Method for producing organic compounds by hydrogenation of carbon-heteroatom bonds

Abstract

To provide a novel technical means for producing organic compounds by hydrogenolysis of carbon-heteroatom bonds, without using strong acids and even when the amount of palladium is reduced compared to conventional palladium catalysts. [Solution] A method for producing a product organic compound in which at least one of the carbon-heteroatom bonds is hydrogenated, comprising reacting a substrate organic compound containing a carbon-heteroatom bond in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound.

Description

[Technical Field]

[0001] This disclosure relates to a method for producing organic compounds obtained by hydrogenation of carbon-heteroatom bonds. [Background technology]

[0002] In the field of organic synthesis, the introduction and deprotection of various protecting groups are extremely important for synthesizing the desired compounds. Carbon-heteroatom bonds are known to be structures that facilitate the introduction and deprotection of various protecting groups.

[0003] Deprotection reactions of protected groups that have been introduced (for example, hydrogenolysis of benzyl groups), i.e., reactions to produce organic compounds through hydrogenolysis of carbon-heteroatom bonds, mainly use catalytic hydrogen reduction with palladium / carbon catalysts. However, a problem exists in that the reaction does not proceed to the deprotection side unless a large amount of palladium is added as a catalyst. Therefore, further improvements are being considered for such deprotection reactions due to the insufficient cost and yield of palladium catalysts.

[0004] For example, Patent Document 1 proposes a method in which hydrogen is reacted in the presence of a palladium catalyst and an amine having one nitrogen atom, thereby the amine having one nitrogen atom modifies the palladium catalyst, and the modified palladium catalyst selectively hydrogenates the protecting group (benzyl group).

[0005] Furthermore, Patent Document 2 proposes a hydrocracking catalyst in which a Brønsted acid catalyst and a palladium catalyst are brought into contact within the reactor. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2017-197484 [Patent Document 2] International Publication No. 2021 / 251248 [Overview of the Initiative]

[0007] However, the method proposed in Patent Document 1, which involves coating the surface of a palladium catalyst with an amine-based compound to adjust its catalytic activity, had the problem that the catalytic activity would decrease due to poisoning.

[0008] Furthermore, the hydrocracking catalyst proposed in Patent Document 2 uses activated carbon treated with strong acids such as nitric acid or sulfuric acid to impart acidic functional groups as a Brønsted acid catalyst, which is then mixed with a palladium-carbon catalyst. However, there are problems with the production process, such as the different deactivation timings of the two catalysts and the need to deal with the heat of dilution with water in the hydrated carbon and the treatment of wastewater, due to the use of strong acids during production.

[0009] In view of the above issues, one objective of this disclosure is to provide a new technical means that enables the production of organic compounds produced by hydrogenolysis of carbon-heteroatom bonds without using strong acids and even when the amount of palladium is reduced compared to conventional palladium catalysts.

[0010] As a result of diligent research, the Disclosing Party has found that, in a reaction system containing a substrate organic compound, molecular hydrogen, and a palladium catalyst, the presence of a nitrile compound makes it possible to produce a product organic compound with a carbon-heteroatom bond undergoing hydrogenation, even when the amount of palladium is reduced. This disclosure is based on this finding.

[0011] According to one embodiment of the present disclosure, a method is provided for producing a product organic compound in which at least one of the carbon-heteroatom bonds is hydrogenocrated, comprising reacting a substrate organic compound containing a carbon-heteroatom bond in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound.

[0012] According to this disclosure, it becomes possible to produce organic compounds in which carbon-heteroatom bonds are hydrolyzed, even when the amount of palladium is reduced and without the use of strong acids. Detailed description of the invention

[0013] [Method for producing organic compounds] According to one embodiment of the present disclosure, a method is provided for producing a product organic compound in which at least one of the carbon-heteroatom bonds is hydrogenocracked, comprising reacting a substrate organic compound containing a carbon-heteroatom bond in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound. The method of the present disclosure will be described in detail below.

[0014] <Reaction Process> According to one embodiment of the present disclosure, a method for producing an organic compound obtained by hydrogenoclastication of a carbon-heteroatom bond is characterized by including a reaction (hereinafter also referred to as the "reaction step") in which a substrate organic compound containing a carbon-heteroatom bond is reacted in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound.

[0015] (Palladium catalyst) The palladium catalysts of this disclosure are not particularly limited, as long as they can hydrogenate the carbon-heteroatom bonds in a substrate organic compound that contains such bonds. Therefore, the palladium catalysts can be used as hydrogenation catalysts. The palladium catalysts only need to contain palladium as a catalyst species, and may contain palladium itself or a compound containing palladium (palladium compound). Known compounds such as particles or various alloys may be used as palladium catalysts.

