroarylmelhyl~minoc~rbonyl, or phenyl which can be subsLituted with Rn Z represents halogen, Cl-C4 alkylsulfonyl or arylsulfonyl, and 1~ rel~l-esents hydlogen or alkali metal caLion.

C
As can be seen from tlle reaction sclleme B above, the present invention provides a process for preparing the desired 2,6-di(4,6-ell~oxypyl imidin-2-yl)oxyben~oic acid oxime ester derivative of formula (I) cl~aracterized in tl~al the coml)ound of formula (V), as defined above, is reacLed wi~h a pyrin i-~inf~ derivative of formula (VI).

Heleinafter, ll~e process accor(ling to tlle re~ction scheme B
be specifically e?cl-laine-l.
The reaction according to Lhe reaction sc~hf rn~ B can be preferably CUI ried out in a solvenL. A~ Llle solvent appropriate for this l~urpose, one or more selecled from a gl'OUI~ consisLing of eLhers SI~CIl as Lclrahydrofuran, dielllyleLhel, etc., pl)lal solvenls SIIC11 as dimelhylfol~n~ le~ dimeLbylslllfoxide, etc., halo~enated hydrocarbons SIICI~
u~ dichloromelharle, carl~on lelrachloride, etc., and aromalic llydrocarbolls sll(:ll as l~en~ene, toluelle, eLc, can be Inenlioned; alld lelral-y(ll of 1ll arl or ~in~e~llylforrlls~ iflf~ arnonlr Lhern is preferable.

l'he reaclion can also be carried out in the presence or absence of u l~ase. A~ e base for ll~is l)ul pose, inorgallie bases SIICIl as liLl~iulll hydl oxide, sodium llydroxide, potassiwn hydroxide, potassium carbonate, sodillm carbonate, sodium hydride, sodiuln hydrogen carbonate, etc., ~referubly polassium carbonate or sodiunl hydride can be used.

Tlle reaction can be usually carlied out in a range of normal ternpelature to 150C, prefelably at 50 to 80C.

According to the process of the present invention as described ubove, the desile(l l~yrilnid)doxybell~oic acid oxilne esler derivalive of forlnllla (I) having a hel bicidal acLivity can be conveniently obtainecl under u mild reacLioll condiLion h~ a ~ood yield.

2l q4~80 While, the coml)ound of folmula (V) used as a starting substance in the above reaction sclleme B can be prepared from a novel 5-(4,6-.limf~ .Qxypyrimidin-2-yl)oxy-4H-(1,3)-benzQ.lioxin-4-one deliva-tive represented by tl-e following formula (IV):

C~130 ~ ~~~ R3 (IV
Ctl10 o R.

in which, R3 and Rl indcl)en(lently of one anothel represent hydrogen, Cl-c4 alkyl, Cl-C.~ Ilalo.llkyl 11aV~ O 5 l1al0gen alom~, benzyl, or phenyl wl~icll can be subslituted with one or two groups selecled from 1 lo 5 halogcn atoms and/or Cl-C.I alkyl, Cl-C4 allcoxy~
Cl-C2 h ~lo:-ll;yl and nilro, or~0 1~:~ and I~ lo~elber rel)resenl CrCfi alkylene cllain which can l)e sul)sLiluled willl 1 to 5 halo~en atoms and/or Cl-c4 alkyl, 4~, R6 ;~)m 1~ also ~eplese.-ls Q R5 or Cl~2 Rg wherein, 30Q represenLs sulfur, oxygen or NRs (Rs represents hydrogen or Cl-c4 alkyl), R5, RG and R7 indel)endently of one anolher represent hy(lrogen, halogen, Cl-c4 alkyl, Cl-C4 alkoxy or Cl-C2 h~lo~lkyl wllicl can be substitùted witll 1 to 5 halogen atoms, or 1~5 and Ru together represent benzo-fused benzene ring, whelein Ihe benzene r ing can be substiLuted will~ one or Iwo groups ~21~4;1)~0 selecle~l from 1 to 5 halogen atoms and/or Cl-C4 alkoxy, Cl-C4 alkylthio, C~-Cz haloalkyl, cyano and nitro, Rs represents l-ydrogen, Cl-C4 alkyl, Cl-C4 haloalkyl having 1 to 5 halogen atoms or alkyll-Pn~ene ring, X and Y in(lPp~llden~ly of one another represent oxygen or sulfur, Rlo, Rll, Rl2 and Rl3 inrlPp~n-lently of one another represent hydrogen, Cl-c4 alkyl or Cl-C4 haloalkyl having 1 to 5 halogen atoms, and m denotes 0 or l.

The process for prel)aring the compound of formula (y) from the 5-(4,6--lim~thoxypyrilnidin-2-yl)oxy-4H-( 1,3)-benzodioxin-4-one derivative of formula (IV) can be represenled by the following reaclion scl-emP c 20 ~e:lclion Scheme C:

, N O
CH3~ ~0~OxR3 + RO~

(IV) (111) /9~(Rl)n ~ CH30 ~N~ ~ =(R
CH30 ~OR

(V) 21 9408r~
in the reaction s~h~m~ C, R, Rl to R4 and n are defined as above.

As can be seen from the reaction s~h~me C above, the compound of formula (V) is prepared by r~ t;r~g the 5- (4,6-imf~thoxypyrimidin-2-yl)oxy-4H-(1,3)-benzodioxin~4~one derivative of formula (IV) with an oxime or it's metal salt of formula (III) to open the hen~o-lio~cine ring.

This reaction can be preferably carried out in a solvent. As the solvent which is appropriate for this purpose, one or more selected from a group consis~ing of ethers such as tetrahydrofuran, diethylether, etc., polar solvents such as dimethylformamide, dimethylsulfoxide, etc., halogenated hydrocarbons such as dichloronl~th~n~o~ carbon tetrachloride, etc., and aromatic hydrocarbons such as bPn~.one, toluene, etc., can be m~ntione~li and tetrahydrofuran or dimethylform~mi-l~ among them is preferable. In this reaction, it is conventionally advisable to use the 20 same solvent as the reaction srheme B above, but such a control is not an in-lisr~ s~hle one.

The reaction can also be cau-ried out in the presence or absence of a base. Particularly, in case the oxime compound of formula (III) is used in the form of a metal salt the reaction can be proceeded satisfactorily without a base. As the base appropriate for this reaction, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydride, so~ m hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., preferably potassium carbonate or sodium hydride can be used. The reaction temperature can vary in a range of -50 to 150-C, however, the reaction is preferably carried out at 0 to 80~C.

The oxime compound of formula (III) as a reZ~-~tin~ substance in the reaction s~h~ome C can also be used in the form of a metal salt _ g _ 21 q408~
wherein R represents alkali metal cation. This oxime metal salt can be prepared by reacting the corresponding oxime (III) (R=H) with the corresponding m.ot~llic compound in a solvent in the presence of a base.
As the base for this reaction, inorganic bases such as lithium hydroxide, sodium hydroxide, pot~ssil-m hydroxide, potassium carbonate, sodium carbonate, sodium hydride, sodium hydrogen carbonate, etc., sodium alkoxides such as sodium methoxide, sodium ethoxide, sodium t-b-ltoxi~le, etc., preferably potassium carbonate or sodium hydride can be used.
And as the solvent for this re~rtion~ one or more selected from a group 10 conci.stir-g of ethers such as tetrahydrofuran, diethylether, etc., polar solvents such as dimethylformimi~le~ dimethylsulfoxide, etc., halogenated hydrocarbons such as dichloronle~h~ne, carbon tetrachloride, etc., aromatic hydrocarbons such as benzene, toluene, etc. can be used, and among them tetrahydrofuran or dimethylform~mille is particularly preferable.

When the compound of formula (V) thus obtained is used for preparing the desired compound of formula (I) according to the reaction scheme B above, it can be directly reacted with the pyrimidine derivative (Vl) without any isolation procedure, or can be isolated and purified 20 before the reaction with pyrimi-line derivative (VI). In the case of isolation free process, the reaction mixture obtained from the reaction represented by sch~mP C can be added dropwise to the pyrimidine derivative (VI)-solution or vice versa.

In the course of developing the process for preparing the compound of forrnula (I), the present inventors have also found that the 5-(4,6-rlim~th~xypyrimidin-2-yl)oxy-4H-(1,3)-h~n~otlioxin-4-one derivat-ive of formula (IV), as ~fine~l above, is a useful interme~ te for preparing the compound (I) as well as a novel compound. Therefore, in 30 another ~spec~ the present invention relates to this novel interme~ te and process for preparation thereof.

~' Among the cyclic acetal compound of formula (IV), a compound of formula (IVa) having the sul~stituents R3 and R4 as defined below can be prepared by re~rting a known compound of formula (VII) and a carbonyl compound of formula (VIII) with thionyl chloride in a solvent in the presence of a catalytic amount of dimethylaminopyridine. The process can be represented by the following reaction schPme D. In this reaction, an ether such as tetrahydrofuran, diethylether, ~limPthoxyeth~nP~? etc., a polar solvent such as dimethylform~mi.le, tlimPthyl sulfoxide, etc., a halogenated hydrocarbon solvent such as dichloromPthArle, carbon tetrachloride, etc., or an aromatic hydrocarbon solvent such as benzene, toluene, etc., preferably rlimethoxyethane or toluene can be used as a solvent. The reaction can be carried out at normal temperature to 150~, preferably at 50 to 80~.

~:lrti~n S~hPmP D:

R3axR4a OH O O
~0 J~ 2, Solveni ~0 CH30~oCH3 CH30~0CH3 (Vll) (IVa) in the reaction schPme D, R3a and R4a independently of one another represent hydrogen, Cl-C4 alkyl, Cl-C4 haloalkyl having 1 to 5 halogen atoms, 4enzyl, or phenyl which can be substituted with one or two groups selected from 1 to 5 halogen atoms and/or Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C2 h~lo~lkyl and nitro, or ~_' 2194080 R3" and R4a together represent C2-C6 alkylene chain which can be substituted with 1 to 5 halogen atoms and/or Cl-C4 alkyl.

