A method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor

Abstract

The present application belongs to the technical field of medicine, and particularly relates to a method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor, comprising the following steps: obtaining solid from mycophenolic acid crystallization mother liquor, adding the solid into ethyl acetate, adjusting pH with acid, separating ethyl acetate phase, adding activated carbon into the ethyl acetate phase for decolorization, filtering, and controlling temperature and reducing pressure to concentrate the filtrate to the content of mycophenolic acid being 71-91 g / L, then controlling the concentration rate to be 5%-10% of the total solution volume per hour, continuing to control temperature and reduce pressure to concentrate to the content of mycophenolic acid being 100-167 g / L, cooling, and filtering to obtain mycophenolic acid, wherein the mycophenolic acid crystallization mother liquor is ethyl acetate crystallization solution of mycophenolic acid; the yield of mycophenolic acid prepared according to the method is greater than 80%, the purity is higher than 99%, and the mycophenolic acid has a good industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis, and specifically relates to a method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor. Background Technology

[0002] Mycophenolic acid, also known as mycophenolic acid or mycophenolic acid, has the chemical name E-4-methyl-6-(1,3-dihydro-7-methyl-4-hydroxy-6-methoxy-3-oxo-5-isobenzofuranyl)-4-hexenoic acid, with the molecular formula C0. 17 H 20 O6, molecular weight 320.34, CAS number 24280-93-1. Mycophenolic acid, after esterification, yields mycophenolic ester, a novel immunosuppressant that has been widely used both domestically and internationally for the prevention and treatment of acute rejection reactions in transplanted organs.

[0003] Currently, existing technologies both domestically and internationally purify mycophenolic acid from fermentation broth or crude product; no methods for recovering and purifying mycophenolic acid from its crystallization mother liquor have been reported. On one hand, existing organic phase crystallization processes, such as those using ethyl acetate, result in mycophenolic acid comprising 5%–15% of the total amount in the mother liquor before crystallization. Without recovery and purification, this increases the difficulty of waste solvent treatment and may cause environmental pollution. On the other hand, the mother liquor contains a variety of impurities, including those difficult to remove during extraction. Liquid chromatography analysis revealed that the purity of mycophenolic acid in the mother liquor is 80%–90%, with higher levels of impurities at relative retention times (RRT) of 0.19, 1.09, and 1.35, and the impurity at RRT 1.09 being particularly difficult to remove. Directly purifying mycophenolic acid from the mother liquor using crude product purification processes yields a product of poor quality.

[0004] This process investigates the impurities in the mycophenolic acid crystallization mother liquor, examining the effects of parameters such as pH value during extraction, the concentration-to-volume ratio during crystallization, and the cooling rate on product yield and purity. A process for purifying mycophenolic acid using the crystallization mother liquor as raw material, through steps including alkali adjustment, extraction decolorization, and crystallization, has been developed. This process is simple and easy to implement industrially. It effectively purifies mycophenolic acid from the crystallization mother liquor, increasing its yield and reducing pollutant emissions. This approach protects the environment and offers significant economic benefits. Summary of the Invention

[0005] To address the above problems, this invention provides a method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor.

[0006] A method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor includes the following steps: obtaining a solid from the mycophenolic acid crystallization mother liquor, adding the solid to ethyl acetate, adjusting the pH with acid, separating the ethyl acetate phase, adding activated carbon to the ethyl acetate phase for decolorization, filtering, concentrating the filtrate under controlled temperature and reduced pressure until the mycophenolic acid content is 71-91 g / L, controlling the concentration rate at 5%-10% of the total solution volume per hour, continuing to concentrate under controlled temperature and reduced pressure until the mycophenolic acid content is 100-167 g / L, cooling, and filtering to obtain mycophenolic acid, wherein the mycophenolic acid crystallization mother liquor is an ethyl acetate crystallization solution of mycophenolic acid.

