JP2002069062A - Method for producing 3-hydroxyisoxazole - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an industrially suitable 3- hydroxyisoxazole, obtaining 3-hydroxyisoxazole from a 3-alkoxyacrylic acid ester in a high yield by a simple method. SOLUTION: This method for producing 3-hydroxyisoxazole is characterized by comprising (A) a first process for reacting a 3-alkoxy acrylic acid ester with hydroxylamine in a lower alcohol solvent in the presence of an alkali metal alkoxide and then (B) a second process for adding an aromatic solvent to the reaction mixture, carrying out a dealcoholization reaction and neutralizing the resultant substance with an acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing 3-hydroxyisoxazole useful as a modifier of a drug substance or an agricultural chemical.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 3-hydroxyisoxazole from a 3-alkoxyacrylate, 3-alkoxyacrylate is reacted with hydroxylamine in the presence of an alkali to produce a 5-alkoxy-3-oxazole.
A method for producing isoxazolidinone (Japanese Patent Application Laid-Open No. 7-154154), and then obtaining 3-hydroxyisoxazole via acylation, dealcoholation and hydrolysis (Japanese Patent Application Laid-Open No.
7-145155), but the number of steps is large,
It was disadvantageous as an industrial production method. Also, in a water, a lower alcohol or a mixed solvent thereof, a 3-alkoxyacrylate is reacted with hydroxylamine in the presence of an alkali metal hydroxide, and then treated with an acid to give a 5-alkoxy-3-isopropyl. Oxazolidinone is formed, followed by water,
A method is disclosed in which a 5-alkoxy-3-isoxazolidinone is reacted with an alkali metal hydroxide in a lower alcohol or a mixed solvent thereof, and then treated with an acid to obtain 3-hydroxyisoxazole (Japanese Patent Application Laid-Open No. H11-157556). JP-A-7-330744). However, in this method, the amount of the alkali metal hydroxide used is large, and the reaction must be performed at a low temperature for a long time to suppress a side reaction. There is a problem that the isolation operation is complicated because the compound is very easily dissolved in alcohol.

[0003]

An object of the present invention is to solve the above-mentioned problems and to obtain 3-hydroxyisoxazole from a 3-alkoxyacrylic ester by a simple method in a high yield. The present invention provides a method for producing 3-hydroxyisoxazole which is suitable for:

[0004]

The object of the present invention is to provide (A)
Formula (1) in a lower alcohol solvent

[0005]

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(Wherein R ¹ and R ² represent lower alkyl groups which may be the same or different from each other)
A first step of reacting in the presence of an alkali metal alkoxide, (B) a second step of adding an aromatic solvent to cause a dealcoholization reaction, and then neutralizing with an acid. Equation (2)

[0007]

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The problem is solved by a method for producing 3-hydroxyisoxazole represented by the formula:

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a first method for reacting (A) a 3-alkoxy acrylate represented by the general formula (1) with hydroxylamine in a lower alcohol solvent in the presence of an alkali metal alkoxide. 3-hydroxyisoxazole is obtained as a reaction product by two steps comprising a step (B), a second step of adding an aromatic solvent to carry out a dealcoholization reaction and then neutralizing with an acid. Things.

Subsequently, the above two steps will be sequentially described. (A) First Step The first step of the present invention is to react a hydroxylamine with a 3-alkoxyacrylate represented by the general formula (1) in a lower alcohol solvent in the presence of an alkali metal alkoxide, This is a step of obtaining an alkali metal salt of 5-alkoxy-3-isoxazolidinone as a main product.

The 3-alkoxyacrylate used in the first step of the present invention is represented by the aforementioned general formula (1). In the general formula (1), R ¹ and R ² are the same or different. May be a lower alkyl group, particularly preferably a lower alkyl group having 1 to 4 carbon atoms, a methyl group,
An ethyl group, a propyl group and a butyl group are preferred, and a methyl group and an ethyl group are particularly preferred. These groups include various isomers.

The lower alcohol solvent used in the first step of the present invention is, for example, methanol, ethanol, n-
Lower alcohols having 1 to 4 carbon atoms such as propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, and s-butyl alcohol are preferably used.

The amount of the lower alcohol solvent used is preferably 1.3 to 1.3 alkoxyalkoxylate.
7.87.8 times by volume, more preferably 2.6 to 5.2 times by volume.
These lower alcohol solvents may be used alone or in combination of two or more.

The hydroxylamine used in the first step of the present invention can be used not only as free hydroxylamine (including hydrates) but also as an acid salt such as hydrochloride, sulfate and the like. Hydrochloride is preferably used.