Alternatively, lhe novel cyclic acetal compound of formula (IVa) can also be obtained by reS~-~ting the known compound of formula (VII) with the carbonyl compound of formula (VIII) or an acetal compound of fomlula (IX) colTesponding lo the compound (VIlI) in the presence of an acid ca-alyst and a dehy(lratin6 agent, if necess~ry by eliminating the water or alcohol produced duling the reaction as a side product through a 10 distillation, as desclibed in the following reaclion s~h~m~ E. When the reaction is performed in a solvent, an ethel such as tetrahydrofuran, diethyleLher, rlimel lloxyelllanc, etc., a halogenaLed hydrocarbon solvent such as dichloromethane, carbon letrachloride, etc., or an aromatic hydl'OCarbOn solvent SUCIl as benzene, toluene, xylene etc., preferably benzene or toluene can bc used as Ihe solvent. If desired, an excessive amount of the acctal coml)ound can be used instead of a solvent. As the catalyst, calion acids such as p-loluenesulfonic acid, sulfuric acid, ~hosl horic acid, etc., Lewis acids such as aluminum chloride, titanium tetrachloride, zinc chlolide, calcium chlolide, st:~nniC chloride, etc. can be 2 0 mentionedi and as Ihe dehydraling a~ent, organic anhydride such as trifluoro~cetic acid anhydride or acetic acid anhydride, or sodium sulfate or calcium chloride can be mentioned. The reaction can be carried OIlt at normal temperature to 150-C, preferably at 80 to 130-C.

' Reaction Scheme E:

OH

RIIO>~ORl~ Sol e (Vlll)(IX) Dehydrating Agent (Vll) 10 in the reaction s-~h~me E, R3;, and R4~ are defined as previously described in connection with the reaction scheme D, Rl~ represents Cl-C4 alkyl.

In some cases, as represented in the following reaclion scheme I~, a known coml)ound of formula (X) (see, Rend. Semin. Fac. Sci. Univ.
C~ ri, 1978, 48, 275-283) is reacted with the pyrimidine derivative of formula (VI) in a solvent in the presence of a base to obtain the compound of formula (IVa). In this reaction, an ether such as 20 tetrahydrofuran, diethylether, ~limethoxyeth~ne, etc., a polar solvent such as ~lim~thylformamide, dimethylsulfoxide, etc., a halogenated hydrocarbon solvent such as dichloromethane, carbon tetrachloride, etc., or an aromatic hydrocarbon solvent such as benzene, toluene, xylene etc., preferably tetrahydrofuran or dimethylformamide can be used as the solvent. This reaction can be carried out at norrnal temperature to 150~C, preferably at 50 to 80-C.

~ 13 -Reaction Scheme F:

R3axR4a (Vl) OCH3 ~

(X) (IV~) 10in Ihe reaclion sr~hPme ~, and R4;. are defined as previously described in connection wiLh the reaclion srhemP D, Z is defined as previously described.

1~urlhcr, Ihe novcl cyclic acelal compollnd of formula (lVa) wherein bo~ and I~ rel)resent l-ydrogen can be obtained by reacting the known compound Or formula (Vll) willl a dihalomethane of formula (Xl) in a solvenl in tlle presence of a base as represented by the followin~
reaction scheme G. In this case, the dihalometh~ne means a haloalkane such as dibromome~h:lne or diiodomethane. As the base, an inorganic 2 o base such as potassium carbonate, sodium carbonate, sodium hydride, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, etc., preferably potassium hydloxide or sodium hydroxide can be used; and as the solvent an ether such as tetrahydl-ofuran, diethylether, rlime~hoxye~h~nP~ elc., a polar solvent such as dimethylfolmamide, dimethylsulfoxide, water etc., a halogenated hydrocarbon solvent such as dichloromPth~nP, cau bon tetrachloride, etc., or an aromatic hydrocarbon solvent such as benzene, toluene, xylene, etc., preferably ~limP~ hylform~mirlP, dimethylsulfoxide or toluene can be used. If nr cess:lry, a phase transfer catalyst such as tetraalkylamrnonium salt 2~ 94û80 derivative can be additionally used. The reaction can be carried out at normal temperature to 150~C, preferably at 80 to 130~C.

Re~tion Scheme G:

~0 11 ~0 CH30 OCH3 (Xl) ~

1 0 (Vll) in the reaction srhPrne G, P represents bromine or iodine Typical examl)les of the compound of formula (IVa) prepared according to the processes as explained above are presented in the following Table 1.

21 q4080 Table 1.

COoM. R3a IRIa IH NMR(CDCI3, 270MHz, ~ ) CHt CHt F.~mr'~ 16 1.05(m, 6H), 1.58(s, 3H), 2.30(m, lH), 4 CHtCH(CH3)) 3.82(s, 6H), 5.74(s, lH), 6.89(d, lH), 6.90(d, lH), 7.53(t, lH) CH3CH2CH~CH~CHt 0.96(d, 6H), 1.68(s, 3H), 1.90(d, 2H), 6 CHtCH2CH(CHt)~ 3.82(s, 6H), 5.75(s, lH), 6.87(d, lH) 6.91(d, lH), 7.54(t, lH) 7 CH3CH(CH3)CH2CH3 0.87(t, 3H), 1.28(m, 2H~, 1.49(m, 2H), 1.56(s 21-1) 166(s 3H), 1.93(m, 2H), 8 Cl~ Cll:~ CH~CH2cH3 382(s 6H) 575(s lH), 6.88(d, lH), 6.92(d, lH), 7.54(t, lH) 9 H H F.x~mp'~ 19 H Ph Fxz mp~? 18 11 H4-methoxyphenyl 1.68(s, 3H), 1.96(s, 3H), 2.89(s, 2H) 12 HCH~CH(CH3)2 3.81(s, 6H), 5.74(s1 lH), 6.91(d, lH) 6.97(d, lH), 7.57(t, lH), 8.55(s, lH) 1.27(d, 6H), 2.98(m, lH), 3.84(s, 6H) 13 H4-isoy-uyyiyhenyl 5.78(s, lH), 6.47(s, lH), 7.04(d, 2H) 7.34(d, 2H), 7.55(d, 2H), 7.58(t, lH) 14 CH32,4-dichlorophenyl CH33-trifluoromethylphenyl 16 CH33-nitrophenyl Table 1. (continued) 1.70(s, 3H), 2.00-2.10(m, 4H), 3.58 19CH3 CH,CH2CH2CI (t, 2H), 3.80(s, 6H), 5.76(s, lH), 6.90(d, lH), 6.93(d, lH), 7.56(t, lH) 21CHs C(O)CH3 1.73(s, 3H), 2.34(d, 2H), 3.30(d, 6H) O - 22CH3 CH~CH(OCE~3)2 3.81(s, 6H), 4.64(t, lH), 5.75(s, lH) 6.91(d, lH), 6.93(d, lH), 7.56(t, lH) l.l9(s, 3H), 1.21(s, 3H), 1.98(s, 3H) 23CH,CE-I(OH)C(OH)(CH3)l 3.81(s, 6H), 4.85(s, lH), 5.80(s, lH) 6.79(d, lH), 6.96(d, lH), 7.51(t, lH) 1.69(s, 3H), 2.16(s, 3H), 3.78(s, 2H) 24CH:l Cl~ C(O)CI~ 5.78(s, 11-1), 6.78-6.89(dd, 2H) - 7.47(t, lH) 1.83(s, 3EI), 3.85(s, 6H), 3.98(s, 21-1) 25Cl-l:, CllMO)CI-l:~Br 5.78(s, lH), 6.86-6.97(q, 2E~) 7.56-7.61-(t, lH) 26CH3 CH~CH~C(O)CH~
27CE 1~CH~CH~CH~C(O)CH3 CO 1-1 1.94(s, 3H), 3.79(s, 6H), 5.75(s, lH) 28CH3 ~ 6.90(d, lH), 7.00(d, lH), 7.25(t, lH) 1.93(s, 3H), 3.73(s, 3H), 3.83(s, 6H) 29CH3 CO2CH3 5.78(s, lH), 6.97(d, lH), 7.00(d, lH) 7.60(t, lH) 30CE~3 CO;~CH~CH3 31CH3 CH=C(CH3)2 Fx~mr'~ 20 32CH3 GH2CH=CH2 33CH3 C(CH3)=CH2 34CH~CE~3 CH2CH3 0.89(t, 6H), 1.47(m, 4H), 1.93(m, 4 35CH2CH~CH3CH2CH2CH3 3.82(s, 6H), 5.74(s, lH), 6.87(d, lH), 6.89(d, lH), 7.53(t, lH) 21 94~0 Table 1. (continlled) 36 O<

37o< F.x: le 17 Among the cyclic acetal compound of formula (IV) above, a ~,R6 coml-ollnd of formula (IVb) wherein R~ represents R5 (wherein, Q, R5, RG and R7 are defined as previously described) can be prepared according to a process characterized in that a compound of formula (XII) is reacted with a pyrimidine derivative of formula (XIII) in 20 a solvent in the presence of a base as described in the following reaction s~h~mP H.

Reaction Scheme H:

R5 ~ ~ ~N ~ B 3s~

R3 o OCH3 (Xll) (Xlll) N~
(IVb) 20 in the rea~tion srhf-me ~I, R3, R5, RG, R7 and Q are defined as previously described.

In the reaction schPme H, an ether such as tetrahydrofuran, diethylether, rlim~oth~xyeth~ne, etc., a polar solvent such as dimelhylform~mide, dimethylsulfoxide, etc., a halogenated hydrocarbon solvent such as dichlorom~th:~ne, carbon tetrachloride, etc., or an aromatic hydrocarbon solvent such as benzene, toluene, xylene etc., preferably tetrahydrofuran or dimethylform~mi~l-o can be used as the solvent. And 3 0 as the base, an inor~anuc base such as potassium carbonate, sodium carbonate, sodium hydride, sodium hydrogen carbonate, etc., preferably potassium carbonate or sodium hydride can be used. This reaction can be carried out at normal temperature to 150-C, preferably at 50 to 80~C.

Typical examples of the compound of formula (IV b) prepared according to the process as explained above are presented in the 21 94~80 following Table 2.

Table 2.

