JP2002173482A - Method for producing 2,4-dihydroxypyridine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 2,4-dihydroxypyridine under a mild condition, in a good yield and industrially advantageously. SOLUTION: This method for producing the 2,4-dihydroxypyridine is characterized by reacting a 2-sulfonylpyridine derivative expressed by the general formula (I) with an alcohol expressed by the general formula (II) in the presence of a base to obtain a 2,4-diaralkyloxypyridine derivative expressed by the general formula (III), and performing a hydrogenolysis of the obtained 2,4- diaralkyloxypyridine derivative in the presence of a catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2,4-dihydroxypyridine. The 2,4-dihydroxypyridine produced by the present invention is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like, for example, as a synthetic intermediate for a therapeutic drug for vascular diseases (see Japanese Patent Application Laid-Open No. 2000-502709).

[0002]

2. Description of the Related Art As a method of synthesizing 2,4-dihydroxypyridine, (1) a method of heating 2,4-dihydroxy-3-pyridinecarboxylate with phosphoric acid containing water (Japanese Patent Application Laid-Open No. 2000-502709). No.),
(2) 1-methoxy-1-buten-3-yne is reacted with diethyl carbonate and sodium ethoxide, and the resulting ethyl 3,5,5-triethoxy-3-pentenoate is reacted with ammonia to give 4-amino- 2-hydroxypyridine, followed by diazotization of the amino group in concentrated sulfuric acid and further hydrolysis (Journal of Heterocyclic Chemistry (J. Heterocyclic)
c Chem. ), Vol. 14, p. 1295 (1977).
), (3) a method of allowing 2,4-dimethoxypyridine to react with hexamethyldisilthiane and sodium methoxide in 1,3-dimethyl-2-imidazolidinone (Heterocycles)
s), 36, 323 (1993)),
(4) A method of treating 4-benzyloxypyridine-N-oxide with acetic anhydride to give 4-benzyloxy-2-pyridone and reducing it with palladium-carbon (Journal of Heterocyclic Chemistry) (J. Heterocyclic chem.) 389
, (1975)).

[0003]

The method of the above (1) is as follows.
In order to obtain 2,4-dihydroxy-3-pyridinecarboxylic acid ester, a step of reacting dialkylacetone dicarboxylate, methyl orthoformate and acetic anhydride, and further reacting ammonium hydroxide with hydrochloric acid is required. In this case, acid-resistant equipment is indispensable, and the equipment burden increases. In the above method (2), it is difficult to industrially obtain 1-methoxy-1-buten-3-yne used as a starting material, and the operation is complicated because it requires multiple steps. The method of the above (3) is based on 2,4-
Both dimethoxypyridine and hexamethyldisilathiane are expensive. The method (4) has a problem that the synthesis of 4-benzyloxypyridine-N-oxide used as a raw material is complicated. Therefore, these methods cannot be said to be industrially advantageous methods for producing 2,4-dihydropyridine.

An object of the present invention is to provide a method for producing 2,4-dihydroxypyridine industrially and advantageously under mild conditions with good yield.

[0005]

According to the present invention, the above objects have been achieved by the general formula (I)

[0006]

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(Wherein, R ¹ represents an optionally substituted alkyl group, cycloalkyl group, aryl group or aralkyl group, and R ² represents an optionally substituted aralkyl group. ) (Hereinafter abbreviated as 2-sulfonylpyridine derivative (I)) in the presence of a base in the general formula (II).

[0008]

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(Wherein, R ³ represents an aralkyl group which may have a substituent) (hereinafter referred to as an aralkyl group).
(Abbreviated as alcohol (II))

[0010]

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(Wherein R ² and R ³ are as defined above) (hereinafter abbreviated as 2,4-diaralkyloxypyridine derivative (III)) 2) and the resulting 2,4
-It is achieved by providing a process for producing 2,4-dihydroxypyridine, which comprises hydrolyzing a diaralkyloxypyridine derivative in the presence of a catalyst.

