JPH07100699B2 - Process for producing 4-methylimidazole - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention relates to highly pure 4-methylimidazole (hereinafter referred to as 4-MI).
Is abbreviated. ) Manufacturing method.

4-MI is a valuable intermediate for manufacturing pharmaceuticals.

[Prior Art] A method for producing 4-MI is described in US Pat. No. 3,715,365. The invention uses an ammonium salt of an acid having an ionization constant of more than 1 × 10 ⁻³ and reacts glyoxal or methylglyoxal (hereinafter abbreviated as MGX) with formaldehyde in an aqueous medium having a pH of 7 or less to form imidazoles. It is produced, and ammonium sulphate and oxalic acid are mentioned as the acid. As a specific example of producing 4-MI from MGX, MGX, ammonium sulfate and formaldehyde are mixed, and aqueous ammonia is added dropwise to the mixture to obtain PH.
After reacting from 4.7 to PH 4.4, calcium hydroxide was added to disperse ammonia to precipitate sulfate as calcium sulfate, and the precipitate was separated by filtration, dehydrated and distilled to give 4-MI. It has been disclosed to obtain.

However, the product purity is 77.2% in area purity by gas chromatographic analysis, and the yield is 59%, and further purification operation is required to use it as a pharmaceutical intermediate, so the yield is lowered, and the method is satisfactory. Not a thing.

Further, as a method for improving the above-mentioned US patent, JP-A-57-9766 is characterized in that the feed order of raw materials is characterized under the condition that PH is 7 or more, and ammonia, aldehyde and MGX are reacted to give 4-MI. It is disclosed that the pH of 7 or more and the use of ammonia eliminates the problem of the corrosion of the reactor and the extra operation with a large amount of the inorganic salt solution, which is more advantageous than US Pat. No. 3,715,365. Disclosure. However, as shown in the examples, MGX decomposition occurs when reacting in the region of PH 9.2 to 9.4, acetaldehyde is generated, and 2,4-dimethylimidazole (hereinafter, 2,4-DMI) is generated.
Is abbreviated. ) Will be more by-products. In the patent, the dilute solution is used to suppress this by-product, but it is not perfect.

Further, in JP-A-60-104072 and JP-A-60-105664,
As an improved method of US Pat. No. 3,716,365, by controlling the total amount of water with respect to MGX, high-purity 4-MI is obtained in high yield, but as in the US patent, ammonium oxalate is used as an ammonia source. For use, the filtration process of 4-MI oxalate and the filtration process of ammonium oxalate after decomposing the salt with ammonia are many and the process becomes complicated, which is not economical.

[Problems to be solved by the invention]

The present inventors suppress the by-product of 2,4-DMI and the by-product of methylenebisimidazoles produced from 4-mol of 2-MI and 1 mol of formaldehyde, and the reaction concentration is high, and complicated steps such as filtration are performed. As a result of studying to develop a process that does not contain, is simplified and can be industrially easily carried out, and can obtain 4-MI of high purity and high yield, while adjusting to PH2-4, M
GX, formalin, and ammonia were reacted in an aqueous medium in the presence of ammonium sulfate to obtain good results, and the application was filed earlier (JP-A-1-139567).

However, MGX, formaldehyde, and ammonia are reacted in the presence of ammonium sulfate to obtain 4-MI sulfate, and then a salt exchange reaction is performed using ammonia to release free 4-
When MI and ammonium sulphate are used, 4-MI and 4,5-DMI are simple, with the major drawback of increasing the by-product of 4,5-dimethylimidazole (hereinafter abbreviated as 4,5-DMI). It was found that it is difficult to separate into 2 and causes a decrease in purity.

[Means and Actions for Solving Problems]

When the present inventors conducted a salt exchange reaction, as a result of diligent studies to suppress the 4,5-DMI byproduct, the 4,5-DMI byproduct was the raw material MG.
It is unclear whether the cause is the diacetyl compound present as an impurity in X, or whether it is generated by the transfer reaction of the by-product intermediate, but it was found that it can be suppressed if the salt exchange reaction is carried out at 50 ° C or lower, The present invention has been completed.

That is, in the present invention, methylglyoxal, formaldehyde, and ammonia are reacted in the presence of ammonium sulfate to obtain a sulfate of 4-methylimidazole, and then a salt exchange reaction is performed using ammonia to give a free 4-
A method for producing 4-methylimidazole, which comprises performing a salt exchange reaction at 50 ° C. or lower when using methylimidazole and ammonium sulfate.

When the salt exchange reaction temperature exceeds 50 ° C, the amount of 4,5-DMI by-produced increases, and it is difficult to easily separate 4-MI and 4,5-DMI, resulting in a decrease in purity.

