JP2003026640A - Method for producing aromatic ketone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an aromatic ketone. SOLUTION: A compound of general formula III (R<1> and R<2> are each independently an alkyl, an alkoxyalkyl or a cycloalkyl or R<1> and R<2> together form a cyclic group; R<3> is H, an alkyl, an alkoxy or phenyl; X is a halogen; and R<4> is a (substituted)aryl, a (substituted)heterocyclic group, an alkoxycarbonyl or an aryloxycarbonyl) is produced by reacting a compound of general formula I with metallic magnesium and reacting the Grignard reagent with a compound of general formula II (R<5> is an alkyl or an aryl).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an aromatic ketone, which is useful as a synthetic intermediate for drugs, agricultural chemicals and the like.

[0002]

2. Description of the Related Art Conventionally, a method of reacting an aromatic Grignard reagent or a lithium reagent with a carboxylic acid derivative has been widely used as a method for producing an aromatic ketone. The Grignard reagent, which is one of the raw materials in this method, can be prepared from an aromatic halogen compound and metallic magnesium stable in air. Therefore, the method using the aromatic Grignard reagent is unstable to moisture in the air. It can be said that the method is more safe than the method using a lithium reagent prepared from butyllithium and the like, and is a method suitable for production on an industrial scale.

On the other hand, as a carboxylic acid derivative which is another raw material, an ester compound is generally easy to synthesize and easy to obtain as a chemical product, and more stable and easy to handle as compared with a carboxylic acid halide. It is considered to be suitable as a raw material for production. However, 4th edition Experimental Chemistry Course, vol. 21, p. 289, the reaction of a Grignard reagent with an ester compound,
There is a problem that the ketone once produced further reacts with the Grignard reagent to produce a tertiary alcohol.

On the other hand, JP-A-3-246268 and JP-A-10-324672 disclose a method for producing an aromatic ketone by reacting an aromatic Grignard reagent with an oxalate ester. However, the patent does not show the synthesis of aromatic ketones having an aminomethyl group in the ortho position of the aromatic ring. Furthermore, the reaction between the Grignard reagent and an ester compound other than the oxalate ester is not exemplified.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a Grignard reagent prepared from an aromatic halogen compound having an aminomethyl group at the ortho position of an aromatic ring as an efficient method for producing an aromatic ketone starting from an ester compound. The present invention provides a manufacturing method using.

[0006]

That is, the present invention provides the following method. [1] General formula (I):

[0007]

[Chemical 5] (In the formula, R ¹ and R ² are each independently alkyl,
Alkoxyalkyl or cycloalkyl; R ³ is a hydrogen atom, alkyl, alkoxy or phenyl; X is a halogen atom. In addition, R ¹ and R ² may be taken together to form a cyclic group. ) A compound represented by
Compound (I) may be added) to a Grignard reagent obtained by reacting metal magnesium with a compound represented by the general formula (II):

[0008]

[Chemical 6] (In the formula, R ⁴ represents optionally substituted aryl, optionally substituted heterocyclic group, alkoxycarbonyl or aryloxycarbonyl; and R ⁵ represents alkyl or aryl.) , Which may be compound (II)), is represented by the general formula (III):

[0009]

[Chemical 7] (In the formula, each symbol has the same meaning as described above.) A method for producing a compound (hereinafter, may be referred to as compound (III)). [2] Reaction of Grignard reagent with compound (II)
The production method according to [1], which is performed at 50 to 10 ° C.

[3] The production method according to [1] or [2], wherein the group represented by R ¹ R ² N- is dimethylamino, diethylamino, morpholino, pyrrolidino or piperidino. [4] Formula (XIII), characterized by including the step according to any one of [1] to [3]:

[Chemical 8] (In the formula, R ³ has the same meaning as described above; Q is aryl which may be substituted, heterocyclic group which may be substituted, mono-substituted or di-substituted methyleneamino, alkyl which may be substituted, substituted Optionally alkenyl, optionally substituted alkynyl; A is an oxygen atom, S (O) n
(N is 0, 1 or 2), NR ⁸ (R ⁸ is hydrogen, alkyl or acyl) or —O—C (R ¹² ) ═N— (R
¹² is hydrogen or alkyl); ^{R 4} 'is a group reacted with either the same as ^{R 4,} or ^{R 4} amine ^{compound; R 11}
Represents alkyl, alkenyl or alkynyl or cycloalkyl. The manufacturing method of the compound represented by these. [5] General formula (I):

[Chemical 9] (In the formula, each symbol has the same meaning as above.) A Grignard reagent obtained by reacting a compound represented by the general formula (II):

[0011]

[Chemical 10] (In the formula, each symbol has the same meaning as above.) After reacting the compound at −50 to 10 ° C., the reaction temperature is 10 to 130.
The compound of the general formula (I
V):

[0012]

[Chemical 11] (In the formula, each symbol has the same meaning as described above.) A method for producing a compound (hereinafter, may be referred to as compound (IV)).

[6] By reducing the compound represented by the general formula (III) obtained by the production method described in any of [1] to [3], the general formula (IV):

[Chemical 12] (In the formula, each symbol has the same meaning as described above.) A method for producing the compound represented by the formula.

[7] The compound represented by the general formula (IV) obtained by the production method described in [5] or [6] has the general formula (V):

[Chemical 13] (In the formula, R ⁶ is alkyl, optionally substituted aryl or alkoxy; Y is a halogen atom or acyloxy.) (Hereinafter, compound (V)
In general formula (VI):

[Chemical 14] (In the formula, each symbol has the same meaning as described above.) A method for producing a compound (hereinafter, may be referred to as compound (VI)).

[8] The compound represented by the general formula (VI) obtained by the production method described in [7] is added to the compound of the general formula (VI)
I):

[Chemical 15] (In the formula, R ⁷ is alkyl; Z is a halogen atom.)
A compound represented by the general formula (VI) characterized by reacting a compound represented by the following (hereinafter sometimes referred to as compound (VII))
II):

[Chemical 16] (In the formula, each symbol has the same meaning as described above.) A method for producing a compound (hereinafter may be referred to as compound (VIII)). [9] The production method according to any one of [5] to [8], wherein the group represented by R ¹ R ² N- is dimethylamino, diethylamino, morpholino, pyrrolidino or piperidino.

[10] The compound represented by the general formula (VIII) obtained by the production method described in [8] or [9] has the general formula (IX):

[Chemical 17] [In the formula, Q is aryl which may be substituted, heterocyclic group which may be substituted, mono- or di-substituted methyleneamino, alkyl which may be substituted, alkenyl which may be substituted or substituted. Optionally alkynyl; A is an oxygen atom, S (O) n (n is 0, 1 or 2), NR ⁸ (R ⁸ is hydrogen, alkyl or acyl)
Alternatively, it represents —O—C (R ¹² ) ═N— (R ¹² is hydrogen or alkyl). ] The compound represented by the formula (hereinafter, may be referred to as compound (IX) in some cases) is reacted with the general formula (X):

[Chemical 18] (In the formula, each symbol has the same meaning as described above.) A method for producing a compound (hereinafter may be referred to as compound (X)).

[11] The compound represented by the general formula (X) obtained by the production method described in [10] is added to the compound of the general formula (X
I):

[Chemical 19] (In the formula, R ⁹ and R ¹⁰ each independently represent hydrogen or alkyl.) An amine compound represented by the general formula (hereinafter, may be referred to as compound (XI)) is reacted. (XII):

[Chemical 20] (In the formula, R ⁴ ′ is the same as R ⁴ , or R ⁴ represents a group reacted with an amine compound. Each other symbol has the same meaning as described above.) XI
I) may be referred to as).

[12] Alkylation of the compound represented by the general formula (XII) obtained by the production method described in [11],
The general formula (XIII) by alkenylation, alkynylation or cycloalkylation:

[Chemical 21] (In the formula, R ¹¹ represents alkyl, alkenyl, alkynyl or cycloalkyl. Other symbols have the same meanings as described above.) (Hereinafter, referred to as compound (XI
II), which is also referred to as II). [13] Q is an optionally substituted phenyl, and A
Is an oxygen atom, The manufacturing method as described in any one of [10]-[12].