[0007] Preferably, obtaining the solid from the mycophenolic acid crystallization mother liquor includes the following steps: adding concentrated ammonia to the mycophenolic acid crystallization mother liquor to adjust the pH value of the solution to 8-10, and filtering to obtain the solid.

[0008] Preferably, the concentrated ammonia solution is a 22% to 25% ammonia solution.

[0009] More preferably, the pH of the solution is adjusted to 8.6-9.5 by adding concentrated ammonia.

[0010] Preferably, obtaining the solid from the mycophenolic acid crystallization mother liquor includes the following steps: distilling the mycophenolic acid crystallization mother liquor under reduced pressure until dry to obtain a solid, adding the solid to ethyl acetate, adding concentrated ammonia to adjust the pH of the solution to 8-10, and filtering to obtain the solid.

[0011] More preferably, the pH of the solution is adjusted to 8.6-9.5 by adding concentrated ammonia.

[0012] Preferably, the temperature-controlled and pressure-reduced concentration is continued until the content of mycophenolic acid is 143 g / L.

[0013] Preferably, the temperature of the temperature-controlled vacuum concentration is 40-60°C, and more preferably, the temperature of the temperature-controlled vacuum concentration is 45-55°C.

[0014] Preferably, the cooling and crystallization temperature is 0–5°C.

[0015] Preferably, the acid is selected from one or more of hydrochloric acid, sulfuric acid, and phosphoric acid.

[0016] Preferably, the pH value is adjusted to 3-5 with acid.

[0017] Preferably, the cooling and crystallization rate is 6-12℃ / h, more preferably 10℃ / h.

[0018] Preferably, the mycophenolic acid content in the mycophenolic acid crystallization mother liquor is 12-35 g / L.

[0019] Preferably, the volume of the ethyl acetate is 16 to 24 times the solid mass, wherein the mass is in kg and the volume is in L.

[0020] Preferably, the cooling and crystallization time is 1 to 2 hours.

[0021] The following details the method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor in this application:

[0022] Add concentrated ammonia to the ethyl acetate crystallization mother liquor containing 25–35 g / L mycophenolic acid to adjust the pH to 8.6–9.5, stir, and filter to obtain a solid. Add the solid to ethyl acetate, adjust the pH to 3.5–4.0 with 1 M / L hydrochloric acid, stir to dissolve, separate the ethyl acetate phase, add activated carbon to the ethyl acetate phase and stir to decolorize, filter, and concentrate the filtrate under reduced pressure at 45–55℃ to a mycophenolic acid content of 71–91 g / L. Control the concentration rate to 5%–10% of the total solution volume per hour, continue to concentrate under reduced pressure at 45–55℃ to a mycophenolic acid content of 100–167 g / L, cool to 0–5℃ at a rate of 6–12℃ / h, filter, wash the filter cake with ethyl acetate, and vacuum dry at 45–55℃ for 4–8 h to obtain mycophenolic acid.

[0023] The following details another method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor in this application:

[0024] The ethyl acetate crystallization mother liquor with a mycophenolic acid content of 12-25 g / L was concentrated under reduced pressure to obtain a solid. The solid was added to ethyl acetate, and the pH of the solution was adjusted to 8.6-9.5 with concentrated ammonia. The mixture was stirred and filtered to obtain a solid. The solid was added to ethyl acetate, and the mixture was stirred. The pH was adjusted to 3.5-4.0 with 2 M / L hydrochloric acid. The ethyl acetate phase was separated, and activated carbon was added to the ethyl acetate phase for decolorization by stirring. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 45-55℃ to a mycophenolic acid content of 71-91 g / L. The concentration rate was controlled at 5%-10% of the total solution volume per hour. The concentration was continued at 45-55℃ to a mycophenolic acid content of 100-167 g / L. The temperature was then lowered to 0-5℃ at a rate of 6-12℃ / h. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 45-55℃ for 4-8 hours to obtain mycophenolic acid.

