JPS59112975A - Preparation of 4-substituted isoxazole - Google Patents

Abstract

PURPOSE:To obtain a 4-substituted isoxazole useful as an intermediate for medicines and agricultural chemicals, etc., by reacting an alkali metallic salt of 2-hydroxymethylene-3,3-dialkoxypropanenitrile, etc. with a mineral acid salt of hydroxylamine. CONSTITUTION:An alkali metallic salt of a 2-hydroxymethylene-3,3-dialkoxypropanenitrile expressed by formula I (R<1> and R<2> are 1-5C alkyl; M is alkali metal) or an alkali metallic salt of a 2-hydroxymethylene-3,3-dialkoxypropionic acid ester expressed by formula II (R<3> is 1-5C alkyl) is reacted with a mineral acid salt of hydroxylamine to give 4-isoxazolecarbonitrile expressed by formula IIIfrom the former expressed by formula I or a 4-isoxazolecarboxylic acid ester expressed by formula IV from the latter expressed by formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4-substituted inoxazoles, viz.
The present invention relates to a novel method for producing 4-inoxazolecarbonyl substituted with a cyanide group at the -position, or 4-isoxazolecarboxylic acid ester substituted with a lower alkoxycarbonyl group at the 4-position.

More specifically, the present invention relates to an alkali metal salt of 2-hydroxymethylene-ro, 3-dialkoxy/furopainitrile, or an alkali metal salt of 2-hydroxymethylene-ro, dialkoxy-7-propionic acid ester; It is characterized by reacting a mineral acid salt of hydroxylamine.

The present invention relates to a novel method for producing 4-substituted inoxazoles.

The 4-substituted inoxazoles produced by the present invention are useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, and the like.

Conventionally, various proposals have been made regarding methods for producing inoxazoles. However, there has been no example of producing 4-substituted inoxazoles substituted with a cyan group or a lower alkoxycarbonyl group at the 4-position by the reaction of the alkali metal salt and mineral acid salt as in the present invention.

The structural formula of the alkali metal salt of 2-hydroquine methylene-B, rhodialcoquinopropane nitrile, which is the raw material of the present invention, can be represented by the following first-order general formula (1).

/11 R20CHOM Further, the structural formula of the alkali metal salt of 2-hydroxymethylene-Hiroroichi dialkoxybropionic acid ester can be represented by the following first-order general formula (n).

However, in general formulas (1) and (II), R1,,
R2 and R3 represent a lower alkyl group having 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, etc., and R1 and R2 or R3 may be the same alkyl group or different alkyl groups. It can also be. 14 in general formulas (1) and (It) is a moat.

Indicates an alkali metal such as sodium, potassium or libram.

These alkali metal salts of 2-hydroxy/methylene-dialkokine propanenitrile and alkali metal salts of 2-hydrogine methylene-dialkokinepropane nitrile can be synthesized by known methods. I can do it. for example.

Ro, 5-dialcoquine propanenitrile trild + Ro,
The filter dialycoquine propionate ester can be synthesized by reacting it with a formylating agent such as a formate or carbon monoxide in the presence of an alkali metal alcoholide at a temperature of 0 to 100°C.

The mineral acid salts of hydroxylamine, which is the other raw material of the present invention, include hydroxylamine hydrochloride, sulfate,
Examples include phosphates. If these hydroxylamine mineral acid salts are used in too large quantities, side reaction products will increase, and if they are used in too small quantities, a large amount of the other raw material will remain unreacted, both of which are unfavorable from an industrial perspective. . Therefore, the amount used is 2-hydroxymethylene-ro, di-dialkoxypropanenitrile alkali metal salt, or 2-hydroxymethylene-ro, di-dialkoxypropanenitrile.
Alkali metal salt of dialcoquine propionate 1
per mole, usually 0.1 to 10 moles, preferably 0.1 to 10 moles.
It is 5 to 5 moles.

The reaction of the present invention is carried out in two solvents. Any solvent that is inert to one reaction is useful. Specific examples include ether solvents such as methanol, ethanol, gropanol, butanol, ethylene glycol natonoalcohol u-solvent diethyl ether, dimethoxyethane, dioxane, and tetrahydrofuran; benzene, toluene, xylene, hexane, heptane, and cyclohexane. Hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; Ester solvents such as methyl acetate, ethyl acetate, and butyl acetate; and acetonitrile dimethylsulfokinde and dinotylformamide. I can give an example. Among these, it is preferable to use an alcohol solvent or a mixed solvent of an alcohol solvent and another solvent at 1%.

The reaction of the present invention is completed by carrying out the reaction at a temperature of 0 to 100°C for 01 to 10 hours.

