Method for producing nitrogen-containing compound

Abstract

The present invention provides a method for producing a nitrogen-containing compound, the method making it possible to efficiently obtain a target nitrogen-containing compound under mild conditions even when a comparatively inexpensive raw material or a highly safe raw material is used. A method for producing a nitrogen-containing compound according to the present invention comprises a substitution step in which a mixture containing a first substance having a first substituent that has a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom, and a second substance having a second substituent that has at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group, is irradiated with microwaves, whereby at least one hydrogen atom of the at least one hydrogen atom bonded to the nitrogen atom is substituted by the organic group.

Description

Method for producing nitrogen-containing compounds

[0001] Some aspects of the present invention relate to methods for producing nitrogen-containing compounds.

[0002] Aliphatic amines and aromatic amines are important base structures in pharmaceuticals, and reactions that introduce organic groups to nitrogen atoms, such as N-alkylation, are key reactions in their chemical modification.

[0003] Conventionally, highly active alkylating agents such as formaldehyde and alkyl halides have typically been used as alkylating agents for N-methylation and other processes.

[0004] However, such highly active alkylating agents have drawbacks, such as being expensive or relatively toxic to humans.

[0005] To date, there are no examples of alternative methods for solving these problems being used industrially, however, in recent years, academic journals have reported on homogeneous and heterogeneous reactions with lower toxicity using cheaper and more stable alcohols.

[0006] In homogeneous systems, N-methylation using inexpensive alcohols as methylating agents in the presence of noble or base metal catalysts such as ruthenium or cobalt has been reported (see, for example, Non-Patent Document 1). Although such reactions yield relatively high yields (around 60-80%), they require long reaction times (around 24 to 48 hours) and are carried out at high temperatures (120°C to 140°C) under pressure, making a pressure vessel essential for the reaction.

[0007] Even in heterogeneous systems such as Pt / C, high temperatures and sufficient reaction time are necessary (see, for example, Non-Patent Document 2). There are also reports on the methylation of indoles using magnesium oxide and dimethyl carbonate as methylating agents, but this reaction needs to be carried out at an extremely high temperature of 170°C (see, for example, Non-Patent Document 3).

[0008] In other words, the reactions reported in the aforementioned academic journals all have problems such as long reaction times and the need to be carried out under high temperature and pressure conditions, making it impossible to efficiently obtain the target compound under mild conditions.

[0009] J. Org. Chem. 2023, 88, 8, 5025-5035.Chem Cat Chem. 2021,13,1722-1729, Asian J. Org. Chem. 2022, 11, e202100678.RSC Adv. 2014, 4, 50271-50276.

[0010] Some aspects of the present invention are aimed at providing a method for producing nitrogen-containing compounds that can efficiently obtain the target nitrogen-containing compound under mild conditions, even when using relatively inexpensive and highly safe raw materials.

[0011] A method for producing a nitrogen-containing compound according to some embodiments of the present invention is characterized by comprising a substitution step in which at least one of the at least one hydrogen atoms bonded to the nitrogen atom is replaced by the organic group by irradiating a mixture containing a first substance having a first substituent having a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom, and a second substance having a second substituent having at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group, with microwaves.

[0012] A method for producing a nitrogen-containing compound according to some embodiments of the present invention comprises a substitution step of irradiating a mixture containing a first substance having a first substituent having a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom, and a second substance having a second substituent having at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group, with microwaves to replace at least one of the at least one hydrogen atoms bonded to the nitrogen atom with the organic group, wherein the second substance is stable isotope labeled.

[0013] In the method for producing nitrogen-containing compounds according to some embodiments of the present invention, the second substance is preferably labeled with the stable isotope deuterium (D).

[0014] In a method for producing nitrogen-containing compounds according to some embodiments of the present invention, the second substance is１３ It is preferable that the product is labeled with the aforementioned stable isotope using C.

[0015] In a method for producing nitrogen-containing compounds according to some embodiments of the present invention, it is preferable that the first substance further has other reactive functional groups different from the first substituent, and that the other reactive functional groups are not protected by protecting groups when subjected to the substitution step.

[0016] In a method for producing nitrogen-containing compounds according to some embodiments of the present invention, it is preferable that the mixture contains a catalyst or a catalyst precursor as a third substance.

[0017] In the method for producing nitrogen-containing compounds according to some embodiments of the present invention, the third substance preferably contains metal atoms.

[0018] In a method for producing nitrogen-containing compounds according to some embodiments of the present invention, it is preferable that the precursor is converted into a fourth substance that functions as a catalyst by a reduction reaction.

[0019] In the method for producing nitrogen-containing compounds according to some embodiments of the present invention, the precursor is preferably ruthenium chloride.

[0020] In the method for producing nitrogen-containing compounds according to some embodiments of the present invention, the precursor as the third substance is preferably cobalt(II) acetylacetonate.

[0021] According to the present invention, it is possible to provide a method for producing nitrogen-containing compounds that can efficiently obtain the target nitrogen-containing compound under mild conditions, even when using relatively inexpensive and highly safe raw materials.

[0022] Figure 1 shows the acetate, which is the first substance obtained in the manufacturing process of the nitrogen-containing compound (butenafine hydrochloride) targeted in Example 6. １ This is a 1H-NMR (in DMSO-d6) chart. Figure 2 shows the target nitrogen-containing compound (butenafine hydrochloride) obtained in Example 6. １1H-NMR (in DMSO-d6) chart. Figure 3 shows the １ 1H-NMR (in DMSO-d6) chart. Figure 4 shows the mass spectrum chart of the target nitrogen-containing compound (imipramine hydrochloride) obtained in Example 8. Figure 5 shows the １ 1H-NMR (in DMSO-d6) chart.

[0023] Hereinafter, the method for producing a nitrogen-containing compound will be described in detail based on embodiments according to some aspects of the present invention (hereinafter referred to as "the present embodiment").

[0024] For the measurements and processes described in the present embodiment, unless otherwise indicated, they are assumed to be carried out at room temperature (23°C).

[0025] [1] Method for producing nitrogen-containing compound The method for producing a nitrogen-containing compound according to the present embodiment (hereinafter also referred to as "the present production method") is a first substance having a first substituent having a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom, and a second substance having a second substituent having at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group. A substitution step is carried out in which at least one of the at least one hydrogen atom bonded to the nitrogen atom is substituted with the organic group by irradiating the mixture with microwaves.

[0026] Thus, it is possible to provide a method for producing a nitrogen-containing compound that can efficiently obtain the target nitrogen-containing compound under mild conditions even when using relatively inexpensive and highly safe raw materials. More specifically, for example, even when the reaction time is relatively short, the target compound can be obtained in a high yield.

[0027] Also, compared to the case of applying energy by ordinary external heating, the energy required for the target chemical reaction can be efficiently supplied to a specific substance. As a result, the target reaction can proceed favorably without raising the temperature of the entire reaction system more than necessary.

[0028] Also, by adjusting the output of microwaves and the heating time, it becomes easier to control the temperature of the reaction system and the like.

[0029] In recent years, deuterated pharmaceuticals (heavy pharmaceuticals) have attracted attention. However, since the deuterated forms of conventional alkylating agents are extremely expensive, it is difficult to develop them into heavy pharmaceuticals. For example, iodoethane is 2,000 yen / 25 g (product of a reagent manufacturer), while iodoethane-D5 is 128,800 yen / 5 g (product of a reagent manufacturer), which is more than 300 times more expensive. In addition, there are many reagents that cannot be handled in Japan, and the synthesis of heavy pharmaceuticals using conventional synthesis methods is extremely difficult. As a result, there are only a very small number of currently approved heavy pharmaceuticals. In contrast, according to the present invention, such heavy pharmaceuticals can also be suitably produced.

[0030] More specifically, the method for producing a nitrogen-containing compound according to the present embodiment includes irradiating a mixture containing a first substance having a first substituent having a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom and a second substance having a second substituent having at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group with microwaves, thereby substituting at least one of the at least one hydrogen atom bonded to the nitrogen atom with the organic group. A compound labeled with a stable isotope may be used as the second substance. Thereby, even when using relatively inexpensive raw materials and highly safe raw materials, it is possible to provide a method for producing a nitrogen-containing compound that can efficiently obtain a target stable isotope-labeled nitrogen-containing compound under mild conditions. More specifically, for example, even when the reaction time is relatively short, the target stable isotope-labeled nitrogen-containing compound can be obtained in a high yield. Also, as described above, compared with the case of applying energy by normal external heating, the energy required for the target chemical reaction can be efficiently supplied to a specific substance, and as a result, the target reaction can proceed suitably without raising the temperature of the entire reaction system more than necessary. Also, as described above, by adjusting the output of microwaves and the heating time, it becomes easier to control the temperature of the reaction system and the like.

[0031] [1-1] Mixture The mixture used in the substitution step will be described below. The mixture used in the substitution step contains a first substance and a second substance.

[0032] [1-1-1] The first substance has a first substituent having a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom.

[0033] For example, the first substituent is an amino group (-NH ２ Examples include amino groups (-NHR, -NRR') and amine groups. The first substituent may also be a salt structure such as a salt of the above amino group or amine group, or a quaternary ammonium salt.

[0034] The first substance may be any compound having a first substituent in its molecule, but it is preferable that it further has other reactive functional groups different from the first substituent, and that these other reactive functional groups are not protected by protecting groups when subjected to the substitution step.

[0035] In this manufacturing method, even if the other reactive functional groups are not protected, the reaction at the first substituent can proceed with high selectivity in the substitution step, which will be described in detail later. Therefore, the steps of protecting the other reactive functional groups with protecting groups and the deprotection steps of removing the protecting groups can be omitted, resulting in better productivity of the target nitrogen-containing compound and cost advantages due to reduced raw material usage. Furthermore, since the yield reduction caused by the above-mentioned protection and deprotection steps can be prevented, the yield of the target nitrogen-containing compound can be increased.

[0036] The content of the first substance in the mixture subjected to the substitution step is not particularly limited, but is preferably 5% by mass or more and 95% by mass or less, more preferably 20% by mass or more and 90% by mass or less, and even more preferably 40% by mass or more and 85% by mass or less.

[0037] As a result, the target reaction in the substitution step can proceed more efficiently, and the productivity and yield of the target nitrogen-containing compound can be made more excellent.

[0038] The mixture subjected to the substitution step may contain a plurality of types of first substances. For example, it may contain a plurality of types of isomers that are difficult to separate as the first substance. Even in such a case, for example, there may be a case where the nitrogen-containing compounds corresponding to these plurality of types of first substances obtained through the substitution step can be easily separated.

[0039] [1-1-2] Second Substance The second substance has a second substituent having at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group.

