A method for preparing methylprednisolone sodium succinate

Abstract

The application provides a preparation method of sodium mycophenolate, which comprises the following steps: mixing mycophenolic acid crystals and first methanol, and obtaining first filtrate after first filtration treatment; mixing the first filtrate and a solid acid catalyst, and reacting at 50-55 DEG C until the content of mycophenolic acid is lower than 1%, and obtaining second filtrate after second filtration treatment; obtaining third filtrate after decolorization treatment and third filtration treatment of the second filtrate; obtaining first crystalline body after first crystallization treatment of the third filtrate; mixing the first crystalline body and second methanol, then adding sodium hydroxide and water, and reacting at 60-64 DEG C until the content of mycophenolate methyl ester is lower than 0.5%, and obtaining sodium mycophenolate concentrate after second crystallization treatment and reduced-pressure drying. By controlling the reaction degree of esterification and hydrolysis reactions and reasonably matching each step, the purity and yield of sodium mycophenolate can be improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical production, and specifically relates to a method for preparing sodium mycophenolate. Background Technology

[0002] Because mycophenolic acid (MPA) has strong gastrointestinal irritation and other side effects, it cannot be directly formulated into a drug. Therefore, sodium mycophenolate is typically used to make enteric-coated oral tablets. After entering the body, it rapidly hydrolyzes into the active metabolite mycophenolic acid, exerting an immunosuppressive effect and reducing gastrointestinal discomfort and other side effects. Currently, sodium mycophenolate is mainly produced by fermentation to generate mycophenolic acid, which is then reacted with alkaline sodium salts (such as sodium hydroxide, sodium methoxide, etc.). Examples include patent documents CN106350550B, CN112645912B, and CN114478452A. The quality requirements for sodium mycophenolate used in pharmaceutical formulations are extremely high; its high-performance liquid chromatography purity needs to reach over 99%, and all other individual impurities must be less than 0.1%. Because these impurities are very similar in nature to mycophenolate sodium, it is difficult to reduce the impurity content in the mycophenolate sodium prepared by the above method to the required limit. Currently, a method of multiple crystallizations of the mother liquor is used to reduce the impurity content; however, because the reduction in impurities with each crystallization is very small, the yield of the mother liquor crystallization is very low. Therefore, how to simultaneously improve the purity and yield of mycophenolate sodium is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0003] This invention provides a method for preparing sodium mycophenolate. By controlling the degree of reaction of esterification and hydrolysis and the reasonable combination of each step, the purity and yield of sodium mycophenolate can be improved.

[0004] The method for preparing sodium mycophenolate provided by the present invention includes the following steps: mixing mycophenolic acid crystals and first methanol, and then performing a first filtration treatment to obtain a first filtrate;

[0005] The first filtrate and solid acid catalyst are mixed and reacted at 50-55°C until the chromatographic purity of mycophenolic acid is less than 1%. After a second filtration, the second filtrate is obtained.

[0006] After decolorizing and filtering the second filtrate, a third filtrate is obtained.

[0007] The third filtrate is subjected to a first crystallization treatment to obtain a first crystal;

[0008] The first crystal and the second methanol were mixed, and then sodium hydroxide and water were added. The mixture was reacted at 60-64°C until the chromatographic purity of mycophenolate methyl ester was less than 0.5%. After a second crystallization and vacuum drying, mycophenolate sodium enrichment was obtained.

[0009] In the preparation method described above, the temperature of the first crystallization treatment is 10~15℃, and the time is 5~7h; and / or,

[0010] The second crystallization treatment is carried out at a temperature of 3-6°C for 5-7 hours.

[0011] In the preparation method described above, the mass-volume content of mycophenolic acid in the first filtrate is 3~5 g / L.

[0012] In the preparation method described above, the solid acid catalyst includes a styrene-based cation exchange resin;

[0013] The water content in the solid acid catalyst is ≤0.5% (g / g).

[0014] In the preparation method described above, the solid acid catalyst is 40-60% of the mass of mycophenolic acid in the first filtrate.

[0015] The preparation method described above, wherein the second filtrate is mixed with activated carbon to perform the decolorization treatment;

[0016] The activated carbon and the second filtrate have a mass-volume percentage of 0.2~0.4 g / mL.

