WO2023167325A1 - Immobilized palladium catalyst and method for producing same, and application of this catalyst to coupling reaction - Google Patents

Immobilized palladium catalyst and method for producing same, and application of this catalyst to coupling reaction Download PDF

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WO2023167325A1
WO2023167325A1 PCT/JP2023/008147 JP2023008147W WO2023167325A1 WO 2023167325 A1 WO2023167325 A1 WO 2023167325A1 JP 2023008147 W JP2023008147 W JP 2023008147W WO 2023167325 A1 WO2023167325 A1 WO 2023167325A1
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陽一 山田
振中 張
綾 大野
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国立研究開発法人理化学研究所
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Definitions

  • the present invention relates to an immobilized palladium catalyst, a method for producing the same, and its application to a continuous-flow Suzuki-Miyaura coupling reaction using the same catalyst.
  • the Suzuki-Miyaura coupling reaction is a reaction that uses a metal catalyst such as palladium to cross-couple an organoboron compound and an organohalogen compound to obtain a biphenyl derivative.
  • the reaction conditions are relatively mild and the functional group selectivity is high, so it is currently widely used in fields such as the synthesis of pharmaceuticals and agrochemicals and the production of functional materials.
  • BACKGROUND ART In recent years, research and development of recoverable and reusable heterogeneous metal catalysts have been actively carried out in order to effectively use metal resources and the like without imposing a load on the environment.
  • Patent Document 1 and Non-Patent Document 1 when a palladium catalyst fixed to silicon carbide, which is an inorganic material, and a palladium catalyst fixed to poly(4-vinylpyridine), which is an organic material, are used, Suzuki-Miyaura coupling reported to accelerate the reaction. However, these reactions are carried out in a batch system, and the desired products are not synthesized continuously.
  • a reaction that continuously obtains the target product by filling a reactor with a heterogeneous catalyst and circulating the substrate is required as a reaction system that is more environmentally friendly and resource-friendly. While the flow-type reaction has the above-mentioned advantages, there is a problem that the catalytic activity is lowered due to metal elution during the reaction.
  • Patent Document 2 a flow-type microreactor filled with a solid palladium catalyst could be applied to many coupling reactions, but there are no examples of Suzuki-Miyaura coupling reactions.
  • Non-Patent Document 2 a cartridge-type column tube was filled with a heterogeneous silica-based palladium catalyst, SiliaCat DPP-Pd, to efficiently promote the Suzuki-Miyaura coupling reaction in a short period of time (5-10 min).
  • SiliaCat DPP-Pd a heterogeneous silica-based palladium catalyst
  • the range of substrates is also limited, and there are few examples in which aryl halides with electron-donating functional groups, in particular, are applied to these reaction conditions.
  • Non-patent document 3 when investigating the application of heterogeneous silica-based palladium catalysts and heterogeneous carbon-based palladium catalysts, which are currently widely used for Suzuki-Miyaura coupling reactions, to continuous flow reactions , reported that a significant decrease in catalytic activity appeared about 1 hour after the start of the reaction.
  • Non-Patent Document 3 it was possible to use a palladium catalyst immobilized on a synthesized phosphine resin continuously for 6 hours or more, but it was possible to suppress the oxidation of the phosphine ligand during the reaction. was difficult, and the activity and stability of the catalyst were greatly affected by the oxidation state of the phosphine.
  • Non-Patent Document 4 a triphenylphosphine structure was introduced into a crosslinked polymer material and developed as a ligand for immobilizing palladium species. Using this catalyst, we succeeded in the cross-coupling reaction of 4-chlorotoluene and phenylboronic acid under continuous flow conditions. not In addition, as mentioned in the literature, phosphine compounds are easily oxidized under Suzuki-Miyaura coupling reaction conditions, making it difficult to use the developed catalyst for long-term continuous flow reactions. Therefore, the development of an immobilized palladium catalyst that is not oxidized during the reaction and is easy to handle in the air is desired.
  • the object of the present invention is to develop a highly durable and highly active metal catalyst that is suitable for continuous-flow organic synthesis reactions.
  • the present inventors have developed a method for improving the dispersibility and stability of metal species in polymer carriers. That is, as a material for immobilizing a catalyst, a copolymer (copolymer) composed of a repeating unit containing a substituted aromatic hydrocarbon ring and a repeating unit containing a nitrogen-containing aromatic heterocycle was developed.
  • Non-Patent Document 5 by the molecular entanglement method reported in Non-Patent Document 5, by immobilizing palladium on the same copolymer to make an immobilized palladium catalyst, the dispersibility and stability of palladium can be improved, and durability It was found that this compound is excellent in catalysis and can catalyze the Suzuki-Miyaura cross-coupling reaction with high activity. Based on such findings, the present invention has been completed. Furthermore, the same catalyst can catalyze the Suzuki-Miyaura cross-coupling reaction not only in organic solvents but also in aqueous solvents.
  • the gist of the present invention is as follows. [1] (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I), and (B) a repeating unit containing a nitrogen-containing aromatic heterocycle represented by the following formula (II) a copolymer consisting of palladium, An immobilized palladium catalyst comprising a complex consisting of:
  • R A1 represents hydrogen or an alkyl group
  • R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent
  • R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent
  • LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mA is an integer greater than or equal to 0
  • nA is an integer greater than or equal to 1
  • the upper limit of mA + nA is the number of possible replacements of the cyclic structure
  • * represents the binding position
  • Ring A represents an aromatic hydrocarbon ring;
  • R B1 represents hydrogen or an alkyl group
  • RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent
  • L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mB is an integer greater than or equal to 0; The upper limit of mB is the number of possible substitutions of the cyclic structure; * represents the binding position; Ring B represents a nitrogen-containing aromatic heterocycle.
  • R A3 is a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, octyl group, phenyl group, methoxy group, ethoxy group, propoxy group, or butoxy group [1] or [2]
  • the immobilized palladium catalyst according to any one of [1] to [4] which is for continuous flow reaction.
  • one aspect of the present invention relates to the following. Use of the immobilized palladium catalyst according to any one of [1] to [4] as a continuous flow reaction catalyst.
  • the immobilized palladium catalyst according to any one of [1] to [5] which is for Suzuki-Miyaura cross-coupling reaction.
  • one aspect of the present invention relates to the following.
  • a catalyst composition comprising the catalyst according to any one of [1] to [6].
  • [8] (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I), and (B) a repeating unit containing a nitrogen-containing aromatic heterocycle represented by the following formula (II) copolymer.
  • R A1 represents hydrogen or an alkyl group
  • R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A1 is independent
  • R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A2 is independent
  • LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mA is an integer greater than or equal to 0
  • nA is an integer greater than or equal to 1
  • the upper limit of mA + nA is the number of possible replacements of the cyclic structure
  • * represents the binding position
  • Ring A represents an aromatic hydrocarbon ring;
  • R B1 represents hydrogen or an alkyl group
  • RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent
  • L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mB is an integer greater than or equal to 0; The upper limit of mB is the number of possible substitutions of the cyclic structure; * represents the binding position; Ring B represents a nitrogen-containing aromatic heterocycle.
  • R A1 represents hydrogen or an alkyl group
  • R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent
  • R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent
  • LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mA is an integer greater than or equal to 0
  • nA is an integer greater than or equal to 1
  • the upper limit of mA + nA is the number of possible substitutions of the cyclic structure
  • * represents the binding position
  • Ring A represents an aromatic hydrocarbon ring;
  • R C1 represents hydrogen or an alkyl group
  • R C2 represents an inert group or atom that does not participate in the catalytic reaction, and each R C2 is independent
  • L C represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mC is an integer greater than or equal to 0
  • nC is an integer greater than or equal to 1
  • the upper limit of mC + nC is the number of substitutable cyclic structural moieties
  • * represents the binding position
  • Ring C represents an aromatic hydrocarbon ring.
  • one aspect of the present invention relates to the following.
  • a method for producing a polycyclic aromatic compound comprising a step of reacting an aromatic halide and an aromatic boron compound to produce a polycyclic aromatic compound by Suzuki-Miyaura cross-coupling reaction.
  • the present invention provides a novel catalyst immobilizing material and an immobilized palladium catalyst immobilized on the same material.
  • the present invention also provides a novel Suzuki-Miyaura cross-coupling method using the catalyst of the present invention.
  • the present invention provides a novel method for producing a polycyclic aromatic compound using the catalyst of the present invention.
  • the catalyst of the present invention has excellent durability and high catalytic activity in the Suzuki-Miyaura cross-coupling reaction, and in the catalyst system using the same catalyst, contamination of palladium in the product is suppressed. .
  • FIG. 1 is a schematic diagram showing a catalyst filling method in an example.
  • FIG. 2 shows the results of continuous synthesis of felbinac and fenbufen in Examples.
  • FIG. 3 shows the results of continuous synthesis of fenbufen in Examples.
  • One embodiment of the present invention includes (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by formula (I) below, and (B) a nitrogen-containing aromatic heterocycle represented by formula (II) below. a copolymer consisting of repeating units, and palladium, It relates to an immobilized palladium catalyst (hereinafter sometimes referred to as "the catalyst of the present invention") containing a complex composed of.
  • the catalyst of the present invention has palladium as a catalytically active site, a repeating unit containing a substituted aromatic hydrocarbon ring represented by (A) the following formula (I) as a ligand, and (B) the following formula (II)
  • a catalyst containing a complex formed by a self-assembly process using a copolymer (hereinafter sometimes referred to as "the copolymer of the present invention") consisting of a repeating unit containing a nitrogen-containing aromatic heterocycle represented by Palladium bridges the polymer through the nitrogen of the nitrogen-containing aromatic heterocycle to form a macromolecular complex.
  • the catalysts of the present invention are believed to promote the reaction as a more stable metal species during the reaction due to electronic and steric effects of the substituents on the substituted aromatic hydrocarbon ring. That is, the catalyst of the present invention can be a highly dispersed polymer-immobilized metal catalyst.
  • the copolymer-immobilized palladium complex thus formed can be used as a catalyst in the present invention.
  • the catalyst of the present invention improves the dispersibility and stability of palladium, is excellent in durability, and can catalyze reactions such as the Suzuki-Miyaura cross-coupling reaction with high activity. Therefore, it is suitable for use in continuous flow reactions. can be done.
  • the copolymer of the present invention used as a catalyst immobilizing material comprises (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I), and (B) the following formula (II) It is a copolymer consisting of a repeating unit containing a nitrogen-containing aromatic heterocycle represented by Each repeating structural unit constituting the copolymer of the present invention is described below.
  • the repeating structural unit containing a substituted aromatic hydrocarbon ring that constitutes the copolymer of the present invention is represented by the following formula (I).
  • R A1 represents hydrogen or an alkyl group
  • R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent
  • R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent
  • LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mA is an integer greater than or equal to 0
  • nA is an integer greater than or equal to 1
  • the upper limit of mA + nA is the number of possible replacements of the cyclic structure
  • * represents the binding position
  • Ring A represents an aromatic hydrocarbon ring.
  • R A1 represents hydrogen or a linear, branched or cyclic alkyl group (having preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 2 carbon atoms). Among these, R A1 is preferably hydrogen.
  • R A2 is not particularly limited as long as it is an inert group or atom that does not participate in the catalytic reaction. alkoxy groups of up to 20, formyl groups, acyl groups of 2 to 20 carbon atoms, alkoxycarbonyl groups of 2 to 20 carbon atoms, cyano groups, nitro groups and the like.
  • halogen examples include fluorine, chlorine, bromine, and iodine.
  • haloalkyl group having 1 to 6 (preferably 1 to 2) carbon atoms examples include a trifluoromethyl group.
  • the hydrocarbon group having 1 to 20 carbon atoms is, for example, an alkyl group having 1 to 20 carbon atoms (preferably 1 to 6, more preferably 1 to 2), and may be a linear, branched or cyclic alkyl group. you can Specific examples of the alkyl group are the same as those described for RA3 below.
  • the hydrocarbon group having 1 to 20 carbon atoms may be, for example, an aryl group having 6 to 20 carbon atoms (preferably 6 to 18, more preferably 6 to 12). Specific examples of the aryl group are the same as those described for RA3 below.
  • alkoxy group having 1 to 20 carbon atoms preferably 1 to 6, more preferably 1 to 2 are the same as those described in R A3 below.
  • acyl group having 2 to 20 carbon atoms preferably 2 to 6, more preferably 2 to 3 are the same as those described in R A3 below.
  • alkoxycarbonyl group having 2 to 20 carbon atoms examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and n-butoxycarbonyl. group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group and the like.
  • Ring A may have one or more identical or different substituents R A2 . Moreover, these R A2 may further have a substituent.
  • the type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like.
  • the substituent R A2 on ring A is preferably a C 1-2 alkyl group or a C 1-2 alkoxy group.
  • the number mA of substituents R A2 on ring A is not limited as long as it does not affect the reaction, but it is an integer of 0 or more, preferably 0 or 1, more preferably 0.
  • the substitution position of the substituent RA2 on the ring A is not particularly limited.
  • R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, more specifically, a linear, branched or cyclic alkyl group (having preferably 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms, 1 to 4 are particularly preferred), aryl groups (preferably 6 to 20 carbon atoms, more preferably 6 to 18 carbon atoms, particularly preferably 6 to 12 carbon atoms), linear, branched or cyclic alkoxy groups (preferably 1 to 20 carbon atoms preferably 1 to 6, particularly preferably 1 to 4), or a linear or branched acyl group (preferably 2 to 20 carbon atoms, more preferably 2 to 6, particularly preferably 2 to 3) mentioned.
  • a linear, branched or cyclic alkyl group having preferably 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms, 1 to 4 are particularly preferred
  • aryl groups preferably 6 to 20 carbon atoms, more preferably 6 to 18 carbon
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2,2 -dimethylpropyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-heptyl group, 2-methylpentyl group, n-octyl group, 2-ethylhexyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-non
  • aryl groups include phenyl, naphthyl, indenyl, biphenyl, anthracenyl, and phenanthrenyl groups.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 2,2- dimethylpropoxy group, n-hexyloxy group, cyclohexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decyloxy group, n-undecyloxy group, n-dodecyloxy group, n -tridecyloxy group, n-tetradecyloxy group, n-pentadecyloxy group, n-hexadecyloxy group, n-heptadecyloxy group, n-octadecyloxy group, n-nonadecyloxy group, n-icosyloxy group, etc. is mentioned.
  • acyl groups include acetyl, propionyl, butyryl, isobutyryl, benzoyl, and naphthoyl groups.
  • R A3 is preferably a straight-chain or branched alkyl group, an aryl group, or a straight-chain or branched alkoxy group, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an octyl group, group, phenyl group, methoxy group, ethoxy group, propoxy group or butoxy group, more preferably methyl group, tert-butyl group, octyl group, phenyl group or tert-butoxy group. .
  • Ring A may have one or more identical or different substituents R A3 . Moreover, these R A3 may further have a substituent.
  • the type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like.
  • the number nA of substituents R A3 on ring A is an integer of 1 or more, preferably 1 or 2, more preferably 1.
  • the substitution position of the substituent R A3 on ring A is not particularly limited, but the substitution position p-position relative to the bonding position of ring A to the copolymer main chain is preferred.
  • LA is a single bond, an alkylene group (preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, particularly preferably 1 to 3 carbon atoms), an arylene group (preferably 6 to 22 carbon atoms, more preferably 6 to 14 ), heteroatoms (oxygen, nitrogen, sulfur are preferred), or combinations thereof.
  • LA is preferably a single bond, a methylene group, an ethylene group, a propylene group, or oxygen, and more preferably a single bond.
  • Adjacent substituents and linking groups may be bonded to each other to form a ring as long as the effects of the present invention are not impaired.
  • Adjacent substituents and linking groups may be bonded to each other to form a ring as long as the effects of the present invention are not impaired.
  • the upper limit of mA + nA is the number of substitutable cyclic structural moieties. For example, it is 5 if ring A in formula (I) is a benzene ring.
  • Ring A represents an aromatic hydrocarbon ring, and the aromatic hydrocarbon ring means an aromatic ring formed only by carbon atoms.
  • the aromatic hydrocarbon ring may be monocyclic or condensed.
  • Aromatic hydrocarbon rings having 6 to 14 carbon atoms are preferred. Examples of aromatic hydrocarbon rings include benzene ring, naphthylene ring, anthracene ring, phenanthrene ring and the like, with benzene ring being preferred.
  • Preferred embodiments of the repeating unit containing a substituted aromatic hydrocarbon ring include, but are not limited to, in formula (I) above, mA is 0; nA is 1; R A1 is hydrogen; L A is a single bond; Ring A is a benzene ring, and examples thereof include those represented by the following formula (I-1).
  • R A3 has the same definition as in formula (I) above, but is preferably a linear or branched alkyl group, an aryl group, or a linear or branched alkoxy group, a methyl group, an ethyl group, more preferably propyl, butyl, pentyl, hexyl, octyl, phenyl, methoxy, ethoxy, propoxy or butoxy, methyl, tert-butyl, octyl or phenyl , or a tert-butoxy group.
  • the repeating structural unit containing the substituted aromatic hydrocarbon ring is more preferably 4-methylstyrene, 4-tert-butylstyrene, 4-n-octylstyrene, 4-vinylbiphenyl, 4-tert-butoxystyrene, or the like. It is a repeating unit derived from.
  • the copolymer may contain repeating structural units selected from repeating structural units containing one or more substituted aromatic hydrocarbon rings.
  • the number of repeating units containing substituted aromatic hydrocarbon rings in the copolymer is 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% of the total number of repeating units. or more. There is no particular upper limit, and it may be less than 100%.
  • the number of repeating structural units containing a substituted aromatic hydrocarbon ring in the copolymer is 50% or more and less than 100% of the total number of repeating units, 60% or more and less than 100%, 70% or more and less than 100%, 80% or more It may be less than 100%, 90% or more and less than 100%, 95% or more and less than 100%, or 99% or more and less than 100%.
  • the repeating structural unit containing a nitrogen-containing aromatic heterocycle constituting the copolymer of the present invention is represented by the following formula (II).
  • R B1 represents hydrogen or an alkyl group
  • RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent
  • L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mB is an integer greater than or equal to 0; The upper limit of mB is the number of possible substitutions of the cyclic structure; * represents the binding position; Ring B represents a nitrogen-containing aromatic heterocycle.
  • R B1 represents hydrogen or a linear, branched or cyclic alkyl group (having preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 2 carbon atoms). Among these, R B1 is preferably hydrogen.
  • R B2 is not particularly limited as long as it is an inert group or atom that does not participate in the catalytic reaction. alkoxy groups of up to 20, formyl groups, acyl groups of 2 to 20 carbon atoms, alkoxycarbonyl groups of 2 to 20 carbon atoms, cyano groups, nitro groups and the like.
  • inert groups or atoms that do not participate in catalytic reactions are the same as those described for RA2 .
  • Ring B may have one or more identical or different substituents R B2 . Moreover, these R B2 may further have a substituent.
  • the type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like.
  • the substituent R B2 on ring B is preferably an alkyl group having 1 to 2 carbon atoms or an alkoxy group having 1 to 2 carbon atoms.
  • the number mB of substituents R B2 on ring B is not limited as long as it does not affect the reaction, but it is an integer of 0 or more, preferably 0 or 1, more preferably 0.
  • the substitution position of the substituent R B on ring B is not particularly limited.
  • L B is a single bond, an alkylene group (preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, particularly preferably 1 to 3 carbon atoms), an arylene group (preferably 6 to 22 carbon atoms, more preferably 6 to 14 ), heteroatoms (oxygen, nitrogen, sulfur are preferred), or combinations thereof.
  • LB is preferably a single bond, a methylene group, an ethylene group, a propylene group, or oxygen, and more preferably a single bond.
  • the upper limit of mB is the number of substitutable cyclic structural moieties. For example, it is 4 if ring B in formula (II) is a pyridine ring, and 3 if it is an imidazole ring.
  • Ring B represents a nitrogen-containing aromatic heterocyclic ring
  • the nitrogen-containing aromatic heterocyclic ring is an aromatic ring formed by carbon atoms and heteroatoms, and has a nitrogen atom as a ring-constituting heteroatom. do.
  • the number of nitrogen atoms contained in the nitrogen-containing aromatic heterocycle is preferably 1 to 3, preferably 1.
  • the nitrogen-containing aromatic heterocycle is preferably a 5- or 6-membered ring.
  • other heteroatoms may also be included as ring-constituting heteroatoms of the nitrogen-containing aromatic heterocyclic ring.
  • Other heteroatoms include, for example, atoms selected from oxygen and sulfur atoms.
  • the nitrogen-containing aromatic hetero ring is a 6-membered ring
  • it is preferably a ring selected from a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, and a triazine ring, more preferably a pyridine ring, a pyrazine ring, and a triazine ring, and a pyridine ring. More preferable.
  • the nitrogen-containing aromatic hetero ring is a five-membered ring
  • a ring selected from a pyrrole ring, an imidazole ring, a pyrazole ring, an oxazole ring, and a thiazole ring is preferable, and an imidazole ring is more preferable.
  • Preferred embodiments of the repeating unit containing a nitrogen-containing aromatic heterocycle include, but are not limited to, in formula (II) above , mB is 0; R B1 is hydrogen; is a bond; ring B is a pyridine ring or an imidal ring, and examples thereof include those represented by the following formula (II-1).
  • the repeating structural unit containing the nitrogen-containing heterocycle is more preferably 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine, 2-vinylpyrazine, 1-vinyl-1,2,4-triazole, 1- It is a repeating structural unit derived from vinylimidazole or the like, and particularly preferably a repeating structural unit derived from 4-vinylpyridine or 1-vinylimidazole.
  • the copolymer may contain repeating structural units selected from repeating structural units containing one, two or more nitrogen-containing heterocycles.
  • the number of repeating structural units containing a nitrogen-containing heterocycle in the copolymer is 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more of the total number of repeating units, 80% or more, 90% or more, 95% or more, or 99% or more. There is no particular upper limit, and it may be less than 100%.
  • the number of repeating structural units containing a nitrogen-containing heterocycle in the copolymer is 10% or more and less than 100% of the total number of repeating units, 20% or more and less than 100%, 30% or more and less than 100%, 40% or more and 100% Less than 50% to less than 100%, 60% to less than 100%, 70% to less than 100%, 80% to less than 100%, 90% to less than 100%, 95% to less than 100%, 99% to less than 100% can be
  • the ratio of (A) the number of repeating structural units containing a substituted aromatic hydrocarbon ring in the copolymer to the number of (B) repeating structural units containing a nitrogen-containing heterocycle ((A):(B)) is, for example, , 1:1 to 5:1, preferably 3:1 to 4:1, more preferably 4:1.
  • the copolymer may be a random copolymer, an alternating copolymer, a periodic copolymer, a block copolymer (e.g., AB, ABA, ABC, etc.), or the like. It is a copolymer.
  • the weight average molecular weight of the copolymer is not limited, but may be 1,000 or more and 1,000,000 or less, 2,000 or more and 500,000 or less, 3,000 or more and 200,000 or less, 5,000 or more and 100,000 or less.
  • the measurement of weight average molecular weight is defined as a value measured by GPC (gel permeation chromatography) method.
  • the copolymers of the present invention can be prepared based on the descriptions herein and conventional methods in the field of chemical synthesis. For example, by mixing a monomer capable of constituting a repeating unit containing a substituted aromatic hydrocarbon ring and a monomer capable of constituting a repeating unit containing a nitrogen-containing aromatic heterocycle under elevated temperature and normal pressure. , insoluble copolymers can be prepared. Copolymers thus formed can be used as the copolymers of the present invention.
  • a monomer capable of constituting a repeating unit containing a substituted aromatic hydrocarbon ring, and a repeating unit containing a nitrogen-containing aromatic heterocycle may be synthesized according to a conventional method, It may be commercially available. After preparing the copolymer, if desired, isolation and purification can be carried out by known isolation and purification methods, for example, general operations such as precipitation, filtration and drying.
  • Azobisisobutyronitrile is added to a 1-dodecanol/toluene solution of the two monomers and stirred at 70° C. for 24 hours to form a solid.
  • the solid is washed with water and methanol, filtered and dried under vacuum. This operation gives 4-vinylpyridine-co-4-tert-butylstyrene.
  • catalysts B1 to B10 shown below Specific examples of the catalyst of the present invention include, but are not limited to, catalysts B1 to B10 shown below.
  • the catalyst of the present invention can be prepared using the copolymer of the present invention and a palladium compound such as a palladium salt, based on the description of the present specification and conventional methods in the field of chemical synthesis.
  • a palladium complex immobilized on an insoluble copolymer can be prepared by mixing the copolymer of the present invention with a palladium compound such as a palladium salt under elevated temperature and normal pressure.
  • the copolymer-immobilized palladium complex thus formed can be used as a catalyst in the present invention.
  • the copolymers of the present invention can be synthesized as described above.
  • the palladium compound may be synthesized according to a conventional method, or may be commercially available. After preparation of the catalyst, if desired, it can be isolated and purified by a known isolation and purification method, for example, general operations such as precipitation, filtration and drying.
  • a 2-propanol solution of the synthesized 4-vinylpyridine-co-4-tert-butylstyrene is mixed with an aqueous solution of ammonium tetrachloropalladate (II) and stirred at 60°C for 20 hours to form a solid.
  • the solid is washed with water and acetone, suction filtered and vacuum dried. This operation yields an immobilized palladium catalyst.
  • the amount of palladium supported on the catalyst is not limited, but may be 0.01-20% by weight, 0.1-15% by weight, or 1-12.5% by weight.
  • Catalyst composition of the present invention Another aspect of the present invention relates to a catalyst composition (hereinafter sometimes referred to as "catalyst composition of the present invention") containing the catalyst of the present invention.
  • the catalyst composition of the present invention may contain components such as known bases, thickeners, reinforcing materials, additives, etc., if necessary.
  • the base used in the catalyst composition of the present invention is not limited as long as it can promote the catalytic reaction.
  • the acid dissociation constant (pKa) in an aqueous solution at 25 ° C. Or 10 to 12 or the like can be used.
  • pyridine methylpyridine, dimethylpyridine, N,N-dimethyl-4-aminopyridine, N-methylmorpholine (NMM), N,N-dimethylethylamine, N-methylpiperidine, N,N- Diethylmethylamine, methylamine, dimethylamine, ethylamine, triethylamine, aniline, dimethylaniline, cyclohexylamine, N,N-diisopropylethylamine, diazabicyclononene (DBN), diazabicycloundecene, piperazine, 1,4-ethylene organic bases such as piperazine, imidazole, oxazole, 1,8-bis(dimethylamino)naphthalene, 1,4-diazabicyclo[2.2.2]octane, triethanolamine, tetramethylethylenediamine, hexamethylenediamine; Lithium hydroxide (LiOH), sodium hydroxide (LiOH
  • inorganic bases or salts obtained by reacting with these bases.
  • these bases may have a substituent.
  • One or a combination of two or more of these bases can be used.
  • the base may be one synthesized according to a conventional method, or may be commercially available.
  • the amount of base used is, for example, 1 to 5 equivalents, or 1.2 to 3 equivalents, relative to the aromatic halide substrate. Moreover, in the present specification, the term “equivalent” simply means “mol equivalent”.
  • the copolymers of the present invention enable the production of highly active metal catalysts with excellent dispersibility and stability of metal species, excellent durability and high activity. That is, the copolymer of the present invention is suitable for use as a material for immobilizing a catalyst.
  • the copolymers of the invention are preferably used as catalyst immobilizing materials for the catalysts of the invention. That is, another aspect of the present invention relates to a catalyst immobilizing material (hereinafter sometimes referred to as "catalyst immobilizing material of the present invention") containing the copolymer of the present invention.
  • the catalyst-immobilizing material may contain, in addition to the copolymer of the present invention, components such as known reinforcing materials and additives for catalyst-immobilizing materials.
  • the above copolymer can improve the dispersibility and stability of palladium, has excellent catalyst durability, and enables a highly active catalytic reaction. That is, the above copolymer is suitably used as a filling material for catalytic reactors.
  • the above copolymers are preferably used as packing materials for catalytic reactors of the catalysts of the invention.
  • the repeating unit containing a substituted aromatic hydrocarbon ring represented by formula (I) is the same as described in the ⁇ Copolymer> section above.
  • a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring is represented by the following formula (III).
  • R C1 represents hydrogen or an alkyl group
  • R C2 represents an inert group or atom that does not participate in the catalytic reaction, and each R C2 is independent
  • L C represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof
  • mC is an integer greater than or equal to 0
  • nC is an integer greater than or equal to 1
  • the upper limit of mC + nC is the number of substitutable cyclic structural moieties
  • * represents the binding position
  • Ring C represents an aromatic hydrocarbon ring.
  • a repeating structural unit containing a vinyl-substituted aromatic hydrocarbon ring has a vinyl group as a substituent and forms a crosslinked structure in the copolymer.
  • the number nC of vinyl groups on ring C is an integer of 1 or more, preferably 1 or 2, more preferably 1.
  • the substitution position of the vinyl group on ring C is not particularly limited, but the substitution position m- or p-position relative to the bonding position of ring C to the copolymer main chain is preferred.
  • R C1 represents hydrogen or a linear, branched or cyclic alkyl group (having preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 2 carbon atoms). Among these, R C1 is preferably hydrogen.
  • R C2 is not particularly limited as long as it is an inert group or atom that does not participate in the catalytic reaction. alkoxy groups of up to 20, formyl groups, acyl groups of 2 to 20 carbon atoms, alkoxycarbonyl groups of 2 to 20 carbon atoms, cyano groups, nitro groups and the like.
  • inert groups or atoms that do not participate in catalytic reactions are the same as those described for RA2 .
  • Ring C may have one or more identical or different substituents R C2 . Moreover, these R C2 may further have a substituent.
  • the type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like.
  • the substituent R C2 on ring C is preferably a C 1-2 alkyl group or a C 1-2 alkoxy group.
  • the number mC of substituents R C2 on ring C is not limited as long as it does not affect the reaction, but is an integer of 0 or more, preferably 0 or 1, more preferably 0.
  • the substitution position of the substituent R C2 on the ring C is not particularly limited.
  • L C is a single bond, an alkylene group (preferably 1 to 12 carbon atoms, more preferably 1 to 6, particularly preferably 1 to 3 carbon atoms), an arylene group (preferably 6 to 22 carbon atoms, more preferably 6 to 14 ), heteroatoms (oxygen, nitrogen, sulfur are preferred), or combinations thereof.
  • L C is preferably a single bond, a methylene group, an ethylene group, a propylene group, or oxygen, and more preferably a single bond.
  • the upper limit of mC + nC is the number of substitutable cyclic structural moieties. For example, it is 5 if ring C in formula (III) is a benzene ring.
  • Ring C represents an aromatic hydrocarbon ring, and the aromatic hydrocarbon ring means an aromatic ring formed only by carbon atoms.
  • the aromatic hydrocarbon ring may be monocyclic or condensed.
  • Aromatic hydrocarbon rings having 6 to 14 carbon atoms are preferred. Examples of aromatic hydrocarbon rings include benzene ring, naphthylene ring, anthracene ring, phenanthrene ring and the like, with benzene ring being preferred.
  • Preferred embodiments of the repeating unit containing a vinyl-substituted aromatic hydrocarbon ring include, but are not limited to, in formula (III) above, mC is 0; nC is 1 ; L C is a single bond; Ring C is a benzene ring, and examples thereof include those represented by the following formula (III-1).
  • the repeating structural unit containing the vinyl-substituted aromatic hydrocarbon ring is more preferably a repeating structural unit derived from divinylbenzene or the like.
  • the copolymer may contain repeating structural units selected from repeating structural units containing one, two or more vinyl-substituted aromatic hydrocarbon rings in the copolymer.
  • the number of repeating units containing a vinyl-substituted aromatic hydrocarbon ring in the copolymer is 1% or more, 10% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% of the total number of repeating units. % or more, 95% or more, or 99% or more. There is no particular upper limit, and it may be less than 100%.
  • the number of repeating structural units containing a vinyl-substituted aromatic hydrocarbon ring in the copolymer is 1% or more and less than 100% of the total number of repeating units, 10% or more and less than 100%, 50% or more and less than 100%, 60% 100% or more, 70% or more and less than 100%, 80% or more and less than 100%, 90% or more and less than 100%, 95% or more and less than 100%, or 99% or more and less than 100%.
  • the ratio of the number of repeating units containing a substituted aromatic hydrocarbon ring in the copolymer to the number of repeating units containing a vinyl-substituted aromatic hydrocarbon ring ((A):(C)) is, for example, 1: It may be 1-10:1, preferably 3:1-4:1, more preferably 4:1.
  • the above copolymers can be prepared based on the descriptions of this specification and conventional methods in the field of chemical synthesis.
  • a monomer capable of constituting a repeating unit containing a substituted aromatic hydrocarbon ring and a monomer capable of constituting a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring are mixed under elevated temperature and normal pressure. can prepare insoluble copolymers.
  • the copolymer thus formed can be used as the copolymer.
  • a monomer capable of forming a repeating unit containing a substituted aromatic hydrocarbon ring and a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring The monomer capable of forming a repeating unit may be synthesized according to a conventional method. , may be commercially available.
  • isolation and purification can be carried out by known isolation and purification methods, for example, general operations such as precipitation, filtration and drying.
  • Azobisisobutyronitrile is added to a 1-dodecanol/toluene solution of the two monomers and stirred at 70° C. for 24 hours to form a solid. The solid is washed with water and methanol, filtered and dried under vacuum. This operation yields the above copolymer.
  • the catalysts of the present invention are capable of catalyzing various reactions.
  • the catalyst of the present invention can be used in the synthesis reaction of polycyclic aromatic compounds by coupling aromatic halides with aromatic boron compounds or the like by Suzuki-Miyaura cross-coupling reaction.
  • one aspect of the present invention relates to the use of the catalyst of the present invention for the Suzuki-Miyaura cross-coupling reaction.
  • one aspect of the present invention is a method of performing a Suzuki-Miyaura cross-coupling reaction by reacting an aromatic halide and an aromatic boron compound in the presence of the catalyst or catalyst composition of the present invention (hereinafter referred to as "the present invention (sometimes referred to as "cross-coupling method").
  • the present invention in the presence of the catalyst or catalyst composition of the present invention, an aromatic halide and an aromatic boron compound are reacted to produce a polycyclic aromatic compound by a Suzuki-Miyaura cross-coupling reaction.
  • the present invention relates to a method for producing a polycyclic aromatic compound (hereinafter sometimes referred to as “the method for producing a polycyclic aromatic compound of the present invention”), including the step of
  • any form that allows contact between the catalyst or catalyst composition of the present invention, the aromatic halide, and the aromatic boron compound is not particularly limited and can be used.
  • the catalyst of the invention may be in bed or column form.
  • aromatic halide used as a substrate in the cross-coupling method and the method for producing a polycyclic aromatic compound of the present invention include: is a compound in which part of the hydrogen contained in the aromatic heterocyclic compound is substituted with halogen, or a compound in which part of the hydrogen contained in the aromatic heterohydrocarbon group of the aromatic heterocyclic compound is substituted with halogen.
  • aromatic halides include compounds represented by the following formula (A).
  • Ar1- (X) m (A) (wherein Ar 1 represents an aromatic hydrocarbon group having 6 to 30 carbon atoms (preferably 6 to 10) or an aromatic heterohydrocarbon group having 4 to 30 carbon atoms (preferably 4 to 8); represents a halogen, each X is independent; m is an integer from 1 to 3.)
  • the aromatic hydrocarbon group represented by Ar 1 means a group in which a part of hydrogen contained in an aromatic compound serves as a bond.
  • Specific examples of the aromatic hydrocarbon group represented by Ar 1 include, for example, monocyclic aromatic hydrocarbon groups such as phenyl group, bicyclic aromatic hydrocarbon groups such as biphenyl group and naphthyl group, fluorenyl group, anthracenyl group, Examples include polycyclic aromatic hydrocarbon groups such as tricyclic aromatic hydrocarbon groups such as phenanthrenyl groups (including those in which one of the polycyclic rings is an aromatic hydrocarbon group).
  • the aromatic heterohydrocarbon group represented by Ar 1 means a group in which a part of hydrogen contained in an aromatic heterocyclic compound serves as a bond. Heteroatoms contained in the aromatic heterohydrocarbon group include, for example, oxygen, sulfur, nitrogen and the like. Specific examples of aromatic heterohydrocarbon groups represented by Ar 1 include monocyclic aromatic heterohydrocarbons such as furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, and pyrazyl.
  • Hydrogen group indolyl group, quinolyl group, isoquinolyl group, quinoxalyl group, bicyclic aromatic heterohydrocarbon groups such as benzofuranyl group, polycyclic aromatic groups such as tricyclic aromatic heterohydrocarbon groups such as carbazolyl group and dibenzofuranyl group hydrocarbon groups (including those in which any of the polycycles is an aromatic heterohydrocarbon group).
  • the aromatic hydrocarbon group or aromatic heterohydrocarbon group in the aromatic halide used in the present invention and the aromatic hydrocarbon group or aromatic heterohydrocarbon group represented by Ar 1 have a substituent that does not affect the reaction. You may have The substituents on Ar 1 are the same as the inert groups or atoms on Ring A that do not participate in the catalytic reaction above. Furthermore, it may be a hydroxy group, a carboxy group, or the like. Ar 1 may have one or more same or different substituents.
  • the substituents of Ar 1 are preferably halogen, haloalkyl group, alkyl group (optionally substituted with carboxyl group), alkoxy group, formyl group, acyl group (optionally substituted with carboxyl group), single A cyclic or polycyclic aryl group, a monocyclic or polycyclic heteroaryl group, an alkoxycarbonyl group, a cyano group, a nitro group, a hydroxy group and a carboxy group.
  • fluorine, chlorine, bromine; trifluoromethyl group methyl group, ethyl group, n-propyl group, n-butyl group; carboxymethyl group; methoxy group, ethoxy group; formyl group, acetyl group; carboxypropionyl group phenyl group; methoxycarbonyl group, ethoxycarbonyl group; hydroxy group; carboxy group.
  • the number of substituents on Ar 1 is not limited as long as it does not affect the reaction, but preferably 0-2.
  • the substitution position of the substituent on Ar 1 is not particularly limited. In the case of a strong electron-withdrawing group or the like, substitution positions other than the p-position with respect to X are preferred.
  • X represents a halogen, and each X is independent.
  • Halogen includes fluorine, chlorine, bromine, iodine and the like, preferably bromine.
  • m is preferably 1.
  • aromatic halides include 4-bromophenol, 2-bromotoluene, 3-bromotoluene, 4-bromotoluene, 4-bromoanisole, 4-bromobenzonitrile, 4-bromobenzaldehyde, 1, 3-dibromobenzene, 4-bromofluorobenzene, 4-bromotrifluoromethylbenzene, 4-bromoacetylbenzene, 4-bromobenzoic acid, ethyl 4-bromobenzoate, 3-(4-bromobenzoyl)propionic acid, 4 -bromophenylacetic acid, 2-bromodibenzofuran, 3-bromo-9-phenylcarbazole, 9-(4-bromophenyl)carbazole and the like.
  • aromatic halides may be used singly or in combination of two or more.
  • the aromatic boron compound used as a substrate in the cross-coupling method of the present invention and the method for producing a polycyclic aromatic compound of the present invention is not particularly limited. group boronic acid esters, organic boranes, organic borates, and the like. Aromatic boronic acids are preferred.
  • aromatic boronic acids and aromatic boronic acid esters include compounds represented by the following formula (B).
  • Ar 2 represents an aromatic hydrocarbon group having 6 to 30 carbon atoms (preferably 6 to 10); Y 1 and Y 2 each independently represent a hydroxy group or 1 to 4 carbon atoms (preferably represents an alkoxy group of 1 to 2), or represents an alkylenedioxy group having 1 to 8 carbon atoms (preferably 1 to 5) formed by combining Y 1 and Y 2. )
  • the aromatic hydrocarbon group represented by Ar 2 is the same as the aromatic hydrocarbon group represented by Ar 1 above.
  • a monocyclic aromatic hydrocarbon group is preferred, and a phenyl group is more preferred.
  • the aromatic hydrocarbon group in the aromatic boron compound used in the present invention may have a substituent that does not affect the reaction.
  • the substituents on Ar 2 are the same as the inert groups or atoms on Ring A that do not participate in the catalytic reaction above. Furthermore, it may be a hydroxy group, a carboxy group, or the like.
  • Ar 2 may have one or more same or different substituents. Ar 2 substituents are preferably halogens, haloalkyl groups, alkyl groups, alkoxy groups.
  • substitution position of the substituent on Ar 2 is not particularly limited. In the case of a strong electron-withdrawing group, substitution positions other than the p-position relative to -B(Y 1 )(Y 2 ) are preferred.
  • the alkoxy group having 1 to 4 carbon atoms represented by Y 1 and Y 2 includes, for example, methoxy group, ethoxy group, n-propoxy group, n-butoxy group and the like.
  • Examples of the alkylenedioxy group having 1 to 8 carbon atoms formed by combining Y 1 and Y 2 include alkylenedioxy groups having linear or branched alkylene.
  • aromatic boronic acid esters include 2-phenyl-1,3,2-dioxaborinane, 5,5-dimethyl-2-phenyl-1,3,2-dioxaborinane, 2-phenyl-1,3 ,2-dioxaborolan and the like.
  • Aromatic boronic acids include phenylboronic acid, 4-methylphenylboronic acid, 4-methoxyphenylboronic acid, 4-fluorophenylboronic acid, 4-amylphenylboronic acid, 4-propoxyphenylboronic acid, 4-(9H -carbazol-9-yl)phenylboronic acid and the like.
  • organic boranes include triorganoborane such as triphenylborane.
  • Examples of organic borates include tetraorganoborates such as trifluoro(phenyl)- ⁇ 4 -borane potassium salt.
  • One of these aromatic boron compounds may be used, or two or more of them may be used in combination.
  • aromatic halides and aromatic boron compounds used in the above production method can be those synthesized by known synthetic methods and those commercially available.
  • the reaction ratio (molar ratio) between the aromatic halide and the aromatic boron compound is usually 1:10 to 10:1, preferably 1:1. ⁇ 1:5 range.
  • the amount of the catalyst composition used is not particularly limited and can be appropriately selected according to the purpose. Or it may be from 0.1 mol % to 2 mol %.
  • the weight ratio of the catalyst composition and the packing material for the catalytic reaction device is, for example, 1:3 to 1:8, 1:4 to 1:7, or 1:5 to May be in the range of 1:6.
  • the reaction temperature can be appropriately selected in consideration of the composition of the reaction solution and the heat resistance temperature of the catalyst, but it is usually 50-130°C. The higher the reaction temperature, the faster the reaction rate and the more efficient reaction can be carried out.
  • the reaction time is not particularly limited, it is set in the range of, for example, 0.5 minutes to 100 hours, 1 minute to 48 hours, and the like.
  • the atmosphere in which the reaction is carried out may be air as long as it is in a gaseous phase, but an atmosphere of an inert gas such as nitrogen or argon is preferred.
  • the solvent that can be used in the above reaction is suitable for forming a homogeneous phase with the reaction raw materials.
  • examples include, but are not limited to, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, Ether solvents such as cyclopentyl methyl ether, alcohol solvents such as ethanol and tert-butanol, aromatic solvents such as toluene and xylene, aprotic polar solvents such as dimethylsulfoxide and dimethylformamide, and aqueous solvents such as water can be used. .
  • Ether solvents such as cyclopentyl methyl ether
  • alcohol solvents such as ethanol and tert-butanol
  • aromatic solvents such as toluene and xylene
  • aprotic polar solvents such as dimethylsulfoxide and dimethylformamide
  • aqueous solvents such as water can be used.
  • the flow rate of the liquid flowing through the reaction system can be appropriately set within a range that maintains a good mixing state and does not cause pressure loss, and can be, for example, 0.1 to 10 mL/min, 0.3 mL/min to 1 mL/min. .
  • the flow rate (unit: mL/min) of the reaction system is the total value of the flow rates when there are multiple solution supply channels.
  • the catalyst or catalyst composition of the present invention may be washed with a washing solvent to remove impure preparations remaining in the catalyst or catalyst composition and prevent a decrease in yield.
  • the washing solvent to be used is not particularly limited as long as it does not dissolve the catalyst or catalyst composition of the present invention, and can be appropriately selected. and other aqueous solvents, mixtures thereof, and the like.
  • the temperature during washing can be selected without any particular limitation, but 50 to 70°C or the like is preferable in consideration of work efficiency.
  • the washing time is also not particularly limited, and is set in the range of 0.5 to 3 hours, for example.
  • the liquid flow rate is also not particularly limited, and may be, for example, 0.3 to 1 mL/min.
  • the product can be isolated/purified by a known isolation/purification method such as filtration, concentration, extraction, distillation, sublimation, recrystallization, column chromatography, or other general operation. can.
  • the catalytic activity of the catalyst of the present invention is not limited. 80% or more, 85% or more, 90% or more, 95% or more, 99% or more. Yield can be determined by a known method, for example, the method described in Examples below.
  • catalyst immobilizing material As a catalyst immobilizing material, a copolymer having a repeating unit containing a substituted aromatic hydrocarbon ring and a repeating unit containing a nitrogen-containing aromatic heterocycle was prepared as follows. and synthesized.
  • Copolymer A1 4-Vinylpyridine (2102.8 mg, 20 mmol) and 4-tert-butylstyrene (3205.2 mg, 20 mmol) were added to a mixed solvent of 1-dodecanol (10 mL) and toluene (2 mL) and stirred with a magnetic stirrer. was introduced, the inside of the reaction vessel was replaced with nitrogen gas.
  • Copolymer A2 Using 4-vinylpyridine (1261.7 mg, 12 mmol), 4-tert-butylstyrene (3846.2 mg, 24 mmol), and azobisisobutyronitrile (51.1 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A2 (3503.0 mg, yield: 79%).
  • Copolymer A2 had a carbon content of 86.56%, a hydrogen content of 9.26% and a nitrogen content of 3.74% as determined by elemental analysis.
  • Copolymer A3 Using 4-vinylpyridine (788.6 mg, 7.5 mmol), 4-tert-butylstyrene (3605.9 mg, 22.5 mmol), and azobisisobutyronitrile (43.9 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A3 (3501.4 mg, yield: 80%). Copolymer A3 had a carbon content of 87.55%, a hydrogen content of 9.54% and a nitrogen content of 2.55% as determined by elemental analysis.
  • Copolymer A4 Using 4-vinylpyridine (841.1 mg, 8 mmol), 4-tert-butylstyrene (5128.3 mg, 32 mmol), and azobisisobutyronitrile (59.7 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A4 (5191.2 mg, yield: 87%). Copolymer A4 had a carbon content of 87.71%, a hydrogen content of 9.69% and a nitrogen content of 2.08% as determined by elemental analysis.
  • Copolymer A5 Using 4-vinylpyridine (841.1 mg, 8 mmol), 4-tert-butylstyrene (6410.4 mg, 40 mmol), and azobisisobutyronitrile (72.5 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A5 (7200.7 mg, yield: 99%).
  • Copolymer A5 as determined by elemental analysis, had a carbon content of 87.16%, a hydrogen content of 10.20% and a nitrogen content of 1.54%.
  • Copolymer A6 Using 4-vinylpyridine (841.1 mg, 8 mmol), 4-methylstyrene (3781.8 mg, 32 mmol), and azobisisobutyronitrile (46.2 mg), perform the same procedure as in the synthesis of copolymer A1. Thus, copolymer A6 (3758.5 mg, yield: 81%) was obtained.
  • Copolymer A7 Using 4-vinylpyridine (1261.7 mg, 12 mmol), 4-tert-butoxystyrene (6345.4 mg, 36 mmol), and azobisisobutyronitrile (76.1 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A7 (5720.5 mg, yield: 75%).
  • Copolymer A8 Using 4-vinylpyridine (157.7 mg, 1.5 mmol), 4-vinylbiphenyl (1081.5 mg, 6 mmol), and azobisisobutyronitrile (12.4 mg), perform the same procedure as in the synthesis of copolymer A1. Thus, copolymer A8 (798.8 mg, yield: 64%) was obtained.
  • Copolymer A9 4-vinylpyridine (841.1 mg, 8 mmol), 4-tert-butylstyrene (3846.2 mg, 24 mmol), 4-n-octylstyrene (1731.0 mg, 8 mmol), and azobisisobutyronitrile (64.2 mg ), and the same procedure as in the synthesis of copolymer A1 was performed to obtain copolymer A9 (5802.3 mg, yield: 90%).
  • Copolymer A10 Using 1-vinylimidazole (753.0 mg, 8 mmol), 4-tert-butylstyrene (5128.3 mg, 32 mmol), and azobisisobutyronitrile (58.8 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A10 (4297.2 mg, yield: 73%).
  • the synthesized copolymer A1 (398.1 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution.
  • the prepared aqueous solution of palladium was added dropwise to the solution of this copolymer A1 over 0.5 hours, and the mixture was stirred at 60° C. for 20 hours.
  • Catalyst B2 Catalyst B2 (435.0 mg, yield: 90%) was obtained.
  • the amount of Pd supported on catalyst B2 evaluated by ICP mass spectrometry was 6.0 wt% (in terms of Pd).
  • Catalyst B3 Catalyst B3 (567.1 mg, yield: 88%).
  • the amount of Pd supported on catalyst B3 evaluated by ICP mass spectrometry was 5.4 wt% (in terms of Pd).
  • Catalyst B4 Catalyst B4 (744.5 mg, yield: 92%).
  • the amount of Pd supported on catalyst B4 evaluated by ICP mass spectrometry was 4.2 wt% (in terms of Pd).
  • Catalyst B5 Catalyst B5 (1031.6 mg, yield: 89%).
  • the amount of Pd supported on catalyst B5 evaluated by ICP mass spectrometry was 3.7 wt% (in terms of Pd).
  • the synthesized copolymer A6 (577.9 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution.
  • the prepared aqueous solution of palladium was added dropwise to the solution of this copolymer A6 over 0.5 hours, and the mixture was stirred at 60° C. for 1 hour and further stirred at 25° C. for 20 hours.
  • the resulting solid was washed with pure water and acetone, filtered by suction, and dried in a vacuum to obtain polymer-immobilized palladium catalyst B6 (569.8 mg, yield: 89%).
  • the synthesized copolymer A7 (647.9 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution.
  • the prepared aqueous solution of palladium was added dropwise to the solution of this copolymer A7 over 0.5 hours, and the mixture was stirred at 25°C for 20 hours.
  • Catalyst B8 Catalyst B8 (445.0 mg, yield: 84%).
  • Catalyst B9 Catalyst B9 (803.0 mg, yield: 93%).
  • the synthesized copolymer A10 (441.1 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution.
  • the prepared palladium aqueous solution was added dropwise to the copolymer A10 solution over 0.5 hours, and the mixture was stirred at 25° C. for 48 hours.
  • Catalyst B11 (comparative example) Catalyst B11 (445.9 mg, Yield: 68%).
  • Catalyst B12 (comparative example) Using ammonium (II) tetrachloropalladate (94.7 mg, 0.33 mmol) and poly(4-vinylpyridine-co-styrene) (203.0 mg), Catalyst B12 was prepared in the same manner as in the synthesis of Catalyst B7. (230.1 mg, yield: 88%) was obtained.
  • Crosslinked polymer material C1 Styrene monomer (2083.0 mg, 20 mmol) and divinylbenzene (m-, p-mixture) (651.0 mg, 5 mmol) were added to a mixed solvent of 1-dodecanol (10 mL) and toluene (2 mL), followed by magnetic After inserting the stirrer, the inside of the reaction vessel was replaced with nitrogen gas.
  • Crosslinked polymer material C2 Using 4-tert-butylstyrene (8013.0 mg, 50 mmol), divinylbenzene (m-, p-mixture) (1627.4 mg, 12.5 mmol), and azobisisobutyronitrile (96.4 mg), a crosslinked polymer material A crosslinked polymer material C2 (8230.5 mg) was obtained by performing the same operation as in the synthesis of C1.
  • Crosslinked polymer material C3 4-tert-butoxystyrene (8813.0 mg, 50 mmol), divinylbenzene (m-, p-mixture) (1627.4 mg, 12.5 mmol), and azobisisobutyronitrile (104.4 mg)
  • a crosslinked polymeric material C3 (9961.0 mg) was obtained by performing the same operation as in the synthesis of the molecular material C1.
  • Catalyst filling method 1 The synthesized catalyst Bx and sea sand (about 9.6 g) were mixed and packed in a glass cartridge column tube (column size: 10 mm ID; 10 cm L). A PTFE filter was attached to both ends of the column tube, and a mixture of polymer-immobilized palladium catalyst and sea sand was packed therein and used for the continuous-flow Suzuki-Miyaura coupling reaction.
  • Catalyst filling method 2 Synthesized catalyst Bx, crosslinked polymer material C1-C3 (284.0 mg) or celite (284.0 mg) and sea sand (about 9.3 g) were mixed, and a glass cartridge column tube (column size: 10 mm ID; 10 cm L). Both ends of the column tube were equipped with PTFE filters, which were filled with a mixture of polymer-immobilized palladium catalyst, crosslinked polymer material (or celite), and sea sand, and used for the continuous-flow Suzuki-Miyaura coupling reaction. .
  • Catalyst filling method 3 The synthesized catalyst Bx, crosslinked polymeric material C2 (284.0 mg) and sea sand (about 9.3 g) were mixed and packed in a glass cartridge column tube (column size: 10 mm ID; 10 cm L). As shown in the figure, filters are attached to both ends of the column tube, and a mixture of polymer-immobilized palladium catalyst, cross-linked polymer material, and sea sand is filled and several (1-5) filters are attached. A column tube packed with a palladium catalyst was prepared and used for the continuous-flow Suzuki-Miyaura coupling reaction.
  • reaction example 1-2 A reaction solution I was prepared by dissolving 4-bromotoluene (3078.7 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents. On the other hand, tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
  • catalyst B11 (10.0 mg (Pd: 2.5 mg, 0.0235 mmol)) and catalyst B12 (18.9 mg (Pd: 2.5 mg, 0.0235 mmol)) were mixed with sea sand (about 9.6 g).
  • the mixture was mixed and packed into a cartridge column using "catalyst packing method 1".
  • the packed column tube was fixed in a flow reactor and heated to 70°C.
  • the prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously fed to the flow reactor.
  • the reaction solution was heated to 70°C in a coil reactor before entering the flow reactor.
  • Reaction Example 10 using celite, which is a conventional packing material, the activity decreased with the lapse of reaction time.
  • Reaction Example 8 using the crosslinked polymer material C1 which is a conventional filler material
  • a decrease in activity was observed over the course of the reaction time, albeit more moderately than with celite.
  • Reaction Example 9 using the crosslinked polymer material C2, which is the filler material of the present invention the activity was higher than that of C1 immediately after the start of the reaction, and the activity was maintained higher than that of C1 even after the reaction time elapsed. Ta.
  • the overall yield was also high.
  • Reaction Examples 11 and 13-15 using the catalysts B6, B8-B10 of the present invention the activity was maintained from immediately after the start of the reaction until after the reaction time had elapsed.
  • Reaction Examples 11, 14, and 15 using Catalysts B6, B9, and B10 maintained an activity of 50% or more even after 4 to 5 hours of reaction time, and in particular Reaction Example 11 using Catalyst B6.
  • the activity maintenance effect was high.
  • Reaction Example 14 using Catalyst B9 the catalytic activity immediately after the start of the reaction was lower than, for example, Reaction Example 11 using Catalyst B6 and Reaction Example 15 using Catalyst B10. was maintained and showed almost no decline.
  • Reaction Example 12 using Catalyst B7, a relatively high catalytic activity was maintained for up to 3 hours. After that, the reaction stopped because the column reactor was clogged. This is probably because under the conditions of Reaction Example 12, the copolymer A7 contained in the catalyst B7 swelled. If it is desired to continue the reaction for a longer period of time, the purpose can be achieved by optimizing the conditions.
  • reaction example 16 Catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and a cartridge was prepared using "catalyst filling method 3". packed into a column. Then, the target product 4-methylbiphenyl was obtained by performing the same operation as in "Reaction Example 1". Table 5 summarizes the yield of 4-methylbiphenyl in the solution collected for each reaction time. For comparison, Table 5 also shows the results using "catalyst loading method 1" (reaction example 6) and “catalyst loading method 2" (reaction example 9).
  • Example 6 using the "catalyst filling method 1" containing no filler, as described above, the activity was maintained from immediately after the start of the reaction until after 4 to 5 hours of reaction time.
  • Catalyst packing method 2 (with PTFE filters attached only to both ends of the column tube)
  • Catalyst packing method 3 (with PTFE filters not only at both ends of the column tube, but also column According to Examples 9 and 16, in which several sheets were also installed inside the tube)
  • the catalytic activity hardly decreased immediately after the start of the reaction even after 4 to 5 hours of reaction time.
  • the drift in the column tube caused by flow reactions etc. is suppressed, can move smoothly in the column tube, even in this “catalyst packing method 3”, it shows relatively high catalytic activity immediately after the reaction starts, and even after 4 to 5 hours of reaction time, it is sufficiently catalytic. It was shown to maintain activity.
  • reaction example 17 A reaction solution I was prepared by dissolving 2-bromotoluene (3078.7 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents. On the other hand, tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • Packing method 2 was used to pack the cartridge column.
  • the packed column tube was secured to the flow reactor and heated to 70°C.
  • the prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump.
  • the reaction solution was heated to 70°C in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor.
  • the catalyst turnover number (TON) is the number of mols of the product generated per 1 mol of the catalyst (converted to palladium, which is a metal species) used in the step of generating the product
  • the TOF is It is a numerical value obtained by dividing the TON by the time (reaction time) (h) for generating the product.
  • reaction example 18 3-Bromotoluene (3078.7 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg). , 36 mmol was dissolved in pure water (30 mL), and the same operation as in “Reaction Example 17" was performed to obtain the target product 3-methylbiphenyl.
  • Table 6 summarizes the yield of 3-methylbiphenyl in the solution and the weight of isolated 3-methylbiphenyl collected for each reaction time.
  • the catalyst turnover frequency (TOF) was 146.2 h -1 .
  • reaction example 19 4-Bromobenzonitrile (3276.4 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate. (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) and the same operation as in “Reaction Example 17" was performed to obtain the desired product 4-cyanobiphenyl.
  • Table 6 summarizes the yield of 4-cyanobiphenyl in the solution collected for each reaction time and the weight of isolated 4-cyanobiphenyl.
  • the catalyst turnover frequency (TOF) was 159.1 h -1 .
  • reaction example 20 4-Bromobenzaldehyde (3330.4 mg, 18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) and the same operation as in “Reaction Example 17" was performed to obtain the desired product biphenyl-4-carboxaldehyde.
  • Table 6 summarizes the yield of biphenyl-4-carboxaldehyde in the solution collected for each reaction time and the weight of the isolated biphenyl-4-carboxaldehyde.
  • the catalyst turnover frequency (TOF) was 155.9 h -1 .
  • reaction example 21 4-Bromofluorobenzene (3150.0 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the same operation as in “Reaction Example 17" was performed to obtain the desired product 4-fluorobiphenyl.
  • Table 6 summarizes the yield of 4-fluorobiphenyl in the solution collected for each reaction time and the weight of isolated 4-fluorobiphenyl.
  • the catalyst turnover frequency (TOF) was 157.5 h -1 .
  • reaction example 22 Ethyl 4-bromobenzoate (4123.3 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the target product ethyl biphenyl-4-carboxylate was obtained by the same operation as in "Reaction Example 17".
  • Table 6 summarizes the yield of ethyl biphenyl-4-carboxylate in the solution recovered for each reaction time and the weight of the isolated ethyl biphenyl-4-carboxylate.
  • the catalyst turnover frequency (TOF) was 157.5 h -1 .
  • reaction example 23 1,3-dibromobenzene (2123.2 mg, 9 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents, and tripotassium phosphate ( 7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the target compound, ethyl biphenyl-4-carboxylate, was obtained by the same operation as in "Reaction Example 17".
  • Table 6 summarizes the yield of m-terphenyl in the solution and the weight of m-terphenyl isolated for each reaction time.
  • the catalyst turnover frequency (TOF) was 79.5 h -1 .
  • reaction example 41 4-bromoanisole (18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol). ) was dissolved in pure water (30 mL), and the same operation as in “Reaction Example 17” was performed to obtain the desired product 4-methoxybiphenyl.
  • Table 6-2 summarizes the yield of 4-methoxybiphenyl in the solution and the weight of isolated 4-methoxybiphenyl collected for each reaction time.
  • the catalyst turnover frequency (TOF) was 125 h -1 .
  • reaction example 42 4-Bromotrifluoromethylbenzene (18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg). , 36 mmol was dissolved in pure water (30 mL), and the target compound 4-(trifluoromethyl)biphenyl was obtained by the same operation as in "Reaction Example 17".
  • Table 6-2 summarizes the yield of 4-(trifluoromethyl)biphenyl in the solution and the weight of isolated 4-(trifluoromethyl)biphenyl collected for each reaction time.
  • the catalyst turnover frequency (TOF) was 72 h -1 .
  • reaction example 43 4-Bromoacetylbenzene (18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the same operation as in “Reaction Example 17” was performed to obtain the desired product 4-acetylbiphenyl.
  • Table 6-2 summarizes the yield of 4-acetylbiphenyl in the solution and the weight of isolated 4-acetylbiphenyl collected for each reaction time.
  • the catalyst turnover frequency (TOF) was 143 h -1 .
  • the yield of 4'-methyl-4-pentylbiphenyl in the solution recovered for each reaction time and the weight of isolated 4'-methyl-4-pentylbiphenyl are summarized in Table 6-2.
  • the catalyst turnover frequency (TOF) was 124 h -1 .
  • reaction example 24 4-bromobenzonitrile (3276.4 mg, 18 mmol) and 4-methylphenylboronic acid (2936.7 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give reaction solution I.
  • tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • Packing method 2 was used to pack the cartridge column.
  • the packed column tube was secured to the flow reactor and heated to 70°C.
  • the prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump.
  • the reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor.
  • reaction example 25 4-Bromobenzonitrile (3276.4 mg, 18 mmol) and 4-methoxyphenylboronic acid (3282.3 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the same operation as in “Reaction Example 24" was performed to obtain the desired product, 4-cyano-4'-methoxybiphenyl.
  • Table 7 summarizes the yield of 4-cyano-4'-methoxybiphenyl in the solution recovered for each reaction time and the weight of isolated 4-cyano-4'-methoxybiphenyl.
  • the catalyst turnover frequency (TOF) was 159.1 h -1 .
  • reaction example 26 4-bromobenzonitrile (3276.4 mg, 18 mmol) and 4-fluorophenylboronic acid (3282.3 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the desired product 4-cyano-4'-fluorobiphenyl was obtained by the same operation as in "Reaction Example 24".
  • Table 7 summarizes the yield of 4-cyano-4'-fluorobiphenyl in the solution collected for each reaction time and the weight of isolated 4-cyano-4'-fluorobiphenyl.
  • the catalyst turnover frequency (TOF) was 154.3 h -1 .
  • Reaction example 27 4-bromobenzonitrile (3276.4 mg, 18 mmol) and 4-amylphenylboronic acid (4148.7 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the desired liquid crystal material 5CB (4-cyano-4'-pentylbiphenyl ).
  • Table 7 summarizes the yield of the liquid crystal material 5CB in the solution recovered for each reaction time and the weight of the isolated liquid crystal material 5CB.
  • the catalyst turnover frequency (TOF) was 149.5 h -1 .
  • reaction example 28 A reaction solution I was prepared by dissolving 2-bromodibenzofuran (2223.9 mg, 9 mmol) and phenylboronic acid (1317.1 mg, 10.8 mmol) in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents. On the other hand, tripotassium phosphate (3820.9 mg, 18 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • the packed column tube was clamped into a flow reactor and heated to 70°C.
  • the prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump.
  • the reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor.
  • Reaction example 29 3-bromo-9-phenylcarbazole (2899.9 mg, 9 mmol) and phenylboronic acid (1317.1 mg, 10.8 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (3820.9 mg, 18 mmol) was dissolved in pure water (30 mL), and the same operation as in “Reaction Example 28" was performed to obtain the target product 3,9-diphenylcarbazole.
  • Table 8 summarizes the yield of 3,9-diphenylcarbazole in the solution collected for each reaction time and the weight of the isolated 3,9-diphenylcarbazole.
  • the catalyst turnover frequency (TOF) was 61.9 h -1 .
  • reaction example 30 9-(4-bromophenyl)carbazole (2899.9 mg, 9 mmol), 4-(9H-carbazol-9-yl)phenylboronic acid (3101.0 mg, 10.8 mmol), tetrahydrofuran (50 mL) and ethanol as solvent (10 mL), tripotassium phosphate (3820.9 mg, 18 mmol) was dissolved in pure water (30 mL), and the desired organic EL material CBP (4,4'-bis(9H-carbazol-9-yl)biphenyl) was obtained.
  • the organic phase of the solution collected for each reaction time was analyzed by 1 H NMR to calculate the yield of the target organic EL material CBP.
  • Table 8 summarizes the NMR yield of the organic EL material CBP and the weight of the isolated CBP.
  • the catalyst turnover frequency (TOF) was 57.1 h -1 .
  • reaction example 31 A reaction solution I was prepared by dissolving 4-bromobenzoic acid (1809.2 mg, 9 mmol) in tetrahydrofuran (37.5 mL) and ethanol (7.5 mL) as solvents. On the other hand, phenylboronic acid (1317.1 mg, 10.8 mmol) and tripotassium phosphate (3820.9 mg, 18 mmol) were dissolved in pure water (45 mL) to prepare reaction solution II.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • the packed column tube was clamped into a flow reactor and heated to 70°C.
  • the prepared reaction solution I (0.15 mL/min) and reaction solution II (0.15 mL/min) were simultaneously sent to the flow reactor using a liquid sending pump.
  • the reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor.
  • reaction example 32 4-Bromophenol (1557.1 mg, 9 mmol) was dissolved in tetrahydrofuran (37.5 mL) and ethanol (7.5 mL) as solvents to give phenylboronic acid (1317.1 mg, 10.8 mmol) and tripotassium phosphate (3820.9 mg, 18 mmol) was dissolved in pure water (45 mL), and the same operation as in “Reaction Example 31" was performed to obtain the desired product 4-phenylphenol.
  • Table 9 summarizes the yield of 4-phenylphenol in the solution collected for each reaction time and the weight of isolated 4-phenylphenol.
  • the catalyst turnover frequency (TOF) was 64.3 h -1 .
  • reaction example 33 3-(4-bromobenzoyl)propionic acid (6941.7 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol) and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL). and prepared as a reaction solution.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • reaction example 34 3-(4-bromobenzoyl)propionic acid (6941.7 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol) and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL). and prepared as a reaction solution.
  • catalyst B1 23.0 mg (Pd: 2.346 mg, 0.0220 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • the catalyst of the present invention maintained high activity from immediately after the start of the reaction until the reaction time elapsed, and the pharmaceutical compound fenbufen was obtained in high yield. It was possible to carry out the reaction in an aqueous solvent.
  • reaction example 35 4-bromophenylacetic acid (5806.4 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol), and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL) to give a reaction solution of prepared.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C3 284.0 mg
  • sea sand about 9.3 g
  • reaction example 36 4-bromophenylacetic acid (5806.4 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol), and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL) to give a reaction solution of prepared.
  • catalyst B1 23.0 mg (Pd: 2.346 mg, 0.0220 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • the catalyst of the present invention maintained high activity from immediately after the start of the reaction to the elapse of the reaction time, and the medicinal compound felbinac was obtained in high yield. It was possible to carry out the reaction in an aqueous solvent.
  • the content of Pd in the crude product (measured by ICP-MS) at 4-5 hours was 0.63 ppm, which satisfies the impurity guidelines for pharmaceuticals, ICH Q3D standards for oral preparations and injections.
  • reaction example 45 To further investigate the advantages of the continuous-flow system of the present invention, continuous-flow synthesis was performed in which multiple products were synthesized in one continuous reaction by changing substrates during the reaction. After synthesizing felbinac by performing the reaction for 5 hours by the method of Reaction Example 36, the column reactor was washed with water at 70°C for 1 hour, the substrate was changed, the reaction was performed for another 5 hours to synthesize fenbufen, and the target product was analyzed. (Table 11-2). The yields of felbinac and fenbufen in the solution collected for each reaction time are summarized in FIG.
  • the yield of felbinac reached 91% and the yield of fenbufen reached 93%, indicating that this catalytic system can be applied to the synthesis of multiple targets without catalyst reloading.
  • reaction example 37 A reaction solution I was prepared by dissolving 4-bromotoluene (6157.4 mg, 36 mmol) and phenylboronic acid (5268.2 mg, 43.2 mmol) in tetrahydrofuran (100 mL) and ethanol (20 mL) as solvents. On the other hand, tripotassium phosphate (15283.4 mg, 72 mmol) was dissolved in pure water (60 mL) to prepare reaction solution II.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • the prepared reaction solution I 0.2 mL/min
  • reaction solution II 0.1 mL/min
  • the reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor.
  • the catalyst of the present invention maintained high activity even after 10 hours from the start of the reaction, and was able to synthesize the target product.
  • reaction example 38 4-bromobenzonitrile (6552.8 mg, 36 mmol) and 4-propoxyphenylboronic acid (7776.4 mg, 43.2 mmol) were dissolved in tetrahydrofuran (100 mL) and ethanol (20 mL) as solvents to give reaction solution I.
  • tripotassium phosphate (15283.4 mg, 72 mmol) was dissolved in pure water (60 mL) to prepare reaction solution II.
  • catalyst B4 56.8 mg (Pd: 2.386 mg, 0.0224 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • the prepared reaction solution I 0.2 mL/min
  • reaction solution II 0.1 mL/min
  • the reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor.
  • the catalyst of the present invention maintained high activity even after 10 hours from immediately after the start of the reaction, and was able to synthesize the target 3OCB, which is a liquid crystal material.
  • reaction example 39 3-(4-bromobenzoyl)propionic acid (13883.4 mg, 54 mmol), phenylboronic acid (7902.4 mg, 64.8 mmol) and tripotassium phosphate (22925.2 mg, 108 mmol) were dissolved in pure water (180 mL). and prepared as a reaction solution.
  • catalyst B1 23.0 mg (Pd: 2.346 mg, 0.0220 mmol)
  • crosslinked polymer material C2 284.0 mg
  • sea sand about 9.3 g
  • the catalyst of the present invention maintained high activity even after 10 hours from immediately after the start of the reaction, and was able to synthesize fenbufen, the target drug compound.
  • the content of Pd in the crude product (measured by ICP-MS) at 4-5 hours was 0.55 ppm, which satisfies the impurity guidelines for pharmaceuticals, ICH Q3D standards for oral preparations and injections.
  • reaction example 40 As a reaction solution for 8 hours, 3-(4-bromobenzoyl)propionic acid (11106.7 mg, 43.2 mmol), phenylboronic acid (6321.9 mg, 51.84 mmol), and tripotassium phosphate (18340.1 mg, 86.4 mmol) were pure. A reaction solution was prepared by dissolving in water (144 mL). Then, catalyst B1 (23.0 mg (Pd: 2.346 mg, 0.0220 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and using "catalyst filling method 2" , the packed column tube was secured in a flow reactor and heated to 70°C.
  • the prepared reaction solution (0.3 mL/min) was sent to the flow reactor.
  • the reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (2 hours/once) was started from the outlet of the flow reactor.
  • An aqueous solution of hydrochloric acid (1N) was added to the recovered reaction solution, followed by extraction with ethyl acetate. Butanoic acid) yield was calculated.
  • the column reactor was washed with pure water (0.3 mL/min) at 70° C., and the temperature of the reactor was lowered to room temperature.
  • the catalyst of the present invention With the catalyst of the present invention, a continuous reaction of 8 hours a day was repeated for 4 days, and even after a reaction time of 32 hours in total, the catalyst of the present invention was able to synthesize fenbufen, the target pharmaceutical compound, while maintaining high activity. . Further, according to the catalyst of the present invention, the activity was maintained even after repeating the reaction for 8 hours and the termination of the reaction.
  • reaction example 46 Furthermore, fenbufen was synthesized by continuous reaction for a long time, and the durability of the catalyst was confirmed. After 32 hours (4 days) of reaction in Reaction Example 40, further reaction was carried out (Table 15-2). The yield dropped to 75% on day 5 (Fig. 3, day 5), but impurities such as biphenyl and 2,4,6-triphenylboroxine (confirmed by gas chromatography-mass spectrometry) increased to 98% on the 6th day after washing the flow reactor with ethanol and water at 50 °C to remove the (Fig. 3, yield determined by gas chromatography). It was considered that the decrease in product yield was mainly due to the accumulation of insoluble organic compounds inside the column.
  • the recovered reaction mixture is acidified with an aqueous solution of hydrochloric acid, filtered, and the resulting powder is lyophilized to isolate the drug without using an organic solvent during isolation.
  • Immobilized palladium catalysts are divided into two types depending on the carrier.
  • Palladium supported on inorganic materials such as carbon and metal oxides is widely used in the chemical industry as a recoverable and reusable catalyst.
  • palladium is likely to be eluted from the carrier side and mixed into the product, which is an important problem in the synthesis of pharmaceuticals and the like.
  • organic materials typified by polymers are capable of electronic interaction with palladium and precise structural design.
  • a highly dispersed and stable immobilized palladium catalyst was developed in consideration of the electronic interaction and steric effect between the metal species and the polymer as the immobilizing material.
  • the designed crosslinked polymer was also prepared as a packing material for the reactor.
  • the reaction system is more environment- and resource-friendly.