The present invention will be described in detail below.
As the “halogen atom”, specifically, a fluorine atom,
Examples thereof include a chlorine atom, a bromine atom and an iodine atom. X
The halogen atom represented by is preferably a chlorine atom or a bromine atom. “Alkyl” includes, for example, straight-chain or branched alkyl having 1 to 8 carbons, preferably 1 to 6 carbons, and more preferably 1 to 4 carbons. Specifically, methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, s
Examples include ec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like. “Alkylcarboxy”, “alkyl halide”, “trialkylsilyl”, “alkylamino”, “dialkylamino”, “phenylalkyl”, “alkylphenyl”, “alkylthio”, “alkylsulfinyl” and “alkylsulfonyl” The alkyl portion of is the same as the above "alkyl".

The substituent of "optionally substituted alkyl" includes, for example, nitro, cyano, halogen atom,
Cycloalkyl, alkoxy, optionally substituted aryl [eg, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl (these are collectively referred to as 2
Abbreviated as-, 3-, 4-chlorophenyl. Hereinafter, the same abbreviations are used in the present specification), 2-, 3-, 4-methylphenyl, 2-, 3-, 4-methoxyphenyl, 1
-Or 2-naphthyl, etc.] and an optionally substituted heterocyclic group (eg, pyridin-2-yl, pyridine-
3-yl, 3-methoxypyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, 2-chloropyrimidin-5-yl, isoxazol-3-yl, 3-
Methylisoxazol-5-yl, pyrrol-2-yl, pyrazol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-.
Yl, imidazol-2-yl, oxazol-2-yl, thiazol-2-yl, etc.) and the like. These substituents may be substituted at any substitutable position.

Examples of the "cycloalkyl" include cycloalkyl having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "alkoxy" includes linear and branched alkoxy having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy. The alkoxy part of “alkoxycarbonyl” and “alkoxyphenyl” is the same as the above “alkoxy”. The “alkoxyalkyl” includes the above “alkyl” substituted with the above “alkoxy”. Specifically, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 3
-Methoxypropyl, 2-ethoxybutyl, 3-propoxypentyl, 1-methoxyhexyl, 2-isopropoxyheptyl, 4-methoxyoctyl and the like.

"Alkenyl" has 2 to 8 carbon atoms.
And preferably linear or branched alkenyl having 3 to 6 carbon atoms. For example, vinyl, allyl, 1
-, 2-propenyl, 1-, 2-, 3-butenyl, 1
-, 2-, 3-, 4-pentenyl and 1-, 2-, 3
-, 4-, 5-hexenyl and the like can be mentioned. "Alkynyl" has 2 to 8 carbon atoms, preferably 2 carbon atoms.
Includes ~ 6 alkynyls. For example, ethynyl, propargyl, 1-, 2-propynyl, 1-, 2-, 3-
Butynyl, 1-, 2-, 3-, 4-pentynyl and 1
-, 2-, 3-, 4-, 5-hexynyl etc. are mentioned. Examples of the substituent of “optionally substituted alkenyl” and “optionally substituted alkynyl” include the same groups as those exemplified as the above-mentioned substituents of “optionally substituted alkyl”.

"Acyl" includes, for example, alkanoyl and aroyl. The alkanoyl has, for example, 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms.
Includes 4 straight or branched alkanoyls.
For example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, propionyl and the like can be mentioned. Further, it may have one or more unsaturated bonds, and includes, for example, acryloyl, methacryloyl, crotonoyl and the like.
Examples of the aroyl include aroyl having 7 to 15 carbon atoms, preferably 7 to 11 carbon atoms. Specific examples thereof include benzoyl and naphthoyl. The acyl moiety of "acyloxy" is the same as the above "acyl". Examples of the substituent of the “optionally substituted carbamoyl” include the above “alkyl” and the like.

The "aryl" is an aryl having 6 to 14 carbon atoms, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl and 2-phenanthryl. Is mentioned. Phenyl is preferred. The aryl part of "aryloxycarbonyl" is the same as the above "aryl".

Examples of the substituent of the "aryl which may be substituted" represented by R ⁴ and R ^{4 ',} for example, alkyl, cycloalkyl, halogenated alkyl (e.g., trifluoromethyl, trichloromethyl, etc.), alkoxy Alkyl (eg, methoxymethyl, 1-, 2-methoxyethyl, ethoxymethyl, 1-, 2-ethoxyethyl, etc.), phenylalkyl (eg, benzyl, 1-, 2-phenylethyl, 1-, 2-, 3) -Phenylpropyl etc.), alkenyl, cycloalkenyl (eg 1-cyclopentenyl, 1-cyclohexenyl etc.), alkynyl, halogen atom, nitro, alkoxy, alkylthio (eg methylthio, ethylthio, propylthio etc.) and phenyl etc. To be These substituents may be substituted at any substitutable position of the aryl, and the number thereof is 1 to 4.

The "optionally substituted ant" represented by Q
Examples of the substituents for "a" include alkyl, cycloalkyl,
The above alkyl halide, the above alkoxy alkyl, above
Phenylalkyl, alkenyl, the above cycloalkenyl
Ru, alkynyl, halogen atom, nitro, cyano, phen
Nyl, trialkylsilyl (eg, trimethylsilyl,
Riethylsilyl, etc., above alkylthio, substituted
Any amino (eg, dimethylamino, diethylami)
No.), acyl, alkoxycarbonyl (eg, methoki)
Sicarbonyl, ethoxycarbonyl, etc.) and -OR
^Thirteen[In the formula, R ^ThirteenIs hydrogen, alkyl, alkenyl,
Alkynyl, alkyl halides (eg trifluorometh
Tyl, trichloromethyl, etc.), phenyl, alkyl group
(Eg, 2-, 3-, 4-methylphenyl, 2-,
3-, 4-ethylphenyl, etc.), halogenated phenyl
(Eg, 2-, 3-, 4-chlorophenyl, 2-, 3-,
4-bromophenyl, etc., alkoxyphenyl (eg,
2-, 3-, 4-methoxyphenyl, 2-, 3-, 4-
Ethoxyphenyl, etc.), nitrophenyl (eg, 2-,
3-, 4-nitrophenyl etc.), cyanophenyl
(Eg, 2-, 3-, 4-cyanophenyl, etc.), phenyl
Rualkyl, tetrahydropyranyl, pyridyl, trif
Luoromethylpyridyl, pyrimidinyl, benzothiazoli
, Quinolyl, etc.] and the like. These substituents
Is substituted at any substitutable position of the aryl
It may be present, and the number is 1 to 4.

The "optionally substituted aryl" for Q is preferably represented by the general formula (XIV):

[Chemical formula 22] (In the formula, U, V and W each independently represent a hydrogen atom, a halogen atom, an alkyl, a halogenated alkyl, an alkoxyalkyl, a phenylalkyl, OR ¹³ , an alkylthio or an alkylamino.).
As the groups represented by U, V and W, alkyl, halogenated alkyl and alkoxyalkyl are preferable,
Methyl, ethyl and trifluoromethyl are more preferred, especially methyl. Examples of the substituent of “optionally substituted phenyl” include the same groups as those exemplified as the substituent of “optionally substituted aryl” for Q above. These substituents may be substituted at any substitutable position of the phenyl,
The number is 1 to 4.

The "heterocyclic group" is, for example, a 5- to 7-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom in the ring, Specifically, pyridyl (eg, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl (eg, pyrimidin-2-yl, pyrimidine-4)
-Yl, pyrimidin-5-yl), isoxazolyl (eg, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, etc.), thiadiazolyl (eg, 1,3,4-thiadiazole-2) -Yl, 1,2,3-thiadiazol-4-yl, etc., pyridazinyl (eg, pyridazin-3-yl, pyridazin-4)
-Yl etc.), pyrrolyl (eg pyrrol-2-yl etc.), pyrazolyl (eg pyrazol-1-yl, pyrazol-3-yl etc.), furyl (eg furan-2-yl, furan-3-yl etc.) ), Thienyl (eg, thiophene-
2-yl, thiophen-3-yl), imidazolyl (eg, imidazol-2-yl), oxazolyl (eg, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), thiazolyl (eg. ,
Thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, etc.), oxadiazolyl (eg, 1,3,
4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, etc.), pyrazinyl (eg, pyrazin-2-yl etc.), quinolyl (eg, quinolin-2-yl etc.), Benzothiazolyl (eg, benzothiazole-2
-Yl) or indolyl (eg, indoline-1-yl, indoline-2-yl, etc.) and the like. These heterocyclic groups may have a bond at any position.

