JP3523661B2 - Method for purifying 2-alkyl-4-halogeno-5-formylimidazole - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for purifying 2-alkyl-4-halogeno-5-formylimidazole useful as a raw material for pharmaceuticals such as diuretics and antihypertensives. . [0002] 2-Alkyl-4-halogeno-5-formylimidazole has useful uses as described above and is a chemical product that has attracted attention in recent years. For example, only a method of producing from 2-amino-3,3-dichloroacrylonitrile and aldehyde via a Schiff base (Japanese Patent Application Laid-Open No. 54-148788) is disclosed. However, in this known technique, it is difficult to obtain 2-amino-3,3-dichloroacrylonitrile as a raw material, which is very disadvantageous in practice on an industrial scale, and cannot be said to be a satisfactory method. Therefore, there has been a strong desire among those skilled in the art to develop a new method for producing 2-alkyl-4-halogeno-5-formylimidazole which can be produced in high yield from industrially available raw materials. Therefore, the present inventors have proposed a method of halogenating 2-alkyl-5-formylimidazole using N-halogenosuccinimide (see Japanese Patent Application No. 3-187117) and the method of producing 2-alkyl-4-halogeno obtained above. −
A method has been proposed in which 5-formylimidazole is separated as a sulfonic acid compound by a sulfonating agent from a by-product and purified (see Japanese Patent Application No. 4-269587). [0003] However, as a result of studies by the present inventors, 2-alkyl-4,5-dihaloimidazole is by-produced during halogenation in such a method. Although the purification method shown is an easy and inexpensive method on an industrial scale and is a very significant invention, it has been found that the final target product still contains some by-products, and further purification. It became clear that improvement was needed. [0004] However, the present inventors have conducted intensive studies to obtain pure 2-alkyl-4-halogeno-5-formylimidazole, and as a result, have obtained 2-alkyl-5-formylimidazole. Is halogenated with N-halogenosuccinimide to give a 2-alkyl-4-halogeno-5-formylimidazole obtained by sulfonating water
It is dissolved in the solution as a sulfonic acid compound at room temperature to the boiling point and at a pH of 1 to 6.5 and separated from by-products. The pH of the obtained sulfonic acid compound solution is adjusted to 6.5 to 8.5, and impurities are further removed. After removing, and then adjusting the pH of the solution to 8.5 to 11, it was found that the intended object was obtained when the intended product was obtained, and the present invention was completed. Hereinafter, the present invention will be described in detail. [0005] The object of the present invention, 2-alkyl-4-
Halogeno-5-formylimidazole is 2-amino as described above.
It is obtained by halogenating alkyl-5-formylimidazole with N-halogenosuccinimide. The alkyl group of 2-alkyl-5-formylimidazole in the above is an alkyl group having 2 to 6 carbon atoms,
The halogeno groups of N-halogenosuccinimide are a chloro group and a bromo group, and the corresponding 2-alkyl-4-halogeno-5-formylimidazole can be produced correspondingly. In the above, the solvent is 0.5 to 1.5 mol, preferably 0.7 to 1.0 mol per mol of the raw material 2-alkyl-5-formylimidazole and the raw material.
The reaction is carried out by charging 15 mol of N-halogenosuccinimide. As the solvent, various organic solvents can be used, for example, halogenated hydrocarbons such as methyl chloride, methylene chloride, chloroform, carbon tetrachloride, 1-chloroethane, 1,2-dichloroethane, pentane, hexane, heptane, and the like. Saturated hydrocarbons such as octane, aromatic hydrocarbons such as benzene, esters such as ethyl acetate and isopropyl acetate, ethers such as ethyl ether, propyl ether and dioxane are used alone or in combination of two or more. The amount of the solvent used can be, in principle, up to the solubility of the starting material 2-alkyl-5-formylimidazole in each solvent, but practically the starting material 2-alkyl-5-
It is used in the range of about 5 to 20 times the weight of formyl imidazole. The reaction temperature is 0 to 150 ° C., preferably 30 ° C.
