JPH07330744A - 5-alkoxy-3-isoxazolidinone, its production and use thereof - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as an intermediate for a medicine, an agrochemlcal, etc. CONSTITUTION:A compound of the formula (R is a lower alkoxyl) such as 5-methoxy-3-isoxazolidinone. The compound is obtained by reacting a 3-lower alkoxyacrylic acid lower alkyl ester with hydroxylamine in water, a lower alcohol or a mixed solvent of water and the lower alcohol in the presence of an alkali metal hydroxide at -20 to 50 deg.C and then treated with an acid (e.g. hydrochloric acid). Further, an alcohol is removed from the compound of the formula in water, a lower alcohol or a mixed solvent of water and the lower alcohol in the presence of an alkali metal hydroxide and the resultant substance is treated with an acid to readily give 3-hydroxyisoxazole useful as a synthetic intermediate for a medicine, an agrochemical, etc., in high yield.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 5-alkoxy-3-
The present invention relates to isoxazolidinone, a method for producing the same, and a method for producing 3-hydroxyisoxazole. For more details,
5-Alkoxy-3, an intermediate of 3-hydroxyisoxazole useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, etc.
-Isoxazolidinone, a process for producing the same, and a process for producing 3-hydroxyisoxazole using the same.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 3-hydroxyisoxazole, a method of reacting an alkyl propiolate with hydroxylamine in the presence of an alkali metal hydroxide (Japanese Patent Publication No. 42-25660), halogenated propione. Method of reacting acid alkyl ester or halogenated acrylic acid alkyl ester with hydroxylamine in the presence of an alkali (earth) metal hydroxide (Japanese Patent Publication No. 43-14704), 3-alkoxy acrylic acid alkyl ester of alkali Method of reacting with hydroxylamine in the presence (Japanese Patent Publication No. S50-3306)
No. 4) is known.

[0003]

However, the method of JP-B-42-25660, which uses a propiolic acid ester, is costly and difficult to obtain in large quantities from the raw material propiolic acid, and reacts with hydroxylamine. The yield due to is only about 60%. In addition, Japanese public examination 4
The method using a halogenated propionic acid ester or a halogenated acrylic acid alkyl ester described in JP-A-3-14704 is used in a large amount because both the halogenated propionic acid ester and the halogenated acrylic acid alkyl ester have mutagenicity. Doing so is unfavorable for safety and hygiene, and has a drawback that a large amount of alkali is required for the reaction with hydroxylamine. Furthermore, the method of Japanese Patent Publication No. 50-33064, which uses a relatively easy-to-use 3-alkoxy acrylate as an industrial raw material, also increases the production cost because the yield of 3-hydroxyisoxazole is as low as 37%. There are drawbacks such as inviting.

[0004]

[Means for Solving the Problems] In order to overcome the above-mentioned problems, the present inventors have earnestly studied a method for producing 3-hydroxyisoxazole using a 3-alkoxyacrylic acid ester which is relatively easily available. As a result, after reacting the 3-lower alkoxyacrylic acid lower alkyl ester with hydroxylamine in the presence of an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof,
When treated with an acid, it has the general formula (I)

[0005]

[Chemical 4]

[In the formula, R represents a lower alkoxyl group. ] It is found that a new compound 5-alkoxy-3-isooxazolidinone represented by the following formula is obtained, and this 5-alkoxy-3-isooxazolidinone is treated with an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof. It was found that 3-hydroxyisoxazole can be easily obtained in good yield by carrying out dealcoholization reaction in the presence of

In the 5-alkoxy-3-isoxazolidinone represented by the general formula, the alkoxyl group is a methoxyl group,
Ethoxyl group, propoxyl group, isopropoxyl group,
It is 5-alkoxy-3-isooxazolidinone which is a lower alkoxyl group such as butoxyl group and t-butoxyl group.

The 5-alkoxy-3-isooxazolidinone of the present invention is obtained by reacting a 3-alkoxyacrylic acid alkyl ester with hydroxylamine in the presence of an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof. Then, it can be produced by treating with an acid such as hydrochloric acid.

