WO1997030965A1

WO1997030965A1 - PROCESS FOR THE PREPARATION OF α-ALKOXYPHENYLACETIC ACID DERIVATIVES

Info

Publication number: WO1997030965A1
Application number: PCT/JP1997/000456
Authority: WO
Inventors: Toshikazu Ohtsuka; Takami Murashi
Original assignee: Shionogi & Co., Ltd.
Priority date: 1996-02-23
Filing date: 1997-02-20
Publication date: 1997-08-28
Also published as: AU1733597A

Abstract

A process for the preparation of compounds of general formula (1), characterized by reacting a compound of general formula (2) with a compound of general formula (6) QOH, or a metal salt thereof in the presence of a base to form a compound of general formula (11) and reacting this compound with a metal alcoholate.

Description

Description Method for producing α_alkoxyphenylacetic acid derivative

The present invention relates to a method for producing an α-alkoxyphenylacetic acid derivative useful as an agricultural fungicide. Background art

Certain poly (alkoxyphenylacetic acid) derivatives have been found to be useful as agricultural fungicides (W095 / 2763, WO96 / 07633). Various methods have also been disclosed for their synthesis. Also, a reaction similar to the reaction from ο — tolylacetic acid to a dihalogen, which constitutes a part of the method of the present invention, is Gazz. Chim. Ita 1., 106, 65 (1997). 6), and Farmaco, Ed. Sci., 40, 777 (1989).

However, the method described in the above publication involves problems in raw material cost, safety, operability, versatility and the like, and was not a satisfactory method as an industrial production method of a monoalkoxyphenylacetic acid derivative. Disclosure of the invention

In view of such circumstances, the present inventors have conducted intensive studies on a novel method for synthesizing an α-alkoxyphenylacetic acid derivative, and as a result, have found a method for efficiently producing an α-alkoxyphenylacetic acid derivative from a -octaphenylphenylacetic acid derivative. We have completed the present invention.

That is, the present invention provides a) a formula (2): PT P97 0456

[Wherein, X and Y each independently represent a halogen atom, and ζ represents an alkoxy or an optionally substituted amino] in the presence of a base. ):

Q O H (6)

[In the formula, Q represents an optionally substituted aryl, an optionally substituted heterocyclic group or a mono- or di-substituted methyleneamino] or a metal thereof. Reacting the salt, formula (11):

X

Wherein each symbol is as defined above, and then a metal salt of an alcohol is reacted therewith, wherein a compound represented by the formula (1):

[Wherein, R ³ represents alkyl, and other symbols have the same meanings as described above]. For more information,

b) The process according to a) above, wherein X and Y are each independently a chlorine atom or a bromine atom.

c) The process according to a) or b) above, wherein Z is methoxy and the alcohol is methanol.

d) The above a) wherein the optionally substituted amino represented by Z is NR′R ² (RR ² is the same or different and is a hydrogen atom or an alkyl) Or b) the process as described.

e) Among the compounds represented by the formula (2), a compound in which X and Y are the same is represented by the formula (3):

^J

Is halogenated using a carboxylic acid halogenating agent and an alkyl side chain halogenating agent, and then the compound represented by the formula (8):

Z H (8)

[Wherein Z is the same as defined above]. The process according to the above a), which is obtained by reacting a compound represented by the formula:

f) The process according to e) above, wherein the carboxylic acid halogenating agent is a thionyl halide.

) The process as described in e) or f) above, wherein the carboxylic acid halogenating agent is used in an amount of 3 to 10 equivalents based on compound (3).

h) The process according to e) above, wherein the alkyl side chain halogenating agent is sulfuryl chloride or halogen.

i) Equation (2c):

[Wherein, R ¹ and R ² have the same meanings as described above, and V and W each independently represent a chlorine atom or a bromine atom.] A compound represented by the formula (6):

Q〇 H (6)

[Wherein Q is as defined above] or a metal salt thereof is reacted to obtain a compound represented by the formula (11a):

Wherein each symbol is as defined above, and then a metal salt of an alcohol is reacted with the compound represented by the formula ( _1a ):

[Wherein each symbol has the same meaning as described above.

j) The compound represented by the formula (2c) is represented by the formula (3):

'

Is halogenated using a carboxylic acid halogenating agent and an alkyl side chain halogenating agent, and then the compound represented by the formula (9)

R ¹ R ² NH (9)

[Wherein the symbols are as defined above]. The process according to i) above, which is obtained by reacting a compound represented by the formula:

k) The process according to j) above, wherein the carboxylic acid halogenating agent is a thionyl halide.

1) The process according to the above item "'), wherein the carboxylic acid halogenating agent is used in an amount of 3 to 10 equivalents based on the compound (3).

m) The process as described in j) above, wherein the alkyl side chain halogenating agent is sulfuryl chloride or halogen.

n) A compound represented by the formula (2) wherein X and Y are the same and Z is alkoxy is represented by the formula (5):

The process according to a) above, which is obtained by halogenating a compound represented by the formula: wherein R represents alkyl.

o) The process according to n) above, wherein the halogenation is carried out using N-halosuccinimide.

P) The compound represented by the formula (2) is a compound represented by the formula (4a):

The process according to the above a), which is obtained by halogenating a compound represented by the formula: wherein each symbol is as defined above, and then, optionally, amidating the compound.

q) The production method according to the above P), wherein the halogenation is performed using N-octyl succinimide or a halogen.

r) The compound represented by the formula (4a) is a compound represented by the formula (3):

Is halogenated using a carboxylic acid halogenating agent and an alkyl side chain halogenating agent, and then the compound represented by the formula (8b):

R O H (8 b)

The process according to p) above, which is obtained by reacting a compound represented by the formula: wherein R is as defined above.

s) The process as described in r) above, wherein the carboxylic acid halogenating agent is thio, thionyl logenide.

t) The carboxylic acid halogenating agent is used in an amount of 1 to 1.5 equivalents based on compound (3). The production method according to the above (1) or (2) to be used.

U) The process as described in r) above, wherein the alkyl side-chain hepatic agent is sulfuryl chloride or halogen.

V) The compound represented by the formula (2) is represented by the formula (10):

Wherein Y is as defined above, is halogenated using a carboxylic acid halogenating agent and an alkyl side chain halogenating agent, and then a compound represented by the formula (8):

Z H (8)

[Wherein Z is the same as defined above]. The process according to a) above, which is obtained by reacting a compound represented by the formula:

w) The process according to V) above, wherein the carboxylic acid halogenating agent is a thionyl halide.

