Catalyst mixture for flow reactions

Abstract

Provided is a catalytic mixture with sufficient catalytic efficiency, wherein pressure loss is small when the catalytic mixture fills a flow reactor and a reactive solution is caused to flow therethrough, and the catalytic efficiency and the small pressure loss are maintained even after a long-term flow reaction.　The catalytic mixture is used to fill a flow reactor and contains (A) a transition metal catalyst that is supported in a carrier and that catalyzes a chemical reaction and (B) a filling agent that does not interfere with the chemical reaction. The filling agent is a polysaccharide.

Description

[Technical field]

[0001] The present invention relates to a catalyst mixture for use in a flow reaction, and to a reaction using the same. [Background technology]

[0002] In industrial organic synthesis reactions for producing organic compounds such as medicines, food additives, pesticides, and plastic materials, batch-type manufacturing methods are predominant, in which a chemical reaction proceeds while stirring a solution containing raw materials in a reaction tank. As another method, synthesis using a flow reaction, in which a chemical reaction is carried out while continuously flowing a solution containing raw materials, has also been attempted. Synthesis using a flow reaction is excellent in environmental compatibility, reaction efficiency, and safety, and allows the target product to be synthesized continuously and efficiently.

[0003] Flow reactions can also be applied to reactions using heterogeneous catalysts such as metal particles. One method involves filling a column arranged in a flow path with a heterogeneous catalyst and passing the reaction liquid through it to carry out the reaction. The disadvantage of this method is that the catalyst may flow out or deteriorate over a long period of time during the flow reaction, reducing the reaction efficiency. In addition, the packed catalyst may obstruct the flow of the reaction liquid, causing pressure loss. If the pressure loss is large, the reaction efficiency decreases, and the load on the pump and reactor increases, requiring expensive pressure-resistant equipment, which is not industrially preferable.

[0004] Various attempts have been made to improve the efficiency of flow reactions using heterogeneous catalysts. Patent Document 1 discloses a flow synthesis system in which a column is packed with a catalyst that is immobilized on a carrier. Non-Patent Document 1 discloses a flow-type reaction in which a polydimethylsilane-supported palladium catalyst (DMPSi-Pd) is diluted with Al2O3, SiO2, or the like, and the resulting DMPSi-Pd / support is packed in a column. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2016 / 143637 [Non-patent literature]

[0006] [Non-Patent Document 1] Osamu Kobayashi and 3 others, ChemistryOpen, (EU), 2017, Vol. 6, pp. 211-215 Summary of the Invention [Problem to be solved by the invention]

[0007] A catalyst for flow reactions that can solve one or more of the drawbacks or problems in the prior art described above is desired. Therefore, an object of the present disclosure is to provide a catalyst mixture that has sufficient catalytic efficiency, has a small pressure drop when filled in a flow reactor and flows a reaction liquid therethrough, and can maintain the catalytic efficiency and small pressure drop even after a long-term flow reaction. [Means for solving the problem]

[0008] In view of the above-mentioned circumstances, the present inventors have conducted extensive research and discovered that high catalytic efficiency and low pressure loss can be achieved by mixing a catalyst supported on a carrier with a filler (diluent) and using the mixture as a catalyst mixture, and that in particular, when polysaccharides are used as the filler, catalytic efficiency and low pressure loss can be maintained even after a long-term flow reaction. Based on this knowledge, the present inventors have completed the present invention.

[0009] That is, in one aspect, the present invention is as follows.

[0010] [1] A catalyst mixture used by filling a flow reactor, (A) A transition metal catalyst supported on a support that catalyzes a chemical reaction (B) a filler that does not interfere with the chemical reaction wherein the filler is a polysaccharide. [2] The catalytic mixture according to claim 1, wherein the polysaccharide is cellulose or starch. [3] The catalytic mixture according to claim 1 or 2, wherein the polysaccharide is cellulose. [4] The catalyst mixture according to any one of [1] to [3], wherein the weight percentage of the component (B) relative to the weight of the component (A) is 20 to 200% by weight. [5] The catalyst mixture according to any one of [1] to [4], wherein the transition metal catalyst is a platinum group metal, a copper group metal, or an iron group metal. [6] The catalyst mixture according to any one of [1] to [4], wherein the transition metal catalyst is a platinum group metal. [7] The catalyst mixture according to any one of [1] to [4], wherein the metal of the transition metal catalyst is platinum or palladium. [8] The catalyst mixture according to any one of [1] to [7], wherein the transition metal catalyst supported on a carrier is platinum supported on carbon or palladium supported on carbon. [9] The catalyst mixture according to any one of [1] to [8], wherein the polysaccharide is in a powder form and has an average particle size of 10 to 50 μm.

[10] The catalyst mixture according to any one of [2] to [8], wherein the cellulose is in a powder form and has an average particle size of 10 to 50 μm.

[11] The catalyst mixture according to any one of [1] to

[10] above, wherein the reaction catalyzed by the transition metal catalyst is a hydrogenation reaction or a hydrocracking reaction.

[12] The catalyst mixture according to any one of [1] to

[10] , wherein the reaction catalyzed by the transition metal catalyst is a dehydrogenation reaction, an oxidation reaction, or a coupling reaction.

[13] A tubular flow reactor packed with the catalyst mixture according to any one of [1] to

[10] .

[14] A process comprising a flow reactor having the catalyst mixture according to any one of [1] to

[10] , the flow reactor being one or more tubular flow reactors.

[15] A process comprising a flow reactor having the catalyst mixture according to any one of [1] to

[10] , the flow reactor being one or two tubular flow reactors.

[16] A tubular flow reactor having the catalyst mixture according to any one of

[13] to

[15] , wherein the equivalent diameter of the tube is 5 mm to 150 mm.

[17] A tubular flow reactor having the catalyst mixture according to any one of

[13] to

[15] , wherein the equivalent diameter of the tube is 5 mm to 50 mm.

[18] A tubular flow reactor having the catalyst mixture according to any one of

[13] to

[15] , wherein the equivalent diameter of the tube is 5 mm to 20 mm.

[19] A method comprising using a tubular flow reactor having the catalyst mixture according to any one of

[13] to

[18] above, the length of the tube being 5 mm to 1000 mm.