The lower alcohol used as the reaction solvent is methanol, ethanol, propanol, isopropanol, butanol, isobutanol or the like. The amount used is 1 to 3 of the alkoxy alkoxyalkyl ester.
10 times the amount. The alkali metal hydroxide is lithium hydroxide, sodium hydroxide, potassium hydroxide or the like, and the amount thereof is a molar equivalent amount or a small excess amount with respect to the 3-alkoxyacrylic acid alkyl ester.

The hydroxylamine reacted with the 3-alkoxyacrylic acid alkyl ester may be a hydrate,
It may also be an acid salt such as hydrochloride or sulfate. The amount used is a molar equivalent or a small excess amount with respect to the 3-alkoxyacrylic acid alkyl ester.

The reaction temperature varies depending on the kind of the alkali metal hydroxide, the solvent, etc., but it is -20 ° C to 50 ° C, preferably 0 ° C to 40 ° C. If the reaction temperature is lower than −20 ° C., the reaction does not proceed sufficiently, and if it is higher than 50 ° C., a side reaction is likely to occur and the yield of 5-alkoxy-3-isooxazolidinone to be formed is lowered.

The reaction time varies depending on the alkali metal hydroxide, the type of solvent, the reaction temperature, etc., but is usually 1 to 10 hours, preferably 2 to 5 hours.

After completion of the reaction, 5-alkoxy-3 formed
-5-alkoxy-3-isooxazolidinone can be obtained in good yield by adding an acid such as hydrochloric acid, hydrogen chloride or sulfuric acid to the reaction solution containing the alkali metal salt of isoxazolidinone to adjust the pH of the reaction system to 3 or less. .

The resulting 5-alkoxy-3-isoxazolidinone is subjected to dealcoholization reaction in the presence of an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof, to give an alkali metal of 3-hydroxyisoxazole. A salt is formed, which is treated with an acid to give highly pure 3-
Hydroxyisoxazole is obtained in good yield.

The type of lower alcohol and alkali metal hydroxide used in the dealcoholation reaction of 5-alkoxy-3-isooxazolidinone may be the same as described above.

The amount of lower alcohol used is 1 to 10 times the amount of 5-alkoxy-3-isooxazolidinone or its alkali metal salt. The amount of alkali metal hydroxide used is 1 to 10 times the molar equivalent of 5-alkoxy-3-isooxazolidinone, preferably 2 to 5 times the molar equivalent.

The reaction temperature varies depending on the type of 5-alkoxy-3-isooxazolidinone or its alkali metal salt, alkali metal hydroxide, solvent, etc., but it is usually 0 to 6
It is 0 ° C., preferably 20 to 40 ° C.

The reaction time varies depending on the alkali metal hydroxide, the type of solvent, the reaction temperature, etc., but is usually 10 to 72 hours, preferably about 20 to 50 hours. After completion of the reaction, when pH of the reaction system is adjusted to about 3 or less by adding an acid such as hydrochloric acid, hydrogen chloride, or sulfuric acid to the reaction solution containing the produced alkali metal salt of 3-hydroxyisoxazole, 3-hydroxyisoxazole is produced. Obtained in good yield.

3-hydroxyisoxazole is also
Isolation of an alkali metal salt of 5-alkoxy-3-isooxazolidinone formed by reacting an alkoxyacrylic acid alkyl ester with hydroxylamine in the presence of an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof. Alternatively, a high yield can be obtained by directly carrying out a dealcoholization reaction in the presence of an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof without any treatment. In this case, in order to accelerate the reaction rate of dealcoholization reaction, it is preferable to increase the concentration of the alkali metal hydroxide.

The 3-hydroxyisoxazole thus obtained can be used as it is as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like, but if it is purified by recrystallization or the like as required, 3-hydroxyisoxazole of higher purity can be obtained. Can be obtained.

The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.