X) The method according to the above V), wherein the alkyl side chain halogenating agent is sulfuryl chloride or halogen.

y) The compound represented by the formula (10) is represented by the formula (3):

The process according to V) above, which is obtained by halogenating a compound represented by the formula:

z) The method according to the above y), wherein the halogenation is carried out using N-halosuccinimide or halogen.

According to the method of the present invention, it is possible to derive a target compound from a commercially available compound in a short process as compared with a method for producing a monoalkoxyphenyl carboxylic acid derivative which is useful as a conventional agricultural fungicide. In addition, the safety of all reactions used is high, and It is suitable for industrial production, because it can lead to the target at low cost.

A carboxylic acid halogenating agent is a reagent that converts a carboxylic acid into an acid halide, and examples thereof include thionyl halide and phosphorus trihalide. In particular, thionyl chloride is preferred.

The alkyl side chain halogenating agent is a reagent for halogenating the methylene at the 2-position or the methyl at the o-position of phenylacetic acid, and is preferably sulfonyl nodogenate, particularly preferably sulfuryl chloride.

Examples of the halogen atom represented by X and Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a chlorine atom and a bromine atom are preferred.

Examples of the alkoxy represented by Z include alkoxy having 1 to 8 carbon atoms, preferably alkoxy having 1 to 4 carbon atoms, specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec butoxy, tert-alkoxy. Butoxy, etc. can be obtained. Of these, methoxy is preferred.

The optionally substituted amino represented by Z is preferably represented by the formula: NR ¹ R ² (wherein R ¹ and R ² are the same or different and are a hydrogen atom or an alkyl).

The alkyl represented by RR ^2, 1 ~ 8 carbon atoms, preferably alkyl having 1 to 4 carbon atoms, such as methyl, Echiru, propyl, i Sopu port pills, heptyl, Lee Sopuchiru, sec-heptyl, tert-butyl And so on. Among them, it is particularly preferable that one of R ¹ and R ² is a hydrogen atom and the other is methyl.

The optionally substituted aryl represented by Q is, for example, an aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl (eg, naphthyl, / 3—naphthyl) Etc.) These are replaced. When the substituent is lower, it is lower (C 1-8, preferably C 1-6, more preferably C 1-4); ) Alkyl (eg, methyl, ethyl, propyl, butyl, etc.), lower alkenyl (eg, vinyl, aryl, crotyl, etc.), lower alkynyl (eg, ethynyl, propargyl, butynyl, etc.), cycloalkyl (eg, cyclopropyl, cyclopentyl) , Cyclohexyl, etc.), lower alkoxy lower alkyl (eg, methoxymethyl, ethoxymethyl, 2-methoxyethyl, etc.), cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, etc.), lower alkylcarbonyl (eg, , Acetyl, propionyl, isobutyryl, etc.), lower alkylsilyl ( , Trimethylsilyl, tritylsilyl, tripropylsilyl, tributylsilyl, etc.), non- □ (lower) alkyl (eg, difluoromethyl, trifluoromethyl, tetramethyl, 2-bromoethyl, 2,3-dichloro) Mouth propyl), di (lower) alkylamino (eg, dimethylamino, getylamino), phenyl, phenyl (lower) alkyl (eg, benzyl, phenethyl, etc.), phenyl (lower) alkenyl (eg, styryl, Cinnamyl, etc.), furyl (lower) alkyl (eg, 3—furylmethyl, 2—furylethyl), furyl (lower) alkenyl (eg, 3—furylvinyl, 2—furylaryl), halogen atom (eg, Fluorine, chlorine, bromine, iodine), nitro, cyano, Lower alkylthio (eg, methylthio, ethylthio, propylthio, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), formyl, amino, mono (lower) alkylamino (eg, Methylamino, ethylamino, etc., —OR ⁶ [wherein is a hydrogen atom, lower alkyl (eg, methyl, ethyl, propyl, butyl, etc.), lower alkenyl (eg, Bier, aryl, crotyl ), Lower alkynyl (eg, ethynyl, 2-propynyl, 3-butynyl) ), No, mouth (lower) alkyl (eg, difluoromethyl, trifluoromethyl, chloromethyl, 2-bromoethyl, 2,3-dichloropropyl, etc.), lower alkyl carbonyl (eg, acetyl, pro Pionyl, butyryl, etc.), lower alkylthiocarbonyl (eg, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, etc.), phenyl, lower alkylphenyl (eg, 2-methylphenyl, 2,5-dimethylphenyl, etc.) , Lower alkoxyphenyl (eg, 3-methoxyphenyl, 4-ethoxyphenyl, etc.), nitrophenyl (eg, 3-nitrophenyl, 4-methoxyphenyl, etc.), phenyl (lower) alkyl (eg, benzyl) , Phenethyl, phenylpropyl, etc.), Siano Enyl (lower) alkyl (eg, 3-cyanophenylmethyl, 4-cyanophenylethyl), benzoyl, tetrahydroviranyl, pyridyl, trifluoromethylpyridyl, pyrimidinyl, benzothiazolyl, quinolyl, benzoyl (lower) Alkyl (eg, benzoylmethyl, benzoylethyl, etc.), benzenesulfonyl, lower alkylbenzenesulfonyl (eg, toluenesulfonyl, etc.), lower alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, propanesulfonyl, etc.), mono or di (lower) Alkyl substitution power rubamoyl (eg, N-monomethylcarbamoyl, N, N-dimethylcarbamoyl, N-monoethylcarbamoyl, etc.)], one CH 2 -G-R ⁷ [where G is —O—, One S — Or — NR ⁸ — (R ⁸ is a hydrogen atom or lower alkyl), and R ⁷ is phenyl, halophenyl (eg, 2-cyclophenyl, 4-fluorophenyl, etc.), lower alkoxyphenyl (eg, 2-methoxyethoxy, 41-ethoxyphenyl, etc.), pyridyl, or pyrimidinyl].

These substituents may be located at any substitutable position on the ring. The total number of substitution groups is from 1 to 5, preferably 1 to 4, more preferably 1 to There are three and these may be the same or different.