NO. R5 R6R7mp.( C) 'H NMR(270 MHz, CDCI3) 38 H O H H H177-179 ~XAmll'e 6 40 CH3 O H H H158-160 ~xAmple 10 7.52(t, lH), 6.90(dd, 2H), 6.22 (d, lH), 5.84(d, lE~), 5.75(s, lH), 41CH:) O CH:, H 3.79(s, 6H), 2.24(s, 3H), 2.04 (s, 3H) 42 CH:) O CII:~ H CH3 43 Et O H H H
44 n-Bu O I{ El E-l - 7.63(t, lH), 7.48(d, lI~), 7.36 H S E~ H H 80-81 (d, lH), 7.1-7.03(m, 3H), 6.74 (s, lH), 5.78(s, lH), 3.83(s, 61-1) 7.63(t, lH), 7.35(d, lH), 7.07-7.02(dd, 2H), 6.89-6.87 47 H S H H CH3177-178 (d lH) 67(s, lH), 5.78(s, lH), 3.84(s, 6H), 2.33(s, 3H) 7.62(t, lH), 7.10-7.00(m, 4H), 48 H S Br H H 6.63(s, lH), 5.78(s, lH), 3.82 (s, 6H) 49 H S H Br H

51 CH3 S H H CH3155-156 EXAInPIe 8 52 CH~ S CICH2 H H

Table 2. (continlle-l) 54 CH3 S MeO H H
CH3 S Cl H H
56 CF~ S H H H
57 Et S H H H
58 ClCHz S H H H
1 o 59 Cl(CHz)z S H H H
H NMe H H H

62 CHI NMe H H E~ 147-149 ~X Im~'c 9 63 CH3 NMe Ph H
64 CH~ NMe 5-CN-Ph H
65 C11) NMc 5-NOz-Ph H
66 CH3 NMe 5-MeS-Ph H

67 CH3 O Ph H 201-203 F~rrr'~ 7 68 CH3 O 5-MeO-Ph H

On the other hand, the compound of formula (XII) used as a:
starting material for preparing the compound of formula (IVb) is a new one, and can be prepared by re~tin~ a known 2,6-dihydroxybenzoic acid having the following formula (XIV) and a carbonyl compound having the 30 following formula (XV) with thionyl chloride in a solvent in the presence of a catalytic amount of dimethylaminopyridine as described in the following reaction schPme I.

21 9408~
Reaction Sch~mP I:

HO~ OH R6~R7 SOC12, Solvent HO~ 5 Q~R D~

(xlv) (xv in the re~tion sch~m- I, R:~ Rs, l~u, I~ and Q are defined as previously desclibed.

In Lhe reaclion s~hPme I, an ether such as tetrahydrofuran, dielhylelher, diln~ hoxyelllane, etc., a polar solvent such as dimetllylformamide, dimethylsulfoxide, etc., a halogenaled hydrocarbon solv(:nt such as dicllll)romelllalle, carlx)n telracllloride, etc., or an aromatic 20 hydlocarbon solvent such as benzene, toluene, xylene etc., preferably tliln~-tlloxyethane or toluene can be used as the solvent. This reaclion can be carried out at 10 to 80C, preferably at 20 to 30C.

Typical examples of the compound of folmula (XII) prepared according to the process as explained above are presented in the following Table 3.

21 94~0 Table 3.

1~3 Q 115 1~ 1~7mp.(-C) ~H NMI~(270 MHz, CDCb) NO.
69 H O H H H 106-109 FY~rnp~? 1 71 CH3 O H EI H 84-86 F~c~mr'e 2 10.17(s, Oll), 7.40(t, lH), 6.60 (d, 111), 6.50(d, lH), 6.25(d, lH), 72Cf-13 O Cll:l 11 El 5.87(d, lH), 2.24(s, 3H), 2.04 (s, 31-1) 73CEI3 O Cl~ 1 Cf-13 74 Et O H H 1-1 75 n-Bu O I I 1~
10.18(s, OIl), 7.54(t, ll-I), 7.50 (s, lI-I), 7.41(d, lH), 7.12(d, lH), 76 H S H H El 126-129 684(s, 11-1), 6.75(d, lH), 6.63 (d, lH) 77 H S CI-13 H f-I
78 El S H H CH3135-136 Fy~mr'e 3 10.24(s, OH), 7.63(t, lH), 7.26 79 fI S 13r 1-1 11 138-140 (dd, 21-1), 6.88(d, ll-I), 6.87~s, lH), 6.74(d, lH) H S H Br El 10.14(s, OH), 7.40(t, lH), 7.08 (d, lH), 6.72(d, lH), 6.55 82 CH3 S H H CH3117-119 (dd 21~), 2.32(s. 3H), 2-04 (s, 311) Table 3. ~continued) 85 CH3 S MeO H H
86 CH3 S Cl H H
87 C~3 S H H H
88 Et S H H H
1 0 89ClCH:~ S H H H
90 Cl(C~)~ S H H H
91 H NMe H H H
92 CH3 NH H H H 138-140 F~ mr'e 4 93 CH:~ NMe H H El 94 CH3 NMe Ph H
95 CH3 NMe 5-CN-Ph H

2 0 96 CH3 NMe5-NO ,-Ph H
97C~L~ NMe5-l~leS-Ph H
98 CH3 O Ph H 138-140 Example 5 99 CH3 0 5-MeOPh H

Among the cyclic acetal compound of formula (IV) above, a Rll R12 ( R13 X ~)m compound of formula (IVc) wherein R4 represents --CH2>~Y

(wherein, Rs, Rlo, Rll, Rl2, Rl3, X, Y and m are defined as previously described) can be prepared as explained in the following reaction s- h.om~
J. According to the reaction sch~me J, a diketone derivative having 21 9~080 the following formula (XVI) is introduced into the known 2,6-dihydroxybenzoic acid of formula (XIV) using a halog~n~ting agent to produce a cyclic acetal compound having the following formula (XVII) in the first reaction step, the compound (XVII) thus obtained is reacted with a compound having the following formula (XVIII) to produce a compound having the following formula (XIX) in the second step, and finally the compound (XIX) thus obtained is reacted with the pyrimidine derivative of formula (VI) in the third reaction to prepare the compound of formula (IVc).
10 Re~r~ion Scheme J:

OH O O O
~C02HR3J~ Rg (XVI) ~ X~~

H ~0 ~ _ A~cnl Rg (XIV) Slcp I (XVII) Rl.3 XH~YH (XVIII) 110~R13 N
(XIX) OCH3 (Vl) ~N 0~R~0>~12 ~=N ~ X X ~)m CH30 ~ Rg (IVc) in the re~tion s- h~mP J, 2 1 94~80 E~3, Rs to Rl3, X, Y, m and Z are defined as previously described.

First, in the first reaction step the compound of formula (XVII) is plepaled by re~cting the known 2,6-dihydroxybenzoic acid of formula (XIV) with the ~ikPtone derivative of formula (XVI) in the presence of a halogen~ting agent. As the halog~n~tin~ agent appropriate for this reaction, phosphorus oxychloride, thionyl chloride, etc., particularly preferably phosphorus oxychloride can be mentioned.

The reaction of the first step can be preferably carried out in a solvent. The solvent suitable for this reaction includes ethers such as tetrahydrofuran, diethylether, ~lim~th~xyeth~n~, etc., polar solvents such as ~imPthylforrn~mi~le, dimethylsulfoxide, etc., halogenated hydrocarbons such as dichlorom.oth~ne, carbon tetrachloride, etc., and aromatic hydrocarbons such as benzene, toluene, xylene, etc.; and a mixture o~ 2 or more of these solvenls can also be used. The reaction temperature of Ihe first step is not specifically limited, however, it is conventionally desiral)le to carry out the reaction at 0 to 50C, preferably 10 to 25C for 4 to 6 hours.

In the second step of the reaction scheme J, the cyclic acetal compound (XVII) obtained in the first step is reacted with the compound of forrnula (XVIII) to produce the compound of formula (XIX). This reaction is carried out for protecting the ketone group which has been introduced by the diketone derivative in the first step.

The introduction of a protecting group by the compound of formula (XVIII) is carried out through a conventional k~t~ ing process.
That is, the compound (XVII) is reacted with the compound (XVIII) in a solvent in the presence of a catalyst while the water produced during the reaction is continuouslY elimin~te~l by an azeotropic distillation.

21 940~0 In this reaction, as the base pyrimidine hydrochloride, pyridine, p-tol-l~neslllfonic acid, selenium oxide, oxalic acid, adipic acid, trifluoroboron diethylether, etc. can be used, and a mixture of 2 or more of these catalysts can also be used. Among these catalysts, p-tol..Pneslllfonic acid or pyridine can be used more preferably. This reaction can also be carried out in the presence of a solvent, and as the solvent appropriate for this purpose, one or more selected from a group 10 consisting of ethers such as tetrahydrofuran, diethylether, ~lim~otl~oxy elh~ne, etc., polar solvents such as dimethylform~mi-l~, dimethylsulfoxide, etc., halogenated hydrocarbons such as dichloromPth~ne, carbon tetrachloride, etc., and aromatic hydrocarbons such as benzene, toluene, xylene, etc. can be exemplified. Among these solvents, toluene, ~iimf~-hQxyethane or dichlorom~th~rle is more preferable. The reaction temperature of the second step is not specifically limited, however, it is conventional to carl~ out the reaction at 110 to 120-C, at which the toluene is azeotropically distilled, for 2 to 4 hours.

In the third step of the reaction sch~m~ J, the compound of formula (XIX) obtained in the second step is reacted with the pyrimidine derivative (VI) to produce the desired 5-(4,6-dimethoxypyrimidin-2-yl)oxy-4H-(1,3)-benzodioxin-4-one derivative of formula (IVc).

The reaction of the third step is preferably carried out in the presence of a base, and as the base appropriate for this purpose, an 30 inorganic base such as pot~ssillm carbonate, sodium carbonate, sodium hydride, sodium hydrogen carbonate, etc., preferably potassium carbonate or sodium hydride can be mentioned. The reaction temperature can vary in a range of normal temperature to 150~C. Preferably, the reaction is carried out at 50 to 80~C for 3 to 5 hours.

Typical examples of the compound of formula (IVc) prepared 21 q40~0 I_ .
according to the process as Pxr~l~inPll above are presente.l in the following Table 4.

Table 4 R3 1~ Rlo Rll Rl2 Rl3 X Y m NO.

101 CE~3 CH3 H H H H O O
102 CH3 CH:~ H H H H S S O
103 CE~3 CH~ H H H H O S O
104 CH:~ CH3 CH3 H CH3 H O O 0 105 CH3 CH3 CH:~ H C2H5 H O O 0 106 CH~ CH3 H H CH3 CH~ O O
107 CH~ CH3 Cl~ I H H O O

The present invention will be more specifically explained by the following examples. However, it should be understood that the following preparations and examples are intended to illustrate the present invention and not to limit the scope of the present invention in any manner.