[0022]

【Example】

Example 1 240 ml of methanol was added to a mixture of 300 ml of methanol and 22.94 g of hydroxylamine hydrochloride.
Add 37.03 g of potassium hydroxide dissolved in
Methyl 3-methoxyacrylate 3 with stirring at 25 ° C
4.84 g was added. After stirring at the same temperature for 3 hours, the reaction solution was adjusted to pH 3 by adding concentrated hydrochloric acid, the solvent was distilled off, the residue was extracted with dichloromethane, dried over magnesium sulfate, and the solvent was distilled off. Was recrystallized from diisopropyl ether to obtain 5-methoxy-3-isooxazolidinone (18.34 g). Yield 52.2%, melting point 90.5
° C Elemental analysis value: C ₄ H ₇ NO ₃ calculated value: C, 41.03; H, 6.03; N, 11.9
6% analytical value: C, 41.06; H, 5.93; N, 11.8
8% Nuclear magnetic resonance spectrum (60MHz, TMS, CDCl ₃ ) δ (ppm):
2.66 (2H, m, 4-position _{- CH 3); 3.47 (3H} , s, -O -CH 3); 5.23
(1H, m, 5th- CH ); 9.43 (1H, s, -N- H ) Infrared absorption spectrum (cm ^-1 ): 3400 (>NH); 3150
(>NH); 1690 (> C = O).

[Example 2] 90 ml of isobutanol and 4
A mixture of 8.25 g of 8% aqueous sodium hydroxide solution was added to 15
Cooled to below 50 ° C., 50% hydroxylamine aqueous solution 6.
24 g was added, followed by cooling to 5 ° C or lower, and 12.98 g of ethyl 3-ethoxyacrylate was added, and gradually increased to 35 ° C.
The temperature was raised to and stirred for 3.5 hours. Then, the same procedure as in Example 1 was repeated to obtain 7.70 g of 5-ethoxy-3-isooxazolidinone. Yield 65.2
%, Melting point 100.5 ° C. Elemental analysis: C ₅ H ₉ NO ₃ Calculated: C, 45.80; H, 6.92 ; N, 10.6
8% analytical value: C, 41.92; H, 6.95; N, 10.5
7% Nuclear magnetic resonance spectrum (60MHz, TMS, CDCl ₃ ) δ (ppm): 1.
23 (3H, t, -O- CH 2 -CH 3); 2.77 (2H, m, 4 -position - CH _{3); 3.}
73 (2H, m, -O- CH ₂ -CH ₃ ); 5.47 (1H, m, 5th- CH ); 9.0
0 (1H, s, -N- H ) Infrared absorption spectrum (cm ^-1 ): 3325 (>NH); 3125
(>NH); 1680 (> C = O).

Example 3 100 ml of isobutanol and 23.42 g of 5-methoxy-3-isooxazolidinone
66.67 g of 48% sodium hydroxide aqueous solution was added to the mixture of 30 ° C. or lower, and the mixture was stirred at 30 ° C. or lower for 48 hours.
This reaction solution was adjusted to pH 3 or less with concentrated hydrochloric acid to separate the isobutanol layer and the aqueous layer, the aqueous layer was extracted with ethyl acetate, the solvent was distilled off together with the isobutanol layer, and 3-hydroxyiso 12.90 g of oxazole was obtained. Yield 7
5.8%, melting point 99.0 ° C.

Example 4 A mixture of 300 ml of isobutanol and 69.67 g of methyl 3-methoxyacrylate was added at a temperature of 30 ° C. or lower to a 48% aqueous sodium hydroxide solution 60.00.
g, and 50% hydroxylamine aqueous solution 4
3.60 g was added dropwise and stirred for 2 hours. Then, 250.00 g of a 48% aqueous sodium hydroxide solution was added, and the mixture was stirred at 30 ° C or lower for 48 hours. The reaction solution was adjusted to pH 3 with concentrated hydrochloric acid to separate the isobutanol layer and the aqueous layer, the aqueous layer was extracted with ethyl acetate, and the solvent was distilled off together with the isobutanol layer to give 3-hydroxyisoxazole. 36.7
2 g was obtained. Yield 72.0%. . [Example 5] 127.73 g of methyl 3-methoxyacrylate cooled to 0 ° C
95.83 g of 48% sodium hydroxide aqueous solution was added to
Then, at the same temperature, a 50% hydroxylamine aqueous solution 95.
83g was dripped and it stirred at 20-25 degreeC for 48 hours. After completion of the reaction, concentrated hydrochloric acid was added to adjust the reaction solution to pH 3, the mixture was extracted with ethyl acetate, and the solvent was distilled off to obtain 63.16 g of 3-hydroxyisoxazole. Yield 67.5%.