Examples of the optionally substituted heterocyclic group represented by Q include 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur as ring-constituting atoms. Membered heterocyclic groups. These heterocyclic groups may form a condensed ring with another hetero ring or a benzene ring. Specifically, pyridyl which may be substituted (eg, pyridin-1-yl, pyridin-13-yl, etc.), pyrimidinyl (eg, pyrimidine-14-yl, Pyrimidine-1-yl, quinolyl (eg, quinolin-4-yl), quinazolinyl (eg, quinazolin-14-yl, etc.), benzothiazolyl (eg, benzothiazol-2-yl) ), Birazolyl

(Eg, pyrazole-5-yl). Of these, pyridyl which may be substituted is preferred.

When these heterocyclic groups are substituted, examples of the substituent include the groups exemplified as the aryl substituent represented by the above Q. Of these, a halogen atom, haloalkyl, alkoxy, alkoxycarbonyl or formyl is preferable, and a chlorine atom or trifluoroethyl is more preferable. These substituents may be located at any substitutable position on the ring. The number of the substituents is 1 to 5, preferably 1 to 4, and more preferably 1 to 3, and they may be the same or different.

The mono-substituted or di-substituted methylamine amino represented by Q is, for example, of the formula

(a): (a)

Wherein, R ', R ⁵ are the same or different and each represents a hydrogen atom, an alkyl but it may also be substituted, Ashiru, alkylthio, alkylsulfinyl, alkyl sulfonyl, optionally substituted § Mi also be Bruno, a cycloalkyl, substituted Is Forming a polycyclic was good monocyclic or even contain heteroatoms bonded force or R ⁴ and R ⁵ showing the heterocyclic group to be optionally be also good § Li Lumpur or substituted optionally To indicate that you are doing this).

In the formula (a), as the optionally substituted alkyl represented by R ⁴ and R ⁵ , the substituted alkyl exemplified as the substituent of the optionally substituted aryl represented by Q can be used. And the same groups as the alkyl which may be used. Of these, methyl and ethyl are preferred.

R · ", as the Ashiru represented by R ^5, for example, alkylcarbonyl, as the. The alkylcarbonyl etc. § re Rukarubo two Le can be mentioned, for example, 1 to 6 carbon atoms, preferably alkyl having 1 to 4 carbon atoms Examples of the alkyl carbonyl include acetyl, trifluoroacetyl, propionyl, and butyryl, etc. Examples of the arylcarbonyl include, for example, aryl having 6 to 14 carbon atoms. Arylcarbonyl, specifically, benzoyl, naphthoyl and the like.

Examples of the alkylthio represented by R ⁴ and R ⁵ include the same groups as the alkylthio exemplified as the substituent of the optionally substituted aryl represented by Q.

R ^4, is as a alkylsulfides alkylsulfonyl represented by R ^[delta], for example 1 to 8 carbon atoms, preferably an alkyl sulfides alkylsulfonyl of 1 to 4 carbon atoms, specifically, Mechirusurufi sulfonyl, E chill sulfinyl, pro Pyrsulfinyl and the like.

The alkylsulfonyl represented by R ⁴ and R ⁵ includes, for example, alkylsulfonyl having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, specifically, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like. Can be

Examples of the optionally substituted amino represented by R ⁴ > R ⁵ include, for example, the substituents of the optionally substituted aryl shown by the aforementioned Q Examples include the same groups as those for amino which may be substituted.

As the cycloalkyl represented by R ⁴ and R ⁵ , cycloalkyl having 3 to 7 carbon atoms, preferably 5 to 6 carbon atoms, specifically, cyclopropyl, cyclopropyl, cyclopentyl and cycloalkyl hexyl, heptyl and the like force ³ ', such as to a consequent Russia.

Examples of the aryl of the optionally substituted aryl represented by R ⁴ and R ^S include the groups exemplified as the optionally substituted aryl represented by the above Q Similar groups are used. Of these, phenyl is preferred. The aryl may be substituted at any possible position of these ring groups, and the number of substituents is 1 to 3. Specific examples of the substituent include a halogen atom, an optionally substituted alkyl, an optionally substituted hydroxyl group, an alkylthio, an optionally substituted amino, nitro, phenyl, cyano and the like. Is lost.

A halogen atom, an optionally substituted alkyl, an optionally substituted hydroxyl group, an alkylthio, an optionally substituted aryl of the optionally substituted aryl represented by R ⁴ and R ⁵ Examples of good aminos include the same groups as the groups exemplified as the substituents on the optionally substituted aryl represented by Q.

Examples of the optionally substituted heterocyclic group represented by R ⁴ and R ⁵ include, for example, a 5- to 7-membered member having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur as ring-constituting atoms. Heterocyclic groups include, for example, pyridyl, pyridazinyl, pyrazolyl, pyrimidinyl, furyl, chenyl, oxazolyl, isoxazolyl, benzothiazolyl, quinolyl, quinazolinyl, vilazinyl, morpholino, piperazinyl and the like. These include furyl (eg, 2-furyl), chenyl (eg, 2-phenyl), pyridyl (eg, 2-pyridyl), virazinyl (eg, 2-virazinyl), Pyrimidinyl (eg, 2-pyrimidinyl, etc.) and morpholino are preferred. These heterocyclic groups may be substituted, and the substituent may be the same as the group exemplified as the substituent of the optionally substituted aryl represented by R ⁴ R ⁵ . Base

R ⁴ and R ⁵ are bonded to a single ring or multi-ring may contain hetero atom is formed is a R ⁴ and R ⁵ are those formed with the carbon atoms to which they are attached heteroatom (e.g. , Oxygen, nitrogen, sulfur, etc.), which may form a condensed ring with another ring. Specific examples of the ring include cyclopentane, cyclohexane, indane, 1,2,3.4-tetrahydrodronaphthalene, 5,6,7,8 tetrahydroquinoline, 4, 5, 6 7 — Tetrahydrobenzo [b] franc and the like. These rings may have a divalent bond at any possible position.

The alkyl represented by R ³ is an alkyl having 18 carbon atoms, preferably an alkyl having 14 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl and the like. Are mentioned. Of these, methyl is preferred. BEST MODE FOR CARRYING OUT THE INVENTION

The method for producing the alkoxyphenyl acetic acid derivative represented by the formula (1) of the present invention will be specifically described.