After the reaction is completed, the 4-substituted inoxazole can be isolated and purified by appropriately employing operations such as filtration, acondensation, extraction, or recrystallization.

That is, when an alkali metal salt of 2-hydroquine methylene-3-alkoxypropanenitrile is used as a raw material, 4-ynoxazolecarbonitrile represented by the 9-order structural formula (III) can be obtained.

When an alkali metal salt of 2-hydroquine methylene-O, O-/alcoquine propionate is used as the raw material for shredding, 4-ynoxazolecarboxylic acid ester represented by the following general formula (IV) is obtained. can be obtained.

R3 in the formula corresponds to R3 in the general formula (n).

Next, examples of the present invention will be described. In addition, the yield of the target product in each column is the 2-hydroquine methylene used.
It is based on the alkali metal salt of dialcoquine propanenitrile or the alkali metal salt of 2-hydroquine methylene to ro-dialkokine propionate.

Example 1 10.0 g of sodium salt of 2-t doroquine methylene, 3-dimethoxy/propanenitrile (purity 91. 6%.

55.5 mmol) and methanol 607 were added.

The liquid temperature was maintained at 25° C. without stirring. Next.

When 3.864 (55.5 mmol) of hydroxylamine hydrochloride powder was added all at once, heat was generated immediately and the liquid temperature reached 65°C. After continuing stirring for 0 minutes.

Methanol was distilled off under reduced pressure at a temperature of 60°C or less.

Add 25 mg of water, dissolve the inorganic salt, and then use methylene chloride at 50 mA! Extracted 5 times. After drying the notylene chloride layer with sodium sulfate, the sodium sulfate was removed and the layer was concentrated to obtain 4.547 pale yellow crude crystals.

Gas chromatography using internal standard method.

The purity of the crude crystals was determined to be 91.0%, and the yield was therefore 79.1%. The crude crystals were recrystallized from water using activated carbon to obtain white needle-like crystals with a melting point of 65.5 to 66.5°C. The IR9NMR, M6t of this is
Consistent with 4-inoxazole carbonitrile.

Example 2 In a three-necked flask with an internal volume of 20 Omg equipped with a thermometer and a reflux condenser with a gel tube, 10,000 y of 2-hydroquine methylene-diethoxy/propylene/ethyl acid salt was added. (Purity? 2-ro candy.

58.5 mmol) and ethanol 1201,
The liquid temperature was maintained at 25° C. without stirring.

Next, hydroxylamine hydrochloride was filtered, and 7 (45,
A powder of 0 mil J mol) was added at once, and the temperature was raised while stirring, and the liquid temperature was maintained at a temperature of 55 to 60° C. for 30 minutes. After cooling, ethanol was distilled off under reduced pressure, and water was added at 25 m/? was added to dissolve the inorganic salt, and the mixture was extracted 5 times with 50% ethyl ether.

After drying the ether layer with sodium sulfate, the sodium sulfate was removed, the ether was concentrated, and then vacuum distilled to give a boiling point of 87-88℃/10 wnH? colorless transparent oil 4
．． 1El' was obtained. What about this thing? R, NMR, and MEt were consistent with 4-ynoxazolecarboxylic acid ethyl ester. Yield 77.0%.

Example 2 Into a 50 ml three-necked flask equipped with a thermometer and a reflux condenser equipped with a silica gel tube, 2.5 oy of sodium salt of 2-hydroxymethylene-di-n-butoxypropanenitrile = ( Purity 90.5%.

9.09 mmol) Hydroxyl/ruami/salt was added with 0.6 y (9,0 9 mmol) and 25 f of n-butanol, stirred, heated, and kept at a temperature of 60 to 65°C for 1 hour. did. The reaction solution was quantified by internal standard method using gas chromatography. As a result, it was confirmed that 4-inoxazolecarbonyl was produced at a yield of 75.6%.

Example 4 1.13 of the sodium salt of 2-hydroquine methylene-ro-dimethoxypropanenitrile was added to the same apparatus as in Example 4.
of (purity: 91.6, 10.0 mmol).

Hydroxylamine hydrochloride o, a21y (s, o mmol) and 40 g of methanol were added and stirred at a temperature of 20-25°C for 6 hours. The reaction solution was quantified by internal standard method using Cass chromatography. As a result, it was confirmed that 4-isoxazole carbonitrile was produced at a yield of 41.5%.

Patent applicant: Ube Industries Co., Ltd.

Claims (1)

[Scope of Claims] An alkali metal salt of 2-hydroxymethylene-3,ro-dialkoxypropanenitrile, or an alkali metal salt of 2-hydroxymethylene-3,ro-dialkoxypropionic acid ester, and a mineral of hydroxylamine. It is characterized by reacting with acid salts. Method for producing 4-substituted inoxazoles.