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Abstract

The present invention addresses the problem of developing a metal catalyst which is suitable for continuous flow organic synthesis reaction, is excellent in durability, and has high activity.　The present invention provides an immobilized palladium catalyst comprising a complex composed of palladium and a copolymer formed from (A) a repeating unit that has a certain substituted aromatic hydrocarbon ring and (B) a repeating unit that has a certain nitrogen-containing aromatic hetero ring.

Description

固定化パラジウム触媒およびその製造方法、並びに同触媒のカップリング反応への応用Immobilized Palladium Catalyst, Production Method Thereof, and Application of the Catalyst to Coupling Reaction
　本発明は、固定化パラジウム触媒およびその製造方法、並びに同触媒を用いた連続フロー式鈴木-宮浦カップリング反応への応用等に関する。 The present invention relates to an immobilized palladium catalyst, a method for producing the same, and its application to a continuous-flow Suzuki-Miyaura coupling reaction using the same catalyst.
　鈴木-宮浦カップリング反応はパラジウム等の金属触媒を用い、有機ホウ素化合物と有機ハロゲン化合物をクロスカップリングさせてビフェニル誘導体を得る反応のことである。反応条件が比較的温和であり官能基選択性も高く、現在医農薬品合成、機能性材料製造等分野で幅広く利用されている。近年、環境に負荷を与えず、金属資源等を有効に利用するため、回収・再利用可能な不均一系金属触媒の研究開発が活発に行われている。例えば、特許文献1及び非特許文献1では、無機材料である炭化珪素に固定したパラジウム触媒、また有機材料であるポリ(4-ビニルピリジン)に固定したパラジウム触媒を利用すると、鈴木-宮浦カップリング反応を促進することが報告されている。しかし、これらの反応はバッチ式で実施されており、目的物を連続的に合成していない。 The Suzuki-Miyaura coupling reaction is a reaction that uses a metal catalyst such as palladium to cross-couple an organoboron compound and an organohalogen compound to obtain a biphenyl derivative. The reaction conditions are relatively mild and the functional group selectivity is high, so it is currently widely used in fields such as the synthesis of pharmaceuticals and agrochemicals and the production of functional materials. BACKGROUND ART In recent years, research and development of recoverable and reusable heterogeneous metal catalysts have been actively carried out in order to effectively use metal resources and the like without imposing a load on the environment. For example, in Patent Document 1 and Non-Patent Document 1, when a palladium catalyst fixed to silicon carbide, which is an inorganic material, and a palladium catalyst fixed to poly(4-vinylpyridine), which is an organic material, are used, Suzuki-Miyaura coupling reported to accelerate the reaction. However, these reactions are carried out in a batch system, and the desired products are not synthesized continuously.
　不均一系触媒を反応器に充填して基質を流通させることで目的物を連続的に得る反応は、より環境・資源にやさしい反応系として求められているが、バッチ式反応と比較すると、連続フロー式反応が先述した利点を有している一方、反応途中で金属溶出に伴い触媒活性が低下する問題が存在している。従来の技術において、連続フロー式鈴木-宮浦カップリング反応に向けた高性能かつ高耐久性の不均一系触媒系の報告例は少ない。例えば、特許文献２では、固体パラジウム触媒を充填したフロー式マイクロリアクターは多数のカップリング反応へと応用できたが、鈴木-宮浦カップリング反応の実施例はない。非特許文献2では、不均一系シリカベースパラジウム触媒SiliaCat DPP-Pdをカートリッジ式カラム管に充填して、短時間（5－10 min）で効率的に鈴木-宮浦カップリング反応の促進ができたが、触媒の耐久性を調査する実験例（8 h）が1つしかない。さらに、基質の範囲も限られ、特に電子供与性官能基を持つアリールハライドがこれらの反応条件に適用される例は少ない。 A reaction that continuously obtains the target product by filling a reactor with a heterogeneous catalyst and circulating the substrate is required as a reaction system that is more environmentally friendly and resource-friendly. While the flow-type reaction has the above-mentioned advantages, there is a problem that the catalytic activity is lowered due to metal elution during the reaction. In the prior art, there are few reports of high-performance and high-durability heterogeneous catalyst systems for continuous-flow Suzuki-Miyaura coupling reactions. For example, in Patent Document 2, a flow-type microreactor filled with a solid palladium catalyst could be applied to many coupling reactions, but there are no examples of Suzuki-Miyaura coupling reactions. In Non-Patent Document 2, a cartridge-type column tube was filled with a heterogeneous silica-based palladium catalyst, SiliaCat DPP-Pd, to efficiently promote the Suzuki-Miyaura coupling reaction in a short period of time (5-10 min). However, there is only one experimental example (8 hours) investigating the durability of the catalyst. Furthermore, the range of substrates is also limited, and there are few examples in which aryl halides with electron-donating functional groups, in particular, are applied to these reaction conditions.
　非特許文献3には、現在、鈴木-宮浦カップリング反応に広く使用されている不均一系シリカベースパラジウム触媒、及び不均一系炭素ベースパラジウム触媒を連続フロー式反応への応用を調査した際に、反応開始約1時間後に触媒活性の低下が顕著に現れることが報告されている。一方、非特許文献3では、合成したホスフィン樹脂に固定したパラジウム触媒を用いて、6時間以上連続的に使用することが可能であったが、反応中のホスフィン配位子の酸化を抑制することは難しく、触媒の活性や安定性はホスフィンの酸化状態に大きく影響された。非特許文献4では、架橋高分子材料にトリフェニルホスフィン構造を導入し、パラジウム種を固定化する配位子として開発した。この触媒を用いて連続フロー条件下で、4-クロロトルエンとフェニルボロン酸のクロスカップリング反応に成功したが、経時変化での活性の低下がみられ、有機合成化学への展開については報告されていない。また、先述した文献のように、ホスフィン類化合物は鈴木-宮浦カップリング反応条件下で酸化されやすく、開発した触媒は長時間で連続フロー反応に使用することは困難であった。そこで、反応中で酸化されることがなく、空気中で取り扱いの容易な固定化パラジウム触媒の開発が求められている。 In non-patent document 3, when investigating the application of heterogeneous silica-based palladium catalysts and heterogeneous carbon-based palladium catalysts, which are currently widely used for Suzuki-Miyaura coupling reactions, to continuous flow reactions , reported that a significant decrease in catalytic activity appeared about 1 hour after the start of the reaction. On the other hand, in Non-Patent Document 3, it was possible to use a palladium catalyst immobilized on a synthesized phosphine resin continuously for 6 hours or more, but it was possible to suppress the oxidation of the phosphine ligand during the reaction. was difficult, and the activity and stability of the catalyst were greatly affected by the oxidation state of the phosphine. In Non-Patent Document 4, a triphenylphosphine structure was introduced into a crosslinked polymer material and developed as a ligand for immobilizing palladium species. Using this catalyst, we succeeded in the cross-coupling reaction of 4-chlorotoluene and phenylboronic acid under continuous flow conditions. not In addition, as mentioned in the literature, phosphine compounds are easily oxidized under Suzuki-Miyaura coupling reaction conditions, making it difficult to use the developed catalyst for long-term continuous flow reactions. Therefore, the development of an immobilized palladium catalyst that is not oxidized during the reaction and is easy to handle in the air is desired.
　さらに、従来の連続フロー式鈴木-宮浦カップリング反応においては、反応剤と生成物を溶解するために、有機溶媒の使用が必要であり、水のみを溶媒として用いる報告例がなかった。しかし、有機溶媒は環境にとって有害であるため、近年、有機溶媒の代わりに、無毒・無害、かつ有機溶媒より極めて安価である水を合成反応に利用することが研究開発だけではなく、工業生産にも望まれている。従って、新規な触媒を用いた水中での連続フロー式鈴木-宮浦カップリング反応によって直接医農薬品等化合物を製造する技術は、戦略的に重要かつ環境負荷の低い革新的な技術である。 Furthermore, in the conventional continuous-flow Suzuki-Miyaura coupling reaction, it is necessary to use an organic solvent to dissolve the reactants and the product, and there have been no reports of using only water as the solvent. However, since organic solvents are harmful to the environment, in recent years, the use of water instead of organic solvents, which is non-toxic, harmless, and much cheaper than organic solvents, has become popular not only for research and development but also for industrial production. is also desired. Therefore, the technology to directly produce compounds such as pharmaceuticals and agrochemicals by the continuous-flow Suzuki-Miyaura coupling reaction in water using a new catalyst is an innovative technology that is strategically important and has a low environmental impact.
WO2014061087A1WO2014061087A1 JP4778710B2JP4778710B2
　本発明は、連続フロー式有機合成反応に好適な、耐久性に優れ、かつ高活性な金属触媒の開発を課題とする。 The object of the present invention is to develop a highly durable and highly active metal catalyst that is suitable for continuous-flow organic synthesis reactions.
　本発明者らは、上記課題を解決すべく鋭意検討を行った結果、高分子担体への金属種の分散性と安定性を向上させる方法を開発した。すなわち、触媒固定化用材料として、置換芳香族炭化水素環を含む繰り返し単位と含窒素芳香族ヘテロ環を含む繰り返し単位からなるコポリマー（共重合体）を開発した。また、例えば非特許文献5に報告された分子もつれ法により、同コポリマーにパラジウムを固定化した、固定化パラジウム触媒とすることで、パラジウムの分散性と安定性を向上させることができ、耐久性に優れ、かつ鈴木－宮浦クロスカップリング反応を高活性で触媒できることを知見した。このような知見に基づき、本発明は完成されたものである。さらに、同触媒は、有機溶媒のみならず、水系溶媒中でも、鈴木－宮浦クロスカップリング反応を触媒できる。 As a result of intensive studies aimed at solving the above problems, the present inventors have developed a method for improving the dispersibility and stability of metal species in polymer carriers. That is, as a material for immobilizing a catalyst, a copolymer (copolymer) composed of a repeating unit containing a substituted aromatic hydrocarbon ring and a repeating unit containing a nitrogen-containing aromatic heterocycle was developed. In addition, for example, by the molecular entanglement method reported in Non-Patent Document 5, by immobilizing palladium on the same copolymer to make an immobilized palladium catalyst, the dispersibility and stability of palladium can be improved, and durability It was found that this compound is excellent in catalysis and can catalyze the Suzuki-Miyaura cross-coupling reaction with high activity. Based on such findings, the present invention has been completed. Furthermore, the same catalyst can catalyze the Suzuki-Miyaura cross-coupling reaction not only in organic solvents but also in aqueous solvents.
　すなわち、本発明の要旨は以下のとおりである。
［１］　（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（B）下記式(II)で示される含窒素芳香族ヘテロ環を含む繰り返し単位、からなるコポリマー、ならびに、
　パラジウム、
　から構成される錯体を含む、固定化パラジウム触媒。 That is, the gist of the present invention is as follows.
[1] (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I), and (B) a repeating unit containing a nitrogen-containing aromatic heterocycle represented by the following formula (II) a copolymer consisting of
palladium,
An immobilized palladium catalyst comprising a complex consisting of:
　式中、
　RA1は、水素、またはアルキル基を表す；
　RA2は、触媒反応に関与しない不活性な基、または原子を表し、RA2はそれぞれ独立である；
　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、RA3はそれぞれ独立である；
　LAは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mAは、0以上の整数である；
　nAは、1以上の整数である；
　mA＋nAの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Aは、芳香族炭化水素環を表す； During the ceremony,
R A1 represents hydrogen or an alkyl group;
R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent;
R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent;
LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mA is an integer greater than or equal to 0;
nA is an integer greater than or equal to 1;
The upper limit of mA + nA is the number of possible replacements of the cyclic structure;
* represents the binding position;
Ring A represents an aromatic hydrocarbon ring;
　式中、
　RB1は、水素、またはアルキル基を表す；
　RB2は、触媒反応に関与しない不活性な基、または原子を表し、RB2はそれぞれ独立である；
　LBは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mBは、0以上の整数である；
　mBの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Bは、含窒素芳香族ヘテロ環を表す。
［２］　前記式(I)において、
　mAが、0であり；
　nAが、1であり；
　RA1が、水素であり；
　LAが、単結合であり；
　環Aが、ベンゼン環である、[１]に記載の固定化パラジウム触媒。
［３］　前記式(I)において、
　RA3が、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、オクチル基、フェニル基、メトキシ基、エトキシ基、プロポキシ基、またはブトキシ基である、［１］または［２］に記載の固定化パラジウム触媒。
［４］　前記式(II)において、
　mBが、0であり； 
　RB1が、水素であり；
　LBが、単結合であり；
　環Bが、ピリジン環、またはイミダール環である、［１］～［３］のいずれかに記載の固定化パラジウム触媒。
　［５］　連続フロー式反応用である、［１］～［４］のいずれかに記載の固定化パラジウム触媒。
　さらに、本発明の一態様は以下に関する。
　［１］～［４］のいずれかに記載の固定化パラジウム触媒の、連続フロー式反応用触媒としての使用。
　［６］　鈴木－宮浦クロスカップリング反応用である、［１］～［５］のいずれかに記載の固定化パラジウム触媒。
　さらに、本発明の一態様は以下に関する。
　［１］～［５］のいずれかに記載の固定化パラジウム触媒の、鈴木－宮浦クロスカップリング反応用触媒としての使用。
　［７］　［１］～［６］のいずれかに記載の触媒を含む、触媒組成物。
　［８］　（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（B）下記式(II)で示される含窒素芳香族ヘテロ環を含む繰り返し単位、からなるコポリマー。 During the ceremony,
R B1 represents hydrogen or an alkyl group;
RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent;
L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mB is an integer greater than or equal to 0;
The upper limit of mB is the number of possible substitutions of the cyclic structure;
* represents the binding position;
Ring B represents a nitrogen-containing aromatic heterocycle.
[2] In the above formula (I),
mA is 0;
nA is 1;
R A1 is hydrogen;
LA is a single bond;
The immobilized palladium catalyst according to [1], wherein ring A is a benzene ring.
[3] In the above formula (I),
R A3 is a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, octyl group, phenyl group, methoxy group, ethoxy group, propoxy group, or butoxy group [1] or [2] An immobilized palladium catalyst as described in .
[4] In the formula (II),
mB is 0;
R B1 is hydrogen;
L B is a single bond;
The immobilized palladium catalyst according to any one of [1] to [3], wherein ring B is a pyridine ring or an imidal ring.
[5] The immobilized palladium catalyst according to any one of [1] to [4], which is for continuous flow reaction.
Furthermore, one aspect of the present invention relates to the following.
Use of the immobilized palladium catalyst according to any one of [1] to [4] as a continuous flow reaction catalyst.
[6] The immobilized palladium catalyst according to any one of [1] to [5], which is for Suzuki-Miyaura cross-coupling reaction.
Furthermore, one aspect of the present invention relates to the following.
Use of the immobilized palladium catalyst according to any one of [1] to [5] as a catalyst for Suzuki-Miyaura cross-coupling reaction.
[7] A catalyst composition comprising the catalyst according to any one of [1] to [6].
[8] (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I), and (B) a repeating unit containing a nitrogen-containing aromatic heterocycle represented by the following formula (II) copolymer.
　式中、
　RA1は、水素、またはアルキル基を表す；
　RA2は、触媒反応に関与しない不活性な基、または原子を表し、RA1はそれぞれ独立である；
　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、RA2はそれぞれ独立である；
　LAは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mAは、0以上の整数である；
　nAは、1以上の整数である；
　mA＋nAの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Aは、芳香族炭化水素環を表す； During the ceremony,
R A1 represents hydrogen or an alkyl group;
R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A1 is independent;
R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A2 is independent;
LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mA is an integer greater than or equal to 0;
nA is an integer greater than or equal to 1;
The upper limit of mA + nA is the number of possible replacements of the cyclic structure;
* represents the binding position;
Ring A represents an aromatic hydrocarbon ring;
　式中、
　RB1は、水素、またはアルキル基を表す；
　RB2は、触媒反応に関与しない不活性な基、または原子を表し、RB2はそれぞれ独立である；
　LBは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mBは、0以上の整数である；
　mBの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Bは、含窒素芳香族ヘテロ環を表す。
　［９］　［８］に記載のコポリマーを含む、触媒固定化用材料。
　さらに、本発明の一態様は以下に関する。
　［８］に記載のコポリマーの、触媒固定化用材料としての使用。
　［１０］　（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（C）下記式(III)で示されるビニル置換芳香族炭化水素環を含む繰り返し単位、からなるコポリマーを含む、
　触媒反応装置用充填材料。 During the ceremony,
R B1 represents hydrogen or an alkyl group;
RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent;
L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mB is an integer greater than or equal to 0;
The upper limit of mB is the number of possible substitutions of the cyclic structure;
* represents the binding position;
Ring B represents a nitrogen-containing aromatic heterocycle.
[9] A material for immobilizing a catalyst, comprising the copolymer of [8].
Furthermore, one aspect of the present invention relates to the following.
Use of the copolymer according to [8] as a material for immobilizing a catalyst.
[10] (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by formula (I) below, and (C) a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring represented by formula (III) below, including copolymers consisting of
Packing material for catalytic reactors.
　式中、
　RA1は、水素、またはアルキル基を表す；
　RA2は、触媒反応に関与しない不活性な基、または原子を表し、RA2はそれぞれ独立である；
　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、RA3はそれぞれ独立である；
　LAは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mAは、0以上の整数である；
　nAは、1以上の整数である；
　mA＋nAの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Aは、芳香族炭化水素環を表す； During the ceremony,
R A1 represents hydrogen or an alkyl group;
R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent;
R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent;
LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mA is an integer greater than or equal to 0;
nA is an integer greater than or equal to 1;
The upper limit of mA + nA is the number of possible substitutions of the cyclic structure;
* represents the binding position;
Ring A represents an aromatic hydrocarbon ring;
　式中、
　RC1は、水素、またはアルキル基を表す；
　RC2は、触媒反応に関与しない不活性な基、または原子を表し、RC2はそれぞれ独立である；
　LCは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mCは、0以上の整数である；
　nCは、1以上の整数である；
　mC＋nCの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Cは、芳香族炭化水素環を表す。
　さらに、本発明の一態様は以下に関する。
　（A）上記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（C）上記式(III)で示されるビニル置換芳香族炭化水素環を含む繰り返し単位、からなるコポリマーの、触媒反応装置用充填材料としての使用。
　［１１］　［１］～［６］のいずれかに記載の触媒、または［７］に記載の触媒組成物の存在下、
　芳香族ハロゲン化物と芳香族ホウ素化合物を反応させ、鈴木－宮浦クロスカップリング反応を行う方法。
　［１２］　［１］～［６］のいずれかに記載の触媒、または［７］に記載の触媒組成物の存在下、
　芳香族ハロゲン化物と芳香族ホウ素化合物を反応させ、鈴木－宮浦クロスカップリング反応により多環式芳香族化合物を製造する工程を含む、多環式芳香族化合物の製造方法。 During the ceremony,
R C1 represents hydrogen or an alkyl group;
R C2 represents an inert group or atom that does not participate in the catalytic reaction, and each R C2 is independent;
L C represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mC is an integer greater than or equal to 0;
nC is an integer greater than or equal to 1;
The upper limit of mC + nC is the number of substitutable cyclic structural moieties;
* represents the binding position;
Ring C represents an aromatic hydrocarbon ring.
Furthermore, one aspect of the present invention relates to the following.
(A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the above formula (I); and (C) a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring represented by the above formula (III). as a packing material for catalytic reactors.
[11] In the presence of the catalyst according to any one of [1] to [6] or the catalyst composition according to [7],
A method in which an aromatic halide and an aromatic boron compound are reacted to perform a Suzuki-Miyaura cross-coupling reaction.
[12] In the presence of the catalyst according to any one of [1] to [6] or the catalyst composition according to [7],
A method for producing a polycyclic aromatic compound, comprising a step of reacting an aromatic halide and an aromatic boron compound to produce a polycyclic aromatic compound by Suzuki-Miyaura cross-coupling reaction.
　本発明は、新規な触媒固定化用材料、同材料に固定化された固定化パラジウム触媒を提供する。また、本発明は、本発明の触媒を用いた新規な鈴木－宮浦クロスカップリング方法を提供する。さらに、本発明は、本発明の触媒を用いた新規な多環式芳香族化合物の製造方法を提供する。
　本発明の触媒は、耐久性に優れ、かつ鈴木－宮浦クロスカップリング反応において高い触媒活性を有し、また、同触媒を用いた触媒系では、パラジウムの生成物への混入が抑制されている。 The present invention provides a novel catalyst immobilizing material and an immobilized palladium catalyst immobilized on the same material. The present invention also provides a novel Suzuki-Miyaura cross-coupling method using the catalyst of the present invention. Furthermore, the present invention provides a novel method for producing a polycyclic aromatic compound using the catalyst of the present invention.
The catalyst of the present invention has excellent durability and high catalytic activity in the Suzuki-Miyaura cross-coupling reaction, and in the catalyst system using the same catalyst, contamination of palladium in the product is suppressed. .
図１は、実施例における触媒の充填法を示す模式図である。FIG. 1 is a schematic diagram showing a catalyst filling method in an example. 図２は、実施例におけるフェルビナクおよびフェンブフェンの連続合成の結果を示す図である。FIG. 2 shows the results of continuous synthesis of felbinac and fenbufen in Examples. 図３は、実施例におけるフェンブフェンの連続合成の結果を示す図である。カラムリアクターは、使用後、水（70 ℃、1時間）で洗浄し、その後空気中で保存した。5日目、7日目、8日目は、使用後にカラムリアクターをEtOH（50 ℃、1時間）および水（70 ℃、1時間）で洗浄し、その後空気中で保存した。FIG. 3 shows the results of continuous synthesis of fenbufen in Examples. After use, the column reactor was washed with water (70°C, 1 hour) and then stored in air. On days 5, 7 and 8, the column reactor was washed with EtOH (50°C, 1 hour) and water (70°C, 1 hour) after use and then stored in air.
　以下、本発明の実施の形態について、詳細に説明する。
＜固定化パラジウム触媒＞
　本発明の一態様は、（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（B）下記式(II)で示される含窒素芳香族ヘテロ環を含む繰り返し単位、からなるコポリマー、ならびに、
　パラジウム、
　から構成される錯体を含む、固定化パラジウム触媒（以下、「本発明の触媒」ということがある）に関する。 BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described in detail.
<Immobilized palladium catalyst>
One embodiment of the present invention includes (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by formula (I) below, and (B) a nitrogen-containing aromatic heterocycle represented by formula (II) below. a copolymer consisting of repeating units, and
palladium,
It relates to an immobilized palladium catalyst (hereinafter sometimes referred to as "the catalyst of the present invention") containing a complex composed of.
　すなわち、本発明の触媒は、触媒活性部位としてパラジウム、配位子として（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（B）下記式(II)で示される含窒素芳香族ヘテロ環を含む繰り返し単位、からなるコポリマー（以下、「本発明のコポリマー」ということがある）を用いた、自己集合プロセスにより形成される錯体を含む触媒である。パラジウムは、含窒素芳香族ヘテロ環の窒素を介して、ポリマーを架橋し、高分子錯体を形成する。さらに、本発明の触媒は、置換芳香族炭化水素環上の置換基の電子効果と立体効果により、反応中により安定した金属種として、反応を促進すると考えられる。すなわち、本発明の触媒は、高分散型高分子固定化金属触媒とすることができる。このようにして形成される、コポリマーに固定化されたパラジウム錯体を、本発明の触媒として用いることができる。本発明の触媒は、パラジウムの分散性と安定性が向上され、耐久性に優れ、かつ鈴木－宮浦クロスカップリング反応等の反応を高活性で触媒できることから、連続フロー式反応において好適に用いることができる。 That is, the catalyst of the present invention has palladium as a catalytically active site, a repeating unit containing a substituted aromatic hydrocarbon ring represented by (A) the following formula (I) as a ligand, and (B) the following formula (II) A catalyst containing a complex formed by a self-assembly process using a copolymer (hereinafter sometimes referred to as "the copolymer of the present invention") consisting of a repeating unit containing a nitrogen-containing aromatic heterocycle represented by Palladium bridges the polymer through the nitrogen of the nitrogen-containing aromatic heterocycle to form a macromolecular complex. Additionally, the catalysts of the present invention are believed to promote the reaction as a more stable metal species during the reaction due to electronic and steric effects of the substituents on the substituted aromatic hydrocarbon ring. That is, the catalyst of the present invention can be a highly dispersed polymer-immobilized metal catalyst. The copolymer-immobilized palladium complex thus formed can be used as a catalyst in the present invention. The catalyst of the present invention improves the dispersibility and stability of palladium, is excellent in durability, and can catalyze reactions such as the Suzuki-Miyaura cross-coupling reaction with high activity. Therefore, it is suitable for use in continuous flow reactions. can be done.
＜コポリマー＞
　本発明において、触媒固定化用材料として用いられる本発明のコポリマーは、（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（B）下記式(II)で示される含窒素芳香族ヘテロ環を含む繰り返し単位、からなるコポリマーである。
　以下、本発明のコポリマーを構成する各繰り返し構成単位について説明する。 <Copolymer>
In the present invention, the copolymer of the present invention used as a catalyst immobilizing material comprises (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I), and (B) the following formula (II) It is a copolymer consisting of a repeating unit containing a nitrogen-containing aromatic heterocycle represented by
Each repeating structural unit constituting the copolymer of the present invention is described below.
≪置換芳香族炭化水素環を含む繰り返し構成単位≫
　本発明のコポリマーを構成する置換芳香族炭化水素環を含む繰り返し構成単位は、下記式(I)で示されるものである。 <<Repeating structural unit containing a substituted aromatic hydrocarbon ring>>
The repeating structural unit containing a substituted aromatic hydrocarbon ring that constitutes the copolymer of the present invention is represented by the following formula (I).
　式中、
　RA1は、水素、またはアルキル基を表す；
　RA2は、触媒反応に関与しない不活性な基、または原子を表し、RA2はそれぞれ独立である；
　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、RA3はそれぞれ独立である；
　LAは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mAは、0以上の整数である；
　nAは、1以上の整数である；
　mA＋nAの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Aは、芳香族炭化水素環を表す。 During the ceremony,
R A1 represents hydrogen or an alkyl group;
R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent;
R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent;
LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mA is an integer greater than or equal to 0;
nA is an integer greater than or equal to 1;
The upper limit of mA + nA is the number of possible replacements of the cyclic structure;
* represents the binding position;
Ring A represents an aromatic hydrocarbon ring.
　RA1は、水素、または直鎖、分岐または環状のアルキル基（炭素数1～12が好ましく、1～6がより好ましく、1～2が特に好ましい）を表す。この中で、RA1が、水素であることが好ましい。 R A1 represents hydrogen or a linear, branched or cyclic alkyl group (having preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 2 carbon atoms). Among these, R A1 is preferably hydrogen.
　RA2は、触媒反応に関与しない不活性な基、または原子であれば特に限定されず、例えば、ハロゲン、炭素数1～6のハロアルキル基、炭素数1～20の炭化水素基、炭素数1～20のアルコキシ基、ホルミル基、炭素数2～20のアシル基、炭素数2～20のアルコキシカルボニル基、シアノ基、ニトロ基等が挙げられる。 R A2 is not particularly limited as long as it is an inert group or atom that does not participate in the catalytic reaction. alkoxy groups of up to 20, formyl groups, acyl groups of 2 to 20 carbon atoms, alkoxycarbonyl groups of 2 to 20 carbon atoms, cyano groups, nitro groups and the like.
　ハロゲンとしては、例えば、フッ素、塩素、臭素、ヨウ素等が挙げられる。 Examples of halogen include fluorine, chlorine, bromine, and iodine.
　炭素数1～6（好ましくは1～2）のハロアルキル基としては、例えば、トリフルオロメチル基が挙げられる。 Examples of the haloalkyl group having 1 to 6 (preferably 1 to 2) carbon atoms include a trifluoromethyl group.
　炭素数1～20の炭化水素基としては、例えば、炭素数1～20（好ましくは1～6、より好ましくは1～2）のアルキル基であり、直鎖、分岐または環状のアルキル基であってよい。アルキル基の具体例は、後記RA3に説明されたものと同様である。 The hydrocarbon group having 1 to 20 carbon atoms is, for example, an alkyl group having 1 to 20 carbon atoms (preferably 1 to 6, more preferably 1 to 2), and may be a linear, branched or cyclic alkyl group. you can Specific examples of the alkyl group are the same as those described for RA3 below.
　炭素数1～20の炭化水素基としては、例えば、炭素数6～20（好ましくは6～18、より好ましくは6～12）のアリール基であってよい。アリール基の具体例は、後記RA3に説明されたものと同様である。 The hydrocarbon group having 1 to 20 carbon atoms may be, for example, an aryl group having 6 to 20 carbon atoms (preferably 6 to 18, more preferably 6 to 12). Specific examples of the aryl group are the same as those described for RA3 below.
　炭素数1～20のアルコキシ基（好ましくは1～6、より好ましくは1～2）の具体例は、後記RA3に説明されたものと同様である。 Specific examples of the alkoxy group having 1 to 20 carbon atoms (preferably 1 to 6, more preferably 1 to 2) are the same as those described in R A3 below.
　炭素数2～20（好ましくは2～6、より好ましくは2～3）のアシル基の具体例は、後記RA3に説明されたものと同様である。 Specific examples of the acyl group having 2 to 20 carbon atoms (preferably 2 to 6, more preferably 2 to 3) are the same as those described in R A3 below.
　上記炭素数2～20（好ましくは2～6、より好ましくは2～3）のアルコキシカルボニル基としては、メトキシカルボニル基、エトキシカルボニル基、n-プロポキシカルボニル基、イソプロポキシカルボニル基、n-ブトキシカルボニル基、イソブトキシカルボニル基、sec-ブトキシカルボニル基、tert-ブトキシカルボニル基等が挙げられる。 Examples of the alkoxycarbonyl group having 2 to 20 carbon atoms (preferably 2 to 6, more preferably 2 to 3) include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and n-butoxycarbonyl. group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group and the like.
　環Aは、1または複数の、同一または異なった置換基RA2を有していてよい。また、これらRA2はさらに置換基を有していてもよい。さらなる置換基の種類、置換位置、および置換基の個数等は特に限定されず、２個以上の置換基を有する場合には、それらは同一でも異なっていてもよい。置換基としては、例えば、アルキル基、アルコキシ基、ヒドロキシ基、カルボキシ基、ハロゲン、スルホ基、アミノ基、アルコキシカルボニル基、オキソ基等を挙げることができるが、これらに限定されることはない。環A上の置換基RA2は、炭素数1～2のアルキル基または炭素数1～2のアルコキシ基が好ましい。 Ring A may have one or more identical or different substituents R A2 . Moreover, these R A2 may further have a substituent. The type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like. The substituent R A2 on ring A is preferably a C 1-2 alkyl group or a C 1-2 alkoxy group.
　なお、環A上の置換基RA2の数mAは、反応に影響を及ぼさない限り限定されないが、0以上の整数であり、好ましくは0または1であり、より好ましくは0である。環A上の置換基RA2の置換位置は特に限定されない。 The number mA of substituents R A2 on ring A is not limited as long as it does not affect the reaction, but it is an integer of 0 or more, preferably 0 or 1, more preferably 0. The substitution position of the substituent RA2 on the ring A is not particularly limited.
　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、より具体的には、直鎖、分岐または環状のアルキル基（炭素数1～20が好ましく、1～8がより好ましく、1～4が特に好ましい）、アリール基（炭素数6～20が好ましく、6～18がより好ましく、6～12が特に好ましい）、直鎖、分岐または環状のアルコキシ基（炭素数1～20が好ましく、1～6がより好ましく、1～4が特に好ましい）、または直鎖、または分岐のアシル基（炭素数2～20が好ましく、2～6がより好ましく、2～3が特に好ましい）が挙げられる。 R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, more specifically, a linear, branched or cyclic alkyl group (having preferably 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms, 1 to 4 are particularly preferred), aryl groups (preferably 6 to 20 carbon atoms, more preferably 6 to 18 carbon atoms, particularly preferably 6 to 12 carbon atoms), linear, branched or cyclic alkoxy groups (preferably 1 to 20 carbon atoms preferably 1 to 6, particularly preferably 1 to 4), or a linear or branched acyl group (preferably 2 to 20 carbon atoms, more preferably 2 to 6, particularly preferably 2 to 3) mentioned.
　アルキル基の具体例としては、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、n-ペンチル基、2,2-ジメチルプロピル基、シクロペンチル基、n-ヘキシル基、シクロヘキシル基、n-ヘプチル基、2-メチルペンチル基、n-オクチル基、2-エチルヘキシル基、n-ノニル基、n-デシル基、n-ウンデシル基、n-ドデシル基、n-トリデシル基、n-テトラデシル基、n-ペンタデシル基、n-ヘキサデシル基、n-ヘプタデシル基、n-オクタデシル基、n-ノナデシル基、n-イコシル基等が挙げられる。 Specific examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2,2 -dimethylpropyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-heptyl group, 2-methylpentyl group, n-octyl group, 2-ethylhexyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group, n-icosyl group, etc. .
　アリール基の具体例としては、例えば、フェニル基、ナフチル基、インデニル基、ビフェニル基、アントラセニル基、フェナントレニル基等が挙げられる。 Specific examples of aryl groups include phenyl, naphthyl, indenyl, biphenyl, anthracenyl, and phenanthrenyl groups.
　アルコキシ基の具体例としては、例えば、メトキシ基、エトキシ基、n-プロポキシ基、イソプロポキシ基、n-ブトキシ基、sec-ブトキシ基、tert-ブトキシ基、n-ペンチルオキシ基、2,2-ジメチルプロポキシ基、n-ヘキシルオキシ基、シクロヘキシルオキシ基、n-ヘプチルオキシ基、n-オクチルオキシ基、n-ノニルオキシ基、n-デシルオキシ基、n-ウンデシルオキシ基、n-ドデシルオキシ基、n-トリデシルオキシ基、n-テトラデシルオキシ基、n-ペンタデシルオキシ基、n-ヘキサデシルオキシ基、n-ヘプタデシルオキシ基、n-オクタデシルオキシ基、n-ノナデシルオキシ基、n-イコシルオキシ基等が挙げられる。 Specific examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 2,2- dimethylpropoxy group, n-hexyloxy group, cyclohexyloxy group, n-heptyloxy group, n-octyloxy group, n-nonyloxy group, n-decyloxy group, n-undecyloxy group, n-dodecyloxy group, n -tridecyloxy group, n-tetradecyloxy group, n-pentadecyloxy group, n-hexadecyloxy group, n-heptadecyloxy group, n-octadecyloxy group, n-nonadecyloxy group, n-icosyloxy group, etc. is mentioned.
　アシル基の具体例としては、例えば、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、ベンゾイル基、ナフトイル基等が挙げられる。 Specific examples of acyl groups include acetyl, propionyl, butyryl, isobutyryl, benzoyl, and naphthoyl groups.
　RA3は、直鎖、または分岐のアルキル基、アリール基、または直鎖、または分岐のアルコキシ基であることが好ましく、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、オクチル基、フェニル基、メトキシ基、エトキシ基、プロポキシ基、またはブトキシ基であることがより好ましく、メチル基、tert-ブチル基、オクチル基、フェニル基、またはtert-ブトキシ基であることがさらに好ましくい。 R A3 is preferably a straight-chain or branched alkyl group, an aryl group, or a straight-chain or branched alkoxy group, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an octyl group, group, phenyl group, methoxy group, ethoxy group, propoxy group or butoxy group, more preferably methyl group, tert-butyl group, octyl group, phenyl group or tert-butoxy group. .
　環Aは、1または複数の、同一または異なった置換基RA3を有していてよい。また、これらRA3はさらに置換基を有していてもよい。さらなる置換基の種類、置換位置、および置換基の個数等は特に限定されず、２個以上の置換基を有する場合には、それらは同一でも異なっていてもよい。置換基としては、例えば、アルキル基、アルコキシ基、ヒドロキシ基、カルボキシ基、ハロゲン、スルホ基、アミノ基、アルコキシカルボニル基、オキソ基等を挙げることができるが、これらに限定されることはない。 Ring A may have one or more identical or different substituents R A3 . Moreover, these R A3 may further have a substituent. The type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like.
　なお、環A上の置換基RA3の数nAは、1以上の整数であり、好ましくは1または2であり、より好ましくは1である。環A上の置換基RA3の置換位置は特に限定されないが、コポリマー主鎖への環Aの結合位置に対してp-位の置換位置が好ましい。 The number nA of substituents R A3 on ring A is an integer of 1 or more, preferably 1 or 2, more preferably 1. The substitution position of the substituent R A3 on ring A is not particularly limited, but the substitution position p-position relative to the bonding position of ring A to the copolymer main chain is preferred.
　LAは、単結合、アルキレン基（炭素数1～12が好ましく、1～6がより好ましく、1～3が特に好ましい）、アリーレン基（炭素数6～22が好ましく、6～14がより好ましい）、ヘテロ原子（酸素、窒素、硫黄が好ましい）、またはそれらの組合せを表す。この中で、LAが、単結合、メチレン基、エチレン基、プロピレン基、または酸素であることが好ましく、単結合であることがより好ましい。 LA is a single bond, an alkylene group (preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, particularly preferably 1 to 3 carbon atoms), an arylene group (preferably 6 to 22 carbon atoms, more preferably 6 to 14 ), heteroatoms (oxygen, nitrogen, sulfur are preferred), or combinations thereof. Among these, LA is preferably a single bond, a methylene group, an ethylene group, a propylene group, or oxygen, and more preferably a single bond.
