CN114763344A - Method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor - Google Patents
Method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor Download PDFInfo
- Publication number
- CN114763344A CN114763344A CN202210016144.0A CN202210016144A CN114763344A CN 114763344 A CN114763344 A CN 114763344A CN 202210016144 A CN202210016144 A CN 202210016144A CN 114763344 A CN114763344 A CN 114763344A
- Authority
- CN
- China
- Prior art keywords
- mycophenolic acid
- mother liquor
- ethyl acetate
- solid
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 title claims abstract description 157
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 title claims abstract description 156
- 229960000951 mycophenolic acid Drugs 0.000 title claims abstract description 156
- 239000012452 mother liquor Substances 0.000 title claims abstract description 64
- 238000002425 crystallisation Methods 0.000 title claims abstract description 47
- 230000008025 crystallization Effects 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 249
- 239000007787 solid Substances 0.000 claims abstract description 58
- 238000001914 filtration Methods 0.000 claims abstract description 43
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000001816 cooling Methods 0.000 claims abstract description 30
- 239000000706 filtrate Substances 0.000 claims abstract description 16
- 239000012141 concentrate Substances 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000011549 crystallization solution Substances 0.000 claims abstract description 3
- 238000004042 decolorization Methods 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 25
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 53
- 239000012071 phase Substances 0.000 description 30
- 239000012535 impurity Substances 0.000 description 17
- 239000012065 filter cake Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 239000013078 crystal Substances 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 238000005191 phase separation Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- -1 Mycophenolic acid ester Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000010887 waste solvent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a method for purifying mycophenolic acid from a mycophenolic acid crystallization mother liquor, which comprises the following steps: obtaining a solid from a mycophenolic acid crystallization mother liquor, adding the solid into ethyl acetate, adjusting the pH value with acid, separating an ethyl acetate phase, adding activated carbon into the ethyl acetate phase for decolorization, filtering, concentrating a filtrate at a controlled temperature under reduced pressure until the content of mycophenolic acid is 71-91g/L, controlling the concentration rate to be 5% -10% of the volume of a solvent concentrated per hour, continuing to concentrate at a controlled temperature under reduced pressure until the content of mycophenolic acid 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; the mycophenolic acid prepared by the method has the yield of more than 80 percent and the purity of more than 99 percent, and has better industrial application prospect.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor.
Background
Mycophenolic acid (Mycophenolic acid) in turnMycophenolic acid, chemical name: e-4-methyl-6- (1, 3-dihydro-7-methyl-4-hydroxy-6-methoxy-3-oxo-5-isobenzofuranyl) -4-hexenoic acid, formula C17H20O6Molecular weight 320.34, CAS number 24280-93-1. Mycophenolic acid ester is generated after esterification of mycophenolic acid, is a novel immunosuppressant, and is widely applied to prevention and treatment of acute rejection of transplanted organs at home and abroad.
At present, the prior art at home and abroad is to purify mycophenolic acid from fermentation liquor or crude products, and no report of a method for recovering and purifying mycophenolic acid from a mycophenolic acid crystallization mother liquor is found. On one hand, in the existing crystallization of organic phases such as ethyl acetate and the like, the mycophenolic acid in the crystallization mother liquor accounts for 5-15% of the total amount before crystallization. The mother liquor, without being subjected to recovery and purification, increases the difficulty of treating the waste solvent and may cause environmental pollution. On the other hand, the mother liquor contains more impurities which are difficult to remove in the extraction process. Liquid phase detection and analysis researches show that the purity of the mycophenolic acid in the mother liquor is 80-90%, wherein the impurity contents of the relative retention time RRT0.19, RRT1.09 and RRT1.35 are higher, and the impurities of RRT1.09 are difficult to remove. The mycophenolic acid is directly purified from the mother liquor by using a crude product purification process, and the obtained product has poor quality.
