CN110938036A

CN110938036A - Preparation method of 4-iodine-1H-imidazole

Info

Publication number: CN110938036A
Application number: CN201911351922.6A
Authority: CN
Inventors: 孙海鹰; 方坤森; 马宗辉; 李联伟
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2019-12-24
Filing date: 2019-12-24
Publication date: 2020-03-31

Abstract

The invention provides a preparation method of 4-iodine-1H-imidazole, which comprises the following steps: (1) imidazole, iodine and a cosolvent for promoting the solubility of iodine in water react by taking water as a solvent under an alkaline condition, the pH value is adjusted to 7-9 after the reaction is finished, the separated white solid is filtered out, the filtrate is extracted, the solvent is evaporated under reduced pressure and the imidazole is recovered by recrystallization, the recrystallized mother liquor is concentrated, and the obtained white solid is combined with the previously separated white solid to obtain a crude product of the 4-iodine-1H-imidazole; (2) the crude product of 4-iodine-1H-imidazole is recrystallized twice to obtain a pure product of white crystal 4-iodine-1H-imidazole. The invention has simple process, high reaction yield, low production cost and recyclable raw materials.

Description

Preparation method of 4-iodine-1H-imidazole

Technical Field

The invention relates to a new synthesis process of a medical intermediate, in particular to a preparation method of 4-iodo-1H-imidazole.

Background

In the pharmaceutical industry, imidazole groups are important structural components of many biologically active molecules. For example, many compounds with affinity for histamine receptors contain imidazole moieties. By utilizing the 4-iodine-1H-imidazole, imidazole groups can be introduced into different molecules through Suzuki reaction, so that the development of an effective novel synthesis process of the 4-iodine-1H-imidazole has wide practical application and higher economic value. The conventional preparation method of 4-iodo-1H-imidazole includes the following methods: (1) imidazole, iodine monochloride and potassium chloride react to obtain 4-iodine-1H-imidazole. However, iodine monochloride has strong oxidizing property, reacts with water to release heat and generate toxic corrosive gas, has strong stimulation effect on eyes, skin and respiratory tract of human body, is corrosive and even carcinogenic, has low economic benefit, and cannot realize large-scale production in industry. (2) Imidazole, potassium iodide and 1, 3-diiodo-5, 5-dimethylhydantoin are reacted to obtain 4-iodo-1H-imidazole. Since 1, 3-diiodo-5, 5-dimethylhydantoin is expensive, it is expensive to apply it to industrial mass production. (3) Imidazole, iodine and sodium iodide react to generate 4, 5-diiodoimidazole and 2, 4, 5-triiodoimidazole, and then potassium sulfite is used for reducing the 4, 5-diiodoimidazole and the 2, 4, 5-triiodoimidazole to prepare the 4-iodo-1H-imidazole. This method has poor atom economy, requires a large amount of iodine, sodium iodide and potassium sulfite in the reaction process, and potassium sulfite can actually reduce 4-iodo-1H-imidazole, thereby reducing the yield. In addition, a large amount of waste liquid containing potassium sulfite is generated by reduction, and the environmental protection pressure is higher.

The traditional preparation method of 4-iodine-1H-imidazole has the defects of large raw material requirement, high cost and poor reaction atom economy. In order to solve the problems, a novel preparation method of 4-iodo-1H-imidazole is provided.

Disclosure of Invention

The invention aims to provide a preparation method of 4-iodo-1H-imidazole, which has the advantages of simple process, high reaction yield, low production cost and recyclable raw materials.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a preparation method of 4-iodo-1H-imidazole comprises the following steps:

(1) iodination reaction: imidazole, iodine and a cosolvent for promoting the solubility of iodine in water react by taking water as a solvent under an alkaline condition, the pH value is adjusted to 7-9 after the reaction is finished, the separated white solid is filtered out, the filtrate is extracted, the solvent is evaporated under reduced pressure and the imidazole is recovered by recrystallization, the recrystallized mother liquor is concentrated, and the obtained white solid is combined with the previously separated white solid to obtain the crude product of the 4-iodine-1H-imidazole.

(2) And (3) recrystallization: and recrystallizing the obtained 4-iodine-1H-imidazole crude product twice to obtain a 4-iodine-1H-imidazole pure product.