　なお、隣接する置換基や連結基は、本発明の効果を損ねない範囲で、互いに結合して環を形成していてもよい。以下、特に断らない限り、本明細書において同様である。 Adjacent substituents and linking groups may be bonded to each other to form a ring as long as the effects of the present invention are not impaired. Hereinafter, unless otherwise specified, the same applies throughout the present specification.
　mA＋nAの上限は、環状構造部の置換可能数である。例えば、式(I)の環Aがベンゼン環であれば5である。 The upper limit of mA + nA is the number of substitutable cyclic structural moieties. For example, it is 5 if ring A in formula (I) is a benzene ring.
　環Aは、芳香族炭化水素環を表し、芳香族炭化水素環は、炭素原子のみにより環を形成している芳香環を意味する。芳香族炭化水素環は、単環であっても縮合環であってもよい。炭素数6～14の芳香族炭化水素環が好ましい。芳香族炭化水素環の例としては、ベンゼン環、ナフチレン環、アントラセン環、フェナントレン環等が挙げられ、ベンゼン環が好ましい。 Ring A represents an aromatic hydrocarbon ring, and the aromatic hydrocarbon ring means an aromatic ring formed only by carbon atoms. The aromatic hydrocarbon ring may be monocyclic or condensed. Aromatic hydrocarbon rings having 6 to 14 carbon atoms are preferred. Examples of aromatic hydrocarbon rings include benzene ring, naphthylene ring, anthracene ring, phenanthrene ring and the like, with benzene ring being preferred.
　置換芳香族炭化水素環を含む繰り返し単位の好ましい態様としては、限定されないが、例えば、上記式(I)において、mAが、0であり；nAが、1であり；RA1が、水素であり；LAが、単結合であり；環Aが、ベンゼン環である、下記式(I-1)で示されるものが挙げられる。RA3は、上記式(I)におけるものと同義であるが、直鎖、または分岐のアルキル基、アリール基、または直鎖、または分岐のアルコキシ基であることが好ましく、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、オクチル基、フェニル基、メトキシ基、エトキシ基、プロポキシ基、またはブトキシ基であることがより好ましく、メチル基、tert-ブチル基、オクチル基、フェニル基、またはtert-ブトキシ基であることがさらに好ましい。 Preferred embodiments of the repeating unit containing a substituted aromatic hydrocarbon ring include, but are not limited to, in formula (I) above, mA is 0; nA is 1; R A1 is hydrogen; L A is a single bond; Ring A is a benzene ring, and examples thereof include those represented by the following formula (I-1). R A3 has the same definition as in formula (I) above, but is preferably a linear or branched alkyl group, an aryl group, or a linear or branched alkoxy group, a methyl group, an ethyl group, more preferably propyl, butyl, pentyl, hexyl, octyl, phenyl, methoxy, ethoxy, propoxy or butoxy, methyl, tert-butyl, octyl or phenyl , or a tert-butoxy group.
　上記置換芳香族炭化水素環を含む繰り返し構成単位は、より好ましくは、4-メチルスチレン、4-tert-ブチルスチレン、4-n-オクチルスチレン、4-ビニルビフェニル、4-tert-ブトキシスチレン等に由来する繰り返し構成単位である。 The repeating structural unit containing the substituted aromatic hydrocarbon ring is more preferably 4-methylstyrene, 4-tert-butylstyrene, 4-n-octylstyrene, 4-vinylbiphenyl, 4-tert-butoxystyrene, or the like. It is a repeating unit derived from.
　コポリマーは、1種、または2種以上の置換芳香族炭化水素環を含む繰り返し構成単位から選択される繰り返し構成単位をコポリマー中に含むものであってよい。 The copolymer may contain repeating structural units selected from repeating structural units containing one or more substituted aromatic hydrocarbon rings.
　コポリマー中の置換芳香族炭化水素環を含む繰り返し構成単位の数は、繰り返し単位の合計数の50 ％以上、60 ％以上、70 ％以上、80 ％以上、90 ％以上、95 ％以上、99 ％以上であってよい。上限値は特になく、100 ％未満であってよい。また、コポリマー中の置換芳香族炭化水素環を含む繰り返し構成単位の数は、繰り返し単位の合計数の50 ％以上100 ％未満、60 ％以上100 ％未満、70 ％以上100 ％未満、80 ％以上100 ％未満、90％以上100 ％未満、95 ％以上100 ％未満、99 ％以上100 ％未満であってよい。 The number of repeating units containing substituted aromatic hydrocarbon rings in the copolymer is 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 99% of the total number of repeating units. or more. There is no particular upper limit, and it may be less than 100%. In addition, the number of repeating structural units containing a substituted aromatic hydrocarbon ring in the copolymer is 50% or more and less than 100% of the total number of repeating units, 60% or more and less than 100%, 70% or more and less than 100%, 80% or more It may be less than 100%, 90% or more and less than 100%, 95% or more and less than 100%, or 99% or more and less than 100%.
≪含窒素芳香族ヘテロ環を含む繰り返し構成単位≫
　本発明のコポリマーを構成する含窒素芳香族ヘテロ環を含む繰り返し構成単位は、下記式(II)で示されるものである。 <<Repeating structural unit containing a nitrogen-containing aromatic heterocycle>>
The repeating structural unit containing a nitrogen-containing aromatic heterocycle constituting the copolymer of the present invention is represented by the following formula (II).
　式中、
　RB1は、水素、またはアルキル基を表す；
　RB2は、触媒反応に関与しない不活性な基、または原子を表し、RB2はそれぞれ独立である；
　LBは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mBは、0以上の整数である；
　mBの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Bは、含窒素芳香族ヘテロ環を表す。 During the ceremony,
R B1 represents hydrogen or an alkyl group;
RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent;
L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mB is an integer greater than or equal to 0;
The upper limit of mB is the number of possible substitutions of the cyclic structure;
* represents the binding position;
Ring B represents a nitrogen-containing aromatic heterocycle.
　RB1は、水素、または直鎖、分岐または環状のアルキル基（炭素数1～12が好ましく、1～6がより好ましく、1～2が特に好ましい）を表す。この中で、RB1が、水素であることが好ましい。 R B1 represents hydrogen or a linear, branched or cyclic alkyl group (having preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 2 carbon atoms). Among these, R B1 is preferably hydrogen.
　RB2は、触媒反応に関与しない不活性な基、または原子であれば特に限定されず、例えば、ハロゲン、炭素数1～6のハロアルキル基、炭素数1～20の炭化水素基、炭素数1～20のアルコキシ基、ホルミル基、炭素数2～20のアシル基、炭素数2～20のアルコキシカルボニル基、シアノ基、ニトロ基等が挙げられる。 R B2 is not particularly limited as long as it is an inert group or atom that does not participate in the catalytic reaction. alkoxy groups of up to 20, formyl groups, acyl groups of 2 to 20 carbon atoms, alkoxycarbonyl groups of 2 to 20 carbon atoms, cyano groups, nitro groups and the like.
　触媒反応に関与しない不活性な基、または原子の具体例は、RA2に説明されたものと同様である。 Specific examples of inert groups or atoms that do not participate in catalytic reactions are the same as those described for RA2 .
　環Bは、1または複数の、同一または異なった置換基RB2を有していてよい。また、これらRB2はさらに置換基を有していてもよい。さらなる置換基の種類、置換位置、および置換基の個数等は特に限定されず、２個以上の置換基を有する場合には、それらは同一でも異なっていてもよい。置換基としては、例えば、アルキル基、アルコキシ基、ヒドロキシ基、カルボキシ基、ハロゲン、スルホ基、アミノ基、アルコキシカルボニル基、オキソ基等を挙げることができるが、これらに限定されることはない。環B上の置換基RB2は、炭素数1～2のアルキル基または炭素数1～2のアルコキシ基が好ましい。 Ring B may have one or more identical or different substituents R B2 . Moreover, these R B2 may further have a substituent. The type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like. The substituent R B2 on ring B is preferably an alkyl group having 1 to 2 carbon atoms or an alkoxy group having 1 to 2 carbon atoms.
　なお、環B上の置換基RB2の数mBは、反応に影響を及ぼさない限り限定されないが、0以上の整数であり、好ましくは0または1であり、より好ましくは0である。環B上の置換基RBの置換位置は特に限定されない。 The number mB of substituents R B2 on ring B is not limited as long as it does not affect the reaction, but it is an integer of 0 or more, preferably 0 or 1, more preferably 0. The substitution position of the substituent R B on ring B is not particularly limited.
　LBは、単結合、アルキレン基（炭素数1～12が好ましく、1～6がより好ましく、1～3が特に好ましい）、アリーレン基（炭素数6～22が好ましく、6～14がより好ましい）、ヘテロ原子（酸素、窒素、硫黄が好ましい）、またはそれらの組合せを表す。この中で、LBが、単結合、メチレン基、エチレン基、プロピレン基、または酸素であることが好ましく、単結合であることがより好ましい。 L B is a single bond, an alkylene group (preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, particularly preferably 1 to 3 carbon atoms), an arylene group (preferably 6 to 22 carbon atoms, more preferably 6 to 14 ), heteroatoms (oxygen, nitrogen, sulfur are preferred), or combinations thereof. Among these, LB is preferably a single bond, a methylene group, an ethylene group, a propylene group, or oxygen, and more preferably a single bond.
　mBの上限は、環状構造部の置換可能数である。例えば、式(II)の環Bがピリジン環であれば4であり、イミダゾール環であれば3である。 The upper limit of mB is the number of substitutable cyclic structural moieties. For example, it is 4 if ring B in formula (II) is a pyridine ring, and 3 if it is an imidazole ring.
　環Bは、含窒素芳香族ヘテロ環を表し、含窒素芳香族ヘテロ環は、炭素原子およびヘテロ原子により環を形成している芳香環であり、環構成ヘテロ原子に窒素原子を有するものを意味する。含窒素芳香族ヘテロ環に含まれる窒素原子の数は1～3個が好ましく、1個が好ましい。含窒素芳香族ヘテロ環は5員環または6員環が好ましい。また、含窒素芳香族ヘテロ環の環構成ヘテロ原子として、窒素原子に加えて他のヘテロ原子を含んでもよい。他のヘテロ原子としては、例えば、酸素原子および硫黄原子から選ばれる原子が挙げられる。 Ring B represents a nitrogen-containing aromatic heterocyclic ring, and the nitrogen-containing aromatic heterocyclic ring is an aromatic ring formed by carbon atoms and heteroatoms, and has a nitrogen atom as a ring-constituting heteroatom. do. The number of nitrogen atoms contained in the nitrogen-containing aromatic heterocycle is preferably 1 to 3, preferably 1. The nitrogen-containing aromatic heterocycle is preferably a 5- or 6-membered ring. In addition to the nitrogen atom, other heteroatoms may also be included as ring-constituting heteroatoms of the nitrogen-containing aromatic heterocyclic ring. Other heteroatoms include, for example, atoms selected from oxygen and sulfur atoms.
　含窒素芳香族ヘテロ環が6員環の場合、ピリジン環、ピリミジン環、ピリダジン環、ピラジン環、およびトリアジン環から選ばれる環が好ましく、ピリジン環、ピラジン環、トリアジン環がより好ましく、ピリジン環がさらに好ましくい。 When the nitrogen-containing aromatic hetero ring is a 6-membered ring, it is preferably a ring selected from a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, and a triazine ring, more preferably a pyridine ring, a pyrazine ring, and a triazine ring, and a pyridine ring. More preferable.
　また、含窒素芳香族ヘテロ環が5員環の場合、ピロール環、イミダゾール環、ピラゾール環、オキサゾール環、およびチアゾール環から選ばれる環が好ましく、イミダゾール環がより好ましい。 Further, when the nitrogen-containing aromatic hetero ring is a five-membered ring, a ring selected from a pyrrole ring, an imidazole ring, a pyrazole ring, an oxazole ring, and a thiazole ring is preferable, and an imidazole ring is more preferable.
　含窒素芳香族ヘテロ環を含む繰り返し単位の好ましい態様としては、限定されないが、例えば、上前記式(II)において、mBが、0であり；RB1が、水素であり；LBが、単結合であり；環Bが、ピリジン環、またはイミダール環である、下記式(II-1)で示されるものが挙げられる。 Preferred embodiments of the repeating unit containing a nitrogen-containing aromatic heterocycle include, but are not limited to, in formula (II) above , mB is 0; R B1 is hydrogen; is a bond; ring B is a pyridine ring or an imidal ring, and examples thereof include those represented by the following formula (II-1).
　上記含窒素ヘテロ環を含む繰り返し構成単位は、より好ましくは、2-ビニルピリジン、3-ビニルピリジン、4-ビニルピリジン、2-ビニルピラジン、1-ビニル-1,2,4-トリアゾール、1-ビニルイミダゾール等に由来する繰り返し構成単位であり、特に好ましくは、4-ビニルピリジン、1-ビニルイミダゾールに由来する繰り返し構成単位である。 The repeating structural unit containing the nitrogen-containing heterocycle is more preferably 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine, 2-vinylpyrazine, 1-vinyl-1,2,4-triazole, 1- It is a repeating structural unit derived from vinylimidazole or the like, and particularly preferably a repeating structural unit derived from 4-vinylpyridine or 1-vinylimidazole.
　コポリマーは、1種、または2種以上の含窒素ヘテロ環を含む繰り返し構成単位から選択される繰り返し構成単位をコポリマー中に含むものであってよい。 The copolymer may contain repeating structural units selected from repeating structural units containing one, two or more nitrogen-containing heterocycles.
　コポリマー中の含窒素ヘテロ環を含む繰り返し構成単位の数は、繰り返し単位の合計数の10 ％以上、20 ％以上、30 ％以上、40 ％以上、50 ％以上、60 ％以上、70 ％以上、80 ％以上、90 ％以上、95 ％以上、99 ％以上であってよい。上限値は特になく、100 ％未満であってよい。また、コポリマー中の含窒素ヘテロ環を含む繰り返し構成単位の数は、繰り返し単位の合計数の10 ％以上100 ％未満、20 ％以上100 ％未満、30 ％以上100％未満、40 ％以上100 ％未満、50 ％以上100 ％未満、60 ％以上100 ％未満、70 ％以上100 ％未満、80 ％以上100 ％未満、90 ％以上100 ％未満、95 ％以上100 ％未満、99 ％以上100 ％未満であってよい。 The number of repeating structural units containing a nitrogen-containing heterocycle in the copolymer is 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more of the total number of repeating units, 80% or more, 90% or more, 95% or more, or 99% or more. There is no particular upper limit, and it may be less than 100%. In addition, the number of repeating structural units containing a nitrogen-containing heterocycle in the copolymer is 10% or more and less than 100% of the total number of repeating units, 20% or more and less than 100%, 30% or more and less than 100%, 40% or more and 100% Less than 50% to less than 100%, 60% to less than 100%, 70% to less than 100%, 80% to less than 100%, 90% to less than 100%, 95% to less than 100%, 99% to less than 100% can be
　コポリマー中の(A)置換芳香族炭化水素環を含む繰り返し構成単位の数と、(B)含窒素ヘテロ環を含む繰り返し構成単位の数との比（(A):(B））は、例えば、1:1～5:1であってよく、好ましくは3:1～4:1であり、より好ましくは4:1である。 The ratio of (A) the number of repeating structural units containing a substituted aromatic hydrocarbon ring in the copolymer to the number of (B) repeating structural units containing a nitrogen-containing heterocycle ((A):(B)) is, for example, , 1:1 to 5:1, preferably 3:1 to 4:1, more preferably 4:1.
　コポリマーは、ランダムコポリマー、交互コポリマー、周期コポリマー（periodiccopolymer）、ブロックコポリマー（例えば、AB、ABA、ABC等）等のいずれであってもよいが、パラジウムの固定化性能の観点から、好ましくは、交互コポリマーである。 The copolymer may be a random copolymer, an alternating copolymer, a periodic copolymer, a block copolymer (e.g., AB, ABA, ABC, etc.), or the like. It is a copolymer.
　コポリマーの重量平均分子量は、限定されないが、1,000以上1,000,000以下、2,000以上500,000以下、3,000以上200,000以下、5,000以上100,000以下等であってよい。本発明において重量平均分子量の測定は、GPC（ゲルパーミエーションクロマトグラフィー）法で測定される値として定義する。 The weight average molecular weight of the copolymer is not limited, but may be 1,000 or more and 1,000,000 or less, 2,000 or more and 500,000 or less, 3,000 or more and 200,000 or less, 5,000 or more and 100,000 or less. In the present invention, the measurement of weight average molecular weight is defined as a value measured by GPC (gel permeation chromatography) method.
　本発明のコポリマーは、本願明細書の記載および化学合成分野における常法に基づき、調製することができる。例えば、置換芳香族炭化水素環を含む繰り返し単位を構成し得るモノマー、および、含窒素芳香族ヘテロ環を含む繰り返し単位繰り返し単位を構成し得るモノマーを、加温下、常圧下で混合することにより、不溶性のコポリマーが調製できる。このようにして形成されるコポリマーを、本発明のコポリマーとして用いることができる。置換芳香族炭化水素環を含む繰り返し単位を構成し得るモノマー、および、含窒素芳香族ヘテロ環を含む繰り返し単位繰り返し単位を構成し得るモノマーは、常法に基づき合成したものであってもよく、市販のものであってもよい。
　コポリマー調製後、所望により、公知の単離・精製方法、例えば、沈殿、ろ過、乾燥等の一般的な操作によって単離・精製することができる。 The copolymers of the present invention can be prepared based on the descriptions herein and conventional methods in the field of chemical synthesis. For example, by mixing a monomer capable of constituting a repeating unit containing a substituted aromatic hydrocarbon ring and a monomer capable of constituting a repeating unit containing a nitrogen-containing aromatic heterocycle under elevated temperature and normal pressure. , insoluble copolymers can be prepared. Copolymers thus formed can be used as the copolymers of the present invention. A monomer capable of constituting a repeating unit containing a substituted aromatic hydrocarbon ring, and a repeating unit containing a nitrogen-containing aromatic heterocycle A monomer capable of constituting a repeating unit may be synthesized according to a conventional method, It may be commercially available.
After preparing the copolymer, if desired, isolation and purification can be carried out by known isolation and purification methods, for example, general operations such as precipitation, filtration and drying.
　以下、本発明のコポリマーの製造方法の一態様として、モノマーとして4-ビニルピリジンおよび4-tert-ブチルスチレンを用いた場合を例示して説明するが、本発明は、この態様に限定されるものではない。 Hereinafter, as one embodiment of the method for producing the copolymer of the present invention, the case of using 4-vinylpyridine and 4-tert-butylstyrene as monomers will be described as an example, but the present invention is limited to this embodiment. isn't it.
　2種のモノマーの1-ドデカノール／トルエン溶液に、アゾビスイソブチロニトリルを添加しし、70 ℃で24時間攪拌すると、固体が生成する。固体を水とメタノールで洗浄し、ろ過、減圧乾燥する。
　この操作により、4-ビニルピリジン-co-4-tert-ブチルスチレンが得られる。 Azobisisobutyronitrile is added to a 1-dodecanol/toluene solution of the two monomers and stirred at 70° C. for 24 hours to form a solid. The solid is washed with water and methanol, filtered and dried under vacuum.
This operation gives 4-vinylpyridine-co-4-tert-butylstyrene.
　本発明の触媒の具体例として、例えば、下記に示す触媒B1-B10が挙げられるが、これらに限定されない。 Specific examples of the catalyst of the present invention include, but are not limited to, catalysts B1 to B10 shown below.
≪固定化パラジウム触媒の製造方法≫
　本発明の触媒は、本発明のコポリマーとパラジウム塩等のパラジウム化合物を用いて、本願明細書の記載および化学合成分野における常法に基づき、調製することができる。例えば、本発明のコポリマーとパラジウム塩等のパラジウム化合物を、加温下、常圧下で混合することにより、不溶性のコポリマーに固定化されたパラジウム錯体が調製できる。このようにして形成される、コポリマーに固定化されたパラジウム錯体を、本発明の触媒として用いることができる。本発明のコポリマーは、前記したように合成したものを用いることができる。パラジウム化合物は、常法に基づき合成したものであってもよく、市販のものであってもよい。
　触媒調製後、所望により、公知の単離・精製方法、例えば、沈殿、ろ過、乾燥等の一般的な操作によって単離・精製することができる。 <<Method for producing immobilized palladium catalyst>>
The catalyst of the present invention can be prepared using the copolymer of the present invention and a palladium compound such as a palladium salt, based on the description of the present specification and conventional methods in the field of chemical synthesis. For example, a palladium complex immobilized on an insoluble copolymer can be prepared by mixing the copolymer of the present invention with a palladium compound such as a palladium salt under elevated temperature and normal pressure. The copolymer-immobilized palladium complex thus formed can be used as a catalyst in the present invention. The copolymers of the present invention can be synthesized as described above. The palladium compound may be synthesized according to a conventional method, or may be commercially available.
After preparation of the catalyst, if desired, it can be isolated and purified by a known isolation and purification method, for example, general operations such as precipitation, filtration and drying.
　以下、本発明の触媒の製造方法の一態様として、コポリマーとして4-ビニルピリジン-co-4-tert-ブチルスチレン、パラジウム塩としてテトラクロロパラジウム酸アンモニウム(II)を用いた場合を例示して説明するが、本発明は、この態様に限定されるものではない。 Hereinafter, as one embodiment of the method for producing the catalyst of the present invention, the case of using 4-vinylpyridine-co-4-tert-butylstyrene as the copolymer and ammonium tetrachloropalladate (II) as the palladium salt will be described as an example. However, the present invention is not limited to this aspect.
　合成した4-ビニルピリジン-co-4-tert-ブチルスチレンの2-プロパノール溶液をテトラクロロパラジウム酸アンモニウム(II)水溶液と混合し、60 ℃で20時間攪拌すると、固体が生成する。固体を水とアセトンで洗浄し、吸引ろ過、真空乾燥する。
　この操作により、固定化パラジウム触媒が得られる。 A 2-propanol solution of the synthesized 4-vinylpyridine-co-4-tert-butylstyrene is mixed with an aqueous solution of ammonium tetrachloropalladate (II) and stirred at 60°C for 20 hours to form a solid. The solid is washed with water and acetone, suction filtered and vacuum dried.
This operation yields an immobilized palladium catalyst.
　触媒におけるパラジウムの担持量は、限定されないが、0.01～20重量％、0.1～15重量％、または1～12.5重量％等であり得る。 The amount of palladium supported on the catalyst is not limited, but may be 0.01-20% by weight, 0.1-15% by weight, or 1-12.5% by weight.
＜触媒組成物＞
　本発明の別の一態様は、本発明の触媒を含む、触媒組成物（以下、「本発明の触媒組成物」ということがある）に関する。 <Catalyst composition>
Another aspect of the present invention relates to a catalyst composition (hereinafter sometimes referred to as "catalyst composition of the present invention") containing the catalyst of the present invention.
　本発明の触媒組成物は、必要に応じて、公知の塩基、増粘剤、補強材、添加剤等の成分を含んでよい。 The catalyst composition of the present invention may contain components such as known bases, thickeners, reinforcing materials, additives, etc., if necessary.
　本発明の触媒組成物において用いる塩基としては、触媒反応を進行させ得るものであれば限定されないが、例えば、25 ℃の水溶液中における酸解離定数（pKa）が、5～14、7～13、または10～12のもの等を用いることができる。 The base used in the catalyst composition of the present invention is not limited as long as it can promote the catalytic reaction. For example, the acid dissociation constant (pKa) in an aqueous solution at 25 ° C. Or 10 to 12 or the like can be used.
　具体的には、例えば、ピリジン、メチルピリジン、ジメチルピリジン、N,N-ジメチル-4-アミノピリジン、N-メチルモルホリン（NMM）、N,N-ジメチルエチルアミン、N-メチルピペリジン、N,N-ジエチルメチルアミン、メチルアミン、ジメチルアミン、エチルアミン、トリエチルアミン、アニリン、ジメチルアニリン、シクロヘキシルアミン、N,N-ジイソプロピルエチルアミン、ジアザビシクロノネン（DBN）、ジアザビシクロウンデセン、ピペラジン、1,4-エチレンピペラジン、イミダゾール、オキサゾール、1,8-ビス（ジメチルアミノ）ナフタレン、1,4-ジアザビシクロ［2.2.2］オクタン、トリエタノールアミン、テトラメチルエチレンジアミン、ヘキサメチレンジアミン等の有機塩基；
　水酸化リチウム（LiOH）、水酸化ナトリウム（NaOH）、水酸化カリウム（KOH）、水酸化ルビジウム（RbOH）、水酸化セシウム（CsOH）、水酸化ベリリウム（Be(OH)2）、水酸化マグネシウム（Mg(OH)2）、水酸化カルシウム（Ca(OH)2）、水酸化ストロンチウム（Sr (OH)2）、水酸化バリウム（Ba(OH)2）、水酸化アルミニウム（Al(OH)3）、水酸化タリウム（TlOH）、水酸化鉄（II、III）（Fe(OH)2、Fe(OH)3）、水酸化マンガン（Mn(OH)2）、水酸化亜鉛（Zn(OH)2）、水酸化銅（II）（Cu(OH)2）、水酸化ランタン（La(OH)3）、炭酸水素ナトリウム（NaHCO3）、炭酸リチウム（Li2CO3）、炭酸ナトリウム（Na2CO3）、炭酸カリウム（K2CO3）、炭酸ルビジウム（Rb2CO3）、炭酸セシウム（Cs2CO3）、リン酸三リチウム（Li3PO4）、リン酸三ナトリウム（Na3PO4）、リン酸三カリウム（K3PO4）、リン酸水素二ナトリウム（Na2HPO4）、リン酸水素二カリウム（K2HPO4）、リチウムtert-ブトキシド（LiOBu）、ナトリウムtert-ブトキシド（NaOBu）、カリウムtert-ブトキシド（KOBu）、フッ化カリウム（KF）、フッ化セシウム（CsF）、テトラブチルアンモニウムフロリド（Bu4NF）、ナトリウムメトキシド（NaOMe）、アンモニア（NH3）、等の無機塩基；またはこれらの塩基と反応して得られる塩が挙げられる。また、これらの塩基は置換基を有していてもよい。塩基は、これらのうち、1種または2種以上を組み合わせて用いることができる。塩基は、常法に基づき合成したものであってもよく、市販のものであってもよい。 Specifically, for example, pyridine, methylpyridine, dimethylpyridine, N,N-dimethyl-4-aminopyridine, N-methylmorpholine (NMM), N,N-dimethylethylamine, N-methylpiperidine, N,N- Diethylmethylamine, methylamine, dimethylamine, ethylamine, triethylamine, aniline, dimethylaniline, cyclohexylamine, N,N-diisopropylethylamine, diazabicyclononene (DBN), diazabicycloundecene, piperazine, 1,4-ethylene organic bases such as piperazine, imidazole, oxazole, 1,8-bis(dimethylamino)naphthalene, 1,4-diazabicyclo[2.2.2]octane, triethanolamine, tetramethylethylenediamine, hexamethylenediamine;
Lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), beryllium hydroxide (Be(OH) 2 ), magnesium hydroxide ( Mg(OH) 2 ), calcium hydroxide (Ca(OH) 2 ), strontium hydroxide (Sr(OH) 2 ), barium hydroxide (Ba(OH) 2 ), aluminum hydroxide (Al(OH) 3 ) , thallium hydroxide (TlOH), iron (II, III) hydroxide (Fe(OH) 2 , Fe(OH) 3 ), manganese hydroxide (Mn(OH) 2 ), zinc hydroxide (Zn(OH) 2 ), copper (II) hydroxide (Cu(OH) 2 ), lanthanum hydroxide (La(OH) 3 ), sodium hydrogen carbonate (NaHCO 3 ), lithium carbonate (Li 2 CO 3 ), sodium carbonate (Na 2 CO 3 ) , potassium carbonate ( K2CO3 ) , rubidium carbonate ( Rb2CO3 ), cesium carbonate ( Cs2CO3 ), trilithium phosphate ( Li3PO4 ), trisodium phosphate ( Na3PO4 ), tripotassium phosphate ( K3PO4 ), disodium hydrogen phosphate ( Na2HPO4 ), dipotassium hydrogen phosphate ( K2HPO4 ), lithium tert - butoxide (LiOBu), sodium tert- butoxide ( NaOBu), potassium tert-butoxide (KOBu), potassium fluoride (KF), cesium fluoride (CsF), tetrabutylammonium fluoride ( Bu4NF ), sodium methoxide (NaOMe), ammonia ( NH3 ), etc. inorganic bases; or salts obtained by reacting with these bases. Moreover, these bases may have a substituent. One or a combination of two or more of these bases can be used. The base may be one synthesized according to a conventional method, or may be commercially available.
　好ましくは、トリエチルアミン、N,N-ジイソプロピルエチルアミン、水酸化バリウム、水酸化タリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、リン酸三ナトリウム、リン酸三カリウム、フッ化カリウム、フッ化セシウム、テトラブチルアンモニウムフロリド、ナトリウムメトキシド等が挙げられ、より好ましくはリン酸三カリウムが挙げられる。 Preferably, triethylamine, N,N-diisopropylethylamine, barium hydroxide, thallium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate, tripotassium phosphate, potassium fluoride, cesium fluoride, tetrabutylammonium Fluoride, sodium methoxide, etc., and more preferably tripotassium phosphate.
　塩基の使用量は、基質である芳香族ハロゲン化物に対して、例えば、1当量～5当量、または1.2当量～3当量である。
　また、本明細書において、単に「当量」というときは、「mol当量」を意味する。 The amount of base used is, for example, 1 to 5 equivalents, or 1.2 to 3 equivalents, relative to the aromatic halide substrate.
Moreover, in the present specification, the term "equivalent" simply means "mol equivalent".
≪触媒固定化用材料≫
　前述のとおり、本発明のコポリマーは、金属種の分散性および安定性に優れ、耐久性に優れ、かつ高活性な金属触媒の製造を可能とする。すなわち、本発明のコポリマーは、触媒固定化用材料として好適に用いられる。本発明のコポリマーは、好ましくは、本発明の触媒の触媒固定化用材料として用いられる。
　すなわち、本発明の別の一態様は、本発明のコポリマーを含む、触媒固定化用材料（以下、「本発明の触媒固定化用材料」ということがある）に関する。 ≪Material for catalyst immobilization≫
As described above, the copolymers of the present invention enable the production of highly active metal catalysts with excellent dispersibility and stability of metal species, excellent durability and high activity. That is, the copolymer of the present invention is suitable for use as a material for immobilizing a catalyst. The copolymers of the invention are preferably used as catalyst immobilizing materials for the catalysts of the invention.
That is, another aspect of the present invention relates to a catalyst immobilizing material (hereinafter sometimes referred to as "catalyst immobilizing material of the present invention") containing the copolymer of the present invention.
　本発明のコポリマーを触媒固定化用材料として用いる手法は、本発明のコポリマーを用いる以外は、公知の手法に準ずる。
　触媒固定化用材料においては、本発明のコポリマー以外に、触媒固定化用材料における公知の補強材、添加剤等の成分を含んでよい。 Techniques for using the copolymer of the present invention as a material for immobilizing a catalyst follow known techniques, except that the copolymer of the present invention is used.
The catalyst-immobilizing material may contain, in addition to the copolymer of the present invention, components such as known reinforcing materials and additives for catalyst-immobilizing materials.
＜触媒反応装置用充填材料＞
　また、本発明の別の一態様は、（A）式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（C）式(III)で示されるビニル置換芳香族炭化水素環を含む繰り返し単位、からなるコポリマーを含む、触媒反応装置用充填材料（以下、「本発明の触媒反応装置用充填材料」、または単に「充填材料」ということがある）である。上記コポリマーは、架橋コポリマーを形成し、反応系における触媒の保持性に優れる。また、上記コポリマーは、パラジウムの分散性と安定性を向上させることができ、触媒の耐久性に優れ、かつ高活性な触媒反応を可能とする。すなわち、上記コポリマーは、触媒反応装置用充填材料として好適に用いられる。上記コポリマーは、好ましくは、本発明の触媒の触媒反応装置用充填材料として用いられる。 <Filling material for catalytic reactor>
In another aspect of the present invention, (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by formula (I), and (C) a vinyl-substituted aromatic hydrocarbon represented by formula (III) It is a filling material for a catalytic reactor (hereinafter sometimes referred to as "the filling material for a catalytic reactor of the present invention" or simply "filling material") containing a copolymer consisting of a repeating unit containing a ring. The above copolymer forms a crosslinked copolymer and is excellent in retention of the catalyst in the reaction system. In addition, the above copolymer can improve the dispersibility and stability of palladium, has excellent catalyst durability, and enables a highly active catalytic reaction. That is, the above copolymer is suitably used as a filling material for catalytic reactors. The above copolymers are preferably used as packing materials for catalytic reactors of the catalysts of the invention.
　式(I)で示される置換芳香族炭化水素環を含む繰り返し単位は、前記＜コポリマー＞の項に説明されたものと同様である。
　ビニル置換芳香族炭化水素環を含む繰り返し単位は、下記式(III)で示されるものである。 The repeating unit containing a substituted aromatic hydrocarbon ring represented by formula (I) is the same as described in the <Copolymer> section above.
A repeating unit containing a vinyl-substituted aromatic hydrocarbon ring is represented by the following formula (III).
　式中、
　RC1は、水素、またはアルキル基を表す；
　RC2は、触媒反応に関与しない不活性な基、または原子を表し、RC2はそれぞれ独立である；
　LCは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
　mCは、0以上の整数である；
　nCは、1以上の整数である；
　mC＋nCの上限は、環状構造部の置換可能数である；
　*は、結合位置を表す；
　環Cは、芳香族炭化水素環を表す。 During the ceremony,
R C1 represents hydrogen or an alkyl group;
R C2 represents an inert group or atom that does not participate in the catalytic reaction, and each R C2 is independent;
L C represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
mC is an integer greater than or equal to 0;
nC is an integer greater than or equal to 1;
The upper limit of mC + nC is the number of substitutable cyclic structural moieties;
* represents the binding position;
Ring C represents an aromatic hydrocarbon ring.
　ビニル置換芳香族炭化水素環を含む繰り返し構成単位は、置換基としてビニル基を有し、コポリマー中に架橋構造を形成する。 A repeating structural unit containing a vinyl-substituted aromatic hydrocarbon ring has a vinyl group as a substituent and forms a crosslinked structure in the copolymer.
　なお、環C上のビニル基の数nCは、1以上の整数であり、好ましくは1または2であり、より好ましくは1である。環C上のビニル基の置換位置は特に限定されないが、コポリマー主鎖への環Cの結合位置に対してm-またはp-位の置換位置が好ましい。 The number nC of vinyl groups on ring C is an integer of 1 or more, preferably 1 or 2, more preferably 1. The substitution position of the vinyl group on ring C is not particularly limited, but the substitution position m- or p-position relative to the bonding position of ring C to the copolymer main chain is preferred.
　RC1は、水素、または直鎖、分岐または環状のアルキル基（炭素数1～12が好ましく、1～6がより好ましく、1～2が特に好ましい）を表す。この中で、RC1が、水素であることが好ましい。 R C1 represents hydrogen or a linear, branched or cyclic alkyl group (having preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and particularly preferably 1 to 2 carbon atoms). Among these, R C1 is preferably hydrogen.
　RC2は、触媒反応に関与しない不活性な基、または原子であれば特に限定されず、例えば、ハロゲン、炭素数1～6のハロアルキル基、炭素数1～20の炭化水素基、炭素数1～20のアルコキシ基、ホルミル基、炭素数2～20のアシル基、炭素数2～20のアルコキシカルボニル基、シアノ基、ニトロ基等が挙げられる。 R C2 is not particularly limited as long as it is an inert group or atom that does not participate in the catalytic reaction. alkoxy groups of up to 20, formyl groups, acyl groups of 2 to 20 carbon atoms, alkoxycarbonyl groups of 2 to 20 carbon atoms, cyano groups, nitro groups and the like.
　触媒反応に関与しない不活性な基、または原子の具体例は、RA2に説明されたものと同様である。 Specific examples of inert groups or atoms that do not participate in catalytic reactions are the same as those described for RA2 .
　環Cは、1または複数の、同一または異なった置換基RC2を有していてよい。また、これらRC2はさらに置換基を有していてもよい。さらなる置換基の種類、置換位置、および置換基の個数等は特に限定されず、２個以上の置換基を有する場合には、それらは同一でも異なっていてもよい。置換基としては、例えば、アルキル基、アルコキシ基、ヒドロキシ基、カルボキシ基、ハロゲン、スルホ基、アミノ基、アルコキシカルボニル基、オキソ基等を挙げることができるが、これらに限定されることはない。環C上の置換基RC2は、炭素数1～2のアルキル基または炭素数1～2のアルコキシ基が好ましい。 Ring C may have one or more identical or different substituents R C2 . Moreover, these R C2 may further have a substituent. The type, substitution position, number of substituents, etc. of further substituents are not particularly limited, and when there are two or more substituents, they may be the same or different. Examples of substituents include, but are not limited to, alkyl groups, alkoxy groups, hydroxy groups, carboxy groups, halogens, sulfo groups, amino groups, alkoxycarbonyl groups, oxo groups, and the like. The substituent R C2 on ring C is preferably a C 1-2 alkyl group or a C 1-2 alkoxy group.
　なお、環C上の置換基RC2の数mCは、反応に影響を及ぼさない限り限定されないが、0以上の整数であり、好ましくは0または1であり、より好ましくは0である。環C上の置換基RC2の置換位置は特に限定されない。 The number mC of substituents R C2 on ring C is not limited as long as it does not affect the reaction, but is an integer of 0 or more, preferably 0 or 1, more preferably 0. The substitution position of the substituent R C2 on the ring C is not particularly limited.
　LCは、単結合、アルキレン基（炭素数1～12が好ましく、1～6がより好ましく、1～3が特に好ましい）、アリーレン基（炭素数6～22が好ましく、6～14がより好ましい）、ヘテロ原子（酸素、窒素、硫黄が好ましい）、またはそれらの組合せを表す。この中で、LCが、単結合、メチレン基、エチレン基、プロピレン基、または酸素であることが好ましく、単結合であることがより好ましい。 L C is a single bond, an alkylene group (preferably 1 to 12 carbon atoms, more preferably 1 to 6, particularly preferably 1 to 3 carbon atoms), an arylene group (preferably 6 to 22 carbon atoms, more preferably 6 to 14 ), heteroatoms (oxygen, nitrogen, sulfur are preferred), or combinations thereof. Among these, L C is preferably a single bond, a methylene group, an ethylene group, a propylene group, or oxygen, and more preferably a single bond.
　mC＋nCの上限は、環状構造部の置換可能数である。例えば、式(III)の環Cがベンゼン環であれば5である。 The upper limit of mC + nC is the number of substitutable cyclic structural moieties. For example, it is 5 if ring C in formula (III) is a benzene ring.
　環Cは、芳香族炭化水素環を表し、芳香族炭化水素環は、炭素原子のみにより環を形成している芳香環を意味する。芳香族炭化水素環は、単環であっても縮合環であってもよい。炭素数6～14の芳香族炭化水素環が好ましい。芳香族炭化水素環の例としては、ベンゼン環、ナフチレン環、アントラセン環、フェナントレン環等が挙げられ、ベンゼン環が好ましい。 Ring C represents an aromatic hydrocarbon ring, and the aromatic hydrocarbon ring means an aromatic ring formed only by carbon atoms. The aromatic hydrocarbon ring may be monocyclic or condensed. Aromatic hydrocarbon rings having 6 to 14 carbon atoms are preferred. Examples of aromatic hydrocarbon rings include benzene ring, naphthylene ring, anthracene ring, phenanthrene ring and the like, with benzene ring being preferred.
　ビニル置換芳香族炭化水素環を含む繰り返し単位の好ましい態様としては、限定されないが、例えば、上記式(III)において、mCが、0であり；nCが、1であり；RC1が、水素であり；LCが、単結合であり；環Cが、ベンゼン環である、下記式(III-1)で示されるものが挙げられる。 Preferred embodiments of the repeating unit containing a vinyl-substituted aromatic hydrocarbon ring include, but are not limited to, in formula (III) above, mC is 0; nC is 1 ; L C is a single bond; Ring C is a benzene ring, and examples thereof include those represented by the following formula (III-1).
　上記ビニル置換芳香族炭化水素環を含む繰り返し構成単位は、より好ましくは、ジビニルベンゼン等に由来する繰り返し構成単位である。 The repeating structural unit containing the vinyl-substituted aromatic hydrocarbon ring is more preferably a repeating structural unit derived from divinylbenzene or the like.
　コポリマーは、1種、または2種以上のビニル置換芳香族炭化水素環を含む繰り返し構成単位から選択される繰り返し構成単位をコポリマー中に含むものであってよい。 The copolymer may contain repeating structural units selected from repeating structural units containing one, two or more vinyl-substituted aromatic hydrocarbon rings in the copolymer.
　コポリマー中のビニル置換芳香族炭化水素環を含む繰り返し構成単位の数は、繰り返し単位の合計数の1 ％以上、10 ％以上、50 ％以上、60 ％以上、70 ％以上、80 ％以上、90 ％以上、95 ％以上、99 ％以上であってよい。上限値は特になく、100 ％未満であってよい。また、コポリマー中のビニル置換芳香族炭化水素環を含む繰り返し構成単位の数は、繰り返し単位の合計数の1 ％以上100 ％未満、10 ％以上100 ％未満、50 ％以上100 ％未満、60 ％以上100 ％未満、70 ％以上100 ％未満、80 ％以上100 ％未満、90 ％以上100 ％未満、95 ％以上100 ％未満、99 ％以上100 ％未満であってよい。 The number of repeating units containing a vinyl-substituted aromatic hydrocarbon ring in the copolymer is 1% or more, 10% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% of the total number of repeating units. % or more, 95% or more, or 99% or more. There is no particular upper limit, and it may be less than 100%. In addition, the number of repeating structural units containing a vinyl-substituted aromatic hydrocarbon ring in the copolymer is 1% or more and less than 100% of the total number of repeating units, 10% or more and less than 100%, 50% or more and less than 100%, 60% 100% or more, 70% or more and less than 100%, 80% or more and less than 100%, 90% or more and less than 100%, 95% or more and less than 100%, or 99% or more and less than 100%.
　コポリマー中の置換芳香族炭化水素環を含む繰り返し構成単位の数と、ビニル置換芳香族炭化水素環を含む繰り返し構成単位の数との比（(A):(C））は、例えば、1:1～10:1であってよく、好ましくは3:1～4:1であり、より好ましくは4:1である。 The ratio of the number of repeating units containing a substituted aromatic hydrocarbon ring in the copolymer to the number of repeating units containing a vinyl-substituted aromatic hydrocarbon ring ((A):(C)) is, for example, 1: It may be 1-10:1, preferably 3:1-4:1, more preferably 4:1.
　上記コポリマーは、本願明細書の記載および化学合成分野における常法に基づき、調製することができる。例えば、置換芳香族炭化水素環を含む繰り返し単位を構成し得るモノマー、および、ビニル置換芳香族炭化水素環を含む繰り返し単位繰り返し単位を構成し得るモノマーを、加温下、常圧下で混合することにより、不溶性のコポリマーが調製できる。このようにして形成されるコポリマーを、上記コポリマーとして用いることができる。置換芳香族炭化水素環を含む繰り返し単位を構成し得るモノマー、および、ビニル置換芳香族炭化水素環を含む繰り返し単位繰り返し単位を構成し得るモノマーは、常法に基づき合成したものであってもよく、市販のものであってもよい。
　コポリマー調製後、所望により、公知の単離・精製方法、例えば、沈殿、ろ過、乾燥等の一般的な操作によって単離・精製することができる。 The above copolymers can be prepared based on the descriptions of this specification and conventional methods in the field of chemical synthesis. For example, a monomer capable of constituting a repeating unit containing a substituted aromatic hydrocarbon ring and a monomer capable of constituting a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring are mixed under elevated temperature and normal pressure. can prepare insoluble copolymers. The copolymer thus formed can be used as the copolymer. A monomer capable of forming a repeating unit containing a substituted aromatic hydrocarbon ring and a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring The monomer capable of forming a repeating unit may be synthesized according to a conventional method. , may be commercially available.
After preparing the copolymer, if desired, isolation and purification can be carried out by known isolation and purification methods, for example, general operations such as precipitation, filtration and drying.
　以下、上記コポリマーの製造方法の一態様として、モノマーとして4-tert-ブチルスチレンおよびジビニルベンゼンを用いた場合を例示して説明するが、本発明は、この態様に限定されるものではない。 As an embodiment of the method for producing the copolymer, the case where 4-tert-butylstyrene and divinylbenzene are used as monomers will be described below, but the present invention is not limited to this embodiment.
　2種のモノマーの1-ドデカノール／トルエン溶液に、アゾビスイソブチロニトリルを添加しし、70 ℃で24時間攪拌すると、固体が生成する。固体を水とメタノールで洗浄し、ろ過、減圧乾燥する。
　この操作により、上記コポリマーが得られる。 Azobisisobutyronitrile is added to a 1-dodecanol/toluene solution of the two monomers and stirred at 70° C. for 24 hours to form a solid. The solid is washed with water and methanol, filtered and dried under vacuum.
This operation yields the above copolymer.
＜触媒の用途ならびに触媒組成物を用いたクロスカップリング方法および製造方法＞
　本発明の触媒は、各種反応を触媒することができる。例えば、本発明の触媒は、鈴木－宮浦クロスカップリング反応による芳香族ハロゲン化物と芳香族ホウ素化合物等とのカップリングによる多環式芳香族化合物の合成反応に使用することができる。 <Application of catalyst and cross-coupling method and production method using catalyst composition>
The catalysts of the present invention are capable of catalyzing various reactions. For example, the catalyst of the present invention can be used in the synthesis reaction of polycyclic aromatic compounds by coupling aromatic halides with aromatic boron compounds or the like by Suzuki-Miyaura cross-coupling reaction.
　すなわち、本発明の一態様は、本発明の触媒の鈴木－宮浦クロスカップリング反応への用途に関する。
　また、本発明の一態様は、本発明の触媒または触媒組成物の存在下、芳香族ハロゲン化物と芳香族ホウ素化合物を反応させ、鈴木－宮浦クロスカップリング反応を行う方法（以下、「本発明のクロスカップリング方法」ということがある）に関する。
　また、本発明の一態様は、本発明の触媒または触媒組成物の存在下、芳香族ハロゲン化物と芳香族ホウ素化合物を反応させ、鈴木－宮浦クロスカップリング反応により多環式芳香族化合物を製造する工程を含む、多環式芳香族化合物の製造方法（以下、「本発明の多環式芳香族化合物の製造方法」ということがある）に関する。 That is, one aspect of the present invention relates to the use of the catalyst of the present invention for the Suzuki-Miyaura cross-coupling reaction.
Further, one aspect of the present invention is a method of performing a Suzuki-Miyaura cross-coupling reaction by reacting an aromatic halide and an aromatic boron compound in the presence of the catalyst or catalyst composition of the present invention (hereinafter referred to as "the present invention (sometimes referred to as "cross-coupling method").
Further, in one aspect of the present invention, in the presence of the catalyst or catalyst composition of the present invention, an aromatic halide and an aromatic boron compound are reacted to produce a polycyclic aromatic compound by a Suzuki-Miyaura cross-coupling reaction. The present invention relates to a method for producing a polycyclic aromatic compound (hereinafter sometimes referred to as “the method for producing a polycyclic aromatic compound of the present invention”), including the step of
　上記反応工程においては、本発明の触媒または触媒組成物と、芳香族ハロゲン化物と芳香族ホウ素化合物との接触を可能にする形態であれば、特に限定されず、使用することができる。例えば、本発明の触媒はベッドまたはカラムの形としてもよい。 In the above reaction step, any form that allows contact between the catalyst or catalyst composition of the present invention, the aromatic halide, and the aromatic boron compound is not particularly limited and can be used. For example, the catalyst of the invention may be in bed or column form.
≪芳香族ハロゲン化物≫
　本発明の本発明のクロスカップリング方法および多環式芳香族化合物の製造方法に基質として用いられる芳香族ハロゲン化物としては、具体的には、例えば、芳香族化合物の芳香族炭化水素基に含まれる水素の一部がハロゲンに置換された化合物、または芳香族ヘテロ環化合物の芳香族ヘテロ炭化水素基に含まれる水素の一部がハロゲンに置換された化合物である。 <<Aromatic Halide>>
Specific examples of the aromatic halide used as a substrate in the cross-coupling method and the method for producing a polycyclic aromatic compound of the present invention include: is a compound in which part of the hydrogen contained in the aromatic heterocyclic compound is substituted with halogen, or a compound in which part of the hydrogen contained in the aromatic heterohydrocarbon group of the aromatic heterocyclic compound is substituted with halogen.
　芳香族ハロゲン化物としては、例えば、下記式(A)で示される化合物を挙げることができる。
　Ar1-(X)m　　　(A)
（式中、Ar1は、炭素数6～30（好ましくは6～10）の芳香族炭化水素基または炭素数4～30（好ましくは4～8）の芳香族ヘテロ炭化水素基を表す；Xは、ハロゲンを表し、Xはそれぞれ独立である；mは1～3の整数である。） Examples of aromatic halides include compounds represented by the following formula (A).
Ar1- (X) m (A)
(wherein Ar 1 represents an aromatic hydrocarbon group having 6 to 30 carbon atoms (preferably 6 to 10) or an aromatic heterohydrocarbon group having 4 to 30 carbon atoms (preferably 4 to 8); represents a halogen, each X is independent; m is an integer from 1 to 3.)
　Ar1が表す芳香族炭化水素基とは、芳香族化合物に含まれる水素の一部が結合手となった基を意味する。Ar1が表す芳香族炭化水素基として具体的には、例えば、フェニル基等の単環芳香族炭化水素基、ビフェニル基、ナフチル基等の二環芳香族炭化水素基、フルオレニル基、アントラセニル基、フェナントレニル基等の三環芳香族炭化水素基等の多環芳香族炭化水素基（多環のいずれかが芳香族炭化水素基であるものを含む）を挙げることができる。 The aromatic hydrocarbon group represented by Ar 1 means a group in which a part of hydrogen contained in an aromatic compound serves as a bond. Specific examples of the aromatic hydrocarbon group represented by Ar 1 include, for example, monocyclic aromatic hydrocarbon groups such as phenyl group, bicyclic aromatic hydrocarbon groups such as biphenyl group and naphthyl group, fluorenyl group, anthracenyl group, Examples include polycyclic aromatic hydrocarbon groups such as tricyclic aromatic hydrocarbon groups such as phenanthrenyl groups (including those in which one of the polycyclic rings is an aromatic hydrocarbon group).
　Ar1が表す芳香族ヘテロ炭化水素基とは、芳香族性を有するヘテロ環式化合物に含まれる水素の一部が結合手となった基を意味する。芳香族ヘテロ炭化水素基に含まれるヘテロ原子としては、例えば、酸素、硫黄、窒素等が挙げられる。Ar1が表す芳香族ヘテロ炭化水素基として具体的には、例えば、フリル基、チオフェニル基、ピロリル基、ピラゾリル基、イミダゾリル基、ピリジル基、ピリミジル基、またはピラジル基等の単環芳香族ヘテロ炭化水素基、インドリル基、キノリル基、イソキノリル基、キノキサリル基、ベンゾフラニル基等の二環芳香族ヘテロ炭化水素基、カルバゾリル基、ジベンゾフラニル基等の三環芳香族ヘテロ炭化水素基等の多環芳香族炭化水素基（多環のいずれかが芳香族ヘテロ炭化水素基であるものを含む）を挙げることができる。 The aromatic heterohydrocarbon group represented by Ar 1 means a group in which a part of hydrogen contained in an aromatic heterocyclic compound serves as a bond. Heteroatoms contained in the aromatic heterohydrocarbon group include, for example, oxygen, sulfur, nitrogen and the like. Specific examples of aromatic heterohydrocarbon groups represented by Ar 1 include monocyclic aromatic heterohydrocarbons such as furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, and pyrazyl. Hydrogen group, indolyl group, quinolyl group, isoquinolyl group, quinoxalyl group, bicyclic aromatic heterohydrocarbon groups such as benzofuranyl group, polycyclic aromatic groups such as tricyclic aromatic heterohydrocarbon groups such as carbazolyl group and dibenzofuranyl group hydrocarbon groups (including those in which any of the polycycles is an aromatic heterohydrocarbon group).
　本発明に用いられる芳香族ハロゲン化物における芳香族炭化水素基または芳香族ヘテロ炭化水素基、およびAr1が表す芳香族炭化水素基または芳香族ヘテロ炭化水素基は、反応に影響しない置換基を有していてもよい。Ar1上の置換基は、上記環A上の触媒反応に関与しない不活性な基、または原子と同様である。さらに、ヒドロキシ基、カルボキシ基等であってもよい。Ar1は、1または複数の、同一または異なった置換基を有していてよい。Ar1の置換基は、好ましくは、ハロゲン、ハロアルキル基、アルキル基（カルボキシ基で置換されていてもよい）、アルコキシ基、ホルミル基、アシル基（カルボキシ基で置換されていてもよい）、単環または多環アリール基、単環または多環ヘテロアリール基、アルコキシカルボニル基、シアノ基、ニトロ基、ヒドロキシ基、カルボキシ基である。より好ましくは、フッ素、塩素、臭素；トリフルオロメチル基：メチル基、エチル基、n-プロピル基、n-ブチル基；カルボキシメチル基；メトキシ基、エトキシ基；ホルミル基、アセチル基；カルボキシプロピオニル基；フェニル基；メトキシカルボニル基、エトキシカルボニル基；ヒドロキシ基；カルボキシ基である。 The aromatic hydrocarbon group or aromatic heterohydrocarbon group in the aromatic halide used in the present invention and the aromatic hydrocarbon group or aromatic heterohydrocarbon group represented by Ar 1 have a substituent that does not affect the reaction. You may have The substituents on Ar 1 are the same as the inert groups or atoms on Ring A that do not participate in the catalytic reaction above. Furthermore, it may be a hydroxy group, a carboxy group, or the like. Ar 1 may have one or more same or different substituents. The substituents of Ar 1 are preferably halogen, haloalkyl group, alkyl group (optionally substituted with carboxyl group), alkoxy group, formyl group, acyl group (optionally substituted with carboxyl group), single A cyclic or polycyclic aryl group, a monocyclic or polycyclic heteroaryl group, an alkoxycarbonyl group, a cyano group, a nitro group, a hydroxy group and a carboxy group. More preferably, fluorine, chlorine, bromine; trifluoromethyl group: methyl group, ethyl group, n-propyl group, n-butyl group; carboxymethyl group; methoxy group, ethoxy group; formyl group, acetyl group; carboxypropionyl group phenyl group; methoxycarbonyl group, ethoxycarbonyl group; hydroxy group; carboxy group.
　なお、Ar1上の置換基の数は、反応に影響を及ぼさない限り限定されないが、好ましくは0～2である。Ar1上の置換基の置換位置は特に限定されない。なお、強い電子吸引性基等の場合、Xに対してp-位以外の置換位置が好ましい。 The number of substituents on Ar 1 is not limited as long as it does not affect the reaction, but preferably 0-2. The substitution position of the substituent on Ar 1 is not particularly limited. In the case of a strong electron-withdrawing group or the like, substitution positions other than the p-position with respect to X are preferred.
　Xは、ハロゲンを表し、Xはそれぞれ独立である。ハロゲンとしては、フッ素、塩素、臭素またはヨウ素等が挙げられ、好ましくは臭素である。mは、好ましくは1である。 　X represents a halogen, and each X is independent. Halogen includes fluorine, chlorine, bromine, iodine and the like, preferably bromine. m is preferably 1.
　芳香族ハロゲン化物としては、具体的には、4-ブロモフェノール、2-ブロモトルエン、3-ブロモトルエン、4-ブロモトルエン、4-ブロモアニソール、4-ブロモベンゾニトリル、4-ブロモベンズアルデヒド、1,3-ジブロモベンゼン、4-ブロモフルオロベンゼン、4-ブロモトリフルオロメチルベンゼン、4-ブロモアセチルベンゼン、4-ブロモ安息香酸、4-ブロモ安息香酸エチル、3-(4-ブロモベンゾイル)プロピオン酸、4-ブロモフェニル酢酸、2-ブロモジベンゾフラン、3-ブロモ-9-フェニルカルバゾール、9-(4-ブロモフェニル)カルバゾール等を挙げることができる。 Specific examples of aromatic halides include 4-bromophenol, 2-bromotoluene, 3-bromotoluene, 4-bromotoluene, 4-bromoanisole, 4-bromobenzonitrile, 4-bromobenzaldehyde, 1, 3-dibromobenzene, 4-bromofluorobenzene, 4-bromotrifluoromethylbenzene, 4-bromoacetylbenzene, 4-bromobenzoic acid, ethyl 4-bromobenzoate, 3-(4-bromobenzoyl)propionic acid, 4 -bromophenylacetic acid, 2-bromodibenzofuran, 3-bromo-9-phenylcarbazole, 9-(4-bromophenyl)carbazole and the like.
　なお、これら芳香族ハロゲン化物は1種を使用してもよいし、2種以上を併用してもよい。 These aromatic halides may be used singly or in combination of two or more.
≪芳香族ホウ素化合物≫
　本発明の本発明のクロスカップリング方法および多環式芳香族化合物の製造方法に基質として用いられる芳香族ホウ素化合物としては、特に限定されないが、芳香族炭化水素基を有する芳香族ボロン酸、芳香族ボロン酸エステル、有機ボラン、または有機ホウ酸塩等である。好ましくは、芳香族ボロン酸である。 ≪Aromatic Boron Compound≫
The aromatic boron compound used as a substrate in the cross-coupling method of the present invention and the method for producing a polycyclic aromatic compound of the present invention is not particularly limited. group boronic acid esters, organic boranes, organic borates, and the like. Aromatic boronic acids are preferred.
　芳香族ボロン酸および芳香族ボロン酸エステルとしては、例えば、下記式(B)で示される化合物を挙げることができる。
　Ar2-B(Y1)(Y2)　　　(B) Examples of aromatic boronic acids and aromatic boronic acid esters include compounds represented by the following formula (B).
Ar2 -B( Y1 )( Y2 ) (B)
（式中、Ar2は、炭素数6～30（好ましくは6～10）の芳香族炭化水素基を表す；Y1およびY2は、それぞれ独立に、ヒドロキシ基または炭素数1～4（好ましくは1～2）のアルコキシ基を表すか、またはY1とY2が結合して形成した炭素数1～8（好ましくは1～5）のアルキレンジオキシ基を表す。） (In the formula, Ar 2 represents an aromatic hydrocarbon group having 6 to 30 carbon atoms (preferably 6 to 10); Y 1 and Y 2 each independently represent a hydroxy group or 1 to 4 carbon atoms (preferably represents an alkoxy group of 1 to 2), or represents an alkylenedioxy group having 1 to 8 carbon atoms (preferably 1 to 5) formed by combining Y 1 and Y 2. )
　Ar2が表す芳香族炭化水素基は、上記Ar1が表す芳香族炭化水素基と同様である。好ましくは、単環芳香族炭化水素基、より好ましくは、フェニル基を挙げることができる。 The aromatic hydrocarbon group represented by Ar 2 is the same as the aromatic hydrocarbon group represented by Ar 1 above. A monocyclic aromatic hydrocarbon group is preferred, and a phenyl group is more preferred.
　本発明に用いられる芳香族ホウ素化合物における芳香族炭化水素基、Ar2が表す芳香族炭化水素基は、反応に影響しない置換基を有していてもよい。Ar2上の置換基は、上記環A上の触媒反応に関与しない不活性な基、または原子と同様である。さらに、ヒドロキシ基、カルボキシ基等であってもよい。Ar2は、1または複数の、同一または異なった置換基を有していてよい。Ar2の置換基は、好ましくは、ハロゲン、ハロアルキル基、アルキル基、アルコキシ基である。より好ましくは、フッ素、塩素、臭素；トリフルオロメチル基；メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、n-ペンチル基；メトキシ基、エトキシ基、n-プロポキシ基である。 The aromatic hydrocarbon group in the aromatic boron compound used in the present invention, the aromatic hydrocarbon group represented by Ar2 , may have a substituent that does not affect the reaction. The substituents on Ar 2 are the same as the inert groups or atoms on Ring A that do not participate in the catalytic reaction above. Furthermore, it may be a hydroxy group, a carboxy group, or the like. Ar 2 may have one or more same or different substituents. Ar 2 substituents are preferably halogens, haloalkyl groups, alkyl groups, alkoxy groups. More preferably fluorine, chlorine, bromine; trifluoromethyl group; methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl Group; methoxy group, ethoxy group, n-propoxy group.
　なお、Ar2上の置換基の数は、反応に影響を及ぼさない限り限定されないが、好ましくは0または1である。Ar2上の置換基の置換位置は特に限定されない。なお、強い電子吸引性基等の場合、-B(Y1)(Y2)に対してp-位以外の置換位置が好ましい。 Although the number of substituents on Ar 2 is not limited as long as it does not affect the reaction, it is preferably 0 or 1. The substitution position of the substituent on Ar 2 is not particularly limited. In the case of a strong electron-withdrawing group, substitution positions other than the p-position relative to -B(Y 1 )(Y 2 ) are preferred.
　Y1およびY2が表す炭素数1～4のアルコキシ基としては、例えば、メトキシ基、エトキシ基、n-プロポキシ基、n-ブトキシ基等が挙げられる。
　Y1とY2が結合して形成した炭素数1～8のアルキレンジオキシ基としては、直鎖または分岐のアルキレンを有するアルキレンジオキシ基が挙げられる。 The alkoxy group having 1 to 4 carbon atoms represented by Y 1 and Y 2 includes, for example, methoxy group, ethoxy group, n-propoxy group, n-butoxy group and the like.
Examples of the alkylenedioxy group having 1 to 8 carbon atoms formed by combining Y 1 and Y 2 include alkylenedioxy groups having linear or branched alkylene.
　芳香族ボロン酸エステルとしては、具体的には、2-フェニル-1,3,2-ジオキサボリナン、5,5-ジメチル-2-フェニル-1,3,2-ジオキサボリナン、2-フェニル-1,3,2-ジオキサボロラン等を挙げることができる。 Specific examples of aromatic boronic acid esters include 2-phenyl-1,3,2-dioxaborinane, 5,5-dimethyl-2-phenyl-1,3,2-dioxaborinane, 2-phenyl-1,3 ,2-dioxaborolan and the like.
　芳香族ボロン酸としては、フェニルボロン酸、4-メチルフェニルボロン酸、4-メトキシフェニルボロン酸、4-フルオロフェニルボロン酸、4-アミルフェニルボロン酸、4-プロポキシフェニルボロン酸、4-(9H-カルバゾール-9-イル)フェニルボロン酸等を挙げることができる。
　有機ボランとしては、例えば、トリフェニルボラン等のトリ有機ボラン等を挙げることができる。
　有機ホウ酸塩としては、例えば、トリフルオロ（フェニル）-λ4-ボランカリウム塩等のテトラ有機ホウ酸塩等を挙げることができる。
　なお、これら芳香族ホウ素化合物は1種を使用してもよいし、2種以上を併用してもよい。 Aromatic boronic acids include phenylboronic acid, 4-methylphenylboronic acid, 4-methoxyphenylboronic acid, 4-fluorophenylboronic acid, 4-amylphenylboronic acid, 4-propoxyphenylboronic acid, 4-(9H -carbazol-9-yl)phenylboronic acid and the like.
Examples of organic boranes include triorganoborane such as triphenylborane.
Examples of organic borates include tetraorganoborates such as trifluoro(phenyl)-λ 4 -borane potassium salt.
One of these aromatic boron compounds may be used, or two or more of them may be used in combination.
　上記製造方法に使用される芳香族ハロゲン化物、および芳香族ホウ素化合物は、公知の合成方法により合成したもの、および市販のものを使用することができる。 The aromatic halides and aromatic boron compounds used in the above production method can be those synthesized by known synthetic methods and those commercially available.
≪反応条件≫
　上記反応における条件等は、従来の鈴木－宮浦クロスカップリング反応を参照して行うことができる。 ≪Reaction conditions≫
The conditions and the like in the above reaction can be performed with reference to the conventional Suzuki-Miyaura cross-coupling reaction.
　より具体的には、鈴木－宮浦クロスカップリング反応であれば、芳香族ハロゲン化物と芳香族ホウ素化合物との反応割合（モル比）は、通常1：10～10：1、好ましくは1：1～1：5の範囲である。 More specifically, in the Suzuki-Miyaura cross-coupling reaction, the reaction ratio (molar ratio) between the aromatic halide and the aromatic boron compound is usually 1:10 to 10:1, preferably 1:1. ~1:5 range.
　上記触媒組成物の使用量としては、特に制限はなく、目的に応じて適宜選択することができるが、基質に対して、パラジウム換算として0.01 mol％～10 mol％、0.02 mol％～5 mol％または0.1 mol％～2 mol％であってよい。
　また、触媒反応装置用充填材料を用いる場合には、触媒組成物と触媒反応装置用充填材料の重量比率は、例えば1：3～1：8、1：4～1：7又は1：5～1：6の範囲であってよい。 The amount of the catalyst composition used is not particularly limited and can be appropriately selected according to the purpose. Or it may be from 0.1 mol % to 2 mol %.
In addition, when the packing material for the catalytic reaction device is used, the weight ratio of the catalyst composition and the packing material for the catalytic reaction device is, for example, 1:3 to 1:8, 1:4 to 1:7, or 1:5 to May be in the range of 1:6.
　反応温度は、反応液の組成や触媒の耐熱温度等を考慮して適宜選定することができるが、通常50～130 ℃である。反応温度は高いほど反応速度が速く効率的に反応が実施でき、低いほど触媒の劣化速度が遅くなり、反応を長時間連続的に実施できる。反応時間は、特に制限されないが、例えば、0.5分～100時間、1分～48時間等の範囲で設定される。また、反応が行われる雰囲気は、気相であれば、空気中でもかまわないが、窒素やアルゴン等の不活性ガス雰囲気下が好ましい。 The reaction temperature can be appropriately selected in consideration of the composition of the reaction solution and the heat resistance temperature of the catalyst, but it is usually 50-130°C. The higher the reaction temperature, the faster the reaction rate and the more efficient reaction can be carried out. Although the reaction time is not particularly limited, it is set in the range of, for example, 0.5 minutes to 100 hours, 1 minute to 48 hours, and the like. The atmosphere in which the reaction is carried out may be air as long as it is in a gaseous phase, but an atmosphere of an inert gas such as nitrogen or argon is preferred.
　反応が行われる雰囲気が液相であれば、上記反応に使用可能な溶媒は、反応原料と均一相をなすものが適しており、限定されないが、例えばテトラヒドロフラン、ジメトキシエタン、1,4-ジオキサン、シクロペンチルメチルエーテル等のエーテル溶媒、エタノール、tert-ブタノール等のアルコール溶媒、トルエン、キシレン等の芳香族溶媒、ジメチルスルホキシド、ジメチルホルムアミド等の非プロトン性極性溶媒、水等の水系溶媒等を用いることできる。これらの中で、テトラヒドロフラン、エタノール、水が好ましく用いることができる。反応系を流通する液の流速は、良好な混合状態を保ちつつかつ圧損が起こらない範囲で適宜設定し得るが、例えば0.1～10 mL/min、0.3 mL/min～1 mL/minであり得る。なお、反応系の流速（単位： mL/min）は、複数の溶液供給流路がある場合、それらの流速の合計値となる。 If the atmosphere in which the reaction is carried out is a liquid phase, the solvent that can be used in the above reaction is suitable for forming a homogeneous phase with the reaction raw materials. Examples include, but are not limited to, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, Ether solvents such as cyclopentyl methyl ether, alcohol solvents such as ethanol and tert-butanol, aromatic solvents such as toluene and xylene, aprotic polar solvents such as dimethylsulfoxide and dimethylformamide, and aqueous solvents such as water can be used. . Among these, tetrahydrofuran, ethanol and water are preferably used. The flow rate of the liquid flowing through the reaction system can be appropriately set within a range that maintains a good mixing state and does not cause pressure loss, and can be, for example, 0.1 to 10 mL/min, 0.3 mL/min to 1 mL/min. . In addition, the flow rate (unit: mL/min) of the reaction system is the total value of the flow rates when there are multiple solution supply channels.
　反応後、本発明の触媒または触媒組成物を洗浄溶媒で洗浄し、触媒または触媒組成物に残留する不純調製物を除去し、収率の低下を防止してもよい。使用する洗浄溶媒としては、本発明の触媒または触媒組成物が溶解しなければ特に制限はなく適宜選択することができ、具体的には、例えば、エタノール、tert-ブタノール等のアルコール系溶媒、水等の水系溶媒、それらの混合物等が挙げられる。洗浄時の温度は特に制限はなく選択することができるが、作業効率を考慮すると50～70 ℃等が好ましい。洗浄時間も特に制限されず、例えば、0.5～3時間等の範囲で設定される。液の流速も特に制限されず、例えば、0.3～1 mL/min等であってよい。 After the reaction, the catalyst or catalyst composition of the present invention may be washed with a washing solvent to remove impure preparations remaining in the catalyst or catalyst composition and prevent a decrease in yield. The washing solvent to be used is not particularly limited as long as it does not dissolve the catalyst or catalyst composition of the present invention, and can be appropriately selected. and other aqueous solvents, mixtures thereof, and the like. The temperature during washing can be selected without any particular limitation, but 50 to 70°C or the like is preferable in consideration of work efficiency. The washing time is also not particularly limited, and is set in the range of 0.5 to 3 hours, for example. The liquid flow rate is also not particularly limited, and may be, for example, 0.3 to 1 mL/min.
　反応後、所望により、公知の単離・精製方法、例えば、ろ過、濃縮、抽出、蒸留、昇華、再結晶、カラムクロマトグラフィー等の一般的な操作によって、生成物を単離・精製することができる。 After the reaction, if desired, the product can be isolated/purified by a known isolation/purification method such as filtration, concentration, extraction, distillation, sublimation, recrystallization, column chromatography, or other general operation. can.
　本発明の触媒の触媒活性は、限定されないが、例えば、収率（例えば、反応時間5時間または10時間後）が30 ％以上、40 ％以上、50 ％以上、60 ％以上、70 ％以上、80 ％以上、85 ％以上、90 ％以上、95 ％以上、99 ％以上である。収率は、公知の方法、例えば後記実施例に記載の方法で求めることができる。 The catalytic activity of the catalyst of the present invention is not limited. 80% or more, 85% or more, 90% or more, 95% or more, 99% or more. Yield can be determined by a known method, for example, the method described in Examples below.
　以下、実施例を挙げて本発明を具体的に説明する。ただし、本発明は以下の実施例の態様に限定されない。 The present invention will be specifically described below with reference to examples. However, the present invention is not limited to the aspects of the following examples.
＜材料および装置＞
　以下実施例に使用した主な薬品類、分析装置は次の通りである。
≪薬品類≫
(1) 　ポリ(4-ビニルピリジン)、Sigma-Aldrich、472352
(2) 　ポリ(4-ビニルピリジン-co-スチレン)、Sigma-Aldrich、192074
(3) 　4-ビニルピリジン、富士フィルム和光純薬
(4) 　4-tert-ブチルスチレン、東京化成工業
(5) 　4-tert-ブトキシスチレン、東京化成工業
(6) 　スチレンモノマー、富士フィルム和光純薬
(7) 　ジビニルベンゼン（m-, p-混合物）、東京化成工業
(8) 　アゾビスイソブチロニトリル、富士フィルム和光純薬
(9) 　テトラクロロパラジウム酸アンモニウム(II)、富士フィルム和光純薬
(10)　塩化パラジウム(II)六水和物、関東化学
(11)　硫酸銅(II)五水和物、富士フィルム和光純薬
(12) 　4-ブロモトルエン、東京化成工業
(13) 　フェニルボロン酸、東京化成工業
(14) 　りん酸三カリウム、富士フィルム和光純薬 <Materials and equipment>
Main chemicals and analyzers used in the following examples are as follows.
≪Drugs≫
(1) Poly(4-vinylpyridine), Sigma-Aldrich, 472352
(2) Poly(4-vinylpyridine-co-styrene), Sigma-Aldrich, 192074
(3) 4-Vinylpyridine, Fuji Film Wako Pure Chemical
(4) 4-tert-butylstyrene, Tokyo Chemical Industry
(5) 4-tert-butoxystyrene, Tokyo Chemical Industry
(6) Styrene Monomer, Fuji Film Wako Pure Chemical
(7) Divinylbenzene (m-, p-mixture), Tokyo Chemical Industry
(8) Azobisisobutyronitrile, Fuji Film Wako Pure Chemical
(9) Ammonium Tetrachloropalladate (II), Fuji Film Wako Pure Chemical
(10) Palladium(II) chloride hexahydrate, Kanto Chemical
(11) Copper(II) Sulfate Pentahydrate, Fuji Film Wako Pure Chemical
(12) 4-Bromotoluene, Tokyo Chemical Industry
(13) Phenylboronic Acid, Tokyo Chemical Industry
(14) Tripotassium Phosphate, Fuji Film Wako Pure Chemical
≪反応装置≫
(1) 　カラム型フローリアクター：東京理化器械株式会社製、MCR-1000型　カラムサイズ：内径10 mm×長さ10 cm
(2) 　高性能高圧タイプシリンジポンプ：株式会社ワイエムシィ製、YSP-301型
(3) 　純水製造装置Direct-Q 5UV：メルク株式会社製 ≪Reactor≫
(1) Column type flow reactor: MCR-1000 type manufactured by Tokyo Rikakikai Co., Ltd. Column size: 10 mm inner diameter x 10 cm long
(2) High-performance high-pressure syringe pump: Model YSP-301 manufactured by YMC Co., Ltd.
(3) Pure water production equipment Direct-Q 5UV: manufactured by Merck Ltd.
≪主な分析装置≫
(1) 　ガスクロマトグラフ：Agilent社製、6850 Series GC System、キャピラリーカラムJ&W Scientific、HP-1 (i.d. 0.32 mm、film thickness 0.25 μm、30 m)
(2) 　NMR装置：日本電子株式会社製、JNM ECA-500 NMR装置、1H NMR (500 MHz)、13C NMR (125 MHz)
(3) 　ICP質量分析装置: PerkinElmer社製、NexION 300D ≪Main analyzers≫
(1) Gas chromatograph: Agilent, 6850 Series GC System, capillary column J&W Scientific, HP-1 (id 0.32 mm, film thickness 0.25 μm, 30 m)
(2) NMR equipment: JNM ECA-500 NMR equipment manufactured by JEOL Ltd., 1 H NMR (500 MHz), 13 C NMR (125 MHz)
(3) ICP mass spectrometer: PerkinElmer, NexION 300D
1.触媒固定化用材料の合成
　触媒固定化用材料として、置換芳香族炭化水素環を含む繰り返し単位、および、含窒素芳香族ヘテロ環を含む繰り返し単位、を有する共重合体を、以下のようにして合成した。 1. Synthesis of catalyst immobilizing material As a catalyst immobilizing material, a copolymer having a repeating unit containing a substituted aromatic hydrocarbon ring and a repeating unit containing a nitrogen-containing aromatic heterocycle was prepared as follows. and synthesized.
「共重合体A1」
　4-ビニルピリジン（2102.8 mg, 20 mmol）及び4-tert-ブチルスチレン（3205.2 mg, 20 mmol）を、1-ドデカノール（10 mL）とトルエン（2 mL）の混合溶媒に添加し、磁気撹拌子を入れた後、反応容器内を窒素ガスで置換した。 "Copolymer A1"
4-Vinylpyridine (2102.8 mg, 20 mmol) and 4-tert-butylstyrene (3205.2 mg, 20 mmol) were added to a mixed solvent of 1-dodecanol (10 mL) and toluene (2 mL) and stirred with a magnetic stirrer. was introduced, the inside of the reaction vessel was replaced with nitrogen gas.
　次いで、アゾビスイソブチロニトリル（53.1 mg）を添加し、窒素ガスで置換した状態を保ちながら70 ℃で24時間撹拌させた。合成した高分子を純水及びメタノールで洗浄後、濾過し、減圧乾燥させることで、4-ビニルピリジン-co-4-tert-ブチルスチレンの共重合体A1（4512.6 mg、収率：85%）を得た。なお、元素分析の測定によって評価した共重合体A1の炭素の含有量は85.13%、水素の含有量は9.07％、窒素の含有量は5.04%であった。 Next, azobisisobutyronitrile (53.1 mg) was added, and the mixture was stirred at 70°C for 24 hours while the nitrogen gas was maintained. The synthesized polymer was washed with pure water and methanol, filtered, and dried under reduced pressure to obtain 4-vinylpyridine-co-4-tert-butylstyrene copolymer A1 (4512.6 mg, yield: 85%). got Copolymer A1, which was evaluated by elemental analysis, had a carbon content of 85.13%, a hydrogen content of 9.07%, and a nitrogen content of 5.04%.
「共重合体A2」
　4-ビニルピリジン（1261.7 mg, 12 mmol）、4-tert-ブチルスチレン（3846.2 mg, 24 mmol）、及びアゾビスイソブチロニトリル（51.1 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A2（3503.0 mg、収率：79%）を得た。元素分析の測定によって評価した共重合体A2の炭素の含有量は86.56%、水素の含有量は9.26％、窒素の含有量は3.74%であった。 "Copolymer A2"
Using 4-vinylpyridine (1261.7 mg, 12 mmol), 4-tert-butylstyrene (3846.2 mg, 24 mmol), and azobisisobutyronitrile (51.1 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A2 (3503.0 mg, yield: 79%). Copolymer A2 had a carbon content of 86.56%, a hydrogen content of 9.26% and a nitrogen content of 3.74% as determined by elemental analysis.
「共重合体A3」
　4-ビニルピリジン（788.6 mg, 7.5 mmol）、4-tert-ブチルスチレン（3605.9 mg, 22.5 mmol）、及びアゾビスイソブチロニトリル（43.9 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A3（3501.4 mg、収率：80%）を得た。元素分析の測定によって評価した共重合体A3の炭素の含有量は87.55%、水素の含有量は9.54％、窒素の含有量は2.55%であった。 "Copolymer A3"
Using 4-vinylpyridine (788.6 mg, 7.5 mmol), 4-tert-butylstyrene (3605.9 mg, 22.5 mmol), and azobisisobutyronitrile (43.9 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A3 (3501.4 mg, yield: 80%). Copolymer A3 had a carbon content of 87.55%, a hydrogen content of 9.54% and a nitrogen content of 2.55% as determined by elemental analysis.
「共重合体A4」
　4-ビニルピリジン（841.1 mg, 8 mmol）、4-tert-ブチルスチレン（5128.3 mg, 32 mmol）、及びアゾビスイソブチロニトリル（59.7 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A4（5191.2 mg、収率：87%）を得た。元素分析の測定によって評価した共重合体A4の炭素の含有量は87.71%、水素の含有量は9.69％、窒素の含有量は2.08%であった。 "Copolymer A4"
Using 4-vinylpyridine (841.1 mg, 8 mmol), 4-tert-butylstyrene (5128.3 mg, 32 mmol), and azobisisobutyronitrile (59.7 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A4 (5191.2 mg, yield: 87%). Copolymer A4 had a carbon content of 87.71%, a hydrogen content of 9.69% and a nitrogen content of 2.08% as determined by elemental analysis.
「共重合体A5」
　4-ビニルピリジン（841.1 mg, 8 mmol）、4-tert-ブチルスチレン（6410.4 mg, 40 mmol）、及びアゾビスイソブチロニトリル（72.5 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A5（7200.7 mg、収率：99%）を得た。元素分析の測定によって評価した共重合体A5の炭素の含有量は87.16%、水素の含有量は10.20％、窒素の含有量は1.54%であった。 "Copolymer A5"
Using 4-vinylpyridine (841.1 mg, 8 mmol), 4-tert-butylstyrene (6410.4 mg, 40 mmol), and azobisisobutyronitrile (72.5 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A5 (7200.7 mg, yield: 99%). Copolymer A5, as determined by elemental analysis, had a carbon content of 87.16%, a hydrogen content of 10.20% and a nitrogen content of 1.54%.
「共重合体A6」
　4-ビニルピリジン（841.1 mg, 8 mmol）、4-メチルスチレン（3781.8 mg, 32 mmol）、及びアゾビスイソブチロニトリル（46.2 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A6（3758.5 mg、収率：81%）を得た。 "Copolymer A6"
Using 4-vinylpyridine (841.1 mg, 8 mmol), 4-methylstyrene (3781.8 mg, 32 mmol), and azobisisobutyronitrile (46.2 mg), perform the same procedure as in the synthesis of copolymer A1. Thus, copolymer A6 (3758.5 mg, yield: 81%) was obtained.
「共重合体A7」
　4-ビニルピリジン（1261.7 mg, 12 mmol）、4-tert-ブトキシスチレン（6345.4 mg, 36 mmol）、及びアゾビスイソブチロニトリル（76.1 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A7（5720.5 mg、収率：75%）を得た。 "Copolymer A7"
Using 4-vinylpyridine (1261.7 mg, 12 mmol), 4-tert-butoxystyrene (6345.4 mg, 36 mmol), and azobisisobutyronitrile (76.1 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A7 (5720.5 mg, yield: 75%).
「共重合体A8」
　4-ビニルピリジン（157.7 mg, 1.5 mmol）、4-ビニルビフェニル（1081.5 mg, 6 mmol）、及びアゾビスイソブチロニトリル（12.4 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A8（798.8 mg、収率：64%）を得た。 "Copolymer A8"
Using 4-vinylpyridine (157.7 mg, 1.5 mmol), 4-vinylbiphenyl (1081.5 mg, 6 mmol), and azobisisobutyronitrile (12.4 mg), perform the same procedure as in the synthesis of copolymer A1. Thus, copolymer A8 (798.8 mg, yield: 64%) was obtained.
「共重合体A9」
　4-ビニルピリジン（841.1 mg, 8 mmol）、4-tert-ブチルスチレン（3846.2 mg, 24 mmol）、4-n-オクチルスチレン（1731.0 mg, 8 mmol）、及びアゾビスイソブチロニトリル（64.2 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A9（5802. 3 mg、収率：90%）を得た。 "Copolymer A9"
4-vinylpyridine (841.1 mg, 8 mmol), 4-tert-butylstyrene (3846.2 mg, 24 mmol), 4-n-octylstyrene (1731.0 mg, 8 mmol), and azobisisobutyronitrile (64.2 mg ), and the same procedure as in the synthesis of copolymer A1 was performed to obtain copolymer A9 (5802.3 mg, yield: 90%).
「共重合体A10」
　1-ビニルイミダゾール（753.0 mg, 8 mmol）、4-tert-ブチルスチレン（5128.3 mg, 32 mmol）、及びアゾビスイソブチロニトリル（58.8 mg）を用い、共重合体A1の合成と同様の操作を行うことにより、共重合体A10（4297.2 mg、収率：73%）を得た。 "Copolymer A10"
Using 1-vinylimidazole (753.0 mg, 8 mmol), 4-tert-butylstyrene (5128.3 mg, 32 mmol), and azobisisobutyronitrile (58.8 mg), the same procedure as in the synthesis of copolymer A1 to obtain copolymer A10 (4297.2 mg, yield: 73%).
2.固定化パラジウム触媒の合成
　固定化パラジウム触媒として、高分子固定化パラジウム触媒を、以下のようにして合成した。 2. Synthesis of Immobilized Palladium Catalyst As an immobilized palladium catalyst, a polymer-immobilized palladium catalyst was synthesized as follows.
「触媒B1」
　テトラクロロパラジウム酸アンモニウム(II)（142.2 mg, 0.5 mmol）を純水（50 mL）に添加し溶解させて、パラジウムの水溶液を調製した。 "Catalyst B1"
Ammonium tetrachloropalladate (II) (142.2 mg, 0.5 mmol) was added to and dissolved in pure water (50 mL) to prepare an aqueous solution of palladium.
　次いで、合成した共重合体A1（398.1 mg）を2-プロパノール（50 mL）に添加し、共重合体の溶液を調製した。次いで、この共重合体A1の溶液に調製したパラジウムの水溶液を0.5時間で滴下して、60 ℃で20時間撹拌させた。 Next, the synthesized copolymer A1 (398.1 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution. Next, the prepared aqueous solution of palladium was added dropwise to the solution of this copolymer A1 over 0.5 hours, and the mixture was stirred at 60° C. for 20 hours.
　生成した固体を純水及びアセトンで洗浄後、吸引濾過し、真空乾燥させることで、高分子固定化パラジウム触媒B1（452.3 mg、収率：93%）を得た。なお、ICP質量分析法の測定によって評価した触媒B1のPd担持量は10.2 wt%（Pd換算）であった。 The resulting solid was washed with pure water and acetone, filtered by suction, and dried in a vacuum to obtain polymer-immobilized palladium catalyst B1 (452.3 mg, yield: 93%). The amount of Pd supported on catalyst B1 evaluated by ICP mass spectrometry was 10.2 wt% (in terms of Pd).