[0017] In the preparation method described above, the first crystal and the second methanol are mixed to obtain a second mixture; the mass-volume content of mycophenolate methyl ester in the second mixture is 6~7 g / L.

[0018] In the preparation method described above, the molar amount of sodium hydroxide is 1.5 to 1.6 times that of methyl mycophenolate in the second mixture.

[0019] In the preparation method described above, the first crystal and the second methanol are mixed, and then sodium hydroxide and water are added to obtain a third mixture; in the third mixture, the volume of water accounts for 5 to 6% of the volume of methanol.

[0020] In the preparation method described above, the first filtration treatment is performed using a filter membrane with a pore size ≤ 0.45 μm.

[0021] The method for preparing sodium mycophenolate provided by this invention involves esterifying mycophenolic acid with methanol to generate methyl mycophenolate. Methyl mycophenolate is then hydrolyzed under alkaline conditions. By controlling the degree of esterification and hydrolysis, the reactants are converted to sodium mycophenolate to the maximum extent, which is beneficial for improving the yield of sodium mycophenolate. The entire preparation process is carried out in methanol, resulting in fewer impurities introduced into the reaction system and thus improving the purity of sodium mycophenolate. Furthermore, the preparation method provided by this invention avoids multiple crystallizations, increasing the utilization rate of the mother liquor. Attached Figure Description

[0022] Figure 1 This is a high-performance liquid chromatogram of the first filtrate in Example 1 of the present invention;

[0023] Figure 2 This is a high-performance liquid chromatography (HPLC) chromatogram of the solution after reaction in Example 1 of this invention;

[0024] Figure 3 This is a high-performance liquid chromatogram of the hygroscopic crystals in Embodiment 1 of the present invention. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0026] This invention provides a method for preparing sodium mycophenolate, comprising the following steps: mixing mycophenolic acid crystals and a first methanol, and then filtering the mixture to obtain a first filtrate; mixing the first filtrate with a solid acid catalyst and reacting the mixture at 50-55°C until the chromatographic purity of mycophenolic acid is less than 1%, and then filtering the mixture to obtain a second filtrate; decolorizing the second filtrate and then filtering the mixture to obtain a third filtrate; performing a first crystallization treatment on the third filtrate to obtain a first crystal; mixing the first crystal with a second methanol, then adding sodium hydroxide and water, and reacting the mixture at 60-64°C until the chromatographic purity of methyl mycophenolate is less than 0.5%, and then performing a second crystallization treatment and drying under reduced pressure to obtain a sodium mycophenolate-rich aggregate.

[0027] Mycophenolic acid crystals can be obtained from mycophenolic acid crystallization mother liquor through concentration, crystallization, and vacuum drying. The mycophenolic acid crystallization mother liquor can be obtained from the fermentation broth containing mycophenolic acid produced by *Penicillium brevicompactum*, after extraction and crystallization. For example, the fermentation broth containing mycophenolic acid produced by *Penicillium brevicompactum* can be subjected to solid-liquid separation to obtain a filtrate. The filtrate is then concentrated to precipitate mycophenolic acid in crystal form. The precipitate is then subjected to one or more crystallization treatments with methanol or ethanol to remove impurities. Finally, the mycophenolic acid crystals are obtained after vacuum drying. The solvent content (excluding methanol) in the mycophenolic acid crystals is ≤0.5%, and further, the alcohol solvent content (excluding methanol) in the mycophenolic acid crystals is ≤0.1%.

[0028] During the mixing of mycophenolic acid crystals and methanol, mycophenolic acid is completely dissolved in methanol. The insoluble matter is removed by a first filtration process, yielding a first filtrate. The first filtrate is then mixed with a solid acid catalyst and reacted at 50-55°C. Essentially, this is an esterification reaction between mycophenolic acid and methanol under the action of the solid acid catalyst, producing methyl mycophenolate. By limiting the reaction extent to ensure that the chromatographic purity of mycophenolic acid in the first filtrate is less than 1%, the maximum conversion of mycophenolic acid to methyl mycophenolate in the first filtrate is ensured, which is beneficial for increasing the yield of the first crystals during the crystallization of the third filtrate. The second filtration process is to remove the solid acid catalyst after the reaction, yielding a second filtrate.

