JP4072623B2 - Method for producing pyridine-N-oxides - Google Patents

Description

  The present invention relates to a process for producing pyridine-N-oxides useful as intermediates for various organic compounds. More specifically, the present invention relates to a water-insoluble pyridine-based oily solution and an aqueous hydrogen peroxide solution that do not use an acid and an organic solvent. The present invention relates to a novel process for producing pyridine-N-oxides by reaction.

  As a method for producing pyridine-N-oxides by oxidizing pyridines, m-chloroperbenzoic acid in a benzene solvent (Non-Patent Document 1), dimethyldioxirane in an acetone solvent (Non-Patent Document 2). ), Or peroxide-t-amyl (non-patent document 3) using molybdenum pentachloride as a catalyst is known as a reaction. Furthermore, a method (non-patent document 4) using bistrimethyl peroxide as an oxidizing agent in a methylene chloride solvent in the presence of a methyl rhenium trioxide complex catalyst has been reported.

However, these methods require a large amount of highly toxic by-products and organic solvents to be processed after the reaction, which makes the operation complicated, and the load on the environment and human body is large. Is hard to say.

  Hydrogen peroxide, on the other hand, has only a harmless water as the co-product after the reaction, so the load on the environment and the human body is small, and there are no problems such as corrosion of the equipment. It can be said that it is an excellent oxidizing agent.

  As a method for producing pyridine-N-oxides from pyridines using hydrogen peroxide as an oxidizing agent, a reaction performed in an acid solvent (Non-patent Document 5) is known. Since a high concentration of peracid is generated, there is a danger of explosion, and it is necessary to remove the acid solvent after the reaction, so that the operation is complicated. Furthermore, corrosion of the equipment by acid is also a problem.

  In order to adjust the pH of the reaction system to 3-9 (about 6) in the presence of a metal catalyst in an aqueous medium, a catalytic amount of high-concentration sulfuric acid (95%) or hydrochloric acid is added to oxidize with pyridines. A method for producing pyridine-N-oxides from hydrogen (Patent Document 1) has also been reported. Since a strong acid is used in this reaction, problems such as corrosion of the apparatus occur, and this is not an industrially excellent synthesis method.

  On the other hand, the formation reaction of pyridine-N-oxides without using an acid has been reported. In a reaction using a methyl rhenium trioxide complex as a catalyst (Non-patent Document 6), methylene chloride is used as a solvent. Moreover, although the oxidation reaction of pyridines with hydrogen peroxide using a hydrotalcite catalyst was reported (Non-patent Document 7), in this reaction, it is necessary to add two equivalents of benzonitrile to the substrate. In order to mix pyridines and aqueous hydrogen peroxide solution, methanol must be used as a solvent.

  In general, when an aqueous hydrogen peroxide solution is used as an oxidizing agent in the oxidation reaction of water-insoluble pyridines, it is necessary to use a solvent amount or high-concentration acid, or dissolve a pyridines oily solution to make a uniform solution. The use of organic solvents is considered essential. As a result, the reaction apparatus corrodes, or when isolating the target product pyridine-N-oxides, a means for removing acid or organic solvent is required, and the reaction operation becomes complicated. Furthermore, their effects on the environment and human body and toxicity have been pointed out. As described above, most of the methods for synthesizing pyridine-N-oxides by using an acid or an organic solvent which is complicated in operation and causes corrosion of the apparatus and is harmful to the environment and the human body. The convenience of hydrogen peroxide, that is, the property that the load on the environment and the human body is small and there is no problem of corrosion of the device, cannot be utilized by using an acid or an organic solvent.

JP 10-324678 Tetrahedron Lett., 4867-4870 (1966) J. Org. Chem., 50, 2847-2553 (1985) Tetrahedron Lett., 2807-2808 (1971) TetrahedronLett., 39, 761-764 (1998) J. Chem. Soc., Chem. Commun., 28-29 (1971) J. Org. Chem., 63, 1740-1741 (1998) NewJ. Chem., 23, 799-801 (1999)

  The present invention has been made in order to overcome the problems of the prior art as described above, from a non-water-soluble pyridine-based oily solution under mild reaction conditions without using an acid and an organic solvent. Pyridine-N-oxides can be obtained in high yield, and the reaction procedure is simple, eliminating the need to remove the acid and solvent after completion of the reaction, reducing the corrosion of the equipment, and affecting the environment and human body. An object of the present invention is to provide a safe, simple and efficient method for producing pyridine-N-oxides by reacting a water-insoluble pyridine-based oily solution with an aqueous hydrogen peroxide solution.

  As a result of intensive studies to solve the above problems, the present inventors have replaced the conventional reaction method in which an oxidation reaction between a water-insoluble pyridine-based oil solution using an acid or an organic solvent and an aqueous hydrogen peroxide solution is performed. If a reaction using a heterogeneous solution system of an aqueous hydrogen peroxide solution and a water-insoluble pyridine-based oil solution is selected in the presence of a specific catalyst without using an acid and an organic solvent, the conventional common sense technical Unlike the findings, the inventors have found that the corresponding pyridine-N-oxides can be produced safely and simply at a high yield, and the present invention has been completed.

That is, according to this application, the following invention is provided.
(1) Pyridine characterized by reacting an oily liquid of a water-insoluble pyridine itself with an aqueous hydrogen peroxide solution in the presence of a tungstic acid catalyst in a heterogeneous solution system without using an acid and an organic solvent. -Method for producing N-oxides.

According to the production method of the present invention, useful pyridine N-oxides widely used as intermediates for various organic compounds can be obtained under mild conditions and in high yield. In addition, since the method of the present invention does not use any acid or organic solvent, the reaction operation is simple, the apparatus is hardly corroded, the influence on the environment and the human body is extremely small, and the effect on the environment is reduced. Thus, pyridine-N-oxides can be obtained safely and efficiently. Therefore, the method of the present invention can be said to be an invention that has a great industrial effect.

The method for producing pyridine-N-oxides by oxidation reaction of water-insoluble pyridines using hydrogen peroxide according to the present invention comprises the step of oxidizing the water-insoluble pyridines themselves in the presence of a tungstic acid catalyst. The oily liquid (hereinafter also referred to as pyridine oily solution) and a hydrogen peroxide aqueous solution are reacted in a heterogeneous solution system without using an acid and an organic solvent.

  Conventionally, in oxidation using hydrogen peroxide, a method has been adopted in which the reaction proceeds smoothly by using an acid as a solvent or adding a catalytic amount of a strong acid and a metal to the system. However, the use of acid leads to corrosion of the equipment, complicating the removal operation of the acid after the reaction, etc., and the risk of explosion due to the generation of peracid, is not suitable for industrial large-scale synthesis. It is.

  Furthermore, in the liquid-liquid reaction, when the raw materials or the raw materials and the reaction reagents such as the oxidizing agent and the reaction accelerator do not have compatibility, the raw materials and the reaction reagents dissolve each other in order to facilitate the reaction. A process in which a homogeneous solution of both is prepared in advance using an organic solvent and then reacted is considered advantageous in terms of selectivity and yield. However, operations such as removal of the organic solvent after the reaction are complicated, and toxicity of the organic solvent itself on the human body is regarded as a problem.

  In the synthesis reaction of pyridine-N-oxides by the reaction of pyridines and hydrogen peroxide, as described above, these ideas are followed, and an acid or organic solvent is used to form an oil solution of pyridines and hydrogen peroxide. Is used to produce pyridine-N-oxides.

  As a result of searching for various studies, experiments, and theoretical considerations from the viewpoint of more efficient and protecting the environment and the human body, the present inventors have found that this hydrogen peroxide is an oxidizing agent. Unlike conventional technology, the oxidation reaction of water-soluble pyridines is carried out in a heterogeneous solution system consisting of a water-insoluble pyridine oil-based solution and an aqueous hydrogen peroxide solution without using any acid or organic solvent. It was found that pyridine-N-oxides were produced with good yield and contributed significantly to reducing the environmental burden. Such knowledge is not expected in the conventional technical common sense, but is a phenomenon found by the continuous accumulation of experimental studies by the present inventor.

As the substrate pyridines in the present invention, any conventionally known pyridines can be used, and usually a compound represented by the following general formula (1) is used.

In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently the same or different and are each a hydrogen atom, a hydroxy group, a halogen atom, a carboxyl group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group Group, aryl group, aralkyl group, alkoxy group, acyl group, acyloxy group, nitro group, sulfonic acid group, alkoxycarbonyl group, silyl group, phosphoryl group, sulfinyl group, sulfonyl group, sulfonate group, etc. Represents a group, and may be optionally substituted with a substituent inert to the oxidation reaction. Further, any two of R ¹ , R ² , R ³ , R ⁴ and R ⁵ may be bonded to each other with a residue obtained by removing a hydrogen atom from each other to form a ring, and further R ¹ , R ² , a residue obtained by removing a hydrogen atom from any ^two of R ³ , R ⁴ and R ⁵ may be bonded to each other via a divalent atom or / and a divalent functional group to form a ring. good.

Examples of pyridines preferably used in the present invention include pyridine, 2-picoline, 3-picoline, 4-picoline, 2-pyridinemethanol, 3-pyridinemethanol, 4-pyridinemethanol, 4-phenylpyridine, 3- Examples include chloropyridine, 2,6-lutidine, 2,4,6-collidine, quinoline and the like.

The amount of hydrogen peroxide used is usually in the range of 1 to 20 equivalents, preferably 1 to 8 equivalents, relative to the nitrogen atoms of the pyridines. The concentration of hydrogen peroxide is not particularly limited, and a commercially available 30% aqueous solution is sufficient, but it may be diluted to about 3-20%.

The catalyst used in the method of the present invention is mainly composed of tungstic acid. Although there is no restriction | limiting in particular in the usage-amount, Usually, it is chosen from the range of 0.000001-0.2 equivalent with respect to pyridines of a raw material, Preferably it is 0.0001-0.1 equivalent.

The catalyst used in the production method of the present invention is mainly composed of the above-described tungstic acid, but an auxiliary catalyst such as a quaternary ammonium salt can be used as necessary.