Preparation 1: Syn~he-sis of acetophenone oxime sodium salt To a mixture of 4.8g of sodium hydride (60%) and 300mQ of tetrahydrofuran was slowly added 12g of acetophenone oxime while 30 k.oeping the temperature below 5~C and the solution was stirred at normal temperature for 20 minutes. Then, the reaction mixture was distilled under re~ etl pressure to obtain 13g (Yield 93.7%) of the title compound having a white color.

~H NMR (DMSO-dG, 270MHz) : ~ 7.60(d, 2H), 7.16(t, 2H), 7.00(t, lH), 1.97(s, 3H) 2 1 94a80 EXAMPLE 1: Synthesi~ of 2-(furan-2-yl)-5-hydroxy-4H-[1,3]-benzo-dioxin-4-one 1.54g of 2,6-dihydroxybçn7Oic acid, 1.0g of 2-furylaldehyde and catalytic amount of dimethylaminopyridine were added to 10mQ of rlimethoxyeth~ne. The reaction temperature was lowered to 20 C and then 1.67g of thionyl chloride was slowly added dropwise to the reaction solution. After the addition was completed, the mixture was stirred for 4 hours and ~listillp~l under reduced pressure to ~limin~te ~limPthoxy etl~z~ne. lOme of dichlorom.~thz-ne was dissolved in the mixture, lOme of aqueous sodium bicarbonate solution was added thereto, and then this mixture was extracted with 20me of dichloromPth~ne. After removing the water contained in the extract over anhydrous magnesium sulfate, the extract was filtered through silica gel and distilled under reduced prcssure to produce a solid compound. The compound thus produced W.IS recrystsllli7e-1 from small amount of dichlorom~th~ne and hexane to obtain 2.2g (9.5mmol, Yield 95%) of the title compound.

~H NMR(CDCI3, 270 MHz): ~ 10.1(s, OH), 7.55(s, lH), 7.49(t, lH), 6.76(d, lH), 6.72(s, lHi, 6.64(s, lH), 6.57(s, lH), 6.49(s, lH) EXAMPLE 2: SynthPcis of 2-(furan-2-yl)-5-hydroxy-2-methyl-4H-tl,3]-benzo~1ioxin-4-one 1.54g of 2,6-dihydroxyben7Oic acid, 1.10g of 2-acetylfuran and 3 ~ catalytic amount of dimethylaminopyridine were added to 10m~ of dim~thoxyethane. The reaction temperature was lowered to 20~C and then 1.67g of thionyl chloride was slowly added dropwise to the reaction solution. After the addition was completed, the mixture was stirred for 4 hours and distilled under reduced pressure to çlimin~te ~linlethoxy eth~ne. 10me of dichloromPt~n~ was dissolved in the mixture, 10me of .. :

21 94~80 aqueous sodium bicarbonate solution was added thereto, and then this mixture was extracted with 20me of dichlorometh~ne. After removing the water cont~ine-l in the extract over anhydrous magnesium sulfate, the extract was filtered through silica gel and distilled under re~ ce-pressure to produce a solid compound. The compound thus produced was recryst~lli7e~1 from small amount of dichlorom~th~ne and hexane to obtain 2.31g (9.39mmol, Yield 94%) of the title compound.
lH NMR(CDCI3, 270 MHz): ~ 10.17(s, OH), 7.5-7.3(m, 2H), 6.65(d, lH), 6.52(d, lH), 6.40(d, lH~, 6.30(d, IH), 2.10(s, 3H) EXAMPLE 3: Synthesis of 5-hydroxy-2-(3-methylthiophen-2-yl)-4H-[1,3] -benzodioxin-4-one 1.54g of 2,6-dihydroxybenzoic acid, 1.26g of 3-methylthiophene aldehyde and catalytic amount of dimethylaminopyridine were added to 10 20 me of ~lime~hoxyeth:lne. The reaction temperature was lowered to 20~C
and then 1.67g of thionyl chloride wàs slowly added dropwise to the reaction solution. After the addition was completed, the mixture was stirred for 4 hours and distilled under reduced pressure to elimin~te ~limethoxy ethAne. lOlne of dichlorom.othzlne was dissolved in the mixture, 10me of aqueous sodium bicarbonate solution was added thereto, and then this mixture was extracted with dichlorom~th~ne. After removing the water contained in the extract over anhydrous magnesium sulfate, the extract was filtered through silica gel and distilled under reduced - pressure to produce a solid compound. The compound thus produced was recryst~lli7e~1 from small amount of dichlorometh~ne and h~x~n~ to obtain 2.3g (8.78mmol, Yield 88%) of the title compound.

H NMR (CDCI3, 270 MHz): ~ 10.18(s, OH), 7.48(t, lH), 7.38(d, lH), 6.89 (d, lH), 6.79(s, lH), 6.74(d, lH), 6.59(d, lH), 2.35(s, 3H) EXAMPLE 4: Synthesis of 5-hydroxy-2-methyl-2-(lH-pyrrol-2-yl)-4H- [1,3] -benzodioxin-4-one 1.54g of 2,6-dihydroxybenzoic acid, 1.09g of 2-acetylpyrrole and caWytic amount of 4-dimethylaminopyridine were added to 10mQ of ~im~thoxyeth~n~. The re~tif)n temperature was lowered to 20~C and then 1.67g of thionyl chloride was slowly added dropwise to the reaction solution. After the addition was comrlete-~, the mixture was stirred for 10 4 hours and ~iistille~l under reduced pressure to elimin~te ~iimPth()xy eth~n~. lOme of dichlororn~th~ne was dissolved in the mixture, lOme of aqueous sodium bicarbonate solution was added thereto, and then this mixture was extracted with dichlorometh~ne. After removing the water cont~in~-l in the extract over anhydrous magnesium sulfate, the extract was filtered through silica gel and distilled under re-lnce-l pressure to produce a solid compound having a deep violet color. The compound Ihus produced was rccrys~ e-l from small amount of hexane to obtain 1.93g (7.~8mmol, Yield 79%) of the title compound.

H NMR (CDCl3, 270 MHz): ~ 10.15(s, OH), 8.32(br, NH), 7.4(t, lH), 6.74 (d, lH), 6.55(d, lH), 6.50(d, lH), 6.25(d, lH), 6.10(d, lH), 2.05(s, 3 H) EXAMPLE 5: Synthesis of 2-(benzofuran-2-yl)-5-hydroxy-2-methyl-4H-[1,3] -benzodioxin-4-one 1.54g (lOmml) of 2,6-dihydroxybenzoic acid, 1.60g of benzofuran-2-ylmethylketone and catalytic amount of 4-dimethylaminopyridine were added to lOme of r1im.o~hoxyeth~n~. The reaction temperature was lowered to 20 C and then 1.67g of thionyl chloride was slowly added dropwise to the reaction solution. After the addition was completed, the mixture was stirred for 4 hours and distilled under re~ ce-l pressure to eliminzte ~limPthoxyethane. lOme of dichloromethane was dissolved in the mi~;ture, 10mQ of aqueous sodium bicarbonate solution was added thereto, and then this mixture was extracted with 20me of dichloromrth~ne. After removing the water contained in the extract over anhydrous magnesium sulfate, the extract was filtered through silica gel and distilled under r~lllce~ pressure to produce a solid compound. The compound thus pro-l.-ce-l was recrystallized from small amount of dichlorometh:~.ne and hexane to obtain 2.29g (7.7mmol, Yield 77%) of the title compound.
'H NMR (CDCl3, 270 MHz): ~ 10.11(s, OH), 7.54-7.21(m, 5H), 6.77 (s, 1 H), 6.58(t, 2H), 2.15(s, 3H) EXAMPLE 6: Synthesis of 5-(4,6--limr~hoxypyrimidin-2-yl)oxy-2-(furan-2-yl) -4H-~1,3] -benzodioxin-4-one 1.16g (5mmol) of 2-(furan-2-yl)-5-hydroxy-4H-[1,3]-benzo-dioxin-4-one prcpared in Example 1 and 2.07g of potassium carbonate were dissolved in 10me of dimethylformamide. 1.09g of 2-methyl sulfonyl-4,6-rlim~othoxypyrimidine was added thereto, and the mixture was stirred at 80C. After the completion of the reaction was confirmed by TLC, the reaction solution was mixed with 100mQ of diethylether and 100 me of water, and then the organic layer was extracted. The water contained in the extract was removed over anhydrous magnesium sulfate and then the extract was distilled under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl ~ret~te = 4/1, v/v) to obtain 1.57g (4.2mmol, Yield 85%) of the title compound.

H NMR (CDCI3, 270 MHz): ~ 7.53(t, lH), 7.42(s, lH), 6.95(d, 2H), 6.52 (d, lH), 6.45(s, lH), 6.38(d, lH), 5.70(s, lH), 3.75(s, 6H) 21 94~

EXAMPLE 7: Synthesis of 2-(benzofuran-2-yl)-5-(4,6--limethoxypyri-midin-2-yl)oxy-2-methyl-4H-[1,3] -benzodioxin-4-one 0.16g (0.54mlnol) of 2-(benzofuran-2-yl)-5-hydroxy-2-methyl-4H-[1,3]-bPn~o~lioxin-4-one prepared in ~:x~mr~le 5 and 40mg of potassium carbonate were dissolved in lOmQ of dimethylform~mi-lP. 0.12g of 2-methylsulfonYl-4~6-(1imethoxypyrimi~lin~ was added thereto, and the mixture was stirred at 80UC. After the completion of the reaction was confirmed by TLC, the reaction solution was mixed with lOOmQ of diethylether and lOOme of water, and then the organic layer was extracted. The water cont~ine-l in the extract was removed over anhydrous magnesium sulfate and then the extract was distilled under re~ e-1 pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl ~q~et~te = 4/1, v/v) to obtain 0.16g (0.38mmol, Yield 70%) of the title compound.

lH NMI~ (CDCI3, 270 MHz): ~ 7.52-7.4Z(m, 3H), 7.29-7.20(m, 3H), 7.00-6.97(d, lH), G.88(d, lH), 6.77(s, lH), 3.62(s, 6H), 2.11(s, 3H) EXAMPLE 8 : Synthesis of 5-(4,6-(lim.othl xypyrimidin-2-yl)oxy-2-(3-methylthiophen-2-yl)-4H-[1,3] -benzodioxin-4-one 0.42g (1.6mmol) of 5-hydroxy-2-(3-methylthiophen-2-yl)-4H-[1,3]-berl~o~lioxin-4-one prepared in 1; ~C~mrlle 3 and 0.46g of potassium carbonate were dissolved in 10mQ of dimethylformamide. 0.60g of 3 ~ 2-methylsulfonyl-4,6-rlim~othoxypyrimidine was added thereto, and the mixture was stirred at 80 C. After the comr letion of the reaction was confirmed by TLC, the reaction solution was mixed with lOOmQ of diethylether and 100me of water, and then the organic layer was extracted. The water contained in the extract was removed over anhydrous magnesium sulfate and then the extract was distilled under c~ 2194~80 red-l~erl pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl ~cet~te = 4/1, v/v) to obtain 0.52g (1.3mmol, Yield 81%) of the title compound.

