JPS5850989B2 - 3-Hydroxy-5-phenylisoxazole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 3-hydroxy-5-phenylisoxazole having the formula % (where φ represents a phenyl group).

It is known that 3-hydroxy-5-phenylisoxazole having the above formula (I) has unique physiological activity and is useful as an agricultural fungicide and its phosphate ester derivative as an insecticide. There is.

Conventional methods for producing 3-hydroxy-5-phenylisoxazole include methods using phenylpropiolic acid ester as a raw material (see Japanese Patent Publication No. 42-25660) and α, β dihalogenopropionic acid ester or α or β - A method using a halogenoacrylic acid ester (see Japanese Patent Publication No. 14704/1983) has been proposed.

However, these methods cannot be said to be industrially advantageous because raw materials are difficult to obtain and are expensive, and the steps are long.

In addition, a method of acid treatment of the ethylene kecool derivative oxamate has also been reported [buretane, dough, u.
Société Simique de France (Bulletin)
de la soc+ete chimique de
france) 1970, 1978-1985
[Page] This method requires a long time to produce the raw material compound, and the critical drawback is that the yield is poor, so that it cannot be said to be an industrially advantageous method as a whole.

The present inventors have discovered that 3-hydroxy-
As a result of various studies on industrially advantageous methods for producing 5-phenylisoxazole, we found that β-ethylenedioxyphenylpropionate (II) and a new substance β- The present invention was completed by discovering that the desired product can be produced in high yield via a mixture of hydroxyethyl (I) ethylenedioxyphenylpropionate.

That is, the gist of the present invention is to react benzoyl acetate represented by the formula (in the formula, φ represents a phenyl group and R represents a lower alkyl group) with a large excess of ethylene glycol (in the formula, φ and R have the above meanings). A mixture of β-ethylenedioxyphenylproponic acid ester and hydroxyethyl β-ethylenedioxyphenylpropionate having bio (in the formula, φ has the above meaning) was obtained, and this was mixed in the presence of an alkali. It consists of reacting with hydroxylamine to convert both into β-ethylenedioxyphenylpropionoozamate and then acid treatment, which can be expressed by the following formula.

(In the formula, φ and R have the above meanings, and n≧2.M represents an alkali metal or an alkaline earth metal.

) In carrying out the present invention, the reaction to obtain a mixture of β-ethylenedioxyphenylpropionate (II) and hydroxyethyl β-ethylenedioxyphenylpropionate (1) from benzoyl acetate and ethylene glycol is carried out using an inert solvent. The inert solvent used is one or more of toluene, cyclohexane, benzene, chloroform, carbon tetrachloride, etc. A mixed solvent of cyclohexane and toluene is particularly preferred; As such, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, trifluoromethanesulfonic acid, etc. are used.

The reaction takes 3 to 30 hours at 50 to 140°C, although it varies depending on the blending ratio of raw materials, solvent, type of catalyst, etc.

In this reaction, it is essential to use ethylene glycol in large excess, ie, 2 moles or more, preferably 2 to 10 times the mole of benzoyl acetate.

This is because if the blending ratio of ethylene glycol to benzoyl acetate is close to the stoichiometric amount, the substance (II) can only be obtained in a low yield and it takes a long time, which is undesirable.

The reaction is carried out under reflux of the solvent, and the by-product water is taken out of the system as an azeotrope with the solvent, and the reaction is allowed to proceed until the generation of water stops. After the reaction is complete, the solvent and unreacted water are removed. If ethylene glycol is recovered, (II) and (I) can be obtained in high yield.

Here, (II) and (I) are obtained as a mixture, and which one is obtained as the main product depends on various reaction conditions, so it cannot be said that they are one set, but usually (n) is the main product. exist.

However, it is also possible to make the product predominantly (I), for example by increasing the amount of catalyst and using high-boiling solvents, by increasing the excess of ethylene glycol.

(I) is a new substance that can be identified by elemental analysis, infrared absorption analysis, and gas chromatography analysis, and in some cases can be isolated and purified from (II).

Next, the reaction to obtain 3-hydroxy-5-phenylisoxazole from (II) and (It) obtained above is β
- It is divided into the step of obtaining ethylenedioxyphenylpropionoozamate and the next step of acid treatment, but in actual practice, water, methanol, ethanol,
It is carried out in propatool, dioxane, tetrahydrofuran, or a mixed solvent thereof.

However, other solvents may be used as long as they are inert to this reaction and are not particularly limited.

The hydroxylamine used is a commonly available one neutralized with hydrochloric acid, sulfuric acid, etc., and the alkali is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkaline earth metal hydroxide, Alkali metal alcolade etc. are used.

