JP2021084897A - Method for Producing Aromatic Amine Compounds from Phenols - Google Patents

Abstract

To provide a method for producing an aromatic amine compound from phenols and amines with a high yield and a high selectivity, which includes ones subjected to polyfunctionalization, under relatively low temperature and relatively low pressure, without using an additive which gives a co-product having high environmental load.SOLUTION: Phenols and hydrogen are introduced into a first catalyst cartridge receiving a solid catalyst containing platinum group elements and continuously hydrogenated into cyclohexanones. The resultant cyclohexanones, along with amines selected from ammonia, primary amines and secondary amines, and hydrogen trapping agents are subsequently introduced into a second catalyst cartridge receiving a solid catalyst containing platinum group elements to continuously produce aromatic amine compounds by dehydration condensation and dehydrogenation with amines.SELECTED DRAWING: Figure 2

Description

The present invention relates to a method for producing an aromatic amine compound. More specifically, phenols and hydrogen are introduced into the first catalyst cartridge containing a solid catalyst containing palladium to hydrogenate the phenols to cyclohexanones, and then the obtained cyclohexanones are converted to ammonia and the first. From phenols and ammonia, primary amines or secondary amines by introduction into a secondary catalyst cartridge containing a solid catalyst containing palladium, along with primary or secondary amines and hydrogen trapping agents. The present invention relates to a method for continuously producing an aromatic amine compound with high selectivity and yield.

As a method for producing an aromatic amine compound by reacting phenols with a primary or secondary amine, for example, (1) converting a primary amine with an excess amount of phenols into a palladium catalyst and hydrogen, or phenols. Method of heating reaction in which corresponding cyclohexanones coexist (Patent Documents 1 and 2), (2) Heating of an equimolar amount of phenols with a primary amine in coexistence of a palladium catalyst and an alicyclic six-membered ring compound. Known methods include a method of reacting (Patent Document 3), (3) a method of heating and reacting an equimolar amount of phenols with a primary amine in the coexistence of a palladium catalyst and hydrogen and ammonia (Patent Document 4). ..
However, in the method (1) above, phenols are used in a molar amount of 2 times or more, preferably 4 to 10 times the molar amount of amine, so that the step of separating and recovering unreacted phenols from the reaction solution is a step. is necessary. Further, when the amount of phenols used is reduced, the amount of by-product of the cyclohexylamine compound increases, and the selectivity of the target product tends to decrease.
Since the method (2) above uses an alicyclic six-membered ring compound such as tetrahydronaphthalene as a hydrogen source, a step of separating a co-product such as naphthalene produced in the reaction from the reaction solution is required.
In the method (3) above, ammonia used as an additive can react with two molecules of phenols to form diphenylamines having a symmetrical structure, and thus the target product produced by the reaction of phenols with primary amines. In order to obtain the aromatic amines with high selectivity, the target product is diphenylamines having the same symmetrical structure as this, and therefore the primary amine used is phenyl having the same structure as the phenyl group of phenols. It needs to be an aniline having a group.
Further, since all the reactions (1) to (3) above are carried out under high temperature and high pressure (150 to 300 ° C., 1 to 30 MPa) using an autoclave, functional groups sensitive to temperature and hydrogenation conditions are used. There is a big limitation on the applicable range of the substrate, for example, it is difficult to use phenols and amines having

On the other hand, as a production method that can be carried out under low temperature and low pressure (140 ° C, less than 1 MPa), phenols having an equimolar amount of primary or secondary amines are used as a palladium catalyst and phenols as an auxiliary catalyst. A method of heating reaction in the presence of 0.5 times molar amount of trifluoroacetic acid and sodium formate as a hydrogen source has been proposed (Non-Patent Document 1).
However, this method requires a step of separating trifluoroacetic acid used as a co-catalyst and a sodium salt derived from a hydrogen source. In addition, since hydrogenation and dehydrogenation proceed sequentially in the same reactor space, it is difficult for functional groups that are susceptible to hydrogenation to coexist.

On the other hand, conventionally, as a method for producing an aromatic amine compound in which many kinds of functional groups can coexist, aromatic halides having various functional groups and amines are heated by coexisting a palladium complex catalyst and a strong base. A cross-coupling reaction that causes agitation is known (Non-Patent Documents 2 and 3). This method is one of the most practical methods for producing polyfunctionalized aromatic amine compounds, which are in high potential demand in the fields of pharmaceuticals and material chemistry.
However, this method requires the preparation of aromatic halides, which are expensive and not easily available. In addition, after the reaction, a step of separating and removing the used palladium complex catalyst, base, and halide salt which is a co-product is required. Furthermore, since a strong base is used, it is difficult to synthesize an aromatic amine compound having a functional group sensitive to basic conditions.

Japanese Unexamined Patent Publication No. 60-193949 Japanese Unexamined Patent Publication No. 6-135910 Japanese Unexamined Patent Publication No. 2000-212133 Japanese Unexamined Patent Publication No. 2000-095736

Li, C.-J. et al. Angew. Chem., Int. Ed. 2015, 54, 14487-14491. Guram, A .; Rennels, R .; Buchwald, S. Angew. Chem., Int. Ed., 1995, 34, 1348-1350. Louie, J .; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609-3612.

As a result of examining conventional production methods for producing an aromatic amine compound from phenols and primary amines or secondary amines, the present inventors have recognized that each has the following problems.
(1) The method of using a large excess amount of phenols with respect to amines described in Patent Document 1 saves energy because it costs a lot to separate and treat unreacted phenols after the reaction. It is not an industrially superior method in terms of.
(2) As a method that does not require the use of an excessive amount of phenols with respect to amines, there is a method of using an additive that functions as a hydrogen source in the reaction system instead of hydrogen gas. However, the method of using cyclohexanones corresponding to phenols described in Patent Document 2 requires time and effort to prepare cyclohexanones in advance. Further, in the method using the alicyclic six-membered ring compound described in Patent Document 3 and the sodium formate described in Non-Patent Document 1, it is very difficult to separate and treat the co-products derived from these. costly.
(3) In the conventional production method, in order to obtain high yield and selectivity, except for Non-Patent Document 1, it is necessary to carry out under high temperature and high pressure (150 to 300 ° C., 1 to 30 MPa). There is a big limitation on the applicable range of the substrate, such as difficulty in using phenols and amines having functional groups sensitive to hydrogenation conditions.
(4) In the conventional manufacturing method, a method (batch method) has been adopted in which a raw material, a catalyst, or the like is added to a kettle-type reactor such as an autoclave and heated and stirred. In this batch method, the product produced by the reaction stays under the reaction conditions in the presence of a catalyst or the like for a long time until the desired reaction is completed. Due to the characteristics of this production method, (i) first, the aromatic amine compound as a product may cause an overreaction with the catalyst, which may lead to a decrease in the yield or purity of the product, and (ii) further. The generated aromatic amine compound acts as a catalyst poison that inhibits the action of the catalyst, which reduces the working efficiency of the catalyst and causes an increase in the amount used.

