JP2002338558A - Method for producing (4-alkyl-1-piperazinylmethyl)benzoic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a high-purity (4-alkyl-1- piperazinylmethyl)benzoic acid in high yield under environmentally friendly conditions. SOLUTION: This method for producing a (4-alkyl-1-piperazinylmethyl)benzoic acid of general formula (4) (wherein, R is an alkyl) is characterized by comprising the steps of reacting a benzyl halide derivative of general formula (1) (wherein, X is a halogen atom; and Y is a nitrile group or alkoxycarbonyl group) with a 1-alkylpiperazine of general formula (2) (wherein, R is an alkyl) to produce a (4-alkyl-1-piperazinyl)methylbenzene derivative of general formula (3) (wherein, Y is a nitrile group or alkoxycarbonyl group; and R is an alkyl) and then hydrolyzing the (4-alkyl-1-piperazinyl)methylbenzene derivative. This method enables easily producing the objective high-purity (4-alkyl-1- piperazinylmethyl)benzoic acid extremely low in demethylated modification content in high yield under environmentally friendly conditions, therefore being very high in industrial usefulness.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to (4-alkyl-1-piperazinylmethyl) useful in the field of medicine and agrochemicals.
The present invention relates to a novel method for producing benzoic acid.

[0002]

2. Description of the Related Art Conventionally, as a method for producing (4-alkyl-1-piperazinylmethyl) benzoic acid, for example, a method of reacting 4-chloromethylbenzoic acid with 1-methylpiperazine in ethanol is known. Yes (5-75
754). However, this method has a very low yield of 35%, which is the final product of 4- (4-methyl-1-piperazinylmethyl) benzoic acid dihydrochloride hemihydrate.
Water-soluble 1-methylpiperazine is used in a large excess, and furthermore, when used on an industrial scale with an ethanol solvent, it is a method that increases the wastewater load, and is a reaction that is environmentally problematic, and is difficult for industrial practice. Was accompanied.

[0003] On the other hand, in the synthesis of a physiologically active substance, a high quality product with few impurities is indispensable due to problems such as physiological activity and toxicity. However, when the present inventors supplemented the above-mentioned production method (the method disclosed in Japanese Patent Publication No. 5-75754), it was found that 4- (piperazinylmethyl) benzoic acid from which a methyl group had been eliminated (hereinafter simply referred to as " It may be described as "methyl form") by-produced by 0.16%, indicating that there is a serious problem of generation of impurities.
Moreover, this demethylated product is difficult to separate from the target substance,
Since it is difficult to remove efficiently even in recrystallization, etc.,
It was found that a significant decrease in yield was inevitable in purifying and purifying the desired product (4-alkyl-1-piperazinylmethyl) benzoic acid.

[0004] Therefore, in high yield and environmentally friendly conditions,
There has been no known method capable of producing high-purity (4-alkyl-1-piperazinylmethyl) benzoic acid.

[0005]

SUMMARY OF THE INVENTION The present invention provides a high yield,
High purity (4-alkyl-1-) under environmentally friendly conditions
An object of the present invention is to provide a method for producing (piperazinylmethyl) benzoic acid.

[0006]

In view of the above situation, the present inventor has conducted intensive studies on a method for producing (4-alkyl-1-piperazinylmethyl) benzoic acid. Using a commercially available halogenomethylbenzoic acid derivative as a starting material, it is reacted with 1-alkylpiperazine to produce a (4-alkyl-1-piperazinylmethyl) benzoic acid derivative, which is hydrolyzed. By doing so, it was found that (4-alkyl-1-piperazinylmethyl) benzoic acid can be produced with high yield and high purity, and the present invention has been completed.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

The present invention has solved the above problems by providing the inventions described in the following [1] and [2].

[1] General formula (1)

[0010]

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(In the formula, X represents a halogen atom, and Y represents a nitrile group or an alkoxycarbonyl group.)

The benzyl halide derivative represented by the general formula (2)

[0013]

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(Wherein, R represents an alkyl group)

By reacting with a 1-alkylpiperazine represented by the following formula:

[0016]

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(In the formula, Y represents a nitrile group or an alkoxycarbonyl group, and R represents an alkyl group.)

A method for producing a (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the following formula:

[0019]

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(Wherein R represents an alkyl group). A process for producing (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the formula:

[2] General formula (1)

[0022]

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(In the formula, X represents a halogen atom, and Y represents a nitrile group or an alkoxycarbonyl group.)

