Method for producing benzodithiol compound

Abstract

The present invention pertains to a method for producing a benzodithiol compound, the method involving: using a flow reaction to react a quinone compound (Q1) and a salt of a dithiocarboxylic acid compound or a salt of an ethene-α, α-dithiol compound; and oxidizing the obtained reaction product to form a benzodithiol ring structure.

Description

Method for producing benzodithiol compounds

[0001] This invention relates to a method for producing benzodithiol compounds.

[0002] Benzodithiol compounds are known as compounds that form the basic framework of organic materials that make up ultraviolet absorbers, display materials, etc. (for example, Patent Documents 1-4). Regarding the synthesis of benzodithiol compounds, an active methylene compound and carbon disulfide (CS) ２ A method is known in which a reaction is carried out with a quinone compound. For example, Patent Document 1 describes a method in which malononitrile is used as the active methylene compound, and this malononitrile is reacted with carbon disulfide in the presence of potassium hydroxide (which functions as an activator for the active methylene compound and is a source of cations in the salt of the reaction product), and the resulting dipotassium = 2,2-dicyanoethene-1,1-dithiolate is reacted with p-benzoquinone to obtain the target benzomonoditiol compound (Paragraph

[0161] of Patent Document 1). Furthermore, Patent Document 2 describes a method in which diethyl malonate, ethyl cyanoethyl, bis(4-tert-butyl-diphenylsilanioxybutyl) ester malonate, etc., are used as the active methylene compound, and this active methylene compound is reacted with carbon disulfide in the presence of sodium hydroxide, and the resulting disodium-ethene-α,α-dithiolate compound is reacted with p-benzoquinone to obtain the target benzomonoditiol compound or benzobisdithiol compound (paragraphs

[0032] to

[0043] of Patent Document 2). In the above reaction, a portion of the quinone compound (p-benzoquinone in the reactions described in Patent Documents 1 and 2) reacts with the salt of the ethene-α,α-dithiol compound, and the remainder functions as an oxidizing agent for forming a benzodithiol ring structure from the reaction product of the salt of the ethene-α,α-dithiol compound and the quinone compound.

[0003] Japanese Patent Publication No. 2010-254949, Japanese Patent Publication No. 2008-297228, Japanese Patent Publication No. 2016-81035, Japanese Patent Publication No. 2009-263616

[0004] As described above, the method for producing benzodithiol compounds is publicly known, but the yield of the resulting benzodithiol compounds is about 50% or less (for example,

[0032] to

[0043] of Patent Document 2). Furthermore, it has become clear that even when the present inventors proceed with optimizing the reaction conditions for these reactions, it is difficult to improve the yield of the resulting benzodithiol compounds.

[0005] The object of this invention is to provide a method for producing benzodithiol compounds that enables the highly efficient production of benzodithiol compounds.

[0006] In view of the above problems, the present inventors have conducted extensive research and have found that, in a method for producing a benzodithiol compound comprising reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound, by applying a flow reaction to this reaction, the target benzodithiol compound can be obtained with a high production efficiency that could not be achieved with a batch reaction. The present invention has been completed based on this finding. The above problems of the present invention are solved by the following means: [1] A method for producing a benzodithiol compound comprising reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1) by a flow reaction, and oxidizing the resulting reactant to form a benzodithiol ring structure. [2] The method for producing a benzodithiol compound according to [1], wherein unreacted quinone compound (Q1) acts on the reactant to produce the oxidation treatment. [3] A method for producing a benzodithiol compound according to [1], wherein the oxidation treatment is produced by mixing the above reactants with an oxidizing agent. [4] A method for producing a benzodithiol compound according to [3], wherein the oxidizing agent contains a quinone compound. [5] A method for producing a benzodithiol compound according to [4], wherein the oxidizing agent contains a benzoquinone. [6] A method for producing a benzodithiol compound according to any one of [1] to [5], comprising obtaining a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound using carbon disulfide as a reaction raw material. [7] A method for producing a benzodithiol compound according to [6], comprising obtaining a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound by reacting an active methylene compound with carbon disulfide in the presence of a basic compound. [8] A method for producing a benzodithiol compound according to [7], wherein the reaction to obtain a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound is a flow reaction.[9] A method for producing a benzodithiol compound according to any one of [1] to [8], wherein in a flow reaction between a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound and a quinone compound (Q1), the liquid containing the salt of the dithiocarboxylic acid compound or the salt of the ethene-α,α-dithiol compound and the liquid containing the quinone compound (Q1) are combined so that the linear velocity of the combined liquid is 0.80 m / sec or more.

[10] A method for producing a benzodithiol compound according to any one of [1] to [9], wherein the flow rate at the reaction outlet of the flow reaction between a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound and a quinone compound (Q1) is 5 mL / min or more.

[0007] In this invention, a numerical range expressed using "~" means a range that includes the numbers written before and after "~" as the lower and upper limits. In this invention, when we refer to "compound X," it means not only X itself, but also structures in which X has substituents to the extent that it does not impair the effects of this invention. For example, "quinone compound" includes not only quinone itself, but also compounds in which quinone has substituents. Similarly, "benzoquinone compound" includes not only benzoquinone itself, but also compounds in which benzoquinone has substituents.

[0008] The method for producing benzodithiol compounds according to the present invention allows for the highly efficient production of benzodithiol compounds.

[0009] Figure 1 is an explanatory diagram showing one embodiment of the manufacturing method of the present invention. Figure 2 is an explanatory diagram showing another embodiment of the manufacturing method of the present invention. Figure 3 is a schematic diagram of one form of the flow reaction system used in the example. Figure 4 is a schematic diagram of another form of the flow reaction system used in the example. Figure 5 is a schematic diagram of yet another form of the flow reaction system used in the example.

[0010] [Method for Producing Benzodiol Compounds] The method for producing benzodiol compounds of the present invention (hereinafter referred to as "the method of production of the present invention") includes reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1) by a flow reaction. By subjecting these reaction products to an oxidation treatment, the desired benzodithiol compound can be obtained. In the present invention, "reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1) by a flow reaction" means reacting one or both of the "salt of a dithiocarboxylic acid compound" and the "salt of an ethene-α,α-dithiol compound" with a quinone compound (Q1) by a flow reaction.

[0011] In the present invention, "benzodithiol compound" means a compound having a benzodithiol ring skeleton (a structure in which an unsaturated five-membered ring (dithiol ring) in which two of the ring constituent atoms are sulfur atoms is fused with a benzene ring). The benzodithiol ring skeleton may also be a benzomonoditiol ring skeleton (a structure in which one dithiol ring is fused with one benzene ring) or a benzobisdithiol ring skeleton (a structure in which two dithiol rings are fused with one benzene ring). In the present invention, as described above, "benzodithiol compounds" are obtained using a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound as a reaction raw material; therefore, the benzomonoditiol ring skeleton is a 1,3-benzodithiol ring skeleton, and the benzobisdithiol ring skeleton is a 1,3,5,7-benzobisdithiol ring skeleton.

[0012] An example of the manufacturing method of the present invention, in which p-benzoquinone is used as the quinone compound (Q1) as the reaction raw material, and a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound is used as the reaction raw material to react with p-benzoquinone, will be described with reference to Figure 1. In the example shown in Figure 1, the salts of the dithiocarboxylic acid compound and the ethene-α,α-dithiol compound, which are the reaction raw materials, are also produced by a flow reaction. Note that in Figure 1, the salt of the ethene-α,α-dithiol compound is simply referred to as "salt of an ethene-dithiol compound".

[0013] In the flow reaction shown in Figure 1, first, 1,2-n-dibutylpyrazolidine-3,5-dione (an active methylene compound, a methylene group sandwiched between two electron-withdrawing groups (-CH)) is formed. ２ Compounds having -) and carbon disulfide (CS ２ A raw material solution, which is a mixture of the above, is introduced into one channel, and a solution of diazabicycloundecene (DBU), a basic compound (activator), is introduced into another channel, and these are combined at the confluence M1. In this combined liquid, the activated methylene compound is activated by DBU and reacts with carbon disulfide, and DBU acts as a countercation to produce a salt of the dithiocarboxylic acid compound. In the salt of the dithiocarboxylic acid compound shown in Figure 1, two DBU cations may be bonded as countercations, as shown on the right. In this case, it becomes a salt of the ethene-α,α-dithiol compound instead of a salt of the dithiocarboxylic acid compound. That is, in the present invention, when an activated methylene compound and carbon disulfide are reacted in the presence of a basic compound, both a salt of the dithiocarboxylic acid compound and a salt of the ethene-α,α-dithiol compound can be produced as reactants. Next, the solution containing a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound is combined with the solution of p-benzoquinone as a reaction starter at confluence M2 and reacts. Further downstream, the solution of p-benzoquinone as an oxidizing agent is combined, and the p-benzoquinone as an oxidizing agent acts on the product (reactant) of the above reaction, causing the reaction to cyclize and produce the target benzodithiol compound. Thus, in the example shown in Figure 1, the p-benzoquinone as a reaction starter (corresponding to "quinone compound (Q1)" in the present invention) combined at confluence M2 reacts with a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound, and the p-benzoquinone as an oxidizing agent combined at confluence M3 acts on this reaction product, causing the reaction to cyclize and produce the target benzodithiol compound (benzomonoditiol compound).

