Method for producing thiophanium salt bromide

Abstract

To provide an efficient production method for a thiophenium salt bromide useful as a biotin synthesis intermediate.SOLUTION: A method for producing a thiophenium salt bromide, the method comprising a step of obtaining a thiophenium salt bromide of formula (2) by contacting a thiophenium salt derivative of formula (1) with a bromine compound. The bromine compound can be an alkali metal bromine compound such as lithium bromide, sodium bromide, or potassium bromide. The contacting of the thiophenium salt derivative with the bromine compound can be performed in a polar solvent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for producing thiophanium chloride bromide, which is useful as a synthetic intermediate for biotin. [Background technology]

[0002] Biotin is a useful compound used in various pharmaceuticals, food additives, feed additives, etc. Biotin is synthesized, for example, by the following method (see Patent Document 1).

[0003] [ka]

[0004] That is, the thiolactone derivative shown in formula (A) is reacted with 3-methoxypropyl magnesium chloride (Grignard reagent) to synthesize the hydroxybiotin derivative shown in formula (B). The hydroxybiotin derivative is then dehydrated and converted to the vinylbiotin derivative shown in formula (C). The resulting vinylbiotin derivative is then subjected to a hydrogenation reaction using a palladium or Raney nickel catalyst to synthesize the biotin derivative shown in formula (D). The biotin derivative is then subjected to a cyclization reaction to synthesize the thiophanium salt derivative shown in formula (E). Finally, the thiophanium salt derivative undergoes coupling with a malonic acid ester and deprotection steps to produce biotin. In the formulas, "Bn" represents a benzyl group, and "Me" represents a methyl group. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 53-027279 Summary of the Invention [Problem to be solved by the invention]

[0006] In Patent Document 1, the thiophanium salt derivative (E) is obtained as a bromide salt. However, to obtain the bromide salt, it is necessary to treat the precursor (D) with an aqueous solution of hydrobromic acid, followed by removal of water and excess hydrogen bromide. The water removal must be carried out at high temperatures, which may result in decomposition of the target product. In addition, hydrogen bromide is highly corrosive, which may cause deterioration of the production equipment.

[0007] Therefore, an object of the present invention is to provide a method for more efficiently producing thiophanium chloride bromide, which is useful as a synthetic intermediate for biotin. [Means for solving the problem]

[0008] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have surprisingly discovered that by contacting a thiophanium salt derivative with a bromine compound in an organic solvent such as a ketone solvent or an alcohol solvent, a salt exchange reaction proceeds, enabling thiophanium chloride bromide to be easily synthesized, thereby completing the present invention.

[0009] That is, the present invention includes the following inventions.

[0010] [1] In an organic solvent, The following formula (1): [ka] [In formula (1), R 1 and R 2 each independently represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent, A - is R 3 -C(=O)(-O) - , X - Or BF4 - and R 3 represents a hydrogen atom or an alkyl group which may have a substituent, X- is a fluoro group, a chloro group, or an iodo group. a thiophanium salt derivative represented by the formula: contacting the mixture with a bromine compound, The following formula (2): [ka] [In formula (2), R 1 and R 2 has the same meaning as in formula (1). obtaining thiophanium chloride bromide represented by the formula: Method for producing thiophanium chloride bromide.

[0011] [2] The method for producing thiophanium chloride bromide according to [1], wherein the bromine compound is an alkali metal bromide.

[0012] [3] The method for producing thiophanium chloride bromide according to [2], wherein the alkali metal bromide is at least one selected from the group consisting of lithium bromide, sodium bromide, and potassium bromide.

[0013] [4] In a polar solvent as the organic solvent, contacting the thiophanium salt derivative represented by formula (1) with the bromine compound; A method for producing thiophanium chloride bromide according to [1] or [2].

[0014] [5] The polar solvent is a ketone or alcohol solvent. contacting the thiophanium salt derivative represented by formula (1) with the bromine compound; [4] A method for producing thiophanium chloride bromide.

[0015] [6] 0.1 to 40 mL of the organic solvent is used per 1 g of the thiophanium salt derivative represented by the formula (1). [1] to [5]. A method for producing thiophanium chloride bromide according to any one of [1] to [5].

[0016] [7] 0.5 to 10.0 moles of the bromine compound are used per mole of the thiophanium salt derivative represented by the formula (1). [1] to [6], the method for producing thiophanium chloride bromide. [Effects of the Invention]

[0017] According to the method for producing thiophanium chlorobromide of the present invention, it is possible to obtain thiophanium chlorobromide without using water or hydrobromic acid. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention relates to a method for producing a thiophanium chloride bromide (2) represented by formula (2) by contacting a thiophanium salt derivative (1) represented by formula (1) with a bromine compound in an organic solvent. The details of the present invention are described below.

[0019] [Terminology] The terms used in this specification are explained below. The following explanations apply throughout this specification unless otherwise specified. The expression "value A to value B" means value A or more and value B or less unless otherwise specified.

[0020] Alkyl group The alkyl group has, for example, 1 to 20 carbon atoms, preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3, and more preferably 1 or 2. The alkyl group may be linear or branched. A linear alkyl group has 1 or more carbon atoms, and a branched alkyl group has 3 or more carbon atoms.

[0021] alkoxy group The alkoxy group is a group represented by the formula: -O-alkyl group, and the explanation regarding the alkyl group is as above.

[0022] aryl group The aryl group is, for example, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic hydrocarbon ring group. The number of carbon atoms in the aryl group is, for example, 3 to 22, preferably 3 to 20, more preferably 4 to 14, more preferably 6 to 14, and more preferably 6 to 10. The polycyclic group is preferably a fused ring group. Examples of the aryl group include a phenyl group and a naphthyl group. The aryl group is preferably a phenyl group.

[0023] Aralkyl groups An aralkyl group is an alkyl group having one or more aryl groups, and the alkyl group and aryl group are as described above. The number of aryl groups contained in the aralkyl group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1. Examples of the aralkyl group include a benzyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl group, and a naphthylmethyl group. The aryl group contained in the aralkyl group is preferably a phenyl group. The aralkyl group is preferably a benzyl group.

[0024] Halogeno group Examples of the halogeno group include a fluoro group, a chloro group, a bromo group, and an iodo group.

[0025] <Thiophanium salt derivatives> In the present invention, the thiophanium salt derivative (1) is a compound represented by the following formula (1).

[0026] [ka]

[0027] (R 1 and R 2 ) In formula (1), R1 and R 2 are each independently a hydrogen atom, an alkyl group which may have a substituent (i.e., an alkyl group or an alkyl group which has a substituent), an aralkyl group which may have a substituent (i.e., an aralkyl group or an aralkyl group which has a substituent), or an aryl group which may have a substituent (i.e., an aryl group or an aryl group which has a substituent). 1 and R 2 may be the same functional group or different types of functional groups.

[0028] The alkyl group which may have a substituent, the aralkyl group which may have a substituent, and the aryl group which may have a substituent will be described below.

[0029] an alkyl group which may have a substituent; In one embodiment, R 1 and / or R 2 is an alkyl group which may have a substituent. The alkyl group may be either linear or branched. The alkyl group has, for example, 1 to 20 carbon atoms, preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4, more preferably 1 to 3, more preferably 1 or 2, and particularly preferably 1. The alkyl group may have a substituent. Examples of the substituent that the alkyl group may have include an aryl group having 3 to 22 carbon atoms (preferably an aryl group having 3 to 20 carbon atoms, more preferably an aryl group having 4 to 14 carbon atoms, more preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms), an alkoxy group having 1 to 6 carbon atoms (preferably an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, more preferably an alkoxy group having 1 or 2 carbon atoms), a halogeno group, and the like. Examples of the substituent that the alkyl group may have include an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and particularly preferably a phenyl group. When the alkyl group has a substituent, the number of the substituents is preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and particularly preferably 1.

[0030] an aralkyl group which may have a substituent; In one embodiment, R 1 and / or R 2 is an aralkyl group which may have a substituent. The aralkyl group is preferably an aralkyl group having 7 to 11 carbon atoms. Examples of suitable aralkyl groups include a benzyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl group, and a naphthylmethyl group. The aralkyl group may have a substituent. Examples of the substituent that the aralkyl group may have include an alkoxy group having 1 to 6 carbon atoms (preferably an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and more preferably an alkoxy group having 1 or 2 carbon atoms), a carboxyl group, a halogeno group, etc. When the aralkyl group has a substituent, the number of the substituent is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0031] an optionally substituted aryl group; In one embodiment, R 1 and / or R 2 is an aryl group which may have a substituent. Examples of the aryl group include monocyclic, bicyclic, and tricyclic groups. The aryl group is preferably an aryl group having 6 to 14 carbon atoms, and particularly preferably a phenyl group. The aryl group may have a substituent. Examples of the substituent that the aryl group may have include an alkoxy group having 1 to 6 carbon atoms (preferably an alkoxy group having 1 to 4 carbon atoms, more preferably an alkoxy group having 1 to 3 carbon atoms, and more preferably an alkoxy group having 1 or 2 carbon atoms), a carboxyl group, a halogeno group, and the like. When the aryl group has a substituent, the number of the substituent is preferably 1 to 5, more preferably 1 to 3, more preferably 1 or 2, and particularly preferably 1.

[0032] In addition, R 1 and R 2In consideration of the fact that it will ultimately be removed in a deprotection step, it is preferably an aralkyl group which may have a substituent, more preferably an aralkyl group, and particularly preferably a benzyl group.

[0033] (R 3 ) In formula (1), A - is R 3 -C(=O)(-O) - ,X - Or BF4 - is a monovalent anion represented by R 3 R is a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. 3 In the above, the alkyl group which may have a substituent, the aralkyl group which may have a substituent, and the aryl group which may have a substituent have the same meanings as defined above.

[0034] R 3 is preferably a hydrogen atom, a monovalent alkyl group, or an aryl group, in terms of reactivity and ease of conversion to biotin, specifically preferably a hydrogen atom, a methyl group, a trifluoromethyl group, or a phenyl group, more preferably a hydrogen atom, a methyl group, or a trifluoromethyl group, and particularly preferably a trifluoromethyl group.

[0035] X - is a monovalent halogeno group, such as a fluoro group, a chloro group, or an iodo group. The halogeno group is particularly preferably a fluoro group or a chloro group.

[0036] (thiophanium salt derivatives) According to the method for producing a thiophanium salt derivative of the present invention, even when a relatively low-purity thiophanium salt derivative (1) is used as a starting material, thiophanium chloride bromide (2) can be produced with a high conversion. Therefore, from the viewpoint of reducing the number of production steps, it is preferable to use the thiophanium salt derivative (1) as a starting material in its crude form without undergoing a purification step. Specifically, as the thiophanium salt derivative (1) used as a starting material in the method for producing a biotin derivative of the present invention, even one having a purity of 95% or less as measured by liquid chromatography (preferably HPLC purity) can be suitably used.

[0037] However, since the purity of the finally obtained thiophanium chloride bromide (2) is preferably high, it is preferable to use a highly pure thiophanium salt derivative (1) as a starting material. For example, by producing the thiophanium salt derivative (1) by the method shown below, the crude purity of the thiophanium salt derivative (1) can be relatively high. By using such a highly pure thiophanium salt derivative (1) as a starting material, the purity of the thiophanium chloride bromide (2) obtained by the method for producing a biotin derivative according to the present invention can also be made higher.

[0038] (Suitable Thiophanium Salt Derivatives) Considering their usefulness, the thiophanium salt derivative (1) represented by formula (1) is preferably a thiophanium derivative trifluoroacetate (1A) represented by the following formula (1A) and a thiophanium derivative tetrafluoroborate (1B) represented by the following formula (1B). The thiophanium derivative trifluoroacetate (1A) is a thiophanium salt derivative (1) in which R 1 and R 2 are both benzyl groups, and A - is CF3-C(=O)(-O) - (i.e., R 3 is a trifluoromethyl group). Thiophanium derivative tetrafluoroborate (1B) is a compound in which R 1 and R 2are both benzyl groups, and A - is a compound in which BF4- is a compound in which "Bn" represents a benzyl group, "Me" represents a methyl group, and "Et" represents an ethyl group. Hereinafter, similar explanations may be omitted.

[0039] [ka]

[0040] [ka]

[0041] <Bromine compounds> In the present invention, thiophanium salt derivative (1) is contacted with a bromine compound to produce thiophanium chloride bromide (2). As the bromine compound used in the present invention, any bromine compound available as an industrial raw material or reagent can be used without any limitation.

[0042] The bromine compound is hydrogen bromide represented by the formula: HBr, an aqueous solution of hydrogen bromide or an organic solvent solution of hydrogen bromide, R 3The bromine compound is an ammonium salt represented by 4NBr or a bromine compound represented by MBr. M is a metal element. Examples of preferred bromine compounds for use in the present invention include hydrogen bromide, alcoholic aqueous solutions such as hydrogen bromide methanol solution and hydrogen bromide ethanol solution, organic solvent solutions such as hydrogen bromide acetic acid solution, ammonium bromide salt bromides such as ammonium bromide, tetramethylammonium bromide salt, tetraethylammonium bromide salt, and tetrabutylammonium bromide salt, alkali metal bromine compounds such as lithium bromide, sodium bromide, potassium bromide, and cesium bromide, and non-alkali metal bromine compounds such as copper(I) bromide, copper(II) bromide, zinc bromide, and nickel bromide. Among these bromine compounds, hydrogen bromide, hydrogen bromide methanol solution, hydrogen bromide acetic acid solution, ammonium bromide, tetramethylammonium bromide salt, tetrabutylammonium bromide salt, lithium bromide, sodium bromide, and potassium bromide are particularly preferred in terms of cost and salt exchange efficiency. In this way, by using various solutions of hydrobromic acid, ammonium bromide salts, or alkali metal bromide salts, it is possible to produce thiophanium bromide salts inexpensively and efficiently.

[0043] The amount of the bromine compound used in the present invention is not particularly limited, but in order to obtain the desired reaction rate while avoiding the complication of post-treatment operations due to an excessive amount of bromine compound, it is preferably in the range of 0.5 to 10.0 moles, and particularly preferably in the range of 1.0 to 5.0 moles, per mole of the reaction substrate (thiophanium salt derivative (1)) in the present invention. When one type of derivative is selected as the reaction substrate in the present invention, the amount of the one type of derivative; when two or more types of derivatives are selected as the reaction substrate in the present invention, the amount of the two or more types of derivatives is the total amount of the two or more types of derivatives (the same applies throughout this specification).

[0044] <Solvent> The thiophanium salt derivative (1) is contacted with the bromine compound in an organic solvent. It is preferable to use a polar solvent as the organic solvent in the present invention. The "polar solvent" in the present invention is not limited to those that are liquid at room temperature. Even if a solvent is solid at room temperature, such as tert-butyl alcohol, it can be used by using it at a temperature above its melting point or by dissolving it in another solvent. It is particularly preferable to use a solvent that is liquid at room temperature. Examples of such polar solvents include ketones such as acetone, 2-butanone, diethyl ketone, methyl isobutyl ketone, cyclopentanone, and cyclohexanone; nitriles such as acetonitrile and propionitrile; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water; and alcohols such as methanol, ethanol, 2-propanol, and tert-butyl alcohol. Among these, in terms of the solubility of the thiophanium salt derivative and the bromine compound, ketone solvents such as acetone, 2-butanone, diethyl ketone, methyl isobutyl ketone, cyclopentanone, and cyclohexanone, and alcohol solvents such as methanol, ethanol, 2-propanol, and tert-butyl alcohol are preferred. Among these, ketone solvents such as acetone, 2-butanone, and diethyl ketone are more preferred, and acetone is particularly preferred. Among alcohol solvents, methanol, ethanol, and 2-propanol are particularly preferred.

[0045] The organic solvent in the present invention may be used alone or as a mixed solvent of two or more solvents, for example, a water-containing ketone solvent or a water-containing alcohol solution mixed in any ratio.

[0046] In the present invention, the amount of organic solvent used is not particularly limited, but considering the yield during post-reaction treatment and filtration, it is, for example, 0.1 to 40 mL, preferably 0.5 to 20 mL, and more preferably 1 mL to 15 mL per 1 g of the reaction substrate (thiophanium salt derivative (1)) in the present invention. When a mixed solvent is used as the organic solvent, the amount used refers to the total amount of the mixed solvent.

[0047] <Method for producing thiophanium chloride bromide> Thiophanium chloride bromide (2) can be produced by contacting the reaction substrate (thiophanium salt derivative (1)) and a bromine compound in an organic solvent. The components are mixed thoroughly so that they can be in contact with each other. The method of the present invention can be carried out under normal pressure, reduced pressure, or increased pressure. The method of the present invention can be carried out not only in the presence of oxygen, such as air, but also in an inert gas atmosphere, such as nitrogen, argon, or carbon dioxide. The method of mixing the components is not particularly limited. For example, all components may be simultaneously charged into a reactor and mixed. Alternatively, one component may be mixed in advance, and the remaining components may be added sequentially. The components may also be diluted with a solvent and supplied to a reactor or the like. To further reduce by-products and increase the purity of thiophanium chloride bromide (2), it is preferable to mix and stir the thiophanium salt derivative (1) and an organic solvent under an inert gas atmosphere, followed by the addition of a bromine compound and stirring. These components may also be diluted with a solvent, as needed.

[0048] In the present invention, the reaction temperature (the temperature in the reaction system after all components are mixed) is not particularly limited, but can usually be carried out in the range of 0 to 100°C. In particular, considering the reaction rate, salt exchange efficiency, etc., it is particularly preferable to carry out the reaction at 0 to 80°C. The reaction time is also not limited and can be appropriately determined while checking the reaction conversion rate described in the examples below. However, under the above reaction conditions, the reaction time is 1 to 72 hours, and preferably 1 to 24 hours. The reaction time here refers to the time during which the reaction substrate, organic solvent, and bromine compound in the present invention are mixed at the set reaction temperature.

[0049] The reaction solution obtained in the present invention may be subjected to appropriate post-treatment. Specifically, when a ketone solvent is used, thiophanium chlorobromide precipitated from the reaction solution can be obtained by filtration. When an alcohol solvent or a water-containing alcohol solvent is used, thiophanium chlorobromide can be obtained by filtering off the inorganic salt precipitated from the reaction solution and concentrating the solution.

[0050] <Thiophanium chloride bromide> The thiophanium chloride bromide (2) obtained in the present invention is a compound represented by the following formula (2).

[0051] [ka]

[0052] In formula (2), R 1 and R 2 are R in Eq. (1), respectively. 1 and R 2 is synonymous with.

[0053] (Preferred thiophanium chloride bromide) When using the thiofanium derivative trifluoroacetate (1A) or thiofanium derivative tetrafluoroborate (1B), which are suitable starting compounds, as substrates, thiofanium salt bromide (2A) represented by formula (2) can be obtained. Thiofanium salt bromide (2A) is a compound in thiofanium salt bromide (2) where both R 1 and R 2 are benzyl groups.

[0054]

Chemical formula

[0055] From thiofanium derivative bromide salt (2A), according to the method described in Patent Document 1, through a carbon chain elongation reaction with malonic ester and a step of removing the benzyl groups corresponding to R 1 and R 2 by deprotection treatment, biotin can be easily produced.

Examples

[0056] Hereinafter, the present invention will be described in detail with reference to examples. However, these are specific examples, and the present invention is not limited thereto. The purity calculation and purity evaluation in the examples and comparative examples were performed by the following method using ultra-high performance liquid chromatography (UPLC).

[0057] <UPLC measurement conditions> The analysis conditions for UPLC analysis are as follows. Apparatus: Ultra-high performance liquid chromatography (UPLC) Model: 1290 infinity II LC system (manufactured by Agilent Technologies) Detector: Ultraviolet absorption photometer (measurement wavelength: 210 nm) Column: ACQUITY UPLC BEH C18 Column, inner diameter 2.1 mm, length 5 cm (particle size: 1.7 μm) (manufactured by Waters) Column temperature: 40 °C (constant) Sample temperature: 25 °C (constant) Mobile phase A: 0.1% formic acid in water Mobile phase B: 0.1% formic acid in acetonitrile Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1 below to control the concentration gradient.

[0058] [Table 1]

[0059] Under the above UPLC measurement conditions, thiophanium chloride bromide (2A) (R 1 , R 2 =Bn) peaks are observed at approximately 4.0 minutes.

[0060] <How to calculate purity> The purity of thiophanium chlorobromide (2A) is a value calculated as a percentage of the peak area value of thiophanium chlorobromide (2A) to the total value of the peak area values ​​of the other peaks.

[0061] Example 1 As shown in the reaction formula below, thiophanium chloride bromide (2A) represented by formula (2A) was synthesized from thiophanium derivative trifluoroacetate (1A) represented by formula (1A). Note that "Bn" in the formula represents a benzyl group.

[0062] [ka]

[0063] A crude thiophanium derivative trifluoroacetate salt (1A) (weight 49.92 g, content 59.1 mmol, purity 92.2%) was weighed into a 300 mL four-neck flask equipped with a stirring blade and dissolved in acetone (115 mL). An acetone solution (115 mL) of lithium bromide (2 eq, 10.3 g) was added to the mixture, resulting in the precipitation of a solid. After stirring for 3 hours at 25°C, the precipitated thiophanium chloride bromide (2A) was recovered as a white solid (24.4 g, purity 99.8%) using a Kiriyama funnel with filter paper.

[0064] Example 2 As shown in the reaction formula below, thiophanium chloride bromide (2A) represented by formula (2A) was synthesized from thiophanium derivative tetrafluoroborate (1B) represented by formula (1B). Note that "Bn" in the formula represents a benzyl group.

[0065] [ka]

[0066] Thiophanium derivative tetrafluoroborate (1B) (3.00 g, purity 96.8%) was weighed into a 100 mL four-neck flask equipped with a stirring blade and dissolved in methanol (12 mL). To this was added 3 mL of an aqueous solution of potassium bromide (1.1 eq, 0.87 g), resulting in the precipitation of a solid. After stirring at 25°C for 1 hour, the precipitated inorganic salt was removed using a Kiriyama funnel with filter paper. The filtrate was concentrated to recover thiophanium chloride bromide (2A) as a white solid (2.99 g, purity 98.8%).

Claims

1. In an organic solvent, The following formula (1): 【Chemistry 1】 [In formula (1), R １ and R ２ each independently represents a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent, A － is R ３ -C(=O)(-O) － , X － or BF ４ － and R ３ represents a hydrogen atom or an alkyl group which may have a substituent, X － is a fluoro group, a chloro group, or an iodo group. a thiophanium salt derivative represented by the formula: contacting the mixture with a bromine compound, The following formula (2): 【Chemistry 2】 [In formula (2), R １ and R ２ has the same meaning as in formula (1). obtaining thiophanium chloride bromide represented by the formula: Method for producing thiophanium chloride bromide.

2. The bromine compound is an alkali metal bromide. A method for producing thiophanium chloride bromide according to claim 1.

3. The alkali metal bromide is at least one selected from the group consisting of lithium bromide, sodium bromide, and potassium bromide. The method for producing thiophanium chloride bromide according to claim 2.

4. In a polar solvent as the organic solvent, contacting the thiophanium salt derivative represented by formula (1) with the bromine compound; A method for producing thiophanium chloride bromide according to claim 1 or 2.

5. The polar solvent is a ketone or alcohol solvent. The method for producing thiophanium chloride bromide according to claim 4.

6. 0.1 to 40 mL of the organic solvent is used per 1 g of the thiophanium salt derivative represented by the formula (1). A method for producing thiophanium chloride bromide according to claim 1 or 2.

7. 0.5 to 10.0 moles of the bromine compound are used per mole of the thiophanium salt derivative represented by the formula (1). A method for producing thiophanium chloride bromide according to claim 1 or 2.

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