JP2003261535A - Method for producing 2-hydroxy-5-methylpyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce 2-hydroxy-5-methylpyridine useful as an intermediate of pharmaceuticals and agricultural chemicals,
Provided is a method for efficiently and conveniently producing from cyano-6-hydroxypyridine. SOLUTION: A method for producing 2-hydroxy-5-methylpyridine, comprising catalytically reducing 3-cyano-6-hydroxypyridine with a reducing catalyst in the presence of an acid and an anionic surfactant using a reducing catalyst. .

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2-hydroxy-5-methylpyridine useful as an intermediate for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art Conventionally, as a method for producing a hydroxymethylpyridine derivative, a method for synthesizing 2-hydroxy-5-methylpyridine from morpholine through a cyclobutylmorpholine derivative (European Patent Publication EP162464, EP).
108483) is known, but there is a problem as an industrial method because desorption of morpholine is required to protect the aldehyde group of the intermediate 2-butanal derivative, which requires multiple steps and results in low yield. In addition, a method of reacting β-amino-acrylonitrile with pyrrole and performing a ring closure reaction using a protonic acid through an open chain intermediate (German Patent Publication DE 42230)
Although 13) is known, there are industrial problems such as the use of a low temperature reaction and a low pass-through rate. In addition, a method (European Patent Publication EP592896) by a reaction of an aminomethyleneated 2-pentenoic acid derivative and an amine is known.
The low yield of 3% is not industrially satisfactory.

[0003]

DISCLOSURE OF THE INVENTION The present invention is intended to provide a novel method for producing 2-hydroxy-5-methylpyridine, which is superior in yield to conventional methods and has a short process.

[0004]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found that 3-cyano-6-
Upon catalytic hydrogen reduction of hydroxypyridine, they have found that the target compound can be efficiently formed in the presence of an anionic surfactant such as sodium lauryl sulfate, and have completed the present invention.

That is, the gist of the present invention is 3-cyano-6-
A method for producing 2-hydroxy-5-methylpyridine, which comprises subjecting hydroxypyridine to catalytic hydrogen reduction using a reduction catalyst in the presence of an acid and an anionic surfactant. Hereinafter, the present invention will be described in detail.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is characterized in that 3-cyano-6-hydroxypyridine is subjected to catalytic hydrogen reduction using a reducing catalyst in the presence of an acid and an anionic surfactant. (Reaction raw material) 3-cyano-6-hydroxypyridine, which is a raw material, is 3-cyanopyridine described in JP-A-6-19778.
It can be synthesized by the method described in JP-A-1.

(Reduction catalyst) The reduction catalyst used in the present invention is not particularly limited as long as it is a solid catalyst usually used for catalytic hydrogen reduction of cyano groups, and specifically, Pd / C, P
Examples include supported catalysts of palladium or platinum such as t / C, Pd / alumina and Pt / alumina. Here, as the carrier, an ordinary carrier such as carbon or alumina can be used, and of these, preferably Pd / C or Pd /
Alumina. The loading ratio of metal atoms is usually
It is 0.5% or more, preferably 1% or more, and 10% or less, especially 8% or less with respect to the carrier.

(Hydrogen) If the hydrogen pressure is too high, a large amount of by-products may be produced.
Less than ² is preferable, more preferably 0.8-1.2 kg
Good results are obtained with pressures around 1 kg / cm ² such as / cm ² . (Acid) Examples of the acid used include C _{1 to} C ₈ carboxylic acids such as formic acid, acetic acid, and propionic acid; C _{1 to} C ₈ such as chloroacetic acid.
A halogen-substituted carboxylic acid of; and methanesulfonic acid,
C ₁ such as trifluorosulfuric acid and paratoluene sulfonic acid
To C ₈ organic sulfonic acids; hard acids such as hydrochloric acid, sulfuric acid, etc., among which those having a pKa of 3 or less are preferable, and 2 or less is particularly preferable. The amount used is usually 1 mol or more, preferably 1.5 mol or more per 1 mol of the substrate, but if too much, it is preferably 10 mol or less, more preferably 8 mol or less from the viewpoint of post-treatment. is there. The acid may be added all at once, or may be added dividedly within the range where the system can be maintained in an acidic state.

(Anionic Surfactant) Examples of the anionic surfactant include alkylsulfates such as sodium dodecyl sulfate and sodium laurin sulfate, preferably C _{4 to} C ₂₀ alkylsulfates, preferably C ₈ ~ C ₂₀
Alkylsulfates of. Examples of the type of salt include alkali metal salts, alkaline earth metal salts, ammonium salts and the like. Of these, alkali metal salts are preferable, and sodium salts are particularly preferable.

