JP5112621B2 - Purification method and production method of 5-substituted oxazole compounds - Google Patents

Description

  The present invention relates to a purification method and a production method of a 5-substituted oxazole compound useful as an intermediate for production of agricultural chemicals, medicines, functional materials and the like.

5-Substituted oxazole compounds such as 5- (4′-nitrophenyl) oxazole compounds are useful as agricultural chemicals, pharmaceuticals, functional materials, or production intermediates thereof.
Conventionally, as a method for producing this 5-substituted oxazole compound, a method of reacting an aldehyde with p-tolylsulfonylmethyl isocyanide (hereinafter abbreviated as “TosMIC”) is known (Patent Document 1, etc.). In this method, the desired 5- (2′-methoxy-4′-nitrophenyl) oxazole is isolated from the reaction mixture using a methanol-water mixed solvent as a crystallization solvent.

WO02 / 076958

According to the production method described in Patent Document 1, the intended 5-substituted oxazole compound can be obtained in good yield.
However, in the method described in Patent Document 1, the obtained 5- (2′-methoxy-4′-nitrophenyl) oxazole is obtained by reducing the nitro group of the compound with hydrogen in the presence of a hydrogenation catalyst. , 5- (2′-methoxy-4′-aminophenyl) oxazole has a problem in that the target product may not be obtained efficiently.

  The present inventors have intensively studied to solve this problem. As a result, the reason why the hydrogen reduction reaction of 5- (2′-methoxy-4′-nitrophenyl) oxazole does not proceed completely and the target product cannot be obtained efficiently is obtained by the method described in Patent Document 1. The resulting 5- (2′-methoxy-4′-nitrophenyl) oxazole was considered to be due to the presence of impurities that inhibit the hydrogenation reaction.

  Therefore, the present invention provides a method for purifying a 5-substituted oxazole compound that can efficiently isolate a 5-substituted oxazole such as high-purity 5- (2′-methoxy-4′-nitrophenyl) oxazole free of impurities. And a method for producing a 5-substituted oxazole compound.

  As a result of further intensive studies, the inventors of the present invention obtained 5- (2 ′ ′) from a reaction mixture containing 5- (2′-methoxy-4′-nitrophenyl) oxazole obtained by the method described in Patent Document 1. When a mixed solvent of methyl isobutyl ketone and water is used as a crystallization solvent for crystallization of -methoxy-4'-nitrophenyl) oxazole, extremely high purity 5- (2'-methoxy-4'-nitro The inventors have found that phenyl) oxazole can be efficiently isolated, and generalized this knowledge to complete the present invention.

Thus, according to the first aspect of the present invention, the purification methods (1) to (7) are provided.
(1) Formula (I)

(Wherein, R ¹ represents a hydrogen atom or a C _1-5 alkyl group, R ² represents a halogen atom, a C _1-5 alkyl group or a C _1-5 alkoxy group, and n is 0, 1 or when .n showing a 2 is 2, R ² is also the same, the solubility at 15 ℃ of the compound represented by the phase may be different.) is less than 4.0 wt%, and water A method for purifying a compound represented by the formula (I), wherein an organic solvent for phase separation is used as a crystallization solvent.
(2) Formula (I)

（式中、Ｒ^１は、水素原子又はＣ_１−５アルキル基を表し、Ｒ^２は、ハロゲン原子、Ｃ_１−５アルキル基又はＣ_１−５アルコキシ基を表し、ｎは、０、１又は２を示す。ｎが２のとき、Ｒ^２は同一であっても、相異なっていてもよい。）で表される化合物の１５℃における溶解度が４．０重量％未満であり、かつ水と相分離する有機溶媒と水との混合溶媒を晶析溶媒として用いることを特徴とする式（Ｉ）で表される化合物の精製方法。
（３）前記式（Ｉ）で表される化合物が、式（Ｉ−１）

(Wherein, R ¹ represents a hydrogen atom or a C _1-5 alkyl group, R ² represents a halogen atom, a C _1-5 alkyl group or a C _1-5 alkoxy group, and n is 0, 1 or when .n showing a 2 is 2, R ² is also the same, the solubility at 15 ℃ of the compound represented by the phase may be different.) is less than 4.0 wt%, and water A method for purifying a compound represented by formula (I), wherein a mixed solvent of an organic solvent and water for phase separation is used as a crystallization solvent.
(3) The compound represented by the formula (I) is represented by the formula (I-1)