[20] A method comprising using a tubular flow reactor having the catalyst mixture according to any one of

[13] to

[18] above, the length of the tube being 5 mm to 500 mm. 〔twenty one〕 A method comprising using a tubular flow reactor having the catalyst mixture according to any one of

[13] to

[18] above, the length of the tube being 5 mm to 150 mm. 〔twenty two〕 A method for carrying out a hydrogenation reaction or a hydrocracking reaction using a flow reactor filled with the catalyst mixture according to any one of [1] to

[10] . 〔twenty three〕 A method for converting a nitro group into an amino group by flowing a compound having a nitro group and hydrogen through a flow reactor having the catalyst mixture according to any one of [1] to

[10] . 〔twenty four〕 A method for converting a benzyloxy group into a hydroxy group by hydrogenolysis by passing a compound having a benzyloxy group and hydrogen through a flow reactor having the catalyst mixture according to any one of [1] to

[10] . 〔twenty five〕 A method for converting a carbonyl group into a hydroxy group or an alkyl group by passing a compound having a carbonyl group and hydrogen through a flow reactor containing the catalyst mixture according to any one of [1] to

[10] .

[26] A method for converting a formyl group into a hydroxy group or a methyl group by flowing a compound having a formyl group and hydrogen through a flow reactor having the catalyst mixture according to any one of [1] to

[10] .

[27] A method for converting an acetyl group into an ethyl group by passing a compound having an acetyl group and hydrogen through a flow reactor containing the catalyst mixture according to any one of [1] to

[10] .

[28] A method for converting a triple bond into a double bond or a single bond by passing a compound having a triple bond and hydrogen through a flow reactor containing the catalyst mixture according to any one of [1] to

[10] .

[29] A method for converting a double bond into a single bond by passing a compound having a double bond and hydrogen through a flow reactor containing the catalyst mixture according to any one of [1] to

[10] .

[30] A method for converting a vinyl group into an ethyl group by flowing a compound having a vinyl group and hydrogen through a flow reactor containing the catalyst mixture according to any one of [1] to

[10] .

[31] A method for converting a cyano group into an aminomethyl group by flowing a compound having a cyano group and hydrogen through a flow reactor containing the catalyst mixture according to any one of [1] to

[10] .

[32] The method according to

[23] , wherein the compound having a nitro group is a compound of the following formula (1), and the compound in which the nitro group is converted into an amino group is a compound of the following formula (2):

[0011] [ka]

[0012] (Here, R is a hydrogen atom or a chlorine atom, and preferably a chlorine atom.)

[33] The method according to

[23] , wherein the compound having a nitro group is a compound of the following formula (3), and the compound in which the nitro group is converted into an amino group is a compound of the following formula (4).

[0013] [ka]

[0014]

[34] The method according to

[24] , wherein the compound having a benzyloxy group is a compound of the following formula (5), and the compound obtained by hydrogenolysis of the benzyloxy group and converting it into a hydroxy group is a compound of the following formula (6).

[0015] [ka]

[0016]

[35] The method according to

[26] , wherein the compound having a formyl group is a compound of the following formula (7), and the compound in which the formyl group is converted into a hydroxy group is a compound of the following formula (8):

[0017] [ka]

[0018]

[36] The method according to

[27] , wherein the compound having an acetyl group is a compound of the following formula (9), and the compound in which the acetyl group is converted into an ethyl group is a compound of the following formula (10).

[0019] [ka]

[0020]

[37] The method according to

[30] , wherein the compound having a vinyl group is a compound of the following formula (11), and the compound in which the vinyl group is converted into an ethyl group is a compound of the following formula (12):

[0021] [ka]

[0022]

[38] A method comprising a flow reactor having the catalyst mixture according to any one of [1] to

[10] , the flow reactor being provided with a temperature control unit for controlling the temperature.

[39] The method according to

[38] , wherein the temperature control section provided in the flow reactor is a bath.

[40] The method according to

[38] , wherein the temperature control unit provided in the flow reactor has a set temperature of 15°C to 100°C.

[41] The method according to

[38] , wherein the temperature control unit provided in the flow reactor has a set temperature of 25°C to 80°C.

[42] A method comprising using a flow reactor having the catalyst mixture according to any one of [1] to

[10] above, wherein the solvent is one or more selected from the group consisting of aromatic hydrocarbon derivatives, nitriles, and alcohols.

[43] A method comprising a flow reactor having the catalyst mixture according to any one of [1] to

[10] , wherein a solvent for aromatic hydrocarbon derivatives, nitriles, and alcohols is one or more selected from the group consisting of toluene, acetonitrile, methanol, ethanol, and 2-propanol.

[44] A process comprising a flow reactor having the catalyst mixture according to any one of [1] to

[10] , wherein a solvent for aromatic hydrocarbon derivatives, nitriles, and alcohols is one or more selected from the group consisting of toluene, acetonitrile, and methanol. Effect of the Invention

[0023] The present disclosure provides a novel catalyst mixture. In addition, the present disclosure allows a flow-type reaction to be carried out using the catalyst mixture. The catalyst mixture of the present disclosure has a combustible filler, so that the metal catalyst can be easily recovered after the reaction is completed. The flow-type reaction using the catalyst mixture of the present disclosure is industrially advantageous because of its long catalyst life and small pressure loss. [Brief description of the drawings]

[0024] [Figure 1] Fig. 1 is a schematic diagram showing an outline of the reaction apparatus of the present invention. Hydrogen gas supplied from a supply port 1 and a substrate solution supplied from a supply port 2 are mixed in a mixer 11. The mixture is introduced into a tubular reaction vessel 12 heated by a temperature control unit 13 (e.g., a bath, a jacket, etc.) and reacted. The reaction mixture is accumulated in a vessel 3, and unreacted hydrogen gas is discharged from an outlet 4. Reference numeral 14 denotes a mass flow controller, 15 denotes a pump, 16 denotes a back pressure valve, and 17 and 18 denote pressure gauges. [Diagram 2] 2 is a graph showing the change over time in pressure on the inlet side and outlet side of the tubular reactor in Comparative Example 1. The difference between the pressure on the inlet side and the pressure on the outlet side is the pressure loss. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The present invention will be described in detail below.

[0026] The terms and symbols used in this specification are explained below.

[0027] The transition metal of the transition metal catalyst of the present invention may be any metal that catalyzes a desired chemical reaction, and known transition metals used as catalysts can be appropriately adopted. Examples of transition metals include platinum group metals (e.g., platinum (Pt), palladium (Pd), ruthenium (Ru), rhodium (Rh) and iridium (Ir), etc.), manganese group metals (e.g., manganese (Mn) and rhenium (Re), etc.), copper group metals (e.g., copper (Cu), silver (Ag) and gold (Au), etc.), and iron group metals (e.g., iron (Fe), cobalt (Co), nickel (Ni), etc.). The transition metal may be a single metal or an alloy of two or more metals. The transition metal is preferably a platinum group metal, more preferably platinum or palladium.

