WO2016208682A1 - Method for producing oxazoledicarboxylic acid compound - Google Patents

Abstract

Provided are: a compound which makes it possible to produce an oxazoledicarboxylic acid compound on an industrial scale at low cost; a method for producing the compound; and a method for producing an oxazoledicarboxylic acid compound using the aforementioned compound. A compound represented by general formula (1). In general formula (1), R¹ and R² independently represent a hydrogen atom, a lithium atom, a sodium atom or a potassium atom; and the ring A represents a bivalent aromatic hydrocarbon group which may have a substituent.

Description

Method for producing oxazole dicarboxylic acid compound

The present invention relates to a novel compound, a method for producing the compound, and a method for producing an oxazole dicarboxylic acid compound using the compound.

Polyester compounds such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT) are rich in flexibility and excellent in gas barrier properties and chemical resistance, so they are used in fields such as packaging films, magnetic tapes, containers, and clothing fibers. Has been.

Among these polyester compounds, for example, Patent Document 1 describes that a polyester compound obtained by reacting an oxazole dicarboxylic acid compound with a diol having a specific structure is excellent in heat resistance.

As shown below, this oxazole dicarboxylic acid compound is obtained by converting AHBA (3-amino-4-hydroxybenzoic acid) into a methyl ester, and then reacting with methyl terephthalaldehyde to form an imine. Patent Document 1 describes that an oxazole ring is constructed by oxidative cyclization with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and finally ester hydrolysis. .

International Publication No. 2014/163096

However, methyl terephthalaldehyde used for industrially producing the oxazole dicarboxylic acid compound described in Patent Document 1 is expensive and difficult to obtain in large quantities. Further, DDQ used for cyclization is expensive and requires 1 mol equivalent, and further, a reductant of DDQ by-produced by 1 mol equivalent contains a cyano group, which may increase the disposal cost.

The present invention has been made to solve the above-described problems, and is a compound that enables an oxazole dicarboxylic acid compound to be produced industrially at a low cost, a method for producing the compound, and an oxazole using the compound. It is an object of the present invention to provide a method for producing a dicarboxylic acid compound.

As a result of intensive studies on the above problems, the present inventors have found that an oxazole dicarboxylic acid compound can be produced industrially at a low cost by a novel reaction route via a novel intermediate, and to complete the present invention. It came.

（一般式（１）中、Ｒ^１及びＲ^２は、それぞれ独立に水素原子、リチウム原子、ナトリウム原子、又はカリウム原子を表し、環Ａは、置換基を有していてもよい２価の芳香族炭化水素基を表す。一般式（ｂ）中、環Ａは、一般式（１）のものと同じでよい。）
［６］　一般式（１）の化合物を得る工程で得られた反応混合物から一般式（１）の化合物を晶析処理し分離する工程をさらに含む、［５］に記載の一般式（１）の化合物の製造方法。
［７］　晶析温度が、０℃～１００℃である、［６］に記載の一般式（１）の化合物の製造方法。
［８］　晶析処理を行う際のｐＨが、２～７である、［６］又は［７］に記載の一般式（１）の化合物の製造方法。
［９］　晶析時間が、０．５時間～３時間である、［６］～［８］のいずれかに記載の一般式（１）の化合物の製造方法。
［１０］　下記一般式（１）の化合物を反応させ、下記一般式（２）の化合物を得る工程を含む、一般式（２）の化合物の製造方法。

（一般式（１）中、Ｒ^１及びＲ^２は、それぞれ独立に水素原子、リチウム原子、ナトリウム原子、又はカリウム原子を表し、環Ａは、置換基を有していてもよい２価の芳香族炭化水素基を表す。一般式（２）中、環Ａは、一般式（１）のものと同じでよい。）
［１１］　酸触媒を使用する、［１０］に記載の一般式（２）の化合物の製造方法。
［１２］　一般式（２）の化合物を得た後、一般式（２）の化合物を非プロトン性極性溶媒で再結晶する、［１０］又は［１１］に記載の一般式（２）の化合物の製造方法。
［１３］　下記一般式（ａ）の化合物及び下記一般式（ｂ）の化合物を反応させ、一般式（１）の化合物を得る工程をさらに含む、［１０］～［１２］のいずれかに記載の一般式（２）の化合物の製造方法。

（一般式（ｂ）中、環Ａは、一般式（１）のものと同じでよい。）
［１４］　一般式（１）の化合物を得る工程で得られた反応混合物から一般式（１）の化合物を晶析処理し分離する工程をさらに含む、［１３］に記載の一般式（２）の化合物の製造方法。
［１５］　晶析温度が、０℃～１００℃である、［１４］に記載の一般式（２）の化合物の製造方法。
［１６］　晶析処理を行う際のｐＨが、２～７である、［１４］又は［１５］に記載の一般式（２）の化合物の製造方法。
［１７］　晶析時間が、０．５時間～３時間である、［１４］～［１６］のいずれかに記載の一般式（２）の化合物の製造方法。 That is, the present invention includes the following contents.
[1] A compound of the following general formula (1).
(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. Represents a hydrocarbon group.)
[2] The compound according to [1], wherein R ¹ and R ^{2 in} the general formula (1) each independently represent a hydrogen atom or a sodium atom.
[3] The compound according to [1] or [2], wherein ^one of R ¹ and R ^{2 in} the general formula (1) represents a sodium atom and the other represents a hydrogen atom.
[4] The compound according to any one of [1] to [3], wherein the ring A in the general formula (1) represents a phenylene group which may have a substituent.
[5] A process for producing a compound of the general formula (1), comprising a step of reacting a compound of the following general formula (a) and a compound of the following general formula (b) to obtain a compound of the following general formula (1).

