JP2012246231A - Method for producing heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a monohalogen-substituted pyridine compound for producing a 2,6-disubstituted pyridine compound highly purely and inexpensively at high yield, which is a method to be executed in an underwater reaction system, by suppressing to the utmost use of a dangerous substance having a low flash point, a combustible chemical or the like.SOLUTION: In a method for producing a monohalogen-substituted heterocyclic compound (for example, 2-chloro-6-phenylanino-4-methyl-3-pyridinecarbonitrile or 6-chloro-2-phenylanino-4-methyl-3-pyridinecarbonitrile), an aniline derivative (for example, aniline) is reacted underwater with a heterocyclic compound (for example, 2,6-dichloro4-methyl-3-pyridinecarbonitrile) having two halogen atoms as a leaving group.

Description

  The present invention relates to a method for producing a heterocyclic compound, and more particularly to a method for producing a monohalogeno-substituted pyridine compound.

  2,6-disubstituted pyridine compounds having different substituents are disperse dyes for fibers excellent in light fastness, compounds used for photographic conversion agents, sensitizing dyes, electronic materials, medical pesticides, etc. Widely used as a body.

  As a conventional production method, for example, Patent Document 1 and Patent Document 2 describe a method of synthesizing a dye from 2,6-dichloro-3-cyano-4-methylpyridine. In US Pat. No. 6,099,097, a solvent is used, and in Patent Document 2, synthesis is performed also as a solvent by using an excessive amount of reagent, which is a costly method and a method with many problems from the viewpoint of work safety. there were.

Japanese Unexamined Patent Publication No. 61-039347 JP 2006-265207 A

  A method for producing a monohalogeno-substituted pyridine compound for producing a 2,6-disubstituted pyridine compound at a high yield, high purity and low cost, and to use as much as possible a dangerous substance having a low flash point or a flammable chemical. To provide a production method that is carried out in an underwater reaction system.

  As a result of intensive studies to solve the above problems, the present inventors have carried out a substitution reaction in water with a pyridine compound having a halogen atom at the 2nd and 6th positions, and an aniline derivative. The present inventors have found that a monohalogeno-substituted pyridine compound can be produced with purity, low cost and safety, and completed the present invention.

［式中、Ｘはそれぞれ独立に塩素原子、臭素原子またはヨウ素原子を表し、Ｒ_１〜Ｒ_３はそれぞれ独立に水素原子、（Ｃ１〜Ｃ６）アルキル基、フェニル基、シアノ基またはニトロ基を表し、Ｒ_４〜Ｒ_８はそれぞれ独立に水素原子、（Ｃ１〜Ｃ６）アルキル基、（Ｃ１〜Ｃ６）アルコキシ基、（Ｃ１〜Ｃ６）アルコキシ（Ｃ１〜Ｃ６）アルコキシ基、置換基を有していてもよいフェニル基を表す。］ That is, the present invention relates to the following 1) to 4).
1) Substitution reaction of an aniline derivative represented by the following formula (2) with a heterocyclic compound having two halogen atoms as a leaving group represented by the following formula (1) in water The manufacturing method of the monohalogeno substituted heterocyclic compound represented by (3).

[Wherein, X independently represents a chlorine atom, a bromine atom or an iodine atom, and R _{1 to} R ₃ each independently represents a hydrogen atom, a (C1 to C6) alkyl group, a phenyl group, a cyano group or a nitro group. , R _{4 to} R ₈ each independently have a hydrogen atom, a (C1 to C6) alkyl group, a (C1 to C6) alkoxy group, a (C1 to C6) alkoxy (C1 to C6) alkoxy group, and a substituent. Represents a good phenyl group. ]

2) The production method according to 1), wherein X is a chlorine atom, R ₁ is a cyano group, R ₂ is a (C1-C3) alkyl group, and R ₃ and R _{4 to} R ₈ are hydrogen atoms.
3) The production method according to 1) or 2) above, wherein at least one base selected from an inorganic base group consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate and calcium carbonate is used for the substitution reaction.
4) The production method according to 3) above, wherein at least one compound selected from the group consisting of zinc oxide, copper iodide and sodium hydroxide is used as a catalyst for promoting the reaction of the substitution reaction.

  The production method characterized by using the water of the present invention as a solvent makes it possible to produce a monohalogeno-substituted pyridine compound with high yield, high purity, low cost and safety.

The present invention is described in detail below.
In the method for producing a monohalogeno-substituted heterocyclic compound represented by the formula (3) of the present invention, the heterocyclic compound having two halogen atoms as the leaving group represented by the formula (1) is added to the formula (2). The aniline derivative represented by the above formula is substituted in water [wherein, X represents independently a chlorine atom, a bromine atom or an iodine atom, R _{1 to} R ₃ each independently represents a hydrogen atom, (C1-C6) represents an alkyl group, a phenyl group, a cyano group, or a nitro group, and R _{4 to} R ₈ each independently represent a hydrogen atom, (C1-C6) alkyl group, (C1-C6) alkoxy group, (C1-C6) C6) represents an alkoxy (C1-C6) alkoxy group and a phenyl group which may have a substituent. ]

.
First, the monohalogeno-substituted heterocyclic compound represented by the formula (3) produced by the production method of the present invention, that is, the monohalogeno-substituted pyridine compound will be described.

Examples of the (C1 to C6) alkyl group in R _{1 to} R ₃ include linear and branched alkyl groups. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, t- A butyl group, n-heptyl group, n-hexyl group, etc. are mentioned.
Preferably, R ₁ is a cyano group, R ₂ is a (C1-C3) alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, R ₃ is a hydrogen atom, and in particular, R ₂ is a methyl group. Is preferred.

Examples of the (C1 to C6) alkyl group for R _{4 to} R ₈ include the same groups as the (C1 to C6) alkyl group for R _{1 to} R ₃ . Examples of the (C1 to C6) alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group, an n-butoxy group, an iso-butoxy group, a sec-butoxy group, an n-pentoxy group, and a methylbutoxy group. Group, ethylpropoxy group, ethylbutoxy group and the like. (C1-C6) alkoxy (C1-C6) alkoxy groups include methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy and the like. Examples of the substituent of the phenyl group which may have a substituent include a halogen atom, a hydroxy group, a carboxy group, a sulfone group, and a phenyl group.
R _{4 to} R ₈ are preferably hydrogen atom compounds.

  In the compound represented by the formula (3), there may be a tautomer or a positional isomer due to the type of the substituent. In the present invention, these isomers and mixtures of these isomers are All are included.

  In the present invention, the monohalogeno-substituted heterocyclic compound represented by the formula (3) may form a salt, and the salt is also included in the present invention. The salt is not particularly limited, for example, a salt with an anion such as halide ion, sulfate ion, carbonate ion, nitrate ion, sulfonate ion, phosphate ion, acetate ion, cation such as metal ion, ammonium ion, etc. And the salt. Further, depending on the substituent, an inner salt may be formed.

Next, the production method of the present invention will be described in detail.
R _{4 to} R ₈ in the aniline derivative represented by the formula (2) used in the production method of the present invention are the same as R _{4 to} R ₈ in the monohalogeno-substituted pyridine compound represented by the formula (3), The preferable group is also the same. The amount used can be selected as appropriate, but usually it can be used in an amount of about 0.5 to 30 mol, more preferably about 1 to 10 mol, per 1 mol of the heterocyclic compound represented by the formula (1). Yes, particularly preferably about 1.5 to 5 mol.

Examples of X in the heterocyclic compound represented by the formula (1) used in the production method of the present invention include a chlorine atom, a bromine atom and an iodine atom. Among them, a compound in which two Xs are both chlorine atoms is preferable. It is done. R ₁ to R ₃ is the same as _R 1 to R ₃ in the monohalogenoacetic substituted heterocyclic compound represented by the formula (3), is the same preferable groups.
As the reaction solvent, it is preferable to use only water, and the amount used is not particularly limited and can be appropriately selected according to the reaction raw material, but is usually based on the heterocyclic compound represented by the formula (1). The mass ratio is about 0.1 to 100 times, preferably about 0.5 to 10 times, and particularly preferably about 1 to 5 times.

  The reaction temperature in the production method of the present invention is not particularly limited and can be appropriately selected, but is usually about 0 to 150 ° C, preferably about 40 to 120 ° C, particularly preferably about 80 to 105 ° C. .

The reaction time in the production method of the present invention is not particularly limited and can be appropriately selected depending on the reaction raw materials. Usually, it is about 1 minute to 50 hours, preferably about 5 to 40 hours, particularly preferably 10 ~ 30 hours.
Completion of the reaction can be confirmed by disappearance of the raw material by HPLC (high resolution liquid chromatography).

In the production method of the present invention, it is preferable to use at least one base selected from the group of inorganic bases consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate and calcium carbonate. When an inorganic base is used, the amount used is about 0.1 to 30 mol, more preferably about 0.5 to 10 mol, particularly preferably about 1 mol of the heterocyclic compound represented by the formula (1). About 1 to 3 moles.
In the production method of the present invention, it is preferable to use at least one compound selected from the group consisting of zinc oxide, copper iodide and sodium hydroxide as the reaction promoting catalyst. When using the reaction promoting catalyst, the amount used is about 0.01 to 10 mol, more preferably about 0.1 to 5 mol, particularly about 1 to 5 mol, based on 1 mol of the heterocyclic compound represented by the formula (1). Preferably it is about 0.2-1 mol.

  The order of addition of the heterocyclic compound represented by the formula (1), the aniline derivative represented by the formula (2), the inorganic base, the reaction promoting catalyst and the reaction solvent into the reaction system may be arbitrary. It is not limited.

Hereinafter, the present invention will be described in more detail with reference to examples. In Examples, unless otherwise specified, parts means parts by weight and% means% by weight.

