JPH11349577A - Isoxazole derivative and 1,2,4-thiadiazol-3-ylacetic acid derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a production raw material for medicines. SOLUTION: This compound is represented by formula I [R<1> is a (substituted) aryl or the like], e.g. a compound of formula II. This compound of formula I is obtained by reacting an acrylonitrile derivative of the formula: (R<1> O)2 C=CH- CN with preferably 1.5-6.0 equivalent hydroxylamine in a solvent such as methanol in the presence of a base (e.g. sodium methoxide). Furthermore, 1,2,4- thiadiazol-3-ylacetic acid derivative (e.g. a compound o formula IV) of formula III [R<2> is a (substituted) alkyl, a (substituted) aryl or the like] obtained by reacting the compound of formula I with a thiocyanic acid salt (e.g. potassium thiocyanate) and an acyl halide is also useful as a raw material for production of medicine compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an isoxazole derivative useful as a raw material for the production of pharmaceuticals such as sulfa drugs, antihypertensive agents, diuretics, etc., and an acylating agent used for the production of 7-acylaminocephalosporins. The present invention relates to a 1,2,4-thiadiazol-3-ylacetic acid derivative useful as a raw material for the synthesis of, and a method for producing the same.

[0002]

2. Description of the Related Art Various types of 7-acylaminocephalosporins have been known as antibiotics, and various methods for producing the same have been disclosed. The most typical one is a method of reacting 7-aminocephalosporins with an acylating agent to obtain 7-acylaminocephalosporins. It is known that the antibacterial activity and antibacterial spectrum of 7-acylaminocephalosporins vary greatly depending on the structure of the 7-position acyl group. Conventionally, compounds having a 7-position acyl group having various structures have been proposed, and various acylating agents corresponding to the structures have been developed. Among them, 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-substituted oxyiminoacetic acid is 7- [2- (5-amino-) produced using this acylating agent. [1,2,4-thiadiazol-3-yl) -2-substituted oxyiminoacetamido] cephalosporins are widely used as raw materials for producing cephalosporins because they generally have excellent antibacterial activity.

[0003] Various methods have conventionally been known as methods for producing 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-substituted oxyiminoacetic acid derivatives. Some disadvantages were the use of highly reactive reagents and the use of reaction conditions unsuitable for industrial scale implementation. For example, J. Antibiotics, 36, pp. 1020-1033, 19
83 has 5-tert-butoxycarbonylamino-3-methyl-
Lithium diisopropylamide is allowed to act on 1,2,4-thiadiazole and then reacted with carbon dioxide to produce 2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) acetic acid Although a method is disclosed, this method involves adding lithium diisopropylamide to -78.
It has the disadvantage of having to be prepared at a low temperature of ° C.

Japanese Patent Application Laid-Open No. Hei 5-194448 discloses an interesting rearrangement reaction in which aminoisoxazoles are reacted with a thiocyanate and an acyl halide to convert them into 1,2,4-thiadiazoles. In this method, 5-alkoxy-3-aminoisoxazoles used as raw materials are
For example, it can be synthesized according to the method described in Japanese Patent Publication No. 45-39702, but the substituent at the 5-position on the isoxazole ring is limited to a lower alkoxy group. No description is given regarding derivatives having a substituent, for example, an aryloxy group.

[0005]

According to the study of the present inventors, among the 5-alkoxy-3-aminoisoxazoles, derivatives having a small number of carbon atoms in the 5-position alkoxy group are generally unstable. It became clear. For example, 3-amino-5-methoxyisoxazole and 3-amino-5-ethoxyisoxazole were colored in a few days at room temperature, and when these colored substances were analyzed by HPLC, an impurity peak was observed. Such an unstable compound is not preferable as an intermediate for drug synthesis. In addition, these aminoisoxazoles have a relatively high water solubility and are difficult to perform post-treatment and isolation and purification after the reaction, and therefore cannot be suitably used for production on an industrial scale.

[0006] On the other hand, aminoisoxazoles are important compounds in the production of medicaments such as sulfa drugs, antihypertensive agents, diuretics and the like, and a method for easily synthesizing aminoisoxazole derivatives having various substituents has been developed. Is an important task.

Accordingly, an object of the present invention is to provide an aminoisoxazole derivative which can be suitably used as a raw material for producing a pharmaceutical, and a method for producing the same. Another object of the present invention is to provide a 1,2,4-thiadiazol-3-ylacetic acid derivative derived from the above aminoisoxazole derivative and useful as a raw material for the production of a medicament, and a method for producing the same. .

[0008]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and found that
Aminoisoxazole derivative represented by (I) and 1,2,4-thiadiazole-3- represented by the following general formula (II)
It has been found that the above problem can be solved by providing an ilacetic acid derivative. The present invention has been completed based on the above findings.

That is, the present invention provides the following general formula (I):

Embedded image (Wherein R ¹ represents an aryl group which may have a substituent) or a salt thereof.

Further, according to the present invention, there is provided a method for producing a compound represented by the above general formula (I) or a salt thereof, wherein (R ¹ O) ₂
There is provided a method comprising reacting a compound represented by C = CH-CN (wherein R ¹ represents an optionally substituted aryl group) with hydroxylamine in the presence of a base. According to a preferred embodiment of this method, there is provided the above method wherein the base is an alkali metal alkoxide or a tertiary organic base, and the above method wherein the base is sodium methoxide.

From another viewpoint, the following general formula (II):

Embedded image (Wherein, R ¹ represents an aryl group which may have a substituent, R ² represents an alkyl group which may have a substituent, an aryl group which may have a substituent, An optionally substituted arylalkyl group, an optionally substituted alkyloxy group, an optionally substituted aryloxy group, or an optionally substituted arylalkyloxy A compound represented by the formula: or a salt thereof is provided by the present invention.

Further, according to the present invention, there is provided a process for producing a compound represented by the above general formula (II) or a salt thereof, wherein the compound represented by the above general formula (I) or a salt thereof is combined with a thiocyanate and an acyl halide. A method comprising the step of reacting is provided.

From a further aspect, there is provided a method for producing a compound represented by the above general formula (II) or a salt thereof, comprising the following steps: (a) (R ¹ O) ₂ C = CH—CN (formula Wherein R ¹ represents an aryl group which may have a substituent)) and a compound represented by the above general formula (I)
A step of producing a compound represented by the formula: and (b) step (a)
And reacting the compound represented by the general formula (I) obtained in the above with a thiocyanate and an acyl halide.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The meanings of the terms used in the present specification are as follows. The aryl group includes, for example, 6 to 18 carbon atoms, preferably 6 to 14 carbon atoms, more preferably 6 to 12 carbon atoms, and particularly preferably 6 to 1 carbon atoms.
Zero monocyclic, bicyclic, tricyclic or tetracyclic aryl groups can be mentioned. In the case of a bicyclic to tetracyclic aryl group, each ring may be either a condensed ring or an independent ring. More specifically, examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a 4-biphenyl group.A phenyl group, a 1-naphthyl group, and a 2-naphthyl group are preferably used. be able to. In a substituent containing an aryl moiety (for example, an aryloxy group or an arylalkyl group), it is preferable that the aryl group constitutes the aryl moiety. Further, the aryl moiety in the aryl group or the substituent containing the aryl moiety may have a substituent.

In the present specification, when a functional group (for example, an aryl group, an aryloxy group, an alkyl group, etc.) is "may have a substituent", the number and kind of the substituent and the position of the substituent Is not particularly limited, and when a plurality of substituents are present, they may be the same or different. Examples of the substituent that can be present on the functional group include a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an aryloxy group, an arylalkyl group, an alkenyl group, an alkynyl group, a cyano group, a hydroxyl group, and an amino group. Group, monoalkylamino group, dialkylamino group, alkylthio group, arylthio group, alkylsulfonyl group, arylsulfonyl group,
Examples include, but are not limited to, nitro, formyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, carbamoyl, sulfamoyl, alkylenedioxy and the like. Further, these substituents may further have one or more substituents. In such a case, the substituents exemplified above can be suitably used as the substituent. For example, a substituent having an aryl group such as an arylalkyl group or an arylcarbonyl group may have an alkyl group, a halogen atom, an alkoxy group, or the like on the aryl ring.
It may have about five, preferably one or two.

In the present specification, the term "halogen atom" may be any of fluorine, chlorine, bromine and iodine, and two or more halogen atoms are present in a substituent containing a halogen atom (for example, a haloalkyl group). If so, they may be the same or different. In the present specification, the term “alkyl group” means, for example, a linear, branched, or cyclic group having 1 to 22 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 8 carbon atoms. Or a combination thereof, and preferably a linear or branched alkyl group. Further, in the present specification, when referring to a substituent containing an alkyl moiety (for example, an alkoxy group, a haloalkyl group, an arylalkyl group, an alkylcarbonyl group, an alkylsulfonyl group, and the like), the alkyl moiety in these substituents is as described above. It is preferably composed of an alkyl group.

More specifically, examples of the alkyl group include a methyl group, an isopropyl group, a t-butyl group and a 1,1-dimethylpropyl group. Examples of the haloalkyl group include a trifluoromethyl group, Examples thereof include a 2-bromoethyl group and a 2,2,2-trichloroethyl group. Examples of the alkoxy group include a methoxy group, an isopropyloxy group, and a t-butoxy group. Examples of the aryloxy group include a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group. The alkyl groups present in the dialkylamino group may be the same or different. Further, these two alkyl groups may be linked to each other to form a 3- to 8-membered ring, and these rings are formed of one or more hetero atoms selected from an oxygen atom, a nitrogen atom, a sulfur atom, and the like. May be further included. When two or more heteroatoms are contained, they may be the same or different. More specifically, examples of the dialkylamino group include a dimethylamino group and a diisopropylamino group.Examples of the ring formed by linking two alkyl groups to each other include, for example, a pyrrolidine ring, an aziridine ring, Examples include a morpholine ring and an indoline ring.
One or more alkyl groups may be present on these rings. An example of such is the 3-methyl-1-piperazinyl group.

Examples of the alkylthio group include a methylthio group and an isopropylthio group, and examples of the arylthio group include a phenylthio group. Examples of the alkylsulfonyl group include a methylsulfonyl group, and examples of the arylsulfonyl group include a phenylsulfonyl group. Examples of the alkylcarbonyl group include, for example, an acetyl group or a pivaloyl group, and examples of the arylcarbonyl group include, for example, a benzoyl group, a 1-naphthoyl group, or
Examples thereof include a 2-naphthoyl group. Examples of the alkoxycarbonyl group include, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group,
Or a benzyloxycarbonyl group.

The compounds of the present invention represented by the above general formulas (I) and (II) may exist as an acid addition salt, and depending on the type of the substituent, may also exist as a base addition salt. The type of salt is not particularly limited, for example,
Mineral salts such as hydrochloride, sulfate, nitrate; or organic acid salts such as p-toluenesulfonate, methanesulfonate, acetate, maleate, fumarate, tartrate, citrate; sodium Metal salts such as salts, potassium salts, calcium salts, and magnesium salts; organic amine salts such as ammonium salts, triethylamine salts, and morpholine salts; and amino acid salts such as arginine salts and aspartates. Although the above compounds of the present invention or salts thereof may exist as hydrates or solvates, these substances are also included in the scope of the present invention. The type of the solvent forming the solvate is not particularly limited, and examples thereof include solvents such as ethanol, acetone, tetrahydrofuran, and isopropyl alcohol.

The above compound of the present invention may have one or more asymmetric carbons depending on the type of the substituent, but any optical isomer based on these asymmetric carbons Or, all diastereoisomers are included in the scope of the present invention. In addition to the isomers in pure form, any mixtures thereof, racemates and the like are also included in the scope of the present invention. Where the compounds of the present invention contain one or more double bonds, any geometric isomers based on these double bonds are also included in the scope of the present invention. Further, the compound represented by the general formula (II) has tautomers, and the chemical structural formula described in the present specification describes one of these tautomers for convenience. You should understand.
It goes without saying that any tautomers are included in the scope of the present invention.

The above general formulas (I) and (II), and (R
¹ O) ₂ C = CH-CN In the compound represented by R ¹ ,
Examples of the unsubstituted aryl group include a phenyl group,
-Naphthyl group or 2-naphthyl group. Examples of the aryl group having a substituent include, for example, 4-
Methoxyphenyl group, 2,6-dimethoxyphenyl group, 4-nitrophenyl group, 2-methoxyphenyl group, 2-chlorophenyl group, 2-fluorophenyl group, 2,6-difluorophenyl group, 2-trifluoromethylphenyl group , A 2-cyanophenyl group, or a 4-pyrrolidinophenyl group.

The 5-aryloxy-3-aminoisoxazole derivative represented by the above general formula (I) is a compound which generally has good crystallinity, is easy to handle and is stable, and is suitable as a raw material for producing pharmaceutical compounds and the like. It can be used for
Hereinafter, preferred specific examples of the 5-aryloxy-3-aminoisoxazole derivative of the present invention represented by the above general formula (I) will be shown, but the present invention is not limited thereto. The ionic group present in the molecule may form a salt with an appropriate counter ion, but the counter ion is omitted in the following specific examples.

[0023]

Embedded image

In the general formula (II), when R ² is an alkyl group which may have a substituent, examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group and a t-
A butyl group, a cyclohexyl group and the like can be mentioned, and a methyl group, an ethyl group and a t-butyl group are preferred. When R ² is an aryl group which may have a substituent, examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a 4-biphenyl group. Preferably phenyl group, 1-naphthyl group,
It is a 2-naphthyl group, and a phenyl group is particularly preferred. Examples of the aryl group having a substituent include a 4-chlorophenyl group. When R ² is an arylalkyl group which may have a substituent, examples thereof include a benzyl group and a phenethyl group, and a benzyl group is preferable. When R ² is an alkyloxy group which may have a substituent, the alkyloxy group includes
For example, a methoxy group, an ethoxy group, an isopropyloxy group, a t-butoxy group, a cyclohexyloxy group and the like can be mentioned, but a methoxy group, an ethoxy group, or a t-butoxy group is preferable, and a methoxy group or t-butoxy group.

When R ² is an optionally substituted aryloxy group, examples of the aryloxy group include a phenoxy group, a 1-naphthyloxy group and a 2-naphthyloxy group. Preferably it is a phenoxy group. When R ² is an arylalkyloxy group which may have a substituent, examples of the arylalkyloxy group include a benzyloxy group. As the aryloxy group having a substituent, for example,
A 4-nitrophenoxy group can be mentioned. Alkyl group represented by R ^2, an aryl group, an arylalkyl group,
As the substituent that may be present on the alkyloxy group, the aryloxy group, and the arylalkyloxy group, preferably, a halogen atom, an alkoxy group, a cyano group, a nitro group, and the like can be given, but it is not limited thereto. Never. As the alkoxy group, for example, one having 1 carbon atom
To 8, preferably an alkoxy group having 1 to 4 carbon atoms, specifically, methoxy group, isopropyloxy group, t-butoxy group and the like.

The 1,2,4-thiadiazol-3-ylacetic acid derivative represented by the general formula (II) is also suitable as a raw material for producing a pharmaceutical compound because it generally has good crystallinity, is easy to handle and is stable. It is. The compound represented by the general formula (II) can be converted to a 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-substituted oxyiminoacetic acid derivative according to a known method. Specific examples of the compound of the present invention represented by the general formula (II) are shown below, but the scope of the present invention is not limited thereto. In the following specific examples, one tautomer is unified and described.

[0027]

Embedded image

The compound represented by the above general formula (I) is (R ¹
O) ₂ C = CH-CN be prepared by a process comprising (wherein, R ¹ is the step of reacting a hydroxylamine compound in the presence of a base represented by the same meaning as defined above) (Step (a)) Can be. The compound represented by the general formula (II) can be produced by a method including a step (step (b)) of reacting the compound represented by the general formula (I) with a thiocyanate and an acyl halide. . In producing the compound represented by the general formula (II), the above step (a) and step (b) may be continuously performed as a so-called one-pot reaction.

The acrylonitrile derivative represented by (R ¹ O) ₂ C = CH—CN (wherein R ¹ has the same meaning as described above) used as a starting material is described in, for example, Japanese Patent Publication No. 7-74188. It can be manufactured according to the method. For this acrylonitrile derivative, for example, in a solvent such as alcohol,
The compound of formula (I) can be prepared by reacting hydroxylamine in the presence of an excess base.
Examples of the alcohol that can be used as the solvent include methanol, ethanol, isopropyl alcohol, t-butyl alcohol, ethylene glycol, and ethylene glycol monomethyl ether.
Preferred solvents include methanol, ethanol, or isopropyl alcohol.

As the base, an alkali metal alkoxide or a tertiary organic base is preferably used. As the alkali metal alkoxide, for example, sodium methoxide,
Sodium ethoxide, potassium t-butoxide and the like can be mentioned. These can be used in powder form, but may be used as a solution such as a 28% sodium methoxide methanol solution. It is also possible to add alcohol to an alkali metal to prepare it at the time of use. Examples of the tertiary organic base include pyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diethylbenzylamine, 2-methylpyridine, 2,6-lutidine and the like. Preferred bases include sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine, or pyridine. Of these, sodium methoxide is particularly preferred.

As the hydroxylamine, any substance in a free form or a salt form may be used. For example, hydroxylamine, hydroxylamine sulfate, hydroxylamine hydrochloride, or the like can be used. Also,
A compound that gives hydroxylamine in the reaction system or a salt thereof, for example, an N-substituted hydroxylamine derivative or the like may be used. For example, hydroxyl urethane, carbamoylhydroxylamine and the like can be used. It should be understood that the term "hydroxylamine" as used herein encompasses substances or salts thereof that provide hydroxylamine in the reaction system. Preferably, hydroxylamine is reacted in an amount of about 1.5 to 6.0 equivalents to the acrylonitrile derivative.

As a specific example of the production method, for example, an excess 28% sodium methoxide methanol solution is added to a methanol solution of hydroxylamine hydrochloride to prepare a methanol solution of hydroxylamine.
A method of adding (2,6-dimethoxyphenyloxy) acrylonitrile, followed by heating and reaction can be mentioned. After completion of the reaction, the insolubles are removed by filtration, the filtrate is appropriately concentrated, and then the desired product is crystallized by adding cold water, and the compound of formula (I) can be produced by isolating the crystals. . In this reaction, a phenolic compound represented by the formula R ¹ —OH (wherein R ¹ has the same meaning as described above) is by-produced, but usually, this by-product can be effectively removed in the crystallization step. . As a method for isolating the target compound, a method involving extraction with an organic solvent such as toluene, ether, or ethyl acetate can be used in addition to the crystallization method.

A 1,2,4-thiadiazole derivative represented by the general formula (II) is obtained by reacting a 5-substituted-3-aminoisoxazole derivative represented by the general formula (I) with a thiocyanate and an acyl halide. Can be manufactured. As the thiocyanate as a reactant, an alkali metal thiocyanate, specifically, potassium thiocyanate,
It is preferred to use sodium thiocyanate. As the acyl halide, a compound represented by the formula R ² —CO—X (where X represents a halogen atom and R ² has the same meaning as described above) is preferable. The reactants thiocyanate and acyl halide may be directly reacted with the isoxazole derivative represented by the general formula (I), but the thiocyanate and the acyl halide are reacted in advance to form the acyl isothiocyanate in the reaction system. Preferably, the acyl isothiocyanate is reacted with an isoxazole derivative represented by the general formula (I). It should be understood that the term "thiocyanate and acyl halide" as used herein includes acyl isothiocyanate, a reactive species prepared from these two reagents.

When preparing the acyl isothiocyanate, the equivalent number of the thiocyanate and the acyl halide is preferably 1.0 to 1.5 equivalents to the acyl halide, and the acyl isothiocyanate is preferably an isoxazole derivative. It is preferable to make the reaction 1.1 to 5.0 equivalents. This reaction proceeds smoothly in an inert organic solvent.
Examples of the solvent that can be used include, for example, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, N-methylpyrrolidone, dimethylsulfoxide, and the like.A preferable solvent is tetrahydrofuran, N, N-dimethylacetamide. , Acetonitrile.

As a specific example of the production method, acyl isothiocyanate is prepared by reacting a small excess of methyl chloroformate with an acetonitrile solution of potassium thiocyanate,
A method of adding 3-amino-5- (2 ′, 6′-dimethoxyphenyloxy) isoxazole to the reaction mixture and reacting the mixture can be mentioned. After appropriately concentrating the reaction mixture,
The target substance can be isolated by extracting with an organic solvent and concentrating the organic layer. As an extraction solvent, toluene,
Ether, ethyl acetate, and the like can be used as appropriate.
As a method for isolating the target compound, besides extraction with an organic solvent, a method of depositing crystals by crystallization and collecting the precipitate by filtration may be employed. The reaction raw materials can be used in the form of a salt. As the salt, those specifically exemplified above can be used.

Since more specific methods of the present invention are described in the examples, those skilled in the art can refer to the above general description and the specific examples to explain the reaction reagents, starting compounds, By appropriately selecting the conditions, or by adding appropriate modifications or alterations to these methods,
The compound of formula (I) or the compound of formula (II) can be easily produced. In addition, the reaction product in each of these steps may be separated or purified by ordinary means as necessary, such as recrystallization, chromatography using silica gel or alumina, extraction,
It can be separated and purified by means such as distillation, or may be omitted and used as a raw material or reagent for production in another production process.

[0037]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the compounds of the present invention and the method for producing them are limited to those described in the following Examples. The compound numbers in the examples are the same as those shown as specific examples above.

[0038]

Embedded image

Example 1 Synthesis of Compound 2 A 28% sodium methoxide methanol solution (40.5 g, 210 mmol) was added dropwise to a solution of hydroxylamine hydrochloride (10.4 g, 150 mmol) in methanol (100 mL), and the reaction mixture was added. Stirred at room temperature for 30 minutes. Intermediate 1 (16.2
g, 50 mmol) and the reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and insolubles were removed by filtration. After the filtrate was appropriately concentrated, about 200 mL of cold water was added to precipitate crystals. After the crystallization solution was stirred at room temperature for 1 hour, the crystals were collected by filtration, washed with cold water, and air-dried to obtain 10.1 g of the desired product (compound 2) as crystals (yield 86.0%). MS: m / z 95, 125, 154, 176, 193, 236 (M ⁺ ) IR: νmax (KBr) 3450 (m), 3300 (w), 2930 (w), 1650
(s), 1600 (m), 1460 (s), 1260 (s), 1210 (m), 1110
(s), 760 (m), 730 (w) cm ^-1

Example 2: Synthesis of compound 12 A solution of potassium thiocyanate (2.14 g, 22 mmol) in acetonitrile (40 mL) was treated with methyl chloroformate (1.89 g, 20 mL).
mmol) was added dropwise at room temperature, and the reaction mixture was heated and stirred at 80 ° C. After cooling the reaction mixture to an internal temperature of 10 ° C.,
A suspension of (2.36 g, 10 mmol) in acetonitrile (10 mL) was added and the reaction mixture was further stirred at 10 ° C. for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 3.12 g of the desired product (compound 12) as crystals (yield: 88.4%). MS: m / z 139, 154, 200, 278, 353 (M ⁺ ) IR: νmax (KBr) 3450 (br.m), 3200 (m), 3000 (m), 1
720 (m), 1640 (s), 1500 (s), 1450 (s), 1320 (s), 1
260 (s), 1240 (s), 1110 (s), 770 (m), 755 (m) cm ^-1

EXAMPLE 3 Synthesis of Compound 5 Hydroxylamine hydrochloride (13.9 g) in ethanol (10
(0 mL), triethylamine (28.3 g) was added dropwise to the solution, and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added 3,3-di (2'-methoxyphenoxy) acrylonitrile (14.9
g) was added while washing with ethanol (15 mL), and the reaction mixture was stirred while heating at reflux for 6 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added thereto, followed by liquid separation, and then the organic layer was separated. The organic layer was washed with water and concentrated, and the resulting residue was treated with hexane / isopropyl alcohol (2 /
Crystallized from the mixed solvent system consisting of 1). After the crystallization liquid was stirred at room temperature for 1 hour, the crystals were collected by filtration, washed with a mixed solvent of hexane / isopropyl alcohol (5/1), and dried to obtain 8.6 g of the desired product (compound 5) as crystals. (Yield 83.5%). MS: m / z 77, 109, 135, 206 (M ⁺ ) IR: νmax (KBr) 3430 (s), 3300 (w), 3250 (w), 3200
(m), 2930 (w), 1650 (s), 1605 (w), 1595 (w), 1515
(s), 1500 (s) 1475 (s), 1260 (s), 1210 (s), 1105
(s), 1040 (m), 1020 (m), 730 (m), 700 (m) cm ^-1

Example 4: Synthesis of compound 15 Potassium thiocyanate (1.60 g) in acetonitrile (20
Methyl chloroformate (1.42 g) was added dropwise to the solution at room temperature, and the reaction mixture was heated and stirred at 80 ° C. for 50 minutes. After the reaction mixture was cooled to an internal temperature of 50 ° C, a suspension of compound 5 (1.03 g) in acetonitrile (10 mL) was added, and the mixture was heated with stirring at 50 ° C for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature,
Ethyl acetate, hexane and water were added to carry out liquid separation, and the organic layer was separated. The organic layer was washed with water and concentrated. The obtained residue was dissolved in methanol and water was added to precipitate crystals. After leaving the crystallization solution at room temperature overnight, the crystals were collected by filtration, washed with a mixed solvent of water / methanol (2/1), and dried to obtain 1.26 g of the desired product (compound 15) as crystals. (Yield 77.8
%). MS: m / z 124, 200, 228, 248, 291, 323 (M ⁺ ) IR: νmax (KBr) 3450 (br.w), 3200 (m), 3005 (m), 1
720 (s), 1640 (s), 1585 (s), 1540 (s), 1500 (s), 1
440 (s), 1330 (s), 1255 (s), 1180 (s), 1040 (s), 10
25 (m), 775 (m), 760 (m), 745 (m), 735 (m), 710
(m) cm ^-1

Example 5: Synthesis of Compounds 1 and 11 According to the method described in Example 1, diphenoxyacrylonitrile was reacted with hydroxylamine to obtain Compound 1.
Next, according to the method of Example 2, the obtained Compound 1 was reacted with potassium thiocyanate and benzyl chloroformate in acetonitrile to obtain Compound 11.

Example 6: Partition coefficient of the isoxazole derivative of the present invention in ethyl acetate / water system 5-alkoxy-3-aminoisoxazoles having a small number of carbon atoms in the 5-position alkoxy group have relatively high water solubility, and the reaction system When extracting from inside, the loss to the aqueous phase is so large that it cannot be ignored. On the other hand, the isoxazole derivative of the present invention has a high fat-solubility, and thus is characterized by an excellent recovery rate. Using 3-amino-5- (2 ′, 6′-dimethoxyphenyloxy) isoxazole as the compound of the present invention, the partition coefficient in an ethyl acetate / water system was compared with that of 3-amino-5-methoxyisoxazole.

About 100 mg of 3-amino-5-methoxyisoxazole or 3-amino-5- (2 ', 6'-dimethoxyphenyloxy) isoxazole was dissolved in 100 mL of ethyl acetate. After shaking the above ethyl acetate solution in a separating funnel with 100 mL of water, 12% NaCl aqueous solution, or 24% NaCl aqueous solution,
The organic and aqueous layers were separated, sampled from each layer and analyzed by HPLC. The HPLC conditions are as follows. Column: TSK gel ODS 80T Eluent: A: distilled water B: methanol / distilled water = 95/5 (0.2% phosphoric acid + 0.2% triethylamine) A / B = 95/5 Detection wavelength: UV 215 nm

[0046]

[Table 1]

From the above experimental results, the isoxazole derivative of the present invention shows an aqueous layer as compared with 3-aminoisoxazole having a small number of carbon atoms in the 5-position alkoxy group such as 3-amino-5-methoxyisoxazole. It is clear that there is little loss to the material and it is easy to handle.

[0048]

The 5-aryloxy-3-aminoisoxazole derivative of the present invention represented by the formula (I) and the compound represented by the formula (II)
The 1,2,4-thiadiazol-3-ylacetic acid derivative represented by is generally stable, has good crystallinity, and is easy to handle. In addition, no special reactor or special reaction conditions are required for the production of these compounds, and a high-purity target product can be produced in a high yield even on an industrial scale. Therefore, the compound and the production method of the present invention are characterized in that they can be suitably used for producing a pharmaceutical compound.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Hideto Mori 2-12-1, Ogimachi, Odawara-shi, Kanagawa Inside Fuji Photo Film Co., Ltd. Odawara Plant

Claims (7)

[Claims] 1. The following general formula (I): (Wherein, R ¹ represents an aryl group which may have a substituent) or a salt thereof. 2. A method for producing a compound represented by the general formula (I) or a salt thereof according to claim 1, wherein (R ¹ O) ₂ C = CH-C
A method comprising reacting a compound represented by N (wherein R ¹ represents an aryl group which may have a substituent) with hydroxylamine in the presence of a base. 3. The base is an alkali metal alkoxide or 3
The production method according to claim 2, which is a grade organic base. 4. The method according to claim 2, wherein the base is sodium methoxide. 5. The following general formula (II): (Wherein, R ¹ represents an aryl group which may have a substituent, R ² represents an alkyl group which may have a substituent, an aryl group which may have a substituent, An optionally substituted arylalkyl group, an optionally substituted alkyloxy group, an optionally substituted aryloxy group, or an optionally substituted arylalkyloxy Or a salt thereof. 6. A method for producing a compound represented by the general formula (II) or a salt thereof according to claim 5, wherein the compound represented by the general formula (I) or the salt thereof is thiocyanate. Reacting with an acid salt and an acyl halide. 7. A method for producing a compound represented by the general formula (II) or a salt thereof according to claim 5, comprising the following steps: (a) (R ¹ O) ₂ C = CH—CN (formula Wherein R ¹ represents an aryl group which may have a substituent), wherein the compound represented by the general formula (I) according to claim 1 is reacted with hydroxylamine in the presence of a base. Manufacturing a;
(b) A method comprising reacting the compound represented by the general formula (I) obtained in the step (a) with a thiocyanate and an acyl halide.