Reaction device using droplet method, and manufacturing method

Abstract

To provide an efficient method using a droplet method in a flow reaction.SOLUTION: A reaction device has a reaction tube for performing a reaction of at least two substrates in a flow method, in the reaction tube, a sea-island structure composed of (i) a discontinuous phase containing a first droplet containing a first substrate, or the first substrate and a first solvent, and a second droplet containing a second substrate, or the second substrate and a second solvent, and (ii) a continuous phase containing no substrate and a liquid medium is formed, the reaction tube is curved, at least one apex of the reaction tube is positioned in a direction where gravity acts more than both the inlet and the outlet of the reaction tube, or in a direction opposite to the direction where the gravity acts, the first droplet and the second droplet are united by action of the gravity to form one united droplet, and the first substrate and the second substrate are brought into contact with each other and are reacted with each other.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a reactor using a droplet system, a reaction tube using a droplet system, and a method for producing a reaction product using a droplet system.The present invention also relates to a reaction prediction method comprising reacting at least two types of substrates in a flow system using a reactor using a droplet system or a reaction tube used in the reactor. [Background technology]

[0002] Research into chemical reactions that involve flowing fluids through microchannels has been attracting attention. Some of these chemical reactions utilize the droplet method, which can take advantage of the microscopic spaces that offer excellent diffusion and thermal efficiency. Reactions that utilize the droplet method are microreactions carried out on the micromolar scale, and examples of flow reactors that utilize droplets (segments) in heterogeneous media are known.

[0003] Patent Document 1 (JP 2005-313140 A) discloses an attraction-driven flow sequence control device comprising a reaction chamber having a plurality of reactant chambers, a plurality of separation microchannels, and a meandering collection microchannel arranged in a stepped pattern, each reactant chamber having an air vent channel, and each pair of adjacent separation microchannels having a U-shaped structure connected to an adjacent pair of separation microchannels. Patent Document 2 (JP 2008-012490 A) discloses a chemical reaction method in which a chemical reaction is carried out in a liquid droplet present in a reaction vessel or on the surface of a reaction substrate, in which a magnetic field fluctuation is applied to droplets formed from an aqueous solution containing magnetic particles with hydrophilic surfaces, so that the magnetic particles transmit a physical force to the surrounding aqueous solution, moving the droplets and performing the operations necessary for the chemical reaction. Patent Document 3 (JP 2004-305939 A) (JP Patent No. 4419419 A) discloses a method for carrying out a chemical reaction, which comprises introducing two or more fluids containing raw materials for a chemical reaction into a microchannel, converting the introduced fluids into microdroplets to form a dispersed phase, and the remaining fluid to form a continuous phase, and causing a chemical reaction between the dispersed phase and the continuous phase. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2005-313140 [Patent Document 2] Japanese Patent Application Laid-Open No. 2008-012490 [Patent Document 3] JP 2004-305939 A (Patent No. 4419419 A) Summary of the Invention [Problem to be solved by the invention]

[0005] The inventors of the present invention have found that the following new problems may arise in reactions using the conventional droplet system.

[0006] Until now, there has been no known method for utilizing ultra-microorganism synthesis reaction methods in flow reactions, linking molecular design, synthetic route development through computational chemistry, synthetic route verification through micro-experimental chemistry, and industrial production using flow reactors.

[0007] The present invention has been made in light of these circumstances. Specifically, the present invention focuses on droplets that utilize microspaces with excellent diffusion efficiency as a concept for achieving ultratrace organic synthesis, and aims to provide a reactor and a manufacturing method that enable verification of reaction systems, such as organic reaction systems, in unprecedentedly small volumes. Another object of the present invention is to provide a reaction tube for use in the reactor. Furthermore, the present invention aims to provide a reaction prediction method that includes reacting at least two types of substrates in a flow format using the reactor or the reaction tube. [Means for solving the problem]

[0008] The present invention provides The present invention relates to a reactor having a reaction tube for reacting at least two kinds of substrates in a flow mode, wherein a sea-island structure is formed in the reaction tube, consisting of (i) a discontinuous phase including a first droplet containing a first substrate or containing the first substrate and a first solvent, and a second droplet containing a second substrate or containing the second substrate and a second solvent, and (ii) a continuous phase containing no substrates but a liquid medium, wherein the reaction tube is curved, and at least one vertex of the reaction tube is positioned in the direction in which gravity acts or in the direction opposite to the direction in which gravity acts relative to both the inlet and outlet positions of the reaction tube, and the first droplet and the second droplet coalesce under the action of gravity to form a single coalesced droplet, and the first substrate and the second substrate come into contact and react.

[0009] Furthermore, the present invention provides A reaction tube in which at least two kinds of substrates are reacted in a flow manner, The present invention relates to a reaction tube in which an islands-in-a-sea structure is formed, consisting of (i) a first droplet containing a first substrate or containing a first substrate and a first solvent, and a second droplet containing a second substrate or containing a second substrate and a second solvent, and (ii) a continuous phase containing no substrate but a liquid medium, the reaction tube being curved, with at least one vertex of the reaction tube positioned in the direction of gravity or opposite to the direction of gravity relative to both the inlet and outlet positions of the reaction tube, the first droplet and the second droplet coming together by the action of gravity to form a single coalesced droplet, and the first substrate and the second substrate coming into contact and reacting.

[0010] In addition, the present invention provides supplying a liquid medium, supplying droplets, and reacting at least two kinds of substrates in the reactor or the reaction tube; The present invention relates to a method for producing a reaction product comprising the steps of:

[0011] Additionally, the present invention provides The present invention relates to a reaction prediction method, which comprises reacting at least two types of substrates in a flow manner in the above-mentioned reaction apparatus or reaction tube.

[0012] Preferred embodiments of the present invention are as follows. Aspect 1: A reactor having a reaction tube for reacting at least two kinds of substrates in a flow mode, wherein a sea-island structure is formed in the reaction tube, consisting of (i) a discontinuous phase including a first droplet containing a first substrate or containing the first substrate and a first solvent, and a second droplet containing a second substrate or containing the second substrate and a second solvent, and (ii) a continuous phase containing no substrates but a liquid medium, wherein the reaction tube is curved, and at least one vertex of the reaction tube is positioned in the direction in which gravity acts or in the direction opposite to the direction in which gravity acts relative to both the inlet and outlet positions of the reaction tube, and the first droplet and the second droplet coalesce under the action of gravity to form a single coalesced droplet, and the first substrate and the second substrate come into contact and react.

[0013] Aspect 2: a reaction tube extending in a direction opposite to the direction of gravity is curved in the direction of gravity, and the density of the liquid medium is greater than the densities of the first and second droplets, so that the first and second droplets are positioned above the liquid medium under the action of gravity; or The reactor of embodiment 1, wherein the reaction tube extends in the direction in which gravity acts and is curved upward in the opposite direction to the direction in which gravity acts, and the density of the liquid medium is lower than the densities of the first droplet and the second droplet, so that the first droplet and the second droplet are positioned below the liquid medium due to the action of gravity.

[0014] Aspect 3: the low-density liquid used as the first solvent, the second solvent, or the liquid medium is at least one non-fluorine-containing compound selected from the group consisting of alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water; A reaction apparatus according to Aspect 1 or 2, wherein the high-density liquid used as the first solvent, the second solvent, or the liquid medium is at least one compound selected from the group consisting of fluorine-containing compounds, ionic liquids, halogen-containing solvents, alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water.

[0015] Aspect 4: A reactor according to any one of aspects 1 to 3, wherein the first droplet is liquid or gas, and the second droplet is liquid or gas.

[0016] Aspect 5: A reactor according to any one of aspects 1 to 4, wherein in addition to the first and second droplets, one or more further droplets form the discontinuous phase.

[0017] Aspect 6: A reactor according to any one of aspects 1 to 5, wherein a third droplet comprising a third substrate or comprising a third substrate and a third solvent forms a discontinuous phase in addition to the first and second droplets.

[0018] Aspect 7: A reaction apparatus according to any one of aspects 1 to 6, wherein the first droplet and the second droplet are united at the top of the curved portion of the tube to form a combined droplet, and a liquid medium passes around the combined droplet, thereby generating a circulating flow in the combined droplet and promoting contact between the first substrate and the second substrate.

[0019] Aspect 8: A reaction apparatus according to any one of aspects 1 to 7, wherein the reaction is an organic reaction, an inorganic reaction, or a biochemical reaction.

[0020] Aspect 9: A reaction apparatus according to any one of aspects 1 to 8, wherein the inner diameter of the tube is 0.1 to 10 mm, and the size (diameter) of the droplets is 0.05 to 10 mm.

[0021] Aspect 10: A reaction apparatus according to any one of aspects 1 to 9, wherein the reaction tube is curved in a direction opposite to the direction of travel of the reaction tube (downward or upward), the curved shape is an arc, and the position of the apex of the curve of the reaction tube is 1 cm to 50 cm away from the position where the curve starts.

[0022] Aspect 11: A reaction apparatus according to any one of aspects 1 to 10, wherein the reaction tube changes from a first straight shape to a curved shape to a second straight shape, and the first straight shape is approximately parallel to the second straight shape.

[0023] Aspect 12: 12. The reactor of any one of aspects 1 to 11, comprising a catalyst within the reaction tube.

[0024] Aspect 13: The reactor comprises: a supply section for supplying a liquid medium, a first droplet, and a second droplet; a reaction section consisting of a reaction tube; and 13. The reaction apparatus according to any one of aspects 1 to 12, further comprising a recovery section for recovering the reaction product.

[0025] Aspect 14: A reaction tube in which at least two kinds of substrates are reacted in a flow manner, forming an islands-in-a-sea structure in a reaction tube, the islands-in-a-sea structure comprising: (i) a discontinuous phase comprising a first droplet containing a first substrate or a first substrate and a first solvent, and a second droplet containing a second substrate or a second substrate and a second solvent; and (ii) a continuous phase containing no substrate and a liquid medium; A reaction tube in which the reaction tube is curved, and at least one vertex of the reaction tube is located in the direction of gravity or opposite to the direction of gravity relative to both the inlet and outlet positions of the reaction tube, and the first droplet and the second droplet come together under the action of gravity to form a single combined droplet, and the first substrate and the second substrate come into contact and react.

[0026] Aspect 15: In the reaction apparatus according to any one of aspects 1 to 13 or the reaction tube according to aspect 14, providing a liquid medium; providing droplets; and React with at least two substrates A method for producing a reaction product comprising:

[0027] Aspect 16: A reaction prediction method comprising reacting at least two types of substrates in a flow manner in the reaction apparatus according to any one of aspects 1 to 13 or the reaction tube according to aspect 14. [Effects of the Invention]

[0028] The present invention achieves high reaction yields, provides a reaction space for small-volume reactions, and provides an ideal reaction space with excellent diffusion efficiency and heat exchange, providing a new reaction mode. [Brief explanation of the drawings]

[0029] [Figure 1] 1 is a diagram showing a schematic diagram of a reaction apparatus according to one embodiment of the present invention. [Figure 2] 1 is a diagram schematically illustrating a reaction tube according to one embodiment of the present invention. [Figure 3] FIG. 1 is a diagram illustrating a schematic view of how a first droplet and a second droplet flow in a reaction tube. [Figure 4] FIG. 1 is a schematic diagram illustrating a reactor including p-th droplet (multiple droplets) according to one embodiment of the present invention. [Figure 5] 1 is a schematic diagram illustrating a reactor including a catalyst layer within a reaction tube, according to one embodiment of the present invention. [Figure 6] FIG. 1 is a diagram illustrating the angle of curvature of a reaction tube. DETAILED DESCRIPTION OF THE INVENTION

[0030] [Reaction and Substrate] In the present invention, (i) a discontinuous phase comprising a first droplet comprising a first substrate or comprising a first substrate and a first solvent, and a second droplet comprising a second substrate or comprising a second substrate and a second solvent; and (ii) a continuous phase that does not contain a substrate and contains a liquid medium; A sea-island structure consisting of the above is formed in the reaction tube. The state of the droplets is not particularly limited as long as it can form a discontinuous phase. For example, the droplets may be liquid or gas. The first droplet and the second droplet may be in the same state (liquid or gas) or in different states. For example, if the first droplet is liquid, the second droplet may also be liquid. If the first droplet is gas, the second droplet may also be gas. If one of the first droplet or the second droplet is liquid, the other droplet may be gas. The first droplet contains a first substrate and optionally a first solvent, and the second droplet contains a second substrate and optionally a second solvent. The state of the substrate is not particularly limited and may be, for example, liquid, solid, or gas. When the substrate is liquid (e.g., at 20°C), no solvent may be used. When the substrate is solid (e.g., at 20°C), the droplet contains a solvent. When the substrate is gas, no solvent is used and only the substrate is used.

[0031] The term "droplet" refers to a space in which a minute amount (e.g., 0.01 ml to 1 ml) of a reaction substrate and / or a reaction reagent is retained. More specifically, the term "droplet" can encompass the meaning of a droplet-shaped or droplet-like "space," "field," "cell," or "system" in which a minute amount of a reaction substrate and / or a reaction reagent is retained. Therefore, the state of a "droplet" is not necessarily liquid, but may also be gas. In other words, the state of a "droplet" may be fluid. Since the term "droplet" can encompass the above meanings, the term should not be overly constrained; for example, "droplet" may be rephrased as "droplet-shaped fluid" or "space in which a reaction substrate and / or a reaction reagent is retained."

[0032] The first substrate and the second substrate undergo an organic, inorganic or biochemical reaction, preferably a reaction using light. Examples of organic reactions include addition reactions, substitution reactions, oxidation-reduction reactions, condensation reactions, catalytic reactions, etc. Specific examples of organic reactions include Diels-Alder reactions, dehydration amidation reactions, esterification reactions, hydrogenation reactions, carbonylation reactions, etc. Examples of inorganic reactions include oxidation-reduction reactions, acid-base reactions, and transmetallation reactions. Examples of biochemical reactions are reactions of nucleic acids, amino acids, lipids, carbohydrates, proteins, etc. An example is PCR (polymerase chain reaction). The present invention can be used, for example, in emulsion PCR.

[0033] The first substrate and the second substrate may be various and may vary depending on the reaction, but are not limited thereto. The first substrate and the second substrate are preferably immiscible with the liquid medium. Specific examples of the combination of the first substrate and the second substrate include, for example, Cyclopentadiene and acrylic acid, Phenyl vinyl sulfone and gamma-butyrolactone, 3-Isopropoxyaniline and 2-trifluoromethylbenzoic acid, Carbon monoxide, 3-isopropoxyaniline and 2-trifluoromethyliodobenzene, And so on. The types of substrates are not limited to two types, the first substrate and the second substrate, but may be three or more types.

[0034] The third substrate may be a substrate that reacts with the first and second substrates to produce a product. Alternatively, for example, it may be a substrate that reacts with a product produced by the reaction of the first and second substrates to produce a new product. The third solvent is a liquid for dissolving the third substrate. When it is not necessary to dissolve the third substrate in a solvent (for example, when the third substrate is liquid), the third droplet may consist of only the third substrate, without containing the third solvent. The above description of the third substrate also applies when a fourth or fifth substrate, i.e., an nth substrate, is used. Here, n may be 2 to 30, 2 to 10, or 2 to 6, particularly 2 or 3. For example, the nth substrate may be a substrate that reacts with another substrate to produce a product. Alternatively, for example, it may be a substrate that reacts with a product produced by the reaction of substrates with each other to produce a new product. The liquid for dissolving the nth substrate may be an mth solvent. Here, m may be 1 to 30, 1 to 10, or 1 to 6, particularly 1, 2, or 3. A droplet containing the nth substrate or containing the nth substrate and the mth solvent may be the pth droplet. Here, p may be 2 to 30, 2 to 10, or 2 to 6, particularly 2 or 3. When it is not necessary to dissolve the nth substrate in a solvent (for example, when the nth substrate is liquid), the pth droplet may not contain the mth solvent and may consist of only the nth substrate. The substrate and solvent forming the pth droplet may be the substrate and solvent used to form the first or second droplet. The first to pth droplets may be supplied to the reaction tube in a cascade or intermittently.

[0035] [Solvents, gaseous and liquid media] In one embodiment, a first solvent, a second solvent, and a liquid medium are used to form an islands-in-the-sea structure consisting of a discontinuous phase and a continuous phase. The first solvent dissolves a first substrate to form a first solution, and the second solvent dissolves a second substrate to form a second solution. The first solution and the second solution form islands in the islands-in-the-sea structure. If necessary, for example, when the first substrate and / or the second substrate are liquid or gas, the first solvent and / or the second solvent may not be used. The first solution (first droplet) and the second solution (second droplet) are generally spherical, cylindrical, or block-like in shape within the liquid medium. The first and second droplets (and the first and second solvents) are immiscible with the liquid medium so that discontinuous and continuous phases are formed. "Immiscible" means that the first droplet (or second droplet) dissolves in the liquid medium in an amount of 10 g or less, 5 g or less, 2 g or less, 1 g or less, 0.5 g or less, 0.1 g or less, 0.01 g or less, or 0 g per 100 g of liquid medium at 20°C. If the first droplet (or second droplet) is gas, this means that the volume of the gas droplet does not change substantially before reaction (e.g., the volume of the gas droplet decreases by 10% or less, 5% or less, or 1% or less, particularly 0.1% or less). "Immiscible" means that the first solvent (or second solvent) dissolves or does not dissolve in the liquid medium in an amount of 10 g or less, 5 g or less, 2 g or less, 1 g or less, 0.5 g or less, 0.1 g, 0.01 g, or 0.001 g per 100 g of liquid medium at 20°C.

[0036] The first and second solvents may be different as long as they are miscible, but are preferably the same. "Miscible" means that the first solvent dissolves in the second solvent at 20°C in an amount of 200 g or more, 30 g or more, 50 g or more, 100 g or more, 300 g or more, 500 g or more, or any amount per 100 g of the second solvent.

[0037] The densities of the first and second droplets (first and second solvents) are different from the density of the liquid medium. The difference between the densities of the first and second solvents and the density of the liquid medium is 0.1 g / cm at 20°C. 3 More than 0.2g / cm 3 More than 0.3g / cm 3 More than 0.4g / cm 3 or more, or 0.5g / cm 3 From the viewpoint of promoting the coalescence of the first droplets and the second droplets and allowing the substrate to react more efficiently, the difference between the density of the first solvent and the second solvent and the density of the liquid medium may be 0.3 g / cm or more. 3 It is preferable that there is more than this.

[0038] In one embodiment, each of the first and second droplets (first and second solvents) has a density that is less than the density of the liquid medium that forms the continuous phase. Low-density solvents include alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water. The density of low-density solvents is 0.5 to 1.5 g / cm. 3 , 0.6~1.2g / cm 3 , 0.7~1.1g / cm 3 or 0.7 to 0.9 g / cm 3 From the viewpoint of promoting the coalescence of the first droplets and the second droplets and allowing the substrate to react more efficiently, the density of the liquid medium having a low density may be 0.7 to 1.1 g / cm 3 or 0.7 to 0.9 g / cm 3 It is preferable that: Examples of liquid media with high density include fluorine-containing compounds, ionic liquids, halogen-containing solvents, alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water. The density of liquid media with high density is 1 to 2.5 g / cm. 3 , 1.1~2.2g / cm 3 , 1.1~2.0g / cm 3 or 1.5 to 2.0 g / cm 3From the viewpoint of promoting the coalescence of the first droplets and the second droplets and allowing the substrate to react more efficiently, the density of the liquid medium having a high density may be 1.1 to 2.0 g / cm. 3 or 1.5 to 2.0 g / cm 3 It is preferable that:

[0039] In another embodiment, each of the first and second droplets (first and second solvents) has a density greater than the density of the liquid medium forming the continuous phase. As solvents with high density, fluorine-containing compounds and ionic liquids (density is, for example, 1.1 to 1.5 g / cm 3 ), halogen-containing solvents, alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water. The density of high-density solvents is 1 to 2.5 g / cm. 3 , 1.1~2.2g / cm 3 , 1.1~2.0g / cm 3 or 1.5 to 2.0 g / cm 3 From the viewpoint of combining the first droplets and the second droplets and reacting the substrate more efficiently, the density of the liquid medium having a high density may be 1.1 to 2.0 g / cm. 3 or 1.5 to 2.0 g / cm 3 It is preferable that: Examples of low-density liquid media include alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water. The density of low-density liquid media is 0.5 to 1.5 g / cm. 3 , 0.6~1.2g / cm 3 , 0.7~1.1g / cm 3 or 0.7 to 0.9 g / cm 3 From the viewpoint of promoting the coalescence of the first droplets and the second droplets and allowing the substrate to react more efficiently, the density of the liquid medium having a low density may be 0.7 to 1.1 g / cm 3 or 0.7 to 0.9 g / cm 3 It is preferable that:

[0040] Specific examples of compounds that can be used as the solvent and liquid medium are not limited, but examples thereof, together with their densities at 20°C, include: Methyl alcohol (0.79 g / cm 3 ), Ethyl alcohol (0.795g / cm 3 ), Diethyl ether (0.71 g / cm 3 ), Acetic acid (1.05 g / cm 3 ), Ethyl acetate (0.90 g / cm 3 ), Acetonitrile (0.78 g / cm 3 ), Acetone (0.79 g / cm 3 ), Methyl ethyl ketone (0.81 g / cm 3 ), Dichloromethane (1.33 g / cm 3 ), o-Dichlorobenzene (1.31 g / cm 3 ), Benzene (0.88 g / cm 3 ), Toluene (0.87 g / cm 3 ), Hexane (0.66g / cm 3 ), Tetrahydrofuran (0.89 g / cm 3 ), N,N-dimethylformamide (0.95 g / cm 3 ), Mineral spirits (0.79g / cm 3 ), Water (1.00g / cm 3 ), Perfluoropolyether (fluorine-containing compound, for example, Galden (registered trademark) (1.72 g / cm 3 ), Perfluorodecalin (fluorine-containing compound, 1.92 g / cm 3 ), Bromine (3.10 g / cm 3 ) Examples include: From the viewpoint of promoting the coalescence of the first droplet and the second droplet and allowing the substrate to react more efficiently, the solvent is preferably acetonitrile or dichloromethane, and from the same viewpoint, the liquid medium is preferably perfluoropolyether.

[0041] In one embodiment, the compound usable as the liquid medium is preferably a fluorine-based solvent. Fluorine-based solvents have relatively low reactivity compared to other solvents and substances. When a fluorine-based solvent is used as the liquid medium, the reaction between the liquid medium and the first and second droplets is easily suppressed, and the first and second droplets are more efficiently combined and react with each other.

[0042] Fluorine-based solvents are difficult to mix with other solvents and substances. Therefore, when the first and second droplets coalesce under the action of gravity to form a single combined droplet, and the first and second substrates come into contact and the reaction is completed, the fluorine-based solvent can be easily selectively separated from the other solvents and substances. In other words, after the reaction is completed, the fluorine-based solvent can be recovered and reused.

[0043] The density of fluorinated solvents is 1 to 2.5 g / cm 3 and preferably 1.1 to 2.2 g / cm 3 , more preferably 1.1 to 2.0 g / cm 3 , and more preferably 1.5 to 2.0 g / cm 3 When the density of the fluorinated solvent is within the above range, the first droplet and the second droplet are more likely to remain near the apex of the curved reaction tube, and the first droplet and the second droplet are more likely to coalesce and react with each other efficiently, as described in detail below. For example, in a reaction tube that forms a convex portion in the direction opposite to the direction of gravity (i.e., a reaction tube that forms an upward U-shape or an inverted U-shape), the fluorine-containing solvent has a higher density than the first and second droplets, making it easier for the first and second droplets to remain near the apex of the curved reaction tube, and the first and second droplets to coalesce and react with each other more efficiently. In addition, in a reaction tube that forms a convex portion along the direction of gravity (i.e., a U-shaped reaction tube), by making the density of the first and second droplets greater than the density of the liquid medium, the first and second droplets are more likely to remain near the apex (bottom) of the curved reaction tube, thereby obtaining the same advantages as in a reaction tube that forms an upward U-shape.

[0044] From the viewpoint of efficient reaction of the first and second droplets and efficient recovery of the fluorine-based solvent, the fluorine-based solvent is preferably a perfluoropolyether and / or a perfluoroalkane. Galden (registered trademark) is preferred as the perfluoropolyether. The perfluoroalkane is preferably a chain-like perfluoroalkane. Specifically, the perfluoroalkane may be perfluoropentane, perfluorohexane, or perfluoropentane.

[0045] Galden (registered trademark) may be, for example, a product manufactured by Solvay Japan KK Examples of Galden (registered trademark) include HT55, HT80, HT110, HT135, HT170, HT200, HT230, HT270, SV55, SV70, SV80, SV110, SV135, LS200, LS215, LS230, HS240, HS260, D02TS, D03, D02, and D05.

[0046] Specific examples of gases or substrates that can be used as droplets are not limited, and include, for example, oxygen, hydrogen, carbon monoxide, carbon dioxide, chlorine, nitric oxide, carbon disulfide, ozone, ethylene, acetylene, hydrogen chloride, hydrogen bromide, hydrogen fluoride, hydrogen sulfide, ammonia, methane, ethane, propane, propylene, butane, butene, butadiene, etc. From the viewpoint of more efficiently reacting the substrate contained in the droplet, the gas or substrate that can be used as a droplet is preferably carbon monoxide.

[0047] Examples of combinations of low density solvents and high density liquid media are: Acetonitrile (0.78 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), Dichloromethane (1.33 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), Methanol (0.79 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), Tetrahydrofuran (0.89 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), N,N-dimethylformamide (0.95 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), Dichloromethane (1.33 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), Ethyl acetate (0.90 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), Diethyl ether (0.71 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ), Ethyl acetate (0.90 g / cm 3 ) and perfluorodecalin (1.92 g / cm3 ), is. Of the above combinations, the combinations of acetonitrile and perfluoropolyether, and dichloromethane and perfluoropolyether are preferred from the viewpoint of promoting the combination of the first droplet and the second droplet and allowing the substrate to react more efficiently.

[0048] Examples of combinations of high density solvents and low density liquid media are: Water (1.00g / cm 3 ) and hexane (0.66 g / cm 3 ), Water (1.00g / cm 3 ) and diethyl ether (0.71 g / cm 3 ), Acetonitrile (0.78 g / cm 3 ) and hexane (0.66 g / cm 3 ), Bromine (3.10 g / cm 3 ) and perfluoropolyether (1.72 g / cm 3 ) is.

[0049] When the first droplet does not contain the first solvent and / or the second droplet does not contain the second solvent, the first substrate forms the first droplet and / or the second substrate forms the second droplet. Thus, the first substrate and the second substrate have a density less than or greater than that of the liquid medium. Preferably, the first substrate and the second substrate have the density values ​​described for the solvent.

[0050] When the first substrate and / or the second substrate is a gas, a first droplet is formed in which the first substrate is a gas and / or a second droplet is formed in which the second substrate is a gas. Gas droplets typically have a lower density than the liquid medium. When gas droplets are used, the type of liquid medium is not particularly limited as long as it is a liquid medium that is immiscible with the gas droplets. In another embodiment, gas droplets and liquid droplets may be used in combination. Specific examples of combinations of gas droplets, liquid droplets, and liquid mediums include carbon monoxide, 3-isopropoxyaniline, 2-trifluoromethyliodobenzene, and perfluoropolyether.

[0051] Although the above describes the use of two solvents, a first solvent and a second solvent, a third solvent may also be used. For example, a first droplet containing a first substrate and a first solvent, a second droplet containing a second substrate and a second solvent, and a third droplet containing a third substrate and / or catalyst and a third solvent may also be used. Furthermore, a fourth solvent, a fifth solvent, i.e., an mth solvent, may also be used. A pth droplet containing an nth substrate and / or catalyst and an mth solvent may also be used.

[0052] [Reaction tube and droplets] The inner diameter of the reaction tube may usually be 0.1 to 10 mm, or 0.1 to 9 mm, and from the viewpoint of improving the reaction efficiency, it may be preferably 0.2 to 9 mm, more preferably 0.2 to 8 mm, and even more preferably 0.3 to 8 mm. The length of the reaction tube may be 3 to 100 cm, 5 to 80 cm, or 10 to 60 cm.

[0053] The droplets may have an average flow velocity in the reaction tube of 0 to 20 cm / sec, 0.01 to 20 cm / sec, 0.1 to 20 cm / sec, 0.2 to 10 cm / sec, or 0.5 to 5 cm / sec. The droplets may have an average residence time in the reaction tube of 1 to 200 seconds, 2 to 100 seconds, or 3 to 50 seconds. The average flow velocity of the liquid medium in the reaction tube may be 0.2 to 50 cm / sec, 0.5 to 30 cm / sec, or 1 to 10 cm / sec. The average residence time of the liquid medium in the reaction tube may be 1 to 300 seconds, 2 to 200 seconds, or 3 to 100 seconds. The droplets move through the reaction tube along with the flow of the liquid medium. Therefore, the average flow velocity of the droplets is affected by the average flow velocity of the liquid medium. The average flow velocity of the droplets is also affected by buoyancy or gravity due to the density difference between the droplets and the liquid medium. For example, if the flow direction of the liquid medium in the reaction tube is the same as the direction of the buoyancy acting on the droplets, the average flow velocity of the droplets may be faster than the average flow velocity of the liquid medium. For example, if the flow direction of the liquid medium in the reaction tube is different from the direction of the buoyancy acting on the droplets, the average flow velocity of the droplets may be slower than the average flow velocity of the liquid medium or may stop. In either case, since the liquid medium flows around the droplet, an internal circulating flow, which will be described later, occurs in the droplet, and the inside of the droplet is stirred.

[0054] The material of the reaction tube is not particularly limited as long as it is a material that is insoluble in the discontinuous phase and the continuous phase. The material of the reaction tube may be, for example, glass, rubber, plastic, or metal. Examples of rubber or plastic include fluorine-based materials, acrylic materials, vinyl chloride materials, polyamide materials, and melamine materials. Examples of metal include stainless steel, aluminum, and copper. The reaction tube is preferably transparent. When a transparent reaction tube is used, light (e.g., ultraviolet light) can pass through the tube and reach the substrate, allowing a reaction (particularly a photoreaction) to occur.

[0055] The size (diameter) of the droplets may usually be 0.1 to 10 mm, or 0.1 to 9 mm, and from the viewpoint of improving the reaction efficiency, may be preferably 0.2 to 9 mm, more preferably 0.2 to 8 mm, and even more preferably 0.3 to 8 mm. The size (diameter) of the droplets may be approximately the same as the inner diameter of the reaction tube.

[0056] When the density of the liquid medium flowing through the reaction tube is greater than the density of the first and second droplets (or the first and second solvents), the liquid medium flowing through the reaction tube will, due to gravity, be positioned below the first droplet containing the first solvent and the second droplet containing the second solvent. At the apex (top) of the tube, the first and second droplets will coalesce to form a coalesced droplet.

[0057] In one embodiment of the present invention, a reaction tube extending upward is curved downward. In other words, a reaction tube extending in the opposite direction to the direction of gravity is curved in the direction of gravity. The density of the liquid medium is greater than that of the first and second droplets, and gravity causes the first and second droplets to be positioned above the liquid medium. The first and second droplets unite at the top of the curved portion of the tube to form a coalesced droplet, and the first substrate and the second substrate come into contact. As the liquid medium passes around the coalesced droplet, a circulating flow is generated in the coalesced droplet, promoting contact between the first substrate and the second substrate. Because the volume of the coalesced droplet where the circulating flow occurs is small, the first substrate and the second substrate come into sufficient contact, resulting in a high conversion rate (and selectivity) of the reaction. The coalesced droplet is then pushed by the liquid medium to move from the top of the curved portion of the tube and down the tube.

[0058] In another embodiment of the present invention, a reaction tube extending downward is curved upward. In other words, a reaction tube extending in the direction of gravity is curved in the opposite direction to the direction of gravity. The density of the liquid medium is lower than that of the first and second droplets, and gravity causes the first and second droplets to be located below the liquid medium. The first and second droplets merge at the bottom of the curved portion of the tube, bringing the first substrate and the second substrate into contact. The liquid medium passes around the merged droplets, generating a circulating flow in the merged droplets, promoting contact between the first substrate and the second substrate. The merged droplets are pushed by the liquid medium and move from the bottom of the curved portion of the tube and upward in the tube.

[0059] "Upward" means, for example, the direction opposite to the direction in which gravity acts. Specifically, when direction A is decomposed into a vertical component and a horizontal component, if the vertical component indicates the direction opposite to the direction in which gravity acts, direction A may be called "upward."

[0060] The "downward direction" means, for example, the direction in which gravity acts. Specifically, when direction B is decomposed into a vertical component and a horizontal component, if the vertical component indicates the direction in which gravity acts, direction B may be called the "downward direction."

[0061] "The reaction tube extends upward" means, for example, that the reaction tube extends in the direction opposite to the direction in which gravity acts. "The reaction tube extends upward" may mean, for example, that the entire reaction tube (e.g., from the inlet to the outlet of the reaction tube, or from one end to the other end of the reaction tube) extends upward, or that at least a portion of the reaction tube extends upward. For example, with reference to FIG. 1, the reaction tube proximal to the supply section extends in the direction opposite to the direction in which gravity acts, i.e., the reaction tube extends upward.

[0062] "An upwardly extending reaction tube is curved downward" means that the upwardly extending reaction tube is curved in an arc. Specifically, it means that the extending direction of the reaction tube is curved so that it changes from upward to "downward." In other words, it means that the reaction tube extends downward to form a convex portion in the direction opposite to the direction in which gravity acts. When characterized by its appearance, it means that the reaction tube is curved in a shape that resembles an upside-down U, or that at least one vertex of the reaction tube is located in the direction opposite to the direction in which gravity acts relative to both the inlet and outlet positions of the reaction tube.

[0063] The reaction tube extending "downward" means, for example, that the reaction tube extends in the direction in which gravity acts. For example, "the reaction tube extends downward" may mean that the entire reaction tube (e.g., from the inlet to the outlet of the reaction tube or from one end to the other end of the reaction tube) extends downward, or that at least a part of the reaction tube extends downward.

[0064] "A reaction tube extending downward is curved upward" means, for example, that the reaction tube extending downward is curved in an arc. Specifically, it means that the extending direction of the reaction tube is curved so as to change from downward to "upward." In other words, it means that the reaction tube extends upward so as to form a convex portion in the direction in which gravity acts. When characterized by appearance, it means that the reaction tube is curved in a U-shape, or that at least one vertex of the reaction tube is located in the direction in which gravity acts, relative to both the inlet and outlet positions of the reaction tube.

[0065] In one embodiment of the present invention, the reaction tube is preferably curved in the direction opposite to the direction of travel of the reaction tube (i.e., downward or upward), and the curved shape is preferably an arc. Specifically, the direction of the curve of the reaction tube is, for example, preferably downward when the reaction tube is traveling upward, and preferably upward when the reaction tube is traveling downward. The arc shape referred to here does not necessarily have to be a strict "arc." Specifically, the arc shape referred to here refers to the curved shape of the reaction tube formed by bending the reaction tube in the direction opposite to the direction of travel of the reaction tube. For example, the reaction tube may be U-shaped, approximately V-shaped, L-shaped, C-shaped, or a combination of one or more of these.

[0066] The position of the apex of the curve of the reaction tube may be 1 cm to 50 cm away from the start position of the curve. From the viewpoint of further improving the reaction efficiency by utilizing gravity, the distance between the start position of the curve and the apex of the curve may be 5 cm to 50 cm, 5 cm to 40 cm, 10 cm to 30 cm, or 15 cm to 25 cm. The position of the apex of the curve of the reaction tube means the position where the moving direction of the reaction tube transitions from upward to downward, or from downward to upward. Referring to Figure 1, the position of the apex of the reaction tube is the position of the reaction tube indicated by a. The start position of the curve may be one end or the other end of the curved part of the reaction tube, for example, as shown in Figure 2.

[0067] The curved reaction tube has at least one vertex. For example, the curved reaction tube may have only one vertex or may have multiple vertices. From the viewpoint of making the reactor more convenient, the curved reaction tube may have only one vertex.

[0068] In one embodiment of the present invention, the reaction tube may change from a first straight shape to a curved shape and then to a second straight shape, with the first straight shape being approximately parallel to the second straight shape. The portion of the reaction tube that can assume the first straight shape is a portion proximal to the supply section of the reaction tube relative to the curved shape. The portion of the reaction tube that can assume the second straight shape is a portion distal to the supply section of the reaction tube relative to the curved section.

[0069] The angle of the curved shape when changing from the first linear shape to the second linear shape is preferably 120° to 240°. Here, the "angle of the curved shape" refers to the angle formed by a line connecting the "center point of curvature" to one end of the curved portion of the reaction tube and a line connecting the center point of curvature to the other end of the curved portion, when the "center point of curvature" is equidistant from one end of the curved portion of the reaction tube, the other end of the curved portion of the reaction tube, and the apex a of the curved portion (or the midpoint between the one end and the other end of the curved portion). Specifically, as shown in FIG. 2, the "center point of curvature" refers to a point where the distance from one end of the curved portion, the distance from the apex of the curved portion, and the distance from the other end of the curved portion are all equal. From the viewpoint of further improving reaction efficiency by utilizing gravity, the angle of the curved shape may be 150° to 210°, 165° to 210°, 165° to 195°, or 180° to 195°.

[0070] In another embodiment of the present invention, the reaction tube may contain a catalyst inside the tube. Various catalysts can be used depending on the reaction contents, and are not limited to these. Examples of catalysts include palladium carbon, silica gel-supported catalysts such as HO-SAS, resins such as Amberlite, metal catalysts such as platinum, and photocatalysts such as titanium oxide. The catalyst may be provided in the reaction tube at a position where the first and second droplets unite to form a combined droplet. Specifically, the catalyst may be provided at the apex of the curved portion of the reaction tube. For example, a filter may be used to form a catalyst layer between two filters, or a single filter may support the catalyst to form a catalyst layer. Examples of filters include fluorine-based resins such as polyvinylidene fluoride, glass resins such as glass fiber, and resins such as nylon. The thickness of the catalyst layer may be 10 microns to 100 mm, for example, 0.1 mm to 20 mm.

[0071] [Reaction apparatus using droplet system] The reactor is a supply section for supplying a liquid medium, a first droplet, and a second droplet; a reaction section consisting of a reaction tube; and It has a recovery section for recovering the reaction product. The supply unit may be composed of a device for supplying a liquid medium, a device for supplying a first droplet, and a device for supplying a second droplet. The device for supplying a liquid medium is a device capable of continuously delivering the liquid medium to the reaction tube, and may be, for example, a supply pump, a syringe pump, a plunger pump, a tube pump, or the like. The device for supplying the first droplet and the device for supplying the second droplet may be a droplet supplying device, for example, a rheodyne injector, an HPLC autoinjector, a microsyringe, or the like. For example, the supply unit may be configured to externally inject a liquid containing a first substrate and a first solvent and a liquid containing a second substrate and a second solvent into the reaction tube 10 through which the liquid medium flows. For example, a three-way cock or the like may be provided on the reaction tube 10 as an injection port for external injection. The reaction section may be composed of only a reaction tube, but may also include a light irradiator, a heater, a microwave irradiator, and the like. The collection section may have a device for collecting the reaction product, such as a test tube, an Erlenmeyer flask, or a fraction collector.

[0072] [Manufacturing method] The manufacturing method of the present invention includes roughly carrying out the following steps in the manufacturing apparatus of the present invention or in the reaction tube 10 used in the manufacturing apparatus of the present invention. (i) providing a liquid medium; (ii) providing droplets; and (iii) Reacting at least two types of substrates.

[0073] First, a liquid medium is continuously fed into a curved reaction tube at a constant flow rate using the supply unit of the manufacturing apparatus of the present invention. Next, a first solvent containing a first substrate is injected into the reaction tube through which the liquid medium continues to flow using a syringe or the like. Because the first solvent containing the first substrate is immiscible with the liquid medium, a first droplet is formed within the reaction tube. The first droplet advances through the reaction tube toward the apex of the curve due to the flow of the liquid medium. After the first droplet is formed, a second solvent containing a second substrate is injected using a syringe or the like. Because the second solvent containing the second substrate is immiscible with the liquid medium, a second droplet 2 is formed within the reaction tube 10. The second droplet advances through the reaction tube 10 toward the apex of the curve due to the flow of the liquid medium. The first and second droplets merge at the apex of the reaction tube 10, and the reaction begins. If necessary, the flow rate of the liquid medium is increased to recover the fused droplets.

[0074] [Prediction of reaction outcomes in flow synthesis] The present invention can be used to predict the reaction results of a flow-type reaction, including a reaction of at least two types of substrates in a flow-type reaction. Specifically, the yield of a reaction product obtained by reacting at least two types of substrates using the reactor of the present invention is approximately the same as the yield of a reaction product obtained by reacting at least two types of substrates in a flow-type reaction. A flow-type reaction is also referred to as flow synthesis. A flow-type reaction or flow synthesis may be, for example, a synthesis performed using a continuous flow reactor. The present invention can be used, for example, to efficiently verify a reaction on a small scale and comprehensively verify reaction conditions prior to a flow-type reaction (i.e., flow synthesis).

[0075] As described above, the present invention does not require the use of glass vessels such as flasks for reactions. While miniaturizing glass vessels or the like to achieve small-scale reactions can impose limitations on experimental procedures, the present invention is less susceptible to such limitations. Therefore, the present invention makes it easier to perform relatively small-scale reactions than conventional methods. In other words, since it is possible to react a small amount of substrate with another small amount of substrate, reaction results can be obtained using minimum (or ultra-minimum) amounts (e.g., 0.01 ml to 1 ml). Because materials such as substrates and / or solvents that are toxic or flammable can be handled relatively safely and easily, making it easier to obtain information for mass production of products (e.g., reaction temperature, time, reaction ratio, etc.). Because reactions in mass production can be viewed microscopically as reactions between droplets, mass production becomes possible if multiple reaction apparatuses of the present invention can be installed.

[0076] The present invention will be specifically described below with reference to the drawings.

[0077] 1 is a schematic diagram showing a reaction apparatus 100 of the present invention. The reaction apparatus 100 has a reaction tube 10, a supply section 20, and a collection section 30. The reaction tube 10 is curved upward, which is opposite to the direction in which gravity acts. One end of the reaction tube 10 is connected to the supply section 20, and the other end of the reaction tube 10 is connected to the collection section 30.

[0078] The supply unit 20 supplies the liquid medium and the first and second droplets 1 and 2 to the reaction tube 10, and the liquid medium and the first and second droplets 1 and 2 flow in the direction of the arrows. In the reaction tube 10, the first droplet 1 and the second droplet 2 form a discontinuous phase, and the liquid medium forms a continuous phase. An island-in-a-sea structure consisting of the discontinuous phase and the continuous phase is formed within the curved reaction tube 10. The first droplet 1 and the second droplet merge near the apex a of the reaction tube 10 to form a merged droplet 3. The reaction takes place in the merged droplet 3. The recovery section 30 recovers the combined droplets 3, i.e., the reaction products.

[0079] FIG. 2 is a schematic diagram showing a reaction tube 10 of the present invention. A fluid flows inside the reaction tube 10. The reaction tube 10 is curved upward, which is opposite to the direction of gravity. The reaction tube 10 has an apex a. The reaction tube is curved by moving upward and then moving downward from apex a.

[0080] 3 is a schematic diagram showing a reaction tube 10 of the present invention. In the reaction tube 10, a reaction of at least two kinds of substrates is carried out in a flow mode. The reaction tube 10 is a tube that is hollow (or hollow) inside and allows a fluid to flow therethrough. The reaction tube 10 has a curved portion. An islands-in-a-sea structure is formed in the reaction tube 10. The islands-in-a-sea structure is composed of (i) a discontinuous phase including a first droplet 1 containing a first substrate or a first substrate and a first solvent, and a second droplet 2 containing a second substrate or a second substrate and a second solvent, and (ii) a continuous phase containing no substrate but a liquid medium. The reaction tube 10 is curved, and at least one vertex of the reaction tube is positioned in the direction of gravity or opposite to the direction of gravity relative to both the inlet and outlet positions of the reaction tube. Therefore, the first droplet 1 and the second droplet 2 coalesce under the action of gravity to form a single coalesced droplet 3, and the first substrate and the second substrate come into contact and react.

[0081] FIG. 4 is a schematic diagram of a reactor according to one embodiment of the present invention, comprising a first droplet 1, a second droplet 2, a third droplet 4, a fourth droplet 5, and a fifth droplet 6. This configuration allows for sequential reactions. Cascading reactions can be achieved by feeding three or more droplets.

[0082] 5 is a schematic diagram illustrating a reactor according to one embodiment of the present invention, including a catalyst layer 40 sandwiched between filters 50 within a reaction tube 10. The catalyst layer 40 is provided at the apex a of the reaction tube 10. A first droplet 1 and a second droplet 2 are combined in the presence of the catalyst layer 40 to form a combined droplet 3. The presence of the catalyst allows the substrates contained in the droplets to react more efficiently.

[0083] FIG. 6 is a diagram illustrating the angle of curvature of a reaction tube. The reaction tube has one end of the curved portion, an apex, and the other end of the curved portion. A center point of curvature is defined. The center point of curvature is the point where the distance from one end of the curved portion, the distance from the apex of the curved portion, and the distance from the other end of the curved portion are all equal. From the viewpoint of further improving reaction efficiency by utilizing gravity, the angle θ of the curved shape may be 150° to 210°, 165° to 210°, 165° to 195°, or 180° to 195°.

[0084] Preferred embodiments of the present invention will now be described.

[0085] The discontinuous phase is a phase formed by the first droplet 1 and the second droplet 2. The discontinuous phase is immiscible with the continuous phase. Therefore, the discontinuous phase is a phase that can exist independently in the reaction tube 10, separate from the continuous phase. More specifically, the first droplet 1 and the second droplet 2 contained in the discontinuous phase are immiscible with the liquid medium contained in the continuous phase. Therefore, the first droplet 1 and the second droplet 2 can exist independently in the reaction tube, separate from the liquid medium. Because the first droplet 1 and the second droplet 2 exist discontinuously (or locally) in the reaction tube 10, the phase containing the first droplet 1 and the second droplet 2 is referred to as a "discontinuous" phase. Within the reaction tube 10, the volume of the discontinuous phase may be greater or less than the combined volume of the first droplet 1 and the second droplet 2.

[0086] The first droplet 1 is a liquid that is first introduced into the reaction tube 10 through which the liquid medium flows. The first droplet 1 comprises a first substrate and a first solvent. The first substrate is a substrate that reacts with a second substrate to produce a product. The first solvent is a liquid for dissolving the first substrate. When it is not necessary to dissolve the first substrate in a solvent (for example, when the first substrate is liquid), the first droplet 1 may not contain the first solvent and may consist of the first substrate.

[0087] The second droplet 2 is a liquid that is introduced into the reaction tube 10, through which the liquid medium flows, after the first droplet 1. The second droplet 2 comprises a second substrate and a second solvent. The second substrate is a substrate that reacts with the first substrate to produce a product. The second solvent is a liquid for dissolving the second substrate. If it is not necessary to dissolve the second substrate in a solvent (for example, if the second substrate is liquid), the second droplet 2 may not contain the second solvent and may consist of the second substrate.

[0088] The continuous phase is a phase comprising a liquid medium different from the first solvent and the second solvent. Specifically, the continuous phase comprises a liquid medium that flows continuously within the reaction tube 10, and the liquid medium is a liquid different from the first solvent and the second solvent. The continuous phase is immiscible with the discontinuous phase. Therefore, the continuous phase is a phase that can exist separately from the continuous phase and independently within the reaction tube 10. More specifically, the liquid medium contained in the continuous phase is immiscible with the first droplet 1 and the second droplet 2 contained in the discontinuous phase. Therefore, the liquid medium is a liquid that can exist separately from each of the first droplet 1 and the second droplet 2 and independently within the reaction tube.

[0089] The liquid medium is a liquid that fills the reaction tube 10 and flows continuously within the reaction tube 10. Therefore, the phase containing the liquid medium within the reaction tube 10 is referred to as the "continuous" phase. Of the phases present within the reaction tube 10, the phase that is present in a relatively greater amount may be referred to as the continuous phase. Because the continuous phase comprises a liquid that flows continuously within the reaction tube 10, the continuous phase can also serve as a mobile phase that moves the discontinuous phase within the reaction tube 10.

[0090] The flow rate of the continuous phase flowing through the reaction tube 10 is not particularly limited as long as it is a flow rate that can transport the discontinuous phase. The flow rate of the continuous phase may be, for example, 0.01 ml / min to 1 ml / min. From the viewpoint of improving the reaction efficiency, the flow rate of the discontinuous phase may be preferably 0.01 ml / min to 0.5 ml / min, more preferably 0.05 ml / min to 0.5 ml / min, even more preferably 0.05 ml / min to 0.3 ml / min, and particularly preferably 0.07 ml / min to 0.3 ml / min.

[0091] The density of the discontinuous phase is different from the density of the continuous phase. Specifically, the density of the liquid medium is different from the density of the first droplet 1 and the second droplet 2.

[0092] The density difference between the liquid medium and the first droplet 1 and the density difference between the liquid medium and the second droplet 2 are, for example, 0.1 g / cm 3From the viewpoint of further improving the reaction efficiency, the density difference is 0.1 g / cm 3 More than 0.2g / cm 3 More than 0.3g / cm 3 More than 0.4g / cm 3 or more than 0.5g / cm 3 It may be more than that.

[0093] In one embodiment of the present invention, as described above, the discontinuous phase and the continuous phase are immiscible with each other. Therefore, in the reaction tube 10, the discontinuous phase and the continuous phase do not mix with each other and are usually separated from each other. Therefore, as shown in FIG. 1 , the continuous phase, which is present continuously in a relatively large amount, exists like a "sea," and the discontinuous phase, which is present discontinuously in a relatively small amount, exists like "islands." In this regard, in the present invention, the discontinuous phase and the continuous phase form a sea-island structure in the reaction tube 10.

[0094] Exemplary embodiments of the present invention will now be described.

[0095] In the present invention, a liquid medium different from the first solvent and the second solvent is flowed into a curved reaction tube 10 to form a continuous phase. Next, a liquid containing a first substrate and the first solvent is introduced into the continuous phase. This liquid has a lower density than the continuous phase and is immiscible with the continuous phase. Therefore, as shown in FIG. 1, the liquid containing the first substrate and the first solvent forms a first droplet 1 in the reaction tube 10. The first droplet 1 moves in the direction of the liquid medium flow within the reaction tube 10 due to the flow of the liquid medium. Next, a liquid containing a second substrate and the second solvent is introduced into the continuous phase. This liquid has a lower density than the continuous phase and is immiscible with the continuous phase. Therefore, as shown in FIG. 1, the liquid containing the second substrate and the second solvent forms a second droplet 2 in the reaction tube 10. The second droplet 2 moves in the direction of the liquid medium flow within the reaction tube 10 due to the flow of the liquid medium.

[0096] The first droplet 1, which travels through the reaction tube 10 prior to the second droplet 2, arrives near the apex a of the curved portion of the reaction tube 10. The first droplet 1, which has arrived near the apex a of the curved portion of the reaction tube 10, then attempts to proceed toward the recovery portion of the reaction tube 10 following the flow of the continuous phase. However, the first droplet 1 has a lower density than the continuous phase, which has a higher density than the first droplet 1. Therefore, the continuous phase in the curved portion is subjected to a force that causes it to sink downward relative to the first droplet 1 due to the action of gravity. On the other hand, the first droplet 1 in the curved portion is subjected to a force that causes it to float upward relative to the continuous phase. That is, due to the action of gravity, the continuous phase is positioned below the reaction tube 10, and the first droplet 1 is positioned above the reaction tube 10. Therefore, the first droplet 1 at the apex a does not flow toward the recovery portion of the reaction tube 10, which is positioned below the apex a, but remains near the apex a of the curved portion.

[0097] The first droplet 1 residing near the apex a of the reaction tube 10 then coalesces with the following second droplet 2 to form a single coalesced droplet 3. The first substrate contained in the first droplet 1 and the second substrate contained in the second droplet 2 come into contact and react, producing a product. In this way, by utilizing the action of gravity, the first droplet 1 and the second droplet 2 flowing through the reaction tube 10 can coalesce to form a single coalesced droplet 3. The liquid medium passing around the coalesced droplet 3 generates a circulating flow within the coalesced droplet, promoting contact between the first substrate and the second substrate and increasing the reaction rate.

[0098] In the present invention, even after the first droplet 1 and the second droplet 2 coalesce to form the coalesced droplet 3, the liquid medium continues to flow at a constant flow rate within the reaction tube 10. Therefore, an internal circulating flow is generated within the coalesced droplet 3 due to the shear flow of the liquid medium. The internal circulating flow is a flow that occurs within the droplet and stirs the inside of the droplet. At the portion where the droplets contact the liquid medium, the internal circulating flow is opposite to the flow direction of the liquid medium. The internal circulating flow generated in the coalesced droplet 3 can efficiently stir the inside of the coalesced droplet 3. Therefore, the reaction between the first substrate and the second substrate contained in the coalesced droplet 3 is further promoted, the reaction rate is increased, and the product can be efficiently produced. [Example]

[0099] Examples of the present invention will be described below, but the present invention is not limited thereto.

[0100] Example 1 TIFF2023118070000002.tif22115

[0101] Galden (registered trademark) (perfluoropolyether, density 1.72 g / cm) was added to the droplet reactor (reaction tube inner diameter 1 mm, length 60 cm) shown in Figure 1. 3 ) was pumped at a flow rate of 0.1 mL / min, and cyclopentadiene (17 mg, 0.27 mmol) and acrylic acid (20 mg, 0.27 mmol) were weighed into syringes and injected into the droplet reactor through the injection port. After approximately 3 minutes of continuous pumping, droplets of cyclopentadiene and acrylic acid were observed to fuse at the top of the reactor. The Galden pumping rate was maintained for 10 minutes, after which the rate was increased to 0.5 mL / min and the fused droplets were collected. 1H NMR of the fused droplets was measured, and the integrals indicated that the desired 5-norbornene-2-carboxylic acid was obtained with an 80% conversion.

[0102] Example 2 TIFF2023118070000003.tif26164

[0103] Galden (registered trademark) (perfluoropolyether, density 1.72 g / cm) was added to the droplet reactor (reaction tube inner diameter 1 mm, length 60 cm) shown in Figure 1. 3 ) was delivered at a flow rate of 0.1 mL / min, and 20 μL of a 0.5 M phenylvinyl sulfone / 0.02 M tetrakis(tetrabutylammonium)decatungstate / acetonitrile solution (density of acetonitrile: 0.78 g / cm ) was delivered from the injection port. 3 ) and γ-butyrolactone (8.6 mg, 0.1 mmol, 10 equiv) were weighed into syringes and injected into the droplet reactor. After approximately 3 minutes of Galden flow, fusion of droplets of phenylvinylsulfone and γ-butyrolactone was confirmed at the top of the reactor. The reaction was then continued for 10 minutes under UV-A black light (352 nm, 15 W) without changing the Galden flow rate. The Galden flow rate was then increased to 0.5 mL / min, and the reacted droplets were collected. The fused droplets were subjected to 1H NMR analysis, and the integrated value indicated that the desired 5-methyl-5-(2-phenylsulfonylethyl)-γ-butyrolactone was obtained at a conversion rate of 46%.

[0104] Example 3 TIFF2023118070000004.tif27164

[0105] Galden (registered trademark) (perfluoropolyether, density 1.72 g / cm) was added to the droplet reactor (reaction tube inner diameter 1 mm, length 60 cm) shown in Figure 1. 3 ) was delivered at a flow rate of 0.1 mL / min, and a 1.0 M 3-isopropoxyaniline / 0.1 M dimethylaminopyridine (DMAP) / dichloromethane solution (density of dichloromethane: 1.33 g / cm ) was injected from the injection port. 3) and 1.0 M 2-trifluoromethylbenzoic acid / 1.0 M ethyl-3-dimethylaminopropylcarbodiimide (EDC) / dichloromethane solution were each measured into syringes and injected into the droplet reactor in appropriate amounts. Galden was continued to flow, and after confirming that the droplets had fused at the top of the reactor, the reaction was continued for an appropriate reaction time without changing the Galden flow rate. The Galden flow rate was then increased to 0.5 mL / min, and the reacted droplets were collected. The fused droplets were subjected to GC analysis, and the yield of flutolanil was calculated from the integrated value. The results are shown in Table 1.

[0106] In addition, a continuous flow reactor was set up to achieve the same reaction conditions, and flutolanil synthesis was performed using a 1.0 M 3-isopropoxyaniline / 0.1 M dimethylaminopyridine (DMAP) / dichloromethane solution and a 1.0 M 2-trifluoromethylbenzoic acid / 1.0 M ethyl-3-dimethylaminopropylcarbodiimide (EDC) / dichloromethane solution. The yields were compared. The results are shown in Table 2. Similar trends were observed in the conventional flow and droplet systems, such as an increase in the reagent equivalents affecting yield improvement. It was found that droplets can predict the results of reactions in a flow format (i.e., flow synthesis).

[0107] [Table 1]

[0108] [Table 2]

[0109] Example 4 TIFF2023118070000007.tif28164 Galden (registered trademark) (perfluoropolyether, density 1.72 g / cm) was added to the droplet reactor (reaction tube inner diameter 1 mm, length 10 cm) shown in Figure 1. 3 ) was delivered at a flow rate of 0.1 mL / min, and carbon monoxide (gas), 1.0 M 2-trifluoromethyliodobenzene, 1.0 M 3-isopropoxyaniline / 0.5 M bis(dibenzylidene)palladium / 0.5 M Xantphos / 2.0 M triethylamine / dimethylformamide solution (density, 0.94 g / cm) was delivered from the inlet. 3 ) were weighed into syringes and injected into the droplet reactor in the following order: carbon monoxide, reaction solution, carbon monoxide. Galden was continued to be pumped, and after confirming that each droplet was waiting at the top of the reactor, the reaction was allowed to proceed for the appropriate reaction time. The Galden pumping rate was then increased to 0.5 mL / min, and the reacted droplets were collected. These droplets were subjected to GC analysis, and the integral value indicated a 10% yield of flutolanil. [Industrial Applicability]

[0110] The present invention is useful as an interface tool for linking the results of computational science with organic synthesis and adding them to industrial production using flow reactors. [Explanation of symbols]

[0111] 100 Reactor 10 reaction tubes 20 Supply section 30 Collection Department 40 Catalyst layer 50 filters 1. First Droplet 2. Second Droplet 3 Combined Droplets 4. Third Droplet 5. 4th Droplet 6. 5th Droplet a) Top of reaction tube

Claims

1. A reactor having a reaction tube for carrying out a reaction of at least two kinds of substrates in a flow manner, forming an islands-in-a-sea structure in a reaction tube, the islands-in-a-sea structure comprising: (i) a discontinuous phase comprising a first droplet containing a first substrate or a first substrate and a first solvent, and a second droplet containing a second substrate or a second substrate and a second solvent; and (ii) a continuous phase containing no substrate and a liquid medium; A reaction apparatus in which the reaction tube is curved, and at least one vertex of the reaction tube is located in the direction in which gravity acts or in the direction opposite to the direction in which gravity acts relative to both the inlet and outlet positions of the reaction tube, and the first droplet and the second droplet merge due to the action of gravity to form a single merged droplet, and the first substrate and the second substrate come into contact and react.

2. a reaction tube extending in a direction opposite to the direction of gravity is curved in the direction of gravity, and the density of the liquid medium is greater than the densities of the first and second droplets, so that the first and second droplets are positioned above the liquid medium due to the action of gravity; or 2. The reactor according to claim 1, wherein the reaction tube extending in the direction in which gravity acts is curved in the direction opposite to the direction in which gravity acts, the density of the liquid medium is lower than the densities of the first droplet and the second droplet, and the first droplet and the second droplet are positioned below the liquid medium due to the action of gravity.

3. the low-density liquid used as the first solvent, the second solvent, or the liquid medium is at least one non-fluorine-containing compound selected from the group consisting of alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water; 3. The reaction apparatus according to claim 1 or 2, wherein the high-density liquid used as the first solvent, the second solvent, or the liquid medium is at least one compound selected from the group consisting of fluorine-containing compounds, ionic liquids, halogen-containing solvents, alcohols, ethers, carboxylic acids, esters, amides, ketones, nitriles, halogen-containing solvents, aromatic solvents, petroleum-based solvents, and water.

4. 3. The reactor of claim 1 or 2, wherein the first droplet is a liquid or a gas and the second droplet is a liquid or a gas.

5. 3. The reactor of claim 1 or 2, wherein in addition to the first and second droplets, one or more further droplets form the discontinuous phase.

6. 3. The reactor of claim 1 or 2, wherein a third droplet comprising a third substrate or comprising a third substrate and a third solvent forms a discontinuous phase in addition to the first and second droplets.

7. 3. The reactor according to claim 1, wherein the first droplet and the second droplet are united at the top of the bent portion of the tube to form a coalesced droplet, and a liquid medium passes around the coalesced droplet, thereby generating a circulating flow in the coalesced droplet and promoting contact between the first substrate and the second substrate.

8. 3. The reactor according to claim 1, wherein the reaction is an organic reaction, an inorganic reaction, or a biochemical reaction.

9. 3. The reactor according to claim 1, wherein the inner diameter of the tube is 0.1 to 10 mm, and the size (diameter) of the droplets is 0.05 to 10 mm.

10. 3. The reaction apparatus according to claim 1, wherein the reaction tube is curved in a direction opposite to the direction of travel of the reaction tube (downward or upward), the curve is arc-shaped, and the apex of the curve of the reaction tube is located 1 cm to 50 cm away from the start position of the curve.

11. 3. The reactor of claim 1, wherein the reaction tube changes from a first straight shape to a curved shape to a second straight shape, the first straight shape being substantially parallel to the second straight shape.

12. 3. The reactor of claim 1 or 2, comprising a catalyst within the reaction tube.

13. The reactor comprises: a supply section for supplying a liquid medium, a first droplet, and a second droplet; a reaction section consisting of a reaction tube; and 3. The reaction apparatus according to claim 1, further comprising a recovery section for recovering the reaction product.

14. A reaction tube in which at least two kinds of substrates are reacted in a flow manner, forming an islands-in-a-sea structure in a reaction tube, the islands-in-a-sea structure comprising: (i) a discontinuous phase comprising a first droplet containing a first substrate or a first substrate and a first solvent, and a second droplet containing a second substrate or a second substrate and a second solvent; and (ii) a continuous phase containing no substrate and a liquid medium; A reaction tube in which the reaction tube is curved, and at least one vertex of the reaction tube is located in the direction in which gravity acts or in the direction opposite to the direction in which gravity acts relative to both the inlet and outlet positions of the reaction tube, and the first droplet and the second droplet come together by the action of gravity to form a single combined droplet, and the first substrate and the second substrate come into contact and react.

15. The reaction apparatus according to claim 1 or the reaction tube according to claim 14, providing a liquid medium; providing droplets; and Reacting at least two types of substrates A method for producing a reaction product comprising:

16. A reaction prediction method, comprising reacting at least two types of substrates in a flow manner in the reaction apparatus according to claim 1 or the reaction tube according to claim 14.

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