WO2023167325A1 - 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 - Google Patents

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 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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