Washing method for flow-type reaction system and detergent for flow-type reaction system

Abstract

Provided are: a washing method for a flow-type reaction system comprising cleaning the inside of a flow channel of a flow-type reaction system using a solution of an organic acid compound having a pKa of 0.50 or less; and a detergent for a flow-type reaction system containing an organic acid compound having a pKa of 0.50 or less as an active ingredient.

Description

Method for cleaning a flow reaction system and cleaning agent for a flow reaction system

[0001] The present invention relates to a method for cleaning a flow reaction system and a cleaning agent for a flow reaction system.

[0002] Chemical reaction systems can be broadly divided into batch and flow systems, and the use of flow reaction systems is expanding due to various advantages. In a flow reaction system, raw materials are continuously introduced into a flow channel, and a chemical reaction occurs while the raw materials are circulating through the channel, allowing the desired reaction product to be continuously obtained. Another advantage is that the reaction temperature, reaction time, and other parameters can be precisely controlled. For example, Patent Documents 1 and 2 describe anionic polymerization reactions using a flow reaction system using an organolithium compound such as n-butyllithium as a polymerization initiator. The techniques described in Patent Documents 1 and 2 are said to enable the continuous and stable production of polymers with excellent monodispersity. Furthermore, Patent Document 3 describes a flow reaction system using a microreactor to monolithiate an o-dihaloaromatic compound with an organolithium reagent, followed by electrophilic substitution to obtain a monosubstituted monohaloaromatic compound, which is then further lithiated with an organolithium reagent and then subjected to electrophilic substitution to obtain an o-disubstituted aromatic compound. In addition to the above reactions, various chemical reactions using flow reaction systems have been proposed.

[0003] JP 2017-66276 A International Publication No. 2019 / 065709 JP 2008-195639 A

[0004] The use of a flow reaction system enables the continuous production of the desired reaction product with greater reliability. However, in flow reaction systems, by-products generated during the reaction, particularly inorganic compounds and complexes insoluble in the reaction solvent, can adhere to the channel walls. If these by-products adhere, they can adversely affect the target reaction or, if left unattended, block the channel. For example, reactions using organometallic compounds can produce solvent-insoluble metal hydroxides and metal salts as by-products, or the reaction product (organic compound) can form solvent-insoluble complexes with the metal, which can adhere to the reaction channel walls. Similar problems can occur in various chemical reactions using flow reaction systems. These adhered materials are difficult to dissolve even when a cleaning solution is passed through the channel. Removing the adhered materials requires long cleaning times, disassembling the reaction system to clean the channel, or replacing the channel. Furthermore, using strong acids such as hydrochloric acid to improve cleaning efficiency can corrode stainless steel (SUS), a material commonly used for channel construction.

[0005] An object of the present invention is to provide a method for cleaning a flow reaction system that can remove deposits on the wall surface of a flow channel with high efficiency without causing corrosion of the flow channel. Another object of the present invention is to provide a cleaning agent for a flow reaction system that can remove deposits on the wall surface of a flow channel with high efficiency without causing corrosion of the flow channel.

[0006] The present inventors have conducted extensive research in light of the above-mentioned problems and have found that cleaning the inside of a flow channel with a solution of an organic acid compound having a pKa (acid dissociation constant) of 0.50 or less can efficiently remove deposits from the wall surface of the flow channel without causing corrosion of the flow channel. Based on this finding, the present invention was completed through further research.

[0007] The above-mentioned problems of the present invention are solved by the following means. [1] A method for cleaning a flow reaction system, comprising cleaning the inside of a channel of the flow reaction system with a solution of an organic acid compound having a pKa of 0.50 or less. [2] The method for cleaning a flow reaction system according to [1], wherein solidified matter on the wall surface of the channel is removed by cleaning the inside of the channel. [3] The method for cleaning a flow reaction system according to [1] or [2], wherein the solidified matter comprises a by-product produced by a chemical reaction under basic conditions. [4] The method for cleaning a flow reaction system according to any one of [1] to [3], wherein the solidified matter comprises a by-product produced by a chemical reaction using an organometallic compound. [5] The method for cleaning a flow reaction system according to [4], wherein the organometallic compound is an organolithium compound or an organomagnesium compound. [6] The method for cleaning a flow reaction system according to [4], wherein the organometallic compound is an organolithium compound. [7] The method for cleaning a flow reaction system according to any one of [1] to [6], wherein the concentration of the organic acid compound in the solution is 0.001 to 10.000 mass %. [8] The method for cleaning a flow reaction system according to any one of [1] to [7], wherein the temperature of the solution is set to -50 to 40°C to clean the inside of the flow channel. [9] The method for cleaning a flow reaction system according to any one of [1] to [8], wherein the solvent of the solution is an organic solvent.

[10] The method for cleaning a flow reaction system according to any one of [1] to [9], wherein the pKa of the organic acid compound is 0.10 or less.

[11] The method for cleaning a flow reaction system according to any one of [1] to

[10] , wherein the organic acid compound comprises a sulfonic acid compound.

[12] The method for cleaning a flow reaction system according to any one of [1] to

[11] , wherein the flow channel is irradiated with ultrasonic waves while the solution is flowing through the flow channel of the flow reaction system.

[13] A cleaning agent for a flow reaction system, comprising an organic acid compound having a pKa of 0.50 or less as an active ingredient.

[14] The cleaning agent for a flow reaction system according to

[13] , wherein the organic acid compound has a pKa of 0.10 or less.

[15] The cleaning agent for a flow reaction system according to

[13] or

[14] , wherein the organic acid compound includes a sulfonic acid compound.

[16] The cleaning agent for a flow reaction system according to any one of

[13] to

[15] , which is a solution obtained by dissolving the organic acid compound having a pKa of 0.50 or less in an organic solvent.

[0008] In the present invention, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits.

[0009] The cleaning method for a flow reaction system of the present invention makes it possible to remove deposits on the wall surface of a flow channel with high efficiency without causing corrosion of the flow channel. Furthermore, by using the cleaning agent for a flow reaction system of the present invention to clean the inside of a flow channel, it is possible to remove deposits on the wall surface of the flow channel with high efficiency without causing corrosion of the flow channel.