The present invention also provides a process for producing a 2,4-diaralkyloxypyridine derivative (III), which comprises reacting a 2-sulfonylpyridine derivative (I) with an alcohol (II) in the presence of a base. , And 2,4
-A method for producing 2,4-dihydroxypyridine, which comprises hydrogenolyzing a diaralkyloxypyridine derivative (III) in the presence of a catalyst.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, examples of the alkyl group represented by R ¹ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group, an isobutyl group and a t-group.
Examples thereof include a linear or branched alkyl group such as an tert-butyl group, an n-pentyl group, and a hexyl group. These alkyl groups may have a substituent, such as a chlorine atom, a bromine atom, an iodine atom,
A halogen atom such as a fluorine atom; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group;
Hydroxyl group; tert-butyldimethylsilyloxy group, t
a trisubstituted silyloxy group such as tert-butyldiphenylsilyloxy group; a nitro group.

Examples of the cycloalkyl group represented by R ¹ include a cyclopropyl group, a cyclopentyl group and a cyclohexyl group, and examples of the aryl group include a phenyl group and a naphthyl group. These cycloalkyl groups and aryl groups may have a substituent, and examples of such a substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a hexyl group. An alkyl group such as a group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a hydroxyl group;
Examples include a trisubstituted silyloxy group such as a t-butyldimethylsilyloxy group and a tert-butyldiphenylsilyloxy group.

The aralkyl groups represented by R ¹ , R ² and R ³ include, for example, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, naphthyldiphenylmethyl and the like. These aralkyl groups may have a substituent, and examples of such a substituent include alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and hexyl. A halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a hydroxyl group; a nitro group; a tert-butyldimethylsilyloxy group and a tert-butyl group Examples include a trisubstituted silyloxy group such as a diphenylsilyloxy group.

Hereinafter, the present invention will be described in detail for each step.

Step (A): Step of reacting 2-sulfonylpyridine derivative (I) with alcohol (II) in the presence of a base to obtain 2,4-diaralkyloxypyridine derivative (III)

Examples of the base include hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; and carbonates such as sodium carbonate and potassium carbonate. The amount of the base used is not particularly limited, but is usually 0.1 to 5 based on 1 mol of the 2-sulfonylpyridine derivative (I).
It is preferably in the range of 0 mol, more preferably in the range of 1 to 10 mol.

Examples of the alcohol (II) include benzyl alcohol, 1-phenylethanol, o-nitrobenzyl alcohol, triphenylmethyl alcohol,
p-methoxyphenyldiphenylmethyl alcohol and the like. The amount of the alcohol (II) to be used is not particularly limited, but is usually 2-sulfonylpyridine derivative (I)
It is preferably in the range of 0.1 to 200 mol, more preferably in the range of 0.1 to 20 mol, per 1 mol.

The reaction of step (A) can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction,
Aliphatic hydrocarbons such as pentane, hexane, heptane, octane, petroleum ether; benzene, toluene,
Aromatic hydrocarbons such as xylene, cumene and mesitylene;
Ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, dimethoxyethane, dibutyl ether; nitriles such as acetonitrile, propionitrile, benzonitrile; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethane;
Halogenated hydrocarbons such as chlorobenzene; dimethyl sulfoxide; ketones such as acetone, 2-butanone, and 3-pentanone are used. These solvents may be used alone or in combination of two or more.
When a solvent is allowed to coexist, the amount of the solvent is not particularly limited, but is usually preferably 0.1 to 200 times the weight of the 2-sulfonylpyridine derivative (I).

[0021] The reaction temperature is preferably in the range of 0 ° C to 200 ° C, more preferably in the range of 40 ° C to 130 ° C. The reaction can be carried out under normal pressure, or under pressure or under reduced pressure. However, from the viewpoint of ease of operation and reaction equipment, it is preferable to carry out the reaction under normal pressure.

The reaction of the step (A) is preferably carried out by mixing the 2-sulfonylpyridine derivative (I), the alcohol (II), the base and, if necessary, the solvent and stirring the mixture at a predetermined temperature.

The 2,4-diaralkyloxypyridine derivative (III) obtained by the above reaction can be isolated and purified by a method generally used for isolating and purifying organic compounds. For example, concentrating the reaction mixture,
Cool and isolate by precipitation of crystals. In addition, the reaction mixture is directly concentrated, and the obtained crude product is purified by distillation, chromatography, or the like, if necessary.

Step (B): Step of obtaining 2,4-dihydroxypyridine by subjecting 2,4-diaralkyloxypyridine derivative (III) to hydrogenolysis in the presence of a catalyst.

As the catalyst, for example, palladium-carbon, platinum-carbon, platinum oxide, Raney nickel, Raney cobalt and the like are used. As these catalysts, commercially available ones can be used as they are.

