JP2017171613A - Method for producing phenylaminopyridine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a technique which makes it possible to produce a phenylaminopyridine compound economically and efficiently under a milder condition than before, with the reduced number of steps, and by convenient operation.SOLUTION: A method for producing a phenylaminopyridine compound includes the step in which an aniline compound and a halogenated pyridine compound react with liquid comprising alkali metal in a reaction solvent to prepare a phenylaminopyridine compound.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a method for producing a phenylaminopyridine compound.

  Phenylaminopyridine compounds are used as raw materials and intermediates for pharmaceuticals, animal drugs, agricultural chemicals and the like. Specifically, it is known to be useful as a raw material or intermediate for anticancer agents, anti-inflammatory agents, agricultural fungicides, insecticides and the like.

  Conventionally, as a method for producing a phenylaminopyridine compound, for example, as described in Patent Document 1, a pyridine-N-oxide compound and an aniline compound are mixed with an alkali metal water in the presence of an alkyl- or aryl-sulfonyl chloride. A method of obtaining a phenylaminopyridine compound by reacting with a basic catalyst such as an oxide, followed by acidic catalytic hydrolysis, a 2-anilinopyridine compound and a halogen under the action of a base such as an alkali metal hydride or an alkali metal amide. A method of obtaining a phenylaminopyridine compound by reacting a halogenated benzene compound, and a method of obtaining a phenylaminopyridine compound by reacting a halogenated pyridine compound and an aniline compound at a high temperature of 150 to 170 ° C. (non-patent document 1) (See Patent Document 1).

Japanese Patent Application Laid-Open No. 6-340631

D. M. Bieley et al., J. Med. Chem., 14 (5), p439-443

  However, the conventional method for producing a phenylaminopyridine compound starting from a pyridine-N-oxide compound and an aniline compound is a reaction with an acidic catalyst after reacting with a basic catalyst. Therefore, there is a problem that a complicated process is required, and the number of processes increases and the process becomes complicated. Methods using alkyl metal hydrides, alkyl metal amides, and the like also have a problem of low reaction efficiency due to low solubility in organic solvents. Furthermore, the method of reacting a halogenated pyridine and an aniline compound at a high temperature requires a large amount of heat energy and requires an apparatus for high-temperature treatment, resulting in an increase in cost.

  Therefore, it is desired to construct a technique capable of producing a phenylaminopyridine compound economically and efficiently by a simple operation with a small number of steps under milder conditions than before.

  As a result of repeated studies to solve the above problems, the present inventors have reacted an aniline compound and a halogenated pyridine compound with a liquid containing an alkali metal such as a dispersion in which an alkali metal is dispersed in a dispersion solvent. Thus, it was found that a phenylaminopyridine compound can be produced stably and efficiently. Such a method for producing a phenylaminopyridine compound is economically advantageous because it does not require expensive reagents and equipment, and it is simple and quick in a short time with a small number of steps without requiring complicated chemical methods. Compounds can be produced. Based on these findings, the present inventors have completed the present invention.

（一般式（I）中、Ｒ^aは−ＯＲ¹又は−Ｒ²であってＲ¹及びＲ²はそれぞれ独立的に炭化水素基であり、ｍは０〜５の整数である）

（前記一般式（II）中、Ｘはハロゲン原子であり、Ｒ^bは−ＯＲ³、−Ｒ⁴、又はハロゲン原子あってＲ³及びＲ⁴はそれぞれ独立的に炭化水素基であり、ｎは０〜４の整数である）

（前記一般式（III）中、Ｒ^aは−ＯＲ¹又は−Ｒ²であってＲ¹及びＲ²はそれぞれ独立的に炭化水素基であり、ｍは０〜５の整数であり、ここで、（Ｒ^a）_mは前記一般式（I）における（Ｒ^a）_mと同一であり、Ｒ^cは−ＯＲ⁵、−Ｒ⁶又はハロゲン原子であってＲ⁵及びＲ⁶はそれぞれ独立的に炭化水素基であり、ｑは０〜４の整数であり、ここで、Ｒ^cは−ＯＲ⁵又は−Ｒ⁶である場合には、（Ｒ^c）_qは前記一般式（II）における（Ｒ^b）_nと同一であり、Ｒ^cはハロゲン原子である場合には、前記一般式（II）における（Ｒ^b）_nのＲ^bと同一であるが、ｑはｎと同じかｎよりも小さな整数である） That is, this invention relates to the manufacturing method of a phenylamino pyridine compound, The characteristic structure contains the aniline compound shown to General formula (I), and the halogenated pyridine compound shown to General formula (II) an alkali metal. It has the process of obtaining the phenylaminopyridine compound shown in general formula (III) by making it react with a liquid in a reaction solvent.

(In the general formula (I), R ^a is —OR ¹ or —R ² , R ¹ and R ² are each independently a hydrocarbon group, and m is an integer of 0 to 5)

(In the general formula (II), X is a halogen atom, R ^b is —OR ³ , —R ⁴ , or a halogen atom, and R ³ and R ⁴ are each independently a hydrocarbon group, and n is (It is an integer from 0 to 4)

(In the general formula (III), R ^a is —OR ¹ or —R ² , R ¹ and R ² are each independently a hydrocarbon group, and m is an integer of 0 to 5, where , (R ^a) _m is the same as (R ^a) _m in the general formula (I), R ^c is -OR ^5, a -R ⁶ or a halogen atom and R ⁵ and R ⁶ are each independently It is a hydrocarbon group, q is an integer of 0 to 4, and when R ^c is —OR ⁵ or —R ⁶ , (R ^c ) _q is (R) in the general formula (II) ^b ) When it is the same as _n and R ^c is a halogen atom, it is the same as R ^b of (R ^b ) _n in the general formula (II), but q is the same as or smaller than n Is an integer)

  According to this configuration, since a liquid containing an alkali metal that is easy to handle is used, phenylaminopyridine can be easily and quickly performed in a small number of steps without requiring a complicated chemical method under mild conditions. The compound can be produced and is very advantageous economically and industrially. Moreover, phenylaminopyridine can be produced stably and efficiently. Here, an alkali metal typified by sodium is a technology excellent in sustainability because it is very widely distributed on the earth.

  Another characteristic configuration is that the m is 0, 1, or 3.

  According to the present configuration, 2-phenylaminopyridine, 2-[(4-methoxyphenyl) amino] pyridine, 2-phenylaminopyridine, starting from an aniline compound having no substituent or having one or three substituents. A method for stably and efficiently producing a phenylaminopyridine compound having no substituent in the phenyl group or having one or three substituents, such as [(3,4,5-trimethoxyphenyl) amino] pyridine Can provide. Accordingly, the phenylaminopyridine compound can be advantageously provided economically and industrially in a simple and short time with a small number of steps without requiring a complicated chemical method under mild conditions.

  Another characteristic configuration is that n is 0.

  According to this configuration, a halogenated pyridine compound having no substituent except for substitution with a halogen atom at the 2-position is used as a starting material, 2-phenylaminopyridine, 2-[(4-methoxyphenyl) amino] A method for stably and efficiently producing a phenylaminopyridine compound having no substituent on the pyridyl group, such as pyridine and 2-[(3,4,5-trimethoxyphenyl) amino] pyridine, can be provided. Accordingly, the phenylaminopyridine compound can be advantageously provided economically and industrially in a simple and short time with a small number of steps without requiring a complicated chemical method under mild conditions.

  Another feature is that the reaction solvent is tetrahydrofuran.

  According to this configuration, there is provided a more economically advantageous method for producing phenylaminopyridine by using tetrahydrofuran (hereinafter sometimes referred to as “THF”) which is an inexpensive and widely used solvent in the technical field. be able to. In addition, since THF has excellent solubility, it is contained in liquids containing alkali metals such as aniline compounds that are starting materials, halogenated pyridine compounds, and dispersions in which alkali metals are dispersed in a dispersion solvent. The efficiency of the reaction can be further increased by increasing the contact efficiency with the alkali metal.

It is a figure which shows the reaction mechanism type | formula of the manufacturing method of the phenylamino pyridine compound concerning this embodiment. It is a figure which summarizes the examination conditions and examination result of the Example which examined the manufacturing method of the phenylaminopyridine compound which concerns on this embodiment.

  Hereinafter, the manufacturing method of the phenylamino pyridine compound which concerns on embodiment of this invention is demonstrated in detail. However, the present invention is not limited to the embodiments described below.

（一般式（I）中、Ｒ^aは−ＯＲ¹又は−Ｒ²であってＲ¹及びＲ²はそれぞれ独立的に炭化水素基であり、ｍは０〜５の整数である）

（前記一般式（II）中、Ｘはハロゲン原子であり、Ｒ^bは−ＯＲ³、−Ｒ⁴、又はハロゲン原子あってＲ³及びＲ⁴はそれぞれ独立的に炭化水素基であり、ｎは０〜４の整数である）

（前記一般式（III）中、Ｒ^aは−ＯＲ¹又は−Ｒ²であってＲ¹及びＲ²はそれぞれ独立的に炭化水素基であり、ｍは０〜５の整数であり、ここで、（Ｒ^a）_mは前記一般式（I）における（Ｒ^a）_mと同一であり、Ｒ^cは−ＯＲ⁵、−Ｒ⁶又はハロゲン原子であってＲ⁵及びＲ⁶はそれぞれ独立的に炭化水素基であり、ｑは０〜４の整数であり、ここで、Ｒ^cは−ＯＲ⁵又は−Ｒ⁶である場合には、（Ｒ^c）_qは前記一般式（II）における（Ｒ^b）_nと同一であり、Ｒ^cはハロゲン原子である場合には、前記一般式（II）における（Ｒ^b）_nのＲ^bと同一であるが、ｑはｎと同じかｎよりも小さな整数である） The method for producing a phenylaminopyridine compound according to the present embodiment uses an aniline compound represented by the following general formula (I) and a halogenated pyridine compound represented by the following general formula (II) as a starting material, and the starting material is converted to an alkali metal. A phenylaminopyridine compound represented by the general formula (III) is produced by reacting with a liquid containing the compound in a reaction solvent.

(In the general formula (I), R ^a is —OR ¹ or —R ² , R ¹ and R ² are each independently a hydrocarbon group, and m is an integer of 0 to 5)

(In the general formula (II), X is a halogen atom, R ^b is —OR ³ , —R ⁴ , or a halogen atom, and R ³ and R ⁴ are each independently a hydrocarbon group, and n is (It is an integer from 0 to 4)

(In the general formula (III), R ^a is —OR ¹ or —R ² , R ¹ and R ² are each independently a hydrocarbon group, and m is an integer of 0 to 5, where , (R ^a) _m is the same as (R ^a) _m in the general formula (I), R ^c is -OR ^5, a -R ⁶ or a halogen atom and R ⁵ and R ⁶ are each independently It is a hydrocarbon group, q is an integer of 0 to 4, and when R ^c is —OR ⁵ or —R ⁶ , (R ^c ) _q is (R) in the general formula (II) ^b ) When it is the same as _n and R ^c is a halogen atom, it is the same as R ^b of (R ^b ) _n in the general formula (II), but q is the same as or smaller than n Is an integer)

  The aniline compound represented by the general formula (I), which is one of the starting materials of the method for producing the phenylaminopyridine compound according to this embodiment, is an aniline which may or may not have a substituent. The presence / absence of a substituent and the position, number and type of the substituent in the case of having a substituent are appropriately set according to the substituent on the phenyl group of the phenylaminopyridine compound represented by the general formula (III) of the target compound. Corresponds to a substituent on the phenyl group.

When the aniline compound represented by the general formula (I) has a substituent, a hydrogen atom at any position other than the position substituted with the amino group on the benzene ring is substituted with ^Ra .

The position and number of ^Ra are appropriately set according to the phenylaminopyridine compound represented by the general formula (III) of the target compound, but the position substituted with the amino group on the benzene ring constituting the aniline is not limited. Assuming the 1-position, any hydrogen atom at positions 2, 3, 4, 5, 6 on the benzene ring may be substituted. Therefore, the hydrogen atoms at all five positions may be substituted, or a part, that is, the hydrogen atoms at one to four positions may be substituted. When R ^a is present at ^a plurality of positions, each may be the same or different.

The type of ^Ra is also appropriately set according to the phenylaminopyridine compound represented by the general formula (III) of the target compound, and is specifically —OR ¹ or —R ² , where , R ¹ and R ² are each independently a hydrocarbon group.

The hydrocarbon group in —OR ¹ or —R ² is not particularly limited as long as the number of carbon atoms is preferably 1 to 5. Accordingly, the hydrocarbon group may be either a linear type, a branched type, or a cyclic type, and may be a saturated type or an unsaturated type. Preferably, the hydrocarbon group is a saturated straight-chain or branched alkyl group, specifically, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, s- Examples include butyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, t-pentyl group, s-pentyl group, 2-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group and the like.

—OR ¹ is preferably an alkoxy group, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, or a pentoxy group. , Isopentoxy group, neopentoxy group, t-pentoxy group, s-pentoxy group, 2-methylbutoxy group, 1-ethylpropoxy group, 2-ethylpropoxy group and the like. —R ² is preferably an alkyl group, and specific alkyl groups are as described above.

Specific examples of the aniline compound represented by the general formula (I) include: (R ^a ) m = 0 _m , that is, aniline not substituted with R ^a , and (R ^a ) _{m where} R ^a is a methoxy group and m 4-methoxyaniline in which R = 1, 3,4,5-trimethoxyaniline in which R ^a is a methoxy group and m = 3 in (R ^a ) _m , and the like.

  As the aniline compound represented by the general formula (I), a commercially available product may be used, or a product produced by a method known in the technical field may be used.

  In the halogenated pyridine compound represented by the general formula (II), which is another starting material of the method for producing a phenylaminopyridine compound according to this embodiment, the hydrogen atom at the 2-position on the pyridine ring is substituted with a halogen atom. . The halogen atom is selected from a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I).

In addition to the substitution with the halogen atom, the halogenated pyridine compound represented by the general formula (II) may or may not have a substituent on the pyridine ring. In the case of having a substituent, the hydrogen atom at any position other than the position substituted with the nitrogen atom which is a hetero atom on the pyridine ring and the halogen atom is substituted with R ^b .

The position and number of R ^b are appropriately set according to the phenylaminopyridine compound represented by the general formula (III) of the target compound, but the position of the nitrogen atom which is the hetero atom of the pyridine ring is the 1st position, halogen If the position substituted with an atom is the 2nd position, any hydrogen atom at the 3, 4, 5 and 6 position on the pyridine ring may be substituted. Therefore, the hydrogen atoms at all four positions may be substituted, or a part, that is, the hydrogen atoms at one to three positions may be substituted. When ^Rb is present at a plurality of positions, each may be the same or different.

The type of R ^b is also appropriately set according to the phenylaminopyridine compound represented by the general formula (III) of the target compound. Specifically, it is —OR ³ , —R ⁴ , or a halogen atom. Here, R ³ and R ⁴ are each independently a hydrocarbon group. The halogen atom is selected from a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), and an iodine atom (I).

The hydrocarbon group in —OR ³ or —R ⁴ is not particularly limited as long as the number of carbon atoms is preferably 1 to 5. Accordingly, the hydrocarbon group may be either a linear type, a branched type, or a cyclic type, and may be a saturated type or an unsaturated type. Preferably, the hydrocarbon group is a saturated straight-chain or branched alkyl group, specifically, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, s- Examples include butyl group, t-butyl group, n-pentyl group, isopentyl group, neopentyl group, t-pentyl group, s-pentyl group, 2-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group and the like.

—OR ³ is preferably an alkoxy group, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, or a pentoxy group. , Isopentoxy group, neopentoxy group, t-pentoxy group, s-pentoxy group, 2-methylbutoxy group, 1-ethylpropoxy group, 2-ethylpropoxy group and the like. —R ⁴ is preferably an alkyl group, and specific alkyl groups are as described above.

When R ^b is -OR ³ or -R ^4, the position of R ^b, number, and type, corresponding to the R ^c on the pyridyl group phenylamino pyridine compound represented by the general formula of the object compound (III) To do. When R ^b is a halogen atom, the types of R ^b corresponds with the type of R ^c phenylamino pyridine compound represented by the general formula of the object compound (III), but in the position and number of R ^b, object Although it may completely correspond to the position and number of R ^c of the phenylaminopyridine compound represented by the general formula (III) of the compound, all or a part of R ^b is dropped during the reaction process, and R ^c It may not be present on the pyridyl group of the phenylaminopyridine compound represented by the general formula (III).

Specific examples of the halogenated pyridine compound represented by the general formula (II) include 2-chloropyridine in which the halogen atom is a chlorine atom and (R ^b ) _n is n = 0, that is, R ^b is not substituted. Is mentioned.

  As the halogenated pyridine compound represented by the general formula (II), a commercially available one may be used, or one produced by a method known in the technical field may be used.

  The target compound obtained by the method for producing a phenylaminopyridine compound according to this embodiment is a phenylaminopyridine compound represented by the general formula (III). The phenylaminopyridine compound represented by the general formula (III) is a secondary amine in which a phenyl group and a pyridyl group are bonded via an amino group (—NH—).

  The phenyl group may or may not have a substituent. Therefore, in the hydrogen atom on the benzene ring of the phenyl group, the hydrogen atom at any position other than the position bonded to the amino group may be substituted with a substituent.

If the phenyl group has a substituent, a hydrogen atom at any position other than the position amino group is bonded is replaced by R ^a, is a substituent of such R ^a is an aniline compound represented by the general formula (I) R ^a Derived from.

Positions and the number of R ^a is aniline compound represented by the general formula (I) but which corresponds to the position and number of R ^a, a position that is bonded to an amino group on the benzene ring constituting the phenyl group When it is in the 1-position, the hydrogen atom at any position of the 2, 3, 4, 5, and 6-positions may be substituted. Accordingly, hydrogen atoms at all five positions may be substituted, or some hydrogen atoms, that is, hydrogen atoms at one to four positions may be substituted. When the phenyl group has R ^a at a plurality of positions, each may be the same or different.

Type of R ^a is, which correspond to the type of R ^a of the aniline compound represented by the general formula (I), the particularly an -OR ¹ or -R ^2, where, R ¹ and R ² Are each independently a hydrocarbon group. Details of —OR ¹ and —R ² are as described above.

The pyridyl group may or may not have a substituent. Therefore, in the hydrogen atom on the pyridine ring of the pyridyl group, the hydrogen atom at any position other than the position of the nitrogen atom which is a hetero atom and the position bonded to the amino group may be substituted with a substituent. If the pyridyl group has a substituent, a hydrogen atom at any position other than the position combined with the position and the amino group of the nitrogen atom is a hetero atom substituted by R ^c, such R ^c represented by the general formula (II) Derived from R ^b of the halogenated pyridine compound.

The type of R ^c corresponds to the type of R ^b of the halogenated pyridine compound represented by the general formula (II), specifically, —OR ⁵ , —R ⁶ , or a halogen atom, where , R ⁵ and R ⁶ are each independently a hydrocarbon group. —OR ⁵ is preferably an alkoxy group, and —R ⁶ is preferably an alkyl group. Details of the alkoxy group, the alkyl group, and the halogen atom are as described above.

The position and number of R ^c are 3, 4, 5, and the position of the nitrogen atom that is a heteroatom on the pyridine ring constituting the pyridyl group as the 1st position and the position bonded to the nitrogen atom as the 2nd position. The hydrogen atom at any position of the 6-position may be substituted. Therefore, hydrogen atoms at all four positions may be substituted, or some hydrogen atoms, that is, 1 to 3 hydrogen atoms may be substituted. When the pyridyl group has R ^c at a plurality of positions, each may be the same or different.

When R ^c is —OR ⁵ or —R ⁶ , it completely corresponds to the position and number of R ^b of the halogenated pyridine compound represented by the general formula (II). On the other hand, when R ^c is a halogen atom, R ^c is a part or all of R ^{b at} a position corresponding to R ^c of the halogenated pyridine compound represented by the general formula (II). May be. Therefore, the method for producing the phenylaminopyridine compound according to this embodiment includes a case where a halogen atom derived from a starting material is dropped during the reaction process.

Specific examples of the phenylaminopyridine compound represented by the general formula (III) as the target compound include the following A to C compounds.
A. 2-Phenylaminopyridine In general formula (III), m = 0 in (R ^a ) _{m and} q = 0 in (R ^c ) _q . Specifically, the phenyl group and the pyridyl group constituting the phenylaminopyridine compound represented by the general formula (III) are both compounds having no substituent.
B. 2-[(4-Methoxyphenyl) amino] pyridine In general formula (III), in (R ^a ) _m , R ^a is a methoxy group and m = 1, and (R ^c ) _q is q = 0. Specifically, it is a compound in which the 4-position of the phenyl group constituting the phenylaminopyridine compound represented by the general formula (III) is substituted with a methoxy group, and the pyridyl group has no substituent.
C. 2-[(3,4,5-trimethoxyphenyl) amino] pyridine In general formula (III), in (R ^a ) _m , R ^a is a methoxy group and m = 3, and (R ^c ) _q is q = 0. Specifically, it is a compound in which the 3, 4 and 5 positions of the phenyl group constituting the phenylaminopyridine compound represented by the general formula (III) are each substituted with a methoxy group, and the pyridyl group has no substituent.

  Examples of the liquid containing an alkali metal in the method for producing a phenylaminopyridine compound according to this embodiment include a dispersion in which an alkali metal is dispersed in a dispersion solvent or an alkali metal melt. Here, the alkali metal in the liquid does not exist as an alkali metal ion or the like, but exists as a single alkali metal. The dispersion in which the alkali metal is dispersed in the dispersion solvent is a dispersion in which the alkali metal is dispersed as fine particles in the insoluble solvent, or the alkali metal is dispersed in the insoluble solvent in a liquid state. Examples of the alkali metal include sodium, potassium, lithium, and alloys thereof. The average particle diameter of the fine particles is preferably less than 10 μm, and particularly preferably less than 5 μm. The average particle diameter was represented by the diameter of a sphere having a projected area equivalent to the projected area obtained by image analysis of micrographs. The alkali metal melt can be obtained by heating the alkali metal to its melting temperature by means known in the art.

  The dispersion solvent is a dispersion in which alkali metal is dispersed as fine particles, or the alkali metal can be dispersed in an insoluble solvent in a liquid state, and the aniline compound, halogenated pyridine compound, and alkali metal are dispersed in the dispersion solvent. Solvents known in the art can be used as long as they do not inhibit the reaction. Examples thereof include aromatic solvents such as xylene and toluene, normal paraffin solvents such as decane, heterocyclic compound solvents such as tetrahydrothiophene, and mixed solvents thereof.

  Hereinafter, a dispersion in which an alkali metal is dispersed in a dispersion solvent may be abbreviated as “SD”. SD is an abbreviation for Sodium Dispersion, and in the examples described below, a dispersion using sodium as an alkali metal is used, so that SD is given. However, it is understood that the sign of SD does not exclude alkali metals other than sodium, and does not intend only a dispersion but also includes a melt.

  As a reaction solvent in the method for producing phenylaminopyridine according to the present embodiment, a solvent known in the art can be used as long as the reaction with an aniline compound, a halogenated pyridine compound, and SD is not inhibited. For example, ether solvents, normal paraffin solvents, aromatic solvents, amine solvents, and heterocyclic compound solvents can be used. As the ether solvent, a cyclic ether solvent is preferable, and tetrahydrofuran (hereinafter sometimes abbreviated as “THF”) is particularly preferable. As the normal paraffin solvent, normal decane and the like are particularly preferable. As the aromatic solvent, xylene, toluene, benzene and the like are preferable. As the amine solvent, ethylenediamine or the like is preferable. Moreover, tetrahydrothiophene etc. can be preferably utilized as the heterocyclic compound solvent. Only one of these may be used, or two or more may be used in combination as a mixed solvent. Here, the dispersion solvent and the reaction solvent described above may be the same type or different types.

  The method for producing a phenylaminopyridine compound according to the present embodiment uses an aniline compound represented by the general formula (I) and a halogenated pyridine compound represented by the general formula (II) as starting materials. In a reaction solvent to produce a phenylaminopyridine compound represented by the general formula (III). The reaction conditions are described in detail below.

  The reaction temperature is not particularly limited and can be appropriately set depending on the types and amounts of the starting material, SD and reaction solvent, reaction pressure, and the like. Specifically, the reaction temperature is preferably set to a temperature that does not exceed the boiling point of the reaction solvent. Since the boiling point under atmospheric pressure is higher than the boiling point, the reaction temperature can be set at a high temperature. The reaction can also be performed at room temperature, preferably 10 to 100 ° C, particularly preferably 20 to 80 ° C, and more preferably room temperature to 50 ° C. It is not necessary to provide a temperature control means for special heating or cooling, but a temperature control means may be provided if necessary.

  The reaction time is not particularly limited, and may be set as appropriate according to the types and amounts of the starting material, SD, and reaction solvent, the reaction pressure, the reaction temperature, and the like. Usually, it is performed for 1 to 24 hours, preferably 1 to 6 hours.

  In addition, since all reagents such as the starting material, SD, and reaction solvent required in the method for producing the phenylaminopyridine compound according to this embodiment can be stably handled in the atmosphere, the reaction is performed in the atmosphere. Under normal pressure conditions. However, since each reagent has high reactivity and generates heat, it is preferable to carry out in an inert gas atmosphere filled with argon gas or nitrogen gas.

  The amount of SD used can be appropriately set according to the type and amount of starting material and reaction solvent. Preferably, the reaction with the aniline compound, halogenated pyridine compound, SD is carried out in the starting material in a reaction solvent of 0.5 to 2.0 ml with respect to 1 mmol of the total amount of starting material. It is preferred to react 2.0 molar equivalents of SD. Here, the amount of substance of SD means the amount of substance in terms of alkali metal contained in SD. The starting material is preferably reacted with aniline compound: halogenated pyridine in a 1: 1 molar equivalent. If the molar equivalent ratio is not satisfied, phenylaminopyridine may not be obtained, and unintended objects such as azobenzene and bipyridine may be generated.

  The phenylaminopyridine compound obtained by the method for producing a phenylaminopyridine compound of the present embodiment may be purified by a purification means known in the art such as column chromatography, distillation, recrystallization and the like. Moreover, you may comprise so that the aniline compound and halogenated pyridine compound which remain | survived unreacted may be collect | recovered, and it may utilize for the manufacturing method of a phenylaminopyridine compound again.

  The reaction mechanism of the method for producing a phenylaminopyridine compound according to this embodiment is shown in FIG. FIG. 1 exemplarily shows a reaction mechanism between an aniline having no substituent and a halogenated pyridine having no substituent, but the reaction proceeds in the same manner even when it has a substituent.

  That is, in the method for producing a phenylaminopyridine compound according to this embodiment, in the first-stage reaction, aniline, which is an aniline compound represented by the general formula (I), reacts with sodium to produce N-sodioaniline 1. In the second stage reaction, N-sodioaniline 1 produced in the first stage reaction is reacted with a halogenated pyridine which is a halogenated pyridine compound represented by the general formula (II). The anilino group of N-sodioaniline 1 reacts with the halogenated carbon atom on the pyridine ring, and sodium reacts with the nitrogen atom on the pyridine ring to form intermediate 2. Subsequently, the sodium halide is liberated to produce phenylaminopyridine, which is a phenylaminopyridine compound represented by the general formula (III).

  As a result, the aniline compound represented by the general formula (I) and the halogenated pyridine compound represented by the general formula (II) are linked via the amino group of the aniline compound, and the target compound is represented by the phenyl represented by the general formula (III). It is thought that an aminopyridine compound is obtained.

  As described above, the method for producing a phenylaminopyridine compound according to this embodiment proceeds in a single step by adding SD, starting from an aniline compound and a halogenated pyridine compound, and stably and efficiently. Phenylaminopyridine compounds can be produced.