Example 1
2,6-dichloro-4-methyl-3-pyridinecarbonitrile (in the above formula (1), X is a chlorine atom, R ₁ is a cyano group, R ₂ is a methyl group, R ₃ is a hydrogen atom; 30 g, 0.16 mol) ) And aniline (in formula (2), R _{4 to} R ₈ are hydrogen atoms; 45 g, 0.48 mol) and water (30 g) were mixed, heated to an elevated temperature, and stirred at 95 to 105 ° C. for 15 hours. This was cooled, and the resulting crystals were collected by filtration and washed with water. A 10% aqueous hydrochloric acid solution is added dropwise to the obtained crystals while stirring, and after stirring for 1 hour, the obtained crystals are collected by filtration, washed with 3% aqueous hydrochloric acid, and the filtrate becomes neutral with water. Until it was washed. This was dried to obtain a mixture of main product 1, main product 2 and by-products (37.7 g, 96%).

Example 2
2,6-dichloro-4-methyl-3-pyridinecarbonitrile (30 g, 0.16 mol), aniline (22 g, 0.24 mol), potassium carbonate (33 g, 0.24 mol), water (60 g) were mixed, The mixture was heated and heated and stirred at 98 to 110 ° C. for 5 hours, 48% aqueous sodium hydroxide solution (6.7 g) was added, and the mixture was further stirred for 10 hours. This was cooled, and the resulting crystals were collected by filtration and washed with water. A 10% aqueous hydrochloric acid solution is added dropwise to the obtained crystals while stirring, and after stirring for 1 hour, the obtained crystals are collected by filtration, washed with 3% aqueous hydrochloric acid, and the filtrate becomes neutral with water. Until it was washed. This was dried to obtain a mixture of main product 1, main product 2, and by-products (36.7 g, 94%).

Example 3
2,6-dichloro-4-methyl-3-pyridinecarbonitrile (20 g, 0.11 mol), aniline (20 g, 0.21 mol), potassium carbonate (22 g, 0.16 mol), water (40 g), zinc oxide ( 0.5 g, 0.006 mol) was mixed, heated and heated, and stirred at 95 to 105 ° C. for 15 hours. This was cooled, and the resulting crystals were collected by filtration and washed with water. A 10% aqueous hydrochloric acid solution is added dropwise to the obtained crystals while stirring, and after stirring for 1 hour, the obtained crystals are collected by filtration, washed with 3% aqueous hydrochloric acid, and the filtrate becomes neutral with water. Until it was washed. This was dried to obtain a mixture of main product 1, main product 2 and by-products (25.4 g, 97%).

Comparative Example 1
2,6-dichloro-4-methyl-3-pyridinecarbonitrile (50 g, 0.27 mol), aniline (80.4 g, 0.86 mol) and isopropanol (54 g) were mixed, heated to 80-95 by heating. The mixture was stirred at 10 ° C. for 10 hours. This was cooled and poured into a cooled 30% aqueous hydrochloric acid solution for crystallization. This was collected by filtration and washed with water until the filtrate became neutral. This was dried to obtain a mixture of main product 1, main product 2 and by-products (63.6 g, 98%).

  Next, HPLC analysis of the obtained mixture was performed, and the composition ratio of the main product 1, the main product 2, and the by-product was determined.

Table 1

HPLC analysis condition model: Shimazu Prominence
Column: Inertsil ODS-3 (5 μm) φ4.6 × 150 mm (40 ° C.)
Detector: UV210nm
Mobile phase and separation conditions:
A: Acetonitrile B: Water A solution 30% → (15 minutes) → 100% → (5 minutes)

As is apparent from Table 1, according to the production method of the present invention in which no organic solvent is used, the ratio of by-products is as low as 5% or less, and a desired mixture of compounds can be obtained in high yield and high purity.
As described above, in the method of synthesizing using isopropanol in the solvent described in Patent Document 1 known as a conventional production method (Comparative Example 1), the by-product ratio is 11%, and the product The purity of the target compound mixture is low. In addition, a large amount of undesired by-products were produced even in the synthesis method using a large excess of the reagent described in Patent Document 2.

Claims (4)

A heterocyclic compound having two halogen atoms as a leaving group represented by the following formula (1) is substituted with an aniline derivative represented by the following formula (2) in water: The manufacturing method of the monohalogeno substituted heterocyclic compound represented by this.

[Wherein, X independently represents a chlorine atom, a bromine atom or an iodine atom, and R _{1 to} R ₃ each independently represents a hydrogen atom, a (C1 to C6) alkyl group, a phenyl group, a cyano group or a nitro group. , R _{4 to} R ₈ each independently have a hydrogen atom, a (C1 to C6) alkyl group, a (C1 to C6) alkoxy group, a (C1 to C6) alkoxy (C1 to C6) alkoxy group, and a substituent. Represents a good phenyl group. ] The production method according to claim 1, wherein X is a chlorine atom, R ₁ is a cyano group, R ₂ is a (C1-C3) alkyl group, and R ₃ and R _{4 to} R ₈ are hydrogen atoms. The production method according to claim 1 or 2, wherein at least one base selected from the group of inorganic bases consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate and calcium carbonate is used for the substitution reaction. 4. The production method according to claim 3, wherein at least one compound selected from the group consisting of zinc oxide, copper iodide and sodium hydroxide is used as a reaction promoting catalyst for the substitution reaction.