[0029] Furthermore, it should be noted that the esterification reaction of mycophenolic acid and methanol has high selectivity. That is, apart from mycophenolic acid, very few other impurities react with methanol under the above-mentioned esterification reaction conditions. Therefore, after the esterification reaction, the first crystallization treatment can be used to significantly remove impurities, thereby improving the chromatographic purity of mycophenolic acid methyl ester. This is because most of the impurities in mycophenolic acid crystals have crystallization properties similar to mycophenolic acid and are difficult to remove by crystallization. Through the esterification reaction, mycophenolic acid is converted into mycophenolic acid methyl ester. Due to the change in physical properties, the impurities are easily removed by the first crystallization treatment, which helps to significantly improve the purity of the product.

[0030] The first crystal and the second methanol are mixed to dissolve the methyl mycophenolate in the first crystal into the second methanol. The second methanol is used to provide a reaction environment and avoid introducing too many impurities that would affect the purity of the product. Then, sodium hydroxide and water are added and reacted at 60-64°C. Essentially, the methyl mycophenolate undergoes a hydrolysis reaction with sodium hydroxide to obtain sodium mycophenolate. The degree of reaction is controlled so that the chromatographic purity of methyl mycophenolate in the first crystal is less than 0.5%. This maximizes the conversion of methyl mycophenolate into sodium mycophenolate, which is beneficial for improving the yield of sodium mycophenolate.

[0031] According to the research of this invention, the method described above for preparing sodium mycophenolate is beneficial for improving the purity and yield of sodium mycophenolate. This is because, on the one hand, crystallization after esterification, by converting mycophenolic acid to methyl mycophenolate through esterification with methanol, and then crystallizing, helps to remove impurities with crystallization properties similar to mycophenolic acid. In addition, by gradually reacting and controlling the degree of esterification and hydrolysis, the reactants are converted to sodium mycophenolate to the maximum extent, which improves the subsequent crystallization yield of sodium mycophenolate. Crystallization also helps to improve the purity of the final product, sodium mycophenolate. On the other hand, by introducing methanol at different stages of the reaction, methanol can serve as both a solvent and a reactant. Sodium mycophenolate can be prepared with only two crystallization processes, avoiding the risk of increased impurities due to excessive raw materials entering the reaction system. This is beneficial for improving the purity of sodium mycophenolate, simplifying the production process, and facilitating the control and management of large-scale production processes.

[0032] This invention does not limit the specific reaction conditions of the first and second crystallization processes, as long as crystal formation is achieved. For example, in some embodiments, the temperature of the first crystallization process is 10-15°C, for example, a range of 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, or any combination thereof; the time is 5-7 hours; and / or, the temperature of the second crystallization process is 3-6°C, for example, a range of 3°C, 4°C, 5°C, 6°C, or any combination thereof; the time is 5-7 hours. If the crystallization temperature is too low, the yield is higher, but the appearance and purity of the precipitate are poorer; if the crystallization temperature is too high, the appearance and color of the precipitate are better, and the purity is higher, but the yield loss is too great. By limiting the crystallization temperature and time, it is possible to improve the yield while ensuring appearance and purity.

[0033] This invention does not limit the amount of reactants added and can be adjusted according to actual needs. For example, in some embodiments, mycophenolic acid crystals and first methanol are mixed to obtain a first mixture; the mass-volume content of mycophenolic acid in the first filtrate is 3~5 g / L, for example, 3 g / L, 4 g / L, 5 g / L or any combination thereof.

[0034] This invention does not limit the specific type of solid acid catalyst, as long as it can perform a catalytic effect. In some embodiments, the solid acid catalyst includes a styrene-based cation exchange resin; the water content in the solid acid catalyst is ≤0.5% by mass. For example, the solid acid catalyst is a 001×8 styrene-based gel-type strong acid cation exchange resin, that is, a cation exchange resin with sulfonic acid groups (-SO3H) on a styrene-divinylbenzene copolymer crosslinked at 8% crosslinking.