A benzyl halide derivative represented by the general formula (2)

[0025]

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(In the formula, R represents an alkyl group.)

The reaction with a 1-alkylpiperazine represented by the formula (1), wherein an aromatic hydrocarbon solvent is used.

[0028]

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(In the formula, R represents an alkyl group.)

A method for producing a (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the formula:

Hereinafter, the present invention will be described in detail.

First, the invention described in the item [1] will be described.

The production method described in [1] is based on the general formula (1)
The benzyl halide derivative represented by the general formula (2)
By producing a (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the general formula (3) by reacting with a 1-alkylpiperazine represented by the following formula, and further subjecting this to a hydrolysis reaction, (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the general formula (4) is obtained.

First, the benzyl halide derivative represented by the general formula (1) used as a raw material in the method of the present invention will be described.

Examples of the halogen atom represented by X in the general formula (1) include a fluorine atom, a chlorine atom and a bromine atom, and Y in the formula represents a nitrile group or an alkoxycarbonyl group. As the alkoxycarbonyl group, a compound represented by the general formula (5)

[0036]

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(Wherein R ¹ is an alkyl group, an aryl group,
Or an aralkyl group. )

Any group may be used as long as it is represented by the formula:

Here, R in the general formula (5)¹Represented by archi
The group having 1 to 10 carbon atoms (hereinafter referred to as such a substituted group)
About carbon number of a group etc., "C1-C10"
Abbreviated as ) Linear, branched or cyclic alkyl
Groups, specifically methyl, ethyl, n-propyl,
Isopropyl group, cyclopropyl group, n-butyl group, s
eC-butyl group, tert-butyl group, n-pentyl
Group, n-hexyl group, cyclohexyl group, n-heptyl
Group, n-octyl group, n-nonyl group and the like.
Yes, R¹The aryl group represented by is a phenyl group, 2
-Chlorophenyl group, 4-chlorophenyl group, 4-metho
And a phenyl group. ¹Represents
As the aralkyl group, benzyl group, 2-chlorophenyl
Methyl group, 4-chlorophenylmethyl group, 4-methoxy
A phenylmethyl group and the like can be exemplified.

The general formula (1) having X and Y as described above
Examples of the benzyl halide derivative represented by
-Chloromethylbenzonitrile, 3-chloromethylbenzonitrile, 4-chloromethylbenzonitrile, 2-bromomethylbenzonitrile, 3-bromomethylbenzonitrile, 4-bromomethylbenzonitrile, 2-chloromethylbenzoic acid methyl ester, 3-chloromethylbenzoic acid methyl ester, 4-chloromethylbenzoic acid methyl ester, 2-chloromethylbenzoic acid ethyl ester,
3-chloromethylbenzoic acid ethyl ester, 4-chloromethylbenzoic acid ethyl ester, 2-bromomethylbenzoic acid methyl ester, 3-bromomethylbenzoic acid methyl ester, 4-bromomethylbenzoic acid methyl ester,
Examples thereof include phenyl 4-chloromethylbenzoate and benzyl 4-chloromethylbenzoate.

The method for obtaining the benzyl halide derivative represented by the general formula (1) is not particularly limited. In the case of nitriles, for example, the side chain halogenation of the corresponding tolunitrile, In such a case, for example, each of them can be easily produced at a high yield by reacting halogenomethylbenzoic acid chloride with an alcohol.

The 1-alkylpiperazine represented by the general formula (2) will be described. The alkyl group represented by R in the general formula (2) may be a C1 to C6 linear or branched alkyl group, specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n-butyl group,
Examples thereof include a sec-butyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group.

The 1-alkylpiperazines represented by the general formula (2) having R as described above include, for example, 1-alkylpiperazines.
Methyl piperazine, 1-ethyl piperazine, 1-n-propyl piperazine, 1-n-butyl piperazine and the like can be mentioned, and the amount of use thereof is based on 1 mol of the benzyl halide derivative represented by the general formula (1). 1-alkylpiperazines represented by the general formula (2)
A range of 5 mol, preferably 1.1 to 3 mol can be exemplified. Excess 1-alkylpiperazines can be recovered by distillation after the completion of the reaction and reused.

By reacting a benzyl halide derivative represented by the general formula (1) with a 1-alkylpiperazine represented by the general formula (2), the (4-alkyl-1) represented by the general formula (3) is obtained. A reaction for obtaining a (piperazinylmethyl) benzene derivative will be described.

