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CN-122010842-A - Separation and purification method for cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid in crude cyclic acid

CN122010842ACN 122010842 ACN122010842 ACN 122010842ACN-122010842-A

Abstract

The invention provides a separation and purification method for cis-1, 3-dibenzyl imidazole-2-ketone-4, 5-dicarboxylic acid in crude cyclic acid. The separation and purification method comprises the steps of S1, dissolving a crude product of cyclic acid in an ethanol solution to obtain a mixed solution, S2, dropwise adding a sodium hydroxide solution into the mixed solution to adjust the pH to 12.8-13.2, carrying out isomerization reaction, adjusting the pH to 6.3-6.7, filtering to obtain clear filtrate, S3, adding calcium salt into the clear filtrate to carry out selective precipitation to obtain metal salt precipitation, S4, mixing and pulping the metal salt precipitation with water, adding hydrochloric acid to acidify, filtering, washing a filter cake with cold water to obtain a crude product of cis-cyclic acid, S5, dissolving the crude product of cis-cyclic acid in a mixed solvent of acetone and water, dropwise adding an alkaline solution to adjust the pH to 4.0-4.8, cooling, crystallizing, and drying in vacuum to obtain the high-purity cis-cyclic acid. The purity of the product obtained by purification of the invention reaches more than 99% through HPLC analysis, the trans-isomer impurity is strictly controlled below 0.5%, and the product is in a regular crystal form and has good consistency.

Inventors

  • GUO DONGCHU
  • ZHANG LIANG
  • CAO MINGJING
  • WANG JIANJUN
  • XU CHENGYONG

Assignees

  • 浙江中贤生物科技有限公司

Dates

Publication Date
20260512
Application Date
20260204

Claims (10)

  1. 1. A separation and purification method for cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid in crude cyclic acid is characterized by comprising the following steps: S1, dissolving a crude cyclic acid product in an ethanol solution to obtain a mixed solution; s2, dropwise adding a sodium hydroxide solution into the mixed solution to adjust the pH to 12.8-13.2, carrying out isomerization reaction, adjusting the pH to 6.3-6.7, and filtering to obtain clear filtrate; s3, adding calcium salt into the clarified filtrate for selective precipitation to obtain metal salt precipitation; s4, mixing and pulping the metal salt precipitate with water, adding hydrochloric acid for acidification, filtering, and washing a filter cake with cold water to obtain a cis-cyclic acid crude product; S5, dissolving the cis-cyclic acid crude product in a mixed solvent of acetone and water, dropwise adding an alkaline solution to adjust the pH to 4.0-4.8, cooling, crystallizing, and vacuum drying to obtain the high-purity cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid.
  2. 2. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 1, wherein in the step S2, the isomerization reaction is carried out at a temperature of 140-160 ℃, the pressure is 1.2-1.6 MPa, and the time is 4-6 hours.
  3. 3. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 1, wherein in the step S3, calcium chloride is selected as the calcium salt, and the concentration of the calcium chloride is 1mol/L; the mass of the calcium chloride is 85-95% of that of the crude cyclic acid product; the temperature of the selective precipitation is 45-50 ℃, the pH is 6.4-6.6, and the time is 1-1.5 h.
  4. 4. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 1, wherein in the step S3, alkali liquor is added into the filtrate after selective precipitation and filtration to adjust the pH to 7.2-7.5, magnesium acetate is added, stirring and filtration are carried out, and then solid is collected and combined with the metal salt precipitate.
  5. 5. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 4, wherein the addition amount of magnesium acetate is 20-30% of the mass of the crude cyclic acid.
  6. 6. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 1, wherein in the step S4, the pH of acidification is 2.0-2.5, and the temperature is 20-30 ℃.
  7. 7. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 1, wherein in the step S5, the volume ratio of acetone to water in the mixed solvent is 1:1-1.2; The dissolution temperature is 60-65 ℃.
  8. 8. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid from crude cyclic acid according to claim 1, wherein in the step S5, the alkaline solution is selected from an ammonia solution or a saturated NaHCO 3 solution with a mass concentration of 5 wt%.
  9. 9. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 1, wherein in the step S5, the condition parameters of cooling crystallization are that cooling is carried out to 20 ℃ at 0.1-0.2 ℃ per minute, and then cooling is carried out for Chen Hua-3 hours at 20 ℃.
  10. 10. The method for separating and purifying cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid in crude cyclic acid according to claim 1 is characterized in that in the step S5, the temperature of vacuum drying is 55-60 ℃ and the time is 6-8 hours.

Description

Separation and purification method for cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid in crude cyclic acid Technical Field The invention relates to the technical field of cis-cyclic acid serving as a biological intermediate, in particular to a separation and purification method for cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid in a crude cyclic acid product. Background Cyclic acids are important pharmaceutical intermediates or functional compounds, and their bioactivity or material properties are often highly dependent on specific steric configurations. In industrial chemical processes, crude cyclic acids are generally obtained as a mixture of two isomers of cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid and trans-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid. Since these two isomers have identical molecular formulas, connecting sequences and functional groups, only the spatial orientation of the two carboxylic acids on the ring is different, resulting in very small differences in the properties of polarity, solubility and crystallization of these two isomers, which makes the separation and purification of the highly cis-cyclic acid a great challenge. At present, the main technical bottleneck faced in obtaining high-purity cis-isomer from crude cyclic acid is low separation selectivity and low process efficiency. The conventional separation method, such as the conventional recrystallization method, mainly utilizes the slight difference of the solubility of the two in a specific solvent, usually needs to undergo multiple and complex crystallization operations, not only the yield substrate of the product is difficult to meet the economic requirement of industrial production, but also the final anti-fouling purity is difficult to stably reach 98%. Although the separation technology based on the chromatography of the preparative high performance liquid chromatography can realize higher separation degree, the method has the advantages of limited treatment capacity, huge solvent consumption and high running cost, and is not suitable for large-scale production. Therefore, how to obtain the cis-cyclic acid with high purity by high-efficiency and high-selectivity purification in the crude cyclic acid product rich in trans-isomer is a problem to be solved. Disclosure of Invention (One) solving the technical problems Aiming at the defects of the prior art, the invention provides a separation and purification method for cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid in crude cyclic acid, which solves the problems in the prior art. (II) technical scheme In order to achieve the above purpose, the invention is realized by the following technical scheme: According to a first aspect of the present invention, there is provided a process for the isolation and purification of cis-1, 3-dibenzylimidazol-2-one-4, 5-dicarboxylic acid from crude cyclic acid comprising the steps of: S1, dissolving a crude cyclic acid product in an ethanol solution to obtain a mixed solution; s2, dropwise adding a sodium hydroxide solution into the mixed solution to adjust the pH to 12.8-13.2, carrying out isomerization reaction, adjusting the pH to 6.3-6.7, and filtering to obtain clear filtrate; s3, adding calcium salt into the clarified filtrate for selective precipitation to obtain metal salt precipitation; s4, mixing and pulping the metal salt precipitate with water, adding hydrochloric acid for acidification, filtering, and washing a filter cake with cold water to obtain a cis-cyclic acid crude product; S5, dissolving the cis-cyclic acid crude product in a mixed solvent of acetone and water, dropwise adding an alkaline solution to adjust the pH to 4.0-4.8, cooling, crystallizing, and vacuum drying to obtain the high-purity cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid. Preferably, before the step S2 is performed, adding activated carbon into the mixed solution for decoloring treatment for 10-15 min, and filtering to obtain a clarified mixed solution, wherein the addition amount of the activated carbon is 1-3% of the crude cyclic acid. Preferably, in the step S2, the temperature of the isomerization reaction is 140-160 ℃, the pressure is 1.2-1.6 MPa, and the time is 4-6 hours. Preferably, in the step S3, the calcium salt is calcium chloride, and the concentration of the calcium chloride is 1mol/L; the mass of the calcium chloride is 85-95% of that of the crude cyclic acid product; the temperature of the selective precipitation is 45-50 ℃, the pH is 6.4-6.6, and the time is 1-1.5 h. Preferably, in the step S3, alkali liquor is added into the filtrate after selective precipitation and filtration to adjust the pH to 7.2-7.5, then magnesium acetate is added, and after stirring and filtration, the solid is collected and combined with the metal salt precipitate. Preferably, the adding amount of the magnesium acetate is 20-30% of the mass of the crude cyclic acid product. Preferably, in ste