According to the process, through the research on impurities in the mycophenolic acid crystallization mother liquor, the influence of parameters such as the pH value of the extraction process, the concentration mass-to-volume ratio in the crystallization process, the cooling speed and the like on the yield and the purity of the product is researched. Develops a process for purifying the mycophenolic acid by taking the mycophenolic acid crystallization mother liquor as a raw material and carrying out the steps of alkali adjustment, extraction decoloration, crystallization and the like. The process has the characteristics of simplicity and easy industrial operation. The process can well purify the mycophenolic acid from the mycophenolic acid crystallization mother liquor, improve the yield of the mycophenolic acid and reduce the discharge of pollutants. Not only protects the environment, but also has good economic benefit.
Disclosure of Invention
In order to solve the problems, the invention provides a method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor.
A method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor comprises the following steps: obtaining a solid from a mycophenolic acid crystallization mother liquor, adding the solid into ethyl acetate, adjusting the pH value with acid, separating an ethyl acetate phase, adding activated carbon into the ethyl acetate phase for decolorization, filtering, concentrating a filtrate at a controlled temperature under reduced pressure until the content of mycophenolic acid is 71-91g/L, controlling the concentration rate to be 5% -10% of the volume of a solvent concentrated per hour, continuing to concentrate at a controlled temperature under reduced pressure until the content of mycophenolic acid 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.
Preferably, the step of obtaining the solid from the mycophenolic acid crystallization mother liquor comprises the following steps: adding concentrated ammonia water into the mycophenolic acid crystallization mother liquor to adjust the pH value of the solution to 8-10, and filtering to obtain a solid.
Preferably, the concentrated ammonia water is 22-25% ammonia water solution.
Further preferably, the pH value of the solution is adjusted to 8.6-9.5 by adding concentrated ammonia water.
Preferably, the step of obtaining the solid from the mycophenolic acid crystallization mother liquor comprises the following steps: distilling the mycophenolic acid crystallization mother liquor under reduced pressure to dryness to obtain a solid, adding the solid into ethyl acetate, adding concentrated ammonia water to adjust the pH value of the solution to 8-10, and filtering to obtain the solid.
Further preferably, the pH value of the solution is adjusted to 8.6-9.5 by adding concentrated ammonia water.
Preferably, the temperature-controlled reduced pressure concentration is continued until the content of the mycophenolic acid is 143 g/L.
Preferably, the temperature for temperature-controlled vacuum concentration is 40-60 ℃, and further preferably, the temperature for temperature-controlled vacuum concentration is 45-55 ℃.
Preferably, the temperature for cooling and crystallizing is 0-5 ℃.
Preferably, the acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
Preferably, the pH value is adjusted to 3-5 by acid.
Preferably, the cooling crystallization rate is 6-12 ℃/h, and more preferably 10 ℃/h.
Preferably, the content of mycophenolic acid in the mycophenolic acid crystallization mother liquor is 12-35 g/L.
Preferably, the volume usage amount of the ethyl acetate is 16-24 times of the solid mass, wherein the mass is Kg, and the volume is L.
Preferably, the time for cooling crystallization is 1-2 h.
The following further details the method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor in the present application:
adding concentrated ammonia water into ethyl acetate crystallization mother liquor with the content of mycophenolic acid of 25-35 g/L to adjust the pH value of the solution to 8.6-9.5, stirring, filtering to obtain a solid, adding the solid into ethyl acetate, adjusting pH to 3.5-4.0 with 1M/L hydrochloric acid, stirring for dissolving, separating ethyl acetate phase, adding activated carbon into the ethyl acetate phase, stirring for decolorizing, filtering, concentrating the filtrate at 45-55 deg.C under reduced pressure until the content of mycophenolic acid is 71-91g/L, controlling the concentration rate to be 5-10% of the volume of the solvent concentrated per hour in the total solution volume, continuously controlling the temperature to be 45-55 ℃, concentrating under reduced pressure until the content of the mycophenolic acid is 100-167 g/L, cooling to 0-5 ℃ at the speed of 6-12 ℃/h, filtering, washing a filter cake with ethyl acetate, and vacuum drying at the temperature of 45-55 ℃ for 4-8 h to obtain the mycophenolic acid.