[0040] In particular, it is preferable that the second substance is at least one in which the second substituent is stable isotope-labeled. In this case, at least one of the constituent atoms of the second substituent is stable isotope-labeled.

[0041] In particular, when the second substance is stable isotope-labeled with deuterium ( ２ H, D), for example, the enzyme resistance of the nitrogen-containing compound (stable isotope-labeled nitrogen-containing compound) produced by this production method in the body is improved.

[0042] Further, when the second substance is １３ C-stable isotope-labeled, for example, even if the nitrogen-containing compound (stable isotope-labeled nitrogen-containing compound) produced by this production method is trace, structural analysis in the body by NMR becomes easy.

[0043] In the following description, regarding the second substituent and the organic group possessed by the second substituent, when indicating the functional group name, the name generally used when expressing a functional group that is not stable isotope-labeled may be used. Similarly, regarding the second substance, when indicating the compound name, the name generally used when expressing a compound that is not stable isotope-labeled may be used. More specifically, for example, in this specification, when expressing a hydrocarbon group, this is C ｖ H ｘIn addition to the stable isotope-unlabeled functional groups shown, １２ C ｖ－ｗ １３ C ｗ １ H ｘ-ｙ ２ H ｙ The concept may also include stable isotope-labeled functional groups represented by (where v is an integer greater than or equal to 1, w is an integer between 0 and v, x is an integer greater than or equal to 3, y is an integer between 0 and x, and at least one of w and y is an integer greater than or equal to 1). Also, for example, when methanol is used in this specification, it includes unstable isotope-labeled CH ３ In addition to OH, CD ３ OH, CHD ２ OH, CH ２ DOH, １３ CH ３ This concept sometimes includes OH, etc.

[0044] The second substituent is not particularly limited, but examples include hydrocarbon groups such as alkyl groups, alkenyl groups, alkynyl groups, and aryl groups, or hydrocarbon groups in which some of the hydrogen atoms of the hydrocarbon group are substituted with other atoms or groups of atoms, or hydrocarbon groups in which at least one atom or group of atoms is inserted between the carbon-carbon bonds.

[0045] In particular, the second substituent is preferably a hydrocarbon group, more preferably an alkyl group, and even more preferably an alkyl group having 1 to 26 carbon atoms.

[0046] This allows the desired reaction to proceed more efficiently in the substitution process, resulting in improved productivity and yield of the target nitrogen-containing compound.

[0047] Specific examples of the second substance include methanol, ethanol, 1-propanol, and 2-propanol.

[0048] The content of the second substance in the mixture subjected to the substitution step is not particularly limited, but is preferably 5% by mass or more and 95% by mass or less, more preferably 20% by mass or more and 90% by mass or less, and even more preferably 40% by mass or more and 85% by mass or less.

[0049] This allows the desired reaction to proceed more efficiently in the substitution process, resulting in improved productivity and yield of the target nitrogen-containing compound.

[0050] Even if the content of the second substance in the mixture subjected to the substitution step is relatively low compared to the stoichiometric ratio of the first substance, the desired reaction can still proceed sufficiently.

[0051] For example, even if the content of the second substance in the mixture subjected to the substitution step is between 1.0 and 2.0 times the stoichiometric ratio to the first substance, the desired reaction can proceed sufficiently, and the desired nitrogen-containing compound can be obtained in high yield.

[0052] Furthermore, for example, when using a second substance that also functions as a solvent, using a large excess amount of the second substance can more effectively facilitate the desired reaction.

[0053] [1-1-3] The mixture subjected to the third substance substitution step may contain at least the first and second substances described above, but may also contain a catalyst or catalyst precursor as the third substance.

[0054] This allows the desired reaction to proceed more efficiently in the substitution process, resulting in improved productivity and yield of the target nitrogen-containing compound.

[0055] The third substance may be a catalyst or a catalyst precursor, but it is preferable that it contains metal atoms.

[0056] This allows the desired reaction in the substitution process to proceed more efficiently, resulting in improved productivity and yield of the target nitrogen-containing compound.

[0057] Examples of metal atoms contained in the third substance include transition metal elements or Lewis acidic main group elements, and more specifically, examples include Ni, Mn, Cr, Mo, W, Nb, Re, Co, Ru, Rh, Pd, Os, Ti, Zr, Ir, Pt, Zn, Cu, Al, Sn, etc.

[0058] When the third substance is a catalyst, the catalyst may be a substance in which the valence of the metal atom at the catalyst center is not the maximum valence that the metal atom can take. Examples of such substances include Tris(1,10-phenanthroline)ruthenium(II)Bis(hexafluorophosphate), Carbonyl(dihydrido)tris(triphenylphosphine)ruthenium(II), Cyclopentadienylbis(triphenylphosphine)ruthenium(II)Chloride, [1,1'-Bis(diphenylphosphino)ferrocene]cobalt(II)Dichloride, Cyclopentadienyl(dimethyl fumarate)(triethyl phosphite)cobalt(I), Tetrakis(triphenylphosphine)palladium(O), etc.

[0059] If the third substance is a catalyst precursor, the precursor can be, for example, one that is converted into a fourth substance that functions as a catalyst through a reduction reaction.

[0060] This allows the desired reaction in the substitution process to proceed more efficiently, resulting in improved productivity and yield of the target nitrogen-containing compound.

[0061] Examples of such precursors (fourth substances) include metal halides and metal salts. More specifically, examples include ruthenium chloride, nickel chloride, cobalt acetate, cobalt hydroxide, and palladium acetate, but ruthenium chloride is preferred. This allows the aforementioned effects to be exhibited more significantly.

[0062] Furthermore, if the third substance is a catalyst precursor, the precursor may function as a catalyst by coordinating with, for example, an imidazole, a ligand containing a phosphorus (P) atom, or carbon monoxide within the reaction system.

[0063] Examples of such precursors include cobalt(II) acetylacetonate (Co(acac) ２ Examples include ruthenium(III) chloride and palladium(II) chloride, but cobalt(II) acetylacetonate is preferred. This allows the aforementioned effects to be exhibited more significantly.

[0064] The content of the third substance in the mixture subjected to the substitution step is not particularly limited, but is preferably 0.0000001% by mass or more and 10% by mass or less, more preferably 0.00001% by mass or more and 5% by mass or less, and even more preferably 0.0001% by mass or more and 1% by mass or less.

[0065] This allows the desired reaction in the substitution process to proceed more efficiently, resulting in improved productivity and yield of the target nitrogen-containing compound.

[0066] For example, the content of the third substance in the mixture subjected to the substitution process is usually sufficiently low compared to the content of the first substance or the second substance.

[0067] More specifically, the content (molar ratio) of the third substance in the mixture subjected to the substitution step is preferably 0.1 times or less the content of the first substance, and more preferably 0.001 times or less the content of the first substance.

[0068] The mixture subjected to the substitution step may contain multiple types of third substances.

[0069] [1-1-4] The mixture subjected to the solvent replacement step may contain, for example, a solvent that dissolves the first substance, the second substance, etc.

[0070] Examples of such solvents include compounds that do not contain any hydroxyl, amino, or amine groups in their molecule.

[0071] Specific examples of such solvents include ketone solvents such as acetone and methyl ethyl ketone; ether solvents such as dioxane, tetrahydrofuran, and diglyme; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; aromatic solvents such as benzene and toluene; nitrile solvents such as acetonitrile; and halogenated solvents such as methylene chloride, chloroform, and dichloroethane. One or more of these can be selected and used in combination.

[0072] When the mixture subjected to the substitution step contains the solvent described above, the solvent content in the mixture subjected to the substitution step is not particularly limited, but is preferably 95% by mass or less, more preferably 80% by mass or less, and even more preferably 60% by mass or less.

[0073] This allows the desired reaction to proceed more efficiently in the substitution process, resulting in improved productivity and yield of the target nitrogen-containing compound.

[0074] Furthermore, if at least one of the first and second substances is a liquid component and also functions as a solvent in the substitution step, the above-mentioned effects can be obtained without using any other solvent components.

[0075] [1-1-5] The mixture subjected to the other component substitution step may contain components other than those listed above. Hereinafter in this section, such components will also be referred to as "other components".

[0076] Other components include, for example, substances that have the function of converting a third substance, which acts as a catalyst precursor, into a catalyst, and substances that coordinate to the metal atoms of the reduced catalyst center.

[0077] The components that have the function of converting a third substance, which acts as a catalyst precursor, into a catalyst vary depending on the type of third substance, but examples include reducing agents such as potassium tert-butoxide and sodium hydride, phosphorus compounds such as tripotassium phosphate, tris[2-(diphenylphosphino)ethyl]phosphine and triphenylphosphine, and unsubstituted or imidazole substances that coordinate to the metal atom that is the catalyst.

[0078] The content of other components in the mixture subjected to the substitution step is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 3% by mass or less.

[0079] This allows for a relatively high content of the aforementioned first component, second component, etc., in the mixture subjected to the substitution step, thereby enabling the desired reaction to proceed more favorably.

[0080] [1-2] Substitution step In the substitution step, a mixture containing the first substance and the second substance is irradiated with microwaves to replace at least one hydrogen atom among the at least one hydrogen atom that was bonded to the nitrogen atom constituting the first substituent contained in the first substance with an organic group (an organic group bonded to the oxygen atom of a hydroxyl group) possessed by the second substance.

[0081] By irradiating with microwaves in this way, it is possible to efficiently obtain the target nitrogen-containing compound under mild conditions, even when using relatively inexpensive and safe raw materials. More specifically, for example, the target compound can be obtained in high yield even when the reaction time is relatively short.

[0082] Furthermore, compared to conventional methods of supplying energy through external heating, this method allows for the efficient delivery of the energy necessary for the target chemical reaction to specific substances. As a result, the desired reaction can proceed smoothly without unnecessarily raising the temperature of the entire reaction system.

[0083] Furthermore, by adjusting the microwave output and heating time, it becomes easier to control the temperature of the reaction system.

[0084] While microwave frequencies are generally set between 300 MHz and 300 GHz, it is preferable to use the frequency band permitted for industrial use as the ISM band (Industrial Scientific and Medical Band). The peak frequency is preferably between 900 MHz and 30 GHz, more preferably between 2.40 GHz and 2.50 GHz, and even more preferably 2.45 GHz. This allows the desired reaction to proceed more efficiently.

[0085] The microwave heating time is preferably 30 seconds to 600 minutes, more preferably 1 minute to 300 minutes, and even more preferably 3 minutes to 90 minutes.

[0086] The temperature of the mixture during microwave irradiation is preferably 100°C to 1200°C, more preferably 300°C to 900°C, and even more preferably 400°C to 700°C.

[0087] This allows the desired reaction to proceed more efficiently while more effectively preventing undesirable side reactions.

[0088] Furthermore, this process may be carried out under any atmosphere, for example, in air, or in an inert gas atmosphere such as nitrogen, helium, neon, or argon. It may also be carried out in an oxidizing or reducing atmosphere. In addition, this process may be carried out under reduced pressure.

[0089] Furthermore, microwave irradiation may be performed in multiple stages. In such cases, it is preferable that the sum of the microwave treatment times satisfies the above-mentioned microwave heating time requirements.

[0090] Furthermore, the microwave irradiation conditions (for example, microwave frequency, power output, and the atmosphere during microwave irradiation) may be changed during the process.

[0091] For example, when irradiating a mixture with microwaves, the microwave irradiation conditions may be kept constant, or the microwave irradiation conditions may be controlled so that the heating rate or heating temperature of the mixture remains constant.

[0092] Furthermore, the mixture may be stirred or otherwise processed during microwave irradiation or between multiple microwave irradiation treatments.

[0093] Furthermore, in this process, external heating may be performed in addition to microwave irradiation.

[0094] [1-3] Other steps In addition to the substitution step described above, this manufacturing method may also include other steps. Examples of such steps include various pre-treatment steps and post-treatment steps.

[0095] For example, the process may include a step of external heat treatment as a pre-treatment or post-treatment step for the substitution process.

[0096] Furthermore, the post-processing steps may include, for example, a quenching step to quench unreacted components and a purification step to purify the target nitrogen-containing compound.

[0097] [2] Nitrogen-containing compounds The nitrogen-containing compounds obtained by the above-described manufacturing method may be used for any purpose.

[0098] More specifically, the nitrogen-containing compounds according to the present invention can be used, for example, as tracers, heavy pharmaceuticals, compounds used in proteomic analysis, and precursors thereof.

[0099] The nitrogen-containing compound obtained by the above-described manufacturing method may be used as the final target compound, or it may be used as a raw material compound (precursor) for other target compounds.

[0100] Although preferred embodiments of the present invention have been described above, the present invention is not limited thereto.

[0101] The present invention will be described in detail below based on specific examples, but the present invention is not limited thereto. In the following examples, processes and measurements where the temperature conditions are not specified were performed at room temperature (23°C).

[0102] [3] Production of nitrogen-containing compounds Nitrogen-containing compounds were produced as follows.

[0103] [3-1] N-methylation reaction of aniline (Example 1) A stirring bar, aniline (250 mg, 2.7 mmol) as the first substance, potassium tert-butoxide (600 mg, 5.4 mmol) as a reducing agent, and methanol (7 mL) as the second substance were added to a 15 mL pressure vessel with a thermowell (manufactured by ace glass).

[0104] After bubbling the reaction solution with nitrogen for 5 minutes, ruthenium-n chloride hydrate (28 mg, 0.1 mmol) as a third substance (catalyst precursor) was added, and the reaction was carried out at 110°C for 6 hours by microwave heating using a μ-reactor manufactured by Shikoku Keisoku Kogyo Co., Ltd.

[0105] The chemical reaction in this example is shown in the following equation.

[0106]

[0107] (Comparative Example 1) The reaction was carried out in the same manner as in Example 1, except that external heating (heater heating) was performed using a heater instead of microwave heating.

[0108] [3-2] N-methylation reaction of 4-aminophenol (Example 2) A stirring bar, 4-aminophenol (500 mg, 4.6 mmol) as the first substance, potassium tert-butoxide (1.0 g, 9.2 mmol) as a reducing agent, and methanol (5 mL) as the second substance were added to a 15 mL pressure vessel with a thermowell (manufactured by ace glass).

[0109] After bubbling the reaction solution with nitrogen for 5 minutes, ruthenium-n chloride hydrate (41 mg, 0.2 mmol) as a third substance (catalyst precursor) was added, and the reaction was carried out at 115°C for 5 hours by microwave heating using a μ-reactor manufactured by Shikoku Keisoku Kogyo Co., Ltd.

[0110] The chemical reaction in this example is shown in the following equation.

[0111]

[0112] (Comparative Example 2) The reaction was carried out in the same manner as in Example 2, except that external heating by a heater (heater heating) was performed instead of microwave heating.

[0113] [3-3] N-methylation reaction of cyclohexylamine (Example 3) A stirring bar, cyclohexylamine (500 mg, 5.0 mmol) as the first substance, potassium tert-butoxide (1.4 g, 12.5 mmol) as a reducing agent, and methanol (7 mL) as the second substance were added to a 15 mL pressure vessel with a thermowell (manufactured by ace glass).

[0114] After bubbling the reaction solution with nitrogen for 5 minutes, ruthenium-n chloride hydrate (100 mg, 0.5 mmol) as a third substance (catalyst precursor) was added, and the reaction was carried out at 110°C for 7 hours by microwave heating using a μ-reactor manufactured by Shikoku Keisoku Kogyo Co., Ltd. The GC yield was 38%.

[0115] The chemical reaction in this example is shown in the following equation.

[0116]

[0117] (Comparative Example 3) The reaction was carried out in the same manner as in Example 3, except that external heating (heater heating) was performed using a heater instead of microwave heating.

[0118] [3-4] N-methylation reaction of 6-amino-1-hexanol (Example 4) A stirring bar, 6-amino-1-hexanol (200 mg, 1.7 mmol) as the first substance, potassium tert-butoxide (19 mg, 1.7 mmol) and tris[2-(diphenylphosphino)ethyl]phosphine (PP3, 228 mg, 0.34 mmol) as reducing agents, and methanol (5 mL) as the second substance were added to a 15 mL pressure vessel with a thermowell (manufactured by ace glass).

[0119] After bubbling the reaction solution with nitrogen for 5 minutes, cobalt(II) acetylacetonate (87 mg, 0.34 mmol) as a third substance (catalyst precursor) was added, and the reaction was carried out at 100°C for 4 hours by microwave heating using a μ-reactor manufactured by Shikoku Keisoku Kogyo Co., Ltd. The GC yield was 45%.

[0120] The chemical reaction in this example is shown in the following equation.

[0121]

[0122] (Comparative Example 4) The reaction was carried out in the same manner as in Example 4, except that external heating (heater heating) was performed using a heater instead of microwave heating. The GC yield was 5%.

[0123] [3-5] N-ethylation reaction of aniline (Example 5) A stirring bar, aniline (502 mg, 5.39 mmol) as the first substance, potassium tert-butoxide (987 mg, 8.79 mmol) as a reducing agent, and ethanol (5 mL) as the second substance were added to a 15 mL pressure vessel with a thermowell (manufactured by ace glass).

[0124] After bubbling the reaction solution with nitrogen for 5 minutes, ruthenium-n chloride hydrate (79 mg, 0.38 mmol) as a third substance (catalyst precursor) was added, and the reaction was carried out at 110°C for 6 hours by microwave heating using a μ-reactor manufactured by Shikoku Keisoku Kogyo Co., Ltd. The GC yield was 13%.

[0125] The chemical reaction in this example is shown in the following equation.

[0126]

[0127] [3-6] Synthesis of Butenafine Hydrochloride (Example 6) A stirring bar, 1-naphthaldehyde (1.99 g, 12.2 mmol), 4-tert-butylbenzylamine (1.9 g, 12.2 mmol), and MeOH (80 mL) were added to a 500 mL four-necked round-bottom flask, and the mixture was irradiated with MW under a nitrogen atmosphere and reacted at 60°C for 30 minutes.

[0128] After cooling, NaBH is added to the reaction solution (Schiff base solution). ４ (690mg, 18.3mmol), H３ BO ３ (1.1 g, 18.3 mmol) was slowly added and stirred at room temperature for 10 minutes.

[0129] Subsequently, the reaction solution was irradiated with microwaves, and the reaction was carried out at 60°C for 1 hour.

[0130] After cooling, deionized water was added to quench the mixture, and it was extracted with ethyl acetate and washed with water. The resulting organic layer was dehydrated with sodium sulfate and the solvent was removed using an evaporator. Diethyl ether was added to the resulting pale yellow oily mixture to dissolve it, and a small amount of acetic acid was added, causing a white solid to precipitate. The obtained white solid was recovered by Kiriyama filtration and washed with diethyl ether to obtain the precursor acetate (3.3 g) in 74% yield.

[0131] A stirring bar, acetate (363 mg, 1.0 mmol) as the first substance, tripotassium phosphate (636 mg), and methanol (6 mL) as the second substance were added to a 15 mL pressure vessel with a thermowell (manufactured by ace glass), and the mixture was reacted at room temperature.

[0132] After 3 hours, tris[2-(diphenylphosphino)ethyl]phosphine (PP3, 260 mg, 0.39 mmol), tripotassium phosphate (212 mg), and methanol (1 mL) as the second substance were added to the reaction solution and nitrogen bubbling was performed for 5 minutes. Then, cobalt(II) acetylacetonate (103 mg, 0.4 mmol) as the third substance (catalyst precursor) was added, and the mixture was reacted at 140°C for 8.5 hours by microwave heating using a μ-reactor manufactured by Shikoku Keisoku Kogyo Co., Ltd.

[0133] Subsequently, the following post-processing was performed: the resulting reaction solution was quenched with deionized water, extracted with ethyl acetate, and washed with water. Furthermore, the resulting organic layer was dehydrated with sodium sulfate, and the solvent was removed using an evaporator. The resulting dark brown oily mixture was purified using silica gel chromatography (developing solvent: a mixed solvent of n-hexane and ethyl acetate). After concentrating the recovered eluent, the resulting pale yellow oil was dissolved in diethyl ether, and a white solid precipitated when HCl gas was blown over it. The obtained white solid was recovered by Kiriyama filtration and washed with diethyl ether to obtain butenafine hydrochloride (19 mg, 5%).

[0134] The chemical reaction in this example is shown in the following equation.

[0135]

[0136] (Comparative Example 6) A mixture containing the first substance, the second substance, and the third substance was reacted and post-treated in the same manner as in Example 6, except that external heating (heater heating) was performed using a heater instead of microwave heating. Subsequently, the butenafine hydrochloride was purified in the same manner as in Example 6.

[0137] [3-7] Synthesis of Imipramine Hydrochloride (Example 7) First, a reflux condenser and nitrogen balloon were attached to a two-necked round-bottom flask, and iminodibenzyl (1.03 g, 5.0 mmol), 1,3-dibromopropane (1.62 g, 7.5 mmol), and toluene (5 mL) were added. LiNH4 was added to this reaction solution. ２ (147 mg, 6.0 mmol) was added and the reaction was carried out at 120°C for 18 hours. After cooling, an aqueous sodium bicarbonate solution was added to quench the mixture, and ethyl acetate was added. The organic layer was extracted with ethyl acetate and washed with water. The resulting organic layer was dehydrated with sodium sulfate and the solvent was removed using an evaporator. The resulting residue was purified using silica gel chromatography (developing solvent: hexane + 1% by mass ethyl acetate). By concentration and vacuum drying, the bromoalkyl compound was obtained as a pale yellow oil (728 mg, yield 45%).