In this reaction, when the 1-alkylpiperazine represented by the general formula (2) is used in excess, the reaction proceeds without using another base. This is preferable from the viewpoint of the reaction rate and the yield.
Examples of the base used for this purpose include alkali metal and alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), alkali metal and alkaline earth metal carbonates (eg, Tertiary amines such as triethylamine, tributylamine, pyridine and the like; and inorganic bases such as sodium carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, barium carbonate and the like. Preferably, it is an inorganic base, more preferably a carbonate of an alkaline earth metal. It is also possible to use 1-alkylpiperazines themselves in excess and use them as a base.

The amount of the base to be used is, for example, 1 to 5 mol, preferably 1.1 to 2 mol, of the base per 1 mol of the benzyl halide derivative represented by the general formula (1).

In particular, when an alkaline earth metal hydroxide is used, it is preferable to use a dehydrating agent such as anhydrous sodium sulfate or anhydrous magnesium sulfate in order to improve the stirring state. The amount of this dehydrating agent used is determined by the general formula (1)
0.1 mole per 1 mole of the benzyl halide derivative represented by the formula
The range of 05 to 2 mol can be exemplified.

As a solvent used in this reaction, a solvent inert to the reaction can be used. Examples of such a solvent include aromatic hydrocarbon solvents, specifically, toluene, xylene, chlorobenzene and the like. Aliphatic hydrocarbon solvents, specifically n-hexane, n-heptane, n-decane, etc .; aliphatic alkyl ester solvents, specifically ethyl acetate, ethyl propionate, etc .; ethers System solvents, specifically tert-butyl methyl ether, dimethoxyethane, diethylene glycol dimethyl ether and the like; aprotic polar solvents, specifically dimethylformamide, dimethylacetamide,
N-methylpyrrolidone, tetramethylurea and the like can be exemplified. It is preferable to use aromatic hydrocarbons such as xylene, which have low solubility in water, are easy to recover and reuse, and are safe in practice on an industrial scale.

The above-mentioned solvents can be used alone or as a mixed solvent having an arbitrary mixing ratio. The amount of the solvent is not particularly limited as long as the reaction system can be sufficiently stirred. The amount of the solvent is 3000 ml or less, preferably 2000 ml or less, per 1 mol of the benzyl halide derivative represented by the general formula (1). I just need.

The reaction temperature of the above reaction is from -10 to 150
C., preferably in the range of 40 to 100 ° C., and the reaction time is in the range of 0.5 to 10 hours. The reaction can be carried out under normal pressure, and it is not usually necessary to apply pressure.

As a reaction method, a method of dropping a benzyl halide derivative represented by the general formula (1) into a base and a 1-alkylpiperazine represented by the general formula (2) is preferable.

As the (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the general formula (3) which can be produced by this reaction, for example, 2- (4-methyl-1-piperazinylmethyl) benzo Nitrile, 3- (4-methyl-1
-Piperazinylmethyl) benzonitrile, 4- (4-methyl-1-piperazinylmethyl) benzonitrile, 2-
(4-ethyl-1-piperazinylmethyl) benzonitrile, 3- (4-ethyl-1-piperazinylmethyl) benzonitrile, 4- (4-ethyl-1-piperazinylmethyl) benzonitrile, 2 -(4-methyl-1-piperazinylmethyl) benzoic acid methyl ester, 3- (4-methyl-1-piperazinylmethyl) benzoic acid methyl ester, 4- (4-methyl-1-piperazinylmethyl) ) Benzoic acid methyl ester, 2- (4-methyl-1-piperazinylmethyl) benzoic acid ethyl ester, 3- (4-methyl-1-piperazinylmethyl) benzoic acid ethyl ester, 4- (4-methyl) -1-Piperazinylmethyl) benzoic acid ethyl ester, 2- (4-ethyl-1-piperazinylmethyl) benzoic acid methyl ester, 3- (4-ethyl-1-piperazinyl) Chill) benzoic acid methyl ester, 4- (4-ethyl-1-piperazinyl-methyl) benzoic acid methyl ester, and the like.

The (4-alkyl-) represented by the general formula (3)
Of the 1-piperazinylmethyl) benzene derivatives, benzoate derivatives in which Y is an alkoxycarbonyl group can be easily converted by alcoholysis of the corresponding benzonitrile derivative in which Y is a nitrile group. It is.

The (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the general formula (3) obtained by the above reaction does not interfere with the subsequent hydrolysis reaction without purification. However, purification steps such as distillation purification and recrystallization may be performed. The recrystallization may be performed, for example, by deriving a salt of an inorganic acid such as hydrochloric acid or sulfuric acid or a salt of an organic acid such as acetic acid or paratoluenesulfonic acid.

