JP2014189486A - Oxidizer consisting of hydrogen peroxide and carboxylate ester compound and method of producing benzoquinone compound - Google Patents

Abstract

The present invention provides an oxidizing agent that is extremely useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and the like and that efficiently produces 1,4-benzoquinone compounds.
[MEANS FOR SOLVING PROBLEMS] A 1,4-benzoquinone represented by the following general formula (A) using an oxidant composed of an acid having an equivalent weight or less with respect to a carboxylic acid ester compound having 2 to 6 carbon atoms, a hydrogen peroxide solution and a substrate. Compounds are prepared from the corresponding alkoxybenzene compounds or phenolic compounds.

^(Wherein, R 1 to R ⁴ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.) Using a solid acid as the acid.
[Selection figure] None

Description

  The present invention relates to an oxidizing agent comprising a carboxylic acid ester compound, hydrogen peroxide solution and an acid, and a method for producing a benzoquinone compound using the oxidizing agent.

The 1,4-benzoquinone compound is used as a hydrogen acceptor, an oxidizing agent, and a dehydrogenating agent in organic synthesis, and also as a parent diene in a Diels-Alder reaction. Benzoquinone is used as a polymerization inhibitor for the raw material of the polyester resin.
In addition, certain quinones are biochemically active, and in particular, 2,3-dimethoxy-5-methyl-1,4-benzoquinone is a metabolic cardiotonic agent, ubidecalenone, a benzoquinone metabolic / psychiatric symptom improving agent. Idebenone, thromboxane A ₂ synthase inhibitor, thromboxane A ₂ receptor antagonist, 5-lipoxygenase inhibitor, active oxygen scavenger, anti-asthma agent, liver disease therapeutic agent and other useful compounds (Patent Document 1, Patent Document 2).
2,3,5-trimethyl-1,4-benzoquinone is known as an intermediate for the production of α-tocophenol (vitamin E) (Patent Document 3).
Therefore, it is industrially important to efficiently synthesize benzoquinone compounds.

As a method for producing 2,3-dimethoxy-5-methyl-1,4-benzoquinone, a method of oxidizing 2,3-dimethoxy-5-methylphenol (Patent Document 4), 3,4,5-trimethoxytoluene A method of oxidizing 3-hydroxy-4,5-dimethoxytoluene (Patent Document 10), a method of oxidizing 2,3,4-trimethoxybenzoic acid (Patent Document 11) A method of oxidizing 2,3,4-trimethoxy-6-methylphenol (Patent Document 12) and the like are conventionally known. Among them, the method for oxidizing 3,4,5-trimethoxytoluene is excellent in that the raw materials are general and easily available.
The method for producing 2,3,5-trimethyl-1,4-benzoquinone is a method of oxidizing 2,3,5-trimethylphenol or 2,3,6-trimethylphenol (Patent Documents 3 and 13). Are known.

However, in these methods, sodium dichromate, potassium permanganate, manganese dioxide or the like is used as an oxidizing agent. However, using these heavy metals is not desirable from the viewpoint of influence on the human body and the environment. Furthermore, although there is a method of using oxygen as an oxidizing agent, it cannot be said that it is preferable from the viewpoint of safety to make an oxygen-rich state in the presence of an organic solvent.
Also, there is a method of using acetic acid or other organic acid as a solvent and oxidizing with hydrogen peroxide. However, using a solvent amount of acid is not preferable as an industrial production method due to the problem of waste liquid treatment.
For these reasons, a method for producing the target benzoquinone compound by an environmentally friendly and industrially safe and simple method has been desired.

JP-A 63-45257 Japanese Patent Application No. 4-49712 Japanese Patent Laid-Open No. 13-278835 Japanese Patent Publication No. 4-15214 Japanese Patent Publication No. 2-2872 Japanese Patent Publication No. 4-55183 Japanese Patent Publication No. 60-24778 Japanese Patent Laid-Open No. 1-313451 JP-A-2-138146 JP 60-78932 A Japanese Patent Publication No. 4-54656 Japanese Examined Patent Publication No. 4-55182 Japanese Patent Laid-Open No. 13-151721

  The present invention has been made in order to solve the above-mentioned circumstances. An oxidant obtained from a carboxylic acid ester compound, a hydrogen peroxide solution and an acid is used to convert a benzoquinone compound as a raw material of a physiologically active substance into an environment. An object is to provide a method which can be manufactured safely and easily with less load.

  The present inventors have used a benzoquinone compound by oxidizing a methoxybenzene compound or a phenol compound using an oxidant obtained from a carboxylic acid ester compound and a hydrogen peroxide solution in the presence of an acid equivalent to or less than the substrate. It is found that the present invention is obtained and the present invention has been completed.

The present invention provides the following inventions.
(1) An oxidant comprising an acid having an equivalent amount or less with respect to a carboxylic acid ester compound having 2 to 6 carbon atoms, a hydrogen peroxide solution and a substrate.

(2) The oxidizing agent using a solid acid as the acid in (1).

(3) In the method for producing a 1,4-benzoquinone compound represented by the following general formula (A), a methoxybenzene compound represented by the following general formula (B) is converted to a carboxylic acid ester compound having 2 to 6 carbon atoms. A method for producing a 1,4-benzoquinone compound, which comprises reacting with an oxidizing agent composed of an acid equivalent to or less than hydrogen peroxide solution and a substrate.
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.)
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.)

(4) A method for producing a 1,4-benzoquinone compound according to (3) above, wherein an oxidizing agent using a solid acid is used as the acid.

(5) In the method for producing a 1,4-benzoquinone compound represented by the following general formula (A), a phenol compound represented by the following general formula (C) is substituted with a carboxylic acid ester compound having 2 to 6 carbon atoms. A method for producing a 1,4-benzoquinone compound, characterized by reacting an aqueous solution of hydrogen peroxide and an oxidizing agent comprising an acid having an equivalent amount or less with respect to a substrate.
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.)
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.)

(6) The method for producing a 1,4-benzoquinone compound according to (5), wherein an oxidizing agent using a solid acid is used as the acid.

The present invention will be described in detail below.
The oxidizing agent used in the present invention comprises a carboxylic acid ester compound having 2 to 6 carbon atoms and a hydrogen peroxide solution and an acid having an equivalent or less.
Specific examples of the carboxylic acid ester compound having 2 to 6 carbon atoms include methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, pentyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, propionic acid Examples include methyl, ethyl propionate, propyl propionate, isopropyl propionate and the like.
These carboxylic acid ester compounds may be used alone or as a mixture of two or more.

Specific examples of the acid include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, o-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid. And camphorsulfonic acid.
Examples of the solid acid used in the present invention include Amberlyst, Amberlite manufactured by Organo, and Nafion manufactured by DuPont.

The target compound of the present invention is a 1,4-benzoquinone compound represented by the following general formula (A).
In the above formula, the substituents ^R 1 to R ⁴ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.

Specific examples of the alkyl group of R ^{1 to} R ⁴ include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, isopentyl, hexyl, and isohexyl groups.
Specific examples of the alkoxyl group of R ^{1 to} R ⁴ include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutyroxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy group and the like.

The method for producing the 1,4-benzoquinone compound represented by the general formula (A) is as follows.
The methoxybenzene compound represented by the following general formula (B) is reacted with an oxidant composed of a carboxylic acid ester compound, hydrogen peroxide solution and an equivalent amount of acid or less.
In said formula, R < ¹ > -R < ⁴ > is the same as the case of R < ¹ > -R < ⁴ > of the ^1, 4- benzoquinone compound shown by the said general formula (A).

Moreover, the method of manufacturing the 1, 4- benzoquinone compound represented by the said general formula (A) is as follows.
The phenol compound represented by the following general formula (C) is reacted with an oxidant composed of a carboxylic acid ester compound, hydrogen peroxide solution and an acid having an equivalent weight or less.
In said formula, R < ¹ > -R < ⁴ > is the same as the case of R < ¹ > -R < ⁴ > of the ^1, 4- benzoquinone compound shown by the said general formula (A).

This novel oxidizing agent proceeds by the following reaction.
In general, hydrogen peroxide has a low oxidizing ability and is difficult to oxidize by itself. Therefore, when hydrogen peroxide solution is reacted with a carboxylic acid ester compound in the presence of an acid, a peracid and a carboxylic acid are generated, and the activity of hydrogen peroxide is increased in the same manner as the reaction of hydrogen peroxide in the carboxylic acid. As a result, it becomes possible to oxidize a methoxybenzene compound or a phenol compound, and the target 1,4-benzoquinone compound can be obtained.

As the amount of hydrogen peroxide used in the reaction for producing the 1,4-benzoquinone compound, the reaction proceeds in a 2-fold molar amount with respect to the alkoxybenzene compound or the phenol compound, but it is more preferable to add 2.2 to 4-fold molar amount. preferable.
A commercially available hydrogen peroxide solution having a concentration of 3 to 80% is used. However, when the concentration is low, the reaction is slow, and when the concentration is high, there is a danger, so a concentration of 10 to 50% is used. Is preferred.

The amount of acid used in the reaction for producing the 1,4-benzoquinone compound may be less than or equal to the alkoxybenzene compound or phenol compound. Specifically, it is good to add in the range of 1-100 mol%.

The reaction temperature can be carried out at a temperature in the range of 0 ° C to 100 ° C. When the temperature is lower than this temperature range, the reaction rate is slow, and when the temperature is too high beyond this range, there are many decomposition reactions and side reactions of hydrogen peroxide. Therefore, the temperature range is preferably in the range of 20 to 60 ° C.
The reaction time depends on the reaction temperature and cannot generally be determined, but is usually 1 to 12 hours.

Illustrative examples of the 1,4-benzoquinone compound obtained by this reaction are compounds represented by the following chemical formulas (1) to (3). However, these compounds are representative examples, and the present invention is not limited to these compounds.

The 1,4-benzoquinone compound represented by the general formula (A) obtained in the present invention is extremely useful as a raw material for physiologically active substances.

The oxidizing agent used in the present invention is produced from a carboxylic acid ester compound and a hydrogen peroxide solution under an acid catalyst. The benzoquinone compound represented by the general formula (A) obtained by the reaction is extremely useful as a raw material for physiologically active substances.
The method for producing a benzoquinone compound represented by the general formula (A) of the present invention comprises reacting a methoxybenzene compound represented by the general formula (B) or a phenol compound represented by the general formula (C) with an oxidizing agent. Therefore, it can be easily synthesized. In addition, the oxidizing agent and the starting material are easily available compounds, and hydrogen peroxide produces only water after the reaction is completed, so it can be said that it is an environmentally friendly oxidizing agent.

Next, the present invention will be described in detail with reference to examples. Examples described below are examples of typical compounds for facilitating the understanding of the present invention, and the present invention is not limited thereto. In addition, the produced compounds (1) to (3) correspond to the compounds (1) to (3) shown above.

In a glass container, 3,4,5-trimethoxytoluene (364 mg, 2 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1 mmol) were dissolved in ethyl formate (4 mL), and 30% hydrogen peroxide solution was added. (0.5 mL, 5 mmol) was added and reacted at room temperature for 3 hours. Methylene chloride and brine were added to the reaction solution, and extraction and washing were performed until no peroxide was observed in the aqueous layer. The organic layer was dried over anhydrous magnesium sulfate, and the product was analyzed by gas chromatography. As a result, the desired product, 2,3-dimethoxy-5-methyl-1,4-benzoquinone (1), was obtained in a yield of 38.0%. Was obtained.

In a glass container, 3,4,5-trimethoxytoluene (364 mg, 2 mmol) is dissolved in ethyl formate (4 mL), and Amberlyst (500 mg) and 30% hydrogen peroxide (0.5 mL, 5 mmol) are added. The reaction was allowed to proceed for 3 hours at room temperature. After filtering the solid acid, methylene chloride and brine were added to the reaction solution, followed by extraction and washing until no peroxide was observed in the aqueous layer. The organic layer was dried over anhydrous magnesium sulfate, and the product was analyzed by gas chromatography. As a result, the desired product 2,3-dimethoxy-5-methyl-1,4-benzoquinone (1) was obtained in a yield of 28.7%. Was obtained.

In Example 2, the same reaction was carried out using Nafion (500 mg) instead of Amberlyst, and the desired product, 2,3-dimethoxy-5-methyl-1,4-benzoquinone (1), was obtained at a yield of 25. Obtained at 1%.

In Example 1, the same reaction was carried out using ethyl acetate (4 mL) instead of ethyl formate, and the target 2,3-dimethoxy-5-methyl-1,4-benzoquinone (1) was obtained in a yield of 21. Obtained at 3%.

In Example 1, the same reaction was carried out using 2,3,6-trimethylphenol (272 mg, 2 mmol) instead of 3,4,5-trimethoxytoluene, and 2,3,5-trimethyl, which was the target product. -1,4-benzoquinone (2) was obtained with a yield of 21.3%.

In Example 1, the same reaction was performed using carvacrol (300 mg, 2 mmol) instead of 3,4,5-trimethoxytoluene, and the target product, 2-isopropyl-5-methyl-1,4. -The benzoquinone (3) was obtained with a yield of 26.5%.

In Example 1, the same reaction was performed using thymol (300 mg, 2 mmol) instead of 3,4,5-trimethoxytoluene, and the target product, 2-isopropyl-5-methyl-1,4-benzoquinone ( 3) was obtained with a yield of 24.5%.

[Comparative Example 1]
In Example 1, the same reaction was carried out without using p-toluenesulfonic acid monohydrate which is an acid. As a result, 2,3-dimethoxy-5-methyl-1,4-benzoquinone (1 ) Was obtained in a yield of 0.7%.

[Comparative Example 2]
In Example 1, a similar reaction was performed using toluene (4 mL) instead of ethyl formate. As a result, 2,3-dimethoxy-5-methyl-1,4-benzoquinone (1), which was the target product, was recovered. The rate was 1.7%.

The use of the oxidizing agent of the present invention is useful because it can efficiently produce a 1,4-benzoquinone compound that is extremely useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and the like.

Claims (6)

An oxidant comprising a carboxylic acid ester compound having 2 to 6 carbon atoms, a hydrogen peroxide solution, and an acid having an equivalent amount or less with respect to the substrate. The oxidizing agent according to claim 1, wherein a solid acid is used as the acid. In the method for producing a 1,4-benzoquinone compound represented by the following general formula (A), a methoxybenzene compound represented by the following general formula (B) is converted into a carboxylic acid ester compound having 2 to 6 carbon atoms and peroxidized. A method for producing a 1,4-benzoquinone compound, characterized by reacting with hydrogen water and an oxidizing agent comprising an acid having an equivalent amount or less with respect to a substrate.
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.)
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.) The method for producing a 1,4-benzoquinone compound according to claim 3, wherein a solid acid is used as the acid. In the method for producing a 1,4-benzoquinone compound represented by the following general formula (A), a phenol compound represented by the following general formula (C) is converted into a carboxylic acid ester compound having 2 to 6 carbon atoms and hydrogen peroxide. A method for producing a 1,4-benzoquinone compound, characterized by reacting with an oxidizing agent comprising an acid equivalent to or less than water and a substrate.
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.)
^(Wherein, R 1 to R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a phenyl group.) The method for producing a 1,4-benzoquinone compound according to claim 5, wherein a solid acid is used as the acid.