WO2016143654A1

WO2016143654A1 - Production method for 1,2,4-oxadiazole derivative

Info

Publication number: WO2016143654A1
Application number: PCT/JP2016/056552
Authority: WO
Inventors: 直輝市野川; 祐小野崎
Original assignee: 旭硝子株式会社
Priority date: 2015-03-06
Filing date: 2016-03-03
Publication date: 2016-09-15

Abstract

　Provided is a production method for a 1,2,4-oxadiazole derivative, said production method being simple and exhibiting excellent production efficiency.　The production method for a 1,2,4-oxadiazole derivative represented by formula (A) is characterized by the reaction of a compound represented by formula (B) and a compound represented by formula (C). (In the formulae, Ar represents an aromatic group or an aromatic group having a substituent group. W, X, Y and Z independently represent -S-, -N=, -CH= or -CR=, with one of W, X, Y and Z representing -S-. R represents a C1-5 alkyl group, a C1-3 alkoxy group, a C1-3 haloalkyl group, a C1-3 haloalkoxy group or a halogen atom.)

Description

Method for producing 1,2,4-oxadiazole derivative

The present invention relates to a method for producing a 1,2,4-oxadiazole derivative.

1,2,4-oxadiazole derivatives substituted with aromatic groups at the 3-position and 5-position are known as physiologically active substances in the pharmaceutical and agricultural fields. As a method for producing the derivative, a method is known in which acyl chloride and aromatic N-hydroxyamidine are reacted in the presence of an organic solvent immiscible with water and an aqueous base (for example, see Patent Document 1). .
Alternatively, thiophene-2-carbaldehyde and benzamide oxime are reacted in the presence of toluene, molecular sieve and piperidine to give 3-phenyl-5- (thiophen-2-yl) -4,5-dihydro-1, It is described that 2,4-oxadiazole was obtained (see Patent Document 2).

International Publication No. 2014/008257 International Publication No. 2014/127195

The above-described method requires many steps in the production of the starting acyl chloride, and is a method using a chemically unstable acyl chloride as a starting material. An object of the present invention is to provide a method for producing a 1,2,4-oxadiazole derivative that can be carried out by a simple operation method and is excellent in production efficiency.

The present invention for solving the above problems is as follows.
[1] A 1,2,4-oxa compound represented by the following formula (A), which comprises reacting a compound represented by the following formula (B) with a compound represented by the following formula (C): A method for producing a diazole derivative.

(In the formula, Ar represents an aromatic group or an aromatic group having a substituent. W, X, Y, and Z each independently represent —S—, —N═, —CH═, or —CR═. And one selected from W, X, Y and Z represents —S—, wherein R represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a haloalkyl having 1 to 3 carbon atoms. Group, a haloalkoxy group having 1 to 3 carbon atoms or a halogen atom.)
[2] A compound represented by the following formula (B) and a compound represented by the following formula (C) are reacted to obtain an intermediate product containing the compound represented by the following formula (D). The intermediate product is subjected to an oxidation reaction to oxidize the compound represented by the formula (D) and convert it to a 1,2,4-oxadiazole derivative represented by the following formula (A). A method for producing a 1,2,4-oxadiazole derivative represented by the following formula (A):

(In the formula, Ar represents an aromatic group or an aromatic group having a substituent. W, X, Y, and Z each independently represent —S—, —N═, —CH═, or —CR═. And one selected from W, X, Y and Z represents —S—, wherein R represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a haloalkyl having 1 to 3 carbon atoms. Group, a haloalkoxy group having 1 to 3 carbon atoms or a halogen atom.)
[3] The method for producing a 1,2,4-oxadiazole derivative according to [2], wherein the intermediate product is purified and then subjected to an oxidation reaction.
[4] The 1,2,4-oxadiazole derivative according to [3], wherein the intermediate product contains a compound represented by the following formula (E) and at least a part of the compound is removed by purification treatment Manufacturing method.

(In the formula, Ar represents the same meaning as [1].)
[5] The content of the compound represented by the formula (E) in the intermediate product after the purification treatment is 1% by mass or less based on the compound represented by the formula (D). Of the 1,2,4-oxadiazole derivative.
[6] The production method according to any one of [2] to [5], wherein the oxidation reaction is performed in the presence of an oxidizing agent.
[7] The compound represented by the formula (B) is a compound represented by the following formula (B ¹ ), and the 1,2,4-oxadiazole derivative represented by the formula (A) is represented by the following formula ( The method for producing a 1,2,4-oxadiazole derivative according to any one of [1] to [6], which is a compound represented by A ¹ ).

(In the formula, Ar represents the same meaning as [1].)
[8] The process for producing a 1,2,4-oxadiazole derivative according to any one of [1] to [7], wherein Ar is a phenyl group or a phenyl group having a substituent.
[9] The reaction according to any one of [1] to [8], wherein the reaction between the compound represented by the formula (B) and the compound represented by the formula (C) is performed in the presence of a solvent. , 2,4-Oxadiazole derivative production method.
[10] The reaction according to any one of [1] to [9], wherein the reaction between the compound represented by the formula (B) and the compound represented by the formula (C) is performed in the presence of an acidic compound. A method for producing a 1,2,4-oxadiazole derivative.
[11] The reaction according to any one of [1] to [10], wherein the reaction between the compound represented by the formula (B) and the compound represented by the formula (C) is performed while dehydrating. , 4-Oxadiazole derivative production method.
[12] After obtaining the compound represented by the formula (C) by the reaction of the compound represented by the following formula (F) and hydroxylamine, the compound is reacted with the compound represented by the formula (B). [1] A process for producing a 1,2,4-oxadiazole derivative according to any one of [11].

(In the formula, Ar represents the same meaning as [1].)
[13] The compound represented by formula (C) is dehydrated and then reacted with the compound represented by formula (B), according to any one of [1] to [12] A method for producing a 4-oxadiazole derivative.
[14] A compound represented by formula (F) and hydroxylamine are reacted in a solvent to obtain a mixture of the compound represented by formula (C) and the solvent, and the mixture is represented by formula (B). A method for producing a 1,2,4-oxadiazole derivative according to [12] or [13], wherein the compound is reacted with a compound to be produced.
[15] When the compound represented by the formula (B) and the compound represented by the formula (C) are reacted, the compound represented by the formula (C) is continuously added to the compound represented by the formula (B). The method for producing a 1,2,4-oxadiazole derivative according to any one of [1] to [14], which is added or sequentially added.
[16] 3-phenyl-5- (thiophen-2-yl) -1,2,4-oxadi having a content of 3,5-diphenyl-1,2,4-oxadiazole of 1% by mass or less Azole.

According to the present invention, there is provided a method for producing a 1,2,4-oxadiazole derivative that can be carried out by a simple operation method and is excellent in production efficiency.

In this specification, the 1,2,4-oxadiazole derivative represented by the following formula (A) is also referred to as oxadiazole derivative A. The compound represented by the following formula (B) is referred to as Compound B, and the same applies to compounds represented by other formulas.
In the present specification, a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.

In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
In the present specification, the “alkyl group having 1 to 5 carbon atoms” means a linear or branched saturated hydrocarbon group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl. Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl and the like.
In the present specification, the “C 1-3 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms, for example, methyl, ethyl, propyl And isopropyl.

In the present specification, the “alkenyl group having 2 to 5 carbon atoms” means a linear or branched unsaturated carbonization having at least one double bond and having 2 to 5 carbon atoms. Means a hydrogen group, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl and the like can be mentioned.
In the present specification, the “alkynyl group having 2 to 5 carbon atoms” means a linear or branched unsaturated hydrocarbon having at least one triple bond and having 2 to 5 carbon atoms. Means a group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and the like.

In the present specification, the “alkoxy group having 1 to 5 carbon atoms” means an oxy group substituted with an “alkyl group having 1 to 5 carbon atoms”, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy , Isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1-ethylpropyloxy and the like.
In the present specification, the “alkoxy group having 1 to 3 carbon atoms” means an oxy group substituted with an “alkyl group having 1 to 3 carbon atoms”, and examples thereof include methoxy, ethoxy, propoxy and isopropoxy. It is done.

In the present specification, the “haloalkyl group having 1 to 5 carbon atoms” means “one carbon atom having 1 carbon atom” substituted with one or more (preferably 1 to 5, more preferably 1 to 3) “halogen atoms”. To 5 alkyl groups ”, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1 -Fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, bromomethyl, 4-fluorobutyl, 5-fluoropentyl and the like.
In the present specification, the “haloalkyl group having 1 to 3 carbon atoms” means “1 carbon atom having 1 or more carbon atoms, preferably 1 to 5, more preferably 1 to 3” substituted with “halogen atom”. -3 alkyl groups ", for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1 -Fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, bromomethyl and the like.

In the present specification, the “haloalkoxy group having 1 to 5 carbon atoms” means “the number of carbon atoms substituted with one or more (preferably 1 to 5, more preferably 1 to 3)“ halogen atoms ”. 1-5 alkoxy groups ”, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, Examples thereof include 1-fluoropropoxy, 2-fluoropropoxy, 3-fluoropropoxy, chloromethoxy, 2-chloroethoxy, 3-chloropropoxy, bromomethoxy, 4-fluorobutoxy, 5-fluoropentyloxy and the like.
In the present specification, the “haloalkoxy group having 1 to 3 carbon atoms” means “the number of carbon atoms substituted with one or more (preferably 1 to 5, more preferably 1 to 3)” halogen atoms. 1 to 3 alkoxy groups ”, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, Examples include 1-fluoropropoxy, 2-fluoropropoxy, 3-fluoropropoxy, chloromethoxy, 2-chloroethoxy, 3-chloropropoxy, bromomethoxy and the like.

In the present specification, “an alkylsulfonyl group having 1 to 5 carbon atoms” means a sulfonyl group to which “an alkyl group having 1 to 5 carbon atoms” is bonded. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropyl Examples include sulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl and the like.

In the present specification, the “aryl group having 6 to 14 carbon atoms” means an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 1- Anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 9-phenanthryl and the like can be mentioned. Among these, “aryl groups having 6 to 10 carbon atoms” are preferable.
In the present specification, the “aryl group having 6 to 10 carbon atoms” means an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like. It is done.

In the present specification, the “acyl group having 2 to 6 carbon atoms” means a carbonyl group to which “an alkyl group having 1 to 5 carbon atoms” or “an alkoxy group having 1 to 5 carbon atoms” is bonded. An alkyl-carbonyl group having 1 to 5 carbon atoms such as acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl; and methoxy Examples thereof include an alkoxy-carbonyl group having 1 to 5 carbon atoms such as carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like.

In the present specification, the “aromatic group” means an aryl group or heteroaryl group having 6 to 14 carbon atoms.
In the present specification, the “heteroaryl group” means at least one (preferably 1 to 4) selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom in addition to a carbon atom as a ring-forming atom. It means a 5- to 12-membered (preferably 5- to 10-membered) aromatic heterocyclic group having a hetero atom. Suitable examples of the “heteroaryl group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3 5- to 6-membered monocyclic aromatic heterocyclic groups such as 1,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl;
Benzothienyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyrim Dinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2,3- b] thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazoly Le, 8 to 12 membered fused polycyclic, such as a cinnolinyl (preferably 2 or tricyclic) an aromatic heterocyclic group.

In the present invention, the oxadiazole derivative A is produced by selecting Compound B and Compound C as raw materials and reacting them.

In the formula, Ar represents an aromatic group or an aromatic group having a substituent. W, X, Y and Z each independently represent -S-, -N =, -CH = or -CR =, and one selected from W, X, Y and Z represents -S- . R represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms, or a halogen atom.

Compound B is a compound that is chemically stable and excellent in handleability and can be easily produced or obtained. That is, the production method of the present invention is a method in which a chemically stable and easily available compound is used as a raw material, and the target compound can be obtained in a production process shorter than the conventional method.

[Compound B]
In the formula (B), W, X, Y and Z each independently represent -S-, -N =, -CH = or -CR = and are selected from W, X, Y and Z Represents -S-. That is, the 5-membered ring moiety in Compound B is a 5-membered aromatic heterocyclic ring that essentially contains at least one carbon atom and one sulfur atom as ring-forming atoms, and may optionally contain a nitrogen atom. It is. Compound B has a structure in which a formyl group is bonded to one of the ring-forming carbon atoms of the 5-membered aromatic heterocycle. In addition, a hydrogen atom or a substituent (R) is bonded to another ring-forming carbon atom of the 5-membered aromatic heterocycle, and a hydrogen atom is preferably bonded. In compound B, X or W is preferably —S—.

Specific examples of the 5-membered aromatic heterocycle include the following examples.

Examples of the 5-membered aromatic heterocyclic group include groups obtained by removing one hydrogen atom bonded to a ring-forming carbon atom from the 5-membered aromatic heterocyclic ring. The position of the bond is not particularly limited as long as it is on a ring-forming carbon atom. As the 5-membered aromatic heterocyclic group, a thienyl group is preferable. The thienyl group may be either a thiophen-2-yl group or a thiophen-3-yl group, and is preferably a thiophen-2-yl group from the viewpoint of usefulness such as physiological activity of the oxadiazole derivative A.

In the formula (B), R represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms, or a halogen atom. . R is preferably an alkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms or a halogen atom, more preferably a methyl group, a trifluoromethoxy group or a halogen atom. When two or more Rs are present in Compound B, Rs may be the same or different.

Preferred examples of compound B include thiophene-2-carbaldehyde, thiophene-3-carbaldehyde, thiazole-2-carbaldehyde, thiazole-4-carbaldehyde, thiazole-5-carbaldehyde, 2,1,3-thiadiazole -4-carbaldehyde, 1,2,3-thiadiazole-4-carbaldehyde, 1,2,3-thiadiazole-5-carbaldehyde, 1,2,4-thiadiazole-3-carbaldehyde, 1,2,4 -Thiadiazole-5-carbaldehyde, 1,3,4-thiadiazole-2-carbaldehyde and the like, among which thiophene-2-carbaldehyde is particularly preferable.

Compound B can be easily produced from a known compound by a known method. Moreover, it can obtain easily industrially.

[Compound C]
Compound C is in an equilibrium state with the compound represented by the following formula (C ′). In the present specification, these are hereinafter collectively referred to as Compound C. The wavy line in the formula (C ′) indicates that the steric configuration regarding the double bond of OH may be E or Z.

In addition, “reaction of compound B and compound C”, “reaction of compound B and compound C ′” and “reaction of compound B with a mixture of compound C and compound C ′” are also referred to herein below. These are collectively referred to as “reaction of compound B and compound C”.

In the formula (C), Ar represents an aromatic group or an aromatic group having a substituent.
The substituent in the “aromatic group having a substituent” is not particularly limited as long as it is a monovalent group that does not affect the reaction of the present invention. Examples of the substituent include an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, and an aryl having 6 to 10 carbon atoms. Group, haloalkyl group having 1 to 5 carbon atoms, haloalkoxy group having 1 to 5 carbon atoms, acyl group having 2 to 6 carbon atoms, halogen atom, hydroxy group, sulfanyl group, amino group, alkylsulfonyl having 1 to 5 carbon atoms Groups and the like. Preferred examples of the substituent include an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, a haloalkoxy group having 1 to 3 carbon atoms, a halogen atom, and a cyano group. Of these, a methyl group, a fluoromethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, a halogen atom, a cyano group and a formyl group are more preferred, and a methyl group and a halogen atom are particularly preferred.

When the number of substituents in Ar is 2 or more, these may be the same or different. The number of substituents is preferably 1 to 5, and more preferably 1 to 3. Further, the substitution position is not particularly limited.

When Ar has two substituents, the two substituents may be connected to each other to form a condensed ring together with Ar. The ring formed by connecting two substituents to each other may be an aromatic ring or a non-aromatic ring, and may be a carbocyclic ring or a group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. It may be a heterocycle having at least one selected heteroatom. Specific examples of such Ar include benzofuryl and the like.

Ar is preferably an aryl group having 6 to 14 carbon atoms or an aryl group having 6 to 14 carbon atoms having a substituent, and an aryl group having 6 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms having a substituent is preferable. More preferably, a phenyl group or a phenyl group having a substituent is more preferable, a phenyl group, or an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a haloalkyl group having 1 to 3 carbon atoms, or 1 carbon atom. More preferred is a phenyl group having a substituent selected from haloalkoxy groups of 3 to 3, a halogen atom and a cyano group, a phenyl group, or a methyl group, a fluoromethyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group Still more preferred is a phenyl group having a substituent selected from a halogen atom, a cyano group and a formyl group. Preferred examples of the phenyl group having such a substituent include an o-, m- or p-fluorophenyl group, an o-, m- or p-chlorophenyl group, an o-, m- or p-tolyl group. , O-, m- or p-fluoromethylphenyl group, difluorophenyl group, trifluorophenyl group. Ar is most preferably a phenyl group from the viewpoint of usefulness such as physiological activity of the oxadiazole derivative A.

Compound C used for the reaction with Compound B is preferably Compound C that has been dehydrated. The dehydration treatment can be performed according to a known method such as an azeotropic dehydration treatment or a dehydration treatment using a dehydrating agent such as molecular sieve. The water content of the compound C used for the reaction with the compound B is preferably 5% by mass or less, and more preferably 1% by mass or less.

Compound C is easy to obtain industrially. Compound C can be produced by a method in which a compound represented by the following formula (F) is reacted with hydroxylamine. Ar in the formula represents the same group as described above.

The reaction is preferably carried out in the presence of a solvent, and can be carried out according to the method described in the literature (for example, Organic Letters, -16 (3), 892-895; 2014). Hydroxylamine may be used in the form of an aqueous solution. Examples of the solvent include alcohols such as ethanol, t-butanol and t-amyl alcohol, ethers such as tetrahydrofuran and 2-methyltetrahydrofuran, and water. The amount of the solvent is preferably 1 to 5 times, particularly 1 to 3 times the volume of the compound F. The lower limit of the reaction temperature is preferably 20 ° C, more preferably 30 ° C. The upper limit of the reaction temperature is preferably 100 ° C, more preferably 80 ° C. If the reaction temperature is equal to or higher than the lower limit, the reaction is likely to react quickly, and if the reaction temperature is equal to or lower than the upper limit, generation of by-products is likely to be suppressed. The reaction time depends on the reaction temperature and reaction pressure, but is preferably 1 to 10 hours. The reaction pressure may be normal pressure, pressurization, or reduced pressure, but normal pressure or pressurization is preferred. The reaction pressure is preferably 0.01 to 0.5 MPa (gauge pressure). The reaction atmosphere may be an air atmosphere or an inert gas atmosphere such as nitrogen.

In the present invention, the reaction between Compound B and Compound C is preferably carried out under the condition that the amount of water in the reaction system is as small as possible for the reasons described later. Therefore, water is removed after the reaction between Compound F and hydroxylamine. It is preferable to obtain the compound C with as little water content as possible.
The removal of water includes a method of isolating compound C after the reaction and a method of performing a dehydration treatment after the reaction.

For example, when the reaction between Compound F and hydroxylamine is performed using water as a solvent, water is removed from the mixture of water and Compound C to obtain Compound C, and Compound C is reacted with Compound B. Is preferred. Here, the water content of the compound C after water removal is preferably 5% by mass or less, and more preferably 1% by mass or less. The removal of water can be performed by a liquid separation operation, and it is preferable to perform a dehydration treatment.

When the reaction between Compound F and hydroxylamine is carried out in the presence of a solvent, a mixture containing Compound C and the solvent is obtained. When the compound C is dissolved in the solvent, the mixture becomes a solvent solution containing the compound C. Here, the water content of the mixture after water removal is preferably 5% by mass or less, and more preferably 1% by mass or less, based on the total mass of the mixture. Examples of the method for removing water include a method for isolating compound C from the mixture and a method for dehydrating the mixture. The latter method is preferred. In the latter method, the compound C can be reacted with the compound B in a mixture state without isolating the compound C from the mixture containing the compound C and the solvent, which can be an efficient production method. That is, it is preferable to react compound F and hydroxylamine in a solvent to obtain a mixture of compound C and solvent, and to react the obtained compound C with compound B in the form of a mixture with the solvent. More preferably, the compound C is reacted with the compound B in the mixture with the solvent after the dehydration treatment of the mixture with the solvent. According to the production method, the reaction in the next step can be carried out using the same reaction apparatus in the state of the mixture, and the production process can be greatly improved in efficiency.

The dehydration treatment can be performed by azeotropic dehydration treatment or dehydration treatment using a dehydrating agent such as molecular sieve. In preparation for the case where the dehydration is carried out by azeotropic dehydration, the solvent used for the reaction of Compound F and hydroxylamine is preferably a solvent capable of azeotropic dehydration, that is, a solvent capable of forming an azeotrope with water. Examples of the solvent include ethanol, t-butanol and t-amyl alcohol.

[Oxadiazole derivative A]
The oxadiazole derivative A which is the target compound of the production method of the present invention is a compound represented by the formula (A). The meanings of Ar, W, X, Y and Z in the formula are the same as those described above, and preferred embodiments are also the same as described above.
The oxadiazole derivative A is preferably a compound represented by the following formula (A ¹ ). Ar in the formula has the same meaning as described above.

Further, specific examples of the oxadiazole derivative A include the following compounds.

[Production method of the present invention]
In the production method of the present invention, compound B and compound C are reacted to produce oxadiazole derivative A. Alternatively, compound B is reacted with compound C to obtain an intermediate product containing a compound represented by the following formula (D), and the intermediate product is further subjected to an oxidation reaction to oxidize compound D. Oxadiazole derivative A may be obtained. The oxidation reaction may be performed without purifying the intermediate product (hereinafter also referred to as “one-step reaction”), but is performed after the intermediate product is purified (hereinafter also referred to as “two-step reaction”). Is preferable. By setting it as a two-stage reaction, content of impurities (for example, the compound E etc. mentioned later) which are difficult to isolate | separate contained in an intermediate product can be reduced very efficiently. The two-step reaction is effective when the reaction between Compound B and Compound C is performed under acidic conditions or neutral conditions (particularly acidic conditions).

The concept of the reaction of the oxadiazole derivative A of the present invention is shown below. Compound D is obtained as an intermediate product containing compound D.

Compound D is produced by the condensation ring closure reaction of Compound B and Compound C. The target oxadiazole derivative A is obtained by oxidizing the compound D.

The reaction in which compound B and compound C are reacted to obtain oxadiazole derivative A can be carried out by bringing compound B and compound C into contact with each other. Examples of the contact include a method in which one compound is dissolved in a solvent and added to the other compound, a method in which compound B and compound C are added to the solvent and agitated, and the like. In addition, the reaction may be performed batchwise or continuously. Moreover, you may carry out by 1 step reaction and you may carry out by 2 step reaction.

In the reaction between Compound B and Compound C, it is preferable to apply optimum conditions depending on the types of Compound B and Compound C.
Although pH conditions at the time of reaction may be any of acidic conditions, basic conditions, and neutral conditions, acidic conditions or neutral conditions are preferable, and acidic conditions are more preferable. When neutral conditions are used, for example, the reaction may be performed in the absence of an acidic compound or a basic compound, or may be performed in a buffer solution. When acidic conditions are used, it is preferable that an acidic compound is present in the reaction system. The acidic compound may be an organic acid or an inorganic acid, organic acids such as p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, sulfuric acid, magnesium oxide, zinc oxide, boron trifluoride, iron chloride. Inorganic acids such as The upper limit of the amount of the acidic compound used is preferably 2 mol, more preferably 1.5 mol, still more preferably 1.2 mol, and particularly preferably 1.0 mol with respect to 1 mol of compound B. The lower limit of the amount of the acidic compound used is preferably 0.01 mol, more preferably 0.05 mol, and still more preferably 0.1 mol with respect to 1 mol of compound B. If the usage-amount of an acidic compound is the said range, a side reaction will not advance easily and reaction will advance easily.

In the case of basic conditions, it is preferable that a basic compound is present in the reaction system. The basic compound may be an organic base or an inorganic base, an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, a lower amine such as triethylamine, piperidine, pyrrolidine or morpholine, Examples thereof include basic aromatic heterocyclic compounds such as pyridine. The upper limit of the amount of the basic compound used is preferably 2 mol, more preferably 1.5 mol, still more preferably 1.2 mol, and particularly preferably 1.0 mol with respect to 1 mol of compound B. The lower limit of the amount of the basic compound used is preferably 0.01 mol, more preferably 0.05 mol, still more preferably 0.1 mol with respect to 1 mol of compound B. If the usage-amount of a basic compound is the said range, a side reaction will not advance easily and reaction will advance easily efficiently.
When primary amine or secondary amine is selected as the basic compound, it reacts with compound B to become an active imine and reacts with compound C. As the primary amine or secondary amine, piperidine, pyrrolidine, morpholine and the like are preferable.

The acidic compound or basic compound may be used as it is, or may be used after being dissolved in a solvent. As this solvent, 1 or 2 or more types of solvents chosen from the reaction solvent mentioned later are mentioned.

The reaction between compound B and compound C is preferably carried out in the presence of a solvent. Solvents include ethanol, propanol, isopropanol, butanol, t-butanol, amyl alcohol, t-amyl alcohol, hexanol, octanol and other alcohols; aromatic hydrocarbons such as toluene and anhydrous toluene; acetic acid; dimethyl sulfoxide, dimethylformamide, sulfolane Preferred are aprotic polar solvents such as dioxane and the like. The solvent is more preferably at least one selected from the group consisting of alcohols, aromatic hydrocarbons and aprotic polar solvents, with alcohols being particularly preferred.
Since it is preferable to remove the water produced by the reaction of Compound B and Compound C for the reasons described later, the solvent is preferably a solvent that can form an azeotrope with water, and can form an azeotrope with water. More preferred is alcohol.
In addition, the solvent used in the reaction of Compound B and Compound C may be mixed in the oxidation step of Compound BH, which will be described later. From the viewpoint of suppressing side reactions in the oxidation step, tertiary alcohol is more preferable. preferable.
The amount of the solvent is preferably 0.2 to 15 times the volume of the compound B, for example. The amount of the compound C is preferably 0.2 to 15 times, and particularly preferably 1 to 10 times. When the volumes of Compound B and Compound C are different, the amount of solvent is preferably determined based on the amount of Compound C.

Reaction conditions such as reaction temperature, reaction time, reaction pressure, reaction atmosphere and the like in the reaction between Compound B and Compound C can be appropriately changed depending on the types of Compound B, Compound C, acidic compound or basic compound, and solvent. In the usual case, the lower limit of the reaction temperature is preferably 40 ° C, more preferably 50 ° C, still more preferably 90 ° C, particularly preferably 100 ° C. The upper limit of the reaction temperature is preferably 160 ° C, more preferably 140 ° C, and particularly preferably 120 ° C.
If the lower limit of the reaction temperature is the above, the reaction is likely to proceed rapidly. Moreover, if the upper limit of reaction temperature is the above, a by-product is hard to produce.
The reaction time depends on the reaction temperature and reaction pressure, but is preferably 1 to 30 hours. The reaction pressure may be normal pressure, increased pressure, or reduced pressure. The reaction atmosphere may be an air atmosphere or an inert gas atmosphere such as nitrogen.

In the reaction between Compound B and Compound C, water is generated. Removing the water produced can shift the reaction equilibrium to the product side. Moreover, when the produced | generated water is removed, there also exists an effect which suppresses the hydrolysis reaction etc. of the compound D which is an intermediate product mentioned later. Therefore, in the present invention, it is preferable to carry out the reaction between Compound B and Compound C while dehydrating. As the dehydration method, a known or well-known method can be adopted, and examples thereof include a method in which a dehydrating agent is present and a method in which water is distilled off by azeotropic distillation. Examples of the dehydrating agent include molecular sieves. Further, when the acidic compound or basic compound present in the reaction of Compound B and Compound C is a compound having a dehydrating action, dehydration can be performed without using a dehydrating agent.

Since oxadiazole derivative A is considered to be obtained by oxidation of compound D, it is preferable to use an oxidizing agent in the production process of oxadiazole derivative A of the present invention. In this case, the reaction between the compound B and the compound C may be performed in the presence of an oxidizing agent, or after reacting the compound B and the compound C, the intermediate product containing the compound D may be reacted with the oxidizing agent. Good. When the intermediate product is reacted with an oxidizing agent, it is preferable to purify the intermediate product in a two-stage reaction and then react with the oxidizing agent. Examples of the oxidizing agent include hydrogen peroxide, manganese dioxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), hypochlorous acid, potassium peroxodisulfate, oxygen, chlorine and the like. . The addition time of the oxidant is not limited, and the compound B and the compound C may be added to the system in which the oxidant is present, and the oxidant is added to the reaction system in which the compound B and the compound C are present. May be. In the case of a two-stage reaction, it is preferable to add an oxidizing agent to the purified intermediate product.
Compound B used in the reaction can also act as an oxidizing agent. However, since the oxidizing effect of only the compound B may be insufficient, it is more preferable to use an oxidizing agent other than the compound B.
The amount of the oxidizing agent can be appropriately changed according to the kind of the oxidizing agent and the like, and is preferably 1 mol or more, more preferably 1.5 mol or more with respect to 1 mol of Compound C. The upper limit of the amount of the oxidizing agent is preferably 10 moles, more preferably 5 moles, and more preferably 2 moles relative to 1 mole of Compound C.
Further, when oxygen in the air or other compounds in the reaction system acts as an oxidizing agent, oxidation may proceed even without using a special oxidizing agent.

The intermediate product contains compound D, but may further contain reaction raw materials and reaction by-products. In addition, a solvent (for example, a solvent used for the reaction of Compound B and Compound C) may be contained.

Examples of by-products include compounds represented by the following formula (E). The compound E is considered to be formed by the condensation of the decomposition product of the compound C and the compound C.

In order to increase the yield of oxadiazole derivative A, it is preferable to set the reaction conditions so that the amount of compound D produced is increased and the amount of by-products is reduced. In particular, among the by-products, compound E has a physicochemical property (for example, crystallinity) similar to that of oxadiazole derivative A, and therefore cannot be easily removed from oxadiazole derivative A. It is preferable to suppress the content of compound E in the product.
As a method for reducing the amount of compound E produced, it is preferable to add compound C continuously or sequentially to the reaction system containing compound B when reacting compound B and compound C.

The amount of compound E produced in the reaction varies depending on reaction conditions such as equivalent weight, reaction catalyst, temperature, solvent, and acidity (basicity) of the reaction system when reacting compound B and compound C. Therefore, the production amount of compound E can be reduced by appropriately adjusting these reaction conditions. The content of Compound E in the intermediate product is preferably 10% by mass or less, more preferably 5% by mass or less, still more preferably 1% by mass or less, and particularly preferably 0.1% by mass or less with respect to Compound D.

When the oxadiazole derivative A is produced by a one-step reaction, the compound B and the compound C may be reacted in the presence of an oxidant, and the intermediate product obtained by reacting the compound B and the compound C You may make it react with an oxidizing agent, without refine | purifying. In the one-step reaction, it is preferable that the intermediate product is subjected to an oxidation treatment continuously without being subjected to a purification treatment or the like, and the operation of the production method is substantially carried out only by mixing raw material compounds.
In the one-step reaction, since the intermediate product is oxidized as it is, the process can be omitted and the desired oxadiazole derivative A can be efficiently produced. In order to carry out more efficiently, it is preferable to carry out from the reaction of Compound B and Compound C to the oxidation reaction in one reaction vessel.

In the case of carrying out a one-step reaction, it is preferable to react an excessive amount of Compound B with Compound C because the excessive amount of Compound B acts as an oxidizing agent. Further, it is preferable to carry out the reaction using an excessive amount of Compound B and without the presence of an oxidizing agent (other than Compound B). In this case, the amount of Compound B is preferably 1.5 mol or more, preferably 1.8 mol or more, and preferably 2 mol or more with respect to 1 mol of Compound C. The upper limit is preferably 10 mol, particularly preferably 5 mol, and further preferably 3 mol or less.

When Compound B acts as an oxidizing agent, a reduced form of Compound B is generated. Examples of the reduced form include compounds represented by the following formula (BH). W, X, Y and Z in the formula have the same meaning as described above. The compound BH is preferably oxidized and used as the compound B again for the reaction between the compound B and the compound C.

For the oxidation reaction of the compound BH, for example, Organic Process Research & Development, 16 (5), 1082-1089, 2012 can be referred to. The oxidation reaction of compound BH can be performed by contacting compound BH with an oxidizing agent. Specific examples of the oxidizing agent include hypochlorites such as sodium hypochlorite and potassium hypochlorite, oxone, hydrogen peroxide and oxygen. The oxidation reaction of compound BH may be performed in the presence of a catalyst such as iron oxide, iron sulfate, or rhodium catalyst. The oxidation reaction of compound BH may be performed in the presence of a solvent. The amount of the oxidizing agent can be appropriately changed according to the kind of the oxidizing agent, and is preferably 1 mol or more, more preferably 1.1 mol or more, and further preferably 1.2 mol or more with respect to 1 mol of the compound BH. The upper limit of the amount of the oxidizing agent is preferably 10 mol, more preferably 5 mol, and even more preferably 2 mol with respect to 1 mol of compound BH. The oxidation reaction of compound BH can be carried out in the presence of a solvent. Examples of the solvent include water, ethyl acetate, chloroform and the like. The amount of the solvent is preferably 1 to 10 times, particularly preferably 3 to 8 times the volume of the compound BH. The reaction temperature is preferably 0 ° C. or higher, more preferably 10 ° C. or higher. Moreover, 30 degrees C or less is preferable and 20 degrees C or less is more preferable. The reaction time depends on the reaction temperature and reaction pressure, but is preferably 1 to 5 hours. The reaction pressure is preferably 0.01 to 0.5 MPa (gauge pressure). The reaction atmosphere may be an air atmosphere or an inert gas atmosphere such as nitrogen.

When the oxadiazole derivative A is produced by a two-step reaction, the compound B and the compound C are reacted to obtain an intermediate product, and then the intermediate product is purified to obtain an intermediate product after purification. Oxidize.
In the two-stage reaction, the lower limit of the amount of Compound C relative to 1 mol of Compound B is preferably 0.2 mol, more preferably 0.5 mol, and even more preferably 0.8 mol. The upper limit of the amount of Compound C with respect to 1 mol of Compound B is preferably 2 mol, more preferably 1.5 mol, and even more preferably 1.2 mol.

In the two-step reaction, by purifying the intermediate product, the raw material of the reaction and the by-product of the reaction are removed, and a purified intermediate product having a high content of compound D can be obtained. By performing an oxidation reaction on the intermediate product, the oxadiazole derivative A can be obtained with higher purity. The purification method of the intermediate product is not particularly limited, and a commonly used purification method can be applied. As the purification method, methods such as liquid separation, filtration, distillation, recrystallization, reprecipitation, and chromatographic treatment are preferable. In addition to compound D, the purified intermediate product may contain a solvent (for example, a solvent used for the reaction of compound B and compound C).

The yield of the compound D contained in the intermediate product after purification is preferably 50% by mass or more, preferably 70% by mass or more, particularly 90% by mass or more, based on the theoretical production amount based on the compound B. preferable. Compound E, which is a by-product, is difficult to separate from oxadiazole derivative A and relatively easy to separate from compound D. Therefore, it is removed as much as possible during the purification of the intermediate product, and the intermediate product after purification It is very important to keep the content of compound E in the product low. If the oxadiazole derivative A contains a large amount of the compound E, the loss in purifying the oxadiazole derivative A by removing the compound E increases, and the yield of the oxadiazole derivative A is greatly reduced. It becomes.
In the intermediate product after purification, the content of compound E relative to compound D is more preferably 5% by mass or less, further preferably 1% by mass or less, and particularly preferably 0.1% by mass or less.
By-products such as Compound E can be removed by filtration of precipitates in the intermediate product. Further, the intermediate product may be removed by chromatography.

In the two-step reaction, the oxadiazole derivative A having a very low content of the compound E, which is an impurity that is difficult to separate, is obtained by oxidizing the purified intermediate product. The intermediate product after the purification can be oxidized by a known method. As the oxidizing agent used in the oxidation reaction, the same oxidizing agents as those described above can be used. The amount of the oxidizing agent used is preferably 0.2 to 2 mol, more preferably 1 to 1.5 mol, per 1 mol of the compound D produced. For example, when the content of compound D in the intermediate product after purification is unknown, such as when an oxidation reaction is performed with the intermediate product without isolating compound D from the intermediate product after purification, An oxidizing agent corresponding to the theoretical production amount of D may be used. The reaction temperature, reaction time, reaction pressure, and reaction atmosphere can be appropriately changed, but the reaction temperature is preferably 40 to 160 ° C. The reaction time depends on the reaction temperature and reaction pressure, but is preferably 1 to 30 hours. The reaction pressure is preferably 0.01 to 0.5 MPa (gauge pressure). The reaction atmosphere may be an air atmosphere or an inert gas atmosphere such as nitrogen.
Further, the oxidation reaction of the intermediate product after purification is preferably performed in the presence of a solvent. Examples of the solvent include the same examples as the solvent used for the reaction of Compound B and Compound C during the above-described one-step reaction. The amount of the solvent is preferably 2 to 10 times that of Compound D. When an oxidation reaction is performed with the intermediate product as it is without isolating compound D from the purified intermediate product, a solvent (for example, a solvent used for the reaction of compound B and compound C, etc.) is used as the intermediate product after purification. ) Is included, it can be directly subjected to an oxidation reaction without the addition of a new solvent.

The oxadiazole derivative A produced by the reaction can be further purified to obtain an oxadiazole derivative A having a purity suitable for the purpose. As the method of the purification treatment, a known or well-known purification method can be applied, and examples thereof include the same method as the above-described intermediate product purification method.
The content of the compound E in the oxadiazole derivative A obtained by the production method by the two-step reaction is preferably 1% by mass or less, and more preferably 0.1% by mass or less with respect to the oxadiazole derivative A. The lower limit of the content of Compound E is not particularly limited, and is 0% by mass or more, or 0.01% by mass or more. According to the production method based on the two-stage reaction, the content of the compound E, which is an impurity that is difficult to separate, can be reduced very efficiently, and the oxadiazole derivative A with high purity can be produced. The oxadiazole derivative obtained by the production method of the present invention has high purity and is particularly useful as a physiologically active substance in the fields of pharmacy and agriculture.

The oxadiazole derivative A obtained by the production method of the present invention has a low content of impurities that are difficult to separate, has high physiological activity, and is a useful compound in the fields of medicine and agricultural chemicals.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples. In addition,% in an Example means mol% unless there is particular description.

[Quantitative method]
In each Example, analysis using high performance liquid chromatography (HPLC) was performed under the following conditions.
Quantification by HPLC was performed under the following conditions.
Equipment: Agilent Technologies 1260 Infinity
Column: YMC-Pack ODS-AM AM12S05-1546WT (150 × 4.6 mm ID, S-5 μm, 12 nm)
Flow rate: 0.6ml / min
Eluent: 0.1% phosphate buffer (0.1% NEt ₃ + H ₃ PO ₄ aq): CH ₃ CN = 50: 50 to 20:80 (0-20 min), 20:80 (20-30 min)
Detector: Diode array detector, Measurement wavelength: 254 nm
Below, the yield was determined based on the amount of benzamide oxime.

[Example 1] Example of one-step reaction A glass eggplant-shaped flask was charged with thiophene-2-carbaldehyde (2-formylthiophene: 1.02 g, 9.1 mmol) and ethanol (14 mL) to obtain a mixed solution. Benzamide oxime (1.25 g, 9.2 mmol) and potassium carbonate (0.13 g, 0.94 mmol) were added to the mixture, and the mixture was heated to reflux for 30.5 hours with stirring. The precipitated solid was collected by filtration and washed with ethanol and water to give 3-phenyl-5- (thiophen-2-yl) -1,2,4-oxadiazole (hereinafter referred to as compound) represented by the following formula: A-1) was obtained in a yield of 33%.

[Example 2]
Thiophene-2-carbaldehyde (1.02 g, 9.1 mmol) and anhydrous toluene (14 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.27 g, 9.4 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.89 mmol) were added to the mixture, and the mixture was heated to reflux with stirring for 6.5 hours. The formation of Compound A-1 was confirmed by HPLC.

[Example 3]
Thiophene-2-carbaldehyde (1.01 g, 9.0 mmol) and ethanol (7 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.27 g, 9.4 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.89 mmol) were added to the mixture, and the mixture was heated to reflux with stirring for 15 hours. The formation of Compound A-1 was confirmed by HPLC.

[Example 4]
A glass eggplant-shaped flask was charged with thiophene-2-carbaldehyde (1.00 g, 8.9 mmol) and acetic acid (7 mL) to obtain a mixed solution. Benzamide oxime (1.27 g, 9.4 mmol) was added to the mixture and heated to reflux with stirring for 15 hours. The formation of Compound A-1 was confirmed by HPLC.

[Example 5]
Thiophene-2-carbaldehyde (1.01 g, 9.0 mmol) and ethanol (7 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.27 g, 9.4 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.89 mmol) were added to the mixture and heated at 40 ° C. with stirring for 15 hours. Compound A-1 was obtained by HPLC.

[Example 6]
Thiophene-2-carbaldehyde (1.01 g, 9.0 mmol) and anhydrous toluene (7 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.27 g, 9.4 mmol) was added to the mixture and heated to reflux with stirring for 14 hours. The formation of Compound A-1 was confirmed by HPLC.

[Example 7]
Thiophene-2-carbaldehyde (1.01 g, 9.0 mmol) and ethanol (7 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.28 g, 9.4 mmol) and acetic acid (0.054 g, 0.90 mmol) were added to the mixture, and the mixture was heated to reflux with stirring for 15 hours. The formation of Compound A-1 was confirmed by HPLC.

[Example 8]
Thiophene-2-carbaldehyde (10.0 g, 89.2 mmol) and anhydrous toluene (70 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (12, 8 g, 93.6 mmol) was added to the mixture and heated to reflux with stirring for 30 hours. At that time, azeotropic dehydration was performed using a Dean-Stark apparatus. The formation of Compound A-1 was confirmed by HPLC.

[Example 9]
Thiophene-2-carbaldehyde (1.02 g, 9.1 mmol) and anhydrous toluene (14 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.27 g, 9.4 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.89 mmol) were added to the mixture, and the mixture was heated to reflux with stirring for 6.5 hours. As a result of quantification by HPLC, 3-phenyl-5- (thiophen-2-yl) -4,5-dihydro-1,2,4-oxadiazole was obtained in a yield of 35%.
3,5-Diphenyl-1,2,4-oxadiazole contained in the obtained 3-phenyl-5- (thiophen-2-yl) -4,5-dihydro-1,2,4-oxadiazole The content of was 31%. Separation by silica gel column chromatography was performed, and the content of 3,5-diphenyl-1,2,4-oxadiazole was reduced to 0.1 mass% or less.
3-Phenyl-5- (thiophen-2-yl) -4,5-dihydro-1,2,4-oxadiazole (0.23 g, 0.99 mmol) and ethanol (0.23 g, 0.99 mmol) obtained in a glass eggplant-shaped flask 2.8 mL) was added to obtain a mixture. To the mixture were added thiophene-2-carbaldehyde (0.13 g, 1.13 mmol, oxidizing agent) and potassium carbonate (0.14 g, 1.0 mmol), and the mixture was heated to reflux with stirring for 7.5 hours. As a result of quantification by HPLC, Compound A-1 was obtained in a yield of 63%.

[Example 10]
Thiophene-2-carbaldehyde (1.02 g, 9.1 mmol) and anhydrous toluene (14 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.27 g, 9.4 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.89 mmol) were added to the mixture, and the mixture was heated to reflux with stirring for 6.5 hours. The 3,5-diphenyl-1,2,4-oxadiazole produced as a by-product was filtered off and the solvent was distilled off to remove 3-phenyl-5- (thiophen-2-yl) -4,5-dihydro -1,2,4-oxadiazole was obtained. By allowing DDQ (2.48 g, 10.9 mmol) to act on the obtained 3-phenyl-5- (thiophen-2-yl) -4,5-dihydro-1,2,4-oxadiazole, a compound was obtained. A-1 was obtained.

[Example 11]
Thiophene-2-carbaldehyde (2.12 g, 18.9 mmol) and dimethyl sulfoxide (9 mL) were placed in a glass eggplant-shaped flask to obtain a mixed solution. Benzamide oxime (1.23 g, 9.03 mmol) and potassium hydroxide (0.058 g, 1.03 mmol) were added to the mixture and heated at 78 ° C. for 30 hours with stirring. As a result of quantification by HPLC, Compound A-1 was obtained in a yield of 66%. In the resulting compound A-1, 3,5-diphenyl-1,2,4-oxadiazole (corresponding to compound E) was not detected.

[Example 12]
Thiophen-2-carbaldehyde (10.0 g, 89.2 mmol), anhydrous toluene (70 mL) and p-toluenesulfonic acid monohydrate (1.76 g, 9.24 mmol) were placed in a glass eggplant-shaped flask and mixed. A liquid was obtained. Benzamide oxime (3.23 g, 23.7 mmol) was added to the mixture and heated to reflux with stirring for 1 hour. Further, benzamide oxime (3.20 g, 23.5 mmol) was added to the mixture, and the mixture was heated to reflux with stirring for 3 hours. Further, benzamide oxime (3.20 g, 23.5 mmol) was added to the mixture, and the mixture was heated to reflux for 2 hours with stirring. Compound A-1 was obtained in 21% yield by HPLC.

This application is based on Japanese Patent Application No. 2015-044489 filed on March 6, 2015 in Japan and Japanese Patent Application No. 2016-012795 filed on January 26, 2016, the contents of which are described in this specification. Are all included.

Claims

A 1,2,4-oxadiazole derivative represented by the following formula (A), characterized by reacting a compound represented by the following formula (B) with a compound represented by the following formula (C) Manufacturing method.

(In the formula, Ar represents an aromatic group or an aromatic group having a substituent. W, X, Y, and Z each independently represent —S—, —N═, —CH═, or —CR═. And one selected from W, X, Y and Z represents —S—, wherein R represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a haloalkyl having 1 to 3 carbon atoms. Group, a haloalkoxy group having 1 to 3 carbon atoms or a halogen atom.)
The compound represented by the following formula (B) and the compound represented by the following formula (C) are reacted to obtain an intermediate product containing the compound represented by the following formula (D), and then the intermediate By subjecting the product to an oxidation reaction, the compound represented by the formula (D) is oxidized and converted into a 1,2,4-oxadiazole derivative represented by the following formula (A). A process for producing a 1,2,4-oxadiazole derivative represented by the following formula (A):

(In the formula, Ar represents an aromatic group or an aromatic group having a substituent. W, X, Y, and Z each independently represent —S—, —N═, —CH═, or —CR═. And one selected from W, X, Y and Z represents —S—, wherein R represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a haloalkyl having 1 to 3 carbon atoms. Group, a haloalkoxy group having 1 to 3 carbon atoms or a halogen atom.)
The method for producing a 1,2,4-oxadiazole derivative according to claim 2, wherein the oxidation reaction is carried out after the intermediate product is purified.
The method for producing a 1,2,4-oxadiazole derivative according to claim 3, wherein the intermediate product contains a compound represented by the following formula (E), and at least a part of the compound is removed by purification treatment. .

(In the formula, Ar represents the same meaning as in claim 1.)
The content of the compound represented by the formula (E) in the intermediate product after the purification treatment is 1% by mass or less based on the compound represented by the formula (D). A method for producing a 2,4-oxadiazole derivative.
The production method according to any one of claims 2 to 5, wherein the oxidation reaction is carried out in the presence of an oxidizing agent.
The compound represented by the formula (B) is a compound represented by the following formula (B 1 ), and the 1,2,4-oxadiazole derivative represented by the formula (A) is represented by the following formula (A 1 ) The method for producing a 1,2,4-oxadiazole derivative according to any one of claims 1 to 6, which is a compound represented by the formula:

(In the formula, Ar represents the same meaning as in claim 1.)
The method for producing a 1,2,4-oxadiazole derivative according to any one of claims 1 to 7, wherein Ar is a phenyl group or a phenyl group having a substituent.
The 1,2,4- of any one of claims 1 to 8, wherein the reaction of the compound represented by formula (B) and the compound represented by formula (C) is carried out in the presence of a solvent. A method for producing an oxadiazole derivative.
The 1,2,4 according to any one of claims 1 to 9, wherein the reaction between the compound represented by formula (B) and the compound represented by formula (C) is carried out in the presence of an acidic compound. A process for producing oxadiazole derivatives.
The 1,2,4-oxadidioxide according to any one of claims 1 to 10, wherein the reaction between the compound represented by the formula (B) and the compound represented by the formula (C) is performed while dehydrating. A method for producing an azole derivative.
The compound represented by the formula (C) is obtained by reacting the compound represented by the following formula (F) with hydroxylamine, and then the compound is reacted with the compound represented by the formula (B). 12. A process for producing a 1,2,4-oxadiazole derivative according to any one of 1 to 11.

(In the formula, Ar represents the same meaning as in claim 1.)
The 1,2,4-oxadiazole according to any one of claims 1 to 12, wherein the compound represented by the formula (C) is dehydrated and then reacted with the compound represented by the formula (B). A method for producing a derivative.
The compound represented by Formula (F) and hydroxylamine are reacted in a solvent to obtain a mixture of the compound represented by Formula (C) and the solvent, and the mixture is represented by Formula (B). The method for producing a 1,2,4-oxadiazole derivative according to claim 12 or 13, wherein the compound is reacted with.
When the compound represented by the formula (B) and the compound represented by the formula (C) are reacted, the compound represented by the formula (C) is continuously added or sequentially added to the compound represented by the formula (B). The method for producing a 1,2,4-oxadiazole derivative according to any one of claims 1 to 14, which is added.
3-phenyl-5- (thiophen-2-yl) -1,2,4-oxadiazole having a content of 3,5-diphenyl-1,2,4-oxadiazole of 1% by mass or less.