Next, the (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the general formula (3) is subjected to a hydrolysis reaction to give the (4-alkyl-1) represented by the general formula (4). The reaction for obtaining (piperazinylmethyl) benzoic acid will be described.

The hydrolysis reaction can be carried out under any of acidic conditions and alkaline conditions, but acidic hydrolysis is generally preferable.

Examples of the acid used for the acidic hydrolysis reaction include inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and organic acids such as acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and paratoluenesulfonic acid. Although it can be used, the use of inorganic acids is common and preferred. The amount of acid used is 4-alkyl-1 represented by the general formula (3).
1 to 1 mole of piperazinylmethylbenzene derivative
The range may be from 20 to 20 mol, preferably from 2 to 10 mol.

Examples of the base used in the alkaline hydrolysis include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; sodium methoxide; Metal alkoxides such as potassium methoxide, sodium tert-butoxide and potassium tert-butoxide can be used. The amount of the base used is 0.01 to 1 with respect to 1 mol of the (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the general formula (3).
It may be 0 mol, preferably in the range of 1 to 5 mol.

The amount of water used in the above hydrolysis reaction is
It is sufficient that 1 mol or more of the (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the general formula (3) is present in an amount of 1 mol or more, including water brought in from an aqueous solution of the acid used. Considering the volumetric efficiency of the reaction vessel and the like, the amount of water is 3,000 per mole of the (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the general formula (3).
ml or less, preferably 2000 ml or less.

In this hydrolysis reaction, since water also serves as a solvent, a solvent is generally not required, but an inert solvent may be used in this hydrolysis reaction. Such solvents include, for example, aromatic hydrocarbon solvents, specifically, toluene, xylene, chlorobenzene, orthodichlorobenzene, etc .; alcohol solvents, specifically, methanol, ethanol, 2-propanol, etc .; Acids, specifically, formic acid, acetic acid, propionic acid and the like can be exemplified. The amount used is represented by the general formula (3) (4
-Alkyl-1-piperazinylmethyl) benzoic acid alkyl ester may be 3000 ml or less, preferably 2000 ml or less, per 1 mol.

The reaction temperature of this hydrolysis reaction is 5 to 150
C., preferably in the range of 20 to 100 ° C., and the reaction time is in the range of 0.5 to 20 hours. The reaction can be carried out under normal pressure, and it is not usually necessary to apply pressure.

The (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the general formula (4) obtained by the method of the present invention can be taken out in a free form or as a salt. However, it is preferable to take out the salt as a salt because the post-treatment operation after the hydrolysis reaction is simple and easy.
When the target substance is taken out as a salt, the amount of an acid such as hydrochloric acid, the amount of a metal such as sodium, or the amount of a cation such as an amine used for forming the salt depends on conditions for forming the salt.
The amount may be other than 1 equivalent based on (4-alkyl-1-piperazinylmethyl) benzoic acid. Further, at the time of removal, the target substance may be a hydrate.

As the (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the general formula (4) obtained by the method of the present invention as described above, or a salt thereof, specifically, (4-methyl-1-piperazinylmethyl) benzoic acid, 3- (4-methyl-1-piperazinylmethyl) benzoic acid, 4- (4-methyl-1-piperazinylmethyl) benzoic acid, 2 -(4-ethyl-1-piperazinylmethyl) benzoic acid, 3- (4-ethyl-1-piperazinylmethyl) benzoic acid, 4- (4-ethyl-1-piperazinylmethyl) benzoic acid, 2- (4-methyl-1-piperazinylmethyl) benzoic acid hydrochloride, 3- (4-methyl-
1-piperazinylmethyl) benzoic acid hydrochloride, 4- (4-
Methyl-1-piperazinylmethyl) benzoate hydrochloride, 2
-(4-ethyl-1-piperazinylmethyl) benzoate, 3- (4-ethyl-1-piperazinylmethyl) benzoate, 4- (4-ethyl-1-piperazinylmethyl) ) Benzoic acid hydrochloride, 2- (4-methyl-1-piperazinylmethyl) benzoic acid sodium salt, 3- (4-methyl-1-piperazinylmethyl) benzoic acid sodium salt,
4- (4-methyl-1-piperazinylmethyl) benzoic acid sodium salt, 2- (4-ethyl-1-piperazinylmethyl) benzoic acid sodium salt, 3- (4-ethyl-1-
Piperazinylmethyl) benzoic acid sodium salt, 4- (4
-Ethyl-1-piperazinylmethyl) benzoic acid sodium salt.

In the method of the present invention, if necessary, the desired product taken out as a salt is neutralized with a suitable acid or base by a conventional method to give free (4-alkyl-1-piperazinylmethyl) benzoic acid. Alternatively, what is taken out as free (4-alkyl-1-piperazinylmethyl) benzoic acid can be converted into a desired salt by a conventional method.

The obtained (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the general formula (4) may be subjected to a purification step such as recrystallization if necessary. Recrystallization is preferably performed by deriving the salt into a salt such as an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or nitric acid, or an organic acid such as methanesulfonic acid or paratoluenesulfonic acid, because crystallization is facilitated.

Among the (4-alkyl-1-piperazinylmethyl) benzene derivatives represented by the general formula (3), a compound wherein Y is an alkoxycarbonyl group, for example, a compound produced in Example 6 described later. 4- (4-methyl-1-piperazinylmethyl) benzoic acid methyl ester (melting point: 32.8-33.8 ° C, boiling point: 180-182)
(C / 667 Pa), (4-alkyl-1-piperazinylmethyl) benzoic acid ester derivatives and salts thereof are novel compounds not described in the literature.

[0067]

According to the present invention, (4-alkyl-1)
A novel industrial process for the production of (piperazinylmethyl) benzoic acid is provided.

According to the method of the present invention, (4-alkyl-1
-Piperazinylmethyl) benzoic acid in a simple, high yield,
The method of the present invention has a very high industrial value because it can produce high-purity (4-alkyl-1-piperazinylmethyl) benzoic acid having extremely low demethylated content under environmentally friendly conditions.

[0069]

EXAMPLES Next, the production method of the compound of the present invention will be specifically described with reference to Comparative Examples, Reference Examples and Examples.
It is not limited at all by these examples.

Comparative Example: Production of 4- (4-methyl-1-piperazinylmethyl) benzoic acid 3.41 g of 4-chloromethylbenzoic acid under a nitrogen atmosphere
8.81 g (0.088 mol) of 1-methylpiperazine was added to a 30 ml ethanol (0.02 mol) solution at room temperature.
l) was added dropwise. After completion of the dropwise addition, the mixture was aged for 21 hours under reflux with heating. After completion of the ripening, the reaction solution was analyzed by the whole area method of high performance liquid chromatography,
(4-methyl-1-piperazinylmethyl) benzoic acid is 8
The content of 4- (1-piperazinylmethyl) benzoic acid (demethylated product) was as high as 0.16%.

Example 1 Preparation of 4- (4-methyl-1-piperazinylmethyl) benzoic acid Under a nitrogen atmosphere, 200.3 g of 1-methylpiperazine
(2.0 mol), 138.2 g of potassium carbonate (1.0
mol) and 500 ml of xylene, heated to 45 ° C., and then heated to 45 to 55 ° C. at 151.6 g (1.0 mol) of xylene 50 of 4-chloromethylbenzonitrile.
The 0 ml solution was added dropwise over 1.5 hours. After dropping,
After aging at 85-90 ° C for 3.5 hours, the solvent and excess 1-methylpiperazine were recovered under reduced pressure (liquid temperature 90 ° C or lower). Analysis of 960.9 g of the recovered solvent revealed that 92.6 g (0.92 mol) of 1-methylpiperazine was contained. Xylene and water were added to the residue, liquid-separated extraction was performed at 50 ° C., and the aqueous layer was re-extracted with xylene. The obtained xylene layer was analyzed by an absolute calibration curve method of high performance liquid chromatography. -Methyl-1-piperazinylmethyl) benzonitrile was 190.1 g (0.88 m
ol) and a yield of 88.3% (based on 4-chloromethylbenzonitrile).

Subsequently, after the xylene layer was concentrated, the residue 4-
To 190.1 g (0.88 mol) of (4-methyl-1-piperazinylmethyl) benzonitrile was added 35% hydrochloric acid 55
2.5 g (5.3 mol) was added, and the mixture was heated under reflux for 8 hours. After completion of the ripening, the reaction solution was analyzed by the whole area method of high performance liquid chromatography to find that the desired 4- (4
-Methyl-1-piperazinylmethyl) benzoic acid is 99.
6%, 1-piperazinylmethylbenzoic acid was 0.03%. 520 ml of water and 8-propanol 8 were added to the reaction solution.
After adding 80 ml and heating to reflux and cooling to 4 ° C., the resulting crystals were filtered and dried under reduced pressure to give the desired 4- (4-
256.9 g (0.81 mol) of methyl-1-piperazinylmethyl) benzoic acid as dihydrochloride / hemihydrate, yield 81.2% (based on 4-chloromethylbenzonitrile)
I got it. The product was analyzed by high performance liquid chromatography by the whole area method. As a result, the purity was 99.9% and the demethylated product was 0.01%.

Example 2 Preparation of 4- (4-methyl-1-piperazinylmethyl) benzoic acid 10.02 g of 1-methylpiperazine under a nitrogen atmosphere
(0.1 mol), 4.49 g of 99% sodium hydroxide
(0.11 mol), 1.42 g of anhydrous sodium sulfate
(0.01 mol) and 25 ml of xylene.
After the temperature was raised to 0 ° C, 8.58 g (0.05 mol) of 4-chloromethylbenzonitrile was added at 80 to 80 ° C.
Added over 5 hours. After the completion of the dropwise addition, the temperature is set at 85 to 90 ° C. for 5 minutes.
Aged for hours. After aging is completed, water is added to the reaction solution, and 50
The liquid layer was separated and extracted at ℃, the aqueous layer was re-extracted with xylene, and the obtained xylene layer was analyzed in the same manner as in Example 1.
9.48 g (0.044 mol) of 4- (4-methyl-1-piperazinylmethyl) benzonitrile, yield: 88.
0% (based on 4-chloromethylbenzonitrile).

Subsequently, after the xylene layer was concentrated, the residue 4-
To 9.48 g (0.044 mol) of (4-methyl-1-piperazinylmethyl) benzonitrile was added 35% hydrochloric acid 4
5.9 g (0.44 mol) was heated under reflux for 8 hours. After completion of the aging, the reaction solution was analyzed by liquid chromatography. As a result, the target 4- (4-methyl-1-piperazinylmethyl) benzoic acid was 99.5%, and the target 1-piperazinylmethylbenzoic acid was 0.1%. 04%. 44 ml of 2-propanol was added to the reaction solution, and the mixture was heated to reflux, cooled to 0 ° C., and the obtained crystals were filtered and dried under reduced pressure to obtain the desired compound.
12.86 g (0.04 mol) of-(4-methyl-1-piperazinylmethyl) benzoic acid as dihydrochloride hemihydrate
1), yield 80.8% (based on 4-chloromethylbenzoic acid methyl ester). The product was analyzed by high performance liquid chromatography in accordance with the whole area method.
At 9.8%, the demethylated product was 0.03%.

Examples 3 to 5: Preparation of 4- (4-methyl-1-piperazinylmethyl) benzoic acid 4-chloromethylbenzonitrile of Example 1 (abbreviation: 4)
CMBN) and 1-methylpiperazine (abbreviation: MP) in the reaction of 1-methylpiperazine, solvent,
Except that the base and the aging time were changed,
-(4-Methyl-1-piperazinylmethyl) benzonitrile (abbreviation: 4MPBN) was produced. The results (Table 1)
Shown in The yield is a value based on 4-chloromethylbenzonitrile calculated from the analytical value of the absolute calibration method of high performance liquid chromatography. These 4- (4-methyl-1-
Piperazinylmethyl) benzonitrile is hydrolyzed with 35% hydrochloric acid in the same manner as in Examples 1 and 2 to give 4- (4-methyl-1-piperazinylmethyl) with high yield and high purity.
Benzoic acid (purity 99.8% or more by analysis by high-performance liquid chromatography whole area method, 0.05% of demethylated product)
Below).

[0076]

[Table 1]

* In Table 1, Xyl represents xylene and To
1 shows toluene.

Example 6: Preparation of methyl 4- (4-methyl-1-piperazinylmethyl) benzoate 60.1 g (0.60 mol) of 1-methylpiperazine,
After charging 82.9 g (0.60 mol) of potassium carbonate and 500 ml of chlorobenzene, the temperature was raised to 80 ° C.,
At 80 to 90 ° C., 92.3 g (0.50 mol) of 4-chloromethylbenzoic acid methyl ester was added dropwise over 2.5 hours. After completion of dropping, aging at 90 ° C for 2 hours,
Water was added to the reaction solution, and the mixture was separated and extracted at 50 ° C. The aqueous layer was re-extracted with chlorobenzene, and the obtained chlorobenzene layer was concentrated and distilled under reduced pressure to give 4- (4-methyl-1-piperazinyl). 94.9 g of methyl) benzoic acid methyl ester
(0.38 mol) was obtained in a yield of 86.4% (based on methyl 4-chloromethylbenzoate).