The amount of the hydroxylamine to be used is preferably 1.0 to 2.0 times, more preferably 1.0 to 1.5 times, the molar amount of hydroxylamine relative to the 3-alkoxyacrylate.

The alkali metal alkoxide used in the first step of the present invention is, for example, lithium methoxide,
Sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium t-butoxide and the like can be mentioned, and preferably, sodium methoxide and sodium ethoxide are used.

The amount of the alkali metal alkoxide to be used is preferably 1.0 to 4.0 times mol, more preferably 1.0 to 3.5 times mol of 3-alkoxyacrylate. These alkali metal alkoxides are used as a solid powder or an alcohol solution, and may be used alone or as a mixture of two or more.

In the first step of the present invention, for example, a 3-alkoxyacrylic acid ester is added to a mixture of an alkali metal alkoxide, hydroxylamine and a lower alcohol solvent, preferably at 0 to 80 ° C., more preferably at 5 to 80 ° C. ~ 50
C., particularly preferably at 10 to 30.degree. C., and the like. The reaction pressure at that time is not particularly limited.

In the first step of the present invention, the main product is
A lower alcohol solution containing an alkali metal salt of 5-alkoxy-3-isoxazolidinone is obtained. In the present invention, the following step is usually carried out as it is or after appropriately concentrating the lower alcohol solution. However, in some cases, the next step may be performed after the generated alkali metal salt of 5-alkoxy-3-isoxazolidinone is once isolated.

(B) Second Step In the second step of the present invention, a fragrance is added to a lower alcohol solution containing an alkali metal salt of 5-alkoxy-3-isoxazolidinone as a main product obtained in the first step. This is a step in which a group-based solvent is added to cause a dealcoholization reaction, and then neutralized with an acid to obtain 3-hydroxyisoxazole as a final product.

The aromatic solvent used in the second step of the present invention includes, for example, benzene, toluene, xylene, mesitylene, anisole, chlorobenzene, dichlorobenzene, etc., preferably toluene, xylene, more preferably Toluene is used.

The amount of the aromatic solvent to be used is preferably 8 to 12 times, more preferably 8 to 10 times, the volume of the 3-alkoxyacrylate used in the first step. These aromatic solvents may be used alone or in combination of two or more.

As the acid used in the present invention, for example, hydrochloric acid, methanol solution of hydrochloric acid, hydrogen chloride gas, sulfuric acid, nitric acid,
Acetic acid, phosphoric acid and the like can be mentioned, but hydrochloric acid, a hydrochloric acid methanol solution, and sulfuric acid are preferably used.

The amount of the acid is not particularly limited as long as it is an amount sufficient to neutralize the alkali metal alkoxide used in the first step, but is preferably based on the alkali metal alkoxide used in the first step. Is 0.5 to 3.0 times mol, more preferably 0.5 to 1.5 times mol.

In the second step of the present invention, for example, an aromatic solvent is added to a lower alcohol solution containing an alkali metal salt of 5-alkoxy-3-isoxazolidinone as a main product obtained in the first step. Mix, preferably 25-12
0 ° C, more preferably 60 to 120 ° C, particularly preferably 65 to 12 ° C.
After reacting at 0 ° C., neutralize with acid, etc.
The reaction is carried out under normal pressure or reduced pressure, and it is particularly preferable to carry out the reaction while removing alcohol (alcohol used in the first step and alcohol produced by the reaction).

The final product, 3-hydroxyisoxazole, is neutralized, for example, after completion of the reaction, and after removing by-product alkali metal salts by washing or filtration,
It is separated and purified by a general method such as crystallization, recrystallization, sublimation, distillation, and column chromatography.

[0027]

EXAMPLES Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples.

EXAMPLE 1 A 300 ml glass flask reactor equipped with a stirrer, thermometer and dropping funnel was charged with hydroxylamine hydrochloride.
16.7 g (0.24 mol) and 90 ml of methanol were added, and 96.5 g (0.50 mol) of a 28% by weight sodium methoxide methanol solution was added dropwise with stirring at 20 to 25 ° C, and then 23.2 g of methyl 3-methoxyacrylate ( (0.20 mol) was slowly added dropwise, and reacted at the same temperature for 2 hours. Thereafter, the precipitate was filtered and the reaction solution was concentrated (80 ml of methanol was distilled off). Then, the above concentrated solution was added to a glass reactor having an internal volume of 500 ml equipped with a stirrer, a thermometer, a reflux condenser, and a Dean-Stark device, and further added with 200 ml of toluene to remove methanol while removing methanol. The reaction was performed at 8484 ° C. for 3 hours. Thereafter, the mixture was cooled to room temperature, and neutralized by adding 47.0 g (0.26 mol) of 20% by weight hydrochloric acid. The organic layer was separated from the reaction solution, and the aqueous layer was further treated with toluene 69
After extracting twice with ml, the extract was combined with the organic layer. Next, after concentrating under reduced pressure, hexane was added to precipitate crystals. After filtering the obtained crystals, the crystals were washed with hexane and dried, and 3-hydroxyisoxazole was reduced to 99.0%.
(Analytical value by high performance liquid chromatography) 10.8 g of a pale yellow crystal was obtained (isolation yield: 62.9%). The melting point of the obtained pale yellow crystal containing 3-hydroxyisoxazole was 96 to 98 ° C.

Example 2 A 300 ml glass flask reactor equipped with a stirrer, a thermometer and a dropping funnel was charged with hydroxylamine hydrochloride.
16.7 g (0.24 mol) and 90 ml of methanol were added, and 96.5 g (0.50 mol) of a 28% by weight sodium methoxide methanol solution was added dropwise with stirring at 20 to 25 ° C, and then 23.2 g of methyl 3-methoxyacrylate ( (0.20 mol) was slowly added dropwise, and reacted at the same temperature for 2 hours. Thereafter, the precipitate was filtered and the reaction solution was concentrated (140 ml of methanol was distilled off). Then
To a 300 ml glass reactor equipped with a stirrer, thermometer, reflux condenser and Dean-Stark device, add the above concentrated liquid, further add 250 ml of xylene, and remove methanol while removing 75-82. The reaction was carried out at 3 ° C. for 3 hours. Thereafter, the mixture was cooled to room temperature, and neutralized by adding 47.0 g (0.26 mol) of 20% by weight hydrochloric acid. The organic layer was separated from the reaction solution, and the aqueous layer was further treated with toluene 69
After extracting twice with ml, the extract was combined with the organic layer. Next, after concentrating under reduced pressure, hexane was added to precipitate crystals. The obtained crystals were filtered, washed with hexane and dried to give 3-hydroxyisoxazole at 99.0%.
(Analysis by high performance liquid chromatography) 9.8 g of pale yellow crystals were obtained (isolation yield: 57.0%).

Comparative Example 1 (Performed in accordance with JP-A-7-330744.) 200 ml of internal volume equipped with a stirrer, a thermometer and a dropping funnel
Was added to 11.6 g (0.10 mol) of methyl 3-methoxyacrylate and 50 ml of isobutyl alcohol. Next, while maintaining the reaction solution temperature at 30 ° C. or lower,
After slowly adding dropwise 10.0 g (0.12 mol) of a weight% aqueous solution of sodium hydroxide and 7.3 g (0.11 mol) of a 50 weight% aqueous solution of hydroxylamine, the mixture was reacted at 20 to 25 ° C. for 2 hours. Further, 41.7 g (0.50 mol) of a 48% by weight aqueous sodium hydroxide solution
Was slowly added dropwise while maintaining the temperature of the reaction solution at 30 ° C. or lower, and then reacted at 20 to 25 ° C. for 48 hours. Thereafter, concentrated hydrochloric acid was slowly added dropwise to adjust the reaction solution to pH 3. After separating the isobutyl alcohol layer and the aqueous layer, the aqueous layer was extracted with 20 ml of ethyl acetate, the isobutyl alcohol layer and the ethyl acetate layer were combined, concentrated to dryness under reduced pressure, washed with hexane and dried, 78.3 3-hydroxyisoxazole
% (Analytical value by high performance liquid chromatography), and 4.7 g of yellow crystals were obtained (43.3% of isolated yield). The melting point of the obtained yellow crystal containing 3-hydroxyisoxazole was 78 to 91 ° C.

[0031]

According to the present invention, a high yield can be obtained by a simple method.
An industrially suitable method for producing 3-hydroxyisoxazole, which is capable of obtaining 3-hydroxyisoxazole from a 3-alkoxyacrylate, can be provided.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C056 AA01 AB01 AC01 AD01 AE03 AF01 4H039 CA42 CG90

Claims (3)

[Claims] (A) In a lower alcohol solvent, a compound represented by the general formula (1): (Wherein R ¹ and R ² may be the same or different,
Shows a lower alkyl group. )), A hydroxylamine is reacted with a 3-alkoxyacrylate in the presence of an alkali metal alkoxide. (B) Then, after an aromatic solvent is added to carry out a dealcoholization reaction, A second step of neutralization, characterized by comprising: A method for producing 3-hydroxyisoxazole represented by the formula: 2. The method for producing 3-hydroxyisoxazole according to claim 1, wherein the second step is carried out at 65 to 120 ° C. 3. The method for producing 3-hydroxyisoxazole according to claim 1, wherein the reaction is carried out while removing the alcohol in the second step.