The reaction conditions for the process of the present invention are not particularly limited, but the reaction is usually carried out in the range of 30 to 120 ° C, preferably 50 to 100 ° C. The reaction pressure may be normal pressure, pressurization, or reduced pressure, but it is desirable to carry out the reaction at normal pressure.

In a preferred production method of the present invention, there is a method in which a solution obtained by mixing a water-insoluble pyridine oil-based solution and a catalyst is heated to a reaction temperature, and then a hydrogen peroxide aqueous solution is gradually added dropwise and reacted while stirring. Taken.

（式中の各記号は、一般式（１）と同じ。） The pyridine-N-oxides obtained by the method of the present invention are usually represented by the following general formula (2).

(Each symbol in the formula is the same as in the general formula (1).)

Examples of such pyridine-N-oxides include pyridine-N-oxide, 2-picoline-N-oxide, 3-picoline-N-oxide, 4-picoline-N-oxide, 2-pyridinemethanol- N-oxide, 3-pyridinemethanol-N-oxide, 4-pyridinemethanol-N-oxide, 4-phenylpyridine-N-oxide, 3-chloropyridine-N-oxide, 2,6-lutidine-N-oxide, Examples include 2,4,6-collidine-N-oxide and quinoline-N-oxide.

  The produced target product, pyridine-N-oxides, can be separated and taken out from the aqueous phase after completion of the reaction, and purified by usual methods such as recrystallization, distillation and sublimation.

EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited at all by these Examples.

Example 1
H ₂ WO ₄ (25.0 mg, 0.100 mmol) and pyridine (0.81 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When the GC and NMR were measured, the yield of pyridine-N-oxide was 97%.

Comparative Example 1
The reaction was performed under the same conditions as in Example 1 except that dioxane (10 mL) was added in advance so that the pyridine and hydrogen peroxide aqueous solution formed a homogeneous phase. As a result, the yield of pyridine-N-oxide was 9%. there were.

Example 2
H ₂ WO ₄ (250.0 mg, 1.000 mmol) and pyridine (8.10 mL, 100 mmol) were mixed and stirred at 60 ° C. for 20 minutes. A 30% aqueous hydrogen peroxide solution (34.0 mL, 300 mmol) was gradually added dropwise to the mixed solution, followed by stirring at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. Excess hydrogen peroxide was decomposed with manganese dioxide. After filtering the solution and distilling off water with an evaporator, the yield of pyridine-N-oxide (8.37 g, 88 mmol) obtained by distillation was 88%.

Reference example 1
H ₃ [P (W ₃ O ₁₀ ) ₄ ] (24.0 mg, 0.0083 mmol) and pyridine (0.81 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. As a result of measuring GC and NMR, the yield of pyridine-N-oxide was 63%.

Reference example 2
MoO ₃ (14.4 mg, 0.100 mmol) and pyridine (0.81 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When the GC and NMR were measured, the yield of pyridine-N-oxide was 12%.

Example 3
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 2-picoline (0.97 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 2-picoline-N-oxide was 100%.

Example 4
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 3-picoline (0.97 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When the GC and NMR were measured, the yield of 3-picoline-N-oxide was 98%.

Example 5
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 4-picoline (0.97 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 4-picoline-N-oxide was 99%.

Example 6
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 2-pyridinemethanol (0.97 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 2-pyridinemethanol-N-oxide was 88%.

Example 7
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 3-pyridinemethanol (0.96 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 3-pyridinemethanol-N-oxide was 83%.

Example 8
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 4-pyridinemethanol (1.091 g, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 4-pyridinemethanol-N-oxide was 90%.

Example 9
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 4-phenylpyridine (1.552 g, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When the GC and NMR were measured, the yield of 4-phenylpyridine-N-oxide was 90%.

Example 10
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 2-chloropyridine (0.94 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. As a result of GC and NMR measurement, the yield of 2-chloropyridine-N-oxide was 85%.

Example 11
H ₂ WO ₄ (25.0 mg, 0.100 mmol) and 3-chloropyridine (0.95 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 3-chloropyridine-N-oxide was 97%.

Example 12
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 2,6-lutidine (1.16 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 2,6-lutidine-N-oxide was 92%.

Example 13
H ₂ WO ₄ (125.0 mg, 0.500 mmol) and 2,4,6-collidine (1.32 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (5.7 mL, 50 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When GC and NMR were measured, the yield of 2,4,6-collidine-N-oxide was 83%.

Example 14
H ₂ WO ₄ (25.0 mg, 0.100 mmol) and quinoline (1.20 mL, 10 mmol) were mixed and stirred at 60 ° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (3.4 mL, 30 mmol) was gradually added dropwise to the mixed solution and stirred at 60 ° C. for 24 hours, and then the reaction solution was cooled to room temperature. When the GC and NMR were measured, the yield of quinoline-N-oxide was 91%.

Claims (1)

Pyridine-N- characterized by reacting an oily liquid of water-insoluble pyridine itself with an aqueous hydrogen peroxide solution in the presence of a tungstic acid catalyst in a heterogeneous solution system without using an acid and an organic solvent. A method for producing oxides.