The reaction in the step (B) is preferably performed in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons such as pentane, hexane, heptane, octane, and cyclohexane; and aromatic hydrocarbons such as benzene, toluene, xylene, cumene, and mesitylene. Hydrogen; alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, and 2-butanol; ethers such as diethyl ether, tetrahydrofuran, and dioxane;
Esters such as methyl acetate and ethyl acetate; acetic acid; water and the like are used.

[0027] The reaction temperature is preferably in the range of 0 ° C to 100 ° C, more preferably in the range of 15 ° C to 40 ° C. The reaction can be carried out under normal pressure or under pressure.

The reaction in the step (B) is carried out by mixing the 2,4-diaralkyloxypyridine derivative (III), a catalyst and, if necessary, a solvent, and replacing the system with hydrogen, followed by stirring at a predetermined temperature. Is preferred.

The 2,4-dihydroxypyridine obtained by the above reaction can be isolated and purified by a method generally used for isolating and purifying organic compounds. For example, the reaction mixture is concentrated and cooled, and the crystals are isolated by precipitation. In addition, the reaction mixture is directly concentrated, and the obtained crude product is purified by distillation, chromatography, or the like, if necessary.

The 2-sulfonylpyridine derivative (I) used as a raw material in the present invention, for example, 2-benzenesulfonyl-4-benzyloxypyridine, is obtained by converting 4-methoxy-3-buten-2-one and benzenesulfonyl cyanide. It can be easily produced by reacting in the presence of benzyl alcohol. Alcohol (II), for example, benzyl alcohol, 1-phenylethanol, and the like are commercially available and easily available.

[0031]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 10.0 g of 4-methoxy-3-buten-2-one was placed in a 100-ml three-necked flask equipped with a thermometer, a magnetic stirrer, a Dean Stark, and a condenser.
(0.10 mol) and 9.8 g (0.050 mol) of benzenesulfonyl cyanide, and 40 ml of toluene was added as a solvent.
8 g (0.10 mmol), trimethyl borate 1.03
After adding g (10 mmol), the mixture was stirred at an internal temperature of 110 ° C. under a nitrogen atmosphere, and heated under reflux for 10 hours while distilling off the solvent by Dean Stark. The solvent was added every hour by the amount distilled off. After cooling the reaction solution to room temperature,
Low-boiling components such as a solvent are distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (developing solution: hexane / ethyl acetate = 1/1 (volume ratio)).
8.94 g of 2-benzenesulfonyl-4-benzyloxypyridine was obtained as a colorless oil (purity 99%,
Yield 55% based on benzenesulfonyl cyanide).

Example 1 To a 50 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a condenser, 1.40 g of 2-benzenesulfonyl-4-benzyloxypyridine (4.
30 mmol) and 0.340 g of sodium hydroxide
(8.60 mmol), and toluene 10 as a solvent.
ml, followed by 1.30 ml of benzyl alcohol
After adding (12.6 mmol), the mixture was stirred at an internal temperature of 110 ° C. for 4 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, the precipitated salt was separated by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution: hexane / ethyl acetate = 4/1 (volume ratio)). )
To give 1.19 g of 2,4-dibenzyloxypyridine (purity 99%, yield 95% based on 2-benzenesulfonyl-4-benzyloxypyridine) having the following physical properties as a colorless oil. Was.

2,4-dibenzyloxypyridine ¹ H-NMR spectrum (270 MHz, CDCl ₃ , T
MS, ppm) [delta]: 5.06 (s, 2H), 5.36
(S, 2H), 6.35 (d, 1H, J = 2.9H)
z), 6.55 (dd, 1H, J = 2.9 Hz, 5.9)
Hz), 7.31-7.49 (m, 10H), 8.00
(D, 1H, J = 5.9Hz)

EXPERIMENTAL EXAMPLE 2 In a 50-ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a condenser, 1.40 g of 2-benzenesulfonyl-4-benzyloxypyridine (4.
30 mmol) and 0.340 g of sodium hydroxide
(8.60 mmol) and acetone 10 as a solvent.
ml, followed by 1.30 ml of benzyl alcohol
After adding (12.6 mmol), the mixture was stirred at an internal temperature of 110 ° C. for 4 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, the precipitated salt was separated by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution: hexane / ethyl acetate = 4/1 (volume ratio)). )
To give 1.16 g of 2,4-dibenzyloxypyridine (purity 99%, yield 93% based on 2-benzenesulfonyl-4-benzyloxypyridine) as a colorless oil.