[0035] The more solid acid catalyst added, the faster the esterification reaction. However, as time increases, the esterification efficiency tends to be uniform, and excessive solid acid catalyst will increase production costs. Therefore, in some embodiments, the solid acid catalyst is 40-60% of the mass of mycophenolic acid in the first filtrate, that is, the weight ratio of mycophenolic acid to solid acid catalyst is 1:(0.4-0.6). This helps to balance esterification reaction efficiency and production costs.

[0036] In some embodiments, the second filtrate is mixed with activated carbon for decolorization. The activated carbon may be type 767 needle-grade activated carbon.

[0037] In some embodiments, the first crystal and the second methanol are mixed to obtain a second mixture; the mass-volume content of mycophenolate methyl ester in the second mixture is 6~7 g / L.

[0038] In some embodiments, the molar amount of sodium hydroxide is 1.5 to 1.6 times that of methyl mycophenolate in the second mixture. By limiting the molar ratio, it is beneficial to ensure that methyl mycophenolate is converted to sodium mycophenolate to the maximum extent.

[0039] In some embodiments, the first crystal and the second methanol are mixed, and then sodium hydroxide and water are added to obtain a third mixture; in the third mixture, the volume of water accounts for 4.5-6% of the volume of the second methanol. This is because adding water facilitates the hydrolysis reaction and promotes the production of mycophenolate sodium.

[0040] In some embodiments, a filter membrane with a pore size ≤ 0.45 μm is used for the first filtration process.

[0041] This invention does not limit the filter used in the filtration process, as long as the pore size can ensure the flow rate and minimize the loss of solution temperature during operation. It can be a filter cloth, filter screen, filter paper, etc., which are conventional in the art.

[0042] In this invention, chromatographic purity is a method of expressing the purity of a drug after detection by chromatographic analysis in drug quality standards. It represents the proportion of the peak area of ​​the analyte at a certain wavelength to the total peak area of ​​all substances that can produce peaks under that concentration condition.

[0043] The present invention will be further described below through specific embodiments and comparative examples.

[0044] Example 1

[0045] The preparation process of mycophenolate sodium in this embodiment includes the following steps:

[0046] 1) The first mycophenolic acid crystals were added to a three-necked flask, along with 1000 mL of methanol. A water bath was placed outside the flask to heat the solution, which was then refluxed and stirred at 60°C for 30 min. The solution was filtered through filter paper while hot to obtain the first filtrate, which was then returned to the three-necked flask and kept warm. The clear first filtrate was subjected to high-performance liquid chromatography (HPLC) analysis. The mass-volume content of mycophenolic acid in the first filtrate was calculated to be 3.4 g / L, and the chromatographic purity was 70.34% (see [link to HPLC analysis]). Figure 1 );

[0047] 2) Add 1.36 g (equivalent to 40% g / g of the total mycophenolic acid in the first filtrate) of 001×8 resin to the first filtrate, and stir and reflux at 50~55℃ for 7 hours to obtain the reaction solution; take a sample of the reaction solution for high performance liquid chromatography analysis to determine the chromatographic purity of mycophenolic acid to be 0.903% (see...). Figure 2 );

[0048] 3) Quickly filter the reaction solution through filter paper to remove the 001×8 resin after the reaction, and obtain the second filtrate; then add 2g of 767 needle-grade activated carbon to the second filtrate, keep it at 52℃ and stir to decolorize it, filter it with a sterilization plate with an average pore size of 0.45μm to remove the activated carbon, and obtain the third filtrate, and continue to keep it at 52℃ for 30 minutes.

[0049] 4) Slowly lower the temperature of the water bath outside the three-necked flask, controlling the cooling rate at 4~5℃ / hour. After lowering it to 10℃, continue to maintain the temperature and stir for crystallization for 7 hours. Then separate the molten crystals (i.e., the first crystals). Take a sample of the molten crystals and test the chromatographic purity of mycophenolic acid methyl ester in the molten crystals. The purity is 97.645%.

