JP2002179612A - Method for producing 2,3-dibromosuccinic acid compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing a 2,3-dibromosuccinic acid compound in high yield under mild conditions. SOLUTION: This method is characterized by comprising brominating a 2-butene-1,4-dicarboxylic acid of formula (I) (wherein, R1 and R2 are each H or an optionally substituted alkyl, aryl or aralkyl) with bromine in the presence of an alkali metal halide or alkaline earth metal halide to obtain the corresponding 2,3-dibromosuccinic acid compound of formula (II) (wherein, R1 and R2 are each the same as defined above).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2,3-dibromosuccinic acids. 2, obtained by the present invention
3-Dibromosuccinic acids are useful, for example, as a raw material for synthesizing 3-hydroxy-2-thiophenecarboxylic acid derivatives, which are intermediates for agricultural chemicals and pharmaceuticals (JP-A-5-7834).
No. 8). Further, by reacting 2,3-dibromosuccinic acid with potassium hydroxide in methanol,
It is known that acetylene dicarboxylic acid is easily derived by elimination of molecular hydrogen bromide and subsequent acid treatment [Organic Synthesis (Organic Synthesis)].
Syntheses), Vol. 2, page 10], acetylenedicarboxylic acid is, for example, an aqueous bactericide 5
It is known to form a 1: 2 inclusion compound with -chloro-2-methyl-4-isothiazolin-3-one (Cl-MIT), suppress skin irritation, and improve thermal stability ( See JP-A-7-330520). Also, it is known that acetylenedicarboxylic acid is easily dimethylesterified in methanol in the presence of an acid catalyst to be derived into dimethyl acetylenedicarboxylate [Journal of American Chemical Society].
75, p. 384 (19).
53)], dimethyl acetylenedicarboxylate is
It is useful as a raw material for synthesizing indole-2-carboxylate derivatives which are agricultural and horticultural fungicides (Japanese Patent Laid-Open No. 10-1).
No. 7548).

[0002]

2. Description of the Related Art Conventionally, as a method for producing 2,3-dibromosuccinic acids, a method of brominating fumaric acid with bromine [Organic Synthesis] is known.
These volumes, vol. 2, p. 177], a method of brominating fumaric acid with an alkali metal bromide or an alkaline earth metal bromide and hypochlorite (Japanese Patent Application Laid-Open No. Sho 49)
A method of brominating diethyl maleate with bromine in the presence of isoquinoline and hydrobromic acid (see JP-A-56-90018);
A method of brominating diethyl maleate with bromine in the presence of hydrobromic acid (see JP-A-56-90017).
Etc. are known.

[0003]

In the above-mentioned method, the reaction is carried out under reflux of water, and when the reaction time is longer than 1 hour, the yield is remarkably reduced accompanied by a side reaction at an accelerated rate. The above method is not satisfactory with a yield of 83 to 86%. The methods (1) and (2) are uneconomical because they require an excess of 3 to 4 times the amount of hydrobromic acid. None of these methods can be said to be industrially advantageous methods for producing 2,3-dibromosuccinic acids.

It is an object of the present invention to provide a method for producing 2,3-dibromosuccinic acids under mild conditions with good yield and industrially advantageous.

[0005]

According to the present invention, the above objects have been achieved by the general formula (I)

[0006]

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(Wherein R ¹ and R ² represent a hydrogen atom or an optionally substituted alkyl group, aryl group or aralkyl group).
A general formula (II) characterized in that a dicarboxylic acid (hereinafter sometimes abbreviated as dicarboxylic acid (I)) is brominated with bromine in the presence of an alkali metal halide or an alkaline earth metal halide. II)

[0008]

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(Wherein R ¹ and R ² are as defined above) [hereinafter sometimes abbreviated as dibromosuccinic acid (II)]. This is achieved by providing a manufacturing method.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, the alkyl group represented by R ¹ and R ² is, for example, a methyl group, an ethyl group, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group and the like. These alkyl groups may have a substituent, and examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group, a propoxy group,
And alkoxyl groups such as butoxy groups.

The aryl groups represented by R ¹ and R ² include:
Examples include a phenyl group and a naphthyl group, and examples of the aralkyl group include a benzyl group, a phenethyl group, and a naphthylethyl group. These aryl group and aralkyl group may have a substituent. Examples of such a substituent include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group, an n-propyl group and an isopropyl group. Groups, alkyl groups such as n-butyl group, isobutyl group and tert-butyl group; alkoxyl groups such as methoxy group, ethoxy group, propoxy group and butoxy group; and aryl groups such as phenyl group and paramethoxyphenyl group. .

The reaction in the present invention is carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, water;
Aliphatic carboxylic acids such as acetic acid, propionic acid and butanoic acid; alcohols such as methanol, ethanol, isopropanol and butanol; aliphatic hydrocarbons such as pentane, hexane, cyclohexane, heptane and octane; benzene, toluene, xylene and mesitylene Aromatic hydrocarbons such as benzene, cumene; ethers such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane; halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and trichloroethane. Hydrogens; chlorobenzene,
Halogenated aromatic hydrocarbons such as bromobenzene and o-dichlorobenzene; or a mixed solvent thereof is used. It is preferable to use water as a solvent because the solubility of the alkali metal halide and the alkaline earth metal halide is high. The amount of the solvent to be used is preferably in the range of 1 to 50 times by weight, more preferably 2 to 10 times by weight, based on the dicarboxylic acid (I).

The amount of bromine used is preferably in the range of 1.0 to 1.1 mole times the dicarboxylic acid (I). When bromine is used in excess with respect to dicarboxylic acid (I), purification operations such as treatment of an excessive amount of bromine become complicated, and when bromine is used in less than 1.0 mole times with respect to dicarboxylic acid (I). , The yield based on dicarboxylic acid (II) is reduced, and any case is not preferred.

The alkali metal halides include, for example, alkali metal fluorides such as lithium fluoride, sodium fluoride and potassium fluoride; lithium chloride, sodium chloride,
An alkali metal chloride such as potassium chloride; an alkali metal bromide such as lithium bromide, sodium bromide, and potassium bromide; and an alkali metal iodide such as lithium iodide, sodium iodide, and potassium iodide are used. Examples of the alkaline earth metal halide include alkaline earth metal fluorides such as magnesium fluoride and calcium fluoride;
Alkaline earth metal chlorides such as magnesium chloride and calcium chloride; alkaline earth metal bromides such as magnesium bromide and calcium bromide; alkaline earth metal iodides such as magnesium iodide and calcium iodide are used. The alkali metal halide and the alkaline earth metal halide can be used in combination. In the present invention, it is particularly preferable to use an alkali metal bromide. The amount of the alkali metal halide and / or the alkaline earth metal halide used is based on the amount of the dicarboxylic acid (I).
The range is preferably from 0.1 to 5 times, more preferably from 0.5 to 2 times.

The order of addition of the reactants is not particularly limited,
A method in which the dicarboxylic acid (I) is dissolved or suspended in a solvent as needed, and a mixed solution of bromine and an alkali metal halide or an alkaline earth metal halide is added to the solution, or the dicarboxylic acid (I) and It is preferable to dissolve or suspend an alkali metal halide or an alkaline earth metal halide in a solvent as required, and to add bromine to the solution.

[0016] The reaction temperature is preferably in the range of 0 to 100 ° C, more preferably in the range of 20 ° C to 60 ° C.

The dibromosuccinic acid (II) thus obtained can be isolated and purified by a method usually used for isolating and purifying organic compounds. For example, by cooling the reaction mixture as it is, the target substance is recrystallized, and the precipitated crystals are separated from the mother liquor by filtration. On the other hand, an alkali metal halide or an alkaline earth metal halide is dissolved in the mother liquor, and can be reused without performing operations such as isolation and purification.

[0018]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Under a nitrogen atmosphere, 40.0 g (345 mmol) of fumaric acid, 35.5 g (345 mmol) of sodium bromide and water were placed in a 300 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel. 200 ml was charged and heated to 50 ° C. 55.2 g of bromine (3
45 mmol) was added dropwise over 1 hour while maintaining the internal temperature at 55 ° C. or lower, and the mixture was further stirred at the same temperature for 1 hour. Thereafter, the mixture was cooled to 5 ° C. while stirring, and the precipitated crystals were filtered and separated from the mother liquor. The obtained crystals are dried under reduced pressure,
88.8 g (322 mmol) of 2,3-dibromosuccinic acid having the following physical properties were obtained as white crystals (purity> 99).
%, Yield: 93.3%).

Melting point: 256-257 ° C. ¹ H-NMR spectrum (270 MHz, DMSO-d
6, ppm) δ: 4.51 (s, 2H)

Example 2 Under a nitrogen atmosphere, 11.6 g (100 mmol) of fumaric acid and potassium bromide 1 were placed in a 100 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel.
Add 1.9 g (100 mmol) and 50 ml of water,
Heated to 50 ° C. 16.0 g of bromine (100
mmol) was added dropwise over 1 hour while maintaining the internal temperature at 55 ° C. or lower, and the mixture was further stirred at the same temperature for 2 hours. afterwards,
Cool to 5 ° C with stirring, filter the precipitated crystals,
Separated from mother liquor. The obtained crystals were dried under reduced pressure to obtain 25.0 g (90.6 m) of white crystals of 2,3-dibromosuccinic acid.
mol) (purity> 99%, yield: 90.6%).

Example 3 Under a nitrogen atmosphere, 5.00 g (43.1 mmol) of fumaric acid and 3.75 g (43.10 g) of lithium bromide were placed in a 100-ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel. 1 mmol) and 40 ml of water and heated to 50 ° C. 6.90 g of bromine (4.
3.1 mmol), while maintaining the internal temperature at 55 ° C. or lower.
The mixture was added dropwise over 5 minutes, and further stirred at the same temperature for 15 hours.
Thereafter, the mixture was cooled to 5 ° C. with stirring, and the precipitated crystals were filtered and separated from the mother liquor. The obtained crystals were dried under reduced pressure, and 8.82 g of white crystals of 2,3-dibromosuccinic acid (3.
2.0 mmol) (purity> 99%, yield: 74.
2%).

Example 4 Under a nitrogen atmosphere, 11.6 g (100 mmol) of fumaric acid, 9.5 g (100 mmol) of sodium chloride and 50 ml of water were placed in a 100 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel. It was placed,
Heated to 50 ° C. 16.0 g of bromine (100
mmol) was added dropwise over 1 hour while maintaining the internal temperature at 55 ° C. or lower, and the mixture was further stirred at the same temperature for 15 hours. Thereafter, the mixture was cooled to 5 ° C. while stirring, and the precipitated crystals were filtered and separated from the mother liquor. The obtained crystals are dried under reduced pressure,
21.0 g of 2,3-dibromosuccinic acid as white crystals (76.
0 mmol) (purity> 99%, yield: 76.0).
%).

Example 5 Under a nitrogen atmosphere, 11.6 g (100 mmol) of fumaric acid, 10.3 g (100 mmol) of sodium bromide and water were placed in a 100 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel. 50 ml, and at 25 ° C., 16.0 g (100 mmol) of bromine,
The solution was added dropwise over 1 hour while maintaining the internal temperature at 30 ° C or lower, and further stirred at 25 ° C for 30 hours. Thereafter, the mixture was cooled to 5 ° C. while stirring, and the precipitated crystals were filtered and separated from the mother liquor. The obtained crystals were dried under reduced pressure to obtain white crystals of 2,3.
19.9 g (72.1 mmol) of dibromosuccinic acid was obtained (purity> 99%, yield: 72.1%).

Example 6 Under a nitrogen atmosphere, 11.6 g (100 mmol) of fumaric acid, 18.4 g (100 mmol) of magnesium bromide and water were placed in a 100 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel. 50 ml, and at 50 ° C., 16.0 g (100 mmol) of bromine,
The solution was added dropwise over 1 hour while maintaining the internal temperature at 55 ° C. or lower, and further stirred at the same temperature for 15 hours. Thereafter, the mixture was cooled to 5 ° C. while stirring, and the precipitated crystals were filtered and separated from the mother liquor. The obtained crystals were dried under reduced pressure to obtain white crystals of 2,3.
19.3 g (70.0 mmol) of -dibromosuccinic acid was obtained (purity> 99%, yield: 70.0%).

Example 7 Under a nitrogen atmosphere, 11.6 g (100 mmol) of maleic acid, 10.3 g (100 mmol) of sodium bromide and water were placed in a 100 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel. 30 ml, and 16.0 g (100 mmol) of bromine at 50 ° C.
The solution was added dropwise over 1 hour while maintaining the internal temperature at 55 ° C. or lower, and further stirred at the same temperature for 15 hours. Thereafter, the mixture was cooled to 5 ° C. while stirring, and the precipitated crystals were filtered and separated from the mother liquor. The obtained crystals were dried under reduced pressure to obtain white crystals of 2,3.
16.9 g (61.3 mmol) of dibromosuccinic acid were obtained (purity> 99%, yield: 61.3%).

Example 8 Under a nitrogen atmosphere, 14.4 g (100 mmol) of dimethyl fumarate, 10.3 g (100 mmol) of sodium bromide and 100 ml of a three-necked flask equipped with a thermometer, a magnetic stirrer, and a dropping funnel were placed. 50m water
and heated to 50 ° C. 16.0 bromine was added to this solution.
g (100 mmol) was added dropwise over 1 hour while maintaining the internal temperature at 55 ° C. or lower, and the mixture was further stirred at the same temperature for 21 hours. Thereafter, the mixture was cooled to 5 ° C. while stirring, and the precipitated crystals were filtered and separated from the mother liquor. The obtained crystals were dried under reduced pressure to obtain 29.7 g (97.7 mmol) of dimethyl 2,3-dibromosuccinate having the following physical properties as white crystals.
(Purity> 99%, yield: 97.7%).

Melting point: 63-65 ° C. ¹ H-NMR spectrum (270 MHz, CDCl ₃ , T
MS, ppm) [delta]: 3.83 (s, 6H), 4.71
(S, 2H)

[0029]

Industrial Applicability According to the present invention, 2,3-dibromosuccinic acids can be industrially advantageously produced under mild conditions with good yield.

Claims (1)

[Claims] 1. A compound of the general formula (I) (Wherein R ¹ and R ² represent a hydrogen atom or an optionally substituted alkyl group, aryl group or aralkyl group) represented by the formula: General formula (II) characterized in that bromination is performed using bromine in the presence of an alkaline earth metal halide. (In the formula, R ¹ and R ² are as defined above.) A method for producing 2,3-dibromosuccinic acids represented by the formula: