JP2001158760A - Method of producing fumaric monoalkyl ester and sodium salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially advantageous method for producing a fumaric monoalkyl ester and its sodium salt of high purity by isomerization of a maleic monoalkyl ester. SOLUTION: In the process for producing a corresponding fumaric monoalkyl ester by isomerization of a maleic monoalkyl ester in the presence of a carboxylic acid chloride, the isomerization reaction is characteristically carried out in at least one aromatic hydrocarbon medium selected from the group consisting of toluene and xylene and the sodium salt of the monoalkyl ester is produced by neutralizing the ester with an aqueous solution of sodium hydroxide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for isomerizing a monoalkyl maleate to produce a high-quality monoalkyl fumarate and its sodium salt in high yield.

[0002]

2. Description of the Related Art Monoalkyl fumarate is useful as an antibacterial agent and as an intermediate of various compounds. In particular, the metal salts (eg, sodium salts) are useful as starch modifiers, surface lubricants for pharmaceutical and nutritional tablets.

[0003] In order to produce monoalkyl fumarate, a method is generally used in which an aliphatic alcohol is reacted with fumaric acid or fumaric acid chloride. However, when fumaric acid is used, the reaction is slow and the yield is low, and it is difficult to selectively obtain a monoalkyl ester. On the other hand, when fumaric acid chloride is used, the reaction proceeds rapidly, but the formation of dialkyl esters is unavoidable, and the selectivity of monoalkyl esters is lowered.

A method for obtaining the corresponding monoalkyl fumarate by isomerizing the monoalkyl maleate in the presence of a catalyst has been proposed (US Pat. No. 3,953,616). Monoalkyl maleate as this raw material can be produced relatively easily by reacting maleic anhydride with an aliphatic alcohol.

In the above proposed method, carboxylic acid chloride or a radical generator and a halogen are used as the isomerization catalyst. The isomerization is carried out without a solvent or using a halogenated hydrocarbon solvent. It is difficult to carry out the reaction smoothly in the absence of a solvent, and it is not easy to obtain a high-purity monoalkyl fumarate. When a halogenated hydrocarbon is used as a solvent, it is not preferable from the viewpoint of environmental hygiene and, furthermore, it is inevitable that the solvent is mixed into the intended monoalkyl fumarate, while a complicated means is required for its removal. I do.

[0006]

The object of the present invention is therefore to obtain high-quality monoalkyl fumarate in high yields without using undesired halogenated hydrocarbon solvents.

[0007]

Means for Solving the Problems The present inventors have conducted research to achieve the object of the present invention. As a result, the present inventors have used carboxylic acid chloride as a catalyst and specific aromatic hydrocarbons as a solvent. When the isomerization reaction is performed, the reaction proceeds promptly, and not only can the desired product be obtained in high yield, but also unreacted raw materials and other impurities are easily dissolved and removed in the solvent, and as a result, It has been found that a high quality object can be obtained, and the present invention has been achieved.

Specifically, the present invention provides a method for producing a corresponding monoalkyl fumarate by isomerizing a monoalkyl maleate in the presence of a carboxylic acid chloride, wherein the isomerization reaction is carried out from the group consisting of toluene and xylene. A method for producing a monoalkyl fumarate, which is carried out in at least one selected aromatic hydrocarbon medium. Hereinafter, the present invention will be described in more detail.

The monoalkyl maleate used in the isomerization of the present invention is an ester of an aliphatic alcohol having 10 to 20 carbon atoms, preferably an aliphatic alcohol having 14 to 18 carbon atoms and maleic anhydride. As a specific embodiment, it can be obtained by reacting tetradecyl alcohol, cetyl alcohol, and stearyl alcohol with maleic anhydride in an approximately equimolar ratio.

This esterification step is carried out, for example, in an aromatic hydrocarbon solvent such as benzene, toluene or xylene under anhydrous conditions at 40 to 150 ° C., preferably 5 to 150 ° C.
It is carried out at a temperature of 0 to 140C. Preferred solvents are toluene or xylene.

[0011] By the esterification step, the desired monoalkyl maleate is obtained in high yield. The obtained monoalkyl maleate is desirably cooled and filtered to obtain a high-purity ester.

The obtained monoalkyl maleate is then isomerized to monoalkyl fumarate. This isomerization step is carried out in at least one aromatic hydrocarbon solvent selected from the group consisting of toluene and xylene, using carboxylic acid chloride as a catalyst.

In the isomerization step, the carboxylic acid chloride as a catalyst is a chloride of an aliphatic or aromatic carboxylic acid, and specifically, oxalic acid dichloride, fumaric acid dichloride, monoalkyl (eg, tetradecyl, cetyl, stearyl) fumaric acid Acid chloride, adipic dichloride, benzoic chloride, terephthalic dichloride and the like are preferred.

The carboxylic acid chloride is used in an amount of 0.05 to 5 parts by weight, preferably 0.1 to 3 parts by weight, per 100 parts by weight of the monoalkyl maleate.

The solvent used in the isomerization step is toluene or xylene, which may be a mixture, and the solvent is used in an amount of 1 to 20 times by weight, preferably 1 to 20 times by weight of the monoalkyl maleate. Used 10 times by weight. The isomerization reaction is carried out at 50-150 ° C., preferably 8
The reaction is advantageously carried out at a temperature of from 0 to 120 ° C., a reaction time of from 2 to 20 hours being sufficient.

