JPH06256314A - Method for synthesizing 2-butyl-4-chloro-5-formylimidazole - Google Patents

Abstract

PURPOSE:To mass-produce 2-butyl-4-chloro-5-formylimidazole useful as an intermediate for medicines. CONSTITUTION:2-Butyl-4-chloro-5-methylimidazole is oxidized with a persulfate in water or a solvent containing water in the presence of a metal salt under heating to synthesize 2-butyl-4-chlori-5-formylimidazole.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing 2-butyl-4-chloro-5-formylimidazole which is useful as an intermediate for pharmaceuticals.

[0002]

2. Description of the Related Art A method for producing 2-butyl-4-chloro-5-formylimidazole is disclosed in JP-A-63-238868.
In the publication, 2-butyl-5-hydroxymethylimidazole is reacted with a chlorinating agent such as N-chlorosuccinimide to synthesize 2-butyl-4-chloro-5-hydroxymethylimidazole. A method of reacting an oxidizing agent is disclosed in Japanese Patent Publication No. 61-2022.
-Amino-3,3-dichloroacrylonitrile and valeroaldehyde are reacted to give a Schiff base, which is treated with hydrochloric acid and then with water, respectively.

According to the former method, however, the starting material, 2-butyl-5-hydroxymethylimidazole, involves an extremely difficult treatment of reacting the imidite ester with dihydroxyacetone in liquid ammonia, and the latter method. 2-Amino-3,3-dichloroacrylonitrile used in the method also has a problem that the synthesis thereof is extremely complicated, and 2-butyl-4
A convenient method for synthesizing -chloro-5-formylimidazole has been desired.

[0004]

The object of the present invention is 2-butyl-4-chloro-, which is useful as an intermediate for pharmaceuticals.
An object of the present invention is to provide a method capable of inexpensively producing a 5-formylimidazole compound in a large amount.

[0005]

The inventors of the present invention have conducted various tests in view of such circumstances, and as a result, 2-butyl-4
2-Chloro-5-methylimidazole can be easily oxidized by adding persulfate to oxidize 2-butyl-5-methylimidazole in water or a solvent containing water in the presence of a metal salt as a catalyst.
It was found that a 4-chloro-5-formylimidazole compound was obtained, and the method of the present invention was completed. The method of the present invention is represented by the following reaction formula.

[0006]

[Chemical 1]

The method for synthesizing the 2-butyl-4-chloro-5-formylimidazole compound of the present invention is as follows. 2-butyl-4-chloro-5-methylimidazole is dissolved in water or a solvent containing water, and this solution is used. After a metal salt acting as a catalyst is added to, a persulfate or an aqueous solution containing a persulfate is further added, and the temperature range of room temperature to 100 ° C.
It is preferable to oxidize by heating in a temperature range of 50 to 100 ° C.

The solvent used in the method of the present invention is preferably a solvent which is compatible with water and stable against oxidation, and typical examples thereof include acetic acid, DMF, dioxane, ethanol and the like.

Typical catalysts used in the practice of the method of the present invention include iron, silver, copper, cobalt, manganese,
It is a metal salt such as vanadium, and for example, ferrous chloride, ferric chloride, ferrous sulfate, ferric sulfate, silver nitrate, copper sulfate and the like are used. The amount of catalyst added was 0. 0 with respect to the starting material, 2-butyl-4-chloro-5-methylimidazole.
It is in the range of 1 to 50% by weight, preferably 0.5 to 10
% By weight.

The persulfates used in the method of the present invention include alkali persulfates such as sodium persulfate and potassium persulfate, and ammonium persulfate. The amount of persulfate added is 0.5 to 4.0 with respect to 2-butyl-4-chloro-5-methylimidazole as a raw material.
The molar amount is double, and preferably 1.0 to 2.5 times. If the amount of persulfate is less than 0.5 times the molar amount, a large amount of unreacted material remains, and if the amount of the persulfate is more than 4.0 times the molar amount, the produced target product is further oxidized and the amount of by-products increases, resulting in purification It gets harder.

If necessary, an acidic substance such as sulfuric acid, hydrochloric acid, nitric acid or acetic acid may be added to the solvent, and sulfuric acid is particularly preferable. The addition amount at this time is 0.1
It is 2.0 times equivalent and preferably 0.5 to 1.0 times equivalent.

The reaction product contains 2-butyl-
In addition to the 4-chloro-5-formylimidazole compound, 2-butyl-4-chloro-5-methylimidazole which is a raw material and 2-butyl-4-chloro- which is a by-product.
5-hydroxymethylimidazole and 2-butyl-4
-Chloroimidazole-5-carboxylic acid and the like are included.
2-Butyl-4-chloro-5-hydroxymethylimidazole can be easily obtained by oxidation with a suitable oxidizing agent to give 2-butyl-4-chloro-5-formylimidazole. -Butyl-4-chloro-5-methylimidazole can also be recovered by any suitable method.

From the reaction mixture, the desired product 2-butyl-4-
The method for isolating and purifying chloro-5-formylimidazole is carried out according to a conventional method. For example, an alkaline aqueous solution is added to the reaction mixture to make it basic, followed by extraction with a suitable solvent, and the extract is decompressed. After drying to dryness, the dry solid may be recrystallized using a suitable solvent, or after subjecting the dry solid obtained by the extraction operation to vacuum distillation,
The distillate obtained may be recrystallized using a suitable solvent.

