Method for producing compound having fluorocarbon group and micro reactor

Abstract

A method for producing a compound by using a flow micro reactor (100) includes: a step for introducing a first liquid containing a raw material compound having a fluorocarbon group into a first introduction tube (101) and introducing a second liquid containing an alkali metal cation and a radical anion of a second aromatic compound into a second introduction tube (103), to thereby obtain a first mixed liquid in a first micro mixer (107); a step for obtaining a first reaction product by causing the first mixed liquid to flow in a first tube reactor (109), and introducing an electrophile into a third introduction tube (105), to thereby obtain a second mixed liquid in a second micro mixer (111); and a step for causing the second mixed liquid to flow in a second tube reactor (113) to thereby obtain a second reaction product containing a compound which is formed by replacing, with atomic groups derived from the electrophile, one or more fluorine atoms in the fluorocarbon group in the raw material compound and which contains a fluorine atom.

Description

Method for producing a compound having a fluorocarbon group and microreactor

[0001] The present invention relates to a method for producing a compound having a fluorocarbon group and a microreactor.

[0002] Compounds containing fluorocarbon groups are used as functional materials in various fields, such as battery materials, electronic materials, pharmaceuticals, and agricultural chemicals. The key factor in achieving the desired functionality of compounds containing fluorocarbon groups is the selection of fluorine and the atomic groups adjacent to it. Therefore, methods for introducing desired atomic groups into compounds containing fluorocarbon groups have been investigated.

[0003] For example, Patent Document 1 describes a method for producing a fluorine-containing substituted compound, which includes a step of introducing an organic fluorine compound and an organic lithium compound into a microreactor equipped with a flow path capable of mixing a plurality of liquids to obtain a reaction product, and a step of introducing the reaction product and an electrophilic agent that exhibits electrophilic action on the reaction product into the microreactor to obtain a fluorine-containing substituted compound (Claim 1).

[0004] Furthermore, Non-Patent Document 1 describes the production of nanoporous carbon materials by completely defluorinating polytetrafluoroethylene with a lithium-naphthalene complex in a batch reaction system (section 3).

[0005] International Publication No. 2012 / 121301

[0006] Takeshi Shiraishi et al., "Method for preparing nanoporous carbon bodies by defluorination," Carbon, Society of Carbon Materials, 2008, No. 232, pp. 92-97

[0007] The present inventors have investigated the introduction of a desired atomic group into a compound having a fluorocarbon group by introducing the desired atomic group into a fluorine moiety in the fluorocarbon group. Specifically, noting that many fluorocarbon groups have multiple fluorine atoms, they have considered substituting the desired atomic group at the fluorine moiety to obtain a compound having a fluorine atom and a desired atomic group adjacent to it.

[0008] The present disclosure provides a technique for efficiently producing a compound having a fluorocarbon group containing a desired atomic group.

[0009] The present inventors have discovered a new method for efficiently substituting a desired atomic group for the fluorine moiety in the fluorocarbon group of a raw material compound by subjecting the raw material compound having a fluorocarbon group containing multiple fluorines to a specific reaction using a flow-type microreactor.

[0010] That is, the aspects of the present invention are as follows. [1] A method for producing a compound having a fluorocarbon group using a flow-type microreactor, the microreactor having first, second, and third flow paths, a first mixing section communicating with the first and second flow paths, a first tube reactor communicating with the first mixing section downstream of the first mixing section, a second mixing section communicating with the first tube reactor and the third flow path, and a second tube reactor communicating with the second mixing section downstream of the second mixing section, the method comprising the steps of: introducing a first liquid containing a raw material compound having a fluorocarbon group containing n (n is an integer of 2 or more) fluorine atoms into the first flow path; and introducing a second liquid containing a radical anion of a second aromatic compound and an alkali metal cation into the second flow path to obtain a first mixed liquid in the first mixing section; flowing the first mixed liquid in the first tube reactor to obtain a first reaction product; and introducing an electrophilic agent having an electrophilic group into the third flow path to obtain a second mixed liquid in the second mixing section; and flowing the second mixed liquid in the second tube reactor to obtain a second reaction product containing the compound having a fluorocarbon group.

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[410] [5] The method for producing a compound having a fluorocarbon group according to any one of [1] to [4], wherein the electrophilic agent is at least one compound selected from the group consisting of alcohols, deuterated alcohols, aldehydes, ketones, isocyanates, organic halogen compounds, halogen molecules, tin compounds, silyl compounds, sulfur compounds, phosphorus compounds, imines, and acid chlorides. [6] A flow-type microreactor used for producing a compound having a fluorocarbon group, comprising: a first flow path into which a first liquid containing a raw material compound having a fluorocarbon group containing n (n is an integer of 2 or more) fluorine atoms is introduced; a second flow path into which a second liquid containing a radical anion of a second aromatic compound and an alkali metal cation is introduced; a first mixing section communicating with the first and second flow paths; a first tube reactor communicating with the first mixing section downstream of the first mixing section, for flowing the first mixed liquid that has passed through the first mixing section to produce a first reaction product; a third flow path into which an electrophilic agent having an electrophilic group is introduced; a second mixing section communicating with the first tube reactor and the third flow path; and a second tube reactor communicating with the second mixing section downstream of the second mixing section, for flowing the second mixed liquid that has passed through the second mixing section to produce a second reaction product containing the compound having a fluorocarbon group, A microreactor, wherein the compound having a fluorocarbon group is a compound in which one or more fluorine atoms in the fluorocarbon group in the raw material compound are substituted with an atomic group derived from an electrophile and the compound contains (n-1) or less fluorine atoms. [7] The microreactor according to [6], wherein the inner diameter of the first tube reactor is 150 μm or more and 1100 μm or less. [8] The microreactor according to [6] or [7], wherein the length of the first tube reactor is 1 cm or more and 250 cm or less. [9] The microreactor according to any one of [6] to [8], wherein the first and second tube reactors are equipped with a heating mechanism.

[10] The microreactor according to any one of [6] to [9], wherein one or more flow paths selected from the group consisting of the first, second, and third flow paths are inside a tube.

[0011] Any combination of these configurations and conversion of the present invention between methods, devices, etc. are also valid aspects of the present invention.

[0012] According to the present invention, a compound having a fluorocarbon group containing a desired atomic group can be efficiently produced.

[0013] FIG. 1 is a diagram schematically illustrating a configuration of a microreactor according to an embodiment of the present invention.

[0014] Hereinafter, embodiments of the present invention will be described. Unless otherwise specified, the "to" in a numerical range indicates a range from above to below, and both end values ​​are included. Furthermore, when a numerical range is indicated, the upper and lower limits can be appropriately combined, and the resulting numerical range is also considered to be disclosed. Furthermore, in this embodiment, the composition can contain each component alone or in combination of two or more types.

[0015] (Method for producing a compound having a fluorocarbon group) The production method in this embodiment is a method for producing a compound having a fluorocarbon group using a flow-type microreactor. The microreactor has first, second, and third flow paths, a first mixing section communicating with the first and second flow paths, a first tube reactor communicating with the first mixing section downstream of the first mixing section, a second mixing section communicating with the first tube reactor and the third flow path, and a second tube reactor communicating with the second mixing section downstream of the second mixing section. The production method in this embodiment has the following steps. (Step 1) A step of introducing a first liquid containing a raw material compound having a fluorocarbon group containing n (n is an integer of 2 or more) fluorine atoms into a first flow path, and a second liquid containing a radical anion of a second aromatic compound and an alkali metal cation into a second flow path, thereby obtaining a first mixed liquid in a first mixing section; (Step 2) A step of flowing the first mixed liquid in a first tube reactor to obtain a first reaction product, and a step of introducing an electrophilic agent having an electrophilic group into a third flow path to obtain a second mixed liquid in a second mixing section; and (Step 3) A step of flowing the second mixed liquid in a second tube reactor to obtain a second reaction product containing a compound having a fluorocarbon group. The compound having a fluorocarbon group produced in this embodiment is a compound in which one or more fluorine atoms in the fluorocarbon group in the raw material compound are substituted with an atomic group derived from the electrophile, and which contains (n-1) or less fluorine atoms. That is, in this embodiment, some of the fluorine atoms constituting the fluorocarbon group in the raw material compound are substituted, preferably one fluorine atom. Hereinafter, the compound having a fluorocarbon group produced in this embodiment will also be referred to as a "substituent-introduced compound" as appropriate. In the manufacturing method of this embodiment, for example, a microreactor having the following configuration can be used.

