JPH01139568A - Production of 4-methylimidazole - Google Patents

Abstract

PURPOSE:To obtain the title substance in high purity and yield, by reacting methylglyoxal with formaldehyde and ammonium in the presence of ammonium sulfate while retaining pH to low region using a lower fatty acid and ammonia. CONSTITUTION:Methylglyoxal(MGX) is reacted with formaldehyde and ammonia in the presence of ammonium sulfate at 70-80 deg.C for 2-5hr while retaining pH to 2-4 by a lower fatty acid (e.g., acetic acid or formic acid) and ammonia to provide the title substance useful as an intermediate for medicine. The reaction method is carried out by adding a lower fatty acid to ammonium sulfate to afford an aqueous solution adjusted to pH2-4 and dropping a mixture of MGX and formaldehyde or each simultaneously MGX and formaldehyde to the aqueous solution while adding ammonium water solution or ammonia gas thereto. According to the above-mentioned method, production of methylene bisimidazoles which are by-products is suppressed and the production process is simplified.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides high purity 4-methylimidazole (hereinafter referred to as 4-methylimidazole).
It is abbreviated as Ml. ).

4-1'II is a valuable intermediate for manufacturing pharmaceuticals.

[Conventional technology]

4-A method for producing phylum I is described in U.S. Patent No. 3,715.3.
It is stated in No. 65. The invention has an ionization constant of t x to
Imidazole is produced by reacting glyoxal or methylglyoxal (hereinafter abbreviated as MGK) with formaldehyde in an aqueous medium with a pH of 7 or less using an ammonium salt of an acid larger than -3, and is particularly useful as a nucleic acid. Ammonium sulfate and oxalic acid are listed.

As a specific example of producing 4-Ml from MGX, MGX
.

Mix ammonium sulfate and formaldehyde, add ammonia water dropwise to this, and adjust the pH from 4.7 to 4.4.
to react, then add calcium hydroxide,
Ammonia is scattered, sulfate radicals are precipitated as calcium sulfate, the precipitate is filtered, dehydrated and distilled to produce 4-M
It is disclosed that I will be obtained. However, the product purity is 77.2% based on area purity as determined by gas chromatography analysis.
, the yield is 59%.

For use as a pharmaceutical intermediate, further purification operations are required, resulting in a lower yield, and the method is not satisfactory. In addition, Japanese Patent Application Laid-Open No. 57-9766 discloses a method for improving the above-mentioned U.S. patent. Under conditions where PI (is 7 or more), ammonia, aldehyde and M
It is disclosed that 4-MI is obtained by reacting GX. By having a pH of 7 or more and using ammonia, the problem of reactor corrosion and the need for extra operations with large volumes of vA@salt solution are avoided, and U.S. Patent No. 3,715,
No. 365 has been shown to be more advantageous.

However, as shown in the examples, pH9.2-9.4
What if you react in the area of ? Decomposition of IGχ occurs, acetaldehyde is produced, and a large amount of 2,4-dimethylimidazole (hereinafter abbreviated as D-old) is produced as a by-product. In this patent, a dilute solution is used to suppress this by-product, but it is not perfect.

Furthermore, JP-A-60-104072 and JP-A-60-10
No. 5664 is an improved method of U.S. Patent No. 3,715,365, in which high-purity 4-Ml is obtained at a high yield by regulating the total amount of water for MGX, but it is the same as the U.S. patent. In order to use ammonium oxalate as an ammonia source, there are many steps such as filtration of 4-old oxalate, filtration of ammonium oxalate after decomposition of the same temperature with ammonia, and the process becomes complicated and uneconomical.

[Problem that the invention seeks to solve]

The present inventors suppressed the by-product of DMI and the by-product of methylene bisimidazoles generated from 2 moles of 4-MI and 1 mole of formaldehyde, and the reaction concentration was high, and it did not involve complicated steps such as filtration. A study was carried out to develop a simplified process that can be easily carried out industrially and which can obtain 4-old with high purity and high yield.

[Means and effects for solving the problem] The present inventors have discovered that acetaldehyde produced by decomposition of the raw material MGX is the cause of the production of the by-product DMI;
MGX is stable in the low PHeI range, and methylene bisimidazoles are also low P! (We have found that this can be suppressed in this region, and have completed the present invention.)

That is, the present invention is a method for producing 4-methylimidazole, which is characterized by reacting methylglyoxal, formaldehyde, and ammonia in the presence of ammonium sulfate while maintaining the pH at 2 to 4 using a lower fatty acid and ammonia. be.

More specifically, the present invention is characterized in that MGX and formaldehyde are reacted in an aqueous medium using a lower fatty acid and ammonia in the presence of ammonium sulfate while adjusting the pH to 2 to 4. This is the manufacturing method.

P) If I exceeds 4, not only DMT but also methylene bisimidazoles will be produced as by-products, resulting in a lower yield, and it will be difficult to separate 4-1ff and DFII using a foil, resulting in poor purity. also decreases.

On the other hand, when the pH is less than 2, the reaction rate decreases rapidly,
This is not preferred because the reaction does not complete completely.

If it takes a long time to complete the reaction or if the reaction is carried out at a high temperature even for a short time, the amount of polymerized products increases and the yield decreases.

In the present invention, since water is contained in the raw materials, the reaction is carried out in an aqueous medium.

According to the production method of the present invention, MGX is reacted with formaldehyde and ammonia in the presence of ammonium sulfate, and the amount of ammonium sulfate used is 1 to MGX.
The molar ratio will be 2 or more since ammonia is used in the reaction and is also used to maintain the reaction P)I at 2 to 4.