[0025] Preferably, the amount of activated carbon used is 5% to 10% of the solid mass.

[0026] The present invention achieves the following beneficial effects compared to the prior art:

[0027] (1) High yield and high purity. The solid purified by the method of this application yields mycophenolic acid with a yield of over 80% and a purity of over 99%.

[0028] (2) Low cost. The purification process does not require repeated extraction with ethyl acetate, so the amount of solvent used is small and the cost is low.

[0029] (3) Simple process. The solid can be obtained by adding concentrated ammonia to the mycophenolic acid crystallization mother liquor or by directly concentrating the mycophenolic acid crystallization mother liquor under reduced pressure. There is no need to repeatedly adjust the pH and extract, and the operation steps are simple.

[0030] Instruction manual illustrations

[0031] Figure 1 HPLC chromatogram of purified mycophenolic acid. Detailed Implementation

[0032] The beneficial effects of the present invention will be further described through the following embodiments. These embodiments are for illustrative purposes only and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by those skilled in the art according to the present invention are also included within the scope of the present invention.

[0033] Example 1:

[0034] Add 500 mL of mycophenolic acid ethyl acetate stock solution (mycophenolic acid content is 30 g / L) to a beaker, stir, adjust the pH value to 9.1 with 22% to 25% concentrated ammonia water, and filter to obtain 26.0 g of solid. 26.0 g of solid was added to 460 mL of ethyl acetate and stirred. The pH was adjusted to 3.5 with 1 M / L hydrochloric acid and stirred to dissolve. After dissolution, the phases were separated. 2.0 g of activated carbon was added to the ethyl acetate phase and stirred for decolorization for 35 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 45–50 °C until the mycophenolic acid content was 83 g / L, at which point crystals precipitated. The concentration rate was then controlled at 40 mL / h, and the concentration was continued at 45–50 °C until the mycophenolic acid content was 143 g / L. Cooling was then started at a rate of 10 °C / h, and the cooling was stopped when the temperature reached 0–5 °C. The mixture was stirred to allow crystals to precipitate for 1 hour, filtered, and the filter cake was washed with ethyl acetate. The mixture was then dried under vacuum at 45–55 °C for 8 hours to obtain 13.40 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 89.33%, the purity was 99.536%, the RRT was 1.09, and the impurities were 0.045%.

[0035] Example 2

[0036] Add 500 mL of mycophenolic acid ethyl acetate stock solution (mycophenolic acid content is 35 g / L) to a beaker, stir, adjust the pH value to 9.5 with 22% to 25% concentrated ammonia water, and filter to obtain 31.2 g of solid. 31.2 g of solid was added to 740 mL of ethyl acetate and stirred. The pH was adjusted to 3.0 with 1 M / L hydrochloric acid and stirred to dissolve. After dissolution, the phases were separated. 2.0 g of activated carbon was added to the ethyl acetate phase and stirred for decolorization for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 50–55 °C until the mycophenolic acid content was 71 g / L, at which point crystals precipitated. The concentration rate was then controlled at 70 mL / h, and the concentration was continued at 50–55 °C until the mycophenolic acid content was 167 g / L. Cooling was then started at a rate of 6 °C / h, and the cooling was stopped when the temperature reached 0–5 °C. The mixture was stirred to allow crystals to precipitate for 2 hours, filtered, and the filter cake was washed with ethyl acetate. The mixture was then dried under vacuum at 45–55 °C for 7 hours to obtain 15.35 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 87.75%, the purity was 99.271%, the RRT was 1.09, and the impurities were 0.120%.