As another method, the dry solid obtained by the extraction operation is dissolved in a solvent, and manganese dioxide of the same amount to 5 times as the dry solid is added to the solution, and the mixture is allowed to stand at room temperature for 2 minutes.
After stirring for at least 10 hours, preferably at least 10 hours, the manganese dioxide is filtered off, the filtrate is concentrated and the concentrate is recrystallized with a suitable solvent, or the concentrate is distilled and then distilled. It can be isolated and purified by a method of recrystallizing the product.

[0015]

EXAMPLES The present invention will be specifically described below with reference to examples and reference examples. (Reference Example) Synthesis of 2-butyl-4-chloro-5-methylimidazole 138 g (1.0 g) of 2-butyl-4-methylimidazole
Mol) was dissolved in 370 ml of chloroform, and N-
146 g (1.1 mol) of chlorosuccinimide was added little by little over 1 hour, and the mixture was further heated at 30 to 40 ° C. for 2 hours.

After completion of the reaction, the succinimide precipitated was filtered off, an aqueous solution of sodium carbonate was added to the filtrate, and the mixture was vigorously stirred, and then separated to separate a chloroform layer, which was condensed under reduced pressure to obtain a dry sample. The solid was extracted with acetone. Next, the extract was concentrated and recrystallized with a small amount of acetone to obtain 80 g of the desired product, 2-butyl-4-chloro-5-methylimidazole (yield 46 mol%).

Example 1 2-Butyl-4-chloro-5
-Methylimidazole 172.5 g (1.0 mol) is dissolved in a sulfuric acid aqueous solution consisting of concentrated sulfuric acid 100 g and water 1660 ml, copper sulphate 8.6 g is added thereto, and at room temperature sodium persulfate 524 g (2.2 mol) and water are added. 1660 ml
An aqueous solution of sodium persulfate consisting of was gradually added dropwise over 15 minutes, and then the mixture was heated under reflux for 1 hour.

370 g of sodium carbonate was added to the obtained reaction product.
(3.5 mol) was added to make it basic, and the oily substance that had liberated was extracted with ethyl acetate by liquid, and after passing the extract through activated clay, it was dried to 120 g dry solid. Got The dry solid was examined by liquid chromatography to give 2-butyl-4-chloro-5-yield of 49 mol%.
It was found that a formyl imidazole compound was produced. Further, the dried solid was purified by recrystallization to obtain 76.5 g (yield 41 mol%) of 2-butyl-4-chloro-5-formylimidazole having a purity of 96.5%. The purity is an analysis value by liquid chromatography.

Example 2 2-Butyl-4-chloro-5
172.5 g (1.0 mol) of methylimidazole was dissolved in a sulfuric acid aqueous solution consisting of 50 g of concentrated sulfuric acid and 1660 ml of water, 10 g of silver nitrate was added to this solution, and the mixture was heated to boiling,
Then, 594 g (2.2 mol) of potassium persulfate was added thereto little by little, and the mixture was heated under reflux for 1 hour.

After cooling the resulting reaction product, Example 1
When treated in the same manner as in (1), 130 g of a dry solid was obtained. When this was examined by liquid chromatography, 2-butyl-4-chloro- was obtained in a yield of 51 mol%.
It was found that a 5-formylimidazole compound was produced. Further, the dried solid was purified by recrystallization to obtain a purity of 9
74.6 g (yield 40 mol%) of 7.0% 2-butyl-4-chloro-5-formylimidazole was obtained.

Example 3 2-Butyl-4-chloro-5
172.5 g (1.0 mol) of methyl imidazole was dissolved in a sulfuric acid aqueous solution consisting of 100 g of concentrated sulfuric acid and 1660 ml of water, and 8.5 g of ferric chloride was added to this solution and heated,
Under reflux, 501 g (2.2 mol) of ammonium persulfate was added to 1
The mixture was added over time, and heating was continued for another 3 hours to allow the reaction to heat up.

When the obtained reaction mixture was treated in the same manner as in Example 1, 150 g of a dry solid was obtained, which was examined by liquid chromatography.
2-butyl-4-chloro-5-formylimidazole compound and 21 mol% 2-butyl-4-chloro-5-hydroxymethylimidazole are included in a yield of mol% (82.1 g). understood.

The dried solid was dissolved in 1500 ml of acetone, and 200 g of manganese dioxide powder was added to the solution. After stirring at room temperature for 15 hours, manganese dioxide was filtered off, and the filtrate was concentrated to purify the concentrate according to a conventional method. However, 2-butyl-4-chloro-5-formyl imidazole 10
0.7 g (54 mol%) was obtained. Recrystallize with isopropyl alcohol to obtain 2 with a purity of 97.5%.
-Butyl-4-chloro-5-formyl imidazole 8
4.0 g (yield 45 mol%) was obtained.

[0024]

Industrial Applicability According to the method of the present invention, a 2-butyl-4-chloro-5-formylimidazole compound useful as an intermediate for pharmaceuticals can be produced using relatively inexpensive raw materials, and It is suitable for industrial scale implementation because it is easy to process in the manufacturing process.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Atsushi Saeki 1472 Onohara, Onohara-cho, Mitoyo-gun, Kagawa Prefecture (72) Inventor Naoki Kano 7164, Higashi-cho, Marugame, Kagawa Prefecture

Claims (1)

[Claims] 1. 2-Butyl-4-chloro-5-methylimidazole is characterized in that persulfate is added and oxidized in the presence of a metal salt in water or a solvent containing water. -Method for synthesizing chloro-5-formyl imidazole.