JPH06279367A - Process for producing ether ester of hydroxynaphthoic acids - Google Patents

Abstract

(57) [Summary] [Object] To provide a method for obtaining an ether ester of hydroxynaphthoic acid in a high yield by a one-step reaction. It is characterized in that hydroxynaphthoic acid or a salt thereof and an alkylating agent are reacted in the presence of a quaternary ammonium salt in an organic solvent containing substantially no water and having a dielectric constant of 15 or more. A method for producing an ether ester of hydroxynaphthoic acids.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing an ether ester of hydroxynaphthoic acids.

[0002]

2. Description of the Related Art Ether esters of hydroxynaphthoic acids are useful as raw materials for medicines, polyesters and the like. Particularly, the methyl ether methyl ester of 2-hydroxy-6-naphthoic acid is useful as a raw material for nabumetone known as an anti-inflammatory agent and an analgesic agent.

The ether ester form of hydroxynaphthoic acids is generally obtained by esterifying hydroxynaphthoic acids and then further etherification, or vice versa. In any case, it requires two reaction steps, which is not economical.

The present inventors previously reacted p-hydroxybenzoic acid or a salt thereof with an alkylating agent in the presence of a quaternary ammonium salt in an organic solvent containing substantially no water to give p-hydroxy. We proposed a method to obtain ether ester of benzoic acid. The solvent specifically used is a water-insoluble aromatic solvent such as xylene, but the yield is extremely low when this method is used for etherification of hydroxynaphthoic acids.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for obtaining an ether ester of hydroxynaphthoic acids in a high yield by a one-step reaction.

[0006]

According to the present invention, hydroxynaphthoic acid or its salt and an alkylating agent are contained in the presence of a quaternary ammonium salt, substantially free of water, and have a dielectric constant of 1.
The present invention relates to a method for producing an ether ester of hydroxynaphthoic acid, which comprises reacting in an organic solvent of 5 or more.

Hydroxynaphthoic acid used in the present invention includes 2-hydroxy-6-naphthoic acid, 2-hydroxy-3-naphthoic acid, 2-hydroxy-1 naphthoic acid, 1-hydroxy-2-naphthoic acid and 1-hydroxy-2-naphthoic acid. Examples thereof include hydroxy-2-naphthoic acid and 1-hydroxy-4-naphthoic acid. Particularly preferable results in the present invention are obtained in the ether ester form of 2-hydroxy-6-naphthoic acid. Further, the hydroxynaphthoic acid of the present invention may have one or more substituents in the naphthalene ring of the above-mentioned hydroxynaphthoic acid, and the substituent on the naphthalene ring may be a lower alkyl group such as methyl or ethyl, Examples thereof include halogen such as fluorine, chlorine and bromine, alkoxy group such as methoxy and ethoxy, phenyl group, benzyl group, hydroxyl group, amino group and carboxyl group. Alkylation occurs when it has a hydroxyl substituent.

As the salt of hydroxynaphthoic acid, a separately prepared salt may be used. It is formed by adding hydroxynaphthoic acid and alkali to the reaction system separately and mechanically contacting them in the system. Good. The latter is preferable for simplifying the process. Examples of the salt include alkali metal salts such as sodium, potassium and lithium, alkaline earth metal salts such as calcium and magnesium, metal salts such as iron and zinc, and salts such as alkanolamines such as ammonia, monoethanolamine and diethanolamine. To be done. Preferred are alkali metal salts, alkaline earth metal salts, ammonium salts and the like. In order to form these salts in the reaction system, it is preferable to use a weak acid salt such as an alkali metal or alkaline earth metal carbonate or bicarbonate. When a hydroxide such as sodium hydroxide is used, a solvent that is azeotropic with water such as toluene may be used as a reaction medium, and water generated during salt formation may be removed azeotropically outside the system.

Examples of the alkylating agent include commonly used alkylating agents such as alkyl sulfuric acid, substituted benzene sulfonic acid alkyl ester, and alkyl iodide, preferably alkyl sulfuric acid such as dimethyl sulfuric acid and diethyl sulfuric acid. can give. The alkylating agent used may be present in an equimolar amount or more with respect to the hydroxynaphthoic acid or its salt, but is preferably 2 mol or more.

As the quaternary ammonium salt, tetraalkyl type, benzyltrialkyl type and polymer type salts are used. Examples thereof include tetraethylammonium chloride, tetrabutylammonium bromide, tetraethylammonium hydroxide, benzyltrimethylammonium chloride, benzyltrimethylammonium acetate, methyltriethylammonium chloride, and polystyrene resin having a quaternary ammonium group. Particularly preferred is a tetraalkyl type quaternary ammonium salt. The quaternary ammonium salt may be formed in the system by allowing a tertiary amine and an alkyl halide or dialkyl sulfate to be present in the system.

Examples of the tertiary amine include trimethylamine, triethylamine, tributylamine, triphenylamine, benzyldiethylamine and the like. The amount of the quaternary ammonium salt used is 0.1 to 50 mol%, preferably 1 to 30 mol% based on the hydroxynaphthoic acid or its salt.