[0037] Example 3

[0038] Add 500 mL of mycophenolic acid ethyl acetate stock solution (mycophenolic acid content is 25 g / L) to a beaker, stir, adjust the pH value to 8.6 with 22% to 25% concentrated ammonia water, and filter to obtain 18.5 g of solid. 18.5 g of solid was added to 320 mL of ethyl acetate and stirred. The pH was adjusted to 5.0 with 1 M / L hydrochloric acid and stirred to dissolve. After dissolution, the phases were separated. 1.5 g of activated carbon was added to the ethyl acetate phase and stirred for decolorization for 40 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 45–50 °C until the mycophenolic acid content was 91 g / L, at which point crystals precipitated. The concentration rate was then controlled at 30 mL / h, and the concentration was continued at 45–50 °C until the mycophenolic acid content was 100 g / L. Cooling was then started at a rate of 12 °C / h, and the cooling was stopped when the temperature reached 0–5 °C. The mixture was stirred to allow crystals to precipitate for 1 hour, filtered, and the filter cake was washed with ethyl acetate. The mixture was then dried under vacuum at 45–55 °C for 6 hours to obtain 10.95 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 87.60%, the purity was 99.185%, the RRT was 1.09, and the impurities were 0.131%.

[0039] Example 4

[0040] Add 500 mL of mycophenolic acid ethyl acetate stock solution (mycophenolic acid content is 30 g / L) to a beaker, stir, adjust the pH value to 8.0 with 22% to 25% concentrated ammonia water, and filter to obtain 23.1 g of solid. 23.1 g of solid was added to 460 mL of ethyl acetate and stirred. The pH was adjusted to 4.0 with 1 M / L sulfuric acid and stirred to dissolve. After dissolution, the phases were separated. 5.0 g of activated carbon was added to the ethyl acetate phase and stirred for decolorization for 35 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 40–45 °C until the mycophenolic acid content was 67 g / L, at which point crystals precipitated. The concentration rate was then controlled at 50 mL / h, and the concentration was continued at 40–45 °C until the mycophenolic acid content was 200 g / L. Cooling was then started at a rate of 10 °C / h, and the cooling was stopped when the temperature reached 0–5 °C. The mixture was stirred to allow crystals to precipitate for 1 hour, filtered, and the filter cake was washed with ethyl acetate. The mixture was then dried under vacuum at 45–55 °C for 5 hours to obtain 12.62 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 84.13%, the purity was 98.817%, the RRT was 1.09, and the impurities were 0.161%.

[0041] Example 5

[0042] Add 500 mL of mycophenolic acid ethyl acetate stock solution (mycophenolic acid content is 30 g / L) to a beaker, stir, adjust the pH to 10 with 22%–25% concentrated ammonia, and filter to obtain 29.6 g of solid. 29.6 g of solid was added to 750 mL of ethyl acetate and stirred. The pH was adjusted to 3.5 with 1 M / L phosphoric acid and stirred to dissolve. After dissolution, the phases were separated. 3.0 g of activated carbon was added to the ethyl acetate phase and stirred for decolorization for 45 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 55–60 °C until the mycophenolic acid content was 100 g / L, at which point crystals precipitated. The concentration rate was then controlled at 70 mL / h, and the concentration was continued at 55–60 °C until the mycophenolic acid content was 200 g / L. Cooling was then started at a rate of 10 °C / h, and the cooling was stopped when the temperature reached 0–5 °C. The mixture was stirred to allow crystals to precipitate for 2 hours, filtered, and the filter cake was washed with ethyl acetate. The mixture was then vacuum dried at 45–55 °C for 10 hours to obtain 12.72 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 84.80%, the purity was 98.762%, the RRT was 1.09, and the impurities were 0.211%.

[0043] Example 6

[0044] 1000 mL of mycophenolic acid ethyl acetate crystallization mother liquor (mycophenolic acid content 20 g / L) was concentrated under reduced pressure to dryness to obtain 32.7 g of solid. The 32.7 g solid was added to 800 mL of ethyl acetate, and the pH was adjusted to 8.6 with 22%–25% concentrated ammonia. After filtration, 35.4 g of solid was obtained. 35.4 g of solid was added to 600 mL of ethyl acetate, and the pH was adjusted to 4.5 with 2 M / L hydrochloric acid. The ethyl acetate phase was separated, and 1.6 g of activated carbon was added to the ethyl acetate phase. The mixture was stirred and decolorized for 50 minutes, filtered, and the filtrate was concentrated under reduced pressure at 50–55 °C until the mycophenolic acid content was 91 g / L, with crystals precipitating. The concentration rate was then controlled at 70 mL / h, and the mixture was further concentrated under reduced pressure at 50–55 °C until the mycophenolic acid content was 125 g / L. The temperature was then lowered to 0–5 °C at a rate of 12 °C / h, and the mixture was stirred to precipitate crystals for 2 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum at 45–55 °C for 8 hours to obtain 17.39 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 86.95%, the purity was 99.224%, the RRT was 1.09, and the impurities were 0.103%.

[0045] Example 7

[0046] 1000 mL of mycophenolic acid ethyl acetate crystallization mother liquor (mycophenolic acid content was 12 g / L) was concentrated under reduced pressure to dryness to obtain 19.4 g of solid. The 19.4 g solid was added to 400 mL of ethyl acetate, and the pH was adjusted to 9.5 with 22%–25% concentrated ammonia. After filtration, 25.2 g of solid was obtained. 25.2 g of solid was added to 550 mL of ethyl acetate, and the pH was adjusted to 4.0 with 2 M / L hydrochloric acid. The ethyl acetate phase was separated, and 1.5 g of activated carbon was added to the ethyl acetate phase. The mixture was stirred and decolorized for 60 minutes, filtered, and the filtrate was concentrated under reduced pressure at 45–50 °C until the mycophenolic acid content was 71 g / L, with crystals precipitating. The concentration rate was then controlled at 30 mL / h, and the mixture was further concentrated under reduced pressure at 45–50 °C until the mycophenolic acid content was 167 g / L. The temperature was then lowered to 0–5 °C at a rate of 10 °C / h, and the mixture was stirred to precipitate crystals for 1 hour. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum at 45–55 °C for 7 hours to obtain 10.40 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 86.67%, the purity was 99.173%, the RRT was 1.09, and the impurities were 0.116%.

[0047] Example 8

[0048] 1000 mL of mycophenolic acid ethyl acetate crystallization mother liquor (mycophenolic acid content 25 g / L) was concentrated under reduced pressure to dryness to obtain 32.3 g of solid. The 32.3 g solid was added to 650 mL of ethyl acetate, and the pH was adjusted to 9.0 with 22%–25% concentrated ammonia. After filtration, 38.1 g of solid was obtained. 38.1 g of solid was added to 650 mL of ethyl acetate, and the pH was adjusted to 3.5 with 2 M / L hydrochloric acid. The ethyl acetate phase was separated, and 3.0 g of activated carbon was added to the ethyl acetate phase. The mixture was stirred and decolorized for 60 minutes, filtered, and the filtrate was concentrated under reduced pressure at 50–55 °C until the mycophenolic acid content was 77 g / L, with crystals precipitating. The concentration rate was then controlled at 45 mL / h, and the mixture was further concentrated under reduced pressure at 50–55 °C until the mycophenolic acid content was 100 g / L. The temperature was then lowered to 0–5 °C at a rate of 12 °C / h, and the mixture was stirred to precipitate crystals for 2 hours. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum at 45–55 °C for 8 hours to obtain 22.26 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 89.04%, the purity was 99.357%, and the RRT was 1.09 with 0.082% impurities.

[0049] Example 9

[0050] Add 500 mL of mycophenolic acid ethyl acetate stock solution (mycophenolic acid content is 30 g / L) to a beaker, stir, adjust the pH value to 9.1 with 22% to 25% concentrated ammonia water, and filter to obtain 27.3 g of solid. 27.3 g of solid was added to 500 mL of ethyl acetate and stirred. The pH was adjusted to 5 with 1 M / L hydrochloric acid and stirred to dissolve. After dissolution, the phases were separated. 2.0 g of activated carbon was added to the ethyl acetate phase and the mixture was stirred to decolorize for 40 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 40–45 °C and a concentration rate of 80 mL / h until the mycophenolic acid content was 167 g / L. The cooling rate was controlled at 10 °C / h, and the cooling was stopped when the temperature reached 0–5 °C. The mixture was stirred to crystallize for 1 hour, filtered, and the filter cake was washed with ethyl acetate. The mixture was then dried under vacuum at 45–55 °C for 8 hours to obtain 12.26 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 81.73%, the purity was 97.365%, the RRT was 1.09, and the impurities were 0.297%.

[0051] Example 10

[0052] Add 500 mL of mycophenolic acid ethyl acetate stock solution (mycophenolic acid content is 30 g / L) to a beaker, stir, adjust the pH value to 9.1 with 22% to 25% concentrated ammonia water, and filter to obtain 27.7 g of solid. 27.7 g of solid was added to 500 mL of ethyl acetate and stirred. The pH was adjusted to 3.5 with 1 M / L hydrochloric acid and stirred to dissolve. After dissolution, the phases were separated. 2.0 g of activated carbon was added to the ethyl acetate phase and stirred for decolorization for 40 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 50–60 °C and a concentration rate of 70 mL / h until the mycophenolic acid content was 200 g / L. The cooling rate was controlled at 3 °C / h, and the cooling was stopped when the temperature reached -10 to -15 °C. The mixture was stirred to crystallize for 1 hour, filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 45–55 °C for 8 hours to obtain 12.38 g of mycophenolic acid. Based on the mass of mycophenolic acid in the mother liquor, the yield was 82.53%, the purity was 97.026%, the RRT was 1.09, and the impurities were 0.953%.

[0053] Comparative Example 1

[0054] 1000 mL of mycophenolic acid ethyl acetate crystallization mother liquor (mycophenolic acid content 25 g / L) was adjusted to pH 9.1 with concentrated ammonia, stirred, and allowed to stand for phase separation to obtain an alkaline suspension. 12.5 mL of ethyl acetate was added to the alkaline suspension, and the pH was adjusted to 9.1 with concentrated ammonia. After stirring and allowing to stand for phase separation, 110 mL of alkaline suspension was obtained. Add 55 mL of ethyl acetate to 110 mL of alkaline suspension, adjust the pH to 5.6 with 2 M / L hydrochloric acid, stir for 30 minutes, and then allow the mixture to stand and separate to obtain an ethyl acetate phase and an aqueous phase. Add another 33 mL of ethyl acetate to the aqueous phase, adjust the pH to 5.9 with concentrated ammonia, stir for 30 minutes, and then allow the mixture to stand and separate to obtain an ethyl acetate phase and an aqueous phase. Combine the ethyl acetate phases from the two acid extractions, concentrate under reduced pressure until the mycophenolic acid content is 200 g / L, then stop the concentration. Stir the concentrate and heat it to 60 °C, continue stirring for 15 minutes, then cool it down at 3 °C / hour to crystallize. Cool it down to -10 °C and continue stirring to crystallize for 3 hours, precipitating mycophenolic acid. Dry it under vacuum at 70 °C for 8 hours to obtain 20.16 g of mycophenolic acid, with a yield of 80.64%, a purity of 95.393%, an RRT of 1.09, and 1.347% impurities. The color is yellowish.

[0055] Comparative Example 2

[0056] 1000 mL of mycophenolic acid ethyl acetate crystallization mother liquor (mycophenolic acid content 25 g / L) was concentrated under reduced pressure to obtain 31.0 g of solid. 31.0 g of solid was added to 800 mL of acetone and 80 mL of 2M hydrochloric acid, stirred, and heated to 45 °C. After dissolving, 3.5 g of activated carbon was added, and the mixture was kept at this temperature and stirred for 30 minutes, then filtered. While stirring, 500 mL of a mixture of n-hexane and heptane (volume ratio 1:1) was added dropwise to the filtrate at 35 °C. After the addition was complete, the mixture was kept at 15 °C and stirred to allow crystallization for 2.5 hours. The crystals were then filtered, and the filter cake was washed with 50 mL of purified water. The mixture was then dried under vacuum at 40 °C for 8 hours to obtain 20.65 g of mycophenolic acid, with a yield of 82.60%, purity of 97.672%, RRT 1.09, and impurities of 0.306%.

[0057] Comparative Example 3

[0058] 1000 mL of mycophenolic acid ethyl acetate crystallization mother liquor (mycophenolic acid content 25 g / L) was concentrated under reduced pressure to obtain 32.1 g of solid. 32.1 g of solid was added to 1000 mL of butyl acetate, stirred, and heated to 90 °C. After dissolving, 3.5 g of activated carbon was added, and the mixture was kept warm and stirred for 30 minutes. The mixture was filtered, and 1000 mL of purified water was added for extraction. After extraction, the upper ester phase was concentrated at 50 °C and a vacuum degree of -0.09 MPa to 60% of its original volume. Crystallization was carried out at 0 °C for 4 hours, filtered, and the filter cake was washed with 50 mL of cold butyl acetate. The cake was then dried under reduced pressure at 60 °C for 8 hours at a vacuum degree of -0.06 MPa. 21.25 g of mycophenolic acid was obtained, with a yield of 85.00%, purity of 96.134%, RRT 1.09, and impurities of 1.192%.

Claims

1. A method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor, characterized in that, Includes the following steps: A solid was obtained from the mother liquor of mycophenolic acid crystallization. The solid was added to ethyl acetate, the pH was adjusted with acid, the ethyl acetate phase was separated, activated carbon was added to the ethyl acetate phase for decolorization, and the mixture was filtered. The filtrate was concentrated under controlled temperature and reduced pressure until the mycophenolic acid content was 71-91 g / L. The concentration rate was controlled at 5%-10% of the total solution volume per hour. The concentration was continued under controlled temperature and reduced pressure until the mycophenolic acid content was 100-167 g / L. The mixture was then cooled to crystallize, and the crystals were filtered to obtain mycophenolic acid. The mother liquor of mycophenolic acid crystallization was an ethyl acetate crystallization solution of mycophenolic acid. The pH was adjusted to 3-5 with acid; the temperature for controlled temperature and reduced pressure concentration was 40-60℃; the temperature for cooling to crystallize was 0-5℃, and the rate of cooling to crystallize was 6-12℃ / h.

2. The method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor as described in claim 1, characterized in that, Obtaining solid from mycophenolic acid crystallization mother liquor includes the following steps: adding concentrated ammonia to the mycophenolic acid crystallization mother liquor to adjust the pH value of the solution to 8-10, and filtering to obtain solid.

3. The method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor as described in claim 1, characterized in that, Obtaining the solid from the mycophenolic acid crystallization mother liquor includes the following steps: distilling the mycophenolic acid crystallization mother liquor under reduced pressure until dry to obtain a solid, adding the solid to ethyl acetate, adding concentrated ammonia to adjust the pH of the solution to 8-10, and filtering to obtain the solid.

4. The method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor as described in claim 2 or 3, characterized in that, The pH of the solution is adjusted to 8.6–9.5 by adding concentrated ammonia.

5. The method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor as described in claim 1, characterized in that, The acid is selected from one or more of hydrochloric acid, sulfuric acid, and phosphoric acid.

6. The method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor as described in claim 1, characterized in that, The temperature for temperature-controlled vacuum concentration is 45–55°C.

7. The method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor as described in claim 1, characterized in that, The mycophenolic acid content in the mycophenolic acid crystallization mother liquor is 12-35 g / L.

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