  Since the method for producing the phenylaminopyridine compound according to the present embodiment uses SD that is easy to handle, it does not require a cumbersome chemical method under mild conditions, and it is simple and quick with a small number of steps. Phenylaminopyridine compounds can be produced, which is very advantageous economically and industrially. Here, an alkali metal typified by sodium is a technology excellent in sustainability because it is very widely distributed on the earth. The obtained phenylaminopyridine compound can be used in medicines, animal drugs, agricultural chemicals, and the like as it is or after functional group modification.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples. The study conditions and study results in the following examples are summarized in FIG. Here, the yield is the percentage of the phenylaminopyridine compound actually obtained relative to the phenylaminopyridine compound that can theoretically be produced from the aniline compound and halogenated pyridine compound added to the reaction system. It is. As SD in the following examples, a dispersion in which metallic sodium is dispersed as fine particles in normal paraffin oil is used, and the amount of SD is a numerical value in terms of metallic sodium contained in SD.

(Example 1) Production method of 2-phenylaminopyridine 0.5 mmol of aniline and 0.5 mmol of 2-chloropyridine are mixed in 2 ml of THF, and then 0.5 mmol of SD is dropped at 50 ° C. for 3 hours. It was. The reaction was carried out under air. As a result, as shown in the following reaction formula (1), 2-phenylaminopyridine was obtained as a main product. The yield was 91.6%.

(Example 2) Method for producing 2-[(4-methoxyphenyl) amino] pyridine
0.5 mmol of 4-methoxyaniline and 0.5 mmol of 2-chloropyridine were mixed in 2 ml of THF, and then 0.5 mmol of SD was added dropwise at 50 ° C. to react for 1 hour. The reaction was carried out under air. As a result, 2-[(4-methoxyphenyl) amino] pyridine was obtained as a main product as shown in the following reaction formula (2). The yield was 65.6%.

(Example 3) Method for producing 2-[(3,4,5-trimethoxyphenyl) amino] pyridine
3,4,5-trimethoxyaniline 0.5 mmol and 2-chloropyridine 0.5 mmol were mixed in 2 ml of THF, and then 0.5 mmol of SD was added dropwise at 25 ° C. and reacted for 3 hours. The reaction was carried out under air. As a result, 2-[(3,4,5-trimethoxyphenyl) amino] pyridine was obtained as a main product as shown in the following reaction formula (3). The yield was 32.3%.

  The present invention is a method for producing a phenylaminopyridine compound, and all technical fields using the phenylaminopyridine compound obtained by such a production method, in particular, as raw materials and intermediates for pharmaceuticals, animal drugs, agricultural chemicals, etc. Can do.

Claims (4)

A method for producing a phenylaminopyridine compound, comprising:
A step of reacting an aniline compound represented by general formula (I) and a halogenated pyridine compound represented by general formula (II) with a liquid containing an alkali metal in a reaction solvent to obtain a phenylaminopyridine compound represented by general formula (III) A process for producing a phenylaminopyridine compound having:

(In the general formula (I), R ^a is —OR ¹ or —R ² , R ¹ and R ² are each independently a hydrocarbon group, and m is an integer of 0 to 5)

(In the general formula (II), X is a halogen atom, R ^b is —OR ³ , —R ⁴ , or a halogen atom, and R ³ and R ⁴ are each independently a hydrocarbon group, and n is (It is an integer from 0 to 4)

(In the general formula (III), R ^a is —OR ¹ or —R ² , R ¹ and R ² are each independently a hydrocarbon group, and m is an integer of 0 to 5, where , (R ^a) _m is the same as (R ^a) _m in the general formula (I), R ^c is -OR ^5, a -R ⁶ or a halogen atom and R ⁵ and R ⁶ are each independently It is a hydrocarbon group, q is an integer of 0 to 4, and when R ^c is —OR ⁵ or —R ⁶ , (R ^c ) _q is (R) in the general formula (II) ^b ) When it is the same as _n and R ^c is a halogen atom, it is the same as R ^b of (R ^b ) _n in the general formula (II), but q is the same as or smaller than n Is an integer)   The method for producing a phenylaminopyridine compound according to claim 1, wherein m is 0, 1, or 3.   The method for producing a phenylaminopyridine compound according to claim 1 or 2, wherein n is 0.   The method for producing a phenylaminopyridine compound according to any one of claims 1 to 3, wherein the reaction solvent is tetrahydrofuran.

Images