JP2022090710A - Production method of chloromethyl benzoate derivative - Google Patents

Abstract

To provide a safe and simple method for producing a chloromethyl benzoate derivative in a high yield.SOLUTION: A methyl benzoate derivative represented by the formula (1) below is chlorinated in the presence of hypochlorous acid in an organic solvent to produce a chloromethyl benzoate derivative represented by the formula (2) below. (in the formula (1) and the formula (2), R indicates an alkyl group of 1-6 carbons, and X indicates a hydrogen atom or a halogen atom.)SELECTED DRAWING: None

Description

The present invention relates to a method for producing a chloromethylbenzoic acid ester derivative by selectively monochromizing a benzoic acid ester derivative having a methyl group on the benzene ring at the benzyl position.

Chloromethylbenzoic acid ester derivatives are important intermediates in the production of various chemicals including pharmaceuticals, pesticides and cosmetic raw materials. This compound can be synthesized by chlorolyzing the benzyl position of the methylbenzoic acid ester derivative.

For example, chlorolysis of the benzylic position of methyl p-methylbenzoate can be realized by reacting a substrate with a chlorine source under UV irradiation conditions or in the presence of an oxidizing agent (Patent Documents 1 and 2 and Non-Patent Document 1).

However, there is room for improvement in these manufacturing methods as follows. For example, in Patent Document 1, the benzyl position is chloroylated by reacting methyl p-methylbenzoate with chlorine gas under UV irradiation conditions at a reaction temperature of 100 ° C. However, under these reaction conditions, there is room for improvement in that a UV irradiation device must be used, by-products are easily generated, the yield remains at about 60%, and a reaction at a high temperature is required. be.

Further, in Patent Document 2 and Non-Patent Document 1, N-chlorosuccinimide (NCS) is used as a chlorine source, and benzoyl peroxide or 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) is used as an oxidizing agent, respectively. As a result, chloroidization of the benzyl position of methyl p-methylbenzoate is realized. However, there is room for improvement in that the reaction conditions require a high temperature of about 80 ° C. and that an expensive oxidizing agent needs to be used.

Chinese Patent Application Publication No. 1014354545 India Publication 2008MU02726

Li, Zi-Hao et al, Org. Biomol. Chem. 2019, 17, 3403-3408.

As described above, since the chloromethylbenzoic acid ester derivative is an important intermediate in the production of various chemical products, it is desired that the chloromethylbenzoic acid ester derivative be produced in a high yield by a safe and simple method.

Therefore, an object of the present invention is to provide a method for producing a chloromethyl benzoic acid ester derivative in a high yield by a safe and convenient method.

The present inventors have conducted diligent studies in order to solve the above-mentioned problems. As a result, they have found that only the benzylic position is selectively monochromolated by reacting hypochlorous acid with a methylbenzoic acid ester derivative, and have completed the present invention.

That is, the present invention
The following formula (1)

(In the formula, R is an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom or a halogen atom. The methyl group and X may be present at arbitrary positions on the benzene ring.)
By chlorinating the methylbenzoic acid ester derivative represented by (1) in the presence of hypochlorous acid in an organic solvent,
The following formula (2)

(In the formula, R and X are synonymous with those in the above formula (1).)
It is a method for producing a chloromethylbenzoic acid ester derivative, which produces the chloromethylbenzoic acid ester derivative represented by.

According to the method of the present invention, by using an inexpensive and easy-to-handle material, specifically hypochlorous acid, a chloromethylbenzoic acid ester derivative represented by the above formula (2) can be obtained under relatively mild conditions. It can be produced in high yield. As described above, since the chloromethylbenzoic acid ester derivative is useful as an intermediate for various chemical products, the industrial utility value of the method of the present invention is high.

In the present invention, the methylbenzoic acid ester derivative represented by the formula (1) is chlorinated in an organic solvent in the presence of hypochlorous acid to obtain the chloromethylbenzoic acid ester derivative represented by the formula (2). It is a method of manufacturing. Hereinafter, the embodiment will be described.

(Methylbenzoic acid ester derivative)
In the present invention, the methylbenzoic acid ester derivative is represented by the following formula (1).

It is a compound indicated by.

In the formula, R is an alkyl group having 1 to 6 carbon atoms. The alkyl group may be linear, branched or cyclic.

X is a hydrogen atom or a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The methyl group and X may be present at any position on the benzene ring.

(Organic solvent)
The organic solvent used in the method of the present invention is not particularly limited as long as it does not inhibit the reaction.

