Method for manufacturing reducing compound

Abstract

To provide: a method for manufacturing a reducing compound; a method for manufacturing pyrrole-imidazole polyamide; and a reducing compound manufacturing system.SOLUTION: A method for manufacturing a reducing compound includes reacting a compound reduced in the presence of a reduction catalyst with hydrogen gas. The method uses a micromixer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a reduced compound, a method for producing a pyrrole-imidazole polyamide, and a system for producing a reduced compound. [Background technology]

[0002] Flow synthesis equipment with micromixers is said to have the following characteristics: by utilizing minute flow channels with tiny cross sections, precise temperature control based on the size of the specific surface area is possible, precise mixing control is possible based on molecular diffusion between stable laminar flow interfaces, and reaction time can be controlled by precise control of residence time within the microchannels. Therefore, these characteristics are used in chemical synthesis, the creation of new substances, etc.

[0003] In such a flow synthesis device, multiple fluids are continuously introduced into a mixing channel of a microchannel in a micromixer and mixed. As mentioned above, mixing in a micromixer utilizes molecular diffusion, but it is not always easy to introduce fluids into a microchannel and mix multiple fluids uniformly by molecular diffusion.

[0004] As a solution to this problem, for example, Patent Document 1 proposes a fluid mixer that has a mixing flow path and a plurality of inflow paths connected to it in order to form the fluids to be mixed in the mixing section into thin, uniform multiple layers, or to slow down the flow rate while maintaining a thin layer, and that mixes the fluids by introducing at least two types of fluids into the mixing flow path from each of the plurality of inflow paths, and that the mixing flow path is provided with a plurality of flow path connectors by connecting the plurality of inflow paths at predetermined intervals in the flow direction, and that is piped so that different types of fluids are introduced into adjacent flow path connectors.

[0005] In addition to the point about uniform mixing by molecular diffusion mentioned above, Patent Document 2 lists the following functions as required for achieving an ideal molecular weight distribution when polymer synthesis by radical polymerization reaction is performed using such a flow synthesis apparatus: (i) uniform temperature control, (ii) high-viscosity liquid delivery of the polymer product, and (iii) gas-liquid mixing / separation. It also describes a configuration for achieving function (iii) in which a special elastic tube that is permeable to gas but not to liquid is provided within a specified pressure chamber, and the reaction is carried out within the elastic tube.

[0006] Pyrrole-imidazole polyamides (PIPs) are linear small molecules consisting of N-methylpyrrole units (Py) and N-methylimidazole units (Im) linked by amide bonds. The molecular design of PIPs is derived from the DNA-binding ability of distamycin A, an anticancer natural product with a pyrrole-amide trimer structure.

[0007] As expected from its molecular design, PIPs can enter the minor groove of DNA and bind to GC base pairs via Im-Py, CG base pairs via Py-Im, and AT or TA base pairs via Py-Py. PIPs specifically recognize and bind to DNA base sequences and can strongly suppress the transcriptional activity of target genes, making them promising candidates for epigenomic drug discovery to suppress target gene expression.

[0008] As a method for synthesizing PIP, a solid-phase synthesis method using a condensing agent developed by Dervan et al. in the 1990s (Non-Patent Documents 1 to 3), a liquid-phase synthesis method using a trichloroacetyl compound (Non-Patent Document 4), and a cross-coupling method using a metal catalyst developed by the present inventors (Patent Document 3) have been proposed. Solid-phase synthesis involves extending peptide chains using polymer-supported compounds, resulting in very poor atom efficiency and making large-scale synthesis difficult. Furthermore, many impurities are synthesized due to side reactions, resulting in low purity crude products, and purification requires column chromatography, which is time-consuming. Liquid-phase synthesis using trichloroacetyl compounds can only synthesize dimers, and the imidazole-containing trichloroacetyl compounds are unstable and difficult to handle. Furthermore, when the reaction is actually carried out, the solubility of the substrate is low, making large-scale synthesis difficult. The cross-coupling method does not require expensive condensing agents or polymers, but requires multiple steps to synthesize the substrate.

[0009] Patent Document 4 discloses sequence-selective pyrrole and imidazole polyamide metal complexes and a method for producing the same. Non-Patent Document 5 discloses monocyclic and polycyclic pyrroles containing N-formamide and imidazole-2-carboxylic acid for use in preparing polyamide molecules. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2006 / 030952 [Patent Document 2] Japanese Patent Application Laid-Open No. 2009-274030 [Patent Document 3] International Publication No. 2017 / 169503 [Patent Document 4] US Patent Application Publication No. 2007 / 0265240 [Non-patent literature]

[0011] [Non-Patent Document 1] Eldon E Baird, and Peter B. Dervan,Journal of the American Chemical Society,1996,vol.118,6141. [Non-patent document 2] David M. Chenoweth,Daniel A, Harki, and Peter B. Dervan,Journal of the American Chemical Society,2009,vol.131,7175. [Non-patent document 3] Wu Su, Stephen J. Gray, Ruggero Dondi and Glenn A. Burley, Organic Letters,2009,vol.11,3910. [Non-patent document 4] Junhua Xiao, Gu Yuan, Weiqiang Huang, Albert SC Chan and K.-L. Daniel Lee, The Journal of Organic Chemistry,2000,vol.65(18),5506. [Non-Patent Document 5] Keith Mulder, Jim Sexton, Zarmeen Taherbhai, Justin Jones, Peter Uthe, Toni Brown and Moses Lee, Synthetic Communications, 2007, vol. 38(1), 33. Summary of the Invention [Problem to be solved by the invention]

[0012] When studying various chemical syntheses and the creation of new substances using a flow synthesis device with a micromixer, starting materials can be in various phases, such as gas and liquid. In order to introduce and mix these phases into a mixing channel in a microchannel, a large pressure is generally required. The properties of the starting materials vary, and the introduction pressure is selected according to the properties. To introduce the starting materials into the mixing channel, the introduction pressure is controlled to minimize the pressure difference between the phases being introduced and achieve pressure balance. When the starting materials are both gas phases or both liquid phases, it is generally easy to introduce them into the mixing channel by controlling the introduction pressure. However, when the starting materials are both liquid and gas phases, their properties differ significantly, making it difficult to achieve pressure balance.

[0013] The inventors attempted to use a conventional T-shaped micromixer to supply gas and liquid phases to it and mix them, but found that the pressure difference was so large that the liquid phase flowed back into the gas phase supply channel, making mixing impossible.

[0014] The aforementioned Patent Documents 1 and 2 list gases, liquids, and the like as applicable fluids. However, the invention described in Patent Document 1 involves forming the fluids to be mixed into thin, uniform multilayers, thereby forming complex microchannels to achieve efficient mixing through molecular diffusion. It is believed that introducing a liquid phase into such a complex microchannel requires a significant high pressure. Therefore, if attempting to mix a liquid phase and a gas phase into such a fluid mixer, the gas phase must be introduced at even higher pressure, which is considered extremely difficult in practice. Furthermore, the invention described in Patent Document 2, as mentioned above, describes the use of a specific elastic tube to move gas between the inside and outside of the elastic tube. However, introducing gas into the elastic tube is also considered to require a significant pressure, making it difficult to achieve. Patent Document 2 specifically describes the movement of gas generated in a liquid phase within an elastic tube by a reaction or the like out of the elastic tube, but does not mention any specific examples of moving gas outside the elastic tube into the elastic tube.

[0015] The above-mentioned problems are also evident in a reaction for producing a reduced compound by reacting a compound to be reduced with hydrogen gas.

[0016] Therefore, an object of the present invention is to provide a method and system for producing a reduced compound that uses a flow synthesis apparatus equipped with a micromixer that can merge a gas phase and a liquid phase in a predetermined volume ratio without the liquid phase flowing back into the gas phase supply channel even if there is a pressure difference between the gas phase and liquid phase when performing flow synthesis in which a gas phase and a liquid phase are merged using a micromixer to cause a continuous gas-liquid reaction. Another object of the present invention is to provide a method for producing a pyrrole-imidazole polyamide as a preferred embodiment of the method for producing a reduced compound. [Means for solving the problem]

[0017] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that when performing flow synthesis in which a gas phase and a liquid phase are joined in a micromixer to cause a continuous gas-liquid reaction, it is possible to prevent the liquid phase from flowing back into the gas phase supply channel by continuously and alternately allowing the gas phase and liquid phase supplied continuously from each supply channel to flow into a synthesis channel, thereby making it possible to continuously cause a gas-liquid reaction between the gas phase and the liquid phase in a desired quantitative ratio.