The amount of hydroxylamine to be used is equivalent to or in excess of 1 mole of the mixture of (II) and (i), and the amount of alkali to be present is equivalent to 1 mole of the mixture of (1) and (I). Use 2 to 3 times the mole amount.

In this case, the amount of alkali may be present in excess, but there is a limit if separation of the salt produced is taken into account.

Regarding the reaction temperature and reaction time, the process of obtaining β-ethylenedioxyphenylpropionoozamate is carried out at a low temperature to suppress the decomposition of hydroxylamine, preferably at -10 to 20°C for several hours to several hours. It is sufficient to carry out the reaction.

Next, acid treatment is carried out, and the acids used here include one or two mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as formic acid and acetic acid, or Lewis acids such as boron fluoride and boron bromide.
The amount used is 3 to 4 times the mole per mole of the mixture of (n) and (]II, and the mixture is treated under strong acidity for several hours under cooling at, for example, about -10 to 10°C. After that, heat treatment is carried out under refluxing of the solvent, and the pH within the reaction system is finally adjusted to 3 to 3.
The reaction is terminated by adjusting the temperature to about 5.

After the reaction is completed, the target product is collected from the reaction mixture by a conventional method.

For example, the desired product can be obtained by separating the by-product salt and distilling off the solvent, and if necessary, it can be further purified by recrystallization using an appropriate solvent.

As described above, according to the present invention, (n) and (1) can be obtained in good yield from benzoyl acetate and a large excess of ethylene glycol, and both can be obtained in high yield and purity with 3-hydroxy-5- phenyl isoxazole can be reached.

Moreover, it can be said that it is an industrially superior method because the desired product can be obtained at a lower cost and in a shorter time than conventional methods.

The present invention will be specifically explained below with reference to actual examples.

Leprosy Example 1 192.2 g (1.0 mol) of ethyl benzoyl acetate and ethylene were placed in a four-necked reactor equipped with a reflux condenser and an attached water separator (Dean Stark device), a stirring device, and a thermometer. Glycol 248.0 (4.0 mol),
Paratoluenesulfonic acid 0.9g, cyclohexane 13
0 g and 70 g of toluene were taken, and after reacting under reflux for 12 hours, the solvent was distilled off to obtain 200.0 g of an oily residue.

The obtained residue contained ethyl β-ethylenedioxyphenylpropionate 154.1 (yield 81.5%) and β-
It contained 18.8.9 hydroxyethyl ethylenedioxyphenylpropionate (yield 9.3%).

Next, in a four-necked reactor equipped with a reflux condenser, a thermometer, and a stirring device, 60 TL of methanol and 7.79 (0.11 mol) of hydroxylamine hydrochloride were added and dissolved at 0°C.
While cooling to , 46.3 g (0.24 mol) of a 28% by weight sodium methylate-methanol solution is added dropwise.

27.5 g (0.1 mol) of the oil obtained above are then added dropwise.

After stirring at 5 to 20°C for 5 hours, add 7.3g of hydrochloric acid gas (
0.2 mol).

After the completion of the reaction, the temperature was raised and the reaction was carried out for 3 hours under methanol reflux.

This reaction solution was neutralized with sulfur hydroxide to pH=5, the solvent was distilled off, water was added, filtered, and dried to obtain crude crystals of 3-hydroxy-5-phenylisoxazole ( 16.3 g of the product (purity 91.0%) was obtained.

(Yield 92.0%). This reaction product was recrystallized from methanol to obtain pure 3-hydroxy-5-phenylisoxazole (I) in the form of colorless needles.

The physical and chemical properties of this product are as follows.

M, P, -166 to 167°C Elemental analysis calculated value C = 67.08%, H = 4.38%, N = 8.6
9% actual value C = 66.24%, H = 3.84%,
N=8.73% Actual Flame Example 2 Oily substance obtained in the first half of Example 1 27.59 (0,1
mol) using the same apparatus and method as in the second half of Example 1.
When the reaction was carried out using 48.1 (0.24 mol) of 20 wt% sodium hydroxide in methanol instead of wt% sodium methylate, crude 3-hydroxy-
Crystals of 5-phenylisoxazole (purity 92.1%)
) was obtained.

(Yield 90.3%). Example 3 44.9 g of 30% by weight potassium hydroxide solution was used instead of the 20% by weight sodium hydroxide/methanol solution in Example 2 (
The crude 3-
16.0 g of hydroxy-5-phenylisoxazole crystals (purity 90.4%) were obtained.

