Hydrogenolysis catalysts of carbon-heteroatom bonds, methods of making the same, and methods of hydrogenolysing carbon-heteroatom bonds

Abstract

Provided is a hydrogenolysis reaction catalyst which does not require the use of a strong acid and which has a catalytic activity equivalent to or more excellent than that of a conventional catalyst even when the amount of palladium is reduced from that of the conventional catalyst. A hydrogenolysis catalyst which hydrogenolyzes a carbon-heteroatom bond of a substrate organic compound containing the carbon-heteroatom bond includes a carbon-based carrier which at least supports: a palladium catalyst; and at least one of a phosphoric acid compound and an acetic acid compound.

Description

Technical Field

[0001] This patent application claims priority to Japanese Patent Application No. 2023-188316, filed on November 2, 2023, the entire disclosure of which forms part of this specification by reference.

[0002] This disclosure relates to a catalyst for hydrogenolysis of carbon-heteroatom bonds and its preparation method, as well as a method for hydrogenolysis of carbon-heteroatom bonds. Background Technology

[0003] In the field of organic synthesis, the introduction and deprotection of various protecting groups are extremely important for synthesizing target compounds. Furthermore, carbon-heteroatom bonds are well-known as structures that facilitate the introduction and deprotection of various protecting groups.

[0004] For deprotection reactions involving introduced protecting groups (such as the hydrogenolysis of benzyl groups), palladium / carbon catalysts are mainly used for contact hydrogen reduction. However, this approach has the following drawback: without the addition of a large amount of palladium as a catalyst, the reaction cannot proceed to the deprotection side. Therefore, for such deprotection reactions, further improvements to palladium catalysts are currently being investigated due to their insufficient cost and yield.

[0005] For example, Patent Document 1 proposes a method in which hydrogen is generated in the presence of a palladium catalyst and an amine having one nitrogen atom, and the amine having one nitrogen atom modifies the palladium catalyst, thereby enabling the modified palladium catalyst to selectively hydrogenate a protecting group (benzyl).

[0006] In addition, Patent Document 2 proposes a hydrogenolysis catalyst that brings Brønsted acid catalyst and palladium catalyst into contact within a reactor.

[0007] Existing technical documents Patent Document 1: Japanese Patent Application Publication No. 2017-197484 Patent Document 2: International Publication No. 2021 / 251248. Summary of the Invention

[0008] However, the method proposed in Patent Document 1, which adjusts the catalytic activity by coating the surface of the palladium catalyst with amine compounds, has the problem of reduced catalytic activity due to poisoning.

[0009] In addition, the hydrogenolysis catalyst proposed in Patent Document 2 is a Brønsted acid catalyst, which uses activated carbon treated with strong acids such as nitric acid and sulfuric acid and endowed with acidic functional groups in combination with a palladium-carbon catalyst. However, there are production-related problems such as the different deactivation times of the two catalysts and the need to deal with the dilution heat of water in the hydrated carbon and waste liquid treatment due to the use of strong acids in the preparation process.

[0010] In view of the above problems, one of the objectives of this disclosure is to provide a hydrogenolysis catalyst that does not require the use of strong acids and still has catalytic activity comparable to or better than that of existing catalysts, even when the palladium content is reduced compared to existing palladium catalysts.

[0011] Through in-depth research, the authors have discovered that by loading palladium and phosphoric acid or acetic acid compounds onto a carbon-based support, a hydrogenolysis catalyst with excellent catalytic activity can be obtained without the use of strong acids. This disclosure is based on the above findings.

[0012] One technical solution disclosed herein provides a hydrogenolysis catalyst for hydrogenolyzing the carbon-heteroatom bonds of a matrix organic compound containing carbon-heteroatom bonds. The hydrogenolysis catalyst comprises a carbon-based support, and the carbon-based support is loaded with at least the following: Palladium catalysts; and At least one of a phosphoric acid compound and an acetic acid compound.

[0013] According to this disclosure, a hydrogenolysis catalyst can be provided that does not require the use of strong acids and still exhibits catalytic activity comparable to or superior to existing catalysts, even when the palladium content is reduced compared to existing palladium catalysts. Detailed Implementation

[0014] [Hydrogenolysis catalyst] In one embodiment of this disclosure, a hydrogenolysis catalyst is used to hydrogenolyze the carbon-heteroatom bonds of a matrix organic compound containing carbon-heteroatom bonds. The catalyst is characterized by comprising a carbon-based support, wherein the carbon-based support is loaded with at least one of: a palladium catalyst; and a phosphoric acid compound and an acetic acid compound. The hydrogenolysis catalyst of this disclosure will be described in detail below.

[0015] (Palladium catalyst) In the hydrogenolysis catalyst disclosed herein, the aforementioned palladium catalyst is used as a hydrogenation catalyst. The palladium catalyst only needs to contain palladium as a catalyst component; it can contain palladium itself or palladium-containing compounds (palladium compounds). Known compounds such as particles and various alloys can also be used as palladium catalysts.

[0016] Examples of palladium compounds include tetra(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride, palladium acetate, tris(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium, bis[4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine chloride, bis(di-tert-butylisopentenylphosphine)palladium chloride, and bis(di-tert-butylcrotonylphosphine)dichloride.

[0017] The amount of palladium catalyst included in the hydrogenolysis catalyst is not particularly limited as long as the purpose of this disclosure is achieved. For example, in 100 parts by mass of the hydrogenolysis catalyst (dry basis), it can be 1 to 20 parts by mass, preferably 1.5 to 18 parts by mass, more preferably 2 to 15 parts by mass, and even more preferably 3 to 13 parts by mass. Similarly, the amount of palladium element included in the hydrogenolysis catalyst is not particularly limited as long as the purpose of this disclosure is achieved. For example, in 100 parts by mass of the hydrogenolysis catalyst (dry basis), it can be 1 to 20 parts by mass, preferably 1.5 to 18 parts by mass, more preferably 2 to 15 parts by mass, and even more preferably 3 to 13 parts by mass. By setting the amount of palladium catalyst or palladium element within the above ranges, the contact area between the palladium catalyst and the matrix organic compound can be ensured, thereby improving reactivity.

[0018] According to one embodiment of this disclosure, the palladium catalyst is palladium itself (i.e., the palladium element).

[0019] (Phosphoric acid compounds, acetic acid compounds) In this disclosure, "phosphoric acid compound" refers to a compound having at least one hydroxyl group bonded to a phosphorus atom. Phosphoric acid compounds can be organic or inorganic.

[0020] The phosphoric acid compound is not limited to the compounds mentioned above, and examples include inorganic phosphoric acid compounds such as phosphoric acid (orthophosphoric acid), phosphorous acid, hypophosphoric acid, pyrophosphoric acid, metaphosphoric acid, and diphosphoric acid pentoxide; organic phosphoric acid compounds such as organic derivatives of phosphonic acid and phosphonic acid. According to one embodiment of this disclosure, the phosphoric acid compound is an inorganic phosphoric acid compound, preferably an inorganic phosphoric acid compound with an acid dissociation constant pKa(H₂O) of 1 or higher. According to a preferred embodiment of this disclosure, the phosphoric acid compound comprises at least one compound selected from the group consisting of phosphoric acid (orthophosphoric acid), pyrophosphoric acid, metaphosphoric acid, and diphosphoric acid pentoxide. According to a more preferred embodiment of this disclosure, the phosphoric acid compound comprises at least phosphoric acid (orthophosphoric acid).

[0021] In this disclosure, "acetic acid compound" refers to a compound having the following structure: "CR3-C(O)OH" (where each R independently represents hydrogen, C...). 1-6 Compounds with an alkyl or halogen structure.

[0022] In this disclosure, "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, but is not limited to this. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0023] In this disclosure, "halogen" may include, for example, fluorine, chlorine, bromine, iodine, etc.

[0024] Examples of acetic acid compounds include, but are not limited to, acetic acid, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and dimethylacetic acid.

[0025] According to one embodiment of the present disclosure, the acetic acid compound is an acetic acid compound with an acid dissociation constant pKa(H2O) of 1 or higher. According to a preferred embodiment of the present disclosure, the acetic acid compound comprises at least one selected from the group consisting of acetic acid, monochloroacetic acid, dichloroacetic acid, and dimethylacetic acid. According to a more preferred embodiment of the present disclosure, the acetic acid compound comprises at least acetic acid.

[0026] According to one embodiment of this disclosure, the hydrogenolysis catalyst of this disclosure comprises at least a phosphoric acid compound. According to a preferred embodiment of this disclosure, the hydrogenolysis catalyst of this disclosure comprises at least phosphoric acid (orthophosphoric acid). Phosphoric acid compounds (preferably phosphoric acid) are advantageous compared to other acids in that they do not produce off-odors and do not change over time due to decomposition during storage.

[0027] The amount of at least one of the phosphoric acid compound and acetic acid compound contained in the hydrogenolysis catalyst is not particularly limited as long as the purpose of this disclosure is achieved. For example, in 100 parts by weight of the hydrogenolysis catalyst (dry basis), it can be 1 to 20 parts by weight, preferably 1.5 to 15 parts by weight, more preferably 2 to 10 parts by weight, and even more preferably 3 to 8 parts by weight. When the hydrogenolysis catalyst contains a phosphoric acid compound, the amount of phosphorus contained in the hydrogenolysis catalyst is not particularly limited as long as the purpose of this disclosure is achieved. For example, in 100 parts by weight of the hydrogenolysis catalyst (dry basis), it can be 0.25 to 5 parts by weight, preferably 0.4 to 4 parts by weight, more preferably 0.5 to 2.5 parts by weight, and even more preferably 0.7 to 2 parts by weight.

[0028] The ratio of palladium catalyst to at least one of phosphoric acid compound and acetic acid compound in the hydrogenolysis catalyst (palladium catalyst: at least one of phosphoric acid compound and acetic acid compound) is not particularly limited as long as it achieves the purpose of this disclosure. For example, based on these mass parts contained in the hydrogenolysis catalyst, it can be 1:20 to 20:1, preferably 1:10 to 10:1, more preferably 1:5 to 5:1, and even more preferably 2:1 to 1:2.

[0029] When the hydrogenation catalyst contains a phosphoric acid compound, the ratio of palladium to phosphorus in the hydrogenolysis catalyst (palladium:phosphorus) is not particularly limited as long as it achieves the purpose of this disclosure. For example, based on the mass parts contained in the hydrogenolysis catalyst, it can be 1:10 to 40:1, preferably 1:5 to 20:1, more preferably 1:3 to 10:1, and even more preferably 1:1 to 5:1.

[0030] (Carbon-based support) In the hydrogenolysis catalyst disclosed herein, the carbon-based support is at least supported with a palladium catalyst and at least one of a phosphoric acid compound and an acetic acid compound. There is no particular limitation on the carbon-based support, as long as it can support at least one of a palladium catalyst and a phosphoric acid compound and an acetic acid compound. Examples of carbon-based supports include, but are not limited to, activated carbon, pulverized activated carbon, mesoporous carbon, graphene, carbon nanotubes, glassy carbon (GC), fine carbon, carbon black, graphite, and carbon fibers. According to one embodiment of this disclosure, the carbon-based support comprises at least one selected from the group consisting of activated carbon, mesoporous carbon, graphene, and carbon nanotubes.

[0031] The specific surface area of ​​the carbon-based support is not particularly limited as long as it achieves the purpose of this disclosure. For example, the specific surface area of ​​the carbon-based support can be 1 m². 3 / g or more, preferably 10m 3 / g or more, preferably 100m 3 / g or higher, further optimized for 300m 3 / g or more. Furthermore, the upper limit of the specific surface area of ​​carbon-based supports can be, for example, 3000 m². 3 / g or less, preferably 2000m 3 / g or less, preferably 1500m 3 Below / g, 1000m is further preferred. 3 / g or less.