[0018] The present invention includes the following aspects. [1] A method for producing a reduced compound, comprising: A production method using a flow synthesis apparatus equipped with a micromixer, The flow synthesis apparatus equipped with the micromixer includes a six-way switching valve, a gas phase supply flow path, a liquid phase supply flow path, a recovery flow path, a synthesis flow path, a reaction unit provided on the synthesis flow path, and a sample loop; the six-way switching valve has a gas phase supply port connected to the gas phase supply channel, a liquid phase supply port connected to the liquid phase supply channel, a recovery outlet connected to the recovery channel, a synthesis outlet connected to the synthesis channel, and two sample loop openings connected to both ends of the sample loop; the six-way switching valve is switchable between a first flow path that communicates the gas phase supply flow path, the sample loop, and the recovery flow path, and simultaneously communicates the liquid phase supply flow path and the synthesis flow path, and a second flow path that communicates the gas phase supply flow path and the recovery flow path, and simultaneously communicates the liquid phase supply flow path, the sample loop, and the synthesis flow path; the reaction section is provided with a reduction catalyst; a first step in which the six-way switching valve is in the state of the first flow path, hydrogen gas is flowed into the gas phase supply flow path, hydrogen is introduced into at least the sample loop, and a liquid phase containing a compound to be reduced is flowed into the liquid phase supply flow path; the six-way switching valve is in the state of the second flow path, and a liquid phase containing a compound to be reduced is flowed into the liquid phase supply flow path, and the hydrogen gas that is present in the sample loop and that has been introduced in the first step is flowed out from the synthesis outlet, and the hydrogen gas is flowed into the gas phase supply flow path; and these steps are repeated alternately; the hydrogen gas and the liquid phase containing the compound to be reduced are alternately discharged from the synthesis outlet, and the compound to be reduced and the hydrogen gas are reacted in the presence of a reduction catalyst in a reaction section. [2] The sample loop opening has a first opening and a second opening, The method for producing a reduced compound according to [1], wherein the gas phase supply port, the first opening of the sample loop opening, the synthesis outlet, the liquid phase supply port, the second opening of the sample loop opening, and the recovery outlet are arranged in this order in the six-way switching valve in a clockwise or counterclockwise direction. [3] The method for producing a reduced compound according to [1] or [2], wherein the liquid phase is recycled from the reaction section and the recovery channel and flows into the liquid phase supply channel. [4] A system for producing a reduced compound, comprising: A flow synthesis device equipped with a micromixer is provided, The flow synthesis apparatus equipped with the micromixer includes a six-way switching valve, a gas phase supply flow path, a liquid phase supply flow path, a recovery flow path, a synthesis flow path, a reaction unit provided on the synthesis flow path, and a sample loop; the six-way switching valve has a gas phase supply port connected to the gas phase supply channel, a liquid phase supply port connected to the liquid phase supply channel, a recovery outlet connected to the recovery channel, a synthesis outlet connected to the synthesis channel, and two sample loop openings connected to both ends of the sample loop; the six-way switching valve is switchable between a first flow path that communicates the gas phase supply flow path, the sample loop, and the recovery flow path, and simultaneously communicates the liquid phase supply flow path and the synthesis flow path, and a second flow path that communicates the gas phase supply flow path and the recovery flow path, and simultaneously communicates the liquid phase supply flow path, the sample loop, and the synthesis flow path; the reaction section is provided with a reduction catalyst; by alternately switching between the first flow path and the second flow path and causing at least the gas phase or the liquid phase that has flowed into the sample loop to flow out into the synthesis flow path, it is possible to alternately cause the liquid phase and the gas phase to flow out into the synthesis flow path, A system for producing a reduced compound, configured so that the liquid phase is recycled from the reaction section and the recovery channel and flows into the liquid phase supply channel. [5] A method for producing pyrrole-imidazole polyamide, comprising: The method includes the following steps A1 and A2: Step A1: A reduction step of reducing a compound 1 represented by the following formula (1) to obtain a compound 2 represented by the following formula (2): Step A2: An elongation step in which a compound 3 represented by the following formula (3) is reacted with the compound 2 to obtain a compound 4 represented by the following formula (4):

[0019] [ka]

[0020] [In formula (1), X 0 each independently represents N or CH, R a represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 25 carbon atoms, a nitrile group, -COOR p (R p represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms, or -CONR q R r (R q and R r each independently represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms.) and n represents 0 or an integer of 1 or more.]

[0021] [ka]

[0022] [In formula (2), X 0 , R a, n is the same as above.]

[0023] [ka]

[0024] [In formula (3), X 1 each independently represents N or CH, Y represents a halogen atom, and m represents 0 or an integer of 1 or more.

[0025] [ka]

[0026] [In formula (4), X 0 , X 1 , R a , n and m are the same as above.], The step A1 is a flow reaction using a flow synthesis apparatus equipped with a micromixer, The flow synthesis apparatus equipped with the micromixer includes a six-way switching valve, a gas phase supply flow path, a liquid phase supply flow path, a recovery flow path, a synthesis flow path, a reaction unit provided on the synthesis flow path, and a sample loop; the six-way switching valve has a gas phase supply port connected to the gas phase supply channel, a liquid phase supply port connected to the liquid phase supply channel, a recovery outlet connected to the recovery channel, a synthesis outlet connected to the synthesis channel, and two sample loop openings connected to both ends of the sample loop; the six-way switching valve is switchable between a first flow path that communicates the gas phase supply flow path, the sample loop, and the recovery flow path, and simultaneously communicates the liquid phase supply flow path and the synthesis flow path, and a second flow path that communicates the gas phase supply flow path and the recovery flow path, and simultaneously communicates the liquid phase supply flow path, the sample loop, and the synthesis flow path; the reaction section is provided with a reduction catalyst; a first step in which the six-way switching valve is in the state of the first flow path, hydrogen gas is flowed into the gas phase supply flow path, hydrogen is introduced into at least the sample loop, and a liquid phase containing the compound 1 represented by formula (1) is flowed into the liquid phase supply flow path; the six-way switching valve is in the state of the second flow path, and a liquid phase containing the compound 1 represented by formula (1) is flowed into the liquid phase supply flow path, and the hydrogen gas that is present in the sample loop and that has been introduced in the first step is flowed out from the synthesis outlet, and the hydrogen gas is flowed into the gas phase supply flow path; and these steps are repeated alternately; The step A1 is a step of alternately discharging the hydrogen gas and a liquid phase containing the compound 1 represented by formula (1) from the synthesis outlet, and reacting the compound to be reduced with the hydrogen gas in the presence of a reduction catalyst in a reaction section; The step A2 is a flow reaction in which a liquid phase containing the compound 3 represented by the formula (3) flowing in a flow path in a micromixer and a liquid phase containing the compound 2 represented by the formula (2) flowing in another flow path are joined together and reacted with each other. [6] The method according to [5], wherein the compound 4 is used as the compound 1 in the next step A1 to carry out continuous elongation. [Effects of the Invention]

[0027] According to the present invention, there are provided a method and a system for producing a reduced compound using a flow synthesis apparatus equipped with a micromixer that can merge a gas phase and a liquid phase in a predetermined volume ratio without causing the liquid phase to flow back into the gas phase supply channel even if there is a pressure difference between the supplied gas and liquid phases in flow synthesis, in which the gas and liquid phases are merged using a micromixer to continuously cause a gas-liquid reaction.The present invention also provides a method for producing a pyrrole-imidazole polyamide. [Brief explanation of the drawings]

[0028] [Figure 1] 1 is an explanatory diagram for explaining an overview of a micromixer for a flow synthesis apparatus according to an embodiment of the present invention, a flow synthesis apparatus having the same, and the flow path configuration thereof.

[0023] FIG. [Figure 2]1. FIG. 4 is an explanatory diagram for explaining the state when a gas phase is made to flow into a sample loop in the micromixer according to the embodiment shown in FIG. 1, when the six-way switching valve has a flow path configuration of the first flow path. [Figure 3] 3 is an explanatory diagram for explaining a state immediately after the six-way switching valve is switched to the second flow path from the state shown in FIG. 2. FIG. [Figure 4] FIG. 4 is an explanatory diagram illustrating a state in which, from the state shown in FIG. 3, a liquid phase is flowed into the sample loop, the gas phase in the sample loop is pushed out by the liquid phase, and the gas phase is discharged into the synthesis channel, and the gas phase is discharged from the gas phase supply channel to the recovery channel. [Figure 5] 5 is an explanatory diagram for explaining a state immediately after the six-way switching valve is switched to the first flow path from the state shown in FIG. 4. FIG. [Figure 6] FIG. 6 is an explanatory diagram illustrating a state in which, from the state shown in FIG. 5, a gas phase is flowed into the sample loop, pushing out the liquid phase in the sample loop and causing it to flow out into the recovery channel, and the liquid phase is caused to flow out from the liquid phase supply channel to the synthesis channel. [Figure 7] 7 is an explanatory diagram for explaining a state immediately after the six-way switching valve is switched to the second flow path from the state shown in FIG. 6. FIG. [Figure 8] 10 is an image showing the state when a gas phase and a liquid phase are continuously and alternately discharged into a synthesis channel using a micromixer according to an embodiment in an experimental example. DETAILED DESCRIPTION OF THE INVENTION

[0029] [Method of producing reduced compounds] [Reduced compound manufacturing system] <Flow synthesis device equipped with a micromixer> The production method of the present invention uses a flow synthesis apparatus equipped with a micromixer. The flow synthesis apparatus equipped with a micromixer will be described in detail below. Hereinafter, an embodiment of a flow synthesis apparatus equipped with a micromixer will be described with reference to the drawings. However, the present invention is not limited to such an example, and it is needless to say that the present invention can be embodied in various forms without departing from the spirit and scope of the present invention.

[0030] FIG. 1 is an explanatory diagram illustrating a micromixer for a flow synthesis apparatus (hereinafter, sometimes referred to as a "micromixer") 1 used in the production method of the present invention and the flow path configuration of a flow synthesis apparatus 2 having the same.

[0031] 1, the micromixer 1 has a six-way switching valve 10, a gas phase supply channel 11, a liquid phase supply channel 12, a recovery channel 13, a synthesis channel 14, and a sample loop 15. The six-way switching valve 10 also has ports (1) to (6), with port (1) corresponding to a gas phase supply port connected to the gas phase supply channel 11, port (2) corresponding to a first sample loop opening connected to one end (first end) 15a of the sample loop 15, port (3) corresponding to a synthesis outlet connected to the synthesis channel 14, port (4) corresponding to a liquid phase supply port connected to the liquid phase supply channel 12, port (5) corresponding to a second sample loop opening connected to the other end (second end) 15b of the sample loop 15, and port (6) corresponding to a recovery outlet connected to the recovery channel 13.

[0032] In a preferred embodiment of the present invention, the sample loop opening has a first opening and a second opening, The gas phase supply port, the first opening of the sample loop opening, the synthesis outlet, the liquid phase supply port, the second opening of the sample loop opening, and the recovery outlet are provided in this order in the six-way switching valve in a clockwise or counterclockwise direction. Specifically, in the example shown in Fig. 1, ports (1) to (6) are arranged clockwise in that order on the same circumference. The intervals between the ports on the circumference are not particularly limited as long as a first flow path and a second flow path, which will be described later, are formed. In the example shown in Fig. 1, the circumference is divided into six equal parts and the ports are provided.

[0033] In the example shown in Figure 1, the six-way switching valve 1 is configured to be switchable between the following first and second flow paths. The first flow path is formed by forming a flow path a, where ports (1) and (2) communicate with each other; a flow path b, where ports (3) and (4) communicate with each other; and a flow path c, where ports (5) and (6) communicate with each other, thereby connecting the gas phase supply flow path 11, the sample loop 15, and the recovery flow path 13, and also connecting the liquid phase supply flow path 12 and the synthesis flow path 14 (see Figures 1, 2, 5, and 6). The second flow path is formed by forming a flow path d, where ports (1) and (6) communicate with each other; a flow path e, where ports (2) and (3) communicate with each other; and a flow path f, where ports (4) and (5) communicate with each other, thereby connecting the gas phase supply flow path 11 and the recovery flow path 13, and also connecting the liquid phase supply flow path 12, the sample loop 15, and the synthesis flow path 14 (see Figures 3, 4, and 7).

[0034] The six-way switching valve 1 can be configured, for example, as a rotary valve including a stator provided with ports (1) to (6) and a rotor formed with three flow channel grooves for forming flow channels a to f. By rotating the rotor, it is possible to switch between the first flow channel and the second flow channel.

[0035] 1, the sample loop 15 has the function of replacing a portion of the liquid phase continuously fed into the synthesis channel 14 with a gas phase, and temporarily storing the gas phase when the gas phase and liquid phase are alternately discharged into the synthesis channel 14. In other words, the mixture ratio of the gas phase and the liquid phase can be adjusted by the amount stored in the sample loop 15. Therefore, the length of the sample loop 15 and other factors can be determined taking into account the conditions of the synthesis reaction between the gas phase and the liquid phase.

[0036] In the example shown in FIG. 1 , the flow synthesis apparatus 2 includes the aforementioned micromixer 1; a check valve 16, a mass flow controller 17 for controlling the flow rate of the gas phase, and a hydrogen gas cylinder 18 for storing hydrogen gas, which are arranged in this order upstream of the gas phase supply flow path 11; a check valve 19, a pump 20, and a liquid phase container 21 for storing the liquid phase, which are arranged in this order upstream of the liquid phase supply flow path 12; a waste tank 22 arranged downstream of the recovery flow path 13; and a reaction section 23 and a recovery container 24 for storing the product, which are arranged in this order downstream of the synthesis flow path 14.

[0037] 1, there is only one gas cylinder 18 and one liquid container 21, but multiple gas cylinders 18 and multiple liquid containers 21 can be provided as needed. Gas phases and liquid phases can be mixed using a general micromixer. The reaction section 23 is provided with a reduction catalyst, such as a catalytic reduction catalyst that reacts hydrogen gas in the presence of a palladium carbon catalyst, a nickel catalyst, or the like. The reaction section 23 may be provided with a heating device or the like as needed.

[0038] The flow synthesis apparatus 2 shown in FIG. 1 may have a control unit that controls the operations of the six-way switching valve 10 , the pump 20 , the check valves 16 and 19 , and the mass flow controller 17 .

[0039] The operation of the micromixer 1 and flow synthesis device 2 shown in Fig. 1 will be explained with reference to Figs. 2 to 7. Fig. 1 shows the stopped state before operation, and in Figs. 2 to 7, the gas phase flow in the flow channel is indicated by a solid line, and the liquid phase flow is indicated by a wavy line. The flow direction is indicated by an arrow.

[0040] First, as shown in Fig. 1, the six-way switching valve 10 is set to the first flow path state, and the desired gas phase, liquid phase, etc. are prepared. Then, as shown in Fig. 2, the gas phase and liquid phase are sent in the first flow path state. The gas phase is sent from flow path 11 to flow path a, sample loop 15, flow path c, and flow path 13, while the flow rate is controlled by mass flow controller 17. In some cases, the gas may reach the waste tank 22. The waste tank 22 is configured so that the gas phase can be safely released to the outside. The gas phase released to the outside may also be recovered and reused. The liquid phase is sent to flow path 12, flow path b, and flow path 14 while the flow rate is controlled by pump 20. In some cases, it may reach reaction section 23 and recovery container 24. After the gas phase is accumulated throughout sample loop 15 and the liquid phase reaches flow path 14, valve 10 is switched to the second flow path as shown in FIG. 3.

[0041] FIG. 3 shows the state of the gas and liquid phases in the flow paths of the micromixer 1 immediately after the valve 10 is switched from the first flow path state shown in FIG. 2 to the second flow path. As shown in FIG. 3, flow paths a, b, and c are formed in the first flow path, and the gas or liquid phase present in each flow path moves to flow paths e, f, and d in the second flow path, respectively. The gas phase in flow path d is pushed into flow path 13 by the gas phase flowing in from flow path 11 and flows into the waste tank 22 while being sandwiched between the gas phases present in flow path 13. The gas phase flowing into the sample loop 15 is pushed into flow path 14 together with the gas phase in flow path e by the liquid phase present in flow path f and the liquid phase flowing in from flow path 12. At this time, because a liquid phase is also present in flow path 14 downstream of the gas phase, the gas phase flows into flow path 14 while being sandwiched between the liquid phases. In other words, the liquid phase flows out of flow path 14 in the following order: liquid, gas, and liquid. Then, as shown in FIG. 4, from the state shown in FIG. 3, all of the gas phase in the sample loop 15 is caused to flow into the flow channel 14.

[0042] Thereafter, the valve 10 is switched to the first flow path. FIG. 5 shows the state of the gas and liquid phases in the flow paths of the micromixer 1 immediately after the valve 10 is switched from the second flow path state shown in FIG. 4 to the first flow path. As shown in FIG. 5, flow paths e, f, and d are formed in the second flow path shown in FIG. 4, and the gas or liquid phase present in each flow path moves to flow paths a, b, and c in the first flow path, respectively. The liquid phase present in flow path b is pushed out by the liquid phase flowing in from flow path 12 and flows into flow path 14 while being sandwiched between the liquid phase present in flow path 14. The liquid phase flowing into the sample loop 15, together with the liquid phase in flow path a and the gas phase in flow path c, is pushed into flow path 13 by the gas phase flowing in from flow path 11. Then, as shown in FIG. 6, the gas phase flows into the sample loop 15 and is stored throughout the loop.

[0043] Thereafter, the valve 10 is switched to the second flow path. FIG. 7 shows the state of the gas and liquid phases in the flow paths of the micromixer 1 immediately after the valve 10 is switched from the first flow path state shown in FIG. 6 to the second flow path. As shown in FIG. 7, flow paths a, b, and c are formed in the first flow path shown in FIG. 6, and the gas or liquid phase present in each flow path moves to flow paths e, f, and d, respectively, in the second flow path. The gas phase in flow path d is pushed into flow path 13 by the gas phase flowing in from flow path 11. In one embodiment, it flows into waste tank 22 connected to flow path 13. In this way, both the gas and liquid phases can flow into waste tank 22. The liquid phase that has flowed in may be configured to be released to the outside and reused, as in the case of the gas phase described above. The gas phase that has flowed into the sample loop 15, together with the gas phase in flow path e, is pushed into flow path 14 by the liquid phase present in flow path f and the liquid phase flowing in from flow path 12. At this time, because a liquid phase is also present in flow path 14 downstream of the gas phase, the gas phase flows into flow path 14 while being sandwiched between the liquid phases. That is, the liquid phase, gas phase, and liquid phase flow out into flow path 14 in this order. Then, after all of the gas phase present in sample loop 15 has been pushed out into flow path 14, as shown in FIG. 4, for example, the valve 10 is switched back to the first flow path as shown in FIG. 5.

[0044] As described above, by repeatedly alternately switching between the first and second flow paths of valve 10, it is possible to repeatedly and continuously flow the gas phase flowed into sample loop 15 between liquid phases when flowing the liquid phase from flow path 12 into flow path 14 without being affected by pressure difference. Furthermore, because the capacity of sample loop 15 is constant, by controlling the flow rate of the liquid phase, the gas phase containing hydrogen gas and the liquid phase containing the compound to be reduced can be alternately discharged into flow path 14 from the synthesis outlet so as to achieve a desired quantitative ratio.

[0045] The liquid and gas phases alternately flowed into flow path 14 in this manner to achieve a predetermined quantitative ratio are continuously reacted with the compound to be reduced and hydrogen gas in reaction section 23, which is equipped with a reduction catalyst. In particular, in the presence of the reduction catalyst equipped in reaction section 23, it is thought that the gaseous hydrogen gas and the liquid phase alternately move between catalyst particles, and that the gas and liquid phases tend to react efficiently via the catalyst.

[0046] The product produced by the gas-liquid reaction in the reaction section 23 is recovered, for example, together with unreacted materials in a recovery container 24. The recovery container 24 can be configured so as to be able to discharge hydrogen gas to the outside.

[0047] In this embodiment, the six-way switching valve 10 is configured to be switchable between a first flow path that connects the gas phase supply flow path 11, the sample loop 15, and the recovery flow path 13, and also connects the liquid phase supply flow path 12 and the synthesis flow path 14, and a second flow path that connects the gas phase supply flow path 11 and the recovery flow path 13, and also connects the liquid phase supply flow path 12, the sample loop 15, and the synthesis flow path 14. By alternately switching between the first flow path and the second flow path, at least the gas phase that has flowed into the sample loop 15 is allowed to flow out into the synthesis flow path 14, and the liquid phase and the gas phase are allowed to flow out alternately into the synthesis flow path 14.

[0048] In a preferred embodiment of the present invention, the liquid phase is recycled from the reaction section 23 and the recovery channel 13 and flows into the liquid phase supply channel 12. By subjecting the reaction solution to the reaction again, the reaction can be sufficiently progressed even if the reactivity of the compound to be reduced is low.

[0049] <Manufacturing method> The method for producing a reduced substance of the present invention includes a first step in which, with the valve 10 in the first flow path state, hydrogen gas is flowed into the gas phase supply flow path 11, hydrogen is introduced into at least the sample loop 15, and a liquid phase containing a compound to be reduced is flowed into the liquid phase supply flow path 12; The valve 10 is in the second flow path state, and a liquid phase containing the compound to be reduced is flowed into the liquid phase supply flow path 12, and the hydrogen gas that is in the sample loop 15 and that was introduced in the first step is flowed out from the synthesis outlet, and the hydrogen gas is flowed into the gas phase supply flow path 11. These steps are repeated alternately. By alternately repeating the first and second steps, hydrogen gas and a liquid phase containing the compound to be reduced are alternately discharged into the synthesis channel 14 and supplied to the reaction section 23.

[0050] The micromixer 1 has the six-way switching valve 10, and therefore, regardless of the pressure difference between the gas phase and the liquid phase, the gas phase and the liquid phase can be alternately discharged into the flow path 14 and merged together. Therefore, even if a pressure adjustment device is not provided downstream of the flow path 14, particularly downstream of the reaction section 23, the gas phase and the liquid phase can be supplied to the reaction section 23 at a desired volume ratio.

[0051] In the production method of the present invention, the compound to be reduced used as a raw material and the reduced compound to be produced are not particularly limited. Examples of the compound to be reduced include alkene-containing compounds, alkyne-containing compounds, nitro group-containing compounds, imine-containing compounds, aldehyde- or ketone-containing compounds, and aryl halide-containing compounds. The amount of catalyst used is not particularly limited, but in the case of flow synthesis, an excess amount of catalyst is usually loaded into the reaction section, and a liquid phase containing hydrogen gas and the compound to be reduced is then introduced into the reaction section. The reaction temperature is preferably 0°C to 100°C, and the reaction time is preferably 0.5 to 24 hours.

[0052] The present invention also relates to a production system for a reduced compound, which has a flow synthesis device equipped with a micromixer and is configured to be able to carry out the above production method.

[0053] [Method of manufacturing pyrrole-imidazole polyamide] Next, a method for producing pyrrole-imidazole polyamide, which is one of the preferred embodiments of the method for producing the reduced compound, will be described in detail. The method for producing a pyrrole-imidazole polyamide of the present invention includes the following steps A1 and A2, and the following step A1 is a flow reaction using the above-mentioned micromixer. Step A1: A reduction step of reducing a compound 1 represented by the following formula (1) to obtain a compound 2 represented by the following formula (2): Step A2: An elongation step in which a compound 3 represented by the following formula (3) is reacted with the compound 2 to obtain a compound 4 represented by the following formula (4):

[0054] [ka] [In formula (1), X 0 each independently represents N or CH, R a represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 25 carbon atoms, a nitrile group, -COOR p (R p represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms, or -CONR q R r (R q and R reach independently represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms.) and n represents 0 or an integer of 1 or more.]

[0055] [ka] [In formula (2), X 0 , R a , n is the same as above.]

[0056] [ka]

[0057] [In formula (3), X 1 each independently represents N or CH, Y represents a halogen atom, and m represents 0 or an integer of 1 or more.

[0058] [ka]

[0059] [In formula (4), X 0 , X 1 , R a , n, and m are the same as above.]

[0060] <Process A1> In step A1, compound 1 represented by formula (1) above is reduced to obtain compound 2 represented by formula (2) above. [Compound 1] Compound 1, which is the starting compound in step A1, is a monomer of N-methylpyrrole or N-methylimidazole having a nitro group, or a pyrrole-imidazole polyamide having a nitro group, and is represented by the above formula (1). X in the above formula (1) 0 Each of X independently represents N or CH. 0 If represents N, then X 0 The nitrogen-containing five-membered ring having X is a pyrrole ring. 0 If represents CH, then X 0The nitrogen-containing five-membered ring having the formula: is an imidazole ring. n represents an integer of 0 or greater than 1. From the viewpoint of reactivity, n is preferably an integer of 0 to 3, more preferably 0 or 1, and even more preferably 0. R a represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 25 carbon atoms, a nitrile group, -COOR p (R p represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms, or -CONR q R r (R q and R r each independently represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms. The alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, an n-hexyl group, and an isohexyl group. The alkyl group may have one to three substituents. The alkoxy group is preferably a linear or branched alkoxy group having from 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentyloxy group, an isopentyloxy group, an n-hexyloxy group, an isohexyloxy group, etc. Among these, an alkoxy group having from 1 to 3 carbon atoms is preferred. The aryl group is preferably an aryl group having 6 to 10 carbon atoms. Specific examples include phenyl, α-naphthyl, and β-naphthyl. Phenyl is particularly preferred. The aryl group may have 1 to 3 substituents. Examples of the substituent include a halogen atom, an alkyl group, and an alkoxy group. The alkyl group in the aralkyl group (arylalkyl group) is the above-mentioned alkyl group, and the aryl group is the above-mentioned aryl group. An example of the aralkyl group is a benzyl group. Compound 1 is available as a commercially available product, or can be obtained from a commercially available product by a known organic synthesis reaction. R a Among these, a hydrogen atom or -COOR is preferable. p , more preferably -COOR p is.

[0061] [Compound 2] The compound 2 obtained in step A1 is an N-methylpyrrole or N-methylimidazole monomer having an amino group, or a pyrrole-imidazole polyamide having an amino group, and is represented by the above formula (2). In formula (2), X 0 , R a , n is defined as in formula (1).

[0062] [Reduction Reaction] In step A1, the nitro group of compound 1 is reduced to an amino group to obtain compound 2. The reduction reaction of the nitro group can be carried out by a known method. Examples of such reduction methods include catalytic reduction, which involves reacting hydrogen gas in the presence of a palladium carbon catalyst, a nickel catalyst, or the like; Bechamp reduction, which involves reacting an acid such as ammonium chloride, hydrochloric acid, or acetic acid in the presence of a metal catalyst such as iron, zinc, or tin; and hydride reduction, which involves reacting a metal hydride. Among these, the reduction reaction is preferably carried out in the presence of a palladium carbon catalyst. From the viewpoint of reaction progress, the reduction reaction is preferably carried out in a solvent, such as an aqueous solvent (e.g., water), an alcoholic solvent (e.g., methanol, ethanol), an ether solvent (e.g., diethyl ether, tetrahydrofuran), or an aprotic polar solvent (e.g., N,N-dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), N-methylpyrrolidone (NMP), acetonitrile, or acetone. The alcoholic solvent is preferably methanol, and the aprotic polar solvent is preferably N,N-dimethylformamide (DMF). In one preferred embodiment of the present invention, the reduction reaction is carried out in an alcoholic solvent, in view of the widespread use of reduction reactions carried out in the presence of, for example, a palladium-carbon catalyst. In another preferred embodiment, the reduction reaction is carried out in an aprotic polar solvent, from the viewpoint of improving the reaction rate, reaction progress, reaction reproducibility, etc., due to the high solubility of the pyrrole-imidazole polyamide. The solvent may be a single solvent or a mixture of two or more solvents.

[0063] The amount of catalyst used is not particularly limited, and usually an excess amount of catalyst is loaded into the reaction section 23, and hydrogen gas and a solution of compound 1 are introduced thereinto. The reaction temperature is preferably 0°C to 100°C, and the reaction time is preferably 0.5 to 24 hours. Step A1 is carried out by a flow reaction using the above-mentioned micromixer.

[0064] <Process A2> Step A2 is an elongation step in which compound 3 represented by the above formula (3) is reacted with compound 2 to obtain compound 4 represented by the above formula (4). [Compound 3] The compound 3 reacted with the compound 2 in step A2 is an acid halide compound and is represented by the above formula (3). X in the above formula (3) 1 each independently represents N or CH. Y represents a halogen atom, such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a chlorine atom from the viewpoint of availability. m represents an integer of 0 or greater than 1. From the viewpoint of reactivity, m is preferably an integer of 0 to 3, more preferably 0 or 1, and even more preferably 0.

[0065] When m is 0, compound 3 is represented by the following formula (3').

[0066] [ka]

[0067] [In formula (3'), 1 , Y is the same as above.]

[0068] Compound 3 is available as a commercially available product or can be obtained from a commercially available product by a known organic synthesis reaction. A specific example is a method in which a carboxylic acid compound is reacted with a halogenating agent such as thionyl chloride or oxalyl chloride. The reaction with the halogenating agent is preferably carried out in a solvent from the viewpoint of reaction progress. The solvent is preferably an ether solvent such as diethyl ether or tetrahydrofuran. The solvent may be a single solvent or a mixed solvent of two or more solvents. The amount of the halogenating agent used is preferably 0.1 equivalent to an excess amount, more preferably 0.2 to 5 equivalents, and even more preferably 0.5 to 2 equivalents, relative to the amount of the carboxylic acid compound. The reaction temperature is preferably 0°C to 100°C, and the reaction time is preferably 0.5 to 24 hours.

[0069] [Compound 4] The compound 4 obtained in step A2 is a pyrrole-imidazole polyamide, and is represented by the above formula (4). In equation (4), X 0 , X 1 , R a , n, and m are defined as in the formulas (1), (2), and (3).

[0070] When m is 0, compound 4 is represented by the following formula (4').

[0071] [ka]

[0072] [In formula (4'), X 0 , X 1 , R a , n is the same as above.]

[0073] [Extension reaction] In step A2, the acid halide group of compound 3 is reacted with the amino group of compound 2 to form an amide bond, thereby obtaining compound 4. The compound 2 can be reacted with the compound 3 in an amount of preferably 0.1 to 10 equivalents, more preferably 0.5 to 2 equivalents. The elongation reaction can be carried out, if necessary, in the presence of a base in an amount of preferably 0.1 to an excess mole, more preferably 0.5 to 10 moles, per mole of compound 3. Examples of the base include organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine (DIPEA). From the viewpoint of reaction progress, the reaction is preferably carried out in a solvent. Examples of the solvent include organic solvents such as ethyl acetate, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, tetrahydrofuran (THF), acetonitrile, and dichloromethane. The solvent may be a single solvent or a mixed solvent of two or more solvents.

[0074] Step A2 may be either a batch system using a flask or the like, or a flow reaction using a flow microreactor, etc. In a preferred embodiment, step A2 is a flow reaction, and more preferably, the reaction is carried out in a microreactor. In particular, it is more preferable that both Step A1 and Step A2 are flow reactions, from the viewpoint of facilitating large-scale synthesis.

[0075] <Process B1 and Process B2> The method for producing a pyrrole-imidazole polyamide of the present invention may further include the following steps B1 and B2. Step B1: A reduction step of reducing the compound 4 obtained by the above production method to obtain the compound 5 represented by the following formula (5): Step B2: An elongation step in which compound 6 represented by the following formula (6) is reacted with the above compound 5 to obtain compound 7 represented by the following formula (7):

[0076] [ka]

[0077] [In formula (5), X 0 , X 1 , R a , n, and m are the same as above.]

[0078] [ka] [In formula (6), X 2 represents N or CH, Y represents a halogen atom, R b represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an aryl group having 6 to 10 carbon atoms. p represents 0 or an integer of 1 or more.]

[0079] [ka] [In formula (7), X 0 , X 1 , X 2 , R a , R b , n, m, and p are the same as above.]

[0080] The method for producing a pyrrole-imidazole polyamide of the present invention includes the above steps B1 and B2, so that a pyrrole-imidazole polyamide having no terminal nitro or amino groups can be produced.

[0081] [Process B1] Step B1 can be carried out in the same manner as Step A1 above, except that Compound 4 obtained by the above production method is used instead of Compound 1.

[0082] When m is 0, compound 5 is represented by the following formula (5').

[0083] [ka]

[0084] [In formula (5'), X 0 , X 1 , R a , n is the same as above.]

[0085] [Process B2] Step B2 can be carried out in the same manner as step A2 above, except that compound 5 obtained in step B1 above and compound 6 above are used instead of compound 3.

[0086] [Compound 6] Compound 6, which is reacted with compound 5 in step B2, is an acid halide compound and is represented by the above formula (6). Unlike compound 3, compound 6 does not have a nitro group. X in the above formula (6) 2 each independently represents N or CH. Y represents a halogen atom, such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a chlorine atom from the viewpoint of availability. R b represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group, alkoxy group, and aryl group are the same as those described above for R a The same aspects as above can be mentioned. p represents an integer of 0 or greater than 1. From the viewpoint of reactivity, p is preferably an integer of 0 to 3, more preferably 0 or 1, and even more preferably 0.

[0087] When p is 0, compound 6 is represented by the following formula (6').

[0088] [ka]

[0089] [In formula (6'), X 1 , Y is the same as above.]

[0090] Like compound 3, compound 6 is available as a commercially available product or can be obtained from a commercially available product by a known organic synthesis reaction.

[0091] In each step of the production method of the present invention, the reaction can be stopped as needed by changing the temperature or pH, or by adding water, a solvent, a saturated aqueous solution of sodium bicarbonate, or the like. Furthermore, the target compound can be obtained through an isolation step such as filtration, concentration, or extraction, as needed. By obtaining the target compound, the solvent used in the next step can also be replaced. The fact that the target compound has been obtained in each step can be confirmed, for example, by 1 H-NMR measurement, 13 This can be confirmed by known means such as C-NMR measurement or mass spectrometry.

[0092] [Compound 7] The compound 7 obtained in step B2 is a pyrrole-imidazole polyamide, and is represented by the above formula (7). In equation (7), X 0 , X 1 , X 2 , R a , n, m, and p are defined as in the formulas (5) and (6).

[0093] When m is 0 and p is 0, compound 7 is represented by the following formula (7').

[0094] [ka]

[0095] [In formula (7'), X 0 , X 1 , X 2 , R a , R b , n is the same as above.]

[0096] Thus, pyrrole-imidazole polyamide is produced. The manufacturing method of the present invention makes it possible to freely and easily produce pyrrole-imidazole polyamides in which pyrrole rings and imidazole rings are arranged in a desired order. The compounds used in the present invention can be easily synthesized from commercially available compounds, and are economical because they do not use condensing agents, which tend to be expensive. Furthermore, the production method of the present invention does not require a condensing agent or a support (a polymer used in solid-phase synthesis), and can be carried out without purification such as column chromatography, so that the amount of waste generated during production is extremely small. Furthermore, the use of a flow microreactor increases reaction efficiency and prevents the formation of by-products such as branched structures. The production method using a flow microreactor has a much shorter reaction time than batch production methods, and also allows for the easy mass production of pyrrole-imidazole polyamides. [Example]

[0097] (Experimental Example I) In the following, an experiment was conducted in which the steps shown in FIGS. 2 to 7 were carried out using the micromixer 1 according to the embodiment shown in FIG. 1 described above, and the gas phase and the liquid phase, which were supplied separately and continuously, were alternately discharged into the synthesis channel 14 at a predetermined volume ratio.

[0098] The conditions are as follows: Gas phase: Nitrogen, flow rate 10cc / min Liquid phase: polyethylene glycol 300, flow rate 1.0 mL / min Sample loop 15: length 100 mm, inner diameter 1.0 mm Width (inner diameter) of channels 11 to 14: 1.0 mm Width of channels a(e), b(f), c(d): 0.25 mm

[0099] As a result, colorless nitrogen gas (gas phase) and pale yellow polyethylene glycol (liquid phase) alternately flowed continuously into flow channel 14, and it was visually confirmed that there was no backflow of the liquid phase into flow channel 11. Figure 8 shows an image of the fluid flowing into synthesis flow channel 14 at this time. As shown in Figure 8, in flow channel 14, boundaries between the gas and liquid phases were observed at the positions indicated by the arrows indicated by the symbols A to D, and it can be seen that the liquid phase (for example, between A and B in Figure 8) and the gas phase (for example, between B and C in Figure 8) continuously flowed alternately. Therefore, it can be seen that when the gas phase and the liquid phase are used as substrates for a desired gas-liquid reaction system, it is possible to continuously perform the desired gas-liquid reaction in a reaction vessel downstream of flow channel 14.

[0100] (Experimental Example II) In the present examples, various measurements were carried out by the following methods. Infrared absorption spectrum (IR) The measurements were carried out by a Fourier transform infrared spectrometer equipped with ATR (attenuated total reflectance). ·Nuclear magnetic resonance (NMR) A 400MHz measurement device was used. The chemical shift in DMSO-d6 is 1 In 1 H-NMR, the signal of the solvent (DMSO) (=2.50 ppm) was used as the internal standard. 13 In C-NMR, the solvent signal (DMSO (=39.52 ppm)) was used as the internal standard for chemical shifts. ·Mass spectrometry Measurement was carried out by electrospray ionization time of flight (ESI-TOF).

[0101] Synthesis Example 1: Dimer synthesis using the batch method

[0102] [ka]

[0103] Commercially available monomers, methyl 4-nitro-1-methylpyrrole-2-carboxylate (Py) and methyl 4-nitro-1-methylimidazole-2-carboxylate (Im), were each added to methanol (MeOH) to form a 0.1 M suspension, and 10% palladium-carbon catalyst (Pd / C) was added under an argon atmosphere. The flask was then vacuumed using an aspirator, and the atmosphere was replaced with hydrogen gas from a rubber balloon. After the reaction was carried out at room temperature (RT) for one day, the hydrogen gas was removed using an aspirator, and the atmosphere in the flask was replaced with argon. The reaction solution was filtered through Celite using methanol to remove the Pd / C. The resulting solution was concentrated under reduced pressure using a rotary evaporator to obtain monomer (iii). The yield was 100% (quant).

[0104] [ka]

[0105] Pyrrole or imidazole carboxylic acid derivative 1 was dissolved in tetrahydrofuran (THF) to prepare a 0.035 M solution, and under an argon atmosphere, 1.1 equivalents of oxalyl chloride was reacted with carboxylic acid derivative (i) in the presence of 1.1 equivalents of N,N-dimethylformamide (DMF) to give monomer (ii). The pyrrole or imidazole derivative monomer (iii) was dissolved in tetrahydrofuran (THF) to give a 0.058 M solution, and 3.0 equivalents of N,N-diisopropylethylamine (DIPEA) relative to the monomer (iii) was added at room temperature under an argon atmosphere. A condensation reaction was performed by dropping a solution of the monomer (iii) (solution B) into a solution of the monomer (ii) (solution A). Four combinations were used: a pyrrole derivative and an imidazole derivative for the monomer (ii), and a pyrrole derivative and an imidazole derivative for the monomer (iii), to synthesize dimer (iv). The reaction was terminated by adding saturated aqueous sodium bicarbonate, and the resulting solution was subjected to separation and extraction with ethyl acetate. The organic solvent was removed from the organic layer under reduced pressure using a rotary evaporator. The residue was suspended in methanol, and the insoluble matter containing dimer (iv) was obtained as a yellow solid by filtration. The yield is shown in Table 1.

[0106] In all four combinations, the desired dimers (iv-a) to (iv-d) were obtained in 53–75% yield after 24 hours of reaction. The reaction was very fast, with dimers 4a–4d being produced in just 30 seconds. The content of PyPy dimer (iv-a) in the insoluble fraction was over 99% by mass.

[0107] [Table 1]

[0108] (iv-a):PyPy dimer

[0109] [ka]

[0110] Yellow solid; 1 H-NMR(400MHz,DMSO-d6) δ 3.74(s,3H),3.85(s,3H),3.95(s,3H),6.8(s,1H),7.46(s,1H),7.55(s,1H),8.19(s,1H),10.28(s,1H); 13 C-NMR(100MHz,DMSO-d6) δ 36.2,37.4,51.0,107.6,108.3,118.8,120.8,122.1,126.1,128.3,133.8,156.9,160.7; HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 13 H 14 N4NaO5 + 329.0862;Found 329.0856.

[0111] (iv-b): PyIm binary

[0112]

change

[0113] Yellow solid; 1 H-NMR (400MHz, DMSO-d6) δ 3.83(s,3H),3.95(s,3H),3.97(s,3H),7.66(s,1H),7.79(s,1H),7.79(s,1H),8.15(s,1H); 13 C-NMR (100MHz, DMSO-d6) δ 35.2,37.4,48.4,51.6,108.6,115.5,125.2,128.4,133.9,137.0,157.2,158.7; HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 12 H 13 N5NaO5 + 330.0814;Found 330.0804.

[0114] (iv-c): ImPy binary

[0115]

change

[0116] Yellow solid; 11H-NMR(600 MHz, DMSO-d6) δ 3.74 (s, 3H), 3.85 (s, 3H), 4.05 (s, 3H), 7.08 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 8.54 (s, 1H), 10.7 (s, 1H); 13 13C-NMR(150 MHz, DMSO-d6) δ 36.0, 36.2, 50.7, 109.1, 118.9, 121.2, 121.5, 126.3, 137.5, 144.2, 154.6, 160.5; IR(ATR) ν 2360, 2338, 1695, 1542, 1452, 1384, 1309, 1255, 1203, 1125 cm -1 ; HRMS(ESI-TOF) m / z: [M+Na] + Calcd for C 12 H 13 N5NaO5 + 330.0814; Found 330.0812.

[0117] (iv-d): ImIm dimer

[0118]

Chem.

[0119] Yellow solid; 1 1H-NMR(400 MHz, DMSO-d6) δ 3.83 (s, 3H), 3.96 (s, 3H), 4.04 (s, 3H), 7.68 (s, 1H), 8.57 (s, 1H), 10.62 (s, 1H); 13 13C-NMR(100 MHz, DMSO-d6) δ 35.4, 36.1, 51.6, 116.1, 116.2, 126.4, 131.5, 135.7, 137.0, 155.1, 158.6; HRMS(ESI-TOF) m / z: [M+Na] + Calcd for C 11 H 12 N6NaO5 +331.0767;Found 331.0760.

[0120] Synthesis Example 2: Trimer synthesis using a batch method

[0121] [ka]

[0122] The dimer (iv) obtained in Synthesis Example 1 above was reduced using 10% Pd / C under a hydrogen atmosphere to obtain dimer (v) in the same manner as in Synthesis Example 1 above. The yields are shown in Table 2. In the table, "quant" indicates that the reaction proceeded quantitatively. The reduction of dimers (iv-a) to (iv-c) to give dimers (va) to (vc) proceeded in high yields.

[0123] [Table 2]

[0124] [ka]

[0125] Except for using the dimer (v) instead of the monomer (iii), the trimer (vii) was obtained in the same manner as in Synthesis Example 1. The yields are shown in Table 3. In a short reaction time of 30 seconds, compounds (vii-a) to (vii-d) were obtained in yields of 12 to 71%.

[0126] [Table 3]

[0127] (vii-a):PyPyPy trimer [ka]

[0128] Yellow solid; 1 1H-NMR(600 MHz, DMSO-d6) δ 3.73 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 6.93 (s, 1H), 7.11 (s, 1H), 7.29 (s, 1H), 7.48 (s, 1H), 7.68 (s, 1H), 8.20 (s, 1H), 10.08 (s, 1H), 10.48 (s, 1H); 13 13C-NMR(150 MHz, DMSO-d6) δ 35.94, 35.98, 37.28, 50.74, 104.82, 107.64, 108.51, 118.49, 118.72, 120.71, 121.43, 122.76, 122.85, 126.24, 127.97, 133.76, 156.89, 158.35, 160.70; HRMS(ESI-TOF) m / z: [M+Na] + Calcd for C 19 H 20 N6NaO6 + 451.1342; Found 451.1337.

[0129] (vii-a): PyPyIm trimer

[0130]

Chem.

[0131] Yellow solid; 1 1H-NMR(600 MHz, DMSO-d6) δ 3.83 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 3.97 (s, 3H), 7.12 (s, 1H), 7.35 (s, 1H), 7.60 (s, 1H), 7.65 (s, 1H), 8.13 (s, 1H), 10.20 (s, 1H), 10.61 (s, 1H); 1313C-NMR (150 MHz, DMSO-d6) δ 35.13, 36.06, 37.14, 51.42, 105.53, 107.47, 115.33, 119.62, 121.28, 121.98, 126.17, 127.82, 130.67, 133.71, 137.63, 156.88, 158.49, 158.72; HRMS (ESI-TOF) m / z: [M + Na] + Calcd for C 18 H 19 N7NaO6 + 452.1295; Found 452.1305.

[0132] (vii-a): PyImPy trimer

[0133]

Chem.

[0134] Yellow solid; 1 1H-NMR (600 MHz, DMSO-d6) δ 3.76 (s, 3H), 3.86 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 7.01 (s, 1H), 7.49 (s, 1H), 7.55 (s, 1H), 7.75 (s, 1H), 8.15 (s, 1H), 9.93 (s, 1H), 10.65 (s, 1H); 13 13C-NMR (150 MHz, DMSO-d6) δ 34.7, 36.0, 37.3, 50.7, 108.4, 108.6, 115.2, 118.8, 120.7, 121.7, 125.3, 128.3, 133.9, 134.2, 135.3, 155.7, 157.4, 160.4; IR (ATR) ν 2361, 1665, 1542, 1441, 1409, 1312, 1216, 1118, 899, 784 cm -1 ; HRMS (ESI-TOF) m / z: [M + Na] + Calcd for C 18 H 19 N7NaO6 +452.1295;Found 452.1288.

[0135] (vii-a):ImPyPy trimer

[0136] [ka]

[0137] Yellow solid; 1 H-NMR(600MHz,DMSO-d6) δ 3.75(s,3H),3.85(s,3H),3.86(s,3H),4.07(s,3H),6.93(d,J=2.4Hz,1H),7 .24(s,1H),7.30(s,1H),7.44(s,1H),8.57(s,1H),9.89(s,1H),10.8(s,1H); 13 C-NMR(150MHz,DMSO-d6) δ 35.9,35.9,36.3,50.7,105.1,108.5,118.5,119.1,120.7,120.9,122.7,122.9,126.3,137.7,144.2,154.6,158.3,160.6; IR(ATR) ν 1688,1548,1441,1365,1308,1205,1112,1060,1005,828cm -1 ; HRMS(ESI-TOF) m / z:[M+Na] + Calcd for C 18 H 19 N7NaO6 + 452.1295;Found 452.1307.

[0138] Synthesis Example 3: Dimer synthesis using a flow microreactor Figure 1 shows a schematic diagram of synthesis using a flow microreactor. The micromixer used was a T-shaped mixer with an inner diameter of 0.25 mm, and the tube used was made of PTFE (polytetrafluoroethylene) with an inner diameter of 0.8 mm. Solution A containing monomer (ii) obtained in the same manner as in Synthesis Example 1 had a concentration of 0.035 M and a flow rate of 2.0 mL / min. Solution B containing monomer (iii) obtained in the same manner as in Synthesis Example 1 had a concentration of 0.058 M and a flow rate of 1.2 mL / min. After passing through the tube of a predetermined length, the reaction was stopped by adding saturated aqueous sodium bicarbonate solution, followed by separation and extraction with ethyl acetate. The organic solvent was removed from the organic layer under reduced pressure using a rotary evaporator. The residue was suspended in methanol, and an insoluble fraction containing dimer 4 was obtained as a yellow solid by filtration.

[0139] 3-1: Synthesis of PyPy dimer (iv-a) PyPy dimer (iv-a) was synthesized using pyrrole derivatives as monomers (ii) and (iii). The length of the tube after the joining of solutions A and B and the reaction temperature were varied. The content of PyPy dimer (iv-a) in the insoluble fraction obtained in the synthesis using a tube length of 410 cm and a reaction temperature of 0°C was 99% by mass or more. The yields under each condition are shown in Table 4.

[0140] [Table 4]

[0141] 3-2: Synthesis of PyIm dimer (iv-b) PyIm dimer (iv-b) was synthesized in the same manner as in 3-1 above, using a pyrrole derivative as monomer (ii) and an imidazole derivative as monomer (iii). The yields under each condition are shown in Table 5.

[0142] [Table 5]

[0143] 3-3: Synthesis of ImPy dimer (iv-c) ImPy dimer (iv-c) was synthesized in the same manner as in 3-1 above, using an imidazole derivative as monomer (ii) and a pyrrole derivative as monomer (iii). The yields under each condition are shown in Table 6.

[0144] [Table 6]

[0145] 3-4: Synthesis of ImIm dimer (iv-d) ImIm dimer (iv-d) was synthesized in the same manner as in 3-1 above, except that imidazole derivatives were used as monomers (ii) and (iii). The yields under each condition are shown in Table 7.

[0146] [Table 7]

[0147] Synthesis Example 4: Trimer synthesis using a flow microreactor 4-1: Synthesis of PyPyPy trimer (vii-a) 1 Using the flow microreactor used in Synthesis Example 3, a pyrrole derivative was used as monomer (ii) and a PyPy dimer (va) was used as monomer (iii), and PyPyPy trimer (vii-a) was synthesized by varying the length of the tube after the joining of solutions A and B and the reaction temperature. The content of PyPyPy trimer (vii-a) in the insoluble fraction obtained in the synthesis under conditions of a tube length of 410 cm and a reaction temperature of 0°C was 99% by mass or more. The yields under each condition are shown in Table 8. [Table 8]

[0148] 4-2: Synthesis of PyPyPy trimer (vii-a) 2 PyPy dimer (iv-a) was reacted with oxalyl chloride in the presence of DMF to give PyPy dimer (va). The PyPyPy trimer (vii-a) was synthesized in the same manner as in 4-1 above, using a pyrrole derivative (monomer) as the monomer (ii) and the PyPy dimer (va) obtained above as the monomer (iii). The yields under each condition are shown in Table 9.

[0149] [Table 9]

[0150] 4-3: Synthesis of PyPyIm(vii-b) trimer PyPyIm trimer (vii-b) was synthesized in the same manner as in 4-1 above, using a pyrrole derivative as monomer (ii) and PyIm dimer (vb) as monomer (iii). The yields under each condition are shown in Table 10.

[0151] [Table 10]

[0152] 4-4: Synthesis of PyImPy trimer (vii-c) The pyrrole derivative and ImPy dimer (vc) were used as monomer (ii) to synthesize PyImPy trimer (vii-c) in the same manner as in 4-1 above. The yields under each condition are shown in Table 11.

[0153] [Table 11]

[0154] 4-5: Synthesis of ImPyPy trimers (vii-d) ImPyPy trimers (vii-d) were synthesized using an imidazole derivative as monomer (ii) and a PyPy dimer (va) as monomer (iii). The yields under each condition are shown in Table 12.

[0155] [Table 12]

[0156] Synthesis Example 5: Tetramer synthesis using a flow microreactor 5-1: Synthesis of PyPyPyPy tetramer (ix-a) The PyPyPy trimer (vii-a) obtained in 4-1 above was reduced with 10% Pd / C under a hydrogen atmosphere to obtain the PyPyPy trimer. The reduction proceeded quantitatively. The PyPyPyPy tetramer (ix-a) was synthesized using the same flow microreactor as in Synthesis Example 3, with a pyrrole derivative as the monomer (ii) and the PyPyPy trimer obtained above as the monomer (iii). The yields under each condition are shown in Table 13.

[0157] [Table 13]

[0158] (ix-a):PyPyPyPy tetramer

[0159] [ka]

[0160] Yellow solid; 1H-NMR(600MHz,DMSO-d6) δ 3.75(s,3H),3.85(s,3H),3.86(s,3H),3.88(s,3H),3.98(s,3H),6.93( d,J=1.8Hz,1H),7.05(d,J=2.4Hz,1H),7.07(d,J=1.8Hz,1H),7.22(d,J =1.8Hz,1H),7.25(d,J=1.2Hz,1H),7.44(d,J=1.2Hz,1H),7.58(d,J=2.4Hz,1H),8.14(d,J=1.2Hz,1H),9.83(s,1H),9.88(s,1H),10.19(s,1H); IR(ATR) ν 3468,1649,1438,1310,1110,889,815,780,751,734cm -1 ; HRMS(ESI-TOF) m / z:[M+Na]+ Calcd for C 25 H 26 N8NaO7 + 573.1822;Found 573.1823.

[0161] 5-2: Synthesis of PyPyImPy tetramer (ix-b) The PyImPy trimer (vii-c) obtained in 4-4 above was reduced with 10% Pd / C under a hydrogen atmosphere to obtain the PyImPy trimer. The reduction proceeded quantitatively. The PyPyImPy tetramer (ix-b) was synthesized using a pyrrole derivative as the monomer (ii) and the PyImPy trimer obtained above in the same manner as in 5-1 above, except that the solvent for solution B was changed from THF to DMF. The desired tetramer was successfully obtained in 39% yield after 57.5 seconds of reaction at room temperature.

[0162] (ix-b):PyPyImPy tetramer

[0163] [ka]

[0164] Yellow solid; 1 H-NMR(400MHz,DMSO-d6) δ 3.75(s,3H),3.86(s,3H),3.88(s,3H),3.97(s,3H),3.99(s,3H),7.01(d,J=2.0Hz,1H),7.10(d,J=2.0Hz,1H),7.34(d,J=1. 6Hz,1H),7.50(d,J=2.0Hz,1H),7.53(s,1H),7.60(d,J=2.0Hz,1H),8.14(s,1H),10.03(s,1H),10.15(s,1H),10.23(s,1H); 13C-NMR(150MHz,DMSO-d6) δ 34.7,36.0,36.0,37.2,50.7,105.3,107.5,108.6,114.9,118.8,119.4,120.8,121.4,121.9,122.1,126.2,127.9,133.7,133.9,135.9; IR(ATR) ν 3461,2945,2350,2338,1440,1365,900,743,664,641cm -1 ; HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C 24 H 25 N9NaO7 + 574.1775;Found 574.1797.

[0165] Synthesis Example 6: Tetramer synthesis by batch method 6-1: Synthesis of PyPyPyPy tetramer (ix-a) The PyPy dimer (iv-a) obtained in 3-1 above was reduced with 10% Pd / C under a hydrogen atmosphere to give the PyPy dimer (va). The reduction proceeded quantitatively. The PyPy dimer (iv-a) obtained in 3-1 above was suspended in a 1:1 mixture of HO and EtOH. Five equivalents of sodium hydroxide were added under ice-cooling, and the mixture was stirred in an oil bath at 95°C for 1 hour. The mixture was then ice-cooled again, and 10 equivalents of 1 mol / L aqueous hydrochloric acid were added. The resulting yellow precipitate was filtered using a Kiriyama funnel, yielding PyPy-COH(xa) in 50% yield.

[0166] [ka]

[0167] Using the flow microreactor used in Synthesis Example 3 above, PyPyPyPy tetramer (ix-a) was synthesized using PyPy-COH(xa) as monomer (ii) and the PyPy dimer obtained above as monomer (iii). The synthesis was carried out in the same manner as in 5-1 above, except that the concentrations of solution A and solution B were changed to 0.018 M and 0.03 M, respectively. After a reaction time of 57.5 seconds at room temperature, PyPyPyPy tetramer (ix-a) was successfully obtained in 64% yield.

[0168] Synthesis Example 7: Amine synthesis by flow method In the micromixer 1 as shown in FIG. 1, a hydrogen gas cylinder 18 was connected to a gas supply port connected to a gas supply flow path 11 of a six-way valve 10 via a mass flow controller (manufactured by Kofloc Corporation, model number: EX-250SC-RJ-24-VV). Commercially available methyl 4-nitro-1-methylpyrrole-2-carboxylate (NO2PyCO2Me) (300 mg) and diisopropylethylamine (0.85 mL) were placed in a flask and dissolved in cyclopentyl methyl ether (28 mL). The flask was then connected to a liquid phase supply port connected to the liquid phase supply flow path 12 of the six-way valve 10 via a plunger pump (manufactured by YMC Corporation, model number: YMCK-24-33P). The reaction section 23 was connected to a column packed with palladium carbon (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product code: 167-28862), and the outlet of the column at the end of the synthesis flow path 14 was connected to a flask containing the solution, thereby forming a circuit in which the recovered reaction liquid flows again into the liquid phase supply flow path 12 for reuse. The column was placed in an oven, and the steps shown in FIGS. 2 to 7 were carried out, and an experiment was carried out in which the gas phase and the liquid phase, which were supplied separately and continuously, were alternately discharged into the synthesis channel 14 at a predetermined volume ratio. The hydrogen flow rate was 10 mL / min, the solution flow rate was 1.0 mL / min, the six-way valve switching time was 2.5 seconds for both gas and solution, and the column temperature was set to 80°C to start the reaction. The reaction was monitored by thin layer chromatography (TLC) or 1The reaction was determined to be complete when the raw material NO2PyCO2Me (nitro form) disappeared and was completely reduced to the product NH2PyCO2Me (amine form) by H NMR. It was confirmed that a cyclopentyl methyl ether solution of NH2PyCO2Me (28 mL) was quantitatively obtained.

[0169] Using the same flow method as for NO2PyCO2Me, NO2PyPyCO2Me was reduced to NH2PyPyCO2Me quantitatively. Furthermore, it was confirmed that the reduction reaction from NO2PyPyPyCO2Me to NH2PyPyPyCO2Me proceeded using the same flow method. The amines obtained by this method (NH2PyCO2Me, NH2PyPyCO2Me, NH2PyPyPyCO2Me) can be used directly for the synthesis of polymers using the flow reactor described above. [Explanation of symbols]

[0170] 1. Micromixer for flow synthesis equipment 2. Flow synthesis apparatus 10 Six-way switching valve 11 Gas phase supply channel 12 Liquid phase supply channel 13 recovery channels; 4 Synthesis channel 15 Sample Loops 15a One end 15b Other end 16, 19 Check valve 17 Mass flow controller 18 Gas cylinder; 20 Pump 21 Liquid phase vessel 22 Waste tank 23 Reaction tank 24 Collection container A, B, C, D The boundary between the gas and liquid phases.

Claims

1. A method for producing a reduced compound, comprising the steps of: A production method using a flow synthesis apparatus equipped with a micromixer, The flow synthesis apparatus equipped with the micromixer includes a six-way switching valve, a gas phase supply flow path, a liquid phase supply flow path, a recovery flow path, a synthesis flow path, a reaction section provided on the synthesis flow path, and a sample loop; the six-way switching valve has a gas phase supply port connected to the gas phase supply flow path, a liquid phase supply port connected to the liquid phase supply flow path, a recovery outlet connected to a recovery flow path, a synthesis outlet connected to a synthesis flow path, and two sample loop openings connected to both ends of the sample loop, the six-way switching valve is switchable between a first flow path in which the gas phase supply flow path, the sample loop, and the recovery flow path communicate with each other and at the same time the liquid phase supply flow path and the synthesis flow path communicate with each other, and a second flow path in which the gas phase supply flow path and the recovery flow path communicate with each other and at the same time the liquid phase supply flow path, the sample loop, and the synthesis flow path communicate with each other; The reaction section includes a reduction catalyst, a first step of flowing hydrogen gas into the gas phase supply flow path while the six-way switching valve is in the first flow path state, flowing hydrogen into at least the sample loop, and flowing a liquid phase containing a compound to be reduced into the liquid phase supply flow path; the six-way switching valve is in the state of the second flow path, a liquid phase containing a compound to be reduced is flowed into the liquid phase supply flow path, and the hydrogen gas that is present in the sample loop and that has been flowed in in the first step is discharged from the synthesis outlet, and the hydrogen gas is flowed into the gas phase supply flow path; and the hydrogen gas and the liquid phase containing the compound to be reduced are alternately discharged from the synthesis outlet, and the compound to be reduced and the hydrogen gas are reacted in the presence of a reduction catalyst in a reaction section.

2. the sample loop opening has a first opening and a second opening, 2. The method for producing a reduced compound according to claim 1, wherein the gas phase supply port, the first opening of the sample loop opening, the synthesis outlet, the liquid phase supply port, the second opening of the sample loop opening, and the recovery outlet are provided in this order in a clockwise or counterclockwise direction on the hexagonal switching valve.

3. The method for producing a reduced compound according to claim 1 , wherein the liquid phase is recycled from the reaction section and the recovery channel and is caused to flow into the liquid phase supply channel.

4. A system for producing a reduced compound, comprising: A flow synthesis device equipped with a micromixer, The flow synthesis apparatus equipped with the micromixer includes a six-way switching valve, a gas phase supply flow path, a liquid phase supply flow path, a recovery flow path, a synthesis flow path, a reaction section provided on the synthesis flow path, and a sample loop; the six-way switching valve has a gas phase supply port connected to the gas phase supply flow path, a liquid phase supply port connected to the liquid phase supply flow path, a recovery outlet connected to a recovery flow path, a synthesis outlet connected to a synthesis flow path, and two sample loop openings connected to both ends of the sample loop, the six-way switching valve is switchable between a first flow path in which the gas phase supply flow path, the sample loop, and the recovery flow path communicate with each other and at the same time the liquid phase supply flow path and the synthesis flow path communicate with each other, and a second flow path in which the gas phase supply flow path and the recovery flow path communicate with each other and at the same time the liquid phase supply flow path, the sample loop, and the synthesis flow path communicate with each other; The reaction section includes a reduction catalyst, by alternately switching between the first flow path and the second flow path and causing at least the gas phase or the liquid phase that has been caused to flow into the sample loop to flow out into the synthesis flow path, the liquid phase and the gas phase can be alternately caused to flow out into the synthesis flow path, A system for producing a reduced compound, configured so that a liquid phase is recycled from the reaction section and the recovery channel and is caused to flow into the liquid phase supply channel.

5. A method for producing a pyrrole-imidazole polyamide, comprising the steps of: The method includes the following steps A1 and A2: Step A1: A reduction step of reducing a compound 1 represented by the following formula (1) to obtain a compound 2 represented by the following formula (2): Step A2: An elongation step in which a compound 3 represented by the following formula (3) is reacted with the compound 2 to obtain a compound 4 represented by the following formula (4): 【Chemistry 1】 [In formula (1), X ０ each independently represents N or CH; R ａ represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 25 carbon atoms, a nitrile group, -COOR ｐ (R ｐ represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms; ｑ R ｒ (R ｑ and R ｒ each independently represents a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms; and n represents 0 or an integer of 1 or more. 【Chemistry 2】 [In formula (2), X ０ , R ａ , n is the same as above.] 【Chemistry 3】 [In formula (3), X １ each independently represents N or CH, Y represents a halogen atom, and m represents an integer of 0 or 1 or more. 【Chemistry 4】 [In formula (4), X ０ , X １ , R ａ , n and m are the same as above. The step A1 is a flow reaction using a flow synthesis apparatus equipped with a micromixer, The flow synthesis apparatus equipped with the micromixer includes a six-way switching valve, a gas phase supply flow path, a liquid phase supply flow path, a recovery flow path, a synthesis flow path, a reaction section provided on the synthesis flow path, and a sample loop; the six-way switching valve has a gas phase supply port connected to the gas phase supply flow path, a liquid phase supply port connected to the liquid phase supply flow path, a recovery outlet connected to a recovery flow path, a synthesis outlet connected to a synthesis flow path, and two sample loop openings connected to both ends of the sample loop, the six-way switching valve is switchable between a first flow path in which the gas phase supply flow path, the sample loop, and the recovery flow path communicate with each other and at the same time the liquid phase supply flow path and the synthesis flow path communicate with each other, and a second flow path in which the gas phase supply flow path and the recovery flow path communicate with each other and at the same time the liquid phase supply flow path, the sample loop, and the synthesis flow path communicate with each other; The reaction section includes a reduction catalyst, a first step of flowing hydrogen gas through the gas phase supply flow path while the six-way switching valve is in the first flow path state, flowing hydrogen into at least the sample loop, and flowing a liquid phase containing the compound 1 represented by the formula (1) through the liquid phase supply flow path; the six-way switching valve is in the state of the second flow path, a liquid phase containing the compound 1 represented by the formula (1) is flowed into the liquid phase supply flow path, the hydrogen gas present in the sample loop that has been flowed in in the first step is discharged from the synthesis outlet, and the hydrogen gas is flowed into the gas phase supply flow path; and The step A1 is a step of alternately discharging the hydrogen gas and a liquid phase containing the compound 1 represented by the formula (1) from the synthesis outlet, and reacting the compound to be reduced in the presence of a reduction catalyst with the hydrogen gas in a reaction section, The process A2 is a flow reaction, in which a liquid phase containing the compound 3 represented by the formula (3) flowing in a flow path in a micromixer and a liquid phase containing the compound 2 represented by the formula (2) flowing in another flow path are joined together and reacted with each other in a production method.

6. The method according to claim 5, wherein the compound 4 is used as compound 1 in the next step A1 for successive elongation.

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