JPH07145154A - 5-alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole and its production - Google Patents

Abstract

PURPOSE:To obtain a new alkoxyteterahydroxoisoxazole, useful e.g. as a modifier for base materials of medicines or agrochemicals. CONSTITUTION:A compound of the formula (R<1> is a 1 to 4C lower alkyl), e.g. 5-methoxy-2,3,4,5-tetrahydro-3-oxoisoxazole. In addition, the compound of the formula can be synthesized by reacting a 3-alkoxyacrylic acid ester such as methyl 3-methoxyacrylate with hydroxylamine in the presence of an alkali such as sodium hydroxide.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 5-alkoxy- which is a novel raw material for inexpensively producing 3-hydroxyisoxazole which is useful as a modifier for the active ingredient of medicines and agricultural chemicals.
It relates to 2,3,4,5-tetrahydro-3-oxoisoxazole.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 3-hydroxyisoxazole, a method of reacting propynic acid ester with hydroxylamine (Chem. Pharm. Bu.
ll. , 14 , 1277 (1966)), a method of reacting 2,3-dibromopropionic acid ester with hydroxylamine (CA74,125521e), and a method of reacting 3-chloroacrylic acid ester with hydroxylamine (FR1534341). However, none of them use expensive raw materials that are difficult to obtain, so they were not economical manufacturing methods. Further, a method of oxidatively cyclizing acrylic hydroxamic acid in the presence of a palladium chloride catalyst (Che
m. Ind. (9) 318 (1979)) is known, but the yield is low and it is not an industrially preferable method.

Further, 3-alkoxyacrylic acid ester and hydroxylamine are reacted in the presence of about 2 equivalents of alkali with respect to hydroxylamine hydrochloride to form a hydroxamic acid derivative as a putative intermediate, followed by acid treatment. A method for obtaining 3-hydroxyisoxazole by cyclization (Japanese Patent Publication No. 50-33064) has also been reported. However, even in this method, there is a problem that the yield is low (36.5%), and the novel 3-
A method for producing hydroxyisoxazole has been desired.

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel raw material for producing 3-hydroxyisoxazole, which is useful as a modifier for drug substances such as pharmaceuticals and agricultural chemicals, in high yield and high purity. It is to be.

[0005]

SUMMARY OF THE INVENTION The present inventors have known 3
As a result of earnest studies to solve the problems of the method for producing hydroxyisoxazole, surprisingly, 3
By reacting an alkoxy acrylate ester with hydroxylamine in the presence of an alkali
-A new compound, 5-alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole, was obtained as the product, instead of the hydroxamic acid derivative that was considered as an intermediate in the production of hydroxyisoxazole. The present invention has been completed by finding out that it is possible. That is, the present invention has the general formula (I)

[0006]

[Chemical 2] (In the formula, R ¹ represents a lower alkyl group having 1 to 4 carbon atoms)

5-alkoxy-2,3,4, represented by
It relates to 5-tetrahydro-3-oxoisoxazole and a method for producing the same.

The method of the present invention will be described in detail below. 5-alkoxy-2,3,4, which is a novel compound of the present invention
5-Tetrahydro-3-oxoisoxazole can be obtained by reacting a 3-alkoxyacrylic acid ester with hydroxylamine in the presence of an alkali, as shown in the reaction formula (II).

[0009]

[Chemical 3] (In the formula, R ¹ and R ² represent a lower alkyl group having 1 to 4 carbon atoms)

The 3-alkoxyacrylic acid ester used in the reaction represented by the reaction formula (II) includes R ¹ and R
² is a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, etc., and R ¹ and R ² are respectively It may be the same or different. Specifically, for example, methyl 3-methoxyacrylate, ethyl 3-ethoxyacrylate, etc. are preferably used. The amount of 3-alkoxyacrylic acid ester used is usually 0.4 to 3.0 mol/l.

The alkali used in the reaction represented by the reaction formula (II) includes alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide. Alcohols of alkali metals such as hydroxide, sodium methylate and sodium ethylate, and alcoholates of alkaline earth metals such as magnesium methylate and magnesium ethylate are used. The amount of alkali used is usually 0.2 to 2.5 equivalents relative to 3-alkoxyacrylic acid ester. However, when an acid salt such as its hydrochloride or sulfate is used as the hydroxylamine in the reaction, an alkali is added in an amount sufficient to neutralize the acid salt.

The hydroxylamine used in the reaction represented by the reaction formula (II) may be in excess of an equivalent amount with respect to the 3-alkoxyacrylic ester used,
If it is too excessive, the economy is impaired, so it is usually preferred to use it in the range of from 1 equivalent to 1.5 equivalents. The hydroxylamine used may be a salt such as hydrochloride or sulfate, or may be a free salt.

The reaction represented by the reaction formula (II) is, for example,
In a solution in which hydroxylamine and alkali are dissolved, 3-
It is carried out by dropwise addition of an alkoxy acrylate, and the reaction temperature is usually -20 to 80°C and 0.5 to
It can be finished in 5 hours. As the solvent used at this time, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso
-Alcohols such as butanol, acetonitrile, water,
It is preferable to use a mixed solvent thereof and the like.

5-alkoxy-2,3,4,5-tetrahydro-3 produced by the reaction represented by the reaction formula (II)
-Oxoisoxazole can be isolated by adding an acid such as hydrochloric acid or sulfuric acid to the reaction solution after the reaction to make the reaction solution acidic, and then extracting it with an organic solvent immiscible with water such as toluene, hexane, or ethyl acetate. It is separated and further purified by recrystallization from toluene, hexane or the like. Thus, 5-alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole, which is a novel compound of the present invention, is, for example, 5-methoxy-2,3,4,
5-tetrahydro-3-oxoisoxazole, 5-
Ethoxy-2,3,4,5-tetrahydro-3-oxoisoxazole can be obtained.