[0032] The amount of carbon-based support contained in the hydrogenolysis catalyst is not particularly limited as long as it can achieve the purpose of this disclosure. For example, in 100 parts by mass of the hydrogenolysis catalyst (dry basis), it can be 10 to 50 parts by mass, preferably 15 to 50 parts by mass, more preferably 25 to 50 parts by mass, and even more preferably 35 to 50 parts by mass.

[0033] The ratio of palladium catalyst to carbon-based support in the hydrogenolysis catalyst (palladium catalyst: carbon-based support) is not particularly limited as long as it achieves the purpose of this disclosure. For example, based on the mass parts contained in the hydrogenolysis catalyst, it can be 1:50 to 2:1, preferably 1:30 to 1:1, more preferably 1:20 to 1:3, and even more preferably 1:10 to 1:4.

[0034] The ratio of at least one of the phosphoric acid compound and acetic acid compound contained in the hydrogenolysis catalyst to the carbon-based support (at least one of the phosphoric acid compound and acetic acid compound: carbon-based support) is not particularly limited as long as it achieves the purpose of this disclosure. For example, based on these mass parts contained in the hydrogenolysis catalyst, it can be 1:50 to 2:1, preferably 1:30 to 1:1, more preferably 1:20 to 1:3, and even more preferably 1:10 to 1:4.

[0035] The hydrogenolysis catalyst disclosed herein may also contain water. By containing water, the hydrogenolysis catalyst of this disclosure helps to prevent catalyst dispersion and fire during use. When the hydrogenolysis catalyst of this disclosure contains water, the water content, for example, in 100 parts by mass of the hydrogenolysis catalyst, can be 5 to 70 parts by mass, more preferably 20 to 60 parts by mass, and even more preferably 45 to 55 parts by mass.

[0036] The hydrogenolysis catalyst disclosed herein may also be supported on a carbon-based support with other components, without prejudice to the purpose of this disclosure. Examples of such other components include, but are not limited to, noble metal elements other than palladium (e.g., platinum, ruthenium, etc.) or their compounds, and compounds having functional groups such as sulfonic acid groups, carboxyl groups, and amino groups.

[0037] The hydrogenolysis catalyst disclosed herein may, without prejudice to the purpose of this disclosure, contain other components (e.g., other catalysts with hydrogenolysis energy, co-catalysts that promote hydrogenolysis reactions, etc.) in addition to a carbon-based support containing at least one of a palladium catalyst, a phosphoric acid compound, and an acetic acid compound.

[0038] (Base organic compounds containing carbon-heteroatom bonds) The hydrogenolysis catalyst disclosed herein is capable of hydrogenolyzing the carbon-heteroatom bond in a matrix organic compound containing a carbon-heteroatom bond.

[0039] As used in this disclosure, "carbon-heteroatom bond" refers to a bond formed between a carbon atom and an atom other than a carbon atom. Examples of atoms other than carbon atoms include nitrogen atoms, oxygen atoms, sulfur atoms, phosphorus atoms, and metal atoms, but the scope is not limited to these; nitrogen atoms and oxygen atoms are preferred. Therefore, examples of carbon-heteroatom bonds include carbon-nitrogen bonds, carbon-oxygen bonds, carbon-sulfur bonds, carbon-phosphorus bonds, and carbon-metal atom bonds. From the perspective of ease of hydrogenolysis reaction, carbon-heteroatom bonds are preferably carbon-nitrogen bonds and carbon-oxygen bonds, and more preferably carbon-nitrogen bonds.

[0040] The carbon-heteroatom bond can be a single bond, a double bond, or a triple bond. According to one embodiment of this disclosure, the carbon-heteroatom bond is a single bond.

[0041] As used in this disclosure, "matrix organic compounds containing carbon-heteroatom bonds" (hereinafter also referred to as "matrix organic compounds") refers to organic compounds containing at least one carbon-heteroatom bond within their molecules, without particular limitation as long as they can serve as a matrix for hydrogenolysis reactions. Matrix organic compounds can be partially or entirely chain-like (e.g., straight-chain, branched) or cyclic. Furthermore, the carbon-carbon bonds in a matrix organic compound can be single bonds or may include one or more double and / or triple bonds. Additionally, one or more hydrogen atoms bonded to carbon atoms in a matrix organic compound can be replaced by any substituents (e.g., they can be replaced by one or more arbitrary substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxy, halogen, carboxyl, aldehyde, hydroxyl, amino, phenyl). Furthermore, one or more carbon atoms constituting a matrix organic compound can be replaced by heteroatoms (e.g., oxygen, nitrogen, sulfur).

[0042] The hydrogenolysis catalyst disclosed herein can be used for the deprotection reaction of a protecting group, which protects a highly reactive site within the molecule from the influence of reactions at other sites. Therefore, the matrix organic compound can also be a compound in which a protecting group is coordinated at a heteroatom site in a carbon-heteroatom bond. The term "protecting group" in this disclosure is not limited to this, and examples include aralkyl groups (e.g., benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, diphenylmethyl, etc.), aromatic... Protecting groups having aromatic ring structures include alkoxycarbonyl groups (e.g., aralkyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2-methoxybenzyloxycarbonyl, 3-methoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, etc., and arylalkyloxycarbonyl groups), alkoxycarbonyl groups (e.g., tert-butyloxycarbonyl, tert-pentyloxycarbonyl, etc.); and trialkylsilylcarbonyl groups (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.). As protecting groups, those having aromatic ring structures are preferred, aralkyl or arylalkyloxycarbonyl groups are more preferred, benzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, and benzyloxycarbonyl are even more preferred, and benzyl is even more preferred.

[0043] According to one embodiment of this disclosure, the carbon-heteroatom bond is a carbon-heteroatom bond adjacent to the aromatic ring (preferably a carbon-nitrogen bond adjacent to the aromatic ring). In this disclosure, "carbon adjacent to the aromatic ring" refers to a carbon atom that is 1 (i.e., directly bonded to the atom constituting the aromatic ring), 2 (i.e., there is one other atom between it and the atom constituting the aromatic ring), or 3 (i.e., there are two other atoms between it and the atom constituting the aromatic ring) away from the atom constituting the aromatic ring. Preferably, the carbon adjacent to the aromatic ring is a carbon atom 1 or 2 atoms away from the atom constituting the aromatic ring, more preferably a carbon atom 1 atom away from the atom constituting the aromatic ring (i.e., a carbon atom directly bonded to the atom constituting the aromatic ring).