Physical properties of methyl 4- (4-methyl-1-piperazinylmethyl) benzoate Melting point: 32.8-33.8 ° C. Boiling point: 180-182 ° C./667 Pa

(Confirmation data) MS m / z: 248 (M ⁺ ) 300 MHz ¹ H-NMR (CDCl ₃ ) δ value: 2.2
5 (s, 3H), 2.44 (s, 8H), 3.52
(S, 2H), 3.88 (s, 3H), 8.38 (d,
8Hz, 2H), 8.95 (d, 8Hz, 2H) IR (KBr tablet, cm ^-1 ): 2938, 2895,
1824, 1611, 1435, 1349, 1281,
1164, 1110, 1013, 925, 821, 85
8,802

Example 7: Production of 4- (4-methyl-1-piperazinylmethyl) benzoic acid Under a nitrogen atmosphere, 40.1 g of 1-methylpiperazine (0.
40mol), potassium carbonate 28.6g (0.20mo
l) and 100 ml of xylene were added, and the temperature was raised to 80 ° C, and then 36.9 g (0.20 mol) of 4-chloromethylbenzoic acid methyl ester was added dropwise at 80 to 90 ° C over 2.5 hours. After completion of the dropwise addition, the mixture was aged at 90 ° C. for 2 hours, and then concentrated under reduced pressure. 98.5 recovered xylene
g was analyzed to find that 1-methylpiperazine was 15.3 g.
(0.15 mol). Xylene and water were added to the residue, liquid separation was performed at 60 ° C., and the aqueous layer was re-extracted with xylene. The obtained xylene layer was analyzed by an absolute calibration curve method of high performance liquid chromatography.
46.6 g (0.19 mol) of (4-methyl-1-piperazinylmethyl) benzoic acid methyl ester, yield 9
3.9% (based on methyl 4-chloromethylbenzoate).

Subsequently, after concentrating the xylene layer, the residue 4-
49.5 g (0.48 mol) of 35% hydrochloric acid and 190 ml of water were charged into 46.6 g (0.19 mol) of (4-methyl-1-piperazinylmethyl) benzoic acid methyl ester, and the mixture was aged at 80 ° C. for 8 hours. . After completion of the ripening, the reaction solution was analyzed by a high-performance liquid chromatography total area method. As a result, the target 4- (4-methyl-1-piperazinylmethyl) benzoic acid was 99.2%, and 1-piperazinyl was obtained. Methylbenzoic acid was 0.09%. Subsequently, the reaction solution was partially concentrated under reduced pressure, and 290 m of 2-propanol was added to the residue.
After heating under reflux and cooling to 30 ° C., the resulting crystals were filtered and dried under reduced pressure to give the desired 4- (4-methyl-1-piperazinylmethyl) benzoic acid in dihydrochloride salt. 54.8 g (0.18 mol) as hydrate, yield 8
6.5% (based on methyl 4-chloromethylbenzoate). When analyzed by the whole area method of high performance liquid chromatography, the purity was 99.8% and the demethylated product was 0.05%.

Example 8: Preparation of 4- (4-methyl-1-piperazinylmethyl) benzoic acid 18.5 g of methyl 4-chloromethylbenzoate
(0.10 mol), 13.8 g of potassium carbonate (0.1
0 mol), 64.6 g of recovered xylene containing 10.0 g (0.10 mol) of 1-methylpiperazine obtained in Example 7, and 10.0 g (0.1%) of 1-methylpiperazine.
0 mol), and the same operation as in Example 7 was carried out.
21.6 g (0.088 mol) of-(4-methyl-1-piperazinylmethyl) benzoic acid methyl ester was obtained in a yield of 88.0% (based on 4-chloromethylbenzoic acid methyl ester).

After concentrating the xylene layer, 35% hydrochloric acid 2 was added to the residue.
8.2 g (0.26 mol) and 44 ml of water were charged.
Aged at 0 ° C. for 12 hours. After completion of the aging, the reaction solution was subjected to high performance liquid chromatography.
99.4% of-(4-methyl-1-piperazinylmethyl) benzoic acid and 0.0 of 1-piperazinylmethylbenzoic acid
8%. After adding 88 ml of 2-propanol to the reaction solution and heating under reflux and cooling to 30 ° C., the obtained crystals were filtered, dried under reduced pressure, filtered, dried, and then dried.
28.6 g (0.09 mol) of (4-methyl-1-piperazinylmethyl) benzoic acid as dihydrochloride hemihydrate,
It was obtained in a yield of 65.1% (based on methyl 4-chloromethylbenzoate). The product was analyzed by high performance liquid chromatography in accordance with the whole area method to find that the purity was 99.8%.
And the demethylated product was 0.03%.

