JP2002363171A - Method of producing 4-substituted-3-amino-isoxazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of producing an industrially suitable 4- substituted-3-aminoisoxazole derivative in high yield, from a readily available dialkoxyamide oxime derivative through a simple process. SOLUTION: The 4-substituted-3-aminoisoxazole derivative is produced characteristically by subjecting a dialkoxyamide oxime to the cyclization reaction in the presence of an acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a 4-substituted-3-aminoisoxazole derivative useful as a raw material for synthesizing pharmaceuticals and agricultural chemicals. In particular, a 4-substituted-3-aminoisoxazole derivative can be used as a raw material for synthesizing a sulfonamide endothelin antagonist compound useful as a hypotensive agent or an anti-atherosclerotic agent (for example, JP-A-6-9598).

[0002]

2. Description of the Related Art Conventionally, as a method for producing a 4-substituted-3-aminoisoxazole derivative, hydroxylamine is reacted with 2- (trifluoroaceto) propionitrile under reflux in an aqueous sodium hydrogen carbonate solution. It is known that 2- (trifluoroaceto) propionamide oxime is obtained, followed by adding concentrated hydrochloric acid thereto and reacting again under reflux to obtain 5-trifluoromethyl-4-methyl-3-aminoisoxazole. (JP-A-62-96479).
However, in this method, the yield of the desired 5-trifluoromethyl-4-methyl-3-aminoisoxazole is low.
In addition to the extremely low 31.7%, there is a problem that 2.6% of 3-trifluoromethyl-4-methyl-5-aminoisoxazole (positional isomer) which is difficult to separate from the target product is by-produced.

[0003]

SUMMARY OF THE INVENTION The object of the present invention is to solve the above-mentioned problems, and to obtain a 4-substituted dialkoxyamide oxime derivative by a simple method in a high yield.
An object of the present invention is to provide an industrially suitable method for producing a 4-substituted-3-aminoisoxazole derivative, which can obtain a 3-aminoisoxazole derivative.

[0004]

The object of the present invention is to provide a compound of the general formula (1) in the presence of an acid.

[0005]

Embedded image

A cyclization reaction of a dialkoxyamide oxime derivative represented by the general formula (2):

[0007]

Embedded image

(In the formula, R ¹ and R ² have the same meanings as described above.) This is solved by a method for producing a 4-substituted-3-aminoisoxazole derivative represented by the formula:

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The dialkoxyamide oxime derivative used in the reaction of the present invention is represented by the above general formula (1).

In the general formula (1), R ¹ is a group which does not participate in the reaction, but is particularly a hydrogen atom, an alkyl group or an aryl group which may have a substituent, and specifically, Examples include a hydrogen atom; an alkyl group such as a methyl group, an ethyl group, a propyl group, and a butyl group; and an aryl group such as a phenyl group, a naphthyl group, and an anthryl group. In addition,
These include various isomers.

Examples of the substituent include an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group and a butoxyl group; and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The number and position of the substituent are not particularly limited.

In the general formula (1), R ² is a group which does not participate in the reaction, but is particularly an alkyl group or an aryl group which may have a substituent. Alkyl groups such as a group, ethyl group, propyl group and butyl group; and aryl groups such as a phenyl group, a naphthyl group and an anthryl group. These include various isomers.

Examples of the substituent include an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group and a butoxyl group; and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The number and position of the substituent are not particularly limited.

In the general formula (1), R ³ and R ⁴ may be the same or different and are groups which do not participate in the reaction. In particular, they are alkyl groups having 1 to 4 carbon atoms. Is, for example, a methyl group, an ethyl group, a propyl group, or a butyl group, preferably a methyl group or an ethyl group. These include various isomers. R ³ and R ⁴ may be linked to each other to form a ring. Examples of the linked group include an ethylene group, a trimethylene group,
Although a tetramethylene group is mentioned, an ethylene group is preferable.

The dialkoxyamide oxime derivative used in the reaction of the present invention is, for example, a compound represented by the following general formula (3):

[0016]

Embedded image

(Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above), and are compounds which can be easily synthesized from cyanoketones by the following reaction steps (see the following reference). Described in the example).

Examples of the acid used in the reaction of the present invention include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as formic acid and acetic acid; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluene. Sulfonic acids such as sulfonic acid may be mentioned, but preferably mineral acids, more preferably hydrochloric acid and sulfuric acid are used.

The amount of the acid used is preferably 0.001 to 20 mol per 1 mol of the dialkoxyamide oxime derivative,
More preferably, it is 0.005 to 10 mol.

The reaction of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol,
alcohols such as n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol; N, N-dimethylformamide;
Amides such as N, N-dimethylacetamide and N, N'-dimethyl-2-imidazolidone; nitriles such as acetonitrile, propionitrile and benzonitrile; aromatic hydrocarbons such as toluene, xylene and cumene; methyl acetate , Ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, carboxylic acid esters such as t-butyl acetate; cyclohexane, cycloheptane, aliphatic hydrocarbons such as cyclooctane, Preferably, alcohols, aromatic hydrocarbons and carboxylic esters are used. In addition, you may use these solvents individually or in mixture of 2 or more types.

The amount of the solvent to be used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 1 to 1000 ml, more preferably 1 to 100 ml, per 1 g of the dialkoxyamide oxime derivative.

