EP-4737441-A1 - METHOD FOR PRODUCING ELECTROPHILIC SUBSTITUTED AROMATIC COMPOUND

Abstract

Disclosed is a method for manufacturing an electrophilic substituted aromatic compound, including continuously carrying out, by a flow-type reaction, a 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 electrophilic substituted aromatic compound, in which the method includes allowing 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 to flow in a flow channel, with each liquid having a moisture content of 200 ppm or less.

Inventors

• TSUNA, Kazuhiro
• IWASAKI, KOICHI
• WADA, KENJI

Assignees

• FUJIFILM Corporation
• FUJIFILM Wako Pure Chemical Corporation

Dates

Publication Date

20260506

Application Date

20240611

Claims (9)

1. A method for manufacturing an electrophilic substituted aromatic compound, comprising: continuously carrying out, by a flow-type reaction, a 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 electrophilic substituted aromatic compound, wherein the method includes allowing 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 to flow in a flow channel, with each liquid having a moisture content of 200 ppm or less.
2. The method for manufacturing an electrophilic substituted aromatic compound according to claim 1, wherein, in a case where the flow-type reaction is a one-stage reaction system, the electrophilic compound is used in an amount of 0.80 molar equivalents or more and less than 1.20 molar equivalents with respect to the halogenated aromatic compound, and in a case where the flow-type reaction is a multi-stage reaction system, the electrophilic compound is supplied to a final stage reaction in an amount of 0.80 molar equivalents or more and less than 2.00 molar equivalents with respect to the halogenated aromatic compound.
3. The method for manufacturing an electrophilic substituted aromatic compound according to claim 1, wherein, in a case where the flow-type reaction is a one-stage reaction system, the electrophilic compound is used in an amount of 0.85 molar equivalents or more and 1.05 molar equivalents or less with respect to the halogenated aromatic compound, and in a case where the flow-type reaction is a multi-stage reaction system, the electrophilic compound is supplied to a final stage reaction in an amount of 0.80 molar equivalents or more and 1.50 molar equivalents or less with respect to the halogenated aromatic compound.
4. The method for manufacturing an electrophilic substituted aromatic compound according to claim 1, wherein the flow-type reaction is a multi-stage reaction system, and the electrophilic compound is supplied to a final stage reaction in an amount of 0.80 molar equivalents or more and 1.20 molar equivalents or less with respect to the halogenated aromatic compound.
5. The method for manufacturing an electrophilic substituted aromatic compound according to any one of claims 1 to 4, further comprising: preparing a liquid A1 containing the halogenated aromatic compound in an organic solvent, a liquid B1 and a liquid B2 each containing the organometallic compound in an organic solvent, and a liquid C1 and a liquid C2 each containing the electrophilic compound in an organic solvent; introducing the liquids A1, B1, B2, C1, and C2 into different flow channels to allow each liquid to flow in each flow channel; and allowing the liquid A1 and the liquid B1 to join together to form a joined liquid M1, in which a metallated halogeno-aromatic compound is produced in the joined liquid M1 while the joined liquid M1 flows downstream in a reaction flow channel F1; allowing the joined liquid M1 and the liquid C1 to join together to form a joined liquid M2, in which an electrophilic monosubstituted halogeno-aromatic compound is produced in the joined liquid M2 while the joined liquid M2 flows downstream in a reaction flow channel F2; allowing the joined liquid M2 and the liquid B2 to join together to form a joined liquid M3, in which a metallated electrophilic monosubstituted aromatic compound is produced in the joined liquid M3 while the joined liquid M3 flows downstream in a reaction flow channel F3; and allowing the joined liquid M3 and the liquid C2 to join together to form a joined liquid M4, in which an electrophilic disubstituted aromatic compound is produced in the joined liquid M4 while the joined liquid M4 flows downstream in a reaction flow channel F4.
6. The method for manufacturing an electrophilic substituted aromatic compound according to any one of claims 1 to 3, further 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 channels to allow each liquid to flow in each flow channel; and allowing the liquid A2 and the liquid B3 to join together to form a joined liquid M6, in which a metallated aromatic compound is produced in the joined liquid M6 while the joined liquid M6 flows downstream in a reaction flow channel F6; and allowing the joined liquid M6 and the liquid C3 to join together to form a joined liquid M7, in which an electrophilic monosubstituted aromatic compound is produced in the joined liquid M7 while the joined liquid M7 flows downstream in a reaction flow channel F7.
7. The method for manufacturing an electrophilic substituted aromatic compound according to any one of claims 1 to 3, further comprising: preparing a liquid A3 and a liquid A4 each containing the halogenated aromatic compound in an organic solvent, a liquid B4 and a liquid B5 each containing the organometallic compound in an organic solvent, and a liquid C4 containing the electrophilic compound in an organic solvent; introducing the liquids A3, A4, B4, B5, and C4 into different flow channels to allow each liquid to flow in each flow channel; and allowing the liquid A3 and the liquid B4 to join together to form a joined liquid M9, in which a metallated aromatic compound is produced in the joined liquid M9 while the joined liquid M9 flows downstream in a reaction flow channel F9; allowing the liquid A4 and the liquid B5 to join together to form a joined liquid M11, in which a metallated aromatic compound is produced in the joined liquid M11 while the joined liquid M11 flows downstream in a reaction flow channel F11; allowing the joined liquid M9 and the liquid C4 to join together to form a joined liquid M10, in which an electrophilic monosubstituted aromatic compound (i) functioning as an electrophilic compound is produced in the joined liquid M10 while the joined liquid M10 flows downstream in a reaction flow channel F10; and allowing the joined liquid M11 and the joined liquid M10 to join together to form a joined liquid M12, in which the metallated aromatic compound in the joined liquid M11 reacts with the electrophilic monosubstituted aromatic compound (i) in the joined liquid M10 to produce an electrophilic monosubstituted aromatic compound in the joined liquid M12 while the joined liquid M12 flows downstream in a reaction flow channel F12.
8. The method for manufacturing an electrophilic substituted aromatic compound according to any one of claims 1 to 3, further comprising: preparing 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; introducing the liquids A5, B6, C5, and D into different flow channels to allow each liquid to flow in each flow channel; and allowing the liquid A5 and the liquid B6 to join together to form a joined liquid M14, in which a metallated aromatic compound is produced in the joined liquid M14 while the joined liquid M14 flows downstream in a reaction flow channel F14; allowing the joined liquid M14 and the liquid C5 to join together to form a joined liquid M15, in which an electrophilic monosubstituted aromatic compound is produced in the joined liquid M15 while the joined liquid M15 flows downstream in a reaction flow channel F15; and allowing the joined liquid M15 and the liquid D to join together to form a joined liquid M16, in which an electrophilic monosubstituted/nucleophilic substituted aromatic compound is produced in the joined liquid M16 while the joined liquid M16 flows downstream in a reaction flow channel F 16.
9. The method for manufacturing an electrophilic substituted aromatic compound according to any one of claims 1 to 4, wherein all of moisture contents 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, each of which is allowed to flow in the flow channel, are controlled to be 100 ppm or less.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for manufacturing an electrophilic substituted aromatic compound. 2. Description of the Related Art A substituted aromatic compound is used in a variety of applications as a physiologically active substance, a functional material, and the like, and as a synthetic intermediate thereof. As a method for synthesizing a substituted aromatic compound, a synthesis route is known in which an organometallic compound is reacted with a halogenated aromatic compound (halogeno-aromatic compound) to produce a metallated aromatic compound, and this metallated aromatic compound is then reacted with an electrophilic compound to produce an electrophilic substituted aromatic compound (hereinafter, also referred to as a "metallation/electrophilic substitution reaction of a halogenated aromatic compound"). The obtained electrophilic substituted aromatic compound is treated with a quenching agent such as water or alcohol, as necessary, or subjected to a desired chemical treatment, washing treatment, purification treatment, or the like to obtain a desired electrophilic substituted aromatic compound. For example, an organolithium compound such as butyl lithium as the organometallic compound is reacted with a brominated aromatic compound as the halogenated aromatic compound to produce a lithiated aromatic compound, and this lithiated aromatic compound is then reacted with an electrophilic compound to introduce a desired substituent into a lithiation site, whereby a desired electrophilic substituted aromatic compound can be obtained. JP2021-8436A describes that, for the purpose of carrying out the manufacture of a lithiated aromatic compound in a higher yield, an organolithium compound and a reaction solvent species are mixed in advance before a reaction between the organolithium compound and a halogenated aromatic compound. In this manner, it is said that the heat generation due to mixing of the organolithium compound and the reaction solvent species during the lithiation reaction can be suppressed, and the production of by-products in the lithiation reaction can be suppressed. The obtained lithiated aromatic compound can be reacted with an electrophilic compound to obtain an electrophilic substituted lithium compound. JP2021-8436A also describes that the above reaction is carried out by a flow-type reaction. In addition, JP2008-195639A describes that, for the purpose of efficiently manufacturing a desired o-disubstituted aromatic compound in a high yield and with a high selectivity using an o-dihalo aromatic compound as a raw material, a lithiation reaction of a halogenated benzene compound and a reaction of the obtained lithiation product with an electrophilic compound are carried out using a microreactor (flow-type reaction). According to the technique described in JP2008-195639A, it is said that the by-production of benzyne in the reaction product can be suppressed even in a case where the reaction is carried out at a relatively high temperature of -80°C to -50°C. SUMMARY OF THE INVENTION In the metallation/electrophilic substitution reaction of a halogenated aromatic compound, it is common to use an excess amount of the electrophilic compound in order to promote the reaction and increase the production rate of the desired compound (the proportion of the molar amount of the desired electrophilic substituted aromatic compound to the molar amount of the halogenated aromatic compound, %). On the other hand, in view of recent social demands based on the SDGs and the like, it has been more strongly required to obtain a desired compound with higher efficiency while reducing waste of raw materials or reagents even in chemical synthesis reactions. In addition, in a case where an excessive amount of the electrophilic compound is used, there is also a problem of increased manufacturing costs, particularly in a case where the electrophilic compound is expensive. An object of the present invention is to provide a method for manufacturing an electrophilic substituted aromatic compound through a metallation/electrophilic substitution reaction of a halogenated aromatic compound, which method makes it possible to obtain a desired electrophilic substituted aromatic compound with a sufficiently high production rate while further reducing the amount of an electrophilic compound used. As a result of extensive studies in view of the above-mentioned problems, the present inventors have found that, in a case where the metallation/electrophilic substitution reaction of a halogenated aromatic compound is continuously carried out by a flow-type reaction, it is possible to obtain a desired electrophilic substituted aromatic compound at a higher production rate while reducing an amount of an electrophilic compound used by reducing a moisture content of each of a liquid containing an organometallic compound in an organic solvent, a liquid containing a halogenate