The problems (1) to (3) above are caused by the fact that this reaction is a hydrogen transfer reaction in which hydrogenation and dehydrogenation are repeated. Hereinafter, the estimated reaction mechanism of this reaction will be described with reference to FIG. 1.
As shown in FIG. 1, in this reaction, hydrogenation A of phenols 1 produces cyclohexanones 2, which are amines 3 (ammonia (R ⁶ , R ⁷ are hydrogen)) and primary amines (R ⁷ is hydrogen). ) Or secondary amine) and dehydration condensation B to give imine intermediate 4 (when 3 is ammonia or primary amine) or iminium intermediate 4'(when 3 is secondary amine). The dehydrogenation C produces the aromatic amine compound 5. At this time, not only the phenols 1 but also the imine intermediate 4 or the iminium intermediate 4'is hydrogenated, and the cyclohexylamine compound 6 is produced as a by-product.
In order to suppress this side reaction, it is necessary to create a situation in which phenols 1 are present in a large excess with respect to imine intermediate 4 or iminium intermediate 4', and for this reason, in Patent Document 1, amines In Patent Document 3 and Non-Patent Document 1, a large excess of phenols is used for the class, and in Patent Document 3 and Non-Patent Document 1, the production rate of imine intermediate or iminium intermediate is suppressed by suppressing the production of cyclohexanone by using a mild hydrogen source. It is considered necessary to adjust.
Further, the problem (4) is also a factor that limits the applicable range of the substrate in the prior art, and also leads to an increase in the manufacturing cost due to an increase in the catalyst load.

Further, regarding the cross-coupling reaction using an aromatic halide, which is known as a method for producing a polyfunctionalized aromatic amine compound, the availability of raw materials is low and the post-treatment step of the reaction is complicated. In addition, it has problems caused by strongly basic reaction conditions.

The present invention has been made against the background of the above-mentioned prior arts and the problems recognized by the present inventors regarding them, without using additives that give co-products having a high environmental load. To provide a production method capable of obtaining aromatic amine compounds from phenols and amines with high yield and selectivity, including those polyfunctionalized under relatively low temperature and pressure. Make it an issue.

When the present inventors are investigating a process for producing an aromatic amine compound from phenols and ammonia or a primary amine or a secondary amine (hereinafter referred to as amines), this conversion reaction is carried out. A hydrogen transfer type consisting of production of cyclohexanones by hydrogenation of phenols (step (1)), dehydration condensation of cyclohexanones and amines generated thereby, and dehydrogenation of condensates (step (2)). Focusing on the sequential reaction, these reactions are sequentially carried out in separate reactors by a continuous flow method using two catalyst cartridges containing a solid catalyst containing a platinum group element such as palladium. It was found that the aromatic amine compound, which is the target product, can be obtained with high yield, selectivity and wide functional group tolerance as compared with the conventional manufacturing method by the batch method using a kettle-type reactor such as an autoclave. It was.

In the present invention, phenols are hydrogenated by continuously supplying phenols and hydrogen to a first catalyst cartridge containing a solid catalyst containing a platinum group element such as palladium, and then obtained. After separating the cyclohexanones from unreacted hydrogen, they are continuously supplied to a second catalyst cartridge containing a solid catalyst containing a platinum group element such as palladium together with amines and a hydrogen trapping agent. By advancing the dehydration condensation of cyclohexanones and amines and the resulting dehydrogenation of the imine intermediate or the iminium intermediate, the desired aromatic amine compound is continuously obtained.

In the present invention, hydrogenation of phenols with hydrogen (step (1)), dehydration condensation of cyclohexanone and amines produced thereby, and dehydrogenation of the imine intermediate or imine intermediate produced thereby (step). By carrying out (2)) in different reactors, and by adding a hydrogen trapping agent such as oxygen or olefins having 8 or less carbon atoms in step (2), the imine intermediate Alternatively, it is possible to effectively suppress side reactions such as by-production of cyclohexylamine due to hydrogenation of an imine intermediate and hydrogenation of the other functional group when these have other functional groups. .. When oxygen or olefins having 8 or less carbon atoms are used as the hydrogen scavenger, the only co-products produced by this reaction are water, which can be easily removed, and alkanes derived from olefins, which have 8 or less carbon atoms. This leads to simplification of the separation and purification process.

Further, in the present invention, the reactions of steps (1) and (2) each use a catalyst cartridge as a reactor, and raw materials are continuously supplied from one of the inlets to proceed with the desired reaction, and vice versa. It is characterized by a circulation method (continuous flow method) in which the product is continuously discharged from the side outlet. In this continuous flow method, the produced product is discharged while being continuously separated from the solid catalyst without staying in the catalyst cartridge which is a reactor. Therefore, the contact time between the catalyst and the product is longer than that in the prior art. It can be shortened significantly.
Thereby, in the present invention, it is possible to suppress an excessive reaction of the aromatic amine compound, which is the target product, with the amine moiety and other functional groups, and the poisoning action of the reaction product on the catalyst. Therefore, it is possible to produce aromatic amine compounds with high yields and selectivity, including polyfunctionalized ones, with less catalyst usage.