[0016] Examples of palladium compounds include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium chloride, palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(dibenzalacetone)palladium, bis[4-(N,N-dimethylamino)phenyl]ditert-butylphosphine palladium chloride, bis(di-tert-butylprenylphosphine)palladium chloride, and bis(di-tert-clotylphosphine)palladium dichloride, which may be used individually or in any combination of two or more.

[0017] According to one embodiment of the present disclosure, the palladium catalyst contains palladium itself (i.e., palladium element).

[0018] The palladium catalyst may be one in which palladium or a palladium compound is supported on a carrier. Examples of such carriers include, but are not limited to, carbon-based carriers, alumina carriers, barium sulfate carriers, silica carriers, calcium carbonate carriers, etc. These may be used alone or in any combination of two or more.

[0019] The amount of palladium or palladium compound supported on the carrier may be 0.1 to 15% by mass, preferably 0.3 to 10% by mass, more preferably 0.5 to 5% by mass, and even more preferably 1 to 3% by mass based on the total mass (dry basis) of the palladium catalyst.

[0020] Other components may be supported on the above carrier within a range that does not impair the object of the present disclosure. Examples of such other components include, but are not limited to, noble metal elements other than palladium (e.g., platinum element, ruthenium element, etc.) or their compounds, and compounds having functional groups such as sulfonic groups, carboxy groups, amino groups, etc.

[0021] According to one embodiment of the present disclosure, the above palladium catalyst is one in which palladium or a palladium compound is supported on a carbon-based carrier. Examples of carbon-based carriers include, but are not limited to, activated carbon, pulverized activated carbon, mesoporous carbon, graphene, carbon nanotubes, glassy carbon (GC), fine carbon, carbon black, graphite, carbon fibers, etc. According to one embodiment of the present disclosure, the carbon-based carrier contains at least one selected from the group consisting of activated carbon, mesoporous carbon, graphene, and carbon nanotubes.

[0022] The specific surface area of the carbon-based carrier is not particularly limited as long as the object of the present disclosure can be achieved. The specific surface area of the carbon-based carrier is, for example, 1 m3 / g or more, preferably 10m 3 / g or more, comfortably 100m 3 / g or more, more preferably 300m 3 It may be more than / g. Also, the upper limit of the specific surface area of ​​the carbon-based support is, for example, 3000m. 3 Less than or equal to / g, preferably 2000m 3 / g or less, more preferably 1500m 3 / g or less, more preferably 1000m 3 It may be less than / g.

[0023] According to one embodiment of the present disclosure, the palladium catalyst may contain water. If the palladium catalyst contains water, the amount of water may be, for example, 5 to 70 parts by mass, preferably 20 to 60 parts by mass, and more preferably 45 to 55 parts by mass, per 100 parts by mass of the palladium catalyst.

[0024] The amount of palladium catalyst used is not particularly limited as long as the objectives of this disclosure can be achieved, and can be appropriately changed considering the reaction time, the yield of the target organic compound produced, the ease of purification, etc. For example, the amount of palladium catalyst used may be 1 to 1,000,000 μmol, preferably 10 to 500,000 μmol, more preferably 100 to 100,000 μmol, and even more preferably 1,000 to 10,000 μmol per 1 mol of the substrate organic compound described later.

[0025] Furthermore, the ratio of the amount of palladium catalyst used to the substrate organic compound described later is not particularly limited as long as it is a ratio that can cause a hydrocracking reaction. For example, the above ratio may 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 of palladium catalyst per 100 parts by mass of substrate organic compound.

[0026] (Platinum catalyst) According to one embodiment of the present disclosure, the reaction step may be further carried out in the presence of a platinum catalyst. The method of the present disclosure is advantageous in that it is possible to hydrogenate the carbon-heteroatom bonds in a substrate organic compound containing carbon-heteroatom bonds, even when a palladium catalyst and a platinum catalyst are combined.

[0027] A platinum catalyst only needs to contain the element platinum as a catalytic species; it may contain platinum itself or a platinum-containing compound (platinum compound). Known compounds such as particles or various alloys may be used as the platinum catalyst.

[0028] Examples of platinum compounds include platinum(II) oxide, platinum(IV) oxide, platinum(II) chloride, platinum(IV) chloride, potassium tetrachlorideplatinate(II), platinum(IV) nitrate, platinum(IV) sulfate, tetraammineplatin(II) chloride, tetraammineplatin(II) bromide, tetraammineplatin(II) nitrate, tetraammineplatin(II) acetate, hexachloroplatin(IV) acid, tetrachloroplatinic acid(II), sodium hexahydroxoplatinate(IV), and hexahydroxoplatin(IV) Examples include water-soluble compounds such as 2-hydroxyethylammonium acid, dinitrodiammineplatinum(II) ammonia aqueous solution, bis(2,4-pentanedionato)platinum(II), dichloro(1,5-cyclooctadiene)platinum(II), dichlorobis(triphenylphosphine)platinum(II), tetrakis(triphenylphosphine)platinum(II), and tris(dibenzylideneacetone)diplatinum(O), which may be used individually or in any combination of two or more.

[0029] According to one embodiment of the present disclosure, the platinum catalyst comprises platinum itself (i.e., the element platinum).

[0030] The platinum catalyst may be one in which platinum or a platinum compound is supported on a carrier. When the palladium catalyst supported on a carrier is included, the platinum catalyst may be supported on the same carrier as the palladium catalyst or may be supported on a different carrier from the palladium catalyst. Examples of such carriers include, but are not limited to, carbon-based carriers, alumina carriers, barium sulfate carriers, silica carriers, calcium carbonate carriers, etc. These may be used alone or in any combination of two or more.

[0031] The amount of platinum or platinum compound supported on the carrier may be 0.1 to 15% by mass, preferably 0.3 to 10% by mass, more preferably 0.5 to 5% by mass, based on the total mass (dry basis) of the platinum catalyst.

[0032] Other components may be supported on the carrier within a range that does not impair the object of the present disclosure. Examples of such other components include, but are not limited to, noble metal elements other than platinum (e.g., ruthenium element, etc.) or their compounds, and compounds having functional groups such as sulfonic groups, carboxy groups, amino groups, etc.

[0033] According to one embodiment of the present disclosure, the platinum catalyst is one in which platinum or a platinum compound is supported on a carbon-based carrier. Examples of the carbon-based carrier include, but are not limited to, activated carbon, pulverized activated carbon, mesoporous carbon, graphene, carbon nanotubes, glassy carbon (GC), fine carbon, carbon black, graphite, carbon fibers, etc. According to one embodiment of the present disclosure, the carbon-based carrier includes at least one selected from the group consisting of activated carbon, mesoporous carbon, graphene, and carbon nanotubes.

[0034] The specific surface area of the carbon-based carrier is not particularly limited as long as the object of the present disclosure can be achieved. The specific surface area of the carbon-based carrier is, for example, 1 m 3 / g or more, preferably 10 m 3 / g or more, more preferably 100 m3 / g or more, more preferably 300m 3 It may be more than / g. Also, the upper limit of the specific surface area of ​​the carbon-based support is, for example, 3000m. 3 Less than or equal to / g, preferably 2000m 3 / g or less, more preferably 1500m 3 / g or less, more preferably 1000m 3 It may be less than / g.

[0035] According to one embodiment of the present disclosure, the platinum catalyst may contain water. If the platinum catalyst contains water, the amount of water may be, for example, 5 to 70 parts by mass, preferably 20 to 60 parts by mass, and more preferably 45 to 55 parts by mass, per 100 parts by mass of the platinum catalyst.

[0036] The amount of platinum catalyst used is not particularly limited as long as the objectives of this disclosure can be achieved, and can be appropriately changed considering the reaction time, the yield of the target organic compound produced, the ease of purification, etc. For example, the amount of platinum catalyst used may be 1 to 1,000,000 μmol, preferably 10 to 500,000 μmol, more preferably 100 to 100,000 μmol, and even more preferably 1,000 to 10,000 μmol per 1 mol of the substrate organic compound described later.

[0037] Furthermore, the ratio of the amount of platinum catalyst used to the substrate organic compound described later is not particularly limited as long as it is a ratio that can cause a hydrocracking reaction. For example, the above ratio may 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 of platinum catalyst per 100 parts by mass of substrate organic compound.

[0038] Furthermore, the ratio of platinum catalyst to palladium catalyst used is not particularly limited as long as it is a ratio that allows for the occurrence of a hydrocracking reaction. For example, the above ratio may be 0.01 to 10,000 parts by mass of platinum catalyst per 100 parts by mass of palladium catalyst (i.e., a mass ratio (platinum element / palladium element) of 0.0001 to 100), preferably 0.1 to 3,000 parts by mass (i.e., a mass ratio (platinum element / palladium element) of 0.001 to 30), more preferably 1 to 1,000 parts by mass (i.e., a mass ratio (platinum element / palladium element) of 0.01 to 10), and even more preferably 10 to 300 parts by mass (i.e., a mass ratio (platinum element / palladium element) of 0.1 to 3). Furthermore, the ratio of the amount of platinum catalyst to palladium catalyst used may be, for example, 0.01 to 100 moles, preferably 0.1 to 10 moles, more preferably 0.2 to 3 moles, and even more preferably 0.3 to 1.5 moles of platinum in the platinum catalyst for every 1 mole of palladium in the palladium catalyst.

[0039] (Nitrile compounds) Nitrile compounds are not particularly limited as long as they have a -CN group and are capable of achieving the objectives of this disclosure. Examples of nitrile compounds include mononitriles such as acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, acrylonitrile, isobutyronitrile, benzonitrile, trichloroacetonitrile, benzonitrile, and methoxyacetonitrile; dinitriles such as 1,4-dicyanoheptane, 1,5-dicyanopentane, 1,6-dicyanohexane, 1,7-dicyanoheptane, 2,6-dicyanoheptane, 1,8-dicyanooctane, 2,7-dicyanooctane, 1,9-dicyanononane, 2,8-dicyanononane, 1,10-dicyanodecane, 1,6-dicyanodecane, 2,4-dimethylglutalonitrile, succinonitrile, glutalonitrile, and adiponitrile; derivatives thereof; and these may be used individually or in any combination of two or more.

[0040] According to one embodiment of the present disclosure, the nitrile compound may be a nitrile compound that generates radicals (preferably a nitrile compound that generates radicals in the presence of a palladium catalyst). The fact that the nitrile compound generates radicals is advantageous from the viewpoint of enabling the hydrocracking reaction to proceed more efficiently.

[0041] According to one embodiment of the present disclosure, the nitrile compound includes mononitrile. According to one embodiment of the present disclosure, the nitrile compound includes at least one selected from the group consisting of acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, acrylonitrile, isobutyronitrile, benzonitrile, and trichloroacetonitrile. According to one embodiment of the present disclosure, the nitrile compound includes at least one linear nitrile compound selected from the group consisting of acetonitrile, propionitrile, and butyronitrile. According to one embodiment of the present disclosure, the nitrile compound includes acetonitrile.

[0042] The amount of nitrile compound used is not particularly limited as long as the objectives of this disclosure can be achieved, and can be appropriately changed considering the reaction time, the yield of the target organic compound produced, the ease of purification, etc. For example, the amount of nitrile compound used may be 0.001 to 100 mol, preferably 0.003 to 50 mol, more preferably 0.01 to 30 mol, and even more preferably 0.03 to 10 mol per 1 mol of the substrate organic compound described later.

[0043] The amount of nitrile compound used may be 1 to 10,000 parts by mass, preferably 5 to 5,000 parts by mass, and more preferably 10 to 3,000 parts by mass, per 100 parts by mass of palladium catalyst. Alternatively, the amount of nitrile compound used may be 1 to 100,000 moles, preferably 5 to 50,000 moles, more preferably 10 to 20,000 moles, and even more preferably 20 to 10,000 moles, per 1 mole of palladium in the palladium catalyst.

[0044] The amount of nitrile compound used may be 1 to 10,000 parts by mass, preferably 5 to 5,000 parts by mass, and more preferably 10 to 3,000 parts by mass, per 100 parts by mass of platinum catalyst, if a platinum catalyst is present. Alternatively, the amount of nitrile compound used may be 1 to 100,000 moles, preferably 5 to 50,000 moles, more preferably 10 to 20,000 moles, and even more preferably 20 to 10,000 moles, per 1 mole of platinum in the platinum catalyst, if a platinum catalyst is present.

[0045] (Molecular hydrogen) Molecular hydrogen is not particularly limited, and commercially available hydrogen gas may be used as is. Furthermore, the amount of molecular hydrogen used is not particularly limited as long as the purpose of this disclosure can be achieved, and for example, 1 mole or more is preferred based on 1 mole of the above-mentioned substrate organic compound.

[0046] Molecular hydrogen may be present in the liquid or gas phase of the reaction system (e.g., in the reaction vessel). The pressure of the hydrogen supplied to the reaction system is not particularly limited as long as it is a pressure at which the hydrocracking reaction can proceed, but may be, for example, 0.01 to 1 MPa, preferably 0.05 to 0.8 MPa, and more preferably 0.1 to 0.6 MPa.

[0047] (Substrate organic compounds containing carbon-heteroatom bonds) As used in this disclosure, "carbon-heteroatom bond" means a bond formed between a carbon atom and an atom other than a carbon atom. Examples of atoms other than carbon atoms are, but are not limited to, nitrogen atoms, oxygen atoms, sulfur atoms, phosphorus atoms, and metal atoms, with nitrogen atoms and oxygen atoms being 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 viewpoint of ease of hydrogenolysis reactions, carbon-heteroatom bonds are preferably carbon-nitrogen bonds and carbon-oxygen bonds, and more preferably carbon-nitrogen bonds.

[0048] The carbon-heteroatom bond may be a single bond, a double bond, or a triple bond. According to one embodiment of the present disclosure, the carbon-heteroatom bond is a single bond.

[0049] The term "substrate organic compound containing a carbon-heteroatom bond" as used in this disclosure (also simply referred to as "substrate organic compound") is not particularly limited as long as it contains at least one carbon-heteroatom bond in its molecule and can serve as a substrate for a hydrogenolysis reaction. The substrate organic compound may be partially or entirely linear (e.g., linear, branched) or cyclic. Furthermore, the carbon-carbon bond in the substrate organic compound may be a single bond or may contain one or more double and / or triple bonds. In addition, one or more hydrogen atoms bonded to the carbon atoms in the substrate organic compound may be substituted with any substituent (e.g., alkyl groups, cycloalkyl groups, alkenyl groups, cycloalkenyl groups, alkynyl groups, alkoxy groups, halogen groups (e.g., fluorine, chlorine, bromine, iodine)), carboxyl groups, aldehyde groups, hydroxyl groups, amino groups, phenyl groups). Furthermore, one or more carbon atoms constituting the substrate organic compound may be substituted with heteroatoms (for example, an oxygen atom, a nitrogen atom, or a sulfur atom).

[0050] The method of this disclosure can be used for the purpose of deprotecting protecting groups that protect highly reactive sites within a molecule from reactions with other sites. Therefore, the substrate organic compound may be a compound in which a protecting group is coordinated to a heteroatomic site in a carbon-heteroatom bond. The "protecting group" in this disclosure is not limited to these, but includes, for example, aralkyl groups (e.g., benzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-nitrobenzyl group, 3-nitrobenzyl group, 4-nitrobenzyl group, 2-methoxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, diphenylmethyl group, etc.) and aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl group, 2-nitrobenzyl group, etc.) Protecting groups having an aromatic ring structure, such as aralkyloxycarbonyl groups (e.g., trobenzyloxycarbonyl group, 3-nitrobenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, 2-bromobenzyloxycarbonyl group, 3-bromobenzyloxycarbonyl group, 4-bromobenzyloxycarbonyl group, 2-methoxybenzyloxycarbonyl group, 3-methoxybenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, etc.), alkyloxycarbonyl groups (e.g., t-butyloxycarbonyl group, t-amyloxycarbonyl group, etc.), and trialkylsilylcarbonyl groups (e.g., trimethylsilyl group, t-butyldimethylsilyl group, etc.). The protecting group is preferably a protecting group having an aromatic ring structure, more preferably an aralkyl group or an aralkyloxycarbonyl group, even more preferably a benzyl group, a 2-methoxybenzyl group, a 3-methoxybenzyl group, a 4-methoxybenzyl group, or a benzyloxycarbonyl group, and still more preferably a benzyl group.

[0051] According to one embodiment of the present disclosure, the carbon-heteroatom bond is a carbon-heteroatom bond adjacent to an aromatic ring (preferably a carbon-nitrogen bond adjacent to an aromatic ring). In the present disclosure, "carbon adjacent to an aromatic ring" means a carbon atom that is one atom away (i.e., directly bonded to an atom constituting the aromatic ring), two atoms away (i.e., with one other atom between it and the atom constituting the aromatic ring), or three atoms away (i.e., with two other atoms between it and the atom constituting the aromatic ring) from an atom constituting the aromatic ring (e.g., a carbon atom, nitrogen atom, sulfur atom, etc.). The carbon adjacent to the aromatic ring is preferably a carbon atom that is one or two atoms away from an atom constituting the aromatic ring, and more preferably a carbon atom that is one atom away from an atom constituting the aromatic ring (i.e., a carbon atom directly bonded to an atom constituting the aromatic ring).

[0052] According to preferred embodiments of the present disclosure, the carbon-heteroatom bond is a bond between the benzyl group and the nitrogen atom.

[0053] According to one embodiment of the present disclosure, the substrate 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 the present disclosure, the substrate organic compound is N-benzyl-N-butyl-3-methylaniline.

[0054] The above method may be carried out in the presence of other elements (e.g., other hydrocracking catalysts, co-catalysts that promote the hydrocracking reaction, etc.) to the extent that it does not impair the purpose of this disclosure.

[0055] (Conditions in the reaction process) The reaction temperature in the above reaction step is not particularly limited as long as it is a temperature at which the hydrogenolysis reaction can proceed, but for example, it may be -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 adjust the above reaction temperature as appropriate, taking into consideration the type of substrate organic compound used, the reaction time, etc.

[0056] The reaction time in the above reaction step is not particularly limited as long as it is sufficient time for the hydrogenolysis reaction to proceed, but for example, it may 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 adjust the above reaction time appropriately, taking into consideration the type of substrate organic compound used, the reaction temperature, etc.

[0057] According to one embodiment of the present disclosure, the reaction step may be carried out in the presence of a desired reaction solvent. The reaction solvent in this disclosure does not include the nitrile compound. Therefore, according to one embodiment of the present disclosure, the reaction solvent may be defined as "reaction solvent (excluding the nitrile compound)". The reaction solvent is not particularly limited as long as it does not completely inhibit the hydrocracking reaction. Furthermore, the reaction solvent may be capable of dissolving at least a portion of the substrate organic compound and / or the palladium catalyst. Examples of the reaction solvent include polar solvents such as esters like ethyl acetate and propyl acetate, ethers such as diethyl ether, t-butyl methyl ether, and tetrahydrofuran, and alcohols such as 2-propanol and ethanol; and nonpolar solvents such as linear hydrocarbons like n-hexane and n-heptane, and cyclic hydrocarbons like cyclohexane. These may be used individually or in any combination of two or more. The method of this disclosure is advantageous in that it is applicable to both polar and nonpolar solvents.

[0058] The amount of the reaction solvent is not particularly limited as long as it is sufficient for the hydrocracking reaction to proceed. However, from the viewpoint of performing a stable hydrocracking reaction, the amount may be 1 to 100,000 parts by mass, preferably 10 to 10,000 parts by mass, and more preferably 100 to 5,000 parts by mass, per 100 parts by mass of the substrate organic compound.

[0059] Furthermore, the amount of the reaction solvent may be 10 to 1,000,000 parts by mass, preferably 30 to 100,000 parts by mass, and more preferably 100 to 30,000 parts by mass, per 100 parts by mass of the nitrile compound.

[0060] In the above reaction step, if bonds other than the target carbon-heteroatom bond (for example, aromatic ring bonds, other double bonds, triple bonds, etc., present in the substrate organic compound) are hydrogenated, the amount of palladium catalyst, the amount of nitrile compound, the amount of molecular hydrogen, the hydrogen pressure, the reaction temperature, the reaction time, etc. may be adjusted as appropriate, or the bonds other than the target carbon-heteroatom bond may be protected in advance with other protecting groups (preferably protecting groups that are not decomposed by the hydrogenolysis reaction with the palladium catalyst and / or platinum catalyst).

[0061] <Isolation Process> After the desired hydrocracking reaction is completed, the resulting organic compounds may be isolated from the post-reaction solution containing the obtained organic compounds by, for example, a known method. Therefore, according to one embodiment of this disclosure, the method may include isolating the organic compounds obtained in the reaction step (also referred to in this disclosure as the "isolation step"). The isolation method is not limited to these, but may include, for example, liquid-liquid extraction, distillation, column chromatography, recrystallization, etc.

[0062] The method of this disclosure may include any other steps in addition to the steps described above. These additional steps may be placed at any position before or after each of the steps described above.

[0063] [Method of hydrocracking] The methods of the present disclosure can be used for the hydrogenation of a carbon-heteroatom bond in a substrate organic compound containing a carbon-heteroatom bond. Another embodiment of the present disclosure provides a method for hydrogenating at least one carbon-heteroatom bond in a substrate organic compound containing a carbon-heteroatom bond, comprising reacting the substrate organic compound in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound. The methods can preferably be used for the purpose of deprotection reactions of protecting groups that protect highly reactive sites within a molecule from reactions to other sites.

[0064] This disclosure includes the following: [1] A method for producing a product organic compound in which at least one of the carbon heteroatom bonds is hydrogenocracked, comprising reacting a substrate organic compound containing a carbon heteroatom bond in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound. [2] The method according to [1], wherein the nitrile compound comprises a nitrile compound that generates radicals. [3] The method according to [1] or [2], wherein the nitrile compound comprises a mononitrile. [4] The method according to any one of [1] to [3], wherein the nitrile compound comprises at least one selected from the group consisting of acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, acrylonitrile, isobutyronitrile, benzonitrile, and trichloroacetonitrile. [5] The method according to any one of [1] to [4], wherein the amount of nitrile compound used is 0.001 to 100 mol per 1 mol of substrate organic compound. [6] The method according to any one of [1] to [5], wherein the amount of nitrile compound used is 0.001 to 10000 mol per 1 mol of palladium in the palladium catalyst. [7] The method according to any one of [1] to [6], wherein the palladium catalyst comprises a catalyst in which palladium and / or a palladium compound is supported on a carbon-based support. [8] The method according to [7], wherein the carbon-based support comprises at least one selected from the group consisting of activated carbon, mesoporous carbon, graphene, and carbon nanotubes. [9] The method of any of [1] to [8], further carried out in the presence of a platinum catalyst.

[10] The method according to [9], wherein the platinum catalyst is 10 to 300 parts by mass per 100 parts by mass of the palladium catalyst.

[11] The method according to [9] or

[10] , wherein the mass ratio of palladium to platinum (platinum / palladium) is 0.001 to 100.

[12] The method according to any one of [1] to

[11] , wherein the carbon-heteroatom bond is a carbon-nitrogen bond.