(Wherein R ² and n represent the same meaning as described above), and the purification method according to (1) or (2).
(4) The organic solvent is one selected from the group consisting of methyl isobutyl ketone, anisole, n-butyl acetate, cyclohexanone, and monochlorobenzene, according to any one of (1) to (3) Purification method.
(5) The purification method according to any one of (1) to (3), wherein methyl isobutyl ketone is used as the organic solvent.
(6) The compound represented by the formula (I) is represented by the formula (I-2)

で表される化合物であることを特徴とする（１）または（２）に記載の精製方法。
（７）前記式（Ｉ）で表される化合物が、式（ＩＩ）

The purification method according to (1) or (2), wherein the compound is represented by the formula:
(7) The compound represented by the formula (I) is represented by the formula (II)

(Wherein R ² and n represent the same meaning as described above), and the formula (III)

(Wherein R ¹ represents the same meaning as described above) and is a compound obtained by reacting with the compound represented by (1) to (6), .

According to the second aspect of the present invention, the following production methods (8) and (9) are provided.
(8) Formula (I)

(Wherein, R ¹ represents a hydrogen atom or a C _1-5 alkyl group, R ² represents a halogen atom, a C _1-5 alkyl group or a C _1-5 alkoxy group, and n is 0, 1 or Wherein R ² may be the same or different when n is 2, and is a method for producing a compound represented by formula (II):

(Wherein R ² and n represent the same meaning as described above), and the formula (III)

(Wherein R ¹ represents the same meaning as described above) and the compound represented by the formula (I) has a solubility at 15 ° C. of less than 4.0% by weight. And having a step of crystallizing the compound represented by the formula (I) using a mixed solvent of an organic solvent and water that is phase-separated from water, and the formula (I), A method for producing the represented compound.
(9) The production method according to (8), wherein methyl isobutyl ketone is used as the organic solvent.

According to the purification method of the present invention, the oxazole compound represented by the formula (I) can be isolated with high purity and efficiency.
According to the production method of the present invention, the oxazole compound represented by the formula (I) can be produced with high purity and efficiency.
By using the oxazole compound represented by the formula (I) obtained by the purification method and the production method of the present invention, it is possible to efficiently obtain agricultural chemicals, pharmaceuticals, functional materials, and the like, which are final target products.

  Hereinafter, the present invention will be described in detail by dividing into 1) a method for purifying the compound represented by the formula (I) and 2) a method for producing the compound represented by the formula (I).

1) Purification method of the compound represented by the formula (I) The purification method of the present invention is a purification method of the compound represented by the formula (I), wherein the compound represented by the formula (I) is purified. An organic solvent having a solubility at 15 ° C. of less than 4.0% by weight and phase-separating with water is used as a crystallization solvent.

(1) Compound Represented by Formula (I) The present invention is a method for purifying a compound represented by the formula (I) (hereinafter sometimes referred to as “compound (I)”).
In the formula (I), R ¹ represents a hydrogen atom or a C _1-5 alkyl group.
_{Examples of the} C _1-5 alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, a t-butyl group, and an n-pentyl group.

R ² represents a halogen atom, a C _1-5 alkyl group or a C _1-5 alkoxy group.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The C _1-5 alkyl group, include the same ones listed as the _{C 1-5} alkyl groups of said ^{R 1.}
_{Examples of the} C _1-5 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, an isobutoxy group, and a t-butoxy group.
n represents 0, 1 or 2. When n is 2, R ² may be the same or different.

Among these, in the present invention, the compound (I) is preferably a compound represented by the formula (I-1), and more preferably a compound represented by the formula (I-2). .
In the formula (I-1), R ² and n represent the same meaning as described above.

(2) Organic solvent In the crystallization method of the present invention, the solubility of the compound (I) at 15 ° C. is less than 4.0 wt%, preferably 1.5 wt% to 4.0 wt% as the crystallization solvent. And an organic solvent that is phase-separated from water.
Here, the solubility of compound (I) at 15 ° C. means the maximum amount of compound (I) dissolved in an organic solvent at 15 ° C., and 4.0% by weight means the whole organic solvent solution of compound (I). It means that the content with respect to is 4.0% by weight.
Moreover, the organic solvent which phase-separates with water means the organic solvent which does not become uniform when mixed with water but separates into two phases.