The present invention has been made based on these findings by the present inventors, and specifically, it is as follows.
<1> Phenols and hydrogen are introduced into the first catalyst cartridge containing a solid catalyst containing a platinum group element to continuously hydrogenate the cyclohexanones, and the obtained cyclohexanones are subsequently subjected to ammonia and the second. Aromatic amine compounds are continuously produced by introducing them into a second catalyst cartridge containing a solid catalyst containing a platinum group element together with amines and hydrogen trapping agents selected from primary amines and secondary amines. A method for producing an aromatic amine compound.
<2> The solid catalysts containing the platinum group elements contained in the first and second catalyst cartridges are independently activated carbon-supported palladium catalyst, activated charcoal-supported palladium hydroxide catalyst, alumina-supported palladium catalyst, and silica-supported palladium. The method for producing an aromatic amine compound according to <1>, wherein the catalyst is one or more catalysts selected from the group consisting of a catalyst, a zirconia-supported palladium catalyst, a zeolite-supported palladium catalyst, and palladium black. ..
<3> The solid catalyst containing a platinum group element contained in the first and second catalyst cart jigs is independently selected from the group consisting of celite, diatomaceous earth, silica, alumina, titania, and zirconia. The method for producing an aromatic amine compound according to <1> or <2>, wherein the aromatic amine compound is contained in the first and second catalyst cartridges in the form of a mixture with two or more kinds of oxides. ..
<4> The primary amine or the secondary amine is characterized in that it is selected from the group consisting of an aliphatic amine, an aromatic amine, an alicyclic amine, and a heteroaromatic amine. > To the method for producing an aromatic amine compound according to any one of <3>.
<5> The hydrogen scavenger introduced into the second catalyst cartridge is selected from the group consisting of oxygen or a primary olefin having 8 or less carbon atoms or a secondary olefin. The method for producing an aromatic amine compound according to any one of <1> to <4>.
<6> The hydrogen scavenger introduced into the second catalyst cartridge is characterized by having a molar amount of 1.0 to 4.0 times that of ammonia, a primary amine or a secondary amine. The method for producing an aromatic amine compound according to any one of <5>.
<7> Any one of <1> to <6>, wherein hydrogen is introduced only into the first catalyst cartridge among the catalyst cartridges, and the hydrogen pressure at that time is 0.1 MPa to 0.3 MPa. The method for producing an aromatic amine compound according to the section.
<8> A catalyst having an inlet for inflowing raw materials at one end, an outlet for discharging reaction products at the other end, and a catalyst in a tubular container provided with an internal temperature control device. It has two cartridges, the inlet of the first catalyst cartridge is connected to the first raw material supply path, the outlet of the first catalyst cartridge is connected to the inlet of the gas-liquid separator, and the gas outlet of the gas-liquid separator. The gas is discharged from the gas, the liquid outlet of the gas-liquid separator is connected to the other inlet of the mixer whose one inlet is connected to the second raw material supply path, and the inlet of the second catalyst cartridge is the mixture. In a continuous flow reactor, which is connected to the outlet of the vessel and the outlet of the second catalyst cartridge is connected to the discharge path of the final reaction product.
The first catalyst cartridge contains a solid catalyst containing a platinum group element for the reaction of hydrogenating phenols to cyclohexanones, and the second catalyst cartridge contains cyclohexanones, ammonia, and a primary amine. And the amines selected from the secondary amines are dehydrated and condensed, and in the presence of a hydrogen trapping agent, a solid catalyst containing a platinum group element for the reaction is dehydrogenated to produce an aromatic amine compound. As one raw material, a mixture of phenols and hydrogen gas is continuously supplied from the first raw material supply path, hydrogen gas is separated in the gas-liquid separator, and ammonia and primary amine are used as the second raw material. And from the final product continuously discharged from the second catalyst cartridge by continuously supplying a mixture of amines selected from secondary amines and a hydrogen trapping agent from the second raw material supply channel. An apparatus for producing an aromatic amine compound, which comprises recovering an aromatic amine compound.
<9> The first raw material supply path is connected to the inlet of each of the supply path for supplying phenols as the first liquid raw material and the supply path for supplying hydrogen gas as the first gas raw material. <8>, wherein the discharge path from which the mixture is discharged has a mixer connected to its outlet, and the discharge path of the mixer is connected to the inlet of the first catalyst cartridge. Equipment.
<10> A back pressure valve is provided between the outlet of the first catalyst cartridge and the inlet of the gas-liquid separator and / or between the outlet of the second catalyst cartridge and the discharge path of the final reaction product. The device according to <8> or <9>.
<11> Between the inlet of the first catalyst cartridge and the first raw material supply path and / or the inlet of the second catalyst cartridge and the outlet of the mixer of the liquid and the second raw material from the gas-liquid separator. The device according to any one of <8> to <10>, wherein a preheating device is provided between the two.

According to the present invention, it is possible to produce an aromatic amine compound from phenols and amines under milder conditions than in the prior art with high selectivity while suppressing by-production of the cyclohexylamine compound.
According to the continuous flow method of the present invention, the produced product is continuously discharged without staying in the reactor, so that the contact time between the catalyst and the product can be minimized. As a result, unwanted actions (excessive reaction and catalyst poisoning) between the catalyst and the product are suppressed, and the yield, selectivity, and catalyst rotation speed of the product can be dramatically improved.
Therefore, even for aromatic amines having functional groups (nitriles, esters, alkenes, indols, amides, amino acid esters, halogen atoms, etc.), which were difficult to produce by the prior art, these can be achieved by using the technique of the present invention. It can be produced from phenols and amines having functional groups with high yield and selectivity.

An explanatory diagram of a reaction mechanism in which an aromatic amine compound is produced from phenols and amines. The schematic diagram of the multi-stage continuous flow reactor used in this invention.

The present invention will be described in detail below.

The present invention uses a multi-stage continuous flow reactor in which a plurality of catalyst cartridges containing a solid catalyst containing a platinum group element such as palladium are connected in series to continuously transfer phenols and hydrogen to the first-stage catalyst cartridge. It is subjected to dehydrogenation and converted to cyclohexanones, which are then converted into ammonia or primary amines or secondary amines (hereinafter referred to as amines) in the flow path, and hydrogen trapping agents. A method of producing the desired aromatic amine compound by mixing it with oxygen or olefins (having 8 or less carbon atoms) and continuously supplying it to the catalyst cartridge in the second stage and subjecting it to dehydration condensation and dehydrogenation. is there.

The multi-stage continuous flow reactor used in the present invention is a reactor in which a plurality of catalyst cartridges are connected in series. Normally, the number of reactors (n) is 2 to 5, preferably 2, but the number of reactors can be arbitrarily determined depending on the reaction conditions. The catalyst cartridge used here is a cylindrical reaction tube filled with a solid catalyst, in which raw materials are continuously supplied from one inlet and products are continuously discharged from the other outlet. is there. Further, the raw material introduction side of the reactor has a preheating pipe and a T-shaped or Y-shaped mixer (mixer) for the purpose of air / liquid mixing or liquid / liquid mixing. On the other hand, on the product discharge side of the reactor, a pressure regulating valve (back pressure valve) for adjusting the inside of the reactor to an arbitrary pressure is arranged. In addition, each catalyst cartridge is provided with a temperature control device (for example, a heater or a cooler with a heat insulating jacket) for adjusting the inside of the reactor to an arbitrary temperature, and further, each catalyst is provided as needed. The temperature of the introduced raw material is regulated in the preheating pipe provided on the raw material introduction side of the cartridge.

In the apparatus for producing an aromatic amine compound of the present invention, in the above-mentioned multi-stage continuous flow reactor, between the reactor that performs hydrogenation in the first stage and the reactor that performs dehydration condensation and dehydrogenation in the second stage, A gas-liquid separator is placed to separate the solution containing unreacted hydrogen and cyclohexanones. This is to prevent hydrogen from being mixed into the reactor in the subsequent stage.

The catalyst used in the present invention is a solid, and a platinum group element such as palladium or a compound thereof is immobilized on a carrier, and is an activated charcoal-supported catalyst, an alumina-supported catalyst, a silica-supported catalyst, a zirconia-supported catalyst, and zeolite. Examples include a supported catalyst. The form of the solid catalyst is cylindrical, extruded, spherical, granular, powdery, honeycomb, or the like, and is not particularly limited as long as it can be filled in a cylindrical reaction tube and does not interfere with the flow of the reaction solution. The catalyst used in the present invention is preferably an activated charcoal-supported palladium catalyst, an activated charcoal-supported palladium hydroxide catalyst, an alumina-supported palladium catalyst, a silica-supported palladium catalyst, a zirconia-supported palladium catalyst, a zeolite-supported palladium catalyst, and the like. An activated charcoal-supported palladium catalyst is more preferable, and an activated charcoal-supported palladium hydroxide catalyst is more preferable for subsequent dehydration condensation and dehydrogenation.

In the present invention, when the above solid catalyst is housed in the catalyst cartridge, the solid catalyst is used by mixing with an arbitrary splitting agent. The splitting agent used is not particularly limited as long as it does not inhibit the progress of the reaction, and examples thereof include celite, diatomaceous earth, silica, alumina, zirconia, zeolite, and activated carbon. The ratio of the splitting agent in the mixture of the solid catalyst and the splitting agent is not particularly specified, but is preferably 0% by mass to 99% by mass, more preferably 50% by mass to 95% by mass, and 80% by mass to 91% by mass. Especially preferable.

(上記式(１)中、Ｒ¹〜Ｒ⁵は、反応の進行を阻害しないものであれば特に制限はないが、例えば、それぞれ互いに独立して、水素原子、アルキル基、シクロアルキル基、アリール基、アルコキシ基、ヒドロキシ基、カルボニル基、またはアルコキシカルボニル基を示す。これらの基はさらに、アルキル基、シクロアルキル基、アリール基、アルコキシ基、ヒドロキシ基、カルボニル基、アルコキシカルボニル基、ハロゲン原子等の置換基を有していてもよい。
Ｒ¹〜Ｒ⁵から選ばれる二か所が結合して環を形成しても良い。) The phenols used in the method according to the invention can be represented by the following general formula (1):

(In the above formula (1), R ^{1 to} R ⁵ are not particularly limited as long as they do not inhibit the progress of the reaction, but for example, they are independent of each other, such as a hydrogen atom, an alkyl group, a cycloalkyl group, and an aryl. A group, an alkoxy group, a hydroxy group, a carbonyl group, or an alkoxycarbonyl group. These groups further indicate an alkyl group, a cycloalkyl group, an aryl group, an alkoxy group, a hydroxy group, a carbonyl group, an alkoxycarbonyl group, a halogen atom and the like. It may have a substituent of.
Two places selected from R ^{1 to} R ⁵ may be combined to form a ring. )

Specific examples of the above-mentioned phenols include phenol, o-cresol, m-cresol, p-cresol, 2,4-dimethylphenol, 2,6-dimethylphenol, 2,3,6-trimethylphenol, 2, 4,6-trimethylphenol, 5-isopropyl-2 methylphenol, 4-isopropylphenol, 4-cyclohexylphenol, 4-phenylphenol, catechol, hydroquinone, catechol monoalkyl ether, hydroquinone monoalkyl ether, 4-hydroxyphenyl Examples thereof include methyl acetate, 1-naphthol, 2-naphthol, bisphenol A and the like.

In the present invention, phenols can be used as a solution containing phenols.
The solvent for the solution of the phenols is not particularly limited as long as it dissolves the phenols well and does not inhibit the progress of the reaction, but for example, aromatic hydrocarbon solvents such as toluene and xylene, hexane, heptane and the like. Aliphatic hydrocarbon solvents, ether solvents such as tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, 4-methyltetrahydropyran, alcohol solvents such as 1-propanol, 2-propanol, ethylene glycol, propylene glycol, acetic acid. Examples thereof include ester solvents such as ethyl and butyl acetate.
Preferred are toluene, xylene, 1,4-dioxane, cyclopentyl methyl ether, 4-methyltetrahydropyran, 2-propanol and butyl acetate. Two or more kinds of these solvents may be mixed.

The concentration of phenols as a substrate is not particularly specified as long as it does not interfere with the distribution to the reactor, but is preferably 0.1% by mass to 100% by mass, more preferably 1% by mass to 50% by mass, and 2% by mass to 20% by mass. Mass% is particularly preferred.

(上記式(１)中、Ｒ⁶およびＲ⁷は、反応の進行を阻害しないものであれば特に制限はないが、例えば、それぞれ互いに独立して、水素原子、アルキル基、シクロアルキル基、アリール基、ヘテロアリール基を示す。これらの置換基はさらに、アルキル基、シクロアルキル基、アルケニル基、アリール基、ヘテロアリール基、アルコキシ基、ヒドロキシ基、カルボニル基、アルコキシカルボニル基、シアノ基、ハロゲン原子等の置換基を有していても良い。
Ｒ⁶およびＲ⁷の二か所が−(ＣＨ₂)_j−Ｘ−(ＣＨ₂)_k−を介して環を形成しても良い。このＸは、ＣＨ₂、ＣＨＲ¹⁰、酸素原子(Ｏ)、硫黄原子(Ｓ)またはＮＲ¹⁰を意味し、Ｒ¹⁰は、水素原子、アルキル基、アリール基を意味し、およびj、kは、１〜５の整数を意味する。) The amines used in the method according to the invention can be represented by the following general formula (2):

(In the above formula (1), R ⁶ and R ⁷ are not particularly limited as long as they do not inhibit the progress of the reaction, but for example, they are independent of each other, such as a hydrogen atom, an alkyl group, a cycloalkyl group, and an aryl. Group, heteroaryl group. These substituents further indicate an alkyl group, a cycloalkyl group, an alkenyl group, an aryl group, a heteroaryl group, an alkoxy group, a hydroxy group, a carbonyl group, an alkoxycarbonyl group, a cyano group, a halogen atom. It may have a substituent such as.
Two places of R ⁶ and R ⁷ may form a ring via _{− (CH 2} ) _j −X− (CH ₂ ) _{k −.} This X means CH ₂ , CHR ¹⁰ , oxygen atom (O), sulfur atom (S) or NR ¹⁰ , R ¹⁰ means hydrogen atom, alkyl group, aryl group, and j, k are It means an integer of 1 to 5. )

The amines are ammonia or primary or secondary amines, and specifically, for example, aniline, o-toluidine, p-toluidine, o-anisidine, p-anisidine, 2,6-dimethylaniline, Aromatic amines such as 2,4,6-trimethylaniline, 2,6-diethylaniline, 4-fluoroaniline, 4-chloroaniline, 2-aminophenol, 3-aminophenol, 4-aminophenol, N-methylaniline, etc. , N-butylamine, n-hexylamine, cyclohexylamine, 2-phenylethylamine, morpholin, aliphatic amines such as piperidi, amino alcohols such as 1-amino-2-propanol, 3-aminopropionitrile, allylamine, etc. Amines having unsaturated bonds, tryptamines, diamines having multiple amino groups in the molecule such as 2- (4-aminophenyl) ethylamine, amino acid esters such as L-phenylalanine methyl ester and L-tyrosine methyl ester. Kind and so on.

In the present invention, amines can be used as a solution containing amines.
The solvent for the solution of the amines is not particularly limited as long as it dissolves the amines well and does not inhibit the progress of the reaction, but for example, aromatic hydrocarbon solvents such as toluene and xylene, hexane, heptane and the like. Hydrocarbon solvents, ether solvents such as tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, 4-methyltetrahydropyran, alcohol solvents such as 1-propanol, 2-propanol, ethylene glycol, propylene glycol, acetic acid Examples thereof include ester solvents such as ethyl and butyl acetate.
Preferred are toluene, xylene, 1,4-dioxane, cyclopentyl methyl ether, 4-methyltetrahydropyran, 2-propanol and butyl acetate. Two or more kinds of these solvents may be mixed.

The concentration of amines as a substrate is not particularly specified as long as it does not interfere with the flow to the reactor, but is preferably 0.1% by mass to 100% by mass, more preferably 1% by mass to 50% by mass, and 2% by mass to 20% by mass. Mass% is particularly preferred.

(上記式(１)中、Ｒ⁸およびＲ⁹は、反応の進行を阻害しないものであれば特に制限はないが、例えば、それぞれ互いに独立して、水素原子、アルキル基、アルケニル基、フェニル基を示す。このアルキル基は、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、s-ブチル、t-ブチル、または炭素数５および６のアルキル基を意味する。
Ｒ⁶およびＲ⁷の二か所が−(ＣＨ₂)_l−を介して環を形成しても良い。このlは、１〜６の整数を意味する。) Examples of the hydrogen scavenger coexisting with amines include oxygen and a mixed gas containing oxygen, and olefins.
Such olefins can be represented by the following general formula (3):

(In the above formula (1), R ⁸ and R ⁹ are not particularly limited as long as they do not inhibit the progress of the reaction, but for example, they are independent of each other and have a hydrogen atom, an alkyl group, an alkenyl group and a phenyl group. This alkyl group means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, or an alkyl group having 5 and 6 carbon atoms.
Two places of R ⁶ and R ⁷ may form a ring via _{− (CH 2} ) _{l −.} This l means an integer of 1 to 6. )

Examples of the olefins include ethylene, propene, 1-butene, 1-pentene, 1-hexene, cyclohexene, cyclooctene, 1-hepten, 1-octene, styrene, butadiene, isoprene, norbornene and the like. It is styrene.
The amount of olefins used is 1 to 5 times the molar amount, preferably 2 times the molar amount, with respect to the amino group contained in the substrate. The olefins may be mixed in advance with the substrate solution, or may be continuously mixed in the flow path.

Regarding the reactor that carries out hydrogenation in the previous stage in the present invention, there is no particular limitation on the reaction temperature, but specifically, it is 60 ° C. to 160 ° C., preferably 120 ° C. to 150 ° C. The pressure continuously supplied to the reactor, that is, the hydrogen pressure, is not particularly specified as long as the reaction proceeds, but is specifically 0.01 MPa to 1 MPa, preferably 0.1 MPa to 0.3. MPa. In addition, "MPa" is a unit of pressure and means megapascal.

Regarding the reactor that carries out dehydration condensation and dehydrogenation in the subsequent stage in the present invention, there is no particular limitation on the reaction temperature, but specifically, it is 60 ° C. to 160 ° C., preferably 120 ° C. to 150 ° C. Further, pressure may be applied to the inside of the reactor by using a back pressure adjusting valve or the like. The range of back pressure is 0 MPa to 1 MPa, preferably 0.1 MPa to 0.5 MPa.

なお、複数種類の原料を用いる場合には、最も使用量の少ない原料のモル数を上式にあてはめて、収率を算出した。
さらに、触媒回転数(TON)は、得られた目的化合物のモル数や触媒カートリッジ内の触媒量をもとに、以下の計算式により算出した。

Next, the present invention will be described in more detail with reference to Examples. The scope of the invention is not limited to the following examples.
In the following Examples and Comparative Examples, the conversion rate and the yield in the synthesis of the aromatic amine compound were calculated by the following formulas based on the weight of the obtained target compound or the result of gas chromatography measurement. ..

When a plurality of types of raw materials were used, the yield was calculated by applying the number of moles of the raw material with the smallest amount to the above formula.
Further, the catalyst rotation speed (TON) was calculated by the following formula based on the number of moles of the obtained target compound and the amount of catalyst in the catalyst cartridge.

Example 1.4 Synthesis of 4-methoxydiphenylamine
Pd / C (93mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium-activated carbon (5%)) and Celite (930mg, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) was mixed well, and the obtained mixture was housed in the first catalyst cartridge (inner diameter 5.0 mm, length 100 mm). Similarly, Pd (OH) ₂ / C (380mg, Pd: 20wt%, 50% water-containing product, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50%) Water-containing product)) and Celite (3.80 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length 100 mm). ).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C., hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then phenol (0.24M) is added at 140 ° C. and 0.2 MPa. The containing toluene solution was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the hydrogenation reaction in the previous stage was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of cyclohexanone from which hydrogen had been removed. This toluene solution containing cyclohexanone and the toluene solution containing p-anisidine (0.20M) and styrene (0.40M) are preheated to 140 ° C and 0.5MPa via a mixing section at a flow velocity of 0.10 ml / min, respectively. (Inner diameter 1.0 mm, length 100 cm) and continuously supplied to the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 22.5 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained crude product was purified by column chromatography to obtain 4.9 g of the desired 4-methoxydiphenylamine (yield 92%).

Comparative example 1.
A reaction similar to that of Example 1 was carried out using a batch reactor (a pressure-resistant glass test tube that can be sealed) instead of the multi-stage continuous flow reactor.
Put a stirrer in a pressure-resistant glass test tube (outer diameter 18 mm, inner volume 27 mL) that can be sealed, and use Pd / C (52 mg, Pd: 5 wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst, trade name: palladium-activity. Carbon (5%)) is added, and phenol (23 mg, 0.24 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and p-anisidine (25 mg, 0.20 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and hydrogen capture are added as substrates. Styrene (42 mg, 0.40 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added as an agent, and toluene (2 mL, manufactured by Kishida Chemical Co., Ltd.) was added as a solvent. After the inside of the container was replaced with hydrogen and sealed, the mixture was stirred at 140 ° C. for 6 hours. Then, n-dodecane (17 mg) was added as an internal standard, and gas chromatography measurement was performed. As a result, the conversion rate of p-anisidine was 28%, and the yield of 4-methoxydiphenylamine was 8%.

Comparative example 2.
The reaction was carried out by a batch reactor in the same manner as in Comparative Example 1 except that styrene, which is a hydrogen scavenger, was not added. As a result, 4-methoxydiphenylamine (yield 15%) and N-cyclohexyl-4-methoxyaniline (yield 33%) were obtained.

Comparative example 3.
An experiment was conducted in which a batch reactor (a pressure-resistant glass test tube that can be sealed) was used instead of the multi-stage continuous flow reactor, and the reaction was carried out by sequentially adding a catalyst, substrate, hydrogen, hydrogen trapping agent, etc. ..
Put a stirrer in a pressure-resistant glass test tube (outer diameter 18 mm, inner volume 27 mL) that can be sealed, and use Pd / C (52 mg, Pd: 5 wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst, trade name: palladium-activity. Carbon (5%)) was added, phenol (23 mg, 0.24 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was further added as a substrate, and toluene (1.0 mL, manufactured by Kishida Chemical Industries, Ltd.) was added as a solvent. After replacing the inside of the container with hydrogen and sealing the container, the mixture was stirred at 140 ° C. for 3 hours. After that, after replacing the hydrogen in the container with argon, p-anisidine (25 mg, 0.20 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was used as a substrate, and styrene (42 mg, 0.40 mmol, Fujifilm Wako Pure Chemical Industries, Ltd.) was used as a hydrogen trapping agent. Toluene (2 mL, manufactured by Kishida Chemical Industries, Ltd.) was added as a solvent. The container was sealed again and then stirred at 140 ° C. for 3 hours. Then, n-dodecane (17 mg) was added as an internal standard, and gas chromatography measurement was performed. As a result, the conversion rate of p-anisidine was 51%, the yield of 4-methoxydiphenylamine was 15%, and the yield of N-cyclohexyl-4-methoxyaniline was 1%.

Example 2.4 168 hours continuous synthesis of 4-methoxydiphenylamine
Pd / C (100mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: palladium-activated carbon (5%)) and Celite (1.00g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: Celite No.545) was mixed well, and the obtained mixture was housed in the first catalyst cartridge (inner diameter 5.0 mm, length 100 mm). Similarly, Pd (OH) ₂ / C (855mg, Pd: 20wt%, 50% water-containing product, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50%) Water-containing product)) and Celite (8.55 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length 200 mm). ).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C., hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then phenol (0.24M) is added at 140 ° C. and 0.2 MPa. The containing toluene solution was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of cyclohexanone from which hydrogen had been removed. This toluene solution containing cyclohexanone and the toluene solution containing p-anisidine (0.20M) and styrene (0.40M) are preheated to 140 ° C and 0.5MPa via a mixing section at a flow velocity of 0.10 ml / min, respectively. (Inner diameter 1.0 mm, length 100 cm) and continuously supplied to the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 168 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained white solid was sufficiently dried under reduced pressure to obtain 38.6 g of the desired 4-methoxydiphenylamine (yield 96%).
As a result of calculating the total number of revolutions of the palladium catalyst contained in each catalyst cartridge in the continuous synthesis for 168 hours, the number of revolutions of Pd / C used for the hydrogenation reaction in the first stage was 5149, and the dehydration condensation and dehydrogenation in the latter stage. The rotation speed of _{Pd (OH) 2} / C used in the chemical reaction was 241.

Example 3. Synthesis of N- (4-Methoxyphenyl) -3-methylaniline
Pd / C (106mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: palladium-activated carbon (5%)) and Celite (1.06mg, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: Celite No.545) was mixed well, and the obtained mixture was housed in the first catalyst cartridge (inner diameter 5.0 mm, length 100 mm). Similarly, Pd (OH) ₂ / C (407mg, Pd: 20wt%, 50% hydrous, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50%) Water-containing product)) and Celite (4.07 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length 100 mm). ).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C, hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then m-cresol (0.24M) at 140 ° C and 0.2 MPa. ) Was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of 3-methylcyclohexanone from which hydrogen had been removed. The toluene solution containing 3-methylcyclohexanone and the toluene solution containing p-anisidine (0.20M) and styrene (0.40M) were set at 140 ° C. and 0.5 MPa at a flow rate of 0.10 ml / min, respectively, via a mixing section. It was continuously supplied to the preheating pipe (inner diameter 1.0 mm, length 100 cm) and the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 13.5 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained crude product was purified by column chromatography to obtain 3.3 g of the desired N- (4-methoxyphenyl) -3-methylaniline (yield 96%).

Example 4.3 Synthesis of 3- (Phenylamino) Propionitrile
Pd / C (98.9mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: palladium-activated carbon (5%)) and Celite (989mg, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: Celite No.545) was well kneaded and filled into the first catalyst cartridge, a SUS cylindrical reactor with a diameter of 5φ x 100 mm. Similarly, Pd (OH) ₂ / C (386mg, Pd: 20wt%, 50% hydrous, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50%) Water-containing product)) and Celite (3.86 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length 100 mm). ).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C., hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then phenol (0.24M) is added at 140 ° C. and 0.2 MPa. The containing toluene solution was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of cyclohexanone from which hydrogen had been removed. The toluene solution containing cyclohexanone and the toluene solution containing 3-aminopropanenitrile (0.20M) and styrene (0.40M) were set at 140 ° C. and 0.5 MPa at a flow rate of 0.10 ml / min, respectively, via a mixing section. It was continuously supplied to the preheating pipe (inner diameter 1.0 mm, length 100 cm) and the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 13.0 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained crude product was purified by column chromatography to obtain 2.2 g of the desired 3- (phenylamino) propanenitrile (yield 96%).

Comparative example 4.
The reaction was carried out using a batch reactor in the same manner as in Comparative Example 1 except that 3-aminopropanenitrile (14 mg, 0.20 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of p-anisidine as amines. As a result, the yield of 3- (phenylamino) propanenitrile was 0%.