H NMR (CDCI3, 270 MHz): ~ 7.52(t, lH), 7.05(d, lH), 6.98(d, lH), 6.78 (d, lH), 6.7(d, lH), 5.71(s, lH), 3.69(s, 6H), 2.3(s, 3H), 2.04(s, 3H) EXAMPLE 9: Synthesis of 5-(4,6--lim~thoxypyrimidin-2-yl)oxy-2-methyl-2- (1 -methylpyrrol-2-yl) -4H-[1,3] -benzodioxin-4-one .

0.87g (3.35mmol) of 5-hydroxy-2-methyl-2-(1-methylpyrrol-2-yl)-4H-~1,3]-benzodioxin-4-one and 0.23g of potassium carbonate were dissolved in lOnle of dimethylformamide. 0.73g of 2-methylsulfonyl-4,6-~imP~I-oxypyrimidine was added thereto, and the mixture was stirred at 80 C. Afler the completion of the reaction was confirmed by TLC, the reaction solulion was mixed wilh lOOIne of diethylether and lOOme of water, and then the organic layer was extracted. The water contained in the extract was removed over anhydrous magnesium sulfate and then the extract was distilled under re-l--cecl pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate = 4/1, v/v) to obtain l.Og (2.52mmol, Yield 75%) of the title compound.

~H NMR (CDCI3, 270 MHz): ~ 7.48(t, lH), 6.87(d, lH), 6.80(d, lH), 6.59 (m, lH), 6.4(m, lH), 6.03(m, lH), 5.73(s, lH), 3.71(s, 6H), 3.53(s, 3 H), 1.96(s, 3H) EXAMPLE 10: Synthesis of 5-(4,6-fiimPthoxyl~y,illlidin-2-yl)oxy-2-(furan-2-yl) -2-methyl-4H-~1,3~ -benzodioxin-4-one l.Og (4mmol) of 2-(furan-2-yl)-5-hydroxy-2-methyl-4H-[1,3]-benzodioxin-4-one prepared in Example 2 and 0.89g of potassium 21 940'80 carbonate were dissolved in 10mQ of dimethylform~mi~le. 0.89g of 2-methylsulfonyl-4,6-dimethoxypyrimi-line was added thereto, and the mixture was stirred at 80 C. After the completion of the reaction was confirmed by TLC, the reaction solution was mixed with lOOme of diethylether and 100me of water, and then the organic layer was extracted. The water cont~ine-l in the extract was removed over anhydrous magnesiurn sulfate and then the extract was distilled under 10 re~ ce-l pressure. The residue was subjected to silica gel column cbromatography (eluent: hexane/ethyl acetate = 4/1, v/v) to obtain 1. lg (~.86mmr~l, Yield 72%) of the title compound.

H NMR (CDCI3, 270 MHz): ~ 7.50(t, lH), 7.32(s, lH), 6.9(dd, 2H), 6.38 (d, lH), 6.25(d, lH), 5.77(s, lH), 3.78(s, 6H), 2.04(s, 3H) EXAMPLE 11: Synthesis of 2,6-di(4,6-rlimP~-hoxypyrimidin-2-yl)oxybenz-oic acid acetophenone oxime ester 16g of acetophenone oxime sodium salt prepared in Preparation 1 was dissolved in 100me of dimethylformamide, and this solution was added dropwise to a solution of 37.0g of 5- (4,6-dimethoxypyrimidin-2-yl)oxy-2-(furan-2-yl)-4H-[1,3]-benzodioxin-4-one prepared in F.~mple 6 in 100me of dimethylformamide at room temperature. The resulting solution was stirred for 30 minutes and added dropwise to a mixture of 21.8g of 4,6--lim~thoxy-2-methylsulfonylpyrimidine and 1.38g of potassium carbonate in 60me of dimethylformamide. The reaction solution was stirred for 1 hour while keeping the temperature at 80 to 85 ~C, and then ~1i5~ille~1 under reduced pressure to remove the solvent. The residue was extracted with water and dichloromPth~nP, and the organic layer separated was dried over anhydrous sodium sulfate, distilled under rerl~l~e-l pressure and recryst~ etl from acetone to obtain 35g of the title compound as a white solid.

_ 35 _ 2 ~ 94080 H NMR (CDCI3, 270 MHz): ~ 7.19-7.62(m, 8H), 5.73(s, 2H), 3.78(s, 12 H), 2.26(s, 3H) MS(FAB) 548 m.p.: 85 to 94 C

EXAMPLE 12: Synthesis of 2,6-di(4,6--lim.oth-)xypyrimidin-2-yl)oxybenz-oic acid acetophenone oxime ester 16g of acetophenone oxime sodium salt prepared in Preparation 1was dissolved in lOOme of dimethylforms~mi-lP, and this solution was added dropwise to a solution of 37.0g of 5-(4,6-rlime~hoxypyrimidin-2-yl)oxy-2-(furan-2-yl)-4H-[1,3]-benzodioxin-4-one prepared in Fx:~mple 6 in lOOme of ~lim~hylform~mill~ at room temperature. The resulting solution was s-irred for 30 minutes and then 21.8g of 4,6--lime~ hoxy-2-metllylsulfonylpyrimidine and 1.3u of potassium 20 carbonate were added thereto. The temperature of the reaction solution was raised to 80 to 85 C, and then the solution was stirred for 3 to 4 hours. The solvent was distilled off under reduced pressure and the residue was treated according to the same procedure as ~x~mr le 11 to obtain 30g of the title compound.

EXAMPLE 13: Synthesis of 2,6-di(4,6-dimethoxypyrimidin-2-yl)oxybenx-oic acid ben~oph~none oxime ester 5.0g of sodium hydride (60%) and 38.4g of 5-(4,6-~limf-thoxypyrirnidin-2-yl)oxy-2-(furan-2-yl)-2-methyl-4H-[1,3]-benzodio xin-4-one prepared in ~x~mrlle 10 were added to lOme of im~thylform:lmi~le and the temperature of the m-ixture was keeped at 5~C.
To this mixture was added dropwise 19.7g of benzophenone oxime dissolved in 40mQ of dimethylformamide and the resulting solution was stirred for 20 minutes at normal temperature. After the reaction was completed, the whole mixture was added dropwise to a mixture of 21.8g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.3g of potassium carbonate in lOOme of dimethylformamide. The reaction solution was stirred for 2 hours while kPep;ng the temperature at 80~C, and then distilled under reduced pressure to remove the solvent. The residue was treated according to the same procedure as Example 11 to obtain 34g of 10 the title compo-m~l, H NMR (CDCI3, 270 MHz): ~ 7.10-7.48(m, 13H), 5.72(s, 2H), 3.72 (s, 1 2H), MS(FAB) 610 m.p.: 128 to 130-C

EXAMPLE 14: Synthesis of 2,6-di(4,6--lime~ho~cypyrimidin-2-yl)oxybenz-oic acid benzophenone oxime ester 5.0g of sodium hydride (60%) and 38g of 5-(4,6--lim~thoxy-pyrimidin-2-yl)oxy-2- (3-methylthiophen-2-yl)-4H-[1,3] -benzodioxin-4-one prepared in Example 8 were added to 150mQ of ~limethylform~mi~leand the temperature of the mixture was kPepe(l at 5C. To this mixture was added dropwise 19.7g of benzophenone oxime dissolved in 40me of dimethylforms3mi.1P. The temperature of the resulting solution was 30 raised to room temperature, and then the solution was stirred for 20 minll~Ps 21.8g of 4,6--limPthoxy-2-methylsulfonylpyrimi-line and 1.3g of potassium carbonate were added thereto and the whole mixture was stirred for 3 to 4 hours while keerins~ the temperature at 80 to 85~C.
The solvent was removed by distillation under retlll~e-l pressure and then the residue was treated according to the sarne procedure as Example 11 to obtain 34g of the title compound.

2 ~ 94 ~8~

~XAMPLE 15: Synthesis of 2,6-di(4,6--limethoxypyrimidin-2-yl)oxybenz-oic acid benzophenone oxime ester 19.7g of benzophenone oxime was added to 5.0g of sodium hydride (60%) dissolved in 300me of tetrahydrofuran and the mixture was stirred for 20 min~1tes at normal temperature. To this reaction mixture was added 37.0g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-(furan-2-yl)-4H-[1,3]-hen~o~liQxin-4-one prepared in F.x~mrlle 6. The whole mixture was stirred for 20 minutes at normal temperature and distilled under reduced pressure to obtain 2-(4,6--lime~hoxypyrimidin-2-yl)oxy-6- hydroxybenzoic acid benzophenone oxime ester sodium salt. Thus produced solid salt was extracted with water and dichlorometh~rle. The organic layer was separated, dried over anhydrous sodium sulfate and distilled under re~ cefl pressure to obtain 30g of 2-(4,6--limethl~xy-pyrimidin-2-yl)oxy-6-hydroxy~er ~oic acid benzophenone oxime ester.
The resulting compound was dissolved in lOOme of dimethylformamide without further isolation or purification step, this solution was added dropwise to a mixture of 1.3g of potassium carbonate and 21.8g of 4,6-llimpthoxy-2- methylsulfonylpyrimidine in 60me of dimethylformamide at 80 C. The whole mixture was stirred for one hour while keeping the temperature at 80 to 85 C and distilled under reduced pressure to remove the solvent. The residue was treated according to the same procedure as ~x~mple 11 to obtain 30g of the title compound.
~XAMPLE 16: Synthesie of 5-(4,6--lim~thnxypyrimidin-2-yl)oxy-2,2-dimethyl-4H-[1,3] -benzodioxin-4-one 2.9g of 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-hydroxybenzoic acid, 60mg of dimethylaminopyridine and lmQ of acetone were added to 10 me of ~lim.othoxyeth~ne The reaction temperature was lowered to 20~C
and then 3g of thionyl chloride dissolved in lme of ~lim~thoxyethane was 21 94~80 slowly added dropwise thereto while keeping- the temperature below 30C.
After the addition was completed, the mixture was stirred for 2 hours.
Then, nitrogen gas was blowed into the reaction vessel to ~limin~te the anhydrous hydrochloric acid and then the reaction solution was ~listille~l under re~ erl pressure. The residue was dissolved in lOOm~ of hf-x:~ne-dichlorom~oth~n~ 1, v/v) solvent mixture, filtered through silica gel and then distilled under reduced pressure. To the residue was added 200me of hex~ne and the resulting solution was allowed to stand at 15-C
until a solid was produced. Thus produced solid was filtered to obtain 1.6g of the title compound.