The substituent of the "optionally substituted heterocyclic group" represented by R ⁴ , R ⁴ 'and R ¹⁶ is:
The same groups as those exemplified as the substituent of the “optionally substituted aryl” for R ⁴ and R ⁴ ′ can be mentioned. Further, as the substituent of the “optionally substituted heterocyclic group” represented by Q, the same groups as those exemplified as the substituents of the “optionally substituted aryl” represented by Q above can be used. Can be mentioned. These substituents may be substituted at any substitutable position of the heterocyclic group, and the number thereof is 1 to 3. "Aryl which may be substituted" represented by R ^6, R ¹⁴ and R
^The substituents of the “optionally substituted aryl” and the “optionally substituted heterocyclic group” for ¹⁵ are the “optionally substituted aryl” for R ⁴ and R ⁴ ′ above. The same groups as those exemplified as the substituent of "" can be mentioned. These substituents may be substituted at any substitutable position of the aryl or the heterocyclic group, and the number thereof is 1 to 4.

The "optionally substituted ant" represented by Q
And “optionally substituted heterocyclic group”
The “optionally substituted amine” shown as a substituent is shown.
No ", R ¹⁴And R¹⁵"Replaced
"May be amino" is, for example, amino, having 1 to 1 carbon atoms.
8, preferably alkyl having 1 to 4 carbons, mono or di
Substituted amino, mono-substituted with formyl
An amino group having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms
Such as amino mono-substituted with lucarbonyl
Be done. “Mono- or di-substituted methyleneamino” is an example
For example, formula (XV):

[Chemical formula 23] [Wherein, R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, optionally substituted alkyl, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkoxyalkyl, or optionally substituted amino. , Cycloalkyl, optionally substituted aryl or optionally substituted heterocyclic group, or a monocyclic or polycyclic ring in which R ¹⁴ and R ¹⁵ may be bonded to each other to contain a hetero atom. indicating that forms a (wherein, R ^{1 4} and R ¹⁵ are simultaneously unless a hydrogen atom) represented by. R ¹⁴
And good monocyclic or polycyclic ring optionally contains heteroatoms R ¹⁵ is formed by bonding, it is formed together with the carbon atom bonded with R ¹⁴ and R ^15, heteroatom (e.g., oxygen , Nitrogen, sulfur, etc.) 4
~ 8-membered ring, which may form a condensed ring with other rings. Specific examples of the ring include cyclopentane, cyclohexane, indane, 1,2,3,4-tetrahydronaphthalene, 5,6,7,8-tetrahydroquinoline,
Examples include 4,5,6,7-tetrahydrobenzo [b] furan. These rings may have a divalent bond at any possible position. R ¹⁴ or R
¹⁵ is preferably methyl, ethyl and phenyl.

R¹And R^TwoTogether form a cyclic group
Formed with the nitrogen atom to which they bind, if
Examples of the cyclic group include pyrrolidine, piperidine
And morpholine. R^Four'In "R^Four
"Is a group reacted with an amine compound" means, for example, -CONR.
⁹R¹⁰(In the formula, R⁹And R¹⁰Each independently
A group represented by hydrogen or alkyl).

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, preferred specific examples of the present invention will be described for each step.

[Scheme 1]

[Chemical formula 24] (In the formula, each symbol has the same meaning as described above.) That is, the aromatic ketone represented by the general formula (III) is an ester compound obtained by reacting a Grignard reagent obtained by reacting the compound (I) with metallic magnesium. (I
It can be produced by reacting I) in a suitable solvent.

In this reaction, metallic magnesium can be used in 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to compound (I). The compound (II) can be used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the compound (I). Examples of usable solvents include ethers (eg, diethyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, etc.), aromatic hydrocarbons (eg, benzene, toluene). , Ethylbenzene, xylene, etc.), triethylamine and a mixed solvent thereof, and the like.

The reaction temperature for reacting the compound (I) with metallic magnesium is 10 ° C. to the reflux temperature of the solvent, preferably 20 ° C. to the reflux temperature of the solvent. The reaction time varies depending on the compound, but the reaction may be performed for 0.5 to 72 hours.
If necessary, a small amount of iodine, 1,2-dibromoethane, ethyl bromide or the like may be added as a reaction initiator. The amount thereof is 0.001 to the compound (I).
The amount is 0.2 equivalent, preferably 0.005 to 0.1 equivalent. The Grignard reagent obtained by reacting the compound (I) with magnesium metal may be isolated, but it is usually used as it is in the reaction solution for the subsequent reaction with the ester compound (II). The reaction temperature for reacting the Grignard reagent with the ester compound (II) is −78 to 10 ° C., preferably −50 to 10 ° C. The reaction time varies depending on the compound, but the reaction may be performed for 0.5 to 24 hours.

The desired aromatic ketone (III) obtained
Can be used in the next step as a crude product or after purification by a conventional method (eg, column chromatography, recrystallization, etc.). According to the method of the present invention in which compound (I) is used as a substrate, JP-A-3-246268 and JP-A-10-26268 are used.
Even when an ester compound (compound II) other than the oxalate ester described in -324672 is used as a raw material,
It is possible to suppress the by-product of the primary alcohol and to produce the aromatic ketone in good yield. In addition, since the reaction product compound (III) is an amine compound, after the reaction is completed, water and an acid such as hydrochloric acid or sulfuric acid are added to the reaction solution to form an aqueous solution of an amine salt, which is washed with an organic solvent such as toluene. To separate the unreacted ester compound (Compound II),
Purification can be easily performed. The secondary alcohol can be synthesized by reducing the aromatic ketone obtained by this production method. The compound (I) used as the starting material in this reaction is known or can be produced by the method described in Reference Example 1 below and a method analogous thereto.

[Scheme 2]

[Chemical 25] (In the formula, each symbol has the same meaning as described above.) That is, the alcohol represented by the general formula (IV) is obtained by reacting the compound (I) with metallic magnesium, and the Grignard reagent obtained by reacting the ester compound (II) ) Is reacted in a suitable solvent, and then the reaction temperature is raised to cause further reaction.

In this reaction, metallic magnesium can be used in 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to compound (I). The compound (II) can be used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the compound (I). Solvents that can be used are the same as in Scheme 1.

The reaction temperature for reacting the compound (I) with metallic magnesium is 10 ° C. to the reflux temperature of the solvent, preferably 20 ° C. to the reflux temperature of the solvent. The reaction time varies depending on the compound, but the reaction may be performed for 0.5 to 72 hours.
If necessary, a small amount of iodine, 1,2-dibromoethane, ethyl bromide or the like may be added as a reaction initiator. The amount thereof is 0.001 to the compound (I).
The amount is 0.2 equivalent, preferably 0.005 to 0.1 equivalent.

The Grignard reagent obtained by the reaction of the compound (I) with metallic magnesium may be isolated, but it is usually used as it is in the reaction solution for the subsequent reaction with the ester compound (II). Grignard reagent and ester compound (I
The reaction with I) has an initial reaction temperature of −78 to 10 ° C., preferably −50 to 10 ° C.
After reacting for 5 to 24 hours, the reaction temperature is adjusted to 10 to 140
C., preferably 20 to 130.degree. C., and allowed to react for 1 to 72 hours. The desired compound (IV) thus obtained can be used in the next step as a crude product or after purification by a conventional method (eg, column chromatography, recrystallization, etc.).

Compound (IV) can also be synthesized by the following method. [Scheme 3]

[Chemical formula 26] (In the formula, each symbol has the same meaning as described above.) That is, the alcohol represented by the general formula (IV) can be produced by reducing the aromatic ketone (III). Examples of the reducing agent that can be used include metal-hydrogen complex compounds (eg, lithium aluminum hydride, sodium borohydride, etc.), and the molar ratio to the compound (III) is 0.25 to 3. , Preferably 0.25 to 1.5 can be used. The reaction temperature is −50 to 150 ° C., preferably −20 to 100 ° C.
Is. The reaction time varies depending on the compound, but is 0.1 to 48
Let them react for a time.