(Reaction formula 1)

11 [Wherein the symbols are as defined above]

First, compound (6) or a metal salt thereof is condensed with compound (2) in the presence of a base to obtain compound (11).

Examples of the metal salt of compound (6) include alkali metal salts (such as sodium salt and potassium salt).

Compound (6) or its metal salt is used in 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (2).

Examples of the base include an organic base (such as sodium methoxide, sodium ethoxide, and potassium t-butoxide), and an inorganic base (such as sodium hydroxide and potassium hydroxide). Lithium, potassium carbonate, sodium hydride, potassium hydride and the like), which are added to the compound (2) in an amount of from 0.5 to 10, 4 to 4 and preferably from 1 to 4. Use 3 equivalents.

Examples of the reaction solvent include aromatic hydrocarbons (toluene, etc.); ethers (tetrahydrofuran, etc.); ditylformamide, dimethylsulfoxide or water. These may be used alone or as a mixture. be able to. However, when water is used, a phase transfer catalyst may be used.

The reaction temperature is a suitable temperature from 0 ° C to the reflux temperature of the solvent, preferably 0 to 80 ° C, and the reaction time is 1 to 48 hours.

Then, the obtained compound (11) is used as a crude product in the form of the reaction solution, or is separated and purified by a conventional method (eg, chromatography, recrystallization, etc.), and then a metal salt of alcohol is obtained. To obtain "a monoalkoxyphenylacetic acid derivative (1).

As the metal salt of alcohol, for example, sodium methoxide, potassium isopropoxide, potassium monobutoxide or the like may be used directly, or alcohols (eg, methanol , Ethanol, etc.) Metal salts (eg, sodium, potassium, etc.) or metal hydrides (eg, sodium hydride, potassium hydride, etc.) to form metal salts of alcohols Used. In either case, the metal salt of alcohol is used in an amount of 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound (11). As the metal salt of alcohol, sodium methoxide is preferable.

Reaction solvents include alcohols (eg, methanol, ethanol, isopropanol, butanol); dimethylformamide; dimethyl sulfoxide; aromatic hydrocarbons (eg, toluene) And the like, and these can be used alone or as a mixture.

The reaction temperature is an appropriate temperature from 0 ° C to the reflux temperature of the solvent, and the reaction time is 1 to 48 hours.

The obtained monoalkoxyphenylacetic acid derivative (1) can be used as a bactericide by a known method.

The compound (2) used as a raw material in the above reaction formula 1 can be produced by the reactions of the following reaction formulas 2 to 5.

(Reaction formula 2)

2a 4a

[Wherein the symbols are as defined above]

Among the compounds (2), a compound in which X and Y are the same, that is, a compound represented by the formula (2a), is obtained by halogenating the compound (3) with a carboxylic acid halogenating agent and an alkyl side chain halogenating agent, Then, it can be produced by reacting with compound (8).

Examples of the carboxylic acid halogenating agent include thionyl halide (eg, chloride) Thionyl, thionyl bromide, etc.); phosphorus trihalide (eg, phosphorus trichloride, phosphorus tribromide, etc.) and the like, and 1 to 10 equivalents, preferably 3 to 10 equivalents to compound (3). Use 10 equivalents.

Examples of the alkyl side chain halogenating agent include sulfuryl chloride; halogen (eg, chlorine, bromine, etc.), and these are used in an amount of 1 to 10 equivalents based on compound (3).

As a reaction solvent, for example, thionyl halide and the like have a function as a solvent, but generally ethers (eg, tetrahydrofuran); halogenated hydrocarbons (eg, 1,2-dichloroethane) It is better to use.

The reaction temperature is an appropriate temperature from room temperature to the reflux temperature of the solvent, and the reaction time is 1 to 48 hours.

Further, when Z is alkoxy, it can be subsequently amidated to give an amino which may be substituted with Z. Amidation can be carried out in the same manner as described in Reaction Scheme 4 below.

Subsequently, after distilling off the reagent, the compound (8) is reacted.

As the reaction solvent, use is made of aromatic hydrocarbons (eg, toluene); ethers (eg, tetrahydrofuran); and halogenated hydrocarbons (eg, methylene chloride, 1,2-dichloroethane).

Compound (8) is used in 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (3).

The reaction temperature is a suitable temperature from 0 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature, and the reaction time is 1 to 24 hours.

The obtained compound (2a) can be separated and purified by a known means (eg, chromatography, recrystallization, etc.).

Compound (3) used as a starting material for this reaction was obtained as a commercial product. can do.

(Reaction formula 3)

5 2b

[Wherein, R represents alkyl, and X is as defined above]

Among the compounds (2), the compound in which X and Y are the same and Z is alkoxy, that is, the compound represented by the formula (2b), is produced by halogenating the compound (5). Can be.

As the alkyl represented by R, alkyl having 1 to 8 carbon atoms, preferably alkyl having 1 to 4 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl Tert-butyl and the like.

Examples of the halogenating agent include N-nitrosuccinimide (eg, N-chlorosuccinimide, N-bromosuccinimide); nodogen (eg, chlorine, bromine, etc.); 1) to 5 equivalents, preferably 1 to 3 equivalents to 5).

Benzoyl peroxide or 2,2′-azobis (isoptyronitrile) may be used as a reaction initiator in an amount of 0.05 to 0.2 equivalents to compound (5), May be irradiated.

As the reaction solvent, aromatic hydrocarbons (such as benzene); halogenated hydrocarbons (such as carbon tetrachloride) may be used.

The reaction temperature is an appropriate temperature from 0 ° C to the reflux temperature of the solvent. The duration of the reaction is between 1 and 24 hours.

The obtained compound (2b) can be separated and purified by a known means (eg, chromatography, crystal, etc.). The compound (5) used as a raw material in the reaction of the reaction formula 3 is obtained by reacting a commercially available compound (3) with the presence of a base F, an alkylating agent (eg, alkyl halide, dialkyl sulfate, etc.). It can be manufactured by the following. Examples of the alkyl halide include methyl chloride, methyl bromide, methyl iodide, butyl bromide, chloro iodide, 1-propane propane, 2-iodopropane, and 1-butane, and dialkyl sulfate. Examples thereof include dimethyl sulfate and getyl sulfate, which are used in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents, based on the compound (3).