[0026]

INDUSTRIAL APPLICABILITY According to the present invention, 3-hydroxyisoxazole, which is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, etc., can be obtained easily and in a high yield, and therefore has very high industrial utility.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] June 20, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0022

[Correction method] Change

[Correction content]

[0022]

EXAMPLES Example 1 240 ml of methanol in a mixture of 300 ml of methanol and 22.94 g of hydroxylamine hydrochloride.
Add 37.03 g of potassium hydroxide dissolved in
Methyl 3-methoxyacrylate 3 with stirring at 25 ° C
4.84 g was added. The mixture was stirred at the same temperature for 3 hours, concentrated hydrochloric acid was added to adjust the reaction solution to pH 3, the solvent was evaporated, the residue was extracted with dichloromethane, dried over magnesium sulfate, and the solvent was evaporated to remove the residue. Was recrystallized from diisopropyl ether to obtain 5-methoxy-3-isooxazolidinone (18.34 g). Yield 52.2%, melting point 90.5
° C Elemental analysis value: C ₄ H ₇ NO ₃ calculated value: C, 41.03; H, 6.03; N, 11.9
6% analytical value: C, 41.06; H, 5.93; N, 11.8
8% Nuclear magnetic resonance spectrum (60MHz, TMS, CDCl ₃ ) δ (ppm):
2.66 (2H, m, 4-position _{- CH 2); 3.47 (3H} , s, -O -CH 3); 5.23
(1H, m, 5th- CH ); 9.43 (1H, s, -N- H ) Infrared absorption spectrum (cm ^-1 ): 3400 (>NH); 3150
(>NH); 1690 (> C = O).

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0023

[Correction method] Change

[Correction content]

[Example 2] 90 ml of isobutanol and 4
A mixture of 8.25 g of 8% aqueous sodium hydroxide solution was added to 15
Cooled to below 50 ° C., 50% hydroxylamine aqueous solution 6.
24 g was added, followed by cooling to 5 ° C or lower, and 12.98 g of ethyl 3-ethoxyacrylate was added, and gradually increased to 35 ° C.
The temperature was raised to and stirred for 3.5 hours. Then, the same procedure as in Example 1 was repeated to obtain 7.70 g of 5-ethoxy-3-isooxazolidinone. Yield 65.2
%, Melting point 100.5 ° C. Elemental analysis: C ₅ H ₉ NO ₃ Calculated: C, 45.80; H, 6.92 ; N, 10.6
8% analytical value: C, 41.92; H, 6.95; N, 10.5
7% Nuclear magnetic resonance spectrum (60MHz, TMS, CDCl ₃ ) δ (ppm): 1.
23 (3H, t, -O- CH 2 -CH 3); 2.77 (2H, m, 4 -position - CH _2); 3.
73 (2H, m, -O- CH ₂ -CH ₃ ); 5.47 (1H, m, 5th- CH ); 9.0
0 (1H, s, -N- H ) Infrared absorption spectrum (cm ^-1 ): 3325 (>NH); 3125
(>NH); 1680 (> C = O).

Claims (3)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R represents a lower alkoxyl group. ] 5-Alkoxy-3-isooxazolidinone represented by 2. A lower alkyl ester of 3-lower alkoxyacrylic acid is reacted with hydroxylamine in the presence of an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof, and then treated with an acid. General formula (I) [In the formula, R represents a lower alkoxyl group. ] The manufacturing method of 5-alkoxy-3-isooxazolidinone represented by these. 3. A compound represented by the general formula (I): [In the formula, R represents a lower alkoxyl group. ] The 5-alkoxy-3-isooxazolidinone represented by the following is dealcoholized in the presence of an alkali metal hydroxide in water, a lower alcohol or a mixed solvent thereof, and then treated with an acid. -Method for producing hydroxyisoxazole.