Refining method of 4-methylimidazole and prepared 4-methylimidazole hydrochloride crystal
By using the method of salting 4-methylimidazole with hydrogen chloride-containing reagents and crystallizing in acetone, the problem of removing 4-ethylimidazole impurities in 4-methylimidazole is solved, and a high purity and stability of 4- is achieved. The preparation of methylimidazole hydrochloride crystals has improved the quality control and industrial production convenience of cimetidine raw materials.
Patent Information
- Application Number
- CN202411436308.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-15
- Publication Date
- 2025-01-17
AI Technical Summary
The prior art cannot effectively remove 4-ethylimidazole impurities in 4-methylimidazole, affecting the quality and safety of cimitidine raw materials and preparations.
The purification method of salting 4-methylimidazole with hydrogen chloride-containing reagents and crystallizing in acetone was used to remove 4-ethylimidazole impurities and form 4-methylimidazole hydrochloride crystals with good properties.
The content of 4-ethylimidazole is effectively reduced from 0.24% to 0.03%, reaching a quality control limit of less than 0.1%, improving the storage stability of intermediates and the flexibility of industrial production.
Smart Images
Figure BDA0005085068780000011 
Figure HDA0005085068790000011 
Figure HDA0005085068790000012
Abstract
Description
Technical Field
[0001] The invention relates to a purifying method of 4-methylimidazole and 4-methylimidazole hydrochloride crystals prepared therefrom, and in particular to a purifying method of 4-methylimidazole suitable for industrialization and 4-methylimidazole hydrochloride crystals prepared therefrom with reliable quality. Background Art
[0002] 4-Methylimidazole is an important synthetic intermediate of the stomach medicine cimetidine, and its quality has an important impact on the quality and safety of cimetidine raw materials and preparations. 4-Ethylimidazole is a common impurity in 4-methylimidazole. Due to the similar structure and properties of the two, 4-Ethylimidazole is also the most difficult impurity to remove in 4-methylimidazole, and it will be conducted to cimetidine raw materials and preparations along with the synthesis process. In addition, 4-Methylimidazole can also be used as agricultural chemicals, epoxy resin curing agent, metal corrosion inhibitor, etc., and is widely used, and its quality will also affect the application performance in other aspects. At present, there is no method that can effectively remove 4-Ethylimidazole in 4-Methylimidazole.
[0003] Summary of the invention
[0004] Purpose of the invention: The present invention aims to provide a purification method capable of effectively removing 4-ethylimidazole impurities in 4-methylimidazole and the obtained 4-methylimidazole hydrochloride crystals.
[0005] Technical solution: The method for refining 4-methylimidazole of the present invention comprises the following steps:
[0006] (1) salifying 4-methylimidazole with a reagent containing hydrogen chloride in a reaction solvent, and removing the reaction solvent;
[0007] (2) The product obtained in step (1) is crystallized in acetone, and then subjected to post-treatment to complete purification, thereby obtaining 4-methylimidazole hydrochloride from which 4-ethylimidazole has been removed.
[0008] Preferably, the content of 4-ethylimidazole in the 4-methylimidazole in step (1) does not exceed 2%.
[0009] More preferably, the content of 4-ethylimidazole in the 4-methylimidazole is no more than 1%.
[0010] More preferably, the content of 4-ethylimidazole in the 4-methylimidazole is no more than 0.5%.
[0011] Still more preferably, the content of 4-ethylimidazole does not exceed 0.3%.
[0012] Preferably, the content of 4-ethylimidazole in the 4-methylimidazole hydrochloride in step (2) does not exceed 0.1%.
[0013] More preferably, the content of 4-ethylimidazole in the 4-methylimidazole hydrochloride does not exceed 0.08%.
[0014] More preferably, the content of 4-ethylimidazole in the 4-methylimidazole hydrochloride does not exceed 0.05%.
[0015] Still more preferably, the content of 4-ethylimidazole in the 4-methylimidazole hydrochloride does not exceed 0.03%.
