JPH07100698B2 - 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.

[Conventional technology]

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, ammonia water is added dropwise to this, and the reaction is carried out at PH4.7 to PH4.4, and then calcium hydroxide is added. It is disclosed that 4-MI is obtained by dispersing ammonia, precipitating sulfate as calcium sulfate, filtering the precipitate, dehydrating and distilling. However, the product purity is 77.2% in area purity by gas chromatography analysis, and the yield is 59%. To be used as a pharmaceutical intermediate, a further purification operation is required, which lowers the yield and the method is not satisfactory.

Further, in JP-A-57-9766, as a method for improving the above-mentioned U.S. Patent, under the condition that PH is 7 or more, the feed order of the raw materials is characterized by reacting ammonia, aldehyde and MGX to give 4-MI. It is disclosed to obtain. Further, a PH of 7 or higher, and the use of ammonia eliminates the problem of reactor corrosion and the extra operation of large amounts of inorganic salt solution, and is shown to be advantageous over US Pat. No. 3,715,365. However, as shown in the examples, PH9.2-9.4
When the reaction occurs in the region of MGX, decomposition of MGX occurs, acetaldehyde is generated, and 2,4-dimethylimidazole (hereinafter, DMI
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. 3,715,365, by controlling the total amount of water with respect to MGX, high-purity 4-MI is obtained in a high yield, but as with the US patent, ammonia 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-production of methylenebisimidazoles produced from 1 mol of formaldehyde and 2 mol of DMI and 4-MI produced as by-products, have a high reaction concentration, and do not include complicated steps such as filtration. It was studied to develop a process that can produce industrially easily implemented, highly pure, high yield 4-MI.

[Means and Actions for Solving Problems]

The present inventors have found that acetaldehyde produced by decomposition of MGX as a raw material is a cause of DMI production as a by-product, that MGX is stable in a low PH region, and methylenebisimidazoles also have low PH. The inventors have found that generation is suppressed in the region and have completed the present invention.

That is, the present invention is characterized by adding MGX and formaldehyde to an ammonium sulfate aqueous solution having a pH of 2 to 4 using sulfuric acid, and reacting while adding ammonia so that the pH of the solution is maintained in the range of 2 to 4. And 4
-MI manufacturing method.

The present invention will be described in detail. The present invention is characterized by reacting MGX with formaldehyde and ammonia in an aqueous medium in the presence of ammonium sulfate while adjusting pH to 2 to 4 using sulfuric acid and ammonia. It is a manufacturing method of MI.

When the pH exceeds 4, not only DMI but also methylenebisimidazole by-products increase and the yield decreases, and 4-
Purity also declines because it is impossible to easily separate MI and DMI. In this case, as described in US Pat. No. 3,715,365, the yield is about 65% and the purity is only about 80%.

On the other hand, if the PH is less than 2, the reaction speed will decrease rapidly,
It is not preferable because the reaction is not completely completed. It takes a long time to complete the reaction, or if the reaction is carried out at a high temperature for a short time, the amount of the polymer increases and the yield decreases.

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

The production method according to the present invention is carried out in the presence of ammonium sulfate in the presence of MG
React X with formaldehyde and ammonia,
The amount of ammonium sulfate used may be 1 or more with respect to MGX, and since ammonia is used for the reaction and for keeping the reaction PH at 2 to 4, the molar ratio is MG.
It is 2 or more for X.

The excess of formaldehyde can be about 1.1 times the molar ratio of MGX, but if it exceeds it, side reactions are promoted, which is inconvenient.

The reaction temperature is 50 to 100 ° C, preferably 70 to 80 ° C.

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

As a reaction method, in order to maintain the pH during the reaction at 2 to 4, a mixed solution of MGX and formaldehyde was added dropwise to an aqueous solution in which sulfuric acid was added to ammonium sulfate to adjust the pH to 2 to 4,
Alternatively, the reaction is carried out by adding an aqueous ammonia solution or ammonia gas while dropping MGX and formaldehyde at the same time.

Since 4-MI sulfate is produced in the reaction system in which the reaction is completed by the above-mentioned method, the reaction system is made alkaline, extracted with a solvent, and distilled under reduced pressure to separate 4-MI.

〔Example〕

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

Example 1 A 1-glass separable flask equipped with a stirrer and a reflux condenser was charged with 316.9 g of distilled water and 145.4 g of ammonium sulfate, and after dissolution, further charged with 16.3 g of 95% by weight sulfuric acid, and a part of ammonium sulfate was changed to acidic ammonium sulfate. At the same time, the pH was adjusted to 2.0 and the temperature was raised to 80 ° C. After heating, 80 ℃
After finely adjusting the pH with, confirming PH2.0, 40 wt% MGX aqueous solution
A mixture of 177.6 g and 37 wt% formalin 80.8 g was added dropwise over 2 hours. In the meantime, in order to maintain PH 2.0, it was performed while adding 55.8 g of 28% by weight aqueous ammonia solution. After completion of the dropping, the reaction was completed by performing an aging reaction for 2 hours at the same PH value. As a result of HPLC analysis, 4-MI yield (versus MGX, the same applies hereinafter) is 8
The yield was 8.90% and the DMI yield was 0.21% (versus MGX).

Example 2 The same reactor as in Example 1 was charged with 328.2 g of distilled water and 145.4 g of ammonium sulfate, heated to 80 ° C. and dissolved therein, and further charged with 2.2 g of 95% by weight sulfuric acid to adjust the PH to 3 to give 1 part of ammonium sulfate. Parts were acid ammonium sulfate. After confirming PH3, 4
A mixture of 177.6 g of 0 wt% MGX aqueous solution and 80.9 g of 37 wt% formalin was added dropwise over 2 hours. In the meantime, in order to maintain PH3.0, it was performed while adding 60 g of 28% by weight aqueous ammonia solution. After completion of the dropping, the reaction was completed by performing an aging reaction for 2 hours at the same PH value. As a result of HPLC analysis, 4-MI yield was 88.8%,
The DMI yield was 0.19%.

Example 3 The same reactor as in Example 1 was charged with 316.9 g of distilled water, 145.4 g of ammonium sulfate, and 0.24 g of 95% by weight sulfuric acid, a part of ammonium sulfate was changed to acidic ammonium sulfate, and PH was adjusted to 4.0.
The temperature was raised to 0 ° C. After confirming PH4.0 at 80 ℃, 40wt% MGX
A mixture of 177.6 g of an aqueous solution and 80.8 g of 37% by weight formalin
85.1% ammonia water 65.1 g was added dropwise while maintaining PH 4.0. After completion of the dropping, the reaction was completed by performing an aging reaction for 2 hours at the same PH value. As a result of HPLC analysis, 4-MI yield was 8
The yield was 5.2% and the DMI yield was 0.35%.

Comparative Example 1 In Example 1, the reaction was carried out in the same manner as in Example 1 while adding 95% by weight sulfuric acid to ammonium sulfate alone and maintaining PH5.1 as it was by adding 28% by weight ammonia water. It was As a result, the 4-MI yield was 80% and the DMI yield was 0.62%.

Comparative Example 2 In Comparative Example 1, 28% by weight aqueous ammonia was not added, and the reaction was carried out while the PH decreased in accordance with the reaction. After 2 hours of aging reaction, the PH was 1.2, resulting in 4
-MI yield was 79.4% and DMI yield was 0.77%.

〔The invention's effect〕

The 4-MI obtained by the method of the present invention has a purity of 97% or more, a DMI yield of 1% or less, and a 4-MI yield of 85% or less without special purification. There is no.

Claims (1)

[Claims] 1. Methylglyoxal and formaldehyde are added to an ammonium sulfate aqueous solution having a pH of 2 to 4 using sulfuric acid, and the reaction is performed while adding ammonia so that the pH of the solution is maintained in the range of 2 to 4. The method for producing 4-methylimidazole.