Separation and purification method for cis-1, 3-dibenzylimidazole-2-one-4, 5-dicarboxylic acid in cyclic acid crude product

Abstract

The invention provides a separation and purification method for cis-1, 3-dibenzylimidazole-2-ketone-4, 5-dicarboxylic acid in a cyclic acid crude product. The separation and purification method comprises the following steps: S1, dissolving a cyclic acid crude 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 value to 12.8-13.2, carrying out an isomerization reaction, then adjusting the pH value to 6.3-6.7, and filtering to obtain a clear filtrate; s3, calcium salt is added into the clarified filtrate for selective precipitation, and metal salt precipitation is obtained; s4, mixing and pulping the metal salt precipitate and water, adding hydrochloric acid for acidification, filtering, and washing a filter cake with cold water to obtain a cis-cyclic acid crude product; and 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 value to 4.0-4.8, cooling, crystallizing, and drying in vacuum to obtain the high-purity cis-cyclic acid. According to HPLC analysis, the purity of the product obtained through purification reaches 99% or above, trans-isomer impurities are strictly controlled to be 0.5% or below, and the product is in a regular crystal form and is good in consistency.

Description

Technical Field

[0001] This invention relates to the field of biological intermediate cis-cyclic acid technology, specifically a method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid. Background Technology

[0002] Cyclic acids, as important pharmaceutical intermediates or functional compounds, often exhibit bioactivity or material properties highly dependent on specific stereoconfigurations. In industrial chemical production, crude cyclic acids are typically obtained as a mixture of two isomers: cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid and trans-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid. Because these two isomers have identical molecular formulas, linkage sequences, and functional groups, differing only in the spatial orientation of the two carboxylic acids on the ring, their polarity, solubility, and crystallinity are very similar. This makes the separation and purification of highly cis-cyclic acids extremely challenging.

[0003] Currently, the main technical bottlenecks in obtaining high-purity cis isomers from crude cyclic acid are low separation selectivity and low process efficiency. Traditional separation methods, such as conventional recrystallization, mainly utilize the slight difference in solubility between the two in specific solvents. These methods typically require multiple, complex crystallization operations, resulting in low product yields that fail to meet the economic requirements of industrial production, and the final purity often struggles to consistently reach 98%. While preparative high-performance liquid chromatography (HPLC) can achieve high separation rates based on chromatographic techniques, its limited throughput, high solvent consumption, and high operating costs make it unsuitable for large-scale production.

[0004] Therefore, finding a process route for the efficient and selective purification of crude cyclic acids rich in trans isomers to obtain high-purity cis-cyclic acids has become an urgent problem to be solved. Summary of the Invention

[0005] (a) Technical problems to be solved To address the shortcomings of existing technologies, this invention provides a method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid, thus solving the problems mentioned in the background section.

[0006] (II) Technical Solution To achieve the above objectives, the present invention provides the following technical solution: According to a first aspect of the present invention, a method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid is provided, comprising the following steps: S1. Dissolve the crude cyclic acid in an ethanol solution to obtain a mixed solution; S2. Add sodium hydroxide solution dropwise to the mixed solution to adjust the pH to 12.8-13.2, carry out the isomerization reaction, then adjust the pH to 6.3-6.7, filter, and obtain a clear filtrate; S3. Add calcium salt to the clarified filtrate to perform selective precipitation and obtain metal salt precipitate; S4. Mix the metal salt precipitate with water and slurry, then add hydrochloric acid for acidification, filter, and wash the filter cake with cold water to obtain crude cis-cyclic acid. S5. Dissolve the crude cis-cyclic acid in a mixed solvent of acetone and water, adjust the pH to 4.0-4.8 by adding an alkaline solution dropwise, cool and crystallize, and then vacuum dry to obtain high-purity cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid.

[0007] Preferably, before step S2, activated carbon is added to the mixed solution for decolorization treatment for 10-15 minutes, and then filtered to obtain a clear mixed solution, wherein the amount of activated carbon added is 1-3% of the crude cyclic acid.

[0008] Preferably, in step S2, the isomerization reaction is carried out at a temperature of 140~160℃, a pressure of 1.2~1.6MPa, and a time of 4~6h.