[0016] At room temperature, 4-methylimidazole is solid, and 4-ethylimidazole is liquid. 4-ethylimidazole will be adsorbed on the solid of 4-methylimidazole, and recrystallization using different solvents has no removal effect on 4-ethylimidazole. The present invention uses 4-methylimidazole and a specific acid to form a salt for refining, which has a good impurity removal rate, and can form a solid form with good properties in a specific solvent. The refining method of the present invention can effectively remove the 4-ethylimidazole impurity in 4-methylimidazole, and can reduce it from 0.24% to 0.03%, thereby reaching a quality control limit of less than 0.1%.
[0017] Preferably, the reaction solvent in step (1) is selected from one or more solvents of water, methanol, ethanol, isopropanol, acetonitrile, dichloromethane and acetone.
[0018] More preferably, the mass ratio of the reaction solvent to 4-methylimidazole is 2:1.
[0019] Preferably, the reagent containing hydrogen chloride in step (1) is selected from one or more of hydrochloric acid, hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, and hydrogen chloride methanol solution.
[0020] More preferably, the reagent containing hydrogen chloride is selected from hydrochloric acid or hydrogen chloride ethanol solution.
[0021] More preferably, in the reagent containing hydrogen chloride, the mass concentration of hydrogen chloride is 15% to 38%.
[0022] Still further preferably, the reagent containing hydrogen chloride is selected from concentrated hydrochloric acid or a 30% mass concentration hydrogen chloride ethanol solution.
[0023] Preferably, the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole in step (1) is (0.9-2):1.
[0024] More preferably, the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is (1.2-1.6):1.
[0025] More preferably, the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 1.5:1.
[0026] Preferably, the salt-forming reaction in step (1) is carried out in a reaction vessel or a microchannel reactor.
[0027] Preferably, the volume of acetone in step (2) is 2 to 5 times the weight of 4-methylimidazole.
[0028] More preferably, the volume of the acetone is 3 times the weight of the 4-methylimidazole.
[0029] Preferably, the acetone is added all at once or in steps to the product obtained in step (1).
[0030] Further preferably, when acetone is added stepwise to the product obtained in step (1), the stepwise addition method is to first add 25% of the total volume of acetone to the product obtained in step (1), continue to remove the solvent, and then add the remaining amount of acetone.
[0031] More preferably, when the volume of acetone is 5 times the weight of 4-methylimidazole, the acetone is added in steps.
[0032] More preferably, when the volume of acetone is 2 to 5 times the weight of 4-methylimidazole, the acetone is added all at once.
[0033] Preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 1.5:1, the volume of acetone in step (2) is 2 to 5 times the weight of 4-methylimidazole.
[0034] Further preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 1.5:1, the acetone is added all at once or in steps to the product obtained in step (1).
[0035] More preferably, when the volume of acetone is 5 times the weight of 4-methylimidazole, the acetone is added in steps.
[0036] Still further preferably, when acetone is added stepwise to the product obtained in step (1), the stepwise addition method is to first add 25% of the total volume of acetone to the product obtained in step (1), continue to remove the solvent, and then add the remaining amount of acetone.
[0037] More preferably, when the volume of acetone is 2 to 5 times the weight of 4-methylimidazole, the acetone is added all at once.
[0038] Further preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 1.5:1, the reagent containing hydrogen chloride in step (1) is selected from hydrochloric acid or hydrogen chloride ethanol solution.
[0039] Further preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 1.5:1, the reaction solvent in step (1) is selected from one or more solvents of water, methanol, ethanol, isopropanol, acetonitrile, dichloromethane, and acetone.
[0040] Preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 0.9:1, the volume of acetone in step (2) is 3 times the weight of 4-methylimidazole.
[0041] More preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 0.9:1, the acetone is added all at once.
[0042] More preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 0.9:1, the reaction solvent is water.
[0043] Preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 2:1, the volume of acetone in step (2) is 3 times the weight of 4-methylimidazole.
[0044] More preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 2:1, the acetone is added all at once.
[0045] More preferably, when the molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole is 2:1, the reaction solvent is water.
