Method for producing electrophilic substituted aromatic compound

Abstract

Disclosed is a method for producing an electrophilic substituted aromatic compound, the method including continuously performing, by a flow reaction, a reaction in which a metallized aromatic compound is produced by reacting a halogenated aromatic compound with an organometallic compound, and subsequently the metallized aromatic compound is reacted with an electrophilic compound so as to produce an electrophilic substituted aromatic compound. This method for producing an electrophilic substituted aromatic compound includes flowing a liquid that contains the halogenated aromatic compound in an organic solvent, a liquid that contains the organometallic compound in an organic solvent, and a liquid that contains the electrophilic compound in an organic solvent in a flow path, while setting the respective water contents of these liquids to 200 ppm or less.

Description

Method for producing electrophilically substituted aromatic compounds

[0001] The present invention relates to a method for producing electrophilically substituted aromatic compounds.

[0002] Substituted aromatic compounds are used in a variety of applications, including as physiologically active substances, functional materials, and synthetic intermediates for these. A known synthetic route for substituted aromatic compounds involves reacting an organometallic compound with a halogenated aromatic compound (halogenoaromatic compound) to produce a metallated aromatic compound, which is then reacted with an electrophilic compound to produce an electrophilically substituted aromatic compound (hereinafter also referred to as the "metallation / electrophilic substitution reaction of a halogenated aromatic compound"). The resulting electrophilically substituted aromatic compound is optionally treated with a quenching agent such as water or alcohol, or subjected to desired chemical treatments, washing, purification, etc., to obtain the desired electrophilically substituted aromatic compound. For example, an organolithium compound such as butyllithium is used as the organometallic compound, and a brominated aromatic compound is used as the halogenated aromatic compound. These are reacted to produce a lithiated aromatic compound, which is then reacted with an electrophilic compound to introduce the desired substituent at the lithiation site, thereby obtaining the desired electrophilically substituted aromatic compound.

[0003] Patent Document 1 describes a method for producing a lithiated aromatic compound with a higher yield by premixing an organolithium compound with a reaction solvent before reacting the organolithium compound with a halogenated aromatic compound. This method is said to suppress heat generation due to mixing of the organolithium compound with the reaction solvent during the lithiation reaction and to inhibit the formation of by-products in the lithiation reaction. An electrophilically substituted lithium compound can be obtained by reacting the resulting lithiated aromatic compound with an electrophilic compound. Patent Document 1 also describes a method for performing the reaction using a flow reactor. Patent Document 2 describes a method for efficiently producing a desired o-disubstituted aromatic compound with high yield and selectivity using an o-dihalo aromatic compound as a raw material by performing the lithiation reaction of a halogenated benzene compound and the reaction of the resulting lithiated product with an electrophilic compound using a microreactor (flow reactor). The technology described in Patent Document 2 is said to suppress the by-production of benzyne in the reaction product even when the reaction is performed at a relatively high temperature of -80°C to -50°C.

[0004] JP 2021-8436 A JP 2008-195639 A

[0005] In the metalation / electrophilic substitution reaction of the halogenated aromatic compound, an excess amount of the electrophilic compound is generally used to promote the reaction and increase the production rate of the target compound (the ratio of the molar amount of the target electrophilically substituted aromatic compound to the molar amount of the halogenated aromatic compound, %). On the other hand, in response to recent social demands based on the SDGs and the like, there is an increasing demand for more efficient production of the target compound in chemical synthesis reactions while reducing waste of raw materials or reagents. Furthermore, the use of an excess amount of the electrophilic compound can also lead to problems such as increased production costs, especially when the electrophilic compound is expensive.

[0006] An object of the present invention is to provide a method for producing an electrophilically substituted aromatic compound via a metallation / electrophilic substitution reaction of a halogenated aromatic compound, which method makes it possible to obtain the target electrophilically substituted aromatic compound at a sufficiently high production rate while further reducing the amount of electrophilic compound used.

[0007]

[0005] In view of the above problems, the present inventors have conducted extensive research and have found that, in carrying out the metallation / electrophilic substitution reaction of the halogenated aromatic compound continuously by a flow reaction, by reducing the water content of each of the liquids containing an organometallic compound in an organic solvent, the liquid containing the halogenated aromatic compound in an organic solvent, and the liquid containing the electrophilic compound in an organic solvent to 200 ppm or less and flowing them through a flow path, it is possible to obtain the desired electrophilically substituted aromatic compound at a higher production rate while reducing the amount of electrophilic compound used. The present invention was completed based on this finding and through further research.

[0008] That is, the object of the present invention has been achieved by the following means: [1] A method for producing an electrophilically substituted aromatic compound, comprising continuously carrying out a flow reaction in which a halogenated aromatic compound is reacted with an organometallic compound to produce a metallated aromatic compound, and the metallated aromatic compound is reacted with an electrophilic compound to produce an electrophilically substituted aromatic compound, the method comprising flowing a liquid containing the halogenated aromatic compound in an organic solvent, a liquid containing the organometallic compound in an organic solvent, and a liquid containing the electrophilic compound in an organic solvent, each with a water content of 200 ppm or less, through a flow path. [2] The method for producing an electrophilically substituted aromatic compound according to [1], wherein, when the flow reaction is a single-stage reaction system, 0.80 to less than 1.20 molar equivalents of the electrophilic compound relative to the halogenated aromatic compound is used, and when the flow reaction is a multi-stage reaction system, 0.80 to less than 2.00 molar equivalents of the electrophilic compound relative to the halogenated aromatic compound is supplied to the final-stage reaction. [3] The method for producing an electrophilically substituted aromatic compound according to [1], wherein, when the flow reaction is a single-stage reaction system, 0.85 to 1.05 molar equivalents of the electrophilic compound are used relative to the halogenated aromatic compound, and when the flow reaction is a multi-stage reaction system, 0.80 to 1.50 molar equivalents of the electrophilic compound relative to the halogenated aromatic compound are supplied to the final-stage reaction. [4] The method for producing an electrophilically substituted aromatic compound according to [1], wherein the flow reaction is a multi-stage reaction system, and 0.80 to 1.20 molar equivalents of the electrophilic compound relative to the halogenated aromatic compound are supplied to the final-stage reaction.[5] A liquid A1 containing the halogenated aromatic compound in an organic solvent, liquids B1 and B2 containing the organometallic compound in an organic solvent, and liquids C1 and C2 containing the electrophilic compound in an organic solvent are prepared, and the liquids A1, B1, B2, C1, and C2 are introduced into different flow paths, respectively, and each liquid is allowed to flow through each flow path; the combined liquid M2 is mixed with the liquid B2, and while the combined liquid M3 is flowing downstream in the reaction flow path F3, an electrophilic mono-substituted aromatic compound is produced in the combined liquid M3; the combined liquid M2 is mixed with the liquid B2, and while the combined liquid M3 is flowing downstream in the reaction flow path F3, an electrophilic mono-substituted aromatic compound is produced in the combined liquid M3; the combined liquid M3 is mixed with the liquid C2, and while the combined liquid M4 is flowing downstream in the reaction flow path F4, an electrophilic di-substituted aromatic compound is produced in the combined liquid M4. [6] A method for producing an electrophilically substituted aromatic compound according to any one of [1] to [3], comprising: preparing a liquid A2 containing the halogenated aromatic compound in an organic solvent, a liquid B3 containing the organometallic compound in an organic solvent, and a liquid C3 containing the electrophilic compound in an organic solvent; introducing the liquids A2, B3, and C3 into different flow paths, respectively, and allowing each liquid to flow through each flow path; combining the liquid A2 and the liquid B3, and producing a metallated aromatic compound in the combined liquid M6 while this combined liquid M6 flows downstream through the reaction flow path F6; combining the combined liquid M6 and the liquid C3, and producing an electrophilic mono-substituted aromatic compound in the combined liquid M7 while this combined liquid M7 flows downstream through the reaction flow path F7.[7] Liquids A3 and A4 containing the halogenated aromatic compound in an organic solvent, liquids B4 and B5 containing the organometallic compound in an organic solvent, and liquid C4 containing the electrophilic compound in an organic solvent are prepared, and the liquids A3, A4, B4, B5, and C4 are introduced into different flow paths, respectively, and each liquid is caused to flow through each flow path, the liquid A3 and the liquid B4 are merged, and while this merged liquid M9 flows downstream in the reaction flow path F9, a metallated aromatic compound is generated in the merged liquid M9, the liquid A4 and the liquid B5 are merged, and while this merged liquid M11 flows downstream in the reaction flow path F11, a metallated aromatic compound is generated in the merged liquid M11, the merged liquid M9 and the liquid C4 are merged, and while this merged liquid M10 flows downstream in the reaction flow path F10, The method for producing an electrophilic substituted aromatic compound according to any one of [1] to [4], comprising: producing an electrophilic mono-substituted aromatic compound (i) that functions as an electrophilic compound in the combined liquid M10; further comprising: combining the combined liquid M11 and the combined liquid M10; and, while the combined liquid M12 flows downstream through a reaction flow path F12, reacting the metallated aromatic compound in the combined liquid M11 with the electrophilic mono-substituted aromatic compound (i) in the combined liquid M10 to produce an electrophilic mono-substituted aromatic compound in the combined liquid M12. [8] A liquid A5 containing the halogenated aromatic compound in an organic solvent, a liquid B6 containing the organometallic compound in an organic solvent, a liquid C5 containing the electrophilic compound in an organic solvent, and a liquid D containing a nucleophilic compound in an organic solvent are prepared, and the liquids A5, B6, C5, and D are introduced into different flow paths, respectively, and each liquid is caused to flow through each flow path, and the liquid A5 and the liquid B6 are merged, and a metallated aromatic compound is produced in the merged liquid M14 while this merged liquid M14 flows downstream in the reaction flow path F14, the merged liquid M14 and the liquid C5 are merged, and an electrophilic mono-substituted aromatic compound is produced in the merged liquid M15 while this merged liquid M15 flows downstream in the reaction flow path F15, and the merged liquid M15 and the liquid D are merged, and an electrophilic mono-substituted and nucleophilic substituted aromatic compound is produced in the merged liquid M16 while this merged liquid M16 flows downstream in the reaction flow path F16. A method for producing the electrophilically substituted aromatic compound according to any one of [1] to [4], comprising:[9] The method for producing an electrophilically substituted aromatic compound according to any one of [1] to [8], wherein the water content of each of the liquid containing the halogenated aromatic compound in an organic solvent, the liquid containing the organometallic compound in an organic solvent, and the liquid containing the electrophilic compound in an organic solvent, which are caused to flow through the flow path, is controlled to 100 ppm or less.

[0009] In the present invention and the specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits. When describing the cross-sectional size (equivalent diameter) of a pipe such as a flow path, a junction, or a mixer in the present invention and the specification, this size excludes the connecting portions between flow paths, the connecting portion between a flow path and a junction, and the connecting portion between a flow path and a mixer. In other words, the size of each connecting portion is appropriately adjusted using a connecting tube or the like so that the fluid flows from upstream to downstream through the connecting portion. In the present invention and the specification, the terms "upstream" and "downstream" are used in relation to the direction of liquid flow, with the side where the liquid is introduced (the side where the liquid flows in) being upstream and the side where the liquid flows out being downstream. In the present invention and the specification, "ppm" is based on mass.

[0010] According to the method for producing an electrophilically substituted aromatic compound of the present invention, it is possible to obtain the target electrophilically substituted aromatic compound at a sufficiently high production yield while reducing the amount of electrophilic compound used in the metallation / electrophilic substitution reaction of a halogenated aromatic compound.

[0011] FIG. 1 is an explanatory diagram showing an outline of one embodiment (two-stage reaction system) of the flow reaction system of the present invention. FIG. 2 is a reaction scheme of an example of a two-stage reaction system applicable to the flow reaction system of FIG. 1. FIG. 3 is a more detailed illustration of the reaction scheme shown in FIG. 2. FIG. 4 is an explanatory diagram showing an outline of another embodiment (single-stage reaction system) of the flow reaction system of the present invention. FIG. 5 is an explanatory diagram showing an outline of yet another embodiment (single-stage reaction system) of the flow reaction system of the present invention. FIG. 6 is a reaction scheme of an example of a single-stage reaction system applicable to the flow reaction system of FIG. 7. FIG. 8 is a reaction scheme of another example of a two-stage reaction system. FIG. 9 is a reaction scheme of another example of a single-stage reaction system.

[0012] [Production of Electrophilically Substituted Aromatic Compounds by Flow Reaction] The production method of electrophilically substituted aromatic compounds of the present invention (hereinafter also referred to as the "production method of the present invention") employs a flow reaction. That is, the production method of the present invention involves continuously carrying out, by flow reaction, at least the following reactions: reacting an organometallic compound with a halogenated aromatic compound to produce a metallated aromatic compound; and reacting this metallated aromatic compound with an electrophilic compound to produce an electrophilically substituted aromatic compound (metallation / electrophilic substitution reaction of a halogenated aromatic compound). If necessary, the target electrophilically substituted aromatic compound can be obtained in a desired form through quenching, chemical treatment (oxidation, etc.), washing, purification, etc.

[0013] In the production method of the present invention, in this flow reaction, liquid (A-I) containing the halogenated aromatic compound in an organic solvent, liquid (B-I) containing the organometallic compound in an organic solvent, and liquid (C-I) containing the electrophilic compound in an organic solvent are circulated through different flow paths, and the respective flow paths are merged appropriately, thereby causing the respective reactions to occur. Typically, liquid (A-I) and liquid (B-I) are merged, and this merged liquid is then merged with liquid (C-I). In the production method of the present invention, the water content of each of the liquids circulating through the respective flow paths is controlled to 200 ppm or less. By reducing the water content of each liquid to 200 ppm or less, it is possible to obtain the target electrophilically substituted aromatic compound at a sufficiently high production rate, even when the amount of electrophilic compound used is reduced (e.g., even when the amount is the minimum amount necessary based on the stoichiometric ratio). Liquids (A-I), (B-I), and (C-I) are typically solutions.

[0014] In the present invention, "passing through a flow path with a water content of 200 ppm or less" includes both a form in which a liquid with a water content reduced to 200 ppm or less is introduced into the flow path, and a form in which a liquid with a water content exceeding 200 ppm is introduced into the flow path and passed through a dehydration device (dehydration column, etc.) disposed in the flow path before merging with other liquids (i.e., before reaction occurs) to reduce the water content to 200 ppm. Various desiccants can be used as the dehydration device. For example, a dehydration column filled with crystalline zeolite such as molecular sieve can be used as the dehydration device. The water content of each of the liquids (liquids (A-I), (B-I) and (C-I)) flowing through the above flow paths is preferably 170 ppm or less, more preferably 150 ppm or less, more preferably 130 ppm or less, even more preferably 120 ppm or less, even more preferably 110 ppm or less, and even more preferably 100 ppm or less. The water content is also preferably 90 ppm or less, also preferably 80 ppm or less, also preferably 70 ppm or less, and also preferably 60 ppm or less. It is practical for the water content of each of the liquids flowing through the above flow paths to be 1 ppm or more, and usually 3 ppm or more, and preferably 5 ppm or more. Therefore, the preferred range of the water content of each liquid flowing through the above-mentioned flow path is preferably 1 to 200 ppm, more preferably 1 to 170 ppm, even more preferably 1 to 150 ppm, still more preferably 3 to 130 ppm, still more preferably 3 to 120 ppm, still more preferably 3 to 110 ppm, and still more preferably 3 to 100 ppm. Furthermore, this water content range may be 5 to 90 ppm, 5 to 80 ppm, 5 to 70 ppm, or 5 to 60 ppm.

[0015] The flow reaction may be a reaction in which the electrophilically substituted aromatic compound obtained from a halogenated aromatic compound is an electrophilic mono-substituted aromatic compound (this flow reaction is referred to as a "single-stage flow reaction system" in the present invention), or a reaction in which the electrophilically substituted aromatic compound obtained from a halogenated aromatic compound is an electrophilic di-substituted aromatic compound (this flow reaction is referred to as a "two-stage flow reaction system" in the present invention). Alternatively, the flow reaction may be a reaction in which one molecule of the electrophilically substituted aromatic compound obtained from a halogenated aromatic compound is substituted with three or more electrophilic compounds (this flow reaction is referred to as a "three or more stage flow reaction system" in the present invention). The two-stage reaction system and the three or more stage reaction system are collectively referred to as a "multi-stage flow reaction system." The flow reaction is preferably a one- to three-stage reaction system, more preferably a one- or two-stage reaction system. For example, in the metalation / electrophilic substitution reaction of a halogenated aromatic compound, if one molecule of the halogenated aromatic compound has only one halogen element to be substituted with a metal, the halogenated aromatic compound is reacted with an organometallic compound, and the resulting monometallated aromatic compound is reacted with an electrophilic compound to produce the desired electrophilic mono-substituted aromatic compound, so this is classified as a one-stage reaction system in the present invention. Also, for example, in the metalation / electrophilic substitution reaction of a halogenated aromatic compound, if one molecule of the halogenated aromatic compound has two halogen elements to be substituted with a metal, the halogenated aromatic compound is first reacted with an organometallic compound, and the resulting metallated halogenated aromatic compound is reacted with an electrophilic compound to produce the electrophilic mono-substituted halogenated aromatic compound (first-stage reaction). Next, this electrophilic monosubstituted halogenoaromatic compound is reacted with an organometallic compound, and the resulting metallated electrophilic monosubstituted aromatic compound is reacted with an electrophilic compound to produce an electrophilic disubstituted aromatic compound (second-stage reaction), whereby the target electrophilic disubstituted aromatic compound can be obtained. In this case, this is classified as a two-stage reaction system in the present invention.

[0016] An embodiment of a flow reaction system used in the present invention will be described with reference to the drawings. Note that the drawings are explanatory diagrams for facilitating understanding of the present invention, and the sizes and relative relationships of the components may be exaggerated for convenience of explanation and do not directly represent their actual relationships. Furthermore, matters other than those specified in the present invention are not limited to the external shapes and forms shown in these drawings. FIG. 1 is a schematic diagram illustrating an example of a flow reaction system used in the production method of the present invention. FIG. 2 is a reaction scheme illustrating an example of a metallation / electrophilic substitution reaction of a halogenated aromatic compound applied to the flow reaction system of FIG. 1. 1,4-dibromonaphthalene is used as the halogenated aromatic compound, n-butyllithium (n-BuLi) is used as the organometallic compound, and 2-phenyl-1,10-phenanthroline is used as the electrophilic compound.

[0017] The flow reaction system 100 shown in FIG. 1 is a two-stage reaction system in which liquids B1 and B2 containing an organometallic compound in an organic solvent and liquids C1 and C2 containing an electrophilic compound in an organic solvent are introduced into liquid A1 containing a halogenated aromatic compound (e.g., a dihalogenated aromatic compound) in an organic solvent in two stages. The organometallic compound contained in liquid B1 and the organometallic compound contained in liquid B2 may be the same or different. Furthermore, the electrophilic compound contained in liquid C1 and the electrophilic compound contained in liquid C2 may be the same or different depending on the chemical structure of the target electrophilic disubstituted aromatic compound. This also applies to the other embodiments. In this flow reaction system 100, the parts involved in the first-stage reaction include flow path 1 into which the liquid A1 is introduced, flow path 2 into which the liquid B1 is introduced, a junction J1 where flow paths 1 and 2 join, a reaction tube F1 connected to the downstream end of the junction J1, flow path 3 into which the liquid C1 is introduced, a junction J2 where the reaction tube F1 and flow path 3 join, and a reaction tube F2 connected to the downstream end of the junction J2. In this first-stage reaction, first, a combined liquid M1 produced when the liquid A1 and the liquid B1 join at the junction J1 flows through the reaction tube F1, and a metallated halogenated aromatic compound is produced while the combined liquid M2 produced when the combined liquid M1 and the liquid C1 join at the junction J2 flows through the reaction tube F2.

[0018] 1 , the flow path 4 into which the liquid B2 is introduced, the confluence J3 where the reaction tube F2 and the flow path 4 join, the reaction tube F3 connected to the downstream end of the confluence J3, the flow path 5 into which the liquid C2 is introduced, the confluence J4 where the reaction tube F3 and the flow path 5 join, and the reaction tube F4 connected to the downstream end of the confluence J4 are parts involved in the second-stage reaction. In the second-stage reaction, first, a metallated electrophilic mono-substituted aromatic compound is produced while the combined liquid M3 produced by the confluence of the combined liquid M2 and the liquid B2 at the confluence J3 flows through the reaction tube F3, and then, a combined liquid M4 produced by the confluence of the combined liquid M3 and the liquid C2 at the confluence J4 generates an electrophilic di-substituted aromatic compound while the combined liquid M4 flows through the reaction tube F4.

[0019] As shown in FIG. 1, the combined liquid M4 flowing through F4 is optionally joined at confluence J5 with a quenching agent (X in FIG. 1) such as water or alcohol, thereby undergoing a quenching treatment (converting metal atoms in the product to hydrogen atoms) while flowing through reaction tube F5. The metallation / electrophilic substitution reaction of the halogenated aromatic compound shown in FIG. 2 is shown in more detail in FIG. 3. The metal (lithium) atom in the metallated (lithiated) aromatic compound is substituted with an electrophilic compound (2-phenyl-1,10-phenanthroline), and the substituted metal (lithium) atom remains bonded to the substituted electrophilic compound (2-phenyl-1,10-phenanthroline). That is, what is produced in the combined liquid M4 flowing through reaction tube F4 is a dimetallated (dilithiated) electrophilic disubstituted aromatic compound having two metal (lithium) atoms derived from the organometallic (lithium) compound, which remains highly reactive. The quenching treatment is a process for converting the metal (lithium) atom from the dimetalated (dilithiated) electrophilic disubstituted aromatic compound to a hydrogen atom and terminating the reaction. If necessary, the organic phase may be oxidized with an oxidizing agent such as p-benzoquinone to obtain the desired electrophilic disubstituted aromatic compound. In the metalation / electrophilic substitution reaction of the halogenated aromatic compound shown in Figures 2 and 3, after the quenching treatment, some of the nitrogen atoms constituting the phenanthroline ring are present in the -NH- form. The oxidation treatment can restore the -NH- to -N= form (phenanthroline skeleton).

[0020] In the reaction schemes of Figures 2 and 3, a phenanthroline compound having a basic group (a nitrogen atom constituting the ring) is used as the electrophilic compound, so that a metal element (lithium) is bonded to the phenanthroline skeleton. However, when a different compound is used as the electrophilic compound, the metal element is not necessarily bonded to the electrophilic compound. For example, when chlorotrimethylsilane is used as the electrophilic compound, lithium is present mainly as lithium chloride.

[0021] 1 , carrying out a flow reaction in which the reaction mixture is allowed to flow up to reaction tube F4 corresponds to carrying out the production method of the present invention. That is, the production method of the present invention encompasses various forms, such as a form in which the flow reaction is carried out up to reaction tube F4, a form in which the flow reaction is carried out up to reaction tube F5, a form in which a quenching treatment is carried out batchwise or the like instead of reaction tube F5, and a form in which a chemical treatment such as the above-mentioned oxidation treatment, various purification treatments, or the like is carried out after the quenching treatment depending on the purpose.

[0022] Another example of a metalation / electrophilic substitution reaction of a halogenated aromatic compound that can be applied to a two-step reaction system is shown in Figure 8. In Figure 8, Bu stands for butyl, Ph stands for phenyl, Bpin stands for pinacolatoboryl group, and TMS stands for trimethylsilyl.

[0023] The flow reaction system 200 shown in Figure 4 is a basic form of a single-stage reaction system in which liquid A2 containing a halogenated aromatic compound (e.g., a monohalogenated aromatic compound) in an organic solvent is introduced once, followed by liquid B3 containing an organometallic compound in an organic solvent and liquid C3 containing an electrophilic compound in an organic solvent. In this flow reaction system 200, the single-stage reaction system includes at least flow path 7 into which liquid A2 is introduced, flow path 8 into which liquid B3 is introduced, junction J6 where flow paths 7 and 8 merge, reaction tube F6 connected to the downstream end of junction J6, flow path 9 into which liquid C3 is introduced, junction J7 where reaction tube F6 and flow path 9 merge, and reaction tube F7 connected to the downstream end of junction J7. In this single-stage reaction system, liquid A2 and liquid B3 merge at junction J6 to form combined liquid M6, which flows through reaction tube F6 to produce a metallated aromatic compound. Next, the combined liquid M6 and the liquid C3 are joined at the joining point J7 to produce a combined liquid M7, which flows through the reaction tube F7 and produces an electrophilic mono-substituted aromatic compound. Thereafter, a quenching treatment or the like can be carried out as necessary in the same manner as described above. Figure 4 shows an embodiment in which the quenching treatment is carried out in the reaction tube F8 (an embodiment in which the steps up to the quenching treatment are carried out continuously by a flow reaction).

[0024] 4, carrying out a flow reaction in which the reaction mixture is allowed to flow up to reaction tube F7 corresponds to carrying out the production method of the present invention. That is, the production method of the present invention encompasses various forms, such as a form in which the flow reaction is carried out up to reaction tube F7, a form in which the flow reaction is carried out up to reaction tube F8, a form in which a quenching treatment is carried out batchwise or the like instead of reaction tube F8, and a form in which a chemical treatment such as the above-mentioned oxidation treatment, various purification treatments, or the like is carried out after the quenching treatment depending on the purpose.

[0025] Figure 5 shows a modified example that is included in the production method of the present invention. The flow reaction system 300 shown in Figure 5 is a modified example of a single-stage reaction system. That is, the liquid containing the halogenated aromatic compound (e.g., monohalogenated aromatic compound) that is the starting material in the present invention is positioned as Liquid A4, not Liquid A3. Liquid A3 is positioned as a raw material for a reaction that produces an electrophilic compound for electrophilic substitution of the halogenated aromatic compound in Liquid A4. Therefore, this form is classified as a single-stage reaction system in the present invention.

[0026] 5, liquids A3 and A4 containing a halogenated aromatic compound in an organic solvent, liquids B4 and B5 containing an organometallic compound in an organic solvent, and liquid C4 containing an electrophilic compound in an organic solvent are prepared. The flow reaction system 300 includes a flow path 11 into which liquid A3 is introduced, a flow path 12 into which liquid B4 is introduced, a junction J9 where the flow paths 11 and 12 join, a reaction tube F9 connected to the downstream end of the junction J9, a flow path 13 into which liquid C4 is introduced, a junction J10 where the reaction tube F9 and the flow path 13 join, and a reaction tube F10 connected to the downstream end of the junction J10. The flow reaction system 300 further includes a flow path 14 into which the liquid A4 is introduced, a flow path 15 into which the liquid B5 is introduced, a confluence J11 where the flow paths 14 and 15 join, a reaction tube F11 connected to the downstream end of the confluence J11, a confluence J12 where the reaction tubes F10 and F11 join, and a reaction tube F12 connected to the downstream end of the confluence J12. In this reaction system, first, a metallated aromatic compound is produced while a combined liquid M9, which is produced when the liquids A3 and B4 join at the confluence J9, flows through the reaction tube F9. Next, a combined liquid M10, which is produced when the combined liquid M9 and liquid C4 join at the confluence J10, flows through the reaction tube F10, producing an electrophilic mono-substituted aromatic compound (i). This electrophilic mono-substituted aromatic compound (i) is not the target compound in the present invention, but rather a compound that functions as an electrophilic compound in the subsequent reaction. Separately, a combined liquid M11, which is produced by combining liquid A4 containing a halogenated aromatic compound (the starting material in the present invention) and liquid B5 at a confluence J11, flows through a reaction tube F11. Then, combined liquid M11 and combined liquid M10 join at a confluence J12 to produce combined liquid M12. While combined liquid M12 flows through a reaction tube F12, the electrophilic mono-substituted aromatic compound (i) in combined liquid M10 reacts with the metallated aromatic compound in combined liquid M11 to produce the desired electrophilic mono-substituted aromatic compound. Therefore, the electrophilic compound in liquid C4 typically has a substituent for electrophilic substitution of the metallated aromatic compound in combined liquid M9, as well as a substituent for electrophilic substitution of the metallated aromatic compound produced in combined liquid 11 after this electrophilic substitution reaction. Thereafter, a quenching treatment or the like can be carried out as necessary in the same manner as described above.FIG. 5 shows an embodiment in which the quenching treatment is carried out in a reaction tube F13 (an embodiment in which the process up to the quenching treatment is carried out continuously by a flow reaction).

[0027] 5, carrying out a flow reaction in which the reaction mixture flows up to the reaction tube F12 corresponds to carrying out the production method of the present invention. That is, the production method of the present invention includes various forms, such as a form in which the flow reaction is carried out up to the reaction tube F12, a form in which the flow reaction is carried out up to the reaction tube F13, a form in which a quenching treatment is carried out batchwise or the like instead of the reaction tube F13, and a form in which a chemical treatment such as the above-mentioned oxidation treatment, various purification treatments, or the like is further carried out after the quenching treatment depending on the purpose.

[0028] FIG. 6 shows another modified example of the production method of the present invention. The flow reaction system 400 shown in FIG. 6 is a modified example of a single-stage reaction system. Specifically, an electrophilic mono-substituted aromatic compound is obtained in a single-stage reaction system using a halogenated aromatic compound (e.g., a monohalogenated aromatic compound) as a starting material. A nucleophilic compound (nucleophilic reagent) is then reacted with the halogenated aromatic compound in a reaction separate from the metallization and electrophilic substitution reaction to obtain an electrophilic mono-substituted or nucleophilically substituted aromatic compound. This configuration is classified as a single-stage reaction system in the present invention. FIG. 7 shows an example of a reaction applied to the flow reaction system of FIG. 6. A bromoaryl (preferably bromobenzene) is used as the halogenated aromatic compound, n-butyllithium as the organometallic compound, 1,10-phenanthroline as the electrophilic compound, and n-butyllithium as the nucleophilic compound are used.

[0029] 6 , liquid A5 containing a halogenated aromatic compound in an organic solvent, liquid B6 containing an organometallic compound in an organic solvent, liquid C5 containing an electrophilic compound in an organic solvent, and liquid D containing a nucleophilic compound in an organic solvent are prepared. The flow reaction system 400 includes a flow path 17 into which liquid A5 is introduced, a flow path 18 into which liquid B6 is introduced, a junction J14 where the flow paths 17 and 18 join, a reaction tube F14 connected to the downstream end of the junction J14, a flow path 19 into which liquid C5 is introduced, a junction J15 where the reaction tube F14 and the flow path 19 join, a reaction tube F15 connected to the downstream end of the junction J15, a flow path 20 into which liquid D is introduced, a junction J16 where the reaction tube F15 and the flow path 20 join, and a reaction tube F16 connected to the downstream end of the junction J16. In this reaction system, first, liquids A5 and B6 join at confluence J14 to form combined liquid M14, which flows through reaction tube F14, producing a metallated aromatic compound. Next, combined liquid M14 and liquid C5 join at confluence J15 to form combined liquid M15, which flows through reaction tube F15, producing an electrophilic mono-substituted aromatic compound. Next, combined liquid M15 and liquid D join at confluence J16 to form combined liquid 16, which flows through reaction tube F16, producing an electrophilic mono-substituted and nucleophilic substituted aromatic compound. Subsequently, a quenching treatment or the like can be performed as described above, if necessary. Figure 6 shows an embodiment in which this quenching treatment is performed in reaction tube F17 (an embodiment in which the process up to the quenching treatment is performed continuously by a flow reaction). It should be noted that the water content of liquid D is preferably controlled to 200 ppm or less, similar to the above-described liquids (A-I), (B-I), and (C-I). Furthermore, the more preferred range of water content of liquid D is the same as the preferred range of water content of liquids (AI), (BI) and (CI) described above.

[0030] 6, carrying out a flow reaction in which the reaction mixture flows up to the reaction tube F15 corresponds to carrying out the production method of the present invention. That is, the production method of the present invention includes various modes, such as a mode in which the flow reaction is carried out up to the reaction tube F15, a mode in which the flow reaction is carried out up to the reaction tube F16, a mode in which the flow reaction is carried out up to the reaction tube F17, a mode in which a quenching treatment is carried out batchwise or the like instead of the reaction tube F17, and a mode in which a chemical treatment such as the above-mentioned oxidation treatment, various purification treatments, or the like is carried out after the quenching treatment depending on the purpose.

[0031] In the above, the halogenated aromatic compound used in the first-stage reaction system is a monohalogenated aromatic compound, but the halogenated aromatic compound used in the first-stage reaction system may be an aromatic compound having multiple halogen atoms in one molecule, such as a dihalogenated aromatic compound or a trihalogenated aromatic compound. Even if these halogenated aromatic compounds are used, the reaction system will be a one-stage reaction system as long as the final compound is an electrophilic monosubstituted aromatic compound. Similarly, the halogenated aromatic compound used in the second-stage reaction system is not limited to a dihalogenated aromatic compound, but may be an aromatic compound having three or more halogen atoms in one molecule.

[0032] Another example of a metalation / electrophilic substitution reaction of a halogenated aromatic compound that can be applied to a one-step reaction system is shown in Figure 9. Me represents methyl, DMF represents dimethylformamide, and MeOTf represents methyl trifluoromethanesulfonate.

[0033] In the production method of the present invention, when the flow reaction is a one-stage reaction system (when the electrophilically substituted aromatic compound obtained from a halogenated aromatic compound is an electrophilic mono-substituted aromatic compound), the electrophilic compound can be used (converged) in an amount of preferably 0.80 molar equivalents or more and less than 1.20 molar equivalents, more preferably 0.80 molar equivalents or more and 1.10 molar equivalents or less, even more preferably 0.85 molar equivalents or more and 1.05 molar equivalents or less, and even more preferably 0.90 molar equivalents or more and 1.00 molar equivalents or less, relative to the halogenated aromatic compound. Here, "using Y molar equivalents of electrophilic compound relative to the halogenated aromatic compound" means that, assuming that a liquid containing the halogenated aromatic compound in an organic solvent introduced into a flow path is merged with a liquid containing the electrophilic compound in an organic solvent without any reaction of the halogenated aromatic compound in this liquid to form a uniform unreacted merged liquid, the concentration of the electrophilic compound in the liquid containing the electrophilic compound in an organic solvent, the flow rate of each liquid, etc. are controlled so that the amount of the electrophilic compound relative to the halogenated aromatic compound in this hypothetical merged liquid is Y molar equivalents.

[0034] In the case of the first-stage reaction system shown in Fig. 4, a combined liquid M6 of Liquids A2 and B3 generates a metallated aromatic compound while flowing through reaction tube F6. Therefore, the phrase "relative to the halogenated aromatic compound" is roughly equivalent to using the amount of this metallated aromatic compound as the standard. That is, in combined liquid M7 immediately after the addition of Liquid C3, the amount of the electrophilic compound relative to the metallated aromatic compound can be adjusted to fall within the above-mentioned preferred molar equivalent range.

[0035] When the first-stage reaction system has the configuration shown in Fig. 5, the liquid containing the halogenated aromatic compound, which is the starting material in the present invention, is Liquid A4, not Liquid A3, as described above. Since the combined liquid M11 of Liquids A4 and B5 produces a metallated aromatic compound while flowing through the reaction tube F11, the phrase "with respect to the halogenated aromatic compound" is roughly equivalent to using the amount of this metallated aromatic compound as the basis. In other words, the amount of the electrophilic compound (electrophilic mono-substituted aromatic compound (i)) produced in the combined liquid M10 relative to the amount of this metallated aromatic compound can be adjusted to fall within the above-mentioned preferred molar equivalent range immediately after the two liquids are combined at the confluence J12.

[0036] In the case where the first-stage reaction system has the configuration shown in Fig. 6, a combined liquid M14 of Liquids A5 and B6 generates a metallated aromatic compound while flowing through the reaction tube F14. Therefore, the phrase "relative to the halogenated aromatic compound" is roughly equivalent to using the amount of this metallated aromatic compound as the standard. That is, in the combined liquid M15 immediately after the addition of Liquid C5, the amount of the electrophilic compound relative to the metallated aromatic compound can be adjusted to fall within the above-mentioned preferred molar equivalent range.

[0037] When the flow reaction is a multi-stage reaction system (when one molecule of the electrophilically substituted aromatic compound obtained from the halogenated aromatic compound has substituents derived from two or more electrophilic compounds), the electrophilic compound can be supplied to the final stage reaction in an amount of preferably 0.80 molar equivalents or more but less than 2.00 molar equivalents, more preferably 0.80 molar equivalents or more but less than 1.50 molar equivalents, even more preferably 0.80 molar equivalents or more but less than 1.20 molar equivalents, and even more preferably 0.90 molar equivalents or more but less than 1.10 molar equivalents, relative to the halogenated aromatic compound. Here, "subjecting Y molar equivalents of the electrophilic compound to the final-stage reaction relative to the halogenated aromatic compound" means that, assuming that the halogenated aromatic compound in the liquid containing the halogenated aromatic compound in an organic solvent introduced into the flow path does not react at all, it merges with the liquid containing the electrophilic compound in an organic solvent in the final stage to form a uniform combined liquid, and the concentration of the electrophilic compound in the liquid containing the electrophilic compound that merges in the final stage, the flow rate of each liquid, etc. are controlled so that the amount of the electrophilic compound merged in the final stage relative to the halogenated aromatic compound in this hypothetical combined liquid is Y molar equivalents. For example, in the case of the two-stage reaction system shown in Figure 1 as an example of a multi-stage reaction system, it is considered that the electrophilic mono-substituted halogenated aromatic compound contained in the combined liquid M2 is substantially subjected to the final-stage reaction (second-stage reaction). That is, a roughly preferred embodiment of the two-stage reaction system is one in which the amount of the electrophilic compound contained in liquid C2 (the amount of the electrophilic compound derived from liquid C2 immediately after joining at confluence J4) is within the above-mentioned preferred molar equivalent range relative to the metallated electrophilic mono-substituted aromatic compound produced by the reaction of this electrophilic mono-substituted halogenoaromatic compound with the organometallic compound in liquid B2.

[0038] Thus, according to the production method of the present invention, the target electrophilic mono-substituted aromatic compound can be obtained at a desired high production yield even when the amount of electrophilic compound used is reduced.

[0039] Furthermore, in the case of a multistage flow reaction system, in the reaction before the final stage (the reaction in each stage other than the final stage), the electrophilic compound may be supplied to the reaction before the final stage in an amount of preferably 0.80 to less than 1.20 molar equivalents, more preferably 0.80 to 1.10 molar equivalents, even more preferably 0.85 to 1.05 molar equivalents, and even more preferably 0.90 to 1.00 molar equivalents relative to the halogenated aromatic compound. For example, referring to Figures 1 to 3, in the reaction before the final stage (first-stage reaction), the halogenated aromatic compound is the dihalogenated aromatic compound contained in Liquid A1. Therefore, it is preferable to adjust the amount of the electrophilic compound contained in Liquid C1 relative to the dihalogenated aromatic compound contained in Liquid A1 to be within the above-mentioned preferred molar equivalent range immediately after the two liquids are joined at the confluence J2.

[0040] In the production method of the present invention, the amount of organometallic compound used will be described. When the flow reaction is a one-stage reaction system, the organometallic compound can be used (confluent) in an amount of preferably 0.80 molar equivalents or more but less than 1.20 molar equivalents, more preferably 0.85 molar equivalents or more but less than 1.15 molar equivalents, even more preferably 0.90 molar equivalents or more but less than 1.10 molar equivalents, even more preferably 1.00 molar equivalents or more but less than 1.05 molar equivalents, and even more preferably 1.02 molar equivalents or more but less than 1.05 molar equivalents, relative to the halogenated aromatic compound.

[0041] Furthermore, when the flow reaction is a multistage reaction system, the amount of the organometallic compound supplied to each stage of the reaction except for the final stage relative to the halogenated aromatic compound can be set to preferably 0.80 molar equivalents or more and less than 2.00 molar equivalents, more preferably 0.90 molar equivalents or more and 1.50 molar equivalents or less, even more preferably 1.00 molar equivalents or more and 1.20 molar equivalents or less, still more preferably 1.00 molar equivalents or more and 1.10 molar equivalents or less, and even more preferably 1.02 molar equivalents or more and 1.05 molar equivalents or less.

[0042] Furthermore, when the flow reaction is a multistage reaction system, the amount of the organometallic compound supplied to the final stage relative to the halogenated aromatic compound in the final stage reaction can be preferably 0.80 molar equivalents or more and less than 2.00 molar equivalents, more preferably 0.90 molar equivalents or more and 1.20 molar equivalents or less, even more preferably 1.00 molar equivalents or more and 1.10 molar equivalents or less, and even more preferably 1.02 molar equivalents or more and 1.05 molar equivalents or less.

[0043] Next, the configuration of each component, reagent, etc. in the flow reaction will be explained, but the present invention is not limited to the configuration explained below except as defined in the present invention.

[0044] <Flow paths> Each flow path (flow paths 1 to 21) through which each liquid flows preferably has an equivalent diameter of 0.2 to 50 mm. By making the equivalent diameter of the flow path 0.2 mm or more, it is possible to suppress pressure increases during liquid transfer and to suppress blockage of the flow path even when insoluble matter is generated. Furthermore, by making the equivalent diameter of each flow path 50 mm or less, it is possible to appropriately control the liquid temperature at the junction. The equivalent diameter of each flow path is more preferably 0.5 to 30 mm, even more preferably 1 to 20 mm, and even more preferably 1 to 10 mm. The above-mentioned "equivalent diameter" is also called the equivalent diameter, and is a term used in the field of mechanical engineering. When a circular pipe equivalent to a piping or flow path with an arbitrary internal cross-sectional shape is imagined, the diameter of the internal cross section of that equivalent circular pipe is called the equivalent diameter. The equivalent diameter (deq) is defined as deq = 4A / p, where A is the inner cross-sectional area of ​​the pipe and p is the wetted edge length (inner circumference) of the pipe. When applied to a circular pipe, this equivalent diameter is equal to the diameter of the inner cross section of the circular pipe. The equivalent diameter is used to estimate the flow or heat transfer characteristics of the pipe based on the data of the equivalent circular pipe, and represents the spatial scale (representative length) of the phenomenon. For a regular square pipe with an inner cross section of side a, the equivalent diameter is deq = 4a ２ / 4a = a, and for an equilateral triangle tube with one side a, deq = a / 3 １／２ In the case of a flow between parallel plates with a flow path height h, deq=2h (see, for example, "Mechanical Engineering Dictionary," edited by the Japan Society of Mechanical Engineers, 1997, Maruzen Co., Ltd.).

[0045] There are no particular restrictions on the length of each flow path, and for example, the flow path can be configured using a tube with a length of approximately 10 cm to 15 m (preferably 30 cm to 10 m). There are no particular restrictions on the material of the tube, and examples include perfluoroalkoxyalkane (PFA), Teflon (registered trademark), aromatic polyether ketone resin, stainless steel, copper or copper alloy, nickel or nickel alloy, titanium or titanium alloy, quartz glass, and lime soda glass. From the viewpoints of flexibility and chemical resistance, the material of the tube is preferably PFA, Teflon (registered trademark), stainless steel, nickel alloy, or titanium.

[0046] There are no particular limitations on the flow rate of each liquid introduced into each flow channel, and it can be set appropriately depending on the purpose, taking into consideration the equivalent diameter of the flow channel, the reaction volume ratio, the liquid concentration, etc. For example, it is preferably 0.1 to 5000 mL / min (minute), more preferably 0.5 to 3000 mL / min, even more preferably 1 to 3000 mL / min, and even more preferably 100 to 2000 mL / min.

[0047] (Liquid containing a halogenated aromatic compound in an organic solvent) In the liquid (A-I) containing a halogenated aromatic compound in an organic solvent, the type of organic solvent used is not particularly limited as long as it has the ability to dissolve the halogenated aromatic compound. Examples include halogen-containing solvents, ether solvents having a linear, branched, or cyclic structure, and hydrocarbon solvents. Examples of halogen-containing solvents include methylene chloride, chloroform, dichloroethane, carbon tetrachloride, chlorobenzene, and o-dichlorobenzene. Examples of ether solvents include tetrahydrofuran (THF), dioxane, methyl tertiary butyl ether, cyclopentyl methyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, and derivatives thereof. Examples of hydrocarbon solvents include hexane, heptane, octane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, mesitylene, decalin, tetralin, and derivatives thereof. In addition, examples of the organic solvent that can be used include ketone solvents such as acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, and methyl isobutyl ketone; nitrile solvents such as acetonitrile; lactone solvents such as γ-butyrolactone; ester solvents such as ethyl acetate and butyl acetate; and amide solvents such as dimethylacetamide, dimethylformamide, N-methyl-2-pyrrolidone, and 1,3-dimethyl-2-imidazolidinone. The organic solvents listed above may be used alone or in combination. Among these, it is preferable to use at least one of methylene chloride, chloroform, chlorobenzene, o-dichlorobenzene, tetrahydrofuran, dioxane, toluene, xylene, mesitylene, cyclohexanone, methyl ethyl ketone, and acetonitrile, and it is more preferable to use at least one of methylene chloride, chlorobenzene, o-dichlorobenzene, tetrahydrofuran, toluene, xylene, mesitylene, and acetonitrile.

[0048] In the above liquid (A-I), the type of halogenated aromatic compound is not particularly limited and is appropriately selected depending on the chemical structure, etc., of the target compound. The number, type, and position of halogen atoms in the halogenated aromatic compound are not particularly limited. Examples of halogen elements include fluorine, chlorine, bromine, and iodine, with bromine being preferred. Examples of ring structures of the halogenated aromatic compound include monocyclic or polycyclic 6- to 10-membered aromatic hydrocarbon rings such as benzene, naphthalene, anthracene, phenanthrene, and fluorene; and 5- to 10-membered monocyclic or polycyclic aromatic heterocycles containing 1 to 4 atoms selected from nitrogen, oxygen, and sulfur, such as pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, thiazole, carbazole, pyridine, pyrazine, pyrimidine, pyridazine, and triazine.

[0049] The concentration of the halogenated aromatic compound in the liquid (AI) is appropriately set in consideration of the concentrations of the liquids (BI), (CI), etc., the flow rate of each liquid, etc. For example, it can be 0.1 to 10 mol / L (hereinafter also referred to as M), and preferably 0.3 to 8 mol / L.

[0050] (Liquid containing an organometallic compound in an organic solvent) In the liquid (BI) containing an organometallic compound in an organic solvent, the type of solvent used is not particularly limited as long as it has the ability to dissolve the organometallic compound. For example, the organic solvents described above as usable for the liquid (AI) can also be suitably used as the organic solvent for the liquid (BI).

[0051] In the liquid (BI), the type of organometallic compound is not particularly limited as long as it can metallize a halogenated aromatic compound. For example, an organolithium compound, an organomagnesium compound, etc. can be used, and among them, an organolithium compound is preferred. The organolithium compound is not particularly limited and can be appropriately selected from conventionally known organolithium compounds. Examples thereof include alkyllithiums such as methyllithium, ethyllithium, propyllithium, butyllithium (n-butyllithium, sec-butyllithium, iso-butyllithium, tert-butyllithium, etc.), pentyllithium, hexyllithium, methoxymethyllithium, and ethoxymethyllithium; benzyllithiums such as α-methylstyryllithium, 1,1-diphenyl-3-methylpentyllithium, and 3-methyl-1,1-diphenylpentyllithium; alkenyllithiums such as vinyllithium, allyllithium, propenyllithium, and butenyllithium; alkynyllithiums such as ethynyllithium, butynyllithium, pentynyllithium, and hexynyllithium; aralkyllithiums such as benzyllithium and phenylethyllithium; aryllithiums such as phenyllithium and naphthyllithium; heterocyclic lithiums such as 2-thienyllithium, 4-pyridyllithium, and 2-quinolyllithium; and alkyllithium magnesium complexes such as tri(n-butyl)magnesiumlithium and trimethylmagnesiumlithium. Among these, alkyllithium is more preferred, and n-butyllithium is particularly preferred, because it has high reactivity and can speed up the initiation reaction.

[0052] The concentration of the organometallic compound in the liquid (BI) is appropriately set in consideration of the concentrations of the liquids (AI) and (CI), the flow rate of each liquid, etc. For example, it can be set to 0.5 to 5 mol / L, and preferably 1 to 3 mol / L.

[0053] (Solution containing an electrophilic compound in an organic solvent) In the solution (C-I) containing an electrophilic compound in an organic solvent, the type of electrophilic compound is not particularly limited as long as it is a compound having a functional group with electron-accepting ability (i.e., a compound that can act as an electrophilic agent). An electrophilic compound that can be used in a metallation reaction by a halogen-metal exchange reaction using an organometallic compound is appropriately selected depending on the chemical structure of the target compound, etc. For example, halogens such as chlorine, bromine, and iodine; inorganic substances such as sulfur, sulfur dioxide, and oxygen; carbon dioxide; sulfonic acids such as trifluoromethylsulfonic acid methyl ester and trifluoromethylbenzenesulfonic acid; dimethyl sulfate; nitriles such as acetonitrile, propionitrile, and benzonitrile; imines such as benzophenone imine and acetophenone imine; silicon halides such as chlorotrimethylsilane, chlorodimethylphenylsilane, chlorodimethylsilane, and bromotrimethylsilane; chlorosilane compounds such as chlorodialkylhydrosilane; boron halides such as trichloroborane and tribromoborane; boronic acid esters such as pinacolboronic acid ester, trimethylboronic acid ester, and triisopropylboronic acid ester; boron compounds such as methoxydiethylborane, tris(dimethylamino)borane, and bis(pinacolato)diborane; tin compounds such as dibutyltin dichloride and diphenyltin dibromide; Aldehydes such as paraformaldehyde, acetaldehyde, propionaldehyde, butylaldehyde, acrylaldehyde, benzaldehyde, and nicotinaldehyde; ketones such as acetone, 2-butanone, benzophenone, acetophenone, DMF, and tert-butyl-4-oxo-1-piperidinecarboxylate; esters such as ethyl chloroformate, phenyl chloroformate, methyl formate, ethyl formate, ethyl acetate, butyl acetate, octyl acetate, phenyl acetate, methyl benzoate, ethyl benzoate, and phenyl benzoate; acid anhydrides such as acetic anhydride, phthalic anhydride, succinic anhydride, and maleic anhydride; acyl halides such as acetyl chloride, benzoyl chloride, and 2-pyridinecarbonyl chloride; oxiranes such as oxirane and 2-methyl-oxirane;Aziridines such as 6-azabicyclo[3,1,0]hexane and 7-azabicyclo[4,1,0]heptane; α,β-unsaturated ketones such as 3-oxo-1,3-diphenyl-1-propene and 2-methyl-3-oxo-3-diphenyl-1-propene; alkyl halides such as methyl iodide, ethyl iodide, butyl iodide, methyl bromide, ethyl bromide, hexyl bromide, octyl bromide, 1,2-diiodoethane, 1,2-dibromoethane, 1,6-diiodohexane, 1,8-dibromooctane, and 1,2-dibromocyclopentene; acid imides such as N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide, and N-bromophthalimide; disulfides such as dimethyl disulfide and diphenyl disulfide; Phosphines such as chlorodiphenylphosphine and chlorodimethylphosphine; phosphine oxides such as chlorodiphenylphosphine oxide and chlorodimethylphosphine oxide; heterocyclic compounds such as pyridine, pyrimidine, pyridazine, phenanthroline, bipyridine, terpyridine, imidazole, pyrazole, oxazole, and thiazole;

[0054] The concentration of the halogenated aromatic compound in the liquid (CI) is appropriately set in consideration of the concentrations of the liquids (AI), (BI), etc., the flow rate of each liquid, etc. For example, it can be 0.1 to 10 mol / L, and preferably 0.3 to 3 mol / L.

[0055] The flow rate of each of the above liquids through the flow channel is not particularly limited and can be set appropriately depending on the purpose, taking into consideration the equivalent diameter of the flow channel, the solution concentration, etc. For example, the flow rate is preferably 0.1 to 5000 mL / min (minute), more preferably 0.5 to 3000 mL / min, even more preferably 1 to 3000 mL / min, and even more preferably 100 to 2000 mL / min.

[0056] <Confluence> There are no particular limitations on the material of each confluence (confluence J1 to J17), and materials such as perfluoroalkoxyalkane (PFA), Teflon (registered trademark), aromatic polyether ketone resin, stainless steel, copper or copper alloy, nickel or nickel alloy, titanium or titanium alloy, quartz glass, and lime soda glass can be used. For each confluence, a wide variety of commercially available connectors, such as T-shaped connectors, Y-shaped connectors, or multilayer tubular connectors, can be used. Furthermore, connectors with cross-shaped or more branches can also be used as needed.

[0057] <Reaction Tube> There are no particular limitations on the form of the reaction tubes (reaction tubes F1 to F17), and tubes are usually used. The preferred materials for the reaction tubes are the same as the preferred materials for the flow paths described above. The reaction time can be adjusted by the equivalent diameter and length of the reaction tube, the flow rate setting of the liquid feed pump, etc. Usually, the equivalent diameter of the reaction tube is preferably 0.1 to 50 mm, more preferably 0.2 to 20 mm, even more preferably 0.4 to 15 mm, even more preferably 0.7 to 12 mm, and even more preferably 1 to 10 mm. The length of the reaction tube is preferably 0.5 to 50 m, more preferably 1 to 30 m.

[0058] Regarding the temperature of the reaction tube (i.e., reaction temperature), the temperature of the reaction tube where metallization occurs by reaction with an organometallic compound is preferably −80 to 100°C, more preferably −30 to 50°C. The temperature of the reaction tube where the substitution reaction of the metallized site with an electrophilic compound occurs is preferably −50 to 120°C, more preferably −20 to 80°C. The temperature of the junction or flow path upstream of the reaction tube is appropriately adjusted so that the temperature of the reaction tube can be precisely controlled. Usually, it is preferable to set the temperature of the flow path or junction and the reaction tube connected downstream thereof to the same temperature.

[0059] The residence time (reaction time) of each of the combined liquids in the reaction tube is preferably 0.1 seconds or more, more preferably 1 to 600 seconds, and even more preferably 3 to 200 seconds.

[0060] The present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

[0061] Reference Example 1 According to the reaction schemes shown in FIGS. 2 and 3 , a target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 100 configured as shown in FIG. 1 , with some of the T-connectors replaced with cross connectors as described below. In Reference Example 1, the solvents for the solutions described below flowing through the flow paths were appropriately selected from a mixture of industrial THF and THF from which water had been removed to reduce the water content, or from solutions whose water content had been adjusted by dehydration. The water contents listed in the table below indicate the water contents of the halogenated aromatic compound solution and the electrophilic compound solution. The organometallic compound solution was anhydrous. This also applies to the references, comparative examples, and examples described below. Specific reaction conditions were as follows:

[0062] Liquid delivery pump (not shown): Five syringe pumps PHDULTRA manufactured by HARVARD and one dual pump KP-22 manufactured by FLOM were used.

[0063] Temperature control: The temperatures of flow paths 1 and 2, the junction J1, and the reaction tube F1 were set to 0°C. The temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 0°C. The temperatures of flow path 4, the junction J3, and the reaction tube F3 were set to -20°C. The temperatures of flow path 5, the junction J4, and the reaction tube F4 were set to 5°C. The temperatures of flow path 6, the junction J5, and the reaction tube F5 were set to 5°C.

[0064] Flow path 1: A single SUS tube was divided into two sections by a T-connector. More specifically, a SUS316 tube with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm was connected to a T-connector (inner diameter 1.0 mm). Two other SUS316 tubes, each with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 3 cm, were connected to this T-connector so as to face each other. This formed flow path 1.

[0065] Flow path 2, flow path 3, flow path 4, flow path 5, flow path 6: SUS316 tubes having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm were used.

[0066] Reaction tube F1: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm was used.

[0067] Reaction tube F2: A single SUS tube was divided into two sections by a T-connector. More specifically, a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m was connected to a T-connector (inner diameter 1.0 mm), and two SUS316 tubes having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 3 cm were connected to the T-connector so as to face each other. This T-connector was used as reaction tube F2.

[0068] Reaction tube F3: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m was used.

[0069] Reaction tube F4: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm and a length of 1.5 m was used.

[0070] Reaction tube F5: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.5 m was used.

[0071] Confluence J1: A cross connector with an inner diameter of 0.5 mm was used. Two SUS316 tubes, connected to the T-connector constituting Flow Channel 1 so as to face each other, were connected to two of the four connection ports of the cross connector, each of which faced each other. One of the remaining two connection ports was connected to Flow Channel 2, and the remaining connection port was used as an outlet for discharging the liquid.

[0072] Confluence J2: A T-connector with an inner diameter of 0.5 mm was used. The reaction tube F1 and the flow path 3 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0073] Junction J3: A cross connector with an inner diameter of 0.5 mm was used. Two SUS316 tubes, which were connected to the T-connector constituting the reaction tube F2 so as to face each other, were connected to two of the four connection ports of the cross connector, each of which faced each other. One of the remaining two connection ports was connected to the flow path 4, and the remaining connection port was used as an outlet for discharging the liquid.

[0074] Junction J4: A T-connector with an inner diameter of 0.5 mm was used. The reaction tube F3 and the flow path 5 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0075] Junction J5: A T-connector with an inner diameter of 1.3 mm was used. The reaction tube F4 and the flow path 6 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0076] Solution A1 containing a dihalogenated aromatic compound in an organic solvent: A solution was prepared by dissolving 1,4-dibromonaphthalene in THF (1,4-dibromonaphthalene solution A1, 1,4-dibromonaphthalene concentration: 0.35 M).

[0077] Solution B1 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B1, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Inc. was used.

[0078] Solution B2 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B2, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Inc. was used.

[0079] Solution C1 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-phenyl-1,10-phenanthroline in THF (2-phenyl-1,10-phenanthroline solution C1, 2-phenyl-1,10-phenanthroline concentration: 0.31 M) was prepared and used in the first-step reaction.

[0080] Solution C2 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-phenyl-1,10-phenanthroline in THF (2-phenyl-1,10-phenanthroline solution C2, 2-phenyl-1,10-phenanthroline concentration: 0.31 M) was prepared and used in the second-step reaction.

[0081] Solution flow conditions: 1,4-dibromonaphthalene solution A1: 5.4 mL / min n-butyllithium solution B1: 1.2 mL / min n-butyllithium solution B2: 1.2 mL / min 2-phenyl-1,10-phenanthroline solution C1: 6.0 mL / min 2-phenyl-1,10-phenanthroline solution C2: 12.0 mL / min Water (X): 1.7 mL / min

[0082] Analyses in each of the Reference Examples, Comparative Examples, and Examples were carried out as follows.

[0083] Measurement of water content of each solution: Measurement was carried out using a trace water content measuring device CA-200 manufactured by Nitto Seiko Analytech Co., Ltd.

[0084] Production rate (%) of target compound: The production rate was defined as the ratio of the molar amount of the target compound to the molar amount of the introduced raw material halogenated aromatic compound. The production rate was determined based on the results of analysis under the following conditions using liquid chromatography (LC), gas chromatography (GC), or 1H-NMR. The production rate (%) was calculated using the calibration curve method or the internal standard method. Note that for Reference Examples, Comparative Examples, and Examples in which the raw material and the target compound were the same, the production rates of the target compound were all analyzed and determined under the same conditions.

[0085] -LC conditions- Measuring instrument: LC-2060C 3D (Shimadzu Corporation) Column: Mightysil RP-8 (4.6 mmφ×250 mm, 5 μm) Column temperature: 45° C. Eluent A: water (0.1% phosphoric acid aqueous solution) Eluent B: acetonitrile / THF=8 / 2 (volume ratio) Flow rate: 1.0 mL / min Detection wavelength: 254 nm Injection volume: 5 μL

[0086] -GC conditions- Measuring instrument: Nexis GC-2030 (Shimadzu Corporation) Column: DB-17MS (30 m x 0.25 mm x 0.25 μm, GL Sciences) Detector temperature: 300°C Vaporization chamber temperature: 250°C Column flow rate: 1.0 mL / min Carrier gas: Helium Injection amount: 1 μL

[0087] -NMR Conditions- Measuring instrument: Ascend NMR400 (manufactured by Bruker) Internal standard: 1,3,5-trimethoxybenzene The target compound was identified by 1H-NMR. １ H-NMR (400 MHz, solvent: CDCl ３ , internal standard: tetramethylsilane (TMS)) chemical shift σ (ppm) = 8.83-8.80 (2H, m), 8.44-8.41 (6H, m), 8.37-8.35 (2H, m), 8.19-8.16 (4H, m), 8.11-8.09 (2H, m), 7.91-7.87 (4H, m), 7.64-7.61 (2H, m), 7.54-7.50 (4H, m), 7.46-7.43 (2H, m)

[0088] The results are shown in the table below. In the table, the molar equivalent is the molar amount relative to 1 mole of the raw material halogenated aromatic compound (dihalogenated aromatic compound (1,4-dibromonaphthalene)). The water content was set to 273 ppm in all of the 1,4-dibromonaphthalene solution A1 and the 2-phenyl-1,10-phenanthroline solutions C1 and C2.

[0089]

[0090] It was confirmed that when an excess amount of electrophilic compound was used in the final (second) stage reaction, the production rate of the target compound increased even when the water content of each solution flowing through the flow path was higher than the limit specified in the present invention (273 ppm).

[0091] The target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 1, except that the amount of electrophilic compound used in the final (second) stage reaction was reduced as shown in the table below by adjusting the flow rate of 2-phenyl-1,10-phenanthroline solution C2. The results are shown in the table below.

[0092]

[0093] It can be seen that when the amount of electrophilic compound used in the final stage (second stage) reaction is less than that in Reference Example 1, and the water content of each solution circulating in the flow path is higher than that specified in the present invention (273 ppm), the production rate of the target compound decreases depending on the amount of electrophilic compound used.

[0094] Examples 1 to 10 Target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 1, except that the water content of each solution (n-butyllithium solutions B1 and B2 are anhydrous as described above, and therefore "each solution" refers to a solution other than n-butyllithium solutions B1 and B2; the same applies hereinafter) flowed through the flow path was set as shown in the table below, and the amount of electrophilic compound used in the final-stage (second-stage) reaction was adjusted by adjusting the flow rate of 2-phenyl-1,10-phenanthroline solution C2.

[0095] Example 11 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Example 5, except that the water contents of the solutions flowing through the channels were as shown in the table below, and the temperatures of channels 4 and 5, confluences J3 and J4, and reaction tubes F3 and F4 were set to 0°C.

[0096] Example 12 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 11, except that the water content of each solution flowing through the flow paths was set as shown in the table below, and the temperatures of the flow path 3, the confluence J2, and the reaction tube F2 were set to 50°C.

[0097] Example 13 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 11, except that the water content of each solution flowing through the flow paths was set as shown in the table below, and the temperatures of flow paths 1 and 2, confluence J1, and reaction tube F1 were set to −20° C.

[0098] Example 14 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 11, except that the water content of each solution flowing through the flow paths was set as shown in the table below, and the temperatures of the flow path 5, the confluence J4, and the reaction tube F4 were set to 50°C.

[0099] [Example 15] The target electrophilically substituted aromatic compounds were prepared in the same manner as in Example 5, except that the water content of each solution flowing through the flow path was as shown in the table below and the quenching treatment was carried out batchwise.

[0100] Example 16 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 5, except that the water content of each solution flowing through the flow paths was as shown in the table below, the flow path 1 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm, the reaction tube F2 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m, and the confluences J1 and J3 were T-connectors (inner diameter 0.5 mm).

[0101] Example 17 The target electrophilically substituted aromatic compound was prepared in the same manner as in Example 5, except that the water content of each solution flowing through the flow path was set as shown in the table below, and the amount of organometallic compound used in the final-stage (second-stage) reaction was adjusted by adjusting the flow rate of n-butyllithium solution B2.

[0102] Example 18 The target electrophilically substituted aromatic compound was prepared in the same manner as in Example 5, except that the water content of each solution flowing through the flow path was set as shown in the table below, and the amount of organometallic compound used in the first-stage reaction was adjusted by adjusting the flow rate of n-butyllithium solution B1.

[0103] Example 19 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 5, except that each solution flowing through the flow paths was passed through a dehydration column disposed in the flow paths to reduce the water content, the temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 50°C, the temperatures of flow path 4, the junction J3, and the reaction tube F3 were set to -15°C, the temperatures of flow path 5, the junction J4, and the reaction tube F4 were set to 15°C, the junction J5 was a T-connector with an inner diameter of 2.3 mm, and the temperatures of flow path 6, the junction J5, and the reaction tube F5 were set to 15°C.

[0104] Example 20 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 19, except that the flow path 1 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm, the reaction tube F2 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m, the confluence J1 was a T-connector having an inner diameter of 1.0 mm, the temperatures of the flow paths 1 and 2, the confluence J1, and the reaction tube F1 were set to −15° C., and the confluences J2, J3, and J4 were T-connectors having an inner diameter of 1.0 mm.

[0105] Example 21 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 20, except that MeOH was fed as the quenching agent X at a rate of 3.4 mL / min, and the temperatures of the flow path 6, the confluence J5, and the reaction tube F5 were set to 0°C.

[0106] Example 22 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 20, except that the amounts of the organometallic compound and electrophilic compound used in the first-stage and second-stage reactions were adjusted by adjusting the flow rates of the n-butyllithium solution B1, the 2-phenyl-1,10-phenanthroline solution C1, the n-butyllithium solution B2, and the 2-phenyl-1,10-phenanthroline solution C2.

[0107] Example 23 The target electrophilically substituted aromatic compound was prepared in the same manner as in Example 22, except that the flow rates of the respective liquids were adjusted to three times that of Example 22.

[0108] Example 24 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 23, except that the flow path 1 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm, the reaction tube F2 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m, and the confluences J2 and J4 were T-connectors having an inner diameter of 2.3 mm.

[0109] The results are shown in the table below.

[0110]

[0111] As shown in the table above, by reducing the water content of each solution flowing through the flow path within the range specified in the present invention, the target compound could be obtained at a sufficiently high production rate even when the amount of electrophilic compound used was reduced.

[0112] Reference Example 2 A target electrophilically substituted aromatic compound (target compound) was prepared in the same manner as in Reference Example 1 using a flow reaction system 100 configured as shown in FIG. 1 . However, the water content of each solution flowing through the flow paths was adjusted as shown in the table below. The temperatures of flow paths 1, 2, and 3, confluences J1 and J2, and reaction tubes F1 and F2 were set to 10°C. A solution obtained by dissolving 1,5-dibromonaphthalene in THF (1,5-dibromonaphthalene solution, 1,5-dibromonaphthalene concentration: 0.35 M) was used as liquid A1 containing a dihalogenated aromatic compound in an organic solvent. The confluence J5 was a T-mixer with an inner diameter of 2.3 mm. The target compound was identified by 1H-NMR. １ H-NMR (400 MHz, solvent: CDCl ３ , internal standard: tetramethylsilane (TMS)) chemical shift σ (ppm) = 8.90-8.88 (2H, m), 8.43-8.40 (6H, m), 8.37-8.35 (2H, m), 8.19-8.17 (2H, m), 8.09-8.04 (4H, m), 7.91-7.87 (4H, m), 7.73-7.70 (2H, m), 7.53-7.49 (4H, m), 7.45-7.41 (2H, m)

[0113] The results are shown in the table below. In the table, the molar equivalent is the molar amount relative to 1 mole of the raw material halogenated aromatic compound.

[0114]

[0115] It was confirmed that when an excess amount of electrophilic compound was used in the final (second) stage reaction, the production rate of the target compound increased even when the water content of each solution flowing through the flow path was higher than the limit specified in the present invention (247 ppm).

[0116] Comparative Examples 5 to 7 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 2, except that the amount of electrophilic compound used in the final (second) stage reaction was reduced as shown in the table below by adjusting the flow rate of 2-phenyl-1,10-phenanthroline solution C2. The results are shown in the table below.

[0117]

[0118] It can be seen that when the amount of electrophilic compound used in the final stage (second stage) reaction is less than that in Reference Example 2, and the water content of each solution circulating in the flow path is higher than that specified in the present invention (247 ppm), the production rate of the target compound decreases depending on the amount of electrophilic compound used.

[0119] Examples 25 to 33 Target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 2, except that the water content of each solution flowing through the flow path was set as shown in the table below, and the amount of the electrophilic compound used in the final-stage (second-stage) reaction was adjusted by adjusting the flow rate of 2-phenyl-1,10-phenanthroline solution C2.

[0120] Example 34 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 28, except that the water content of each solution flowing through the flow paths was set as shown in the table below, the temperatures of flow paths 1 and 2, the junction J1, and the reaction tube F1 were set to 0°C, and the temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 20°C.

[0121] Example 35 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 34, except that the water content of each solution to be passed through the flow paths was as shown in the table below, the length of reaction tube F1 was set to 30 cm, the length of reaction tube F2 to the T-connector was set to 1.2 m, the length of reaction tube F3 was set to 1.0 m, and the length of reaction tube F4 was set to 4.0 m, and the temperatures of flow path 4, junction J3, and reaction tube F3 were set to 0°C.

[0122] Example 36 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Example 35, except that the water content of each solution to be passed through the flow channel was set as shown in the table below.

[0123] Example 37 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Example 36, except that the water content of each solution flowing through the flow paths was set as shown in the table below, and the temperatures of the flow paths 1 to 6, the confluences J1 to J5, and the reaction tubes F1 to F5 were set to 10°C.

[0124] Example 38 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 28, except that the water content of each solution flowing through the flow paths was as shown in the table below, the temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 50°C, and the temperatures of flow path 5, the junction J4, and the reaction tube F4 were set to 20°C.

[0125] Example 39 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 28, except that the water content of each solution flowing through the flow paths was as shown in the table below, the flow path 1 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm, the reaction tube F2 was a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m, and the confluences J1 and J3 were T-connectors (inner diameter 1.0 mm).

[0126] The results are shown in the table below.

[0127]

[0128] As shown in the table above, by reducing the water content of each solution flowing through the flow path within the range specified in the present invention, the target compound could be obtained at a sufficiently high production rate even when the amount of electrophilic compound used was reduced.

[0129] Reference Example 3 A target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 100 having the configuration shown in Figure 1. The target electrophilically substituted aromatic compound was prepared in the same manner as in Reference Example 1, except that the water content of each solution flowing through the flow path was set as shown in the table below and the reaction conditions were set as follows. The specific reaction conditions were as follows:

[0130] Temperature control: The temperatures of flow paths 1 and 2, the junction J1, and the reaction tube F1 were set to 0°C. The temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 50°C. The temperatures of flow path 4, the junction J3, and the reaction tube F3 were set to -20°C. The temperatures of flow path 5, the junction J4, and the reaction tube F4 were set to 5°C. The temperatures of flow path 6, the junction J5, and the reaction tube F5 were set to 5°C.

[0131] Reaction tubes F1 to F4: All of them were made of SUS316 tubes with an outer diameter of 1 / 16 inch and an inner diameter of 1.0 mm. The lengths of each flow path were as follows: Reaction tube F1: 0.8 m Reaction tube F2: 1.0 m Reaction tube F3: 1.0 m Reaction tube F4: 1.0 m

[0132] Reaction tube F5: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.5 m was used.

[0133] Junction J5: A T-connector with an inner diameter of 2.3 mm was used.

[0134] Solution A1 containing a dihalogenated aromatic compound in an organic solvent: A solution (1,3-dibromobenzene solution A1, 1,3-dibromobenzene concentration: 0.34 M) was prepared by dissolving 1,3-dibromobenzene in THF.

[0135] Solution B1 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B1, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Inc. was used.

[0136] Solution B2 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B2, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Inc. was used.

[0137] Solution C1 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-phenyl-1,10-phenanthroline in THF (2-phenyl-1,10-phenanthroline solution C1, 2-phenyl-1,10-phenanthroline concentration: 0.27 M) was prepared and used in the first-step reaction.

[0138] Solution C2 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-phenyl-1,10-phenanthroline in THF (2-phenyl-1,10-phenanthroline solution C2, 2-phenyl-1,10-phenanthroline concentration: 0.27 M) was prepared and used in the second-step reaction.

[0139] Solution flow conditions: 1,3-Dibromobenzene solution: 5.1 mL / min n-Butyllithium solution B1: 1.1 mL / min n-Butyllithium solution B2: 1.1 mL / min 2-Phenyl-1,10-phenanthroline solution C1: 6.4 mL / min 2-Phenyl-1,10-phenanthroline solution C2: 12.8 mL / min Water (X): 6.9 mL / min The target compound was identified by 1H-NMR. １ H-NMR (400 MHz, solvent: DMSO-d6, internal standard: tetramethylsilane (TMS)) chemical shifts σ (ppm) = 9.84 (1H, m), 8.74-8.72 (4H, m), 8.67-8.60 (4H, m), 8.54-8.52 (4H, m), 8.41-8.39 (2H, m), 8.13-8.07 (4H, m), 7.94-7.90 (1H, m), 7.46-7.40 (6H, m)

[0140] The results are shown in the table below. In the table, the molar equivalent is the molar amount relative to 1 mole of the raw material halogenated aromatic compound.

[0141]

[0142] It was confirmed that when an excess amount of electrophilic compound was used in the final (second) stage reaction, the production rate of the target compound increased even when the water content of each solution flowing through the flow path was higher than the limit specified in the present invention (258 ppm).

[0143] Comparative Examples 8 and 9 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 3, except that the amount of electrophilic compound used in the final (second) stage reaction was reduced as shown in the table below by adjusting the flow rate of 2-phenyl-1,10-phenanthroline solution C2. The results are shown in the table below.

[0144]

[0145] It can be seen that when the amount of electrophilic compound used in the final stage (second stage) reaction is less than that in Reference Example 3, and the water content of each solution circulating in the flow path is higher than that specified in the present invention (258 ppm), the production rate of the target compound decreases depending on the amount of electrophilic compound used.

[0146] Examples 40 and 41 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 3, except that the water content of each solution flowing through the flow path was set as shown in the table below and the amount of electrophilic compound used in the final (second) stage reaction was adjusted by adjusting the flow rate of 2-phenyl-1,10-phenanthroline solution C2. The results are shown in the table below.

[0147]

[0148] As shown in the table above, by reducing the water content of each solution flowing through the flow path within the range specified in the present invention, the target compound could be obtained at a sufficiently high production rate even when the amount of electrophilic compound used was reduced.

[0149] Reference Example 4 A target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 200 having the configuration shown in Figure 4. The target electrophilically substituted aromatic compound was prepared in the same manner as in Reference Example 1, except that the water content of each solution flowing through the flow path was set as shown in the table below and the reaction conditions were set as follows. The specific reaction conditions were as follows:

[0150] Temperature control: The temperatures of flow paths 7 and 8, the junction J6, and the reaction tube F6 were set to 10° C. The temperatures of flow path 9, the junction J7, and the reaction tube F7 were set to 50° C. The temperatures of flow path 10, the junction J8, and the reaction tube F8 were set to 10° C.

[0151] Flow paths 7 to 10: All of them used SUS316 tubes with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm.

[0152] Reaction tubes F6 to F7: All of them were made of SUS316 tubes with an outer diameter of 1 / 16 inch and an inner diameter of 1.0 mm. The length of each flow path was as follows: Reaction tube F6: 3.0 m Reaction tube F7: 1.0 m

[0153] Reaction tube F8: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.5 m was used.

[0154] Confluence J6: A T-connector with an inner diameter of 1.3 mm was used. The flow paths 7 and 8 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0155] Junction J7: A T-connector with an inner diameter of 1.3 mm was used. The reaction tube F6 and the flow path 9 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0156] Junction J8: A T-connector with an inner diameter of 2.3 mm was used. The reaction tube F7 and the flow path 10 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0157] Liquid A2 containing a halogenated aromatic compound in an organic solvent: A solution (bromobenzene solution, bromobenzene concentration: 3.2 M) was prepared by dissolving bromobenzene in THF.

[0158] Solution B3 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B3, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0159] Solution C3 containing an electrophilic compound in an organic solvent: A solution was prepared by dissolving 1,10-phenanthroline in THF (1,10-phenanthroline solution C3, 1,10-phenanthroline concentration: 0.89 M).

[0160] Solution flow conditions: Bromobenzene solution A2: 1.4 mL / min n-Butyllithium solution B3: 2.8 mL / min 1,10-phenanthroline solution C3: 6.0 mL / min Water (X): 4.0 mL / min The target compound was identified by 1H-NMR. １Chemical shifts σ (ppm) by H-NMR (400 MHz, solvent: DMSO-d6, internal standard: tetramethylsilane (TMS)) = 9.18-9.17 (1H, m), 8.60-8.39 (5H, m), 8.05-7.98 (2H, m), 7.82-7.79 (1H, m), 7.64-7.54 (3H, m)

[0161] The results are shown in the table below. In the table, the molar equivalent is the molar amount relative to 1 mole of the raw material halogenated aromatic compound.

[0162]

[0163] It was confirmed that when an excess amount of electrophilic compound was used, the production rate of the target compound increased even when the water content of each solution flowing through the flow path was higher than that specified in the present invention (316 ppm).

[0164] The target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 4, except that the amount of electrophilic compound used in the reaction was reduced as shown in the table below by adjusting the flow rate of 1,10-phenanthroline solution C3. The results are shown in the table below.

[0165]

[0166] When the amount of electrophilic compound used is less than that in Reference Example 4, and the water content of each solution flowing through the flow path is higher than that specified in the present invention (316 ppm), it can be seen that the production rate of the target compound decreases depending on the amount of electrophilic compound used.

[0167] Examples 42 to 45 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Reference Example 4, except that the water content of each solution flowing through the flow path was set as shown in the table below, and the amount of the electrophilic compound used in the reaction was adjusted by adjusting the flow rate of 1,10-phenanthroline solution C3.

[0168] Example 46 The target electrophilically substituted aromatic compounds were prepared in the same manner as in Example 42, except that the water content of each solution flowing through the flow path was adjusted by passing it through a dehydration column disposed in the flow path.

[0169] Example 47 The target electrophilically substituted aromatic compound was prepared in the same manner as in Example 46, except that the water content of each solution flowing through the flow path was adjusted by passing it through a dehydration column disposed in the flow path, and the quenching treatment was carried out batchwise.

[0170] Example 48 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 46, except that the water content of each solution flowing through the flow paths was adjusted by passing it through a dehydration column disposed in the flow paths, the temperatures of flow paths 7 and 8, the junction J6, and the reaction tube F6 were set to 30°C, and the length of the reaction tube F6 was set to 1.0 m.

[0171] Example 49 A target electrophilically substituted aromatic compound was prepared in the same manner as in Example 46, except that the water content of each solution flowing through the flow path was adjusted by passing it through a dehydration column disposed in the flow path, and the flow rates of n-BuLi Solution B3 and 1,10-phenanthroline Solution C3 were adjusted to thereby adjust the amounts of the organometallic compound and the electrophilic compound used in the reaction.

[0172] The results are shown in the table below.

[0173]

[0174] As shown in the table above, by reducing the water content of each solution flowing through the flow path within the range specified in the present invention, the target compound could be obtained at a sufficiently high production rate even when the amount of electrophilic compound used was reduced.

[0175] Comparative Example 12 A target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 100 having the configuration shown in Figure 1. The target electrophilically substituted aromatic compound was prepared in the same manner as in Reference Example 1, except that the water content of each solution flowing through the flow path was adjusted and the reaction conditions were as follows: Specific reaction conditions were as follows:

[0176] Temperature control: The temperatures of flow paths 1 and 2, the junction J1, and the reaction tube F1 were set to 0°C. The temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 0°C. The temperatures of flow path 4, the junction J3, and the reaction tube F3 were set to -20°C. The temperatures of flow path 5, the junction J4, and the reaction tube F4 were set to 5°C. The temperatures of flow path 6, the junction J5, and the reaction tube F5 were set to 5°C.

[0177] Flow paths 1 to 6: All of them used SUS316 tubes with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm.

[0178] Reaction tubes F1 to F4: All of them were made of SUS316 tubes with an outer diameter of 1 / 16 inch and an inner diameter of 1.0 mm. The lengths of each flow path were as follows: Reaction tube F1: 0.5 m Reaction tube F2: 1.5 m Reaction tube F3: 2.0 m Reaction tube F4: 1.5 m

[0179] Reaction tube F5: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.0 m was used.

[0180] Confluence J1: A T-connector with an inner diameter of 1.0 mm was used. Flow path 1 and flow path 2 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0181] Confluence J2: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F1 and the flow path 3 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0182] Confluence J3: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F2 and the flow path 4 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0183] Junction J4: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F3 and the flow path 5 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0184] Junction J5: A T-connector with an inner diameter of 2.3 mm was used. The reaction tube F4 and the flow path 6 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0185] Liquid A1 containing a dihalogenated aromatic compound in an organic solvent: A solution was prepared by dissolving 1,4-dibromobenzene in THF (1,4-dibromobenzene solution, 1,4-dibromobenzene concentration: 0.34 M).

[0186] Solution B1 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B1, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0187] Solution B2 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B2, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0188] Liquid C1 containing an electrophilic compound in an organic solvent: A solution (chlorotrimethylsilane solution C1, chlorotrimethylsilane concentration: 0.23 M) was prepared by dissolving chlorotrimethylsilane in THF, and used in the first-stage reaction.

[0189] Liquid C2 containing an electrophilic compound in an organic solvent: A solution (benzaldehyde solution C2, benzaldehyde concentration: 0.24 M) was prepared by dissolving benzaldehyde in THF and used in the second-stage reaction.

[0190] Solution flow conditions: 1,4-dibromobenzene solution A1: 4.1 mL / min n-butyllithium solution B1: 0.9 mL / min n-butyllithium solution B2: 0.9 mL / min Chlorotrimethylsilane solution C1: 6.0 mL / min Benzaldehyde solution C2: 7.1 mL / min Water (X): 1.5 mL / min

[0191] Comparative Example 13 The target electrophilically substituted aromatic compound was prepared in the same manner as in Comparative Example 12, except that the amount of the electrophilic compound used in the reaction was reduced as shown in the table below by adjusting the flow rate of the benzaldehyde solution C2.

[0192] Examples 50 and 51 Target electrophilically substituted aromatic compounds were prepared in the same manner as in Comparative Example 12, except that the water content of each solution flowing through the flow path was set as shown in the table below, and the amount of electrophilic compound used in the reaction was adjusted as shown in the table below by adjusting the flow rate of benzaldehyde solution C2.

[0193] The results are shown in the table below.

[0194]

[0195] Comparative Example 14 A target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 100 having the configuration shown in Figure 1. The target electrophilically substituted aromatic compound was prepared in the same manner as in Comparative Example 12, except that the water content of each solution flowing through the flow path was set as shown in the table below and the reaction conditions were set as follows. The specific reaction conditions were as follows:

[0196] Liquid A1 containing a dihalogenated aromatic compound in an organic solvent: A solution was prepared by dissolving 1,3-dibromobenzene in THF (1,3-dibromobenzene solution, 1,3-dibromobenzene concentration: 0.68 M).

[0197] Solution B1 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B1, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0198] Solution B2 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B2, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0199] Liquid C1 containing an electrophilic compound in an organic solvent: A solution (chlorotrimethylsilane solution C1, chlorotrimethylsilane concentration: 0.23 M) was prepared by dissolving chlorotrimethylsilane in THF, and used in the first-stage reaction.

[0200] Liquid C2 containing an electrophilic compound in an organic solvent: A solution (chlorotrimethylsilane solution C2, chlorotrimethylsilane concentration: 0.23 M) was prepared by dissolving chlorotrimethylsilane in THF, and used in the second-stage reaction.

[0201] Solution flow conditions: 1,3-dibromobenzene solution A1: 2.0 mL / min n-butyllithium solution B1: 0.9 mL / min n-butyllithium solution B2: 0.9 mL / min Chlorotrimethylsilane solution C1: 6.0 mL / min Chlorotrimethylsilane solution C2: 7.2 mL / min Water (X): 1.5 mL / min

[0202] Comparative Example 15 The target electrophilically substituted aromatic compound was prepared in the same manner as in Comparative Example 14, except that the amount of the electrophilic compound used in the reaction was reduced as shown in the table below by adjusting the flow rate of the chlorotrimethylsilane solution C2.

[0203] [Examples 52 and 53] The target electrophilically substituted aromatic compounds were prepared in the same manner as in Comparative Example 14, except that the amounts of the electrophilic compounds used in the reaction were adjusted as shown in the table below by adjusting the water content of each solution flowing through the flow path and adjusting the flow rate of chlorotrimethylsilane solution C2.

[0204] The results are shown in the table below.

[0205]

[0206] Comparative Example 16 A target electrophilically substituted aromatic compound (target compound) was prepared using the flow reaction system 400 configured as shown in Figure 6 according to the reaction scheme shown in Figure 7. The water content of each solution flowing through the flow path was set as shown in the table below, and the target electrophilically substituted aromatic compound was prepared under the following reaction conditions. The specific reaction conditions are as follows:

[0207] Temperature control: The temperatures of flow paths 17, 18, junction J14, and reaction tube F14 were set to 10°C. The temperatures of flow path 19, junction J15, and reaction tube F15 were set to 10°C. The temperatures of flow path 20, junction J16, and reaction tube F16 were set to 50°C. The temperatures of flow path 21, junction J17, and reaction tube F17 were set to 5°C.

[0208] Flow paths 17, 18, 19, 20, 21: SUS316 tubes having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm were used.

[0209] Reaction tube F14: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm and a length of 1.5 m was used.

[0210] Reaction tube F15: A single SUS tube was divided into two parts by a T-connector. More specifically, a SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 1.0 m was connected to a T-connector (inner diameter 1.0 mm), and two SUS316 tubes having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 3 cm were connected to the T-connector so as to face each other. This reaction tube F15 was thus obtained.

[0211] Reaction tube F16: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 3.0 m was used.

[0212] Reaction tube F17: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.5 m was used.

[0213] Confluence J14: A T-connector with an inner diameter of 1.0 mm was used. The flow paths 17 and 18 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0214] Junction J15: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F14 and the flow path 19 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0215] Junction J16: A cross connector with an inner diameter of 1.0 mm was used. Two SUS316 tubes, which were connected to the T-connector constituting the reaction tube F15 so as to face each other, were connected to two of the four connection ports of the cross connector, each of which faced each other. One of the remaining two connection ports was connected to the flow path 20, and the remaining connection port was used as an outlet for discharging the liquid.

[0216] Junction J17: A T-connector with an inner diameter of 2.3 mm was used. The reaction tube F16 and the flow path 21 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0217] Liquid A5 containing a halogenated aromatic compound in an organic solvent: A solution (bromobenzene solution, bromobenzene concentration: 0.64 M) was prepared by dissolving bromobenzene in THF.

[0218] Solution B6 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B6, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0219] Solution C5 containing an electrophilic compound in an organic solvent: A solution was prepared by dissolving 1,10-phenanthroline in THF (1,10-phenanthroline solution C5, 1,10-phenanthroline concentration: 0.55 M).

[0220] Solution D containing a nucleophilic compound in an organic solvent: n-BuLi (n-butyllithium solution D, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0221] Solution flow conditions: Bromobenzene solution A5: 5.2 mL / min n-Butyllithium solution B6: 2.1 mL / min 1,10-phenanthroline solution C5: 6.0 mL / min n-Butyllithium solution D: 2.1 mL / min Water (X): 3.0 mL / min

[0222] Comparative Example 17 A target electrophilically substituted aromatic compound was prepared in the same manner as in Comparative Example 16, except that the amount of the electrophilic compound used in the reaction was reduced as shown in the table below by adjusting the flow rate of the 1,10-phenanthroline solution C5.

[0223] [Examples 54 to 55] Target electrophilically substituted aromatic compounds were prepared in the same manner as in Comparative Example 16, except that the amounts of the electrophilic compounds used in the reaction were adjusted as shown in the table below by adjusting the water content of each solution flowing through the flow path and adjusting the flow rate of 1,10-phenanthroline solution C5.

[0224] The results are shown in the table below.

[0225]

[0226] Comparative Example 18 A target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 300 having the configuration shown in Figure 5. The water content of each solution flowing through the flow path was adjusted, and the target electrophilically substituted aromatic compound was prepared under the following reaction conditions. The specific reaction conditions are as follows:

[0227] Temperature control: The temperatures of flow paths 11, 12, junction J9, and reaction tube F9 were set to 0°C. The temperatures of flow path 13, junction J10, and reaction tube F10 were set to 0°C. The temperatures of flow paths 14, 15, junction J11, and reaction tube F11 were set to 0°C. The temperatures of junction J12 and reaction tube F12 were set to 30°C. The temperatures of flow path 16, junction J13, and reaction tube F13 were set to 5°C.

[0228] Flow path 11, flow path 12, flow path 13, flow path 14, flow path 15, flow path 16: SUS316 tubes having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm were used.

[0229] Reaction tube F9: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm and a length of 1.5 m was used.

[0230] Reaction tube F10: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 1.0 m was used.

[0231] Reaction tube F11: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 1.5 m was used.

[0232] Reaction tube F12: A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2.0 m was used.

[0233] Reaction tube F13: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.5 m was used.

[0234] Confluence J9: A T-connector with an inner diameter of 1.0 mm was used. The flow paths 11 and 12 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0235] Junction J10: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F9 and the flow path 13 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0236] Confluence J11: A T-connector with an inner diameter of 1.0 mm was used. The flow paths 14 and 15 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0237] Junction J12: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F10 and the reaction tube F11 were connected to two of the three connection ports of the T-connector, which were facing each other. The remaining connection port was used as an outlet for discharging the liquid.

[0238] Junction J13: A T-connector with an inner diameter of 2.3 mm was used. The reaction tube F12 and the flow path 16 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0239] Liquid A3 containing a halogenated aromatic compound in an organic solvent: A solution (bromobenzene solution, bromobenzene concentration: 0.32 M) was prepared by dissolving bromobenzene in THF.

[0240] Liquid A4 containing a halogenated aromatic compound in an organic solvent: A solution (bromobenzene solution, bromobenzene concentration: 0.32 M) was prepared by dissolving bromobenzene in THF.

[0241] Solution B4 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B4, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0242] Solution B5 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B5, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0243] Liquid C4 containing an electrophilic compound in an organic solvent: A solution (terephthalaldehyde solution C4, terephthalaldehyde concentration: 0.37 M) was prepared by dissolving terephthalaldehyde in THF.

[0244] Solution flow conditions: Bromobenzene solution A3: 6.0 mL / min Bromobenzene solution A4: 6.0 mL / min n-Butyllithium solution B4: 1.2 mL / min n-Butyllithium solution B5: 1.2 mL / min Terephthalaldehyde solution C4: 5.1 mL / min Water (X): 1.7 mL / min

[0245] Comparative Example 19 The target electrophilically substituted aromatic compound was prepared in the same manner as in Comparative Example 18, except that the amount of the electrophilic compound used in the reaction was reduced as shown in the table below by adjusting the flow rate of the terephthalaldehyde solution C4.

[0246] [Examples 56 to 57] The target electrophilically substituted aromatic compounds were prepared in the same manner as in Comparative Example 18, except that the amounts of the electrophilic compounds used in the reaction were adjusted as shown in the table below by adjusting the water content of each solution flowing through the flow path and adjusting the flow rate of terephthalaldehyde solution C4.

[0247] The results are shown in the table below. The flow paths shown in the table indicate the flow paths into which each compound (solution) was introduced.

[0248]

[0249] Comparative Example 20 A target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 100 having the configuration shown in Figure 1. The water content of each solution flowing through the flow path was adjusted, and the target electrophilically substituted aromatic compound was prepared under the following reaction conditions. The specific reaction conditions are as follows:

[0250] Temperature control: The temperatures of flow paths 1 and 2, the junction J1, and the reaction tube F1 were set to 0°C. The temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 0°C. The temperatures of flow path 4, the junction J3, and the reaction tube F3 were set to -20°C. The temperatures of flow path 5, the junction J4, and the reaction tube F4 were set to 5°C. The temperatures of flow path 6, the junction J5, and the reaction tube F5 were set to 5°C.