[0050] 5) Mix the mycophenolic crystals with 448 mL of anhydrous methanol, heat in a water bath at 60 °C with stirring until dissolved, and take a sample for high-performance liquid chromatography (HPLC) analysis. The calculated mass-volume content of mycophenolic acid methyl ester was 6.83 g / L, the weight of mycophenolic acid methyl ester was 3.06 g, the molecular weight of mycophenolic acid methyl ester was 334.36, and the molar amount was 0.00915 mol. Then add 0.55 g of solid sodium hydroxide at a 1.5 molar ratio, dissolve and clarify, then add 21 mL of water, maintain the reaction in a water bath at 60-64 °C with methanol under reflux for 7 hours, and take a sample for HPLC analysis. The chromatographic purity of mycophenolic acid methyl ester in the solution was 0.36%.

[0051] 6) Stop water bath heating, and slowly cool down at a rate of 3-4℃ / hour. After cooling to 3℃, continue to maintain the temperature and stir for crystallization for 8 hours, then separate the molten crystals. Dry the molten crystals under reduced pressure to obtain 2.53g of white crystals (i.e., sodium mycophenolate enriched group). High-performance liquid chromatography analysis showed that the chromatographic purity of sodium mycophenolate was 99.63% (see...). Figure 3 ).

[0052] Example 2

[0053] The preparation process of mycophenolate sodium in this embodiment includes the following steps:

[0054] 1) Add the second mycophenolic acid crystal to a three-necked flask, add 1000 mL of methanol, and heat the flask with a water bath at 60°C for 30 min. Filter the solution while hot with filter paper to obtain the first filtrate, and transfer it back to the three-necked flask to continue keeping it warm. Take the clear first filtrate for high-performance liquid chromatography analysis and calculate the mycophenolic acid content in the solution as 4.8 g / L, with a chromatographic purity of 89.62%.

[0055] 2) Add 2.88g (equivalent to 60% g / g of the total amount of mycophenolic acid in the first filtrate) of 001×8 resin to the first filtrate, stir and reflux at 50~55℃ for 7 hours to obtain the reaction solution; take a sample of the reaction solution and perform high performance liquid chromatography analysis to detect the chromatographic purity of mycophenolic acid, which is 0.61%.

[0056] 3) Quickly filter the reaction solution through filter paper to remove the 001×8 resin after the reaction, and obtain the second filtrate; then add 4g of 767 needle-grade activated carbon to the second filtrate, keep it at 54℃ and stir to decolorize it, filter it with a sterilization plate with an average pore size of 0.45μm to remove the activated carbon, and obtain the third filtrate, and continue to keep it at 54℃ for 30 minutes.

[0057] 4) Slowly lower the temperature of the water bath outside the three-necked flask, controlling the cooling rate at 4~5℃ / hour. After lowering it to 15℃, continue to maintain the temperature and stir for crystallization for 7 hours. Then separate the molten crystals (i.e., the first crystals). Take a sample of the molten crystals and test the chromatographic purity of mycophenolic acid methyl ester in the molten crystals. The purity is 99.1%.

[0058] 5) Mix the mycophenolic crystals with 716 mL of anhydrous methanol, heat in a water bath at 60 °C with stirring until dissolved, and take a sample for high-performance liquid chromatography (HPLC) analysis. The calculated mass-volume content of mycophenolic acid methyl ester is 6.16 g / L, the weight of mycophenolic acid methyl ester is 4.41 g, the molecular weight of mycophenolic acid methyl ester is 334.36, and the molar amount is 0.01319 mol. Then add 0.84 g of solid sodium hydroxide at a molar ratio of 1.6, dissolve and clarify, then add 43 mL of water, maintain the reaction in a water bath at 60-64 °C with methanol under reflux for 7 hours, and take a sample for HPLC analysis. The chromatographic purity of mycophenolic acid methyl ester in the solution is 0.43%.

[0059] 6) Stop water bath heating, control the solution temperature to slowly cool down at 3~4℃ / hour, and continue to keep warm and stir for 8 hours after cooling down to 6℃, and separate the hygroscopic crystals; dry the hygroscopic crystals under reduced pressure to obtain 3.31g of white crystals (i.e., sodium mycophenolate enrichment); the chromatographic purity of sodium mycophenolate was detected by high performance liquid chromatography and found to be 99.8%.

[0060] Example 3

[0061] The preparation process is basically the same as in Example 2, except that the amount of 001×8 resin added is different. In this example, 1.92g of 001×8 resin (equivalent to 40% g / g of the total amount of mycophenolic acid in the first filtrate) is added to the first filtrate, and other conditions remain unchanged.

[0062] Example 4

[0063] The preparation process is basically the same as in Example 2, except that the amount of 001×8 resin added is different. In this example, 2.4g of 001×8 resin (equivalent to 50% g / g of the total amount of mycophenolic acid in the first filtrate) is added to the first filtrate, and other conditions remain unchanged.

[0064] Example 5

[0065] The preparation process is basically the same as in Example 2, except that the amount of 001×8 resin added is different. In this example, 3.36g of 001×8 resin (equivalent to 70% g / g of the total amount of mycophenolic acid in the first filtrate) is added to the first filtrate, and other conditions remain unchanged.

[0066] Example 6

[0067] The preparation process is basically the same as in Example 2, except that the amount of 001×8 resin added is different. In this example, 3.84g of 001×8 resin (equivalent to 80% g / g of the total amount of mycophenolic acid in the first filtrate) is added to the first filtrate, and other conditions remain unchanged.

[0068] Comparative Example 1

[0069] The preparation process is basically the same as in Example 2, except that the amount of 001×8 resin added and the reaction time are different. In this example, 0.96g of 001×8 resin (equivalent to 20% g / g of the total amount of mycophenolic acid in the first filtrate) is added to the first filtrate and stirred and refluxed at 50~55℃ for 8 hours, while other conditions remain unchanged.

[0070] Comparative Example 2

[0071] The preparation process is basically the same as in Example 2, except that the amount of 001×8 resin added and the reaction time are different. In this example, 1.44g of 001×8 resin (equivalent to 30% g / g of the total amount of mycophenolic acid in the first filtrate) is added to the first filtrate and stirred and refluxed at 50~55℃ for 8 hours, while other conditions remain unchanged.

[0072] Test case

[0073] 1. In step 2): 1.36g (equivalent to 40% g / g of the total amount of mycophenolic acid in the first filtrate) of 001×8 resin was added to the first filtrate and stirred and refluxed at 50~55℃. The chromatographic purity of mycophenolic acid in the solution was tested at different stirring and reflux times. The results are shown in Table 1.

[0074] Table 1

[0075]

[0076] 2. Mycophenolate Methyl Acetate Crystallization Temperature Experiment

[0077] To verify the optimal crystallization conditions of mycophenolate methyl in methanol, a material with a lower chromatographic purity than that in Example 2 (89.62%) was selected for more reference. The specific testing procedure is as follows:

[0078] 1) The second mycophenolic acid crystal was added to a three-necked flask, followed by 1000 mL of methanol. A water bath was placed outside the flask to heat the solution, which was then refluxed and stirred at 60°C for 30 min. The solution was filtered through filter paper while hot to obtain the first filtrate, which was then returned to the three-necked flask and kept at the same temperature. The clear first filtrate was subjected to high-performance liquid chromatography (HPLC) analysis. The total mycophenolic acid content in the solution was calculated to be 4.3 g / L, and the chromatographic purity was 78.9%.

[0079] 2) Add 2.58g (equivalent to 60% g / g of the total amount of mycophenolic acid in the first filtrate) of 001×8 resin to the first filtrate, stir and reflux at 50~55℃ for 7 hours to obtain the reaction solution; take a sample of the reaction solution and perform high performance liquid chromatography analysis to detect the residual amount of mycophenolic acid, which is 0.56%.

[0080] 3) The reaction solution was quickly filtered through filter paper to remove the 001×8 resin after the reaction, yielding a second filtrate. Then, 4g of 767 needle-grade activated carbon was added to the second filtrate, and the mixture was kept at 53℃ with stirring for decolorization. The activated carbon was removed by filtration through a sterile plate with an average pore size of 0.45μm, yielding a third filtrate, which was then kept at 54℃. A sample was taken and analyzed using high-performance liquid chromatography (HPLC) with external standard method, revealing that the methyl mycophenolate mofetil content in the decolorized methanol solution was 4.12g / L.

[0081] 4) Take out 100mL of the filtered and decarbonized solution and seal it into a 150mL beaker. Add a magnetic stir bar to the beaker and continue to keep it warm at 54℃. Prepare a total of 8 portions.

[0082] 5) Start cooling and crystallization. The 8 samples were cooled at different endpoint temperatures (see Table 2).

[0083] 6) After crystallization, the damp crystals are filtered out by vacuum filtration and then dried in a vacuum drying oven to obtain crystals.

[0084] 7) Weigh and record the dried methyl mycophenolate crystals, and record their appearance. Then, take a small amount of crystals for high-performance liquid chromatography (HPLC) analysis, and calculate the absolute content of methyl mycophenolate in the crystals using the external standard method.

[0085] 8) Calculate the crystallization yield by the weight of mycophenolate methyl ester in the methanol solution before crystallization and the weight of mycophenolate methyl ester in the crystal after crystallization.

[0086] Table 2

[0087]

[0088] As shown in Tables 1 and 2, the method for preparing sodium mycophenolate provided by the present invention, by controlling the degree of reaction of esterification reaction and hydrolysis reaction and the reasonable combination of each step, is beneficial to improving the purity and yield of sodium mycophenolate.

[0089] The preferred embodiments and experimental verifications of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A process for the preparation of methylprednisolone sodium succinate characterized in that, The method comprises the following steps: mixing mycophenolic acid crystals and first methanol, and obtaining first filtrate after first filtration treatment; mixing the first filtrate and solid acid catalyst, and reacting at 50-55 DEG C until the chromatographic purity of mycophenolic acid is less than 1%, and obtaining second filtrate after second filtration treatment; the solid acid catalyst is 40-80% of the mass of mycophenolic acid in the first filtrate; wherein the chromatographic purity of mycophenolic acid in the first filtrate is less than 1%, which is used to ensure that mycophenolic acid in the first filtrate is maximally converted into mycophenolic acid methyl ester; carrying out decolorization treatment and third filtration treatment on the second filtrate, and obtaining third filtrate; carrying out first crystallization treatment on the third filtrate, and obtaining first crystals; the temperature of the first crystallization treatment is 10-15 DEG C; mixing the first crystals and second methanol, and then adding sodium hydroxide and water, and reacting at 60-64 DEG C until the chromatographic purity of mycophenolic acid methyl ester is less than 0.5%, and obtaining mycophenolic acid sodium concentrate after second crystallization treatment and reduced-pressure drying; wherein the chromatographic purity of mycophenolic acid methyl ester is less than 0.5%, which is used to ensure that mycophenolic acid methyl ester is maximally converted into mycophenolic acid sodium; the solid acid catalyst is 001x8 styrene-based gel-type strong acid cation exchange resin; the mass content of water in the solid acid catalyst is ≤0.5%; the solid acid catalyst is 40-60% of the mass of mycophenolic acid in the first filtrate.

2. The production method according to claim 1, characterized by, the time of the first crystallization treatment is 5-7 h; and / or the temperature of the second crystallization treatment is 3-6 DEG C, and the time is 5-7 h.

3. The production method according to claim 1 or 2, characterized by, the mass-volume content of mycophenolic acid in the first filtrate is 3-5 g / L.

4. The method of any one of claims 1-2, wherein, mixing the second filtrate and activated carbon to carry out the decolorization treatment; the mass-volume percentage content of the activated carbon in the second filtrate is 0.2-0.4 g / mL.

5. The method of any one of claims 1-2, wherein, mixing the first crystals and second methanol to obtain second mixed liquor; the mass-volume content of mycophenolic acid methyl ester in the second mixed liquor is 6-7 g / L.

6. The preparation method according to claim 5, characterized in that, the molar amount of sodium hydroxide is 1.5-1.6 times of that of mycophenolic acid methyl ester in the second mixed liquor.

7. The method of any one of claims 1-2, wherein, mixing the first crystals and second methanol, and then adding sodium hydroxide and water to obtain third mixed liquor; in the third mixed liquor, the volume of water accounts for 4.5-6% of the volume of the second methanol.

8. The method of any one of claims 1-2, wherein, the first filtration treatment is carried out by using filter membrane with pore size ≤0.45 μm.

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