~H NMR (270MHz, CDCI3): ~ 1.72(s, 6H), 3.82(s, 6H), 5.75(s, lH), 6.91(q, 2H), 7.55(t, lH) EXAMPLE 17: Synthesis of 5-(4,fi--limethoxypyrimidin-2-yl)oxy-2-cyclohexylene-4H-[1,3] -benzodioxin-4-one 3.1g of 2-(4,6--limethoxypyrimidin-2-yl)oxy-6-hydroxybenzoic acid, 62mg of of 4-dimethylaminopyridine and 1.32g of cycloh~x~none were added to lOme of dimethoxyeth:~-le. The reaclion temperature was lowered to 20 C and then 3g of thionyl chloride dissolved in lme of tlimPthoxyethane was slowly added dropwise thereto while keeping the temperature below 30~C. After the addition was completed, the mixture was stirred for 2 hours. Then, nitro~en gas was blowed into the reaction vessel to elimin~e the anhydrous hydrochloric acid and then the reaction solution was distilled under reduced pressure. The residue was treated according to the same procedure as ~x~mr)le 16 to obtain 1.29g of the title compound havin~~ a white color.

H NMR (270MHz, CDCI3): ~ 1.39-1.69(m, 6H), 1.87-2.03(m, 4H), 3.81(s, 6 H), 5.77(s, lH), 6.41(d, lH), 6.56(d, lH), 7.35(t, lH), 10.29(s, lH) '_ EXAMPLE 18: Syn~hesi~s of 5-(4,6--limethoxypyrimidin-2-yl)oxy-2-phenyl-4H-tl,3] -benzodioxin-4-one 0.8g of 5-hydroxy-2-phenyl-4H-[1,3]-benzodioxin-4-one, 0.68g of potassium carbonate and 0.72g of 4,6-dim~thoxy-2-methylsulfonyl-pyrimi~line were added to 50mQ of dimethylform~mi~e. The reaction solution was stirred for 6 hours while h~ting to 80 to 85~C. The solvent was evaporated from the solution and then water and 10 dichloronleth~ne were added to the residue to extract the organic layer.
The separated organic layer was dried over anhydrous sodium sulfate, evaporated, and subjected to silica gel column chromatographythy to obtain l.lg of the title compound.

~H NMR (270MHz, CDCI3): 83.83(s, 6H), 5.78(s, lH), 6.49(s, lH), 7.04(d, 2H), 7.41-7.48(m, 3H), 7.61-7.65(m, 3H) EXAMPLE 19: Synthesis of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-4H-tl,3] -benzodioxin-4-one 6.0~ of 2-(4,6--iimPthoxypyrimidin-2-yl)oxy-6-hydroxybenzoic acid, 20g of dibromometh~n~o and 2g of potassium hydroxide were dissolved in 300l of dimethylformamide, and the mixture was stirred under reflux for 10 hours. Then, the solvent was distilled off under re-luce-l pressùre and the residue was subjected to silica gel column chromatography to obtain 0.55g of the title compound.

~H NMR (270MHz, CDCW: ~ 7.58(t,1H), 7.01(d,1H), 6.97(d,1H), 5.76 (s,l H), 5.60 (s,2H), 3.81(s,6H) EXAMPLE 20: Syn~heci~s of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-methyl-2-(2-methylpropen-1-yl)-4H-[1,3]-benzodioxin-4 -one 21 94C~O

2.9g of 2-(4,6-llimethoxypyrimidin-2-yl)oxy-6-hydroxybenzoic acid, 60mg of 4-dimethylaminopyridine and l.Og of 4-methyl-3-penten-2-one were added to lOmQ of dimethoxyethane. The reaction temperature was lowered to 20~C and then 3g of thionyl chloride dissolved in lmQ of tlimf~thoxyethane was slowly added dropwise thereto while kPeping the temperature below 30 C. After the addition was completed, the mixture was stirred for 2 hours. Then, nitrogen gas was blowed into the reaction vessel to ~limin:lte the anhydrous hydrochloric acid and then the reaction solution was distilled under reduced pressure. The residue was dissolved in lOOme of hexane-dichlorom.oth~ne (1:1, v/v) solvent mixture, filtered through silica gel and tllen distilled under reduced pressure. To the residue was added 200me of hexane and the resulting solution was allowed to stand at 15~C until a solid was produced. Thus produced solid was filtered to obtain 1.9g of the title compound.

~H NMR (270M~Iz, CDCI~ 1.64(s,3~1), 1.80(s,6H), 3.79(s,6H), 5.35(s,1 H), 5.74 (s,lH), 6.88(t,2H), 7.51(t,1H) EXAMPLE 21: Synth~osic of 2,6-di(4,6--limethoxypyrimidin-2-yl)oxybenz-oic acid acetophenone oxime ester 13g of acetophenone oxime sodium salt prepared in Preparation 1 was dissolved in 40me of dimethylformamide, and this solution was added dropwise at room temperature to 27.0g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2,2-dimethyl-4H-[1,3]-benzodioxin-4-one dissolved in lOOmQ of 30 r1imf~thylformz~mi~1~o The resulting solution was stirred for 30 minutes and added dropwise to a mixture of 18.0g of 4,6-(limethoxy-2-methylsulfonylpyrimidine and 11.4g of potassium carbonate in 60mQ of ~imPthylform~mirle. The reaction solution was stirred for 1 hour while kf~eping the temperature at 80 to 85~C, and then distilled under reduced pressure to remove the solvent. The residue was extracted with water 2194~

and dichlorom~th~ne, and the separated organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure and recryst~lli7-e-l from acetone to obtain 24g of the title compound as a white solid.

EXAMPLE 22: Syn~hPcis of 2,6-di(4,6-dimethoxypyrimidin-2-yl)oxybenz-oic acid benzophenone oxime ester 5.0g of sodium hydride (60%) and 38g of 5-(4,6-Pthoxypyrimidin-2-yl)oxy-2-phenyl-4H-[1,3]-benzodioxin-4-one were added to 100me of dimethylformamide and the temperature of the mixture was kPepe-l at 5 C. To this mixture was added dropwise 19.7g of benzophenone oxime dissolved in 40me of dimethylformamide and the resulting solution was stirred for 20 minutes at normal temperature.
After the reaction was comrlletefl, the whole mixture was added dropwise to a mixture of 21.8g of 4,6--1imethQxy-2-methylsulfonylpyrimidine and 20 1.3g of potassium carbonate in lOOmQ of dimethylformamide. The reaction solution was stirred for 2 hours while keeping the temperature at 80~C, and then flistille-l under reduced pressure to remove the solvent. The residue was treated according to the same procedure as ~x~mple 21 to obtain 38g of the title compound.

EXAMPLE 23: Synthesis of 2,6-di(4,6-dimethoxypyrimidin-2-yl)oxybenz-oic acid ben7~1-1oxime ester 3 ~ 5.0g of sodium hydride (60%) and 33.2~ of 5- (4,6-~lim-~h~xypyrimidin-2-yl)oxy-2,2-dimethyl-4H-[1,3] -benzodioxin-4-one were added to lOme of dimethylformamide and the temperature of the mixture was kPer~e~l at 5C. To this mixture was added dropwise 12.1g of ben7~ phyde oxime dissolved in 40mQ of dimethylformamide and the res~ ing solution was stirred for 20 nunutes at normal temperature.

C 2 1 940~0 After the reaction was completed, the whole mixture was added dropwise to a mixture of 21.8g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.3g of potassium carbonate in lOOmQ of dimethylformamide. The reaction solution was stirred for 2 hours while k~eping the temperature at 80~C, and then distilled under reduced pressure to remove the solvent. The residue was treated according to the same procedure as F:x~mple 21 to obtain 42.1g of the title compound.

H NMR (CDCb, 270MHz): ~ 8.09(s, lH), 7.20-7.61(m, 8H), 5.73(s, 2H), 3.78(s, 12H) EXAMPLE 24: Synthesis of 2,6-di(4,6-dimethoxypyrimidin-2-yl)oxybenz-oic acid 4-nitrobPn7S-l~loxime ester 5.0g of sodium hydride (60%) and 38g of 5-(4,6-flime~ hoxypyrimidin-2-yl)oxy-2,2-dimethyl-4H-[1,3]-benzodioxin-4-one 20 were added to 150n~e of dimethylform~mi-l~ and the temperature was k~epe-l at 5 C. To this mixture was added dropwise 16.6g of 4-nitrohen~ldoxime dissolved in 40mQ of dimethylform~mi~le and the resulting solution was stirred for 20 min-ltes at room temperature. 21.8g of 4,6--lim~hoxy-2-methylsulfonylpyrimidine and 1.3g of potassium carbonate were added to this reaction mixture and the temperature was raised to 80 to 85C. Then, the solution was stirred for 3 to 4 hours at that temperature and distilled under reduced pressure to remove the solvent. The residue was treated according to the same procedure as Fx~mple 21 to obtain 39.9g of the title compound.

lH NMR (CDCI3, 270MHz): ~ 7.21-8.27(m, 8H), 5.74(s, 2H), 3.79(s, 12H) EXAMPLE 25: Synthesis of 2,6-di(4,6--limPthoxypyrimidin-2-yl)oxybenz-oic acid 4-mP~hQxyben~ loxime ester 15. lg of 4-methoxybenzaldoxime was added to 5.0g of sodium hydride (60%) dissolved in 300me of tetrahydrofuran and the mixture was stirred for 20 minutes at normal temperature. To this reaction mixture was added 38.0g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-phenyl-4H-~1,3]-hen7o~1ioxin-4-one. The whole mixture was stirred for further 20 minlltes at normal temperature and distilled under reduced pressure to obtain 2-(4,6-~1imPthoxypyrimidin-2-yl)oxy-6-hydroxybenzoic acid 4-methoxyl~Pr~7~ oxime ester sodium salt. Thus produced solid salt was extracted with water and dichlorometh~nP. The separated organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 30g of 2-(4,6-~1imPthoxypyrimidin-2-yl)oxy-6-hydroxybenzoic acid 4-methoxyben~ oxime ester. The resulting compound was dissolved in lOOme of dimethylform~mi-le without further isolation or purification step, and the solution thus obtained was added dropwise to a mixture of 1.3g of potassium carbonate and 21.8g of 4,6--iimPtlloxy-2-melhylsulfonylpyrimidine dissolved in 60me of r~imPthylform~mirle at 80 C. The whole mixture was stirred for one hour while kPeping the temperature at 80 to 85~C and distilled under reduced pressure to remove the solvent. The residue was trèated according to the same procedure as Fx~mr-le 21 to obtain 35g of the title compound.