According to the production method of the present invention, MGX, formaldehyde and ammonia are reacted in the presence of ammonium sulfate to give 4-
After obtaining the sulfate of MI, the salt exchange reaction is performed with ammonia to make free 4-MI and ammonium sulfate, but the amount of ammonia used in the salt exchange reaction is sufficient to neutralize the acid content in the reaction solution. It is sufficient to use the amount. Also, the sulfate is MG
Presence of ammonium sulfate under the condition that X and formaldehyde are adjusted to a reaction temperature of 50 to 100 ° C., a reaction time of 2 to 5 hours, PH2 to 4 or initial PH value = PH value of ammonium sulfate aqueous solution to PH2 to 4 during the reaction. It is obtained by reacting ammonia underneath.

As the ammonia used in the salt exchange reaction, an aqueous ammonia solution or ammonia gas is used.

The salt exchange reaction time does not have to be specified in particular, and the time is adjusted so that the reaction temperature is 50 ° C. or lower. As a salt exchange reaction method, an aqueous ammonia solution or ammonia gas is added to the reaction solution to carry out the salt exchange reaction while maintaining the temperature during the reaction at 50 ° C. or lower.

An organic solvent insoluble in water, for example, isobutanol is added to the liquid in which the salt exchange reaction has been completed by the above-mentioned method to extract 4-MI, and the extract is distilled under reduced pressure to separate 4-MI.

〔Example〕

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

Example 1 A 3 l glass separable flask equipped with a stirrer and a reflux condenser was charged with 1331 g of distilled water and 608 g of ammonium sulfate. After dissolution, the temperature was raised to 80 ° C. and 53 g of 95% by weight sulfuric acid was charged to obtain a PH of 2. Then, a mixed solution of 750 g of 40 wt% MGX aqueous solution and 338 g of 37 wt% formalin was added dropwise over 2 hours. Meanwhile, 239 g of 28 wt% aqueous ammonia solution to maintain PH2
Was done while adding. After completion of the dropping, the reaction was completed by performing an aging reaction for 2 hours at the same PH value. HPLC analysis results, 4
-MI yield (relative to MGX, same hereafter) is 87.5%, 4 of 4,5-DMI
-Area% by liquid chromatography analysis for MI (hereinafter abbreviated as liquid chromatography analysis) was 0.08%.

Using 200 g of this reaction solution, 28% by weight aqueous ammonia solution 31.8
g was added so that the temperature was kept at 20 ° C., and a salt exchange reaction was performed.
As a result, the area% by liquid chromatography analysis of 4,5-DMI with respect to 4-MI was 0.20%.

Example 2 Using 200 g of the reaction solution obtained in Example 1, 31.8 g of 28% by weight aqueous ammonia solution was added so as to keep the temperature at 40 ° C. to carry out a salt exchange reaction. As a result, the area% by liquid chromatography analysis of 4,5-DMI with respect to 4-MI was 0.20%.

Example 3 Using 200 g of the reaction solution obtained in Example 1, 31.8 g of 28% by weight aqueous ammonia solution was added so as to keep the temperature at 50 ° C. to carry out a salt exchange reaction. As a result, the area% of 4,5-DMI with respect to 4-MI measured by liquid chromatography was 0.24%.

Comparative Example 1 Using 200 g of the reaction solution obtained in Example 1, 31.8 g of 28% by weight aqueous ammonia solution was added while keeping the temperature at 60 ° C. to carry out a salt exchange reaction. As a result, the area% of 4,5-DMI with respect to 4-MI by liquid chromatography was 0.65%.

Comparative Example 2 Using 200 g of the reaction solution obtained in Example 1, 31.8 g of 28% by weight aqueous ammonia solution was added so as to keep the temperature at 80 ° C. to carry out a salt exchange reaction. As a result, the area% of 4,5-DMI with respect to 4-MI by liquid chromatography analysis was 1.15%.

〔The invention's effect〕

The method of the present invention is a simplified process in which by-products of 2,4-DMI, 4,5-DMI and dimers are suppressed and 4-MI of high purity and high yield is obtained.

The 4-MI obtained by the method of the present invention has a purity of 97% or more without any special purification, and the area% by liquid chromatography analysis of 4,5-DMI with respect to 4-MI is 0.5% or less.

Claims (1)

[Claims] 1. A method of reacting methylglyoxal with formaldehyde and ammonia in the presence of ammonium sulfate to obtain a sulfate of 4-methylimidazole, and then performing a salt exchange reaction with ammonia to give free 4-methylimidazole. And ammonium sulfate, the salt exchange reaction is carried out at 50 ° C. or lower.