Examples of the organic solvent include esters such as ethyl acetate, methyl acetate, butyl acetate and isopropyl acetate; nitriles such as acetonitrile and propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane. Kind is mentioned. Halogenated hydrocarbons are preferable, and dichloromethane and chloroform are more preferable, because the reaction can proceed easily. These organic solvents can be used alone or as a mixed solvent thereof.

The amount of the organic solvent used is not particularly limited. It is preferable to use an amount corresponding to the concentration of the methyl benzoate ester derivative represented by the formula (1) of 0.05 to 5 mol / L, and the concentration of the methyl benzoate ester derivative is 0.2 to 1 mol / L. It is more preferable to use a corresponding amount. When a mixed solvent is used, it is desirable that the total amount of the mixed solvent satisfies the above range.

(Hypochlorous acid)
In the method of the present invention, hypochlorous acid is used as a chlorinating agent when producing the chloromethylbenzoic acid ester derivative represented by the formula (2) from the methylbenzoic acid ester derivative represented by the formula (1). .. That is, in the presence of hypochlorous acid, the methylbenzoic acid ester derivative represented by the formula (1) is chlorinated to produce the chloromethylbenzoic acid ester derivative represented by the formula (2).

The hypochlorous acid is not particularly limited, and an aqueous solution of hypochlorous acid may be used, but hypochlorous acid is unstable in the aqueous solution and decomposes. Therefore, it is preferable to generate hypochlorous acid by contacting the hypochlorous acid metal salt with the acid immediately before or during the production of the chloromethylbenzoic acid ester derivative.

Examples of the hypochlorite metal salt include alkali metal salts such as sodium hypochlorite and potassium hypochlorite, alkaline earth metal salts such as calcium hypochlorite and barium hypochlorite, and copper hypochlorite. , Transition metal salts such as cupric hypochlorite. Among these, sodium hypochlorite is preferable from the viewpoint of industrial availability and salt stability.

The hypochlorous acid metal salt is preferably used as an aqueous solution from the viewpoint of stability. When the sodium hypochlorite metal salt is sodium hypochlorite, the concentration of the sodium hypochlorite aqueous solution used is not particularly limited, but it is 5 to 12% by mass due to its availability. Preferably, 8 to 12% by mass is more preferable because of the ease of progress of chlorination.

The type of acid used is not particularly limited as long as it does not inhibit the chlorination reaction. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; and organic acids such as acetic acid and formic acid. Hydrochloric acid is preferable because of the ease of progress of chlorination.

The concentration of the acid used is not particularly limited, but it is preferable to use it without diluting it because of the ease of progress of chlorination.

The equivalent of hypochlorous acid used for chlorination is not particularly limited. Preferably, 2 to 10 mol is used with respect to 1 mol of the methylbenzoic acid ester derivative represented by the formula (1). More preferably, 2 to 6 mol is used.

The molar ratio of the hypochlorous acid metal salt to the acid used when the hypochlorite metal salt and the acid are brought into contact with each other to generate the hypochlorous acid is such that the equivalent amount of the generated hypochlorite is in the above range. The molar ratio of the hypochlorite metal salt to the acid is preferably 1: 1 in order to reduce side reactions, although it is not particularly limited as long as it satisfies the requirements.

(Chloromethylbenzoic acid ester derivative)
In the present invention, the chloromethyl benzoic acid ester derivative obtained by the chlorination reaction is represented by the following formula (2).

It is a compound indicated by.

In the formula, R and X are synonymous with those in the above formula (1).

(Reaction condition)
In the method of the present invention, the methyl benzoic acid ester derivative represented by the formula (1) may be chlorinated in the presence of hypochlorous acid in an organic solvent, and the methyl benzoic acid ester derivative represented by the formula (1) may be chlorinated. , The order of addition of the organic solvent and hypochlorous acid to the reaction vessel is not particularly limited. It is preferable to prepare a methylbenzoic acid ester derivative represented by the formula (1) and an organic solvent in a reaction vessel, and to allow hypochlorous acid to be present therein.