Examples 9 to 16: 4- (4-methyl-1-
Production of piperazinylmethyl) benzoic acid In the reaction between 4-chloromethylbenzoic acid methyl ester and 1-methylpiperazine (abbreviation: MP) in Example 6, the molar ratio of 1-methylpiperazine, solvent, reaction temperature,
4- (4)
-Methyl-1-piperazinylmethyl) benzoic acid methyl ester (abbreviation: 4MPBM) was produced. The results are shown in (Table 2). The yield is a value based on 4-chloromethylbenzoic acid methyl ester calculated from the analytical value of the absolute calibration curve method of high performance liquid chromatography. These 4- (4-
Methyl-1-piperazinylmethyl) benzoic acid methyl ester was hydrolyzed with 35% hydrochloric acid in the same manner as in Examples 6 and 8 to give 4- (4-methyl-1) with high yield and high purity.
-Piperazinylmethyl) benzoic acid (purity of 99.8% or more, and demethylated form of 0.05% or less, as analyzed by the high-performance liquid chromatography whole area method).

[0086]

[Table 2]

* In Table 2, Xyl represents xylene and To
l is toluene, CB is monochlorobenzene, tB
uOMe indicates tert-butyl methyl ether.

Example 17: Preparation of 4- (4-methyl-1-piperazinylmethyl) benzoic acid 36.9 g of methyl 4-chloromethylbenzoate
(0.20 mol), 10.1 g of 1-methylpiperazine
(0.40 mol), potassium carbonate 28.6 g (0.2
0 mol) and 100 ml of xylene.
The same operation as described above was carried out to obtain 4- (4-methyl-1-piperazinylmethyl) benzoic acid methyl ester.
Using 34.8 g (0.40 mol) of sodium hydroxide and 200 ml of water, the mixture was aged at room temperature for 3 hours. After completion of the ripening, the product was analyzed by high performance liquid chromatography to find that the desired 4- (4-methyl-1-piperazinylmethyl) benzoic acid (purity 99.1%, demethylated product was 0.1%).
09%) in a yield of 93.5% (based on methyl 4-chloromethylbenzoate).

Reference Example: Preparation of 4- (4-methyl-1-piperazinylmethyl) benzoic acid methyl ester 43.1 g (0.20 mol) of 4- (4-methyl-1-piperazinylmethyl) benzonitrile And toluene 200
and 0.2% of 98% sulfuric acid at room temperature (2.
0 mol) was added dropwise at 60 ° C. for 2 hours and 90 ° C. for 2 hours.
Aged for hours. After completion of the ripening, the mixture was cooled, charged with 128.2 g (4.0 mol) of methanol at room temperature, and aged for 4 hours while heating under reflux. After completion of the ripening, the product was analyzed by gas chromatography to confirm the formation of methyl 4- (4-methyl-1-piperazinylmethyl) benzoate.

Claims (2)

[Claims] 1. A compound of the general formula (1) (Wherein, X represents a halogen atom, Y represents a nitrile group or an alkoxycarbonyl group), and a benzyl halide derivative represented by the following general formula (2): (Wherein R represents an alkyl group) by reacting with 1-alkylpiperazine represented by the following general formula (3): (Wherein, Y represents a nitrile group or an alkoxycarbonyl group, and R represents an alkyl group), and a (4-alkyl-1-piperazinylmethyl) benzene derivative represented by the formula: Reacting, characterized by the general formula (4): (Wherein, R represents an alkyl group.) A method for producing (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the formula: 2. A compound of the general formula (1) (Wherein, X represents a halogen atom, Y represents a nitrile group or an alkoxycarbonyl group) and a benzyl halide derivative represented by the following general formula (2): In the reaction with 1-alkylpiperazine represented by the formula (wherein R represents an alkyl group), an aromatic hydrocarbon solvent is used, wherein the general formula (4) is used. Embedded image (Wherein, R represents an alkyl group.) A method for producing (4-alkyl-1-piperazinylmethyl) benzoic acid represented by the formula: