JP2005082570A - Manufacturing method of 2-substituted imidazole compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a high-yield manufacturing method of a 2-substituted imidazole which is expected to be useful as a curing agent for epoxy resins, polyurethane resins or the like, as an intermediate of various agrochemicals, antibiotics or pharmaceuticals such as anti-AIDS agents or the like, or as dye intermediates. <P>SOLUTION: An aldehyde compound is reacted with ammonia (I) to give an imine compound, and subsequently an α,β-dicarbonyl compound and ammonia (II) are added and allowed to react with the imine compound. Preferably, the α,β-dicarbonyl compound and ammonia (II) are simultaneously added. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention provides high yields of 2-substituted imidazoles that are expected to be useful as curing agents such as epoxy resins and polyurethane resins, pharmaceutical intermediates such as various agricultural chemicals, antibiotics and anti-AIDS drugs, and dye intermediates. It relates to a method of manufacturing.

2-Substituted imidazoles have useful uses as described above, and the production method thereof includes, for example, aqueous alcohol containing glyoxal bisulfite adduct, aliphatic aldehyde and weak acid ammonium salt containing isopropanol or butanol. A method of condensing at a pH of 6 to 8 in a medium (for example, see Patent Document 1) and a method of adding ammonia after mixing an aldehyde compound and glyoxal (for example, see Patent Document 2) are known.
Japanese Patent Publication No.59-38228 German Patent Publication No. 2360175

However, in the method disclosed in Patent Document 1, a large amount of ammonium carbonate is used and the post-treatment is complicated, and it is necessary to strictly adjust the pH to 6 to 8, and an aliphatic aldehyde as a raw material remains. Therefore, it is necessary to remove such aldehyde by distillation, and the total yield is 60% or less, and there is still room for improvement.
Further, the method of Patent Document 2 has a drawback that the yield is about 70% and the by-product of imidazole is increased to about 20%.

  Therefore, as a result of intensive studies in view of the above-mentioned present situation, the present inventor reacted an aldehyde compound with ammonia (I) to produce an imine compound, and then added an α, β-dicarbonyl compound and ammonia (II). The present invention was completed by finding that 2-substituted imidazoles can be produced in a high yield when reacted.

  The production method of the present invention increases 2-substituted imidazoles which are expected to be useful as curing agents such as epoxy resins and polyurethane resins, intermediates for pharmaceuticals such as various agricultural chemicals, antibiotics and anti-AIDS drugs, and dye intermediates. It can be produced in a yield.

Examples of the aldehyde compound used in the present invention include formaldehyde, acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde, cyclohexanecarboxaldehyde, benzaldehyde, phenylacetaldehyde, etc. Usually, formaldehyde is used as an aqueous solution of 30 to 50% by weight, and acetaldehyde is used as an aqueous solution of 60 to 90% by weight in view of industrial handling.
Ammonia (I) is supplied as liquid ammonia or an aqueous ammonia solution, but is usually used as an aqueous solution of 5 to 30% by weight.

  In the present invention, the above aldehyde compound and ammonia (I) are first reacted to form an imine compound, and this reaction is represented by the following reaction formula.

（上記においてＲ１は炭素数１〜２０の炭化水素基、複素環基のいずれかを示す。）

(In the above, R1 represents either a hydrocarbon group having 1 to 20 carbon atoms or a heterocyclic group.)

  The amount of ammonia (I) used in producing the imine is preferably 0.5 to 2.0 mol, more preferably 0.9 to 1.3 mol, relative to 1 mol of the aldehyde compound. It is. If the amount is less than 0.5 mol, an unreacted aldehyde compound remains and the yield decreases. If the amount exceeds 2.0 mol, by-product of imidazole increases, and the yield is not further improved.

  In carrying out such a reaction, the aldehyde compound and ammonia (I) may be mixed, and the mixing method is not limited. This reaction is usually carried out in an aqueous solvent, but when a water-insoluble aldehyde compound or the like is used as a raw material, it may be carried out in a mixed solvent of water and a water-soluble solvent. Examples of the water-soluble solvent include alcohols such as methanol, ethanol and propanol, nitriles such as acetonitrile, and dimethylformamide.

  Such a reaction is an exothermic reaction. Usually, the reaction system is allowed to react at 0 to 30 ° C. for about 10 to 60 minutes while cooling the reaction system. Perform the process.

  In the present invention, once an imine compound is produced by the above reaction, as a next step, an α, β-dicarbonyl compound and ammonia are added to the reaction system and reacted.

（上記においてＲ１は炭素数１〜２０の炭化水素基、複素環基のいずれか、Ｒ２、Ｒ３はそれぞれ水素又は炭素数１〜５の炭化水素基を示す。）

(In the above, R1 represents either a hydrocarbon group having 1 to 20 carbon atoms or a heterocyclic group, and R2 and R3 each represents hydrogen or a hydrocarbon group having 1 to 5 carbon atoms.)