The following further details another method for purifying mycophenolic acid from a mycophenolic acid crystallization mother liquor in the present application:
concentrating ethyl acetate crystallization mother liquor with the content of mycophenolic acid of 12-25 g/L under reduced pressure to obtain solid, adding the solid into ethyl acetate, adjusting the pH value of the solution to 8.6-9.5 by using strong ammonia water, stirring, filtering to obtain a solid, adding the solid into ethyl acetate, stirring, adjusting the pH value to 3.5-4.0 by using 2M/L hydrochloric acid, separating an ethyl acetate phase, adding activated carbon into the ethyl acetate phase, stirring and decoloring, filtering, concentrating the filtrate at 45-55 ℃ under reduced pressure until the content of mycophenolic acid is 71-91g/L, controlling the concentration rate to be 5-10% of the volume of the solvent concentrated per hour in the total solution volume, continuously controlling the temperature to be 45-55 ℃, carrying out reduced pressure concentration until the content of the mycophenolic acid is 100-167 g/L, cooling to 0-5 ℃ at the speed of 6-12 ℃/h, filtering, washing a filter cake with ethyl acetate, and vacuum drying at the temperature of 45-55 ℃ for 4-8 h to obtain the mycophenolic acid.
Preferably, the amount of activated carbon is 5% to 10% of the mass of the solid.
Compared with the prior art, the invention has the following beneficial effects:
(1) high yield and high purity. The yield of mycophenolic acid prepared by solid purification by the method is higher than 80%, and the purity is higher than 99%.
(2) The cost is low. The purification process does not need to repeatedly use ethyl acetate for extraction, the dosage of the solvent is less, and the cost is low.
(3) The process is simple. Concentrated ammonia water is added into the mycophenolic acid crystallization mother liquor or the mycophenolic acid crystallization mother liquor is directly subjected to reduced pressure concentration to obtain a solid, the pH value does not need to be repeatedly adjusted, extraction is not needed, and the operation steps are simple.
Drawings
FIG. 1 HPLC detection profile of purified mycophenolic acid.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
Example 1:
500mL of mother liquor of mycophenolic acid in ethyl acetate (the content of mycophenolic acid is 30g/L) is added into a beaker, stirred, adjusted to pH value of 9.1 by using 22-25% concentrated ammonia water, and filtered to obtain 26.0g of solid. Adding 26.0g of solid into 460mL of ethyl acetate, stirring, adjusting the pH value to 3.5 by using 1M/L hydrochloric acid, stirring for dissolving, splitting phases after dissolving, adding 2.0g of activated carbon into the ethyl acetate phase, stirring for decoloring for 35 minutes, filtering, concentrating the filtrate at 45-50 ℃ under reduced pressure until the content of mycophenolic acid is 83g/L, separating out crystals, controlling the concentration rate to be 40mL/h, continuing to concentrate at 45-50 ℃ under reduced pressure until the content of mycophenolic acid is 143g/L, cooling at 10 ℃/h, stopping cooling when the temperature is 0-5 ℃, stirring for crystallizing for 1 hour, filtering, washing a filter cake by using ethyl acetate, and drying at 45-55 ℃ for 8 hours under vacuum to obtain 13.40g of mycophenolic acid, wherein the yield is 89.33%, the purity is 99.536%, and the RRT1.09 impurity is 0.045% by mass of mycophenolic acid in the mother liquor.
