JPH09227437A - Production of catechol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject high-purity derivative useful for synthesizing medicines, hardly preparing a by-product, in high yield, slight in admixture of position isomer, by reacting a phenol (derivative) as a raw material under a specific condition at two stages. SOLUTION: In production of this compound of formula I (R is H, an alkyl, a cycloalkyl, an aralkyl, an alkoxyl, a halogen, allyl or an aryl; R<1> is an OH- protecting group), a phenol or a phenol derivative of formula II is reacted with a base and paraformaldehyde in an organic solvent in the presence of stannous chloride and/or stannic chloride at 60-85 deg.C until the reaction rate reaches 30-80%. Then the reaction is completed at 95-105 deg.C and a prepared salicylaldehyde of formula III is treated with an alkylating agent in water and/or an organic solvent in the presence of a base. A prepared formyl ether of formula IV is oxidized with an oxidizing agent in water and/or an organic solvent and then hydrolyzed with an acid or a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a catechol derivative represented by the following formula (1), which is an important basic skeleton of a compound which is a drug or an agricultural chemical.

[0002]

BACKGROUND OF THE INVENTION Monoalkylcatechol derivatives have been used as synthetic intermediates for medicines and agricultural chemicals. In this method, only one hydroxyl group of the corresponding catechol derivative has been conventionally used. A method of synthesizing by alkyl ether formation and a method of synthesizing by corresponding hydroxylation of an alkoxybenzene derivative are known. Examples of the former include an alkyl etherification method using dialkyl sulfuric acid (JP-A-5-112485), an alkyl etherification method using an alcohol and an acid catalyst (JP-A-4-305546), and the latter include formic acid. Method of reacting with hydrogen peroxide in the coexistence (Bull. Chem. Soc. Jpn., 198)
9, 62, 1652 to 1657), Fe (IV) -ED
Method of reacting with TA-ascorbic acid system (J. Mo
l. Catal. , 1982, 14, 333-34
0), a method of reacting with peracetic acid (Journal of the Chemical Society of Japan, 197).
9, 370 to 374), and a method of synthesizing by photooxidation in the presence of a Lewis acid (Chem. Lett., 1972, 179).
~ 180) and the like.

However, the above-mentioned conventional methods are generally low in yield and poor in regioselectivity, so that they become a mixture of regioisomers, which are difficult to separate, and thus are preferable as intermediates for pharmaceuticals and agricultural chemicals requiring high purity. Not a thing. In addition, expensive reagents and raw materials that are difficult to obtain may be used, which is not preferable as an industrial production method.

[0004]

Means for Solving the Problems The inventors of the present invention have made extensive studies in view of the above-mentioned problems, and as a result, almost no by-products, high yields, and very little mixing of positional isomers. The inventors have found a method for synthesizing a high-purity catechol derivative.

The present invention is a method for producing a catechol derivative represented by the formula (1), characterized in that the catechol derivative is produced through the following three steps. (1) A phenol or a phenol derivative represented by the formula (2) is mixed with a base and paraformaldehyde in the presence of stannous chloride and / or stannic chloride in an organic solvent at 60 to 85 ° C.
Reaction until the reaction rate reaches 30 to 80%, and then 95
Step of completing the reaction at ~ 105 ° C to produce a salicylaldehyde derivative represented by the formula (3) (2) The salicylaldehyde derivative represented by the formula (3) is present in water and / or an organic solvent in the presence of a base. A step of producing a formyl ether body represented by the formula (4) by treating with an alkylating agent below to protect a hydroxyl group (3) The formyl ether body represented by the formula (4) in water and / or an organic solvent In order to produce a catechol derivative represented by the formula (1) by oxidizing with an oxidizing agent and then hydrolyzing with an acid or a base.

[0006]

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[0007]

[Chemical 6]

[0008]

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[0009]

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In the above formulas (1) to (4), R is hydrogen or an alkyl group, a cycloalkyl group, an aralkyl group,
Alkoxyl group, halogen atom, group selected from allyl group and aryl group, R ¹ is a hydroxyl group-protecting group, which is appropriately selected from known hydroxyl group-protecting groups, but is eliminated by oxidation and hydrolysis in the step (3). Those not included are preferable, and examples thereof include a group selected from an alkyl group, a benzyl group, an o-nitrobenzyl group, a p-methoxybenzyl group and an allyl group.

The above steps will be described in detail below. (1)
In the step of, the alkyl group of R of the phenol derivative of the formula (2) has 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl and the like. Straight-chain or branched-chain alkyl group, cyclopropyl as a cycloalkyl group, cyclobutyl,
Cycloalkyl groups having 3 to 6 carbon atoms such as cyclopentyl and cyclohexyl, benzyl as aralkyl groups, phenylalkyl groups having an alkyl moiety having 1 to 3 carbon atoms such as phenylethyl, and alkoxyl groups such as methyloxy, ethyloxy and n-. Propyloxy, i-propyloxy, n-butyloxy, sec-butyloxy, t
ert-butyloxy or other straight-chain or branched-chain alkoxyl groups having 1 to 4 carbon atoms, halogen atoms include chlorine, bromine,
As aryl groups such as iodine, phenyl, o-tolyl,
m-Tolyl, p-tolyl and the like are mentioned as preferable groups. Of these, an alkyl group, an alkoxyl group, or an allyl group is particularly preferable as R.

Typical examples of the above-mentioned phenol derivative are o-cresol, 2-ethylphenol, 2-cyclopropylphenol, 2-cyclobutylphenol, 2
-Benzylphenol, 2- (phenolethyl) phenol, 2-methyloxyphenol (guaiacol), 2-ethyloxyphenol, 2-chlorophenol, 2-bromophenol, 2-iodophenol,
2-allylphenol, 2-hydroxybiphenyl, 2
Examples include-(o-tolyl) phenol and the like.

As the base used in the step (1), an alkyl moiety such as trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine, trihexylamine, triheptylamine or trioctylamine has 1 to 10 carbon atoms. Aliphatic trialkylamines with 10, N, N-dimethylaniline, N, N-
Preferred bases include aromatic amines such as diethylaniline and nitrogen-containing heterocyclic compounds such as 2,6-lutidine and pyridine.

The reaction in the step (1) is carried out by reacting phenol or a phenol derivative with a base and paraformaldehyde in an organic solvent in the presence of stannous chloride and / or stannic chloride.
The reaction rate at 0 to 85 ° C is 30 to 80%, preferably 50 to 8
By reacting to 0% and then completing the reaction at 95 to 105 ° C, the salicylaldehyde derivative represented by the formula (3) can be obtained in high yield and high selectivity.

Regarding the technique for synthesizing the salicylaldehyde derivative of the formula (3) in the above step (1), one step is carried out at a reaction temperature of 90 to 150 ° C., preferably 110 ° C., using the same raw material and catalyst as in the present invention. A method of carrying out the reaction is known (Japanese Patent Application Laid-Open No. 53-34737). However, in this known method, the raw material paraformaldehyde undergoes rapid thermal decomposition, the polymerization reaction occurs preferentially, and oligomers are produced as a by-product, resulting in a significant decrease in yield, and the introduction position of the aldehyde group is also o. It was divided into −, m−, and p− positions, and the selectivity was not sufficient.

According to the present invention, by carrying out the reaction in two steps under the specific conditions as described above in the step (1), the by-product ratio of undesired oligomers is suppressed, and the aldehyde group is exclusively in the o-position. Since it is introduced, it is based on the finding that the salicylaldehyde derivative as an intermediate can be obtained in a high yield and a high selectivity, and by using this intermediate, the final target product of the formula (1) can be obtained. The catechol derivative represented is obtained in high purity.

In the first-step reaction, when the reaction rate is less than 30%, the raw material paraformaldehyde undergoes thermal decomposition in the second-step reaction, and the salicylaldehyde derivative obtained is polymerized with paraformaldehyde. The yield is significantly reduced. When the reaction rate exceeds 80%, the reaction in the first step takes too much time, and the obtained salicylaldehyde product undergoes a polymerization reaction, resulting in a decrease in yield. Therefore, by controlling the first step reaction within the above reaction rate at a reaction temperature of 60 to 85 ° C., the reaction can be efficiently performed and a salicylaldehyde derivative can be obtained in a high yield.

In the second stage reaction, the reaction temperature is 95 ° C.
If it is lower, it takes too much time to complete the reaction, and 105 ° C.
If it exceeds the above range, the yield is markedly reduced due to the decomposition of the raw material paraformaldehyde and the polymerization reaction of the obtained salicylaldehyde.

The amount of stannous chloride and / or stannic chloride used in the step (1) is 0.025 to 5 equivalents, preferably 0.025 to 1 based on the starting phenol or phenol derivative. It is an equivalent, and the amount of the base used is 0.1 to 20 equivalents, preferably 0.1 to 4 equivalents, relative to the above raw materials. The amount of paraformaldehyde used is 2 to 10 equivalents, preferably 2 to 5 equivalents, relative to the above raw materials. As the organic solvent to be used, aromatic solvents such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, ether solvents such as diethylene glycol monomethyl ether, dichloromethane. Examples thereof include chlorine-based solvents such as dichloroethane and chloroform, and mixed solvents thereof may be used. The obtained salicylaldehyde compound may be isolated and purified by distillation or the like, or may be used as it is as a raw material in the step (2).

In the reaction of the step (2), the salicylaldehyde derivative obtained in the step (1) is treated with an alkylating agent in the presence of a base in water and / or an organic solvent by a conventional method to remove a hydroxyl group. The protected formyl ether represented by the formula (4) is obtained, and examples of the alkylating agent include halogenated alkyls, aralkyl halides, allyl halides and the like, and dialkyl sulfuric acid.

As the alkyl halide, methyl chloride,
Methyl bromide, methyl iodide, ethyl chloride, ethyl bromide,
Examples thereof include alkyl halides having 1 to 4 carbon atoms such as ethyl iodide, propyl chloride, propyl bromide, propyl iodide, butyl chloride, butyl bromide, and butyl iodide. Examples of aralkyl halides include benzyl chloride and bromide. Benzyl, benzyl iodide, 2,6-dichlorobenzyl chloride, o
-Nitrobenzyl, o-nitrobenzyl bromide, o-iodide
-Nitrobenzyl, p-methoxybenzyl chloride, p-bromide
Selected from a halogen atom, a nitro group, an alkoxyl group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4 carbon atoms in a benzene ring such as -methoxybenzyl, p-methoxybenzyl iodide, and 2,6-dimethylbenzyl chloride. Examples thereof include phenylalkyl which may have a substituent and whose alkyl portion has 1 to 4 carbon atoms, and examples of allyl halides include allyl chloride and allyl bromide. Examples of the dialkyl sulfuric acid include dialkyl sulfuric acid having an alkyl group of 1 to 4 carbon atoms such as dimethyl sulfuric acid and diethyl sulfuric acid. The amount of the alkylating agent used is 1 to the salicylaldehyde derivative.
It is 5 equivalents, preferably 1 to 3 equivalents.

As the base used in the step (2), alkali metal or alkaline earth metal hydrides, oxides,
Hydroxides, carbonates, hydrogen carbonates are preferable, and specifically, potassium hydride, sodium hydride, calcium hydride, potassium oxide, sodium oxide, calcium oxide,
Inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate,
Alkoxides such as potassium methoxide, potassium ethoxide, sodium methoxide, sodium ethoxide,
Preferred examples include organic bases such as alkyllithium such as methyllithium, ethyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, and phenyllithium. The amount of the above base used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the salicylaldehyde.

The solvent used in the step (2) is an aromatic solvent such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, diethylene glycol. Ether-based solvents such as monomethyl ether, chlorine-based solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, sulfolane and hexamethylphosphoramide, acetone, methyl ethyl ketone, methyl-iso. -Ketone solvents such as propyl ketone, alcohol solvents such as methanol, ethanol and i-propyl alcohol, acetonitrile, water and the like, and a mixed solvent thereof may be used.

The reaction temperature in the step (2) may be from 20 ° C. to the boiling point of the solvent used, and if the reaction temperature is too low, the reaction rate is significantly lowered and the yield is deteriorated, which is not preferable. The formyl ether body obtained above may be isolated and purified by distillation or the like, or may be used as it is as a raw material for the next step.

In the present invention, the catechol derivative of interest is obtained by oxidizing the formyl ether compound in water and / or an organic solvent with an oxidizing agent in the step (3) and then hydrolyzing it with an acid or a base. When the oxidation is carried out in the coexistence of an acid or a base, hydrolysis occurs simultaneously with the oxidation, whereby the desired product can be obtained all at once. In this case as well, the formate represented by the following formula (5) or its equivalent is once produced by oxidation, but it is considered that it is immediately hydrolyzed and converted into a catechol derivative.

[0026]

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[0027] In the formula (5), R and R ¹ have the same meanings as R and R ¹ of formula (1).

The oxidizing agent used in the step (3) is preferably a peroxide, specifically, hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, perbenzoic acid, monoperoxy orthophthalic acid, mono Typical examples include peroxymaleic acid, formic acid, p-nitroperbenzoic acid, tert-butyl peroxide and the like. The amount of the oxidizing agent used is 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to the formyl ether form.

Examples of the acid used in the step (3) include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, acidic salts of mineral acids such as sodium hydrogensulfate, potassium hydrogensulfate and sodium dihydrogenphosphate, and formic acid. , Organic acids such as acetic acid, methanesulfonic acid and p-toluenesulfonic acid. Examples of the base include the same inorganic bases and organic bases used in step (2). The amount of acid or base used is 0.1 to 5 equivalents, preferably 0.1 to 3 with respect to the formyl ether form.
Is equivalent.

As the solvent used in the step (3),
The same organic solvents as those used in the step (1), for example, aromatic solvents, ether solvents, chlorine solvents, alcohol solvents such as methanol, ethanol and i-propyl alcohol, water and the like can be mentioned. A mixed system of these may be used.
The reaction temperature for oxidation and hydrolysis in the step (3) may be from 0 ° C. to the boiling point of the solvent, and if the reaction temperature is too low, the reaction rate will be significantly reduced, which is not practical.

[0031]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a target product is produced through 3 steps as described above. In addition to the production methods shown in the following examples, the compound obtained in each step is isolated and purified. It is also possible to employ a method of using as a raw material for the next step without any treatment.

In the following examples, as the step (1), an example in which the type of catalyst is changed and an example in which the reaction temperatures of the first and second steps are changed are shown. As a comparative example of this step, the first step is shown. The reaction temperature was lower than the specified range of the present invention. A comparative example in which the reaction is carried out in one step is also shown. As examples of the step (2), examples in which the type of base, the type of alkylating agent, and the type of solvent are changed are shown. As an example of the step (3), an example in which the reaction was carried out by oxidation and hydrolysis at once under acidic conditions and an example in which the reaction was carried out separately by oxidation and hydrolysis were shown.
In the following examples, the reaction rate in the step (1) was calculated as follows. Reaction rate (%) = (HPLC area of salicylaldehyde / HPLC area of phenol derivative) × 100 Each of the above areas is the area of the liquid chromatogram obtained under the following analysis conditions. Analytical conditions Column: Daiso Pack SP-120-5-ODS-A
P (manufactured by Daiso) Mobile phase: phosphoric acid-acetonitrile-water = 0.0001: 6
0:40 (volume ratio) Flow rate: 1.0 ml / min. Detection: 210nm

[0033]

【Example】

Example (Synthesis of salicylaldehyde) Synthesis Example 1- (1) 20.0 g (185 mmol) of o-cresol was dissolved in 400 ml of toluene, and 18.4 g of 2,6-lutidine was dissolved.
(171 mmol) was added, and then stannic chloride 4.8 g
(19 mmol) was added and the mixture was stirred at 20 ° C. for 30 minutes.
Paraformaldehyde having a purity of 95% by weight was used as 12.9.
g (470 mmol) was added, and the mixture was stirred at a reaction temperature of 80 ° C. for 5 hours (reaction rate 78%). Reaction temperature 100 ℃
The reaction was carried out for 10 hours and the disappearance of the raw material o-cresol was confirmed. The reaction solution was returned to room temperature, liquid-extracted with water-toluene, and the organic layer was dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure to give 24.9 g of 2-hydroxy-
3-Methylbenzaldehyde was obtained (yield 99%, selectivity 99%).

Synthesis Example 1- (2) In place of 4.8 g of stannic chloride, 3.5 g of stannous chloride (19
mmol) was used, and 24.4 g of 2-hydroxy-3-methylbenzaldehyde was obtained in the same manner as in Synthesis Example 1- (1) except that the reaction rate in the first step was 70% (yield 97.
%, Selectivity 98%).

Synthesis Example 1- (3) Synthesis Example 1- (1) except that the first step was carried out at a reaction temperature of 65 ° C. for 7 hours at a reaction rate of 51% and the second step was carried out at a reaction temperature of 95 ° C. for 13 hours. 24.4 g of 2-hydroxy-3-methylbenzaldehyde was obtained in the same manner as in (). (Yield 97%,
Selectivity 99%).

Synthesis Comparative Example 1- (1) Synthesis Example 1-Except that the first step was carried out at a reaction temperature of 40 ° C. for 7 hours at a reaction rate of 25% and the second step was carried out at 95 ° C. for 13 hours.
10.5 g of 2-hydroxy-3-as in (1)
Methylbenzaldehyde was obtained (yield 42%, selectivity 7
5%).

Synthesis Comparative Example 1- (2) 12.0 was carried out in the same manner as in Synthesis Example 1- (1) except that the reaction was carried out at a reaction temperature of 100 ° C. for 7 hours in a one-step reaction rate of 99%.
g of 2-hydroxy-3-methylbenzaldehyde was obtained (yield 48%, selectivity 62%).

Synthesis Comparative Example 1- (3) 11.7 was carried out in the same manner as in Synthesis Example 1- (1) except that the reaction was carried out at a reaction temperature of 70 ° C. for 35 hours at a reaction rate of 99%.
g of 2-hydroxy-3-methylbenzaldehyde was obtained (47% yield, 60% selectivity).

(Synthesis of Formyl Ether Form) Synthesis Example 2- (1) 6.5 g (163 mmo) of sodium hydride having a purity of 60%
l) and 40 ml of dimethylformamide (DMF) in a suspension of 2-hydroxy-3 of Synthesis Example 1- (1) in an ice bath.
-Methylbenzaldehyde 20.0 g (147 mmo
l) DMF 100 ml solution was added dropwise. After completion of hydrogen generation, 25.0 g (147 mmo) of benzyl bromide in an ice bath.
l) was added dropwise. Stirring was continued at 20 ° C. for 4 hours, after the disappearance of the raw materials, water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 29.9 g of 2-benzyloxy-3-methylbenzaldehyde. Was obtained (yield 91%).

Synthesis Example 2- (2) 20.0 g (147 mmol) of 2-hydroxy-3-methylbenzaldehyde of Synthesis Example 1- (1) was added to DMF10.
It was dissolved in 0 ml, and 31.0 g (22
1 mmol) was added and benzyl bromide 25.0 g (147
mmol) was added dropwise. Stirring was continued at 20 ° C. for 2 hours, after the disappearance of the raw materials, the reaction solution was filtered, the solvent was removed under reduced pressure, and purification was performed in the same manner as in Synthesis Example 2- (1) to obtain 24.2 g of 2-benzyloxy-3. -Methylbenzaldehyde was obtained (yield 73%).

Synthetic Example 2- (3) 24.9 g of 2- was obtained in the same manner as in Synthetic Example 2- (2) except that the raw material was dissolved in 100 ml of methyl ethyl ketone (MEK) for reaction instead of being dissolved in 100 ml of DMF.
Benzyloxy-3-methylbenzaldehyde was obtained (yield 75%).

Synthesis Example 2- (4) Synthesis Example 2 except that the raw materials were dissolved in 100 ml of acetonitrile and reacted instead of being dissolved in 100 ml of DMF.
In the same manner as in-(2), 25.4 g of 2-benzyloxy-3-methylbenzaldehyde was obtained (yield 77%).

Synthesis Example 2- (5) Benzyl chloride 18.
25.9 g of 2 in the same manner as in Synthesis Example 2- (2) except that 6 g (147 mmol) was used and the reaction temperature was 50 ° C.
-Benzyloxy-3-methylbenzaldehyde was obtained (yield 79%).

(Synthesis of Catechol Derivatives) Synthesis Example 3- (1) 2-benzyloxy-3-methylbenzaldehyde (20.0 g, 88.4 mmol) obtained in Synthesis Example 2- (1) was dissolved in 100 ml of methanol. Sulfuric acid 20.0 g (2
03 mmol), and 30% hydrogen peroxide 30.1 g
(265 mmol) was added. After refluxing for 2 hours, the raw materials disappeared, the mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with methylene chloride. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 13.3 g of 2-benzyloxy-3.
-Methylphenol was obtained (yield 70%).

Synthesis Example 3- (2) 20.0 g (88.4 mmol) of 2-benzyloxy-3-methylbenzaldehyde of Synthesis Example 2- (1) was dissolved in 100 ml of methylene chloride, and m-chloroperbenzoic acid was added thereto. An acid (16.8 g, 97.2 mmol) was added, and the mixture was reacted at 20 ° C. for 10 hours with stirring. After disappearance of the raw materials, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. Obtained extract (2-benzyloxy-3-formyloxytoluene)
10% NaOH aqueous solution 38.9 g (97.2 mmo)
1) was added in an ice bath and stirred for 3 hours. The reaction solution is 5% H
The mixture was neutralized with Cl aqueous solution and extracted with methylene chloride. The solvent was removed under reduced pressure, and the product was purified in the same manner as in Synthesis Example 3- (1) to obtain 16.7 g of 2-benzyloxy-3-methylphenol (yield 88%).

[0046]

INDUSTRIAL APPLICABILITY The present invention suppresses the decomposition of the raw material paraformaldehyde and the polymerization reaction during the reaction by carrying out the reaction in the step (1) in two stages under specific conditions, so that the intermediate product containing no positional isomers is present. The catechol derivative, which is the final product, can be obtained in high purity.

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Claims (9)

[Claims] 1. A method for producing a catechol derivative represented by the formula (1), which is produced through the following three steps. (1) A phenol or a phenol derivative represented by the formula (2) is mixed with a base and paraformaldehyde in the presence of stannous chloride and / or stannic chloride in an organic solvent at 60 to 85 ° C.
Reaction until the reaction rate reaches 30 to 80%, and then 95
Step of completing the reaction at ~ 105 ° C to produce a salicylaldehyde derivative represented by the formula (3) (2) The salicylaldehyde derivative represented by the formula (3) is present in water and / or an organic solvent in the presence of a base. A step of producing a formyl ether body represented by the formula (4) by treating with an alkylating agent below to protect a hydroxyl group (3) The formyl ether body represented by the formula (4) in water and / or an organic solvent In order to produce a catechol derivative represented by the formula (1) by oxidizing with an oxidizing agent and then hydrolyzing with an acid or a base. Embedded image Embedded image Embedded image In formulas (1) to (4), R represents hydrogen or a group selected from an alkyl group, a cycloalkyl group, an aralkyl group, an alkoxyl group, a halogen atom, an allyl group and an aryl group, and R ¹ represents a hydroxyl group-protecting group. . 2. The production method according to claim 1, wherein the base used in the step (1) is a base selected from aliphatic trialkylamines, aromatic amines and nitrogen-containing heterocyclic compounds. 3. The aliphatic trialkylamine is an amine whose alkyl moiety is selected from alkyl having 1 to 10 carbon atoms, and the aromatic amine is N, N-dimethylaniline or N, N-dimethylaniline.
The production method according to claim 2, which is N-diethylaniline and the nitrogen-containing heterocyclic compound is 2,6-lutidine or pyridine. 4. The base used in the step (2) is an alkali metal or alkaline earth metal hydride, oxide, hydroxide, carbonate or hydrogen carbonate, or an organic base. Item 4. The method according to any one of Items 1 to 3. 5. The alkylating agent used in the step (2) is a halide selected from alkyl halides, aralkyl halides and allyl halides or dialkyl sulfuric acid. Manufacturing method. 6. The method according to claim 1, wherein the oxidizing agent used in the step (3) is a peroxide. 7. The peroxide is hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid, perbenzoic acid, monoperoxyorthophthalic acid, monoperoxymaleic acid, performic acid, p-nitroperbenzoic acid and tert-. The method according to any one of claims 1 to 6, which is selected from butyl peroxide. 8. The acid used in the step (3) is a mineral acid selected from hydrochloric acid, sulfuric acid and nitric acid, or an organic acid selected from formic acid, acetic acid, methanesulfonic acid and p-toluenesulfonic acid. The method according to claim 1, which is an acid. 9. The base used in step (3) is an alkali metal or alkaline earth metal hydride, oxide, hydroxide, carbonate or hydrogen carbonate, or an organic base. Item 8. The method according to any one of Items 1 to 7.