It is possible to use formaldehyde in excess of about 1.1 times that of MGX, but if it exceeds this, side reactions will be promoted, which is disadvantageous. Moreover, if it is less than 1, the by-product of DMI will increase, which is not preferable.

The reaction temperature is 50-ioo'c, preferably 70-80
℃ is good.

The reaction time depends on the temperature, but may be 2 to 5 hours.

The reaction method involves adding lower fatty acids to ammonium sulfate to maintain the pH during the reaction between 2 and 4.
A mixture of MGX and formaldehyde is added dropwise to the aqueous solution prepared in Examples 2 to 4, or an ammonia aqueous solution or ammonia gas is added while simultaneously dropping MGX and formaldehyde to carry out the reaction.

In the reaction system where the reaction was completed by the above method, 4-? lI
Since sulfates and lower fatty acid salts of
- Separate Ml.

〔Example〕

The present invention will be specifically described below with reference to Examples.

Example 1' 316.9 g of distilled water and 14 ammonium sulfate were placed in a 12 glass separable flask equipped with a stirrer and a reflux condenser.
5.4 g was charged, and after dissolving, 14.8 g of acetic acid was further charged, the pH was adjusted to 3, and the temperature was raised to 80°C. After raising the temperature,
After finely adjusting P)l at 80°C and confirming PH3,
A mixed solution of 177.6 g of 0 wt % MGX aqueous solution and 80.8 g of 37 wt % formalin was added dropwise over 2 hours. Meanwhile P
28 wt% ammonia aqueous solution 51 to maintain H3
．． After 0 dropwise addition, which was carried out while adding 9 g, the aging reaction was carried out for 2 hours at the same pH value to complete the reaction.

As a result of HPLC analysis, the yield of 4-M1 (relative to MGX, the same applies below) is 87.5%, and the DMI (relative to MGX, the same applies below) is 0.2.
It was 5%.

Example 2 Using a reactor similar to Example 1, 316.9 g of distilled water,
Charge 145.4 g of ammonium sulfate, raise the temperature to 80°C to melt it, and then charge 0.5 g of acetic acid to adjust the pH to 4.
And so. After confirming PH4, 40% by weight MGX aqueous solution 17
A mixed solution of 7.6 g and 80.8 g of 37% by weight formalin was added dropwise over 2 hours. 28 to maintain pH4 during that time.
The process was carried out while adding 63.8 g of a wt% ammonia aqueous solution. After completing the dropwise addition, an aging reaction was carried out for 2 hours at the same pH value.
The reaction was completed. HPLC analysis results showed that the 4-old yield was 86.0% and the DM+ yield was 0.44%.

Example 3 Using the same reactor as in Example 1, 316.9 g of distilled water,
Charge 145.4 g of ammonium sulfate, raise the temperature to 80°C to dissolve it, and then charge 0.5 g of acetic acid to adjust the pH to 4.
And so. After confirming PH4, add 40% by weight GX aqueous solution 17
A mixed solution of 7.6 g and 80.8 g of 37% by weight formalin was added dropwise over 2 hours. During this time, 56.9 g of a 28% by weight ammonia aqueous solution was added to maintain the pH at 2.5.

After completion of the dropwise addition, an aging reaction was carried out for 2 hours at the same pH value to complete the reaction. As a result of HPLC analysis, the 4-former yield was 87.
9%, and the DMI yield was 0.33%.

Example 4 Using the same reactor as in Example 1, 316.9 g of Fukidashi water,
Charge 145.4 g of ammonium sulfate, raise the temperature to 80°C to dissolve it, and further charge 0.2 g of formic acid to adjust the pH to 4.
And so. After confirming PH4, 40% by weight MGX aqueous solution 17
7.6g and 37% by weight hol? A mixed solution containing 80.8 g of phosphorus was added dropwise over 2 hours. 2 to maintain pH4 during that time.
This was carried out while adding 60.3 g of an 8% ammonia aqueous solution. After completion of the dropwise addition, an aging reaction was carried out for 2 hours at the same pH value to complete the reaction. As a result of HPLC analysis, the yield of 4-M1 was 85.7% and the yield of D was 0.41%.

Comparative Example 1 The reaction was carried out in the same manner as in Example 1, without adding acetic acid, using only ammonium sulfate, and maintaining the same pH of 5.1 by adding a 28% by weight ammonia aqueous solution. As a result, the 4-M1 yield was 80%, D
The previous yield was 0.62%.

Comparative Example 2 In Comparative Example 1, the 28 wt % ammonia aqueous solution was not added, and the reaction was carried out with the PI decreasing as the reaction progressed. The pH after 2 hours of the aging reaction was 1.2, and as a result, 4-M1 yield was 79.4%, DMI yield was 0.
It was 77%.

〔Effect of the invention〕

The 4-old obtained by the method of the present invention has a purity of 97% or more without special purification, and the D-old yield is 1% or less, and the 4-old yield is less than 85%. There isn't.

Patent applicant: Mitsui Toatsu Chemical Co., Ltd.

Claims (2)

[Claims] (1) A method for producing 4-methylimidazole, which comprises reacting methylglyoxal, formaldehyde, and ammonia in the presence of ammonium sulfate while keeping the pH at 2 to 4 using a lower fatty acid and ammonia. (2) The method according to claim 1, wherein the lower fatty acid is acetic acid or formic acid.