Example 2
500mL of mother liquor of mycophenolic acid in ethyl acetate (the content of mycophenolic acid is 35g/L) is added into a beaker, stirred, adjusted to pH value of 9.5 by using 22% -25% concentrated ammonia water, and filtered to obtain 31.2g of solid. Adding 31.2g of solid into 740mL of ethyl acetate, stirring, adjusting the pH value to 3.0 by using 1M/L hydrochloric acid, stirring for dissolving, carrying out phase separation after dissolving, adding 2.0g of activated carbon into the ethyl acetate phase, stirring for decoloring for 30 minutes, filtering, concentrating the filtrate at 50-55 ℃ under reduced pressure until the content of mycophenolic acid is 71g/L, separating out crystals, controlling the concentration rate to be 70mL/h, continuing to concentrate at 50-55 ℃ under reduced pressure until the content of mycophenolic acid is 167g/L, cooling at the rate of 6 ℃/h, stopping cooling when the temperature is 0-5 ℃, stirring for crystallizing for 2 hours, filtering, washing a filter cake by using ethyl acetate, and carrying out vacuum drying at 45-55 ℃ for 7 hours to obtain 15.35g of mycophenolic acid, wherein the yield is 87.75%, the purity is 99.271%, and the RRT is 1.09 impurity content is 0.120% based on the mass of mycophenolic acid in the mother liquor.
Example 3
500mL of an ethyl acetate mother liquor of mycophenolic acid (the content of mycophenolic acid is 25g/L) is added into a beaker, stirred, the pH value is adjusted to 8.6 by using 22% -25% concentrated ammonia water, and the mixture is filtered to obtain 18.5g of solid. Adding 18.5g of solid into 320mL of ethyl acetate, stirring, adjusting the pH value to 5.0 by using 1M/L hydrochloric acid, stirring for dissolving, carrying out phase separation after dissolving, adding 1.5g of activated carbon into the ethyl acetate phase, stirring for decoloring for 40 minutes, filtering, concentrating the filtrate at 45-50 ℃ under reduced pressure until the content of mycophenolic acid is 91g/L, separating out crystals, controlling the concentration rate to be 30mL/h, continuing to concentrate at 45-50 ℃ under reduced pressure until the content of mycophenolic acid is 100g/L, cooling at the rate of 12 ℃/h, stopping cooling when the temperature is 0-5 ℃, stirring for crystallizing for 1 hour, filtering, washing a filter cake by using ethyl acetate, and carrying out vacuum drying at 45-55 ℃ for 6 hours to obtain 10.95g of mycophenolic acid, wherein the yield is 87.60%, the purity is 99.185%, and the RRT1.09 impurity content is 0.131% by mass of mycophenolic acid in the mother liquor.
Example 4
500mL of mother liquor of mycophenolic acid in ethyl acetate (the content of mycophenolic acid is 30g/L) is added into a beaker, stirred, adjusted to pH value of 8.0 by using 22% -25% concentrated ammonia water, and filtered to obtain 23.1g of solid. Adding 23.1g of solid into 460mL of ethyl acetate, stirring, adjusting the pH value to 4.0 by using 1M/L sulfuric acid, stirring for dissolving, carrying out phase separation after dissolving, adding 5.0g of activated carbon into the ethyl acetate phase, stirring for decoloring for 35 minutes, filtering, concentrating the filtrate at 40-45 ℃ under reduced pressure until the content of mycophenolic acid is 67g/L, separating out crystals, controlling the concentration rate to be 50mL/h, continuing to concentrate at 40-45 ℃ under reduced pressure until the content of mycophenolic acid is 200g/L, cooling at the rate of 10 ℃/h, stopping cooling when the temperature is 0-5 ℃, stirring for crystallizing for 1 hour, filtering, washing a filter cake with ethyl acetate, and carrying out vacuum drying at 45-55 ℃ for 5 hours to obtain 12.62g of mycophenolic acid, wherein the yield is 84.13%, the purity is 98.817%, and the RRT1.09 impurity content is 0.161% based on the mass of mycophenolic acid in the mother liquor.
Example 5
500mL of mother liquor of mycophenolic acid in ethyl acetate (the content of mycophenolic acid is 30g/L) is added into a beaker, stirred, adjusted to pH 10 by using 22% -25% concentrated ammonia water, and filtered to obtain 29.6g of solid. Adding 29.6g of solid into 750mL of ethyl acetate, stirring, adjusting the pH value to 3.5 by using 1M/L phosphoric acid, stirring for dissolving, splitting phases after dissolving, adding 3.0g of activated carbon into the ethyl acetate phase, stirring for decoloring for 45 minutes, filtering, concentrating the filtrate at 55-60 ℃ under reduced pressure until the content of the mycophenolic acid is 100g/L, separating out crystals, controlling the concentration rate to be 70mL/h, continuing to concentrate at 55-60 ℃ under reduced pressure until the content of the mycophenolic acid is 200g/L, cooling at the rate of 10 ℃/h, stopping cooling when the temperature is 0-5 ℃, stirring for crystallizing for 2 hours, filtering, washing a filter cake with ethyl acetate, and drying at 45-55 ℃ for 10 hours under vacuum to obtain 12.72g of mycophenolic acid, wherein the yield is 84.80%, the purity is 98.762%, and the RRT1.09 impurity is 0.211% by mass of the mycophenolic acid in the mother liquor.
Example 6
1000mL of the mother liquor of the mycophenolic acid in ethyl acetate crystals (the content of the mycophenolic acid is 20g/L) is decompressed and concentrated to be dry to obtain 32.7g of solid, 32.7g of the solid is added into 800mL of ethyl acetate, 22 to 25 percent of concentrated ammonia water is used for adjusting the pH value to 8.6, and 35.4g of solid is obtained by filtration. Adding 35.4g of solid into 600mL of ethyl acetate, adjusting the pH value to 4.5 by using 2M/L hydrochloric acid, separating an ethyl acetate phase, adding 1.6g of activated carbon into the ethyl acetate phase, stirring and decoloring for 50 minutes, filtering, concentrating the filtrate at 50-55 ℃ under reduced pressure until the content of mycophenolic acid is 91g/L, separating out crystals, controlling the concentration rate to be 70mL/h, continuing to concentrate at 50-55 ℃ under reduced pressure until the content of mycophenolic acid is 125g/L, cooling to 0-5 ℃ at the rate of 12 ℃/h, stirring and crystallizing for 2 hours, filtering, washing a filter cake by using ethyl acetate, and drying at 45-55 ℃ in vacuum for 8 hours to obtain 17.39g of mycophenolic acid, wherein the yield is 86.95% based on the mass of mycophenolic acid in the mother liquor, the purity is 99.224%, and the RRT1.09 impurity is 0.103%.
Example 7
1000mL of an ethyl acetate crystallization mother liquor of mycophenolic acid (the content of mycophenolic acid is 12g/L) is decompressed and concentrated to be dry to obtain 19.4g of solid, 19.4g of the solid is added into 400mL of ethyl acetate, 22% -25% concentrated ammonia water is used for adjusting the pH value to 9.5, and 25.2g of solid is obtained by filtration. Adding 25.2g of solid into 550mL of ethyl acetate, adjusting the pH value to 4.0 by using 2M/L hydrochloric acid, separating an ethyl acetate phase, adding 1.5g of activated carbon into the ethyl acetate phase, stirring and decoloring for 60 minutes, filtering, concentrating the filtrate at 45-50 ℃ under reduced pressure until the content of mycophenolic acid is 71g/L, separating out crystals, controlling the concentration rate to be 30mL/h, continuing to concentrate at 45-50 ℃ under reduced pressure until the content of mycophenolic acid is 167g/L, cooling to 0-5 ℃ at the rate of 10 ℃/h, stirring and crystallizing for 1 hour, filtering, washing a filter cake by using ethyl acetate, and drying for 7 hours at 45-55 ℃ in vacuum to obtain 10.40g of mycophenolic acid, wherein the yield is 86.67%, the purity is 99.173%, and the RRT1.09 impurity is 0.116% by mass of the mycophenolic acid in the mother liquor.