As described above, hypochlorous acid is preferably generated by bringing the metal salt of hypochlorous acid into contact with the acid. in this case,
(I) A method of adding hypochlorite generated by contacting a hypochlorous acid metal salt and an acid to a methylbenzoic acid ester derivative represented by the formula (1) and an organic solvent in a reaction vessel.
(Ii) A method of adding a hypochlorous acid metal salt to a methylbenzoic acid ester derivative represented by the formula (1) and an organic solvent in a reaction vessel, and then adding an acid to generate hypochlorous acid.
(Iii) There is a method of adding a hypochlorous acid metal salt after adding an acid to the methylbenzoic acid ester derivative represented by the formula (1) and an organic solvent in the reaction vessel to generate hypochlorous acid. Among them, (ii) a method of adding an acid to generate hypochlorous acid after adding a hypochlorous acid metal salt to the methylbenzoic acid ester derivative represented by the formula (1) and an organic solvent in the reaction vessel (hereinafter). , Also referred to as method (ii)) is preferable because it is possible to reduce the decomposition of the generated hypochlorous acid and the hydrolysis of the methylbenzoic acid ester derivative represented by the formula (1). The hypochlorous acid metal salt is preferably used as an aqueous solution as described above.

In the method (ii), the required amount of the acid can be added all at once, but it is preferable to add the acid continuously in small amounts or in several portions.

In the method of the present invention, the reaction time is not particularly limited and may be determined while appropriately confirming the conversion rate to the product chloromethylbenzoic acid ester derivative, but usually, it is 1 hour or more and 48 hours or less. However, it is preferably 2 hours or more and 24 hours or less.

In the method of the present invention, the reaction temperature is not particularly limited and can be carried out in the range of 0 ° C. or higher and the boiling point or lower of the organic solvent, but the range of 20 ° C. to 30 ° C. is preferable from the viewpoint of ease of carrying out. ..

(Post-treatment of reaction)
In the method of the present invention, after carrying out the above reaction, the chloromethyl benzoic acid ester derivative represented by the formula (2) can be separated by the following method. For example, after completion of the reaction, the two layers are separated, the aqueous layer is extracted with dichloromethane, and then the organic layers are combined and washed with an aqueous solution of sodium thiosulfate. By concentrating the washed organic layer under reduced pressure, the chloromethylbenzoic acid ester derivative represented by the formula (2) can be obtained.

When impurities are contained in the chloromethyl benzoic acid ester derivative represented by the formula (2), high purity can be achieved by applying known methods such as column separation and recrystallization.

The present invention will be specifically described below with reference to examples, but these examples do not limit the scope of the present invention.

<HPLC conditions>
Equipment: Liquid chromatograph equipment (manufactured by Waters Corporation)
Detector: Ultraviolet absorptiometer Measurement wavelength: 210nm
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm filled with octadecylsilylated silica gel for liquid chromatography having a particle diameter of 5 μm. Mobile phase A: 0.1% aqueous phosphate solution Mobile phase B: acetonitrile mobile phase Liquid delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

Flow rate: 1.0 ml / min
Column temperature: Constant temperature around 35 ° C. Measurement time: 45 minutes The conversion rate of the reaction is calculated by the following formula using the area value of the methylbenzoic acid ester derivative and the area value of the chloromethylbenzoic acid ester derivative measured under the above conditions. Calculated from.

(Reaction conversion rate) = (Area value of chloromethyl benzoate ester derivative) / {(Area value of chloromethyl benzoate ester derivative) + (Area value of methyl benzoate ester derivative)}

(Production Example 1) Production of 2-chloro-4-methylbenzoic acid methyl ester

2-Chloro-4-methylbenzoic acid [Combi-Blocks Inc. Manufactured by] (0.96 g, 5.63 mmol) in methanol (9.6 mL) was cooled to 5 ° C. with stirring, and thionyl chloride (0.61 mL, 1.5 eq) was added dropwise thereto. After completion of the dropping, the temperature was raised to 65 ° C., and the mixture was stirred overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Methanol was added to the obtained residue and concentrated again to obtain 0.77 g of methyl 2-chloro-4-methylbenzoate (yield 74%).

(Production Example 2) Production of 3-Chloro-4-methylbenzoic acid methyl ester

Using 3-chloro-4-methylbenzoic acid [manufactured by Tokyo Kasei Kogyo Co., Ltd.] as a substrate, the same operation as in Production Example 1 was carried out to obtain methyl 3-chloro-4-methylbenzoate (yield 82). %).

(Production Example 3) Production of 2-fluoro-4-methylbenzoic acid methyl ester

Using 2-fluoro-4-methylbenzoic acid [manufactured by Tokyo Kasei Kogyo Co., Ltd.] as a substrate, the same operation as in Production Example 1 was carried out to obtain methyl 2-fluoro-4-methylbenzoate (yield 87). %).

(Production Example 4) Production of 3-fluoro-4-methylbenzoic acid methyl ester

Using 3-fluoro-4-methylbenzoic acid [manufactured by Tokyo Kasei Kogyo Co., Ltd.] as a substrate, the same operation as in Production Example 1 was carried out to obtain methyl 3-fluoro-4-methylbenzoate (yield 72). %).

(Example 1) Chlorization of methyl p-methylbenzoate

8.8% by mass sodium hypochlorite aqueous solution (1.69 g, 4.) with respect to a dichloromethane solution (1 mL) of methyl p-methylbenzoate (75 mg, 0.5 mmol) [manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.]. 0eq) was added at room temperature. Then, concentrated hydrochloric acid (0.18 mL, 4.0 eq) was slowly added dropwise. After stirring at room temperature for 18 hours, the reaction proceeded at a conversion rate of 81%. After separating the two layers and extracting the aqueous layer with dichloromethane, the organic layers were combined and washed with an aqueous sodium thiosulfate solution. Anhydrous sodium sulfate was added to the washed organic layer and dried, and then the residue obtained by filtration and concentration was purified by silica gel chromatography to obtain 68 mg of methyl p-chloromethylbenzoate (yield 74). %).

(Example 2)

8.8% by mass sodium hypochlorite aqueous solution (1.69 g, 4.) with respect to an acetonitrile solution (1 mL) of methyl p-methylbenzoate (75 mg, 0.5 mmol) [manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.]. 0eq) was added at room temperature. Then, concentrated hydrochloric acid (0.18 mL, 4.0 eq) was slowly added dropwise. After stirring at room temperature for 18 hours, the reaction proceeded at a conversion rate of 68%.

(Example 3)

When the same operation as in Example 2 was carried out except that chloroform was used as the solvent, the reaction proceeded at a conversion rate of 99%.

(Example 4) Chlorization of methyl o-methylbenzoate

When the same operation as in Example 2 was carried out except that methyl o-methylbenzoate [manufactured by Tokyo Chemical Industry Co., Ltd.] was used, the reaction proceeded at a conversion rate of 89%.

(Example 5) Chlorization of methyl m-methylbenzoate

When the same operation as in Example 2 was carried out except that methyl m-methylbenzoate [manufactured by Tokyo Chemical Industry Co., Ltd.] was used, the reaction proceeded with a conversion rate of 93%.

(Example 6) Chlorization of ethyl p-methylbenzoate

When the same operation as in Example 2 was carried out except that ethyl p-methylbenzoate [manufactured by Tokyo Chemical Industry Co., Ltd.] was used, the reaction proceeded at a conversion rate of 58%.

(Example 7) Chlorization of methyl 2-chloro-4-methylbenzoate

When the same operation as in Example 2 was carried out except that methyl 2-chloro-4-methylbenzoate obtained in Production Example 1 was used, the reaction proceeded at a conversion rate of 51%.

(Example 8) Chlorization of methyl 3-chloro-4-methylbenzoate

When the same operation as in Example 2 was carried out except that methyl 3-chloro-4-methylbenzoate obtained in Production Example 2 was used, the reaction proceeded at a conversion rate of 69%.

(Example 9) Chlorosis of methyl 2-fluoro-4-methylbenzoate

When the same operation as in Example 2 was carried out except that methyl 2-fluoro-4-methylbenzoate obtained in Production Example 3 was used, the reaction proceeded at a conversion rate of 50%.

(Example 10) Chlorosis of methyl 3-fluoro-4-methylbenzoate

When the same operation as in Example 2 was carried out except that methyl 3-fluoro-4-methylbenzoate obtained in Production Example 4 was used, the reaction proceeded at a conversion rate of 59%.

(Comparative Example 1) Chlorization of p-methylbenzoic acid

When the same operation as in Example 2 was carried out except that p-methylbenzoic acid [manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.] was used, a compound having a chlorolated benzyl position was not obtained, and the benzene ring was chloroylated. 3-Chloro-4-methylbenzoic acid was quantitatively obtained.

Claims (1)

The following formula (1)

(In the formula, R is an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom or a halogen atom. The methyl group and X may be present at arbitrary positions on the benzene ring.)
By chlorinating the methylbenzoic acid ester derivative represented by (1) in the presence of hypochlorous acid in an organic solvent,
The following formula (2)

(In the formula, R and X are synonymous with those in the above formula (1).)
A method for producing a chloromethylbenzoic acid ester derivative, which comprises producing the chloromethylbenzoic acid ester derivative represented by.