[0016] (Microreactor) Fig. 1 is a diagram schematically showing the configuration of a microreactor in this embodiment. The flow microreactor 100 shown in Fig. 1 is a flow-type microreactor used for producing the compound having a fluorocarbon group (substituted compound), and includes a first flow path (first inlet tube 101) into which a first liquid containing a raw material compound having a fluorocarbon group containing n (n is an integer of 2 or more) fluorine atoms is introduced, a second flow path (second inlet tube 103) into which a second liquid containing a radical anion of a second aromatic compound and an alkali metal cation is introduced, a first mixing section (first micromixer 107) communicating with the first inlet tube 101 and the second inlet tube 103, and a second mixing section (second micromixer 108) communicating with the first inlet tube 101 and the second inlet tube 103, and a second mixing section (second micromixer 109) communicating with the first inlet tube 101 and the second inlet tube 103, and a second mixing section (second micromixer 110) communicating with the second inlet tube 101 and the second inlet tube 103, and a second mixing section (second micromixer 111) communicating with the second inlet tube 101 and the second inlet tube 103, and a second mixing section (second micromixer 112) communicating with the second inlet tube 101 and the second inlet tube 103, and a second mixing section (second micromixer 113) communicating with the second inlet tube 101 and the second inlet tube 103, and a second mixing section (first micromixer 114) downstream of the first micromixer 114. the first tube reactor 109 communicating with the first micromixer 107 and flowing the first mixed liquid that has passed through the first micromixer 107 to produce a first reaction product; a third flow path (third inlet tube 105) into which an electrophilic agent having an electrophilic group is introduced; a second mixing section (second micromixer 111) communicating with the first tube reactor 109 and the third inlet tube 105; and a second tube reactor 113 downstream of the second micromixer 111 and communicating with the second micromixer 111 and flowing the second mixed liquid that has passed through the second micromixer 111 to produce a second reaction product containing a substituent-introduced compound.

[0017] The manufacturing method of this embodiment will be described below using the flow microreactor 100 shown in FIG. 1 as an example.

[0018] (Step 1) In step 1, a first liquid containing a raw material compound and a second liquid containing a radical anion of a second aromatic compound and an alkali metal cation are introduced into a first inlet tube 101 and a second inlet tube 103, respectively, and a first mixed liquid, which is a mixture of these, is obtained in a first micromixer 107.

[0019] The inner diameters of first inlet tube 101, second inlet tube 103, and third inlet tube 105 (described later) are, for example, 500 μm or more, preferably 800 μm or more, and for example, 1500 μm or less, preferably 1200 μm or less. The inner diameters of the inlet tubes may be the same or different, and it is preferable that these inner diameters are the same.

[0020] The lengths of first inlet tube 101, second inlet tube 103, and third inlet tube 105 (described later) are, for example, 50 cm or more, preferably 80 cm or more, and preferably 150 cm or less, preferably 120 cm or less. The lengths of the inlet tubes may be the same or different, and it is preferable that these lengths are the same.

[0021] The first liquid introduced into the first inlet tube 101 specifically includes a raw material compound and a first solvent. The raw material compound and the first solvent may be introduced into the first inlet tube 101 in a mixed state, i.e., as the first liquid, or they may be introduced separately to form the first liquid within the first inlet tube 101. For example, the raw material compound may be placed in a recovery flask and diluted with the first solvent to a predetermined concentration, and the diluted solution may be introduced into a syringe and set on a syringe pump to carry out the reaction. Alternatively, the preparation of the first liquid by dilution to a predetermined concentration may be carried out in a flow process. Alternatively, the raw material compound and the first solvent may be placed in a first and a second syringe, respectively, and mixed by the flow of the first inlet tube 101 to a predetermined concentration, which may then be used in the reaction as is.

[0022] A compound having a fluorocarbon group containing n fluorine atoms (n is an integer of 2 or more) is used as the raw material compound. That is, the raw material compound has a fluorocarbon group in its molecular structure, and this fluorocarbon group contains two or more fluorine atoms. n is 2 or more, preferably 3 or more, and for example, 9 or less, preferably 7 or less, more preferably 5 or less, and even more preferably 3 or less. n can be set, for example, depending on the number of carbon atoms constituting the fluorocarbon group. The number of carbon atoms constituting the fluorocarbon group is 1 or more, and for example, 5 or less, preferably 4 or less, more preferably 3 or less, and even more preferably 2 or less.

[0023] The starting compound is preferably an aromatic compound (first aromatic compound), more preferably an aromatic compound in which a fluorocarbon group is directly bonded to an atom constituting a ring. This can further improve the production stability of the substituent-introduced compound. In a similar respect, the starting compound is preferably a compound having a fluorocarbon group containing n fluorine atoms and an aryl group in its molecular structure.

[0024] The first aromatic compound includes both aromatic compounds whose ring structure is composed of carbon atoms and heteroaromatic compounds containing a heteroatom in the ring structure. The first aromatic compound may be either of these. Furthermore, the aryl group in the raw material compound may contain a heteroatom. The heteroatom is, for example, one or more atoms selected from the group consisting of N, O, and S, preferably at least one atom selected from the group consisting of N and S, and more preferably N, or N and S. This can further improve the production stability of the substituent-introduced compound.

[0025] Examples of the first aromatic compound include six-membered ring compounds such as benzene and six-membered heterocyclic compounds (e.g., pyridine, pyrimidine, pyrazine, pyridazine, triazine, and tetrazine); and (hetero)fused ring compounds such as phenothiazine, quinoline, and carbazole.

[0026] The first aromatic compound has a fluorocarbon group containing n fluorine atoms in a side chain. The carbon number of the fluorocarbon group containing n fluorine atoms is 1 or more, and preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less. This can further improve the production stability of the substituent-introduced compound. In the same respect, the fluorocarbon group containing n fluorine atoms is preferably a trifluoromethyl group.

[0027] The first aromatic compound may further have a side chain (a group substituted on an aryl, hereinafter also referred to as "another side chain") other than a fluorocarbon group containing n fluorine atoms. The position of the other side chain may be any of the ortho, meta, and para positions. The other side chains may be substituted on the first aromatic compound in any number and in any combination. Examples of other side chains include: a halogen atom (at least one selected from the group consisting of fluorine, chlorine, bromine, and iodine); a nitrile group; a linear or branched chain or cyclic (when the number of carbon atoms is 3 or more) saturated hydrocarbon group having from 1 to 20 carbon atoms, which may have at least one of a substituent and a heteroatom; an aryl group having from 6 to 20 carbon atoms; an aromatic heterocyclic group; a silyl group; an unsaturated hydrocarbon group having from 2 to 15 carbon atoms, which may have at least one of a halogen atom (at least one selected from the group consisting of fluorine, chlorine, bromine, and iodine), a nitrile group, a substituent, and a heteroatom; an amino group which may have a substituent; a hydroxyl group which may have a substituent; and a group containing a carbonyl group. Examples of substituents or heteroatoms in the other side chain include halogens; nitrile groups; heteroatoms; aryl groups; aromatic oxy groups such as phenoxy and naphthoxy; aliphatic heterocyclic groups such as piperidyl, piperazino, and morpholinyl; protected hydroxyl groups, protected amino groups, protected thiol groups, and protected carboxyl groups. Other side chains substituted on the first aromatic compound may also include sugar chains and nucleic acids. Furthermore, in the saturated hydrocarbon groups in the other side chains, any carbon-carbon single bonds in the saturated hydrocarbon group may be replaced with carbon-carbon double bonds or carbon-carbon triple bonds in any number and in any combination. Furthermore, the saturated hydrocarbon groups replacing these unsaturated bonds may also have the above-mentioned substituents and heteroatoms.

[0028] Next, preferred groups among the other side chains that may be substituted on the first aromatic compound are exemplified below. Among the other side chains, examples of saturated hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Among the other side chains, examples of aryl groups include phenyl, naphthyl, and anthryl groups. Among the other side chains, examples of aromatic heterocyclic groups include pyridinyl and phenothiazino groups. Among the other side chains, examples of halogen atoms include fluorine atoms. Examples of saturated hydrocarbon groups having heteroatoms include alkylthio groups such as methylthio, ethylthio, and propylthio groups. Examples of unsaturated hydrocarbon groups include alkenyl groups, alkynyl groups, and styrene derivatives. Examples of substituted hydroxyl groups include alkoxy groups such as methoxy, ethoxy, and propoxy groups; and haloalkoxy groups such as fluoromethoxy, chloromethoxy, and bromomethoxy groups. Examples of groups containing a carbonyl group include an alkoxycarbonyl group (-C(=O)OR, where R is alkyl); an aminocarbonyl group (-C(=O)NH2); an acyl group (-C(=O)R, where R is alkyl or aryl), and a urea group (H2N-C(=O)-NH2). The number of carbon atoms in the above R is, for example, 1 to 6, and if it is a chain, it may be either a straight chain or a branched chain. When R is an alkyl group, R is, for example, methyl, ethyl, or propyl.

[0029] Specific examples of the raw material compound include the compounds described in the Examples section below. The raw material compound is preferably at least one selected from the group consisting of trifluoromethyl compounds and difluoromethyl compounds, and more preferably a derivative bonded to an unsaturated hydrocarbon group, such as trifluoropropyne or 1-chloro-3,3,3-trifluoropropene (at least one of cis- and trans-isomers), trifluoromethylarenes, difluoromethylarenes, trifluoromethylacetic acid derivatives, difluoromethylacetic acid derivatives, 2,2,2-trifluoroacetophenone derivatives, 2,2-difluoromethyl derivatives, or a compound having a trifluoromethyl group or a difluoromethyl group at the allylic position.

[0030] The concentration of the raw material compound in the first solution is preferably 0.01 M or more, more preferably 0.05 M or more, and even more preferably 0.08 M or more. This allows the first reaction product to be obtained more efficiently. Furthermore, the concentration of the raw material compound in the first solution is preferably 0.5 M or less, more preferably 0.3 M or less, and even more preferably 0.2 M or less. This allows the first reaction product to be obtained more stably.

[0031] Examples of the first solvent include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), dimethylformamide (DMF), nitromethane, acetonitrile, hexamethylphosphoric triamide (HMPA), glyme (ethylene glycol dimethyl ether), diglyme (diethylene glycol dimethyl ether), 1,2-diethoxyethane, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc. The first solvent may be a single solvent or a mixed solvent such as THF / 1,2-diethoxyethane.

[0032] The flow rate of the first liquid in the first inlet tube 101 is preferably 1 mL / min or more, more preferably 3 mL / min or more, and even more preferably 5 mL / min or more. This allows the first liquid to be sent to the first tube reactor 109 more efficiently. Furthermore, the flow rate of the first liquid is preferably 15 mL / min or less, more preferably 12 mL / min or less, and even more preferably 10 mL / min or less. This allows the first reaction product to be obtained more stably.

[0033] The second liquid introduced into the second inlet tube 103 contains a radical anion of a second aromatic compound and an alkali metal cation, for example, a compound consisting of a radical anion of a second aromatic compound and an alkali metal cation (hereinafter also referred to as a "reductive metallation agent"), and a second solvent. The second liquid may also be a mixed liquid obtained by mixing an alkali metal element and the second aromatic compound in the second solvent. The following description will be given taking as an example a case where the second liquid contains a reductive metallation agent.

[0034] The second aromatic compound in the radical anion of the second aromatic compound is preferably at least one compound selected from the group consisting of naphthalene, biphenyl, and derivatives thereof (e.g., 4,4'-di-tert-butylbiphenyl), more preferably naphthalene. That is, the reductive metallation agent preferably has a naphthalene radical anion.

[0035] The alkyl metal cation is, for example, a Li, Na or K cation, preferably a K cation.

[0036] The combination of the radical anion of the second aromatic compound and the alkyl metal cation in the second liquid is preferably a combination of a Li, Na, or K cation and a naphthalene radical anion, more preferably a combination of a K cation and a naphthalene radical anion. The reductive metallation agent is preferably lithium naphthalenide, potassium naphthalenide, or sodium naphthalenide.

[0037] The concentration of the reductive metallation agent in the second liquid is preferably 0.05 M or more, more preferably 0.1 M or more, and even more preferably 0.15 M or more. This allows the first reaction product to be obtained more efficiently. Furthermore, the concentration of the reductive metallation agent in the second liquid is preferably 1 M or less, more preferably 0.5 M or less, and even more preferably 0.3 M or less. This allows the first reaction product to be obtained more stably.

[0038] Examples of the second solvent include aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), dimethylformamide (DMF), nitromethane, acetonitrile, hexamethylphosphoric triamide (HMPA), glyme (ethylene glycol dimethyl ether), diglyme (diethylene glycol dimethyl ether), diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. The second solvent may be a single solvent or a mixed solvent, preferably a single solvent, and more preferably THF. This allows the first reaction product to be obtained more stably. The first and second solvents and the third solvent described below may be the same or different from each other, and preferably at least some of them contain a common solvent, and more preferably all of them contain a common solvent. This allows the miscibility of each liquid to be improved.

[0039] The flow rate of the second liquid in the second inlet tube 103 is preferably 1 mL / min or more, more preferably 3 mL / min or more, and even more preferably 5 mL / min or more. This allows the second liquid to be sent to the first tube reactor 109 more efficiently. Furthermore, the flow rate of the second liquid is preferably 15 mL / min or less, more preferably 12 mL / min or less, and even more preferably 10 mL / min or less. This allows the first reaction product to be obtained more stably. The flow rates of the first liquid and the second liquid may be the same or different.

[0040] In step 1, the first liquid and the second liquid come into contact in the first micromixer 107 to produce a first mixed liquid. The first micromixer 107 may have a configuration that allows the first mixed liquid to be produced, and may have a mixing section equipped with a mixing mechanism, or may be a flow path without a mixing mechanism. When the first micromixer 107 is equipped with a mixing mechanism, the first reaction product can be produced more stably.

[0041] As the first micromixer 107, for example, a commercially available T-shaped micromixer can be used. The flow path of the first micromixer 107 may be the inside of a tube. In this case, the inner diameter of the first micromixer 107 is preferably 50 μm or more, more preferably 100 μm or more, even more preferably 150 μm or more, still more preferably 200 μm or more, and preferably 500 μm or less, more preferably 400 μm or less, and even more preferably 300 μm or less. This allows the contents from the first inlet tube 101 and the second inlet tube 103 to be mixed more efficiently.

[0042] (Step 2) In step 2, the first mixed solution and the electrophile are introduced into the first tube reactor 109 and the third introduction tube 105, respectively.

[0043] The first mixed solution flows through the first tube reactor 109, and the first reaction product is present at least in the first tube reactor 109. The first reaction product may be produced in the first micromixer 107, in addition to being produced in the first tube reactor 109.

[0044] Specifically, the first reaction product contains a metal carbenoid species (fluorine-containing metal carbenoid species) in which some carbon-fluorine bonds in the fluorocarbon group containing n fluorine atoms in the raw material compound are cleaved. By using the metal carbenoid species as a key intermediate, a more efficient reaction with an electrophile becomes possible.

[0045] The residence time t in the first tube reactor 109 is preferably 0.001 second or more, more preferably 0.005 second or more, even more preferably 0.01 second or more, and even more preferably 0.02 second or more. This can improve the yield of the substituent-introduced compound in step 3. From the same perspective, the residence time t in the first tube reactor 109 is preferably 10 seconds or less, more preferably 5 seconds or less, even more preferably 1 second or less, even more preferably 0.5 seconds or less, even more preferably 0.2 seconds or less, and still more preferably 0.1 seconds or less. Here, the residence time t in the first tube reactor 109 can be controlled, for example, by adjusting the inner diameter and length of the first tube reactor 109.

[0046] The inner diameter of the first tube reactor 109 is preferably 150 μm or more, more preferably 250 μm or more. This allows the key intermediate to be obtained more efficiently. From the same viewpoint, the inner diameter of the first tube reactor 109 is preferably 1100 μm or less, more preferably 1000 μm or less.

[0047] The length of the first tube reactor 109 is preferably 1 cm or more, and more preferably 3.5 cm or more. This allows the key intermediate to be obtained more efficiently. From the same viewpoint, the length of the first tube reactor 109 is preferably 250 cm or less, more preferably 150 cm or less, and even more preferably 80 cm or less.

[0048] The temperature of the first tube reactor 109 is preferably −100° C. or higher, more preferably −90° C. or higher, and even more preferably −80° C. or higher. This allows the key intermediate to be obtained more efficiently. The temperature of the first tube reactor 109 is also preferably 0° C. or lower, more preferably −10° C. or lower, even more preferably −30° C. or lower, and even more preferably −50° C. or lower. This allows the key intermediate to be obtained more stably.

[0049] The first tube reactor 109 and the second tube reactor 113 (described later) are preferably equipped with a cooling mechanism. This allows for improved control of the progress of the reaction, such as suppressing over-reaction. In addition, in terms of improved temperature control, the first tube reactor 109 and the second tube reactor 113 (described later) are preferably equipped with a heating mechanism.

[0050] On the other hand, in order to suppress temperature changes throughout the entire flow path included in the flow microreactor 100, the flow microreactor 100 may be provided with a thermostatic mechanism that adjusts the temperature of the entire flow microreactor 100. Alternatively, the temperature of the entire flow microreactor 100 may be adjusted by placing the entire flow microreactor 100 in a thermostatic device.

[0051] The electrophilic agent introduced into the third introduction tube 105 can be, for example, a compound having a known electrophilic group. When the electrophilic group is an organic group, the number of carbon atoms in the organic group is, for example, 1 or more and, for example, 30 or less, preferably 20 or less, more preferably 10 or less, even more preferably 5 or less, and still more preferably 3 or less. This can make the reactivity between the electrophilic agent and the key intermediate more favorable.

[0052] The electrophile may generally be any one that exhibits electrophilicity. The electrophile is preferably water; an acid (including deuterated acid); an acid chloride (for example, an organic acid chloride such as benzoyl chloride or 2,2-dimethyl-5-(2,5-dimethylphenoxy)pentanoic acid chloride); an acid anhydride; an alcohol such as methanol; a deuterated alcohol such as deuterated methanol; an aldehyde (for example, benzaldehyde or α-hexylcinnamaldehyde); a ketone (for example, a saturated aliphatic ketone which may have a substituent such as menthone, haloperidol and its hydroxy-protected derivatives, an unsaturated aliphatic ketone such as teprenone, or an aromatic ketone such as benzophenone); an amide (for example, dimethylformamide); an isocyanate (for example, an aromatic isocyanate such as phenylisocyanate); an imine (for example, N-tosylbenzenemethanimine); an azide compound; a three-membered heterocyclic compound (for example, oxirane, aziridine, thiirane); an organic halogen compound (for example, ethyl chloroformate). The electrophile is preferably at least one compound selected from the group consisting of esters such as methyl iodide, alkyl halides such as iodomethane, iodopropane, and hexachloroethane; alkenyl halides such as allyl iodide; 1-Boc-4-iodopiperidine; halogen molecules (e.g., Br, I); tin compounds (e.g., n-CH(CH)SnCl); silyl compounds (e.g., (CH)SiCl); sulfur compounds (e.g., diphenyl disulfide); phosphorus compounds (e.g., diethyl chlorophosphate) and metals (tin, zinc, palladium, nickel, copper, magnesium, iron, cobalt, etc.), more preferably at least one compound selected from the group consisting of alcohols, deuterated alcohols, aldehydes, ketones, isocyanates, organic halogen compounds, halogen molecules, tin compounds, silyl compounds, sulfur compounds, phosphorus compounds, imines, and acid chlorides, and even more preferably alcohols. This can enhance the reactivity with the key intermediate. The electrophile may contain an isotope atom. That is, the electrophile may be isotopically labeled. The halogen in the electrophile is preferably a halogen other than fluorine. Specific examples of the electrophile include the compounds described in the Examples section below. The electrophile is preferably dehydrated.Alternatively, the electrophile may be mixed with an activator (e.g., a Lewis acid or a Bronsted acid) to activate the fourth liquid containing the first reaction product (which may be mixed with the electrophile in advance in the third liquid), and then reacted.

[0053] It is preferable to dilute the electrophilic agent with a third solvent and introduce the diluted electrophilic agent as a third liquid into the third inlet tube 105. This can improve the controllability of the supply rate of the electrophilic agent.

[0054] The concentration of the electrophile in the third liquid is preferably 0.1 M or more, more preferably 0.2 M or more, and even more preferably 0.3 M or more. This allows the second reaction product to be obtained more efficiently. Furthermore, the concentration of the electrophile in the third liquid is preferably 1.2 M or less, more preferably 1 M or less, even more preferably 0.8 M or less, and even more preferably 0.5 M or less. This allows the second reaction product to be obtained more stably.

[0055] Examples of the third solvent include ethers such as tetrahydrofuran (THF) and 1,2-diethoxyethane; and other aprotic polar solvents. Examples of other aprotic polar solvents include those described above as the first or second solvent. The third solvent may be a single solvent such as THF, or a mixed solvent such as THF / 1,2-diethoxyethane.

[0056] The flow rate of the third liquid in the third inlet tube 105 is preferably 1 mL / min or more, more preferably 2 mL / min or more, and even more preferably 3 mL / min or more. This allows the third liquid to be sent to the second tube reactor 113 more efficiently. Furthermore, the flow rate of the third liquid is preferably 12 mL / min or less, more preferably 10 mL / min or less, and even more preferably 8 mL / min or less. This allows the second reaction product to be obtained more stably. The flow rate of the third liquid may be the same as or different from the flow rates of the first liquid and the second liquid.

[0057] In step 2, the first reaction product and the electrophile come into contact in the second micromixer 111 to produce a second mixed liquid. The second micromixer 111 only needs to have a configuration that allows the second mixed liquid to be produced, and may have a mixing section equipped with a mixing mechanism, or may be a flow path without a mixing mechanism. By providing the second micromixer 111 with a mixing mechanism, the second reaction product can be produced more stably.

[0058] The second micromixer 111 can be, for example, a commercially available T-shaped micromixer. The flow path of the second micromixer 111 may be inside a tube. In this case, the inner diameter of the second micromixer 111 is preferably 50 μm or more, more preferably 100 μm or more, even more preferably 150 μm or more, still more preferably 200 μm or more, and preferably 500 μm or less, more preferably 400 μm or less, and even more preferably 300 μm or less. This allows the contents from the first tube reactor 109 and the third inlet tube 105 to be mixed more efficiently. The first micromixer 107 and the second micromixer 111 may have the same configuration or different configurations.

[0059] (Step 3) In step 3, the second mixture is introduced into the second tube reactor 113. The second mixture flows through the second tube reactor 113, and a second reaction product is present at least in the second tube reactor 113. The second reaction product may be produced in the second micromixer 111, in addition to being produced in the second tube reactor 113. The second reaction product contains a substituent-introduced product, which is the desired compound.

[0060] The inner diameter of the second tube reactor 113 is preferably 150 μm or more, more preferably 300 μm or more. This allows the substituent-introduced product to be obtained more efficiently. From the same viewpoint, the inner diameter of the second tube reactor 113 is preferably 1100 μm or less, more preferably 1000 μm or less. The inner diameter of the second tube reactor 113 may be the same as or different from the inner diameter of the first tube reactor 109.

[0061] The length of the second tube reactor 113 is preferably 10 cm or more, more preferably 50 cm or more, and even more preferably 100 cm or more. This allows the substituent-introduced product to be obtained more efficiently. From the same perspective, the length of the second tube reactor 113 is preferably 500 cm or less, more preferably 400 cm or less, even more preferably 300 cm or less, and even more preferably 250 cm or less. The length of the second tube reactor 113 may be the same as or different from that of the first tube reactor 109.

[0062] The temperature of the second tube reactor 113 is preferably −100° C. or higher, more preferably −90° C. or higher, and even more preferably −80° C. or higher. This allows the substituent-introduced product to be obtained more efficiently. The temperature of the second tube reactor 113 is preferably 0° C. or lower, more preferably −10° C. or lower, even more preferably −30° C. or lower, and even more preferably −50° C. or lower. This prevents over-reaction and improves the yield of the substituent-introduced product. The temperature of the second tube reactor 113 may be the same as or different from the temperature of the first tube reactor 109.

[0063] By the above procedure, a substituted compound can be obtained using the flow microreactor 100. When the number of fluorine atoms constituting the fluorocarbon group in the raw material compound is an integer n of 2 or more, the number of fluorine atoms constituting the fluorocarbon group in the substituted compound is 1 or more and (n-1) or less, preferably (n-1). Furthermore, the number of substituents introduced into the substituted compound is 1 or more and (n-1) or less, preferably 1. Examples of the substituted compound include compounds in which the trifluoromethyl group in the raw material compound is difluoromethylated, and compounds in which the difluoromethyl group in the raw material compound is monofluoromethylated.

[0064] In this embodiment, the raw material compound is fed to the flow microreactor 100, and a fluorine-containing metal carbenoid species is converted into a key intermediate by reductive metallation in the flow microreactor 100, thereby efficiently functionalizing the carbon-fluorine bond of the raw material compound. This allows for efficient production of a substituent-introduced product, i.e., a compound having a fluorocarbon group containing a desired atomic group. The desired atomic group, i.e., the substituent, is specifically a group derived from an electrophile and can be adjusted, for example, by selecting the type of electrophile. The substituent may be, for example, (deuterium) hydrogen or a halogen.

[0065] By using the flow microreactor 100, it is possible to carry out chemical reactions in a structure having a cross-sectional dimension of, for example, less than 1 mm. By carrying out reactions in such a microspace, the specific surface area to volume is large, resulting in excellent heat exchange efficiency. This makes it possible to perform, for example, precise temperature control. Furthermore, by using the flow microreactor 100, not only is high-speed reaction possible due to the short diffusion distance, but the time spent flowing through the flow channel can be treated as the reaction time in a batch-type reaction, making it possible to control reactions that are impossible to control using a batch-type reactor.

[0066] According to this embodiment, a reductive metallation agent is applied to a raw material compound, such as a trifluoromethyl compound, in the flow microreactor 100, thereby cleaving the carbon-fluorine bond and instantly generating a key intermediate, a fluorine-containing metal carbenoid species, in the absence of an electrophile. This allows the fluorine-containing metal carbenoid species to react with the electrophile through precise residence time control. As a result, it is possible to introduce functional groups that were previously limited in their introduction in conventional methods. Furthermore, whereas in a batch reactor, the product is always present in the reactor, in the flow microreactor 100, active species are generated and reacted instantaneously, and are discharged to the outside, thereby preventing overreaction. Because these active species are highly unstable, the yield of substituted compounds, such as difluoromethyl compounds, remains low when a batch reactor is used (Comparative Examples 1 to 4, described below). In contrast, in this embodiment, the flow microreactor 100 allows selective production of groups, such as difluoromethyl groups, in which some fluorine atoms have been removed from the raw material compound. For example, it is also possible to selectively produce substituted compounds in which one fluorine atom has been substituted from the raw material compound.

[0067] Furthermore, in this embodiment, the flow microreactor 100 is used to generate active species by reductive metallation in the absence of an electrophile, and precise residence time control allows for the introduction of various functional groups in place of carbon-fluorine bonds, providing excellent flexibility in the selection of substituents. For example, the C-F bond of a trifluoromethyl or difluoromethyl group can be cleaved to directly introduce various functional groups containing hydrogen, enabling late-stage functionalization of pharmaceuticals and pesticides. Furthermore, the synthesis steps for these physiologically active substances can be shortened, enabling rapid access to physiologically active substances such as fluorine-containing pharmaceuticals, or their intermediates.

[0068] Next, a modified example of this embodiment will be described. The microreactor used in the manufacturing method of this embodiment may have a configuration other than the flow microreactor 100 shown in Fig. 1. Specifically, the flow microreactor may be a device capable of carrying out a chemical reaction in a structure having a cross-sectional dimension of less than a millimeter.

[0069] For example, in the above description, the first, second, and third flow paths function as inlet ports to each micromixer, and the first liquid, second liquid, and electrophile are directly introduced into these flow paths, respectively. However, an inlet port communicating with each flow path may be provided upstream of each flow path, and the first liquid, second liquid, and electrophile may be introduced into each flow path via each inlet port.

[0070] The flow microreactor 100 may also have a pump (for example, a syringe pump) that controls the flow rate in the first inlet tube 101 , the second inlet tube 103 , and the third inlet tube 105 .

[0071] One or more of the first inlet tube 101, the second inlet tube 103, the third inlet tube 105, the first tube reactor 109, and the second micromixer 111 may be wound, thereby making it possible to reduce the space required for the flow microreactor 100.

[0072] In the above, the flow microreactor 100 has been described as having the first inlet tube 101, the second inlet tube 103, and the third inlet tube 105, but the first, second, and third flow paths are not limited to being regions within the tubes. By having one or more flow paths selected from the group consisting of the first, second, and third flow paths within the tubes, the inner diameter and length of each flow path can be easily controlled, thereby further improving the controllability of the reaction in each step.

[0073] A recovery section for recovering the second reaction product may be provided downstream of the second tube reactor 113. The recovery section may contain a solvent in advance. Examples of the solvent include a saturated aqueous ammonium chloride solution and an alcohol (e.g., methanol).

[0074] The substituent-introduced product may be separated from the second reaction product recovered in the second tube reactor 113 or the recovery section using a known method or the like. The substituent-introduced product may be separated and purified. Alternatively, the substituent-introduced product may be used as a reagent for another reaction without being isolated. Furthermore, a second aromatic compound derived from the reductive metallation agent, such as naphthalene, may be separated from the recovered second reaction product using a known method or the like. Furthermore, the separated second aromatic compound may be reused to produce a reductive metallation agent again and subjected to the reaction of this embodiment.

[0075] Furthermore, an analysis unit for confirming the production of the first and second reaction products, other intermediates, etc. may be provided at a predetermined position in the flow microreactor 100. The analysis unit may have an analytical instrument such as in-line FTIR, in-line IR, or in-line NMR, and can be installed in, for example, the first tube reactor 109 or the second tube reactor 113. By configuring the flow microreactor 100 to have an analysis means, the progress of the reaction can be more reliably tracked, and it becomes possible to terminate the reaction as the end point, for example, when it is confirmed that the reaction conversion rate has reached a predetermined value.

[0076] Although the embodiments of the present invention have been described above, these are merely examples of the present invention, and various configurations other than those described above can be adopted.

[0077] The present invention includes the following aspects: 1. A method for producing a compound having a fluorocarbon unit, comprising the steps of: introducing into a microreactor equipped with a flow path capable of mixing a plurality of liquids: a compound having a fluorocarbon group having at least two fluorines; and a metalating agent including a compound consisting of an aromatic compound anion having a radical and an alkali metal cation, to obtain a first reaction product; and introducing an electrophilic agent having an electrophilic group into the microreactor to obtain a second reaction product of the first reaction product and the electrophilic agent, wherein the second reaction product is a compound in which some of the fluorocarbon groups having at least two fluorines are substituted with atomic groups derived from the electrophilic agent. 2. The method for producing a compound having a fluorocarbon group according to 1., wherein the first reaction product is produced by converting some fluorine sites of the fluorocarbon groups having at least two fluorines into metal carbenoides. 3. The method for producing a compound having a fluorocarbon group according to claim 1 or 2, wherein the fluorocarbon group having at least two fluorines is a trifluoromethyl group. 4. Any of 1. to 3., wherein the compound having a fluorocarbon group having at least two fluorines is an aromatic compound. 5. The method for producing a compound having a fluorocarbon group according to any one of 1. to 4., wherein the electrophile is at least one compound selected from the group consisting of alcohols, deuterated alcohols, aldehydes, ketones, isocyanates, organic halogen compounds, halogen molecules, tin compounds, silyl compounds, sulfur compounds, phosphorus compounds, imines, and acid chlorides.6. A microreactor comprising: a first liquid guide portion; a second liquid introduction portion; a third liquid introduction portion; a first micromixer connected to the first introduction portion and the second introduction portion; the first tube reactor receiving a mixture of the first liquid and the second liquid from the first micromixer and forming a fourth liquid containing a first reaction product; a second micromixer connected to the first tube reactor and the third introduction portion; and the second tube reactor receiving a mixture of the third liquid and the fourth liquid from the second micromixer and containing a second reaction product; and a reaction system comprising the first liquid, the second liquid, and the third liquid, wherein the first liquid contains a compound having a fluorocarbon group having at least two fluorines, the second liquid contains a metallation agent containing a compound consisting of an aromatic compound anion having a radical and an alkali metal cation, and the third liquid contains an electrophile. 7. The reaction system according to 6., wherein the inner diameter of the first tube reactor is 150 μm to 1100 μm. 8. The reaction system according to 6. or 7., wherein the length of the first tube reactor is 1 cm to 250 cm. 9. The reaction system according to any one of 6. to 8., wherein the first tube reactor and the second tube reactor are equipped with heating mechanisms. 10. The reaction system according to any one of 6. to 9., wherein at least one selected from the group consisting of the first liquid guide part, the second liquid introduction part, and the third liquid introduction part is a tube.

[0078] The embodiments of the present invention will be described in detail based on examples and comparative examples. The present invention is not limited to these examples. In the examples and comparative examples, the yield (%) is the percentage of the product obtained by the nuclear magnetic resonance spectrum 19 This value was obtained by quantification using the internal standard method (hexafluorobenzene was used as the internal standard) through F-NMR analysis.

[0079] In the following examples, a substitute-introduced product was produced using the flow microreactor 100 shown in Figure 1. The abbreviations used in the following examples are as follows: Me: methyl Ph: phenyl Piv: pivaloyl Boc: tert-butoxycarbonyl Ts: tosyl Et: ethyl Bz: benzoyl

[0080] Example 1 T-shaped pipe joint micromixers (manufactured by Sanko Seiki Kogyo Co., Ltd., inner diameter 250 μm) were used as the first micromixer 107 and the second micromixer 111. The flow path in the first micromixer 107 consisted of a portion of the first inlet tube 101 serving as the first inlet path, a portion of the second inlet tube 103 serving as the second inlet path, and a portion of the first tube reactor 109 serving as the first reaction flow path, all of which had the same inner diameter. The flow path in the second micromixer 111 consisted of a portion of the first tube reactor 109 serving as the first reaction flow path, a portion of the third inlet tube 105 serving as the third inlet path, and a portion of the second tube reactor 113 serving as the second reaction flow path, all of which had the same inner diameter. The first inlet tube 101, the second inlet tube 103, and the third inlet tube 105 were stainless steel tubes (outer diameter 1 / 16 inch, inner diameter 1000 μm) manufactured by GL Sciences, Inc., each 100 cm long. Stainless steel tubes (outer diameter 1 / 16 inch) manufactured by GL Sciences were used as the first tube reactor 109 and the second tube reactor 113. The second tube reactor 113 had an inner diameter of 1000 μm and a length of 200 cm. A syringe pump Model 11 Plus manufactured by Harvard was used as a pump for feeding liquid to each introduction tube.

[0081] The substrate (raw material compound), benzotrifluoride, was diluted with a solvent (THF or THF / 1,2-dimethoxyethane) to prepare a first introduction solution with a concentration of 0.1 M. A second introduction solution was prepared by diluting potassium naphthalenide from metallic potassium (Merck) and naphthalene (Fujifilm Wako Pure Chemical Industries, Ltd.) with THF to a concentration of 0.22 M. An electrophilic agent, ultra-dehydrated methanol (Fujifilm Wako Pure Chemical Industries, Ltd.), was diluted with a solvent (THF or THF / 1,2-dimethoxyethane) to prepare a third introduction solution with a concentration of 0.45 M. The first introduction solution was introduced through a first introduction tube 101, and the second introduction solution was introduced through a second introduction tube 103. The first introduction solution and the second introduction solution were mixed in a first micromixer 107, allowing a continuous reaction to occur within a first tube reactor 109. Furthermore, a third feed liquid was introduced through the third feed tube 105 and mixed with the mixed liquid supplied from the first tube reactor 109 in the second micromixer 111, and the mixture was reacted in the second tube reactor 113 to obtain difluoromethylbenzene. Each feed liquid was introduced by drawing it up into a gas-tight syringe and then using a Harvard syringe pump. The reaction liquid obtained from the second tube reactor 113 was discarded for 15 to 30 seconds until the reaction stabilized, and then collected for 20 seconds in a sampling tube containing saturated aqueous ammonium chloride or methanol. Undecane was added to the obtained sample as an internal standard substance, and the organic phase was analyzed by gas chromatography (GC-2014, Shimadzu Corporation), and the yield was calculated by the internal standard method.

[0082] The flow rate of the first introduced liquid was 7.5 mL / min, the flow rate of the second introduced liquid was 7.5 mL / min, and the flow rate of the third introduced liquid was 5.0 mL / min. The temperature T of the first reaction channel and the residence time t of the mixed liquid in the first reaction channel were adjusted as shown in Table 1. The temperature T of the first reaction channel (and the temperature of the second reaction channel as well) was adjusted by immersing the entire flow microreactor 100 in a constant temperature bath. The residence time t was adjusted by changing the inner diameter and length of the first tube reactor 109 as shown in Table 1. The results of each test are shown in Table 1. The results of Test 3, -78°C, are also shown in Table 2.

[0083]

[0084] Example 2 The same procedure as in Example 1 (Test 1) was carried out at −78°C, except that a substrate (raw material compound) represented by the following formula was diluted with a solvent to prepare a first introduction solution having a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0085]

[0086] (Example 3) The same procedure as in Example 1 (Test 2) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0087]

[0088] (Example 4) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0089]

[0090] (Example 5) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0091]

[0092] (Example 6) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0093]

[0094] (Example 7) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0095]

[0096] (Example 8) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0097]

[0098] (Example 9) The same procedure as in Example 1 (Test 1) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0099]

[0100] (Example 10) The same procedure as in Example 1 (Test 4) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0101]

[0102] (Example 11) The same procedure as in Example 1 (Test 6) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0103]

[0104] Example 12 The same procedure as in Example 1 (Test 6) was carried out at -78°C, except that a substrate represented by the following formula was diluted with THF / dicrim solvent to prepare a first introduction solution having a concentration of 0.1 M, anhydrous methanol was diluted with THF / dicrim solvent to prepare a third introduction solution having a concentration of 0.45 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0105]

[0106] (Example 13) The same procedure as in Example 1 (Test 4) was carried out at -78°C, except that a substrate represented by the following formula was diluted with THF / dicrim solvent to prepare a first introduction solution having a concentration of 0.1 M, anhydrous methanol was diluted with THF / dicrim solvent to prepare a third introduction solution having a concentration of 0.45 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0107]

[0108] Example 14 The same procedure as in Example 1 (Test 1) was carried out at -78°C, except that a substrate represented by the following formula was diluted with THF / dicrim solvent to prepare a first introduction solution having a concentration of 0.1 M, anhydrous methanol was diluted with THF / dicrim solvent to prepare a third introduction solution having a concentration of 0.45 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0109]

[0110] (Example 15) The same procedure as in Example 1 (Test 1) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0111]

[0112] (Example 16) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0113]

[0114] (Example 17) The same procedure as in Example 1 (Test 1) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0115]

[0116] (Example 18) The same procedure as in Example 1 (Test 1) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0117]

[0118] (Example 19) The same procedure as in Example 1 (Test 4) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0119]

[0120] (Example 20) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0121]

[0122] (Example 21) The same procedure as in Example 1 (Test 6) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0123]

[0124] (Example 22) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0125]

[0126] (Example 23) The same procedure as in Example 1 (Test 3) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0127]

[0128] (Example 24) The same procedure as in Example 1 (Test 1) was carried out at -78°C, except that a substrate represented by the following formula was diluted with a solvent to prepare a first introduction solution with a concentration of 0.1 M, and the residence time was set as shown in Table 2. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 2.

[0129]

[0130]

[0131] Example 25: Benzotrifluoride was diluted with THF / 1,2-dimethoxyethane (10:1) to prepare a first introduction liquid with a concentration of 0.1 M. Potassium naphthalenide was prepared from metallic potassium (Merck) and naphthalene (Fujifilm Wako Pure Chemical Industries, Ltd.) by diluting it with THF to a concentration of 0.22 M to prepare a second introduction liquid. Deuterated methanol-d1 was diluted with THF / 1,2-dimethoxyethane (10:1) to prepare a third introduction liquid with a concentration of 0.45 M. The first introduction liquid was introduced through the first introduction tube 101, and the second introduction liquid was introduced through the second introduction tube 103. The first introduction liquid and the second introduction liquid were mixed in the first micromixer 107, and a continuous reaction was carried out in the first tube reactor 109. Furthermore, a third introduction liquid was introduced through the third introduction tube 105 and mixed with the mixed liquid supplied from the first tube reactor 109 in the second micromixer 111, and the mixture was reacted in the second tube reactor 113 to obtain the corresponding difluoromethyl compound. Each introduction liquid was introduced by sucking it up into a gas-tight syringe and then using a Harvard syringe pump. The reaction liquid obtained from the second tube reactor 113 was discarded for 15 to 30 seconds until the reaction stabilized, and then collected for 20 seconds in a sampling tube containing saturated aqueous ammonium chloride or methanol. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated.

[0132] The flow rate of the first introduced liquid was 7.5 mL / min, the flow rate of the second introduced liquid was 7.5 mL / min, and the flow rate of the third introduced liquid was 5.0 mL / min. The temperature of the first reaction channel was set to -78°C, and the residence time of the mixed liquid in the first reaction channel was adjusted to 0.11 seconds. The temperature of the first reaction channel was -78°C (the temperature of the second reaction channel was also the same) by immersing the entire flow microreactor 100 in a thermostatic bath. The residence time of 0.11 seconds was adjusted by setting the inner diameter of the first tube reactor 109 to 1000 μm and the length to 3.5 cm. The respective results are shown in Table 3.

[0133] Example 26 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0134]

[0135] Example 27 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0136]

[0137] Example 28 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0138]

[0139] Example 29 The same procedure as in Example 25 was carried out at −78° C., except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution having a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0140]

[0141] Example 30 The same procedure as in Example 25 was carried out at −78° C., except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution having a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0142]

[0143] (Example 31) The same procedure as in Example 25 was carried out at -78°C, except that the electrophile was PhNCO, which was diluted with a solvent to prepare a third introduction solution having a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0144] Example 32 The same procedure as in Example 25 was carried out at −78° C., except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0145]

[0146] Example 33: The same procedure as in Example 25 was carried out at -78°C, except that the electrophile was MeI, which was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the retention time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the yield was calculated after isolation. Detailed results are shown in Table 3. Example 34: The same procedure as in Example 25 was carried out at -78°C, except that the electrophile was n-CH3(CH2)7I, which was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the retention time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the yield was calculated after isolation. Detailed results are shown in Table 3.

[0147] Example 35 The same procedure as in Example 25 was carried out at −78° C., except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution having a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0148]

[0149] Example 36 The same procedure as in Example 25 was carried out at −78°C, except that the electrophile was I, which was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0150] Example 37 The same procedure as in Example 25 was carried out at -78°C, except that the electrophile was Br2, which was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0151] Example 38 The same procedure as in Example 25 was carried out at -78°C, except that the electrophile was C2Cl6, which was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0152] Example 39 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0153]

[0154] Example 40 The same procedure as in Example 25 was carried out at -78°C, except that the electrophile was (CH)SiCl, which was diluted with a solvent to prepare a third introduction solution with a concentration of 0.6 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0155] Example 41 The same procedure as in Example 25 was carried out at -78°C, except that the electrophile was n-CH(CH)SnCl, which was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0156] Example 42 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0157]

[0158] Example 43 The same procedure as in Example 25 was carried out at −78° C., except that 4-fluorobenzotrifluoride was diluted with a solvent to prepare a first introducing solution having a concentration of 0.1 M, an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introducing solution having a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0159]

[0160] Example 44 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0161]

[0162] Example 45 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0163]

[0164] Example 46 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the sample was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0165]

[0166] Example 47 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0167]

[0168] Example 48 The same procedure as in Example 25 was carried out at −78°C, except that an electrophilic agent represented by the following formula was diluted with a solvent to prepare a third introduction solution with a concentration of 0.45 M, and the residence time was set as shown in Table 3. An internal standard substance was added to the obtained sample, and the organic phase was subjected to NMR analysis, and the yield was calculated by the internal standard method, or the product was isolated and the yield was calculated. Detailed results are shown in Table 3.

[0169]

[0170]

[0171]

[0172] A comparative example in a batch reactor is described below.

[0173] (Comparative Example 1) (Conditions for Coexistence of Electrophile, Solvent: THF / 1,2-Dimethoxyethane) A polytetrafluoroethylene (PTFE) stir bar was placed in a test tube, the tube was capped with a septum rubber, and the tube was dried up while evacuating. The inside of the test tube was then purged with argon. This evacuation and argon substitution procedure was performed three times in total. 0.2 mmol of benzotrifluoride and 1 mL of a solvent, THF / 1,2-dimethoxyethane (10:1), were added, and 4.3 equivalents of methanol were added thereto. The mixture was then cooled to -78°C and vigorously stirred. A potassium naphthalenide / THF solution prepared from 0.22 M potassium metal (manufactured by Merck) and naphthalene (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was slowly added dropwise thereto, followed by stirring at -78°C for 10 minutes after the addition. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride, and the resulting crude reaction mixture was added with an internal standard substance and analyzed by gas chromatography (GC-2014, manufactured by Shimadzu Corporation). The yield of difluoromethylbenzene was calculated by the internal standard method and found to be 18%. The results are shown in Table 4.

[0174] (Comparative Example 2) (Electrophile Coexistence Conditions, THF Solvent) A polytetrafluoroethylene (PTFE) stir bar was placed in a test tube, the tube was capped with a septum rubber, and the tube was dried up while evacuating. The inside of the test tube was then purged with argon. This evacuation and argon substitution procedure was performed a total of three times. 0.2 mmol of benzotrifluoride and 1 mL of THF solvent were added, and 3.1 equivalents of methanol were then added. The mixture was then cooled to -78°C and vigorously stirred. A potassium naphthalenide / THF solution prepared from 0.22 M potassium metal (manufactured by Merck) and naphthalene (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was slowly added dropwise thereto, and the mixture was stirred at -78°C for 10 minutes after the addition. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride, and the resulting crude reaction mixture was added with an internal standard substance and analyzed by gas chromatography (GC-2014, manufactured by Shimadzu Corporation). The yield of difluoromethylbenzene was calculated by the internal standard method and was found to be 3%. The results are shown in Table 4.

[0175] (Comparative Example 3) (Conditions without electrophile coexistence, THF / 1,2-dimethoxyethane solvent) A polytetrafluoroethylene (PTFE) stir bar was placed in a test tube, the tube was capped with a septum rubber, and the tube was dried up while evacuating. The inside of the test tube was then purged with argon. This evacuation and argon substitution procedure was performed three times in total. 0.2 mmol of benzotrifluoride and 1 mL of THF / 1,2-dimethoxyethane (10:1) solvent were added, cooled to -78°C, and vigorously stirred. A potassium naphthalenide / THF solution prepared from 0.22 M potassium metal (Merck) and naphthalene (Fujifilm Wako Pure Chemical Industries, Ltd.) was added dropwise to the mixture, and after stirring for 10 seconds, 5.2 equivalents of methanol were added and the mixture was further stirred at -78°C for 10 minutes. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride, and the resulting crude reaction mixture was added with an internal standard substance and analyzed by gas chromatography (GC-2014, manufactured by Shimadzu Corporation). The yield of difluoromethylbenzene was calculated by the internal standard method and found to be 4%. The results are shown in Table 4.

[0176] (Comparative Example 4) (Conditions without electrophile coexistence, THF solvent) A polytetrafluoroethylene (PTFE) stirring bar was placed in a test tube, the tube was capped with a septum rubber, and the tube was dried up while evacuating. The inside of the test tube was then purged with argon. This evacuation and argon substitution procedure was performed three times in total. 0.2 mmol of benzotrifluoride and 1 mL of THF solvent were added, cooled to -78°C, and vigorously stirred. A potassium naphthalenide / THF solution prepared from 0.22 M potassium metal (manufactured by Merck) and naphthalene (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added dropwise to the mixture, stirred for 10 seconds, and then 4.3 equivalents of methanol was added and the mixture was stirred for an additional 10 minutes at -78°C. The reaction mixture was then quenched with a saturated aqueous solution of ammonium chloride, and the resulting crude reaction mixture was added with an internal standard substance and analyzed by gas chromatography (GC-2014, manufactured by Shimadzu Corporation). The yield of difluoromethylbenzene was calculated by the internal standard method and found to be 1%. The results are shown in Table 4.

[0177]

[0178] This application claims priority based on Japanese Patent Application No. 2024-072560, filed April 26, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0179] 100 Flow microreactor 101 First inlet tube 103 Second inlet tube 105 Third inlet tube 107 First micromixer 109 First tube reactor 111 Second micromixer 113 Second tube reactor

Claims

1. A method for producing a compound having a fluorocarbon group using a flow-type microreactor, the microreactor having first, second, and third flow paths, a first mixing section communicating with the first and second flow paths, a first tube reactor communicating with the first mixing section downstream of the first mixing section, a second mixing section communicating with the first tube reactor and the third flow path, and a second tube reactor communicating with the second mixing section downstream of the second mixing section, the method comprising the steps of: introducing a first liquid containing a raw material compound having a fluorocarbon group containing n fluorine atoms (n is an integer of 2 or more) into the first flow path; and introducing a second liquid containing a radical anion of a second aromatic compound and an alkali metal cation into the second flow path to obtain a first mixed liquid in the first mixing section; flowing the first mixed liquid in the first tube reactor to obtain a first reaction product; introducing an electrophilic agent having an electrophilic group into the third flow path to obtain a second mixed liquid in the second mixing section; and flowing the second mixed liquid in the second tube reactor to obtain a second reaction product containing the compound having a fluorocarbon group. wherein the compound having a fluorocarbon group is a compound in which one or more fluorine atoms in the fluorocarbon group in the raw material compound are substituted with an atomic group derived from an electrophile and the compound contains (n-1) or less fluorine atoms.

2. The method for producing a compound having a fluorocarbon group according to claim 1, wherein the first reaction product comprises a metal carbenoid species in which some of the carbon-fluorine bonds in the fluorocarbon group containing n fluorine atoms in the starting compound are cleaved.

3. The method for producing a compound having a fluorocarbon group according to claim 1 or 2, wherein the fluorocarbon group containing n fluorine atoms in the starting compound is a trifluoromethyl group.

4. The method for producing a compound having a fluorocarbon group according to claim 1 or 2, wherein the starting compound is a first aromatic compound.

5. The method for producing a compound having a fluorocarbon group according to claim 1 or 2, wherein the electrophile is at least one compound selected from the group consisting of alcohols, deuterated alcohols, aldehydes, ketones, isocyanates, organic halogen compounds, halogen molecules, tin compounds, silyl compounds, sulfur compounds, phosphorus compounds, imines, and acid chlorides.

6. A flow-type microreactor used in the production of a compound having a fluorocarbon group, comprising: a first flow path into which a first liquid containing a raw material compound having a fluorocarbon group containing n (n is an integer of 2 or more) fluorine atoms is introduced; a second flow path into which a second liquid containing a radical anion of a second aromatic compound and an alkali metal cation is introduced; a first mixing section communicating with the first and second flow paths; a first tube reactor communicating with the first mixing section downstream of the first mixing section, for flowing the first mixed liquid that has passed through the first mixing section to produce a first reaction product; a third flow path into which an electrophilic agent having an electrophilic group is introduced; a second mixing section communicating with the first tube reactor and the third flow path; and a second tube reactor communicating with the second mixing section downstream of the second mixing section, for flowing the second mixed liquid that has passed through the second mixing section to produce a second reaction product containing the compound having a fluorocarbon group, The compound having a fluorocarbon group is a compound in which one or more fluorine atoms in the fluorocarbon group in the raw material compound are substituted with an atomic group derived from an electrophile and the compound contains (n-1) or less fluorine atoms.

7. The microreactor according to claim 6, wherein the inner diameter of the first tube reactor is 150 μm or more and 1100 μm or less.

8. The microreactor according to claim 6 or 7, wherein the length of the first tube reactor is 1 cm or more and 250 cm or less.

9. The microreactor according to claim 6 or 7, wherein the first and second tube reactors are equipped with a heating mechanism.

10. The microreactor according to claim 6 or 7, wherein one or more of the flow paths selected from the group consisting of the first, second and third flow paths are in a tube.

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