[0009] Preferably, in step S3, the calcium salt is selected as calcium chloride, and the concentration of the calcium chloride is 1 mol / L; The mass of the calcium chloride is 85-95% of the crude cyclic acid product; The selective precipitation is carried out at a temperature of 45-50°C, a pH of 6.4-6.6, and a time of 1-1.5 hours.

[0010] Preferably, in step S3, an alkaline solution is added to the filtrate after selective precipitation filtration to adjust it 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.

[0011] Preferably, the amount of magnesium acetate added is 20-30% of the crude cyclic acid mass.

[0012] Preferably, in step S4, the pH of the acidification is 2.0 to 2.5, and the temperature is 20 to 30°C.

[0013] Preferably, in step S5, the volume ratio of acetone to water in the mixed solvent is 1:1 to 1.2; The melting temperature is 60~65℃.

[0014] Preferably, in step S5, the alkaline solution is selected from an ammonia solution with a mass concentration of 5 wt% or a saturated NaHCO3 solution.

[0015] Preferably, in step S5, the cooling crystallization conditions are: cooling to 20°C at a rate of 0.1~0.2°C / min, and then aging at 20°C for 2~3 hours.

[0016] Preferably, in step S5, the vacuum drying temperature is 55~60℃ and the time is 6~8h.

[0017] Specifically, this invention provides a method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid, comprising the following steps: Step 1: Dissolve crude cyclic acid in ethanol solution, heat to 50-60℃ and stir to completely dissolve the crude cyclic acid. Then add 1-3% activated carbon, decolorize for 10-15 minutes, filter, and obtain a clear mixed solution. Step 2: Add 5M sodium hydroxide solution to the mixed solution to adjust the pH to 12.8-13.2. Perform isomerization reaction at 140-160℃ and 1.2-1.6MPa for 4-6 hours to convert trans-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid to cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid. After the isomerization reaction is complete, lower the temperature to below 60℃ and slowly release the pressure to atmospheric pressure. Simultaneously, add 2M hydrochloric acid to adjust the pH of the reaction system to 6.3-6.7. After filtration, obtain a clear filtrate. Step 3: Add a 1.0M calcium chloride aqueous solution to the clarified filtrate, and grow crystals at 45~50℃ and pH 6.4~6.6 for 1~1.5h. After filtration, rinse with hot water at 50~60℃ to obtain metal salt precipitate. Step 4: Add alkali solution to the filtrate after filtering in step 3 to adjust to 7.2~7.5, then add magnesium acetate at 20~30% of the crude cyclic acid mass, stir for 0.5~1h, filter, collect the solid, and combine the collected solid with the metal precipitate; Step 5: Add 3 to 5 times the amount of water to the combined metal precipitate and slurry it. Then add a 2M hydrochloric acid solution and acidify it at 20 to 30°C and pH 2.0 to 2.5. This will cause the metal precipitate to gradually dissolve. As the acidification proceeds, the free cis-cyclic acid in the solution will recrystallize and precipitate out in solid form. Filter the solution and wash the filter cake with cold water to obtain crude cis-cyclic acid. Step 6: Dissolve the crude cis-cyclic acid in a mixed solvent of acetone and water at 60-65℃, adjust the pH to 4.0-4.8 by adding alkaline solution dropwise, cool to 20℃ at a rate of 0.1-0.2℃ / min, and then age for 2-3 hours. After filtration, wash the crystals with a mixed solvent, and finally dry at 55-60℃ under vacuum for 6-8 hours to obtain a white crystalline powder, which is high-purity cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid.

[0018] (III) Beneficial Effects This invention provides a method for the separation and purification of cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acids. It has the following beneficial effects: (1) This scheme provides a method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid. It combines alkaline high-pressure isomerization reaction with selective precipitation of metal ions and pH-controlled crystallization to achieve efficient and highly selective separation of cis-trans isomers from crude cyclic acid. Furthermore, it uses inexpensive inorganic metal salts, resulting in low cost and easy scalability.

[0019] (2) This solution provides a method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid. The purity reaches more than 99% after HPLC analysis, the trans isomer impurities are strictly controlled below 0.5%, and the product is in a regular crystal form with good consistency. Detailed Implementation

[0020] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] The crude cyclic acid in this application, as analyzed by HPLC, contains 60% cis isomers, 38% trans isomers, and 2% other impurities.