Examples of bases include: organic bases (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.): inorganic bases (eg, sodium hydroxide, potassium hydroxide) Lithium, sodium hydride, potassium hydride, etc.) are used, and they are used in 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (3).

As the reaction solvent, ethers such as getyl ether and tetrahydrofuran; N.N-dimethylformamide; dimethylsulfoxide; toluene, and the like can be used.

The reaction temperature is an appropriate temperature from 120 to the reflux temperature of the solvent, preferably 0 to 50 ° C, and the reaction time is 0.5 to 48 β, preferably 0.5 to 10 hours. is there.

The obtained compound (5) can be separated and purified by a known means (eg, chromatography, recrystallization, etc.).

(Reaction formula 4)

Amidation

4a

[Wherein the symbols are as defined above] The compound (2) can be produced by halogenating the compound (4a) with a carboxylic acid halogenating agent and an alkyl side-chain hepatic agent, and then, if necessary, amidating the compound (4a).

Halogenation can be carried out in the same manner as in the reaction of the above Reaction Scheme 3. The amidation is preferably effected by amides (9):

R ¹ R ² NH (9)

[Wherein, RR ² is as defined above]

Is reacted.

The amines (9) are used in 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (4a).

As the reaction solvent, alcohols (eg, methanol and ethanol); aromatic hydrocarbons (eg, toluene); and halogenated hydrocarbons (eg, methylene chloride) may be used.

The reaction temperature is 0X: a suitable temperature up to the reflux temperature of the solvent, and the reaction time is 1 to 48 hours.

The obtained compound (2) can be separated and purified by a known means (eg, chromatography, recrystallization, etc.).

The compound (4) containing the compound (4a) used as a starting material for this reaction can be obtained as a mixture with the compound (2) by the reaction of the above Reaction Scheme 2. In particular, it is preferable to use 1 to 1.5 equivalents of the thionyl halide with respect to the compound (3) because the compound (4) is preferentially obtained.

(Reaction formula 5)

Amidation

4a

[Wherein, Y is as defined above] Compound (2) can be produced by halogenating compound (10) with a carboxylic acid halogenating agent and an alkyl side chain halogenating agent, and then reacting with compound (8).

The halogenation and the reaction with the compound (8) can be carried out in the same manner as in the reaction of the above-mentioned reaction formula 2.

The compound (10) as a starting material for this reaction can be produced according to the following reaction formula 6.

(Reaction formula 6)

3 10

[Expression B, Y is as defined above]

The compound (10) can be produced by halogenating the compound (3).

The halogenation can be carried out in the same manner as in the reaction of the above-mentioned reaction formula 3. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

The spin coupling constant (J) in the NMR data is indicated by Hertz (Hz).

Synthesis of methyl acetate 2 — [2 — (2, 5 — dimethylphenoxymethyl) phenyl] methyl acetate

To a solution of 2,5_xylenol (0.31 g, 2.554 mmol) in dimethyl sulfoxide (3 ml) was added sodium hydroxide (0.11 g, 2.74 mmol). 1) was added, and the mixture was stirred at 130 with stirring for 1 hour. After cooling to room temperature, 2 g of methyl 2- (chloromethyl) phenyl] 2- (chloromethyl) phenyl (0.1 g) solution of 2.14 mmo 1) in dimethyl sulfoxide (2 ml) Add Then, the mixture was stirred at room temperature for 2 hours. Water (20 ml) was added to the reaction solution, extracted with ether, washed with brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 9: 1), and the target compound, 2-chloro-2--2 [[2- (5 —Dimethylphenoxymethyl) phenyl] methyl acetate (0.20 g, 30%) was obtained as an oil.

NMR (δ ppm, TMS / CDC 1 3): 2.19 (3H, s), 2.34 (3H, s), 3.75 (3H, s), 5.13 (2H, s), 5.83 (1H, s), 6.75 (1H , d, J = 7.9), 6.78 (lH, s), 7.03 (1H, d, J = 7.9), 7.30-7.40 (3H, m), 7.60-7.65 (1H, m).

Example 2

Synthesis of 2—Chloro-N-methyl-2— [2— (2,5—dimethylphenoxymethyl) phenyl] acetic acid amide

2—Clot mouth—2— [2— (Chloromethyl) phenyl] —N-Methyldronic acid amide (1.00 g, 4.31 mmol) in dimethyl sulfoxide (5 ml) solution , 5-Xylenol (0.779 g, 6.47 mmol) and potassium carbonate (1.19 g, 8.61 mmol) were added, and the mixture was stirred at room temperature for 7 hours. Water (30 ml) was added to the reaction solution, extracted with ether, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 7: 3) to give the target compound 2 —chloro □ —N-methyl-2 — [2 — (2,5-Dimethylphenoxymethyl) phenyl] acetic acid amide (1.00 g, 73%) was obtained as crystals.

NMR (δ ppm, TMS / CDC 1 3): 2.20 (3H, s), 2.33 (3H, s), 2.88 (3H, d, J = 4.9), 5.15 (1H, d, J = l 1.6), 5.18 (1H, d, J = 11.6), 5.78 (lH, s). 6.71 (1H, brs), 6.73 (1H, d, J = 7.9), 6.78 (1H, s), 7.04 (1H, d, J = 7.9), 7.35-7.52 (4H, m).

Example 3

2—Chloro N—methyl-1-2— [2— (1-Methyl-14-cyclobenzylbenzylidenaminooxymethyl) phenyl] synthesis of acid amide

2— [2— (chloromethyl) phenyl] —N-methylacetate amide (1.0 g, 4.31 mmol) in dimethylsulfoxide (4 ml) solution 4 Monochloroacetophenonoxime (1.09 g, 6.42 mmol) and potassium carbonate (1.19 g, 8.61 mmol) were calorie, and the mixture was stirred at room temperature for 7 hours. Water (30 ml) was added to the reaction solution, extracted with ether, washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 7: 3), and the desired product 2—chloro-N—methyl 2 -— [2— (Α-Methyl-41-methylbenzylideneaminooxymethyl) phenyl] acetamide (1.05 g, 67%) was obtained as a crystal.