[13] The method according to any one of [1] to

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

[14] The method according to any one of [1] to

[13] , wherein the carbon-nitrogen bond is a bond between the benzyl group and the nitrogen atom.

[15] A method for hydrogenating at least one carbon-heteroatom bond in a substrate organic compound containing a carbon-heteroatom bond, comprising reacting the substrate organic compound in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound. [Examples]

[0065] The methods of this disclosure will be described in more detail below using examples. However, the following examples are not intended to limit the methods of this disclosure in any way. Unless otherwise specified, the percentages and ratios described herein are in terms of mass. Unless otherwise specified, the units and measurement methods described herein are in accordance with the provisions of the Japanese Industrial Standards (JIS).

[0066] [Example 1: Hydrocracking reaction (debenzyl reaction) using a Pd / C catalyst 1] [ka] 825 μL (2.5 mmol) of the substrate organic compound N-benzyl-N-butyl-3-methylaniline was mixed with 32 mg of 2% Pd / C catalyst (manufactured by N.E. Chemcat Corporation) (5% by mass in weight ratio of substrate organic compound to Pd / C catalyst (dry base)), 13 μL of acetonitrile (0.1 mol equivalent per 1 mol of substrate organic compound), and 10 mL (0.25 M) of ethyl acetate solvent. The debenzyl reaction was then carried out at a hydrogen pressure of 0.2 MPa and 60°C for 1 hour with stirring. The resulting post-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 from the decrease in the substrate organic compound. The results are shown in Table 1. A peak of N-butyl-m-toluidine was observed in the resulting post-reaction solution, suggesting that a debenzyl reaction had occurred.

[0067] [Examples 2-3: Hydrocracking reaction (debenzyl reaction) using Pd / C catalyst 2] The same procedure as in Example 1 was followed, except that the amount of acetonitrile added was changed to the amount shown in Table 1. The results are shown in Table 1.

[0068] [Comparative Example 1: Hydrocracking reaction (debenzyl reaction) using a Pd / C catalyst 3] The same procedure as in Example 1 was followed, except that acetonitrile was not added. The results are shown in Table 1.

[0069] [Reference Example 1: Hydrocracking reaction (debenzyl reaction) using a Pd / C catalyst 4] In Example 1, the same procedure was followed except that the 2% Pd / C catalyst was replaced with a 10% Pd / C catalyst (manufactured by N.E. Chemcat Co., Ltd.) and acetonitrile was not added. The results are shown in Table 1.

[0070] [Table 1]

[0071] [Example 4: Hydrocracking reaction (debenzyl reaction) using Pd / C catalyst and Pt / C catalyst 1] [ka] 825 μL (2.5 mmol) of the substrate organic compound N-benzyl-N-butyl-3-methylaniline was mixed with 32 mg of 2% Pd / C catalyst (manufactured by N.E. Chemcat Corporation) (5% by weight ratio of substrate organic compound to Pd / C catalyst (dry base)), 32 mg of 3% Pt / C catalyst (manufactured by N.E. Chemcat Corporation) (5% by weight ratio of substrate organic compound to Pt / C catalyst (dry base)), 13 μL of acetonitrile (0.1 mol equivalent per 1 mol of substrate organic compound), and 10 mL (0.25 M) of ethyl acetate solvent. The debenzyl reaction was then carried out at a hydrogen pressure of 0.2 MPa and 60°C for 1 hour with stirring. The resulting post-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 from the decrease in the substrate organic compound. The results are shown in Table 2. The resulting post-reaction solution showed a peak of N-butyl-m-toluidine, suggesting that a debenzylation reaction had occurred.

[0072] [Examples 5-6: Hydrocracking reaction (debenzyl reaction) using Pd / C catalyst and Pt / C catalyst 2] In Example 4, the same procedure was followed except that the amount of acetonitrile added was changed to the amount shown in Table 2. The results are shown in Table 2.

[0073] [Examples 7-8: Hydrocracking reaction (debenzyl reaction) using Pd / C catalyst and Pt / C catalyst 3] In Example 4, the same procedure was followed except that the reaction temperature was changed to the temperature shown in Table 2 and the amount of acetonitrile added was changed to the amount shown in Table 2. The results are shown in Table 2.

[0074] [Comparative Example 2: Hydrocracking reaction (debenzyl reaction) using Pd / C catalyst and Pt / C catalyst 4] In Example 4, the same procedure was followed except that acetonitrile was not added. The results are shown in Table 2.

[0075] [Comparative Examples 3-4: Hydrocracking reaction (debenzyl reaction) using Pd / C catalyst and Pt / C catalyst 5] In Example 4, the same procedure was followed except that the reaction temperature was changed to the temperature shown in Table 2 and acetonitrile was not added. The results are shown in Table 2.

[0076] [Reference Example 2: Hydrocracking reaction (debenzyl reaction) using a Pt / C catalyst 1] In Example 4, the same procedure was followed, except that a Pd / C catalyst was not used and acetonitrile was not added. The results are shown in Table 2.

[0077] [Reference Example 3: Hydrocracking reaction (debenzyl reaction) using a Pt / C catalyst 2] In Example 4, the same procedure was followed except that the Pd / C catalyst was not used and the amount of acetonitrile added was changed to the amount shown in Table 2. The results are shown in Table 2.

[0078] [Table 2]

[0079] As is clear from the results of Examples 1-3, the hydrocracking catalyst containing palladium showed excellent conversion rates in the presence of a nitrile compound (e.g., acetonitrile) (Table 1). Furthermore, even an amount of 0.1 mol of the nitrile compound was effective in improving the conversion rate, and it is thought that the conversion rate would further improve depending on the amount added (Table 1). This result is remarkable because it shows that even when the amount of palladium in the system of Reference Example 1 is reduced to one-fifth, a conversion rate equivalent to that of Reference Example 1 can be obtained by carrying out the reaction in the presence of a nitrile compound. The results from Examples 4-8 showed that even when palladium catalysts and platinum catalysts were used in combination, excellent conversion rates were observed in the presence of nitrile compounds (Table 2). It is a surprising result that the conversion rate improved when combined with a palladium catalyst in the presence of a nitrile compound, even though the platinum catalyst alone did not show hydrogenation decomposition ability (Reference Examples 2-3).

[0080] Although not bound by theory, it is thought that carrying out the above reaction in the presence of a nitrile compound improves the reaction rate of the hydrocracking reaction using a hydrocracking catalyst including a palladium catalyst.

[0081] Further investigations by the Discloser have revealed that the above reaction in the presence of a nitrile compound may exhibit a reduced conversion rate improvement effect in the presence of a radical scavenger. While not bound by theory, it is thought that radical species may be involved in the above reaction in the presence of a nitrile compound.

[0082] Although not bound by theory, the method disclosed herein is thought to allow the hydrocracking reaction to proceed with a smaller amount of catalyst than conventional methods, due to the presence of many radicals in the reaction system. The method disclosed herein is particularly advantageous for the hydrocracking of carbon-nitrogen bonds in substrate organic compounds (preferably bonds between carbon atoms adjacent to an aromatic ring and nitrogen atoms, more preferably bonds between a benzyl group and a nitrogen atom), where radicals are thought to contribute to the reaction.

Claims

1. A method for producing a product organic compound in which at least one of the carbon-heteroatom bonds is hydrogenocrated, comprising reacting a substrate organic compound containing a carbon-heteroatom bond in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound.

2. The method according to claim 1, wherein the nitrile compound includes a nitrile compound that generates radicals.

3. The method according to claim 1, wherein the nitrile compound includes mononitrile.

4. The method according to claim 1, wherein the nitrile compound comprises at least one selected from the group consisting of acetonitrile, propionitrile, butyronitrile, valeronitrile, capronitrile, acrylonitrile, isobutyronitrile, benzonitrile, and trichloroacetonitrile.

5. The method according to claim 1, wherein the amount of nitrile compound used is 0.001 to 100 mol per 1 mol of substrate organic compound.

6. The method according to claim 1, wherein the amount of nitrile compound used is 0.001 to 10,000 mol per 1 mol of palladium in the palladium catalyst.

7. The method according to claim 1, wherein the palladium catalyst comprises a catalyst in which palladium and / or a palladium compound is supported on a carbon-based support.

8. The method according to claim 7, wherein the carbon-based support comprises at least one selected from the group consisting of activated carbon, mesoporous carbon, graphene, and carbon nanotubes.

9. The method according to claim 1, further carried out in the presence of a platinum catalyst.

10. The method according to claim 9, wherein the amount of platinum catalyst is 10 to 300 parts by mass per 100 parts by mass of palladium catalyst.

11. The method according to claim 9, wherein the mass ratio of palladium to platinum (platinum / palladium) is 0.0001 to 100.

12. The method according to any one of claims 1 to 11, wherein the carbon-heteroatom bond is a carbon-nitrogen bond.

13. The method according to claim 12, wherein the carbon-nitrogen bond is a bond between a carbon atom adjacent to an aromatic ring and a nitrogen atom.

14. The method according to claim 12, wherein the carbon-nitrogen bond is a bond between a benzyl group and a nitrogen atom.

15. A method for hydrogenolysis of at least one carbon-heteroatom bond in a substrate organic compound containing a carbon-heteroatom bond, comprising reacting the substrate organic compound in the presence of a palladium catalyst, molecular hydrogen, and a nitrile compound.

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