[0044] According to a preferred embodiment of this disclosure, the carbon-heteroatom bond is a bond between a benzyl group and a nitrogen atom.

[0045] According to one embodiment of this disclosure, the matrix organic compound is a compound in which a benzyl group is coordinated to the nitrogen atom of an aniline structure. According to a preferred embodiment of this disclosure, the matrix organic compound is N-benzyl-N-butyl-3-methylaniline.

[0046] [Preparation method of hydrogenolysis catalyst] According to another embodiment of this disclosure, a method for preparing a hydrogenolysis catalyst is provided, the hydrogenolysis catalyst being used to hydrogenolyze the carbon-heteroatom bonds of a matrix organic compound containing carbon-heteroatom bonds, the method comprising: A carbon-based support loaded with palladium catalyst was mixed with water; and The obtained mixture is then mixed with either a phosphoric acid compound or an acetic acid compound.

[0047] (The mixing process of a carbon-based support loaded with palladium catalyst and water) According to one embodiment of this disclosure, in the above-described preparation method, a step of mixing a carbon-based support loaded with palladium catalyst with water is performed (also referred to herein as the "first mixing step"). In the first mixing step, the carbon-based support loaded with palladium catalyst and water can be mixed using, for example, a desired stirring device (e.g., a known stirring device) to obtain a mixture (also referred to herein as the "first mixture"). The first mixture may be in slurry form.

[0048] The carbon-based support for the palladium catalyst used in the first mixing step can be a commercially available palladium-supported carbon-based support, which can be used to load the palladium catalyst onto the carbon-based support using known methods.

[0049] In the first mixing step, the mixing ratio of the carbon-based support loaded with palladium catalyst to water is not particularly limited. For example, relative to 100 parts by mass of the carbon-based support loaded with palladium catalyst (dry weight), the water can be 10 to 10,000 parts by mass, preferably 50 to 5,000 parts by mass, more preferably 200 to 3,000 parts by mass, and even more preferably 500 to 1,000 parts by mass.

[0050] In the first mixing step, those skilled in the art can make appropriate adjustments to the mixing conditions (temperature, time, stirring speed, etc.) between the carbon-based support loaded with palladium catalyst and water.

[0051] In the first mixing step, other ingredients may be mixed sequentially or simultaneously as needed, without prejudice to the purpose of this disclosure.

[0052] (The process of mixing the obtained mixture with at least one of the phosphoric acid compound and the acetic acid compound) According to one embodiment of this disclosure, in the above-described preparation method, a step is performed to mix the mixture obtained in the first mixing step (the first mixture) with a phosphoric acid compound or an acetic acid compound (also referred to in this disclosure as the "second mixing step"). In the second mixing step, the first mixture obtained in the first mixing step (i.e., a mixture containing a carbon-based support loaded with a palladium catalyst and water) can be mixed with at least one of the phosphoric acid compound and the acetic acid compound using, for example, a suitable stirring device (e.g., a known stirring device) to obtain a mixture (also referred to in this disclosure as the "second mixture").

[0053] In the second mixing step, the mixing ratio of the first mixture with at least one of the phosphoric acid compound and the acetic acid compound is not particularly limited. For example, relative to 100 parts by mass of the first mixture, at least one of the phosphoric acid compound and the acetic acid compound can be 0.001 to 100 parts by mass, preferably 0.01 to 30 parts by mass, more preferably 0.1 to 10 parts by mass, and even more preferably 0.3 to 5 parts by mass.

[0054] In the second mixing step, those skilled in the art can appropriately adjust the mixing conditions (temperature, time, stirring speed, etc.) of the first mixture with at least one of the phosphoric acid compound and acetic acid compound.

[0055] In the second mixing step, other ingredients may be mixed sequentially or simultaneously as needed, without prejudice to the purpose of this disclosure.

[0056] (Filtration process) According to one embodiment of this disclosure, the method for preparing the hydrogenolysis catalyst includes a step of filtering a second mixture (also referred to herein as a "filtration step"). By implementing the filtration step, it is beneficial to remove impurities (e.g., at least one of unreacted phosphoric acid compounds and acetic acid compounds) and excess moisture from the hydrogenolysis catalyst.

[0057] In the filtration process, the second mixture (or the substance after further processing of the second mixture) is filtered to obtain a filter. The filter contains at least a carbon-based support loaded with a palladium catalyst and at least one of a phosphoric acid compound and an acetic acid compound.

[0058] In the filtration process, the filtration method is not limited to this; for example, filter filtration, centrifugal filtration, etc. can be listed.

[0059] In the filtration process, those skilled in the art can make appropriate adjustments to the filtration conditions (temperature, time, type of filter, etc.).

[0060] (Dehydration process) According to one embodiment of this disclosure, a process for dehydrating the second mixture (or the substance after further processing of the second mixture) or the filter material described above is performed (also referred to herein as a "dehydration process"). By performing the dehydration process, it is advantageous to set the water content in the hydrogenolysis catalyst to a desired range.

[0061] In the dehydration process, the second mixture (or the substance after further processing of the second mixture) or the filter material can also be dehydrated by the required methods (such as drying, centrifugation, etc.).

[0062] In the dehydration process, those skilled in the art can make appropriate adjustments to the conditions (temperature, time, stirring speed, etc.) during dehydration.

[0063] The order of the above-mentioned filtration and dehydration processes can be changed as needed.

[0064] In addition to the steps described above, other steps may be added as needed to the preparation method of the hydrogenolysis catalyst disclosed herein.

[0065] [Applications of hydrogenolysis catalysts] The hydrogenolysis catalyst disclosed herein can be used for the hydrogenolysis of carbon-heteroatom bonds in matrix organic compounds containing carbon-heteroatom bonds. The hydrogenolysis catalyst disclosed herein can also be used for the deprotection reaction of protecting groups that protect highly reactive sites within the molecule from the influence of reactions at other sites. Therefore, according to one embodiment of this disclosure, the hydrogenolysis catalyst disclosed herein is used for the deprotection of the aforementioned matrix compounds.