_{NMR ((5 ppm TMSZCDC 1 3} ):. 2.22 (3H, s), 2.84 (3Η, d, J = 4.9), 5.37 (1H, d, J = 12.0), 5.39 (1H, d, J = 12.0) '5.91 (1H, s), 6.65 (1H, brs), 7.30-7.45 (6H, m), 7.56 (2H, d, J = 8.5)-Example 4

Synthesis of 2-Methoxy-2- (2- (2,5-dimethylphenoxymethyl) phenyl) methyl oxalate

2—Cross mouth 2— [2- (2,5—Dimethylphenoxymethyl) phenyl] Methyl sulphonate (0.70 g, 2.20 mmol) in methanol (2 ml) Sodium methoxide (0.85 g, 4.40 mmol) was added to the solution, and the mixture was refluxed for 4 hours. After cooling to room temperature, water (20 ml) was added to the reaction solution, extracted with methylene chloride, and dried over magnesium sulfate. Distill solvent The residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 9: 1), and the desired product 2—methoxy—2— [2— (2,5—dimethylphenoxy) was removed. (Cimethyl) phenyl] methyl acetate (0.26 g, 38%) was obtained as an oil.

NMR ((5 ppm, TMS / CDC 1 3): 2.21 (3H, s), 2.33 (3H, s), 3.40 (3Η, s), 3.71 (3H, s), 5.09 (1Η, d, J = 12.2 ), 5.13 (1H, s), 5.27 (1H, d, J = 12.2), 6.70 (1H, d, J = 7.3), 6.76 (1H, s), 7.04 (1H, d, J = 7.3), 7.35 -7.40 (2H, m), 7.50-7.55 (2H, m) .Example 5

Synthesis of 2—Methoxy N—methyl-2— [2— (2,5—dimethylphenoxymethyl) phenyl] acetic acid amide

2-Methyl-N-methyl-2-[[2- (2,5-dimethylphenoxymethyl) phenyl] g] Acid amide (0.50 g, 1.57 mmol) To this solution (2 ml) was added sodium methoxide (1.36 g, 7.05 mmol), and the mixture was refluxed for 3 hours. After cooling to room temperature, water (20 ml) was added to the reaction solution, extracted with methylene chloride, and dried over magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 1: 1) to give the desired product, 2-methoxy-N-methyl-2— [2- (2,5-Dimethylphenoxymethyl) phenyl] acetic acid amide (0.30 g, 61%) was obtained as crystals.

NMR (<5 ppm, TMS / CDC 1 3): 2.19 (3H, s), 2.33 (3H, s), 2.82 (3Η, d, J = 4.9), 3.35 (3H, s), 5.03 (1H, s ), 5.05 (1H, d, J = 12.2), 5.47 (1H, d, J = 12.2), 6.69 (1H, d, J = 7.3), 6.74 (1H, brs), 6.76 (1H, s) .7.03 (1H, d, J = 7.3), 7.30-7.41 (3H, m), 7.49-7.51 (1H, m).

Example 6 2—Methoxy-1-N-methyl-2— [2— (α—methyl-4 benzylideneaminooxymethyl) phenyl] acetamide

2—Chlorol—Methyl mono 2— [2— (α—Methyl-4 monocyclobenzylideneaminooxymethyl) phenyl] acetate amide (0.50 g, 1.37 mmo 1) methanol ( 2 ml) solution was added with sodium methoxide (1.18 g, 6.11 mmo 1) and heated under reflux for 3 hours. After cooling to room temperature, water (20 ml) was added to the reaction solution, extracted with methylene chloride, and dried over magnesium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 1: 1).> The target substance, 2-Methoxy-1-N-methyl-1— 2-((α-methyl-4-chloro benzylideneaminooxymethyl) phenyl] acetamide (0.322 g, 65%) was obtained as a crystalline product.

NMR ((5 ppm, TMSZCDC 1 3): 2.22 (3H, s), 2.83 (3Η, d, J = 4.9), 3.32 (3Η, s), 5.12 (1Η, s), 5.26 (1H, d, J = 12.2), 5.66 (1H, d, J = 12.2), 6.75 (lH, brs), 7.30-7.40 (5H, m), 7.41- 7.50 (1H, m), 7.57 (2H, d, J = 8.6) .

Example 7

2—Chloro-2 -— [2- (chloromethyl) phenyl] methyl acetate

Ortho-tolylacetic acid (5.00 g, 33.3 mmol), thionyl chloride (11.88 g, 99.9 mmol), sulfuryl chloride (44.93 g) , 332.9 mmo 1) was added, and the mixture was stirred at 75 for 24 hours. After cooling to room temperature, excess reagent was distilled off, methylene chloride (40 ml) was added, and the mixture was stirred under ice-cooling. Methanol (20 ml) was added dropwise thereto, and the mixture was stirred for 1 hour after the addition. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane: g †: ethyl acetate = 9: 1) to obtain the target compound 2 —Chloro-2— [2- (chloromethyl) phenyl] methyl acetate (6.40 g, 82%) was obtained as an oil.

NMR (δ ppm, TMS / CDC 1 3): 3.79 (3H, s), 4.69 (1H, d, J = 12.0), 4.74 (1H, d, J = 12.0), 5.81 (1H, s), 7.34- 7.45 (3H, m), 7.57-7.61 (1H, m).

Example 8

2 —Chloro-2 — [2- (Chloromethyl) phenyl] Synthesis of 1-N-Cyclic Acid Amide

Ortho-tolylacetic acid (5.00 g, 33.3 mmo1), thionyl chloride (15.84 g, 133.4 lmmol), sulfuryl chloride (44.9 g) 3 g, 332.2.9 mmo 1) were added, and the mixture was stirred at 75 ° C. for 24 hours. After cooling to room temperature, excess reagent was distilled off, methylene chloride (40 ml) was added, and the mixture was stirred under ice-cooling. A 40% aqueous solution of methylamine (6.45 g, 83.2 mmol) was added dropwise thereto, and the mixture was stirred for 1 hour after the addition. Water (40 ml) was added to the reaction solution, extracted with methylene chloride, and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 7: 3), and the desired product, 2-chloro-2-

[2- (Chloromethyl) phenyl] -N-methylacetic acid amide (4.30 g, 56%) was obtained as an oil.

_{NMR (6 ppm, TMSZCDC 1 3} ): 2.91 (3H, d, J = 4.9), 4.68

(1Η, d, J = 12.2), 4.88 (1H, d, J = 12.2), 5.81 (1H, s), 6.75 (1H, brs), 7.30-7.50 (4H, m).

Example 9

2 — Promote 2 — [2 — (Bumomethyl) phenyl] Synthesis of methyl acetate

2 — (2-Methylphenyl) methyl acetate (0.33 g, 2.01 mm) o 1) in a solution of carbon tetrachloride (3 ml) in N-promosque cinimide (0.48 g, 2-70 mm o1), 2,2'-azobis (isobutyronitrile) (0 0.3 g) and benzoyl peroxide (0.04 g) were added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, insolubles were filtered off, and the filtrate was washed with a saturated aqueous solution of sodium thiosulfate and dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 9: 1), followed by high-performance liquid chromatography (n-hexane: ethyl acetate). = 9: 1) to give the desired 2-promo 2— [2-bromomethylphenyl] methyl acetate (0.12 g, 19%) as an oil.

NMR (δ ppm, TMS / CDC 1 3):. 3.82 (3H, s) 4.56 (1H, d, J = 11.0), 4.61 (1H, d, J = 11.0), 5.83 (1H, s) 7.20-. 7.40 (4H, m). Example 10

Synthesis of 2-chloro-2- (2-methylphenyl) methyl acetate

Ortho-tolylacetic acid (5.0 g, 33.3 mmol), thionyl chloride (5.94 g, 49.99 mmol), sulfuryl chloride (22.46 g, 166.4 mm0 1) was added, and the mixture was stirred at 75 for 10 hours. After cooling to room temperature, excess reagent was distilled off, methylene chloride (40 in 1) was added, and the mixture was stirred under ice-cooling. Methanol (20 ml) was added dropwise thereto, and the mixture was stirred for 1 hour after the addition. After evaporating the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 9: 1), and the target compound, 2-chloro-2- (2-methylphenyl) methyl acetate (5. (80 g, 88%) as an oil.

NMR (<5 ppm, TMS / CDC 1 3): 2.43 (3H, s), 3.78 (3H, s), 5.63 (1H, s), 7.20-7.25 (3H, m), 7.46-7.51 (1H, m ) · Example 1 1 Synthesis of 2-promo 2- (2-methylphenyl) methyl acetate

Ortho-toluic acid (5.00 g, 33.3 mmol), thionyl chloride (15.84 g, 133.3 lmmol), bromine (6.38 g, 39.9 mmo 1) was added, and the mixture was stirred at 75 for 24 hours. After cooling to room temperature, excess reagent was distilled off, methylene chloride (40 ml) was added, and the mixture was stirred under ice-cooling. Methanol (20 ml) was added dropwise thereto, and the mixture was stirred for 1 hour after the addition. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 9: 1), and the desired product, 2- (promo-2-)-(2-methylphenyl) methyl sulfate (5.90 g, 73%) was obtained as an oil.

NMR ((5 ppm, TMS / CDC 1 3): 2.42 (3H, s), 3.86 (3H, s), 5.65 (lH, s), 7.10-7.30 (3Η, m), 7.56-7.60 (1Η, m ).

Project 1 2

2 —C □ guchi ichi 2 [2- (Chloromethyl) phenyl] methyl acetate

2— (2-methylphenyl) 2- (2-methylphenyl) methyl acetate (6.00 g, 30.2 mmo 1) in benzene (30 ml) solution was added to N-chlorosuccinimide (4.2. 0 g, 33.2 mm o 1), 2,2'-azobis (isobutylonitrile) (0.25 g), benzoyl peroxide (0.35 g) For 2 hours.

After cooling to room temperature, insolubles were filtered and the filtrate was distilled off. The residue was purified by silica gel force chromatography (eluted with n-hexane: ethyl acetate = 9: 1), and the desired product, 2 _chloro-2 -— [2— (chloromethyl) phenyl] acetic acid, was obtained. Methyl (4.80 g, 68%) was obtained as an oil.

NR (<5 ppm, TM S Roh _{CDC 1 3): 3.79 (3H} , s), 4.69 (1H, d, J = 12.0), 4.74 (1H, d, J = 12.0), 5.81 (1H, s), 7.34-7.45 (3H, m), 7.57-7.61 (1H, m).

Example 13

2—Chloro-2— [2— (Promomethyl) phenyl] Synthesis of methyl acetate

2—Cross mouth—2— (2-Methylphenyl) N-bromosuccinimide (4.0 δ) was added to a solution of methyl acetate (4.50 g, 22.7 mmo 1) in benzene (22 ml). g, 22.8 mm o 1), 2,2'-azobis (isobutylonitrile) (0.20 g), and benzoyl peroxide (0.30 g) were added, and the mixture was heated under reflux for 2 hours. . After cooling to room temperature, insolubles were filtered, and the filtrate was distilled off. The residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 9: 1), and the desired product, 2-chloro 2-[2- (bromomethyl) phenyl] methyl acetate (5. (50 g, 87%) as an oil.

NMR ((5 ppm, TMSZCDC 1 3): 3.80 (3H, s), 4.58 (1H, d, J = 1.4), 4.64 (1H, d, J = 10.4), 5.83 (1H, s), 7.30-7.40 (3H, m), 7.56-7.61 (] H, m).

Example 14

Synthesis of 2-bromo-2- [2- (chloromethyl) phenyl] methyl acetate

2—Promo 2— (2—Methylphenyl) N-chlorosuccinimide (1.51 g) was added to a solution of methyl prussate (2.50 g, 10.3 mmol) in benzene (10 ml). , 11.3 mmo 1), 2,2'-azobis (isobutylonitrile) (0.10 g) and benzoyl peroxide (0.13 g) were added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, insolubles were filtered, and the filtrate was distilled off. The residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl acetate = 9: 1), and the desired product 2—promo 2— [2 Methyl [(chloromethyl) phenyl] acetate (1.60 g, 56%) was obtained as an oil.

NMR ((5 ppm, TMS / CDC 1 3): 3.80 (3H, s), 4.56 (1H, d, J = 11.0), 4.68 (1H, d, J = 11.0), 5.82 (1H, s), 7.20 -7.45 (4H, m). Example 15

2 — Promo 2 _ [2 — (Promomethyl) phenyl] Synthesis of methyl acetate

2-Promo 2- (2-methylphenyl) N-bromosuccinimide (1.83 g, 10) was added to a solution of methyl acetate (2.50, 10.3 mmo1) in benzene (10 ml). 2,2'-azobis (isobutyronitrile) (0.10 g) and benzoyl peroxide (0.13 g) were added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, insolubles were filtered, and the filtrate was distilled off. The residue was purified by silica gel column chromatography (eluted with n-hexane: ethyl ester = 9: 1), and the target substance, 2—promo 2 _ [21- (bromomethyl) phenyl] β-methyl acid ( 5.50 g, 87) were obtained as an oil.

NMR ((5 ppm, TMSZCDC 1 3): 3.82 (3H, s), 4.56 (1Η, d, J = 11.0), 4.61 (1H, d, J = 11.0), 5.83 (1H, s), 7.20-7.40 (4H, m) .Example 16

2—Chloro-2— [2— (Chloromethyl) phenyl] -N-Methyl Sulfate Amide Synthesis

2 — Black 2 — [2 — (Chloromethyl) phenyl] methyl acetate (1.

Of methanol (4 ml) was stirred under ice-cooling, and a 40% aqueous solution of methylamine (0.999 g, 12.9 mm) was added thereto. o])), and the mixture was stirred for 1 hour after the addition. After distilling off the solvent, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 7: 3), and the desired product, 2—chloro-2— [2— (chloromethyl) phenyl] —N-methylacetamide (0.80 g, 80%), was obtained as an oil. Was.

NMR ((5 ppm, TMS / CDC 1 3): 2.91 (3H, d, J = 4.9), 4.68 (1H, d, J = 12.2)), 4.88 (1H, d, J = 122), 5.81 (1H , s), 6.75 (1H, brs), 7.30-7.50 (4H, m). Industrial applicability

It can be used as an industrial method for producing α-alkoxyphenylacetic acid derivatives useful as agricultural fungicides.

Claims

The scope of the claims

Equation (2)

[Wherein, X and Y each independently represent a halogen atom, and Z represents an alkoxy or an optionally substituted amino] in the presence of a base. ):

Q O H (6)

[In the formula, Q represents an optionally substituted aryl, an optionally substituted heterocyclic group or a mono- or di-substituted methyleneamino] or a metal salt thereof. And react with the equation (11):

Wherein a compound represented by the formula (1) is obtained by reacting a compound represented by the formula (1) with a metal salt of an alcohol.

[Wherein R ³ represents alkyl, and other symbols have the same meanings as described above].

2. The method according to claim 1, wherein X and Y are each independently a chlorine atom or a bromine atom.

3. Z is methoxy and the alcohol is methanol. The production method according to 1 or 2.

4. The process according to claim 1, wherein the optionally substituted amino represented by Z is NR′R ² (R ¹ and R ² are the same or different and are a hydrogen atom or an alkyl). Law.

5. Among the compounds represented by the formula (2), a compound in which X and Y are the same-is a compound represented by the formula (3):

^Three

Z I I (8)

2. The method according to claim 1, wherein the compound is obtained by reacting a compound represented by the formula: wherein Z is as defined above.

6. The method according to claim 5, wherein the carboxylic acid halogenating agent is a thionyl halide.

7. The method according to claim 5, wherein the carboxylic acid halogenating agent is used in an amount of 3 to 10 equivalents based on the compound (3).

8. The process according to claim 5, wherein the alkyl side chain halogenating agent is sulfuryl chloride or halogen.

9. Equation (2c):

[Wherein, R ¹ and R ² have the same meanings as described above, and V and W each independently represent a chlorine atom or a bromine atom.] In the presence of a base, a compound represented by the formula (6): QOH (6)

[Wherein each symbol is as defined above], and then reacting with a metal salt of an alcohol. Formula (la): 1H ²

la

[Wherein the symbols are as defined above]

10. The compound represented by the formula (2c) is represented by the formula (3):

^Three

Is halogenated using a carboxylic acid halogenating agent and an alkyl side chain halogenating agent, and then the compound represented by the formula (9):

R ¹ R ² NH (9)

10. The process according to claim 9, wherein the compound is obtained by reacting a compound represented by the formula: wherein each symbol is as defined above.

11. The production method according to claim 10, wherein the carboxylic acid halogenating agent is a thionyl halide.

12. The process according to claim 10, wherein the carboxylic acid halogenating agent is used in an amount of 3 to 10 equivalents based on the compound (3).

13. The process according to claim 10, wherein said alkyl side chain halogenating agent is sulfuryl chloride or halogen.

14. Compounds of the formula (2) wherein X and Y are the same and Z alkoxy are represented by the formula (5)

2. The method according to claim 1, wherein the compound is obtained by halogenating a compound represented by the formula: wherein R represents alkyl.

15. The production method according to claim 14, wherein the halogenation is performed using N-halosuccinimide.

1 6. The compound represented by the formula (2) is represented by the formula (4a):

2. The process according to claim 1, wherein the compound is obtained by halogenating a compound represented by the formula: wherein each symbol is as defined above, and then, optionally, amidating the compound.

17. The production method according to claim 16, wherein the halogenation is carried out using N-8 rosuccinimide or halogen.

1 8. The compound represented by the formula (4a) is a compound represented by the formula (3):

^Three

R 0 H (8 b)

17. The production method according to claim 16, wherein the compound is obtained by reacting a compound represented by the formula: wherein R is as defined above.

1 9. The carboxylic acid halogenating agent is a thionyl halide 18. The production method according to 18.

20. The process according to claim 18 or 19, wherein the carboxylic acid halogenating agent is used in an amount of 1 to 1.5 equivalents to the compound (3).

21. The production method according to claim 18, wherein the alkyl side chain halogenating agent is sulfuryl chloride or halogen.

2 2. The compound represented by the formula (2) is represented by the formula (10):

Wherein Y is as defined above, is halogenated using a carboxylic acid halogenating agent and an alkyl side chain halogenating agent;

(8)

Z H (8)

2. The process according to claim 1, wherein the compound is obtained by reacting a compound represented by the formula: wherein Z is as defined above.

23. The method according to claim 22, wherein the carboxylic acid halogenating agent is a thionyl halide.

24. The process according to claim 22, wherein the alkyl side chain halogenating agent is sulfuryl chloride or halogen.

2 5. The compound represented by the formula (10) is converted to the compound represented by the formula (3)

Three

The method according to claim 22, which is obtained by halogenating a compound represented by the formula:

26. The production method according to claim 25, wherein the halogenation is performed using N-halosuccinimide or halogen.