Comparative example 5.
According to the experimental section described in Non-Patent Document 1 (Li, C.-J. Et al. Angew. Chem., Int. Ed. 2015, 54, 14487-14491.), A batch reactor (pressure-resistant glass that can be sealed) The reaction between phenol and 3-aminopropanenitrile was carried out using a test tube).
Put a stirrer in a pressure-resistant glass test tube (outer diameter 18 mm, inner volume 27 mL) that can be sealed, and use Pd / C (45 mg, Pd: 5 wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as a catalyst, trade name: palladium-activity. Carbon (5%)) was added, and sodium formate (21 mg, 0.30 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added, and then the inside of the container was replaced with argon gas. Next, phenol (19 mg, 0.20 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and 3-aminopropanenitrile (20 mg, 0.28 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) were added as substrates, and toluene (1 mL, xida) was added as a solvent. (Made by Chemical Industries, Ltd.) was added. Finally, trifluoroacetic acid (11 mg, 0.10 mmol, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added as a co-catalyst to seal the container, and then the mixture was stirred at 140 ° C. for 12 hours. Then, n-dodecane (17 mg) was added as an internal standard, and gas chromatography measurement was performed. As a result, the yield of 3- (phenylamino) propanenitrile was 0%.

Example 5.1-Synthesis of 1- (Phenylamino) Propan-2-ol
Pd / C (98.9mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: palladium-activated carbon (5%)) and Celite (989mg, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: Celite No.545) was well kneaded and filled into the first catalyst cartridge, a SUS cylindrical reactor with a diameter of 5φ x 100 mm. Similarly, Pd (OH) ₂ / C (387 mg, Pd: 20 wt%, 50% hydrous, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50) % Water-containing product)) and Celite (3.87 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length). It was housed in 100 mm).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C., hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then phenol (0.24M) is added at 140 ° C. and 0.2 MPa. The containing toluene solution was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of cyclohexanone from which hydrogen had been removed. The toluene solution containing cyclohexanone and the toluene solution containing 3-aminopropane-2-ol (0.20M) and styrene (0.40M) were mixed at a flow rate of 0.10 ml / min to 140 ° C. and 0.5 MPa, respectively. It was continuously supplied to the set preheating pipe (inner diameter 1.0 mm, length 100 cm) and the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 9.5 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained crude product was purified by column chromatography to obtain 1.44 g of the desired 1- (phenylamino) propan-2-ol (yield 83%).

Example 6. Synthesis of N- (2- (1H-indole-3-yl) ethyl) aniline (N-phenyltryptamine)
Pd / C (108mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: palladium-activated carbon (5%)) and Celite (1.08mg, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: Celite No.545) was well kneaded and filled into the first catalyst cartridge, a SUS cylindrical reactor with a diameter of 5φ x 100 mm. Similarly, Pd (OH) ₂ / C (382mg, Pd: 20wt%, 50% hydrous, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50%) Water-containing product)) and Celite (3.82 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length 100 mm). ).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C., hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then phenol (0.24M) is added at 140 ° C. and 0.2 MPa. The containing toluene solution was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of cyclohexanone from which hydrogen had been removed. This toluene solution containing cyclohexanone and the toluene solution containing tryptamine (0.20M) and styrene (0.40M) are preheated pipes (inner diameter) set to 140 ° C and 0.5MPa via a mixing section at a flow velocity of 0.10 ml / min, respectively. 1.0 mm, length 100 cm) and continuously supplied to the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 12.5 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained crude product was purified by column chromatography to obtain 3.1 g of the desired N-phenyltryptamine (yield 88%).

Comparative example 6.
The reaction was carried out using a batch reactor in the same manner as in Comparative Example 3 except that tryptamine (32 mg, 0.20 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.) was used instead of p-anisidine as amines. As a result, the yield of N-phenyltryptamine was 0%.

Example 7. Synthesis of N- (Phenyl) -L-Phenylalanine Methyl Ester
Pd / C (108mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: palladium-activated carbon (5%)) and Celite (1.08mg, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: Celite No.545) was well kneaded and filled into the first catalyst cartridge, a SUS cylindrical reactor with a diameter of 5φ x 100 mm. Similarly, Pd (OH) ₂ / C (385mg, Pd: 20wt%, 50% water-containing product, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50%) Water-containing product)) and Celite (3.85 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length 100 mm). ).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C., hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then phenol (0.24M) is added at 140 ° C. and 0.2 MPa. The containing toluene solution was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of cyclohexanone from which hydrogen had been removed. The toluene solution containing cyclohexanone and the toluene solution containing L-phenylalanine methyl ester (0.20M) and styrene (0.40M) were set at 140 ° C. and 0.5 MPa at a flow rate of 0.10 ml / min, respectively, via a mixing section. It was continuously supplied to the preheating pipe (inner diameter 1.0 mm, length 100 cm) and the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 11.0 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained crude product was purified by column chromatography to obtain 3.37 g of the desired N- (phenyl) -L-phenylalanine methyl ester (yield> 99%). The optical purity of N- (phenyl) -L-phenylalanine methyl ester was 98% ee.

Comparative example 7.
Similar to Comparative Example 3, batch formula except that L-phenylalanine methyl ester (36 mg, 0.20 mmol, prepared from L-phenylalanine methyl ester hydrochloride manufactured by Tokyo Kasei Kogyo Co., Ltd.) is used instead of p-anisidine as amines. The reaction was carried out using a reactor. As a result, the yield of N- (phenyl) -L-phenylalanine methyl ester was 67%, and its optical purity was 66% ee.

Example 8. Synthesis of N-phenylmorpholine
Pd / C (108mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: palladium-activated carbon (5%)) and Celite (1.08mg, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., product name: Celite No.545) was well kneaded and filled into the first catalyst cartridge, a SUS cylindrical reactor with a diameter of 5φ x 100 mm. Similarly, Pd (OH) ₂ / C (750mg, Pd: 20wt%, 50% water-containing product, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: palladium hydroxide-activated carbon (Pd 20%) (about 50%) Water-containing product)) and Celite (7.50 g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., trade name: Celite No.545) are mixed well, and the obtained mixture is used as the second catalyst cartridge (inner diameter 10.0 mm, length 200 mm). ).
The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. The first catalyst cartridge is heated to 140 ° C., hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then phenol (0.24M) is added at 140 ° C. and 0.2 MPa. The containing toluene solution was supplied at a flow rate of 0.10 ml / min, and hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction was stabilized, a reaction solution containing unreacted hydrogen gas was supplied to a gas-liquid separator to obtain a toluene solution of cyclohexanone from which hydrogen had been removed. This toluene solution containing cyclohexanone and the toluene solution containing morpholine (0.20M) and styrene (0.40M) are preheated pipes (inner diameter) set to 140 ° C and 0.5MPa via a mixing section at a flow velocity of 0.10 ml / min, respectively. 1.0 mm, length 100 cm) and continuously supplied to the second catalyst cartridge. The reaction solution was collected from the outlet of the pressure control valve every 30 minutes and analyzed by gas chromatography. After confirming that the series of reactions had stabilized from the analysis results, the reaction solution was collected from the outlet of the reactor for 10.0 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. The obtained crude product was purified by column chromatography to obtain the desired N-phenylmorpholine (yield 76%).