Although the organic solvent used in the present invention depends on the type of compound (I), generally, it is a ketone solvent such as diethyl ketone, methyl isobutyl ketone or cyclohexanone; an ether solvent such as dibutyl ether, anisole or ethoxybenzene. Solvents; ester solvents such as n-butyl acetate; halogenated hydrocarbon solvents such as monochlorobenzene; These organic solvents can be used individually by 1 type or in mixture of 2 or more types.
Among these, when the compound (I) is a compound represented by the formula (I-1), a kind selected from the group consisting of methyl isobutyl ketone, anisole, n-butyl acetate, cyclohexanone, and monochlorobenzene. Is preferred, and methyl isobutyl ketone is more preferred.

  In the present invention, it is more preferable to use a mixed solvent of one or more organic solvents and water as a crystallization solvent. Especially, when compound (I) is a compound represented by said Formula (I-2), use of the mixed solvent of methyl isobutyl ketone and water is especially preferable.

  The mixing ratio of the organic solvent and water is not particularly limited, and can be appropriately determined in consideration of the purity and recovery rate of the target product. For example, when the compound (I) is 4- (2′-methoxy-4′-nitrophenyl) oxazole, the mixing ratio of water and the organic solvent is usually a water: organic solvent = weight ratio. The range is 5: 1 to 1: 5, preferably 3: 1 to 1: 3.

  In the purification method of the present invention, the compound (I) to be purified is a compound represented by the above formula (II) (hereinafter sometimes referred to as “compound (II)”) and the formula (III). It is preferable that it is a compound obtained by making it react with the compound (henceforth "compound (III)") represented by these.

In the formula (II), R ² and n represent the same meaning as described above.
Specific examples of compound (II) include 4-nitrobenzaldehyde, 2-methoxy-4-nitrobenzaldehyde, 2-ethoxy-4-nitrobenzaldehyde, 3-methoxy-4-nitrobenzaldehyde, 2-chloro-4-nitrobenzaldehyde. 2-methyl-4-nitrobenzaldehyde, 3-nitrobenzaldehyde, 4-methyl-3-nitrobenzaldehyde, 4-chloro-3-nitrobenzaldehyde, 4-methoxy-3-nitrobenzaldehyde, 4-methoxy-2-nitrobenzaldehyde , 4-methyl-2-nitrobenzaldehyde, 5-methoxy-2-nitrobenzaldehyde and the like, but are not limited thereto.

Compound (III) is a compound generally called isonitrile.
In formula (III), R ¹ represents the same meaning as described above.
In the present invention, among the compounds (III), the use of the compound (TosMIC) in which R ¹ is a hydrogen atom is easy to obtain, and the compound (I) can be obtained in high yield. Particularly preferred.

  For example, TosMIC is a method in which N- (p-tolylsulfonylmethyl) formamide (TosMFA) is used in 1,2-dimethoxyethane (DME) with phosphorus oxychloride (Organic Synthesis, Vol. 57, 102-106, Synthesis). , 400-402 (1985), Tetrahedron Lett., 2367 (1972) and the like, and methods using phosgene and diphosgene (Angew. Chem. Int. Ed. Engl. 16, 259, (1977). Year), Angew.Chem.77, p.492, (1965), DE 4032925, etc.) and the like.

  When the compound (II) and the compound (III) are reacted, the use ratio of both is an amount such that the compound (III) is usually 1 to 3 moles per 1 mole of the compound (II).

The reaction of compound (II) and compound (III) can be carried out in a suitable solvent.
The solvent to be used is not particularly limited as long as it is an inert solvent for the reaction. For example, water; halogen solvents such as methylene chloride, chloroform and dichloroethane; aromatic solvents such as benzene, toluene, xylene, benzonitrile, benzotrifluoride and chlorobenzene; ester solvents such as methyl acetate, ethyl acetate and isopropyl acetate Ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone; ether solvents such as diethyl ether and tetrahydrofuran (THF); nitrile solvents such as acetonitrile; These solvents can be used alone or in combination of two or more.

  Among these, solvents that can be used for the synthesis of compound (III) or extraction after post-treatment, for example, halogen solvents such as methylene chloride; aromatic solvents such as toluene, xylene, chlorobenzene; ester solvents such as ethyl acetate; A ketone solvent such as methyl isobutyl ketone; THF; acetonitrile; a mixed solvent of water and the organic solvent exemplified above is preferable.

  Although the usage-amount of a solvent is not specifically limited, It is 1-1000 weight part with respect to 1 weight part of compound (II) or compound (I), Preferably it is the range of 5-100 weight part.

  More specifically, the reaction between compound (II) and compound (III) can be carried out by the production methods 1 to 3 shown below.

(Production Method 1) A method in which a solution of compound (III) and compound (II) are reacted in the presence of a base in a mixed solvent of an aprotic solvent and a protic solvent.

  As the base to be used, either an organic base or an inorganic base can be used. Examples of organic bases include alkylamines such as dicyclohexylamine, diisopropylamine, diethylamine, triethylamine, tributylamine and diisopropylethylamine; alkylanilines such as N, N-dimethylaniline; piperidine, pyrrolidine, 2,2,6,6-tetramethyl Piperidine, morpholine, piperazine, imidazole, 1-ethylpiperidine, 4-methylmorpholine, 1-methylpyrrolidine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- Heterocyclic amines such as 7-undecene; quaternary ammonium salts such as benzyltriethylammonium chloride and methyltrioctylammonium chloride or diamines such as N, N, N ′, N′-tetramethylethylenediamine; It can be exemplified. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like.

  The aprotic solvent is preferably a solvent that can be used for the synthesis or extraction of compound (III). For example, halogen solvents such as methylene chloride, chloroform, dichloroethane, methylene chloride; aromatic solvents such as benzene, chlorobenzene, toluene, xylene, nitrobenzene, benzonitrile; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate; Examples thereof include ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as diethyl ether and tetrahydrofuran; nitrile solvents such as acetonitrile; and the like. Moreover, you may mix and use these.

  The protic solvent is preferably at least one selected from the group consisting of water, C1-C10 alcohols, mono- or polyalkylene glycols. Specific examples include alcohols such as water, methanol, ethanol, and propanol; glycols such as ethylene glycol, diethylene glycol, and ethylene glycol monomethyl ether. Among these, use of methanol, ethylene glycol, and 2-methoxyethanol is preferable.

  The reaction is carried out using a base in an amount of 2.0 mol or more, preferably 2.0 to 2.5 mol, more preferably 2.0 to 2.2 mol, relative to 1 mol of compound (II). Is called.

  The amount of compound (III) used is not particularly limited, but is preferably in the range of 0.8 to 1.5 mol, more preferably in the range of 0.9 to 1.2 mol, relative to 1 mol of compound (II). .

  The amount of the aprotic solvent to be used is not particularly limited, and the compound (III) may be an amount capable of dissolving, and the mixing ratio of the aprotic solvent and the protic solvent is not particularly limited, and an arbitrary value is set. it can.

  The amount of the protic solvent to be used is not particularly limited as long as the base can be dissolved to some extent, but it is preferably 1 liter or more with respect to 1 mol of the compound (II).

  The reaction is carried out, for example, by mixing a solution of compound (II) and compound (III) and a protic solvent with a base dissolved or suspended and reacting at a temperature ranging from 0 ° C. to the boiling point of the solvent, preferably 20 to 60 ° C. Let The reaction is preferably performed under a nitrogen stream or under a nitrogen atmosphere.

While the reaction time varies depending on the compound to be reacted and the conditions, it is usually about several minutes to 48 hours.
After completion of the reaction, the reaction solution can be cooled as necessary, and the desired product can be obtained by ordinary post-treatment operations.

(Production Method 2) A method in which compound (II) and compound (III) are reacted in the presence of a phase transfer catalyst and an inorganic base.
Examples of the phase transfer catalyst used include onium salts such as quaternary ammonium salts and quaternary phosphonium salts; crown compounds; organic bases and the like.

  The quaternary ammonium salts include tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, trimethylbenzylammonium hydroxide, tetramethylammonium bromide, tetraethylammonium bromide, tetrabutylammonium bromide, triethyl bromide. Benzylammonium, trimethylphenylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium chloride, trimethylphenylammonium chloride, trioctylmethylammonium chloride, tributylbenzylammonium chloride, trimethylbenzylammonium chloride, chloride N-laurylpyridinium, N-benzylpicolinium chloride, tricap Methyl ammonium iodide, tetramethylammonium iodide tetrabutyl ammonium, tetrabutyl ammonium sulfate and the like.

Examples of the quaternary phosphonium salt include tetraethylphosphonium chloride, tetraethylphosphonium bromide, tetraethylphosphonium iodide, tetrabutylphosphonium bromide, tetraphenylphosphonium bromide, triphenylbenzylphosphonium bromide and the like.
Examples of the crown compound include crown ethers such as 15-crown-5,18-crown-6; cryptands; and the like.

  Examples of the organic base include 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 6-dibutylamino-1,8- And diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, N, N-dimethylaminopyridine and the like.

  The amount of the phase transfer catalyst used is not particularly limited, but is usually 0.0001 to 5 equivalent moles, preferably 0.01 to 0.5 equivalent moles with respect to 1 mole of the compound (II) used.

Examples of the inorganic base used include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like.
Although the usage-amount of an inorganic base is not restrict | limited in particular, Preferably it is 0.5-10 mol with respect to 1 mol of compound (II), More preferably, it is 1.0-3 mol.

  Specific examples of the solvent used in the reaction include halogen solvents such as water, methylene chloride, chloroform and dichloroethane; aromatic solvents such as benzene, toluene, xylene, benzonitrile, benzotrifluoride and chlorobenzene; methyl acetate and acetic acid. Examples include ester solvents such as ethyl and isopropyl acetate; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone; ether solvents such as diethyl ether and THF; nitrile solvents such as acetonitrile; and the like.

  Among these, solvents that can be used for the synthesis of compound (III) or extraction after post-treatment, for example, halogen solvents such as methylene chloride, aromatic solvents such as toluene, xylene, chlorobenzene, ester solvents such as ethyl acetate, A ketone solvent such as methyl isobutyl ketone, THF, acetonitrile and the like are preferable, and these may be used in combination. Among them, a mixed system other than water and the water exemplified above is preferable.

  Although the usage-amount of a solvent is not restrict | limited in particular, Usually, it is 1-1000 weight part with respect to 1 weight part of compound (II), Preferably it is the range of 5-100 weight part.

  As a method of reacting compound (II) and compound (III) in the presence of a phase transfer catalyst and an inorganic base, for example, compound (II) and compound (III) or a solution thereof are mixed in an appropriate solvent, Examples thereof include a method in which an inorganic base and a phase transfer catalyst dissolved in water are added, and the reaction is carried out in a temperature range from 0 ° C. to the boiling point of the solvent, preferably 20 to 60 ° C.

  Although the usage-amount of compound (III) is not restrict | limited in particular, It is 0.8-2.0 mol normally with respect to 1 mol of compound (II), Preferably, it is the range of 1.0-1.5 mol.

The reaction is preferably performed in a nitrogen stream or a nitrogen atmosphere.
While the reaction time varies depending on the compound to be reacted and the conditions, it is usually from several minutes to 48 hours. After completion of the reaction, the reaction solution can be cooled as necessary, and the desired product can be obtained by ordinary post-treatment operations.

(Production Method 3) A method in which compound (II) and compound (III) are reacted in the presence of an organic base.
As the organic base used in this method, those having a pKa of 12 or more are preferable. Specifically, 1 · 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [ 4.3.0] non-5-ene, 6-dibutylamino-1,8-diazabicyclo [5.4.0] undec-7-ene, triethylenediamine, 4-dimethylaminopyridine (AP), N, N , N ′, N′-tetramethylethylenediamine and the like. These can be used individually by 1 type or in mixture of 2 or more types.
Among these, use of DBU or AP is preferable.

  The total amount of the organic base to be used is generally 0.9 to 10 mol, preferably 1.0 to 3.0 mol, per 1 mol of compound (II).

  As a method of reacting compound (II) and compound (III) in the presence of an organic base, for example, compound (II), compound (III), and organic base are dissolved and mixed in an appropriate solvent,- A method of reacting in a temperature range from 20 ° C. to the boiling point of the solvent, preferably 10 to 60 ° C. can be mentioned.

  Although the usage-amount of compound (III) is not restrict | limited in particular, Preferably it is 0.8-1.5 mol with respect to 1 mol of compound (II), More preferably, it is 0.9-1.2 mol.

  As the solvent to be used, halogen solvents such as methylene chloride, chloroform, dichloroethane; aromatic solvents such as benzene, toluene, xylene, benzonitrile, benzotrifluoride or chlorobenzene; methyl acetate, ethyl acetate, isopropyl acetate, etc. Ester solvents; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, and methyl isobutyl ketone; ether solvents such as diethyl ether and tetrahydrofuran; nitrile solvents such as acetonitrile; and the like.

  Among these, solvents that can be used for the synthesis of compound (III) or extraction after post-treatment, for example, halogen solvents such as methylene chloride; aromatic solvents such as toluene, xylene, chlorobenzene; ester solvents such as ethyl acetate; Ketone solvents such as methyl isobutyl ketone; THF, acetonitrile and the like are preferable, and these may be used in combination.

  The amount of the solvent to be used is generally 1-1000 parts by weight, preferably 5-100 parts by weight, per 1 part by weight of compound (II).

  The reaction is preferably performed in a nitrogen stream or a nitrogen atmosphere. While the reaction time varies depending on the compound to be reacted and the conditions, it is usually from several minutes to 48 hours. After completion of the reaction, the reaction solution can be cooled as necessary, and the desired product can be obtained by ordinary post-treatment operations.

  The method for crystallizing Compound (I) is not particularly limited, and a normal crystallization method is employed. For example, the method of cooling after melt | dissolving compound (I) in a crystallization solvent is mentioned.

  Moreover, when using the reaction product obtained by making compound (II) and compound (III) react as compound (I), it reacts from the reaction mixture of compound (II) and compound (III). What is necessary is just to cool, after making the mixture obtained by removing a solvent heat-dissolve in a crystallization solvent. In this case, if necessary, an operation of removing the inorganic salts by washing the reaction solution with water can be performed.

As described above, compound (I) can be isolated with high purity and efficiency.
Therefore, for example, even when the catalytic hydrogen reduction of compound (I) is carried out in the presence of a palladium-carbon (Pd—C) catalyst, the hydrogen reduction reaction can be completely advanced in a short time.

2) Method for Producing Compound Represented by Formula (I) The production method of the present invention is a method for producing a compound represented by formula (I), wherein compound (II) and compound (III) are reacted. And using a mixed solvent of water and an organic solvent that has a solubility of the compound represented by the formula (I) at 15 ° C. of less than 4.0% by weight and phase-separates with water from the reaction mixture. And crystallization of the compound represented by the formula (I).

Specifically, the step of reacting compound (II) and compound (III) can be carried out in the same manner as described in the above-mentioned production methods 1 to 3.
Moreover, from the obtained reaction mixture, the solubility of the compound represented by the formula (I) at 15 ° C. is less than 4.0% by weight, and a mixed solvent of an organic solvent and water that is phase-separated from water is used. And the process of crystallizing the compound represented by the said formula (I) can also be performed similarly to having demonstrated with the purification method of the said this invention.

According to the production method of the present invention, compound (I) can be produced with high purity and efficiency.
By using the compound (I) obtained by the purification method and the production method of the present invention, it is possible to efficiently obtain end products such as agricultural chemicals, pharmaceuticals and functional materials.

  Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the examples.

(Reference Example 1)
To 100 ml of ethylene glycol containing 14.0 g of potassium hydroxide, 19.5 g of 2-methoxy-4-nitrobenzaldehyde was added at room temperature. To this mixture, 342.5 g of a methylene chloride solution containing 20.5 g of TosMIC was dropped. The whole volume was stirred at room temperature, and the reaction was continued until the raw material disappeared by high performance liquid chromatography (HPLC). After completion of the reaction, the reaction solution was washed with water, and the organic layer was separated to obtain 420 g of a methylene chloride solution containing 20.6 g of 5- (2′-methoxy-4′-nitrophenyl) oxazole.

Example 1
(Crystallization process)
After adding 100 ml of water to 420 g of methylene chloride solution containing 20.6 g of 5- (2′-methoxy-4′-nitrophenyl) oxazole, the whole volume was heated and methylene chloride was completely distilled off. To the residue, 100 ml of methyl isobutyl ketone was added and heated to 80 ° C. to dissolve 5- (2-methoxy-4-nitrophenyl) oxazole in methyl isobutyl ketone. Thereafter, cooling was performed to precipitate crystals, followed by filtration and drying to obtain 19.2 g of the desired product (recovery rate: 93%).

(Reduction process)
2.0 g of 5- (2′-methoxy-4′-nitrophenyl) oxazole obtained above was dissolved in 20 ml of acetic acid isopropyl ester and charged into a glass pressure vessel. After charging 120 mg of 5% Pd—C, hydrogen was blown to 40 psi and the whole volume was stirred at room temperature for 4 hours. Pd—C was removed from the reaction solution by Celite filtration, and HPLC analysis of the filtrate was performed to confirm that the raw materials disappeared and only the target product was obtained.

  Type of crystallization solvent, solubility of 5- (2′-methoxy-4′-nitrophenyl) oxazole at 15 ° C. in the organic solvent used for the crystallization solvent (% by weight, “solubility” in the table), crystallization The recovery rate (%) of 5- (2′-methoxy-4′-nitrophenyl) oxazole in the step and the reduction rate (%) in the reduction step are summarized in Table 1.

Examples 2-5
In the same manner as in Example 1, crystallization was performed using the solvents shown in Table 1 in the crystallization step.
Type of crystallization solvent, solubility of 5- (2′-methoxy-4′-nitrophenyl) oxazole at 15 ° C. in the organic solvent used for the crystallization solvent (% by weight, “solubility” in the table), crystallization The recovery rate (%) of 5- (2′-methoxy-4′-nitrophenyl) oxazole in the step and the reduction rate (%) in the reduction step are summarized in Table 1.

Comparative Examples 1-3
In the same manner as in Example 1, crystallization was performed using the solvents shown in Table 1 in the crystallization step.
Type of crystallization solvent, solubility of 5- (2′-methoxy-4′-nitrophenyl) oxazole at 15 ° C. in the organic solvent used for the crystallization solvent (% by weight, “solubility” in the table), crystallization The recovery rate (%) of 5- (2′-methoxy-4′-nitrophenyl) oxazole in the step and the reduction rate (%) in the reduction step are summarized in Table 1.

  From Table 1, when a crystallization solvent composed of an organic solvent having water solubility at 15 ° C. of less than 4.0% by weight of 5- (2′-methoxy-4′-nitrophenyl) oxazole and water is used ( In Examples 1 to 5), the reduction rate in the reduction step was high, and it was found that high-purity 5- (2′-methoxy-4′-nitrophenyl) oxazole was obtained by crystallization. Moreover, the recovery rate in the crystallization process was also high.

On the other hand, a crystallization solvent comprising 5- (2′-methoxy-4′-nitrophenyl) oxazole having a solubility at 15 ° C. of 4.0% by weight or more and an organic solvent that is phase-separated from water and water. When used (Comparative Examples 1 and 2), although the recovery rate in the crystallization step is high, the reduction rate in the reduction step is low and crystallization causes 5- (2′-methoxy-4′-nitro). This suggests that phenyl) oxazole was obtained.
Further, in the case where only water is used as the crystallization solvent (Comparative Example 3), although the recovery rate in the crystallization process is high, the reduction process does not proceed, and crystallization includes 5- (2 ′ It is suggested that -methoxy-4'-nitrophenyl) oxazole was obtained.

Comparative Example 4
When the crystals obtained by concentrating and drying the methylene chloride solution of 5- (2′-methoxy-4′-nitrophenyl) oxazole were subjected to the reduction evaluation shown in Example 1, the reduction hardly proceeded. .

Claims (3)

Formula (I)

(Wherein, R ¹ represents a hydrogen atom or a C _1-5 alkyl group, R ² represents a halogen atom, a C _1-5 alkyl group or a C _1-5 alkoxy group, and n is 0, 1 or Wherein, when n is 2, R ² may be the same or different from each other), in a inert solvent, the compound of formula (II)

(Wherein R ² and n represent the same meaning as described above), and the formula (III)

(Wherein R ¹ represents the same meaning as described above), and a step of reacting with the compound represented by:
From the reaction mixture obtained by removing the inert solvent from the reaction solution, an organic compound selected from the group consisting of diethyl ketone, methyl isobutyl ketone, cyclohexanone, dibutyl ether, anisole, ethoxybenzene, n-butyl acetate, and monochlorobenzene And a step of crystallizing the compound represented by the formula (I) by using a mixed solvent of one or more of the solvents and water, and represented by the formula (I) Compound production method.   The production method according to claim 1, wherein a solvent selected from the group consisting of methyl isobutyl ketone, anisole, n-butyl acetate, cyclohexanone, and monochlorobenzene is used as the organic solvent.   The method according to claim 1, wherein methyl isobutyl ketone is used as the organic solvent.