Example 3 In a 50 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a condenser, 1.40 g of 2-benzenesulfonyl-4-benzyloxypyridine (4.
30 mmol) and 0.340 g of sodium hydroxide
(8.60 mmol), benzyl alcohol 10.0 m
1 (96.6 mmol) and an internal temperature of 1 under a nitrogen atmosphere.
Stirred at 10 ° C. for 4 hours. After the reaction solution was cooled to room temperature, the precipitated salt was separated by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solution: hexane / ethyl acetate = 4/1 (volume ratio)). ) To give 1.19 g of 2,4-benzyloxypyridine (purity 99%, yield 95% based on benzenesulfonyl cyanide) as a colorless oil.

Example 4 0.95 g (3.2 mmol) of 2,4-dibenzyloxypyridine was placed in a 100-ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a balloon, and 2-propanol was used as a solvent. 10 ml were added, followed by 10% palladium-carbon 50 mg (0.047 mmol
After l) was added, the balloon was filled with hydrogen and stirred at an internal temperature of 25 ° C. for 4 hours under a hydrogen atmosphere. The reaction solution was filtered using Celite (registered trademark), and the solvent was distilled off under reduced pressure.
The obtained residue was purified by recrystallization from methanol, and as a white solid, 0.25 g of 2,4-dihydroxypyridine having the following physical properties (purity: 99%, yield based on 2,4-dibenzyloxypyridine) 71%).

2,4-dihydroxypyridine ¹ H-NMR spectrum (270 MHz, CD ₃ OD, T
MS, ppm) δ: 5.47 (d, 1H, J = 2.9)
Hz), 5.76 (dd, 1H, J = 2.9 Hz, 6.
9 Hz), 7.17 (d, 1H, J = 6.9 Hz), 1
0.45 (br, 1H), 10.90 (br, 1H)

Example 5 A 100 ml three-necked flask equipped with a thermometer, a magnetic stirrer, and a balloon was charged with 3.0 g (10 mmol) of 2,4-dibenzyloxypyridine, and 50 ml of methanol was added as a solvent. Subsequently, 150 mg (0.14 mmol) of 10% palladium-carbon was added, and then the balloon was filled with hydrogen, and the internal temperature was 25 ° C. under a hydrogen atmosphere.
For 4 hours. This reaction solution is transferred to Celite (registered trademark).
, The solvent was distilled off under reduced pressure, and the obtained residue was purified by recrystallization from methanol. As a white solid, 0.84 g of 2,4-dihydroxypyridine (purity 99%, 2,4 (76% yield based on 4-dibenzyloxypyridine).

[0040]

Industrial Applicability The 2,4-dihydroxypyridine derivative can be produced industrially and advantageously in a good yield under mild conditions.

Claims (3)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ is an alkyl group which may have a substituent,
Represents a cycloalkyl group, an aryl group or an aralkyl group, and R ² represents an aralkyl group which may have a substituent. The 2-sulfonylpyridine derivative represented by the general formula (II) in the presence of a base: (Wherein R ³ represents an aralkyl group which may have a substituent) by reacting with an alcohol represented by the general formula (III): (Wherein R ² and R ³ are as defined above), and the obtained 2,4-diaralkyloxypyridine derivative is treated with a catalyst in the presence of a catalyst. To produce 2,4-dihydroxypyridine. 2. A compound of the general formula (I) (Wherein, R ¹ is an alkyl group which may have a substituent,
Represents a cycloalkyl group, an aryl group or an aralkyl group, and R ² represents an aralkyl group which may have a substituent. The 2-sulfonylpyridine derivative represented by the general formula (II) in the presence of a base: (Wherein R ³ represents an aralkyl group which may have a substituent (s)), characterized by reacting with an alcohol represented by the following general formula (III): (In the formula, R ² and R ³ are as defined above.) A method for producing a 2,4-diaralkyloxypyridine derivative represented by the formula: 3. A compound of the general formula (III) (Wherein R ² and R ³ represent an aralkyl group which may have a substituent). Hydrogenolysis of a 2,4-diaralkyloxypyridine derivative represented by the following formula: A method for producing 2,4-dihydroxypyridine.