[0251] Flow paths 1 to 6: All of them used SUS316 tubes with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm.

[0252] Reaction tubes F1 to F4: All of them were made of SUS316 tubes with an outer diameter of 1 / 16 inch and an inner diameter of 1.0 mm. The lengths of each flow path were as follows: Reaction tube F1: 0.5 m Reaction tube F2: 2.0 m Reaction tube F3: 2.0 m Reaction tube F4: 1.5 m

[0253] Reaction tube F5: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.5 m was used.

[0254] Confluence J1: A T-connector with an inner diameter of 1.0 mm was used. Flow path 1 and flow path 2 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0255] Confluence J2: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F1 and the flow path 3 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0256] Confluence J3: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F2 and the flow path 4 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0257] Junction J4: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F3 and the flow path 5 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0258] Junction J5: A T-connector with an inner diameter of 2.3 mm was used. The reaction tube F4 and the flow path 6 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0259] Liquid A1 containing a dihalogenated aromatic compound in an organic solvent: A solution obtained by dissolving 2.7-dibromo-9.9-dimethylfluorene in THF (2.7-dibromo-9.9-dimethylfluorene solution, 2.7-dibromo-9.9-dimethylfluorene concentration: 0.28 M) was prepared.

[0260] Solution B1 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B1, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0261] Solution B2 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B2, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0262] Liquid C1 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C1, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane concentration: 0.27 M) was prepared and used in the first-step reaction.

[0263] Liquid C2 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C1, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane concentration: 0.27 M) was prepared and used in the second-step reaction.

[0264] Solution flow conditions: 2,7-dibromo-9,9-dimethylfluorene solution A1: 5.7 mL / min n-butyllithium solution B1: 1.0 mL / min n-butyllithium solution B2: 1.0 mL / min 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C1: 6.0 mL / min 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C2: 7.2 mL / min Water (X): 1.5 mL / min

[0265] Comparative Example 21 The target electrophilically substituted aromatic compound was prepared in the same manner as in Comparative Example 20, except that the amount of the electrophilic compound used in the reaction was reduced as shown in the table below by adjusting the flow rate of the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C2.

[0266] [Examples 58 to 59] The target electrophilically substituted aromatic compounds were prepared in the same manner as in Comparative Example 20, except that the amounts of electrophilic compounds used in the reaction were adjusted as shown in the table below by adjusting the water content of each solution flowing through the flow channel and adjusting the flow rate of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C2. The results are shown in the table below.

[0267]

[0268] Comparative Example 22 A target electrophilically substituted aromatic compound (target compound) was prepared using a flow reaction system 100 having the configuration shown in Figure 1. The water content of each solution flowing through the flow path was adjusted, and the target electrophilically substituted aromatic compound was prepared under the following reaction conditions. The specific reaction conditions are as follows:

[0269] Temperature control: The temperatures of flow paths 1 and 2, the junction J1, and the reaction tube F1 were set to 0°C. The temperatures of flow path 3, the junction J2, and the reaction tube F2 were set to 0°C. The temperatures of flow path 4, the junction J3, and the reaction tube F3 were set to -20°C. The temperatures of flow path 5, the junction J4, and the reaction tube F4 were set to 5°C. The temperatures of flow path 6, the junction J5, and the reaction tube F5 were set to 5°C.

[0270] Flow paths 1 to 6: All of them used SUS316 tubes with an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 50 cm.

[0271] Reaction tubes F1 to F4: All of them were made of SUS316 tubes with an outer diameter of 1 / 16 inch and an inner diameter of 1.0 mm. The lengths of each flow path were as follows: Reaction tube F1: 0.5 m Reaction tube F2: 2.0 m Reaction tube F3: 2.0 m Reaction tube F4: 1.5 m

[0272] Reaction tube F5: A PTFE tube having an outer diameter of 1 / 8 inch, an inner diameter of 1.6 mm, and a length of 1.5 m was used.

[0273] Confluence J1: A T-connector with an inner diameter of 1.0 mm was used. Flow path 1 and flow path 2 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0274] Confluence J2: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F1 and the flow path 3 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0275] Confluence J3: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F2 and the flow path 4 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0276] Junction J4: A T-connector with an inner diameter of 1.0 mm was used. The reaction tube F3 and the flow path 5 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0277] Junction J5: A T-connector with an inner diameter of 2.3 mm was used. The reaction tube F4 and the flow path 6 were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as an outlet for discharging the liquid.

[0278] Liquid A1 containing a dihalogenated aromatic compound in an organic solvent: A solution obtained by dissolving 3,6-dibromo-9-phenylcarbazole in THF (3.6-dibromo-9-phenylcarbazole solution, 3.6-dibromo-9-phenylcarbazole concentration: 0.25 M) was prepared.

[0279] Solution B1 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B1, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0280] Solution B2 containing an organometallic compound in an organic solvent: n-BuLi (n-butyllithium solution B2, n-BuLi concentration: 1.6 M, n-hexane solution) manufactured by Kanto Chemical Co., Ltd. was used.

[0281] Liquid C1 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C1, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane concentration: 0.27 M) was prepared and used in the first-step reaction.

[0282] Liquid C2 containing an electrophilic compound in an organic solvent: A solution obtained by dissolving 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in THF (2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C1, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane concentration: 0.27 M) was prepared and used in the second-step reaction.

[0283] Solution flow conditions: 3,6-dibromo-9-phenylcarbazole solution A1: 6.5 mL / min n-butyllithium solution B1: 1.0 mL / min n-butyllithium solution B2: 1.0 mL / min 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C1: 6.0 mL / min 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C2: 7.2 mL / min Water (X): 1.5 mL / min

[0284] Comparative Example 23 The target electrophilically substituted aromatic compound was prepared in the same manner as in Comparative Example 22, except that the amount of the electrophilic compound used in the reaction was reduced as shown in the table below by adjusting the flow rate of the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C2.

[0285] Examples 60 to 61 Target electrophilically substituted aromatic compounds were prepared in the same manner as in Comparative Example 22, except that the amounts of electrophilic compounds used in the reaction were adjusted as shown in the table below by adjusting the water content of each solution flowing through the flow path and adjusting the flow rate of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution C2.

[0286] The results are shown in the table below.

[0287]

[0288] While the present invention has been described in connection with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless otherwise specified, and believe that the claims should be construed broadly without departing from the spirit and scope of the invention as set forth in the appended claims.

[0289] This application claims priority based on Japanese Patent Application No. 2023-106114, filed in Japan on June 28, 2023, the contents of which are incorporated herein by reference.

[0290] 100, 200, 300, 400 Flow type reaction system 1-21 Flow paths (raw material supply flow paths) J1-J17 Junction F1-F17 Reaction tube (reaction flow path) A1 Liquid containing a halogenated aromatic compound in an organic solvent (dihalogenated aromatic compound solution) A2-A5 Liquid containing a halogenated aromatic compound in an organic solvent (monohalogenated aromatic compound solution) B1-B6 Liquid containing an organometallic compound in an organic solvent (organometallic compound solution) C1-C5 Liquid containing an electrophilic compound in an organic solvent (electrophilic compound solution) D Liquid containing a nucleophilic compound in an organic solvent (nucleophilic compound solution) X Quenching agent

Claims

1. A method for producing an electrophilically substituted aromatic compound, comprising continuously carrying out a flow reaction of reacting a halogenated aromatic compound with an organometallic compound to produce a metallized aromatic compound, and reacting this metallized aromatic compound with an electrophilic compound to produce an electrophilically substituted aromatic compound, wherein the water contents of a liquid containing the halogenated aromatic compound in an organic solvent, a liquid containing the organometallic compound in an organic solvent, and a liquid containing the electrophilic compound in an organic solvent are each adjusted to 200 ppm or less and circulated through a flow path.

2. A method for producing an electrophilically substituted aromatic compound according to claim 1, wherein, when the flow reaction is a single-stage reaction system, 0.80 molar equivalents or more and less than 1.20 molar equivalents of the electrophilic compound are used relative to the halogenated aromatic compound, and when the flow reaction is a multi-stage reaction system, 0.80 molar equivalents or more and less than 2.00 molar equivalents of the electrophilic compound relative to the halogenated aromatic compound are provided to the final stage of the reaction.

3. A method for producing an electrophilically substituted aromatic compound according to claim 1, wherein, when the flow reaction is a single-stage reaction system, 0.85 to 1.05 molar equivalents of the electrophilic compound are used relative to the halogenated aromatic compound, and when the flow reaction is a multi-stage reaction system, 0.80 to 1.50 molar equivalents of the electrophilic compound relative to the halogenated aromatic compound are provided to the final stage of the reaction.

4. The method for producing an electrophilically substituted aromatic compound according to claim 1, wherein the flow reaction is a multi-stage reaction system, and 0.80 to 1.20 molar equivalents of the electrophilic compound relative to the halogenated aromatic compound are subjected to the final stage reaction.

5. Prepare a liquid A1 containing the halogenated aromatic compound in an organic solvent, liquids B1 and B2 containing the organometallic compound in an organic solvent, and liquids C1 and C2 containing the electrophilic compound in an organic solvent; introduce the liquids A1, B1, B2, C1, and C2 into different flow paths, respectively, and allow each liquid to flow through each flow path; the liquid A1 and the liquid B1 are joined, and while this joined liquid M1 flows downstream in a reaction flow path F1, a metallized halogenated aromatic compound is generated in the joined liquid M1; the joined liquid M1 and the liquid C1 are joined, and while this joined liquid M2 flows downstream in a reaction flow path F2, an electrophilic mono-substituted halogenated aromatic compound is generated in the joined liquid M2; the joined liquid M2 and the liquid B2 are joined, and while this joined liquid M3 flows downstream in a reaction flow path F3, a metallized electrophilic mono-substituted aromatic compound is generated in the joined liquid M3; the joined liquid M3 and the liquid C2 are joined, and while this joined liquid M4 flows downstream in a reaction flow path F4, an electrophilic di-substituted aromatic compound is generated in the joined liquid M4.

6. A method for producing an electrophilic substituted aromatic compound according to any one of claims 1 to 3, comprising the steps of: preparing a liquid A2 containing said halogenated aromatic compound in an organic solvent, a liquid B3 containing said organometallic compound in an organic solvent, and a liquid C3 containing said electrophilic compound in an organic solvent; introducing liquids A2, B3, and C3 into different flow paths, respectively, and allowing each liquid to flow through each flow path; combining said liquid A2 and said liquid B3, and producing a metallized aromatic compound in said combined liquid M6 while this combined liquid M6 flows downstream through reaction flow path F6; combining said combined liquid M6 and said liquid C3, and producing an electrophilic mono-substituted aromatic compound in said combined liquid M7 while this combined liquid M7 flows downstream through reaction flow path F7.

7. Prepare liquids A3 and A4 containing the halogenated aromatic compound in an organic solvent, liquids B4 and B5 containing the organometallic compound in an organic solvent, and liquid C4 containing the electrophilic compound in an organic solvent; introduce liquids A3, A4, B4, B5, and C4 into different flow paths, respectively, and allow each liquid to flow through each flow path; combine liquid A3 and liquid B4, generate a metallized aromatic compound in the combined liquid M9 while the combined liquid M9 flows downstream in reaction flow path F9, combine liquid A4 and liquid B5, generate a metallized aromatic compound in the combined liquid M11 while the combined liquid M11 flows downstream in reaction flow path F11, combine liquid M9 and liquid C4, and generate a metallized aromatic compound in the combined liquid M10 while the combined liquid M10 flows downstream in reaction flow path F10, the combined liquid M11 and the combined liquid M10 are joined, and while the combined liquid M12 flows downstream through a reaction flow path F12, the metallized aromatic compound in the combined liquid M11 reacts with the electrophilic mono-substituted aromatic compound (i) in the combined liquid M10 to produce an electrophilic mono-substituted aromatic compound in the combined liquid M12.

8. Prepare liquid A5 containing the halogenated aromatic compound in an organic solvent, liquid B6 containing the organometallic compound in an organic solvent, liquid C5 containing the electrophilic compound in an organic solvent, and liquid D containing a nucleophilic compound in an organic solvent; introduce liquids A5, B6, C5, and D into different flow paths, respectively, and allow each liquid to flow through each flow path; combine liquid A5 and liquid B6, and generate a metallized aromatic compound in the combined liquid M14 while the combined liquid M14 flows downstream through reaction flow path F14; combine liquid M14 and liquid C5, and generate an electrophilic mono-substituted aromatic compound in the combined liquid M15 while the combined liquid M15 flows downstream through reaction flow path F15; combine liquid M15 and liquid D, and generate an electrophilic mono-substituted and nucleophilic substituted aromatic compound in the combined liquid M16 while the combined liquid M16 flows downstream through reaction flow path F16. A method for producing the electrophilically substituted aromatic compound according to any one of claims 1 to 3, comprising:

9. A method for producing an electrophilically substituted aromatic compound according to any one of claims 1 to 4, wherein the water content of each of the liquid containing the halogenated aromatic compound in an organic solvent, the liquid containing the organometallic compound in an organic solvent, and the liquid containing the electrophilic compound in an organic solvent, which are caused to flow through the flow path, is controlled to 100 ppm or less.

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