The reaction mixture obtained by the isomerization step is
By cooling, the monoalkyl fumarate is precipitated, and the precipitate can be separated by filtration.
Thus, unreacted raw materials and impurities are removed in the solvent. The precipitate can be made into a higher purity monoalkyl fumarate by washing with an aromatic hydrocarbon solvent.

The obtained monoalkyl fumarate can be used as a product per se or as an intermediate. If desired, the monoalkyl fumarate can be neutralized to a sodium salt.

In the neutralization step, it is desirable to use sodium hydroxide as an aqueous solution and to carry out the reaction in an organic solvent such as acetone or methyl ethyl ketone. The sodium hydroxide is advantageously used in approximately equimolar amounts with the monoalkyl fumarate. If used excessively, side reactions occur, which is not desirable. The neutralization reaction is suitably carried out at a temperature in the range of 10 to 60C, preferably 15 to 55C. After completion of the reaction, the sodium salt of fumaric acid monoalkyl ester can be separated by filtration.

[0019]

EXAMPLES In the examples, "parts" means "parts by weight". Example 1 A reactor equipped with a condenser and a stirrer was charged with 200 parts of monostearyl maleate, 300 parts of toluene and 2 parts of fumaric acid dichloride, and heated at 90 to 100 ° C for 5 hours. After cooling to room temperature, the precipitated crystals were separated by filtration, washed with 300 parts of toluene, and dried under reduced pressure at 50 ° C. for 3 hours. The yield of the obtained monostearyl fumarate was 181 parts, the yield was 90.5%, and the purity was 99.8%.

Comparative Example 200 parts of monostearyl maleate, 2 parts of fumaric acid dichloride and 800 parts of carbon tetrachloride were placed in the same reactor as in Example 1, and the reaction and treatment were carried out in the same manner as in Example 1. Example 1 after washing the crystals with 300 parts of carbon tetrachloride
In the same manner as in the above, 170 parts (yield 85%) were obtained. Purity 9
It was 9.0%.

Examples 2 to 6 The same reactor as in Example 1 was charged with the monoalkyl maleate and toluene or xylene shown in the table below and heated at a temperature of 90 to 100 ° C. for 5 hours. The reaction solution was cooled, and the generated crystals were separated by filtration. The crystals were dried in the same manner as in Example 1 to obtain the desired monoalkyl fumarate. The results are shown in the table.

[0022]

[Table 1]

Example 7 [Synthesis of maleic acid monostearyl ester]
A reactor equipped with a stirrer was charged with 38 parts of maleic anhydride, 105 parts of stearyl alcohol, and 175 parts of toluene, reacted at 100 ° C. for 2 hours with stirring, and then cooled to room temperature.

[Synthesis of Monostearyl Fumarate] 1.3 parts of fumaric acid dichloride was added to the above reaction solution, and the mixture was heated at 90 to 100 ° C. for 5 hours. Thereafter, the solution was cooled to room temperature and precipitated. The crystals were separated by filtration, washed with 190 parts of toluene, and dried under reduced pressure at 40 ° C. for 3 hours. The yield of the obtained monostearyl fumarate was 130 parts, and the yield was 91.
%, Purity 99.8%.

[Synthesis of sodium salt of monostearyl fumarate] 130 parts of the above monostearyl fumarate and 575 parts of acetone were placed in a reactor equipped with a stirrer and a cooler, and 94 parts of 15% aqueous NaOH were added at 40 ° C for 4 hours. It was added over time to perform a neutralization reaction. After the reaction, the mixture was cooled to room temperature, separated by filtration, washed with 100 parts of acetone, and dried under reduced pressure at 80 ° C. for 5 hours. Yield 124 parts, yield 90%, purity 99.
5%.

[0026]

According to the present invention, the corresponding monoalkyl fumarate of high quality and high yield can be easily obtained by the isomerization reaction of the monoalkyl maleate.

Claims (4)

[Claims] 1. A method for producing a corresponding monoalkyl fumarate by isomerizing a monoalkyl maleate in the presence of a carboxylic acid chloride, wherein the isomerization reaction is performed by at least one selected from the group consisting of toluene and xylene. A process for producing a monoalkyl fumarate, which is carried out in a kind of aromatic hydrocarbon medium. 2. An alkyl group in a monoalkyl maleate and a monoalkyl fumarate is:
The method according to claim 1, wherein the alkyl group has 14 to 18 carbon atoms. 3. The process according to claim 1, wherein the carboxylic acid chloride is an aliphatic or aromatic monocarboxylic acid or dicarboxylic acid chloride. 4. The following step (1) Esterification step of reacting maleic anhydride with an aliphatic monoalcohol in a substantially equimolar ratio to obtain a monoalkyl maleate ester. (2) Obtained monoalkyl maleate ester. Isomerization in the presence of a carboxylic acid chloride in at least one aromatic hydrocarbon medium selected from the group consisting of toluene and xylene to obtain a monoalkyl fumarate; and (3) Producing a sodium salt of a monoalkyl fumarate by neutralizing the monoalkyl fumarate in an aqueous medium containing sodium hydroxide to obtain a sodium salt of the monoalkyl fumarate. Law.