(Yield 89.6%). Example 4 In a reactor similar to Example 1, 96% of ethyl benzoyl acetate was added.
．． 2g (0.5 mol), 155g ethylene glycol (
2.5 mol), 0.1 g of para-toluenesulfonic acid, and 100 g of toluene were taken and reacted under reflux for 10 hours, and then the solvent was distilled off to obtain 121.4 g of an oily residue.

The obtained residue contained 33.2 g of ethyl β-ethylenedioxyphenylpropionate (yield 28.2%) and β-ethyl
It contained 52.2.9 hydroxyethyl ethylenedioxyphenylpropionate (yield 41.4%).

Next, 35.0 g (0.1 mol) of this oily residue was reacted with hydroxylamine in the same manner as in the second half of Example 1, resulting in crude crystals of 3-hydroxy-5 phenyl isoxazole (purity 85 .3%) was obtained.

(Yield 81.5%) Example 5 27.5 g (0.1 g) of the oil obtained in the first half of Example 1
mol), the reaction was carried out in the same manner as in the apparatus and method in the second half of Example 1, except that 48.0 g (0.24 mol) of a 20 wt% methanol solution of sodium hydroxide was used instead of the 28 wt% sodium methylate. , and when 15.7 g (0.16 mol) of concentrated sulfuric acid was used instead of hydrochloric acid gas,
16.4 g of crude 3-hydroxy 5-phenylisoxazole crystals (purity 87.3%) were obtained.

(Yield 88.7%). Example 6 Using 27.5 g (0.1 mol) of the oil obtained in the first half of Example 1 and using the apparatus of the second half of Example 1, 10.7 g (
0.13 mol) was added, stirred, and heated to 20°C while cooling to 0°C.
Weight% sodium hydroxide/methanol solution 57g (0,2
8 mol) was added dropwise.

After the addition, the mixture was stirred at 5°C for 3 hours, and then the above oil was added dropwise.

After stirring at 5 to 20°C for 5 hours, 7.3 g of hydrochloric acid gas (0,
2 mol).

After the completion of the reaction, the temperature was raised and the reaction was carried out for 3 hours under refluxing of Meknol.

The reaction solution was neutralized with I-IJ hydroxide to pH=5, the solvent was distilled off, water was added, filtered, and dried to obtain crude crystals of 3-hydroxy-5-phenylisoxazole. (purity 90.5%) 15.6g was obtained.

(Yield 87.8%).

Example 7 In Example 6, 15.7 g of concentrated sulfuric acid (
The reaction was carried out in the same manner except that 3-hydroxy-5-phenylisoxazole (purity: 91.1%) was obtained in the same manner as above.

(Yield 86.7%). Reference Example Oily residue obtained in Example 4 (mixture of ethyl β-ethylenedioxyphenylpropionate and hydroxyethyl β-ethylenedioxyphenylpropionate) 82.
2. ? (containing 35.0 g of hydroxyethyl β-ethylenedioxyphenylpropionate) was diluted with n-hexane and washed with a 2% by weight aqueous solution of sulfur hydroxide, then washed with water until neutral, and diluted with sulfuric acid. - After drying over IJum, the solvent was distilled off to remove ethyl β-ethylenedioxyphenylpropionate, and the residue was separated and purified by column chromatography (silica gel, n-hexane-acetone). 28.3 g of pure hydroxyethyl ethylenedioxyphenylpropionate was obtained.

The physical and chemical properties of this product are as follows.

Specific gravity d≦3=1.2495 (supercooled), refractive index n palm-
1,5156 (supercooled) Boiling point 151-1538CO0
3 degrees Hg, melting point 23-24° CIRcfIl maX
1735,1035,1165゜705.1221
．． 1080 Elemental analysis (C13H1605) Calculated value C: 61.90%, H: 6.39%, molecular weight 25
2.27 Actual value C: 62.68%, H: 6.42%, molecular weight 25
1.7 Next, 25.2 g (0.1 mol) of this hydroxyethyl β-ethylenedioxyphenylpropionate was reacted with hydroxylamine in the same manner as in the second half of Example 1, resulting in crude 3- 15.4 g of hydroxy 5-phenylisoxazole crystals (purity 82.0%) were obtained.

Claims (1)

[Claims] 1 formula. (In the formula, φ represents a phenyl group and R represents a lower alkyl group) A benzoylacetic ester represented by A mixture of dioxyphenylpropionate and hydroxyethyl β-ethylenedioxyphenylpropionate (wherein φ has the above meaning) was obtained, and this was reacted with hydroxylamine in the presence of an alkali to form β-ethylene. A method for producing 3-hydroxy-5-oxazole represented by (wherein φ has the above-mentioned meaning), which comprises obtaining dioxyphenylpropionoozamate and then treating with an acid.