JP2024146829A - Method for producing water-soluble thioamide compound carboxylate - Google Patents

Abstract

To provide a method for producing a water-soluble thioamide compound carboxylate, which has improved productivity.SOLUTION: A method for producing a water-soluble thioamide compound carboxylate (E), comprises the steps of: (1) reacting a hydrophobic amide compound (A) having a carboxylic acid ester group with a thioamidating agent (B) in a hydrophobic solvent to obtain a thioamide compound (C) having an ester group; (2) adding a basic compound (D-1), which is capable of decomposing the thioamidating agent (B) and its residue, and water to the hydrophobic solvent containing the obtained thioamide compound (C) having an ester group, removing the water layer by a separation operation, and removing water-soluble decomposition products of the thioamidating agent (B) and its residue; and (3) adding a basic compound (D-2), which is capable of hydrolyzing the ester group of the thioamide compound (C) obtained by step (2), and water to the hydrophobic solvent containing the thioamide compound (C) having an ester group, and thereafter obtaining an aqueous solution of the thioamide compound carboxylate (E) by a separation operation. The basic compound (D-1) has a weaker basicity than the basic compound (D-2).SELECTED DRAWING: None

Description

The present invention relates to a method for producing a water-soluble thioamide compound carboxylate.

2. Description of the Related Art In recent years, water-soluble thioamide compound carboxylates have been used as intermediates for materials that can be applied to optical films such as polarizing plates and retardation plates used in flat panel displays (FPDs).
In Non-Patent Document 1, a hydrophobic amide compound having a dicarboxylate group is reacted with a thioamidating agent in the absence of a solvent to obtain a solution containing a thioamide compound having an ester group, and the solution is purified using a silica gel column, and then concentrated and dried to extract the thioamide compound having an ester group as a powder.

European Journal of Medical Chemistry, 123 (2016), 514-522

Conventional methods include a concentration step and a drying step to extract the thioamide compound having an ester group, which is a precursor of the carboxylate salt of the thioamide compound, and are therefore not suitable for industrial-scale production.

The objective of the present invention is to provide a method for producing a water-soluble thioamide compound carboxylate with improved productivity.

［式中、
Ｒ^１～Ｒ^４は、それぞれ独立に、水素原子、炭素数１～８のアルキル基、炭素数３～８の脂環式炭化水素基、炭素数１～８のアルコキシ基、炭素数１～８のチオエーテル基、炭素数１～８のスルホニル基およびハロゲン原子からなる群から選択される基を表し、
Ｒ^５は単結合、アルキレン基または炭素数３～８の二価の脂環式炭化水素基を表し、
Ｒ^６は炭素数１～４のアルキル基を表す］
で示されるアミド化合物である、［１］～［４］のいずれかに記載の方法。
［６］ 水溶性チオアミド化合物カルボン酸塩（Ｅ）が式（Ｅ１）：

［式中、
Ｒ^１～Ｒ^５は、それぞれ、前記式（Ａ１）のＲ^１～Ｒ^５と同じ意味を表し、
Ｍは、アルカリ金属原子またはアルカリ土類金属原子を表し、
ｍはＭで表されるアルカリ金属またはアルカリ土類金属の価数を表す］
で示されるチオアミド化合物カルボン酸塩である、［１］～［５］のいずれかに記載の方法。
［７］ 塩基性化合物（Ｄ－３）の存在下、［１］または［２］に記載の方法により得られるチオアミド化合物カルボン酸塩（Ｅ）の水溶液に酸化剤（Ｆ）を添加して、カルボキシル基を有するベンゾチアゾールカルボン酸塩（Ｇ）を得ることを含む、ベンゾチアゾールカルボン酸塩（Ｇ）の製造方法。
［８］ ［７］に記載の方法により得られるベンゾチアゾールカルボン酸塩（Ｇ）と酸との反応によりベンゾチアゾールカルボン酸（Ｈ）を得ることを含む、ベンゾチアゾールカルボン酸塩（Ｈ）の製造方法。 The present inventors have conducted extensive research to solve the above problems and have completed the present invention. That is, the present invention provides the following preferred embodiments.
[1] A method for producing a water-soluble thioamide compound carboxylate (E), comprising the following steps:
(1) a step of reacting a hydrophobic amide compound (A) having a carboxylate group with a thioamidating agent (B) in a hydrophobic solvent to obtain a thioamide compound (C) having an ester group;
(2) adding a basic compound (D-1) capable of decomposing a thioamidating agent (B) and its residue and water to a hydrophobic solvent containing the obtained thioamide compound (C) having an ester group, and then removing the aqueous layer by a liquid separation operation to remove water-soluble decomposition products of the thioamidating agent (B) and its residue; and (3) adding a basic compound (D-2) capable of hydrolyzing an ester group of the thioamide compound (C) and water to a hydrophobic solvent containing the thioamide compound (C) having an ester group obtained by the step (2), and then obtaining an aqueous solution of a thioamide compound carboxylate (E) by a liquid separation operation,
The method, wherein the basic compound (D-1) has a weaker basicity than the basic compound (D-2).
[2] The method according to [1], wherein the basic compound (D-1) is one or more compounds selected from the group consisting of potassium hydrogen carbonate, sodium hydrogen carbonate, cesium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, sodium phosphate, monopotassium dihydrogen phosphate, dipotassium monohydrogen phosphate, monosodium dihydrogen phosphate, and disodium monohydrogen phosphate.
[3] The method according to [1] or [2], wherein the basic compound (D-2) is one or more compounds selected from the group consisting of sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, and tetrabutylammonium hydride.
[4] The method according to any one of [1] to [3], wherein the hydrophobic amide compound (A) having a carboxylate group has an aromatic ring structure selected from the group consisting of a benzene ring, a naphthalene ring, an anthracene ring, a furan ring, a thiophene ring, a thiazole ring, a benzofuran ring, a benzothiophene ring, a benzothiazole ring, and a thienothiophene ring, each of which may have a substituent.
[5] The hydrophobic amide compound (A) having a carboxylate group is represented by the formula (A1):

[Wherein,
R ¹ to R ⁴ each independently represent a group selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a thioether group having 1 to 8 carbon atoms, a sulfonyl group having 1 to 8 carbon atoms, and a halogen atom;
^R5 represents a single bond, an alkylene group, or a divalent alicyclic hydrocarbon group having 3 to 8 carbon atoms;
R ⁶ represents an alkyl group having 1 to 4 carbon atoms.
The method according to any one of [1] to [4], wherein the compound is an amide compound represented by the formula:
[6] The water-soluble thioamide compound carboxylate (E) is represented by the formula (E1):

[Wherein,
R ¹ to R ⁵ each have the same meaning as R ¹ to R ⁵ in formula (A1),
M represents an alkali metal atom or an alkaline earth metal atom;
m represents the valence of the alkali metal or alkaline earth metal represented by M.
The method according to any one of [1] to [5], wherein the compound is a thioamide compound carboxylate represented by the formula:
[7] A method for producing a benzothiazole carboxylate (G) comprising adding an oxidizing agent (F) to an aqueous solution of a thioamide compound carboxylate (E) obtained by the method according to [1] or [2] in the presence of a basic compound (D-3), to obtain a benzothiazole carboxylate (G) having a carboxyl group.
[8] A method for producing a benzothiazole carboxylate (H), comprising reacting a benzothiazole carboxylate (G) obtained by the method according to [7] with an acid to obtain a benzothiazole carboxylic acid (H).

The present invention provides a method for producing a water-soluble thioamide compound carboxylate salt with improved productivity.

The method for producing the water-soluble thioamide compound carboxylate (E) of the present invention comprises the following steps:
(1) a step of reacting a hydrophobic amide compound (A) having a carboxylate group with a thioamidating agent (B) in a hydrophobic solvent to obtain a thioamide compound (C) having an ester group;
(2) adding a basic compound (D-1) capable of decomposing a thioamidating agent (B) and its residue and water to a hydrophobic solvent containing the obtained thioamide compound (C) having an ester group, and then removing the aqueous layer by a liquid separation operation to remove water-soluble decomposition products of the thioamidating agent (B) and its residue; and (3) adding a basic compound (D-2) capable of hydrolyzing an ester group of the thioamide compound (C) and water to a hydrophobic solvent containing the thioamide compound (C) having an ester group obtained by the step (2), and then obtaining an aqueous solution of a thioamide compound carboxylate (E) by a liquid separation operation,
The basic compound (D-1) has a weaker basicity than the basic compound (D-2).

<Step (1)>
Step (1) is a step of producing a thioamide compound (C) having an ester group by reacting a hydrophobic amide compound (A) having a carboxylate group with a thioamidating agent (B) in a hydrophobic solvent.

The amount of the thioamidating agent used is preferably 0.5 to 1.0 molar equivalent, more preferably 0.5 to 0.8 molar equivalent, and even more preferably 0.5 to 0.6 molar equivalent, relative to 1 molar equivalent of the hydrophobic amide compound (A) having a carboxylate group.

The temperature of the thioamidation reaction is preferably 60 to 90° C., more preferably 65 to 85° C., and even more preferably 70 to 80° C. The time of the thioamidation reaction is preferably 2 to 12 hours, more preferably 2 to 8 hours, and even more preferably 2 to 6 hours.
By carrying out the thioamidation reaction within the above-mentioned temperature and time ranges, the reaction yield tends to be improved and productivity tends to be higher.

［式中、
Ｒ^１～Ｒ^４は、それぞれ独立に、水素原子、炭素数１～８のアルキル基、炭素数３～８の脂環式炭化水素基、炭素数１～８のアルコキシ基、炭素数１～８のチオエーテル基、炭素数１～８のスルホニル基およびハロゲン原子からなる群から選択される基を表し、
Ｒ^５は単結合、アルキレン基または炭素数３～８の二価の脂環式炭化水素基を表し、
Ｒ^６は炭素数１～４のアルキル基を表す］
で示されるアミド化合物であることが好ましい。カルボン酸エステル基を有する疎水性アミド化合物（Ａ）は、所望する構造に応じて公知の有機合成法を用いることにより合成できる。 <Hydrophobic Amide Compound (A) Having Carboxylic Acid Ester Group>
The hydrophobic amide compound (A) having a carboxylate group is appropriately selected according to the structure of the water-soluble thioamide compound carboxylate (E) to be targeted. For example, the hydrophobic amide compound (A) having a carboxylate group may be a compound having an aromatic ring structure selected from the group consisting of a benzene ring, a naphthalene ring, an anthracene ring, a furan ring, a thiophene ring, a thiazole ring, a benzofuran ring, a benzothiophene ring, a benzothiazole ring and a thienothiophene ring, each of which may have a substituent, and is represented by the formula (A1):

[Wherein,
R ¹ to R ⁴ each independently represent a group selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a thioether group having 1 to 8 carbon atoms, a sulfonyl group having 1 to 8 carbon atoms, and a halogen atom;
^R5 represents a single bond, an alkylene group, or a divalent alicyclic hydrocarbon group having 3 to 8 carbon atoms;
R ⁶ represents an alkyl group having 1 to 4 carbon atoms.
The hydrophobic amide compound (A) having a carboxylate group can be synthesized by using a known organic synthesis method according to the desired structure.

Examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group.
Examples of the alicyclic hydrocarbon group having 3 to 8 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
Examples of the alkoxy group having 1 to 8 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a tert-butoxy group, a sec-butoxy group, an n-pentyloxy group, an n-hexyloxy group, an n-heptyloxy group, and an n-octyloxy group.
Examples of the thioether group having 1 to 8 carbon atoms include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a pentylthio group, a hexylthio group, a heptylthio group, and an octylthio group.
Examples of the sulfonyl group having 1 to 8 carbon atoms include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group, a hexylsulfonyl group, an n-heptylsulfonyl group, and an n-octylsulfonyl group.
Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.
Examples of the alkylene group include an ethylene group, a propane-1,3-diyl group, a propane-1,2-diyl group, a butane-1,4-diyl group, a pentane-1,5-diyl group, a hexane-1,6-diyl group, an ethane-1,1-diyl group, a propane-1,1-diyl group, a propane-2,2-diyl group, a propane-1,2-diyl group, a pentane-2,4-diyl group, a 2-methylpropane-1,3-diyl group, a pentane-1,4-diyl group, and a 2-methylbutane-1,4-diyl group.
Examples of the divalent alicyclic hydrocarbon group having 3 to 8 carbon atoms include a cyclopentane-1,3-diyl group and a cyclohexane-1,4-diyl group.

Specific examples of the hydrophobic amide compound (A) having a carboxylate group include compounds (A1-1) to (A1-13) in which R ¹ to R ⁶ in formula (A1) are each the following substituents, and compound (A1-3) is preferred.

<Thioamidating Agent>
Examples of the thioamidating agent include Lawesson's reagent and diphosphorus pentasulfide, and preferably Lawesson's reagent.

<Hydrophobic Solvent>
In this specification, the hydrophobic solvent means a solvent having a solubility of 300 g or less in 1 L of water at 25° C. Examples of hydrophobic solvents include:
Aromatic solvents such as benzene, toluene, xylene, and anisole;
Acetate solvents such as methyl acetate, ethyl acetate, and butyl acetate;
Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, chlorobenzene, and dichlorobenzene;
Ketone solvents such as methyl isobutyl ketone, methyl ethyl ketone, and cyclohexanone;
etc.
Among them, aromatic solvents are preferable as the hydrophobic solvent. The hydrophobic solvents may be used alone or in combination.

The amount of the hydrophobic solvent used is not particularly limited as long as it is an amount sufficient for the reaction between the hydrophobic amide compound (A) having a carboxylate group and the thioamidating agent. For example, the amount may be 1 to 80 parts by mass, and preferably 2 to 50 parts by mass, per part by mass of the hydrophobic amide compound (A) having a carboxylate group so that each component is sufficiently dissolved and the reaction can proceed efficiently.

<Solvents other than hydrophobic solvents>
In step (1), in addition to the hydrophobic solvent, a solvent other than the hydrophobic solvent may be contained. Examples of the solvent other than the hydrophobic solvent include ketone solvents such as acetone and methyl ethyl ketone; aliphatic hydrocarbon solvents such as pentane, hexane, and heptane; nitrile solvents such as acetonitrile; ether solvents such as tetrahydrofuran and dimethoxyethane; ester solvents such as ethyl lactate; aprotic polar solvents such as dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and hexamethylphosphoric triamide; cellosolve solvents such as ethyl cellosolve; glycol ether solvents such as propylene glycol monomethyl ether; and methanol. These solvents may be used alone or in combination.

When a solvent other than a hydrophobic solvent is used, the amount used is preferably 0.001 to 10 parts by mass, more preferably 0.001 to 1 part by mass, and even more preferably 0.001 to 0.5 parts by mass, per part by mass of the hydrophobic solvent.

［式中、
Ｒ^１～Ｒ^６は、それぞれ上記と同じ意味を表す］ <Thioamide compound (C) having an ester group>
The thioamide compound (C) having an ester group is determined according to the structure of the hydrophobic amide compound (A) having a carboxylic acid ester group. For example, when the amide compound represented by the formula (A1) is used as the hydrophobic amide compound (A) having a carboxylic acid ester group, the thioamide compound (C) having an ester group is a compound represented by the formula (C1).

[Wherein,
R ¹ to R ⁶ each have the same meaning as above.

<Step (2)>
Step (2) is a step of adding a basic compound (D-1) capable of decomposing the thioamidating agent (B) and its residue and water to a hydrophobic solvent containing the obtained thioamide compound (C) having an ester group, and then removing the water layer by a liquid separation operation to remove the water-soluble decomposition products of the thioamidating agent (B) and its residue. In the presence of water, the thioamidating agent (B) and its residue are decomposed by the basic compound (D-1) and the decomposition product is removed by a liquid separation operation, thereby enabling the solution to be connected to the next step. Therefore, the method of the present invention employing the operation of step (2) enables the production of a water-soluble thioamide compound carboxylate with high production efficiency. In addition, the thioamidating agent (B) and its residue can be effectively decomposed and removed, and finally, a water-soluble thioamide compound carboxylate (E) can be obtained with high purity and with few impurities derived from the thioamidating agent (B) and the like.

The amount of the basic compound (D-1) used is preferably 2.0 to 6.0 molar equivalents, more preferably 3.0 to 5.0 molar equivalents, and even more preferably 4.0 to 4.6 molar equivalents, relative to 1 molar equivalent of the hydrophobic amide compound (A) having a carboxylate group.

The amount of water used is preferably 0.5 to 50 parts by mass, more preferably 1 to 20 parts by mass, and even more preferably 1 to 10 parts by mass, per part by mass of the hydrophobic amide compound (A) having a carboxylate group.

A basic compound (D-1) and water are added to a hydrophobic solvent containing a thioamide compound (C) having an ester group, and then the thioamidating agent (B) and its residue are reacted with the basic compound (D-1). The reaction temperature is preferably 25 to 70° C., more preferably 30 to 60° C., and even more preferably 30 to 50° C. The reaction time is preferably 2 to 36 hours, more preferably 4 to 24 hours, and even more preferably 6 to 16 hours.
By carrying out the reaction within the above temperature and time ranges, the reaction yield tends to be improved and productivity tends to be higher.

<Basic Compound (D-1)>
Examples of the basic compound (D-1) include
Amine compounds such as ammonia, methylamine, and N,N,N',N'-tetramethylethylenediamine;
Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide;
Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide;
quaternary ammonium hydroxides such as tetramethylammonium hydroxide and tetrabutylammonium hydroxide;
Alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate;
Alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate;
Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate;
Alkaline earth metal bicarbonates such as magnesium bicarbonate and calcium bicarbonate;
Alkali metal salts of organic acids, such as sodium citrate, sodium gluconate, sodium ethylenediaminetetraacetate, sodium lactate, sodium oxalate, sodium tartrate, and sodium ascorbate;
Among these, a compound selected from the group consisting of potassium hydrogen carbonate, sodium hydrogen carbonate, cesium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, sodium phosphate, monopotassium dihydrogen phosphate, dipotassium monohydrogen phosphate, monosodium dihydrogen phosphate, and disodium monohydrogen phosphate is preferred. The basic compound (D-1) may be used alone or in combination.

In the present invention, as the basic compound (D-1), a compound exhibiting weaker basicity than the basic compound (D-2) described below is used, and can be appropriately selected from compounds exhibiting weaker basicity in relation to the basic compound (D-2) used in step (3). By using a weakly basic compound as the basic compound (D-1) in step (2), it becomes possible to decompose and remove the thioamidating agent (B) and its residue while suppressing the occurrence of ester hydrolysis of the thioamide compound (C) having an ester group, and the target water-soluble thioamide compound carboxylate (E) can be obtained in high yield.
The basicity of the basic compound (D-1) and the basic compound (D-2) can be determined, for example, by the ionization constant (pKa).

<Water>
The step (2) is carried out in the presence of water, which may contain, in addition to water, alcohols such as methanol, ethanol, and isopropanol.
When an alcohol is contained, the content thereof is preferably 0.0001 to 0.1 part by mass, more preferably 0.0001 to 0.05 part by mass, and even more preferably 0.0005 to 0.01 part by mass, per part by mass of water.

In step (2), the method for recovering the aqueous layer from the reaction mixture is not particularly limited, and any separation method known to those skilled in the art can be used.

<Step (3)>
The step (3) is a step of adding a basic compound (D-2) capable of hydrolyzing an ester group of the thioamide compound (C) and water to a hydrophobic solvent containing the thioamide compound (C) having an ester group obtained in the step (2), and then obtaining an aqueous solution of a thioamide compound carboxylate (E) by a liquid separation operation.

The amount of the basic compound (D-2) used is preferably 0.8 to 4.0 molar equivalents, more preferably 0.8 to 2.0 molar equivalents, and even more preferably 1.0 to 1.3 molar equivalents, relative to 1 molar equivalent of the hydrophobic amide compound (A) having a carboxylate group.

The amount of water used is preferably 0.5 to 50 parts by mass, more preferably 1 to 20 parts by mass, and even more preferably 1 to 10 parts by mass, per part by mass of the hydrophobic amide compound (A) having a carboxylate group.

A basic compound (D-2) and water are added to a hydrophobic solvent containing a thioamide compound (C) having an ester group, and then the thioamide compound (C) having an ester group is reacted with the basic compound (D-2). The reaction temperature is preferably 25 to 70° C., more preferably 30 to 60° C., and even more preferably 35 to 55° C. The reaction time is preferably 1 to 20 hours, more preferably 2 to 15 hours, and even more preferably 2 to 10 hours.
By carrying out the reaction within the above temperature and time ranges, the reaction yield tends to be improved and productivity tends to be higher.

<Basic Compound (D-2)>
In the present invention, as the basic compound (D-2), a basic compound exhibiting stronger basicity than the basic compound (D-1) is used. Examples of the basic compound (D-2) include:
Amine compounds such as ammonia, methylamine, and N,N,N',N'-tetramethylethylenediamine;
Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide;
Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide;
quaternary ammonium hydroxides such as tetramethylammonium hydroxide and tetrabutylammonium hydroxide;
Alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate;
Alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate;
Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate;
Alkaline earth metal bicarbonates such as magnesium bicarbonate and calcium bicarbonate;
Alkali metal salts of organic acids, such as sodium citrate, sodium gluconate, sodium ethylenediaminetetraacetate, sodium lactate, sodium oxalate, sodium tartrate, and sodium ascorbate;
and can be appropriately selected from compounds that exhibit stronger basicity in relation to the basic compound (D-1) used in step (2). In one embodiment of the present invention, the basic compound (D-2) is preferably a compound selected from the group consisting of sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, and tetrabutylammonium hydride.

In step (3), the method for recovering the aqueous solution of the thioamide compound carboxylate (E) from the reaction mixture is not particularly limited, and any separation method known to those skilled in the art can be used.

［式中、
Ｒ^１～Ｒ^５は、それぞれ、前記式（Ａ１）のＲ^１～Ｒ^５と同じ意味を表し、
Ｍは、アルカリ金属原子またはアルカリ土類金属原子を表し、
ｍはＭで表されるアルカリ金属またはアルカリ土類金属の価数を表す］ <Water-soluble thioamide compound carboxylate (E)>
By the step (3), a water-soluble thioamide compound carboxylate (E) is obtained in a state of being dissolved in an aqueous solution. The water-soluble thioamide compound carboxylate (E) is determined depending on the structure of the hydrophobic amide compound (A) having a carboxylate group as the starting material. In one embodiment of the present invention, the water-soluble thioamide compound carboxylate (E) is represented, for example, by formula (E1).

[Wherein,
R ¹ to R ⁵ each have the same meaning as R ¹ to R ⁵ in formula (A1),
M represents an alkali metal atom or an alkaline earth metal atom;
m represents the valence of the alkali metal or alkaline earth metal represented by M.

Examples of alkali metal atoms include lithium, sodium, potassium, and cesium. Examples of alkaline earth metal atoms include beryllium, magnesium, and calcium. Of these, M is preferably potassium.

<Benzothiazole carboxylate (G)>
A benzothiazole carboxylate (G) having a carboxyl group can be obtained by adding an oxidizing agent (F) to the thioamide compound carboxylate (E) obtained by the above method in the presence of a basic compound (D-3).

As the basic compound (D-3), for example, the basic compounds listed as the basic compounds (D-1) and/or (D-2) that can be used can be used.

The amount of the basic compound (D-3) used is preferably 1 to 20 molar equivalents, and more preferably 2 to 10 molar equivalents, per molar equivalent of the thioamide compound carboxylate (E).

Examples of the oxidizing agent (F) include potassium ferricyanide, iron (II) chloride, iron (III) chloride, iron (II) bromide, iron (III) bromide, iron acetylacetonate, palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, and ruthenium (III) chloride. As an oxidizing assistant, it may be used in combination with ammonium persulfate, sodium persulfate, potassium persulfate, and the like.

The amount of the oxidizing agent (F) used is preferably 1 to 10 molar equivalents, and more preferably 2 to 5 molar equivalents, per molar equivalent of the thioamide compound carboxylate (E).

The step of obtaining benzothiazole carboxylate (G) having a carboxyl group by adding oxidizing agent (F) to thioamide compound carboxylate (E) in the presence of the basic compound (D-3) is usually carried out in the presence of water. The amount of water used is preferably 10 to 30 parts by mass, more preferably 15 to 25 parts by mass, per part by mass of thioamide compound carboxylate (E). In this case, water may be used alone or in combination with an aprotic polar solvent. Examples of such aprotic polar solvents include acetonitrile, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetone, and N-methylpyrrolidone.

The temperature in the above process is preferably 15 to 40°C, more preferably 20 to 35°C. The reaction time is preferably 2 to 15 hours, more preferably 4 to 10 hours.

［式中、
Ｒ^１～Ｒ^５は、それぞれ、前記式（Ａ１）のＲ^１～Ｒ^５と同じ意味を表し、
Ｍは、アルカリ金属原子またはアルカリ土類金属原子を表し、
ｍはＭで表されるアルカリ金属またはアルカリ土類金属の価数を表す］ The above steps provide an aqueous solution of benzothiazole carboxylate (G) having a carboxyl group. The benzothiazole carboxylate (G) having a carboxyl group is determined according to the structure of the thioamide compound carboxylate (E). In one embodiment of the present invention, the benzothiazole carboxylate (G) having a carboxyl group is represented by, for example, formula (G1).

[Wherein,
R ¹ to R ⁵ each have the same meaning as R ¹ to R ⁵ in formula (A1),
M represents an alkali metal atom or an alkaline earth metal atom;
m represents the valence of the alkali metal or alkaline earth metal represented by M.

Examples of alkali metal atoms include lithium, sodium, potassium, and cesium. Examples of alkaline earth metal atoms include beryllium, magnesium, and calcium. Of these, M is preferably potassium.

<Benzothiazole carboxylic acid (H)>
The benzothiazole acid salt (G) having a carboxyl group obtained above can be reacted with an acid to obtain a benzothiazole carboxylic acid (H).

The acid used here is not particularly limited as long as it can neutralize the benzothiazole salt (G) having a carboxyl group, and both inorganic and organic acids can be used. Examples of inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and boric acid. Examples of organic acids include formic acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, succinic acid, tartaric acid, and methanesulfonic acid.

The amount of acid in the above step is preferably 1 to 5 moles, more preferably 1 to 3 moles, per mole of benzothiazole salt (G) having a carboxyl group.

The step of adding an acid to the benzothiazole salt (G) having a carboxyl group can be carried out by any method. For example, a method of adding a predetermined amount of acid all at once to an aqueous solution of the benzothiazole salt (G) having a carboxyl group and then stirring the solution, a method of continuously dropping an acid into an aqueous solution of the benzothiazole salt (G) having a carboxyl group, and mixing the acid, etc. are included. In order to improve the yield and filterability of the benzothiazole carboxylic acid (H), a method of continuously dropping an acid into an aqueous solution of the benzothiazole salt (G) having a carboxyl group is preferred.

After mixing with the acid, the crystals in the aqueous solution are separated by a known method such as filtration, washed with water, etc., and then dried to obtain benzothiazole carboxylic acid (H).

［式中、Ｒ^１～Ｒ^５は、それぞれ、前記式（Ａ１）のＲ^１～Ｒ^５と同じ意味を表す。］ The above steps provide benzothiazole carboxylic acid (H). The benzothiazole carboxylic acid (H) is determined depending on the structure of the benzothiazole salt (G) having a carboxyl group. In one embodiment of the present invention, the benzothiazole carboxylic acid (H) is represented by, for example, formula (H1).

[In the formula, R ¹ to R ⁵ respectively have the same meanings as R ¹ to R ⁵ in the formula (A1).]

The present invention will be described in more detail below with reference to the following examples. In this specification, "%" and "parts" refer to % by mass and parts by mass, respectively, unless otherwise specified.

Example 1
(Step (1))
A 500 mL four-neck flask equipped with a thermometer was placed in a nitrogen atmosphere, and 20.2 g of an amide compound (A1-1) having a substituent as shown in Table 2 in the amide compound represented by the above formula (A1), as a hydrophobic amide compound (A) having a carboxylate group, and 21.3 g of Lawesson's reagent (0.6 molar equivalent relative to 1 molar equivalent of compound (A1-1)) as a thioamidating agent (B) were reacted in 63.0 g of xylene at 75° C. for 5 hours to obtain a solution containing a thioamide compound (C1-1) having an ester group.

(Step (2))
To the resulting solution, 40.3 g of sodium hydrogen carbonate (4.4 molar equivalents relative to 1 molar equivalent of compound (A1-1)) as basic compound (D-1) and 161.2 g of water (8.0 parts by mass relative to 1 part by mass of compound (A1-1)) were added, and the mixture was reacted at 40° C. for 12 hours, after which the aqueous layer was removed by a separation operation. 76.6 g of water (3.8 parts by weight relative to 1 part by mass of compound (A1-1)) was added and stirred, the oil layer was washed with water, and then the aqueous layer was removed.

(Step (3))
To the solution obtained in the step (2), 5.6 g of potassium hydroxide (1.1 molar equivalents relative to 1 molar equivalent of the compound (A1-1)) as a basic compound (D-2) and 16.9 g of water (3.0 parts by mass relative to 1 part by mass of the compound (A1-1)) were added, and the mixture was reacted at 45° C. for 4 hours. After that, an aqueous solution of a thioamide compound carboxylate (E) was obtained by a separation operation.
Note that sodium bicarbonate is a weaker basic compound than potassium hydroxide.
The obtained aqueous solution was analyzed by HPLC measurement under the conditions described below, and the yield of the thioamide compound carboxylate (E) was 87%. The purity of the thioamide compound carboxylate (E) was 93% in terms of area percentage. Furthermore, the solid content in the aqueous solution of the thioamide compound carboxylate (E) was analyzed by ICP emission spectrometry, and the quantitative P content was 620 ppm.

<Examples 2 to 25 and Reference Example 1>
As shown in Table 2, water-soluble thioamide compound carboxylates (E) were obtained in the same manner as in Example 1, except that the type of hydrophobic amide compound (A) having a carboxylate group, and the types and/or amounts of basic compound (D-1) and basic compound (D-2) used were changed.
In each of Examples 2 to 25, the basic compound used as the basic compound (D-1) is a weaker basic compound than the basic compound used as the basic compound (D-2). In addition, with respect to R ⁶ in Table 2, Et represents an ethyl group, Me represents a methyl group, Bu represents a butyl group, and Cy represents a cyclohexane-1,4-diyl group.

<HPLC measurement conditions>
Equipment: Shimadzu Corporation LC-20AT
Column: Kinetex_2.6μm_C18, 100Å, 100mm×4.6mm
Mobile phase: Solution A: Water containing 0.1% (v/v) TFA Solution B: Acetonitrile containing 0.1% (v/v) TFA Gradient conditions:
B solution; 10% → (30min) → 100% (5min)
Temperature: 40°C
Flow rate: 1.0mL/min Injection volume: 5μL
Detector: UV (254 nm)

(Yield Evaluation Criteria)
Based on the results of the HPLC measurements, the yield in each example was evaluated according to the following criteria. The results are shown in Table 2.
A: 85% or more B: 70% or more but less than 85% C: 60% or more but less than 70% D: Less than 60%

(Purity Evaluation Criteria)
Based on the results of the HPLC measurements, the purity of each example was evaluated according to the following criteria. The results are shown in Table 2.
A: 90% or more B: 70% or more but less than 90% C: 60% or more but less than 70% D: Less than 60%

<ICP optical emission spectrometry>
The phosphorus content (P content) in the aqueous solution of the thioamide compound carboxylate (E) was measured using an ICP emission spectrometer, and the P content relative to the solid content in the aqueous solution of the thioamide compound carboxylate (E) was calculated.
(Evaluation Criteria for Phosphorus Content)
Based on the results of the ICP emission spectrometry, the P content in each example was evaluated according to the following criteria. The results are shown in Table 2.
A: Less than 700 ppm B: 700 ppm or more and less than 1500 ppm C: 1500 ppm or more

<Example 26>
A 500 mL four-neck flask equipped with a thermometer was placed in a nitrogen atmosphere. 31 g of a 25% KOH aqueous solution as a basic compound (D-3), 44 g of potassium ferricyanide as an oxidizing agent (F), and 160 g of water were charged into the solution. 35 g of the aqueous solution of the thioamide compound carboxylate (E) obtained in Example 3 was added dropwise to the solution at room temperature over 6 hours, and the mixture was allowed to react for 1 hour to derive benzothiazole carboxylic acid (G).

Next, 4.9 g of 40% sulfuric acid was added dropwise to the aqueous solution containing benzothiazole carboxylic acid (G) over a period of 5 hours at room temperature to precipitate a powder of benzothiazole carboxylic acid (H). The resulting powder was collected by filtration and washed with 42 g of water. It was dried at 50°C to obtain 7.7 g of a white powder. Analysis by HPLC measurement under the conditions described below revealed a yield of 72.0% and an LC purity of 78.0%.

When the content of phosphorus compounds contained in the aqueous solution of thioamide compound carboxylate (E) used in the reaction is low, the content of phosphorus compounds in benzothiazole carboxylic acid (H) can also be reduced.

<HPLC measurement conditions>
Equipment: Shimadzu Corporation LC-20AT
Column: Kinetex_2.6μm_C18, 100Å, 100mm×4.6mm
Mobile phase: Solution A: 10 mM ammonium formate solution; Solution B: acetonitrile Gradient conditions:
B solution; 10% → (30min) → 100% (5min)
Temperature: 40°C
Flow rate: 1.0mL/min Injection volume: 5μL
Detector: UV (254 nm)

Claims (8)

A method for producing a water-soluble thioamide compound carboxylate (E), comprising the steps of:
(1) a step of reacting a hydrophobic amide compound (A) having a carboxylate group with a thioamidating agent (B) in a hydrophobic solvent to obtain a thioamide compound (C) having an ester group;
(2) adding a basic compound (D-1) capable of decomposing a thioamidating agent (B) and its residue and water to a hydrophobic solvent containing the obtained thioamide compound (C) having an ester group, and then removing the aqueous layer by a liquid separation operation to remove water-soluble decomposition products of the thioamidating agent (B) and its residue; and (3) adding a basic compound (D-2) capable of hydrolyzing an ester group of the thioamide compound (C) and water to a hydrophobic solvent containing the thioamide compound (C) having an ester group obtained by the step (2), and then obtaining an aqueous solution of a thioamide compound carboxylate (E) by a liquid separation operation,
The method, wherein the basic compound (D-1) has a weaker basicity than the basic compound (D-2). The method according to claim 1, wherein the basic compound (D-1) is one or more compounds selected from the group consisting of potassium hydrogen carbonate, sodium hydrogen carbonate, cesium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, sodium phosphate, monopotassium dihydrogen phosphate, dipotassium monohydrogen phosphate, monosodium dihydrogen phosphate, and disodium monohydrogen phosphate. The method according to claim 1 or 2, wherein the basic compound (D-2) is one or more compounds selected from the group consisting of sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, and tetrabutylammonium hydride. The method according to claim 1 or 2, wherein the hydrophobic amide compound (A) having a carboxylate group has an aromatic ring structure selected from the group consisting of a benzene ring, a naphthalene ring, an anthracene ring, a furan ring, a thiophene ring, a thiazole ring, a benzofuran ring, a benzothiophene ring, a benzothiazole ring, and a thienothiophene ring, each of which may have a substituent. The hydrophobic amide compound (A) having a carboxylate group is represented by the formula (A1):

[Wherein,
R ¹ to R ⁴ each independently represent a group selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alicyclic hydrocarbon group having 3 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a thioether group having 1 to 8 carbon atoms, a sulfonyl group having 1 to 8 carbon atoms, and a halogen atom;
^R5 represents a single bond, an alkylene group, or a divalent alicyclic hydrocarbon group having 3 to 8 carbon atoms;
R ⁶ represents an alkyl group having 1 to 4 carbon atoms.
The method according to claim 1 or 2, wherein the compound is an amide compound represented by the formula: The water-soluble thioamide compound carboxylate (E) is represented by the formula (E1):

[Wherein,
R ¹ to R ⁵ each have the same meaning as R ¹ to R ⁵ in formula (A1),
M represents an alkali metal atom or an alkaline earth metal atom;
m represents the valence of the alkali metal or alkaline earth metal represented by M.
The method according to claim 1 or 2, wherein the thioamide compound is a carboxylate represented by the formula: A method for producing benzothiazole carboxylate (G), comprising adding an oxidizing agent (F) to an aqueous solution of thioamide compound carboxylate (E) obtained by the method according to claim 1 or 2 in the presence of a basic compound (D-3) to obtain benzothiazole carboxylate (G) having a carboxyl group. A method for producing benzothiazole carboxylate (H), comprising reacting benzothiazole carboxylate (G) obtained by the method according to claim 7 with an acid to obtain benzothiazole carboxylic acid (H).