[0014] In the present invention, when reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1) as a reaction material by a flow reaction, the molar amount of the quinone compound (Q1) relative to the total molar amount of the salt of the dithiocarboxylic acid compound and the salt of the ethene-α,α-dithiol compound can be appropriately determined depending on whether the target benzodithiol compound is a mono or bis compound, and also considering the chemical structure of the raw materials, the reaction temperature, the stoichiometric ratio, etc. If it is a mono compound, the reaction temperature can be, for example, -100 to 40°C, preferably -100 to 35°C, more preferably -100 to 20°C, even more preferably -100 to 0°C, even more preferably -70 to -10°C, and even more preferably -50 to -20°C, depending on the type of solvent. In this case, the molar amount of the quinone compound (Q1) as a reaction raw material can be 0.9 to 1.2, preferably 0.95 to 1.05, relative to a total molar amount of 1.0 of the salt of the dithiocarboxylic acid compound and the salt of the ethene-α,α-dithiol compound. If it is a bis-isomer, the reaction temperature can be set to 0°C or higher and below the boiling point of the solvent used, taking into consideration the chemical structure of the raw materials, the type of solvent, etc. Examples of reaction temperatures in the production of the bis-isomer can be shown as ranges, for example, 0 to 60°C, 10 to 60°C, 20 to 60°C, or 30 to 50°C. In this case, the molar amount of the quinone compound (Q1) as a reaction raw material can be 1.5 or higher, preferably 2.0 to 3.0, relative to a total molar amount of 1.0 of the salt of the dithiocarboxylic acid compound and the salt of the ethene-α,α-dithiol compound. The reaction time for the flow reaction between a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound and a quinone compound (Q1) as a reaction material (the flow time of the combined liquid of the salt of the dithiocarboxylic acid compound or the salt of an ethene-α,α-dithiol compound and the quinone compound (Q1) as a reaction material) can be, for example, 0.1 to 300 seconds, and preferably 5 to 60 seconds.

[0015] In the present invention, the temperature at which the reaction product of a flow reaction between a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound and a quinone compound (Q1) as a reaction raw material is oxidized (ring-closing reaction temperature) is preferably -100 to 30°C, and more preferably -60 to 10°C. The oxidation treatment time can be 0.1 to 300 seconds, and preferably 10 to 180 seconds. This oxidation treatment is preferably carried out by a flow reaction.

[0016] The manufacturing method of the present invention may include a step of obtaining a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound using carbon disulfide as a reaction raw material. A specific example is shown above with reference to Figure 1, but this reaction is not limited to a flow reaction and may be carried out in a batch reaction. When the manufacturing method of the present invention includes a reaction of an activated methylene compound and carbon disulfide in the presence of a basic compound to obtain a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound, the molar ratio of the two can be 0.7 to 1.3 molar amounts of carbon disulfide per 1.0 molar amount of activated methylene compound, and more preferably 0.8 to 1.3 molar amounts. This reaction is carried out in the presence of a basic compound (activator). The molar amount of the basic compound (activator) used in this reaction can be 0.8 to 5.0 molar amounts of activated methylene compound per 1.0 molar amount, and more preferably 1.0 to 3.0 molar amounts. The temperature of this reaction is preferably -20 to 85°C, and more preferably -10 to 75°C. Furthermore, the reaction time can be 30 seconds to 3 hours, and preferably 60 seconds to 2 hours.

[0017] Figure 2 illustrates the production method of the present invention, focusing on a salt of an ethene-α,α-dithiol compound as another reaction material that reacts with the quinone compound (Q1) (2-tert-butyl-1,4-benzoquinone). In the example shown in Figure 2, the salt of the ethene-α,α-dithiol compound, which is the reaction material, is also produced by a flow reaction. As mentioned above, in the production of the salt of the ethene-α,α-dithiol compound by this flow reaction, in addition to the "salt of the ethene-α,α-dithiol compound," a "salt of a dithiocarboxylic acid compound" with the corresponding chemical structure can also be produced. However, Figure 2 does not consider the production of the "salt of the dithiocarboxylic acid compound." The reaction of the active methylene compound and carbon disulfide in the presence of a basic compound, and the combinations of the chemical structures of the "salt of the dithiocarboxylic acid compound" and the "salt of the ethene-α,α-dithiol compound" that can be produced will be explained later with reference to specific examples. Note that in Figure 2, salts of ethene-α,α-dithiol compounds are simply referred to as "salts of ethenedithiol compounds."

[0018] In the flow reaction shown in Figure 2, first, a malononitrile is used as the active methylene compound, and carbon disulfide (CS) ２A raw material solution, which is a mixture of the above, is introduced into one channel, and a solution of potassium hydroxide (KOH aq.), a basic compound (activator), is introduced into another channel, and these are combined at the confluence M1. In this combined liquid, the activated methylene compound is activated by KOH and reacts with carbon disulfide, and the K ion acts as a countercation to produce a salt of the ethene-α,α-dithiol compound, as shown in the upper left of Figure 2. Next, the solution containing the salt of the ethene-α,α-dithiol compound is combined with the solution of 2-tert-butyl-1,4-benzoquinone, the reaction raw material, at the confluence M2 and reacts. At the confluence M3, p-benzoquinone, which is added separately as an oxidizing agent, acts on this reactant, causing the reaction product to cyclize and produce the desired benzodithiol compound. The solution of 2-tert-butyl-1,4-benzoquinone and / or the solution of p-benzoquinone may contain an acidic compound (a neutralizing agent for basic compounds, e.g., acetic acid) to neutralize the KOH to the desired level. It is speculated that if the above solution contains an acidic compound, then some or all of the salt of the ethene-α,α-dithiol compound (which may actually also include a salt of a dithiocarboxylic acid compound) may react with the quinone compound (Q1) in compound form rather than as a salt, due to the action of this acidic compound. That is, in the present invention, the forms in which "a salt of a dithiocarboxylic acid compound and a quinone compound (Q1)" are reacted, and the forms in which "a salt of an ethene-α,α-dithiol compound and a quinone compound (Q1)" are reacted, include a form in which the salt of the dithiocarboxylic acid compound or the salt of the ethene-α,α-dithiol compound reacts with the quinone compound (Q1) in salt form, as well as a form in which the salt is no longer in salt form due to the action of an acidic compound and then reacts with (-S － This also includes the form in which it reacts with a quinone compound (Q1) after being converted to -SH.

[0019] In the examples shown in Figures 1 and 2, the salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound is first combined with the quinone compound (Q1) as a reaction material, and then downstream, the quinone compound that functions as an oxidizing agent is added. In other words, the addition of the quinone compound as a reaction material and the addition of the oxidizing agent are separated. However, it is not always necessary to separate the addition of the quinone compound (Q1) as a reaction material and the addition of the oxidizing agent. For example, the oxidizing agent may be added at the same time as the addition of the quinone compound (Q1) as a reaction material, or the quinone compound (Q1) and the oxidizing agent may be mixed beforehand and then combined with the salt of the dithiocarboxylic acid compound or the salt of an ethene-α,α-dithiol compound. Even in this case, the quinone compound can react sufficiently with the salt of the dithiocarboxylic acid compound or the salt of the ethene-α,α-dithiol compound, and the oxidizing agent can act on this reactant to form a benzodithiol ring structure. In this case, the same quinone compound (Q1) used as the reaction raw material can be used as the oxidizing agent. That is, an excess amount of quinone compound (Q1) can be used with a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound, allowing the unreacted quinone compound (Q1) to function as an oxidizing agent. In this invention, when simply referred to as "quinone compound (Q1)," unless otherwise specified, it means the quinone compound used as the reaction raw material and does not mean the quinone compound that acts as an oxidizing agent.

[0020] In particular, from the viewpoint of improving yield, the production method of the present invention is preferable in which a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound is first combined with a quinone compound (Q1) as a reaction raw material to be reacted with, and then a quinone compound that functions as an oxidizing agent is added downstream. The quinone compound (Q1) as a raw material may be added once, or it may be added sequentially to the downstream side in two or more steps. Similarly, the quinone compound that functions as an oxidizing agent may be added once, or it may be added sequentially to the downstream side in two or more steps.

[0021] Next, the raw materials, reagents, etc., used in the manufacturing method of the present invention will be described.

[0022] <Salts of dithiocarboxylic acid compounds> In the present invention, salts of dithiocarboxylic acid compounds that can be used as raw materials are dithiocarboxylic acid compounds (R １ -C(=S)-SH,R １ As long as it is a salt of a substituent, its chemical structure is not particularly limited. For example, those obtained using carbon disulfide as a reaction raw material are preferred, and those obtained by reacting an activated methylene compound with carbon disulfide in the presence of a basic compound (activator) are more preferred. Examples of countercations constituting the salt of a dithiocarboxylic acid compound include alkali metal ions and ammonium cations. Preferred specific examples of dithiocarboxylic acid compound salts that can be used in the present invention are shown below, but the present invention is not limited to these specific examples other than those specified in the present invention. In the following structural formula, R ｃ The symbols indicate the countercations that make up the salt: Me represents methyl, Et represents ethyl, Ph represents phenyl, and Bu represents butyl.

[0023]

[0024] When preparing a solution containing a salt of a dithiocarboxylic acid compound, the solvent used can be appropriately selected within a range that does not impair the effects of the present invention. Depending on the type of salt of the dithiocarboxylic acid compound used, for example, nitrile solvents, amide solvents, ester solvents, sulfoxide solvents, ether solvents, halogenated hydrocarbon solvents, ketone solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, carbonate ester solvents, sulfone solvents, urea solvents, alcohol solvents, water, etc., can be used as appropriate. Examples of nitrile solvents include acetonitrile and propionitrile. Examples of amide solvents include N,N-dimethylformamide and N,N-dimethylacetamide. Examples of ester solvents include ethyl acetate, n-propyl acetate, and n-butyl acetate. Examples of sulfoxide solvents include dimethyl sulfoxide. Examples of ether-based solvents include diethyl ether, dibutyl ether, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and 1,4-dioxane-1,2-dimethoxyethane. Examples of halogenated hydrocarbon solvents include dichloromethane, chloroform, carbon tetrachloride, and dichlorobenzene. Examples of ketone-based solvents include acetone, 2-butanone, and methyl isobutyl ketone. Examples of aliphatic hydrocarbon solvents include hexane, heptane, octane, and decane. Examples of aromatic hydrocarbon solvents include benzene, toluene, xylene, dichlorobenzene, benzotrifluoride, and nitrobenzene. Examples of carbonate ester solvents include ethylene carbonate and propylene carbonate. Examples of sulfone-based solvents include 3-methylsulfolane and sulfolane. Examples of urea-based solvents include 1,3-dimethyl-2-imidazolidinone, N,N'-dimethylpropyleneurea, and N,N,N',N'-tetramethylurea.Examples of the alcohol-based solvents include methanol, ethanol, isopropyl alcohol, normal propyl alcohol, normal butyl alcohol, t-butyl alcohol and the like.

[0025] <Ethene-α,α-dithiol compound salt> In the present invention, the salt of the ethene-α,α-dithiol compound that can be used as a raw material is not particularly limited in its chemical structure as long as it is a salt of an ethene-α,α-dithiol compound (C(−R ２ ), ２ =C(−SH) ２ , R ２ : substituent, two Rs ２ may be linked to each other to form a ring). The salt of the ethene-α,α-dithiol compound can be obtained, for example, using carbon disulfide as a reaction raw material, and is preferably obtained by reacting an active methylene compound and carbon disulfide in the presence of a basic compound (activator). Examples of the counter cation constituting the salt of the ethene-α,α-dithiol compound include an alkali metal ion, an ammonium ion and the like. Regarding the salt of the ethene-α,α-dithiol compound that can be used in the present invention, preferred specific examples are shown below, but the present invention is not limited to these specific examples other than as defined in the present invention.

[0026]

[0027] When preparing a solution containing a salt of an ethene-α,α-dithiol compound, the solvent used can be appropriately selected within a range that does not impair the effects of the present invention. Depending on the type of ethene-α,α-dithiol compound salt used, for example, the above-mentioned nitrile solvents, amide solvents, ester solvents, sulfoxide solvents, ether solvents, halogenated hydrocarbon solvents, ketone solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, carbonate ester solvents, sulfone solvents, urea solvents, alcohol solvents, water, etc., can be used as appropriate. As described above, in the present invention, a salt of an ethene-α,α-dithiol compound may also be produced in the reaction that produces a salt of a dithiocarboxylic acid compound (in other words, a salt of a dithiocarboxylic acid compound may also be produced in the reaction that produces a salt of an ethene-α,α-dithiol compound). Therefore, the solvent used to prepare a solution containing a salt of a dithiocarboxylic acid compound and the solvent used to prepare a solution containing a salt of an ethene-α,α-dithiol compound are usually the same.

[0028] <Quinone compound (Q1) as reaction raw material> In the production method of the present invention, the quinone compound (Q1) used as a reaction raw material is not particularly limited as long as it is a quinone compound. Examples include benzoquinone compounds, naphthoquinone compounds, anthraquinone compounds, etc., with benzoquinone compounds being preferred. Furthermore, the above quinone compound (Q1) may be either the para or ortho isomer, with the para isomer being preferred. The above quinone compound (Q1) is more preferably a p-benzoquinone compound.

[0029] When preparing a solution containing a quinone compound as a reaction raw material, the solvent used can be appropriately selected within a range that does not impair the effects of the present invention. Depending on the type of quinone compound (Q1) used as a reaction raw material, for example, the above-mentioned nitrile solvents, amide solvents, ester solvents, sulfoxide solvents, ether solvents, halogenated hydrocarbon solvents, ketone solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, carbonate ester solvents, sulfone solvents, urea solvents, alcohol solvents, water, etc., can be used as appropriate.

[0030] <Oxidizing Agent> The production method of the present invention involves reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1) as a reaction raw material by a flow reaction, and oxidizing the resulting reactant to form a benzodithiol ring structure. This oxidation treatment can be carried out by reacting the reactant with an oxidizing agent. Examples of oxidizing agents include quinone compounds, hypochlorites, hydrogen peroxide, hypervalent iodine compounds, periodates, cerium ammonium nitrate, potassium peroxymonosulfate, and metachloroperbenzoic acid, with quinone compounds being preferred.

[0031] The quinone compound used as an oxidizing agent may be the same type of quinone compound as the quinone compound (Q1) used as a reaction raw material as described above, or it may be a different type of quinone compound. When the quinone compound used as an oxidizing agent is the same type of quinone compound as the quinone compound (Q1) used as a reaction raw material as described above, and the quinone compound used as a reaction raw material and the quinone compound used as an oxidizing agent are added to the reaction system together without being separated, the unreacted portion of the added quinone compound will function as an oxidizing agent. In this case, the amount of quinone compound added to the reaction system is usually in excess of the stoichiometric ratio (for example, twice the equivalent amount) relative to the total molar amount of the dithiocarboxylic acid salt or ethene-α,α-dithiol salt, which are other raw materials to react with it. That is, the excess amount of quinone compound functions as an oxidizing agent.

[0032] In the manufacturing method of the present invention, as shown in Figures 1 and 2, a quinone compound (Q1) as a reaction raw material (p-benzoquinone in the example in Figure 1, and 2-tert-butyl-1,4 in the example in Figure 2) and an oxidizing agent (p-benzoquinone in both the examples in Figures 1 and 2) can be added to the reaction system in this order. That is, after thoroughly reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with the quinone compound as a reaction raw material, the oxidizing agent can be added and the reaction carried out. In this case, the quinone compound (Q1) used as a reaction raw material and the oxidizing agent may be the same type of quinone compound as in the example in Figure 1, but it is also possible to use different types of quinone compounds as in the example in Figure 2. For example, it is possible to use an expensive quinone compound with substituents as the quinone compound (Q1) used as a reaction raw material, and an inexpensive unsubstituted benzoquinone as the oxidizing agent, thereby improving economic efficiency. That is, a preferred embodiment of the present invention can be specified as follows.

[0033] A method for producing a benzodithiol compound, comprising reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1) by a flow reaction, and then mixing the resulting reactant with an oxidizing agent to oxidize the reactant and form a benzodithiol ring structure. In this production method, the oxidizing agent preferably contains a quinone compound, and is also preferably a quinone compound. The oxidizing agent may contain a quinone compound of the same type as quinone compound (Q1) (having the same chemical structure as quinone compound (Q1)), or may be a quinone compound of the same type as quinone compound (Q1). The oxidizing agent may contain a quinone compound (Q2) (a quinone compound with a different chemical structure from quinone compound (Q1)), or may be quinone compound (Q2). From the viewpoint of oxidation treatment efficiency and economy, the oxidizing agent preferably contains a benzoquinone compound, more preferably contains benzoquinone (meaning unsubstituted benzoquinone, preferably p- or o-benzoquinone, more preferably p-benzoquinone), and more preferably is benzoquinone. The above oxidizing agent more preferably contains p-benzoquinone, and even more preferably is p-benzoquinone.

[0034] When preparing a solution containing an oxidizing agent, the solvent to be used can be appropriately selected as long as it does not impair the effects of the present invention. Depending on the type of the oxidizing agent, for example, the above-mentioned nitrile solvents, amide solvents, ester solvents, sulfoxide solvents, ether solvents, halogenated hydrocarbon solvents, ketone solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, carbonate ester solvents, sulfone solvents, urea solvents, alcohol solvents, water, etc. can be appropriately used.

[0035] <Active methylene compound> As described above, the production method of the present invention can include obtaining a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound by reacting an active methylene compound and carbon disulfide in the presence of a basic compound. As described above, the active methylene compound has a methylene group sandwiched between two electron-withdrawing groups and is a highly reactive compound. Preferred specific examples of the active methylene compound, and combinations of salts of dithiocarboxylic acid compounds and salts of ethene-α,α-dithiol compounds that can be formed by reacting each specific example with carbon disulfide in the presence of a basic compound are shown below.

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042] <Basic Compounds (Activators for Active Methylene Compounds, Counter-Cation Sources)> As described above, the production method of the present invention involves the coexistence of a basic compound with the active methylene compound during the reaction with carbon disulfide. In the present invention, "basic compound" means a compound that can abstract highly acidic protons from the active methylene compound and produce an anion of the active methylene compound. The basic compound is not particularly limited as long as it performs the desired function. Examples of basic compounds include 1,8-diazabicyclo[5.4.0]-7-undecene, 1,5-diazabicyclo[4.3.0]-5-nonene, trialkylamines, pyridines, t-butoxy alkali metal salts, metal hydrides, alkali metal carbonates, alkali metal bicarbonates, lithium diisopropylamide, lithium bis(trimethylsilyl)amide alkali metal salts, alkyllithium compounds, 1,8-bis(dimethylamino)naphthalene, alkali metal hydroxides, alkaline earth metal hydrides, and the like.

[0043] The reaction solvent for the activated methylene compound and carbon disulfide can be appropriately selected within a range that does not impair the effects of the present invention. For example, the above-mentioned nitrile solvents, amide solvents, ester solvents, sulfoxide solvents, ether solvents, halogenated hydrocarbon solvents, ketone solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, carbonate ester solvents, sulfone solvents, urea solvents, alcohol solvents, water, etc., can be used as appropriate.

[0044] <Flow Reaction> In the production method of the present invention, the reaction system for the flow reaction in which a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound reacts with a quinone compound (Q1) can be appropriately selected according to the purpose, including the size, shape, material, and flow rate of the flow path, confluence, etc. Furthermore, the concentration of each solution, solvent, etc., can be appropriately adjusted to a level that allows the flow reaction to be carried out. The act of carrying out a chemical reaction in a flow reaction system is well known, and a flow reaction system applicable to the production method of the present invention can be constructed by appropriately referring to existing flow reaction systems. This is also true when obtaining a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound in a flow reaction system.

[0045] In the production method of the present invention, in a flow reaction in which a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound is reacted with a quinone compound (Q1), it is preferable to combine the liquid containing the salt of the dithiocarboxylic acid compound or the salt of the ethene-α,α-dithiol compound and the liquid containing the quinone compound (Q1) such that the linear velocity of the combined liquid is 0.80 m / sec (seconds) or higher. By increasing the linear velocity in this way, blockage of the flow path over time can be effectively prevented, and the flow reaction can be carried out stably for a long time. In other words, in the present invention, by carrying out the reaction at a linear velocity faster than that of a typical flow reaction, it is possible to carry out the flow reaction stably for a long time. The linear velocity of the combined liquid is preferably 0.80 to 50.00 m / sec, more preferably 1.00 to 40.00 m / sec, even more preferably 1.10 to 30.00 m / sec, even more preferably 1.20 to 20.00 m / sec, even more preferably 1.30 to 15.00 m / sec, and also preferably 1.40 to 10.00 m / sec.

[0046] In a flow reaction involving the reaction of a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1), the flow rate at the outlet of this flow reaction can be set to, for example, 5 mL / min or more. That is, when a solution containing a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound and a solution containing a quinone compound (Q1) are flowed through separate channels and then merged for the reaction, it is preferable to increase the flow rate of each channel above a certain level at the point of merging. This tends to improve the mixing efficiency of the raw material solutions at the merging point, leading to an improvement in reaction efficiency.

[0047] The present invention will be described in more detail based on examples, but the present invention is not limited to these examples except as provided herein.

[0048] [Example 1] A benzodithiol compound with the following structure ("1,2-di(n-butyl)-4-(4,7-dihydroxy-1,3-benzodithiol-2-ylidene)pyrazolidine-3,5-dione") was prepared using the flow reaction system shown in Figure 4. Note that the flow reaction system shown in the figure is a schematic diagram to facilitate understanding of the invention and does not directly represent the actual size, length, size relationships, etc.

[0049]

[0050] The flow reaction system shown in Figure 4, used in Example 1, will be described in detail in the <Flow Reaction> section below, but it involves reacting an activated methylene compound with carbon disulfide in the presence of a basic compound to produce a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound (either one or both of the dithiocarboxylic acid compound salt and the ethene-α,α-dithiol compound salt), and then reacting these salts with a quinone compound (Q1). Furthermore, the quinone compound (Q1) is p-benzoquinone, and the p-benzoquinone is supplied to the reaction system all at once, with the p-benzoquinone serving as both the reaction raw material and the oxidizing agent. In the flow reaction system shown in Figure 4, the details of the flow paths indicated by each symbol are as follows.

[0051] Stream 1b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 2b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 3b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Confluence 4b: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 5b: PTFE tube with an outer diameter of 1 / 8 inch, an inner diameter of 1.58 mm, and a length of 8 m Confluence 6b: SUS316 T-shaped union tee (inner diameter 0.25 mm) Stream 7b: PTFE tube with an outer diameter of 1 / 8 inch, an inner diameter of 1.58 mm, and a length of 2 m

[0052] Flow paths 1b, 2b, junction 4b, and 5b were placed in a constant temperature bath at a set temperature of 60°C, while flow paths 3b, junction 6b, and 7b were placed in a constant temperature bath at a set temperature of -30°C.

[0053] <Flow Reaction> 100 mL of a solution was prepared by mixing 1,2-n-dibutylpyrazolidine-3,5-dione and carbon disulfide in N,N-dimethylformamide to concentrations of 0.10 M and 0.13 M, respectively, and this was designated as starting material solution A-1. 50 mL of a solution was prepared by dissolving diazabicycloundecene (DBU: 1,8-Diazabicyclo[5.4.0]-7-undecene) in N,N-dimethylformamide to a concentration of 0.60 M, and this was designated as activator solution B-1. 100 mL of a solution was prepared by dissolving p-benzoquinone in N,N-dimethylformamide to a concentration of 0.21 M, and this was designated as starting material / oxidizing agent solution C-1.

[0054] Raw material solution A-1 was delivered into channel 1b from inlet 1B at a flow rate of 2.00 mL / min, activator solution B-1 was delivered into channel 2b from inlet 2B at a flow rate of 0.84 mL / min, and raw material / oxidant solution C-1 was delivered into channel 3b from inlet 3B at a flow rate of 2.24 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. - 1,2-n-dibutylpyrazolidine-3,5-dione (1.00 equivalent, 0.40 mmol) - Carbon disulfide (1.25 equivalent, 0.50 mmol) - DBU (1.25 equivalent, 0.50 mmol) - p-benzoquinone (2.30 equivalent, 0.92 mmol) Furthermore, the linear velocity of the liquid flowing through channel 5b immediately after it is introduced into confluence 6b is 0.81 m / sec, the linear velocity of the liquid flowing through channel 3b immediately after it is introduced into confluence 6b is 0.63 m / sec, and the linear velocity of the combined liquid in confluence 6b (linear velocity just before the outlet of confluence 6b to channel 7b) is 1.44 m / sec.

[0055] Under the above conditions, the residence time (reaction time) in channels 5b and 7b (each reaction channel) was 166 seconds in channel 5b and 46 seconds in channel 7b. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 8b (outlet 8b of the flow-type reaction) was collected in a sample container. The collected liquid was analyzed by high-performance liquid chromatography (HPLC), and the amount of the target benzodithiol compound produced was quantified by applying the area value of the target benzodithiol compound to a pre-prepared calibration curve. The molar amount of the target benzodithiol compound was 75% (yield based on 1,2-n-dibutylpyrazolidine-3,5-dione (hereinafter simply referred to as yield) was 75%) relative to 100 mol% of the starting material 1,2-n-dibutylpyrazolidine-3,5-dione.

[0056] [Example 2] The same benzodithiol compound as in Example 1 was prepared using the flow reaction system shown in Figure 5.

[0057] The flow reaction system shown in Figure 5, used in Example 2, will be described in detail in the <Flow Reaction> section below, but it involves reacting an activated methylene compound with carbon disulfide to produce a salt of a dithiocarboxylic acid compound or an ethene-α,α-dithiol compound, and then reacting these salts with a quinone compound (Q1). In addition, the quinone compound (Q1) is p-benzoquinone, and separately, p-benzoquinone is also added as an oxidizing agent. In the flow reaction system shown in Figure 5, the details of the flow paths indicated by each symbol are as follows.

[0058] Stream 1c: SUS316 (stainless steel) tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 2c: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 3c: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 4c: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Confluence 5c: SUS316 T-type union tee (inner diameter 0.50 mm) Stream 6c: PTFE (polytetrafluoroethylene) tube with an outer diameter of 1 / 8 inch, an inner diameter of 1.58 mm, and a length of 36 m Confluence 7c: SUS316 T-type union tee (inner diameter 0.25 mm) Stream 8c: Confluence 9c: PTFE tube with outer diameter 1 / 8 inch, inner diameter 1.58 mm, and length 4 m; SUS316 T-type union tee (inner diameter 0.25 mm); Flow path 10c: PTFE tube with outer diameter 1 / 8 inch, inner diameter 1.58 mm, and length 4 m

[0059] Flow paths 1c, 2c, junction 5c, and 6c were placed in a constant temperature bath at a set temperature of 60°C, while flow paths 3c, 4c, junction 7c, 8c, junction 9c, and 10c were placed in a constant temperature bath at a set temperature of -50°C.

[0060] <Flow Reaction> 1,2-n-dibutylpyrazolidine-3,5-dione and carbon disulfide were mixed in N,N-dimethylformamide to concentrations of 0.50 M and 0.62 M, respectively. 200 mL of this solution was prepared and designated as starting material solution A-2. DBU was dissolved in N,N-dimethylformamide to a concentration of 2.0 M. 200 mL of this solution was prepared and designated as activator solution B-2. p-benzoquinone was dissolved in N,N-dimethylformamide to a concentration of 0.60 M. 200 mL of this solution was prepared and designated as starting material solution C-2. p-benzoquinone was dissolved in N,N-dimethylformamide to a concentration of 0.60 M. 200 mL of this solution was prepared and designated as oxidizing agent solution D-2.

[0061] The raw material solution A-2 was delivered into channel 1c from inlet 1C at a flow rate of 8.00 mL / min, the activator solution B-2 was delivered into channel 2c from inlet 2C at a flow rate of 4.99 mL / min, the raw material solution C-2 was delivered into channel 3c from inlet 3C at a flow rate of 7.36 mL / min, and the oxidizing agent solution D-2 was delivered into channel 4c from inlet 4C at a flow rate of 6.02 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. - 1,2-n-dibutylpyrazolidine-3,5-dione (1.00 equivalent, 4.00 mmol) - Carbon disulfide (1.25 equivalent, 0.50 mmol) - DBU (2.50 equivalent, 9.99 mmol) - p-benzoquinone as a raw material introduced from inlet 3C (1.10 equivalent, 4.40 mmol) - p-benzoquinone as an oxidizing agent introduced from inlet 4C (0.90 equivalent, 3.60 mmol) Furthermore, the linear velocity of the liquid flowing through channel 6c immediately after it is introduced into confluence 7c is 4.42 m / sec, the linear velocity of the liquid flowing through channel 3c immediately after it is introduced into confluence 7c is 2.50 m / sec, and the linear velocity of the combined liquid in confluence 7c (linear velocity just before the outlet of confluence 7c to channel 8c) is 6.92 m / sec.

[0062] Under the above conditions, the residence times (reaction times) in channels 6c, 8c, and 10c (each reaction channel) were 326 seconds in channel 6c, 23 seconds in channel 8c, and 18 seconds in channel 10c. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 11c (outlet 11c of the flow-type reaction) was collected in a sample container. The yield of the target benzodithiol compound, calculated in the same manner as in Example 1, was 84%. In comparison with Example 1, it was found that separating the quinone compound and the oxidizing agent as raw materials and sequentially combining them effectively increased the yield of the target benzodithiol compound.

[0063] [Example 3] The same benzodithiol compound as in Example 1 was prepared using the flow reaction system shown in Figure 4.

[0064] Example 3 involves preparing a salt of a dithiocarboxylic acid compound or an ethene-α,α-dithiol compound by reacting an activated methylene compound with carbon disulfide in a batch manner, and then reacting this salt of dithiocarboxylic acid compound or ethene-α,α-dithiol compound with a quinone compound (Q1) using the flow reaction system shown in Figure 4. Further details will be described in the <Flow Reaction> section below, but the quinone compound (Q1) is p-benzoquinone, and separately, p-benzoquinone is also added as an oxidizing agent. In the flow reaction system shown in Figure 4, the details of the flow paths indicated by each symbol are as follows.

[0065] Stream 1b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 2b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 3b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Confluence 4b: SUS316 T-shaped union tee (inner diameter 0.25 mm) Stream 5b: PTFE tube with an outer diameter of 1 / 8 inch, an inner diameter of 1.58 mm, and a length of 4 m Confluence 6b: SUS316 T-shaped union tee (inner diameter 0.25 mm) Stream 7b: PTFE tube with an outer diameter of 1 / 8 inch, an inner diameter of 1.58 mm, and a length of 4 m

[0066] All flow paths and junctions were placed in a constant temperature bath maintained at a set temperature of -50°C.

[0067] <Batch Reaction> 8.0 g (37.8 mmol) of 1,2-n-dibutylpyrazolidine-3,5-dione was mixed with 98.6 mL of N,N-dimethylformamide under a nitrogen atmosphere and dissolved. Then, 11.3 mL (75.7 mmol) of DBU was added dropwise to this solution and the mixture was stirred at room temperature for 1 hour. Subsequently, 2.29 mL (37.8 mmol) of carbon disulfide was added dropwise and the mixture was stirred at room temperature (25°C) for 45 minutes. The resulting reaction solution was designated as starting material solution A-3.

[0068] <Flow Reaction> Prepare 100 mL of a solution by dissolving p-benzoquinone in N,N-dimethylformamide to a concentration of 0.60 M, and this will be used as the starting material solution B-3. Prepare 100 mL of a solution by dissolving p-benzoquinone in N,N-dimethylformamide to a concentration of 0.60 M, and this will be used as the oxidizing agent solution C-3.

[0069] Raw material solution A-3 was delivered into channel 1b from inlet 1B at a flow rate of 13.0 mL / min, raw material solution B-3 was delivered into channel 2b from inlet 2B at a flow rate of 7.42 mL / min, and oxidizing agent solution C-3 was delivered into channel 3b from inlet 3B at a flow rate of 6.07 mL / min, using pumps (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. - 1,2-n-dibutylpyrazolidine-3,5-dione (1.00 equivalent, 4.03 mmol) - Carbon disulfide (1.00 equivalent, 4.03 mmol) - DBU (2.00 equivalent, 8.05 mmol) - p-benzoquinone as a raw material introduced from inlet 2B (1.10 equivalent, 4.43 mmol) - p-benzoquinone as an oxidizing agent introduced from inlet 3B (0.90 equivalent, 3.62 mmol) Furthermore, the linear velocity of the liquid flowing through channel 1b immediately after it is introduced into confluence 4b is 4.42 m / sec, the linear velocity of the liquid flowing through channel 2b immediately after it is introduced into confluence 4b is 2.52 m / sec, and the linear velocity of the combined liquid in confluence 4b (linear velocity just before the outlet of confluence 4b to channel 5b) is 6.94 m / sec.

[0070] Under the above conditions, the residence time (reaction time) in channels 5b and 7b (each reaction channel) was 23 seconds in channel 5b and 18 seconds in channel 7b. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 8b (outlet 8b of the flow-type reaction) was collected in a sample container. The yield of the target benzodithiol compound, calculated in the same manner as in Example 1, was 90%.

[0071] [Example 4] A benzodithiol compound with the following structure ("2-(5-(tert-butyl)-4,7-dihydroxy-1,3-benzodithiol-2-ylidene)malononitrile") was prepared using the flow reaction system shown in Figure 4.

[0072]

[0073] The flow reaction system shown in Figure 4, adopted in Example 4, will be described in detail in the <Flow Reaction> section below, but involves reacting an activated methylene compound with carbon disulfide to produce a salt of an ethene-α,α-dithiol compound or a salt of a dithiocarboxylic acid compound (either one or both of these), and then reacting this salt of ethene-α,α-dithiol compound or dithiocarboxylic acid compound with a quinone compound (Q1). Furthermore, the quinone compound (Q1) is 2-tert-butyl-1,4-benzoquinone, and 2-tert-butyl-1,4-benzoquinone is supplied to the reaction system all at once, with 2-tert-butyl-1,4-benzoquinone serving as both the reaction raw material and the oxidizing agent. In the flow reaction system shown in Figure 4, the details of the flow paths indicated by each symbol are as follows.

[0074] Stream 1b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 2b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 3b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Confluence 4b: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 5b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m Confluence 6b: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 7b: PTFE tube with an outer diameter of 1 / 4 inch, an inner diameter of 4.35 mm, and a length of 2.47 m

[0075] Flow paths 1b, 2b, junction 4b, and 5b are placed in a constant temperature bath at a set temperature of 0°C, while flow paths 3b, junction 6b, and 7b are placed in a constant temperature bath at a set temperature of 30°C.

[0076] <Flow Reaction> A 200 mL solution was prepared by mixing malononitrile and carbon disulfide in an N,N-dimethylformamide / ethanol mixed solvent to a concentration of 1.21 M each, and this was designated as starting material solution A-4. A 100 mL solution was prepared by dissolving potassium hydroxide in deionized water to a concentration of 8.0 M, and this was designated as activator solution B-4. A 200 mL solution was prepared by dissolving 2-tert-butyl-1,4-benzoquinone in acetone to a concentration of 1.31 M and acetic acid in acetone to a concentration of 1.61 M, and this was designated as starting material / oxidizing agent solution C-4.

[0077] Raw material solution A-4 was delivered into channel 1b from inlet 1B at a flow rate of 11.06 mL / min, activator solution B-4 was delivered into channel 2b from inlet 2B at a flow rate of 3.34 mL / min, and raw material / oxidant solution C-4 was delivered into channel 3b from inlet 3B at a flow rate of 20.96 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. - Malononitrile (1.00 equivalent, 13.38 mmol) - Carbon disulfide (1.00 equivalent, 13.38 mmol) - Potassium hydroxide (2.00 equivalent, 26.75 mmol) - 2-tert-butyl-1,4-benzoquinone (2.06 equivalent, 27.49 mmol) - Acetic acid (2.52 equivalent, 33.76 mmol) Furthermore, the linear velocity of the liquid flowing through channel 5b immediately after it is introduced into confluence 6b is 1.19 m / sec, the linear velocity of the liquid flowing through channel 3b immediately after it is introduced into confluence 6b is 1.81 m / sec, and the linear velocity of the combined liquid in confluence 6b (linear velocity just before the outlet of confluence 6b to channel 7b) is 3.00 m / sec.

[0078] Under the above conditions, the residence time (reaction time) in channels 5b and 7b (each reaction channel) was 6.5 seconds in channel 5b and 63 seconds in channel 7b. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 8b (outlet 8b of the flow-type reaction) was collected in a sample container. The collected liquid was analyzed by high-performance liquid chromatography (HPLC), and the area value of the target benzodithiol compound was applied to a pre-prepared calibration curve to quantify the amount of the target benzodithiol compound produced. The molar amount of the target benzodithiol compound (yield based on malononitrile) was 81% relative to 100 mol% of the starting material malononitrile.

[0079] [Example 5] The same benzodithiol compound as in Example 4 was prepared using the flow reaction system shown in Figure 5.

[0080] The flow reaction system shown in Figure 5, used in Example 5, involves reacting an activated methylene compound with carbon disulfide to produce a salt of an ethene-α,α-dithiol compound or a salt of a dithiocarboxylic acid compound, and then reacting this salt of ethene-α,α-dithiol compound or dithiocarboxylic acid compound with a quinone compound (Q1). In addition, the quinone compound (Q1) is 2-tert-butyl-1,4-benzoquinone, and separately, p-benzoquinone is added as an oxidizing agent. In the flow reaction system shown in Figure 5, the details of the flow paths indicated by each symbol are as follows.

[0081] Stream 1c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 2c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 3c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 4c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Confluence 5c: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 6c: SUS316 tube with outer diameter 1 / 8 inch, inner diameter 2.17 mm, and length 4.25 m Confluence 7c: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 8c: Confluence 9c: PTFE tube with outer diameter 1 / 4 inch, inner diameter 4.35 mm, and length 3.75 m; SUS316 T-type union tee (inner diameter 1.30 mm); Flow path 10c: PTFE tube with outer diameter 1 / 4 inch, inner diameter 4.35 mm, and length 5.75 m

[0082] Flow paths 1c, 2c, junction 5c, and 6c are placed in a constant temperature bath at a set temperature of 0°C, while flow paths 3c, 4c, junction 7c, 8c, junction 9c, and 10c are placed in a constant temperature bath at a set temperature of 35°C.

[0083] <Flow Reaction> A 200 mL solution was prepared by mixing malononitrile and carbon disulfide in an N,N-dimethylformamide / ethanol mixed solvent to a concentration of 1.82 M each, and this was designated as starting material solution A-5. A 100 mL solution was prepared by dissolving potassium hydroxide in deionized water to a concentration of 8.0 M, and this was designated as activator solution B-5. A 200 mL solution was prepared by dissolving 2-tert-butyl-1,4-benzoquinone and acetic acid in acetone to concentrations of 1.30 M and 3.38 M, respectively, and this was designated as starting material solution C-5. A 200 mL solution was prepared by dissolving p-benzoquinone and acetic acid in acetone to concentrations of 1.61 M and 1.79 M, respectively, and this was designated as oxidizing agent solution D-5.

[0084] Raw material solution A-5 was delivered into channel 1c from inlet 1C at a flow rate of 8.62 mL / min, activator solution B-5 into channel 2c from inlet 2C at a flow rate of 4.05 mL / min, raw material solution C-5 into channel 3c from inlet 3C at a flow rate of 12.73 mL / min, and oxidizing agent solution D-5 into channel 4c from inlet 4C at a flow rate of 9.22 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. • Malononitrile (1.00 equivalent, 15.65 mmol) • Carbon disulfide (1.00 equivalent, 15.65 mmol) • Potassium hydroxide (2.07 equivalent, 32.39 mmol) • 2-tert-butyl-1,4-benzoquinone as a raw material introduced from inlet 3C (1.00 equivalent, 15.65 mmol) • Acetic acid introduced from inlet 3C (1.75 equivalent, 27.39 mmol) • p-benzoquinone as an oxidizing agent introduced from inlet 4C (0.95 equivalent, 14.86 mmol) • Acetic acid introduced from inlet 4C (1.00 equivalent, 15.65 mmol) Furthermore, the linear velocity of the liquid flowing through channel 6c immediately after it is introduced into the confluence section 7c is 1.08 m / sec, the linear velocity of the liquid flowing through channel 3c immediately after it is introduced into the confluence section 7c is 1.08 m / sec, and the linear velocity of the combined liquid within the confluence section 7c (linear velocity just before the outlet of the confluence section 7c to channel 8c) is 2.16 m / sec.

[0085] Under the above conditions, the residence times (reaction times) in channels 6c, 8c, and 10c (each reaction channel) were 74 seconds in channel 6c, 132 seconds in channel 8c, and 148 seconds in channel 10c. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 11c (outlet 11c of the flow-type reaction) was collected in a sample container. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 93%. In comparison with Example 4, it was found that separating the quinone compound and the oxidizing agent as raw materials and sequentially combining them effectively increased the yield of the target benzodithiol compound.

[0086] [Example 5-2] The same benzodithiol compound as in Example 4 was prepared using the flow reaction system shown in Figure 5.

[0087] The flow reaction system shown in Figure 5, used in Example 5-2, involves reacting an activated methylene compound with carbon disulfide to produce a salt of an ethene-α,α-dithiol compound or a salt of a dithiocarboxylic acid compound, and then reacting this salt of ethene-α,α-dithiol compound or dithiocarboxylic acid compound with a quinone compound (Q1). The quinone compound (Q1) is 2-tert-butyl-1,4-benzoquinone, and separately, p-benzoquinone is added as an oxidizing agent. In the flow reaction system shown in Figure 5, the details of the flow paths indicated by each symbol are as follows.

[0088] Stream 1c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 2c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 3c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 4c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Confluence 5c: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 6c: SUS316 tube with outer diameter 1 / 8 inch, inner diameter 2.17 mm, and length 4.25 m Confluence 7c: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 8c: Confluence 9c: PTFE T-type 3-way joint (1.00 mm inner diameter) with an outer diameter of 1 / 8 inch, an inner diameter of 2.18 mm, and a length of 20.0 m. Flow channel 10c: PTFE tube with an outer diameter of 1 / 8 inch, an inner diameter of 2.18 mm, and a length of 20.0 m.

[0089] Flow paths 1c, 2c, junction 5c, and 6c are placed in a constant temperature bath at a set temperature of 0°C, while flow paths 3c, 4c, junction 7c, 8c, junction 9c, and 10c are placed in a constant temperature bath at a set temperature of 35°C.

[0090] <Flow Reaction> 1000 mL of a solution was prepared by mixing malononitrile and carbon disulfide in an N,N-dimethylformamide / ethanol mixed solvent to a concentration of 1.82 M each, and this was designated as starting material solution A-5-2. 200 mL of a solution was prepared by dissolving potassium hydroxide in ion-exchanged water to a concentration of 8.0 M, and this was designated as activator solution B-5-2. 1000 mL of a solution was prepared by dissolving 2-tert-butyl-1,4-benzoquinone and acetic acid in acetone to concentrations of 1.30 M and 3.38 M, respectively, and this was designated as starting material solution C-5-2. 1900 mL of a solution was prepared by dissolving p-benzoquinone and acetic acid in an acetone / methanol / isopropyl alcohol mixed solvent to concentrations of 0.42 M and 0.47 M, respectively, and this was designated as oxidizing agent solution D-5-2.

[0091] The raw material solution A-5-2 was delivered into channel 1c from inlet 1C at a flow rate of 8.62 mL / min, the activator solution B-5-2 was delivered into channel 2c from inlet 2C at a flow rate of 4.05 mL / min, the raw material solution C-5-2 was delivered into channel 3c from inlet 3C at a flow rate of 12.73 mL / min, and the oxidizing agent solution D-5-2 was delivered into channel 4c from inlet 4C at a flow rate of 34.76 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. • Malononitrile (1.00 equivalent, 15.65 mmol) • Carbon disulfide (1.00 equivalent, 15.65 mmol) • Potassium hydroxide (2.07 equivalent, 32.39 mmol) • 2-tert-butyl-1,4-benzoquinone as a raw material introduced from inlet 3C (1.00 equivalent, 15.65 mmol) • Acetic acid introduced from inlet 3C (1.75 equivalent, 27.39 mmol) • p-benzoquinone as an oxidizing agent introduced from inlet 4C (0.94 equivalent, 14.71 mmol) • Acetic acid introduced from inlet 4C (1.05 equivalent, 16.43 mmol) Furthermore, the linear velocity of the liquid flowing through channel 6c immediately after it is introduced into the confluence section 7c is 1.08 m / sec, the linear velocity of the liquid flowing through channel 3c immediately after it is introduced into the confluence section 7c is 1.08 m / sec, and the linear velocity of the combined liquid within the confluence section 7c (linear velocity just before the outlet of the confluence section 7c to channel 8c) is 2.16 m / sec.

[0092] Under the above conditions, the residence times (reaction times) in channels 6c, 8c, and 10c (each reaction channel) were 74 seconds in channel 6c, 176 seconds in channel 8c, and 74 seconds in channel 10c. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 11c (outlet 11c of the flow-type reaction) was collected in a sample container. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 93%.

[0093] [Example 5-3] The same benzodithiol compound as in Example 4 was prepared using the flow reaction system shown in Figure 5.

[0094] The flow reaction system shown in Figure 5, used in Example 5-3, involves reacting an activated methylene compound with carbon disulfide to produce a salt of an ethene-α,α-dithiol compound or a salt of a dithiocarboxylic acid compound, and then reacting this salt of ethene-α,α-dithiol compound or dithiocarboxylic acid compound with a quinone compound (Q1). The quinone compound (Q1) is 2-tert-butyl-1,4-benzoquinone, and separately, p-benzoquinone is added as an oxidizing agent. In the flow reaction system shown in Figure 5, the details of the flow paths indicated by each symbol are as follows.

[0095] Stream 1c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 2c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 3c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 4c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Confluence 5c: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 6c: SUS316 tube with outer diameter 1 / 8 inch, inner diameter 2.17 mm, and length 4.25 m Confluence 7c: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 8c: Confluence 9c: PTFE T-type 3-way joint (1.00 mm inner diameter) with an outer diameter of 1 / 8 inch, an inner diameter of 2.18 mm, and a length of 20.0 m. Flow channel 10c: PTFE tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.00 mm, and a length of 3.0 m.

[0096] Flow paths 1c, 2c, junction 5c, and 6c are placed in a constant temperature bath at a set temperature of 0°C, while flow paths 3c, 4c, junction 7c, 8c, junction 9c, and 10c are placed in a constant temperature bath at a set temperature of 35°C.

[0097] <Flow Reaction> 1000 mL of a solution was prepared by mixing malononitrile and carbon disulfide in an N,N-dimethylformamide / ethanol mixed solvent to a concentration of 1.82 M each, and this was designated as starting material solution A-5-3. 200 mL of a solution was prepared by dissolving potassium hydroxide in deionized water to a concentration of 8.0 M, and this was designated as activator solution B-5-3. 1000 mL of a solution was prepared by dissolving 2-tert-butyl-1,4-benzoquinone and acetic acid in acetone to concentrations of 1.30 M and 3.38 M, respectively, and this was designated as starting material solution C-5-3. 1900 mL of a solution was prepared by dissolving p-benzoquinone and acetic acid in an acetone / isopropyl alcohol mixed solvent to concentrations of 0.42 M and 0.47 M, respectively, and this was designated as oxidizing agent solution D-5-3.

[0098] The raw material solution A-5-3 was delivered into channel 1c from inlet 1C at a flow rate of 8.62 mL / min, the activator solution B-5-3 was delivered into channel 2c from inlet 2C at a flow rate of 4.05 mL / min, the raw material solution C-5-3 was delivered into channel 3c from inlet 3C at a flow rate of 12.73 mL / min, and the oxidizing agent solution D-5-3 was delivered into channel 4c from inlet 4C at a flow rate of 34.76 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. • Malononitrile (1.00 equivalent, 15.65 mmol) • Carbon disulfide (1.00 equivalent, 15.65 mmol) • Potassium hydroxide (2.07 equivalent, 32.39 mmol) • 2-tert-butyl-1,4-benzoquinone as a raw material introduced from inlet 3C (1.00 equivalent, 15.65 mmol) • Acetic acid introduced from inlet 3C (1.75 equivalent, 27.39 mmol) • p-benzoquinone as an oxidizing agent introduced from inlet 4C (0.94 equivalent, 14.71 mmol) • Acetic acid introduced from inlet 4C (1.05 equivalent, 16.43 mmol) Furthermore, the linear velocity of the liquid flowing through channel 6c immediately after it is introduced into the confluence section 7c is 1.08 m / sec, the linear velocity of the liquid flowing through channel 3c immediately after it is introduced into the confluence section 7c is 1.08 m / sec, and the linear velocity of the combined liquid within the confluence section 7c (linear velocity just before the outlet of the confluence section 7c to channel 8c) is 2.16 m / sec.

[0099] Under the above conditions, the residence times (reaction times) in channels 6c, 8c, and 10c (each reaction channel) were 74 seconds in channel 6c, 176 seconds in channel 8c, and 2.4 seconds in channel 10c. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 11c (outlet 11c of the flow-type reaction) was collected in a sample container. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 92%.

[0100] [Example 5-4] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-3, except that the solvent of the oxidizing agent solution D-5-3 was changed from an acetone / isopropyl alcohol mixed solvent to an acetone / ethyl acetate mixed solvent. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 95%.

[0101] [Example 5-5] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-3, except that the solvent of the oxidizing agent solution D-5-3 was changed from an acetone / isopropyl alcohol mixed solvent to acetone solvent. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 91%.

[0102] [Example 5-6] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-3, except that the solvent of the oxidizing agent solution D-5-3 was changed from an acetone / isopropyl alcohol mixed solvent to an acetone / tetrahydrofuran mixed solvent. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 87%.

[0103] [Example 5-7] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-3, except that the solvent of the oxidizing agent solution D-5-3 was changed from an acetone / isopropyl alcohol mixed solvent to an acetone / N,N-dimethylformamide mixed solvent. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 83%.

[0104] [Example 5-8] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-3, except that the concentrations of p-benzoquinone and acetic acid in the oxidizing agent solution D-5-3 were changed from 0.42 M and 0.47 M to 0.67 M and 0.75 M, respectively, and the oxidizing agent solution D-5-3 was delivered into the flow path 4c from the inlet 4C at a flow rate of 21.95 mL / min. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 92%.

[0105] [Example 5-9] In Example 5-9, the same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-3, except that the concentrations of p-benzoquinone and acetic acid in the oxidizing agent solution D-5-3 were changed from 0.42 M and 0.47 M to 0.52 M and 0.58 M, respectively, and the oxidizing agent solution D-5-3 was delivered into the flow path 4c from the inlet 4C at a flow rate of 28.36 mL / min. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 88%.

[0106] [Example 5-10] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-9, except that a SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.00 mm, and a length of 3.0 m was used for the flow path 10c. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 93%.

[0107] [Example 5-11] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-9, except that a Sulfinert® tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.00 mm, and a length of 3.0 m was used in the flow path 10c. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 92%.

[0108] [Example 5-12] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-9, except that a SilcoNert 1000 (registered trademark) tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.00 mm, and a length of 3.0 m was used for the flow path 10c. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 93%.

[0109] [Example 5-13] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-10, except that a SUS316 T-type union tee (inner diameter 1.00 mm) was used at the confluence 9c. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 91%.

[0110] [Example 5-14] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-13, except that a Sulfinert® tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.00 mm, and a length of 3.0 m was used in the flow path 10c. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 91%.

[0111] [Example 5-15] The same benzodithiol compound as in Example 4 was prepared in the same manner as in Example 5-14, except that a SUS316 T-type union tee (inner diameter 1.30 mm) was used at the confluence 9c. The yield of the target benzodithiol compound, calculated in the same manner as in Example 4, was 93%.

[0112] [Example 6] The same benzodithiol compound as in Example 4 is prepared using the flow reaction system shown in Figure 3.

[0113] Example 6 involves preparing a salt of an ethene-α,α-dithiol compound or a dithiocarboxylic acid compound by reacting an activated methylene compound with carbon disulfide in a batch manner beforehand. This salt of the ethene-α,α-dithiol compound or dithiocarboxylic acid compound is then reacted with a quinone compound (Q1) using the flow reaction system shown in Figure 3. In this case, the quinone compound (Q1) is 2-tert-butyl-1,4-benzoquinone, and the 2-tert-butyl-1,4-benzoquinone is supplied to the reaction system all at once, with the 2-tert-butyl-1,4-benzoquinone serving as both the reaction raw material and the oxidizing agent. In the flow reaction system shown in Figure 3, the details of the flow paths indicated by each symbol are as follows.

[0114] Channel 1a: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm. Channel 2a: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm. Confluence 3a: SUS316 T-shaped union tee (inner diameter of 0.50 mm). Channel 4a: PTFE tube with an outer diameter of 1 / 4 inch, an inner diameter of 4.35 mm, and a length of 2.50 m.

[0115] All flow paths and junctions are placed in a constant temperature bath maintained at a set temperature of 30°C.

[0116] <Batch Reaction> 2.8 g of potassium hydroxide was suspended in 11 g of acetonitrile, and 1.65 g of malononitrile was added dropwise to the solution, with the internal temperature limit set at 20°C. The mixture was then stirred at 20°C for 10 minutes, after which 1.7 g of carbon disulfide was added dropwise. After the addition was complete, the mixture was stirred at 20°C for 1 hour, and the precipitated solid was filtered. The solid was washed three times with 5 mL of acetonitrile and then air-dried. In this way, 4.7 g of a pale yellow solid was obtained (yield 86%).

[0117] <Flow Reaction> Dissolve 4.7 g of the pale yellow solid obtained in the batch reaction above in a mixed solvent of 52 g of N,N-dimethylformamide, 58 g of ethanol, and 30 g of water to prepare starting material solution A-6. Dissolve 2-tert-butyl-1,4-benzoquinone in a mixed solvent of acetone / acetic acid = 5.33 / 1 (volume ratio) to a concentration of 1.30 M to prepare starting material / oxidizing agent solution B-6.

[0118] Raw material solution A-6 is delivered into channel 1a from inlet 1A at a flow rate of 14.40 mL / min, and raw material / oxidant solution B-6 is delivered into channel 2a from inlet 2A at a flow rate of 21.14 mL / min, using pumps (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows: Malononitrile (1.00 equivalent, 15.65 mmol) and 2-tert-butyl-1,4-benzoquinone (2.06 equivalent, 27.49 mmol). Furthermore, the linear velocity of the liquid flowing through channel 1a immediately after it is introduced into the confluence section 3a is 1.21 m / sec, the linear velocity of the liquid flowing through channel 2a immediately after it is introduced into the confluence section 3a is 1.78 m / sec, and the linear velocity of the confluence liquid within the confluence section 3a (linear velocity just before the outlet of the confluence section 3a to channel 4a) is 2.99 m / sec.

[0119] Under the above conditions, the residence time (reaction time) in the flow path 4a (each reaction flow path) is 63 seconds. After a certain period of time has elapsed since the start of liquid delivery, and the liquid in each flow path of the flow-type reaction system has been sufficiently replaced, the liquid discharged from the outlet 5a (outlet 5a of the flow-type reaction) is collected in a sample container, and the yield of the target benzodithiol compound is calculated in the same manner as in Example 4, which is approximately 80%.

[0120] [Comparative Example 1] The target benzodithiol compound in Example 1 was prepared by a batch reaction. 1.6 g (7.7 mmol) of 1,2-n-dibutylpyrazolidine-3,5-dione was dissolved in 20 mL of N,N-dimethylformamide under a nitrogen atmosphere. 2.3 mL (15.4 mmol) of DBU was added to this solution, and the mixture was stirred at 25°C for 1 hour. Subsequently, 0.5 mL (7.7 mmol) of carbon disulfide was added dropwise, and the mixture was stirred at 25°C for another 1 hour to obtain a reaction mixture. To the above reaction mixture, a solution prepared by dissolving 1.6 g (15.4 mmol) of p-benzoquinone in 24 mL of N,N-dimethylformamide was added dropwise over 10 minutes at -50°C and the mixture was allowed to react. Approximately 2 mL of the resulting reaction solution was taken. The yield of the target benzodithiol, calculated in the same manner as in Example 1, was 63%. Compared to the 63% yield of Comparative Example 1, the yields of Examples 1 to 3 were all 75% or higher, indicating that the yield is significantly higher in the embodiments of the present invention.

[0121] [Comparative Example 2] The target benzodithiol compound in Example 4 was prepared by a batch reaction. For the example in Comparative Example 2, the method described in Justus Liebigs, Annalen der Chemie, 726, pp. 103-109 (1969) was referred to. Under a nitrogen stream, 2.0 g (36.64 mmol) of potassium hydroxide with an 86% by mass content was dissolved in a mixed solvent of 6 mL of isopropyl alcohol and 5 mL of water. To this solution, under water cooling and stirring at a temperature of 5°C or below, a solution of 1.0 g (15.14 mmol) of malononitrile dissolved in 4 mL of isopropyl alcohol was added. Next, the temperature of this solution was reduced to 10°C or below, and 1.2 g (15.76 mmol) of carbon disulfide was added dropwise, followed by stirring under water cooling for 30 minutes. To this reaction mixture, a solution of 5.1 g (47.18 mmol) of 2-tert-butyl-1,4-benzoquinone dissolved in a mixed solvent of 2 mL of acetic acid and 17 mL of acetone was slowly added dropwise at a temperature of 2°C or lower. After stirring at the same temperature for 30 minutes, the temperature was raised to 25°C and 32 mL of water was added. Next, the precipitated crystals were filtered off, washed with 85 mL of water, and then washed with a mixed solution of water / acetone (9 mL / 9 mL) to obtain a crude product. Next, under a nitrogen stream, the crude product and 10 mL of tetrahydrofuran (THF) were mixed and stirred, the temperature was raised to 40°C, and 15 mL of water was added dropwise. After that, the mixture was cooled to 5°C to precipitate crystals, and stirred at 5°C for 1 hour. The precipitated crystals were filtered off, washed with a mixed solution of THF / water (4 ml / 12 ml), and then dried under reduced pressure at 60°C to obtain 3.0 g of the target benzodithiol compound as a pale yellow solid with a yield of 65%. It can be seen that the yields of Examples 4 to 6 were all significantly higher than the 65% yield of Comparative Example 2.

[0122] [Example 7] The same benzodithiol compound as in Example 4 was prepared using the flow reaction system shown in Figure 5.

[0123] The flow reaction system shown in Figure 5, used in Example 7, involves reacting an activated methylene compound with carbon disulfide to produce a salt of an ethene-α,α-dithiol compound or a salt of a dithiocarboxylic acid compound, and then reacting this salt of ethene-α,α-dithiol compound or dithiocarboxylic acid compound with a quinone compound (Q1). The quinone compound (Q1) is 2-tert-butyl-1,4-benzoquinone, and separately, p-benzoquinone is added as an oxidizing agent. In the flow reaction system shown in Figure 5, the details of the flow paths indicated by each symbol are as follows.

[0124] Stream 1c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 2c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 3c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Stream 4c: SUS316 tube with outer diameter 1 / 16 inch, inner diameter 1.0 mm, and length 50 cm Confluence 5c: SUS316 T-shaped union tee (inner diameter 0.25 mm) Stream 6c: PTFE tube with outer diameter 1 / 8 inch, inner diameter 1.58 mm, and length 2 m Confluence 7c: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 8c: Confluence 9c: PTFE tube with outer diameter 1 / 4 inch, inner diameter 4.35 mm, and length 1.0 m; SUS316 T-type union tee (inner diameter 1.30 mm); Flow path 10c: PTFE tube with outer diameter 1 / 4 inch, inner diameter 4.35 mm, and length 1.5 m

[0125] Flow paths 1c, 2c, junction 5c, and 6c are placed in a constant temperature bath at a set temperature of 0°C, while flow paths 3c, 4c, junction 7c, 8c, junction 9c, and 10c are placed in a constant temperature bath at a set temperature of 35°C.