[0138] Next, a nitrogen balloon was attached to a round-bottom flask, and the bromoalkyl compound obtained as described above (1.59 g, 5.03 mmol) and a 40% by mass methylamine methanol solution (6 mL) were added. Potassium carbonate (692 mg, 1.0 mmol) was added to this reaction solution, and the reaction was carried out at room temperature for 18 hours while monitoring the reaction by thin-layer chromatography (TLC). After quenching the reaction solution with deionized water, it was extracted with ethyl acetate and washed with water. The resulting organic layer was dehydrated with sodium sulfate, and the solvent was removed using an evaporator. The resulting pale yellow oil was dissolved in diethyl ether, and a white solid precipitated when HCl gas was blown over it. The obtained white solid was recovered by Kiriyama filtration and washed with diethyl ether to obtain the precursor desipramine hydrochloride (1.0 g) in 68% yield.

[0139] In a round-necked flask, the desipramine hydrochloride (180 mg, 0.59 mmol) obtained as described above, NaOH (120 mg), water (1 mL), and methanol (5 mL) were added and the mixture was reacted at room temperature. After 3 hours, the reaction solution was extracted with ethyl acetate and washed with water. The resulting organic layer was dehydrated with sodium sulfate and the solvent was removed using an evaporator.

[0140] The pale yellow oil obtained as the first substance was dissolved in methanol (4 mL) as the second substance and added to a 15 mL pressure vessel with a thermowell (Ace Glass). Furthermore, tris[2-(diphenylphosphino)ethyl]phosphine (PP3, 80 mg, 0.12 mmol) and KOTBu (66 mg, 0.59 mmol) were added to the reaction solution and nitrogen bubbling was performed for 5 minutes. Cobalt(II) acetylacetonate (31 mg, 0.12 mmol) as the third substance (catalyst precursor) was added to the reaction solution and the mixture was reacted at 100°C for 1 hour by microwave heating using Wavemagic (EYELA Tokyo Rikakikai Co., Ltd.).

[0141] Subsequently, the following post-processing was performed. Specifically, the obtained reaction solution was quenched with deionized water, extracted with ethyl acetate, and washed with water. Furthermore, the obtained organic layer was dehydrated with sodium sulfate, and the solvent was removed using an evaporator. The obtained dark brown oily mixture was purified using column chromatography with activated alumina as a packing material (developing solvent: ethyl acetate / hexane = 2 / 1 + 1% triethylamine by mass ratio). After concentrating the recovered eluent, the obtained pale yellow oil was measured by NMR and identified as imipramine (131 mg, yield 78%). In addition, when the obtained pale yellow oil was dissolved in diethyl ether and HCl gas was blown onto it, a white solid precipitated. The obtained white solid was recovered by Kiriyama filtration and washed with diethyl ether to obtain imipramine hydrochloride (130 mg, yield 69%).

[0142] The chemical reaction in this example is shown in the following equation.

[0143]

[0144] (Comparative Example 7) A mixture containing the first substance, the second substance, and the third substance was reacted and post-treated in the same manner as in Example 7, except that external heating by a heater (heater heating) was performed instead of microwave heating.

[0145] [4] Evaluation For each of the above examples and comparative examples, the reaction solution was measured by GC-MS, and the proportions of unreacted raw materials, target product, and by-products were calculated. In addition, for Example 6, Comparative Example 6, Example 7, and Comparative Example 7, the isolation yield of the target compound (nitrogen-containing compound) purified by the post-treatment described above was also determined. These results are shown in Tables 1, 2, 3, 4, and 5.

[0146] Furthermore, the acetate salt obtained as the first substance in the production process of the nitrogen-containing compound (butenafine hydrochloride) in Example 6 １ Figure 1 shows the H-NMR (in DMSO-d6) chart, and the target nitrogen-containing compound (butenafine hydrochloride) obtained in Example 6 １Figure 2 shows the H-NMR (in DMSO-d6) chart, and the target nitrogen-containing compound (imipramine hydrochloride) obtained in Example 7 １ The H-NMR (in DMSO-d6) chart is shown in Figure 3.

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] As is clear from Tables 1 to 5, in each example, significantly better results were obtained compared to the corresponding comparative example.

[0153] [5] Preparation of stable isotope-labeled nitrogen-containing compounds [5-1] Synthesis of stable isotope-labeled imipramine hydrochloride (Example 8) First, a reflux condenser and nitrogen balloon were attached to a two-necked round-bottom flask, and iminodibenzyl (1.03 g, 5.0 mmol), 1,3-dibromopropane (1.62 g, 7.5 mmol), and toluene (5 mL) were added. LiNH4 was added to this reaction solution. ２ (147 mg, 6.0 mmol) was added and the reaction was carried out at 120°C for 18 hours. After cooling, an aqueous sodium bicarbonate solution was added to quench the mixture, and ethyl acetate was added. The organic layer was extracted with ethyl acetate and washed with water. The resulting organic layer was dehydrated with sodium sulfate and the solvent was removed using an evaporator. The resulting residue was purified using silica gel chromatography (developing solvent: hexane + 1% by mass ethyl acetate). By concentration and vacuum drying, the bromoalkyl compound was obtained as a pale yellow oil (728 mg, yield 45%).

[0154] Next, a nitrogen balloon was attached to a round-bottom flask, and the bromoalkyl compound obtained as described above (1.59 g, 5.03 mmol) and a 40% by mass methylamine methanol solution (6 mL) were added. Potassium carbonate (692 mg, 1.0 mmol) was added to this reaction solution, and the reaction was carried out at room temperature for 18 hours while monitoring the reaction by thin-layer chromatography (TLC). After quenching the reaction solution with deionized water, it was extracted with ethyl acetate and washed with water. The resulting organic layer was dehydrated with sodium sulfate, and the solvent was removed using an evaporator. The resulting pale yellow oil was dissolved in diethyl ether, and a white solid precipitated when HCl gas was blown over it. The obtained white solid was recovered by Kiriyama filtration and washed with diethyl ether to obtain the precursor desipramine hydrochloride (1.0 g) in 68% yield.

[0155] A 15 mL pressure vessel with a thermowell (ace glass) contains a stirring bar, the first substance obtained as described above (desipramine hydrochloride (200 mg, 0.66 mmol) and potassium tert-butoxide (74 mg, 0.66 mmol) and the second substance (deuterium methanol (CD)). ３ Add OD (3 mL) and allow to react at room temperature.

[0156] After 1 hour, tris[2-(diphenylphosphino)ethyl]phosphine (PP3, 87 mg, 0.13 mmol) and potassium tert-butoxide (74 mg, 0.66 mmol) were added to the reaction solution and the mixture was bubbling with nitrogen for 5 minutes.

[0157] In the reaction solution, Co(acac) is added as a third substance. ２ (33 mg, 0.13 mmol) was added and the mixture was reacted at 100°C for 1 hour using a microwave oscillator (EYELA: Wave Magic). The microwave oscillator was set to a heating power of 100 W.

[0158] Subsequently, the following post-processing was performed. First, the reaction solution was quenched with deionized water, then extracted with ethyl acetate and washed with water. Furthermore, the obtained organic layer was dehydrated with sodium sulfate and the solvent was removed using an evaporator. The resulting dark brown oily mixture was purified using activated alumina (developing solvent: ethyl acetate / hexane = 2 / 1 + 1% triethylamine by mass ratio). After concentrating the recovered eluent, the resulting pale yellow oil was dissolved in diethyl ether (2 mL), and hydrochloric acid gas was blown over it to confirm the precipitation of a white solid. A white solid was obtained by suction filtration while washing with diethyl ether. After vacuum drying, the white solid was measured by NMR and identified as imipramine hydrochloride-d3.

[0159] The chemical reaction in this example is shown in the following equation.

[0160]

[0161] Furthermore, Figure 4 shows the mass spectral chart of the target nitrogen-containing compound (imipramine hydrochloride) obtained in Example 8. １ H-NMR (in DMSO-d ６ The chart is shown in Figure 5.

[0162] (Comparative Example 8) A mixture containing the first substance, the second substance, and the third substance was subjected to the same reaction and post-treatment as in Example 8, except that external heating (heater heating) was performed using a heater instead of microwave heating. In this comparative example, the raw materials were recovered, and the isolation of the target compound was not achieved.

[0163] According to the present invention, it is possible to provide a method for producing nitrogen-containing compounds that can efficiently obtain the target nitrogen-containing compound under mild conditions, even when using relatively inexpensive and highly safe raw materials. Therefore, the present invention has industrial applicability.

Claims

1. A method for producing a nitrogen-containing compound, characterized by comprising a substitution step of irradiating a mixture containing a first substance having a first substituent having a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom, and a second substance having a second substituent having at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group, with microwaves, thereby substituting at least one of the at least one hydrogen atoms bonded to the nitrogen atom with the organic group.

2. A method for producing a nitrogen-containing compound, comprising a substitution step of irradiating a mixture containing a first substance having a first substituent having a chemical structure in which at least one hydrogen atom is directly bonded to a nitrogen atom, and a second substance having a second substituent having at least one hydroxyl group and an organic group bonded to the oxygen atom of the hydroxyl group, with microwaves to replace at least one of the at least one hydrogen atoms bonded to the nitrogen atom with the organic group, wherein the second substance is stable isotope labeled.

3. The method for producing a nitrogen-containing compound according to claim 2, wherein the second substance is labeled with the stable isotope deuterium (D).

4. The second substance is, １３ A method for producing the nitrogen-containing compound according to claim 2 or 3, wherein the compound is labeled with the stable isotope C.

5. The method for producing a nitrogen-containing compound according to claim 1 or 2, wherein the first substance further has other reactive functional groups different from the first substituent, and the other reactive functional groups are subjected to the substitution step in a state that they are not protected by protecting groups.

6. The method for producing a nitrogen-containing compound according to claim 1 or 2, wherein the mixture contains a catalyst or a catalyst precursor as a third substance.

7. The method for producing a nitrogen-containing compound according to claim 6, wherein the third substance contains a metal atom.

8. The method for producing a nitrogen-containing compound according to claim 6, wherein the precursor is converted into a fourth substance that functions as a catalyst by a reduction reaction.

9. The method for producing a nitrogen-containing compound according to claim 8, wherein the precursor is ruthenium chloride.

10. The method for producing a nitrogen-containing compound according to claim 7, wherein the precursor as the third substance is cobalt(II) acetylacetonate.

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