Example 8
1000mL of the mother liquor of the ethyl acetate crystallization of the mycophenolic acid (the content of the mycophenolic acid is 25g/L) is decompressed and concentrated to be dry to obtain 32.3g of solid, 32.3g of the solid is added into 650mL of ethyl acetate, 22 to 25 percent of concentrated ammonia water is used for adjusting the pH value to 9.0, and 38.1g of the solid is obtained by filtration. Adding 38.1g of solid into 650mL of ethyl acetate, adjusting the pH value to 3.5 by using 2M/L hydrochloric acid, separating an ethyl acetate phase, adding 3.0g of activated carbon into the ethyl acetate phase, stirring and decoloring for 60 minutes, filtering, concentrating the filtrate at 50-55 ℃ under reduced pressure until the content of mycophenolic acid is 77g/L, separating out crystals, controlling the concentration rate to be 45mL/h, continuing to concentrate at 50-55 ℃ under reduced pressure until the content of mycophenolic acid is 100g/L, cooling to 0-5 ℃ at the rate of 12 ℃/h, stirring and crystallizing for 2 hours, filtering, washing a filter cake by using ethyl acetate, and drying under vacuum at 45-55 ℃ for 8 hours to obtain 22.26g of mycophenolic acid, wherein the yield is 89.04%, the purity is 99.357%, and the RRT1.09 impurity content is 0.082 by mass of mycophenolic acid in mother liquor.
Example 9
500mL of an ethyl acetate mother liquor of mycophenolic acid (the content of mycophenolic acid is 30g/L) is added into a beaker, stirred, the pH value is adjusted to 9.1 by using 22% -25% concentrated ammonia water, and the mixture is filtered to obtain 27.3g of solid. Adding 27.3g of solid into 500mL of ethyl acetate, stirring, adjusting the pH value of 5 with 1M/L hydrochloric acid, stirring for dissolving, splitting phases after dissolving, adding 2.0g of activated carbon into the ethyl acetate phase, stirring for decoloring for 40 minutes, filtering, concentrating the filtrate at 40-45 ℃ and at a concentration rate of 80mL/h under reduced pressure until the content of mycophenolic acid is 167g/L, controlling the cooling rate to be 10 ℃/h, stopping cooling when the temperature is reduced to 0-5 ℃, stirring for crystallizing for 1 hour, filtering, washing a filter cake with ethyl acetate, and vacuum-drying for 8 hours at 45-55 ℃ to obtain 12.26g of mycophenolic acid, wherein the yield is 81.73% by mass of mycophenolic acid in a mother solution, the purity is 97.365%, and the impurity content of RRT1.09 is 0.297% by mass of mycophenolic acid.
Example 10
500mL of mother liquor of mycophenolic acid in ethyl acetate (the content of mycophenolic acid is 30g/L) is added into a beaker, stirred, adjusted to pH value of 9.1 by using 22-25% concentrated ammonia water, and filtered to obtain 27.7g of solid. Adding 27.7g of solid into 500mL of ethyl acetate, stirring, adjusting the pH value to 3.5 by using 1M/L hydrochloric acid, stirring for dissolving, splitting phases after dissolving, adding 2.0g of activated carbon into the ethyl acetate phase, stirring for decoloring for 40 minutes, filtering, concentrating the filtrate at 50-60 ℃ and at a concentration rate of 70mL/h under reduced pressure until the content of mycophenolic acid is 200g/L, controlling the cooling rate to be 3 ℃/h, stopping cooling when the temperature is reduced to-10 to-15 ℃, stirring for crystallizing for 1 hour, filtering, washing a filter cake by using ethyl acetate, and vacuum drying for 8 hours at 45-55 ℃ to obtain 12.38g of mycophenolic acid, wherein the yield is 82.53%, the purity is 97.026%, and the RRT1.09 impurity is 0.953% based on the mass of the mycophenolic acid in the mother liquor.
Comparative example 1
1000mL of the mother liquor of the mycophenolic acid in ethyl acetate crystals (the content of the mycophenolic acid is 25g/L) is adjusted to pH value of 9.1 by using concentrated ammonia water, and the alkaline suspension solution is obtained by static phase separation after stirring. Adding 12.5mL of ethyl acetate into the alkaline suspension solution, adjusting the pH value to 9.1 by using concentrated ammonia water, stirring, standing, and carrying out phase separation to obtain 110mL of alkaline suspension solution. Adding 55mL of ethyl acetate into 110mL of alkaline suspension, adjusting the pH value to 5.6 by using 2M/L hydrochloric acid, stirring for 30 minutes, standing for phase separation to obtain an ethyl acetate phase and a water phase, adding 33mL of ethyl acetate into the water phase again, adjusting the pH value to 5.9 by using concentrated ammonia water, stirring for 30 minutes, standing for phase separation to obtain the ethyl acetate phase and the water phase, combining the ethyl acetate phases obtained by two times of acidic extraction, concentrating under reduced pressure until the content of mycophenolic acid is 200g/L, stopping concentrating, stirring and heating the concentrated solution to 60 ℃, continuing stirring for 15 minutes, then cooling at 3 ℃/h for crystallization, cooling to-10 ℃, continuing stirring and crystallizing for 3 hours, separating out mycophenolic acid, and drying in vacuum at 70 ℃ for 8 hours to obtain 20.16g of mycophenolic acid, wherein the yield is 80.64%, the purity is 95.393%, RRT1.09 impurity 1.347%, and the color is yellowish.
Comparative example 2
Concentrating 1000mL of ethyl acetate crystalline mother liquor of mycophenolic acid (the content of mycophenolic acid is 25g/L) under reduced pressure to obtain 31.0g of solid, adding 800mL of acetone and 80mL of 2M hydrochloric acid into 31.0g of solid, stirring and heating to 45 ℃, adding 3.5g of activated carbon after dissolving clear, preserving heat, stirring for 30 minutes, and filtering; under stirring, dripping 500mL of mixed solution of n-hexane and heptane (volume ratio 1:1) into the filtrate at 35 deg.C, and finishing dripping; keeping the temperature at 15 ℃, stirring and crystallizing for 2.5 hours, filtering, and pulping and washing a filter cake by using 50mL of purified water; vacuum drying at 40 deg.C for 8 hr to obtain mycophenolic acid 20.65g, yield 82.60%, purity 97.672%, and RRT1.09 impurity 0.306%.
Comparative example 3
Concentrating 1000mL of mother liquor of ethyl acetate crystals of mycophenolic acid (the content of mycophenolic acid is 25g/L) under reduced pressure to obtain 32.1g of solid, adding 1000mL of butyl acetate into 32.1g of solid, stirring and heating to 90 ℃; dissolving, adding 3.5g of activated carbon, keeping the temperature and stirring for 30 minutes, filtering, adding 1000mL of purified water for extraction, concentrating the upper ester phase after extraction, wherein the concentration temperature is 50 ℃, the vacuum degree is-0.09 MPa, concentrating to 60% of the original volume, keeping the temperature and crystallizing for 4 hours at 0 ℃, filtering, washing a filter cake by using 50mL of cold butyl acetate, and carrying out vacuum drying for 8 hours at 60 ℃ under reduced pressure, wherein the vacuum degree is-0.06 MPa; 21.25g of mycophenolic acid is obtained, the yield is 85.00%, the purity is 96.134%, and the content of RRT1.09 impurity is 1.192%.
Claims (10)
1. A method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor is characterized by comprising the following steps: obtaining a solid from a mycophenolic acid crystallization mother liquor, adding the solid into ethyl acetate, adjusting the pH value with acid, separating an ethyl acetate phase, adding activated carbon into the ethyl acetate phase for decolorization, filtering, concentrating the filtrate at a controlled temperature under reduced pressure until the content of mycophenolic acid is 71-91g/L, controlling the concentration rate to be 5% -10% of the volume of the solvent concentrated per hour in the total solution volume, continuing to concentrate at a controlled temperature under reduced pressure until the content of mycophenolic acid 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.
2. The method of claim 1, wherein obtaining the solid from the mother liquor of mycophenolic acid crystallization comprises the steps of: adding strong ammonia water into the mycophenolic acid crystallization mother liquor to adjust the pH value of the solution to 8-10, and filtering to obtain a solid.
3. The method of claim 1, wherein obtaining the solid from the mother liquor of mycophenolic acid crystallization comprises the steps of: and distilling the mycophenolic acid crystallization mother liquor under reduced pressure until the mycophenolic acid crystallization mother liquor is dried to obtain a solid, adding the solid into ethyl acetate, adding concentrated ammonia water to adjust the pH value of the solution to 8-10, and filtering to obtain a solid.
4. The method for purifying mycophenolic acid from a mycophenolic acid crystallization mother liquor according to claim 2 or 3, wherein concentrated ammonia water is added to adjust the pH value of the solution to 8.6-9.5.
5. The method of claim 1, wherein the temperature for cooling and crystallizing is 0-5 ℃.
6. The method of claim 1, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid.
7. The method of claim 1, wherein the pH of the mycophenolic acid is adjusted to 3 to 5 with an acid.
8. The method for purifying mycophenolic acid from a mycophenolic acid crystallization mother liquor as claimed in claim 1, wherein the rate of cooling crystallization is 6-12 ℃/h.
9. The method for purifying mycophenolic acid from a mycophenolic acid crystallization mother liquor according to claim 1, wherein the temperature of the temperature-controlled reduced pressure concentration is 40-60 ℃, preferably 45-55 ℃.
10. The method of claim 1, wherein the mycophenolic acid content of the mycophenolic acid mother liquor is 12-35 g/L.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021100304488 | 2021-01-11 | ||
| CN202110030448 | 2021-01-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114763344A true CN114763344A (en) | 2022-07-19 |
Family
ID=82364839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210016144.0A Pending CN114763344A (en) | 2021-01-11 | 2022-01-07 | Method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114763344A (en) |
-
2022
- 2022-01-07 CN CN202210016144.0A patent/CN114763344A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109553645B (en) | Method for extracting low-content erythromycin A in fermentation solution | |
| CN109851568B (en) | Method for purifying prothioconazole | |
| CN114763344A (en) | Method for purifying mycophenolic acid from mycophenolic acid crystallization mother liquor | |
| WO2020207130A1 (en) | Process for separating and purifying artemisinin | |
| CN114015732B (en) | Industrial preparation method of andrographolide and dehydroandrographolide | |
| CN112358514B (en) | Synthesis process of arbutin | |
| CN115231990A (en) | Preparation method of high-purity dipentaerythritol | |
| CN114014835A (en) | Glycolide purification process | |
| CN108147988B (en) | Preparation method of lactam compound with high chiral purity | |
| CN110642722A (en) | Method for preparing N, N-tetramethyl decamethylene diamine | |
| CN104513151B (en) | A kind of method extracting high purity butylene diacid from succinate fermentation liquid | |
| CN111620774A (en) | Production method for preparing high-purity solid malonic acid from calcium malonate | |
| WO2024082175A1 (en) | Preparation method for sucralose refined product | |
| CN116768910B (en) | Refining method of rifabutin | |
| CN114315627B (en) | Method for synthesizing doxycycline dehydrate by catalyzing with normal-temperature ionic liquid and zeolite | |
| CN114702487B (en) | Purification method of lysergic acid | |
| CN112661719B (en) | Clean preparation process of aminothiazoly loximate | |
| CN115181011B (en) | Preparation process of high-purity phenoxyethanol | |
| CN114736118B (en) | Method for separating 3-methoxy-4-hydroxy mandelic acid and preparing high-purity product thereof | |
| CN111171084B (en) | Improved fructose diacetone reaction liquid post-treatment method | |
| CN112661727B (en) | Purification method of 7- (2, 2-trichloroethyl oxycarbonyl) taxol | |
| CN112375031B (en) | Preparation method of cilnidipine | |
| CN117843716A (en) | Refining method of carfilzomib | |
| RU2078758C1 (en) | Method for production of sodium formiate | |
| CN113801086A (en) | High-purity high-yield extraction and purification method of dihydroquercetin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |