JP3216673B2 - Method for producing 3-hydroxyisoxazole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel process for producing 3-hydroxyisoxazole. 3-Hydroxyisoxazole is a compound useful as a modifier of a drug or agricultural chemical.

[0002]

2. Description of the Related Art Conventionally, as a method for producing 3-hydroxyisoxazole, a method of reacting a propynate ester with hydroxylamine (Chem. Pharm. Bu.
ll. , 14 , 1277 (1966)), a method of reacting 2,3-dibromopropionate with hydroxylamine (CA74, 125521e), and a method of reacting 3-chloroacrylate with hydroxylamine (FR1534601). However, none of these methods use expensive raw materials that are difficult to obtain and are not economical production methods.

Further, a method is known in which a 3-alkoxyacrylic acid ester is reacted with hydroxylamine in the presence of an alkali and then cyclized by acid treatment to obtain 3-hydroxyisoxazole (Japanese Patent Publication No. 50-33064). However, the yield is low and this is not an industrially preferable method. Further, a method of oxidatively cyclizing acrylic hydroxamic acid in the presence of a palladium chloride catalyst (Chem. In
d. (9) 318 (1979)),
This method also has a problem that the yield is low.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to produce 3-hydroxyisoxazole useful as a modifying agent for a drug substance, a pesticide or the like in high yield and high purity using inexpensive raw materials. Is to provide a way to

[0005]

SUMMARY OF THE INVENTION The object of the present invention is as follows.
Inexpensive 5-alkoxy-2, represented by the general formula (I),
After acylating 3,4,5-tetrahydro-3-oxoisoxazole with an acylating agent as shown in the following reaction formula (II), the obtained acylate is dealcoholized and then hydrolyzed. This is achieved by a method for producing 3-hydroxyisoxazole.

[0006]

Embedded image (Wherein, R ¹ represents a lower alkyl group having 1 to 4 carbon atoms)

[0007]

Embedded image (Wherein, R ¹ and R ² each represent a lower alkyl group having 1 to 4 carbon atoms)

Hereinafter, the method of the present invention will be described in detail. The 5-alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole used in the present invention includes R
Formula ¹ is a lower alkyl group having 1 to 4 carbon atoms (I)
The compound shown by these is mentioned. Specifically, 5-methoxy-2,3,4,5-tetrahydro-3-oxoisoxazole, 5-ethoxy-2,3,4,5-tetrahydro-5-ethoxy-3-oxoisoxazole, etc. Can be mentioned.

These compounds can be obtained by reacting a 3-alkoxyacrylate with hydroxylamine in the presence of an alkali, as shown in reaction formula (III).

[0010]

Embedded image (Wherein, R ¹ , R ² and R ³ represent a lower alkyl group having 1 to 4 carbon atoms)

In the acylation of the present invention, the above-mentioned 5-alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole is usually reacted with an acid in the presence of a base to suppress the formation of by-products. It is carried out by reacting with an acylating agent such as a halide or an acid anhydride. The reaction is, for example,
5-alkoxy-2,3,4,5-tetrahydro-3-
The reaction is carried out by dropping an acylating agent into a solution in which oxoisoxazole and a base are dissolved, and the reaction can be usually completed at a reaction temperature of −20 to 50 ° C. in 0.1 to 2 hours.

At this time, 5-alkoxy-2,3,4,
The amount of 5-tetrahydro-3-oxoisoxazole used is usually preferably 0.3 to 2 mol / l. As acylating agents, acetyl chloride, propionyl chloride, acid halides such as butyryl chloride, acetic anhydride, propionic anhydride,
An acid anhydride such as butyric anhydride is preferably used, and the amount of the acid anhydride is 5-alkoxy-2,3,4,5-tetrahydro-3-.
Usually, 1 to 3 equivalents are suitable for oxoisoxazole. As the base, a tertiary amine such as triethylamine, tributylamine, pyridine or 4-dimethylaminopyridine is preferably used, and the amount thereof is 5-alkoxy-2,3,4,5-tetrahydro-3-oxo. Usually, 1 to 3.5 equivalents are suitable for isoxazole.

The reaction solvent is not particularly limited as long as it is inert to acylation, and examples thereof include hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride, nitriles such as acetonitrile, and N-methyl. Pyrrolidones such as pyrrolidone and a mixed solvent thereof are preferably used.

The dealcoholation of the present invention is carried out by heating the above-mentioned acylated reaction solution as it is or after filtering off the salt formed by the acylation, and usually heating the reaction solution at 50 to 100 ° C. Heating for two to three hours can complete the dealcoholization.

The hydrolysis of the present invention is usually carried out by adding an aqueous alkali solution to the reaction solution after the completion of the dealcoholation.
It can be easily performed by reacting at a temperature of ５０50 ° C. Examples of the aqueous alkali solution used include an aqueous solution of a hydroxide of an alkali metal such as sodium hydroxide and potassium hydroxide, and an aqueous solution of a hydroxide of an alkaline earth metal such as calcium hydroxide and magnesium hydroxide. The amount used depends on the amount of the base or acylating agent used for the acylation, but it is necessary that the amount of the reaction solution be 8 to 11 and the 5-alkoxy-2,3,4,5
It is usually 0.5 to 6 equivalents based on -tetrahydro-3-oxoisoxazole.

3-Hydroxyisoxazole is prepared by adding an acid such as hydrochloric acid or sulfuric acid to the reaction solution after the above-mentioned hydrolysis to make the reaction solution acidic, and then adding an organic compound such as ethyl acetate, toluene, hexane, or methylene chloride. It can be isolated by extraction with a solvent. Then, it is further purified by recrystallization or sublimation with hexane or the like.

[0017]

Next, the method of the present invention will be described in detail with reference to examples. Example 1 5-methoxy-2,3,4,5-tetrahydro-3 was added to a mixed solvent of 340 ml of toluene and 85 ml of acetonitrile.
-Oxoisoxazole (40 g) was dissolved, and 86 g of triethylamine was further added. The temperature of this solution is
While maintaining the temperature at 10 ° C., 87 g of acetic anhydride was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour for acylation.
The temperature was raised to ８０80 ° C., and the mixture was stirred at this temperature for 4 hours to remove alcohol.

After the dealcoholation is completed, the reaction solution is
under ice-cooling, and 60 g of sodium hydroxide was added to 35 of water.
A solution dissolved in 0 ml was added. At this time, the pH of the aqueous layer
Was about 10. This solution was stirred at 30 to 40 ° C. for 1 hour to carry out hydrolysis, and then, under ice-cooling, 130 ml of concentrated hydrochloric acid.
And extracted three times with 300 ml of ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, concentrated, and the precipitated crystals were collected by filtration. The filtrate is hot hexane 100
The mixture was extracted twice with ml, cooled, and the precipitated crystals were collected by filtration, combined with the previous one, and dried at room temperature under reduced pressure. The crystals were confirmed to be pure 3-hydroxyisoxazole by mass spectrometry and NMR analysis (yield: 2
2 g, yield: 76%). The measured physical properties are shown below.

Melting point: 97-99 ° C. MS spectrum: 85 (M ⁺ ) ¹ H-NMR spectrum: 6.04 (1H d J =
1.8 Hz CH), 8.11 (1H d J = 1.8)
Hz CH), 11.47 (1Hbs NH)

Example 2 1.17 g of 5-methoxy-2,3,4,5-tetrahydro-3-oxoisoxazole was dissolved in a mixed solvent of 10 ml of toluene and 3 ml of acetonitrile, and 1.06 g of triethylamine was further added. 0.82 g of acetyl chloride was slowly added dropwise to this solution while maintaining the temperature at 5 to 10 ° C., and the mixture was stirred at room temperature for 0.5 hour to perform acylation. It was filtered off. 1.06 g of triethylamine was added to the filtrate to give 7
The temperature was raised to 0 to 80 ° C., and the mixture was stirred at this temperature for 2 hours to remove alcohol.

After the dealcoholation is completed, the reaction solution is concentrated to about 6 ml, and 10 ml of a 1N aqueous sodium hydroxide solution is added under ice-cooling.
Was added. At this time, the pH of the aqueous layer was about 10.
The solution was stirred at 30 to 40 ° C. for 0.5 hour to carry out hydrolysis, and then 2 ml of concentrated hydrochloric acid was added under ice-cooling, followed by extraction with 10 ml of ethyl acetate three times. The obtained extract was concentrated, and the concentrate was heated to 90 to 100 ° C. at 20 mmHg to isolate a compound that sublimated. This compound was confirmed to be pure 3-hydroxyisoxazole by mass spectrometry and NMR analysis (yield: 0.6 g, yield: 71%). The measured physical properties are shown below.

Melting point: 97-99 ° C. MS spectrum: 85 (M ⁺ ) ¹ H-NMR spectrum: 6.04 (1H d J =
1.8 Hz CH), 8.11 (1H d J = 1.8)
Hz CH), 11.47 (1Hbs NH)

[0023]

According to the method of the present invention, 3-hydroxyisoxazole, which is useful as a modifying agent for a drug substance or an agricultural chemical, can be converted into an inexpensive 5-alkoxy-2,3,4,5-tetrahydro-3-oxoisobenzene. It can be produced in high yield and high purity using oxazole as a starting material.

Continuation of the front page (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 261/00-261/18 C07D 275/00-275/03 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (1)

(57) [Claims] 1. A method comprising acylating 5-alkoxy-2,3,4,5-tetrahydro-3-oxoisoxazole with an acylating agent, dealcoholizing the obtained acylated product, and then hydrolyzing the acylated product. A method for producing 3-hydroxyisoxazole.