To 100 ° C, and the reaction time is 0.5 to 7.0.
The time, preferably 1.0 to 3.0 hours, is advantageous. After completion of the reaction, the reaction-terminated liquid is concentrated under reduced pressure, and a mineral acid aqueous solution such as hydrochloric acid is added to the bottom of the bottom for the purpose of removing water and impurities, followed by treatment with a salt such as sodium chloride to increase the yield of the target product. After the addition, the crystallized target product is collected by filtration or extraction to obtain crude 2-alkyl-4-halogeno-5-formylimidazole. Crude 2-alkyl-4 obtained above
-Halogeno-5-formylimidazole is subsequently subjected to a purification step. [0008] room temperature to the boiling point and the purification method of the crude 2-alkyl-4-halogeno-5-formyl imidazole sulfonating agent solution in the present invention, to dissolve the water soluble acid compound PH1～6.5, It is separated from the by-product 2-alkyl-4,5-dihaloimidazole which is hardly soluble in water, and the pH of the obtained aqueous solution of the sulfonic acid compound is adjusted to 6.5 to 8.5. 2-alkyl-4-
2-alkyl-4,5-dihaloimidazo-, an impurity partially dissolved in halogeno-5-formylimidazole
And the pH of the solution is adjusted to 8.5 to 11 to release the sulfonating agent and to precipitate crystals of the target product. The sulfonating agent in the present invention includes sodium bisulfite, potassium bisulfite, sodium sulfite, potassium sulfite, sulfur dioxide and the like.
The amount of the sulfonating agent used is 0.8 to 1 mol of 2-alkyl-4-halogeno-5-formylimidazole.
５5 mol, preferably 1.0-2.5 mol is suitable. In carrying out the purification in the present invention, specifically, first, crude 2-alkyl-4-halogeno-5-formylimidazole is added to an aqueous solution of a sulfonating agent and dissolved in the solution as a water-soluble sulfonic acid compound. Then, insoluble by-products are removed by filtration or extraction.
In such a case, it is preferable to add activated carbon for the purpose of decolorization and further reduction of by-products and impurities. The temperature conditions for such an operation must be from room temperature to the boiling point , and
0-80 ° C, pH must be 1-6.5
In is adjusted preferably in the range of 2-5. The dissolution time of the sulfonic acid compound in the solution is slightly different depending on the above conditions, but is about 10 minutes to 5 hours. PH above
There are no particular restrictions on the pH adjuster for adjusting the pH, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and acetic acid, propionic acid, lactic acid, and organic acids such as oxalic acid. It is also possible to use metal hydroxides such as sodium and potassium hydroxide, ammonia, amines and alkalis such as sodium dihydrogen phosphate, sodium phosphate and sodium carbonate. As the extractant for performing the extraction operation in the above, benzene, toluene, 1,2-dichloroethane, chloroform, ethyl acetate, propyl acetate,
Methyl ethyl ketone, methyl isobutyl ketone and the like are used. Next, an alkali is added to the filtrate or the aqueous layer of the extraction residue, and the pH is adjusted to 6.5 to 8.5.
Further, 2-alkyl-4,5-dihaloimidazole as an impurity is precipitated and removed by filtration or extraction. If the pH is less than 6.5, the precipitation of impurities is not sufficient,
When it exceeds 8.5, 2-alkyl-4-halogeno-5
-Most of the formyl imidazole is not preferable because it crystallizes. Such alkali is not particularly limited, and includes metal hydroxides such as sodium hydroxide and potassium hydroxide, ammonia, amines, sodium dihydrogen phosphate, sodium phosphate, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, hydrogen hydrogen carbonate Potassium and the like. As the extractant for performing the extraction operation, the same extractant as described above is used. Then, 100% pure 2-alkyl-4-halogeno-5-formylimidazole was added to the filtrate or the extraction residue obtained above by further adding an alkali and adjusting the pH to 8.5 to 11. Crystallize and isolate by filtration or extraction to obtain the desired product. If the pH is lower than 8.5, the precipitation of 2-alkyl-4-halogeno-5-formylimidazole is not sufficient, and if the pH is higher than 11, the decomposition of 2-alkyl-4-halogeno-5-formylimidazole occurs, which is not preferable. . In such an operation, it is preferable to add a salt such as sodium chloride which is soluble in the solution since the precipitation amount of the target substance increases due to a salting out effect. As the extractant for performing the extraction operation, the same extractant as described above is used. The object thus obtained is 100
% Pure 2-alkyl-4-halogeno-5-formylimidazole. The present invention relates to a method for purifying a 2-alkyl-4-halogeno-5-formylimidazole obtained by halogenating a 2-alkyl-5-formylimidazole with N-halogenosuccinimide, which is an industrial process. It is possible to obtain the target product 100% pure by using an inexpensive method. The present invention will be described below in further detail with reference to examples. Example 1 In 3.80 kg of dioxane, 200 g (1.30 mol) of 2-butyl-5-formylimidazole and 139 g (1.04 mol) of N-chlorosuccinimide were charged, and the mixture was stirred at 70 ° C. for 1.5 hours. The reaction was performed. After the reaction,
The reaction solution was concentrated under reduced pressure to obtain 363 g of a brown concentrate. 356 g of 10% hydrochloric acid was added thereto, and the mixture was stirred at 50 ° C. for 2.5 hours, cooled to room temperature, and added with 1.79 kg of 15% saline. Then, a 40% aqueous sodium hydroxide solution was added to adjust the pH to 2.0, and the precipitated crystals were filtered. After sufficiently washing the filter cake, it was dried to obtain 104.0 g of a pale yellow powder. As a result of quantitative analysis of these crystals by high performance liquid chromatography, 2-butyl-4-chloro-5-formylimidazole, 92.2 g and 2-butyl-4,5-
It contained 11.2 g of dichloroimidazole. 21.3 g of the crystals obtained above (2-butyl-4-chloro-5-formylimidazole 18.9)
g, 2-butyl-4,5-dichloroimidazole 2.3
0 g) in a 6.0% aqueous sodium bisulfite solution 4
After adding 18 g and adjusting the pH to 3.47 with 6.3 g of acetic acid, the mixture was stirred at 60 ° C. for 3 hours. Then, the insoluble matter is filtered,
2.0 g of 50% aqueous activated carbon was added to the filtrate, and the mixture was stirred for 45 minutes while cooling to room temperature. The activated carbon was filtered off, and a 48.8% aqueous sodium hydroxide solution was slowly added to the filtrate until crystals precipitated. When 19.8 g was added, a small amount of crystals precipitated, and the addition was stopped. The p of the solution at this time
H was 7.55. After stirring for 15 minutes as it was, the crystals were separated by filtration. A 40% aqueous sodium hydroxide solution was further added to the obtained filtrate to adjust the pH to 9.01.
60 g of common salt was added and the mixture was stirred for 15 minutes, and the precipitated crystals were separated by filtration. 13. Wash the cake with a small amount of water and dry.
0 g of crystals were obtained. According to the result of analysis by liquid chromatography, the crystals were found to be 100% of 2-butyl-4-chloro-5-formylimidazole and 2-butyl-4,5
-Dichloroimidazole was not included. Example 2 In Example 1, 85% phosphoric acid was used without using acetic acid.
8 g was added to adjust the pH to 3.0, and the treatment was performed. After filtration with water-containing activated carbon, a 40% aqueous sodium hydroxide solution was slowly added to the filtrate until crystals precipitated. When 23.3 g was added, a small amount of crystals precipitated, and the addition was stopped. At this time, the pH of the solution was 7.53. After stirring for 10 minutes as it was, the crystals were separated by filtration. An additional 40 is added to the filtrate obtained.
A 20% aqueous solution of sodium hydroxide was added to adjust the pH to 9.02, followed by stirring for 20 minutes, and the precipitated crystals were separated by filtration. The filter cake was washed with a small amount of water and dried to obtain 14.3 g of crystals. According to the results of liquid chromatography, the crystals were found to be 100% of 2-butyl-4-chloro-5-formylimidazole, and did not contain 2-butyl-4,5-dichloroimidazole. Example 3 Into 1380 g of dioxane, 69.1 g (0.50 mol) of 2-propyl-5-formylimidazole and 53.4 g (0.40 mol) of N-chlorosuccinimide were charged.
The reaction was stirred at a temperature of 70 ° C. for 1.5 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 133 g of a brown concentrate.
To this, 146 g of 10% hydrochloric acid was added, and the mixture was stirred at 50 ° C. for 2.5 hours, and then 190 g of 20% saline was added. Then, a 40% aqueous sodium hydroxide solution was added to adjust the pH to 2.0, and the mixture was cooled to 10 ° C. The precipitated crystals were filtered, and the cake was sufficiently washed and dried to obtain 35.3 g of a pale yellow powder. As a result of quantitative analysis of these crystals by high performance liquid chromatography, 2-propyl-4-chloro-5-formylimidazole, 31.8 g, and 2-propyl-4,
It contained 3.3 g of 5-dichloroimidazole. 19.4 g of the crystals obtained above (2-propyl-4-chloro-5-formylimidazole 17.5 g).
g, 2-propyl-4,5-dichloroimidazole
418 g of a 5.0% aqueous sodium bisulfite solution was added to the mixture (containing 82 g), the pH was adjusted to 2.0 with 50% sulfuric acid, and the mixture was stirred at 60 ° C. for 2 hours. Next, the insoluble matter was filtered, and 2.3 g of 50% aqueous activated carbon was added to the filtrate, and the mixture was stirred for 45 minutes while cooling to room temperature. The activated carbon was filtered off, and a 40% aqueous sodium hydroxide solution was slowly added to the filtrate until crystals precipitated. When 25.8 g was added, a small amount of crystals precipitated, and the addition was stopped. The p of the solution at this time
H was 7.74. After stirring for 15 minutes as it was, the crystals were separated by filtration. A 40% aqueous sodium hydroxide solution was further added to the obtained filtrate to adjust the pH to 9.05.
60 g of common salt was added and stirred for 15 minutes, and the precipitated crystals were separated by filtration. The filter cake is washed with a little cold water and dried to 14.6.
g of crystals were obtained. According to the result of liquid chromatography analysis, the crystals were found to be 2-propyl-4-chloro-5-formylimidazole 100%, 2-propyl-4,
5-Dichloroimidazole was not included. According to the present invention, there is provided a 2-alkyl-4-halogeno-5 obtained by halogenating a 2-alkyl-5-formylimidazole using N-halogenosuccinimide.
In purifying formyl imidazole, the imidazole is converted into a water-soluble sulfonic acid compound, and then a 100% pure target product is obtained by a two-stage crystallization method.

Claims (1)

(57) [Claim 1] 2-alkyl-4-halogeno-5-formylimidazole obtained by halogenating 2-alkyl-5-formylimidazole with N-halogenosuccinimide is used as a sulfonating agent. Room temperature to boiling point, pH 1 in aqueous solution
The solution was dissolved as a sulfonic acid compound at ~ 6.5 and separated from by-products.
The pH was adjusted to 5 to 8.5 to further remove impurities, and then the pH of the solution was adjusted to 8.5 to 11 to obtain 2-
A method for purifying 2-alkyl-4-halogeno-5-formylimidazole, comprising isolating alkyl-4-halogeno-5-formylimidazole .