When lithium aluminum hydride is used as the reducing agent, examples of usable solvents include the above ethers, the above aromatic hydrocarbons and mixed solvents thereof. When sodium borohydride is used as the reducing agent, for example, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, etc.), ethers (eg, diethyl ether, dibutyl ether, tert)
-Butyl methyl ether, tetrahydrofuran, 1,4
-Dioxane, ethylene glycol dimethyl ether, etc.), the above aromatic hydrocarbons, water and a mixed solvent thereof and the like. The desired compound (IV) obtained
Can be used in the next step as a crude product or after purification by a conventional method (eg, column chromatography, recrystallization, etc.).

[Scheme 4]

[Chemical 27] (In the formula, each symbol is as defined above.) That is, the compound represented by the general formula (VI) is the compound (I
V) and compound (V) can be produced by reacting in a suitable solvent in the presence or absence of a base.

In this reaction, the amount of the compound (V) is 1 equivalent or more, preferably 1
It can be used in 10 to 10 equivalents. Examples of usable solvents include the above-mentioned aromatic hydrocarbons, saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.),
Ethers (eg, diethyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitrites (eg, acetonitrile, etc.) , Dimethylsulfoxide (hereinafter referred to as DMSO), N, N-dimethylformamide (hereinafter referred to as DMF), N, N-dimethylacetamide (hereinafter referred to as DMA)
, 1-methyl-2-pyrrolidone (hereinafter referred to as NMP
And 1,3-dimethyl-2-imidazolidinone (hereinafter referred to as DMI) and a mixed solvent thereof.

Examples of the base that can be used include metal carbonates (eg sodium carbonate, potassium carbonate etc.), metal alkoxides (eg sodium methoxide,
Sodium ethoxide, sodium isopropoxide,
Potassium isopropoxide, potassium tert-butoxide, etc.), amine compounds (alkylamines (eg, trimethylamine, triethylamine, tributylamine,
Diisopropylethylamine), pyridine, etc.) and the like. The amount used is 1 to compound (IV)
It is 50 equivalents, preferably 1 to 20 equivalents. When the amine compound is used as the base, no solvent may be used.

The reaction temperature varies depending on the starting materials used and the reaction solvent, but is in the range of -20 to 120 ° C, preferably 0 to 100 ° C. The reaction time also varies depending on the raw materials and the reaction solvent, but the reaction may be performed for 0.5 to 200 hours. The desired compound (VI) thus obtained can be used in the next step as a crude product or after purification by a conventional method (eg, column chromatography, recrystallization, etc.).

[Scheme 5]

[Chemical 28] (In the formula, each symbol has the same meaning as described above.) That is, the compound represented by the general formula (VIII) can be produced by reacting the compound (VI) with the compound (VII) in a suitable solvent.

In this reaction, the compound (VII) can be used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, relative to the compound (VI). Examples of the solvent that can be used include the aromatic hydrocarbons, the saturated hydrocarbons, the halogenated hydrocarbons, the ethers, the ketones, the nitriles, and mixed solvents thereof.

The reaction temperature varies depending on the starting materials used and the reaction solvent, but is in the range of -20 to 120 ° C, preferably 0 to 100 ° C. The reaction time also varies depending on the raw materials and the reaction solvent, but the reaction may be performed for 0.5 to 200 hours. The desired compound (VIII) thus obtained can be used in the next step as a crude product or after purification by a conventional method (eg, column chromatography, recrystallization, etc.).

[Scheme 6]

[Chemical 29] (In the formula, each symbol has the same meaning as described above.) That is, the compound represented by the general formula (X) is a compound (VI
It can be produced by reacting II) with compound (IX) in a suitable solvent in the presence of a base.

In this reaction, compound (IX) is used in the amount of 1 to 10 equivalents, preferably 1 to 10 equivalents, relative to compound (VIII).
3 equivalents can be used. Examples of the solvent that can be used include the aromatic hydrocarbons, the saturated hydrocarbons, the halogenated hydrocarbons, the ethers, the alcohols, the ketones, the nitriles, and DMS.
Examples thereof include O, DMF, DMA, NMP, DMI, water and a mixed solvent thereof.

Examples of the base that can be used include metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), the above metal carbonates, the above metal alkoxides and the like. The amount used is 1-10 equivalents, preferably 1-5 equivalents, relative to compound (IV). In addition, inorganic salts such as sodium iodide and potassium iodide, tetra-n-butylammonium chloride, tetra-n-
A phase transfer catalyst such as butylammonium bromide, tetra-n-butylammonium hydrosulfate, tetra-n-butylammonium iodide, tetra-n-butylammonium hydroxide and benzyltriethylammonium chloride may be mixed. The amount used is 0.0 with respect to compound (VIII).
The amount is 01 to 0.2 equivalent, preferably 0.005 to 0.1 equivalent.

The reaction temperature varies depending on the starting materials used and the reaction solvent, but is in the range of -20 to 120 ° C, preferably 0 to 100 ° C. The reaction time also varies depending on the raw materials and the reaction solvent, but the reaction may be performed for 0.5 to 200 hours. The desired compound (X) thus obtained can be used in the next step as a crude product or after purification by a conventional method (eg, column chromatography, recrystallization, etc.).

[Scheme 7]

[Chemical 30] (In the formula, each symbol has the same meaning as described above.) That is, the compound represented by the general formula (XII) can be produced by reacting the compound (X) with the compound (XI) in a suitable solvent.

In this reaction, compound (XI) can be used in an amount of 1 to 20 equivalents, preferably 1 to 10 equivalents, relative to compound (X). Examples of the solvent that can be used include the alcohols, the aromatic hydrocarbons, the saturated hydrocarbons, the halogenated hydrocarbons, the ethers, the nitriles, DMSO, DMF, DMA, and the like.
Examples thereof include NMP, DMI, water and a mixed solvent thereof.

The reaction temperature varies depending on the starting materials used and the reaction solvent, but is in the range of -20 to 120 ° C, preferably 0 to 100 ° C. The reaction time also varies depending on the raw materials and the reaction solvent, but the reaction may be performed for 0.5 to 200 hours.

R ⁴ 'of compound (XII) is the same as R ⁴ of compound (X), or R ^4'
When is a group capable of reacting with compound (XI), it includes a group reacted with them. For example, R ⁴ ′ corresponding to the above-mentioned specific examples of the organic residue represented by R ⁴ is aryl which may be substituted, heterocyclic group which may be substituted or carbamoyl which may be substituted ( Alkoxy carbonyl or aryloxy carbonyl reacted with the compound (XI)). The desired compound (XII) thus obtained can be used in the next step as a crude product or after purification by a conventional method (eg, column chromatography, recrystallization, etc.).

[Scheme 8]

[Chemical 31] (In the formula, each symbol has the same meaning as described above.) That is, the compound represented by the general formula (XIII) is obtained by reacting the compound (XII) in the presence of a base in a suitable solvent with dialkyl sulfuric acid, alkyl chloride, bromide It can be produced by reacting with an alkylating agent such as alkyl or alkyl iodide, an alkenylating agent such as allyl bromide, an alkynylating agent such as propargyl bromide or a cycloalkylating agent.

In this reaction, the alkylating agent, alkenylating agent, alkynylating agent or cycloalkylating agent is
1 to 10 equivalents relative to compound (XII), preferably 1
~ 3 equivalents can be used. Examples of the solvent that can be used include DMF, DMSO, the above aromatic hydrocarbons, the above saturated hydrocarbons, and halogenated hydrocarbons (eg,
Dichloromethane, 1,2-dichloroethane, etc.), the above ethers, the above ketones, the above nitriles, water and a mixed solvent thereof.