The reaction of the present invention is carried out, for example, by a method in which a dialkoxyamide oxime derivative, an acid and a solvent are mixed and stirred in an inert gas atmosphere. The reaction temperature at that time is preferably 20 to 200 ° C, more preferably 50 to 150 ° C, and the reaction pressure is not particularly limited.

4-Substituted-3- obtained by the reaction of the present invention
After completion of the reaction, the aminoisoxazole derivative is subjected to, for example, neutralization, extraction, concentration, filtration, and the like, and then isolated and purified by a general method such as recrystallization, distillation, or column chromatography.

[0024]

EXAMPLES Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples.

Reference Example 1 (Synthesis of sodium salt of 3-cyano-2-butanone) 300 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
13.0 g of sodium methoxide (0.
24 mol), 19.9 g (0.36 mol) of propionitrile, 37.2 g (0.32 mol) of n-butyl acetate and 100 ml of toluene were added and reacted at 90 ° C. for 24 hours in a nitrogen atmosphere. After the completion of the reaction, the mixture is cooled to room temperature, and the precipitate is filtered and dried to obtain a colorless powder.
12.0 g of sodium salt of 3-cyano-2-butanone was obtained (isolation yield; 41.7%). Physical properties of the sodium salt of 3-cyano-2-butanone were as follows.

¹ H-NMR (DMSO-d ₆ , δ (ppm)); 1.45 (3H, s),
1.75 (3H, s)

Reference Example 2 (Synthesis of 2- (β-ethylenedioxyaceto) propionitrile) Stirrer, thermometer, dropping funnel, reflux condenser, Dean-Sta
In a 200 ml glass flask equipped with an rk device, 16.7 g (0.14 mol) of sodium salt of 3-cyano-2-butanone synthesized in the same manner as in Reference Example 1 and 17.4 g of ethylene glycol
g (0.28 mol) and 72 ml of toluene were added, and 12.5 g (0.12 mol) of concentrated sulfuric acid was added dropwise while cooling to 5 ° C. and stirring. Thereafter, the reaction was carried out for 7 hours under heating and refluxing (105 to 110 ° C.) in a nitrogen atmosphere while distilling off water generated in the reaction. After completion of the reaction, the reaction solution was cooled to room temperature,
Washing was performed in the order of 15 ml of a 1 / L aqueous sodium hydroxide solution. Next, the organic layer was taken out, and the organic layer was concentrated under reduced pressure to obtain 18.4 g of 2- (β-ethylenedioxyaceto) propionitrile as a colorless liquid (isolation yield; 93%). Physical properties of 2- (β-ethylenedioxyaceto) propionitrile were as follows. .

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.30 (3H, d), 1.4
0 (3H, s), 2.90 (1H, q), 4.0 ~ 4.1 (4H, m)

Reference Example 3 (Synthesis of 2- (β-ethylenedioxyaceto) propionamide oxime) 4 mol / L was placed in a 100 ml glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser. A mixture of 10 ml (40 mmol) of an aqueous sodium hydroxide solution and 8.7 ml of methanol was mixed under ice-cooling with 2.33 g of hydroxylamine hydrochloride (33.6 mmo).
l) was added and allowed to stir for 10 minutes. Then, the temperature was raised to room temperature, and 2.12 g (15 mmol) of 2- (β-ethylenedioxyaceto) propionitrile synthesized in the same manner as in Reference Example 2 was slowly added dropwise. (70-75 ℃)
For 5 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with 30 ml of ethyl acetate. The organic layer was removed, and the organic layer was concentrated under reduced pressure to obtain 2.30 g of 2- (β-ethylenedioxyaceto) propionamide oxime as a colorless powder (isolation yield: 87%). Physical properties of 2- (β-ethylenedioxyaceto) propionamide oxime were as follows.

[0030] _{^{1 H-NMR (CDCl 3,}} δ (ppm)); 1.18 (3H, d, J = 7.4
Hz), 1.32 (3H, s), 2.60 (1H, q, J = 7.4Hz), 3.95 to 5.00 (4
H, m), 5.0 (2H, brs), 5.7-6.4 (1H, brs)

Example 1 (Synthesis of 3-amino-4,5-dimethylisoxazole) A 50 ml glass flask equipped with a stirrer, thermometer and reflux condenser was prepared in the same manner as in Reference Example 3. Synthesized
1.74 g (10 mmol) of 2- (β-ethylenedioxyaceto) propionamide oxime, ethanol 10 ml and concentrated sulfuric acid 0.1 ml
(1.8 mmol) and heated under reflux in a nitrogen atmosphere (75 to 7
(8 ° C.) for 12 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Thereafter, 10 ml of ethyl acetate and 3 ml of a 15% by mass aqueous sodium carbonate solution were added to the concentrate, and the organic layer was taken out. Then, the aqueous layer was ethyl acetate 5m
Extracted with l, combined with the previous organic layer and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the obtained concentrate is toluene / n-hexane (= 3/1 (volume ratio))
To give 0.90 g of 3-amino-4,5-dimethylisoxazole as colorless needle crystals (isolation yield; 80).
%). Physical properties of 3-amino-4,5-dimethylisoxazole were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.80 (3H, s), 2.2
0 (3H, s), 3.80 (2H, s)

Example 2 (Synthesis of 3-amino-4,5-dimethylisoxazole) 200 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
19.4 g (110 mmol) of 2- (β-ethylenedioxyaceto) propionamide oxime synthesized in the same manner as in Reference Example 3, 77 ml of isopropyl alcohol and 13.3 ml (160 mmol) of concentrated hydrochloric acid were added to The reaction was carried out in an atmosphere under heating and reflux (80 to 82 ° C) for 7 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Thereafter, 400 ml of ethyl acetate and 170 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was recrystallized from 13 ml of isopropyl alcohol to obtain 11.4 g of 3-amino-4,5-dimethylisoxazole as a colorless powder (isolation yield) ; 92%).