[0066] According to another embodiment of this disclosure, a method for hydrogenolysis of the carbon-heteroatom bond is provided, comprising contacting a matrix organic compound containing the carbon-heteroatom bond, molecular hydrogen, and the hydrogenolysis catalyst.

[0067] (The contact process between the matrix organic compound, molecular hydrogen, and hydrogenolysis catalyst) According to one embodiment of this disclosure, in the above-described hydrogenolysis method, a step (also referred to herein as a "contact step") is performed in which the matrix organic compound containing the carbon-heteroatom bonds, molecular hydrogen, and the hydrogenolysis catalyst are brought into contact. In the contact step, the matrix organic compound containing the carbon-heteroatom bonds, molecular hydrogen, and the hydrogenolysis catalyst can be brought into contact within, for example, a desired reaction system (e.g., a reaction vessel), thereby carrying out the hydrogenolysis reaction.

[0068] The ratio of the hydrogenolysis catalyst to the matrix organic compound is not particularly limited, as long as it is a ratio that allows the hydrogenolysis reaction to occur. For example, relative to 100 parts by mass of the matrix organic compound, the hydrogenolysis catalyst can be 0.001 to 100 parts by mass, preferably 0.01 to 50 parts by mass, more preferably 0.1 to 20 parts by mass, and even more preferably 1 to 10 parts by mass. Furthermore, the ratio of the hydrogenolysis catalyst to the matrix organic compound, for example, relative to 1 mol of the matrix organic compound, can be 0.001 to 100 mol, preferably 0.01 to 10 mol, more preferably 0.05 to 5 mol, and even more preferably 0.1 to 3 mol.

[0069] Molecular hydrogen can exist in either the liquid or gas phase of the reaction system (e.g., within a reaction vessel). The pressure of the hydrogen supplied to the reaction system is not particularly limited, as long as it is a pressure that allows the hydrogenolysis reaction to proceed; for example, it can be 0.01–1 MPa, preferably 0.05–0.8 MPa, and more preferably 0.1–0.6 MPa.

[0070] The above-described hydrogenolysis reaction can be carried out in the presence of a desired reaction solvent. The reaction solvent can be a substance capable of dissolving at least a portion of the above-described matrix organic compound and / or the above-described hydrogenolysis catalyst. Furthermore, the reaction solvent is not particularly limited as long as it does not completely inhibit the hydrogenolysis reaction; examples include polar solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, etc.; alcohols such as 2-propanol, methanol, ethanol, etc.; and non-polar solvents such as ethyl acetate, propyl acetate, etc.; chain hydrocarbons such as n-hexane, n-heptane, etc.; and cyclic hydrocarbons such as cyclohexane, etc. The hydrogenolysis catalyst and / or hydrogenolysis method disclosed herein are advantageous in terms of applicability, regardless of whether a polar or non-polar solvent is used.

[0071] The amount of the reaction solvent is not particularly limited, as long as it is sufficient to carry out the hydrogenolysis reaction. From the perspective of stably carrying out the hydrogenolysis reaction, relative to 100 parts by mass of the matrix organic compound, it can be, for example, 1 to 10,000 parts by mass, preferably 1 to 100 parts by mass, more preferably 10 to 50 parts by mass, and even more preferably 10 to 20 parts by mass.

[0072] There is no particular limitation on the reaction temperature for carrying out the hydrogenolysis reaction; any temperature suitable for the hydrogenolysis reaction can be used, such as -30 to 80°C, preferably -15 to 60°C, more preferably 0 to 50°C, and even more preferably 10 to 30°C. Those skilled in the art can make appropriate adjustments to the above reaction temperature by considering the type of matrix organic compound used, the reaction time, etc.

[0073] There is no particular limitation on the reaction time for hydrogenolysis, as long as the time is sufficient for the hydrogenolysis reaction to proceed. For example, it can be 0.1 to 48 hours, preferably 0.1 to 24 hours, and more preferably 0.1 to 10 hours. Those skilled in the art can make appropriate adjustments to the above reaction time by considering the type of matrix organic compound used, the reaction temperature, etc.

[0074] In the above-mentioned hydrogenolysis reaction, when bonds other than the target carbon-heteroatom bond (e.g., aromatic ring bonds, other double bonds, triple bonds, etc. present in the matrix organic compound) are hydrogenated, the amount of hydrogenolysis catalyst, the amount of molecular hydrogen, the hydrogen pressure, the reaction temperature, the reaction time, etc. can be appropriately adjusted. Alternatively, other protecting groups (preferably protecting groups that will not be decomposed by the hydrogenolysis reaction generated by the hydrogenolysis catalyst of this disclosure) can be used in advance to protect the bonds other than the target carbon-heteroatom bond.

[0075] [Preparation methods for generating organic compounds] Through the above-described hydrogenolysis reaction, a generative organic compound containing a carbon-heteroatom bond can be prepared by hydrogenolysis of at least one of the carbon-heteroatom bonds in a matrix organic compound. Therefore, according to another embodiment of this disclosure, a method for preparing at least one generative organic compound containing the above-described carbon-heteroatom bond by hydrogenolysis is provided, comprising the step of contacting (preferably reacting) the matrix organic compound containing the above-described carbon-heteroatom bond, the above-described molecular hydrogen, and the above-described hydrogenolysis catalyst, for example, in a reactor.

[0076] Alternatively, after the desired hydrogenolysis reaction is completed, the generated organic compound can be separated from the reaction post-solution containing the generated organic compound by, for example, a known method. Therefore, according to one embodiment of this disclosure, the preparation method may also include a step of separating the generated organic compound obtained in the above reaction step. The separation method is not limited to this; for example, liquid-liquid separation, distillation, column chromatography, recrystallization, etc., may also be used.

[0077] This disclosure includes the following.