Examples of the base that can be used include metal hydrides (eg sodium hydride, potassium hydride etc.), metal hydroxides (eg sodium hydroxide, potassium hydroxide, calcium hydroxide, water). Examples thereof include barium oxide), metal carbonates (eg, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, etc.), the above metal alkoxides, sodium hydrogen carbonate, metal sodium and the like. The amount used is 1-10 equivalents, preferably 1-5 equivalents, relative to compound (XII). In addition, tetra-n-butylammonium chloride, tetra-n
A phase transfer catalyst such as -butylammonium bromide, tetra-n-butylammonium hydrosulfate, tetra-n-butylammonium iodide, tetra-n-butylammonium hydroxide and benzyltriethylammonium chloride may be mixed. The amount used is 0.00 with respect to the compound (XII).
It is 1 to 0.2 equivalent, preferably 0.005 to 0.1 equivalent.

The reaction temperature varies depending on the starting materials used and the reaction solvent, but is in the range of -20 to 120 ° C, preferably 0 to 100 ° C. The reaction time also varies depending on the raw materials and the reaction solvent, but the reaction may be performed for 0.5 to 200 hours. The desired compound (XIII) thus obtained can be purified as a crude product or by a conventional method (eg, column chromatography, recrystallization, etc.). Optically active compound (XII
When I) is desired, the racemic compound (XIII) thus obtained may be optically resolved by a conventional method such as high performance liquid chromatography using an optically active column.
In addition, the racemic compound (XI
It is also possible to optically resolve I) in the same manner and then subject it to the reaction of Scheme 8 to obtain the desired optically active compound (XIII). The compound (XIII) thus obtained is W
It is a compound described in O95 / 27693 and is known to be useful as a bactericide. Particularly preferred is a compound in which Q is 2,5-dimethylphenyl, A is an oxygen atom and R ⁴ ′ is methylcarbamoyl.

The compounds (III) obtained by the method of scheme 1 or the secondary alcohol compounds (IV) obtained by the method of scheme 2 or 3 are used as intermediates to prepare WO95 / 26956 and WO97 / 12863.
It is also possible to synthesize the fungicide / insecticide for agricultural chemicals described in the above.
For example, the substituted aminomethyl group of compound (III) is changed to a CH ₂ -AQ group by a conventional method to obtain compound (A),
By subjecting the compound (A) to the following reaction, WO
The compound (B) described in 95/26956 can be obtained. The reaction shown in the following scheme may be carried out at any appropriate stage before or after changing the substituted aminomethyl group into a CH ₂ -AQ group or in the course of a series of reactions.

[Chemical 32] (Wherein Q, A, R ³ and R ¹¹ have the same meanings as described above; R
¹⁶ is an optionally substituted heterocyclic group; the wavy line is E
Body, Z body or a mixture thereof)

The compound represented by the formula (B) is obtained by compounding the compound (A) with R ¹¹ ONH ₂ or NH ₂ OH or a salt thereof (eg, hydrochloride, sulfate) in a suitable solvent (single or mixed). It can be produced by reacting inside. In this reaction, R ¹¹ ONH ₂ or NH ₂ OH can be used in an amount of 1 equivalent or more, preferably 1 to 4 equivalents, relative to compound (A). Examples of the solvent that can be used include the above aromatic hydrocarbons, the above saturated hydrocarbons, the above alcohols, water and mixed solvents thereof. The reaction temperature is 0 ° C to 160 ° C, preferably 6 ° C.
It is 0 ° C to 130 ° C. The reaction time varies depending on the compound, but the reaction may be performed for 0.5 to 90 hours. When the compound (A) is reacted with NH ₂ OH, the target compound (B) is obtained by subjecting it to the same reaction as in Scheme 8 subsequently. If necessary, the obtained compound (B) can be purified by a conventional method (eg, chromatography, recrystallization, etc.).

Further, the substituted aminomethyl group of the compound (IV) was changed to a CH ₂ -AQ group by a conventional method to obtain a compound (C), and the compound (C) was reacted in the same manner as in Scheme 8. By attaching it, the target compound (D) described in WO97 / 12863 can be obtained. A reaction similar to that in Scheme 8 may be carried out at an appropriate stage before or after changing the substituted aminomethyl group into a CH ₂ -AQ group, or in the middle of a series of reactions.

[Chemical 33] (In the formula, each symbol has the same meaning as above)

The compound represented by the general formula (D) can be produced by reacting the compound (C) with an alkylating agent, an alkenylating agent, an alkynylating agent or a cycloalkylating agent in the same manner as in Scheme 8. . The desired compound (D) thus obtained can be purified by a conventional method (eg, column chromatography, recrystallization, etc.) if necessary.

[0066]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. The ¹ H-NMR values described in the examples were measured using tetramethylsilane in a deuterated chloroform (CDCl ₃ ) solvent as an internal standard. The δ value is in ppm, and the binding constant (J) is in Hz. In the data, s is a singlet, d
Is a doublet, t is a triplet, q is a quartet, quint is a quintet, sext is a sextet, m is a multiplet, and br is a wide line.

Reference Example 1 Synthesis of 2- (dimethylaminomethyl) chlorobenzene 2-chlorobenzyl chloride 80.5 was added to a round bottom flask.
2 g (0.50 mol) was added and the mixture was cooled in an ice bath. Fifty
% Dimethylamine aqueous solution 135.27 g (1.50 mo
1) was added dropwise, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, extraction was performed with diethyl ether, the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by distillation under reduced pressure to give 2- (dimethylaminomethyl) chlorobenzene 8
1.02 g (96%) was obtained as a colorless oil. bp 84 ° C./1197 Pa ¹ H-NMR (CDCl ₃ ) δppm: 2.29 (s, 6H), 3.53 (s, 2
H), 7.14 7.26 (m, 2H), 7.31-7.43 (m, 2H).

Reference Example 2 Synthesis of 2- (morpholinomethyl) chlorobenzene 2-chlorobenzyl chloride 32.2 was added to an eggplant flask.
1 g (0.20 mol) was added and dissolved in 100 ml of toluene. Morpholine 43.56 g (0.50 mol)
100 ml of a toluene solution of was added dropwise and stirred at 100 ° C. for 5 hours. After allowing to cool to room temperature, 300 ml of 2 mol / l hydrochloric acid was added to the reaction liquid to separate it. Toluene layer is water 50m
It was washed with 1 and the aqueous layers were combined and washed with 200 ml of toluene. Add sodium hydroxide to the water layer to make it alkaline,
It was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2-
39.95 g of (morpholinomethyl) chlorobenzene (9
4%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δppm: 2.50 2.53 (m, 4H), 3.62
(s, 2H), 3.70 3.74 (m, 4H), 7.15 7.27 (m, 2H), 7.
35 (dd, J = 7.6, 1.7Hz, 1H), 7.47 (dd, J = 7.3, 2.
3Hz, 1H).

Example 1 Synthesis of butyl 2- (2- (dimethylaminomethyl) phenyl) -2-oxoacetate The inside of a 2-neck flask was replaced with nitrogen gas to obtain 0.79 g (32.5 mmol) of magnesium, 2 -(Dimethylaminomethyl) chlorobenzene 4.24 g (25.0 mmo
1) and 8 ml of toluene were added. To this, 0.27 g (2.5 mmol) of ethyl bromide and 3.61 g (50.0 mmol) of tetrahydrofuran were added and stirred at 80 ° C. for 4 hours to prepare a Grignard reagent solution. The system inside the 3-necked flask was replaced with nitrogen gas, 6.07 g (30.0 mmol) of dibutyl oxalate and 5 ml of toluene were added, and the mixture was cooled in a dry ice-acetone bath. The Grignard reagent solution prepared above was added dropwise to the mixture while maintaining the internal temperature at -10 to 0 ° C. After stirring at −10 to 0 ° C. for 3 hours, 12 mol of 5 mol / l hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was transferred to a separating funnel and separated, and the organic layer was washed with 1 mol / l hydrochloric acid. Combine the water layers and 1mo
neutralize with 1 / l sodium hydroxide aqueous solution and sodium bicarbonate,
It was extracted with diethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate), and 2- (2-
4.61 g (70%) of butyl (dimethylaminomethyl) phenyl) -2-oxoacetate was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.94 (t, J = 7.3Hz, 3H),
1.41 (sext, J = 7.3Hz, 2H), 1.73 (tt, J = 7.3, 6.9H
z, 2H), 2.11 (s, 6H), 3.61 (s, 2H), 4.26 (t, J = 6.
9Hz, 2H), 7.15 (d, J = 7.3Hz, 1H), 7.27 7.41 (m,
3H).

Example 2 Synthesis of 2- (dimethylaminomethyl) benzophenone A Grignard reagent solution was prepared in the same manner as in Example 1. The inside of the system of the 3-necked flask was replaced with nitrogen gas, and 4.08 g (30.0 mmol) of methyl benzoate and 5 m of toluene
1 was added and the mixture was cooled in a dry ice-acetone bath. The Grignard reagent solution was added dropwise to this at −20 to 0 ° C. while maintaining the internal temperature. After stirring at -20 to 0 ° C for 2 hours,
60 ml of 1 mol / l hydrochloric acid was added, and the mixture was stirred at room temperature for 16 hours. Transfer the reaction mixture to a separatory funnel and separate the layers.
It was washed with mol / l hydrochloric acid and water. The aqueous layers were combined, made alkaline with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain 2- (dimethylaminomethyl) benzophenone (3.49 g, 58%) as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 1.90 (s, 6H), 3.38 (s, 2
H), 7.30 7.54 (m, 7H), 7.71 7.74 (m, 2H).

Example 3 Synthesis of 4-chloro-2 '-(dimethylaminomethyl) benzophenone Same as Example 2 except 6.38 g (30.0 mmol) of butyl 4-chlorobenzoate was used instead of methyl benzoate. Then, 4.96 g (78%) of 4-chloro-2 ′-(dimethylaminomethyl) benzophenone was obtained as a pale yellow oily substance. ¹ H-NMR (CDCl ₃ ) δppm: 1.89 (s, 6H), 3.37 (s, 2
H), 7.22 7.43 (m, 6H), 7.63 7.68 (m, 2H).

Example 4 Synthesis of 3- (2- (dimethylaminomethyl) benzoyl) pyridine 4.54 g of ethyl nicotinate instead of methyl benzoate
The procedure is the same as in Example 2 except that (30.0 mmol) is used, and 3- (2- (dimethylaminomethyl) benzoyl) is used.
3.69 g (61%) of pyridine was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 1.87 (s, 6H), 3.38 (s, 2
H), 7.26 7.45 (m, 5H), 8.06 (dd, J = 7.9, 2.0Hz, 1
H), 8.72 (dd, J = 4.6, 2.0Hz, 1H), 8.83 (d, J = 2.0
Hz, 1H).

Example 5 Synthesis of 5-tert-butyl-3- (2- (dimethylaminomethyl) benzoyl) isoxazole 5.92 g ethyl 5-tert-butyl-3-isoxazolecarboxylate instead of methyl benzoate (30.0mmo
The procedure is the same as in Example 2 except that l) is used, and 5-tert-
Butyl-3- (2- (dimethylaminomethyl) benzoyl)
5.33 g (74%) of isoxazole was obtained as a pale yellow solid. mp 59.5-60.5 ° C. ¹ H-NMR (CDCl ₃ ) δppm: 1.38 (s, 9H), 1.90 (s, 6
H), 3.51 (s, 2H), 6.41 (s, 1H), 7.22 (d, J = 7.3H
z, 1H), 7.30 7.45 (m, 4H).

Example 6 Synthesis of butyl 2- (2- (morpholinomethyl) phenyl) -2-oxoacetate The inside of a 3-neck flask was replaced with nitrogen gas, and 1.46 g (60.0 mmol) of magnesium and 5 ml of tetrahydrofuran. , 0.54 g (5.0 mmol) of ethyl bromide were added, and the mixture was stirred at room temperature for 10 minutes. 2- (morpholinomethyl) chlorobenzene 10.59 g (50.0 mmol)
Tetrahydrofuran solution (20 ml) was added and the mixture was refluxed for 42 hours to prepare a Grignard reagent solution. The inside of the system of another 3-neck flask was replaced with nitrogen gas, a solution of 15.17 g (75.0 mmol) of dibutyl oxalate in tetrahydrofuran (5 ml) was added, and the mixture was cooled in a dry ice-acetone bath. The Grignard reagent solution prepared above was added dropwise to the mixture while maintaining the internal temperature at -20 to 0 ° C. After washing with 15 ml of tetrahydrofuran and stirring at −20 to 0 ° C. for 3 hours, 60 mol of 2 mol / l hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was transferred to a separating funnel and 150 ml of toluene was added to separate the layers. The aqueous layer was made alkaline with sodium bicarbonate and extracted with toluene. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate), and 2-
7.47 g (49%) of butyl (2- (morpholinomethyl) phenyl) -2-oxoacetate was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.95 (t, J = 7.3Hz, 3H),
1.42 (sext, J = 7.3Hz, 2H), 1.74 (tt, J = 7.3, 6.9H
z, 2H), 2.39 (t, J = 4.6Hz, 4H), 3.59 (t, J = 4.6H
z, 1H), 3.60 (s, 2H), 4.25 (t, J = 6.9Hz, 2H), 7.1
9 (d, J = 7.6Hz, 1H), 7.30 7.44 (m, 3H).

Example 7 Synthesis of 2- (2- (dimethylaminomethyl) phenyl) -2-hydroxyacetate-1 The inside of a 3-neck flask was replaced with nitrogen gas to obtain 0.79 g (32.5 mmol) of magnesium. , Tetrahydrofuran 5 ml, and ethyl bromide 0.27 g (2.5 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. 2- (Dimethylaminomethyl) chlorobenzene 4.24 g (25.0 mmol)
Of toluene (5 ml) was added and the mixture was stirred at 80 ° C. for 5 hours to prepare a Grignard reagent solution. The interior of the 4-neck flask was replaced with nitrogen gas, and dibutyl oxalate 6.07 was added.
g (30.0 mmol) and 5 ml of toluene were added, and the mixture was cooled in a dry ice-acetone bath. The Grignard reagent solution prepared above was added dropwise to the mixture at −20 to −10 ° C. while maintaining the internal temperature. After stirring at -20 to -10 ° C for 1 hour, the temperature was raised to 100 ° C and stirring was performed for 16 hours. The mixture was cooled in an ice bath, 60 ml of 1 mol / l hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was transferred to a separating funnel and separated, and the organic layer was washed with 1 mol / l hydrochloric acid and water. The aqueous layers were combined, made alkaline with sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-
3.80 g (49%) of butyl (dimethylaminomethyl) phenyl) -2-hydroxyacetate was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.84 (t, J = 7.4 Hz, 3H),
1.10-1.30 (m, 2H), 1.40-1.60 (m, 2H), 2.26 (s,
6H), 3.06 (d, J = 12.7 Hz, 1H), 3,91 (d, J = 12.7
Hz, 1H), 4.00-4.30 (m, 2H), 5.15 (s, 1H), 7.10-
7.40 (m, 4H), 9.32 (brs, 1H).

Example 8 Synthesis of 2- (2- (dimethylaminomethyl) phenyl) -2-hydroxyacetate Butyl-22- (2- (dimethylaminomethyl) phenyl) -2-oxoacetate 15.0 g (57) ．
0 mmol) was dissolved in 75 ml of methanol. Under ice cooling, sodium borohydride 0.65 g (17.1 mm)
ol) was added little by little over several times and stirred for 30 minutes. The reaction solution was 1 mol / l hydrochloric acid 70 ml and toluene 50
It was poured into a mixed solution of ml and stirred for 5 minutes. After 70 ml of a 1 mol / l sodium hydroxide aqueous solution was added to adjust the liquidity to pH 9, 100 ml of toluene was additionally added for liquid separation. The aqueous layer was extracted with toluene, and the organic layers were combined and washed with water and saturated saline. After drying the extract over anhydrous magnesium sulfate,
2- (2- (dimethylaminomethyl) phenyl)
Obtained 14.6 g (97%) of butyl 2-hydroxyacetate as a yellow oil.

Example 9 Synthesis of 2-hydroxy-2- (2- (morpholinomethyl) phenyl) butyl acetate Butyl 2- (2- (morpholinomethyl) phenyl) -2-oxoacetate 3.05 g (10.0 mmol) 20m of ethanol
It was dissolved in 1. Sodium borohydride 0.1 under ice cooling
9 g (5.0 mmol) was added and stirred for 15 minutes. 1m
10 ml of ol / l hydrochloric acid and water were added, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- Hydroxy-2- (2
-(Morpholinomethyl) phenyl) butyl acetate 2.30 g
(75%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.84 (t, J = 7.3 Hz, 3H),
1.16-1.30 (m, 2H), 1.50-1.57 (m, 2H), 2.44 2.
65 (m, 4H), 3.22 (d, J = 12.9 Hz, 1H), 3.653.79
(m, 4H), 3,92 (d, J = 12.9 Hz, 1H), 4.05-4.22
(m, 2H), 5.18 (s, 1H), 7.19-7.40 (m, 4H), 8.71 (b
rs, 1H).

Example 10 Synthesis of 2-acetoxy-2- (2- (dimethylaminomethyl) phenyl) butyl acetate Butyl 2- (2- (dimethylaminomethyl) phenyl) -2-hydroxyacetate 5.0 g (18. 8 mmol) Toluene 2
Dissolved in 5 ml, 1.95 ml acetic anhydride (20.7 mm
ol) was added and the mixture was stirred at room temperature for 3 hours. 50 saturated sodium bicarbonate water
After adding ml, the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off,
Butyl 2-acetoxy-2- (2- (dimethylaminomethyl) phenyl) acetate (5.62 g, 96%) was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.85 (t, J = 7.4 Hz, 3H),
1.10-1.40 (m, 2H), 1.40-1.60 (m, 2H), 2.17 (s,
3H), 2.20 (s, 6H), 3.40 (d, J = 13.0 Hz, 1H), 3.6
7 (d, J = 13.0 Hz, 1H), 4.00-4.20 (m, 2H), 6.68
(s, 1H), 7.20 -7.50 (m, 4H).

Example 11 Synthesis of butyl 2- (2- (dimethylaminomethyl) phenyl) -2-methoxycarbonyloxyacetate 1.70 g of butyl 2- (2- (dimethylaminomethyl) phenyl) -2-hydroxyacetate 6.4 mmol) was dissolved in 10 ml of toluene. Methyl chloroformate 0.59 ml
(7.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 hours. 40 ml of saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer was washed with water and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off and 2- (2
2.0 g (96%) of butyl- (dimethylaminomethyl) phenyl) -2-methoxycarbonyloxyacetate was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.86 (t, J = 7.3 Hz, 3H),
1.10-1.40 (m, 2H), 1.50-1.70 (m, 2H), 2.20 (s,
6H), 3.41 (d, J = 13.0 Hz, 1H), 3,69 (d, J = 13.0
Hz, 1H), 3.83 (s, 3H), 4.10-4.20 (m, 2H), 6.66
(s, 1H), 7.20 -7.50 (m, 4H).

Example 12 Synthesis of 2-methoxycarbonyloxy-2- (2- (morpholinomethyl) phenyl) butyl acetate Butyl 2-hydroxy-2- (2- (morpholinomethyl) phenyl) acetate 2.15 g (7. 0 mmol) in toluene 20
Dissolve in ml, methyl chloroformate 0.72 g (7.7 m
mol) was added and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, extracted with toluene, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2-methoxycarbonyloxy-2- (2- (morpholino). 2.02 g (79%) of methyl) phenyl) butyl acetate was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.86 (t, J = 7.3 Hz, 3H),
1.26 (sext, J = 7.3 Hz, 2H), 1.51-1.62 (m, 2H),
2.40 2.44 (m, 4H), 3.49 (d, J = 12.9 Hz, 1H), 3.6
4 (t, J = 4.6 Hz, 4H), 3,79 (d, J = 12.9 Hz, 1H),
3.84 (s, 3H), 4.16 (t, J = 7.6 Hz, 2H), 6.76 (s, 1
H), 7.23-7.45 (m, 4H).

Example 13 Synthesis of butyl 2-acetoxy-2- (2-chloromethylphenyl) acetate 5.62 g (18.3 mmol) of butyl 2-acetoxy-2- (2- (dimethylaminomethyl) phenyl) acetate was added. Dissolved in 17 ml of toluene, 2.82 ml of methyl chloroformate
(36.6 mmol) was added and the mixture was stirred at 25 to 30 ° C. for 18 hours. 30 ml of water was added to the reaction mixture for liquid separation, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2-acetoxy-2-
Butyl (2-chloromethylphenyl) acetate 4.58 g (8
4%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.85 (t, J = 7.4 Hz, 3H),
1.10-1.40 (m, 2H), 1.50-1.70 (m, 2H), 2.20 (s,
3H), 4.00-4.30 (m, 2H), 4.71 (d, J = 11.9Hz, 1
H), 4.87 (d, J = 11.9 Hz, 1H), 6.30 (s, 1H), 7.30
-7.60 (m, 4H).

Example 14 Synthesis of butyl 2- (2-chloromethylphenyl) -2-methoxycarbonyloxyacetate-1 2.00 g Butyl 2- (2- (dimethylaminomethyl) phenyl) -2-methoxycarbonyloxyacetate (6.2 mmo
l) was dissolved in 20 ml of toluene, 0.96 ml (12.4 mmol) of methyl chloroformate was added, and the mixture was stirred at room temperature for 18 hours. 20 ml of water was added to the reaction mixture for partitioning the mixture, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (n-
Purification with hexane / ethyl acetate) gave 1.60 g (82%) of butyl 2- (2-chloromethylphenyl) -2-methoxycarbonyloxyacetate as a colorless oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.85 (t, J = 7.3 Hz, 3H),
1.10-1.40 (m, 2H), 1.50-1.70 (m, 2H), 2.20 (s,
6H), 3.86 (s, 3H), 4.00-4.30 (m, 2H), 4.69 (d,
J = 12.0 Hz, 1H), 4.89 (d, J = 12.0 Hz, 1H), 6.23
(s, 1H), 7.30 -7.60 (m, 4H).

Example 15 Synthesis of butyl 2- (2-chloromethylphenyl) -2-methoxycarbonyloxyacetate-2 Butyl 2-methoxycarbonyloxy-2- (2- (morpholinomethyl) phenyl) acetate 0.91 g ( 2.5 mmol)
Was dissolved in 10 ml of toluene and methyl chloroformate 0.7 was added.
Add 1 g (7.5 mmol), 72 hours at room temperature, 50 ° C
The mixture was stirred for 15 hours at 80 ° C. for 6 hours. Water and ethyl acetate were added to the reaction mixture for liquid separation, and the organic layer was washed successively with water and saturated brine. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2-chloromethylphenyl) -2-methoxy. 0.71 g (91%) of butyl carbonyloxyacetate was obtained as a colorless oil.

Example 16 Synthesis of butyl 2-acetoxy-2- (2- (2,5-dimethylphenoxymethyl) phenyl) acetate Under a nitrogen stream, 0.40 g (3.25 g) of 2,5-xylenol was obtained.
mmol) to N, N-dimethylacetamide (DMA)
It was dissolved in 1.4 ml and 0.69 g (3.58 mmol) of 28% sodium methoxide-methanol solution was added dropwise. After stirring at room temperature for 5 minutes at 55-60 ° C. for 5 minutes, the solvent was concentrated under reduced pressure. To the residue, potassium iodide 6.8 mg (0.041 mmol), 2-acetoxy-2
-(2-Chloromethylphenyl) butyl acetate 1.00g
(3.25 mmol) in DMA (2 ml) was added,
The mixture was stirred at 55-60 ° C for 3 hours. After returning to room temperature, the reaction mixture was poured into 3.6 ml of 1 mol / l hydrochloric acid and stirred for 5 minutes. Toluene was added for extraction, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to give crude 2-acetoxy-2- (2- (2,5-dimethylphenoxymethyl)
1.21 g (content 82%) of phenyl) butyl acetate was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.83 (t, J = 7.3 Hz, 3H),
1.10-1.30 (m, 2H), 1.40-1.60 (m, 2H), 2.18 (s,
3H), 2.21 (s, 3H), 2.32 (s, 3H), 4.00-4.20 (m,
2H), 5.20 (d, J = 12.4 Hz, 1H), 5.25 (d, J = 12.4
Hz, 1H), 6.29 (s, 1H), 6.70 (d, J = 7.6 Hz, 1H),
6.73 (s, 1H), 7.03 (d, J = 7.5 Hz, 1H), 7.30-7.60
(m, 4H).

Example 17 2- (2- (2,5-dimethylphenoxymethyl) phenyl)-
Synthesis of 2-hydroxy-N-methylacetamide-1 1.21 g of crude butyl 2-acetoxy-2- (2- (2,5-dimethylphenoxymethyl) phenyl) acetate was dissolved in 5 ml of methanol to obtain 40% methylamine. Aqueous solution 2.5
Add 2 ml (32.5 mmol), oil bath temperature 50-5
The mixture was stirred at 5 ° C for 6 hours. After returning to room temperature, add water,
It was extracted with ethyl acetate. The organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give 2- (2- (2,5-dimethylphenoxymethyl) phenyl) -2-hydroxy-N-. 0.64 g of methylacetamide (66% over 2 steps) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δppm: 2.16 (s, 3H), 2.35 (s, 3
H), 2.78 (d, J = 4.9Hz, 3H), 4.35 (d, J = 3.7Hz, 1
H), 4.94 (d, J = 11.0Hz, 1H), 5.34 (d, J = 11.0Hz,
1H), 5.35 (d, J = 3.7Hz, 1H), 6.49 (brs, 1H), 6.7
8 (d, J = 7.3Hz, 1H), 6.87 (s, 1H), 6.87 (d, J =
7.3Hz, 1H), 7.32-7.48 (m, 4H).

Example 18 2- (2- (2,5-dimethylphenoxymethyl) phenyl)
Synthesis of butyl 2-methoxycarbonyloxyacetate 0.39 g (3.18 mmol) of 2,5-xylenol was dissolved in 1.4 ml of DMA, and 0.68 g (3.50 mmol) of 28% sodium methoxide-methanol solution was added dropwise. Added. After stirring at room temperature for 5 minutes at 55-60 ° C. for 5 minutes, the solvent was concentrated under reduced pressure. To the residue, potassium iodide 6.6 mg (0.040 mmol), butyl 2- (2-chloromethylphenyl) -2-methoxycarbonyloxyacetate 1.00 g (3.18 mmol) DMA (2 m
l) The solution was added and stirred at 55-60 ° C. for 3 hours. After returning to room temperature, the reaction mixture was 1 mol / l hydrochloric acid 3.5 m
It was poured into 1 and stirred for 5 minutes. Toluene was added for extraction, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off to give crude 2- (2- (2,5-dimethylphenoxymethyl) phenyl) -2-methoxycarbonyloxyacetate 1.23 g (content 78%). Was obtained as a yellow oil. ¹ H-NMR (CDCl ₃ ) δppm: 0.83 (t, J = 7.3 Hz, 3H),
1.10-1.30 (m, 2H), 1.40-1.60 (m, 2H), 2.21 (s,
3H), 2.32 (s, 3H), 3.83 (s, 3H), 4.10-4.20 (m,
2H), 5.20 (d, J = 12.2 Hz, 1H), 5.27 (d, J = 12.2
Hz, 1H), 6.23 (s, 1H), 6.71 (d, J = 7.4 Hz, 1H),
6.75 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H), 7.30-7.60
(m, 4H).

Example 19 2- (2- (2,5-dimethylphenoxymethyl) phenyl)-
Synthesis of 2-hydroxy-N-methylacetamide-2-2- (2- (2,5-dimethylphenoxymethyl) phenyl)
1.23 g of butyl-2-methoxycarbonyloxyacetate was dissolved in 5 ml of methanol, 2.47 ml of 40% methylamine aqueous solution was added, and the mixture was stirred at an oil bath temperature of 50 to 55 ° C. for 6 hours. After returning to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue obtained is purified by silica gel column chromatography (n-hexane / ethyl acetate) and
-(2- (2,5-Dimethylphenoxymethyl) phenyl) -2-
0.59 g of hydroxy-N-methylacetamide (62% in total over 2 steps) was obtained as a colorless oil.

Example 20 2- (2- (2,5-dimethylphenoxymethyl) phenyl)-
Synthesis of 2-methoxy-N-methylacetamide 2- (2- (2,5-dimethylphenoxymethyl) phenyl)-
2-Hydroxy-N-methylacetamide 11.97 g
(40.0 mmol) was dissolved in 30 ml of toluene, and 4
8% sodium hydroxide aqueous solution 10.0 g (120 mmo
l) was added, 6.06 g of dimethylsulfate (48 mmo
10 ml of a toluene solution of 1) was added dropwise, and the mixture was stirred at room temperature for 6 hours. Water was added and the mixture was extracted with toluene. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was recrystallized from a mixed solution of n-hexane / ethyl acetate (5: 1, 60 ml) to give 2- (2
11.08 g (88%) of-(2,5-dimethylphenoxymethyl) phenyl) -2-methoxy-N-methylacetamide was obtained as white crystals. mp107-108 ° C. ¹ H-NMR (CDCl ₃ ) δppm: 2.19 (s, 3H), 2.32 (s, 3)
H), 2.83 (d, J = 4.9 Hz, 3H), 3.36 (s, 3H), 5.03
(s, 1H), 5.06 (d, J = 11.7 Hz, 1H), 5.47 (d, J = 1
1.7 Hz, 1H), 6.70 (d, J = 7.3 Hz, 1H), 6.80 (s, 1
H), 6.80 (brs, 1H), 7.03 (d, J = 7.3 Hz, 1H), 7.31
-7.43 (m, 3H), 7.50-7.54 (m, 1H).

[0089]

Industrial Applicability The aromatic ketone having an o-substituted aminomethyl group, which can be used as an intermediate for the production of agricultural chemicals and pharmaceuticals, can be produced safely and on an industrial scale.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 213/50 C07D 213/50 261/08 261/08 295/14 295/14 Z F term (reference) 4C055 AA01 BA01 CA02 CA18 CB17 DA01 FA11 FA32 FA34 FA37 4C056 AA01 AB01 AC01 AD01 AE02 AF05 FA09 FB01 FC01 4H006 AA02 AC24 AC44

Claims (4)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ and R ² are each independently alkyl,
Alkoxyalkyl or cycloalkyl; R ³ is a hydrogen atom, alkyl, alkoxy or phenyl; X is a halogen atom. In addition, R ¹ and R ² may be taken together to form a cyclic group. ) Is added to the Grignard reagent obtained by reacting the compound represented by the general formula (II): (Wherein R ⁴ is an optionally substituted aryl, an optionally substituted heterocyclic group, an alkoxycarbonyl or an aryloxycarbonyl; and R ⁵ is an alkyl or an aryl). A compound of general formula (III): (In the formula, each symbol has the same meaning as described above.) A method for producing the compound represented by the formula. 2. The production method according to claim 1, wherein the reaction between the Grignard reagent and the compound (II) is performed at −50 to 10 ° C. 3. The production method according to claim 1, wherein the group represented by R ¹ R ² N— is dimethylamino, diethylamino, morpholino, pyrrolidino or piperidino. 4. Formula (XIII): characterized in that it comprises a process according to any one of claims 1 to 3. (In the formula, R ³ has the same meaning as described above; Q is aryl which may be substituted, heterocyclic group which may be substituted, mono-substituted or di-substituted methyleneamino, alkyl which may be substituted, substituted Optionally alkenyl, optionally substituted alkynyl; A is an oxygen atom, S (O) n
(N is 0, 1 or 2), NR ⁸ (R ⁸ is a hydrogen atom, alkyl or acyl) or —O—C (R ¹² ) ═N—
^{(R 12} is a hydrogen atom or an alkyl); ^{R 4} 'is ^{R 4} and identical whether or ^{R 4} group is reacted with an amine ^{compound,; R 11} represents alkyl, alkenyl, alkynyl or cycloalkyl. The manufacturing method of the compound represented by these.