[0126] <Flow Reaction> A 200 mL solution was prepared by mixing malononitrile and carbon disulfide in an N,N-dimethylformamide / ethanol mixed solvent to a concentration of 1.82 M each, and this was designated as starting material solution A-7. A 100 mL solution was prepared by dissolving potassium hydroxide in deionized water to a concentration of 8.0 M, and this was designated as activator solution B-7. A 200 mL solution was prepared by dissolving 2-tert-butyl-1,4-benzoquinone and acetic acid in acetone to concentrations of 1.23 M and 3.38 M, respectively, and this was designated as starting material solution C-7. A 200 mL solution was prepared by dissolving p-benzoquinone and acetic acid in acetone to concentrations of 1.61 M and 1.79 M, respectively, and this was designated as oxidizing agent solution D-7.

[0127] The raw material solution A-7 was delivered into channel 1c from inlet 1C at a flow rate of 2.16 mL / min, the activator solution B-7 was delivered into channel 2c from inlet 2C at a flow rate of 1.01 mL / min, the raw material solution C-7 was delivered into channel 3c from inlet 3C at a flow rate of 3.19 mL / min, and the oxidizing agent solution D-7 was delivered into channel 4c from inlet 4C at a flow rate of 2.31 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. • Malononitrile (1.00 equivalent, 3.92 mmol) • Carbon disulfide (1.00 equivalent, 3.92 mmol) • Potassium hydroxide (2.07 equivalent, 8.12 mmol) • 2-tert-butyl-1,4-benzoquinone as a raw material introduced from inlet 3C (1.00 equivalent, 3.92 mmol) • Acetic acid introduced from inlet 3C (1.75 equivalent, 6.86 mmol) • p-benzoquinone as an oxidizing agent introduced from inlet 4C (0.95 equivalent, 3.72 mmol) • Acetic acid introduced from inlet 4C (1.00 equivalent, 3.92 mmol) Furthermore, the linear velocity of the liquid flowing through channel 6c immediately after it is introduced into the confluence section 7c is 0.27 m / sec, the linear velocity of the liquid flowing through channel 3c immediately after it is introduced into the confluence section 7c is 0.27 m / sec, and the linear velocity of the combined liquid within the confluence section 7c (linear velocity just before the outlet of the confluence section 7c to channel 8c) is 0.54 m / sec.

[0128] Under the above conditions, the residence times (reaction times) in channels 6c, 8c, and 10c (each reaction channel) were 74 seconds in channel 6c, 140 seconds in channel 8c, and 154 seconds in channel 10c. The desired liquid delivery and reaction could proceed until a certain period of time had elapsed from the start of liquid delivery. On the other hand, blockage of the channels began to occur about 10 minutes after the start of liquid delivery, and thereafter the stability of liquid delivery was impaired.

[0129] [Example 8] Using the flow reaction system shown in Figure 4, a benzodithiol compound with the following structure (whereas the benzodithiol compound in Example 1 was a mono-isomer, Example 8 is a bis-isomer) was prepared.

[0130]

[0131] The flow reaction system shown in Figure 4, used in Example 8, will be described in detail in the <Flow Reaction> section below, but it involves reacting an activated methylene compound with carbon disulfide to produce a salt of a dithiocarboxylic acid compound, and then reacting this salt of the dithiocarboxylic acid compound with a quinone compound (Q1). Furthermore, the quinone compound (Q1) is p-benzoquinone, and the p-benzoquinone is supplied to the reaction system all at once, with the p-benzoquinone serving as both the reaction raw material and the oxidizing agent. In the flow reaction system shown in Figure 4, the details of the flow paths indicated by each symbol are as follows.

[0132] Stream 1b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 2b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Stream 3b: SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm Confluence 4b: SUS316 T-shaped union tee (inner diameter 0.50 mm) Stream 5b: PTFE tube with an outer diameter of 1 / 8 inch, an inner diameter of 1.58 mm, and a length of 8 m Confluence 6b: SUS316 T-shaped union tee (inner diameter 0.25 mm) Stream 7b: PTFE tube with an outer diameter of 1 / 8 inch, an inner diameter of 1.58 mm, and a length of 2 m

[0133] Flow paths 1b, 2b, junction 4b, and 5b were placed in a constant temperature bath at a set temperature of 60°C, while flow paths 3b, junction 6b, and 7b were placed in a constant temperature bath at a set temperature of 0°C. By setting the temperature of junction 6b and flow path 7b, where the reaction takes place, to 0°C, which is higher than that of Examples 1 to 3 (below -30°C), the formation of mono-compounds was suppressed and the formation of bis-compounds was promoted.

[0134] <Flow Reaction> 10 mL of a solution was prepared by mixing 1,2-n-dibutylpyrazolidine-3,5-dione and carbon disulfide in N,N-dimethylformamide to concentrations of 0.40 M and 0.50 M, respectively, and this was designated as starting material solution A-8. 100 mL of a solution was prepared by dissolving DBU in N,N-dimethylformamide to a concentration of 1.05 M, and this was designated as activator solution B-8. 100 mL of a solution was prepared by dissolving p-benzoquinone in acetone to a concentration of 1.43 M, and this was designated as starting material / oxidizing agent solution C-8.

[0135] Raw material solution A-8 was delivered into channel 1b from inlet 1B at a flow rate of 4.00 mL / min, activator solution B-8 was delivered into channel 2b from inlet 2B at a flow rate of 1.68 mL / min, and raw material / oxidant solution C-8 was delivered into channel 3b from inlet 3B at a flow rate of 4.48 mL / min, using a pump (Fromm, UI-22-410S). The molar equivalent ratios of each raw material and reagent are as follows. - 1,2-Dibutylpyrazolidine-3,5-dione (1.00 equivalent, 1.60 mmol) - Carbon disulfide (1.25 equivalent, 2.00 mmol) - DBU (1.10 equivalent, 1.76 mmol) - p-Benzoquinone (2.00 equivalent, 6.41 mmol) Furthermore, the linear velocity of the liquid flowing through channel 5b immediately after it is introduced into confluence 6b is 1.93 m / sec, the linear velocity of the liquid flowing through channel 3b immediately after it is introduced into confluence 6b is 1.52 m / sec, and the linear velocity of the combined liquid in confluence 6b (linear velocity just before the outlet of confluence 6b to channel 7b) is 3.45 m / sec.

[0136] Under the above conditions, the residence time (reaction time) in channels 5b and 7b (each reaction channel) was 166 seconds in channel 5b and 23 seconds in channel 7b. After a certain period of time had elapsed since the start of liquid delivery and the liquid in each channel of the flow-type reaction system had been sufficiently replaced, the liquid discharged from outlet 8b (outlet 8b of the flow-type reaction) was collected in a sample container. The yield of the target benzodithiol, calculated according to Example 1, was 39%.

[0137] [Comparative Example 3] The target benzobisdithiol compound in Example 8 was prepared by a batch reaction. 1.6 g (7.7 mmol) of 1,2-n-dibutylpyrazolidine-3,5-dione was dissolved in 20 mL of N,N-dimethylformamide under a nitrogen atmosphere. 2.3 mL (15.4 mmol) of DBU was added to this solution, and the mixture was stirred at 25°C for 1 hour. Subsequently, 0.5 mL (7.7 mmol) of carbon disulfide was added dropwise, and the mixture was stirred at 25°C for another 1 hour to obtain a reaction mixture. To the above reaction mixture, a solution prepared by dissolving 1.6 g (15.4 mmol) of p-benzoquinone in 24 mL of N,N-dimethylformamide was added dropwise over 10 minutes at 25°C to allow the reaction to proceed. Approximately 2 mL of the resulting reaction solution was taken. The yield of the target benzobisdithiol, calculated in the same manner as in Example 1, was 17%. Compared to the 17% yield of Comparative Example 3, the yield of Example 8 was 39%, indicating that the yield of the bis-isomer is significantly higher in the embodiment of the present invention.

[0138] Although we have described the present invention along with its embodiments, we do not intend to limit our invention in any detail of the description unless specifically designated, and we believe that it should be interpreted broadly without contradicting the spirit and scope of the invention as set forth in the appended claims.

[0139] This application claims priority based on Japanese Patent Application No. 2024-169936, filed in Japan on 30 September 2024, the contents of which are incorporated herein by reference as part of this specification.

Claims

A method for producing a benzodithiol compound, comprising reacting a salt of a dithiocarboxylic acid compound or a salt of an ethene-α,α-dithiol compound with a quinone compound (Q1) by a flow reaction, and oxidizing the resulting reactant to form a benzodithiol ring structure. 　 A method for producing a benzodithiol compound according to claim 1, wherein unreacted quinone compounds (Q1) act on the reactants to produce the oxidation treatment. 　 A method for producing a benzodithiol compound according to claim 1, wherein the oxidation treatment is produced by mixing the reactant with an oxidizing agent. 　 A method for producing a benzodithiol compound according to claim 3, wherein the oxidizing agent comprises a quinone compound. 　 A method for producing a benzodithiol compound according to claim 4, wherein the oxidizing agent comprises benzoquinone. 　 A method for producing a benzodithiol compound according to any one of claims 1 to 5, comprising obtaining a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound using carbon disulfide as a reaction raw material. 　 A method for producing a benzodithiol compound according to claim 6, comprising reacting an active methylene compound with carbon disulfide in the presence of a basic compound to obtain a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound. 　 The method for producing a benzodithiol compound according to claim 7, wherein the reaction to obtain a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound is a flow reaction. 　 A method for producing a benzodithiol compound according to claim 8, wherein in a flow reaction between a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound and a quinone compound (Q1), a liquid containing the salt of the dithiocarboxylic acid compound or the salt of the ethene-α,α-dithiol compound and a liquid containing the quinone compound (Q1) are combined such that the linear velocity of the combined liquid is 0.80 m / sec or more. 　 A method for producing a benzodithiol compound according to claim 9, wherein the flow rate at the reaction outlet of a flow reaction between a salt of the dithiocarboxylic acid compound or a salt of the ethene-α,α-dithiol compound and a quinone compound (Q1) is 5 mL / min or more.

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