[0022] Example 1 Step 1: Weigh 100g of crude cyclic acid and place it in a 500mL three-necked flask. Add 500mL of ethanol solution, heat to 55℃, stir to completely dissolve the solid, then add 2g of activated carbon, keep warm and dehydrate for 12min, filter under reduced pressure to obtain a clear yellow solution. Step 2: Transfer the clear yellow solution to a high-pressure reactor. Add a 5M sodium hydroxide solution dropwise while stirring to adjust the pH to 13.0. In the sealed reactor, heat the solution to 150℃ at a rate of 50℃ / h and increase the system pressure to 1.4MPa. Stir continuously at 300rpm for 5h. After the reaction is complete, cool the solution to 55℃ at a rate of 40℃ / h and depressurize it to room temperature. Then, add a 2M HCl solution dropwise while stirring to adjust the pH to 6.5. Filter to remove insoluble matter and obtain 580mL of clear filtrate. Step 3: Heat the clarified filtrate to 48°C, and slowly add 82 mL of 1.0 M CaCl2 aqueous solution while stirring at a constant temperature. Continue stirring and crystallizing for 1.2 h at pH 6.5. Filter the solution and wash the filter cake twice with 55°C hot water to obtain a white metal precipitate with a wet weight of about 145 g. Collect the filtrate, adjust the pH to 7.4 with 2 M sodium hydroxide solution, add 25 g of magnesium acetate, stir at room temperature for 45 min, filter, and collect the solid with a wet weight of about 15 g and combine it with the white metal precipitate. Step 4: Add 400 mL of water to the combined metal salt precipitate and slurry. While stirring at 25 °C, slowly add 2 M HCl solution to adjust the pH of the system to 2.3. Continue stirring for 30 min to obtain solid crystals. Filter the crystals and wash the filter cake three times with cold water. Dry the cake under vacuum at 60 °C for 4 h to obtain 78.5 g of crude cis-cyclic acid. Step 5: Place the crude cis-cyclic acid in a crystallization flask, add 160 mL of a 1:1.2 volume ratio of acetone and water, heat to 63°C and stir to dissolve. After clarification, slowly add 5% ammonia solution dropwise using a peristaltic pump to adjust the pH to 4.5. Then cool to 20°C at a rate of 0.15°C / min and age at 20°C for 2.5 h. Filter, wash the crystals with a pre-cooled 1:1 volume ratio of acetone and water, and finally dry at 58°C under vacuum for 7 h to obtain 71.2 g of white crystalline powder.

[0023] The obtained white crystalline powder was analyzed by HPLC and found that the purity of cis-cyclic acid was 99.3%, the content of trans-cyclic acid was 0.4%, the calcium ion residue was less than 15 ppm, and the yield based on cis-cyclic acid was 84.5%.

[0024] Example 2 The difference between this embodiment and Example 1 is that in step 3, the filtrate is not collected and magnesium acetate is added for purification, while the subsequent steps remain unchanged, resulting in 64.1g of white crystalline powder.

[0025] The obtained white crystalline powder was analyzed by HPLC and found that the purity of cis-cyclic acid was 99.1%, the content of trans-cyclic acid was 0.5%, the calcium ion residue was less than 15 ppm, and the yield based on cis-cyclic acid was 76.1%.

[0026] Comparative Example 1 The preparation method of this comparative example is the same as that of Example 1, except that the alkaline high-pressure isomerization reaction in step 2 is omitted, and calcium chloride aqueous solution is directly added dropwise to the clear mixed solution obtained in step 1. The subsequent steps remain unchanged, and 58.7g of white crystalline powder is obtained.

[0027] The obtained white crystalline powder was analyzed by HPLC and found that the purity of cis-cyclic acid was 98.7%, the content of trans-cyclic acid was 0.7%, the calcium ion residue was less than 15 ppm, and the yield based on cis-cyclic acid was 58.7%.

[0028] Comparative Example 2 The preparation method of this comparative example is the same as that of Example 1, except that in step 3, after adding the CaCl2 aqueous solution, sodium hydroxide solution is added to adjust the pH to 7.2, and crystallization is carried out for 1.2 hours under stirring. Subsequent steps are the same as in Example 1. 68.5 g of white crystalline powder was obtained.

[0029] The obtained white crystalline powder was analyzed by HPLC and found that the purity of cis-cyclic acid was 98.5%, the content of trans-cyclic acid was 1.2%, the calcium ion residue was less than 15 ppm, and the yield based on cis-cyclic acid was 81.3%.

[0030] Comparative Example 3 The preparation method of this comparative example is the same as that of Example 1, except that in step 5, the cooling rate of crystallization is changed to natural cooling, with a cooling rate of 0.5~1.0℃ / min. The subsequent steps remain unchanged, and 69.8g of white crystalline powder is obtained.

[0031] The obtained white crystalline powder was analyzed by HPLC and found that the purity of cis-cyclic acid was 98.7%, the content of trans-cyclic acid was 0.9%, the calcium ion residue was less than 15 ppm, and the yield based on cis-cyclic acid was 82.8%.

[0032] As can be seen from the comparison between Comparative Example 1 and Example 1, by omitting the alkaline high-pressure isomerization treatment, most of the trans-cyclic acids in the crude cyclic acid cannot be converted into the target cis product, resulting in a significant reduction in the yield of cis-cyclic acids.

[0033] Comparing Comparative Example 2 with Example 1, it can be seen that under high pH conditions, the degree of carboxyl dissociation of trans-cyclic acid increases, and the non-specific binding with calcium ions is enhanced, leading to an increase in co-precipitation and consequently a decrease in purity.

[0034] As can be seen from the comparison between Comparative Example 3 and Comparative Example 1, the faster cooling rate cannot provide sufficient time for the cis-cyclic acid to arrange itself in an orderly manner, allowing trace impurities and trans-cyclic acid to enter the crystal lattice, thus making it impossible to obtain high-purity, highly uniform, and fluid crystal grains.

[0035] In summary, the alkaline high-pressure isomerization step can avoid the waste of trans isomers in the raw materials. Based on the synergistic effect of calcium and magnesium ion dual-stage precipitation, the purity of the product can be improved by slowly cooling during the crystallization process.

[0036] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid, characterized in that: Includes the following steps: S1. Dissolve the crude cyclic acid in an ethanol solution to obtain a mixed solution; S2. Add sodium hydroxide solution dropwise to the mixed solution to adjust the pH to 12.8-13.2, carry out the isomerization reaction, then adjust the pH to 6.3-6.7, filter, and obtain a clear filtrate; S3. Add calcium salt to the clarified filtrate to perform selective precipitation and obtain metal salt precipitate; S4. Mix the metal salt precipitate with water and slurry, then add hydrochloric acid for acidification, filter, and wash the filter cake with cold water to obtain crude cis-cyclic acid. S5. Dissolve the crude cis-cyclic acid in a mixed solvent of acetone and water, adjust the pH to 4.0-4.8 by adding an alkaline solution dropwise, cool and crystallize, and then vacuum dry to obtain high-purity cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid.

2. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 1, characterized in that: In step S2, the isomerization reaction is carried out at a temperature of 140~160℃, a pressure of 1.2~1.6MPa, and a time of 4~6h.

3. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 1, characterized in that: In step S3, the calcium salt is selected as calcium chloride, and the concentration of calcium chloride is 1 mol / L; The mass of the calcium chloride is 85-95% of the crude cyclic acid product; The selective precipitation is carried out at a temperature of 45-50°C, a pH of 6.4-6.6, and a time of 1-1.5 hours.

4. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 1, characterized in that: In step S3, an alkaline solution is added to 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.

5. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 4, characterized in that: The amount of magnesium acetate added is 20-30% of the crude cyclic acid mass.

6. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 1, characterized in that: In step S4, the pH of the acidification is 2.0~2.5, and the temperature is 20~30℃.

7. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 1, characterized in that: In step S5, the volume ratio of acetone to water in the mixed solvent is 1:1 to 1.2; The melting temperature is 60~65℃.

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, characterized in that: In step S5, the alkaline solution is selected from an ammonia solution with a mass concentration of 5 wt% or a saturated NaHCO3 solution.

9. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 1, characterized in that: In step S5, the cooling crystallization conditions are as follows: cooling to 20°C at a rate of 0.1~0.2°C / min, and then aging at 20°C for 2~3 hours.

10. The method for separating and purifying cis-1,3-dibenzylimidazol-2-one-4,5-dicarboxylic acid from crude cyclic acid according to claim 1, characterized in that: In step S5, the vacuum drying temperature is 55~60℃ and the time is 6~8h.