[0078] [1] A hydrogenolysis catalyst for hydrogenolyzing the carbon-heteroatom bond of a matrix organic compound containing a carbon-heteroatom bond, comprising a carbon-based support, wherein the carbon-based support is loaded with at least: Palladium catalysts; and At least one of a phosphoric acid compound and an acetic acid compound.

[0079] [2] The hydrogenolysis catalyst according to [1] comprises a carbon-based support at least loaded with a phosphoric acid compound.

[0080] [3] According to the hydrogenolysis catalyst described in [1] or [2], the phosphoric acid compound comprises at least one selected from the group consisting of phosphoric acid (orthophosphoric acid), pyrophosphoric acid, metaphosphoric acid and diphosphoric acid pentoxide.

[0081] [4] The hydrogenolysis catalyst according to any one of [1] to [3] contains at least phosphoric acid (orthophosphoric acid).

[0082] [5] According to the hydrogenolysis catalyst of [1], the acetic acid compound comprises at least one selected from the group consisting of acetic acid, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid and dimethylacetic acid.

[0083] [6] The hydrogenolysis catalyst according to any one of [1] to [5], wherein the carbon-based support comprises at least one selected from the group consisting of activated carbon, mesoporous carbon, graphene and carbon nanotubes.

[0084] [7] In any one of [1] to [6], 100 parts by mass of the hydrogenolysis catalyst (dry basis) comprises 1 to 20 parts by mass of palladium catalyst, 1 to 20 parts by mass of phosphoric acid compound or acetic acid compound, and 10 to 50 parts by mass of carbon-based support.

[0085] [8] In any one of [1] to [7], the water content in 100 parts by mass of the hydrogenolysis catalyst is 5 to 70 parts by mass.

[0086] [9] In any one of [1] to [8], the hydrogenolysis catalyst contains 0.25 to 5 parts by mass of phosphorus in 100 parts by mass of the hydrogenolysis catalyst (dry basis).

[0087]

[10] The hydrogenolysis catalyst according to any one of [1] to [9], wherein the carbon-heteroatom bond is a carbon-nitrogen bond.

[0088]

[11] According to the hydrogenolysis catalyst of

[10] , the carbon-nitrogen bond is a bond between a carbon atom and a nitrogen atom adjacent to the aromatic ring.

[0089]

[12] A method for preparing a hydrogenolysis catalyst, said hydrogenolysis catalyst hydrogenating the carbon-heteroatom bond of a matrix organic compound containing a carbon-heteroatom bond, said method comprising: A carbon-based support loaded with palladium catalyst was mixed with water; and The resulting mixture is mixed with at least one of a phosphoric acid compound and an acetic acid compound.

[0090]

[13] A method for preparing an organic compound by hydrogenolysis of at least one carbon-heteroatom bond, comprising the step of contacting a matrix organic compound containing the carbon-heteroatom bond, molecular hydrogen, and a hydrogenolysis catalyst in a reactor, wherein the hydrogenolysis catalyst comprises a carbon-based support, the carbon-based support being loaded with at least one of a palladium catalyst and a phosphoric acid compound and an acetic acid compound.

[0091] Example The hydrogenolysis catalyst of this disclosure will be described in more detail below using examples. However, the following examples are not intended to limit the hydrogenolysis catalyst of this disclosure in any way. Furthermore, unless otherwise specified, percentages and ratios stated in this specification are based on mass. Additionally, unless otherwise specified, the units and measurement methods described in this specification are performed in accordance with Japanese Industrial Standards (JIS).

[0092] [Example 1: Phosphoric acid supported 5% Pd / C catalyst] 120 g of 5% Pd / C (manufactured by NECHEMCAT Co., Ltd., trade name: Pd / C PE type (Pd5%) (containing water)) was mixed with 960 mL of pure water and stirred for 5 minutes to obtain an aqueous Pd / C solution. Next, the above aqueous Pd / C solution was mixed with 10.3 mL of 85% phosphoric acid solution and stirred for 30 minutes. The mixture was then filtered and dehydrated to obtain the hydrogenolysis catalyst of Example 1 (phosphoric acid-supported 5% Pd / C catalyst).

[0093] Elemental analysis was performed on the 5% Pd / C used as raw material. The results showed that the amount of palladium in the support was 4.73%. Therefore, it was estimated that the amount of carbon-based support in the 5% Pd / C was 95.27% (on a dry basis).

[0094] The hydrogenolysis catalyst obtained in Example 1 had a water content of 51.34%. Furthermore, elemental analysis of the hydrogenolysis catalyst of Example 1 revealed a phosphorus content of 1.63% (on a dry basis), suggesting that each 100g of hydrogenolysis catalyst (on a dry basis) contained 5.4g of phosphoric acid. Therefore, the hydrogenolysis catalyst of Example 1 is presumed to contain approximately 5% palladium catalyst (on a dry basis) and approximately 44% carbon-based support (on a dry basis).

[0095] [Example 2: Phosphoric acid supported 10% Pd / C catalyst] 5.0 g of dried 10% Pd / C (manufactured by NECHEMCAT Co., Ltd., trade name: P-10D (containing water)) was mixed with 40 mL of pure water and stirred for 5 minutes to obtain an aqueous Pd / C solution. Next, the above aqueous Pd / C solution was mixed with 0.43 mL of 85% phosphoric acid, stirred for 30 minutes, filtered, and dehydrated to obtain the hydrogenolysis catalyst of Example 2 (phosphoric acid-supported 10% Pd / C catalyst).

[0096] The hydrogenolysis catalyst obtained in Example 2 had a water content of 50%.

[0097] [Example 3: Acetic acid-supported 10% Pd / C catalyst] 5.0 g of dried 10% Pd / C (manufactured by NECHEMCAT Co., Ltd., trade name: P-10D (containing water)) was mixed with 40 mL of pure water and stirred for 5 minutes to obtain an aqueous Pd / C solution. Next, the above aqueous Pd / C solution was mixed with 0.43 mL of acetic acid and stirred for 30 minutes. The mixture was then filtered and dehydrated to obtain the hydrogenolysis catalyst of Example 3 (acetic acid-supported 10% Pd / C catalyst).

[0098] The hydrogenolysis catalyst obtained in Example 3 had a water content of 50%.

[0099] [Reference Example 1: 5% Pd / C catalyst] 5% Pd / C (manufactured by NECHEMCAT Co., Ltd., trade name: Pd / C PE type (Pd5%) (containing water)) was used as the hydrogenolysis catalyst in Reference Example 1.

[0100] [Reference Examples 2 and 3: 10% Pd / C catalyst] 10% Pd / C (manufactured by NECHEMCAT Co., Ltd., trade name: P-10D (containing water)) was used as the hydrogenolysis catalyst in Reference Examples 2 and 3.

[0101] [Reference Example 4: A mixture of 10% Pd / C catalyst and sulfonic acid-based activated carbon] 20 mg of 10% Pd / C (manufactured by NECHEMCAT Co., Ltd., trade name: P-10D (containing water)) was mixed with sulfonic acid-containing activated carbon (manufactured by FUTAMURA Chemical Co., Ltd., trade name: Taiko CP, product parameters: moisture 60-70%, particle size less than 0.18 mm, specific surface area less than 50 m²) 2 Mix 30 mg of (2.0-2.5 mmol / g of sulfonic acid group) to obtain the hydrogenolysis catalyst of Reference Example 4.

[0102] The hydrogenation catalyst obtained in Reference Example 4 contains approximately 5% Pd (on a dry basis).

[0103] [Experimental Example 1: Hydrogenolysis (Debenzylation) 1 / Reaction in Ethyl Acetate] [Formula 1]

[0104] The matrix organic compound, N-benzyl-N-butyl-3-methylaniline (0.8 mmol), and the hydrogenolysis catalyst of Examples 1 or 1-4 were mixed in ethyl acetate solvent, and the debenzylation reaction was carried out under hydrogen pressure of 0.2 MPa and at room temperature (23°C) for 1 hour with stirring. The resulting reaction solution was analyzed by gas chromatography (apparatus: Shimadzu Corporation GC-2010, column: DB-1 30.0 m, mobile phase: He), and the conversion rate was calculated based on the reduction of the matrix organic compound. The results are shown in Table 1. Only the peak of N-butyl-m-methylaniline was observed in the resulting reaction solution, indicating that the debenzylation reaction had occurred. In Table 1, the weight ratio of the matrix organic compound to Pd is taken as the catalyst amount (wt%).

[0105] [Table 1]

[0106] [Experimental Example 2: Hydrogenolysis (Debenzylation) 2 / Reaction in Cyclohexane] [Equation 2]

[0107] The matrix organic compound, namely 0.8 mmol of N-benzyl-N-butyl-3-methylaniline, and the hydrogenolysis catalyst obtained in Examples 2-3 or Reference Example 2 were mixed in cyclohexane solvent, and the debenzylation reaction was carried out while stirring at a hydrogen pressure of 0.2 MPa and room temperature (set to 23°C) for 1 time. The resulting reaction solution was analyzed by gas chromatography (under the same conditions as in Experimental Example 1), and the conversion rate was calculated based on the reduction in the amount of matrix organic compound. The results are shown in Table 2. In Table 2, the weight ratio of matrix organic compound to Pd is set as the catalyst amount (wt%).

[0108] [Table 2]

[0109] [Experimental Example 3: Hydrogenolysis Reaction (Debenzylation Reaction) 3 / Reaction in Various Solvents] [Formula 3]

[0110] 2.5 mmol of the matrix organic compound, N-benzyl-N-butyl-3-methylaniline, and the hydrogenolysis catalyst obtained in Example 1 were mixed in the solvents listed in Table 3, and the debenzylation reaction was carried out under hydrogen pressure of 0.2 MPa and at room temperature (set to 23 °C) for 1 hour with stirring. The resulting reaction solution was analyzed by gas chromatography (under the same conditions as in Example 1), and the conversion rate was calculated based on the reduction in the amount of matrix organic compound. The results are shown in Table 3. Furthermore, in Table 3, the weight ratio of the matrix organic compound to Pd is taken as the catalyst amount (wt%).

[0111] [Table 3]

[0112] ※: DMF: N,N-dimethylformamide, THF: tetrahydrofuran, MeOH: methanol, EtOH: ethanol, 2-PrOH: 2-propanol [Experimental Examples 4-6: Hydrogenolysis (Debenzylation) 4 / Reactions in Various Matrices] [Equation 4]

[0113] 2.5 mmol of the matrix organic compound listed in Table 4 and the hydrogenolysis catalyst obtained in Example 1 were mixed in the solvent listed in Table 4, and a debenzylation reaction was carried out while stirring at a hydrogen pressure of 0.2 MPa and room temperature (set to 23°C) for 1 hour. The resulting reaction solution was analyzed by gas chromatography (under the same conditions as in Example 1), and the conversion rate was calculated based on the reduction in the amount of matrix organic compound. The results are shown in Table 5. In Table 5, the weight ratio of the matrix organic compound to Pd is taken as the catalyst amount (wt%).

[0114] [Table 4]

[0115] ※: DMF: N,N-dimethylformamide, AcOEt: ethyl acetate [Table 5]

[0116] As clearly demonstrated by the results of Example 1, the hydrogenolysis catalyst of this disclosure exhibits superior catalytic activity in polar solvents (e.g., ethyl acetate) compared to existing hydrogenolysis catalysts (e.g., Reference Example 1) supported on an equal amount of palladium. Furthermore, the hydrogenolysis catalyst of this disclosure exhibits equal or superior catalytic activity compared to existing hydrogenolysis catalysts (e.g., Reference Example 2) supported on approximately twice the amount of palladium. Additionally, the hydrogenation catalyst of this disclosure exhibits equal or superior catalytic activity compared to the hydrogenation catalyst of Reference Example 4 (equivalent to the hydrogenation catalyst described in Patent Document 2).

[0117] The hydrogenolysis catalyst described in Patent Document 2 suffers from different deactivation times between the two catalysts, and the use of strong acids in the preparation process leads to production-related problems such as the dilution heat from water in the aqueous carbon and wastewater treatment. On the other hand, the hydrogenolysis catalyst disclosed herein does not require the use of two catalysts or a strong acid, thus avoiding the aforementioned problems, giving it an advantage. Furthermore, although the hydrogenolysis catalyst disclosed herein does not require the use of two catalysts or a strong acid, it still exhibits equal or superior catalytic activity compared to the hydrogenation catalyst described in Patent Document 2, which is particularly advantageous.

[0118] The results of Example 2 clearly demonstrate that the hydrogenolysis catalyst of this disclosure exhibits superior catalytic activity even in nonpolar solvents (e.g., cyclohexane) compared to existing hydrogenolysis catalysts supported on an equal amount of palladium (e.g., Reference Example 2). Furthermore, the results of Example 3 clearly demonstrate that the hydrogenolysis catalyst of this disclosure exhibits excellent catalytic activity even when using a variety of solvents. Therefore, the hydrogenolysis catalyst of this disclosure is advantageous in that it can exert catalytic activity in a wide range of solvents.

[0119] The results of Examples 4-6 clearly demonstrate that the hydrogenolysis catalyst of this disclosure exhibits catalytic activity for various organic bases. In particular, Examples 4 and 6 show that the hydrogenolysis catalyst of this disclosure can not only undergo debenzylation but also hydrogenolyze the double bonds (carbon-carbon double bonds) of the side chains. Therefore, the hydrogenolysis catalyst of this disclosure is advantageous in that it can hydrogenolyze not only carbon-heteroatom bonds but also carbon-carbon unsaturated bonds.

[0120] The hydrogenolysis catalyst disclosed herein exhibits excellent hydrogenolysis of carbon-heteroatom bonds. While not bound by theory, it can be considered that, for example, when using N-benzyl-N-butyl-3-methylaniline as the matrix organic compound, a phosphoric acid or acetic acid compound (preferably phosphoric acid or acetic acid) donates a proton to the nitrogen site coordinated to the benzyl group, whereby the palladium catalyst contacts the site, resulting in hydrogenolysis (debenzylation). In particular, since the proton-donating reaction destabilizes the benzyl group, palladium hydrogenolysis can occur at a lower activation energy than previously possible. Consequently, even with a smaller amount of palladium compared to existing catalysts, equivalent or superior catalytic activity can be obtained.

[0121] It is currently believed that the above reaction requires functional groups to be attached to the support based on the distance from the catalyst. However, surprisingly, the above effect can also be obtained by loading phosphoric acid compounds or acetic acid compounds (preferably phosphoric acid or acetic acid) onto the support.

[0122] It is also known that aromatic rings such as benzyl groups are more likely to cause heteroatoms at coordination sites to undergo radicalization reactions compared to resonance forms. Therefore, it is believed that, regardless of the embodiments disclosed herein, organic compounds that coordinate a protecting group with an aromatic ring to a heteroatom will undergo exceptionally good hydrogenolysis reactions.

Claims

1. A hydrogenolysis catalyst for hydrogenolyzing the carbon-heteroatom bond in a matrix organic compound containing a carbon-heteroatom bond, wherein, The hydrogenolysis catalyst comprises a carbon-based support, wherein the carbon-based support is loaded with at least: Palladium catalysts; and At least one of a phosphoric acid compound and an acetic acid compound.

2. The hydrogenolysis catalyst according to claim 1, wherein, It contains a carbon-based support loaded with at least a phosphoric acid compound.

3. The hydrogenolysis catalyst according to claim 1, wherein, Phosphoric acid compounds include at least one selected from the group consisting of phosphoric acid (orthophosphoric acid), pyrophosphoric acid, metaphosphoric acid, and diphosphoric acid pentoxide.

4. The hydrogenolysis catalyst according to claim 1, wherein, Phosphoric acid compounds contain at least phosphoric acid (orthophosphoric acid).

5. The hydrogenolysis catalyst according to claim 1, wherein, Acetic acid compounds include at least one selected from the group consisting of acetic acid, trifluoroacetic acid, monochloroacetic acid, dichloroacetic acid, and dimethylacetic acid.

6. The hydrogenolysis catalyst according to claim 1, wherein, Carbon-based supports include at least one selected from the group consisting of activated carbon, mesoporous carbon, graphene, and carbon nanotubes.

7. The hydrogenolysis catalyst according to claim 1, wherein, In 100 parts by mass of hydrogenolysis catalyst (dry basis), palladium catalyst is 1-20 parts by mass, phosphoric acid compound or acetic acid compound is 1-20 parts by mass, and carbon-based support is 10-50 parts by mass.

8. The hydrogenolysis catalyst according to claim 1, wherein, In 100 parts by mass of hydrogenolysis catalyst, the water content is 5 to 70 parts by mass.

9. The hydrogenolysis catalyst according to claim 1, wherein, In 100 parts by mass of hydrogenolysis catalyst (dry basis), phosphorus element is 0.25 to 5 parts by mass.

10. The hydrogenolysis catalyst according to any one of claims 1 to 9, wherein, The carbon-heteroatom bond is a carbon-nitrogen bond.

11. The hydrogenolysis catalyst according to claim 10, wherein, The carbon-nitrogen bond is a bond between a carbon atom and a nitrogen atom adjacent to the aromatic ring.

12. A method for preparing a hydrogenolysis catalyst, wherein the hydrogenolysis catalyst hydrogenates the carbon-heteroatom bond of a matrix organic compound containing a carbon-heteroatom bond, wherein, The method for preparing the hydrogenolysis catalyst includes: A carbon-based support loaded with palladium catalyst was mixed with water; and The resulting mixture is mixed with at least one of a phosphoric acid compound and an acetic acid compound.

13. A method for preparing an organic compound by hydrogenolysis of at least one carbon-heteroatom bond, comprising the step of contacting a matrix organic compound containing the carbon-heteroatom bond, molecular hydrogen, and a hydrogenolysis catalyst in a reactor, wherein, The hydrogenolysis catalyst comprises a carbon-based support, wherein the carbon-based support is loaded with at least one of a palladium catalyst and a phosphoric acid compound and an acetic acid compound.

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