「触媒B2」
　テトラクロロパラジウム酸アンモニウム(II)（94.7 mg, 0.33 mmol）、共重合体A2（425.7 mg）を用い、触媒B1の合成法と同様の操作を行うことにより、触媒B2（435.0 mg、収率：90%）を得た。ICP質量分析法の測定によって評価した触媒B2のPd担持量は6.0 wt%（Pd換算）であった。 "Catalyst B2"
Catalyst B2 (435.0 mg, yield: 90%) was obtained. The amount of Pd supported on catalyst B2 evaluated by ICP mass spectrometry was 6.0 wt% (in terms of Pd).
「触媒B3」
　テトラクロロパラジウム酸アンモニウム(II)（94.7 mg, 0.33 mmol）、共重合体A3（585.9 mg）を用い、触媒B1の合成法と同様の操作を行うことにより、触媒B3（567.1 mg、収率：88%）を得た。ICP質量分析法の測定によって評価した触媒B3のPd担持量は5.4 wt%（Pd換算）であった。 "Catalyst B3"
Catalyst B3 (567.1 mg, yield: 88%). The amount of Pd supported on catalyst B3 evaluated by ICP mass spectrometry was 5.4 wt% (in terms of Pd).
「触媒B4」
　テトラクロロパラジウム酸アンモニウム(II)（94.7 mg, 0.33 mmol）、共重合体A4（746.2 mg）を用い、触媒B1の合成法と同様の操作を行うことにより、触媒B4（744.5 mg、収率：92%）を得た。ICP質量分析法の測定によって評価した触媒B4のPd担持量は4.2 wt%（Pd換算）であった。 "Catalyst B4"
Catalyst B4 (744.5 mg, yield: 92%). The amount of Pd supported on catalyst B4 evaluated by ICP mass spectrometry was 4.2 wt% (in terms of Pd).
「触媒B5」
　テトラクロロパラジウム酸アンモニウム(II)（113.7 mg, 0.4 mmol）、共重合体A5（1087.7 mg）を用い、触媒B1の合成法と同様の操作を行うことにより、触媒B5（1031.6 mg、収率：89%）を得た。ICP質量分析法の測定によって評価した触媒B5のPd担持量は3.7 wt%（Pd換算）であった。 "Catalyst B5"
Catalyst B5 (1031.6 mg, yield: 89%). The amount of Pd supported on catalyst B5 evaluated by ICP mass spectrometry was 3.7 wt% (in terms of Pd).
「触媒B6」
　テトラクロロパラジウム酸アンモニウム(II)（94.7 mg, 0.33 mmol）を純水（50 mL）に添加し溶解させて、パラジウムの水溶液を調製した。 "Catalyst B6"
Ammonium tetrachloropalladate (II) (94.7 mg, 0.33 mmol) was added to and dissolved in pure water (50 mL) to prepare an aqueous solution of palladium.
　次いで、合成した共重合体A6（577.9 mg）を2-プロパノール（50 mL）に添加し、共重合体の溶液を調製した。次いで、この共重合体A6の溶液に調製したパラジウムの水溶液を0.5時間で滴下して、60 ℃で1時間撹拌させてから、さらに25 ℃で20時間撹拌させた。
生成した固体を純水及びアセトンで洗浄後、吸引濾過し、真空乾燥させることで、高分子固定化パラジウム触媒B6（569.8 mg、収率：89%）を得た。 Next, the synthesized copolymer A6 (577.9 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution. Next, the prepared aqueous solution of palladium was added dropwise to the solution of this copolymer A6 over 0.5 hours, and the mixture was stirred at 60° C. for 1 hour and further stirred at 25° C. for 20 hours.
The resulting solid was washed with pure water and acetone, filtered by suction, and dried in a vacuum to obtain polymer-immobilized palladium catalyst B6 (569.8 mg, yield: 89%).
「触媒B7」
　テトラクロロパラジウム酸アンモニウム(II)（94.7 mg, 0.33 mmol）を純水（50 mL）に添加し溶解させて、パラジウムの水溶液を調製した。 "Catalyst B7"
Ammonium tetrachloropalladate (II) (94.7 mg, 0.33 mmol) was added to and dissolved in pure water (50 mL) to prepare an aqueous solution of palladium.
　次いで、合成した共重合体A7（647.9 mg）を2-プロパノール（50 mL）に添加し、共重合体の溶液を調製した。次いで、この共重合体A7の溶液に調製したパラジウムの水溶液を0.5時間で滴下して、25 ℃で20時間撹拌させた。 Next, the synthesized copolymer A7 (647.9 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution. Next, the prepared aqueous solution of palladium was added dropwise to the solution of this copolymer A7 over 0.5 hours, and the mixture was stirred at 25°C for 20 hours.
　生成した固体を純水及びアセトンで洗浄後、吸引濾過し、真空乾燥させることで、高分子固定化パラジウム触媒B7（352.8 mg、収率：50%）を得た。 The resulting solid was washed with pure water and acetone, filtered by suction, and dried in a vacuum to obtain polymer-immobilized palladium catalyst B7 (352.8 mg, yield: 50%).
「触媒B8」
　テトラクロロパラジウム酸アンモニウム(II)（56.9 mg, 0.2 mmol）、共重合体A8（495.7 mg）を用い、触媒B6の合成法と同様の操作を行うことにより、触媒B8（445.0 mg、収率：84%）を得た。 "Catalyst B8"
Catalyst B8 (445.0 mg, yield: 84%).
「触媒B9」
　テトラクロロパラジウム酸アンモニウム(II)（94.7 mg, 0.33 mmol）、共重合体A9（802.3 mg）を用い、触媒B1の合成法と同様の操作を行うことにより、触媒B9（803.0 mg、収率：93%）を得た。 "Catalyst B9"
Catalyst B9 (803.0 mg, yield: 93%).
「触媒B10」
　テトラクロロパラジウム酸アンモニウム(II)（56.9 mg, 0.2 mmol）を純水（50 mL）に添加し溶解させて、パラジウムの水溶液を調製した。 "Catalyst B10"
Ammonium (II) tetrachloropalladate (56.9 mg, 0.2 mmol) was added to and dissolved in pure water (50 mL) to prepare an aqueous solution of palladium.
　次いで、合成した共重合体A10（441.1 mg）を2-プロパノール（50 mL）に添加し、共重合体の溶液を調製した。次いで、この共重合体A10の溶液に調製したパラジウムの水溶液を0.5時間で滴下して、25 ℃で48時間撹拌させた。 Next, the synthesized copolymer A10 (441.1 mg) was added to 2-propanol (50 mL) to prepare a copolymer solution. Next, the prepared palladium aqueous solution was added dropwise to the copolymer A10 solution over 0.5 hours, and the mixture was stirred at 25° C. for 48 hours.
　生成した固体を純水及びアセトンで洗浄後、吸引濾過し、真空乾燥させることで、高分子固定化パラジウム触媒B10（385.8 mg、収率：81%）を得た。 The resulting solid was washed with pure water and acetone, filtered by suction, and dried in a vacuum to obtain polymer-immobilized palladium catalyst B10 (385.8 mg, yield: 81%).
「触媒B11」（比較例）
　テトラクロロパラジウム酸アンモニウム(II)（378.1 mg, 1.33 mmol）、ポリ(4-ビニルピリジン)（420.0 mg）を用い、触媒B7の合成法と同様の操作を行うことにより、触媒B11（445.9 mg、収率：68%）を得た。 "Catalyst B11" (comparative example)
Catalyst B11 (445.9 mg, Yield: 68%).
「触媒B12」（比較例）
　テトラクロロパラジウム酸アンモニウム(II)（94.7 mg, 0.33 mmol）、ポリ(4-ビニルピリジン-co-スチレン)（203.0 mg）を用い、触媒B7の合成法と同様の操作を行うことにより、触媒B12（230.1 mg、収率：88%）を得た。 "Catalyst B12" (comparative example)
Using ammonium (II) tetrachloropalladate (94.7 mg, 0.33 mmol) and poly(4-vinylpyridine-co-styrene) (203.0 mg), Catalyst B12 was prepared in the same manner as in the synthesis of Catalyst B7. (230.1 mg, yield: 88%) was obtained.
3.触媒反応装置用充填材料の合成
　触媒反応装置用充填材料として、架橋された高分子材料を、以下のようにして合成した。 3. Synthesis of Filling Material for Catalytic Reactor As a packing material for catalytic reactor, a crosslinked polymeric material was synthesized in the following manner.
「架橋高分子材料C1」
　スチレンモノマー（2083.0 mg, 20 mmol）、ジビニルベンゼン(m-, p-混合物)（651.0 mg, 5 mmol）を、1-ドデカノール（10 mL）とトルエン（2 mL）の混合溶媒に添加し、磁気撹拌子を入れた後、反応容器内を窒素ガスで置換した。 "Crosslinked polymer material C1"
Styrene monomer (2083.0 mg, 20 mmol) and divinylbenzene (m-, p-mixture) (651.0 mg, 5 mmol) were added to a mixed solvent of 1-dodecanol (10 mL) and toluene (2 mL), followed by magnetic After inserting the stirrer, the inside of the reaction vessel was replaced with nitrogen gas.
　次いで、アゾビスイソブチロニトリル（27.3 mg）を添加し、窒素ガスで置換した状態を保ちながら70 ℃で24時間撹拌させた。合成した高分子を蒸留水及びメタノールで洗浄後、濾過し、減圧乾燥させることで、架橋高分子材料C1（2183.7 mg）を得た。 Next, azobisisobutyronitrile (27.3 mg) was added, and the mixture was stirred at 70°C for 24 hours while the nitrogen gas was maintained. The synthesized polymer was washed with distilled water and methanol, filtered, and dried under reduced pressure to obtain a crosslinked polymer material C1 (2183.7 mg).
「架橋高分子材料C2」
　4-tert-ブチルスチレン（8013.0 mg, 50 mmol）、ジビニルベンゼン(m-, p-混合物)（1627.4 mg, 12.5 mmol）、及びアゾビスイソブチロニトリル（96.4 mg）を用い、架橋高分子材料C1の合成と同様の操作を行うことにより、架橋高分子材料C2（8230.5 mg）を得た。 "Crosslinked polymer material C2"
Using 4-tert-butylstyrene (8013.0 mg, 50 mmol), divinylbenzene (m-, p-mixture) (1627.4 mg, 12.5 mmol), and azobisisobutyronitrile (96.4 mg), a crosslinked polymer material A crosslinked polymer material C2 (8230.5 mg) was obtained by performing the same operation as in the synthesis of C1.
「架橋高分子材料C3」
　4-tert-ブトキシスチレン（8813.0 mg, 50 mmol）、ジビニルベンゼン(m-, p-混合物)（1627.4 mg, 12.5 mmol）、及びアゾビスイソブチロニトリル（104.4 mg）を用い、架橋された高分子材料C1の合成と同様の操作を行うことにより、架橋された高分子材料C3（9961.0 mg）を得た。 "Crosslinked polymer material C3"
4-tert-butoxystyrene (8813.0 mg, 50 mmol), divinylbenzene (m-, p-mixture) (1627.4 mg, 12.5 mmol), and azobisisobutyronitrile (104.4 mg) A crosslinked polymeric material C3 (9961.0 mg) was obtained by performing the same operation as in the synthesis of the molecular material C1.
4. 触媒の充填方法
　触媒を、図１および以下のようにして、カラムに充填した。 4. Catalyst Packing Method The catalyst was packed in a column as shown in FIG. 1 and as follows.
「触媒の充填法1」
　合成した触媒Bxと海砂（約9.6 g）を混合し、ガラス製カートリッジ式カラム管（カラムサイズ：10 mm ID; 10 cm L）に充填した。カラム管の両末端にPTFEフィルターを装着し、そこに高分子固定化パラジウム触媒-海砂の混合物を充填し、連続フロー式鈴木-宮浦カップリング反応に用いた。 "Catalyst filling method 1"
The synthesized catalyst Bx and sea sand (about 9.6 g) were mixed and packed in a glass cartridge column tube (column size: 10 mm ID; 10 cm L). A PTFE filter was attached to both ends of the column tube, and a mixture of polymer-immobilized palladium catalyst and sea sand was packed therein and used for the continuous-flow Suzuki-Miyaura coupling reaction.
「触媒の充填法2」
　合成した触媒Bx、架橋された高分子材料C1-C3（284.0 mg）或いはセライト（284.0 mg）と海砂（約9.3 g）を混合し、ガラス製カートリッジ式カラム管（カラムサイズ：10 mm ID; 10 cm L）に充填した。カラム管の両末端にPTFEフィルターを装着し、そこに高分子固定化パラジウム触媒-架橋高分子材料（或いはセライト）-海砂の混合物を充填し、連続フロー式鈴木-宮浦カップリング反応に用いた。 "Catalyst filling method 2"
Synthesized catalyst Bx, crosslinked polymer material C1-C3 (284.0 mg) or celite (284.0 mg) and sea sand (about 9.3 g) were mixed, and a glass cartridge column tube (column size: 10 mm ID; 10 cm L). Both ends of the column tube were equipped with PTFE filters, which were filled with a mixture of polymer-immobilized palladium catalyst, crosslinked polymer material (or celite), and sea sand, and used for the continuous-flow Suzuki-Miyaura coupling reaction. .
「触媒の充填法3」
　合成した触媒Bx、架橋された高分子材料C2（284.0 mg）と海砂（約9.3 g）を混合し、ガラス製カートリッジ式カラム管（カラムサイズ：10 mm ID; 10 cm L）に充填した。図のように、カラム管の両末端にフィルターを装着し、そこに高分子固定化パラジウム触媒-架橋高分子材料-海砂の混合物を充填するとともに数枚（1-5枚）のフィルターを取り付けたパラジウム触媒充填カラム管を用意し、連続フロー式鈴木-宮浦カップリング反応に用いた。 "Catalyst filling method 3"
The synthesized catalyst Bx, crosslinked polymeric material C2 (284.0 mg) and sea sand (about 9.3 g) were mixed and packed in a glass cartridge column tube (column size: 10 mm ID; 10 cm L). As shown in the figure, filters are attached to both ends of the column tube, and a mixture of polymer-immobilized palladium catalyst, cross-linked polymer material, and sea sand is filled and several (1-5) filters are attached. A column tube packed with a palladium catalyst was prepared and used for the continuous-flow Suzuki-Miyaura coupling reaction.
5. 固定化金属触媒を用いた連続フロー式鈴木-宮浦カップリング反応
　固定化金属触媒を用いた連続フロー式鈴木-宮浦カップリング反応を、以下のようにして行った。 5. Continuous Flow Suzuki-Miyaura Coupling Reaction Using Immobilized Metal Catalysts Continuous flow Suzuki-Miyaura coupling reactions using immobilized metal catalysts were carried out as follows.
「反応例1-2」
　4-ブロモトルエン（3078.7 mg, 18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、反応溶液Iとして調製した。一方、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、反応溶液IIとして調製した。 "Reaction example 1-2"
A reaction solution I was prepared by dissolving 4-bromotoluene (3078.7 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents. On the other hand, tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
　次いで、下の図のように、触媒B11（10.0 mg (Pd:2.5 mg, 0.0235 mmol)）、触媒B12（18.9 mg (Pd:2.5 mg, 0.0235 mmol)）それぞれを海砂（約9.6 g）と混合し、「触媒の充填法1」を用いて、カートリッジ式カラムに充填した。充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液I（0.2 mL/min）及び反応溶液II（0.1 mL/min）を同時にフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に水を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物4-メチルビフェニルの収率を計算した。反応時間ごとに回収した溶液中の4-メチルビフェニルの収率を表1にまとめて示す。 Next, as shown in the figure below, catalyst B11 (10.0 mg (Pd: 2.5 mg, 0.0235 mmol)) and catalyst B12 (18.9 mg (Pd: 2.5 mg, 0.0235 mmol)) were mixed with sea sand (about 9.6 g). The mixture was mixed and packed into a cartridge column using "catalyst packing method 1". The packed column tube was fixed in a flow reactor and heated to 70°C. Using a feed pump, the prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously fed to the flow reactor. The reaction solution was heated to 70°C in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. After water was added to the collected reaction solution, extraction was performed with ethyl acetate, and the organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance, and the yield of the desired product 4-methylbiphenyl was calculated. Table 1 summarizes the yield of 4-methylbiphenyl in the solution collected for each reaction time.
「反応例3-7」
　触媒B1（23.0 mg (Pd:2.346 mg, 0.0220 mmol)）、触媒B2（34.3 mg (Pd:2.058 mg, 0. 0193 mmol)）、触媒B3（45.5 mg (Pd:2.457 mg, 0.0231 mmol)）、触媒B4（56.8 mg (Pd: 2.386 mg, 0.0224 mmol)）、触媒B5（67.9 mg (Pd:2.512 mg, 0.0236 mmol)）それぞれを海砂（約9.6 g）と混合し、「触媒の充填法1」を用いて、カートリッジ式カラムに充填した。次いで、「反応例1」と同様の操作を行うことにより、目的物4-メチルビフェニルを得た。反応時間ごとに回収した溶液中の4-メチルビフェニルの収率を表2にまとめて示す。 "Reaction example 3-7"
Catalyst B1 (23.0 mg (Pd: 2.346 mg, 0.0220 mmol)), Catalyst B2 (34.3 mg (Pd: 2.058 mg, 0. 0193 mmol)), Catalyst B3 (45.5 mg (Pd: 2.457 mg, 0.0231 mmol)), Catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)) and catalyst B5 (67.9 mg (Pd: 2.512 mg, 0.0236 mmol)) were mixed with sea sand (approximately 9.6 g), and the catalyst filling method 1 ” was used to fill the cartridge type column. Then, the target product 4-methylbiphenyl was obtained by performing the same operation as in "Reaction Example 1". Table 2 summarizes the yield of 4-methylbiphenyl in the solution collected for each reaction time.
　従来の触媒B11-B12を用いた反応例1-2（比較例）では、反応開始直後は触媒は活性を有したが、反応時間が経過すると活性が失われた。
　他方、本発明の触媒B1-B5（m：nは、触媒B1ではおおよそ1:1、触媒B2ではおおよそ1:2、触媒B3ではおおよそ1:3、触媒B4ではおおよそ1:4、触媒B5ではおおよそ1:5）を用いた反応例3-7では、反応開始直後から活性が高く、かつ、反応時間が経過しても活性が高く維持された。その結果、全収率も高かった。触媒B1-B5の中でもm：nがそれぞれおおよそ1:3、1:4である触媒B3、B4を用いた反応例5、6では、反応時間が4～5時間経過しても50%以上の活性が維持されており、特に触媒B4を用いた例6の活性維持効果が高かった。 In Reaction Example 1-2 (comparative example) using the conventional catalysts B11-B12, the catalysts had activity immediately after the start of the reaction, but the activity was lost after the reaction time.
On the other hand, catalysts B1-B5 of the present invention (m:n is approximately 1:1 for catalyst B1, approximately 1:2 for catalyst B2, approximately 1:3 for catalyst B3, approximately 1:4 for catalyst B4, approximately 1:4 for catalyst B5, In Reaction Example 3-7 using (approximately 1:5), the activity was high immediately after the start of the reaction, and the activity was maintained high even after the reaction time elapsed. As a result, the overall yield was also high. Among the catalysts B1-B5, in Reaction Examples 5 and 6 using catalysts B3 and B4 with m:n ratios of approximately 1:3 and 1:4, respectively, 50% or more of the The activity was maintained, and the effect of maintaining activity was particularly high in Example 6 using catalyst B4.
「反応例8-10」
　充填材料として架橋高分子材料C1（284.0 mg）、架橋高分子材料C2（284.0 mg）、セライト（284.0 mg）のそれぞれを、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、カートリッジ式カラムに充填した。次いで、「反応例1」と同様の操作を行うことにより、目的物4-メチルビフェニルを得た。反応時間ごとに回収した溶液中の4-メチルビフェニルの収率を表3にまとめて示す。 "Reaction example 8-10"
Crosslinked polymer material C1 (284.0 mg), crosslinked polymer material C2 (284.0 mg), Celite (284.0 mg), catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), and sea It was mixed with sand (approximately 9.3 g) and packed into a cartridge column using "catalyst packing method 2". Then, the target product 4-methylbiphenyl was obtained by performing the same operation as in "Reaction Example 1". Table 3 summarizes the yield of 4-methylbiphenyl in the solution collected for each reaction time.
　従来の充填材料であるセライトを用いた反応例10では、反応時間が経過すると活性が低減した。
　また、従来の充填材料である架橋高分子材料C1を用いた反応例8では、反応時間が経過すると、セライトと比較して緩やかではあるものの、活性の低減が見られた。
　本発明の充填材料である架橋高分子材料C2を用いた反応例9では、反応開始直後からC1に比べより活性が高く、かつ、反応時間が経過しても活性がC1に比べより高く維持された。その結果、全収率も高かった。 In Reaction Example 10 using celite, which is a conventional packing material, the activity decreased with the lapse of reaction time.
In addition, in Reaction Example 8 using the crosslinked polymer material C1, which is a conventional filler material, a decrease in activity was observed over the course of the reaction time, albeit more moderately than with celite.
In Reaction Example 9 using the crosslinked polymer material C2, which is the filler material of the present invention, the activity was higher than that of C1 immediately after the start of the reaction, and the activity was maintained higher than that of C1 even after the reaction time elapsed. Ta. As a result, the overall yield was also high.
「反応例11-15」
　触媒B6（45.1 mg (Pd:2.5 mg, 0.0235 mmol)）、触媒B7（50.0 mg (Pd:2.5 mg, 0.0235 mmol)）、触媒B8（62.5 mg (Pd:2.5 mg, 0.0235 mmol)）、触媒B9（61.0 mg (Pd:2.5 mg, 0.0235 mmol)）、触媒B10（55.7 mg (Pd:2.5 mg, 0.0235 mmol)）それぞれを架橋高分子材料C2（使用量は各触媒の重量の5倍）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、カートリッジ式カラムに充填した。次いで、「反応例1」と同様の操作を行うことにより、目的物4-メチルビフェニルを得た。反応時間ごとに回収した溶液中の4-メチルビフェニルの収率を表4にまとめて示す。 "Reaction example 11-15"
Catalyst B6 (45.1 mg (Pd:2.5 mg, 0.0235 mmol)), Catalyst B7 (50.0 mg (Pd:2.5 mg, 0.0235 mmol)), Catalyst B8 (62.5 mg (Pd:2.5 mg, 0.0235 mmol)), Catalyst B9 (61.0 mg (Pd: 2.5 mg, 0.0235 mmol)), catalyst B10 (55.7 mg (Pd: 2.5 mg, 0.0235 mmol)), respectively, to crosslinked polymeric material C2 (the amount used is 5 times the weight of each catalyst), and It was mixed with sea sand (approximately 9.3 g) and packed into a cartridge column using "catalyst packing method 2". Then, the target product 4-methylbiphenyl was obtained by performing the same operation as in "Reaction Example 1". Table 4 summarizes the yield of 4-methylbiphenyl in the solution collected for each reaction time.
　本発明の触媒B6，B8-B10を用いた反応例11、13-15では、反応開始直後から反応時間経過後まで活性が維持された。特に触媒B6，B9，B10を用いた反応例11，14，15は反応時間が4～5時間経過しても50%以上の活性が維持されており、特に触媒B6を用いた反応例11の活性維持効果が高かった。また、触媒B9を用いた反応例14は、反応開始直後の触媒活性は、例えば触媒B6を用いた反応例11、触媒B10を用いた反応例15と比較して低かったが、その後、触媒活性は維持され、ほとんど低下が見られなかった。
　なお、触媒B7を用いた反応例12では、3時間までは比較的高い触媒活性が維持された。その後、カラムリアクターが詰まったために反応が停止したが、これは反応例12の条件下では、触媒B7に含まれる共重合体A7の膨潤が生じたためと考えられる。より長期間、反応を継続させたい場合には、条件の最適化を図ることで、その目的を達成し得る。 In Reaction Examples 11 and 13-15 using the catalysts B6, B8-B10 of the present invention, the activity was maintained from immediately after the start of the reaction until after the reaction time had elapsed. In particular, Reaction Examples 11, 14, and 15 using Catalysts B6, B9, and B10 maintained an activity of 50% or more even after 4 to 5 hours of reaction time, and in particular Reaction Example 11 using Catalyst B6. The activity maintenance effect was high. In Reaction Example 14 using Catalyst B9, the catalytic activity immediately after the start of the reaction was lower than, for example, Reaction Example 11 using Catalyst B6 and Reaction Example 15 using Catalyst B10. was maintained and showed almost no decline.
In Reaction Example 12 using Catalyst B7, a relatively high catalytic activity was maintained for up to 3 hours. After that, the reaction stopped because the column reactor was clogged. This is probably because under the conditions of Reaction Example 12, the copolymer A7 contained in the catalyst B7 swelled. If it is desired to continue the reaction for a longer period of time, the purpose can be achieved by optimizing the conditions.
「反応例16」
　触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法3」を用いて、カートリッジ式カラムに充填した。次いで、「反応例1」と同様の操作を行うことにより、目的物4-メチルビフェニルを得た。反応時間ごとに回収した溶液中の4-メチルビフェニルの収率を表5にまとめて示す。比較として、「触媒の充填法1」（反応例6）及び「触媒の充填法2」（反応例9）を用いた結果も表5に記入している。 "Reaction example 16"
Catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and a cartridge was prepared using "catalyst filling method 3". packed into a column. Then, the target product 4-methylbiphenyl was obtained by performing the same operation as in "Reaction Example 1". Table 5 summarizes the yield of 4-methylbiphenyl in the solution collected for each reaction time. For comparison, Table 5 also shows the results using "catalyst loading method 1" (reaction example 6) and "catalyst loading method 2" (reaction example 9).
　充填剤を含まない「触媒の充填法1」を用いた例6では、上述のとおり、反応開始直後から反応時間が4～5時間経過後まで活性が維持された。
　また、充填剤を含む「触媒の充填法2」（PTFEフィルターをカラム管の両末端にのみ装着）と「触媒の充填法3」（PTFEフィルターを、カラム管の両末端だけではなく、さらにカラム管の内部にも数枚装着）を用いた例9，16によれば、反応時間が4～5時間経過しても、反応開始直後から触媒活性がほとんど低下しなかった。
　特に、PTFEフィルターを、カラム管の両末端だけではなく、さらにカラム管の内部にも数枚装着した「触媒の充填法3」では、フロー反応等により生じるカラム管内の偏流を抑制し、内容物がカラム管内をスムーズに移動することができるが、こうした「触媒の充填法3」においても、反応開始直後から比較的高い触媒活性を示し、反応時間が4～5時間経過しても十分に触媒活性が維持されることが示された。 In Example 6 using the "catalyst filling method 1" containing no filler, as described above, the activity was maintained from immediately after the start of the reaction until after 4 to 5 hours of reaction time.
In addition, "catalyst packing method 2" (with PTFE filters attached only to both ends of the column tube) and "catalyst packing method 3" (with PTFE filters not only at both ends of the column tube, but also column According to Examples 9 and 16, in which several sheets were also installed inside the tube), the catalytic activity hardly decreased immediately after the start of the reaction even after 4 to 5 hours of reaction time.
In particular, in the "catalyst filling method 3", in which PTFE filters are installed not only at both ends of the column tube, but also several inside the column tube, the drift in the column tube caused by flow reactions etc. is suppressed, can move smoothly in the column tube, even in this “catalyst packing method 3”, it shows relatively high catalytic activity immediately after the reaction starts, and even after 4 to 5 hours of reaction time, it is sufficiently catalytic. It was shown to maintain activity.
「反応例17」
　2-ブロモトルエン（3078.7 mg, 18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、反応溶液Iとして調製した。一方、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、反応溶液IIとして調製した。 "Reaction example 17"
A reaction solution I was prepared by dissolving 2-bromotoluene (3078.7 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents. On the other hand, tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
　次いで、下の図のように、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、カートリッジ式カラムに充填した。充填されたカラム管をフローリアクターに固定し、70℃に加熱した。送液ポンプを利用して、調製した反応溶液I（0.2 mL/min）及び反応溶液II（0.1 mL/min）を同時にフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に水を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物2-メチルビフェニルの収率を計算した。反応時間ごとに回収した溶液中の2-メチルビフェニルの収率及び単離した2-メチルビフェニルの重量を表6にまとめて示す。なお、触媒回転頻度（TOF）は138.2 h-1であった。
　なお、本明細書において、触媒回転数（TON）は、生成物を発生させる工程において使用した触媒（金属種であるパラジウム換算）1 mol当たり発生した生成物のmol数であり、前記TOFは、前記TONを、前記生成物を発生させる時間（反応時間）（h）で割って求めた数値である。 Next, as shown in the figure below, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed to form a catalyst. Packing method 2” was used to pack the cartridge column. The packed column tube was secured to the flow reactor and heated to 70°C. The prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump. The reaction solution was heated to 70°C in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. After water was added to the recovered reaction solution, the mixture was extracted with ethyl acetate, and the organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance, and the yield of the desired product, 2-methylbiphenyl, was calculated. Table 6 summarizes the yield of 2-methylbiphenyl in the solution collected for each reaction time and the weight of isolated 2-methylbiphenyl. The catalyst turnover frequency (TOF) was 138.2 h -1 .
In this specification, the catalyst turnover number (TON) is the number of mols of the product generated per 1 mol of the catalyst (converted to palladium, which is a metal species) used in the step of generating the product, and the TOF is It is a numerical value obtained by dividing the TON by the time (reaction time) (h) for generating the product.
「反応例18」
　3-ブロモトルエン（3078.7 mg, 18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物3-メチルビフェニルを得た。 "Reaction example 18"
3-Bromotoluene (3078.7 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg). , 36 mmol) was dissolved in pure water (30 mL), and the same operation as in "Reaction Example 17" was performed to obtain the target product 3-methylbiphenyl.
　反応時間ごとに回収した溶液中の3-メチルビフェニルの収率及び単離した3-メチルビフェニルの重量を表6にまとめて示す。なお、触媒回転頻度（TOF）は146.2 h-1であった。 Table 6 summarizes the yield of 3-methylbiphenyl in the solution and the weight of isolated 3-methylbiphenyl collected for each reaction time. The catalyst turnover frequency (TOF) was 146.2 h -1 .
「反応例19」
　4-ブロモベンゾニトリル（3276.4 mg, 18 mmol）、フェニルボロン酸（2634.1 mg, 21. 6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物4-シアノビフェニルを得た。 "Reaction example 19"
4-Bromobenzonitrile (3276.4 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate. (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) and the same operation as in "Reaction Example 17" was performed to obtain the desired product 4-cyanobiphenyl.
　反応時間ごとに回収した溶液中の4-シアノビフェニルの収率及び単離した4-シアノビフェニルの重量を表6にまとめて示す。なお、触媒回転頻度（TOF）は159.1 h-1であった。 Table 6 summarizes the yield of 4-cyanobiphenyl in the solution collected for each reaction time and the weight of isolated 4-cyanobiphenyl. The catalyst turnover frequency (TOF) was 159.1 h -1 .
「反応例20」
　4-ブロモベンズアルデヒド（3330.4 mg, 18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物ビフェニル-4-カルボキシアルデヒドを得た。 "Reaction example 20"
4-Bromobenzaldehyde (3330.4 mg, 18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) and the same operation as in "Reaction Example 17" was performed to obtain the desired product biphenyl-4-carboxaldehyde.
　反応時間ごとに回収した溶液中のビフェニル-4-カルボキシアルデヒドの収率及び単離したビフェニル-4-カルボキシアルデヒドの重量を表6にまとめて示す。なお、触媒回転頻度（TOF）は155.9 h-1であった。 Table 6 summarizes the yield of biphenyl-4-carboxaldehyde in the solution collected for each reaction time and the weight of the isolated biphenyl-4-carboxaldehyde. The catalyst turnover frequency (TOF) was 155.9 h -1 .
「反応例21」
　4-ブロモフルオロベンゼン（3150.0 mg, 18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物4-フルオロビフェニルを得た。 "Reaction example 21"
4-Bromofluorobenzene (3150.0 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the same operation as in "Reaction Example 17" was performed to obtain the desired product 4-fluorobiphenyl.
　反応時間ごとに回収した溶液中の4-フルオロビフェニルの収率及び単離した4-フルオロビフェニルの重量を表6にまとめて示す。なお、触媒回転頻度（TOF）は157.5 h-1であった。 Table 6 summarizes the yield of 4-fluorobiphenyl in the solution collected for each reaction time and the weight of isolated 4-fluorobiphenyl. The catalyst turnover frequency (TOF) was 157.5 h -1 .
「反応例22」
　4-ブロモ安息香酸エチル（4123.3 mg, 18 mmol）、フェニルボロン酸（2634.1 mg, 21. 6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物ビフェニル-4-カルボン酸エチルを得た。 "Reaction example 22"
Ethyl 4-bromobenzoate (4123.3 mg, 18 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the target product ethyl biphenyl-4-carboxylate was obtained by the same operation as in "Reaction Example 17".
　反応時間ごとに回収した溶液中のビフェニル-4-カルボン酸エチルの収率及び単離したビフェニル-4-カルボン酸エチルの重量を表6にまとめて示す。なお、触媒回転頻度（TOF）は157.5 h-1であった。 Table 6 summarizes the yield of ethyl biphenyl-4-carboxylate in the solution recovered for each reaction time and the weight of the isolated ethyl biphenyl-4-carboxylate. The catalyst turnover frequency (TOF) was 157.5 h -1 .
「反応例23」
　1,3-ジブロモベンゼン（2123.2 mg, 9 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物ビフェニル-4-カルボン酸エチルを得た。 "Reaction example 23"
1,3-dibromobenzene (2123.2 mg, 9 mmol) and phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents, and tripotassium phosphate ( 7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the target compound, ethyl biphenyl-4-carboxylate, was obtained by the same operation as in "Reaction Example 17".
　反応時間ごとに回収した溶液中のm-テルフェニルの収率及び単離したm-テルフェニルの重量を表6にまとめて示す。なお、触媒回転頻度（TOF）は79.5 h-1であった。 Table 6 summarizes the yield of m-terphenyl in the solution and the weight of m-terphenyl isolated for each reaction time. The catalyst turnover frequency (TOF) was 79.5 h -1 .
「反応例41」
　4-ブロモアニソール（18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物4-メトキシビフェニルを得た。 "Reaction example 41"
4-bromoanisole (18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol). ) was dissolved in pure water (30 mL), and the same operation as in "Reaction Example 17" was performed to obtain the desired product 4-methoxybiphenyl.
　反応時間ごとに回収した溶液中の4-メトキシビフェニルの収率及び単離した4-メトキシビフェニルの重量を表6-2にまとめて示す。なお、触媒回転頻度（TOF）は125 h-1であった。 Table 6-2 summarizes the yield of 4-methoxybiphenyl in the solution and the weight of isolated 4-methoxybiphenyl collected for each reaction time. The catalyst turnover frequency (TOF) was 125 h -1 .
「反応例42」
　4-ブロモトリフルオロメチルベンゼン（18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物4-（トリフルオロメチル）ビフェニルを得た。 "Reaction example 42"
4-Bromotrifluoromethylbenzene (18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg). , 36 mmol) was dissolved in pure water (30 mL), and the target compound 4-(trifluoromethyl)biphenyl was obtained by the same operation as in "Reaction Example 17".
　反応時間ごとに回収した溶液中の4-（トリフルオロメチル）ビフェニルの収率及び単離した4-（トリフルオロメチル）ビフェニルの重量を表6-2にまとめて示す。なお、触媒回転頻度（TOF）は72 h-1であった。 Table 6-2 summarizes the yield of 4-(trifluoromethyl)biphenyl in the solution and the weight of isolated 4-(trifluoromethyl)biphenyl collected for each reaction time. The catalyst turnover frequency (TOF) was 72 h -1 .
「反応例43」
　4-ブロモアセチルベンゼン（18 mmol）、フェニルボロン酸（2634.1 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物4-アセチルビフェニルを得た。 "Reaction example 43"
4-Bromoacetylbenzene (18 mmol), phenylboronic acid (2634.1 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the same operation as in "Reaction Example 17" was performed to obtain the desired product 4-acetylbiphenyl.
　反応時間ごとに回収した溶液中の4-アセチルビフェニルの収率及び単離した4-アセチルビフェニルの重量を表6-2にまとめて示す。なお、触媒回転頻度（TOF）は143 h-1であった。 Table 6-2 summarizes the yield of 4-acetylbiphenyl in the solution and the weight of isolated 4-acetylbiphenyl collected for each reaction time. The catalyst turnover frequency (TOF) was 143 h -1 .
「反応例44」
　2-ブロモトルエン（3078.7 mg, 18 mmol）、4-アミルフェニルボロン酸（4148.7 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例17」と同様の操作を行うことにより、目的物4'-メチル-4-ペンチルビフェニルを得た。 "Reaction example 44"
2-Bromotoluene (3078.7 mg, 18 mmol) and 4-amylphenylboronic acid (4148.7 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give tripotassium phosphate. (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) and the same operation as in "Reaction Example 17" was performed to obtain the desired product 4'-methyl-4-pentylbiphenyl.
　反応時間ごとに回収した溶液中の4'-メチル-4-ペンチルビフェニルの収率及び単離した4'-メチル-4-ペンチルビフェニルの重量を表6-2にまとめて示す。なお、触媒回転頻度（TOF）は124 h-1であった。 The yield of 4'-methyl-4-pentylbiphenyl in the solution recovered for each reaction time and the weight of isolated 4'-methyl-4-pentylbiphenyl are summarized in Table 6-2. The catalyst turnover frequency (TOF) was 124 h -1 .
　本発明の触媒を用いて、各種基質（芳香族ハロゲン化物）を用いて連続フロー式鈴木-宮浦カップリング反応を行ったところ、反応開始直後から反応時間経過まで活性が高く維持され、高収率で目的物が得られた。 Using the catalyst of the present invention, a continuous-flow Suzuki-Miyaura coupling reaction was performed using various substrates (aromatic halides). obtained the target.
「反応例24」
　4-ブロモベンゾニトリル（3276.4 mg, 18 mmol）、4-メチルフェニルボロン酸（2936.7 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、反応溶液Iとして調製した。一方、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、反応溶液IIとして調製した。 "Reaction example 24"
4-bromobenzonitrile (3276.4 mg, 18 mmol) and 4-methylphenylboronic acid (2936.7 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give reaction solution I. Prepared as On the other hand, tripotassium phosphate (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
　次いで、下の図のように、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、カートリッジ式カラムに充填した。充填されたカラム管をフローリアクターに固定し、70℃に加熱した。送液ポンプを利用して、調製した反応溶液I（0.2 mL/min）及び反応溶液II（0.1 mL/min）を同時にフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に水を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物4-シアノ-4′-メチルビフェニルの収率を計算した。反応時間ごとに回収した溶液中の4-シアノ-4′-メチルビフェニルの収率及び単離した4-シアノ-4′-メチルビフェニルの重量を表7にまとめて示す。なお、触媒回転頻度（TOF）は154.3 h-1であった。 Next, as shown in the figure below, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed to form a catalyst. Packing method 2” was used to pack the cartridge column. The packed column tube was secured to the flow reactor and heated to 70°C. The prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. After water was added to the recovered reaction solution, it was extracted with ethyl acetate, and the organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance to determine the yield of the desired product, 4-cyano-4'-methylbiphenyl. was calculated. Table 7 summarizes the yield of 4-cyano-4'-methylbiphenyl in the solution recovered for each reaction time and the weight of isolated 4-cyano-4'-methylbiphenyl. The catalyst turnover frequency (TOF) was 154.3 h -1 .
「反応例25」
　4-ブロモベンゾニトリル（3276.4 mg, 18 mmol）、4-メトキシフェニルボロン酸（3282.3 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例24」と同様の操作を行うことにより、目的物4-シアノ-4′-メトキシビフェニルを得た。 "Reaction example 25"
4-Bromobenzonitrile (3276.4 mg, 18 mmol) and 4-methoxyphenylboronic acid (3282.3 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the same operation as in "Reaction Example 24" was performed to obtain the desired product, 4-cyano-4'-methoxybiphenyl.
　反応時間ごとに回収した溶液中の4-シアノ-4′-メトキシビフェニルの収率及び単離した4-シアノ-4′-メトキシビフェニルの重量を表7にまとめて示す。なお、触媒回転頻度（TOF）は159.1 h-1であった。 Table 7 summarizes the yield of 4-cyano-4'-methoxybiphenyl in the solution recovered for each reaction time and the weight of isolated 4-cyano-4'-methoxybiphenyl. The catalyst turnover frequency (TOF) was 159.1 h -1 .
「反応例26」
　4-ブロモベンゾニトリル（3276.4 mg, 18 mmol）、4-フルオロフェニルボロン酸（3282.3 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例24」と同様の操作を行うことにより、目的物4-シアノ-4′-フルオロビフェニルを得た。 "Reaction example 26"
4-bromobenzonitrile (3276.4 mg, 18 mmol) and 4-fluorophenylboronic acid (3282.3 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the desired product 4-cyano-4'-fluorobiphenyl was obtained by the same operation as in "Reaction Example 24".
　反応時間ごとに回収した溶液中の4-シアノ-4′-フルオロビフェニルの収率及び単離した4-シアノ-4′-フルオロビフェニルの重量を表7にまとめて示す。なお、触媒回転頻度（TOF）は154.3 h-1であった。 Table 7 summarizes the yield of 4-cyano-4'-fluorobiphenyl in the solution collected for each reaction time and the weight of isolated 4-cyano-4'-fluorobiphenyl. The catalyst turnover frequency (TOF) was 154.3 h -1 .
「反応例27」
　4-ブロモベンゾニトリル（3276.4 mg, 18 mmol）、4-アミルフェニルボロン酸（4148.7 mg, 21.6 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（7641.7 mg, 36 mmol）を純水（30 mL）に溶解させて、「反応例24」と同様の操作を行うことにより、目的物の液晶材料5CB（4-シアノ-4'-ペンチルビフェニル）を得た。 "Reaction example 27"
4-bromobenzonitrile (3276.4 mg, 18 mmol) and 4-amylphenylboronic acid (4148.7 mg, 21.6 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (7641.7 mg, 36 mmol) was dissolved in pure water (30 mL), and the desired liquid crystal material 5CB (4-cyano-4'-pentylbiphenyl ).
　反応時間ごとに回収した溶液中の液晶材料5CBの収率及び単離した液晶材料5CBの重量を表7にまとめて示す。なお、触媒回転頻度（TOF）は149.5 h-1であった。 Table 7 summarizes the yield of the liquid crystal material 5CB in the solution recovered for each reaction time and the weight of the isolated liquid crystal material 5CB. The catalyst turnover frequency (TOF) was 149.5 h -1 .
　本発明の触媒を用いて、各種基質（芳香族ホウ素化合物）を用いて連続フロー式鈴木-宮浦カップリング反応を行ったところ、反応開始直後から反応時間経過まで活性が高く維持され、高収率で目的物が得られた。 Using the catalyst of the present invention, a continuous flow Suzuki-Miyaura coupling reaction was performed using various substrates (aromatic boron compounds). obtained the target.
「反応例28」
　2-ブロモジベンゾフラン（2223.9 mg, 9 mmol）、フェニルボロン酸（1317.1 mg, 10.8 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、反応溶液Iとして調製した。一方、りん酸三カリウム（3820.9 mg, 18 mmol）を純水（30 mL）に溶解させて、反応溶液IIとして調製した。 "Reaction example 28"
A reaction solution I was prepared by dissolving 2-bromodibenzofuran (2223.9 mg, 9 mmol) and phenylboronic acid (1317.1 mg, 10.8 mmol) in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents. On the other hand, tripotassium phosphate (3820.9 mg, 18 mmol) was dissolved in pure water (30 mL) to prepare reaction solution II.
　次いで、下の図のように、触媒B4（56.8 mg (Pd: 2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液I（0.2 mL/min）及び反応溶液II（0.1 mL/min）を同時にフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に水を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物2-フェニルジベンゾフランの収率を計算した。反応時間ごとに回収した溶液中の2-フェニルジベンゾフランの収率及び単離した2-フェニルジベンゾフランの重量を表8にまとめて示す。なお、触媒回転頻度（TOF）は78.0 h-1であった。 Next, as shown in the figure below, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed to form a catalyst. Using Packing Method 2”, the packed column tube was clamped into a flow reactor and heated to 70°C. The prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. After water was added to the collected reaction solution, extraction was performed with ethyl acetate, and the organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance, and the yield of the desired product, 2-phenyldibenzofuran, was calculated. Table 8 summarizes the yield of 2-phenyldibenzofuran in the solution collected for each reaction time and the weight of the isolated 2-phenyldibenzofuran. The catalyst turnover frequency (TOF) was 78.0 h -1 .
「反応例29」
　3-ブロモ-9-フェニルカルバゾール（2899.9 mg, 9 mmol）、フェニルボロン酸（1317.1 mg, 10.8 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（3820.9 mg, 18 mmol）を純水（30 mL）に溶解させて、「反応例28」と同様の操作を行うことにより、目的物3,9-ジフェニルカルバゾールを得た。 "Reaction example 29"
3-bromo-9-phenylcarbazole (2899.9 mg, 9 mmol) and phenylboronic acid (1317.1 mg, 10.8 mmol) were dissolved in tetrahydrofuran (50 mL) and ethanol (10 mL) as solvents to give triphosphate. Potassium (3820.9 mg, 18 mmol) was dissolved in pure water (30 mL), and the same operation as in "Reaction Example 28" was performed to obtain the target product 3,9-diphenylcarbazole.
　反応時間ごとに回収した溶液中の3,9-ジフェニルカルバゾールの収率及び単離した3,9-ジフェニルカルバゾールの重量を表8にまとめて示す。なお、触媒回転頻度（TOF）は61.9 h-1であった。 Table 8 summarizes the yield of 3,9-diphenylcarbazole in the solution collected for each reaction time and the weight of the isolated 3,9-diphenylcarbazole. The catalyst turnover frequency (TOF) was 61.9 h -1 .
「反応例30」
　9-(4-ブロモフェニル)カルバゾール（2899.9 mg, 9 mmol）、4-(9H-カルバゾール-9-イル)フェニルボロン酸（3101.0 mg, 10.8 mmol）を、溶媒としてのテトラヒドロフラン（50 mL）及びエタノール（10 mL）に溶解させて、りん酸三カリウム（3820.9 mg, 18 mmol）を純水（30 mL）に溶解させて、「反応例28」と同様の操作を行うことにより、目的物の有機EL材料CBP（4,4'-ビス(9H-カルバゾール-9-イル)ビフェニル）を得た。 "Reaction example 30"
9-(4-bromophenyl)carbazole (2899.9 mg, 9 mmol), 4-(9H-carbazol-9-yl)phenylboronic acid (3101.0 mg, 10.8 mmol), tetrahydrofuran (50 mL) and ethanol as solvent (10 mL), tripotassium phosphate (3820.9 mg, 18 mmol) was dissolved in pure water (30 mL), and the desired organic EL material CBP (4,4'-bis(9H-carbazol-9-yl)biphenyl) was obtained.
　反応時間ごとに回収した溶液の有機相を1H NMRの分析を行って、目的物の有機EL材料CBPの収率を計算した。有機EL材料CBPのNMR収率及び単離したCBPの重量を表8にまとめて示す。なお、触媒回転頻度（TOF）は57.1 h-1であった。 The organic phase of the solution collected for each reaction time was analyzed by 1 H NMR to calculate the yield of the target organic EL material CBP. Table 8 summarizes the NMR yield of the organic EL material CBP and the weight of the isolated CBP. The catalyst turnover frequency (TOF) was 57.1 h -1 .
　本発明の触媒を用いて、各種基質を用いて連続フロー式鈴木-宮浦カップリング反応を行ったところ、高収率で目的物が得られた。 Using the catalyst of the present invention, continuous-flow Suzuki-Miyaura coupling reactions were performed using various substrates, and the target product was obtained in high yield.
「反応例31」
　4-ブロモ安息香酸（1809.2 mg, 9 mmol）を溶媒としてのテトラヒドロフラン（37.5 mL）及びエタノール（7.5 mL）に溶解させて、反応溶液Iとして調製した。一方、フェニルボロン酸（1317.1 mg, 10.8 mmol）、りん酸三カリウム（3820.9 mg, 18 mmol）を純水（45 mL）に溶解させて、反応溶液IIとして調製した。 "Reaction example 31"
A reaction solution I was prepared by dissolving 4-bromobenzoic acid (1809.2 mg, 9 mmol) in tetrahydrofuran (37.5 mL) and ethanol (7.5 mL) as solvents. On the other hand, phenylboronic acid (1317.1 mg, 10.8 mmol) and tripotassium phosphate (3820.9 mg, 18 mmol) were dissolved in pure water (45 mL) to prepare reaction solution II.
　次いで、下の図のように、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液I（0.15 mL/min）及び反応溶液II（0.15 mL/min）を同時にフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に水を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物4-フェニル安息香酸の収率を計算した。反応時間ごとに回収した溶液中の4-フェニル安息香酸の収率及び単離した4-フェニル安息香酸の重量を表9にまとめて示す。なお、触媒回転頻度（TOF）は71.6 h-1であった。 Next, as shown in the figure below, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed to form a catalyst. Using Packing Method 2”, the packed column tube was clamped into a flow reactor and heated to 70°C. The prepared reaction solution I (0.15 mL/min) and reaction solution II (0.15 mL/min) were simultaneously sent to the flow reactor using a liquid sending pump. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. After water was added to the recovered reaction solution, extraction was performed with ethyl acetate, and the organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance, and the yield of the desired product, 4-phenylbenzoic acid, was calculated. Table 9 summarizes the yield of 4-phenylbenzoic acid in the solution collected for each reaction time and the weight of isolated 4-phenylbenzoic acid. The catalyst turnover frequency (TOF) was 71.6 h -1 .
「反応例32」
　4-ブロモフェノール（1557.1 mg, 9 mmol）を溶媒としてのテトラヒドロフラン（37.5 mL）及びエタノール（7.5 mL）に溶解させて、フェニルボロン酸（1317.1 mg, 10.8 mmol）、りん酸三カリウム（3820.9 mg, 18 mmol）を純水（45 mL）に溶解させて、「反応例31」と同様の操作を行うことにより、目的物4-フェニルフェノールを得た。 "Reaction example 32"
4-Bromophenol (1557.1 mg, 9 mmol) was dissolved in tetrahydrofuran (37.5 mL) and ethanol (7.5 mL) as solvents to give phenylboronic acid (1317.1 mg, 10.8 mmol) and tripotassium phosphate (3820.9 mg, 18 mmol) was dissolved in pure water (45 mL), and the same operation as in "Reaction Example 31" was performed to obtain the desired product 4-phenylphenol.
　反応時間ごとに回収した溶液中の4-フェニルフェノールの収率及び単離した4-フェニルフェノールの重量を表9にまとめて示す。なお、触媒回転頻度（TOF）は64.3 h-1であった。 Table 9 summarizes the yield of 4-phenylphenol in the solution collected for each reaction time and the weight of isolated 4-phenylphenol. The catalyst turnover frequency (TOF) was 64.3 h -1 .
　本発明の触媒を用いて、各種基質（芳香族ハロゲン化物）を用いて連続フロー式鈴木-宮浦カップリング反応を行ったところ、反応開始直後から反応時間経過まで活性が高く維持され、高収率で目的物が得られた。 Using the catalyst of the present invention, a continuous-flow Suzuki-Miyaura coupling reaction was performed using various substrates (aromatic halides). obtained the target.
「反応例33」
　3-(4-ブロモベンゾイル)プロピオン酸（6941.7 mg, 27 mmol）、フェニルボロン酸（3951.2 mg, 32.4 mmol）、りん酸三カリウム（11462.6 mg, 54 mmol）を純水（90 mL）に溶解させて、反応溶液として調製した。 "Reaction example 33"
3-(4-bromobenzoyl)propionic acid (6941.7 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol) and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL). and prepared as a reaction solution.
　次いで、下の図のように、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液（0.3 mL/min）をフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に塩酸水溶液（１N）を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物フェンブフェン（γ-オキソ-(1,1′-ビフェニル)-4-ブタン酸）の収率を計算した。反応時間ごとに回収した溶液中のフェンブフェンの収率及び単離したフェンブフェンの重量を表10にまとめて示す。なお、触媒回転頻度（TOF）は226.6 h-1であった。 Next, as shown in the figure below, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed to form a catalyst. Using Packing Method 2”, the packed column tube was clamped into a flow reactor and heated to 70°C. Using a liquid-sending pump, the prepared reaction solution (0.3 mL/min) was sent to the flow reactor. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. An aqueous hydrochloric acid solution (1N) was added to the recovered reaction solution, followed by extraction with ethyl acetate. The organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance to obtain the desired product, fenbufen (γ-oxo-(1 ,1′-biphenyl)-4-butanoic acid) was calculated. Table 10 summarizes the yield of fenbufen in the solution collected for each reaction time and the weight of isolated fenbufen. The catalyst turnover frequency (TOF) was 226.6 h -1 .
「反応例34」
　3-(4-ブロモベンゾイル)プロピオン酸（6941.7 mg, 27 mmol）、フェニルボロン酸（3951.2 mg, 32.4 mmol）、りん酸三カリウム（11462.6 mg, 54 mmol）を純水（90 mL）に溶解させて、反応溶液として調製した。 "Reaction example 34"
3-(4-bromobenzoyl)propionic acid (6941.7 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol) and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL). and prepared as a reaction solution.
　次いで、触媒B1（23.0 mg (Pd:2.346 mg, 0.0220 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液（0.3 mL/min）をフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に塩酸水溶液（１N）を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物フェンブフェン（γ-オキソ-(1,1′-ビフェニル)-4-ブタン酸）の収率を計算した。反応時間ごとに回収した溶液中のフェンブフェンの収率及び単離したフェンブフェンの重量を表10にまとめて示す。なお、触媒回転頻度（TOF）は243.0 h-1であった。 Then, catalyst B1 (23.0 mg (Pd: 2.346 mg, 0.0220 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and using "catalyst filling method 2" , the packed column tube was secured in a flow reactor and heated to 70°C. Using a liquid-sending pump, the prepared reaction solution (0.3 mL/min) was sent to the flow reactor. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. An aqueous hydrochloric acid solution (1N) was added to the recovered reaction solution, followed by extraction with ethyl acetate. The organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance to obtain the desired product, fenbufen (γ-oxo-(1 ,1′-biphenyl)-4-butanoic acid) was calculated. Table 10 summarizes the yield of fenbufen in the solution collected for each reaction time and the weight of isolated fenbufen. The catalyst turnover frequency (TOF) was 243.0 h -1 .
　本発明の触媒は、反応開始直後から反応時間経過まで活性が高く維持され、高収率で医薬品化合物であるフェンブフェンが得られた。反応は、水系溶媒中で行うことが可能であった。 The catalyst of the present invention maintained high activity from immediately after the start of the reaction until the reaction time elapsed, and the pharmaceutical compound fenbufen was obtained in high yield. It was possible to carry out the reaction in an aqueous solvent.
「反応例35」
　4-ブロモフェニル酢酸（5806.4 mg, 27 mmol）、フェニルボロン酸（3951.2 mg, 32.4 mmol）、りん酸三カリウム（11462.6 mg, 54 mmol）を純水（90 mL）に溶解させて、反応溶液として調製した。 "Reaction example 35"
4-bromophenylacetic acid (5806.4 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol), and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL) to give a reaction solution of prepared.
　次いで、下の図のように、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C3（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液（0.3 mL/min）をフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に塩酸水溶液（１N）を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物フェルビナク（4-ビフェニル酢酸）の収率を計算した。反応時間ごとに回収した溶液中のフェルビナクの収率及び単離したフェルビナクの重量を表11にまとめて示す。なお、触媒回転頻度（TOF）は229.0 h-1であった。ICP質量分析法の測定を行った結果、1時間ごとに回収した溶液中に溶出したパラジウムの濃度は0.02 ppmであった。また、1時間ごとに単離した目的物のフェルビナク中のパラジウムの濃度は0.30 ppmであった。 Next, as shown in the figure below, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C3 (284.0 mg), and sea sand (about 9.3 g) were mixed to form a catalyst. Using Packing Method 2”, the packed column tube was clamped into a flow reactor and heated to 70°C. Using a liquid-sending pump, the prepared reaction solution (0.3 mL/min) was sent to the flow reactor. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. An aqueous solution of hydrochloric acid (1N) was added to the recovered reaction solution, followed by extraction with ethyl acetate. The organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance to identify the target product, felbinac (4-biphenylacetic acid). Yield was calculated. Table 11 summarizes the yield of felbinac in the solution collected for each reaction time and the weight of isolated felbinac. The catalyst turnover frequency (TOF) was 229.0 h -1 . As a result of ICP mass spectrometry measurement, the concentration of eluted palladium in the solution collected every hour was 0.02 ppm. In addition, the concentration of palladium in the target felbinac isolated every hour was 0.30 ppm.
「反応例36」
　4-ブロモフェニル酢酸（5806.4 mg, 27 mmol）、フェニルボロン酸（3951.2 mg, 32.4 mmol）、りん酸三カリウム（11462.6 mg, 54 mmol）を純水（90 mL）に溶解させて、反応溶液として調製した。 "Reaction example 36"
4-bromophenylacetic acid (5806.4 mg, 27 mmol), phenylboronic acid (3951.2 mg, 32.4 mmol), and tripotassium phosphate (11462.6 mg, 54 mmol) were dissolved in pure water (90 mL) to give a reaction solution of prepared.
　次いで、下の図のように、触媒B1（23.0 mg (Pd:2.346 mg, 0.0220 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液（0.3 mL/min）をフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に塩酸水溶液（１N）を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物フェルビナク（4-ビフェニル酢酸）の収率を計算した。反応時間ごとに回収した溶液中のフェルビナクの収率を表11にまとめて示す。なお、触媒回転頻度（TOF）は233.2 h-1であった。 Next, as shown in the figure below, catalyst B1 (23.0 mg (Pd: 2.346 mg, 0.0220 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed to form a catalyst. Using Packing Method 2”, the packed column tube was clamped into a flow reactor and heated to 70°C. Using a liquid-sending pump, the prepared reaction solution (0.3 mL/min) was sent to the flow reactor. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. An aqueous solution of hydrochloric acid (1N) was added to the recovered reaction solution, followed by extraction with ethyl acetate. The organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance to identify the target product, felbinac (4-biphenylacetic acid). Yield was calculated. Table 11 summarizes the yield of felbinac in the solution collected for each reaction time. The catalyst turnover frequency (TOF) was 233.2 h -1 .
　本発明の触媒は、反応開始直後から反応時間経過まで活性が高く維持され、高収率で、医薬品化合物であるフェルビナクが得られた。反応は、水系溶媒中で行うことが可能であった。また、4-5hにおける粗生成物中のPdの含有量（ICP-MSの測定結果）は、0.63ppmであり、医薬品の不純物ガイドライン, ICH Q3Dの経口製剤、注射剤の基準を満たしている。 The catalyst of the present invention maintained high activity from immediately after the start of the reaction to the elapse of the reaction time, and the medicinal compound felbinac was obtained in high yield. It was possible to carry out the reaction in an aqueous solvent. In addition, the content of Pd in the crude product (measured by ICP-MS) at 4-5 hours was 0.63 ppm, which satisfies the impurity guidelines for pharmaceuticals, ICH Q3D standards for oral preparations and injections.
「反応例45」
　本発明の連続フローシステムの利点をさらに検討するため、反応の途中で基質を変えることにより、1回の連続反応で複数の生成物を合成する連続フロー合成を行った。反応例36の方法で5時間反応を行いフェルビナクを合成した後、カラムリアクターを70 ℃で1時間水で洗浄し、基質を変え、さらに5時間反応を行いフェンブフェンを合成し、目的物を分析した（表11-2）。
　反応時間ごとに回収した溶液中のフェルビナクおよびフェンブフェンの収率を図2にまとめて示す。 "Reaction example 45"
To further investigate the advantages of the continuous-flow system of the present invention, continuous-flow synthesis was performed in which multiple products were synthesized in one continuous reaction by changing substrates during the reaction. After synthesizing felbinac by performing the reaction for 5 hours by the method of Reaction Example 36, the column reactor was washed with water at 70°C for 1 hour, the substrate was changed, the reaction was performed for another 5 hours to synthesize fenbufen, and the target product was analyzed. (Table 11-2).
The yields of felbinac and fenbufen in the solution collected for each reaction time are summarized in FIG.
　フェルビナクの収率は91 %、フェンブフェンの収率は93 ％に達し、この触媒系が触媒の再装填なしに複数の目的物の合成に適用できることが示された。 The yield of felbinac reached 91% and the yield of fenbufen reached 93%, indicating that this catalytic system can be applied to the synthesis of multiple targets without catalyst reloading.
「反応例37」
　4-ブロモトルエン（6157.4 mg, 36 mmol）、フェニルボロン酸（5268.2 mg, 43.2 mmol）を、溶媒としてのテトラヒドロフラン（100 mL）及びエタノール（20 mL）に溶解させて、反応溶液Iとして調製した。一方、りん酸三カリウム（15283.4 mg, 72 mmol）を純水（60 mL）に溶解させて、反応溶液IIとして調製した。 "Reaction example 37"
A reaction solution I was prepared by dissolving 4-bromotoluene (6157.4 mg, 36 mmol) and phenylboronic acid (5268.2 mg, 43.2 mmol) in tetrahydrofuran (100 mL) and ethanol (20 mL) as solvents. On the other hand, tripotassium phosphate (15283.4 mg, 72 mmol) was dissolved in pure water (60 mL) to prepare reaction solution II.
　次いで、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、カートリッジ式カラムに充填した。充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液I（0.2 mL/min）及び反応溶液II（0.1 mL/min）を同時にフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に水を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物4-メチルビフェニルの収率を計算した。反応時間ごとに回収した溶液中の4-メチルビフェニルの収率を表12にまとめて示す。なお、触媒回転頻度（TOF）は128.6 h-1であった。 Then, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and using "catalyst filling method 2" , was packed in a cartridge column. The packed column tube was secured to the flow reactor and heated to 70°C. The prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. After water was added to the collected reaction solution, extraction was performed with ethyl acetate, and the organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance, and the yield of the desired product 4-methylbiphenyl was calculated. Table 12 summarizes the yield of 4-methylbiphenyl in the solution collected for each reaction time. The catalyst turnover frequency (TOF) was 128.6 h -1 .
　本発明の触媒は、反応開始直後から10時間経過後でも活性が高く維持され、目的物を合成できた。 The catalyst of the present invention maintained high activity even after 10 hours from the start of the reaction, and was able to synthesize the target product.
「反応例38」
　4-ブロモベンゾニトリル（6552.8 mg, 36 mmol）、4-プロポキシフェニルボロン酸（7776.4 mg, 43.2 mmol）を、溶媒としてのテトラヒドロフラン（100 mL）及びエタノール（20 mL）に溶解させて、反応溶液Iとして調製した。一方、りん酸三カリウム（15283.4 mg, 72 mmol）を純水（60 mL）に溶解させて、反応溶液IIとして調製した。 "Reaction example 38"
4-bromobenzonitrile (6552.8 mg, 36 mmol) and 4-propoxyphenylboronic acid (7776.4 mg, 43.2 mmol) were dissolved in tetrahydrofuran (100 mL) and ethanol (20 mL) as solvents to give reaction solution I. Prepared as On the other hand, tripotassium phosphate (15283.4 mg, 72 mmol) was dissolved in pure water (60 mL) to prepare reaction solution II.
　次いで、触媒B4（56.8 mg (Pd:2.386 mg, 0.0224 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、カートリッジ式カラムに充填した。充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液I（0.2 mL/min）及び反応溶液II（0.1 mL/min）を同時にフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に水を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物液晶材料3OCB（4-シアノ-4'-プロポキシ-1,1'-ビフェニル）の収率を計算した。反応時間ごとに回収した溶液中の液晶材料3OCBの収率を表13にまとめて示す。なお、触媒回転頻度（TOF）は155.9 h-1であった。 Then, catalyst B4 (56.8 mg (Pd: 2.386 mg, 0.0224 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and using "catalyst filling method 2" , was packed in a cartridge column. The packed column tube was secured to the flow reactor and heated to 70°C. The prepared reaction solution I (0.2 mL/min) and reaction solution II (0.1 mL/min) were simultaneously sent to the flow reactor using a liquid-sending pump. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. After water was added to the collected reaction solution, it was extracted with ethyl acetate. -1,1′-biphenyl) was calculated. Table 13 summarizes the yield of the liquid crystal material 3OCB in the solution recovered for each reaction time. The catalyst turnover frequency (TOF) was 155.9 h -1 .
　本発明の触媒は、反応開始直後から10時間経過後でも活性が高く維持され、液晶材料である目的物の3OCBを合成できた。 The catalyst of the present invention maintained high activity even after 10 hours from immediately after the start of the reaction, and was able to synthesize the target 3OCB, which is a liquid crystal material.
「反応例39」
　3-(4-ブロモベンゾイル)プロピオン酸（13883.4 mg, 54 mmol）、フェニルボロン酸（7902.4 mg, 64.8 mmol）、りん酸三カリウム（22925.2 mg, 108 mmol）を純水（180 mL）に溶解させて、反応溶液として調製した。 "Reaction example 39"
3-(4-bromobenzoyl)propionic acid (13883.4 mg, 54 mmol), phenylboronic acid (7902.4 mg, 64.8 mmol) and tripotassium phosphate (22925.2 mg, 108 mmol) were dissolved in pure water (180 mL). and prepared as a reaction solution.
　次いで、触媒B1（23.0 mg (Pd:2.346 mg, 0.0220 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液（0.3 mL/min）をフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（1時間/1回）を開始した。回収した反応溶液に塩酸水溶液（１N）を添加した後、酢酸エチルで抽出し、有機相を、メシチレンを内部標準物質として用いてガスクロマトグラフィーで分析し、目的物フェンブフェン（γ-オキソ-(1,1′-ビフェニル)-4-ブタン酸）の収率を計算した。反応時間ごとに回収した溶液中のフェンブフェンの収率及び単離したフェンブフェンの重量を表14にまとめて示す。なお、触媒回転頻度（TOF）は240.6 h-1であった。 Then, catalyst B1 (23.0 mg (Pd: 2.346 mg, 0.0220 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and using "catalyst filling method 2" , the packed column tube was secured in a flow reactor and heated to 70°C. Using a liquid-sending pump, the prepared reaction solution (0.3 mL/min) was sent to the flow reactor. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (1 hour/once) was started from the outlet of the flow reactor. An aqueous hydrochloric acid solution (1N) was added to the recovered reaction solution, followed by extraction with ethyl acetate. The organic phase was analyzed by gas chromatography using mesitylene as an internal standard substance to obtain the desired product, fenbufen (γ-oxo-(1 ,1′-biphenyl)-4-butanoic acid) was calculated. Table 14 summarizes the yield of fenbufen in the solution collected for each reaction time and the weight of isolated fenbufen. The catalyst turnover frequency (TOF) was 240.6 h -1 .
　本発明の触媒は、反応開始直後から10時間経過後でも活性が高く維持され、医薬品化合物である目的物のフェンブフェンを合成できた。また、4-5hにおける粗生成物中のPdの含有量（ICP-MSの測定結果）は、0.55 ppmであり、医薬品の不純物ガイドライン, ICH Q3Dの経口製剤、注射剤の基準を満たしている。 The catalyst of the present invention maintained high activity even after 10 hours from immediately after the start of the reaction, and was able to synthesize fenbufen, the target drug compound. In addition, the content of Pd in the crude product (measured by ICP-MS) at 4-5 hours was 0.55 ppm, which satisfies the impurity guidelines for pharmaceuticals, ICH Q3D standards for oral preparations and injections.
「反応例40」
　８時間用の反応溶液として、3-(4-ブロモベンゾイル)プロピオン酸（11106.7 mg, 43.2 mmol）、フェニルボロン酸（6321.9 mg, 51.84 mmol）、りん酸三カリウム（18340.1 mg, 86.4 mmol）を純水（144 mL）に溶解させて、反応溶液を調製した。
　次いで、触媒B1（23.0 mg (Pd:2.346 mg, 0.0220 mmol)）、架橋高分子材料C2（284.0 mg）、及び海砂（約9.3 g）と混合し、「触媒の充填法2」を用いて、充填されたカラム管をフローリアクターに固定し、70 ℃に加熱した。送液ポンプを利用して、調製した反応溶液（0.3 mL/min）をフローリアクターに送液した。反応溶液がフローリアクターに入る前に、コイルリアクターで70 ℃に加熱した。フローリアクターに30 min流した後、フローリアクターの出口から溶液の回収（2時間/1回）を開始した。回収した反応溶液に塩酸水溶液（１N）を添加した後、酢酸エチルで抽出し、有機相をガスクロマトグラフィーで分析し、目的物フェンブフェン（γ-オキソ-(1,1′-ビフェニル)-4-ブタン酸）の収率を計算した。反応を８時間で行った後、純水（0.3 mL/min）を用いて70 ℃でカラムリアクターを洗浄してから、リアクターの温度を室温まで下げた。
　次の日は、同様の操作を行うことにより、反応溶液を調製し、８時間で反応を行った。目的物フェンブフェン（γ-オキソ-(1,1′-ビフェニル)-4-ブタン酸）を得た。
　この様な操作をさらに２日（８時間×２）行って、合計３２時間反応が進行した。反応時間ごとに回収した溶液中のフェンブフェンの収率を表15にまとめて示す。 "Reaction example 40"
As a reaction solution for 8 hours, 3-(4-bromobenzoyl)propionic acid (11106.7 mg, 43.2 mmol), phenylboronic acid (6321.9 mg, 51.84 mmol), and tripotassium phosphate (18340.1 mg, 86.4 mmol) were pure. A reaction solution was prepared by dissolving in water (144 mL).
Then, catalyst B1 (23.0 mg (Pd: 2.346 mg, 0.0220 mmol)), crosslinked polymer material C2 (284.0 mg), and sea sand (about 9.3 g) were mixed, and using "catalyst filling method 2" , the packed column tube was secured in a flow reactor and heated to 70°C. Using a liquid-sending pump, the prepared reaction solution (0.3 mL/min) was sent to the flow reactor. The reaction solution was heated to 70° C. in a coil reactor before entering the flow reactor. After flowing through the flow reactor for 30 min, collection of the solution (2 hours/once) was started from the outlet of the flow reactor. An aqueous solution of hydrochloric acid (1N) was added to the recovered reaction solution, followed by extraction with ethyl acetate. Butanoic acid) yield was calculated. After the reaction was carried out for 8 hours, the column reactor was washed with pure water (0.3 mL/min) at 70° C., and the temperature of the reactor was lowered to room temperature.
On the next day, a reaction solution was prepared by performing the same operation, and the reaction was carried out for 8 hours. The desired product, fenbufen (γ-oxo-(1,1′-biphenyl)-4-butanoic acid), was obtained.
This operation was carried out for another 2 days (8 hours x 2), and the reaction proceeded for a total of 32 hours. Table 15 summarizes the yield of fenbufen in the solution collected for each reaction time.
　本発明の触媒は、1日8時間の連続反応を4日間繰り返し、反応時間が計32時間に上っても、なお高い活性を維持したまま、医薬品化合物である目的物のフェンブフェンを合成できた。また、本発明の触媒によれば、8時間の反応と、反応の停止を繰り返しても活性が維持されたままであった。 With the catalyst of the present invention, a continuous reaction of 8 hours a day was repeated for 4 days, and even after a reaction time of 32 hours in total, the catalyst of the present invention was able to synthesize fenbufen, the target pharmaceutical compound, while maintaining high activity. . Further, according to the catalyst of the present invention, the activity was maintained even after repeating the reaction for 8 hours and the termination of the reaction.
「反応例46」
　さらに長時間の連続反応によりフェンブフェンを合成し、触媒の耐久性を確認した。反応例40の32時間（4日間）の反応後、さらに反応を行った（表15-2）。5日目には収率が75 %に低下したが（図3、5日目）、ビフェニルや2,4,6-トリフェニルボロキシン（ガスクロマトグラフィー－質量分析計で確認した）等の不純物を取り除くため、50 ℃のエタノールと水でフローリアクターを洗浄した後の6日目には98 %に上昇した（図3、収率はガスクロマトグラフィーで測定）。生成物の収率の低下は、主に不溶性有機化合物がカラム内部に蓄積したことに起因していると考えられた。エタノールによる洗浄の効果を確認するため、6日目以降、リアクターを水のみで洗浄したところ、7日目のフェンブフェンの収率は74 %に減少していた。7日目と8日目にカラムリアクターをエタノールと水で洗浄した後、8日目と9日目の3qa（フェンブフェン）の収率は88-95 %を維持した。全体として67時間フロー反応を行い、平均収率92 ％でフェンブフェンを得た。触媒回転数（TON）は14109に達し、TOFは211 h-1に達した。1日目から4日目までに採取した生成物3qaは92 %の収率で単離された（合計25.3 g；1日あたり6.3 g）。回収した反応混合物は、塩酸水溶液で酸性化した後、ろ過し、得られた粉末を凍結乾燥することにより、単離する際に有機溶媒を使用することなく、医薬品を単離することができ、これらの結果は、水中フロー触媒システムが医薬品の連続生産に適していることを示している。。 "Reaction example 46"
Furthermore, fenbufen was synthesized by continuous reaction for a long time, and the durability of the catalyst was confirmed. After 32 hours (4 days) of reaction in Reaction Example 40, further reaction was carried out (Table 15-2). The yield dropped to 75% on day 5 (Fig. 3, day 5), but impurities such as biphenyl and 2,4,6-triphenylboroxine (confirmed by gas chromatography-mass spectrometry) increased to 98% on the 6th day after washing the flow reactor with ethanol and water at 50 °C to remove the (Fig. 3, yield determined by gas chromatography). It was considered that the decrease in product yield was mainly due to the accumulation of insoluble organic compounds inside the column. To confirm the effect of washing with ethanol, the reactor was washed only with water after the 6th day, and the yield of fenbufen on the 7th day decreased to 74%. After washing the column reactor with ethanol and water on days 7 and 8, the yield of 3qa (fenbufen) on days 8 and 9 remained 88-95%. The flow reaction was carried out for a total of 67 hours to obtain fenbufen with an average yield of 92%. The catalyst turnover number (TON) reached 14109 and the TOF reached 211 h -1 . Product 3qa harvested from day 1 to day 4 was isolated in 92% yield (25.3 g total; 6.3 g per day). The recovered reaction mixture is acidified with an aqueous solution of hydrochloric acid, filtered, and the resulting powder is lyophilized to isolate the drug without using an organic solvent during isolation. These results demonstrate that the submerged flow catalyst system is suitable for continuous pharmaceutical production. .
　固定化金属触媒、特にパラジウム触媒を用いた鈴木-宮浦カップリング反応を、従来のバッチ式反応器から連続生産が可能な触媒充填床反応器に転換することは、効率的で環境に優しく、安全な技術として注目されている。 Converting the Suzuki-Miyaura coupling reaction using immobilized metal catalysts, especially palladium catalysts, from conventional batch reactors to catalyst packed bed reactors capable of continuous production is efficient, environmentally friendly and safe. It is attracting attention as a technology.
　固定化パラジウム触媒は、その担体によって2種類に分けられている。炭素や金属酸化物等の無機物に担持されたパラジウムは、回収・再利用可能な触媒として化学工業分野で広く利用されている。しかし、これらの担体の表面構造が多様であるため、担持されたパラジウム種のサイズと分散度を精密に制御することが難しく、触媒の活性と選択性が低下する場合が多い。また、パラジウムが担体側から溶出して生成物に混入しやすいことも、医薬品の合成等において重要な問題である。一方、高分子に代表される有機材料は、パラジウムとの電子的相互作用や精密な構造設計が可能であることから、触媒の担体として広く研究・開発が行われ、数多くのバッチ式鈴木-宮浦カップリング反応の例も報告された。しかしながら、これらの触媒は長時間や苛酷な反応条件下、特に強塩基性物質を使用した場合、触媒の耐久性が低いため、連続フロー式鈴木-宮浦カップリング反応への応用例がまだ少ないのが現状である。 Immobilized palladium catalysts are divided into two types depending on the carrier. Palladium supported on inorganic materials such as carbon and metal oxides is widely used in the chemical industry as a recoverable and reusable catalyst. However, due to the variety of surface structures of these supports, it is difficult to precisely control the size and dispersity of the supported palladium species, often resulting in reduced catalytic activity and selectivity. In addition, palladium is likely to be eluted from the carrier side and mixed into the product, which is an important problem in the synthesis of pharmaceuticals and the like. On the other hand, organic materials typified by polymers are capable of electronic interaction with palladium and precise structural design. Therefore, they have been widely researched and developed as catalyst carriers, and many batch-type Suzuki-Miyaura Examples of coupling reactions were also reported. However, these catalysts have low durability under long-term and severe reaction conditions, especially when strongly basic substances are used. is the current situation.
　本発明では、金属種と固定材料である高分子の間の電子的な相互作用と立体効果を配慮し、高分散かつ安定な固定化パラジウム触媒を開発した。また、設計した架橋高分子を反応器の充填材料として調製した。この充填材料を混合した触媒を充填した、連続フロー式の反応器を流通させることで目的物を長時間かつ連続的に得ることが実現した。さらに、本発明では、金属触媒の再利用が容易にできるため、より環境・資源にやさしい反応系である。開発した触媒系を用いて、医薬品や有機電子材料を含む有用なビフェニル化合物を連続的に鈴木-宮浦カップリング反応で製造することを達成した。また、本発明では、有機溶媒を使わずに、水中での連続フロー式鈴木-宮浦カップリング反応による医薬品化合物の合成に初めて成功した。
  In the present invention, a highly dispersed and stable immobilized palladium catalyst was developed in consideration of the electronic interaction and steric effect between the metal species and the polymer as the immobilizing material. The designed crosslinked polymer was also prepared as a packing material for the reactor. By circulating a continuous flow type reactor filled with a catalyst mixed with this filling material, it was realized to obtain the desired product continuously for a long period of time. Furthermore, in the present invention, since the metal catalyst can be easily reused, the reaction system is more environment- and resource-friendly. Using the developed catalyst system, we succeeded in continuously producing useful biphenyl compounds, including pharmaceuticals and organic electronic materials, by the Suzuki-Miyaura coupling reaction. In addition, in the present invention, we succeeded for the first time in synthesizing a pharmaceutical compound by a continuous-flow Suzuki-Miyaura coupling reaction in water without using an organic solvent.

Claims (12)

  1. 　（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（B）下記式(II)で示される含窒素芳香族ヘテロ環を含む繰り返し単位、からなるコポリマー、ならびに、
    　パラジウム、
    　から構成される錯体を含む、固定化パラジウム触媒。

    　式中、
    　RA1は、水素、またはアルキル基を表す；
    　RA2は、触媒反応に関与しない不活性な基、または原子を表し、RA2はそれぞれ独立である；
    　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、RA3はそれぞれ独立である；
    　LAは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
    　mAは、0以上の整数である；
    　nAは、1以上の整数である；
    　mA＋nAの上限は、環状構造部の置換可能数である；
    　*は、結合位置を表す；
    　環Aは、芳香族炭化水素環を表す；

    　式中、
    　RB1は、水素、またはアルキル基を表す；
    　RB2は、触媒反応に関与しない不活性な基、または原子を表し、RB2はそれぞれ独立である；
    　LBは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
    　mBは、0以上の整数である；
    　mBの上限は、環状構造部の置換可能数である；
    　*は、結合位置を表す；
    　環Bは、含窒素芳香族ヘテロ環を表す。     (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I); and (B) a repeating unit containing a nitrogen-containing aromatic heterocycle represented by the following formula (II). and
    palladium,
    An immobilized palladium catalyst comprising a complex consisting of:

    During the ceremony,
    R A1 represents hydrogen or an alkyl group;
    R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent;
    R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent;
    LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
    mA is an integer greater than or equal to 0;
    nA is an integer greater than or equal to 1;
    The upper limit of mA + nA is the number of possible substitutions of the cyclic structure;
    * represents the binding position;
    Ring A represents an aromatic hydrocarbon ring;

    During the ceremony,
    R B1 represents hydrogen or an alkyl group;
    RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent;
    L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
    mB is an integer greater than or equal to 0;
    The upper limit of mB is the number of possible substitutions of the cyclic structure;
    * represents the binding position;
    Ring B represents a nitrogen-containing aromatic heterocycle.
  2. 　前記式(I)において、
    　mAが、0であり；
    　nAが、1であり；
    　RA1が、水素であり；
    　LAが、単結合であり；
    　環Aが、ベンゼン環である、請求項１に記載の固定化パラジウム触媒。     In the above formula (I),
    mA is 0;
    nA is 1;
    R A1 is hydrogen;
    LA is a single bond;
    An immobilized palladium catalyst according to claim 1, wherein ring A is a benzene ring.
  3. 　前記式(I)において、
    　RA3が、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、オクチル基、フェニル基、メトキシ基、エトキシ基、プロポキシ基、またはブトキシ基である、請求項１または２に記載の固定化パラジウム触媒。     In the above formula (I),
    3. A group according to claim 1 or 2, wherein R A3 is a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, octyl group, phenyl group, methoxy group, ethoxy group, propoxy group, or butoxy group. immobilized palladium catalyst.
  4. 　前記式(II)において、
    　mBが、0であり； 
    　RB1が、水素であり；
    　LBが、単結合であり；
    　環Bが、ピリジン環、またはイミダール環である、請求項１～３のいずれか１項に記載の固定化パラジウム触媒。     In the formula (II),
    mB is 0;
    R B1 is hydrogen;
    L B is a single bond;
    The immobilized palladium catalyst according to any one of claims 1 to 3, wherein ring B is a pyridine ring or an imidal ring.
  5. 　連続フロー式反応用である、請求項１～４のいずれか１項に記載の固定化パラジウム触媒。 The immobilized palladium catalyst according to any one of claims 1 to 4, which is for continuous flow reactions.
  6. 　鈴木－宮浦クロスカップリング反応用である、請求項１～５のいずれか１項に記載の固定化パラジウム触媒。 The immobilized palladium catalyst according to any one of claims 1 to 5, which is for Suzuki-Miyaura cross-coupling reaction.
  7. 　請求項１～６のいずれか１項に記載の触媒を含む、触媒組成物。 A catalyst composition comprising the catalyst according to any one of claims 1 to 6.
  8. 　（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（B）下記式(II)で示される含窒素芳香族ヘテロ環を含む繰り返し単位、からなるコポリマー。

    　式中、
    　RA1は、水素、またはアルキル基を表す；
    　RA2は、触媒反応に関与しない不活性な基、または原子を表し、RA1はそれぞれ独立である；
    　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、RA2はそれぞれ独立である；
    　LAは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
    　mAは、0以上の整数である；
    　nAは、1以上の整数である；
    　mA＋nAの上限は、環状構造部の置換可能数である；
    　*は、結合位置を表す；
    　環Aは、芳香族炭化水素環を表す；

    　式中、
    　RB1は、水素、またはアルキル基を表す；
    　RB2は、触媒反応に関与しない不活性な基、または原子を表し、RB2はそれぞれ独立である；
    　LBは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
    　mBは、0以上の整数である；
    　mBの上限は、環状構造部の置換可能数である；
    　*は、結合位置を表す；
    　環Bは、含窒素芳香族ヘテロ環を表す。     A copolymer comprising (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I) and (B) a repeating unit containing a nitrogen-containing aromatic heterocycle represented by the following formula (II).

    During the ceremony,
    R A1 represents hydrogen or an alkyl group;
    R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A1 is independent;
    R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A2 is independent;
    LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
    mA is an integer greater than or equal to 0;
    nA is an integer greater than or equal to 1;
    The upper limit of mA + nA is the number of possible substitutions of the cyclic structure;
    * represents the binding position;
    Ring A represents an aromatic hydrocarbon ring;

    During the ceremony,
    R B1 represents hydrogen or an alkyl group;
    RB2 represents an inert group or atom that does not participate in the catalytic reaction, and each RB2 is independent;
    L B represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
    mB is an integer greater than or equal to 0;
    The upper limit of mB is the number of possible substitutions of the cyclic structure;
    * represents the binding position;
    Ring B represents a nitrogen-containing aromatic heterocycle.
  9. 　請求項８に記載のコポリマーを含む、触媒固定化用材料。 A material for immobilizing a catalyst, comprising the copolymer according to claim 8.
  10. 　（A）下記式(I)で示される置換芳香族炭化水素環を含む繰り返し単位、および、（C）下記式(III)で示されるビニル置換芳香族炭化水素環を含む繰り返し単位、からなるコポリマーを含む、
    　触媒反応装置用充填材料。

    　式中、
    　RA1は、水素、またはアルキル基を表す；
    　RA2は、触媒反応に関与しない不活性な基、または原子を表し、RA2はそれぞれ独立である；
    　RA3は、アルキル基、アリール基、アルコキシ基、またはアシル基を表し、RA3はそれぞれ独立である；
    　LAは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
    　mAは、0以上の整数である；
    　nAは、1以上の整数である；
    　mA＋nAの上限は、環状構造部の置換可能数である；
    　*は、結合位置を表す；
    　環Aは、芳香族炭化水素環を表す；

    　式中、
    　RC1は、水素、またはアルキル基を表す；
    　RC2は、触媒反応に関与しない不活性な基、または原子を表し、RC2はそれぞれ独立である；
    　LCは、単結合、アルキレン基、アリーレン基、ヘテロ原子、またはそれらの組合せを表す；
    　mCは、0以上の整数である；
    　nCは、1以上の整数である；
    　mC＋nCの上限は、環状構造部の置換可能数である；
    　*は、結合位置を表す；
    　環Cは、芳香族炭化水素環を表す。     (A) a repeating unit containing a substituted aromatic hydrocarbon ring represented by the following formula (I); and (C) a repeating unit containing a vinyl-substituted aromatic hydrocarbon ring represented by the following formula (III). including,
    Packing material for catalytic reactors.

    During the ceremony,
    R A1 represents hydrogen or an alkyl group;
    R A2 represents an inert group or atom that does not participate in the catalytic reaction, and each R A2 is independent;
    R A3 represents an alkyl group, an aryl group, an alkoxy group, or an acyl group, and each R A3 is independent;
    LA represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
    mA is an integer greater than or equal to 0;
    nA is an integer greater than or equal to 1;
    The upper limit of mA + nA is the number of possible substitutions of the cyclic structure;
    * represents the binding position;
    Ring A represents an aromatic hydrocarbon ring;

    During the ceremony,
    R C1 represents hydrogen or an alkyl group;
    R C2 represents an inert group or atom that does not participate in the catalytic reaction, and each R C2 is independent;
    L C represents a single bond, an alkylene group, an arylene group, a heteroatom, or a combination thereof;
    mC is an integer greater than or equal to 0;
    nC is an integer greater than or equal to 1;
    The upper limit of mC + nC is the number of substitutable cyclic structural moieties;
    * represents the binding position;
    Ring C represents an aromatic hydrocarbon ring.
  11. 　請求項１～６のいずれか１項に記載の触媒、または請求項７に記載の触媒組成物の存在下、
    　芳香族ハロゲン化物と芳香族ホウ素化合物を反応させ、鈴木－宮浦クロスカップリング反応を行う方法。     In the presence of the catalyst according to any one of claims 1 to 6 or the catalyst composition according to claim 7,
    A method in which an aromatic halide and an aromatic boron compound are reacted to perform a Suzuki-Miyaura cross-coupling reaction.
  12. 　請求項１～６のいずれか１項に記載の触媒、または請求項７に記載の触媒組成物の存在下、
    　芳香族ハロゲン化物と芳香族ホウ素化合物を反応させ、鈴木－宮浦クロスカップリング反応により多環式芳香族化合物を製造する工程を含む、多環式芳香族化合物の製造方法。
          In the presence of the catalyst according to any one of claims 1 to 6 or the catalyst composition according to claim 7,
    A method for producing a polycyclic aromatic compound, comprising a step of reacting an aromatic halide and an aromatic boron compound to produce a polycyclic aromatic compound by Suzuki-Miyaura cross-coupling reaction.
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