[0010] Figure 1 is a graph showing the results of a dissolution test of solidified materials using various organic acid compounds with different pKa. Figure 2 is a diagram showing a schematic diagram of a flow type reaction system used in the examples. Figure 3 is a diagram showing a schematic diagram of a flow type reaction system used in the examples.

[0011] [Method for Cleaning a Flow Reaction System] The method for cleaning a flow reaction system of the present invention (hereinafter referred to as the "cleaning method of the present invention") involves cleaning the inside of a flow channel of a flow reaction system with a solution of an organic acid compound having a pKa of 0.50 or less (hereinafter also referred to as the "cleaning solution"). This cleaning may be performed by filling the flow channel with the cleaning solution, leaving it standing for a certain period of time, and then discharging the cleaning solution. Alternatively, the inside of the flow channel may be cleaned by continuously circulating the cleaning solution through the flow channel. From the viewpoint of further improving cleaning efficiency, it is preferable to clean the inside of the flow channel by continuously circulating the cleaning solution through the flow channel. By contacting the cleaning solution with the flow channel wall surface, contamination on the flow channel wall surface of the flow reaction system can be removed. The cleaning solution can, for example, react with solid matter (insoluble matter solidified on the flow channel wall surface) on the flow channel wall surface and convert the solid matter into a compound soluble in the cleaning solution, thereby enabling efficient and sufficient removal of the solid matter on the flow channel wall surface. In the present invention, the "flow channel wall surface" refers to the inner wall surface of the flow channel that comes into contact with the fluid flowing through the flow channel. Furthermore, in the present invention, unless otherwise specified, the term "flow path" includes all passages through which fluids flow in a flow reaction system, such as flow paths through which raw materials, reagents, etc. flow, and junctions where two or more flow paths join. Furthermore, "solidified matter on the wall surface of a flow path" refers to solidified matter that is solidified on at least a portion of the inner wall surface of a flow path in a flow reaction system. In the present invention, "insoluble matter" or "insoluble substance" refers to a substance that is insoluble in a solvent used in a chemical reaction carried out in a flow reaction system. Therefore, solid matter that is solidified on the wall surface of a flow path in a flow reaction system is an insoluble matter.

[0012] The above-mentioned adhered matter usually includes by-products generated by flow-type reactions. The adhered matter on the channel wall surface is firmly adhered to the channel wall surface, is usually insoluble in solvents, and is difficult to sufficiently remove even by washing the inside of the channel with a solvent or a cleaning solution containing a surfactant. However, even such strongly adhered matter can be removed with high efficiency by applying the cleaning method of the present invention.

[0013] As an example, n-butyllithium ( ｎThe following describes deposits on the channel wall surface that occur in a flow reaction using toluenesulfonic acid (BuLi) and the cleaning of the deposits with a cleaning solution that uses p-toluenesulfonic acid as an organic acid compound having a pKa of 0.50 or less.

[0014] ｎ BuLi is hydrolyzed by the water in the organic solvent or raw materials to produce lithium hydroxide (LiOH), as shown below. This LiOH is further converted into carbon dioxide (CO ２ ) reacts with lithium carbonate (Li ２ CO ３ ) is produced. ２ CO ３ is insoluble in organic solvents and is thought to adhere and accumulate on the wall surface of the flow channel.

[0015]

[0016] As mentioned above, LiOH and Li ２ CO ３ When the cleaning solution is circulated through the flow channel in a state where the adhering materials are adhered to the wall surface of the flow channel, the following reaction occurs between p-toluenesulfonic acid in the cleaning solution and the adhering materials, and a Li salt soluble in the cleaning solution is produced.

[0017]

[0018] In this way, by flowing the cleaning solution through the flow channel, the deposits on the wall surface of the flow channel are converted into compounds that are soluble in the cleaning solution, and the cleaning efficiency inside the flow channel can be effectively improved. Although the above example describes the removal of deposits made of inorganic compounds, the cleaning solution also exhibits excellent cleaning effects for removing deposits made of, for example, complexes of organic reaction products or by-products with metals, as will be shown in the examples described below.

[0019] The deposits on the flow channel wall surface may include by-products generated by chemical reactions under basic conditions using a flow reaction system. In reactions using bases such as organometallic compounds or metal salts as raw materials, catalysts, reaction initiators, etc., by-products are likely to be insoluble inorganic compounds containing metals or insoluble complexes containing organic substances and metals.

[0020] ​The deposits on the flow channel wall surface may include by-products produced by chemical reactions using organometallic compounds in the flow reaction system. For example, they include insoluble inorganic compounds (preferably metal salts and / or metal hydroxides of the metals derived from the organometallic compounds). If the organometallic compound is an organolithium compound, the deposits include at least lithium carbonate and / or lithium hydroxide. Examples of the organometallic compound include organolithium compounds and organomagnesium compounds (e.g., Grignard reagents). Specific examples of the organic lithium compound include alkyllithiums such as methyllithium, ethyllithium, propyllithium, butyllithium (n-butyllithium, sec-butyllithium, iso-butyllithium, tert-butyllithium, etc.), pentyllithium, hexyllithium, methoxymethyllithium, and ethoxymethyllithium; benzyllithiums such as α-methylstyryllithium, 1,1-diphenyl-3-methylpentyllithium, and 3-methyl-1,1-diphenylpentyllithium; alkenyllithiums such as vinyllithium, allyllithium, propenyllithium, and butenyllithium; alkynyllithiums such as ethynyllithium, butynyllithium, pentynyllithium, and hexynyllithium; aralkyllithiums such as benzyllithium and phenylethyllithium; aryllithiums such as phenyllithium and naphthyllithium; heterocyclic lithiums such as 2-thienyllithium, 4-pyridyllithium, and 2-quinolyllithium; and alkyllithium magnesium complexes such as tri(n-butyl)magnesiumlithium and trimethylmagnesiumlithium.Specific examples of Grignard reagents include methylmagnesium chloride, methylmagnesium iodide, (trimethylsilyl)methylmagnesium chloride, ethylmagnesium chloride, ethylmagnesium bromide, vinylmagnesium chloride, isopropylmagnesium chloride, isopropylmagnesium bromide, cyclopropylmagnesium bromide, allylmagnesium chloride, butylmagnesium chloride, isobutenylmagnesium bromide, cyclopentylmagnesium bromide, phenylmagnesium bromide, benzylmagnesium chloride, isopropylmagnesium chloride-lithium chloride complex, 2-butylmagnesium chloride-lithium chloride complex, isopropylmagnesium chloride-zinc(II) ate complex, and the like.

[0021] The organic acid compound, which is the active ingredient of the cleaning solution, has a pKa of 0.50 or less, and exhibits significantly superior cleaning effectiveness compared to organic acid compounds with higher pKas. For example, weak acids such as acetic acid (pKa 4.79), lauric acid (pKa 4.78), and benzoic acid (pKa 4.20) are almost ineffective at cleaning hardened materials, while phosphoric acid (pKa 1.97), methanesulfonic acid (pKa 1.75), saccharin (pKa 1.60), and dichloroacetic acid (pKa 1.37) are also barely effective at cleaning hardened materials. In contrast, lowering the pKa of the organic acid compound to 0.50 or less dramatically improves cleaning effectiveness. While the reason for this is unclear, the following examples provide experimental evidence. From the viewpoint of further improving the cleaning efficiency, the pKa of the organic acid compound used in the cleaning solution is more preferably 0.40 or less, even more preferably 0.30 or less, even more preferably 0.20 or less, even more preferably 0.10 or less, even more preferably 0.00 or less, even more preferably −0.10 or less, even more preferably −0.20 or less, even more preferably −0.30 or less, even more preferably −0.35 or less, and particularly preferably −0.40 or less. Taking into consideration the need to more reliably prevent deterioration of the flow path, the pKa of the organic acid compound used in the cleaning solution is preferably in the range of -5.00 to 0.50, more preferably -4.00 to 0.40, even more preferably -3.00 to 0.30, even more preferably -2.00 to 0.20, even more preferably -1.80 to 0.10, even more preferably -1.60 to 0.00, even more preferably -1.40 to -0.10, even more preferably -1.20 to -0.20, even more preferably -1.10 to -0.30, and particularly preferably -1.00 to -0.40. In the present invention, the pKa is calculated using the values ​​provided by SciFinder, a database provided by Chemical Abstracts Service. This calculated value is calculated using Advanced Chemistry Development (ACD / Labs) Software V11.02.

[0022] The cleaning method of the present invention uses a strong acid with a pKa of 0.50 or less, but employs an organic acid rather than an inorganic acid, thereby achieving sufficient cleaning effectiveness while preventing corrosion of metals (e.g., stainless steel (SUS)) commonly used as materials for flow paths. The cleaning method of the present invention exhibits sufficient cleaning effectiveness even when the organic acid compound in the cleaning solution is at a low concentration, and is less likely to corrode metal (e.g., SUS) flow paths even when the organic acid compound is at a relatively high concentration. Therefore, the concentration of the organic acid compound in the cleaning solution can be appropriately set depending on the type of organic acid compound used and the material of the flow path used. For example, the content of the organic acid compound with a pKa of 0.50 or less in the cleaning solution can be 0.001 to 10.000 mass%. In consideration of both cleaning efficiency and cost, the content of the organic acid compound having a pKa of 0.50 or less in the cleaning solution is more preferably 0.005 to 8.000 mass%, even more preferably 0.010 to 6.000 mass%, even more preferably 0.020 to 4.000 mass%, even more preferably 0.040 to 2.000 mass%, even more preferably 0.080 to 1.000 mass%, and even more preferably 0.100 to 0.500 mass%. For example, when an organic solution of hydrochloric acid, which is a strong inorganic acid, is used, not only is it unable to dissolve and remove the fixed deposits, but corrosion occurs in SUS flow paths even when the hydrochloric acid in the cleaning solution is at a low concentration.

[0023] Specific examples of organic acid compounds having a pKa of 0.50 or less contained in the cleaning solution include trichloroacetic acid (pKa: 0.09), trifluoroacetic acid (pKa: 0.05), p-toluenesulfonic acid (pKa: -0.43), dodecylbenzenesulfonic acid (pKa: -0.45), mesitylenesulfonic acid (pKa: -0.29), 2-naphthalenesulfonic acid (pKa: 0.27), trifluoromethanesulfonic acid (pKa: -3.91), 2,4-dimethylbenzenesulfonic acid (pKa: -0.36), 4,4'-biphenylsulfonic acid (pKa: -0.50), and the like. Examples of suitable organic acid compounds include phenyldisulfonic acid (pKa: -1.14), p-chlorobenzenesulfonic acid (pKa: -0.83), 2,5-dimethylbenzenesulfonic acid (pKa: -0.47), 4-nitrobenzenesulfonic acid (pKa: -1.38), 4-hydroxybenzenesulfonic acid (pKa: -0.23), 4-(2-bromoethyl)benzenesulfonic acid (pKa: -0.56), 2-nitrobenzenesulfonic acid (pKa: -1.43), and 2,4,5-trichlorobenzenesulfonic acid (pKa: -1.70). The organic acid compound having a pKa of 0.50 or less contained in the cleaning solution preferably has a molecular weight of 100 to 400. A sulfonic acid compound (an organic compound having a sulfo group) can be suitably used as the organic acid compound having a pKa of 0.50 or less contained in the cleaning solution.

[0024] The cleaning solution is usually a solution obtained by dissolving the organic acid compound in an organic solvent. The organic solvent is not particularly limited, and hydrocarbon solvents, ether solvents, ester solvents, amide solvents, halogen-containing solvents, alcohol solvents, ketone solvents, etc. can be used appropriately. One or more organic solvents can be used in the cleaning solution.

[0025] Examples of the hydrocarbon solvent include hexane, heptane, octane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, mesitylene, decalin, tetralin, and derivatives thereof. Examples of the ether solvent include tetrahydrofuran, dioxane, methyl tertiary butyl ether, cyclopentyl methyl ether, ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, and derivatives thereof. Examples of the ester solvent include ethyl acetate and butyl acetate. Examples of the amide solvent include dimethylacetamide and dimethylformamide. Examples of the halogen-containing solvent include methylene chloride, chloroform, dichloroethane, carbon tetrachloride, chlorobenzene, and o-dichlorobenzene. Examples of the alcohol solvent include ethanol, isopropanol, butanol, cyclohexanol, and 1-methoxy-2-propanol. Examples of the ketone solvent include acetone, methyl ethyl ketone, diisobutyl ketone, cyclohexanone, and methyl isobutyl ketone.

[0026] In addition to the organic acid compound and organic solvent, the cleaning solution may contain a cationic surfactant, an anionic surfactant, an amphoteric surfactant, a nonionic surfactant, or the like, as long as the effects of the present invention are not impaired.

[0027] The temperature of the cleaning solution used to clean the inside of the flow channel of the flow reaction is set appropriately depending on the solubility of the organic acid compound and the type of organic solvent. For example, it can be set to −50 to 40° C. From the viewpoints of the boiling point of the solvent, the reaction temperature, and the solubility of by-products, the temperature of the cleaning solution is more preferably −50 to 30° C., even more preferably −45 to 30° C., and even more preferably −40 to 30° C.

[0028] In the cleaning method of the present invention, the flow rate and flow time (cleaning time) of the cleaning solution flowing through the flow channel are appropriately adjusted within a range in which the desired cleaning effect can be obtained.

[0029] In the cleaning method of the present invention, it is also preferable to irradiate the flow channel of the flow reaction system with ultrasonic waves while flowing the cleaning solution through the flow channel. This ultrasonic irradiation can further increase the dissolution rate of the solidified materials.

[0030] [Cleaning Agent for Flow Reaction System] The cleaning agent for a flow reaction system of the present invention (hereinafter referred to as "cleaning agent of the present invention") contains, as an active ingredient, an organic acid compound having a pKa of 0.50 or less. The cleaning agent of the present invention may be an organic acid compound having a pKa of 0.50 or less itself, or may contain other components (excluding organic solvents) in addition to the organic acid compound having a pKa of 0.50 or less. In this case, when flowing through the flow channels of the flow reaction system, the cleaning agent of the present invention is dissolved in a solvent (preferably an organic solvent) and flowed through the flow channels as a solution.

[0031] The cleaning agent of the present invention may be in the form of a solution in which an organic acid compound having a pKa of 0.50 or less is dissolved in a solvent. When the cleaning agent of the present invention is in the form of a solution, the concentration of the organic acid compound in the solution is not particularly limited. The concentration may be adjusted so that the solution can flow directly through the flow path, or the solution may be diluted with a solvent before flowing through the flow path.

[0032] The organic acid compound having a pKa of 0.50 or less contained in the cleaning agent of the present invention has the same meaning as the organic acid compound having a pKa of 0.50 or less contained in the cleaning solution, and the preferred forms are also the same. Furthermore, as the other components, the components described for the cleaning solution above can be used as appropriate. Furthermore, when the cleaning agent of the present invention is dissolved in a solvent to form a solution, the solvent is usually an organic solvent. There are no particular limitations on the organic solvent, and for example, the organic solvents described for the cleaning solution above can be used as appropriate.

[0033] The present invention will be described in more detail based on examples, but the present invention should not be construed as being limited to these examples except as defined in the present invention.

[0034] Test Example 1 Dissolution Test of Fixed Material 8 g of tetrahydrofuran (THF), 0.1 g of lithium carbonate as a model of fixed material in a reaction system using an organometallic compound, and 0.5 g of an acid compound shown in Table 1 below were mixed and stirred at 25°C for 1 hour. After stirring, the liquid was filtered to remove insoluble matter, and the amount of lithium dissolved in the filtrate was determined by inductively coupled plasma atomic emission spectroscopy (ICP atomic emission spectroscopy, measurement conditions are as described below). The lithium elution rate (mass%) was calculated using the following formula: Lithium elution rate (mass%) = 100 × [amount of lithium dissolved in the filtrate (mass)] / amount of lithium in 0.1 g of lithium carbonate (mass)]

[0035] The results are shown in Table 1 below and FIG.

[0036] As shown in Table 1 and Figure 1, the lithium elution rate was only 1.1% with an organic acid compound (dichloroacetic acid) with a pKa of 1.37, meaning that the fixed deposits remained insoluble and did not actually dissolve, whereas the lithium elution rate increased to 27% with an organic acid compound (trichloroacetic acid) with a pKa of 0.09, and the lithium elution rate increased even further as the pKa decreased. The results in Figure 1 show that a pKa of 0.50 is approximately the threshold for the effectiveness of cleaning fixed deposits.

[0037] [Test Example 2] 1. Construction of a flow reaction system and implementation of an anionic polymerization reaction A polymer (poly(pt-t-butoxystyrene)) was synthesized by an anionic polymerization reaction using a flow reaction system configured as shown in Figure 2. This flow reaction system is the same as the flow reaction system described in Example 1 of WO 2019 / 065709. Details of each part are shown below.

[0038] Liquid delivery pumps (5, 6, 9): All pumps were PU716B manufactured by GL Science Co., Ltd., and a pulse damper HPD-1, a back pressure valve (44-2361-24) manufactured by Tescom Co., Ltd., and a relief valve RHA (4 MPa) manufactured by IBS Co., Ltd. were sequentially installed on the flow outlet side.

[0039] Low temperature constant temperature bath (R1): A small desktop low temperature water bath CBi-270A manufactured by AS ONE was used and set to -10°C.

[0040] Anionically polymerizable monomer supply channel (1): A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm and a length of 2 m was used.

[0041] Anionic polymerization initiator supply channel (2): A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm, and a length of 2 m was used.

[0042] Confluence Region (3) (Two-Layer Cylindrical Mixer): A union tee (SS-400-3) manufactured by Swagelok Corporation was used as the concentric cylindrical two-layer cylindrical mixer 3b.

[0043] Reaction tube (4): A SUS316 tube having an outer diameter of 1 / 8 inch, an inner diameter of 2.17 mm, and a length of 4.8 m was used.

[0044] Polymerization terminator supply channel (7): A SUS316 tube having an outer diameter of 1 / 16 inch, an inner diameter of 1.0 mm and a length of 2 m was used.

[0045] Confluence region (8) (T-connector): A union T-shaped connector (SS-200-3) manufactured by Swagelok Corporation was used. The reaction tube (4) and the polymerization terminator supply channel (7) were connected to two of the three connection ports of the T-connector, each of which was opposite to each other. The remaining connection port was used as a discharge port for discharging the liquid.

[0046] Piping (10): An SUS316 tube having an outer diameter of 1 / 8 inch, an inner diameter of 2.17 mm, and a length of 1.7 m; a back pressure valve (44-2361-24) manufactured by Tescom; and an SUS316 tube having an outer diameter of 1 / 8 inch, an inner diameter of 2.17 mm, and a length of 0.3 m were connected in this order.

[0047] Monomer-containing liquid A to be introduced into the anionic polymerizable monomer supply flow path (1): <pt-butoxystyrene / tetrahydrofuran (THF)> THF (deoxidizing grade) and pt-t-butoxystyrene (special grade) were added to a 2 L SUS tank to prepare 2 L of a 2M-pt-butoxystyrene / THF solution. This solution was dehydrated using a molecular sieve 4A to obtain liquid A. In this example, the expression "xM-y / z" means a solution in which y is dissolved in solvent z, and the concentration of y in this solution is xM.

[0048] Liquid B containing an initiator to be introduced into the anionic polymerization initiator supply flow path (2): <n-butyllithium (nBuLi) / toluene> Toluene (deoxidizing grade) was added to a 5 L SUS tank and cooled to 0° C. nBuLi (1.6 M nBuLi / hexane solution) was added, and titration was performed with menthol / bipyridine to prepare 4 L of a 0.05 M nBuLi / toluene solution, which was designated as liquid B.

[0049] Polymerization terminator introduced into polymerization terminator supply line (7): <Methanol (MeOH) / THF> THF (deoxygenation grade) and MeOH (deoxygenation grade) were added to a 3 L SUS tank to prepare 4 L of a 0.5 M MeOH / THF solution, which was used as a polymerization terminator.

[0050] Liquid flow conditions: Liquid A (2M p-t-butoxystyrene / THF): 56.5 mL / min Liquid B (0.05M nBuLi / toluene): 39.4 mL / min Polymerization terminator (0.5M MeOH / THF): 47.3 mL / min

[0051] Flow time in reaction tube (4): 11.1 seconds

[0052] Withdrawal: 10 mL of a solution containing a polymer (poly(pt-butoxystyrene)) was collected from the outlet of the pipe (10), and the molecular weight and molecular weight distribution were measured by gel permeation chromatography (GPC). As a result, the number average molecular weight (Mn) was 4,300, and the molecular weight distribution (dispersity, Mw / Mn) was 1.19. In this specification, GPC was measured under the following conditions. Apparatus: HLC-8220GPC (manufactured by Tosoh Corporation) Detector: Differential refractometer (RI (Refractive Index) detector) Precolumn: TSKGUARDCOLUMN HXL-L 6 mm x 40 mm (manufactured by Tosoh Corporation) Sample side columns: The following three columns were directly connected in order (all manufactured by Tosoh Corporation): TSK-GEL GMHXL 7.8 mm x 300 mm TSK-GEL G4000HXL 7.8 mm x 300 mm TSK-GEL G2000HXL 7.8 mm x 300 mm Reference side column: TSK-GEL G1000HXL 7.8 mm x 300 mm Thermostatic bath temperature: 40°C Mobile phase: THF Sample side mobile phase flow rate: 1.0 mL / min Reference side mobile layer flow rate: 1.0 mL / min Sample concentration: 0.1 mass% Sample injection amount: 100 μL Data collection time: 5 to 45 minutes after sample injection Sampling pitch: 300 msec

[0053] 2. Cleaning of the Inside of the Flow Channels - Example 1 - Liquid A, Liquid B, and the polymerization terminator were fed for 20 minutes under the above-mentioned liquid feeding conditions to continuously carry out the polymerization reaction, and then the inside of the flow channels was cleaned as follows. The low-temperature constant temperature bath (R1) was set to -30°C. THF was fed for 30 minutes into each of the anionic polymerizable monomer supply flow channel (1), the anionic polymerization initiator supply flow channel (2), and the polymerization terminator supply flow channel (7) at a total flow rate of 20 mL / min through each flow channel, and then a mixed solution of MeOH / water = 8 / 2 (volume ratio) was fed for 30 minutes at a total flow rate of 20 mL / min through each flow channel. Note that when the total flow rate through each flow channel was 20 mL / min, the flow rates of the liquids flowing through each flow channel were approximately the same (the same applies below). Next, a THF solution containing 0.1% by mass of p-toluenesulfonic acid was pumped through each flow path for 30 minutes at a total flow rate of 20 mL / min, thereby cleaning the inside of the flow path with an organic acid compound solution (cleaning solution). Finally, THF was pumped through each flow path at a total flow rate of 20 mL / min, and the liquid (discharged liquid) discharged from the pipe (10) between 1 minute and 30 minutes later was subjected to GPC measurement under the above conditions and ICP measurement under the following conditions. As a result, the polymer (poly(p-t-butoxystyrene)) concentration was 0.4 ppm, the lithium concentration was 0.1 ppm, and the amount of polymer and lithium eluted was small. The higher the cleaning effect, the lower these concentrations. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0054] (ICP measurement method) 1 g of sample is diluted with 20 mL of dimethylacetamide and measured under the following conditions: Apparatus: Shimadzu ICPS8100, standard mode; High frequency output: 1.4 kW; Torch observation height: 11.0; Coolant gas: 14.0 L / min; Plasma gas: 1.2 L / min; Carrier gas: 0.8 L / min; Rinse time: 40; Sampling time: 40; Rinse liquid: Ultrapure water; Detection wavelengths: Li 670.85 nm, Cr 267.716 nm, Fe 259.94 nm, Ni 231.604 nm

[0055] Example 2 The discharged solution was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the concentration of p-toluenesulfonic acid in the cleaning solution was changed from 0.1% by mass to 0.001% by mass. The results were that the polymer concentration was 0.5 ppm and the lithium concentration was 0.3 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0056] Example 3 The discharged solution was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the concentration of p-toluenesulfonic acid in the cleaning solution was changed from 0.1% by mass to 10% by mass. The results were that the polymer concentration was 0.2 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0057] Example 4 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the set temperature of the low-temperature thermostatic bath (R1) was changed from -30°C to -50°C. As a result, the polymer concentration was 0.4 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0058] Example 5 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the set temperature of the low-temperature constant temperature bath (R1) was changed from -30°C to 40°C. As a result, the polymer concentration was 0.4 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0059] Example 6 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the solvent of the cleaning solution was changed from THF to ethyl acetate. The results were that the polymer concentration was 0.3 ppm and the lithium concentration was 0.3 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0060] Example 7 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the solvent of the cleaning solution was changed from THF to dimethylacetamide. The results were that the polymer concentration was 0.4 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0061] Example 8 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the solvent of the cleaning solution in Example 1 was changed from THF to chloroform. The results were that the polymer concentration was 0.4 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0062] Example 9 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the solvent of the cleaning solution was changed from THF to MeOH. The results were that the polymer concentration was 0.4 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0063] Example 10: The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the solvent of the cleaning solution was changed from THF to acetone. The results were that the polymer concentration was 0.4 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0064] Example 11 The discharged solution was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the organic acid compound in the cleaning solution in Example 1 was changed from p-toluenesulfonic acid to dodecylbenzenesulfonic acid (a THF solution containing dodecylbenzenesulfonic acid at a concentration of 0.1% by mass was used as the cleaning solution). The results were that the polymer concentration was 1.4 ppm and the lithium concentration was 1.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0065] Example 12 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the organic acid compound in the cleaning solution in Example 1 was changed from p-toluenesulfonic acid to trichloroacetic acid (a THF solution containing trichloroacetic acid at a concentration of 0.1% by mass was used as the cleaning solution). The results were that the polymer concentration was 2.2 ppm and the lithium concentration was 2.0 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0066] Example 13 The discharged solution was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the organic acid compound in the cleaning solution in Example 1 was changed from p-toluenesulfonic acid to trifluoroacetic acid (a THF solution containing trifluoroacetic acid at a concentration of 0.1% by mass was used as the cleaning solution). The results were that the polymer concentration was 1.4 ppm and the lithium concentration was 1.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0067] Example 14 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 11, except that ultrasonic waves (Honda Electronics tabletop ultrasonic cleaner WTC-404, standard mode) were irradiated to the anionic polymerizable monomer supply flow path (1), the anionic polymerization initiator supply flow path (2), and the polymerization terminator supply flow path (3) during the supply of THF, the mixed solution of MeOH / water = 8 / 2 (volume ratio), and the cleaning solution. The results were that the polymer concentration was 0.0 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0068] Example 15 In Example 1, after the cleaning solution was delivered, all of the flow paths were filled with this cleaning solution and allowed to stand for 120 hours. Then, THF was delivered to each flow path at a total flow rate of 20 mL / min, and the liquid (discharged liquid) discharged from the pipe (10) between 1 minute and 30 minutes later was subjected to GPC and ICP measurements in the same manner as above. The results were that the polymer concentration was 0.2 ppm and the lithium concentration was 0.0 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0069] Comparative Example 1 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that after the delivery of the mixed liquid of MeOH / water = 8 / 2 (volume ratio) and before the delivery of the final THF, no cleaning solution was delivered. As a result, the polymer concentration was 400 ppm and the lithium concentration was 300 ppm, both of which were higher than those in the examples. Note that Fe was not detected.

[0070] Comparative Example 2 The discharged liquid was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the organic acid compound in the cleaning solution in Example 1 was changed from p-toluenesulfonic acid to benzoic acid (a THF solution containing benzoic acid at a concentration of 0.1% by mass was used as the cleaning solution). The results showed that the polymer concentration was 300 ppm and the lithium concentration was 200 ppm, both of which were higher than those in the examples. No Fe was detected.

[0071] Comparative Example 3 The discharged solution was subjected to GPC measurement and ICP measurement in the same manner as in Example 1, except that the organic acid compound in the cleaning solution in Example 1 was changed from p-toluenesulfonic acid to hydrochloric acid (a THF solution containing hydrochloric acid at a concentration of 0.1% by mass was used as the cleaning solution). The results showed that the polymer concentration was 400 ppm and the lithium concentration was 300 ppm, both of which were higher than in the Examples. In addition, the Fe concentration was as high as 200 ppm, indicating that the SUS was corroded even with hydrochloric acid at a low concentration of 0.1% by mass.

[0072] Test Example 3 1. Construction of a Flow Reaction System and Implementation of a Synthesis Reaction of 1,3-Diacetyl BCP <Preparation of the Raw Material [1.1.1]propellane> 100 mL of cyclopentyl methyl ether (CPME) and 10 g of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane were placed in a 500 mL three-neck flask and cooled to -78°C under a nitrogen atmosphere. 42 mL of a 1.6 M solution of n-butyllithium in n-hexane was added thereto, and the mixture was stirred for 10 minutes to allow the reaction to proceed. The mixture was then heated to 0°C and stirred for an additional 30 minutes. In this way, [1.1.1]propellane was obtained in the solvent. 30 mL of water was added thereto, and the mixture was heated to room temperature (25°C), followed by separation to obtain an organic layer. The organic layer was cooled to 0°C, a distillation apparatus was connected, and the receiving flask was cooled to -78°C and subjected to a distillation treatment, and [1.1.1]propellane was transferred to the receiving flask. In this way, a CPME / n-hexane (3.6 / 1, mass ratio) solution containing [1.1.1]propellane at a concentration of 0.15 M was obtained, which contained a certain amount of lithium.

[0073] <Synthesis of 1,3-diacetyl BCP> 1,3-diacetyl BCP [also known as 1,1'-(bicyclo[1.1.1]pentane-1,3-diyl)bis(ethan-1-one)] was synthesized by the photoreaction of [1.1.1]propellane and 2,3-butanedione using a flow reaction system configured as shown in Figure 3. This flow reaction system is the same as the flow reaction system described in Example 1 (paragraph

[0034] ) of WO 2023 / 037935. Details are described below.

[0074] This flow reaction system consisted of a stainless steel (SUS316) tube (103) with an inner diameter of 1.0 mm and a length of 1.0 m placed in a thermostatic bath (102) set at 0°C, and a tetrafluoroethylene-perfluoroalkyl vinyl ether copolymer (PFA) tube (104) with an inner diameter of 1.6 mm and a length of 3.0 m connected downstream. This PFA tube (104) was wrapped around a light source cooling tube (105). A 385 nm LED (100 W) lamp was placed in the light source cooling tube (105) as a light source. The temperature of the light source cooling tube (105) (corresponding to the reaction temperature of the photoreaction) was set to 0°C. The following reaction substrate solution (101) was delivered using a syringe pump. The CPME / n-hexane (3.6 / 1, mass ratio) solution containing 0.15 M [1.1.1]propellane prepared above was mixed with 2.0 molar equivalents of 2,3-butanedione relative to [1.1.1]propellane (twice the molar amount of [1.1.1]propellane), followed by the addition of THF to a concentration of 6.5 mass%. This mixture was cooled to 5°C and subjected to nitrogen bubbling for 5 minutes to obtain a reaction substrate solution (101, reaction solution prior to photoreaction). This reaction substrate solution (101) was pumped through the flow path of the flow-type reaction system at a flow rate of 1.2 mL / min, and 1,3-diacetyl BCP was produced by photoreaction. The reaction time for this photoreaction (flow time through the PFA tube wrapped around the light source cooling tube 5) was 5 minutes.

[0075] 2. Cleaning of the Flow Channel - Example 16 - The reactant solution (101) was pumped into the flow channel of the flow reaction system under the above-mentioned pumping conditions for 20 minutes to continuously synthesize 1,3-diacetyl BCP by photoreaction. The flow channel was then cleaned as follows. The thermostatic bath (102) was set to -30°C. From the inlet of the reactant solution (101), THF in an amount three times the total flow channel volume was pumped into the flow channel at a flow rate of 20 mL / min. Next, a mixed solution of MeOH / water (8 / 2 by volume) in an amount five times the total flow channel volume was pumped into the flow channel at a flow rate of 20 mL / min. Next, a THF solution containing 0.1% by mass of p-toluenesulfonic acid (cleaning solution) was pumped into the flow channel at a flow rate of 20 mL / min in an amount five times the total flow channel volume. Finally, THF, three times the total flow volume, was pumped into the flow channel at a flow rate of 20 mL / min, and the discharged THF was subjected to NMR and ICP measurements. The results showed that the concentration of the raw material [1,1,1]propellane was below the detection limit, and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0076] Comparative Example 4 The discharged liquid was subjected to NMR measurement and ICP measurement in the same manner as in Example 16, except that after the delivery of the mixed liquid of MeOH / water = 8 / 2 (volume ratio) and before the delivery of the final THF, no cleaning solution was delivered. As a result, the [1,1,1]propellane concentration was 3000 ppm and the lithium concentration was 200 ppm, both of which were higher concentrations than in Example 16. Note that Fe was not detected.

[0077] Comparative Example 5 The effluent was subjected to NMR measurement and ICP measurement in the same manner as in Example 16, except that the organic acid compound in the cleaning solution in Example 16 was changed from p-toluenesulfonic acid to benzoic acid (a THF solution containing benzoic acid at a concentration of 0.1% by mass was used as the cleaning solution). As a result, the [1,1,1]propellane concentration was 1000 ppm and the lithium concentration was 100 ppm, both of which were higher concentrations than in Example 16. Note that Fe was not detected.

[0078] Test Example 4 1. Construction of a flow reaction system and implementation of a synthesis reaction of 3-bromophenylboronic acid Using the flow reaction system shown in Figure 2 used in Test Example 2, 1,3-bromoiodobenzene was reacted with an isopropyl magnesium chloride-lithium chloride complex (iPrMgCl.LiCl), and then trimethyl borate was reacted to obtain 3-bromophenylboronic acid. Specifically, a "1.5 M 1,3-bromoiodobenzene / THF solution" was used in place of Liquid A "2 M p-t-butoxystyrene / THF solution" in Test Example 2, a "1.3 M iPrMgCl.LiCl / THF solution" was used in place of Liquid B "0.05 M nBuLi / toluene solution" in Test Example 2, and a "0.68 M trimethyl borate / THF solution" was used in place of the polymerization terminator "0.5 M MeOH / THF solution." The reaction temperature was room temperature (25°C), and the liquid flow conditions were as follows: "0.5 M 1,3-bromoiodobenzene / THF solution": 3.42 mL / min, "1.3 M iPrMgCl.LiCl / THF solution": 1.58 mL / min, "0.68 M trimethyl borate / THF solution": 2.77 mL / min

[0079] 2. Cleaning of the Inside of the Flow Channel - Example 17 - After carrying out the synthesis reaction of 3-bromophenylboronic acid by feeding the solution for 20 minutes under the above-mentioned feeding conditions, the inside of the flow channel was cleaned as follows. The cleaning temperature was set to 22°C. THF was fed into each of flow channels (1), (2), and (7) shown in FIG. 2 for 30 minutes at a total flow rate of 20 mL / min through each flow channel, and then a mixed solution of MeOH / water = 8 / 2 (volume ratio) was fed into each flow channel for 30 minutes at a total flow rate of 20 mL / min through each flow channel. Next, a THF solution containing p-toluenesulfonic acid at a concentration of 0.1% by mass was fed into each flow channel for 30 minutes at a total flow rate of 20 mL / min through each flow channel, thereby cleaning the inside of the flow channel with an organic acid compound solution (cleaning solution). Finally, THF was pumped through each flow path at a total flow rate of 20 mL / min, and the liquid (discharged liquid) discharged from the pipe (10) between 1 and 30 minutes later was measured by high-performance liquid chromatography (HPLC) and also by ICP under the same conditions. The results showed that the 3-bromophenylboronic acid concentration was 0.4 ppm and the magnesium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0080] Comparative Example 6 The discharged liquid was subjected to HPLC measurement and ICP measurement in the same manner as in Example 17, except that after the delivery of the mixed liquid of MeOH / water = 8 / 2 (volume ratio) and before the delivery of the final THF, no cleaning solution was delivered. As a result, the 3-bromophenylboronic acid concentration was 800 ppm and the lithium concentration was 100 ppm, both of which were higher concentrations than in Example 17. Note that Fe was not detected.

[0081] Comparative Example 7 The effluent was subjected to HPLC measurement and ICP measurement in the same manner as in Example 17, except that the organic acid compound in the cleaning solution in Example 17 was changed from p-toluenesulfonic acid to benzoic acid (a THF solution containing benzoic acid at a concentration of 0.1% by mass was used as the cleaning solution). As a result, the 3-bromophenylboronic acid concentration was 400 ppm and the lithium concentration was 50 ppm, both of which were higher concentrations than in Example 17. Note that Fe was not detected.

[0082] Test Example 5 1. Construction of a flow reaction system, and production of an o-benzyne compound - Diels-Alder reaction Using the flow reaction system shown in Figure 2 used in Test Example 2, 1-bromo-2-chlorobenzene was used as a precursor of the o-benzyne compound, which was reacted with n-butyllithium to produce o-benzyne via a monolithiation product, and a Diels-Alder reaction was carried out between this o-benzyne and furan to obtain 1,4-epoxy-1,4-dihydronaphthalene. Specifically, "0.1 M bromo-2-chlorobenzene / THF solution" was used instead of Liquid A "2 M p-t-butoxystyrene / THF solution" in Test Example 2, "0.2 M nBuLi / hexane solution" was used instead of Liquid B "0.05 M nBuLi / toluene solution" in Test Example 2, and "9.0 M furan / THF solution" was used instead of the polymerization terminator "0.5 M MeOH / THF solution". The low-temperature constant temperature bath (R1) was set to -70°C, and the liquid feeding conditions were as follows: "0.1 M bromo-2-chlorobenzene / THF solution": 8.2 mL / min, "0.2 M nBuLi / hexane solution": 3.5 mL / min, "9.0 M furan / THF solution": 4.6 mL / min

[0083] 2. Cleaning of the Inside of the Flow Channels - Example 18 - After carrying out the synthesis reaction of 1,4-epoxy-1,4-dihydronaphthalene by feeding the solution for 20 minutes under the above-mentioned feeding conditions, the inside of the flow channels was cleaned as follows. The low-temperature constant temperature bath (R1) was set to -30°C. THF was fed into each of the flow channels (1), (2), and (7) shown in FIG. 2 for 30 minutes at a total flow rate of 20 mL / min through each channel, and then a mixed solution of MeOH / water = 8 / 2 (volume ratio) was fed into each of the flow channels at a total flow rate of 20 mL / min through each channel for 30 minutes. Next, a THF solution containing p-toluenesulfonic acid at a concentration of 0.1% by mass was fed into each of the flow channels at a total flow rate of 20 mL / min through each channel for 30 minutes, thereby cleaning the inside of the flow channels with an organic acid compound solution (cleaning solution). Finally, THF was pumped through each flow path at a total flow rate of 20 mL / min, and the liquid (discharged liquid) discharged from the pipe (10) between 1 and 30 minutes later was measured by HPLC and also by ICP under the same conditions. The results showed that the 1,4-epoxy-1,4-dihydronaphthalene concentration was 0.4 ppm and the lithium concentration was 0.1 ppm. Furthermore, no Fe was detected, confirming that the SUS was not corroded.

[0084] Comparative Example 8 The discharged liquid was subjected to HPLC measurement and ICP measurement in the same manner as in Example 18, except that after the delivery of the mixed liquid of MeOH / water = 8 / 2 (volume ratio) and before the delivery of the final THF, no cleaning solution was delivered. As a result, the 1,4-epoxy-1,4-dihydronaphthalene concentration was 3000 ppm and the lithium concentration was 200 ppm, both of which were higher concentrations than in Example 18. Note that Fe was not detected.

[0085] Comparative Example 9 The effluent was subjected to HPLC measurement and ICP measurement in the same manner as in Example 18, except that the organic acid compound in the cleaning solution in Example 18 was changed from p-toluenesulfonic acid to benzoic acid (a THF solution containing benzoic acid at a concentration of 0.1% by mass was used as the cleaning solution). As a result, the 1,4-epoxy-1,4-dihydronaphthalene concentration was 1000 ppm and the lithium concentration was 100 ppm, both of which were higher concentrations than in Example 18. Note that no Fe was detected.

[0086] A comparison between the Examples and Comparative Examples in the above test examples shows that by cleaning the inside of the flow channel of a flow reaction system with a solution of an organic acid compound having a pKa of 0.50 or less, it is possible to remove solids inside the flow channel with high efficiency.

[0087] While the present invention has been described in connection with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless otherwise specified, and believe that the claims should be construed broadly without departing from the spirit and scope of the invention as set forth in the appended claims.

[0088] This application claims priority based on Japanese Patent Application No. 2024-042857, filed on March 18, 2024, the contents of which are incorporated herein by reference as part of the present specification.

Claims

1. A method for cleaning a flow reaction system, comprising cleaning the inside of a flow channel of the flow reaction system with a solution of an organic acid compound having a pKa of 0.50 or less.

2. The method for cleaning a flow reaction system according to claim 1, wherein the cleaning of the inside of the flow channel removes any solid matter adhering to the wall surface of the flow channel.

3. The method for cleaning a flow reaction system according to claim 2, wherein the deposits include by-products produced by a chemical reaction under basic conditions.

4. The method for cleaning a flow reaction system according to claim 2, wherein the deposits include by-products produced by a chemical reaction using an organometallic compound.

5. The method for cleaning a flow reaction system according to claim 4, wherein the organometallic compound is an organolithium compound or an organomagnesium compound.

6. The method for cleaning a flow reaction system according to claim 4, wherein the organometallic compound is an organolithium compound.

7. The method for cleaning a flow reaction system according to any one of claims 3 to 6, wherein the concentration of the organic acid compound in the solution is 0.001 to 10.000 mass %.

8. The method for cleaning a flow reaction system according to claim 7, wherein the temperature of the solution is set to -50 to 40°C to clean the inside of the flow channel.

9. The method for cleaning a flow reaction system according to claim 8, wherein the solvent of the solution is an organic solvent.

10. The method for cleaning a flow reaction system according to claim 9, wherein the pKa of the organic acid compound is 0.10 or less.

11. The method for cleaning a flow reaction system according to claim 10, wherein the organic acid compound comprises a sulfonic acid compound.

12. The method for cleaning a flow reaction system according to claim 11, wherein ultrasonic waves are applied to the flow channel of the flow reaction system while the solution is flowing through the flow channel.

13. A cleaning agent for a flow reaction system containing an organic acid compound with a pKa of 0.50 or less as an active ingredient.

14. The cleaning agent for a flow reaction system according to claim 13, wherein the organic acid compound has a pKa of 0.10 or less.

15. The cleaning agent for a flow reaction system according to claim 13 or 14, wherein the organic acid compound comprises a sulfonic acid compound.

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