Examples of the α, β-dicarbonyl compound include glyoxal and methylglyoxal, and are usually used as an aqueous solution of about 40% by weight which is industrially easily available.
Such an α, β-dicarbonyl compound may be used in an equimolar amount with the imine compound produced in the first step, and since the production of the imine compound usually proceeds quantitatively, it is practically charged in the first step. What is necessary is just to make it the same as the mole number of the smaller one of ammonia or an aldehyde compound.
The amount of ammonia (II) used in the above reaction is preferably 0.5 to 2.0 mol, more preferably 0.75 to 1.5 mol, relative to 1 mol of the α, β-dicarbonyl compound. Particularly, it is 0.9 to 1.1 times mol. If the amount used is less than 0.5 mol, the yield of the target product may be low, and if it exceeds 2.0 mol, a large reaction vessel is required, which is not preferable.
In some cases, ammonia (I) may remain in the ammonia reaction system, but usually after mixing the aldehyde compound and ammonia (I) to produce an imine compound, a part of the remaining ammonia (I) is outside the system. Therefore, the amount of ammonia (II) may be added in the above amount without considering the residual amount of ammonia (I).
Ammonia (II) is supplied as liquid ammonia or an aqueous ammonia solution, but it is usually preferable to supply it as an aqueous solution of 5 to 30% by weight because it is easy to handle.

  As a method of charging the α, β-dicarbonyl compound and ammonia (II), (1) a method of adding them separately at the same time, (2) a method of adding them separately in sequence, (3) ammonia and α, β-dicarbonyl Although the method of adding after mixing a compound first is mentioned, the method of (1) is preferable at the point which can suppress the byproduct of imidazole and the yield of 2-substituted imidazoles improves, Furthermore, addition Examples of the method include methods such as a batch method, a division method, and a dropping method, but a dropping method is preferable.

  The charging time when charging the α, β-dicarbonyl compound and ammonia (II) in a divided or dropwise manner is not particularly limited, but it may be normally charged in about 30 minutes to 10 hours. This reaction is also an exothermic reaction, and the reaction temperature at the time of preparation may be adjusted to 5 to 100 ° C., preferably 10 to 80 ° C. The reaction occurs simultaneously with the charging and is almost completed after the charging is completed, but the reaction may be matured at the above temperature for about 1 to 10 hours.

  After completion of the reaction, unreacted ammonia is distilled off, and the resulting reaction solution is extracted with alcohols such as butanol and pentanol, acetate esters, ketones, etc., or distilled, packed column treatment, partial concentration, What is necessary is just to isolate | separate 2-substituted imidazoles by methods, such as recrystallization.

Hereinafter, the present invention will be described in detail with reference to examples. “%” Is based on weight, and the yield was determined by liquid chromatography analysis.
Example 1
A 500 mL four-necked flask equipped with a stirrer and a dropping funnel was charged with 72.11 g (1.0 mol) of isobutyraldehyde and 45 mL of methanol, and cooled with 60.8 g (1.0 mol) of 28% aqueous ammonia (I). The mixture was charged at 25 ° C. and stirred for 1 hour.
After confirming the formation of the imine compound by liquid chromatography, 145.1 g (1.0 mol) of 40% aqueous glyoxal solution and 60.8 g (1.0 mol) of 28% aqueous ammonia solution (II) were simultaneously added dropwise (drop time 1 hour) ) And reacted for 1 hour at 25 ° C. After completion of aging, water and remaining raw materials were distilled off to obtain an oily reaction product.
The reaction product contained 98% 2-isopropylimidazole and 2% imidazole.
The reaction product was distilled to obtain 104.7 g of 2-isopropylimidazole (purity 99.9%). The yield was 95%.

Example 2
An oily reaction product was obtained in the same manner as in Example 1 except that 86.1 g (1 mol) of valeraldehyde was used instead of isobutyraldehyde.
The reaction product contained 95% 2-butylimidazole and 2% imidazole.
The reaction product was distilled to obtain 111.8 g (purity 99.8%) of 2-butylimidazole. The yield was 93%.

Example 3
An oily reaction product was obtained in the same manner as in Example 1 except that 58.1 g (1 mol) of propionaldehyde was used instead of isobutyraldehyde.
The reaction product contained 85% 2-ethylimidazole and 3% imidazole.
The reaction product was distilled to obtain 78.8 g (99.8%) of 2-ethylimidazole. The yield was 82%.

Comparative Example 1
A 500 ml three-necked flask equipped with a stirrer and a dropping funnel was charged with 145.1 g (1 mol) of 40% aqueous glyoxal solution and 72.1 g (1 mol) of isobutyraldehyde. To this mixed solution, 121.6 g (2 mol) of 28% aqueous ammonia solution was added and reacted at 25 ° C., followed by aging for 1 hour. After aging, water and remaining raw materials were distilled off to obtain an oily reaction product.
The reaction product contained 58% 2-isopropylimidazole and 23% imidazole.
The reaction product was distilled to obtain 61.7 g (purity 98%) of 2-isopropylimidazole. The yield was 56%.

The present invention is an efficient production of 2-substituted imidazoles that are expected to be useful as curing agents such as epoxy resins and polyurethane resins, pharmaceutical intermediates such as various agricultural chemicals, antibiotics, anti-AIDS drugs, and dye intermediates. Used in the method.

Claims (3)

Reaction of an aldehyde compound with ammonia (I) to produce an imine compound, followed by α
, Β-dicarbonyl compound and ammonia (II) are added and reacted, a method for producing 2-substituted imidazoles. The method for producing 2-substituted imidazoles according to claim 1, wherein the α, β-dicarbonyl compound and ammonia (II) are simultaneously added and reacted. 3. The method for producing a 2-substituted imidazole according to claim 1, wherein when the α, β-dicarbonyl compound and ammonia (II) are added, both are charged by a dropping method.