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. (In the general formula (b), the ring A may be the same as that in the general formula (1).)
[6] The general formula (1) according to [5], further including a step of crystallizing and separating the compound of the general formula (1) from the reaction mixture obtained in the step of obtaining the compound of the general formula (1). A method for producing the compound.
[7] The process for producing a compound of the general formula (1) according to [6], wherein the crystallization temperature is 0 ° C. to 100 ° C.
[8] The process for producing a compound of the general formula (1) according to [6] or [7], wherein the pH during crystallization treatment is 2 to 7.
[9] The process for producing a compound of general formula (1) according to any one of [6] to [8], wherein the crystallization time is 0.5 to 3 hours.
[10] A method for producing a compound of the general formula (2), comprising a step of reacting a compound of the following general formula (1) to obtain a compound of the following general formula (2).

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. (In the general formula (2), the ring A may be the same as that in the general formula (1).)
[11] The method for producing a compound of the general formula (2) according to [10], wherein an acid catalyst is used.
[12] After obtaining the compound of the general formula (2), the compound of the general formula (2) is recrystallized with an aprotic polar solvent, and the compound of the general formula (2) according to [10] or [11] Manufacturing method.
[13] The method according to any one of [10] to [12], further comprising a step of reacting a compound of the following general formula (a) and a compound of the following general formula (b) to obtain a compound of the general formula (1) The manufacturing method of the compound of General formula (2).

(In general formula (b), ring A may be the same as that in general formula (1).)
[14] The general formula (2) according to [13], further including a step of crystallizing and separating the compound of the general formula (1) from the reaction mixture obtained in the step of obtaining the compound of the general formula (1). A method for producing the compound.
[15] The process for producing a compound of the general formula (2) according to [14], wherein the crystallization temperature is 0 ° C. to 100 ° C.
[16] The process for producing a compound of the general formula (2) according to [14] or [15], wherein the pH at the time of crystallization treatment is 2 to 7.
[17] The process for producing a compound of the general formula (2) according to any one of [14] to [16], wherein the crystallization time is 0.5 hour to 3 hours.

ADVANTAGE OF THE INVENTION According to this invention, the compound which can manufacture an oxazole dicarboxylic acid compound industrially cheaply, the manufacturing method of the compound, and the manufacturing method of the oxazole dicarboxylic acid compound using the compound are provided. It has become possible.

Hereinafter, the compound of the present invention, the method for producing the compound, and the method for producing the oxazole dicarboxylic acid compound using the compound will be described in detail.

In the present specification, the term “which may have a substituent” attached immediately before a group means that the hydrogen atom of the group is not substituted with a substituent, and the hydrogen atom of the group It means both when a part or all of is substituted with a substituent.

In this specification, the term “C _p -C _q ” (p and q are positive integers satisfying p <q) means that the number of carbon atoms of the organic group described immediately after this term is p. Represents q. For example, the expression “C ₁ -C ₁₀ alkyl group” represents an alkyl group having 1 to 10 carbon atoms, and the expression “C ₁ -C ₁₀ alkyl ester” represents an alkyl group having 1 to 10 carbon atoms. The ester of is shown.

（一般式（１）中、Ｒ^１及びＲ^２は、それぞれ独立に水素原子、リチウム原子、ナトリウム原子、又はカリウム原子を表し、環Ａは、置換基を有していてもよい２価の芳香族炭化水素基を表す。） [Compound that can be an intermediate of an oxazole dicarboxylic acid compound]
The compound that can be an intermediate of the oxazole dicarboxylic acid compound of the present invention is a compound of the following general formula (1).

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. Represents a hydrocarbon group.)

R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom. R ¹ and R ² each independently preferably represent a hydrogen atom or a sodium atom, more preferably ^one of R ¹ and R ² represents a sodium atom and the other represents a hydrogen atom. That is, the compound of the general formula (1) is preferably a monosodium salt.

The bonding site of COOR ^{1 with} the benzene ring is not particularly limited, but it is preferable that the OH group bonded to the benzene ring is bonded to the position where it is in the 4-position (position para to the OH group).

Ring A represents a divalent aromatic hydrocarbon group which may have a substituent. The divalent aromatic hydrocarbon group represented by ring A is not particularly limited as long as it is a divalent hydrocarbon group containing an aromatic ring structure, but preferably has 6 to 24 carbon atoms, and has 6 to 14 carbon atoms. More preferred is 6 to 10 carbon atoms. The aromatic ring structure may be a single ring or a condensed ring, and may have two or more aromatic rings. Examples of the divalent aromatic hydrocarbon group include phenylene group, naphthylene group, biphenylene group, anthracenylene group, terphenylene group, phenanthrene diyl group, triphenylene diyl group, pyrenediyl group, fluorenediyl group, and biphenyl fluorenediyl group. Phenylene group, naphthylene group and biphenylene group are preferable, and phenylene group is more preferable. Among the phenylene groups, 1,4-phenylene group, 1,3-phenylene group and 1,2-phenylene group are preferable, 1,4-phenylene group and 1,3-phenylene group are more preferable, and 1,4-phenylene group is preferable. More preferred are groups.

The divalent aromatic hydrocarbon group represented by ring A may have a substituent. The substituent is not particularly limited, and examples thereof include halogen atoms, alkyl groups, cycloalkyl groups, alkoxy groups, cycloalkyloxy groups, aryl groups, aryloxy groups, arylalkyl groups, arylalkoxy groups, and monovalent heterocyclic rings. Group, alkylidene group, amino group, silyl group, acyl group, acyloxy group, carboxy group, sulfo group, cyano group, nitro group, hydroxy group, mercapto group, oxo group and the like.

Examples of the halogen atom used as a substituent include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The alkyl group used as a substituent may be either linear or branched. The number of carbon atoms of the alkyl group is preferably 1 to 12, more preferably 1 to 6, and more preferably 1 to 3. Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group and nonyl group. And decyl group.

The number of carbon atoms of the cycloalkyl group used as a substituent is preferably 3 to 12, more preferably 3 to 6. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

The alkoxy group used as a substituent may be either linear or branched. The number of carbon atoms of the alkoxy group is preferably 1-20, more preferably 1-12, still more preferably 1-6. Examples of the alkoxy group include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butoxy group, s-butoxy group, isobutoxy group, t-butoxy group, pentyloxy group, hexyloxy group, heptyloxy group, Examples include octyloxy group, nonyloxy group, and decyloxy group.

The number of carbon atoms of the cycloalkyloxy group used as a substituent is preferably 3 to 20, more preferably 3 to 12, and still more preferably 3 to 6. Examples of the cycloalkyloxy group include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

An aryl group used as a substituent is a group obtained by removing one hydrogen atom on an aromatic ring from an aromatic hydrocarbon. The number of carbon atoms of the aryl group used as a substituent is preferably 6 to 24, more preferably 6 to 18, still more preferably 6 to 14, and even more preferably 6 to 10. Examples of the aryl group include a phenyl group, a naphthyl group, and an anthracenyl group.

The number of carbon atoms of the aryloxy group used as a substituent is preferably 6 to 24, more preferably 6 to 18, still more preferably 6 to 14, and even more preferably 6 to 10. Examples of the aryloxy group used as a substituent include a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.

The number of carbon atoms of the arylalkyl group used as a substituent is preferably 7 to 25, more preferably 7 to 19, still more preferably 7 to 15, and even more preferably 7 to 11. Examples of the arylalkyl group include a phenyl-C ₁ -C ₁₂ alkyl group, a naphthyl-C ₁ -C ₁₂ alkyl group, and an anthracenyl-C ₁ -C ₁₂ alkyl group.

The number of carbon atoms of the arylalkoxy group used as a substituent is preferably 7 to 25, more preferably 7 to 19, still more preferably 7 to 15, and even more preferably 7 to 11. Examples of the arylalkoxy group include a phenyl-C ₁ -C ₁₂ alkoxy group and a naphthyl-C ₁ -C ₁₂ alkoxy group.

The monovalent heterocyclic group used as a substituent refers to a group obtained by removing one hydrogen atom from a heterocyclic ring of a heterocyclic compound. The number of carbon atoms of the monovalent heterocyclic group is preferably 3 to 21, more preferably 3 to 15, and still more preferably 3 to 9. The monovalent heterocyclic group includes a monovalent aromatic heterocyclic group (heteroaryl group). Examples of the monovalent heterocyclic ring include thienyl group, pyrrolyl group, furanyl group, furyl group, pyridyl group, pyridazinyl group, pyrimidyl group, pyrazinyl group, triazinyl group, pyrrolidyl group, piperidyl group, quinolyl group, and isoquinolyl group. Is mentioned.

An alkylidene group used as a substituent refers to a group obtained by removing two hydrogen atoms from the same carbon atom of an alkane. The number of carbon atoms of the alkylidene group is preferably 1-20, more preferably 1-14, still more preferably 1-12, still more preferably 1-6, and particularly preferably 1-3. Examples of the alkylidene group include, for example, methylidene group, ethylidene group, propylidene group, isopropylidene group, butylidene group, s-butylidene group, isobutylidene group, t-butylidene group, pentylidene group, hexylidene group, heptylidene group, octylidene group, nonylidene group. Group and decylidene group.

The acyl group used as a substituent refers to a group represented by the formula: —C (═O) —R (wherein R is an alkyl group or an aryl group). The alkyl group represented by R may be linear or branched. Examples of the aryl group represented by R include a phenyl group, a naphthyl group, and an anthracenyl group. The number of carbon atoms of the acyl group is preferably 2 to 20, more preferably 2 to 13, and further preferably 2 to 7. Examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, and a benzoyl group.

The acyloxy group used as a substituent refers to a group represented by the formula: —O—C (═O) —R (wherein R is an alkyl group or an aryl group). The alkyl group represented by R may be linear or branched. Examples of the aryl group represented by R include a phenyl group, a naphthyl group, and an anthracenyl group. The number of carbon atoms of the acyloxy group is preferably 2 to 20, more preferably 2 to 13, and further preferably 2 to 7. Examples of the acyloxy group include an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a pivaloyloxy group, and a benzoyloxy group.

The above-described substituents may further have a substituent (hereinafter sometimes referred to as “secondary substituent”). As the secondary substituent, the same substituents as described above may be used unless otherwise specified.

（一般式（１－１）中、Ｒ^１及びＲ^２は、一般式（１）のものと同じでよい。） The compound of the general formula (1) is preferably a compound of the general formula (1-1).

(In general formula (1-1), R ¹ and R ² may be the same as those in general formula (1).)

R ¹ and ^{R 2,} the general formula (1) it has the same meaning as ^{R 1} and ^{R 2,} and preferred ranges are also the same.

In a preferred embodiment, the compound of the general formula (1) is a compound represented by the following formulas (1-2) to (1-5), and the following formulas (1-3) to (1-5) Are more preferable, and compounds represented by the following formulas (1-3) to (1-4) are more preferable.

（一般式（１）中、Ｒ^１及びＲ^２は、それぞれ独立に水素原子、リチウム原子、ナトリウム原子、又はカリウム原子を表し、環Ａは、置換基を有していてもよい２価の芳香族炭化水素基を表す。一般式（ｂ）中、環Ａは、一般式（１）のものと同じでよい。） [Method for producing compound of general formula (1)]
The method for producing a compound of the general formula (1) of the present invention includes a step of reacting a compound of the following general formula (a) and a compound of the following general formula (b) to obtain a compound of the following general formula (1). It is characterized by.

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. (In the general formula (b), the ring A may be the same as that in the general formula (1).)

The compound of the general formula (1) is as described above in [Compound that can be an intermediate of an oxazole dicarboxylic acid compound].

In general formula (a), the binding site of COOH with the benzene ring is not particularly limited, but it binds to the position where the OH group bonded to the benzene ring is in the 4-position (position para-positioned to the OH group). It is preferable. A preferred embodiment of the compound of the general formula (a) is 3-amino-4-hydroxybenzoic acid represented by the following formula (a-1).

In general formula (b), ring A may be the same as that in general formula (1), and the preferred range is also the same.

A preferred embodiment of the compound of the general formula (b) is terephthalic acid chloride (hereinafter also referred to as “TPC”) represented by the following formula (b-1).

One preferred embodiment of the method for producing the compound of the general formula (1) of the present invention is 3-amino-4-hydroxybenzoic acid represented by the general formula (a-1) and the general formula (b-1). A step of reacting the represented terephthalic acid chloride to obtain a compound of the general formula (1-1).

As the compound of the general formula (a) and the compound of the general formula (b), commercially available products may be used, or they may be synthesized using a known synthesis method.

As a molar ratio of the compound of the general formula (a) and the compound of the general formula (b) (compound of the general formula (a) / compound of the general formula (b)), R ¹ and R ² of the general formula (1) , And ring A can be appropriately changed, and is not particularly limited, but is preferably 1/1 to 1/5, more preferably 1/1 to 1/2, and 1 / 1.3 to 1 / More preferably, 1.7, 1 / 1.4 to 1 / 1.6, or 1 / 1.5.

The reaction atmosphere is not particularly limited, but it is preferably carried out under an atmospheric pressure (normal pressure) and an inert gas atmosphere such as argon or nitrogen. Here, atmospheric pressure refers to 1 atmosphere (about 0.1 MPa).

When a solvent is used, examples of the solvent to be used include N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, tetrahydrofuran, methylcyclopentyl ether, and the like. N, N— Dimethylacetamide and tetrahydrofuran are preferred. A solvent may be used individually by 1 type and may be used in combination of 2 or more type.

The reaction temperature is preferably −78 ° C. to 100 ° C., more preferably −40 ° C. to 0 ° C., −30 ° C. to −10 ° C., −25 ° C. to −15 ° C., or — 20 ° C. is more preferable.

The reaction time can be appropriately changed according to the types of R ¹ , R ² and ring A in the general formula (1), and is not particularly limited, but is preferably 0.1 to 12 hours, preferably 0.2 hours -6 hours are more preferable, and 0.5 hours to 1 hour are more preferable.

After the reaction, the reaction mixture is separated into an organic layer and an aqueous layer (for example, the reaction mixture is separated with water / ethyl acetate), further treated with a base component, and a monometallic salt of the general formula (1) and / or Alternatively, a dimetal salt, that is, a compound in which R ¹ and / or R ^{2 in the} general formula (1) is a lithium atom, a sodium atom, or a potassium atom may be obtained. This process may be performed a plurality of times.

Examples of the base component include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and sodium hydroxide is preferable. When the base component is used as an aqueous solution, the concentration of the aqueous solution of the base component is not particularly limited, but is preferably 10 w / w% to 48 w / w%, more preferably 15 w / v% to 48 w / w%, and 20 w / v%. More preferably, it is ˜48 w / w%.

The base component is preferably added so that the pH is 8 to 14, more preferably 9 to 13, and even more preferably 10 to 12.

The compound of the general formula (1) can be purified from the reaction mixture according to various known separation methods. Among these separation methods, a preferred embodiment is a step of crystallizing and separating the compound of the general formula (1) from the reaction mixture. By performing a predetermined crystallization process, the crystal form becomes large. Thereby, the reaction mixture can be efficiently separated in a short time, and the compound of the general formula (1) can be isolated with high purity. In the method for producing the compound of the general formula (1) of the present invention, the separation step may be omitted as necessary, and the general formula (1) described later without separating the compound of the general formula (1) from the reaction mixture. You may provide to the manufacturing method of the compound of 2).

The solvent used for the crystallization treatment is not particularly limited, but water is preferable. Note that water may contain 5 v / v% or less of any of N, N-dimethylacetamide (DMAc), tetrahydrofuran (THF), methanol, and ethyl acetate.

The crystallization treatment is preferably performed for aging in order to increase the precipitation efficiency of the compound of the general formula (1).

The crystallization temperature (ripening temperature) can be appropriately changed according to the type of solvent used for the crystallization treatment, and is not particularly limited, but is preferably 0 ° C. to 100 ° C., more preferably 25 ° C. to 80 ° C., 50 More preferably, the temperature is from 70 ° C to 70 ° C, 55 ° C to 65 ° C, or 60 ° C.

The pH for the crystallization treatment is preferably 2 to 7, more preferably 4 to 6, and further preferably 4.5 to 5.5 or 5. An acid may be added to adjust the pH. Examples of the acid to be added include hydrochloric acid, sulfuric acid, acetic acid, and phosphoric acid, and hydrochloric acid is preferred. In particular, a monometallic salt having a large crystal form can be obtained by adjusting the pH to 4.5 or more, and it can be easily separated from the reaction mixture. Can be improved.

The crystallization time (ripening time) is not particularly limited, but is preferably 0.5 hours to 3 hours, more preferably 0.5 hours to 2 hours, 0.5 hours to 1.5 hours, and 0.75 hours. More preferred is ˜1,25 hours or 1 hour.

From the viewpoint of improving the recovery efficiency of the compound of the general formula (1) using the difference in solubility between the compound of the general formula (1) and the reaction mixture after completion of the crystallization time, 10 ° C. to 30 ° C. (preferably room temperature (preferably It is preferred to reduce the temperature to about 20 ° C)). After the temperature is lowered, the compound of the general formula (1) and the reaction mixture are separated by a known separation means such as filtration.

The crystal form of the compound of the general formula (1) is not particularly limited, but an acicular crystal is preferable from the viewpoint of improving separability from a reaction mixture such as a by-product. The acicular crystal includes not only a crystal having a pointed shape like a needle but also a crystal having a columnar shape, a prismatic shape, and an elliptical columnar shape.

（一般式（１）中、Ｒ^１及びＲ^２は、それぞれ独立に水素原子、リチウム原子、ナトリウム原子、又はカリウム原子を表し、環Ａは、置換基を有していてもよい２価の芳香族炭化水素基を表す。一般式（２）中、環Ａは、一般式（１）のものと同じでよい。） [Method for producing compound of general formula (2)]
The method for producing the compound of general formula (2) (oxazole dicarboxylic acid compound) of the present invention includes a step of reacting the compound of general formula (1) to obtain the compound of general formula (2).

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. (In the general formula (2), the ring A may be the same as that in the general formula (1).)

The compound of the general formula (1) is as described above in [Compound that can be an intermediate of an oxazole dicarboxylic acid compound].

In general formula (2), ring A may be the same as that in general formula (1), and the preferred range is also the same.

In general formula (2), the bonding site of COOH with the benzene ring is not particularly limited, but it is preferably bonded to the para-position relative to the oxygen atom of the oxazole ring condensed with the benzene ring. That is, the compound of the general formula (2) is preferably a compound of the general formula (2-1).

A preferred embodiment of the compound of the general formula (2) is 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid represented by the following formula (2-2). Accordingly, a preferred embodiment of the method for producing a compound of the general formula (2) of the present invention is a reaction of a compound of the general formula (1-1) with a 2- Obtaining (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid.

The reaction atmosphere is not particularly limited, but it is preferably carried out under an atmospheric pressure (normal pressure) and an inert gas atmosphere such as argon or nitrogen. Here, atmospheric pressure refers to 1 atmosphere (about 0.1 MPa).

When a solvent is used, examples of the solvent to be used include toluene, p-xylene, o-xylene, tetrahydrofuran, N-methyl-2-pyrrolidone and the like, and p-xylene and o-xylene are preferable. A solvent may be used individually by 1 type and may be used in combination of 2 or more type.

In the method for synthesizing the compound of the general formula (2) of the present invention, it is preferable to use an acid catalyst in order to promote a ring formation (ring closure) reaction. Examples of the acid catalyst include p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, methanesulfonic acid, a mixture of methanesulfonic acid and pyridine, sulfuric acid, and the like, and a mixture of methanesulfonic acid and pyridine is preferable. An acid catalyst may be used individually by 1 type, and may be used in combination of 2 or more type.

When R ¹ and R ^{2 in} the compound of the general formula (1) both represent a hydrogen atom, the acid catalyst is 1 mol of the general formula from the viewpoint of shortening the reaction time and reducing the generation of a reaction mixture such as a by-product. It is preferable to use 0.1 mol to 2 mol, more preferably 0.2 mol to 1.5 mol, and still more preferably 0.3 mol to 1 mol with respect to the compound (1). When using 2 or more types of acid catalysts, or when an acid catalyst is a mixture, the total value of the number of moles of each acid catalyst should just be in the said range.

When the compound of the general formula (1) is a monometal salt or a dimetal salt, the acid catalyst neutralizes the metal salt in addition to shortening the reaction time and reducing the generation of a reaction mixture such as a by-product. From this viewpoint, it is preferable to use 0.5 mol to 10 mol, more preferably 0.5 mol to 8 mol, and even more preferably 1 mol to 5 mol with respect to 1 mol of the compound of the general formula (1). When using 2 or more types of acid catalysts, or when an acid catalyst is a mixture, the total value of the number of moles of each acid catalyst should just be in the said range.

The reaction temperature is preferably 50 ° C. to 250 ° C., more preferably 100 ° C. to 200 ° C., further preferably 150 ° C. to 170 ° C., 155 ° C. to 165 ° C., or 160 ° C. from the viewpoint of efficiently proceeding with the ring closure reaction.

The reaction time can be appropriately changed according to the type of ring A in the general formula (2), and is not particularly limited, but is preferably 6 hours to 48 hours, more preferably 12 hours to 36 hours, and more preferably 18 hours to 24 hours. Time is even more preferred.

After completion of the reaction, the compound of the general formula (2) can be isolated from the reaction mixture according to various known separation methods. For example, the compound of the general formula (2) can be obtained by removing unnecessary substances by filtration, if necessary, adding a solvent such as toluene, washing and extracting, and drying if necessary.

In the method for producing the compound of the general formula (2) of the present invention, it is preferable to recrystallize the compound of the general formula (2) with an aprotic polar solvent as necessary. Recrystallization with an aprotic polar solvent facilitates separation and purification from the reaction mixture and shortens the separation time. Moreover, the manufacturing method of the compound of General formula (2) of this invention may wash | clean and filter with a recrystallization solvent before performing recrystallization.

The recrystallization solvent is not particularly limited as long as it is an aprotic polar solvent, but is preferably an aprotic polar solvent having a nitrogen atom. Examples of the aprotic polar solvent include dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and the like. N, N-dimethylacetamide, N-methyl- 2-pyrrolidone is preferred. A recrystallization solvent may be used individually by 1 type, and may be used in combination of 2 or more type.

The dissolution temperature can be appropriately changed according to the type of the recrystallization solvent, and is not particularly limited, but is preferably 0 ° C. to 150 ° C., more preferably 25 ° C. to 120 ° C., and further preferably 60 ° C. to 100 ° C. .

The aging time (dissolution time) for dissolution is preferably 0.5 hours to 3 hours, more preferably 0.75 hours to 2 hours, further preferably 0.75 hours to 1.5 hours, or 1 hour. .

The crystallization temperature is preferably −20 ° C. to 100 ° C., more preferably 0 ° C. to 50 ° C., and further preferably 15 ° C. to 30 ° C., 20 ° C. to 28 ° C., 20 ° C., or 25 ° C. The final crystallization temperature is preferably 15 ° C. to 25 ° C., more preferably 17 ° C. to 22 ° C., and more preferably 18 ° C. to 21 ° C. or 20 ° C.

The cooling time from the dissolution temperature to the crystallization temperature is preferably 4 hours to 36 hours, more preferably 8 hours to 24 hours, and even more preferably 12 hours to 16 hours.

For recrystallization to obtain the compound of the general formula (2), a method of further adding a poor solvent to precipitate the compound of the general formula (2) may be used. As a poor solvent, water, methanol, ethanol, acetone etc. are mentioned, for example, Water and methanol are preferable. A poor solvent may be used individually by 1 type, and may be used in combination of 2 or more type.

When the poor solvent is added, the addition time of the poor solvent is preferably 0.5 hours to 2 hours, more preferably 0.75 hours to 1.5 hours, or 1 hour.

As the crystal form of the compound of the general formula (2), a plate-like crystal is preferable from the viewpoint of improving separability from a reaction mixture such as a by-product. The plate-like crystal means a plate-like diameter having an aspect ratio of 2.0 or more with respect to the thickness.

（一般式（ｂ）中、環Ａは、一般式（１）のものと同じでよい。） The method for producing a compound of the general formula (2) of the present invention further includes a step of reacting a compound of the following general formula (a) and a compound of the following general formula (b) to obtain a compound of the general formula (1). Is preferred.

(In general formula (b), ring A may be the same as that in general formula (1).)

The step of obtaining the compound of the general formula (1) by reacting the compound of the general formula (a) and the compound of the general formula (b) is as described in the above [Production method of the compound of general formula (1)]. .

It is preferable that the method further includes a step of crystallizing and separating the compound of the general formula (1) from the obtained reaction mixture after completion of the step of obtaining the compound of the general formula (1). The step of crystallizing and separating the compound of the general formula (1) from the reaction mixture obtained in the step of obtaining the compound of the general formula (1) has been explained in the above [Method for producing compound of general formula (1)]. It is as follows.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. As for the structure of the synthesized compound, the chemical shift (δ) identified by the proton nuclear magnetic resonance ( ¹ H-NMR) spectrum using a nuclear magnetic resonance apparatus (“AVANCE400” (400 MHz) manufactured by Bruker) is ppm.

[Example 1]
<Synthesis of 3- (4-carboxybenzoylamino) -4-hydroxybenzoic acid monosodium salt>
30.45 g (150 mmol) of terephthalic acid chloride was dissolved in 76.6 ml of a mixed solvent of N, N-dimethylacetamide and 76.6 ml of tetrahydrofuran, cooled to −20 ° C., and then 15.31 g of 3-amino- 4-hydroxybenzoic acid (100 mmol) was added, and the mixture was cooled and stirred at −20 ° C. for 1 hour. After quenching by adding 55 ml of methanol, the temperature was raised to 20 ° C., 352 ml of ethyl acetate and 505 ml of water were added, and the pH was adjusted to 8.5 by adding 25 w / v% aqueous sodium hydroxide solution. An aqueous layer (lower layer) was obtained. The obtained aqueous layer was heated to 50 ° C., adjusted to pH 11.5 by adding 25 w / v% sodium hydroxide aqueous solution, then heated to 60 ° C., adjusted to pH 5 by adding hydrochloric acid, and subjected to crystallization for 1 hour. did. The slurry was cooled to room temperature and separated (the time taken for separation was 25 minutes) to obtain a light brown solid. This was dried overnight at 40 ° C. under reduced pressure to obtain 31.79 g (content 84.1 w% (mass%), 82.73 mmol, needle crystals) of the title compound (yield 82.7%). The HPLC purity of the title compound (title compound: impurity) was 1: 0.005.

< ¹ H-NMR of 3- (4-carboxybenzoylamino) -4-hydroxybenzoic acid monosodium salt>
¹ H-NMR (400 MHz, DMSO-d6) δ: 6.96-7.04 (1H, m), 7.63 (1H, dd, J = 8.4, 2.2 Hz), 7.88-8 .01 (4H, m), 8.36-8.45 (1H, m), 9.69 (s, 1H).

<Synthesis of 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid>
8.45 g (22 mmol) of 3- (4-carboxybenzoylamino) -4-hydroxybenzoic acid monosodium salt was suspended in 127 ml of p-xylene, where 3.14 g (48.4 mmol) of methanesulfonic acid and 1.22 g (15.4 mmol) of pyridine was added, and the mixture was heated and stirred at 160 ° C. overnight. After cooling to room temperature, the mixture was separated by filtration and washed with 12.7 ml of toluene to obtain a brown solid. This was dried overnight at 40 ° C. under reduced pressure to obtain 12.8 g (content 45.6 w%, 20.61 mmol) of crude crystals of the title compound (yield 93.7%).

<Recrystallization of 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid>
9.03 g (content 47.1 w%, 15 mmol) of crude crystal of 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid was added to 85 ml of N, N-dimethylacetamide and 1 at 60 ° C. Stir for hours. The resultant was filtered to remove insoluble matters, and washed with 4.25 ml of N, N-dimethylacetamide to obtain a reddish brown filtrate. This was cooled from 60 ° C. to room temperature over 14 hours, 38.25 ml of water was added over 1 hour, filtered and separated (the time taken for filtration was 9 minutes), washed with 12.75 ml of water, A pale yellow solid was obtained. This was dried at 80 ° C. under reduced pressure overnight to obtain 4.20 g of the title compound (content 91.9 w%, 13.62 mmol, plate crystal) (yield 90.8%). The HPLC purity of the title compound (title compound: impurity) was 1: 0.075.

[Example 2]
In Example 1, 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid was recrystallized as follows in the same manner as in Example 1, except that 2- (4-carboxyphenyl) Benzo [d] oxazole-5-carboxylic acid was synthesized.

<Recrystallization of 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid>
9.03 g (content 47.1 w%, 15 mmol) of crude crystal of 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid was added to 55.25 ml of N-methyl-2-pyrrolidone. The mixture was heated and stirred at 1 ° C. for 1 hour. The resultant was filtered to remove insoluble matters, and washed with 4.25 ml of N-methyl-2-pyrrolidone to obtain a reddish brown filtrate. This was cooled from 60 ° C. to room temperature (20 ° C.) over 14 hours, 25.5 ml of water was added over 1 hour, filtered and washed with 12.75 ml of water to obtain 24 ml of solid. Was stirred at room temperature for 1 hour. This was separated by filtration (the time required for the filtration was 3 minutes) and washed with 7.2 ml of methanol to obtain a pale yellow solid. This was dried at 40 ° C. under reduced pressure overnight to obtain 3.95 g of the title compound (content 95.8 w%, 13.36 mmol, plate crystal) (yield 89.2%). The HPLC purity of the title compound (title compound: impurity) was 1: 0.053.

[Example 3]
In Example 1, 2- (4-carboxyphenyl) benzo [d] oxazole- was synthesized in the same manner as in Example 1 except that 3- (4-carboxybenzoylamino) -4-hydroxybenzoic acid was synthesized as follows. 5-carboxylic acid was synthesized.

<Synthesis of 3- (4-carboxybenzoylamino) -4-hydroxybenzoic acid>
3.05 g (15 mmol) of terephthalic acid chloride was dissolved in 7.5 ml of a mixed solvent of N ′, N-dimethylacetamide and 7.5 ml of tetrahydrofuran, cooled to −20 ° C., and then 1.53 g of 3-amino -4-hydroxybenzoic acid (10 mmol) was added, and the mixture was cooled and stirred at -20 ° C for 1 hour. After quenching by adding 5 ml of methanol, the temperature was raised to 20 ° C., 35 ml of ethyl acetate and 50 ml of water were added, and 25 w / v% sodium hydroxide aqueous solution was added to adjust the pH to 8.5. An aqueous layer (lower layer) was obtained. 30 ml of ethyl acetate was added and stirred and washed, and then an aqueous layer (lower layer) was obtained as a separated layer, and this washing operation was performed twice. The obtained aqueous layer was heated to 50 ° C., 25 w / v% aqueous sodium hydroxide solution was added to adjust the pH to 11.5, hydrolysis was performed, and the mixture was cooled to room temperature, adjusted to pH 2 with hydrochloric acid, and crystallized. For 18 hours. The slurry was separated by filtration (the time taken for filtration was 180 minutes) to obtain a light brown solid. This was dried at 40 ° C. under reduced pressure overnight to obtain 3.19 g (content 80.3 w%, 8.51 mmol, fine crystals) of the title compound (yield 85.1%). The HPLC purity of the title compound (title compound: impurity) was 1: 0.177.

< ¹ H-NMR of 3- (4-carboxybenzoylamino) -4-hydroxybenzoic acid>
¹ H-NMR (400 MHz, DMSO-d6) δ: 7.00 (1H, d, J = 8.5 Hz), 7.69 (1H, dd, J = 8.4, 2.2 Hz), 8.04 (1H, s), 8.07 (3H, s), 8.30 (1H, d, J = 8.5 Hz), 9.72 (s, 1H).

[Example 4]
In Example 1, 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid was synthesized as follows, except that 2- (4-carboxyphenyl) benzo [d Oxazole-5-carboxylic acid was synthesized.

<Synthesis of 2- (4-carboxyphenyl) benzo [d] oxazole-5-carboxylic acid>
2.82 g (content 78.4 w%, 7.33 mmol) of 3- (4-carboxybenzoylamino) -4-hydroxybenzoic acid monosodium salt was suspended in 42.3 ml of xylene, and 1.55 g (16 0.1 mmol) of methanesulfonic acid and 0.41 g (5.1 mmol) of pyridine were added, and the mixture was heated and stirred at 160 ° C. overnight. After cooling to room temperature, the solution was separated by filtration (the time required for the filtration was 1 minute). The HPLC purity of the title compound at this time (title compound: impurity) was 1: 0.333. The solid obtained by washing with 4.2 ml of toluene was added to 17.1 ml of methanol and stirred at 60 ° C. for 1 hour. This was separated by filtration (the time taken for filtration was 20 minutes). The HPLC purity of the title compound at this time (title compound: impurity) was 1: 0.064. The solid obtained by washing with 6 ml of methanol was added to 11.5 ml of water and stirred at room temperature for 1 hour. This was separated by filtration (the time required for the separation by filtration was 85 minutes) and washed with 6 ml of water to obtain a pale yellow solid. The HPLC purity of the title compound at this time (title compound: impurity) was 1: 0.064. This was dried overnight at 60 ° C. under reduced pressure to obtain 2.14 g (content 87.7 w%, 6.63 mmol, fine crystals) of the title compound (yield 90.4%).

Claims (17)

The compound of the following general formula (1).

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. Represents a hydrocarbon group.) The compound according to claim 1, wherein R ¹ and R ^{2 in} the general formula (1) each independently represent a hydrogen atom or a sodium atom. The compound according to claim 1 or 2, wherein ^one of R ¹ and R ^{2 in} the general formula (1) represents a sodium atom and the other represents a hydrogen atom. The compound according to any one of claims 1 to 3, wherein the ring A in the general formula (1) represents a phenylene group which may have a substituent. The manufacturing method of the compound of General formula (1) including the process of making the compound of the following general formula (a) and the compound of the following general formula (b) react, and obtaining the compound of the following general formula (1).

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. (In the general formula (b), the ring A may be the same as that in the general formula (1).) The method further comprises the step of crystallizing and separating the compound of the general formula (1) from the reaction mixture obtained in the step of obtaining the compound of the general formula (1). Production method. The method for producing a compound of the general formula (1) according to claim 6, wherein the crystallization temperature is 0 ° C to 100 ° C. The method for producing a compound of the general formula (1) according to claim 6 or 7, wherein the pH during the crystallization treatment is 2 to 7. The method for producing a compound of the general formula (1) according to any one of claims 6 to 8, wherein the crystallization time is 0.5 to 3 hours. The manufacturing method of the compound of General formula (2) including the process of making the compound of the following General formula (1) react, and obtaining the compound of the following General formula (2).

(In general formula (1), R ¹ and R ² each independently represent a hydrogen atom, a lithium atom, a sodium atom, or a potassium atom, and ring A is a divalent aromatic that may have a substituent. (In the general formula (2), the ring A may be the same as that in the general formula (1).) The manufacturing method of the compound of General formula (2) of Claim 10 which uses an acid catalyst. The method for producing a compound of the general formula (2) according to claim 10 or 11, wherein after obtaining the compound of the general formula (2), the compound of the general formula (2) is recrystallized with an aprotic polar solvent. The general formula according to any one of claims 10 to 12, further comprising a step of reacting a compound of the following general formula (a) and a compound of the following general formula (b) to obtain a compound of the general formula (1). A method for producing the compound of (2).

(In general formula (b), ring A may be the same as that in general formula (1).) The compound of the general formula (2) according to claim 13, further comprising a step of crystallizing and separating the compound of the general formula (1) from the reaction mixture obtained in the step of obtaining the compound of the general formula (1). Production method. The method for producing a compound of the general formula (2) according to claim 14, wherein the crystallization temperature is 0 ° C to 100 ° C. The method for producing a compound of the general formula (2) according to claim 14 or 15, wherein the pH during the crystallization treatment is 2 to 7. The method for producing a compound of the general formula (2) according to any one of claims 14 to 16, wherein the crystallization time is 0.5 hours to 3 hours.