JPS60105664A - Production of 4-methylimidazole - Google Patents

Abstract

PURPOSE:To obtain the titled substance, by bringing methylglyoxal into contact with ammonium oxalate, formaldehyde and water, removing partially the water, adding an alcohol thereto, filtering the oxalate of the titled substance, and removing the oxalic acid from the resultant product. CONSTITUTION:Methylglyoxal is added to an aqueous solution of ammonium oxalate and formaldehyde, etc. to carry out the reaction, and the water is then removed to an amount equal to that of the methylglyoxal or below. An alcohol, e.g. methanol or ethanol, is added to the reaction mixture, and the oxalate of the titled substance in filtered. Oxalic acid is then removed from the resultant reaction product to afford the titled subtance. The amount of the water in bringing the methylglyoxal into contact with the ammonium oxalate, etc. is 4-30 times, preferably 5-15 times of that of the methylglyoxal. Preferably, the oxalate of 4-methylimidazole is subjected to the removal of the oxalic acid with an aqueous ammonia, and the resultant ammonium oxalate is circulated for use.

Description

[Detailed description of the invention] The present invention relates to a method for producing 4-methylimidazole.

The method for producing 4-methylimidazole is described in U.S. Patent No. 3.
It is described in No. 715365. The present invention discloses that glyoxal or methylglyoxal (Pyruvaldehy
cle) with formaldehyde to produce imidazoles, and the strong acids include sulfuric acid and oxalic acid. As a specific example of producing 4-methylimidazole from methylglyoxal,
Methylglyoxal, ammonium sulfate and formalin are mixed, aqueous ammonia is added dropwise to the mixture to cause a reaction, and then hydroxyl acidic acid 11 is added to scatter the ammonia and the sulfate radical is precipitated as calcium sulfate. The company discloses that after filtering the precipitate, it is dehydrated and distilled to obtain 4-methylimidazole.However, the purity of the product is 77% according to gas chromatography analysis, and the yield is 59%, so both purity and yield are satisfactory. It's hard to say that it's a thing.

The present inventors tried using ammonium oxalate instead of ammonium sulfate in the disclosed example, but in this case as well, the yield and purity were similarly unsatisfactory. 4
- Methylimidazole is used as a raw material for medicine, but it cannot be used at this level of purity and requires further purification.

In addition to the target 4-methylimidazole, 2,4
- It was recognized that dimethyl forms, dimers, and even unknown polymers were produced as by-products, and these by-products were significantly reduced when methylglyoxal was reacted with a combination of ammonium oxalate and formaldehyde at a specific concentration. It has been found that not only the product purity is increased, but also the yield is improved.

Its main composition is characterized by contacting methylglyoxal, ammonium oxalate, formaldehyde, and 4 to 30 times as much water as methylglyoxal. A method, for example, by making the reaction system alkaline,
After extraction with a solvent, water is recovered from the reaction system under reduced pressure by distillation under reduced pressure, and the obtained oxalic acid J, L< of 4-methylimidazole is used as it is or once filtered.
After washing and cooling with alcohol etc., it is made alkaline and decomposed,
After removing the alkali oxalate salt, the 4-methylimidazole obtained by fractionation by vacuum distillation has a purity of 95% or more without special purification, and the yield is less than 75%. There isn't.

The inventors of the present invention continued their research, even when they reacted with specific combinations in such specific aqueous solutions.

They found that, depending on the method of post-treatment, it is possible to further improve the purity of the product without any special purification method, and the yield can also be improved, thereby completing the present invention.

That is, the object of the present invention is to industrially easily obtain 4-methylimidazole of high purity and high yield using methylglyoxal as a starting material, and its composition is methylglyoxal, ammonium 11 oxalate, and pol 11 aldehyde. and 4 to 30 times as much water as methylglyoxal, and then remove the amount of water in the reaction mass until it is equal to or less than the amount of methylglyoxal used, and add alcohol.