The amount of the above surfactant used is 0.01 to 10 mol, preferably 0.05 to 5 mol, based on 1 mol of the substrate. (Solvent) The solvent used is water; nitrile solvents such as acetonitrile and propionnitrile; alcohol solvents such as methanol and ethanol, and preferably water, methanol, ethanol, propanol, n-butanol and acetonitrile. Although these may be used alone, a mixed solvent is preferably used from the viewpoint of kettle efficiency, and a mixed solvent of water and n-butanol is particularly preferable.

The amount of the solvent is 0.5 to 50 volume equivalent, preferably 1 to 20 volume equivalent to the substrate. (Reaction temperature) As the reaction temperature, any temperature can be set as long as it is usually 5 ° C or higher, preferably 10 ° C or higher and lower than the reflux temperature of the solvent. Here, when the temperature is high, the amount of dissolved hydrogen in the liquid tends to decrease, so it is more preferable to set the reaction temperature lower in order to increase the reaction efficiency with a simple reaction apparatus, but the reaction temperature is lower. If the temperature is too low, the substrate will not dissolve easily, so it should be 25 ℃ or higher, preferably 40 ℃.
It is preferable to carry out the reaction at an arbitrary temperature after dissolving the substrate at a higher temperature as described above.

After completion of the reaction, the catalyst is removed by filtration according to a conventional method, the remaining reaction solution is neutralized with an alkaline solution, and then 2-hydroxy-5-methylpyridine is added to an organic solution such as chloroform or n-butanol. Extract from the aqueous layer with a solvent,
Further, these organic solvents can be distilled off under reduced pressure to obtain crude 2-hydroxy-5-methylpyridine, which can be further purified by a commonly used purification method such as column chromatography or crystallization. You can

The obtained 2-hydroxy-5-methylpyridine can be converted into 2-bromo-5-methylpyridine useful as an agricultural chemical intermediate by, for example, brominating with bromine. Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

[0014]

Example 1 1.0 g of 3-cyano-6-hydroxypyridine and 0.24 g of sodium lauryl sulfate were added to a mixed solvent of 8 ml of n-butanol and 1 ml of water. Subsequently, the temperature was raised to 50 ° C., and sulfuric acid water obtained by dissolving 1.67 g of 98% sulfuric acid (pKa = 1.99) in 1 ml of water was added dropwise at the temperature. After stirring for about 20 minutes, the mixture was cooled to room temperature, 0.354 g of 5% Pd / C (manufactured by NE Chemcat) was added, the system was replaced with hydrogen, and hydrogenation was carried out at atmospheric pressure for 6 hours. After the reaction was completed, the catalyst was removed by filtration, and the solution was washed with 10% sodium hydroxide aqueous solution to remove p.
After partially neutralizing to H = 5, extraction with n-butanol,
A solution of crude 3-methyl-6-hydroxypyridine in butanol was obtained. When this solution was quantified by liquid chromatography, the pass-through rate was 99.2% and the yield of 2-hydroxy-5-methylpyridine was 83%.

Comparative Example 1 1.0 g of 3-cyano-6-hydroxypyridine and 5% P
d / C 0.177 g and 98% sulfuric acid 1.67 g in water 1
A suspension was prepared by mixing with 0.4 ml. The system was replaced with hydrogen at room temperature, and hydrogenation was carried out at normal pressure and room temperature for 10 hours. After completion of the reaction, the catalyst was removed by filtration, neutralized with 47% aqueous sodium hydroxide solution and extracted with chloroform to obtain a solution of crude 3-methyl-6-hydroxypyridine. When this solution is quantified by liquid chromatography,
The pass-through rate was 99.6%, which was equivalent to that in Example 1, but the yield of 2-hydroxy-5-methylpyridine was 65%.

[0016]

According to the present invention, the cyano group of 3-cyano-6-hydroxypyridine can be efficiently converted into a methyl group by catalytic hydrogen reduction.

Claims (4)

[Claims] 1. Production of 2-hydroxy-5-methylpyridine, which comprises catalytically reducing 3-cyano-6-hydroxypyridine with a reducing catalyst in the presence of an acid and an anionic surfactant. Method. 2. The reducing catalyst used is Pd / C, Pt / C,
The manufacturing method according to claim 1, which is Pd / alumina or Pt / alumina. 3. The method according to claim 1, wherein an acid having a PKa of 3 or less is used. 4. The method according to claim 1, wherein the anionic surfactant is a sulfonate.