The method is characterized in that the proportion of the fed amount of reactants is optimized, the generation of by-products, namely diiodo-substituted imidazole and triiodo-substituted imidazole, is inhibited by increasing the molar ratio of imidazole, and the pure 4-iodo-1H-imidazole is obtained by a recrystallization method, so that the reduction operation is avoided, and the generation of a large amount of waste liquid containing potassium sulfite is avoided. Under optimized conditions, the generation of 2, 4, 5-triiodoimidazole can be completely inhibited, and the generation amount of 4, 5-diiodoimidazole is greatly reduced. The excess imidazole in the reaction can be recovered by extracting the reaction solution and recrystallizing without significantly increasing the cost.

Preferably, in step (1), the molar ratio of iodine to imidazole is 1: 2-5.

Preferably, in the step (1), the cosolvent for promoting the solubility of iodine in water is one or both of potassium iodide and sodium iodide.

Preferably, in step (1), the molar ratio of iodine to co-solvent is 1: 1-4.

Preferably, in the step (1), the alkaline substance providing alkaline conditions is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate.

Preferably, in step (1), the molar ratio of iodine to basic substance is 1: 1-5.

Preferably, in the step (1), the solvent for recovering imidazole by recrystallization is one or more of isopropanol, n-butanol, dichloromethane, tetrahydrofuran, ethyl acetate and n-hexane. The ratio of the crude product to the solvent is 1 g: 1-20 mL.

Preferably, in the step (2), the solvent used for recrystallization is one or more of water, methanol, ethanol, isopropanol, ethyl acetate and n-hexane. The ratio of the 4-iodine-1H-imidazole crude product to the solvent is 1 g: 1-20 mL.

The invention has the following beneficial effects:

(1) the invention optimizes the proportion of the material amount, increases the molar ratio of imidazole and reduces the generation ratio of the by-products of diiodo substituted imidazole and triiodo substituted imidazole. The excessive imidazole can be recovered by recrystallization, so that the increase of the raw material cost can be avoided.

(2) The method provided by the invention is used for purifying the 4-iodo-1H-imidazole crude product generated by the iodination reaction by recrystallization, so that reduction by a reducing agent can be avoided, the cost can be reduced, and generation of polluting waste can be avoided.

Detailed Description

The present invention will be described in further detail with reference to examples. It should be noted that these embodiments are preferable examples, and are mainly used for understanding the present invention, but the present invention is not limited to these embodiments. The equipment and materials used in the examples are commercially available or commonly used in the industry, and all methods used are conventional in the art.

Example 1

Sodium hydroxide (24.0 g, 0.60mol) was dissolved in 150mL of water, the temperature was reduced to room temperature, then imidazole (40.8 g, 0.60mol) was added and dissolved with stirring. Sodium iodide (33.8 g, 0.23mol) was dissolved in 45mL of water, the temperature was reduced to room temperature, and iodine (38.1 g, 0.15mol) was added. At 0 ℃, dropwise adding aqueous solution of iodine and sodium iodide into aqueous solution of sodium hydroxide and imidazole, and reacting for 6 hours at 0 ℃ after dropwise adding. After the reaction, the pH was adjusted to 7-8 with concentrated hydrochloric acid, and a solid was precipitated, filtered and dried to obtain 17.1 g of a white solid. The filtrate was saturated with 50 g of sodium chloride, extracted with 300 mL. times.2 of ethyl acetate, the organic layers were combined and concentrated to dryness under reduced pressure to give 19 g of a pale yellow solid, and the 19 g of the pale yellow solid was recrystallized from a mixed solvent containing 20mL of ethyl acetate and 20mL of n-hexane, and dried by suction filtration to give 9.5 g of a white solid, which was the recovered raw material imidazole. Mother liquor is decompressed and concentrated to obtain 9.1 g of white solid, and the white solid is combined with 17.1 g of white solid separated out after the reaction and the neutralization, so that the crude product of the 4-iodine-1H-imidazole is obtained.

And adding the combined 26.2 g of solid into a mixed solvent containing 120mL of water and 4mL of ethanol, heating, refluxing for 1 hour, and filtering while the mixture is hot to obtain a filter cake of 4, 5-diiodo-1H-imidazole. The filtrate was cooled to room temperature and crystallized, and 24.7 g of a white solid was obtained by suction filtration. The white solid was recrystallized from a mixed solvent containing 24mL of isopropyl alcohol and 12mL of n-hexane to obtain 18.4 g of white crystals, i.e., pure 4-iodo-1H-imidazole, with a total yield of 70.2%.

Example 2

Sodium hydroxide (190 g, 4.73mol) was dissolved in 800mL of water, the temperature was reduced to room temperature, and then imidazole (320 g, 4.73mol) was added and dissolved with stirring. Sodium iodide (265 g, 1.77mol) was dissolved in 200mL of water, the temperature was reduced to room temperature, and iodine (300 g, 1.18mol) was added. At 0 ℃, dropwise adding aqueous solution of iodine and sodium iodide into aqueous solution of sodium hydroxide and imidazole, and reacting for 10 hours at 0 ℃ after dropwise adding. After the reaction is finished, the pH value is adjusted to 7-8 by concentrated hydrochloric acid, solid is separated out, and 130 g of white solid is obtained by suction filtration and drying. The filtrate was extracted with ethyl acetate 500mL × 3, the organic layers were combined, concentrated to dryness under reduced pressure to obtain 148 g of a pale yellow solid, which was recrystallized from a mixed solvent containing 100mL of ethyl acetate and 100mL of n-hexane, and dried by suction filtration to obtain 76 g of a white solid, which was the recovered raw material imidazole. The mother liquor is decompressed and concentrated to obtain 70 g of white solid, and the white solid separated out after the reaction and the neutralization is combined to obtain the crude product of the 4-iodine-1H-imidazole.

800mL of water and 25mL of ethanol are added to 201 g of the combined solid, the mixture is heated and refluxed for 1 hour, and the hot mixture is filtered by suction, so that the obtained filter cake is 4, 5-diiodo-1H-imidazole. The filtrate was cooled to room temperature and crystallized, and 190 g of a white solid was obtained by suction filtration. The white solid was recrystallized from a mixed solvent containing 180mL of isopropanol and 120mL of n-hexane to obtain 139 g of white crystals, i.e., pure 4-iodo-1H-imidazole, with a total yield of 69.2%.

The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.

Claims

1. A preparation method of 4-iodine-1H-imidazole is characterized by comprising the following steps:

(1) iodination reaction: imidazole, iodine and a cosolvent for promoting the solubility of iodine in water react by taking water as a solvent under an alkaline condition, the pH value is adjusted to 7-9 after the reaction is finished, the separated white solid is filtered out, the filtrate is extracted, the solvent is evaporated under reduced pressure and the imidazole is recovered by recrystallization, the recrystallized mother liquor is concentrated, and the obtained white solid and the previously separated solid are combined to obtain a crude product of the 4-iodine-1H-imidazole.

(2) And (3) recrystallization: and recrystallizing the crude 4-iodo-1H-imidazole product twice to obtain a pure 4-iodo-1H-imidazole product.

2. The process according to claim 1, wherein in step (1), the molar ratio of iodine to imidazole is 1: 2-5.

3. The preparation method according to claim 1, wherein in the step (1), the cosolvent for promoting the solubility of iodine in water is one or both of potassium iodide and sodium iodide.

4. The process according to claim 1, wherein in step (1), the molar ratio of iodine to co-solvent is 1: 1-4.

5. The preparation method according to claim 1, wherein in the step (1), the alkaline substance providing the alkaline condition is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium bicarbonate.

6. The process according to claim 1, wherein in step (1), the molar ratio of iodine to basic substance is 1: 1-5.

7. The preparation method according to claim 1, wherein in the step (1), the solvent for recovering imidazole by recrystallization is one or more of isopropanol, n-butanol, dichloromethane, tetrahydrofuran, ethyl acetate and n-hexane. The ratio of the crude product to the solvent is 1 g: 1-20 mL.

8. The method according to claim 1, wherein in step (2), the solvent used for recrystallization in step (2) is one or more selected from water, methanol, ethanol, isopropanol, ethyl acetate and n-hexane. The ratio of the 4-iodine-1H-imidazole crude product to the solvent is 1 g: 1-20 mL.