It consists of filtering the oxalate of 4-methylimidazole and then deoxalating to obtain 4-methylimidazole.

In the present invention, the amount of water during the catalytic reaction refers to the total amount of water of crystallization or water content of each raw material used, added water, water produced by the reaction, etc., and this total amount of water is 4 to 30% of the amount of methylglyoxal used. It must be adjusted to double. For example, when each raw material is dissolved or dispersed in water alone or in a mixture to form an aqueous solution of an appropriate concentration, water may be freely distributed to an operationally advantageous amount as long as the total amount of water is within the scope of the invention. Bye. When the total amount of water is less than 4 times the amount of methylglyoxal, many by-products are produced and the yield is sharply reduced. This tendency is especially remarkable when the number is 2 times or less.
If the amount is 15 times or more, the yield will not change, but the reaction rate will be slow, and if it is more than 30 times, problems will occur in productivity or post-treatment steps, so the total amount of water is preferably 5 to 15 times that of methylglyoxal. . In the production method of the present invention, methylglyoxal is brought into contact with formaldehyde and ammonium oxalate in a specific amount of water to react, and the amount used is preferably 1:1:1, for example. Although an excess of ammonium 11 oxalate is not disadvantageous, an excess of formaldehyde promotes side reactions and is disadvantageous.

The reaction temperature is 20-iooC, preferably 40-80C. Although the reaction time depends on the reaction temperature, it is completed in 2 to 5 hours.

Even if the total amount of water in the reaction system is strictly specified in the present invention, it is not possible to mix each h:1 size at once and then raise the temperature to react, or to mix each raw material and only use formaldehyde or ammonium oxalate. If a method is adopted in which the compound is added later, side reactions will occur significantly, making it impossible to obtain satisfactory results in terms of purity and yield. In order to further exhibit the effects of the method of the present invention, the preferred method of adding raw materials υ is as shown below.

(1) Add methylglyoxal to an aqueous solution of ammonium oxalate and formaldehyde.

(2) A mixture of methylglyoxal and formaldehyde, or each of them, is added simultaneously to an aqueous ammonium oxalate solution.

(3) Simultaneously add methylglyoxal, formaldehyde, and ammonium oxalate to the previously prepared water.

Although 4-methylimidazole oxalate is produced in the reaction system after the reaction has been completed in this manner, it is dissolved, so water is separated. Preferably, water is recovered under reduced pressure with stirring, and the amount of water recovered is such that the amount of water in the mass is equal to or less than the amount of methylglyoxal charged, preferably 172. If the water content exceeds the equivalent amount of methylglyoxal, dissolution loss will occur even if the next operation is taken into consideration.

A solvent is added to the dehydrated reaction mass within the range of the present invention, which is insoluble or poorly soluble in oxalate of 4-methylimidazole, and which dissolves coexisting heavy impurities such as inorganic and organic by-products. Stir and filter as needed. The amount of solvent to be added may be such that the reaction mass slurry has sufficient fluidity and can be easily discharged and filtered, and the amount beyond this is not particularly limited within an economical range.

Preferred solvents compatible with ISI are methanol, ethanol, and n-propyl alcohol, which are easily water-soluble lower aliphatic alcohols.

Or 1so-propyl alcohol. Among them, methanol is most suitable.

The solvent mixture slurry is filtered, and if necessary, the filter cake of 4-methylimidazole oxalate is washed with a small plate of methanol.
The filter cake is poured into aqueous ammonia, kept warm at 40 to 70°C for 2 to 3 hours to remove oxalic acid, cooled to below 20°C, and filtered to recover ammonium oxalate. By selecting ammonia as the base for deoxalation, it is possible to reuse ammonium oxalate recovered as a raw material for the next production, which is industrially advantageous. After removing ammonium oxalate, it is dehydrated under reduced pressure and then distilled to easily obtain high purity 4-methylimidazole.

According to the production method of the present invention, highly purified 4-methylimidazole with a purity of 99.0% or more can be easily obtained in high yield and used as it is as a pharmaceutical raw material.

As the raw material methylglyoxal, low-purity products obtained by air oxidation of propylene glycol can also be advantageously used. Methylglyoxal produced by air oxidation of propylene glycol usually leaves a large amount of propylene glycol in the product aqueous solution, and other by-products such as formaldehyde, 1-hydroxy-2-propanone, formic acid, and acetic acid are released. , even if these are used as they are without removing them, the effects of the method of the present invention are expressed.
- A highly purified product of methylimidazole can be obtained in high yield, and there is no need to take special purification measures.

The reason why the yield and purity were significantly improved by the method of the present invention has not yet been fully elucidated, but specific 1: (?'
) By reacting one reaction system in a specific dilute aqueous solution and by limiting the order of addition of each raw material, it is possible to generate by-products such as 2,4-dimethyl, dimers, or polymers. It is presumed that the small amount of by-products produced could be easily separated and removed by adopting a specific separation method that would not damage the target product.

Next, the present invention will be further explained using Examples, Comparative Examples, and Reference Examples.

Reference example 3 67.2g of ammonium oxalate was added to water 80 resistant,
disperse. Furthermore, 37% formaldehyde aqueous solution 31
．． 4g was injected and heated to 55°C. 42% MethylglyAxal 71.8(H (0.43 mol) 55-
The dropwise addition took one hour at 60°C. After keeping at the same temperature for 2 hours, the reaction mass was sampled, decomposed with an alkali, and analyzed for the content of 4-methylimidazole by gas chromatography (internal standard method) to calculate the yield immediately after the reaction.

The results are shown in Table 1.

Gas chromatography method: Using Shimadzu GC-7A, column:
TENAX GC60/80mesh, Jy ram temperature: 190℃, injection temperature: 250”C,
Carrier gas: Nitrogen 70ml/min, detector: F
It was analyzed under the conditions of DI and internal standard diethylene glycol.

Reference Examples 1.2.4-7 In Reference Example 3, instead of 80ml of water, 0.5o, 12
9.181.491.867m1 is used, and the following reference example 3 is used.
The yield of 4-methylimidazole was determined in the same manner as above.

The results are shown in Table 1.

Magnification = (amount of mixture water)/(100% methylglyoxal) From Reference Examples 1 to 7, it can be seen that the yield increases as the reaction system is diluted with water.

Example 1 67.2 g of ammonium oxalate is charged and dispersed in 129 ml of water. Further, 31.4 g of a 37% formaldehyde aqueous solution was added and heated to 55°C. 73.8 g (0.43 mol) of 42% methylclyoxal in 55
The mixture was dropped at -60''C for 1 hour and kept at the same temperature for 72 hours.

After the reaction is completed, one reaction mass is dehydrated under reduced pressure. Recovered water 17
(Iff, (the amount of water in the mass is 0.7frf of methylglyoxal) oxalate of 4-methylimidazole precipitates, and 45 methanol is added to the slurry-like system.
ml, cooled while stirring, and filtered at 5°C.
Washed with a small amount of methanol. The obtained 4-methylimidazole oxalate cake was poured into 70 ml of water,
25γ and 59 g of ammonia water were added dropwise, and after the dropwise addition, the mixture was kept at 50° C. for 1 hour, cooled, and filtered at 5° C. to separate ammonium oxalate. The filtrate was dehydrated under reduced pressure and then reduced)
' Distilled to obtain 28.7 g of 4-methylimidazole.

Purity 99.2%, Yield 8O, 6% Comparative Example 1 In Example 1, after the reaction was completed, 134g of reduced pressure sewage was collected, and the amount of water in the mass was reduced to 1.9% of methylglyoxal.
After doubling the amount, the same procedure as in Example 1 was carried out to obtain 24.8 g of 4-methylimidazole with a purity of 99.5%. The yield was 70%.

Comparative Example 2 67.2 g of ammonium oxalate is charged into 129+ liters of water and dispersed. 42% Methylglyoxal 73.
8 g (0°43 mol) was injected and heated to 55°C.

55-50 g of 37% formaldehyde aqueous solution
The dropwise addition took 1 hour at ℃. It was kept at the same temperature for 2 hours. Thereafter, it was treated in the same manner as in Example 1 to obtain a purity of 98.0%.
19.8 g of 4-methylimidazole was obtained. Yield 55
Comparative Example 3: 31.4 g of 37% formaldehyde aqueous solution in water 129 %
and 42% methylglyoxal 73.8H (0,43
mol) was dissolved and heated to 55°C. Ammonium oxalate 67.2g was heated to 55-60℃ for 1#,
Added. It was kept at the same temperature for 2 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 18.0 g of 4-methylimidazole with a purity of 98.0% (yield: 50%).

Example 2 67.2 g of ammonium oxalate was charged into a 129-proof water tank, and the temperature was raised to 55°C. To this, 37% formaldehyde aqueous solution 31.4. , and 42% methylglyoxal 73
．． 8g (0゜4311IOJ) if +1 mixture 55~6
The dropwise addition took 1 hour at 0°C. It was kept at the same temperature for 2 hours. Thereafter, it was treated in the same manner as in Example 1 to obtain a purity of 99.2%.
27.8 g of 4-methylimidazole was obtained. Yield 78
%Met.

Example 3 67.2 g of ammonium oxalate was dissolved in 29 ml of water, and 31.2 g of ammonium oxalate was dissolved separately in 37% aqueous pol-11 aldehyde solution.
4g and 42% methylglyoxal 73.8g (0,4
Prepare 3 mol) and add 5 to 00 ml of warmed water.
While maintaining the temperature at 5 to 60°C, each of these three solutions was added dropwise independently and simultaneously over a period of 1 hour. It was kept at the same temperature for 2 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain a purity of 99.
27.3 g of 0% 4-methylimidazole was obtained. The yield was 76.5%.

Example 4 In Example 1, after the reaction was completed, 192 g of water was collected under reduced pressure and brought to a dry state. The dry cake was crushed, immersed in a small amount of methanol, and filtered to obtain the oxalate salt of 4-methylimidazole, which was then treated in the same manner as in Example 1 to obtain 4-methylimidazole 29 with a purity of 99.0%. .3g
I got it. Yield 82% Patent applicant: Taoka Chemical Industry Co., Ltd.

Claims (8)

[Claims] (1) Methylglyoxal, ammonium oxalate and formaldehyde and methylglyoxal 4-
Contact with 30 times as much water, then remove the water in the reaction mass until the amount is equal to or less than the amount of methylglyoxal used,
The 4-method consists of adding alcohol, filtering the oxalate of 4-methylidazole, and then deoxalating it.
Method for producing methylimidazole. (2) Water claws at the time of contact are 5 to 1 of methylglyoxal
The manufacturing method according to claim 1, which is 5 times as large. (3) Ammonium oxalate and formaldehyde water f
Fl? The method according to claim 1, which comprises adding methylglyoxal to ltj to initiate the reaction. (4) The manufacturing method according to claim 1, which comprises adding a mixture of methylglyoxal and formaldehyde, or each of them simultaneously, to an aqueous ammonium oxalate solution and reacting them. (5) Claims consisting of adding ammonium oxalate to the previously prepared water at the same time as a mixture of methylglyoxal and formaldehyde, or adding methylglyoxal, formaldehyde, and ammonium oxalate simultaneously and causing a reaction. The manufacturing method according to item 1. (6) The manufacturing method according to claim 1, wherein the alcohol is selected from methanol, ethanol, n-propyl alcohol, and 1so-propyl alcohol. (7) The manufacturing method according to claim 1, which comprises deoxalating the oxalate of 4-methylimidazole with aqueous ammonia and separating it as ammonium oxalate. (8) The manufacturing method according to claim 7, which comprises repeatedly using the separated ammonium oxalate in the reaction with methylglyoxal.