[0046] Preferably, acetone is added to the product obtained in step (1) by dripping, spraying or atomizing injection.
[0047] More preferably, acetone is added dropwise to the product obtained in step (1).
[0048] More preferably, acetone is added dropwise to the product obtained in step (1) by gravity drive or pump drive.
[0049] Preferably, the crystallization temperature in step (2) is -10 to 0°C.
[0050] More preferably, the crystallization temperature is -5 to 0°C.
[0051] More preferably, the crystallization is static crystallization or stirring crystallization.
[0052] More preferably, the crystallization is performed with or without adding seed crystals.
[0053] Still more preferably, when seed crystals are added for crystallization, the amount of the seed crystals added is 0.1% to 5% of the mass of the 4-methylimidazole to be purified.
[0054] Still more preferably, when seed crystals are added for crystallization, the purity of the seed crystals is not less than 99%.
[0055] Still more preferably, when seed crystals are added for crystallization, the purity of the seed crystals is not less than 99.5%.
[0056] Preferably, the temperature for removing the reaction solvent in step (1) is 40 to 60°C.
[0057] Preferably, the post-treatment process described in step (2) is solid-liquid separation and solvent removal.
[0058] Further preferably, the solid-liquid separation is selected from natural filtration, pressure filtration, suction filtration, centrifugation or sedimentation.
[0059] More preferably, the natural filtration, pressure filtration or suction filtration uses a filter membrane, filter paper or filter cloth.
[0060] More preferably, the solvent removal is drying.
[0061] More preferably, the drying is selected from forced air drying, vacuum drying, boiling drying, fluidized bed drying or freeze drying.
[0062] The 4-methylimidazole hydrochloride crystals of the present invention are prepared by the purification method of the present invention, and are salified with a reagent containing hydrogen chloride and crystallized in acetone to obtain a hydrochloride solid form with good product properties and purity.
[0063] Preferably, the 4-methylimidazole hydrochloride crystals have characteristic diffraction peaks at 17.86°, 21.77°, 23.26°, 23.76°, 24.57°, 25.93°, 27.25°, 28.79°, 30.70°, 31.81°, 32.93°, and 35.71°, based on 2θ±0.2°.
[0064] Further preferably, the 4-methylimidazole hydrochloride crystals have characteristic diffraction peaks at 14.47°, 17.86°, 21.77°, 22.34°, 22.70°, 23.26°, 23.76°, 24.57°, 25.93°, 26.30°, 27.25°, 28.79°, 29.66°, 29.67°, 29.97°, 30.70°, 31.81°, 32.93°, 35.71°, and 37.51°, based on 2θ±0.2°.
[0065] Preferably, the 4-methylimidazole hydrochloride crystals have an endothermic peak at 115.6±3°C.
[0066] Preferably, the weight loss of the 4-methylimidazole hydrochloride crystals before 150° C. is 3.0%±0.5%.
[0067] The melting point of the 4-methylimidazole hydrochloride prepared by the present invention is 115° C., which is 62° C. higher than the melting point of 4-methylimidazole, which is 53° C., thereby improving the storage stability. The hydrochloride can be directly used in the next synthesis process without being freed into 4-methylimidazole.
[0068] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:
[0069] The refining method designed by the present invention can effectively remove the 4-ethylimidazole impurity in the 4-methylimidazole by salifying the 4-methylimidazole with a specific acid and adopting a specific crystallization solvent, which is beneficial to the quality control of the cimetidine bulk drug and preparation prepared subsequently. At the same time, the refined product is a hydrochloride solid product with good properties, which improves the stability of intermediate storage and transportation, and makes the industrial production cycle arrangement more flexible. In addition, the hydrochloride refined product does not need to be free and can be directly used in the subsequent synthesis process, making industrial production more convenient. BRIEF DESCRIPTION OF THE DRAWINGS
[0070] Figure 1 The XRD pattern of the 4-methylimidazole hydrochloride crystals prepared in Example 2;
[0071] Figure 2 The DSC spectrum of the 4-methylimidazole hydrochloride crystals prepared in Example 2;
[0072] Figure 3 This is the TGA spectrum of the 4-methylimidazole hydrochloride crystals obtained in Example 2;
[0073] Figure 4 The XRD pattern of the 4-methylimidazole crystal prepared in Comparative Example 1;
[0074] Figure 5 The DSC spectrum of the 4-methylimidazole crystals prepared in Comparative Example 1;
[0075] Figure 6 This is the TGA spectrum of 4-methylimidazole prepared in Comparative Example 1. DETAILED DESCRIPTION
[0076] The technical solution of the present invention is further described below in conjunction with embodiments.
[0077] Example 1
[0078] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 5 ml of acetone was added to continue concentrating, 20 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.25 g, with a yield of 85.0%, a purity of 99.90%, and a 4-ethylimidazole impurity content of 0.05%.
[0079] Example 2
[0080] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 N hydrochloric acid was added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, cooled to -5 to 0 ° C, filtered, and dried to obtain 4.45 g, with a yield of 89.0%, a purity of 99.89%, and a 4-ethylimidazole impurity content of 0.06%.
[0081] Example 3
[0082] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 0.9 N hydrochloric acid was added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, cooled to -5 to 0 ° C, filtered, and dried to obtain 4.35 g, with a yield of 87.0%, a purity of 99.88%, and a 4-ethylimidazole impurity content of 0.05%.
[0083] Example 4
[0084] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 2.0 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.51 g, with a yield of 90.2%, a purity of 99.87%, and a 4-ethylimidazole impurity content of 0.05%.
[0085] Example 5
[0086] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of ethanolic hydrogen chloride were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.50 g, with a yield of 90.0%, a purity of 99.85%, and a 4-ethylimidazole impurity content of 0.06%.
[0087] Example 6
[0088] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 10 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.60 g, with a yield of 92.0%, a purity of 99.83%, and a 4-ethylimidazole impurity content of 0.08%.
[0089] Example 7
[0090] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 25 ml of acetone was added dropwise, cooled to -5 to 0 ° C, filtered, and dried, 4.00 g, 80.0%, 99.91%, 4-ethylimidazole content 0.03%.
[0091] Example 8
[0092] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of methanol, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.40 g, with a yield of 88.0%, a purity of 99.87%, and a 4-ethylimidazole content of 0.05%.
[0093] Example 9
[0094] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of ethanol, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered and dried to obtain 4.45 g, with a yield of 89.0%, a purity of 99.87%, and a 4-ethylimidazole content of 0.05%.
[0095] Example 10
[0096] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of isopropanol, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, cooled to -5 to 0 ° C, filtered and dried to obtain 4.50 g, with a yield of 90.0%, a purity of 99.85%, and a 4-ethylimidazole content of 0.06%.
[0097] Embodiment 11
[0098] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of acetonitrile, 1.5 equivalents of ethanolic hydrogen chloride were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.43 g, with a yield of 88.60%, a purity of 99.86%, and a 4-ethylimidazole content of 0.05%.
[0099] Example 12
[0100] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of dichloromethane, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.55 g, with a yield of 91.0%, a purity of 99.84%, and a 4-ethylimidazole content of 0.06%.
[0101] Embodiment 13
[0102] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of acetone, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 15 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.53 g, with a yield of 90.6%, a purity of 99.89%, and a 4-ethylimidazole content of 0.04%.
[0103] It can be seen from the refining methods of Examples 1 to 13 that the refining method parameters adopted in the present invention can effectively remove 4-ethylimidazole impurities, and can minimize the material loss caused by refining, and can also obtain a solid form with a specific crystal form, which is beneficial to maintaining the stability of material storage and transportation, and is more convenient for flexible arrangement of production cycles in industrial production.
[0104] Comparative Example 1
[0105] 5 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was added to 50 ml of n-heptane, heated to 50°C to melt, then cooled to -10-0°C to begin solidification and precipitate solids, stirred and dispersed, stirred for 1 hour, filtered, and dried to obtain 4.80 g, with a yield of 96%, a purity of 99.14%, and a 4-ethylimidazole content of 0.25%.
[0106] Comparative Example 2
[0107] 5 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was added to 5 ml of ethyl acetate, heated to 50°C to melt, and dropped into 50 ml of n-heptane at -10 to 0°C. After solidification, the solid was dispersed after stirring. After stirring for 1 hour, it was filtered and dried to obtain 4.50 g, with a yield of 90%, a purity of 99.21%, and a 4-ethylimidazole content of 0.24%.
[0108] Comparative Example 3
[0109] 5 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was added to 5 ml of tert-methyl ether, heated to 50°C to melt, and dropped into 50 ml of n-heptane at -10 to 0°C. After solidification, a solid precipitated, stirred and dispersed, stirred for 1 hour, filtered, and dried to obtain 4.37 g, with a yield of 87.4%, a purity of 99.11%, and a 4-ethylimidazole content of 0.27%.
[0110] Comparative Example 4
[0111] 5g 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was added to 5ml tert-methyl ether, heated to 50°C to melt, cooled to -10-0°C, added dropwise to 50ml n-heptane, and 10ml solid was solidified and precipitated. After stirring, the solid was dispersed and continued to be added dropwise until the solid was finished. Stirred for 1h, filtered, and dried to obtain 4.88g, with a yield of 97.6%, a purity of 99.22%, and a 4-ethylimidazole content of 0.23%.
[0112] Comparative Example 5
[0113] 5g 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was added to 5ml ethyl acetate, heated to 50°C to melt, cooled to -10-0°C, added dropwise to 50ml n-heptane, and 10ml solid was solidified and precipitated, stirred and dispersed, continued to add dropwise until the solid was finished, stirred for 1h, filtered, and dried to obtain 4.60g, with a yield of 92.0%, a purity of 99.18%, and a 4-ethylimidazole content of 0.25%.
[0114] Comparative Example 6
[0115] 5 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was added to 5 ml of tert-methyl ether and 50 ml of n-heptane, heated to 50 ° C to melt, cooled to 30 ° C to add seed crystals, stirred for 30 min to precipitate solid powder, slowly cooled to 10 ° C, stirred for 1 h, filtered and dried to obtain 4.55 g, with a yield of 91%, a purity of 99.25%, and a 4-ethylimidazole content of 0.24%.
[0116] From the comparison of the refining methods of Examples 1 to 2 with Comparative Examples 1 to 6, it can be seen that it is difficult to remove 4-ethylimidazole from 4-methylimidazole by using a conventional solvent recrystallization method.
[0117] Comparative Example 7
[0118] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of oxalic acid were added, stirred for 1 h, concentrated to dryness, 5 ml of acetone was added to continue concentrating, 20 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 3.70 g, with a yield of 74.0%, a purity of 99.12%, and a 4-ethylimidazole content of 0.25%.
[0119] Comparative Example 8
[0120] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of maleic acid were added, stirred for 1 h, concentrated to dryness, 5 ml of acetone was added to continue concentrating, 20 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.00 g, with a yield of 80.0%, a purity of 99.15%, and a 4-ethylimidazole content of 0.23%.
[0121] Comparative Example 9
[0122] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of citric acid were added, stirred for 1 h, concentrated to dryness, 5 ml of acetone was added to continue concentrating, 20 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 4.12 g, with a yield of 82.4%, a purity of 99.20%, and a 4-ethylimidazole content of 0.21%.
[0123] Comparative Example 10
[0124] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of sulfuric acid were added, stirred for 1 h, concentrated to dryness, 5 ml of acetone was added to continue concentrating, 20 ml of acetone was added dropwise, the temperature was lowered to -5 to 0 ° C, filtered, and dried to obtain 3.85 g, with a yield of 75.0%, a purity of 99.18%, and a 4-ethylimidazole content of 0.24%.
[0125] From the comparison of the refining methods of Example 1 and Comparative Examples 7 to 10, it can be seen that only the formation of hydrochloride has a significant removal effect on 4-ethylimidazole.
[0126] Comparative Example 11
[0127] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 N hydrochloric acid was added, stirred for 1 h, concentrated to dryness, 15 ml of toluene was added dropwise, and the temperature was lowered to -5 to 0 ° C. The precipitated solid formed a hard lump and could not be filtered.
[0128] Comparative Example 12
[0129] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 N hydrochloric acid was added, stirred for 1 h, concentrated to dryness, 15 ml of n-heptane was added dropwise, and the temperature was lowered to -5 to 0 ° C. The precipitated solid formed a hard lump and could not be filtered.
[0130] Comparative Example 13
[0131] 5.00g 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10g water, 1.5 equivalents of hydrochloric acid were added, stirred for 1h, concentrated to dryness, 15ml of ethanol was added dropwise, and the temperature was lowered to -5 to 0°C. No solid was precipitated.
[0132] Comparative Example 14
[0133] 5.00g 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10g water, 1.5 equivalents of hydrochloric acid were added, stirred for 1h, concentrated to dryness, 15ml of ethyl acetate was added dropwise, cooled to -5~0℃, filtered and dried to obtain 4.60g, with a yield of 92.0%, a purity of 99.16%, and a 4-ethylimidazole content of 0.23%.
[0134] Comparative Example 15
[0135] 5.00g 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10g water, 1.5 equivalents of hydrochloric acid were added, stirred for 1h, concentrated to dryness, 15ml of tert-methyl ether was added dropwise, the temperature was lowered to -5~0℃, filtered and dried to obtain 4.56g, with a yield of 91.2%, a purity of 99.15%, and a 4-ethylimidazole content of 0.23%.
[0136] Comparative Example 16
[0137] 5.00 g of 4-methylimidazole (purity 99.18%, 4-ethylimidazole impurity content 0.24%) was dissolved in 10 g of water, 1.5 equivalents of hydrochloric acid were added, stirred for 1 h, concentrated to dryness, 15 ml of acetonitrile was added dropwise, and the temperature was lowered to -5 to 0°C. No solid was precipitated.
[0138] From the comparison of the refining methods of Example 2 and Comparative Examples 11 to 16, it can be seen that the hydrochloride can form dispersed solids only in acetone and has a significant removal effect on 4-ethylimidazole.
Claims
1. A method for refining 4-methylimidazole, characterized in that: The following steps are involved: (1) salifying 4-methylimidazole with a reagent containing hydrogen chloride in a reaction solvent, and removing the reaction solvent; (2) The product obtained in step (1) is crystallized in acetone, and then subjected to post-treatment to complete purification, thereby obtaining 4-methylimidazole hydrochloride from which 4-ethylimidazole has been removed.
2. The refining method according to claim 1, characterized in that The reaction solvent described in step (1) is selected from one or more solvents of water, methanol, ethanol, isopropanol, acetonitrile, dichloromethane and acetone.
3. The refining method according to claim 1, characterized in that: The reagent containing hydrogen chloride in step (1) is selected from one or more of hydrochloric acid, hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, and hydrogen chloride methanol solution.
4. The refining method according to claim 1, characterized in that: The molar ratio of the reagent containing hydrogen chloride to 4-methylimidazole in step (1) is (0.9-2):
1.
5. The purification method according to claim 1, characterized in that: The volume of acetone in step (2) is 2 to 5 times the weight of 4-methylimidazole.
6. The purification method according to claim 1, characterized in that: The crystallization temperature in step (2) is -10 to 0°C.
7. The purification method according to claim 1, characterized in that: The removal temperature of the reaction solvent in step (1) is 40-60°C.
8. A 4-methylimidazole hydrochloride crystal, characterized in that: In terms of 2θ±0.2°, there are characteristic diffraction peaks at 17.86°, 21.77°, 23.26°, 23.76°, 24.57°, 25.93°, 27.25°, 28.79°, 30.70°, 31.81°, 32.93°, and 35.71°.
9. The 4-methylimidazole hydrochloride crystal according to claim 8, characterized in that There is an endothermic peak at 115.6±3℃.
10. The 4-methylimidazole hydrochloride crystal according to claim 8, characterized in that: The weight loss before 150°C is 3.0%±0.5%.