Preparation 2: Synthesis of 5-hydroxy-2-methyl-2-(2-oxo-propyl)-benzo[l,3]dioxin-4-one 15.4g of 2,6-dihydroxybenzoic acid, 13.0g of 2,4-pentandione and 7.3g Of ~limPthylform~mitlP were dissolved in 150m~ of toluene and the resulting mixture was stirred while kPepin~ the temperature at lO C. To this m~ixture was slowly added dropwise 15.3g of phosphorus oxychloride while keeping the temperature in a range of 10 to 20~C and the resulting 3 ~ solution was stirred for 6 hours at normal temperature to complete the re~tion After the completion of the re~tion was confirmed by TLC, (Thin Layer Chromatography) sodium carbonate solution and aqueous sodium bicarbonate solution were sequentially used to neutralize the organic layer. The separated organic layer was washed with saline and water (once per each), dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: ethyl~cet~te/hexane=10/1) to obtain 20.2g (Yield 85.5%) of the title compound having a white color.

H NMR (CDCl3 270MHz): ~ 10.24(s, lH), 7.45(t, lH), 6.67(d, lH), 6.48(d, lH), 3.14(q, 2H), 2.27(s, 3H), 1.83(s, 3H) Preparation 3: Synthesis of 5-hydroxy-2-methyl-2-(2-methyl-[1,3]-dioxaran-2-ylmelhyl)benzo[1,3]dioxin-4-one Method A:

11.8~ of 5-hydroxy-2-methyl-2-(2-oxo-propyl)-benzo[1,3]-dioxin-4-one prepared in Preparation 2 and 12.4g of ethylene glycol were dissolved in lOOme of toluene, and to this solution were added 0.95g of p-toll-~nPslllfonic acid and 0.4g of pyridine. The resulting solution was refluxed for 2 hours while continuously removing the water. After the completion of the reaction was confilmed by TLC, the organic layer was separated, washed three times with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to silica 30 gel column chromatography (eluent: ethyl~et~t~/he~c~ne=10/1) to obtain 12.9g (Yield 92.1%) of the title compound.

H Nl\~R (CDCl3 270MHz): ~ 10.24(s, lH), 7.33(t, lH), 6.56(d, lH), 6.35(d, lH), 3.88(m, 4H), 2.30(s,2H), 1.77(s, 3H), 1.34 (s, 3H) Method B:

15.4g of 2,6-dihydroxybenzoic acid, 13.0g of 2,4-pentandione and 7.3g of riim~thylform~mif~f- were dissolved in 150me of toluene and stirred while kP~r in~ the temperature at 10~C . To this rruxture was slowly added dropwise 15.3g of phosphorus oxychloride while keeping the temperature in a range of 10 to 20 C and the resulting solution was stirred for 6 hours at normal temperature to complete the reaction. After the re~tion was completed, sodium carbonate solution and aqueous sodium bicarbonate solution were seqll~nti~lly used to neutralize the reaction solution from which a toluene layer was separated. The separated toluene layer was dried over anhydrous sodium sulfate and filtered. Then, to this filtrate were added 21.0g of ethylene glycol, l.~g of p-toluenesulfonic acid and 0.7g of pyridine, and the resulting solution was reacted for 2 hours while removing the water under azeotropic distillation. Afler the reaction was completed, the organic layer was 2 ~ separated, washed with aqueous sodium bicarbonate solution and then washed twice with water. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 22.6g (Yield 80.7%) of the title compound as a syrup. The NMR data of the compound thus obtained was identical to those as mentioned in Method A.

Preparation 4: Synthesis of 5-hydroxy-2-metllyl-2-(2-methyl-[1,3]-dithioran-2-ylmethyl)benzo[1,3]dioxin-4-one 11.8g of 5-hydroxy-2-methyl-2-(2-oxo-propyl)-benzo[1,3]-dioxin-4-one prepared in Preparation 2, 18.8g of 1,2-eth~n~thiol, 0.95g of p-tol-l~nes.llfonic acid and 0.4g of pyridine were dissolved in lOOmQ of toluene and this solution was refluxed for 4 hours while continuously removing the water. After the completion of the reaction was confirmed ..

by TLC, the organic layer was separated, washed three times with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to silica gel column chromatography (eluent:
ethyl~ret~/hP~ne= 10/1) to obtain 13.7g (Yield 87.8%) of the title compound.

Preparation 5: Syn~hesis of 5-hydroxy-2-methyl-2-(2,5,5-trimethyl-[ 1,3]dioxan-2-ylmethyl)benzo[1,3]dioxin-4 -one 11.8g of 5-hydroxy-2-methyl-2-(2-oxo-propyl)-benzotl,3]-dioxin-4-one ple~)ared in Preparation 2, 20.8g of 2,2-dimethyl-1,3-propandiol, 0.95g of p-toh~en.osl-lfonic acid and 0.4g of pyridine were dissolved in lOOme of toluene and this solution was refluxed for 4 hours while continuously removing the water. After the completion of the reaction was confirmed by TLC, the organic layer was separated, washed 2 0 three times with aqueous sodium bicarbonate solutionr dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: ethyl~et~t~ x~nP=10/1) to obtain 12.9g (Yield 80.0%) of the title compound.

Preparation 6: Synthesis of 5-hydroxy-2-methyl-2-(2,4,5-tlimethyl-[1,3]dioxaran-2-ylmethyl)benzotl,3]dioxin-4-one 11.8g of 5-hydroxy-2-methyl-2-(2-oxo-propyl)benzo[1,3]
dioxin-4-one prepared in Preparation 2, 18.0g of 2,3-butandiol, 0.95g of p-toluenesulfonic acid and 0.4g of pyridine were dissolved in lOOme of toluene and this solution was refluxed for 4 hours while continuously removing the water. After the comr~letion of the reaction was confirmed by TLC, the organic layer was, separated, washed three times with 21 94~a~
aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to silica gel column chromatography (eluent:
ethyl~ret~t~/hexane= 10/1) to obtain 12.7g (Yield 82.4%) of the title compound.

EXAMPLE 26: Synthesis of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-methyl-2-(2-methyl-[1,3]dioxaran-2-ylmethyl)-benzotl,3]~0 dioxin-4-one 14.0g of 5-hydroxy-2-methyl-2-(2-methyl-[1,3]-dioxaran-2-yl methyl)-benzo-[1,3]dioxin-4-one prepared in Preparation 3 and 12.0g of 2-rnelhylsulfonyl-4,6-~iim~tho~rypyrimidine were dissolved in 150me of toluene, and to this solution was introfl--cefl 10.4g of potassium carbonate as a base. The resulting solution was stirred for 3 hours under reflux.
Afler the completion of the reaction was confirmed by TLC, the organic 20 layer was separated, washed with lOOme of water three times to remove the potassium carbonate, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to silica gel column chromatography (eluent ethyl~ et~/h~x~ne=10/1) to obtain 20.1g (Yield 96.0%) of the title compound having a white color.

H NMR (CDCI3 270MHz): ~ 7.56(t, lH), 6.94(d, lH), 6.88(d, lH), 5.75(s, lH), 3.91~3.95(m, 4H), 3.82(s, 6H), 2.38(q, 2Hj, 1.82 (s, 3H), 1.40(s, 3H) EXAMPLE 27: Synthesi~ of 5-(4,6--lim~thoxypyrimidin-2-yl)oxy-2-methyl-2-(2-methyl-[1,3]dithioran-2-ylmethyl)-benzo[1,3]
dioxin-4-one 15.6g of 5-hydroxy-2-methyl-2-(2-methyl-[1,3]-dithioran-2-yl 2 1 940~0 methyl)benzo-[1,3]dioxin-4-one prepared in Preparation 4 and 12.0g of 2-methylsulfonyl-4,6-dimethoxypyrimidine were dissolved in 150mQ of toluene, and to this solution was introduced 10.4g of potassium carbonate as a base. The resulting solution was stirred for 3 hours under reflux.
After the comrletion of the reaction was confirmed by TLC, the organic layer was separated, washed with lOOme of water three times to remove the potassium carbon ~le, dried over anhydrous sodium sulfate and 10 filtered. The filtrate was distilled under re~ ce~ pressure and the residue was subiected to silica gel column chromatography (eluent ethyl~ret~tP/hexane= 10/1) to obtain 18.8g (Yield 83.4%) of the title co~nro~lntl having a white color.

EXAMPLE 28: Synthesis of 5-(4,6--limethQxypyrimidin-2-yl)oxy-2-methyl-2-(2,5,5-trimethyl-[1,3]dioxan-2-ylmethyl)-benzo [1,3]dioxin-4-one 16.1g of 5-hydroxy-2-methyl-2-(2,5,5-trimethyl-~1,3]-dioxan-2-yl methyl)benzo-[1,3]dioxin-4-one prepared in Preparation 5 and 12.0g of 2-methylsulfonyl-4,6-~1im~qthoxypyrimidine were dissolved in 150me of toluene, and to this solution was introduced 10.4g of potassium carbonate as a base. The resulting solution was stirred for 3 hours under reflux.
After the comlletion of the reaction was confirmed by TLC, the organic layer was separated, washed with lOOme of water three times to remove the potassium carbonate, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was subjected to silica gel column chromatography (eluent ethyl~.~et~t.o~h~x~ne=10/1) to obtain 22.4g (Yield 91.0%) of the title compound having a white color.