The organic solvent used in the present invention is not particularly limited as long as it has a dielectric constant of 15 or more. A solvent having a dielectric constant of 15 to 50 is particularly preferable. In particular,
For example, but not limited to, methanol, ethanol, n-propanol, m-propanol, isopropanol, m-butanol, isobutanol, 2-
Butanol, 1-pentanol, isoamyl alcohol, cyclohexanol and other alcohols, furfural and other ethers, acetone, methyl ethyl ketone, diethyl ketone, acetophenone and other ketones, ethyl acetoacetate and other esters, ethylene glycol, ethylene glycol monomethyl ether, Polyhydric alcohol derivatives such as ethylene chlorohydrin, propylene glycol and glycerin, nitro compounds such as nitromethane and nitrobenzene, formamide, N, N-dimethylformamide, acetamide, acetonitrile, benzonitrile, acid amides such as pyridine, dimethyl Examples thereof include sulfur-containing compounds such as sulfoxide, unsaturated cyclic compounds such as cyclohexanone, and mixtures of two or more thereof.

During the reaction, the organic solvent is used in an amount of about 0.5 to 30 times, preferably 2 to 10 times the weight of the raw material mixture. As a reaction medium, substantially no water is used. When two phases are formed between the organic solvent phase and a large amount of water, the quaternary ammonium acts as a phase transfer catalyst, making it difficult to form an ester. The reaction temperature varies depending on the type of organic solvent used, but is usually 40 to 250 ° C, preferably 5
It is 0 to 200 ° C.

The obtained ether ester of naphthoic acid is washed or extracted by a conventional method after recovering or separating the solvent.
It may be crystallized and further purified by recrystallization, distillation or the like if necessary. Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1 282.3 g of 2-hydroxy-6-naphthoic acid, 518.3 g of anhydrous potassium carbonate as an alkali source and 48.4 g of tetrabutylammonium bromide as a quaternary ammonium salt were used, and these were treated with n-butanol ( 2258.0 g of a dielectric constant of 17.1 (25 ° C) and heated to 90 ° C under a nitrogen gas stream, and then dimethylsulfate 438.2.
g was added dropwise over 1.5 hours for reaction.

The reaction solution was subjected to HPLC (JASCO detector 875-UV manufactured by JASCO Corporation: detection wavelength 229 nm) to give 2-
When methoxy-6-naphthoic acid methyl ester was quantified, unreacted 2-hydroxy-6-naphthoic acid was not detected, and 2-methoxy-6-naphthoic acid methyl ester was contained at 8.9% by weight. Yield of 2-methoxy-6-naphthoic acid methyl ester 93.1%.

Water was added to the reaction solution and shaken at 70 ° C. to extract and remove inorganic salts. When the obtained organic phase was cooled, a white solid was deposited. This is collected by filtration and 268.
8 g of solid and 2815 g of filtrate were obtained. Quantitative analysis of the recovered solid and filtrate by HPLC revealed that the solid contained 96.0% purity (yield 79.6%) and the filtrate contained 1.1% by weight of 2-methoxy-6-naphthoic acid methyl ester. (Yield 9.5%). Further, the water content in the filtrate is measured by a Karl Fischer water content meter (KK Electronics Co., Ltd .; MK-AII).
Water) in the filtrate as measured by
Was included.

Example 2 A raw material mixture consisting of 37.6 g of 2 -hydroxy-6-naphthoic acid, 56.1 g of anhydrous potassium carbonate and 6.4 g of tetrabutylammonium bromide was added to methanol (dielectric constant 3
3.1 (25 ° C.) (564.0 g) and heated to 50 ° C. under a nitrogen gas stream. 53.9g dimethyl sulfate
Was added dropwise over 1.0 hour to react, then 50
The reaction was carried out at 0 ° C for 1 hour. Then 27.0 g of dimethylsulfate
Was added dropwise over 0.5 hour to react, then 50
The reaction was carried out for 2 hours while maintaining the temperature at ℃.

Quantitative analysis of the reaction solution by HPLC revealed that unreacted 2-hydroxy-6-naphthoic acid was 0.0.
8% by weight and 5.1% by weight of 2-methoxy-6-naphthoic acid methyl ester were contained. Yield of 2-methoxy-6-naphthoic acid methyl ester 87.9%.

Example 3 A raw material mixture consisting of 56.5 g of 2-hydroxy-6-naphthoic acid, 84.2 g of anhydrous potassium carbonate and 9.7 g of tetrabutylammonium bromide was mixed with N, N-dimethylformamide (16.1 (25 )) 282.7 g, and heated to 105 ° C. under a nitrogen gas stream. 81.0 g of dimethylsulfate was added dropwise over 0.5 hour to the reaction,
Further, the reaction was carried out at 105 ° C. for 2 hours.

Analysis of the reaction solution by HPLC revealed that unreacted 2-hydroxy-6-naphthoic acid was 0.01% by weight and 2-methoxy-6-naphthoic acid methyl ester was 1%.
The content was 0.7% by weight. Yield 84.8% of 2-methoxy-6-naphthoic acid methyl ester.

Example 4 A raw material mixture consisting of 28.3 g of 2-hydroxy-6-naphthoic acid, 62.2 g of anhydrous potassium carbonate and 4.8 g of tetrabutylammonium bromide was mixed with cyclohexanone (dielectric constant 18.3 (20 ° C.)) 366. In addition to 0.6 g, the temperature was raised to 100 ° C. under a nitrogen gas stream. Dimethyl sulfate 5
The reaction was carried out while 7.8 g was added dropwise over 0.5 hour, and then at 100 ° C. for 2 hours. Subsequently, 13.0 g of anhydrous potassium carbonate was added, and 19.9 g of dimethylsulfate was added to 0.5
The reaction is carried out while dripping over a period of time, and at 100 ° C.
It reacted for time. When the reaction solution was analyzed by HPLC, unreacted 2-hydroxy-6-naphthoic acid was found to be 0.0.
6% by weight, and 2-methoxy-6-naphthoic acid methyl ester was included at 5.1% by weight. Yield 84.8% of 2-methoxy-6-naphthoic acid methyl ester.

Comparative Example 1 A raw material mixture consisting of 37.6 g of 2-hydroxy-6-naphthoic acid, 56.1 g of anhydrous potassium carbonate and 6.4 g of tetrabutylammonium bromide was mixed with methyl isobutyl ketone (dielectric constant 13.1 (20 ° C.)). ) 451.2 g, and heated to 90 ° C. under a nitrogen gas stream. 53.9 g of dimethylsulfate was added dropwise to the mixture over 1 hour for reaction.

When the reaction solution was analyzed by HPLC, it was found that unreacted 2-hydroxy-6-naphthoic acid was 3.66% by weight and 2-methoxy-6-naphthoic acid methyl ester was 0.6% by weight in the reaction solution. % Was included. The yield of 2-methoxy-6-naphthoic acid methyl ester is 9.0%.

Comparative Example 2 A raw material mixture consisting of 94.1 g of 2 -hydroxy-6-naphthoic acid, 140.3 g of anhydrous potassium carbonate and 10.0 g of tetrabutylammonium bromide was mixed with xylene (dielectric constant 2.27 (20 ° C.)) 376. It was added to 0.4 g and the temperature was raised to 100 ° C. under a nitrogen gas stream. Dimethyl sulfate 13
The reaction was carried out while dropping 4.7 g of the solution over 1.5 hours and further at 120 ° C. for 3 hours.

Analysis of the reaction solution by HPLC revealed that unreacted 2-hydroxy-6-naphthoic acid was contained in an amount of 6.9% by weight and 2-methoxy-6-naphthoic acid methyl ester was contained in an amount of 3.1% by weight. It was Yield of 2-methoxy-6-naphthoic acid methyl ester 21.3%.

Comparative Example 3 28.2 g of 2-hydroxy-6-naphthoic acid, 42.1 g of anhydrous potassium carbonate and 4.8 g of tetrabutylammonium bromide were mixed with chlorobenzene (dielectric constant 5.65 (20
)) 282.0 g, and heated to 90 ° C. under a nitrogen gas stream. Dimethylsulfate (40.4 g) was added dropwise to the reaction mixture over 0.5 hour, and the reaction was continued at 110 ° C. for 2 hours.

Analysis of the reaction solution by HPLC revealed that unreacted 2-hydroxy-6-naphthoic acid was 4.21% by weight and 2-methoxy-6-naphthoic acid methyl ester was 0.4% by weight. It was Yield of methyl 2-methoxy-6-naphthoate 5.7%.

Comparative Example 4 A raw material mixture consisting of 28.2 g of 2-hydroxy-6-naphthoic acid, 42.2 g of anhydrous potassium carbonate and 4.8 g of tetrabutylammonium bromide was mixed with 2-ethylhexanol (dielectric constant 3.4 (18 ° C.). )) 366.5 g, and heated to 100 ° C. under a nitrogen gas stream. Dimethylsulfate (40.4 g) was added dropwise and the reaction was carried out over 1.5 hours.

When the reaction solution was analyzed by HPLC, unreacted 2-hydroxy-6-naphthoic acid was contained in an amount of 4.39% by weight and 2-methoxy-6-naphthoic acid methyl ester was contained in an amount of 0.2% by weight. . Yield of 2-methoxy-6-naphthoic acid methyl ester 2.7%.

[0031]

EFFECTS OF THE INVENTION According to the present invention, an ether ester of hydroxynaphthoic acid can be obtained in a high yield in one reaction step.

Claims (1)

[Claims] 1. A method of reacting hydroxynaphthoic acid or a salt thereof with an alkylating agent in the presence of a quaternary ammonium salt in an organic solvent containing substantially no water and having a dielectric constant of 15 or more. And a method for producing an ether ester of hydroxynaphthoic acid.