The production method according to the present invention is suitable for producing various aromatic amine compounds, particularly aromatic amine compounds having a polyfunctional group, and is particularly used in fields such as pharmaceuticals and material chemistry fields in which such compounds are used. It is expected to be done.

In FIG. 1, the following reference numerals mean:
1: Phenols 2: Cyclohexanones 3: Amines (ammonia, primary amines, secondary amines)
4: Imine intermediate (when 3 is ammonia and primary amine)
4': Iminium intermediate (when 3 is a secondary amine)
5: Aromatic amine compound 6: Cyclohexylamine compound A: Hydrogenation B: Dehydration condensation
C: Dehydrogenation D: Hydrogenation (side reaction)
In FIG. 2, the symbols shown below mean:
1: First liquid raw material tank (solution containing phenols)
2: Liquid feed pump 3: Mixer of first liquid raw material and first gas raw material 4: Gas flow rate adjusting device 5: Preheating device 6: First catalyst cartridge 7: Temperature controlling device 8: Back pressure valve 9: Air Liquid separator 10: Mixer of liquid from gas-liquid separator 11: Liquid feed pump 12: Second raw material tank (solution containing amines and hydrogen trapping agent)
13: Preheating device 14: Second catalyst cartridge 15: Temperature control device 16: Back pressure valve 17: Final product recovery tank

Claims (11)

Phenols and hydrogen were introduced into the first catalyst cartridge containing a solid catalyst containing a platinum group element to continuously hydrogenate the cyclohexanones, and the obtained cyclohexanones were subsequently converted to ammonia and a primary amine. And, together with amines and hydrogen trapping agents selected from secondary amines, it is introduced into a second catalyst cartridge containing a solid catalyst containing a platinum group element to continuously produce an aromatic amine compound. A characteristic method for producing an aromatic amine compound. The solid catalysts containing platinum group elements contained in the first and second catalyst cartridges are independently activated carbon-supported palladium catalyst, activated carbon-supported palladium hydroxide catalyst, alumina-supported palladium catalyst, silica-supported palladium catalyst, and zirconia. The method for producing an aromatic amine compound according to claim 1, wherein the catalyst is one type or two or more types selected from the group consisting of a supported palladium catalyst, a zeolite-supported palladium catalyst, and palladium black. The solid catalyst containing a platinum group element contained in the first and second catalyst cartridges is independently selected from the group consisting of Celite, diatomaceous earth, silica, alumina, titania, and zirconia. The method for producing an aromatic amine compound according to claim 1 or 2, wherein the mixture is contained in the first and second catalyst cartridges in the state of a mixture with the above oxides. The primary amine or the secondary amine is selected from the group consisting of an aliphatic amine, an aromatic amine, an alicyclic amine, and a heteroaromatic amine, according to claims 1 to 3. The method for producing an aromatic amine compound according to any one of the above items. The hydrogen scavenger to be introduced into the second catalyst cartridge is selected from the group consisting of oxygen or a primary olefin having 8 or less carbon atoms or a secondary olefin. The method for producing an aromatic amine compound according to any one of 4 to 4. Any of claims 1 to 5, wherein the hydrogen scavenger introduced into the second catalyst cartridge has a molar amount of 1.0 to 4.0 times that of ammonia, a primary amine or a secondary amine. The method for producing an aromatic amine compound according to item 1. The fragrance according to any one of claims 1 to 6, wherein hydrogen is introduced only into the first catalyst cartridge among the catalyst cartridges, and the hydrogen pressure at that time is 0.1 MPa to 0.3 MPa. A method for producing a group amine compound. A catalyst cartridge having an inlet for inflowing raw materials at one end, an outlet for discharging reaction products at the other end, and a catalyst cartridge in which a catalyst is housed in a tubular container provided with an internal temperature control device. The inlet of the first catalyst cartridge is connected to the first raw material supply path, the outlet of the first catalyst cartridge is connected to the inlet of the gas-liquid separator, and the gas is discharged from the gas outlet of the gas-liquid separator. The liquid outlet of the discharged gas-liquid separator is connected to the other inlet of the mixer, one inlet of which is connected to the second raw material supply path, and the inlet of the second catalyst cartridge is the outlet of the mixer. In a continuous flow reactor, the outlet of the second catalyst cartridge is connected to the discharge path of the final reaction product.
The first catalyst cartridge contains a solid catalyst containing a platinum group element for the reaction of hydrogenating phenols to cyclohexanones, and the second catalyst cartridge contains cyclohexanones, ammonia, and a primary amine. And the amines selected from the secondary amines are dehydrated and condensed, and in the presence of a hydrogen trapping agent, a solid catalyst containing a platinum group element for the reaction is dehydrogenated to produce an aromatic amine compound. As one raw material, a mixture of phenols and hydrogen gas is continuously supplied from the first raw material supply path, hydrogen gas is separated in the gas-liquid separator, and ammonia and primary amine are used as the second raw material. And from the final product continuously discharged from the second catalyst cartridge by continuously supplying a mixture of amines selected from secondary amines and a hydrogen trapping agent from the second raw material supply channel. An apparatus for producing an aromatic amine compound, which comprises recovering an aromatic amine compound. The first raw material supply channel is connected to the inlet of each of the supply channel for supplying phenols which is the first liquid raw material and the supply channel for supplying hydrogen gas which is the first gas raw material, and a mixture thereof is discharged. The apparatus according to claim 8, wherein the discharge path to be operated has a mixer connected to its outlet, and the discharge path of the mixer is connected to the inlet of the first catalyst cartridge. A back pressure valve is provided between the outlet of the first catalyst cartridge and the inlet of the gas-liquid separator and / or between the outlet of the second catalyst cartridge and the discharge path of the final reaction product. The device according to claim 8 or 9. Between the inlet of the first catalyst cartridge and the first feedstock supply path and / or between the inlet of the second catalyst cartridge and the outlet of the liquid / second feedstock mixer from the gas-liquid separator. The device according to any one of claims 8 to 10, further comprising a preheating device.

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