In the present invention, a novel compound, 5-alkoxy-2,3,4,5-tetrahydro-3-oxoiso, is obtained by reacting a 3-alkoxy acrylate with hydroxylamine in the presence of an alkali. The cause of obtaining oxazole is presumed as follows. That is, as shown in the following reaction formula (III), the addition of hydroxylamine to a 3-alkoxyacrylic acid ester does not occur at the carbonyl carbon of the ester group as has been conventionally estimated, but a double bond is generated. Of the 3-alkoxy-3-aminooxypropanoic acid ester as an intermediate, and then the compound is cyclized to give 5-alkoxy-2, a novel compound of the present invention. It is considered that 3,4,5-tetrahydro-3-oxoisoxazole is produced.

[0016]

[Chemical 4] (In the formula, R ¹ and R ² represent a lower alkyl group having 1 to 4 carbon atoms)

The 3-hydroxyisoxazole is the 5-alkoxy-2, obtained as described above.
It can be obtained by acylating 3,4,5-tetrahydro-3-oxoisoxazole with an acylating agent, dealcoholating the resulting acylated product, and then hydrolyzing it.

[0018]

[Synthesis of 5-methoxy-2,3,4,5-tetrahydro-3-oxoisoxazole]

76.5 g of hydroxylamine hydrochloride was dissolved in 150 ml of water, and 280 g of 20% aqueous sodium hydroxide solution was added. While maintaining the reaction temperature at 5 to 10°C, 116 g of methyl 3-methoxyacrylate was slowly added dropwise to this solution, and then a 20% aqueous sodium hydroxide solution was further added at the same temperature until the pH of the reaction solution became 13. Dropped. After that, the pH decreases as the reaction progresses, so
A 20% aqueous sodium hydroxide solution was added dropwise at any time so as to maintain 3 and the reaction was carried out for 4 hours. The amount of 20% aqueous sodium hydroxide solution added after starting the reaction was 280 g.

After completion of the reaction, 130 g of concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 2, and the mixture was extracted 4 times with 150 ml of ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, concentrated, and further extracted with 200 ml of hot toluene three times. The toluene layer was cooled, and the precipitated crystals were collected by filtration and dried under reduced pressure. This crystal was confirmed to be pure 5-methoxy-2,3,4,5-tetrahydro-3-oxoisoxazole by mass spectrometry and NMR analysis (yield: 64 g, yield: 55%). .. The measured physical property values are shown below.

Melting point: 90 to 92° C. MS spectrum: 117 (M ⁺ ) ¹ H-NMR spectrum: 2.54 (1H d J=1
6.8 Hz CH ₂ ), 3.01 (1H dd J=1)
_{6.8Hz, 5.5Hz CH 2), 3.47} (3H
s OCH ₃ ), 5.32 (1H d J=5.5 Hz
CH), 8.0 (1H bs NH ) 13 C-NMR _{spectrum: 39.0 (CH 2), 55} .
5 (OCH ₃ ), 103.9 (CH), 173.0 (C
=O)

Example 2 [5-methoxy-2,3,4,5-tetrahydro-3-
Synthesis of oxoisoxazole] Hydroxylamine hydrochloride 7.6 in 30 ml of methanol
Dissolve 5 g and add 28% sodium methylate solution 2
7 g was added. A reaction temperature of 5 to 10 is added to the suspension solution.
Methyl 3-methoxyacrylate 1 while maintaining at ℃
After 1.6 g was slowly added dropwise, the reaction was carried out by stirring at a temperature of 20 to 30° C. for 2 hours.

After the reaction was completed, 47 g of 2N hydrochloric acid was added to the reaction solution to adjust the pH to 2, and the mixture was extracted 4 times with 20 ml of ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, concentrated, and further extracted with 20 ml of hot toluene three times. The toluene layer was cooled, and the precipitated crystals were collected by filtration and dried under reduced pressure. This crystal was confirmed to be pure 5-methoxy-2,3,4,5-tetrahydro-3-oxoisoxazole by mass spectrometry and NMR analysis (yield: 6.2 g, yield: 53). %). The measured physical property values are shown below.

Melting point: 90 to 92° C. MS spectrum: 117(M ⁺ ) ¹ H-NMR spectrum: 2.54 (1H d J=1
6.8 Hz CH ₂ ), 3.01 (1H dd J=1)
_{6.8Hz, 5.5Hz CH 2), 3.47} (3H
s OCH ₃ ), 5.32 (1H d J=5.5 Hz
CH), 8.0 (1H bs NH ) 13 C-NMR _{spectrum: 39.0 (CH 2), 55} .
5 (OCH ₃ ), 103.9 (CH), 173.0 (C
=O)

[0024]

INDUSTRIAL APPLICABILITY According to the method of the present invention, it is a novel raw material for producing 3-hydroxyisoxazole useful as a modifier of the active ingredient of medicines and agricultural chemicals at high yield and high purity at low cost. Alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole can be easily obtained.

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ represents a lower alkyl group having 1 to 4 carbon atoms)
5-alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole represented by: 2. The 5-alkoxy-2,3,3 according to claim 1, wherein the 3-alkoxy acrylate is reacted with hydroxylamine in the presence of an alkali.
Process for producing 4,5-tetrahydro-3-oxoisoxazole.