The manufacturing method of oxidation dyes

Abstract

To provide a method for producing an oxidized dye capable obtaining an acid salt of 5,6-dihydroxyindoline with high purity using a simple operation.SOLUTION: There is provided a method for producing an oxidized dye which comprises (I) a step of converting an indole derivative into an indoline derivative by a hydrogenation reaction in the presence of a carboxylic acid to obtain a solution containing the indoline derivative and (II) a step of adding hydrogen bromide into the solution containing the indoline derivative, wherein the hydrogenation reaction in the step (I) uses a catalyst and the addition amount of xmol% of the catalyst and the reaction temperature y°C satisfy the conditions of the following expression (1) and the following expression (2): y≤-2.5x+59.00 Expression (1) and 0<x≤20.0 Expression (2).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to a method for producing an oxidation dye. [Background technology]

[0002] The acid salts of 5,6-dihydroxyindoline have the property of being oxidized by oxygen in the air to form black melanin, and therefore have long been used as precursor oxidation dyes.

[0003] For example, Patent Document 1 describes a method for producing an oxidation dye by oxidation of a dye precursor, the method being characterized in that the dye precursor is indoline represented by a specific structural formula or a salt thereof, and the oxidation dye is produced by oxidizing the dye precursor in one step without isolating an indole intermediate.

[0004] As a method for producing 5,6-dihydroxyindoline hydrobromide, for example, Patent Document 2 describes a composition for dyeing keratin fibers, particularly human hair, which contains at least 5,6-dihydroxyindoline corresponding to a specific structural formula and an acid addition salt thereof.

[0005] As a method for producing 5,6-dihydroxyindoline hydrobromide, for example, Patent Document 3 describes a method for producing 5,6-dihydroxyindoline represented by a specific structural formula, in which an indoline ether represented by a specific structural formula is reacted with hydrobromic acid and 5,6-dihydroxyindoline is directly crystallized from the aqueous reaction mixture. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] DE 4016177 A1 [Patent Document 2] Japanese Patent No. 2997564 [Patent Document 3] Japanese Patent Publication No. 2006 - 510054 [Summary of the Invention] [Problems to be Solved by the Invention]

[0007] However, in conventional methods such as those of Patent Documents 1 to 3, it is necessary to perform a purification operation to extract 5,6 - dihydroxyindoline hydrobromide as high - purity crystals, which poses problems in terms of time or production efficiency. Therefore, there is a need for a method for producing an oxidation dye that can obtain an acid salt of 5,6 - dihydroxyindoline with high purity using a simple operation.

[0008] The problem to be solved by one embodiment of the present disclosure is to provide a method for producing an oxidation dye that can obtain an acid salt of 5,6 - dihydroxyindoline with high purity using a simple operation. [Means for Solving the Problems]

[0009] Means for solving the above problems include the following aspects. <1> A step (I) of converting an indole derivative into an indoline derivative by a hydrogenation reaction in the presence of a carboxylic acid to obtain a solution containing the indoline derivative, and a step (II) of adding hydrogen bromide to the solution containing the indoline derivative, and the hydrogenation reaction in the step (I) uses a catalyst, and the production method of the oxidation dye in which the addition amount x mol% of the catalyst and the reaction temperature y °C satisfy the conditions of the following formula (1) and the following formula (2). y ≦ - 2.5x + 59.00 Formula (1) 0 < x ≦ 20.0 Formula (2) <2> The production method of the oxidation dye according to <1>, wherein the catalyst contains tetravalent platinum. <3> The production method of the oxidation dye according to <1> or <2>, wherein the carboxylic acid is represented by XCOOH and X is an alkyl group having 1 to 20 carbon atoms. <4> In the hydrogenation reaction in the step (I), the amount of the catalyst added x mol % and the reaction temperature y ° C. satisfy the condition of the following formula (1-1): <1> ~ <3> 13. A method for producing an oxidative dye according to any one of the above. y≦-2.5x+57.50 Formula (1-1) <5> In the hydrogenation reaction in the step (I), the amount of the catalyst added x mol % and the reaction temperature y ° C. satisfy the condition of the following formula (1-2): <1> ~ <4> 13. A method for producing an oxidative dye according to any one of the above. y≦-2.5x+55.00 Formula (1-2) <6> In the hydrogenation reaction in the step (I), the amount of the catalyst added x mol % is 0.2 to 15. <1> ~ <5> 13. A method for producing an oxidative dye according to any one of the above. <7> In the hydrogenation reaction in the step (I), the amount of the catalyst added is x mol % of 0.5 to 10. <1> ~ <6> 13. A method for producing an oxidative dye according to any one of the above. <8> In the hydrogenation reaction in the step (I), the reaction temperature y° C. is 0 to 50° C. <1> ~ <7> 13. A method for producing an oxidative dye according to any one of the above. <9> In the hydrogenation reaction in the step (I), the reaction temperature y°C is 5 to 45°C. <1> ~ <8> 13. A method for producing an oxidative dye according to any one of the above. <10> The indoline derivative includes a compound represented by the following formula (II-I): <1> ~ <9> 13. A method for producing an oxidative dye according to any one of the above.

[0010] [ka]

[0011] [In formula (II-I), R 1 ~R 4 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, an oxygen-containing group, or a halogen atom. 6 and R 7are each independently an aliphatic group having 1 to 12 carbon atoms, or together represent an alkylene group having 1 to 4 carbon atoms, X is a chlorine atom or a bromine atom, and n is 0 or 1. <11> In the above formula (II-I), R 1 ~R 4 is a hydrogen atom <10> A method for producing an oxidation dye according to claim 1. Effect of the Invention

[0012] According to one embodiment of the present disclosure, it is possible to provide a method for producing an oxidation dye, which can provide a highly pure acid salt of 5,6-dihydroxyindoline using a simple procedure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The contents of the present disclosure will be described in detail below. The following description of the components may be based on a representative embodiment of the present disclosure, but the present disclosure is not limited to such an embodiment. In the present disclosure, a numerical range indicated using "~" indicates a range that includes the numerical values ​​before and after "~" as the minimum and maximum values, respectively. In the present disclosure, the term "step" refers not only to an independent step, but also to a step that cannot be clearly distinguished from other steps, as long as the purpose of the step is achieved. In the present disclosure, the content of each component in a composition means, when multiple substances corresponding to each component are present in the composition, the total amount of those multiple substances present in the composition, unless otherwise specified.

[0014] <Production method of oxidation dyes> The method for producing an oxidation dye of the present disclosure includes a step (I) of converting an indole derivative into an indoline derivative by a hydrogenation reaction in the presence of a carboxylic acid to obtain a solution containing the indoline derivative, and a step (II) of adding hydrogen bromide to the solution containing the indoline derivative, In the hydrogenation reaction in the step (I), a catalyst is used, and the addition amount x mol% of the catalyst and the reaction temperature y °C satisfy the conditions of the following formula (1) and the following formula (2). y ≦ -2.5x + 59.00 Formula (1) 0 < x ≦ 20.0 Formula (2) Note that the unit of the addition amount x of the catalyst is mol%, and the unit of the reaction temperature y is °C.

[0015] In the present disclosure, the oxidative dye is an oxidative dye of the melanin precursor type, and is a concept including both a compound in which no substituent is introduced into the indole skeleton of melanin and a compound in which a substituent is introduced into the indole skeleton of melanin. In the present disclosure, the indole derivative is a concept including both a compound in which no substituent is introduced into the indole skeleton of the indole derivative and a compound in which a substituent is introduced into the indole skeleton of the indole derivative. In the present disclosure, the indoline derivative is a concept including both a compound in which no substituent is introduced into the indoline skeleton of the indoline derivative and a compound in which a substituent is introduced into the indoline skeleton of the indoline derivative.

[0016] In the present disclosure, "purity (mass%)" means the percentage of the value obtained by dividing the amount of the target product by the total amount of the actually obtained product. In the present disclosure, "yield (mass%)" means the percentage of the value obtained by dividing the actually obtained amount by the theoretically calculated amount. The addition amount x mol% of the catalyst means the percentage of the amount of the catalyst with respect to the amount of the indole derivative.

[0017] Since the oxidative dye is easily oxidized to melanin, the yield was likely to decrease when producing the oxidative dye. Therefore, there has been a demand for a method for efficiently synthesizing a high-purity oxidative dye precursor and oxidative dye using a simple operation.

[0018] The present inventors have found that after a hydrogenation reaction for obtaining an indoline derivative from an indole derivative, a carboxylic acid and an indoline derivative may react to generate a by-product in which the nitrogen atom of the indoline derivative is acylated. That is, after a hydrogenation reaction for obtaining an indoline derivative from an indole derivative, the indoline derivative may include a main product in which the nitrogen atom of the indoline derivative is not acylated and a by-product in which the nitrogen atom of the indoline derivative is acylated. An example of the main product is a compound represented by the following formula (A). An example of the by-product is a compound represented by the following formula (B): In formula (B), R represents, for example, an acetyl group.

[0019] [ka]

[0020] The present inventors have found that the by-products cause a decrease in the purity of the acid salt of 5,6-dihydroxyindoline obtained after the reaction of an indoline derivative with hydrogen bromide. Conventionally, a purification step has been carried out to avoid this decrease in purity, but the purification step has the problem of decreasing the yield. In response to this, the present inventors conducted extensive research and came up with a method for producing an oxidation dye according to the present disclosure. That is, the method for producing an oxidation dye according to the present disclosure includes step (I) according to the present disclosure and step (II) according to the present disclosure, and the hydrogenation reaction in step (I) uses a catalyst, and the amount of catalyst added (x mol %) and the reaction temperature (y° C.) satisfy specific conditions, thereby suppressing the generation of by-products and enabling the production of a high-purity acid salt of 5,6-dihydroxyindoline to be obtained using a simple operation. The method for producing the oxidation dye of the present disclosure does not necessarily require a purification step. The method for producing the oxidation dye of the present disclosure can obtain a highly pure acid salt of 5,6-dihydroxyindoline even without a purification step. Moreover, the method for producing an oxidation dye of the present disclosure can also obtain an acid salt of 5,6-dihydroxyindoline in a high yield.

[0021] <Step (I)> Step (I) is a step of converting an indole derivative into an indoline derivative by a hydrogenation reaction in the presence of a carboxylic acid to obtain a solution containing the indoline derivative. In the hydrogenation reaction in Step (I), a catalyst is used, and the addition amount x mol% of the catalyst and the reaction temperature y °C satisfy the conditions of the following formula (1) and the following formula (2). y ≦ -2.5x + 59.00 Formula (1) 0 < x ≦ 20.0 Formula (2)

[0022] Formula (1) defines the range of the reaction temperature y °C in the hydrogenation reaction in Step (I). By satisfying formula (1) with the addition amount x mol% of the catalyst and the reaction temperature y °C, the formation of by-products can be suppressed, and the purity and yield of the oxidation dye can be increased.

[0023] From the viewpoint of suppressing the formation of by-products and increasing the purity and yield of the oxidation dye, in the hydrogenation reaction in Step (I), it is preferable that the addition amount x mol% of the catalyst and the reaction temperature y °C satisfy the conditions of the following formula (1-1). y ≦ -2.5x + 57.50 Formula (1-1)

[0024] From the viewpoint of suppressing the formation of by-products and increasing the purity and yield of the oxidation dye, in the hydrogenation reaction in Step (I), it is more preferable that the addition amount x mol% of the catalyst and the reaction temperature y °C satisfy the conditions of the following formula (1-2). y ≦ -2.5x + 55.00 Formula (1-2)

[0025] From the viewpoint of appropriately maintaining the production efficiency, it is preferable that y °C satisfies 0 ≦ y, more preferably 5.00 ≦ y, even more preferably 10.00 ≦ y, particularly preferably 15.00 ≦ y, and even more preferably 20.00 ≦ y.

[0026] From the viewpoint of suppressing the generation of by-products and increasing the purity and yield of the oxidation dye, it is preferable to satisfy y≤50.00, more preferably to satisfy y≤45, and even more preferably to satisfy y≤40.00.

[0027] In the hydrogenation reaction in step (I), it is preferable that the reaction temperature y °C satisfies the following formula (1-3), and more preferably satisfies the following formula (1-4). 0≤y≤50.00 Formula (1-3) 5.00≤y≤45.00 Formula (1-4)

[0028] Formula (2) defines the range of the addition amount x mol% of the catalyst used in the hydrogenation reaction in step (I). By satisfying x≤20.0 for the addition amount x mol% of the catalyst, the generation of by-products can be suppressed, and the purity and yield of the oxidation dye can be increased. From the above viewpoints, it is preferable that the addition amount x mol% of the catalyst satisfies x≤15.0, and more preferably satisfies x≤10.0. By satisfying 0<x for the addition amount x mol% of the catalyst, the production efficiency can be appropriately maintained. From the above viewpoints and from the viewpoint of enhancing the reproducibility of the effects of the present disclosure, it is preferable that the addition amount x mol% of the catalyst satisfies 0.2≤x, and more preferably satisfies 0.5≤x. Specifically, the above-mentioned "enhancing the reproducibility of the effects of the present disclosure" means, for example, enhancing the reproducibility of the effects of the present disclosure by uniformly presenting the catalyst in the reaction kettle and allowing the reaction to proceed uniformly in the reaction kettle.

[0029] In the hydrogenation reaction in step (I), it is preferable that the addition amount x mol% of the catalyst satisfies the following formula (2-1), and more preferably satisfies the following formula (2-2). 0.2≤x≤15.0 Formula (2-1) 0.5≤x≤10.0 Formula (2-2)

[0030] <Solvent> Step (I) is carried out using a solvent. The solvent contains at least a carboxylic acid. (Carboxylic Acid) In step (I), an indole derivative is converted into an indoline derivative by a hydrogenation reaction in the presence of a carboxylic acid to obtain a solution containing the indoline derivative. By carrying out step (I) in the presence of a carboxylic acid, the reaction activity of the hydrogenation reaction can be increased while suppressing corrosion of the reaction vessel. The carboxylic acid may be a compound represented by XCOOH, where X is a hydrogen atom or a hydrocarbon group having 1 to 50 carbon atoms, and preferably a hydrocarbon group having 1 to 20 carbon atoms.

[0031] Examples of X include a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, an aralkyl group, and a monovalent heterocyclic group. The above hydrocarbon groups may also contain a substituent. Examples of the substituent include a hydroxyl group, an alkoxy group, a carbonyl group, an aldehyde group, a carboxylic acid group, an ester group, an amino group, an imino group, a nitrile group, and a halogen atom.

[0032] The carboxylic acid is represented by XCOOH, where X is preferably an alkyl group having 1 to 20 carbon atoms.

[0033] When X is an alkyl group, examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a 1-methylpropyl group, a pentyl group, a 1-methylbutyl group, a hexyl group, a 1-methylpentyl group, a heptyl group, an octyl group, a 1-methylheptyl group, a nonyl group, a decyl group, a dodecyl group, a tetradecyl group, a hexadecyl group, and an octadecyl group.

[0034] When X is an alkyl group, specific examples of the carboxylic acid include acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, stearic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, tartaric acid, malic acid, and lactic acid.

[0035] When X is a cycloalkyl group, specific examples of the carboxylic acid include 2-cyclopropene carboxylic acid, cyclopentane carboxylic acid, cyclohexane carboxylic acid, and 1-tetralin carboxylic acid.

[0036] When X is an alkenyl group, specific examples of the carboxylic acid include acrylic acid, methacrylic acid, crotonic acid, senecioic acid, 2-pentenoic acid, 2-hexenoic acid, 2-heptenoic acid, 2-octenoic acid, 2-nonenoic acid, geranic acid, 2-decenoic acid, 2-dodecenoic acid, 2-octadecenoic acid, farnesylic acid, geranylgeranic acid, cinnamic acid, maleic acid, fumaric acid, traumatic acid, cinnamylideneacetic acid, sorbic acid, muconic acid, and 2,4-octadienoic acid.

[0037] When X is an aryl group, the aryl group preferably has 6 to 20 carbon atoms. Examples of the aryl group include a phenyl group, a tolyl group, a xylyl group, a halogenated phenyl group, a naphthyl group, an anthryl group, a phenanthrene group, and a perylene group. When X is an aryl group, specific examples of the carboxylic acid include benzoic acid, o-toluic acid, m-toluic acid, p-toluic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, p-fluorobenzoic acid, 2,3,4,5,6-pentafluorobenzoic acid, o-chlorobenzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid, 4-methoxybenzoic acid, naphthoic acid, anthracenecarboxylic acid, phenanthrenecarboxylic acid, perylenecarboxylic acid, phthalic acid, isophthalic acid, and terephthalic acid.

[0038] When X is an aralkyl group, the aralkyl group preferably has 7 to 21 carbon atoms. Examples of the aralkyl group include a benzyl group, a naphthylmethyl group, and an anthrylmethyl group. When X is an aralkyl group, specific examples of the carboxylic acid include phenylacetic acid, naphthylacetic acid, and anthrylacetic acid.

[0039] When X is a monovalent heterocyclic group, the monovalent heterocyclic group preferably contains 4 to 20 carbon atoms. When X is a monovalent group of a heterocycle, specific examples of the carboxylic acid include 2-furan carboxylic acid, 3-furan carboxylic acid, nicotinic acid, and isonicotinic acid.

[0040] Among the above, particularly preferred carboxylic acids include acrylic acid, methacrylic acid, crotonic acid, senecioic acid, 2-pentenoic acid, 2-hexenoic acid, 2-heptenoic acid, 2-octenoic acid, 2-nonenoic acid, geranic acid, 2-decenoic acid, 2-dodecenoic acid, 2-octadecenoic acid, farnesyl acid, geranylgeranic acid, cinnamic acid, maleic acid, fumaric acid, traumatic acid, cinnamylidene acetic acid, sorbic acid, muconic acid, 2,4-octadienoic acid, and benzoic acid. Examples of the benzoic acid include o-toluic acid, m-toluic acid, p-toluic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, p-fluorobenzoic acid, 2,3,4,5,6-pentafluorobenzoic acid, o-chlorobenzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid, 4-methoxybenzoic acid, naphthoic acid, anthracenecarboxylic acid, phenanthrenecarboxylic acid, perylenecarboxylic acid, phthalic acid, isophthalic acid, and terephthalic acid. The present disclosure may contain one type or multiple types of carboxylic acids.

[0041] Among the above, from the viewpoints of increasing reactivity, cost, ease of handling, and not corroding a reaction vessel, X is preferably an alkyl group having 1 to 20 carbon atoms, more preferably an alkyl group having 1 to 10 carbon atoms, even more preferably an alkyl group having 1 to 5 carbon atoms, and particularly preferably a methyl group.

[0042] Step (I) may contain a solvent other than the carboxylic acid as long as the effect of the present disclosure is not impaired. The solvent containing the carboxylic acid is preferably capable of dissolving the indole derivative as a raw material as a whole, and is preferably capable of being mixed homogeneously as a whole.

[0043] The ratio of the substance amount (mol) of the indole derivative to the amount (L) of the carboxylic acid is preferably 0.01 to 0.8. When the ratio of the substance amount (mol) of the indole derivative to the amount (L) of the carboxylic acid is 0.01 or more, the production cost can be reduced and the productivity can be improved. By setting the ratio of the substance amount (mol) of the indole derivative to the amount (L) of the carboxylic acid to be 0.8 or less, the progress of side reactions can be suppressed and the purity of the oxidation dye can be increased. From the same viewpoint as above, the ratio of the substance amount (mol) of the indole derivative to the amount (L) of the carboxylic acid is more preferably 0.05 to 0.6, further preferably 0.1 to 0.5, and particularly preferably 0.2 to 0.5.

[0044] (Other additives) From the viewpoint of further accelerating the hydrogenation reaction, at least one selected from the group consisting of Lewis acids and Bronsted acids may be used in step (I). Examples of the Lewis acid include tin chloride and cerium chloride. Examples of Bronsted acids include sulfuric acid, nitric acid, hydrogen halides (eg, hydrogen iodide, hydrogen bromide, hydrogen chloride, etc.), organic compounds having sulfonic acid, and organic compounds having phosphoric acid.

[0045] (Indole derivatives) The indole derivative can be used without any particular limitation. For example, the indole derivative includes a compound represented by the following formula (I).

[0046] [ka]

[0047] [In formula (I), R 1 and R 3 R are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, an oxygen-containing group, or a halogen atom. 6 and R 7 each independently represents an aliphatic group having 1 to 12 carbon atoms, or together represent an alkylene group having 1 to 4 carbon atoms. Details of the substituents in formula (I) will be described later.

[0048] (Indoline derivatives) In step (I), the indoline derivative is obtained by converting the indole derivative by a hydrogenation reaction in the presence of a carboxylic acid. As described above, after the hydrogenation reaction for obtaining an indoline derivative from an indole derivative, the indoline derivative may include a main product in which the nitrogen atom of the indoline derivative is not acylated and a by-product in which the nitrogen atom of the indoline derivative is acylated. The by-products cause a decrease in the purity of the acid salt of 5,6-dihydroxyindoline obtained after the reaction of the indoline derivative with hydrogen bromide. In the method for producing an oxidation dye according to the present disclosure, it is possible to obtain a highly pure acid salt of 5,6-dihydroxyindoline by suppressing the production of the above-mentioned by-products that may be generated when an indole derivative is converted by a hydrogenation reaction.

[0049] The indoline derivative may be in the form of an acid salt, such as a hydrochloride or a hydrobromide. The acid salt of the indoline derivative can be obtained by simply treating the indoline derivative generated by the hydrogenation reaction with hydrochloric acid, hydrobromic acid or the like without carrying out the deprotection in step (II). The acid salt of the indoline derivative may be deprotected in step (II) to form an oxidation dye, or the acid salt of the indoline derivative itself may be used as the oxidation dye.

[0050] The indoline derivative preferably includes a compound represented by the following formula (II-I): The compound represented by formula (II-I) is an indoline derivative corresponding to the above-mentioned main product.

[0051] [ka]

[0052] [In formula (II-I), R 1 ~R 4 are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, an oxygen-containing group, or a halogen atom. 6 and R 7 are each independently an aliphatic group having 1 to 12 carbon atoms, or together represent an alkylene group having 1 to 4 carbon atoms, X is a chlorine atom or a bromine atom, and n is 0 or 1. The substituents in the above formula (I) and formula (II-I) are described in detail below.

[0053] Specific examples of the substituent in the substituted alkyl group and the substituted aryl group include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, and an aryloxy group. The alkyl group or aryl group may be substituted with only one of these substituents, or may be substituted with two or more of these substituents. When two or more of these substituents are substituted on an alkyl group or an aryl group, each substituent may be substituted with a single substituent or may be substituted with different types of substituents.

[0054] Specific examples of the substituted or unsubstituted alkyl group include linear alkyl groups having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, and an n-octyl group; isopropyl, isobutyl, sec-butyl, isopentyl, sec-pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-n-propylbutyl, 1-iso-propylbutyl, 1-iso-propyl-2-methylpropyl, 1-methylheptyl monoalkyl-substituted alkyl groups having 2 to 10 carbon atoms, such as a 2-methylheptyl group, a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a 1-n-propylpentyl group, a 2-n-propylpentyl group, a 1-iso-propylpentyl group, a 2-iso-propylpentyl group, a 1-n-butylbutyl group, a 1-iso-butylbutyl group, a 1-sec-butylbutyl group, a 1-tert-butylbutyl group, or a 2-tert-butylbutyl group; tert-Butyl, tert-pentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethyl-2-methylpropyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl butyl group, 1-ethyl-1-methylbutyl group, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group, 2-ethyl-1-methylbutyl group, 2-ethyl-3-methylbutyl group, 1,1-dimethylhexyl group, 1,2-dimethylhexyl group, 1,3-dimethylhexyl group, 1,4-dimethylhexyl group, 1,5-dimethylhexyl group, 2,2-dimethylhexyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 3 ,3-dimethylhexyl group, 3,4-dimethylhexyl group, 3,5-dimethylhexyl group, 4,4-dimethylhexyl group, 4,5-dimethylhexyl group, 1-ethyl-2-methylpentyl group, 1-ethyl-3-methylpentyl group, 1-ethyl-4-methylpentyl group, 2-ethyl-1-methylpentyl group, 2-ethyl-2-methylpentyl group, 2-ethyl-3-methylpentyl group, 2-ethyl-4-methylpentyl group, 3-ethyl-1-methylpentyl group, 3-ethyl-2 dialkyl-substituted alkyl groups having 3 to 10 carbon atoms, such as a -methylpentyl group, a 3-ethyl-3-methylpentyl group, a 3-ethyl-4-methylpentyl group, a 1-n-propyl-1-methylbutyl group, a 1-n-propyl-2-methylbutyl group, a 1-n-propyl-3-methylbutyl group, a 1-iso-propyl-1-methylbutyl group, a 1-iso-propyl-2-methylbutyl group, a 1-iso-propyl-3-methylbutyl group, a 1,1-diethylbutyl group, and a 1,2-diethylbutyl group; 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1,1,2-trimethylbutyl group, 1,1,3-trimethylbutyl group, 1,2,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,3,3-trimethylbutyl group, 2,3,3-trimethylbutyl group, 1,1,2-trimethylpentyl group, 1,1,3-trimethylpentyl group, 1,1,4-trimethylpentyl group, 1,2,2-trimethylpentyl group, 1,2,3-trimethylpentyl group, 1,2,4-trimethylpentyl group, 1,3,4-trimethylpentyl group, 2,2,3-trimethylpentyl group, 2,2,4-trimethylpentyl group trialkyl-substituted alkyl groups having 4 to 10 carbon atoms, such as a 2,3,4-trimethylpentyl group, a 1,3,3-trimethylpentyl group, a 2,3,3-trimethylpentyl group, a 3,3,4-trimethylpentyl group, a 1,4,4-trimethylpentyl group, a 2,4,4-trimethylpentyl group, a 3,4,4-trimethylpentyl group, a 1-ethyl-1,2-dimethylbutyl group, a 1-ethyl-1,3-dimethylbutyl group, a 1-ethyl-2,3-dimethylbutyl group, a 2-ethyl-1,1-dimethylbutyl group, a 2-ethyl-1,2-dimethylbutyl group, a 2-ethyl-1,3-dimethylbutyl group, or a 2-ethyl-2,3-dimethylbutyl group; Cyclic alkyl groups having 3 to 20 carbon atoms, such as a cyclopentyl group and a cyclohexyl group; alkyl-substituted cyclic alkyl groups having 4 to 10 carbon atoms, such as a methylcyclopentyl group, a methylcyclohexyl group, a 1,2-dimethylcyclohexyl group, a 1,3-dimethylcyclohexyl group, a 1,4-dimethylcyclohexyl group, or an ethylcyclohexyl group; Aryl-substituted alkyl groups having 7 to 10 carbon atoms, such as a benzyl group and a 4-methylbenzyl group; halogenated alkyl groups having 1 to 10 carbon atoms and partially or completely substituted with halogen atoms, such as a fluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a fluoroethyl group, a chloroethyl group, a bromoethyl group, a trifluoroethyl group, a pentafluoroethyl group, a tetrachloroethyl group, or a hexafluoroisopropyl group;

[0055] Specific examples of the substituted or unsubstituted aryl group include: Aryl groups having 6 to 10 carbon atoms, such as a phenyl group or a naphthyl group; monoalkyl-substituted aryl groups having 7 to 10 carbon atoms, such as a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-ethylphenyl group, a propylphenyl group, or a butylphenyl group; dialkyl-substituted aryl groups having 8 to 10 carbon atoms, such as a 2,3-dimethylphenyl group, a 2,4-dimethylphenyl group, a 2,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 3,4-dimethylphenyl group, a 3,5-dimethylphenyl group, or a 3,6-dimethylphenyl group; trialkyl-substituted aryl groups having 9 or 10 carbon atoms, such as a 2,3,4-trimethylphenyl group, a 2,3,5-trimethylphenyl group, a 2,3,6-trimethylphenyl group, a 2,4,5-trimethylphenyl group, a 2,4,6-trimethylphenyl group, or a 3,4,5-trimethylphenyl group; monoalkoxyaryl groups having 7 to 10 carbon atoms substituted with a substituted or unsubstituted alkoxy group having 4 or less carbon atoms, such as a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-ethoxyphenyl group, a propoxyphenyl group, or a butoxyphenyl group; dialkoxyaryl groups having 8 to 10 carbon atoms substituted with a substituted or unsubstituted alkoxy group having 4 or less carbon atoms, such as a 2,3-dimethoxyphenyl group, a 2,4-dimethoxyphenyl group, a 2,5-dimethoxyphenyl group, a 2,6-dimethoxyphenyl group, a 3,4-dimethoxyphenyl group, a 3,5-dimethoxyphenyl group, or a 3,6-dimethoxyphenyl group; trialkoxyaryl groups having 9 or 10 carbon atoms substituted with a substituted or unsubstituted alkoxy group having 4 or less carbon atoms, such as a 2,3,4-trimethoxyphenyl group, a 2,3,5-trimethoxyphenyl group, a 2,3,6-trimethoxyphenyl group, a 2,4,5-trimethoxyphenyl group, a 2,4,6-trimethoxyphenyl group, or a 3,4,5-trimethoxyphenyl group; aryl groups having 6 to 10 carbon atoms substituted with a halogen atom, such as a chlorophenyl group, a dichlorophenyl group, a trichlorophenyl group, a bromophenyl group, a dibromophenyl group, an iodophenyl group, a fluorophenyl group, a chloronaphthyl group, a bromonaphthyl group, a difluorophenyl group, a trifluorophenyl group, a tetrafluorophenyl group, or a pentafluorophenyl group; halogenated alkylaryl groups having 7 to 10 carbon atoms substituted with an alkyl group having 4 or less carbon atoms which is partially or completely substituted with a halogen, such as a trifluoromethylphenyl group or a trichloromethylphenyl group; N,N-disubstituted amino-substituted aryl groups having 10 or less carbon atoms, such as an N,N-dimethylaminophenyl group, an N,N-diethylaminophenyl group, an N-phenyl-N-methylaminophenyl group, an N-tolyl-N-ethylaminophenyl group, an N-chlorophenyl-N-cyclohexylaminophenyl group, or an N,N-ditolylaminophenyl group; alkylthioaryl groups or arylthioaryl groups such as a methylthiophenyl group, an ethylthiophenyl group, a methylthionaphthyl group, and a phenylthiophenyl group; and the like.

[0056] Examples of the oxygen-containing group include an alkoxy group, an aryloxy group, an ester group, an ether group, an acyl group, a carboxyl group, a carbonate group, a hydroxy group, a peroxy group, and a carboxylic anhydride group.

[0057] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0058] R 1 ~R 4 When represents a substituted or unsubstituted alkyl group, the alkyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms, and even more preferably 1 carbon atom. Also, R 1 ~R 4 When represents a substituted or unsubstituted aryl group, the aryl group preferably contains 6 to 10 carbon atoms, and more preferably 6 carbon atoms.

[0059] R 6 and R 7 each independently represents an aliphatic group having 1 to 12 carbon atoms, or together represent an alkylene group having 1 to 4 carbon atoms. That is, R 6 and R 7 may be bonded to each other. R 6 and R 7 When bonded to each other, they form an alkylene group having 1 to 4 carbon atoms.

[0060] The aliphatic group having 1 to 12 carbon atoms may be a saturated aliphatic group (i.e., an alkyl group) or an unsaturated aliphatic group (i.e., an alkenyl group or an alkynyl group), and may have at least one of a branched structure and a cyclic structure.

[0061] Specific examples of the aliphatic group having 1 to 12 carbon atoms include linear or branched saturated aliphatic groups (i.e., alkyl groups) such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a 1-ethylpropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a 2-methylbutyl group, a 3,3-dimethylbutyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a 1-methylpentyl group, an n-hexyl group, an isohexyl group, a sec-hexyl group, a tert-hexyl group, an n-heptyl group, an isoheptyl group, a sec-heptyl group, a tert-heptyl group, an n-octyl group, an isooctyl group, a sec-octyl group, a tert-octyl group, a nonyl group, a decyl group, an undecyl group, and a dodecyl group; Vinyl, 1-propenyl, allyl (2-propenyl), isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, hexenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, hexenyl, ethynyl, 1-propynyl, 2-propynyl (synonymous with propargyl), 1-butynyl, 2-butynyl, 3-butynyl linear or branched unsaturated aliphatic groups (i.e., alkenyl or alkynyl groups), such as 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexynyl, 1-methyl-2-propynyl, 2-methyl-3-butynyl, 2-methyl-3-pentynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1,1-dimethyl-2-butynyl, and 1-hexynyl groups; cycloaliphatic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopentenyl, and 1-cyclohexenyl groups; etc.

[0062] As the aliphatic group having 1 to 12 carbon atoms, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a vinyl group, an allyl group, and an ethynyl group are preferable, a methyl group and an ethyl group are more preferable, and a methyl group is further preferable.

[0063] The alkylene group having 1 to 4 carbon atoms may be a linear alkylene group or a branched alkylene group.

[0064] The alkylene group having 1 to 4 carbon atoms is preferably at least one selected from the group consisting of a methylene group, an ethylene group, a propylene group, a butylene group, and an isopropylidene group, more preferably at least one selected from the group consisting of a methylene group, an ethylene group, and an isopropylidene group, and even more preferably a methylene group.

[0065] X is a chlorine atom or a bromine atom, and n is 0 or 1. That is, the indoline derivative represented by formula (II-I) may not be in the form of a salt, and may be in the form of a hydrochloride or hydrobromide salt.

[0066] Specific examples of the compound represented by formula (II-I) include the following compounds. However, the compound represented by formula (II-I) is not limited to these.

[0067] [ka]

[0068] From the viewpoint of efficiently producing an oxidation dye (i.e., a 5,6-dihydroxyindoline derivative), 1 ~R 4 is preferably a hydrogen atom.

[0069] (catalyst) The hydrogenation reaction in step (I) uses a catalyst. Examples of the catalyst include platinum-based catalysts such as platinum powder, platinum-activated carbon, platinum-alumina, platinum(IV) oxide, platinum(II) chloride, and platinum(IV) chloride.

[0070] The catalyst preferably comprises tetravalent platinum. Examples of catalysts containing tetravalent platinum include platinum(IV) oxide and platinum(IV) chloride.

[0071] The hydrogenation reaction can be carried out either under normal pressure or under elevated pressure. In addition, from the viewpoint of preventing oxidation of the indoline derivative produced, the hydrogenation reaction can also be carried out in a mixed atmosphere of hydrogen and an inert gas (eg, nitrogen, argon, etc.).

[0072] 〔purification〕 In the method for producing an oxidation dye of the present disclosure, the solution of the indoline derivative obtained by the hydrogenation reaction in step (I) can suppress the generation of by-products. Therefore, in the production method of the oxidation dye of the present disclosure, the solution of the indoline derivative obtained by the hydrogenation reaction in step (I) can be used in the subsequent step (II) without any particular purification treatment such as crystallization. If necessary, a step of removing catalyst ash may be carried out.

[0073] From the viewpoint of efficiently producing a high-purity oxidation dye, the content of the main product in which the nitrogen atom of the indoline derivative is not acylated (preferably a compound represented by formula (II-I)) is preferably 92 mass% or more, more preferably 94 mass% or more, and even more preferably 98 mass% or more, based on the total mass of the indoline derivative.

[0074] The reaction time of the hydrogenation reaction is not particularly limited. From the viewpoint of improving production efficiency, the reaction time of the hydrogenation reaction is preferably 70 hours or less, more preferably 50 hours or less, further preferably 30 hours or less, and particularly preferably 15 hours or less. The lower limit of the reaction time of the hydrogenation reaction is not particularly limited, and the reaction time of the hydrogenation reaction may be, for example, 1 minute or more.

[0075] <Process (II)> The method for producing an oxidation dye of the present disclosure includes a step (II) of adding hydrogen bromide to a solution containing an indoline derivative. This allows the indoline derivative to be deprotected to give the acid salt of 5,6-dihydroxyindoline, which is an oxidation dye.

[0076] Hydrogen bromide is used as a deprotecting agent. As the hydrogen bromide, hydrogen bromide gas may be used as it is, or hydrobromic acid in the form of an aqueous solution may be used, or hydrogen bromide may be used in a state of being dissolved in a solvent such as acetic acid.

[0077] Examples of the solvent used in step (II) include water, acetic acid, ethyl acetate, acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, hexane, cyclohexane, heptane, toluene, xylene (i.e., ortho-xylene, meta-xylene, or para-xylene), and cyclohexanone.

[0078] The reaction in step (II) can be carried out either under normal pressure or under reduced pressure. The reaction in step (II) is preferably carried out in an inert atmosphere (for example, a nitrogen atmosphere, an argon atmosphere, etc.) from the viewpoint of preventing oxidation (melanization) of the generated oxidation dye.

[0079] The reaction temperature in the step (II) is preferably 60°C to 150°C. By setting the reaction temperature at 60° C. or higher, the production of the oxidation dye can be further promoted. By controlling the reaction temperature to 150° C. or lower, decomposition of the generated oxidation dye can be suppressed, and the generation rate can be further improved. From the same viewpoint as above, the reaction temperature in step (II) is more preferably 80°C to 140°C, and further preferably 100°C to 130°C.

[0080] The reaction time in the step (II) is preferably 30 minutes to 12 hours, and more preferably 1 hour to 6 hours, from the viewpoint of efficiently proceeding with the reaction between the indoline derivative and hydrogen bromide.

[0081] In the method for producing an oxidation dye of the present disclosure, the target oxidation dye (i.e., 5,6-dihydroxyindoline derivative) can be isolated in high purity by distilling off the solvent from the reaction solution obtained in step (II). Even if, after step (II), part or all of the obtained oxidized dye is in the form of a slurry in which it has precipitated, it is preferable from the viewpoint of operational simplicity to distill off the solvent as it is without any special treatment such as separation or filtration.

[0082] In the method for producing an oxidized dye of the present disclosure, the wet solid of the oxidized dye obtained by distilling off the solvent after step (II) can also be washed with a low-boiling solvent such as methanol, acetone, or acetonitrile. This enables subsequent drying to proceed efficiently.

[0083] Examples of the method for drying the extracted oxidized dye include a static drying method using a shelf dryer; a fluidized drying method using a conical dryer; a method of drying using devices such as a hot plate or an oven; a method of supplying warm air or hot air using a dryer such as a drier; and the like.

[0084] The pressure when drying the extracted oxidized dye may be either normal pressure or reduced pressure. The temperature when drying the extracted oxidized dye is preferably 40°C to 150°C. When the temperature is 40°C or higher, the drying efficiency is excellent. When the temperature is 150°C or lower, decomposition of the produced oxidized dye is suppressed, and it can be taken out in a stable state. From the same viewpoints as above, the temperature when drying the extracted oxidized dye is more preferably 50°C to 140°C, and even more preferably 60°C to 130°C.

[0085] The extracted oxidized dye may be used as it is, or may be used, for example, dispersed or dissolved in a solvent, or mixed with other substances.

[0086] <Oxidized Dye Composition> The oxidized dye composition of the present disclosure contains an acid salt of 5,6-dihydroxyindoline.

[0087] (Other Components) The oxidative dye compositions of the present disclosure may contain other ingredients besides the acid salt of 5,6-dihydroxyindoline. Other ingredients include, for example, antioxidants. By including an antioxidant in the oxidative dye composition of the present disclosure, the oxidative stability can be improved. Examples of the antioxidant include sodium sulfite, sodium hydrogen sulfite, sodium thiosulfate, and sodium dithionite. Among these, sodium thiosulfate and sodium dithionite are preferred, and sodium dithionite is more preferred. EXAMPLES

[0088] Examples of the present disclosure will be described below, but the present disclosure is not limited to the following examples.

[0089] Example 1 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.76 g (3.35 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g (143 ml) of acetic acid as a carboxylic acid were added and mixed with stirring. While stirring at room temperature (25°C), hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the inside of the flask was slightly pressurized with hydrogen to start the reaction. Stirring was continued for 10 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction solution was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution A containing the product of the hydrogenation reaction. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and at 80°C to obtain a small amount of light brown crystals.

[0090] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the main skeleton of the product of the hydrogenation reaction was 5,6-dimethoxyindoline and that no impurities were contained.

[0091] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0092] [ka]

[0093] Next, the above-mentioned solution A and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while treating and concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by treating for another hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 8.54 g of a dark brown powder. The yield was 92% by mass.

[0094] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 11H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 6.81 ppm (1H), 6.87 ppm (1H), 9.02 ppm (1H), 10.59 ppm (2H)

[0095] In addition, the obtained powder was analyzed for Br content by combustion decomposition ion chromatography. The result was Br: 34.2 mass%. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4 mass%, the purity of the 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 99.4 mass%.

[0096] From the above, it was shown that the production method of Example 1 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme.

[0097]

Chemical formula

[0098] 〔Example 2〕 A 300 mL flask equipped with a stirrer, thermometer, gas inlet line, exhaust line, and condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.015 g (0.066 mmol) of platinum(IV) oxide as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added thereto and stirred and mixed. While heating and stirring at 40 °C, hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the reaction was started by making the inside of the flask slightly pressurized with hydrogen. The reaction was continued at 40 °C for 40 hours. When the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. To the solution obtained by filtering this reaction solution to remove the catalyst ash, 7.57 g (0.044 mol) of hydrobromic acid (47 mass% HBr) was added to obtain solution A containing the product of the hydrogenation reaction. Approximately 1 mL of this solution A was taken and dried under reduced pressure at 80 °C under 2 kPa or less to obtain a small amount of light brown crystals.

[0099] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.15H), 3.07ppm(0.10H), 3.43ppm(0.15H), 3.77ppm(0.15H), 4.04ppm(0.10H), 6.86ppm(0.05H), 7.80ppm(0.05H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction contained 93.8% by mass of the main product 5,6-dimethoxyindoline, but also contained 6.2% by mass of N-acetyl-5,6-dimethoxyindoline.

[0100] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0101] [ka]

[0102] Next, the above-mentioned solution A and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried with dry nitrogen at 80°C to obtain 8.35 g of a dark brown powder. The yield was 90% by mass.

[0103] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 3.04ppm(2H), 3.67ppm(2H), 6.81ppm(1H), 6.87ppm(1H), 8.48ppm(1H), 10.60ppm(2H).

[0104] The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 33.5% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide was 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 97.3% by mass.

[0105] From the above, it was shown that the production method of Example 2 produces 5,6-dihydroxyindoline hydrobromide according to the following reaction scheme.

[0106] [ka]

[0107] Example 3 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.50 g (2.2 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added and mixed with stirring. The mixture was heated to 40°C and stirred while introducing hydrogen into the gas inlet line, and the exhaust line was closed to slightly pressurize the inside of the flask with hydrogen to start the reaction. The reaction was continued at 40°C for 12 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction solution was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid, to obtain a solution containing the reduction reaction product B. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and at 80°C, to obtain a small amount of light brown crystals.

[0108] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.06H), 3.07ppm(0.04H), 3.43ppm(0.06H), 3.77ppm(0.06H), 4.04ppm(0.04H), 6.86ppm(0.02H), 7.80ppm(0.02H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the reduction reaction mainly contained 5,6-dimethoxyindoline at 97.8 mass%, but also contained 2.2 mass% N-acetyl-5,6-dimethoxyindoline. From the above, it was demonstrated that this reduction reaction produces an indoline compound according to the following reaction scheme.

[0109] [ka]

[0110] Next, the above-mentioned solution B and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 8.67 g of a dark brown powder. The yield was 93.4% by mass.

[0111] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent. 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:3.04ppm(2H), 3.67ppm(2H), 6.81ppm(1H), 6.87ppm(1H), 8.48ppm(1H), 10.60ppm(2H)

[0112] The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 34.1% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 99.1% by mass.

[0113] From the above, it was shown that the production method of Example 3 produces 5,6-dihydroxyindoline hydrobromide according to the following reaction scheme.

[0114] [ka]

[0115] Example 4 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 1.12 g (4.93 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added and mixed with stirring. While stirring at room temperature (25°C), hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the inside of the flask was slightly pressurized with hydrogen to start the reaction. Stirring was continued for 8 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction solution was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid, to obtain a solution containing the reduction reaction product B. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and at 80°C, to obtain a small amount of light brown crystals.

[0116] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.12H), 3.07ppm(0.08H), 3.43ppm(0.12H), 3.77ppm(0.12H), 4.04ppm(0.08H), 6.86ppm(0.04H), 7.80ppm(0.04H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the reduction reaction mainly contained 5,6-dimethoxyindoline at 95.2 mass%, but also contained 4.8 mass% N-acetyl-5,6-dimethoxyindoline.

[0117] From the above, it was demonstrated that this reduction reaction produces an indoline compound according to the following reaction scheme.

[0118] [ka]

[0119] Next, the above-mentioned solution B and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 8.79 g of a dark brown powder. The yield was 94.7% by mass.

[0120] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:3.04ppm(2H), 3.67ppm(2H), 6.81ppm(1H), 6.87ppm(1H), 8.48ppm(1H), 10.60ppm(2H)

[0121] The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 33.3 mass %. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 96.8% by mass.

[0122] From the above, it was shown that the production method of Example 4 produces 5,6-dihydroxyindoline hydrobromide according to the following reaction scheme.

[0123] [ka]

[0124] Example 5 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 1.50 g (6.6 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added and mixed with stirring. The mixture was cooled to 10°C, hydrogen was introduced into the gas inlet line while stirring, the exhaust line was closed, and the inside of the flask was put into a hydrogen slightly pressurized state to start the reaction. The reaction was continued at 10°C for 6 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction liquid was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution B containing the product of the reduction reaction. About 1 ml of this solution was sampled and dried under reduced pressure of 2 kPa or less and at 80° C. to obtain a small amount of light brown crystals. The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.15H), 3.07ppm(0.10H), 3.43ppm(0.15H), 3.77ppm(0.15H), 4.04ppm(0.10H), 6.86ppm(0.05H), 7.80ppm(0.05H) the above 1From the H-NMR spectrum pattern, it was confirmed that the product of the reduction reaction mainly contained 5,6-dimethoxyindoline at 94.2 mass%, but also contained 5.8 mass% N-acetyl-5,6-dimethoxyindoline.

[0125] From the above, it was demonstrated that this reduction reaction produces an indoline compound according to the following reaction scheme.

[0126] [ka]

[0127] Next, the above-mentioned solution B and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while treating and concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by treating for another hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 8.24 g of a dark brown powder. The yield was 88.8% by mass.

[0128] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent. 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 3.04ppm(2H), 3.67ppm(2H), 6.81ppm(1H), 6.87ppm(1H), 8.48ppm(1H), 10.60ppm(2H). The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 33.5% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of the 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 97.4% by mass.

[0129] From the above, it was shown that the production method of Example 5 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme.

[0130]

Chemical formula

[0131] 〔Example 6〕 A 300 mL flask equipped with a stirrer, thermometer, gas inlet line, exhaust line, and condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.25 g (1.1 mmol) of platinum(IV) oxide as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were placed therein and stirred and mixed. While heating and stirring at 45 °C, hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the reaction was started by making the inside of the flask slightly pressurized with hydrogen. The reaction was continued at 45 °C for 20 hours. When the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. To the solution obtained by filtering this reaction solution to remove the catalyst ash, 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to obtain solution B containing the product of the reduction reaction. Approximately 1 ml of this solution was taken and dried under reduced pressure under the conditions of 2 kPa and 80 °C to obtain a small amount of light brown crystals.

[0132] The obtained crystals were dissolved in a deuterated dimethyl sulfoxide solvent, 1 and 1H-NMR analysis was performed. The chemical shifts [ppm] and integral values (ratios) of the obtained spectra were as follows. 1H-NMR: 2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.07H), 3.07ppm(0.05H), 3.43ppm(0.07H), 3.77ppm(0.07H), 4.04ppm(0.05H), 6.86ppm(0.02H), 7.80ppm(0.02H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the reduction reaction mainly contained 5,6-dimethoxyindoline at 97.1 mass%, but also contained 2.9 mass% N-acetyl-5,6-dimethoxyindoline.

[0133] From the above, it was demonstrated that this reduction reaction produces an indoline compound according to the following reaction scheme.

[0134] [ka]

[0135] Next, the above-mentioned solution B and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 8.55 g of a dark brown powder. The yield was 92.2% by mass. The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1H-NMR:3.04ppm(2H), 3.67ppm(2H), 6.81ppm(1H), 6.87ppm(1H), 8.48ppm(1H), 10.60ppm(2H)

[0136] The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 34.1% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 99.1% by mass.

[0137] From the above, it was shown that the production method of Example 6 produces 5,6-dihydroxyindoline hydrobromide according to the following reaction scheme. [ka]

[0138] Example 7 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.76 g (3.35 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added thereto and stirred and mixed. While heating and stirring at 35°C, hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the inside of the flask was put into a hydrogen slight pressure state to start the reaction. The reaction was continued at 35°C for 8 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction liquid was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution A containing the product of the hydrogenation reaction. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and 80° C. to obtain a small amount of light brown crystals.

[0139] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent,1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.11H), 3.07ppm(0.07H), 3.43ppm(0.11H), 3.77ppm(0.11H), 4.04ppm(0.07H), 6.86ppm(0.04H), 7.80ppm(0.04H) . the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 95.6 mass%, but also contained 4.4 mass% N-acetyl-5,6-dimethoxyindoline.

[0140] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0141] [ka]

[0142] Next, the above-mentioned solution A and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60 ° C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150 ° C., and the reaction was carried out while treating and concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150 ° C., and the operation was terminated by treating for another hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80 ° C. to obtain 8.68 g of a dark brown powder. The yield was 93.5% by mass.

[0143] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent.1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values (ratios) of the obtained spectra were as follows. 1 H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 6.81 ppm (1H), 6.87 ppm (1H), 9.02 ppm (1H), 10.59 ppm (2H)

[0144] Also, the obtained powder was analyzed for Br content by combustion decomposition ion chromatography. The result was Br: 34.0 mass%. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4 mass%, the purity of the 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 98.8 mass%.

[0145] From the above, it was shown that the production method of Example 7 gave 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme.

Chemical formula

[0146] 〔Example 8〕 A 300 mL flask equipped with a stirrer, thermometer, gas inlet line, exhaust line, and condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 1.32 g (5.8 mmol) of platinum(IV) oxide as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added thereto and stirred and mixed. While maintaining the temperature at 20 °C and stirring, hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the reaction was started by making the inside of the flask slightly pressurized with hydrogen. The reaction was continued at 20 °C for 6 hours. When the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. To the solution obtained by filtering the reaction solution to remove the catalyst ash, 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to obtain solution B containing the product of the hydrogenation reaction. Approximately 1 ml of this solution was taken and dried under reduced pressure at 80 °C under 2 kPa or less to obtain a small amount of light brown crystals.

[0147] The obtained crystals were dissolved in a deuterated dimethyl sulfoxide solvent, 1 and \(^1\)H-NMR analysis was performed. The chemical shifts [ppm] and integral values (ratios) of the obtained spectrum were as follows. 1 \(^1\)H-NMR: 2.81 ppm (2H), 3.35 ppm (2H), 3.62 ppm (3H), 3.66 ppm (3H), 5.05 ppm (1H), 6.24 ppm (1H), 6.73 ppm (1H), 2.10 ppm (0.14H), 3.07 ppm (0.09H), 3.43 ppm (0.14H), 3.77 ppm (0.14H), 4.04 ppm (0.09H), 6.86 ppm (0.05H), 7.80 ppm (0.05H). From the above 1 \(^1\)H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contains 94.5% by mass of 5,6-dimethoxyindoline, but also contains 5.5% by mass of N-acetyl-5,6-dimethoxyindoline.

[0148] From the above, it was shown that this hydrogenation reaction produces an indoline derivative as shown in the following reaction scheme.

[0149]

Chemical formula

[0150] Next, the above-mentioned solution B and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 8.28 g of dark brown powder. The yield was 89.2% by mass.

[0151] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:3.04ppm(2H), 3.67ppm(2H), 6.81ppm(1H), 6.87ppm(1H), 8.48ppm(1H), 10.60ppm(2H) The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 33.2% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 96.5% by mass.

[0152] From the above, it was demonstrated that the production method of Example 8 can produce 5,6-dihydroxyindoline hydrobromide according to the following reaction scheme.

[0153] [ka]

[0154] Example 9 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 1.12 g (4.93 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added and mixed with stirring. The mixture was cooled to 0°C, hydrogen was introduced into the gas inlet line while stirring, the exhaust line was closed, and the inside of the flask was slightly pressurized with hydrogen to start the reaction. The reaction was continued at 0°C for 24 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction solution was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution containing the hydrogenation reaction product B. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and at 80°C to obtain a small amount of light brown crystals.

[0155] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.04H), 3.07ppm(0.03H), 3.43ppm(0.04H), 3.77ppm(0.04H), 4.04ppm(0.03H), 6.86ppm(0.01H), 7.80ppm(0.01H) . the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 98.5 mass%, but also contained N-acetyl-5,6-dimethoxyindoline at 1.5 mass%.

[0156] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0157] [ka]

[0158] Next, the above-mentioned solution B and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 8.79 g of a dark brown powder. The yield was 94.7% by mass.

[0159] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent. 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:3.04ppm(2H), 3.67ppm(2H), 6.81ppm(1H), 6.87ppm(1H), 8.48ppm(1H), 10.60ppm(2H) The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 34.2% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 99.4% by mass.

[0160] From the above, it was demonstrated that the production method of Example 9 can produce 5,6-dihydroxyindoline hydrobromide according to the following reaction scheme.

[0161] [ka]

[0162] Comparative Example 1 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.015 g (0.066 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added and mixed with stirring. The mixture was heated to 60°C and stirred while being introduced into the gas inlet line, and the exhaust line was closed to start the reaction by slightly pressurizing the inside of the flask with hydrogen. The reaction was continued at 60°C for 30 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction liquid was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution C containing the product of the hydrogenation reaction. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and 80° C. to obtain a small amount of light brown crystals.

[0163] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.60H), 3.07ppm(0.40H), 3.43ppm(0.60H), 3.77ppm(0.60H), 4.04ppm(0.40H), 6.86ppm(0.20H), 7.80ppm(0.20H) the above 1From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 79.9 mass%, but also contained N-acetyl-5,6-dimethoxyindoline at 20.1 mass%.

[0164] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0165] [ka]

[0166] Next, the above-mentioned solution C and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 4.80 g of black powder. The yield was 51.7% by mass.

[0167] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 5.76 (0.8H), 6.80 ppm (1H), 6.86 ppm (1H), 9.20 ppm (1.5H), 10.54 ppm (2H), and many other baseline noises.

[0168] The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 23.3% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of the 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 67.7% by mass.

[0169] From the above, the production method of Comparative Example 1 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme, but the purity was low.

[0170]

Chemical formula

[0171] 〔Comparative Example 2〕 A 300 mL flask equipped with a stirrer, thermometer, gas inlet line, exhaust line, and condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.76 g (3.35 mmol) of platinum(IV) oxide as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added thereto and stirred and mixed. While heating and stirring at 40 °C, hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the reaction was started by making the inside of the flask in a slightly pressurized hydrogen state. The reaction was continued at 40 °C for 8 hours. When the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the solution obtained by filtering the reaction solution to remove the catalyst ash to obtain a solution C containing the product of the hydrogenation reaction. About 1 mL of this solution was taken and dried under reduced pressure under the conditions of 2 kPa or less and 80 °C to obtain a small amount of light brown crystals.

[0172] The obtained crystals were dissolved in a deuterated dimethyl sulfoxide solvent, 1 and 1H-NMR analysis was performed. The chemical shifts [ppm] and integral values (ratios) of the obtained spectra were as follows. 1H-NMR: 2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.45H), 3.07ppm(0.30H), 3.43ppm(0.45H), 3.77ppm(0.45H), 4.04ppm(0.30H), 6.86ppm(0.15H), 7.80ppm(0.15H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 83.2 mass%, but also contained N-acetyl-5,6-dimethoxyindoline at 16.8 mass%.

[0173] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0174] [ka]

[0175] Next, the above-mentioned solution C and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 6.80 g of black powder. The yield was 73.3% by mass.

[0176] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 5.76 (0.8H), 6.80 ppm (1H), 6.86 ppm (1H), 9.20 ppm (1.5H), 10.54 ppm (2H), and many other baseline noises.

[0177] The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 23.7% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 68.9% by mass.

[0178] From the above, the production method of Comparative Example 2 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme, but the purity was low.

[0179] [ka]

[0180] Comparative Example 3 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 1.50 g (6.6 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added thereto and stirred and mixed. While stirring at room temperature (25°C), hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the inside of the flask was put into a hydrogen slight pressure state to start the reaction. Stirring was continued for 6 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction liquid was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47 mass% HBr) was added to the liquid to obtain a solution C containing the product of the hydrogenation reaction. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and 80° C. to obtain a small amount of light brown crystals.

[0181] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.24H), 3.07ppm(0.16H), 3.43ppm(0.24H), 3.77ppm(0.24H), 4.04ppm(0.16H), 6.86ppm(0.08H), 7.80ppm(0.08H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 90.8 mass%, but also contained N-acetyl-5,6-dimethoxyindoline at 9.2 mass%.

[0182] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0183] [ka]

[0184] Next, the above-mentioned solution C and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while treating and concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by treating for another hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 7.43 g of black powder. The yield was 80.1% by mass.

[0185] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent. 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 5.76 (0.8H), 6.80 ppm (1H), 6.86 ppm (1H), 9.20 ppm (1.5H), 10.54 ppm (2H) Others, baseline noise. The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 27.0% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 78.5% by mass.

[0186] From the above, the production method of Comparative Example 3 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme, but the purity was low.

[0187] [ka]

[0188] Comparative Example 4 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 0.50 g (2.2 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added thereto and stirred and mixed. The mixture was heated to 50°C and stirred while being introduced into the gas inlet line, and the exhaust line was closed to start the reaction by placing the inside of the flask in a hydrogen slightly pressurized state. The reaction was continued at 50°C for 12 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction liquid was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution C containing the product of the hydrogenation reaction. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and 80° C. to obtain a small amount of light brown crystals.

[0189] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.27H), 3.07ppm(0.18H), 3.43ppm(0.27H), 3.77ppm(0.27H), 4.04ppm(0.18H), 6.86ppm(0.09H), 7.80ppm(0.09H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 89.8 mass%, but also contained N-acetyl-5,6-dimethoxyindoline at 10.2 mass%.

[0190] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0191] [ka]

[0192] Next, the above-mentioned solution C and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 7.36 g of black powder. The yield was 79.3% by mass.

[0193] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 5.76 (0.8H), 6.80 ppm (1H), 6.86 ppm (1H), 9.20 ppm (1.5H), 10.54 ppm (2H) Others, baseline noise. The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 27.1% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 78.8% by mass.

[0194] From the above, the production method of Comparative Example 4 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme, but the purity was low.

[0195] [ka]

[0196] Comparative Example 5 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 1.12 g (4.93 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added and mixed with stirring. The mixture was heated to 30°C and stirred while being introduced into the gas inlet line, and the exhaust line was closed to start the reaction by slightly pressurizing the inside of the flask with hydrogen. The reaction was continued at 30°C for 8 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction liquid was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution C containing the product of the hydrogenation reaction. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and 80° C. to obtain a small amount of light brown crystals.

[0197] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.24H), 3.07ppm(0.16H), 3.43ppm(0.24H), 3.77ppm(0.24H), 4.04ppm(0.16H), 6.86ppm(0.08H), 7.80ppm(0.08H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 90.8 mass%, but also contained N-acetyl-5,6-dimethoxyindoline at 9.2 mass%.

[0198] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0199] [ka]

[0200] Next, the above-mentioned solution C and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 7.66 g of black powder. The yield was 82.5% by mass.

[0201] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent. 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 5.76 (0.8H), 6.80 ppm (1H), 6.86 ppm (1H), 9.20 ppm (1.5H), 10.54 ppm (2H) Others, baseline noise. The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 27.6% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 80.2% by mass.

[0202] From the above, the production method of Comparative Example 5 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme, but the purity was low.

[0203] [ka]

[0204] Comparative Example 6 A 300 mL flask equipped with a stirrer, a thermometer, a gas inlet line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 1.71 g (7.53 mmol) of platinum oxide (IV) as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were added and mixed with stirring. While keeping the temperature at 22°C and stirring, hydrogen was introduced into the gas inlet line, the exhaust line was closed, and the inside of the flask was put into a hydrogen slight pressure state to start the reaction. The reaction was continued at 22°C for 6 hours, and when the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. This reaction liquid was filtered to remove the catalyst ash, and 7.57 g (0.044 mol) of hydrobromic acid (47% by mass HBr) was added to the liquid to obtain a solution C containing the product of the hydrogenation reaction. About 1 ml of this solution was sampled and dried under reduced pressure at 2 kPa or less and 80° C. to obtain a small amount of light brown crystals.

[0205] The obtained crystals were dissolved in deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR:2.81ppm(2H), 3.35ppm(2H), 3.62ppm(3H), 3.66ppm(3H), 5.05ppm(1H), 6.24ppm(1H), 6.73ppm(1H), 2.10ppm (0.42H), 3.07ppm(0.28H), 3.43ppm(0.42H), 3.77ppm(0.42H), 4.04ppm(0.28H), 6.86ppm(0.14H), 7.80ppm(0.14H) the above 1 From the H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 5,6-dimethoxyindoline at 84.9 mass%, but also contained N-acetyl-5,6-dimethoxyindoline at 15.1 mass%.

[0206] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0207] [ka]

[0208] Next, the above-mentioned solution C and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 7.29 g of black powder. The yield was 78.6% by mass.

[0209] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 5.76 (0.8H), 6.80 ppm (1H), 6.86 ppm (1H), 9.20 ppm (1.5H), 10.54 ppm (2H), and many other baseline noises. The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 25.6% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 74.4% by mass.

[0210] From the above, the production method of Comparative Example 6 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme, but the purity was low.

[0211] [ka]

[0212] Comparative Example 7 A 300 mL flask equipped with a stirring device, a thermometer, a gas introduction line, an exhaust line, and a condenser was prepared. After purging the 300 mL flask with dry nitrogen gas, 2.00 g (8.8 mmol) of platinum(IV) oxide as a catalyst, 7.09 g (0.04 mol) of 5,6-dimethoxyindole as an indole derivative, and 150 g of acetic acid as a carboxylic acid were placed therein and stirred and mixed. While cooling and stirring at 10 °C, hydrogen was introduced into the gas introduction line, the exhaust line was closed, and the reaction was started by making the inside of the flask in a slightly pressurized hydrogen state. The reaction was continued at 10 °C for 6 hours. When the absorption of hydrogen reached saturation, the inside of the flask was purged with nitrogen gas to stop the reaction. 7.57 g (0.044 mol) of hydrobromic acid (47 mass% HBr) was added to the solution obtained by filtering the reaction solution to remove the catalyst ash, and a solution C containing the product of the hydrogenation reaction was obtained. About 1 ml of this solution was taken and dried under reduced pressure under the conditions of 2 kPa or less and 80 °C to obtain a small amount of light brown crystals.

[0213] The obtained crystals were dissolved in a deuterated dimethyl sulfoxide solvent, 1 and \(^1\)H-NMR analysis was performed. The chemical shifts [ppm] and integral values (ratios) of the obtained spectrum were as follows. 1 \(^1\)H-NMR: 2.81 ppm (2H), 3.35 ppm (2H), 3.62 ppm (3H), 3.66 ppm (3H), 5.05 ppm (1H), 6.24 ppm (1H), 6.73 ppm (1H), 2.10 ppm (0.33H), 3.07 ppm (0.22H), 3.43 ppm (0.33H), 3.77 ppm (0.33H), 4.04 ppm (0.22H), 6.86 ppm (0.11H), 7.80 ppm (0.11H) From the above 1 \(^1\)H-NMR spectrum pattern, it was confirmed that the product of the hydrogenation reaction mainly contained 87.8 mass% of 5,6-dimethoxyindoline, but also contained 12.2 mass% of N-acetyl-5,6-dimethoxyindoline.

[0214] From the above, it was demonstrated that this hydrogenation reaction produces an indoline derivative according to the following reaction scheme.

[0215] [ka]

[0216] Next, the above-mentioned solution C and 61.23 g (0.356 mol) of hydrobromic acid (47% by mass HBr) were placed in a concentrator, and acetic acid was distilled off under conditions of 5 kPa or less and 60°C. When the distillation of acetic acid stopped, the pressure was returned to normal, the heating temperature was raised to 150°C, and the reaction was carried out while concentrating for 3 hours under these conditions. After that, the pressure was reduced to 5 kPa or less while heating at 150°C, and the operation was terminated by further treating for 1 hour. 100 g of acetonitrile was added to the solid obtained in the concentrator to make a slurry, and the solid was filtered and extracted, and dried by blowing dry nitrogen at 80°C to obtain 7.12 g of black powder. The yield was 76.7% by mass.

[0217] The obtained powder was dissolved in a deuterated dimethyl sulfoxide solvent, 1 H-NMR analysis was performed. The chemical shifts [ppm] and integral values ​​(ratios) of the obtained spectrum were as follows: 1 H-NMR: 3.04 ppm (2H), 3.67 ppm (2H), 5.76 (0.8H), 6.80 ppm (1H), 6.86 ppm (1H), 9.20 ppm (1.5H), 10.54 ppm (2H), and many other baseline noises. The powder was analyzed for Br content by combustion decomposition ion chromatography, and the result was Br: 24.2% by mass. Since the theoretical Br content of 5,6-dihydroxyindoline hydrobromide is 34.4% by mass, the purity of 5,6-dihydroxyindoline hydrobromide obtained in this synthesis was 70.3% by mass.

[0218] From the above, the production method of Comparative Example 7 produced 5,6-dihydroxyindoline hydrobromide as shown in the following reaction scheme, but the purity was low.

[0219] [ka]

[0220] For each of the Examples and Comparative Examples, Table 1 shows the amount of catalyst added in step (I) (x mol %), the reaction temperature (y° C.), the reaction time, and the content of the main product in which the nitrogen atom in the indoline derivative is not acylated. For each of the Examples and Comparative Examples, the yield and purity of 5,6-dihydroxyindoline hydrobromide in step (II) are shown in Table 1. The amount of catalyst added, x, was calculated to one decimal place, and -2.5x+59.00 was calculated to two decimal places.

[0221] [Table 1]

[0222] As shown in Table 1, in the example using the production method for an oxidation dye, which includes a step (I) of converting an indole derivative to an indoline derivative by a hydrogenation reaction in the presence of a carboxylic acid to obtain a solution containing the indoline derivative, and a step (II) of adding hydrogen bromide to the solution containing the indoline derivative, the hydrogenation reaction in the step (I) uses a catalyst, and the amount of catalyst added x mol % and the reaction temperature y° C. satisfy the conditions of the formulas (1) and (2), it was possible to obtain a highly pure acid salt of 5,6-dihydroxyindoline using a simple operation without performing any special operation such as purification. Moreover, the examples were excellent in yield. On the other hand, in Comparative Examples 1 to 7, which do not satisfy formula (1) because y>-2.5x+59.00, a high-purity acid salt of 5,6-dihydroxyindoline could not be obtained. Also, the yields of the Comparative Examples were low.

[0223] Tables 2 and 3 show the final yield, production rate index 1, and production rate index 2 for each example. The final yield [%] is calculated by the formula: yield [%] × purity [%] / 100. The production rate index 1 [% / hr] is a value calculated by final yield [%] / reaction time [hr]. Production rate index 2 [% / hr / mol%] is a value calculated by production rate index 1 [% / hr] / amount of catalyst added x [mol%].

[0224] [Table 2]

[0225] As shown in Table 2, Example 3, which has a lower reaction temperature, is superior in final yield, production rate index 1, and production rate index 2 compared to Comparative Example 4, which has a higher reaction temperature. Moreover, Example 4, which has a lower reaction temperature, is superior in final yield, production rate index 1, and production rate index 2 compared to Comparative Example 5, which has a higher reaction temperature. Generally, the reaction rate tends to increase when the reaction temperature is increased. However, as described above, it has been found that by using the method for producing an oxidation dye of the present disclosure, an excellent final yield and reaction rate can be obtained even when the reaction temperature is decreased.

[0226] [Table 3]

[0227] As shown in Table 3, Example 3, in which the amount x of catalyst added is smaller, is superior in final yield, production rate index 1, and production rate index 2 compared to Comparative Example 2, in which the amount x of catalyst added is larger. Moreover, Example 5, in which the amount x of catalyst added is smaller, is superior in final yield, production rate index 1, and production rate index 2 compared to Comparative Example 7, in which the amount x of catalyst added is larger. Generally, the reaction rate tends to increase when the amount of catalyst added x is increased. However, as described above, it has been found that by using the method for producing an oxidation dye of the present disclosure, an excellent final yield and reaction rate can be obtained even when the amount of catalyst added x is reduced.

Claims

1. A step (I) of converting an indole derivative represented by the following formula (I) into an indoline derivative represented by the following formula (II-1) by a hydrogenation reaction in the presence of a carboxylic acid to obtain a solution containing the indoline derivative represented by the formula (II-1); 【Chemistry 1】 [In formula (I), R 1 and R 3 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, an oxygen-containing group, or a halogen atom. R 6 and R 7 each independently represent an aliphatic group having 1 to 12 carbon atoms, or together represent an alkylene group having 1 to 4 carbon atoms.] 【Chemistry 2】 [In formula (II-I), R 1 to R 4 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl group having 6 to 10 carbon atoms, an oxygen-containing group, or a halogen atom. R 6 and R 7 each independently represent an aliphatic group having 1 to 12 carbon atoms, or together represent an alkylene group having 1 to 4 carbon atoms. X represents a chlorine atom or a bromine atom, and n is 0.] A step (II) of adding hydrogen bromide to a solution containing the indoline derivative represented by the formula (II-1); Including, The hydrogenation reaction in the step (I) uses a catalyst, and the amount of the catalyst added (x mol %) and the reaction temperature (y °C) satisfy the conditions of the following formula (1) and formula (2). y≦-2.5x+59.00 Formula (1) 0<x≦20.0 Formula (2)

2. The method for producing an oxidation dye according to claim 1 , wherein the catalyst contains tetravalent platinum.

3. 3. The method for producing an oxidative dye according to claim 1, wherein the carboxylic acid is represented by XCOOH, and X is an alkyl group having 1 to 20 carbon atoms.

4. The method for producing an oxidative dye according to any one of claims 1 to 3, wherein the hydrogenation reaction in the step (I) further satisfies the condition of the following formula (1-1) in terms of the amount of the catalyst added (x mol %) and the reaction temperature (y °C). y≦-2.5x+57.50 Formula (1-1)

5. The method for producing an oxidative dye according to any one of claims 1 to 4, wherein the hydrogenation reaction in the step (I) further satisfies the condition of the following formula (1-2) in terms of the amount of the catalyst added (x mol %) and the reaction temperature (y °C). y≦-2.5x+55.00 Formula (1-2)

6. The method for producing an oxidative dye according to any one of claims 1 to 5, wherein in the hydrogenation reaction in the step (I), the amount of the catalyst added x mol % satisfies the following formula (2-1): 0.2≦x≦15.0 Formula (2-1)

7. The method for producing an oxidative dye according to any one of claims 1 to 6, wherein in the hydrogenation reaction in the step (I), the amount of the catalyst added x mol % satisfies the following formula (2-2): 0.5≦x≦10.0 Formula (2-2)

8. The method for producing an oxidation dye according to any one of claims 1 to 7, wherein the hydrogenation reaction in the step (I) is carried out at a reaction temperature y°C that satisfies the following formula (1-3): 0≦y≦50.00 Formula (1-3)

9. The method for producing an oxidation dye according to any one of claims 1 to 8, wherein the hydrogenation reaction in the step (I) is carried out at a reaction temperature y ° C. that satisfies the following formula (1-4): 5≦y≦45.00 Formula (1-4)

10. In the formula (II-I), R １ ~R ４ The method for producing an oxidation dye according to any one of claims 1 to 9, wherein

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