[0028] The support for the transition metal catalyst supported on a support may be anything that can support a transition metal, allows the catalytic reaction to proceed, and does not result in significant leakage of the catalytic metal during the reaction. Any known material used as a catalyst support can be appropriately used, and examples of such materials include carbon supports (e.g., activated carbon, carbon black, graphite, etc.), polysilanes (e.g., polydimethylsilane, polymethylphenylsilane, etc.), metal oxides (e.g., silicon oxide, aluminum oxide, silica alumina, titanium oxide, chromium oxide, etc.), etc.

[0029] Preferred examples of the transition metal catalyst supported on a carrier include palladium on carbon (Pd / C), platinum on carbon (Pt / C), and palladium on polydimethylsilane (DMPSi-Pd), and more preferred examples include palladium on carbon (Pd / C) and platinum on carbon (Pt / C).

[0030] The filler is selected so that it does not dissolve in the reaction liquid being distributed and does not interfere with the catalytic reaction. By "not interfering," the yield and conversion rate do not decrease when the filler is used compared to when the filler is not used. The filler of the present invention is a polysaccharide. By using a polysaccharide as the filler (diluent), the polysaccharide itself burns, so that the metal catalyst can be easily recovered.

[0031] In this specification, polysaccharides means starch (amylose or amylopectin and mixtures thereof), cellulose, chitin, agarose, carrageenan, pectin and derivatives thereof and mixtures thereof. The polysaccharide is not particularly limited as long as it does not interfere with the catalytic reaction and does not dissolve in the reaction solution, and any known polysaccharide can be appropriately used. Examples of polysaccharides include starch (amylose or amylopectin), cellulose, chitin, agarose, carrageenan, pectin, and derivatives thereof, preferably starch and cellulose, and more preferably cellulose. As used herein, starch is a compound in which α-glucose molecules are polymerized by glycosidic bonds. The botanical origin of starch is not limited. Suitable sources of starch are corn, pea, potato, sweet potato, sorghum, banana, barley, wheat, rice, sago, amaranth, tapioca, arrowroot, canna, and their low amylose (containing about 10% or less by weight of amylose, preferably 5% or less by weight of amylose) or high amylose (containing at least about 40% by weight of amylose) varieties. As used herein, cellulose is a compound in which β-glucose molecules are polymerized through glycosidic bonds. Examples of the derivatives include cellulose derivatives and amylose derivatives. Examples of the cellulose derivatives include alkyl cellulose, hydroxyalkyl cellulose, alkyl (hydroxyalkyl) cellulose, carboxyalkyl cellulose, acetyl cellulose, and the like. Specific examples of the cellulose derivatives include methyl cellulose, ethyl cellulose, ethyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hypromellose, carmellose, carboxymethyl ethyl cellulose, and acetyl cellulose. In this specification, powdered cellulose is also called cellulose powder. The terms powdered cellulose and cellulose powder refer to cellulose that has been processed into a powder form, and there are no particular limitations on the raw material, manufacturing method, degree of purification, etc., and any known powdered cellulose can be used as appropriate.

[0032] The shape of the polysaccharide is not particularly limited as long as it can be filled into a reaction vessel, but in one embodiment, the polysaccharide is a powdered polysaccharide. The particle size of the powdered polysaccharide is preferably larger than the particle size of the transition metal catalyst supported on the carrier. Examples of the average particle size of the polysaccharide powder include 1 to 100 μm, 1 to 80 μm, 1 to 50 μm, and 1 to 30 μm, and preferably 2 to 100 μm, 5 to 50 μm, and 10 to 50 μm. Examples of apparent specific gravity (bulk density) of powdered polysaccharides are 0.1 to 1.0 g / cm 3 , 0.1~0.8g / cm 3 , 0.1~0.6g / cm 3 , 0.1~0.5g / cm 3 , preferably 0.2 to 0.6 g / cm 3 , 0.3~0.5g / cm 3 The range includes, but is not limited to,

[0033] Examples of the ratio of the polysaccharide as a filler in the catalyst mixture include ranges of 5 to 500% by weight, 5 to 300% by weight, 5 to 200% by weight, 5 to 150% by weight, or 20 to 100% by weight, preferably 10 to 300% by weight, 20 to 200% by weight, 25 to 200% by weight, or 50 to 150% by weight, in terms of the weight % of the polysaccharide when the weight of the transition metal catalyst supported on the carrier is taken as 100% by weight.

[0034] The chemical reaction catalyzed by the transition metal catalyst can be any reaction that can be catalyzed by a transition metal catalyst, but in one embodiment, the reaction is a hydrogenation, dehydrogenation, isomerization, reduction, oxidation, hydration, or coupling reaction. In one embodiment, hydrogenation is a hydrogen addition reaction or hydrogenolysis, and includes a reaction of converting a nitro group to an amino group by hydrogenation, a method of converting a carbonyl group to a hydroxy group or an alkyl group by hydrogenation, a reaction of converting an aldehyde group to a hydroxy group or an alkyl group by hydrogenation, a reaction of converting an acetyl group to a hydroxy group or an alkyl group by hydrogenation, a reaction of converting a double bond in a group having a double bond to a single bond by hydrogenation, a reaction of converting a triple bond in a group having a triple bond to a double bond or a single bond by hydrogenation, a reaction of converting a cyano group to an aminomethylene group by hydrogenation, and a reaction of reducing an aromatic ring by hydrogenation, or a reaction of converting a benzyloxy group to a hydroxy group by hydrogenolysis, a reaction of converting a halogen group to a hydrogen atom by hydrogenolysis, and a reaction of converting a sulfonyloxy group to a hydroxy group by hydrogenolysis. The benzyloxy group is (phenyl)-CH2-O-, and the phenyl may have a substituent. In another embodiment, the reaction of converting a double bond of a group having a double bond to a single bond by a hydrogenation reaction is a reaction of converting a double bond of a group having a carbon-carbon double bond to a carbon-carbon single bond by a hydrogenation reaction, a reaction of converting an alkenyl group to an alkyl group by a hydrogenation reaction, or a reaction of converting a vinyl group to an ethyl group by a hydrogenation reaction. In yet another embodiment, the reaction of converting a triple bond of a group having a triple bond into a double bond or a single bond by a hydrogenation reaction is a reaction of converting a triple bond of a group having a carbon-carbon triple bond into a carbon-carbon double bond or a carbon-carbon single bond by a hydrogenation reaction, or a reaction of converting an alkynyl group into an alkenyl group or an alkyl group by a hydrogenation reaction. In yet another embodiment, the reaction of reducing an aromatic ring by hydrogenation is the reduction of a phenyl group to a cyclohexyl group, the reduction of a furyl group to a tetrahydrofuryl group, or the reduction of a pyrrolyl group to a pyrrolidyl group. In yet another embodiment, the coupling reaction is a Suzuki-Miyaura coupling reaction, a Negishi coupling reaction, an Ullmann reaction, a Glaser reaction, a Mizoroki-Heck reaction, a Stille coupling reaction, a Sonogashira coupling reaction, a Kumada-Tamao coupling reaction, a Tsuji-Trost coupling reaction, and a Buchwald-Hartwig reaction.

[0035] (Flow reaction) The flow reaction is a reaction in which raw materials are continuously supplied, the reaction is continuously carried out, and the reaction mixture is continuously recovered. In one embodiment, the flow reaction is a reaction using a tubular flow reactor, and the catalyst mixture is filled in the tubular reactor. In one embodiment, the flow reactor may be provided with a temperature control means for controlling the temperature of the flow reactor, for example, a temperature control unit for heating and / or cooling. The temperature control unit may be any suitable type, and examples of the temperature control unit include a bath, a jacket, and the like. Examples of the temperature setting range of the temperature control section include 15°C to 100°C, 20°C to 80°C, 25°C to 60°C, 25°C to 50°C, 25°C to 40°C, 30°C to 60°C, 30°C to 50°C, 40°C to 60°C, and preferably 25°C to 80°C. In addition, examples of the material of the flow reactor are not particularly limited as long as it is not corroded by the raw materials and the solvent, and examples thereof include metals (e.g., titanium, nickel, stainless steel, various alloys such as Hastelloy C, etc.), resins (e.g., fluororesins, etc.), glass (e.g., silicon, quartz, etc.), and ceramics (e.g., cordierite, ceramics, etc.).

[0036] In one embodiment, the tubular flow reactor may be any reactor capable of continuously flowing a liquid or gas-liquid mixture, and the cross-sectional shape of the tube may be any of a circular tube, a square tube, a polygonal tube, an elliptical tube, etc., or a combination of these shapes, but is preferably a column (circular tube) shape. There are no particular limitations on the paths for supplying raw materials to the tubes or for recovering the reaction mixture, but they can be connected by polytetrafluoroethylene (PTFE) tubes, metal tubes, or the like. The shape of the tube in the tubular flow reactor is not particularly limited, and may be, for example, straight, curved, or coiled. A preferred shape is, for example, a straight tube reactor. The tube may be one, or two or more tubes may be bundled regularly or irregularly at appropriate intervals. Alternatively, tubular reactors may be connected in series and hydrogen gas may be introduced either from the beginning or midway through the tube.

[0037] In one embodiment, the flow reactor may be provided with a back pressure control means for controlling the back pressure. For example, the back pressure can be controlled by providing a back pressure valve in the flow path on the outlet side of the tube filled with the catalyst. In one embodiment, the flow reactor may be provided with a pressure measuring means for measuring the pressure of the flow reactor, for example, pressure gauges may be provided on both the inlet and outlet sides of the tube filled with the catalyst. In one embodiment, the flow reactor may have a mixer as necessary. The mixer is not particularly limited as long as it has a function of continuously mixing two or more fluids such as a gas and a liquid or a liquid and a liquid, and examples of the mixer include a Y-shaped mixer, a T-shaped mixer, a cross-shaped mixer, and a pipeline mixer (a line mixer including a static mixer, etc.). The equivalent diameter of the tube in the tubular reactor is not particularly limited as long as it is a size that allows a liquid or gas-liquid mixture to flow continuously, but for high reaction efficiency and reduced pressure loss, it is preferably 5 mm or more per tube. Preferred examples of the equivalent diameter are 5 mm to 150 mm, 5 mm to 100 mm, 5 mm to 50 mm, more preferably about 10 mm to 150 mm, 10 mm to 100 mm, 10 mm to 50 mm, and 10 mm to 30 mm per tube. As used herein, the term "equivalent diameter (De)" refers to a value defined by the following formula. De = 4·Af / Wp (In the formula, Af represents the cross-sectional area of ​​the flow path, and Wp represents the wetted perimeter.) For example, the equivalent diameter of a cylindrical tube of radius r is De = 4 πr 2 / 2πr = 2r It becomes. The length of the tube in the tubular reactor can be appropriately set taking into consideration the equivalent diameter of the tube, the flow rate, and the time required for the reaction.

[0038] In this specification, the term "pressure loss" refers to the value obtained by subtracting the pressure on the outlet side from the pressure on the inlet side of a tube filled with a catalyst mixture in a flow reactor in a steady state (when the reaction is stable). In a flow reactor having a plurality of tubes arranged in series, the inlet pressure means the pressure before the first tube, and the outlet pressure means the pressure after the last tube. The pressure on the inlet side may be any desired pressure as long as it is less than the pressure limit of the reaction apparatus. In one embodiment, examples of the pressure on the inlet side include a range of 0.1 MPa to 10 MPa, 0.2 to 5 MPa, 0.2 to 1 MPa, and preferably 0.4 to 1.0 MPa. The pressure loss is desirably small, and is desirably less than 0.3 MPa, less than 0.2 MPa, or less than 0.1 MPa, and preferably less than 0.05 MPa. In terms of the ratio to the inlet pressure, the pressure loss is desirably less than 20%, less than 15%, or less than 10%, and preferably less than 5%.

[0039] (Hydrogenation reaction) In one embodiment, the catalyst mixture is used for a hydrogenation reaction. FIG. 1 shows an example of a reaction apparatus having a tubular flow reactor for hydrogenation, but the reaction apparatus of the present invention is not limited to this. 1, hydrogen gas supplied from a supply port 1 and a substrate solution supplied from a supply port 2 are mixed in a mixer 11. Although not shown, three or more types of raw materials and solvents may be supplied to the mixer if necessary. The mixture is introduced into a tubular reactor 12 filled with a catalytic mixture and reacted therein. The reaction mixture is collected in a vessel 3, and unreacted hydrogen gas is discharged from an outlet 4. An example of the equivalent diameter of the tube of the tubular reaction vessel 12 is preferably 5 mm or more per tube. Preferable equivalent diameters per tube include about 5 mm to 150 mm, 5 mm to 100 mm, and 5 mm to 50 mm, and more preferably about 10 mm to 150 mm, 10 mm to 100 mm, 10 mm to 50 mm, and 10 mm to 30 mm. The length of the tube of the tubular reaction vessel 12 is, for example, in the range of 50 mm to 1000 mm, 50 mm to 500 mm, 50 mm to 300 mm, and preferably 100 mm to 200 mm.

[0040] From the viewpoint of smooth progress of the reaction, it is preferable to carry out the reaction in the presence of a solvent. Examples of the solvent include, but are not limited to, the following: Aromatic hydrocarbon derivatives (e.g., benzene, toluene, xylene, chlorobenzene, dichlorobenzene, etc.); Halogenated aliphatic hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers (e.g., diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), tetrahydrofuran (THF), 1,4-dioxane, monoglyme, diglyme, etc.), Alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, t-butanol, etc.), Amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), etc.); Sulfoxides (e.g., dimethyl sulfoxide (DMSO) etc.), Nitriles (e.g., acetonitrile, etc.), and Any combination of them in any proportion.

[0041] Preferred examples include toluene, acetonitrile, methanol, ethanol, 2-propanol, and any combination thereof in any proportion, and more preferred examples include toluene, acetonitrile, methanol, and any combination thereof in any proportion.

[0042] In order to suppress the pressure rise during the reaction, an additive can be used. However, as can be seen from the examples in this specification, the effect of the present invention can be essentially obtained by using a polysaccharide as a packing material. Those skilled in the art can appropriately decide whether or not to use an additive. Examples of additives include water, formic acid, and acetic acid. Examples of the amount of additive used include an equivalent (eq.) relative to the number of moles of the substrate in the range of 0 (zero) to 10, 0 to 5.0, or 0 to 3.0, preferably 0.05 to 10, 0.1 to 5.0, or 0.1 to 3.0, and more preferably 0.1 to 1.0 equivalents.

[0043] Examples of the substrate concentration to be delivered include ranges of 0.1 to 5.0 mol / L, 0.1 to 3.0 mol / L, 0.1 to 2.0 mol / L, and 0.1 to 1.5 mol / L, but the substrate concentration can be appropriately adjusted by those skilled in the art.

[0044] In the reaction apparatus illustrated in FIG. 1, the flow rate of hydrogen gas is controlled by a mass flow controller 14 , and the flow rate of the substrate solution is controlled by a pump 15 . The total equivalent (eq.) of hydrogen gas relative to the number of moles of the substrate is preferably 1 or more, and may be in the range of 1.0 to 10, 1.0 to 7, 1.0 to 5, or 1.0 to 3.0, preferably 1.1 to 6.0. Formates may be used as hydrogen equivalents. Preferred examples of formates include, but are not limited to, formic acid, formate salts (e.g., sodium formate, potassium formate, ammonium formate, etc.), formate esters (e.g., methyl formate, ethyl formate, etc.), and the like.

[0045] The tubular reaction vessel 12 can be heated by a temperature control unit 13 (for example, a bath, a jacket, etc.). Examples of the set temperature of the temperature control unit (e.g., bath, jacket, etc.) include ranges of 15°C to 100°C, 20°C to 80°C, 25°C to 60°C, 25°C to 50°C, 25°C to 40°C, 30°C to 60°C, 30°C to 50°C, 40°C to 60°C, and preferably 25°C to 80°C. The inlet pressure can be measured by pressure gauge 17, and the outlet pressure can be measured by pressure gauge 18, and the back pressure can be controlled by back pressure valve 16. Examples of the pressure on the inlet side include a range of 0.1 MPa to 10 MPa, 0.2 to 5 MPa, 0.2 to 1 MPa, and preferably 0.4 to 1.0 MPa.

[0046] Unless otherwise indicated, numbers expressing quantities, sizes, concentrations, reaction conditions, and the like used herein are understood to be modified by the term "about." In some aspects, the disclosed numerical values ​​are interpreted based on the number of reported significant digits and by applying ordinary rounding techniques. In some aspects, the disclosed numerical values ​​are interpreted to include errors necessarily resulting from the standard deviation found in their respective testing measurement methods.

[0047] In this specification, room temperature is between 15°C and 30°C.

[0048] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0049] In the present specification, the following instruments and conditions were used for the analyses of the Examples and Comparative Examples.

[0050] The reaction was carried out using a flow-type reaction vessel (KeyChem-H (registered trademark) manufactured by YMC Corporation) shown in Fig. 1. A substrate solution was delivered from a supply port 2 using a single plunger pump 15, and hydrogen gas, the hydrogen source of which was a hydrogen storage alloy canister (YMH-500LF manufactured by YMC Corporation) or a hydrogen cylinder, was supplied from a supply port 1 with its flow rate adjusted by a mass flow controller 14. The substrate solution and hydrogen gas were mixed in a mixer 11 and introduced into a column-type reaction vessel 12 heated by a temperature control unit 13. The column-type reaction vessel 12 was filled with a catalyst mixture in advance. The pressure at the column inlet side was adjusted by a back pressure valve 16. The reaction mixture was accumulated in a container 3 capable of discharging unreacted hydrogen gas, and the reaction mixture was analyzed by high performance liquid chromatography. The lines connecting each flow path used PTFE tubes with a diameter of 1.0 mm and lengths of 10 mm to 1000 mm.

[0051] (High Performance Liquid Chromatography) Instrument: 1260 Infinity (Agilent Technologies) or LC-2010C (Shimadzu)

[0052] In the examples and comparative examples, the following products were used as polysaccharides. (1) KC Flock (registered trademark), W-400G (manufactured by Nippon Paper Industries Co., Ltd.) Powdered cellulose Average particle size: approx. 24μm (2) KC Flock (registered trademark), W-400Y (manufactured by Nippon Paper Industries Co., Ltd.) Powdered cellulose Average particle size: approx. 24μm (3) Manufactured by Serva Electrophoresis GmbH, sold by Fujifilm Wako Pure Chemical Industries, Ltd., manufacturer code 14205.02 Microcrystalline Cellulose Average particle size: approx. 20μm The above-mentioned crystalline cellulose is a type of powdered cellulose that has been refined to a high purity. (4) Starch (soluble), (Sold by Fujifilm Wako Pure Chemical Industries, Ltd., product code: 193-09925) Average particle size: approx. 15μm

[0053] Example 1 Hydrogenation of 3-chloro-N-(4-methoxyphenyl)-2-nitroaniline (CMNA)

[0054] [ka]

[0055] 1%Pt / C (water content 57%, 2.56g, 0.056mmol as Pt, N.E. Chemcat Corporation, product name: STAF-1M) and cellulose powder (2.56g, 100wt% for 1%Pt / C, Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400G) were mixed in advance and packed into a column-type reaction vessel (YMC Corporation) with a diameter of 10mm and a length of 100mm, connected with a PTFE tube, and placed in a bath adjusted to 80℃. A 1.01mol / l CMNA toluene solution (CMNA 27.9g, 0.1mol + toluene 65.0g, 0.75L / mol) was pumped at room temperature at a flow rate of 0.2ml / min. At the same time, hydrogen gas was introduced at a set rate of 16 ml / min (3.5 eq.) and the column inlet pressure was adjusted to 0.4 to 1.0 MPa using a back pressure valve, and the gas and liquid were mixed while being introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. As a result, the conversion rate was maintained at 97% or more for up to 36 hours. During this time, the pressure loss between the inlet and outlet of the column-type reaction vessel was 0.05 MPa or less.

[0056] Comparative Example 1 1% Pt / C (water content 57%, 2.56g, 0.056mmol as Pt, N.E. Chemcat Corporation, product name: STAF-1M) was packed into a column-type reaction vessel (YMC Corporation) with a diameter of 10mm and a length of 50mm, and the column-type reaction vessel was connected with a PTFE tube as described above and placed in a bath adjusted to 80℃. A 1.01mol / l CMNA toluene solution (CMNA 27.9g, 0.1mol + toluene 65.0g, 0.75L / mol) was pumped at a flow rate of 0.2ml / min at room temperature. At the same time, hydrogen gas was introduced at a set value of 14ml / min (3.1eq.), and the column inlet pressure was adjusted to 0.4MPa to 1.0MPa with a back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. As a result, the conversion rate was 97% or more up to 0.5 hours. However, after that, the conversion rate dropped to less than 97%. Figure 2 shows the change in pressure at the inlet and outlet of the column-type reaction vessel. A pressure loss of 0.3 MPa to 0.4 MPa was confirmed.

[0057] Comparative Example 2 1%Pt / C (water content 57%, 2.65g, 0.058mmol as Pt, manufactured by N.E. Chemcat Corporation, product name: STAF-1M) and activated clay (2.65g, 100wt% relative to 1%Pt / C) were mixed in advance, and then filled into a column-type reaction vessel (manufactured by YMC Corporation) with a diameter of 10mm and a length of 150mm, and the reaction was carried out under the same conditions as in Example 1. As a result, at the start of the reaction, the conversion rate was 97% or more, and the pressure loss at the inlet and outlet sides of the column-type reaction vessel was 0.05MPa or less. However, it was confirmed that the conversion rate decreased over time, and the reaction was not stable.

[0058] Comparative Example 3 1%Pt / C (water content 55.5%, 2.54g, 0.058mmol as Pt, manufactured by N.E. Chemcat Corporation, product name: STAF-1M) and silica gel (2.54g, 100wt% relative to 1%Pt / C, manufactured by Kanto Chemical Co., Ltd., product name: Silica Gel 60N) were mixed in advance and then filled into a column-type reaction vessel (manufactured by YMC Corporation) with a diameter of 10mm and a length of 100mm, and the reaction was carried out under the same conditions as in Example 1. As a result, the conversion rate was maintained at 97% or more for up to 4 hours. However, the pressure loss increased with time, and the inlet pressure exceeded 1MPa, so the operation was stopped.

[0059] Comparative Example 4 1%Pt / C (water content 57%, 1.51g, 0.033mmol as Pt, N.E. Chemcat Corporation, product name: STAF-1M) and alumina (1.51g, 100wt% for 1%Pt / C) were mixed in advance and packed into a column-type reaction vessel (YMC Corporation) with a diameter of 10mm and a length of 50mm, connected to the column-type reaction vessel with a PTFE tube and placed in a bath adjusted to 60℃. A 1.01mol / l CMNA toluene solution (CMNA 27.9g, 0.1mol + toluene 65.0g, 0.75L / mol) was pumped at room temperature at a flow rate of 0.2ml / min. At the same time, hydrogen gas was introduced at a set rate of 16 ml / min (3.5 eq.), and the column inlet pressure was adjusted to 0.4 to 1.0 MPa using the back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. As a result, the conversion rate was 97% or more at the start of the reaction, and the pressure loss at the inlet and outlet sides of the column-type reaction vessel was 0.05 MPa or less. However, the conversion rate decreased over time, and the conversion rate after 9 hours was 54.6%, and after 11 hours the conversion rate had decreased to 5.1%.

[0060] Example 2 1% Pt / C (water content 55.5%, 1.85g, 0.042mmol as Pt, manufactured by N.E. Chemcat Corporation, product name: STAF-1M) and cellulose powder (0.46g, 24.9wt% relative to 1% Pt / C, manufactured by Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400Y) were mixed in advance and then packed into a column-type reaction vessel (manufactured by YMC Corporation) with a diameter of 10mm and a length of 50mm, and the reaction was carried out under the same conditions as in Example 1. As a result, the conversion rate was maintained at 98% or more for 12 hours or more.

[0061] Example 3 1% Pt / C (water content 55.5%, 2.47g, 0.056mmol as Pt, manufactured by N.E. Chemcat Corporation, product name: STAF-1M) and cellulose powder (0.13g, 5.3wt% relative to 1% Pt / C, manufactured by Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400Y) were mixed in advance and then packed into a column-type reaction vessel (manufactured by YMC Corporation) with a diameter of 10mm and a length of 50mm, and the reaction was carried out under the same conditions as in Example 1. As a result, the inlet pressure exceeded 1MPa after 50 minutes, so the operation was stopped. The conversion rate up to 50 minutes was 82.4%.

[0062] Example 4

[0063] [ka]

[0064] 1%Pt / C (water content 55.5%, 1.00g, 0.023mmol as Pt, N.E. Chemcat Corporation, product name: STAF-1M) and cellulose powder (1.00g, 100wt% for 1%Pt / C, Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400Y) were mixed in advance and packed into a column-type reaction vessel (YMC Corporation) with a diameter of 10mm and a length of 50mm. As described above, the column-type reaction vessel was connected with a PTFE tube and placed in a bath adjusted to 50℃. A CMNA acetonitrile solution adjusted to 0.50mol / l (CMNA 27.9g, 0.1mol + acetonitrile 131.3g, 1.51L / mol) was pumped at room temperature at a flow rate of 0.4ml / min. At the same time, hydrogen gas was introduced at a set rate of 27 ml / min (6 eq.), and the column inlet pressure was adjusted to 0.4 to 1.0 MPa using the back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. As a result, the conversion rate was maintained at 98% or more at the 3-hour mark.

[0065] Examples 5-7 Examples 5-7 were carried out under the same conditions as Example 4, except that the scale was changed as shown in Table 1. The results are shown in Table 1. In all of the examples, the average conversion was maintained at 98% or more during the total operating time shown in Table 1.

[0066] [Table 1]

[0067] Example 8 1%Pt / C (water content 55.5%, 8.51g, 0.194mmol as Pt, manufactured by N.E. Chemcat Corporation, product name: STAF-1M) and cellulose powder (crystalline cellulose, 8.51g, 100wt% relative to 1%Pt / C, manufactured by Serva, sold by Fujifilm Wako Pure Chemical Corporation, manufacturer code 14205.02) were mixed in advance, and then packed into a column-type reaction vessel (manufactured by YMC Corporation) with a diameter of 20mm and a length of 100mm, and the reaction was carried out under the same conditions as in Example 6. As a result, the conversion rate was maintained at 98% or more for more than 5 hours.

[0068] Example 9

[0069] [ka]

[0070] 1%Pt / C (water content 55.5%, 0.98g, 0.022mmol as Pt, manufactured by N.E. Chemcat Corporation, product name: STAF-1M) and starch (1.47g, 150wt% relative to 1%Pt / C, manufactured by Fujifilm Wako Pure Chemical Corporation, product name: Starch (soluble)) were mixed in advance and packed into a column-type reaction vessel (manufactured by YMC Corporation) with a diameter of 10mm and a length of 50mm, connected to the column-type reaction vessel with a Teflon tube and placed in a bath adjusted to 50℃. A CMNA acetonitrile solution adjusted to 0.50mol / l (CMNA 27.9g, 0.1mol + acetonitrile 131.3g, 1.51L / mol) was pumped at room temperature at a flow rate of 0.4ml / min. At the same time, hydrogen gas was introduced at a set value of 27 ml / min (6 eq.), and the pressure at the column inlet side was adjusted to 0.4 MPa to 1.0 MPa using the back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. As a result, the conversion rate was maintained at 98% or more at the 4-hour point. At this time, the pressure loss at the inlet and outlet sides of the column-type reaction vessel was 0.07 MPa or less.

[0071] Hydrogenolysis of the benzyl group in benzyl ether derivatives (ISAMe-Bn) of methyl 6-[1-(N-methoxyimino)ethyl]salicylate (ISAMe) Example 10

[0072] [ka]

[0073] 10% Pd / C (water content 55%, 1.80 g, 0.761 mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and cellulose powder (0.75 g, 41.7% relative to 10% Pd / C, manufactured by Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400G) were mixed in advance and then packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10 mm and a length of 50 mm. The column-type reaction vessel was connected to a hydrogenation reactor (manufactured by YMC Co., Ltd.) with a PTFE tube and placed in a water bath adjusted to 30°C. A 0.15 mol / l ISAME-Bn solution (50 wt% ISAME-Bn toluene solution 31.3 g, 0.05 mol + methanol 233.7 g, 5.90 L / mol + formic acid 0.46 g, 0.2 eq.) was pumped at room temperature at a flow rate of 1.5 ml / min. At the same time, hydrogen gas was introduced at a flow rate of 6 ml / min (1.1 eq.), and the column inlet pressure was adjusted to 0.4 to 1.0 MPa with a back pressure valve. The gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. The conversion rate after 3 hours was 92.5%. At this time, the pressure loss between the inlet and outlet of the column-type reaction vessel was 0.05 MPa or less.

[0074] Comparative Example 5 10% Pd / C (water content 55%, 3.39 g, 1.433 mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) was packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10 mm and a length of 50 mm. The reaction was carried out under the same conditions as in Example 10 except for the above. As a result, the conversion rate after 3 hours was 70.5%. At this time, the pressure loss between the inlet and outlet of the column-type reaction vessel was 0.10 MPa.

[0075] Example 11 10% Pd / C (moisture content 55%, 1.59g, 0.672mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and cellulose powder (0.66g, 41.5% as 10% Pd / C, Nippon Paper Industries Co., Ltd., product name: KC Floc, W-400G) were mixed in advance and then packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10mm and a length of 50mm. Similarly, 10% Pd / C (moisture content 55%, 1.82g, 0.770mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and cellulose powder (0.76g, 41.8% as 10% Pd / C, Nippon Paper Industries Co., Ltd., product name: KC Floc, W-400G) were mixed in advance and then packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10mm and a length of 50mm. The two column-type reaction vessels were connected with a PTFE tube, and the reaction was carried out under the same conditions as in Example 9 except for the conditions in Table 2. As a result, the average conversion rate was maintained at 99% or more after a total operation time of 60 hours.

[0076] [Table 2]

[0077] Hydrogenation of 2-[(4,6-dimethoxypyrimidin-2-yl)hydroxymethyl]-6-methoxymethyl-nitrobenzene (NPA) Example 12

[0078] [ka]

[0079] 10% Pd / C (water content 55%, 1.74g, 0.736mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and cellulose powder (0.73g, 42.0% relative to 10% Pd / C, manufactured by Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400Y) were mixed in advance and packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10mm and a length of 50mm. The column-type reaction vessel was connected to a hydrogenation reactor (manufactured by YMC Co., Ltd.) with a PTFE tube and placed in a water bath adjusted to 60°C. An NPA solution adjusted to 0.18mol / l (NPA 33.53g, 0.1mol + acetonitrile 416.02g, 5.29L / mol) was pumped at room temperature at a flow rate of 0.8ml / min. At the same time, hydrogen gas was introduced at a set value of 11 ml / min (3.5 eq.), and the column inlet pressure was adjusted to 0.4 MPa to 1.0 MPa using the back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. As a result, the conversion rate after 4 hours was 90.6%. At this time, the pressure loss between the inlet and outlet of the column-type reaction vessel was 0.05 MPa or less.

[0080] Comparative Example 6 10% Pd / C (water content 55%, 2.05 g, 0.867 mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and silica gel (0.86 g, 42.0 wt% relative to 1% Pt / C, Kanto Chemical Co., Ltd., product name: Silica Gel 60N) were mixed in advance and then packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10 mm and a length of 50 mm. The reaction was carried out under the same conditions as in Example 12 except for this, and the conversion rate after 4 hours was 71.5%. At this time, the pressure loss on the inlet and outlet sides of the column-type reaction vessel was 0.05 MPa or less.

[0081] Example 13

[0082] Hydrogenation of benzaldehyde

[0083] [ka]

[0084] 10% Pd / C (water content 55%, 1.63 g, 0.689 mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and cellulose powder (0.68 g, 41.7% relative to 10% Pd / C, manufactured by Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400Y) were mixed in advance and packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10 mm and a length of 50 mm. The column-type reaction vessel was connected to a hydrogenation reactor (manufactured by YMC Co., Ltd.) with a Teflon tube and placed in a water bath adjusted to 40°C. A benzaldehyde solution adjusted to 0.5 mol / l (benzaldehyde 10.6 g, 0.1 mol + methanol 149.6 g, 1.89 L / mol) was pumped at room temperature at a flow rate of 0.7 ml / min. At the same time, hydrogen gas was introduced at a set value of 8 ml / min (1.0 eq.), and the column inlet pressure was adjusted to 0.1 MPa to 1.0 MPa using the back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by gas chromatography. As a result, the conversion rate after 4 hours was 98.7%. The pressure loss between the inlet and outlet of the column-type reaction vessel after 4 hours was 0.02 MPa.

[0085] Example 14

[0086] Hydrogenation of Acetophenone

[0087] [ka]

[0088] 10% Pd / C (water content 55%, 1.63 g, 0.689 mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and cellulose powder (0.68 g, 41.7 wt% relative to 10% Pd / C, manufactured by Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400Y) were mixed in advance and packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10 mm and a length of 50 mm. The column-type reaction vessel was connected to a hydrogenation reactor (manufactured by YMC Co., Ltd.) with a Teflon tube and placed in a water bath adjusted to 70°C. An acetophenone solution adjusted to 0.5 mol / l (acetophenone 12.0 g, 0.1 mol + methanol 149.9 g, 1.89 L / mol) was pumped at room temperature at a flow rate of 0.4 ml / min. At the same time, hydrogen gas was introduced at a set value of 27 ml / min (6.0 eq.), and the pressure at the column inlet side was adjusted to 0.1 MPa to 1.0 MPa using the back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by high performance liquid chromatography. As a result, the conversion rate after 4 hours was 99.7%. At this time, the pressure loss between the inlet and outlet sides of the column-type reaction vessel was 0.15 MPa or less.

[0089] Example 15

[0090] Hydrogenation of styrene

[0091] [ka]

[0092] 10% Pd / C (water content 55%, 1.76g, 0.744mmol as Pd, manufactured by Tokyo Chemical Industry Co., Ltd.) and cellulose powder (0.73g, 41.7wt% relative to 10% Pd / C, manufactured by Nippon Paper Industries Co., Ltd., product name: KC Flock, W-400Y) were mixed in advance and packed into a column-type reaction vessel (manufactured by YMC Co., Ltd.) with a diameter of 10mm and a length of 50mm. The column-type reaction vessel was connected to a hydrogenation reactor (manufactured by YMC Co., Ltd.) with a Teflon tube and placed in a water bath adjusted to 40℃. A styrene solution adjusted to 0.5mol / l (styrene 10.4g, 0.1mol + methanol 148.6g, 1.88L / mol) was pumped at room temperature at a flow rate of 0.4ml / min. At the same time, hydrogen gas was introduced at a set value of 9 ml / min (2.0 eq.), and the column inlet pressure was adjusted to 0.1 MPa to 1.0 MPa using the back pressure valve, and the gas and liquid were mixed and introduced into the column-type reaction vessel. The discharged reaction mixture was analyzed by gas chromatography. As a result, the conversion rate after 4 hours was 100%. The pressure loss between the inlet and outlet of the column-type reaction vessel after 4 hours was 0.09 MPa.

[0093] In Example 1, powdered cellulose was used as the filler. A high conversion rate was maintained for a long period of time, and the pressure loss was small. Comparative Example 1 is an example in which a reaction was attempted without using a polysaccharide as a filler under substantially the same conditions as in Example 1. The pressure loss was large, and the conversion rate also decreased over time. In Comparative Example 2-4, activated clay, silica gel, and alumina were mixed instead of polysaccharides as fillers. At the beginning of the reaction, a high conversion rate and small pressure drop were obtained, but the conversion rate decreased or the pressure drop increased over time. Examples 2 and 3 are examples in which the weight ratio of the filler in the catalyst mixture was changed. Example 4 is an example in which the solvent was changed from toluene to acetonitrile. It can be seen that a high conversion rate was maintained. Examples 5 to 7 are examples in which the column diameter and flow rate were changed from Example 4. In all examples, a high conversion rate was maintained throughout the operation time. Example 8 is an example in which crystalline cellulose was used as the filler. In this example as well, a high conversion rate was maintained for a long period of time. Example 10 and Comparative Example 5 are examples in which the catalyst mixture of the present invention was applied to hydrocracking reactions. These comparisons also show that the use of the catalyst mixture of the present invention reduces pressure loss and allows for a long-term high conversion rate. Example 11 is an example in which the scale was changed from Example 10. A high conversion rate was maintained for a long period of time. Example 12 and Comparative Example 6 are examples in which the catalyst mixture of the present invention was applied to a reaction different from that of Example 1. These comparisons also show that the use of the catalyst mixture of the present invention reduces pressure loss and allows a high conversion rate to be obtained for a long period of time. [Industrial Applicability]

[0094] The present disclosure provides a catalyst mixture for efficient flow reactions. Flow reactions using the catalyst mixture of the present disclosure are industrially advantageous due to their small pressure loss and long catalyst life. Therefore, the present invention has high industrial applicability.

Claims

1. A catalyst mixture used by filling a flow reactor, (A) A transition metal catalyst supported on a carrier and catalyzing a chemical reaction (B) A filler that does not interfere with the chemical reaction. wherein the filler is a polysaccharide and the chemical reaction is a hydrogenation reaction or a hydrogenolysis reaction.

2. 2. The catalytic mixture of claim 1, wherein the polysaccharide is cellulose.

3. 3. The catalyst mixture according to claim 1, wherein the weight percentage of component (B) relative to the weight of component (A) is 20 to 200% by weight.

4. 4. The catalyst mixture according to claim 1, wherein the transition metal catalyst is a metal of the platinum group, copper group or iron group.

5. 4. The catalyst mixture according to claim 1, wherein the transition metal catalyst is a platinum group metal.

6. 4. The catalyst mixture according to claim 1, wherein the metal of the transition metal catalyst is platinum or palladium.

7. 7. The catalyst mixture according to claim 1, wherein the transition metal catalyst supported on a carrier is platinum on carbon or palladium on carbon.

8. The catalytic mixture according to claims 1 to 7, wherein the polysaccharide is in powder form and has an average particle size of 10 to 50 μm.

9. 3. The catalytic mixture according to claim 2, wherein the cellulose is in powder form and has an average particle size of 10 to 50 μm.

10. A tubular flow reactor packed with the catalyst mixture according to any one of claims 1 to 9.

11. A method for carrying out a hydrogenation reaction or a hydrocracking reaction using a flow reactor filled with the catalyst mixture according to any one of claims 1 to 9.

12. A method for converting a nitro group into an amino group by flowing a compound having a nitro group and hydrogen through a flow reactor having the catalyst mixture according to any one of claims 1 to 9.

13. A method for converting a benzyloxy group into a hydroxy group by hydrogenolysis, comprising passing a compound having a benzyloxy group and hydrogen through a flow reactor having the catalyst mixture according to any one of claims 1 to 9.

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