Example 3 (Synthesis of 3-amino-4,5-dimethylisoxazole) An inner volume of 100 ml equipped with a stirrer, a thermometer and a reflux condenser.
7.98 g (45.8 mmol) of 2- (β-ethylenedioxyaceto) propionamide oxime synthesized in the same manner as in Reference Example 3, 40 ml of ethyl acetate and 4.4 ml of concentrated hydrochloric acid.
ml (53 mmol) and heated under reflux in a nitrogen atmosphere (75-
(77 ° C.) for 7 hours. After the completion of the reaction, the mixture was cooled to room temperature, and 39 ml of a 15% aqueous sodium carbonate solution was added. After separating the organic layer and the aqueous layer, the aqueous layer was extracted with 20 ml of ethyl acetate, and the extract was combined with the organic layer and dried over anhydrous magnesium sulfate. After filtration, 50 g of toluene was added to the filtrate, and the content was 15 g.
It was concentrated under reduced pressure until. Thereafter, the obtained concentrate was heated to 70 ° C. and then cooled to 5 ° C. to precipitate crystals. The crystals are filtered and dried to give colorless needles
4.20 g of 3-amino-4,5-dimethylisoxazole was obtained.
(Isolation yield; 82%).

Example 4 (Synthesis of 3-amino-4,5-dimethylisoxazole) 2- (β-ethylenedioxyaceto) synthesized in the same apparatus as in Example 3 by the same method as in Reference Example 3. 7.98 g (45.8 mmol) of propionamide oxime, 50 ml of toluene and 4.4 of concentrated hydrochloric acid
ml (53 mmol) and heated under reflux in a nitrogen atmosphere (105
〜110 ° C.) for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and 20 ml of a 15% aqueous sodium carbonate solution and 100 ml of ethyl acetate
l was added. The organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was recrystallized from isopropyl alcohol to obtain 3.80 g of 3-amino-4,5-dimethylisoxazole as colorless needles (isolated yield). Rate; 74%).

Reference Example 4 (Synthesis of 3-cyano-2-butanone) A sodium flask of 3-cyano-2-butanone synthesized in the same manner as in Reference Example 1 was placed in a glass flask having an internal volume of 300 ml.
0 g (0.25 mol), 40 ml of water and 100 ml of ethyl acetate were added. Next, after adding 21.7 ml (0.26 mol) of concentrated hydrochloric acid, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate was concentrated under reduced pressure to give 3-cyano-2- as a colorless liquid.
22.3 g of butanone was obtained (isolation yield; 92%). Physical properties of 3-cyano-2-butanone were as follows.

¹ H-NMR (DMSO-d ₆ , δ (ppm)); 1.50 (3H, d),
2.38 (3H, s), 3.60 (1H, q)

REFERENCE EXAMPLE 5 (Synthesis of 2-methylbutyronitrile-3-one-diethylacetal) 10 mg (0.1 mmol) of concentrated sulfuric acid was placed in a 25-ml glass flask equipped with a stirrer and a thermometer. 1.94 g (20 mmol) of 3-cyano-2-butanone, 3.56 g (24 mmol) of ethyl orthoformate and 5 ml of ethanol synthesized in the same manner as in Example 4 were added, and the mixture was reacted at room temperature for 7 hours in a nitrogen atmosphere. After the reaction,
0.75 g (5 mmol) of potassium carbonate was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. The precipitate is filtered and the filtrate is concentrated under reduced pressure to give 2-methylbutyronitrile as a pale yellow liquid
2.91 g of -3-one-diethyl acetal was obtained (isolation yield; 85
%). The physical properties of 2-methylbutyronitrile-3-one-diethylacetal are as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.0 to 1.3 (9H,
m), 1.40 (3H, s), 3.2-3.6 (4H, m), 4.10 (1H, q)

Reference Example 6 (2-methylbutyramide oxime
Synthesis of 3-one-diethyl acetal) A sodium flask (1.46) was placed in a 25-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser.
g (36.5 mmol), water 7 ml and hydroxylamine hydrochloride 1.97
g (28.3 mmol), and a solution prepared by dissolving 2.40 g (14.0 mmol) of 2-methylbutyronitrile-3-one-diethylacetal synthesized in the same manner as in Reference Example 5 in 7 ml of methanol under ice cooling. Slowly in a nitrogen atmosphere at 10 ° C. for 2 hours, at room temperature for 13 hours, and further under heating and refluxing (70-75 ° C.) for 1.5 hours.
Allowed to react for hours. After completion of the reaction, the mixture was cooled to room temperature and extracted three times with 20 ml of ethyl acetate. The organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.45 g of 2-methylbutyramidooxime-3-one-diethylacetal as a pale yellow liquid (isolation yield;
86%). The physical property values of 2-methylbutyramidooxime-3-one-diethylacetal are as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.1 to 1.3 (9H,
m), 1.40 (3H, s), 2.8-3.2 (1H, m), 3.2-4.3 (5H, m), 5.
0-5.2 (2H, brs)

Example 5 (Synthesis of 3-Amino-4,5-dimethylisoxazole) A 25-ml glass flask equipped with a stirrer and a thermometer was synthesized in the same manner as in Reference Example 6 to obtain a 2-amino-4,5-dimethylisoxazole. 2.25 g of methylbutylamidooxime-3-one-diethylacetal (11
mmol), 13 ml of ethanol and 20 mg (0.2 mmol) of concentrated sulfuric acid, and reacted at room temperature for 15 hours in a nitrogen atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrate was recrystallized from 1 ml of isopropyl alcohol to obtain 1.00 g of 3-amino-4,5-dimethylisoxazole as a colorless powder (isolation yield; 81%).

Reference Example 7 (Synthesis of 2-acetylbenzyl cyanide) 300 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
10.8 g of sodium methoxide (0.
20 mol), 11.7 g (0.10 mol) of benzyl cyanide, 17.4 g (0.15 mol) of n-butyl acetate and 100 ml of toluene were added, and the mixture was reacted in a nitrogen atmosphere under reflux with heating (105 to 110 ° C.) for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, and water (120 ml) and concentrated hydrochloric acid (1) were added.
7 ml (0.2 mol) were added. Next, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 15.4 g of 2-acetylbenzyl cyanide as a light flesh-colored powder (isolation yield; 97%). Physical properties of 2-acetylbenzyl cyanide were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 2.30 (3H, s), 4.7
0 (1H, s), 7.4 to 7.6 (5H, m)

Reference Example 8 (Synthesis of 2- (β-ethylenedioxyaceto) benzyl cyanide) A 100 ml glass flask equipped with a stirrer, a thermometer, a reflux condenser, and a Dean-Stark apparatus was charged with p. -950 mg (5 mmol) of toluenesulfonic acid monohydrate, 7.95 g (50 mmo) of 2-acetylbenzylnitrile synthesized in the same manner as in Reference Example 7.
l), ethylene glycol 4.97 g (80 mol) and toluene 25 ml
Was added thereto, and the mixture was allowed to react for 15 hours under a reflux atmosphere (105 to 110 ° C.) in a nitrogen atmosphere while distilling off water produced by the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction solution was washed with 3 ml of saturated saline, 10 ml of a 2 mol / L aqueous sodium hydroxide solution, and 3 ml of water in this order. Next, the organic layer was taken out, and the organic layer was concentrated under reduced pressure. This concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4/1 (volume ratio))
To give 8.51 g of 2- (β-ethylenedioxyaceto) benzyl cyanide as a light brown liquid (isolation yield; 84
%). Physical properties of 2- (β-ethylenedioxyaceto) benzyl cyanide were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.36 (3H, s), 3.8
5 to 3.91 (1H, m), 3.93 to 4.10 (4H, m), 7.35 to 7.45 (5H, m)

Reference Example 9 (Synthesis of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime) A 25-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser was placed in a flask. 0.43 g (6.2 mmol) of hydroxylamine hydrochloride and 3 ml of methanol were mixed, and 0.79 g (8.8 mmol) of triethylamine was added thereto under ice-cooling, followed by stirring. Then, 0.63 g (3.1 mmo) of 2- (β-ethylenedioxyaceto) benzyl cyanide synthesized in the same manner as in Example 8.
l) A solution of 1) dissolved in 1 ml of methanol is slowly added dropwise.
The reaction was carried out in a nitrogen atmosphere under reflux with heating (60 to 64 ° C.) for 20 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 15 ml of ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1/3 (volume ratio)) to give a colorless powder. 0.60 g of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime was obtained (isolation yield; 81%). Physical properties of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.44 (3H, s), 3.3
3 to 3.40 (1H, m), 3.65 to 4.00 (5H, m), 4.50 (1H, brs), 5.2
4 (2H, brs), 7.20 ~ 7.50 (5H, m)

Example 6 (Synthesis of 3-amino-5-methyl-4-phenylmethylisoxazole) A 50 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was charged in the same manner as in Reference Example 9. Synthesized by the method
3.1 g (13.0 mmol) of 2- (β-ethylenedioxyaceto) -2-phenylacetamidooxime, isopropyl alcohol 10
ml and concentrated hydrochloric acid 1.3 ml (16 mmol) were added, and in a nitrogen atmosphere,
The reaction was performed under reflux (80-82 ° C) for 10 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate was concentrated under reduced pressure to obtain 2.0 g of 3-amino-5-methyl-4-phenylmethylisoxazole as a pale yellow powder (isolation yield: 88%). Physical properties of 3-amino-5-methyl-4-phenylmethylisoxazole were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 2.34 (3H, s), 4.0
0 (2H, brs), 7.30 ~ 7.55 (5H, m)

Reference Example 10 (Synthesis of 2-formylbenzyl cyanide) 200 ml of internal volume equipped with a stirrer, thermometer and reflux condenser
8.1 g of sodium methoxide (0.1 g
5mol), benzyl cyanide 17.6g (0.15mol), ethyl formate 1
2.3 g (0.17 mol) and 70 ml of methanol were added, and reacted at room temperature for 6 hours in a nitrogen atmosphere. After the completion of the reaction, a solid precipitated, and was filtered and dried. This solid in water 20
The solution was dissolved in 0 ml, and 5.8 ml (70 mol) of concentrated hydrochloric acid was added. The precipitated crystals were filtered and dried to obtain 9.0 g of 2-formylbenzyl cyanide as a colorless powder (isolation yield; 41%). 2-
The physical properties of formylbenzyl cyanide were as follows.

¹ H-NMR (DMSO-d ₆ , δ (ppm)); 7.32 to 7.70 (6
H, m) 、 8.06 (1H, s)

Reference Example 11 (Synthesis of 2- (β-ethylenedioxyformyl) benzyl cyanide) A 100 ml glass flask equipped with a stirrer, a thermometer, a reflux condenser, and a Dean-Stark apparatus was charged with p. -950 mg (5 mmol) of toluenesulfonic acid monohydrate, 4.10 g (28.2 g) of 2-formylbenzyl cyanide synthesized in the same manner as in Reference Example 10.
mmol), 2.81 g (45.2 mmol) of ethylene glycol, and 40 ml of toluene, and the mixture was reacted under a refluxing atmosphere (105 to 110 ° C.) for 16 hours in a nitrogen atmosphere while distilling off water produced by the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction solution was diluted with 10 ml of a saturated saline solution, 10 ml of a 2 mol / L aqueous sodium hydroxide solution, and water
Washing was performed in the order of 5 ml. Next, the organic layer was taken out, and the organic layer was concentrated under reduced pressure. This concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4/1 (volume ratio)) to give a pale yellow liquid. As a result, 4.00 g of 2- (β-ethylenedioxyformyl) benzyl cyanide was obtained (isolation yield; 75%). The physical properties of 2- (β-ethylenedioxyformyl) benzyl cyanide were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.85 to 3.95 (2H,
m), 4.00-4.15 (3H, m), 5.17 (1H, d), 7.30-7.45 (5H, m)

Reference Example 12 (Synthesis of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime) A 100 ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser was placed in a flask. 2.78 g (40 mmol) of hydroxylamine hydrochloride and 18 ml of methanol were mixed, and 5.06 g (50 mmol) of triethylamine was added thereto under ice cooling, followed by stirring. Then, 2-synthesized in the same manner as in Reference Example 11
(β-ethylenedioxyformyl) benzyl cyanide 3.79 g
A solution of (20 mmol) dissolved in 5 ml of methanol was slowly added dropwise, and the mixture was reacted under a refluxing atmosphere (60 to 64 ° C.) for 6 hours in a nitrogen atmosphere. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 60 ml of ethyl acetate and 10 ml of water were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure.
This concentrate was subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-
Hexane / ethyl acetate = 1/2 (volume ratio)) to give 0.60 g of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime as a colorless powder (isolation yield; 14).
%). Physical properties of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.75 (1 H, d, J = 3.9
Hz), 3.81 to 3.90 (4H, m), 4.83 (2H, brs), 5.40 (1H, d, J =
(3.9Hz), 7.25 to 7.44 (6H, m)

Example 7 (Synthesis of 3-amino-4-phenylisoxazole) A 25 ml glass flask equipped with a stirrer, thermometer and reflux condenser was synthesized in the same manner as in Reference Example 12. 0.34 g (1.5 mmol) of 2- (β-ethylenedioxyformyl) -2-phenylacetamidooxime, 3 ml of isopropyl alcohol and 0.2 ml (2.4 mmol) of concentrated hydrochloric acid were added, and the mixture was refluxed under a nitrogen atmosphere (80 to 82 ° C.). ) For 20 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
Then, 5 ml of a saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel).
Purified with C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1/1 → 1/2 (volume ratio), and 3-amino-4-phenyl was obtained as colorless needle crystals. 0.10 g of isoxazole was obtained.
(Isolation yield; 41%). Physical properties of 3-amino-4-phenylisoxazole were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 4.08 (2H, brs),
7.35 to 7.48 (5H, m), 8.19 (1H, s)

Reference Example 13 (Synthesis of 2-formylpropionitrile) In a 300-ml glass flask equipped with a stirrer and a thermometer, 15.5 g (0.24 mol) of 37.5% sodium hydride and 13.2 g of propionitrile were placed. (0.24 mol) and 100 ml of ether were added. Then, under ice-cooling, 40 ml (0.50 mol) of ethyl formate was slowly added dropwise, followed by reaction at room temperature for 20 hours. After the completion of the reaction, 50 ml of water and 25.5 ml (0.31 mol) of concentrated hydrochloric acid were added, and the organic layer was taken out and dried over anhydrous magnesium sulfate.
After filtration, the filtrate was concentrated under reduced pressure, and the inner lower layer of the obtained concentrated liquid was separated to obtain 3.5 g of 2-formylpropionitrile as a colorless liquid (isolation yield; 18%). Physical properties of 2-formylpropionitrile were as follows.

EI-MS (m / e); 83 (M +) CI-MS (m / e); 84 (M + 1)

Reference Example 14 (Synthesis of 2- (β-ethylenedioxyformyl) propionitrile) A 100 ml glass flask equipped with a stirrer, a thermometer, a reflux condenser, and a Dean-Stark apparatus was charged with p. -Toluenesulfonic acid monohydrate 40 mg (0.2 mmol), 2-formylpropionitrile 1.90 g (2
2.9 mmol), 2.28 g (36.7 mmol) of ethylene glycol and 20 ml of toluene were added, and the mixture was reacted for 9 hours under heating and refluxing (105 to 110 ° C.) in a nitrogen atmosphere while distilling off water produced by the reaction. After completion of the reaction, the reaction solution was cooled to room temperature, and the reaction solution was diluted with 5 ml of a saturated saline solution,
And dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 2- (β-
1.20 g of ethylenedioxyformyl) propionitrile was obtained (isolation yield; 41%). Physical properties of 2- (β-ethylenedioxyformyl) propionitrile were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.36 (3H, d), 2.80
~ 2.95 (1H, m), 3.90 ~ 4.20 (4H, m), 4.95 (1H, d)

Reference Example 15 (Synthesis of 2- (β-ethylenedioxyformyl) propionamidoxime) Hydroxylamine hydrochloride was placed in a 25-ml glass flask equipped with a stirrer, thermometer, dropping funnel and reflux condenser. 0.82 g (12 mmol) of a salt and 8 ml of methanol were mixed, and 1.45 g (14 mmol) of triethylamine was added thereto under ice cooling, followed by stirring. Then, 2- (β-
Ethylenedioxyformyl) propionitrile 0.75 g (5.9
(mmol) in 2 ml of methanol was slowly added dropwise, and the mixture was reacted under a nitrogen atmosphere under reflux with heating (60 to 64 ° C) for 20 hours. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 20 ml of ethyl acetate and 2 ml of water were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. This concentrate was purified by silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1/2 (volume ratio)) to give a colorless liquid. 0.60 g of 2- (β-ethylenedioxyformyl) propionamide oxime was obtained (isolation yield; 63%). 2- (β-
Physical properties of (ethylenedioxyformyl) propionamide oxime were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.20 (3H, d, J = 7.3
Hz), 2.58-2.68 (1H, m), 3.83-4.04 (5H, m), 4.87 (2H, b
rs), 4.92 (1H, d, J = 3.4Hz)

Example 8 (Synthesis of 3-amino-4-methylisoxazole) A 25 ml glass flask equipped with a stirrer, thermometer and reflux condenser was synthesized in the same manner as in Reference Example 15. 0.50 g (3.1 mmol) of 2- (β-ethylenedioxyformyl) propionamide oxime, 5 ml of isopropyl alcohol
And 0.5 ml (6.0 mmol) of concentrated hydrochloric acid was added, and the mixture was reacted under reflux (80 to 82 ° C.) for 20 hours in a nitrogen atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 20 ml of ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200).
(Manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 1 /
1 → 1/2 (volume ratio)) to give 3-amino as a colorless liquid
0.23 g of 4-methylisoxazole was obtained (isolation yield: 76
%). Physical properties of 3-amino-4-methylisoxazole were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.91 (3H, s), 3.9
6 (2H, brs), 7.85 (1H, s)

Reference Example 16 (2-methylbutyronitrile-3-
Synthesis of on-dimethyl acetal) In a 50 ml glass flask equipped with a stirrer and a thermometer, 10 mg (0.1 mmol) of concentrated sulfuric acid, 3-cyano-2-butanone 7.14 synthesized in the same manner as in Reference Example 4. g (73.5 mmol), 15.6 g (147 mmol) of methyl orthoformate and 30 ml of methanol were added, and the mixture was reacted at room temperature for 23 hours in a nitrogen atmosphere. After completion of the reaction, 1.02 g (6.8 mmol) of potassium carbonate was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. The precipitate is filtered, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 3 / 1 (volume ratio))
Purified with 2-methylbutyronitrile as a pale yellow liquid
9.5 g of 3-one-dimethylacetal was obtained (isolation yield; 90
%). The physical properties of 2-methylbutyronitrile-3-one-dimethylacetal were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.23 (3H, d), 1.4
0 (3H, s), 3.02 (1H, q), 3.17 (3H, s), 3.28 (3H, s)

Reference Example 17 (Synthesis of 2-methylbutylamidooxime-3-one-dimethylacetal) A hydroxylamine hydrochloride was placed in a 50-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 3.48 g (50.0 mmol) of a salt and 10 ml of methanol were mixed, and under ice-cooling, 6.33 g (62.6 mmol) of triethylamine, Reference Example 16
3.58 g (25.0 mmol) of 2-methylbutyronitrile-3-one-dimethylacetal synthesized in a similar manner to methanol 5m
The solution dissolved in l was slowly and gradually added dropwise, and the mixture was reacted for 8 hours in a nitrogen atmosphere under heating and refluxing (60 to 64 ° C). After completion of the reaction, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.
120 ml of ethyl acetate and 40 ml of water were added to the concentrate. Next, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.15 g of 2-methylbutylamidooxime-3-one-dimethylacetal as a colorless powder (isolation yield; 72%). Physical properties of 2-methylbutyramidooxime-3-one-dimethylacetal were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.12 (3H, d, J = 7.1
Hz), 1.25 (3H, s), 2.73 (1H, q, J = 7.1Hz), 3.20 (1H, br
s), 3.21 (3H, s), 3.26 (3H, s), 5.03 (2H, br)

Example 9 (Synthesis of 3-amino-4,5-dimethylisoxazole) A 25-ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was prepared in the same manner as in Reference Example 17. 2.98 g (17 mmol) of the synthesized 2-methylbutyramidooxime-3-one-dimethylacetal, 13 ml of isopropyl alcohol and 2 ml (24 mmol) of concentrated hydrochloric acid are added, and the mixture is refluxed (80 to 82 ° C.) for 3 hours in a nitrogen atmosphere. Reacted. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate and 20 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 3-amino- as a colorless solid.
1.60 g of 4,5-dimethylisoxazole was obtained (isolation yield;
84%).

Reference Example 18 (Synthesis of 2-formylbenzyl cyanide) 200 ml of internal volume equipped with a stirrer, thermometer and reflux condenser
8.1 g of sodium methoxide (0.1 g
5mol), benzyl cyanide 17.6g (0.15mol), ethyl formate 1
2.3 g (0.17 mol) and 70 ml of methanol were added, and reacted at room temperature for 6 hours in a nitrogen atmosphere. After the completion of the reaction, a solid precipitated, and the reaction solution was filtered and dried. This solid was dissolved in 200 ml of water, and 5.8 ml (70 mol) of concentrated hydrochloric acid was added. The precipitated crystals were filtered and dried to obtain 9.0 g of 2-formylbenzyl cyanide as a colorless powder (isolation yield; 41%). Physical properties of 2-formylbenzyl cyanide were as follows.

¹ H-NMR (DMSO-d ₆ , δ (ppm)); 7.32 to 7.70 (6
H, m) 、 8.06 (1H, s)

Reference Example 19 (2- (β-diethoxyformyl)
Synthesis of benzyl cyanide) In a 100-ml glass flask equipped with a stirrer and a thermometer, 10 mg (0.1 mmol) of concentrated sulfuric acid and 5.81 g of 2-formylbenzyl cyanide synthesized by the same method as in Reference Example 18 ( 40mm
ol), 17.76 g (120 mmol) of methyl orthoformate and ethanol
After adding 40 ml, the mixture was reacted at room temperature for 15 hours in a nitrogen atmosphere. After the reaction, 4.0 g (5 mmol) of potassium carbonate was added to the reaction solution.
Was added and further stirred at room temperature for 1 hour. The precipitate is filtered, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4 / 1 (volume ratio)) to obtain 4.1 g of 2- (β-diethoxyformyl) benzyl cyanide as a colorless powder (isolated yield; 47).
%). The physical properties of 2- (β-diethoxyformyl) benzyl cyanide were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.09 (3H, t), 1.2
2 (3H, t), 3.30-3.80 (4H, m), 4.00 (2H, d), 4.62 (2H,
d), 7.30-7.41 (5H, m)

Reference Example 20 (2- (β-diethoxyformyl)-
Synthesis of 2-phenylacetamido oxime) A hydroxylamine hydrochloride (695 mg, 10 mmol) and methanol (5 ml) were mixed in a 25-ml glass flask equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser. A solution prepared by dissolving 1.52 g (15 mmol) of triethylamine and 1.1 g (5 mmol) of 2- (β-diethoxyformyl) benzyl cyanide synthesized in the same manner as in Reference Example 19 in 1 ml of methanol was slowly and gradually added dropwise. The reaction was carried out in a nitrogen atmosphere under reflux with heating (60 to 64 ° C.) for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and 30 ml of ethyl acetate and 3 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate. Next, the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane /
Ethyl acetate = 1/2 (volume ratio)) as a colorless powder
0.8 g of 2- (β-diethoxyformyl) -2-phenylacetamidooxime was obtained (isolation yield; 64%). The physical properties of 2- (β-diethoxyformyl) -2-phenylacetamidooxime were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 1.12 (3H, t, J = 7.1
Hz), 1.20 (3H, t, J = 7.1Hz), 3.50-3.85 (5H, m), 4.84 (1
(H, d, J = 4.9Hz), 5.03 (2H, br), 7.25-7.45 (6H, m)

Example 10 (Synthesis of 3-amino-4-phenylisoxazole) A 25 ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was synthesized in the same manner as in Reference Example 20. 1.48 g (5.9 mmol) of 2- (β-diethoxyformyl) -2-phenylacetamidooxime, 13 ml of isopropyl alcohol
Then, 0.7 ml (8.4 mmol) of concentrated hydrochloric acid was added, and the mixture was reacted in a nitrogen atmosphere under reflux (80 to 82 ° C.) for 7.5 hours. After the reaction,
The reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate and 20 ml of a saturated aqueous sodium hydrogen carbonate solution were added to the concentrate, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate.
After filtration, the filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-20).
0 (manufactured by Wako Pure Chemical Industries), developing solvent: n-hexane / ethyl acetate = 3
/ 1 (volume ratio)) to give 3-amino-4- as a colorless powder.
0.70 of phenylisoxazole was obtained (isolation yield: 74)
%).

¹ H-NMR (CDCl ₃ , δ (ppm));

Reference Example 21 (Synthesis of 2-benzoylbenzyl cyanide) 300 ml in internal volume equipped with a stirrer, thermometer and reflux condenser
10.8 g of sodium methoxide (0.
20 mol), 11.7 g (0.10 mol) of benzyl cyanide, 20.4 g (0.15 mol) of methyl benzoate and 60 ml of toluene were added, and reacted under reflux with heating (105 to 110 ° C.) for 2.5 hours. After the reaction,
120 ml of water and 17 ml (0.2 mol) of concentrated hydrochloric acid were added, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate was concentrated under reduced pressure. The concentrate was recrystallized from 15 ml of toluene to obtain 15.4 g of 2-benzoylbenzyl cyanide as colorless needles (isolation yield; 70%). Physical property values of 2-benzoylbenzyl cyanide were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 5.60 (1 H, s), 7.3
5 to 8.20 (10H, m)

Reference Example 22 (Synthesis of 2- (β-ethylenedioxybenzoyl) benzyl cyanide) A 100 ml glass flask equipped with a stirrer, thermometer, reflux condenser and Dean-Stark apparatus was charged with p -Toluenesulfonic acid monohydrate 950 mg (5 mmol), 4.43 g of 2-benzoylbenzylnitrile synthesized in the same manner as in Reference Example 21 (2
(0.0 mmol), 4.97 g (80.0 mmol) of ethylene glycol, and 40 ml of xylene, and the mixture was allowed to react under a nitrogen atmosphere under heating and refluxing (135 to 140 ° C.) for 25 hours while distilling off water produced by the reaction. After completion of the reaction, the mixture was cooled to room temperature, and 60 ml of a 10% aqueous sodium carbonate solution was added. Since a solid was deposited, the reaction solution was filtered, 10 ml of water was added to the filtrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration,
The filtrate is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 4/1 (volume ratio)) To give 1.51 g of 2- (β-ethylenedioxybenzoyl) benzyl cyanide as a pale yellow liquid (isolation yield; 29%). Physical properties of 2- (β-ethylenedioxybenzoyl) benzyl cyanide were as follows.

[0083] _{^{1 H-NMR (CDCl 3,}} δ (ppm)); 3.82~4.20 (4H,
m), 4.23 (1H, s), 7.10 ~ 7.40 (10H, m)

Reference Example 23 (Synthesis of 2- (β-ethylenedioxybenzoyl) -2-phenylacetamidooxime) A 25 ml glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser was placed in a flask. 0.23 g (3.3 mmol) of hydroxylamine hydrochloride and 3 ml of methanol were mixed, and under ice-cooling, 0.41 g (4.1 mmol) of triethylamine was added and stirred. Then, 2- (β-
0.43 g of ethylenedioxybenzoyl) benzyl cyanide
A solution prepared by dissolving (1.6 mmol) in 1 ml of methanol was slowly added dropwise, and the mixture was reacted under a refluxing atmosphere (60 to 64 ° C.) for 20 hours in a nitrogen atmosphere. After the completion of the reaction, the resultant was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Next, 20 ml of ethyl acetate and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate were added to the concentrate, and the organic layer was taken out and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate is added to this concentrate.
After adding 3 ml and refluxing, the precipitate was filtered and dried,
2- (β-ethylenedioxybenzoyl) -2- as a colorless powder
0.30 g of phenylacetamidooxime was obtained (isolation yield;
63%). Physical properties of 2- (β-ethylenedioxybenzoyl) -2-phenylacetamidooxime were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.74 to 3.86 (3H,
m), 3.95-4.00 (2H, m), 5.23 (2H, brs), 5.72 (1H, brs),
7.19 to 7.44 (10H, m)

Example 11 (Synthesis of 3-amino-4,5-diphenylisoxazole) A 25-ml glass flask equipped with a stirrer, a thermometer and a reflux condenser was prepared in the same manner as in Reference Example 23. 0.50 (1.7 mmol) of the synthesized 2- (β-ethylenedioxybenzoyl) -2-phenylacetamidooxime, 5 ml of isopropyl alcohol and 0.5 ml (6.0 mmol) of concentrated hydrochloric acid were added, and the mixture was refluxed (80 to 82 C) for 30 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure.
ml and a saturated aqueous solution of sodium bicarbonate (10 ml) were added, the organic layer was taken out, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure to give a colorless powder
0.30 g of 3-amino-4,5-diphenylisoxazole was obtained.
(Isolation yield; 76%).

¹ H-NMR (CDCl ₃ , δ (ppm)); 5.33 (2H, brs),
7.10 to 7.40 (10H, m)

[0088]

According to the present invention, an industrially suitable 4-substituted 4-substituted-3-aminoisoxazole derivative is obtained from a readily available dialkoxyamide oxime derivative by a simple method in a high yield. A method for producing a -3-aminoisoxazole derivative can be provided.

Continuing from the front page (72) Inventor Taku Nakamura 5-1978 Kogushi, Oji, Ube City, Yamaguchi Prefecture Inside Ube Research Laboratories (72) Inventor Shuji Yamada 5 1978 Kogushi, Oji City, Ube City, Yamaguchi Ube F-term in the laboratory (reference) 4C056 AA01 AB01 AC01 AD01 AE03 AF01 FA03 FA04 FB10 FC01 4H039 CA42 CH10

Claims (2)

[Claims] (1) In the presence of an acid, a compound represented by the following general formula (1): (Wherein R ¹ and R ² are groups not participating in the reaction (provided that R ¹ and R ² are
² excludes a hydrogen atom), R ³ and R ⁴ may be the same or different and represent a group which does not participate in the reaction. Note that R
³ and R ⁴ may be linked to form a ring. ), Wherein the dialkoxyamide oxime derivative represented by the general formula (2) is subjected to a cyclization reaction. (Wherein, R ¹ and R ² have the same meanings as described above.) A method for producing a 4-substituted-3-aminoisoxazole derivative represented by the formula: 2. The 4-substitution according to claim 1, wherein the reaction is carried out in a solvent.
Production method of -3-aminoisoxazole derivative.