EXAMPLE 29: Synthesis of 2,6-di(4,6--lim.othoxypyrimidin-2-yl)oxybenz-oic acid acetophenone oxime ester C_ 219408~
- 0.75g of acetophenone oxime sodium salt prepared in Preparation 1 was dissolved in 5mQ of dimethylform~mi(1~, and this solution was added dropwise to 4.2g of 5-(4,6--lim~thoxypyrimidin-2-yl)oxy-2-methyl-2-(2-methyl-~1,3~-dioxaran-2-ylmethyl)-benzo[1,3~dioxin-4-one prepared in F.x~mple 26 dissolved in 20mQ of dimethylform~mi-ie at room temperature.
The res-llting solution was stirred for 30 minutes and added dropwise to a mixture of 2.3g of 4,6-r1imPthoxy-2-methylsulfonylpyrimidine and 0.15g of potassium carbonate in lOmQ of dimethylformamide. The reaction solution was stirred for 2 hours while keeping the temperature at 80 to 85 C, and then ~istille-l under reduced pressure to remove the solvent.
The residue was extracted with water and dichloromPtllzln~, and the separated organic layer was dried over anhydrous sodium sulfate, distilled under re.l-lce-i pressure and recryst~ e-l from acetone to obtain 4. lg (Yield 85.0~o) of the title compound as a whute solid.

EXAMPLE 30: Synthesis of 2,6-di(4,6--lim~hoxypyrimidin-2-yl)oxybenz-oic acid benzophenone oxime ester 4.4g of sodium hydride (60%) and 41.8g of 5-(4,6-~1im~th~xypyrimidin-2-yl)oxy-2-methyl-2-(2-methyl-~1,3]dioxaran-2-yl methyl)-benzo[1,3]dioxin-4-one prepared in Example 26 were added to 200me of dimethylform~miri~ and the temperature was kPepe~l at 5 C. To this mixture was added dropwise 19.8g of benzophenone oxime dissolved in lOOmQ of dimethylformamide and the resulting solution was stirred for 30 20 minutes at normal temperature. After the reaction was completed, the whole mixture was added dropwise to a mixture of 24.0g of 4,6--lim~thl xy-2-methylsulfonylpyrimi-line and 1.4g of potassium carbonate in 150mQ of dimethylformamide. Then, the solution was stirred for 2 hours while k~eping the temperature at 80~C and distilled under re-lnce-l pressure to remove the solvent. The residue was treated according to the same procedure as F.XzmI~l~ 29 to obtain 52g (Yield 21 940~
,, .
85.4%) of the title compound.

EXAMPLE 31: Synthesis of 2,6-di(4,6-dimethoxypyrimidin-2-yl)oxybenz-oic acid benzophenone oxime ester 0.44g of sodium hydride (60%) and 4.5g of 5- (4,6-~lim~thoxypyrimidin-2-yl)oxy-2-methyl-2-(2-methyl-[1,3]dithioran-2-yl methyl)-benzotl,3]dioxin-4-one prepared in F.x~mple 27 were added to 20 me of ~lim~thylform~mi-le and the temperature was keeped at 5C. To this mixture was added dropwise 2.0g of benzophenone oxime dissolved in 10 me of ~limPthylform~mitle and the resulting solution was stirred for 20 minutes at normal temperature. After the reaction was completed, the whole mixture was added dropwise to a mixture of 2.4g of 4,6--limPthoxy-2-methylsulfonylpyrimirline and 0.15g of potassium carbonate in 15me of dimethylformamide. Then, the solution was stirred for 2 hours while keeping the temperature at 80 C and distilled under 2 0 re-l-.ce-l pressure to remove the solvent. The residue was treatedaccording to the same procedure as l; xz~mple 29 to obtain 4.4g (Yield 72.0%) of the title compound.

EXAMPLE 32: Synthesis of 2,6-di(4,6-dimethoxypyrimidin-2-yl)oxybenz-oic acid benzophenone oxime ester 0.44g of sodium hydride (60%) and 4.9g of 5- (4,6-~limelhoxypyrimidin-2-yl)oxy-2-methyl-2-(2,5,5-trimethyl-tl,3]dioxan-2-3 0 ylmethyl) -benzo[1,3]dioxin-4-one prepared in ~x~mr~le 28 were added to 20mQ of ~limpthylformamide and the temperature was k~epel at 5C. To this mixture was added dropwise 2.0g of benzophenone oxime dissolved in lOme of dimethylformamide and the resl-lting solution was stirred for 20 minutes at normal temperature. After the reaction was completed, the whole mixture was added dropwise to a mixture of 2.4g of . -- 51 --4,6-1lim~thoxy-2-methylsulfonylpyrimidine and 0.15g of potassium carbonate in 15me of dimethylform~mitl~. Then, the solution was stirred for 2 hours while keeping the temperature at 80~C and distilled under re~ e l pressure to remove the solvent. The residue was treated according to the same procedure as F.x~mr)le 29 to obtain 4.6g (Yield 76.1%) of the title compound.

EXAMPLE 33: Synth.osis of 2,6-di(4,6-~limethoxypyrimidin-2-yl)oxybenz-oic acid benzaldoxime ester 0.44g of sodium hydride (60%) and 4.2g of 5-(4,6-~1im~thoxypyrimidin-2-yl)oxy-2-methyl-2-(2-methyl-[1,3]dioxaran-2-yl methyl)-benzo[1,3]dioxin-4-one prepared in Ex~mple 26 were added to 20 me of ~lim~thylformamide and the temperature was k~epe~l at 5 C. To this mixture was added dropwise 1.2g of ber-7~1-1ehyde oxime dissolved in 10 me of ~iimPthylform,lmide and the resulting solution was stirred for 20 20 minlltes at normal temperature. After the reaction was completed, the whole mixture was added dropwise to a mixture of 2.4g of 4,6--lim~thQxy-2-methylsulfonylpyrimidine and 0.15g of potassium carbonate in 20me of dimethylform~mi-le. Then, the solution wàs stirred for 2 hours while keeping the temperature at 80 C and distilled under re~ erl pressure to remove the solvent. The residue was treated according to the same procedure as Fx~mple 29 to obtain 4.6g (Yield 86%) of the title compound.

EXAMPLE 34: Synthe-si-s of 2,6-di(4,6--limethoxypyrimidin-2-yl)oxybenz-oic acid 4-nitrob~on~ loxime ester 0.44g of sodium hydride (60%) and 4.2g of 5-(4,6-mf~thQxypyrimidin-2-yl)Qxy-2-methyl-2-(2-methyl-[l~3]dioxaran-2-yl methyl)-benzo[1,3]dioxin-4-one prepared in Fx~rnple 26 were added to 20 ~ 2194~80 me of ~limP~hylform~mi-le and the temperature was keepe~ at 5 C. To this mixture was added dropwise 1.7g of 4-nitroben~l(lnxime dissolved in 10 me of ~lim~hylform~mi~lP and the resulting solution was warmed to room temperature and then stirred for 20 minutes. To this reaction mixture were added 2.4g of 4,6--lim.othoxy-2-methylsulfonylpyrimi(lin~ and 0.3g of potassium carbonate. The reaction mixture was heated to 80 to 85~C, stirred for 3 to 4 hours and distilled under reduced pressure to remove 10 the solvent. The residue was treated according to the same procedure as Fx:lmple 29 to obtain 4.5g (Yield 78.0%) of the title compound.

Claims (4)

1. A process for preparing a 2,6-di(4,6-dimethoxypyrimidin-2-yl) oxybenzoic acid oxime ester derivative having the following formula (I), in which R1 represents hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C3-C6;
cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C1-C4 alkylthio, amino which can be substituted with C1-C4 alkyl, aryl, aryloxy, C1-C4 acyl or C1-C4 acyloxy, n denotes an integer of 1 to 5, and R2 represents hydrogen, halogen, cyano, nitro, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkoxycarbonyl, C2-C4 alkenyloxycarbonyl, arylmethoxycarbonyl, heteroarylmethoxy carbonyl, C1-C4 alkylaminocarbonyl, di(C1-C4 alkyl)aminocarbonyl, arylmethylaminocarbonyl, heteroarylmethylaminocarbonyl, or phenyl which can lie substituted with R1, characterized in that a compound having the following formula (V), in which R represents hydrogen or alkali metal canon, and R1, R2 and n are defined as above, is reacted with a pyrimidine derivative having the following formula (VI), in which Z represents halogen, C1-C4 alkylsulfonyl or arylsulfonyl.

2. The process according to claim 1, wherein tile compound of formula (V) is prepared by reacting a 5-(4,6-dimethoxy-pyrimidin-2-yl)oxy-4H-(1,3)-benzodioxin-4-one derivative having the following formula (IV), in which R3 and R4 independently of one another represent hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms, benzyl, or phenyl which can be substituted with one or two groups selected from 1 to 5 halogen atoms and/or C1-C4 alkyl, C1-C4 alkoxy, C1-C2 haloalkyl and nitro, or R3 and R4 together represent C2-C6 alkylene chain which can be substituted with 1 to 5 halogen atoms and/or C1-C4 alkyl, R4 also represents wherein, Q represents sulfur, oxygen or NR8 (R8 represents hydrogen or C1-C4 alkyl), R6, R6 and R7 independently of one another represent hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy or C1-C2 haloalkyl which can be substituted with 1 to 5 halogen atoms, or R5 and R6 together represent benzo-fused benzene ring, wherein the benzene ring can be substituted with one or two groups selected from 1 to 5 halogen atoms and/or C1-C4 alkoxy, C1-C4 alkylthio, C1-C2 haloalkyl, cyano and nitro, R9 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl having 1 to 5 halogen atoms or alkylbenzene ring, X and Y independently of one another represent oxygen or sulfur, R10, R11, R12 and R13 independently of one another represent hydrogen, C1-C4 alkyl or C1-C4 haloalkyl having 1 to 5 halogen atoms, m denotes 0 or 1, with an oxime or a metal salt thereof having the following formula (III), in which R, R1, R2 and n are defined as claim 1.

3. The process according to claim 1 or 2, wherein the reaction is carried out in one or more solvents selected from a group consisting of tetrahydrofuran, diethylether, dimethylformamide, dimethylsulfoxide, dichloromethane, carbon tetrachloride, benzene and toluene.

4. The process according to claim 1,2 or3, wherein the reaction is carried out in the presence of one or more bases selected from a group consisting of potassium carbonate, sodium carbonate, sodium hydride, sodium hydrogen carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide.