A purification process of mycophenolate sodium

Abstract

The invention belongs to the technical field of drug preparation, and specifically relates to a purification process of mycophenol sodium. The purification process of mycophenol sodium provided by the invention can efficiently remove mycophenol sodium EP impurities A, EP impurities B, and EP impurities C through the synergistic effects of multiple steps such as multiple alkalization, acidification, activated carbon impurity removal, and high-temperature reflux, with a maximum impurity of less than 0.10% and a total impurity of no more than 0.1%, which is suitable for use in pharmaceutical preparations. The purification process of mycophenol sodium provided by the invention is simple and easy to control, the solvent is convenient to recycle and use, the purification effect is good, the yield is high, the impurities of mycophenol sodium-related substances can be effectively removed, and the M2 crystal form of mycophenol sodium is obtained, which is suitable for use in pharmaceutical preparations.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a purification process of mycophenolic acid sodium. Background Art

[0002] Mycophenolic acid sodium, also known as mycophenolate sodium, is another immunosuppressant with mycophenolic acid (also known as mycophenolic acid) as the active drug ingredient after mycophenolate mofetil. It is metabolized in the body to produce mycophenolic acid (MPA). Mycophenolic acid is an antibiotic produced by Penicillium breviscompactum that has antifungal, antitumor and immunosuppressive effects. It is a highly effective, selective, non-competitive and reversible inhibitor of hypoxanthine mononucleotide dehydrogenase (MPDH). It can inhibit the initial synthesis pathway of guanine nucleotides, deplete guanine nucleotides, and then block DNA synthesis.

[0003] The preparation of mycophenolic acid sodium is usually firstly obtained by fermenting Penicillium Brevicompactum to obtain a fermentation broth containing mycophenolic acid, and then the intermediate mycophenolic acid is extracted and purified by solvent extraction or acid-base method, and the mycophenolic acid is further sodiumized with organic base or inorganic base to obtain mycophenolic acid sodium. The medicinal mycophenolic acid sodium is an anhydrous monosodium salt, and the related impurities of mycophenolic acid sodium include mycophenolic acid sodium EP impurity A (mycophenolic acid mofetil related impurity B in USP), mycophenolic acid sodium EP impurity B (Z isomer), mycophenolic acid sodium EP impurity C, mycophenolic acid sodium hydrate and mycophenolic acid sodium disodium salt, etc., which are difficult to remove because of their highly similar structure to mycophenolic acid sodium.

[0004] Chinese patent application CN103880798A discloses a method for purifying mycophenolic acid, which comprises the following steps: 1) providing an ethanol solution of mycophenolic acid at a temperature of 50°C to 70°C; 2) cooling the ethanol solution in step 1) to 10°C to 30°C to allow mycophenolic acid to crystallize and separate mycophenolic acid crystals; 3) dissolving the mycophenolic acid crystals obtained in step 2) with ethanol, mixing the obtained solution with water at a temperature of 5°C to 12°C to allow mycophenolic acid to recrystallize and separate mycophenolic acid recrystallized crystals. However, the yield of the product obtained in this patent is low.

[0005] Mycophenolic acid sodium has up to 28 crystal forms. WO2006 / 012379 (Chinese patent CN200580024065.9, preparation method of crystalline mycophenolic acid sodium) discloses anhydrous mycophenolic acid monosodium M2 crystal form and its preparation method. In this patented technology, the M1 crystal form is easily obtained by preparing mycophenolic acid sodium with a C1-C4 alcohol solution of mycophenolic acid, and the yield is low. The crystals prepared by mixing a C3-C8 ketone solution of mycophenolic acid with an alkali and a sodium source are likely to contain crystal water and easily generate mycophenolic acid disodium salt; or a mother liquor of multiple solvents such as ketones and alcohols is obtained, which is not easy to recover the solvent and is not conducive to green production.

[0006] South African Patent No. 6804959 describes the preparation of monosodium and disodium mycophenolic acid. After one molar equivalent of sodium methoxide reacts with mycophenolic acid in a mixed solvent of methanol and chloroform, mycophenolic acid monosodium can be separated by precipitation with n-pentane. The preparation of the corresponding disodium salt is also described, that is, two molar equivalents of sodium methoxide are added to a mycophenolic acid benzene-chloroform mixed solvent, and the evaporated material is crystallized with acetone / water. The patent provides an embodiment of the preparation of monosodium mycophenolic acid: an anhydrous methanol solution of sodium methoxide is added to a chloroform solution of mycophenolic acid, and then the monosodium salt is precipitated by adding n-pentane, and filtered, collected and vacuum dried. However, the patent technology does not specifically describe the name and characteristics of the crystal form, and requires multi-step reactions, and uses a variety of organic solvents and reagents, which increases the risk of impurity introduction.

[0007] WO97 / 38689 (Chinese patent CN97193760.5) describes the sodium salt of mycophenolate known in South African patent No. 6804959, which can be obtained by recrystallization in acetone-ethanol to obtain a crystalline monosodium salt with a melting point of 189-191° C. However, the patent technology does not specifically describe the name and characteristics of the crystal form, and the methanol and acetone solvents used are miscible and have similar boiling points, which makes it inconvenient to recover the solvent and increases the production cost.

[0008] US Patent US2008176937A1 discloses a method for preparing CG1 crystalline form and M2 crystalline form of mycophenolic acid sodium by toluene reflux, but does not involve the separation of related substances.

[0009] The above-mentioned disclosed extraction and purification technologies for mycophenolic acid and mycophenolic acid sodium have a certain purification effect on mycophenolic acid, but still have the disadvantages of complex purification process, difficulty in recovery using multiple organic solvents, poor purification effect, etc., or the prepared mycophenolic acid is not M2 crystalline mycophenolic acid sodium.

[0010] Therefore, there is an urgent need to develop a purification process for mycophenolate sodium that can effectively remove impurities of mycophenolate sodium-related substances and obtain M2 crystalline mycophenolate sodium, with a simple and easy-to-control method, convenient solvent recovery and reuse, good purification effect and high yield. Summary of the invention

[0011] In view of the shortcomings of the prior art, the object of the present invention is to provide a purification process for mycophenol sodium. The purification process for mycophenol sodium provided by the present invention can effectively remove impurities of mycophenol sodium-related substances, and obtains M2 crystal form mycophenol sodium, the method is simple and easy to control, the solvent is convenient to recycle and use, the purification effect is good, and the yield is high.

[0012] The technical solution of the present invention is:

[0013] A purification process for mycophenolate sodium comprises the following steps:

[0014] S1. adding an alkaline solution to a fermentation culture broth containing mycophenolic acid, adjusting the pH, and stirring the mixture under warm conditions to obtain an alkaline fermentation broth;

[0015] S2, cooling the alkalized fermentation liquid obtained in step S1, filtering, collecting the filtrate, adding an organic solvent to the filtrate, adjusting the pH, stirring, standing, separating and discarding the lower aqueous phase, concentrating the organic phase under reduced pressure, adding activated carbon, stirring, filtering, and obtaining a filtrate after impurity removal;

[0016] S3, adding water to the impurity-removed filtrate obtained in step S2, adjusting the temperature, adding an alkaline solution, adjusting the pH, stirring, standing, and separating and collecting the lower aqueous phase;

[0017] S4, adding an organic solvent to the aqueous phase obtained in step S3, adjusting the pH, stirring, standing, separating and discarding the lower aqueous phase, adding an acidic solution to the organic phase, stirring, standing, separating and discarding the lower aqueous phase, and collecting the organic phase;

[0018] S5, adding water to the organic phase obtained in step S4, adding an alkaline solution, adjusting the pH, heating to azeotropically remove the water in the organic phase, continuing to heat and reflux, then cooling to precipitate crystals, filtering the crystallization liquid to obtain wet crystals of mycophenol sodium, and drying the wet crystals of mycophenol sodium under reduced pressure to obtain a finished product of mycophenol sodium.

[0019] Furthermore, in step S1, the pH is adjusted to 12.0-13.0, and the mixture is kept warm at 50-60° C. and stirred for 30-60 minutes.

[0020] Furthermore, the step S2 adjusts the pH to 3.0-4.0.

[0021] Furthermore, the alkaline solutions in step S1, step S3 and step S5 are all sodium hydroxide aqueous solutions with a mass concentration of 30-50%.

[0022] Furthermore, the organic solvent in step S2 and step S4 is toluene or butyl acetate.

[0023] Furthermore, in step S3, the pH is adjusted to 8.5-9.0 and stirred for 0.5-1.5 hours.

[0024] Furthermore, the step S4 adjusts the pH to 3.0-4.0.

[0025] Furthermore, the pH of the acidic solution in step S4 is 3.0-4.0.

[0026] Furthermore, the step S5 adjusts the pH to 7.5-8.0.

[0027] Furthermore, when the organic solvent is toluene, the specific operation of heating and azeotropic removal of moisture in the organic phase in step S5, continuing heating and reflux, and then cooling is: heating and azeotropic removal of moisture in the organic phase, continuing heating and reflux to 105-110°C and maintaining for 2-3 hours, then cooling to 25-35°C and keeping warm for 2-4 hours; when the organic solvent is butyl acetate, the specific operation of heating and azeotropic removal of moisture in the organic phase in step S5, continuing heating and reflux, and then cooling is: heating and azeotropic removal of moisture in the organic phase, continuing heating and reflux to 120-126°C and maintaining for 2-3 hours, then cooling to 25-35°C and keeping warm for 2-4 hours.

[0028] Compared with the prior art, the purification process of mycophenolic acid sodium provided by the present invention has the following advantages:

[0029] (1) The purification process of mycophenolic acid sodium provided by the present invention is simple and easy to operate, the method is simple and easy to control, the production cost is low, and it is conducive to industrial promotion and application.

[0030] (2) The purification process of mycophenolic acid sodium provided by the present invention can effectively remove mycophenolic acid sodium EP impurities A, EP impurities B, and EP impurities C through the synergistic effects of multiple steps such as multiple alkalization, acidification, activated carbon impurity removal, and high-temperature reflux. The maximum impurity is less than 0.10%, and the total impurity is not higher than 0.1%, which is suitable for use in pharmaceutical preparations.

[0031] (3) The present invention obtains M2 crystalline mycophenolate sodium, which is suitable for use in pharmaceutical preparations.

[0032] (4) The present invention uses only one organic solvent, which is a hydrophobic solvent and can be easily recycled, greatly reducing the emission of organic solvents, and is safe and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The X-ray powder diffraction pattern of mycophenolate sodium prepared in Example 1 of the present invention;

[0034] Figure 2 The X-ray powder diffraction pattern of mycophenolate sodium prepared in Comparative Example 3 is shown. DETAILED DESCRIPTION

[0035] The present invention is further illustrated below through the description of specific implementation modes, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0036] In the following examples and comparative examples, reagents not otherwise specified are conventional reagents and can be purchased from conventional reagent production and sales companies.

[0037] Example 1: A purification process for mycophenolate sodium

[0038] The purification process of mycophenolic acid sodium comprises the following steps:

[0039] S1. Add a 50% sodium hydroxide aqueous solution to the fermentation broth containing mycophenolic acid, adjust the pH to 12.2, and stir at 55° C. for 60 minutes to obtain an alkalized fermentation broth. Sampling is performed to determine the amount of mycophenolic acid product in the organic phase, 90 g.

[0040] S2, cooling the alkalized fermentation liquid obtained in step S1 to 28°C and filtering it through a plate and frame filter press, collecting 10L of filtrate, adding 10L of toluene at a temperature of 40°C to the filtrate, slowly adding 85% phosphoric acid under stirring to make the pH value reach 3.5, stirring for 1 hour, stopping stirring and standing for 2 hours, separating and discarding the lower aqueous phase, concentrating the organic phase under reduced pressure at 65°C to 1350mL, adding 4.5g of activated carbon, keeping warm at 55°C for 1 hour under stirring, filtering to remove the activated carbon, and collecting 1250mL of the filtrate after impurity removal;

[0041] S3, add 1250mL of water to the filtrate after impurity removal obtained in step S2, adjust the temperature to 30°C, slowly add a 50% sodium hydroxide aqueous solution to make the pH reach 8.6, stir for 1 hour, stop stirring and let stand for 2 hours, separate and collect 1250mL of the lower aqueous phase;

[0042] S4, add 2500mL of toluene at a temperature of 40°C to the aqueous phase obtained in step S3, slowly add 85% phosphoric acid under stirring to make the pH value reach 3.5, stir for 1 hour, stop stirring and let stand for 2 hours, separate and discard the lower aqueous phase, collect the organic phase, sample and measure the amount of mycophenolic acid product in the organic phase, 84g, add 250mL of drinking water pre-adjusted to pH 3.4 with 85% phosphoric acid to the organic phase, stir for 1 hour, stop stirring and let stand for 2 hours, separate and discard the lower aqueous phase, and collect the organic phase;

[0043] S5. Add 168 mL of purified water to the organic phase obtained in step S4, then slowly add a 50% sodium hydroxide aqueous solution until the pH reaches 7.9, heat and azeotropically remove water from the organic phase, continue heating and reflux to 110° C. and maintain for 2.5 hours, then cool to 30° C. and keep warm for 2 hours to precipitate crystals, filter the crystallization liquid to obtain wet crystals of mycophenolic sodium, and dry the wet crystals of mycophenolic sodium under reduced pressure at 60° C. to a drying loss of 0.1%, to obtain 83 g of mycophenolic sodium finished product.

[0044] The fermentation broth containing mycophenolic acid in step S1 is a fermentation broth containing mycophenolic acid obtained by conventional fermentation of Penicillium Brevicompactum. The specific preparation method is the method disclosed in Example 2 of the specification of a fermentation process of mycophenolic acid in Chinese patent CN109929890B.

[0045] Example 2: A purification process for mycophenolate sodium

[0046] The purification process of mycophenolic acid sodium comprises the following steps:

[0047] S1. Add a 50% sodium hydroxide aqueous solution to the fermentation broth containing mycophenolic acid, adjust the pH to 12.5, and stir at 60° C. for 30 minutes to obtain an alkalized fermentation broth. Sampling is performed to determine the amount of mycophenolic acid product in the organic phase, 80 g.

[0048] S2, cooling the alkalized fermentation liquid obtained in step S1 to 25°C and filtering it through a plate and frame filter press, collecting 10L of filtrate, adding 10L of toluene at a temperature of 40°C to the filtrate, slowly adding 85% phosphoric acid under stirring to make the pH value reach 3.0, stirring for 1 hour, stopping stirring and standing for 2 hours, separating and discarding the lower aqueous phase, concentrating the organic phase under reduced pressure at 60°C to 1200mL, adding 4g of activated carbon, keeping warm at 50°C for 1 hour under stirring, filtering to remove the activated carbon, and collecting 1150mL of the filtrate after impurity removal;

[0049] S3, add 1150mL of water to the impurity-removed filtrate obtained in step S2, adjust the temperature to 30°C, slowly add a 50% sodium hydroxide aqueous solution to make the pH reach 8.5, stir for 1 hour, stop stirring and let stand for 2 hours, separate and collect 1100mL of the lower aqueous phase;

[0050] S4, add 2200mL of toluene at a temperature of 40°C to the aqueous phase obtained in step S3, slowly add 85% phosphoric acid under stirring to make the pH value reach 3.0, stir for 1 hour, stop stirring and let stand for 2 hours, separate and discard the lower aqueous phase, collect the organic phase, sample and measure the amount of mycophenolic acid product in the organic phase, 75g, add 220mL of drinking water pre-adjusted to pH 3.0 with 85% phosphoric acid to the organic phase, stir for 1 hour, stop stirring and let stand for 2 hours, separate and discard the lower aqueous phase, and collect the organic phase;

[0051] S5. Add 150 mL of purified water to the organic phase obtained in step S4, then slowly add a 50% sodium hydroxide aqueous solution until the pH reaches 7.8, heat to remove moisture in the organic phase by azeotropy, continue heating and reflux to 110° C. and maintain for 2 hours, then cool to 30° C. and keep warm for 2 hours to precipitate crystals, filter the crystallization liquid to obtain wet crystals of mycophenolic sodium, and dry the wet crystals of mycophenolic sodium under reduced pressure at 50° C. to a drying loss of 0.2%, to obtain 73 g of mycophenolic sodium finished product.

[0052] The fermentation broth containing mycophenolic acid in step S1 is a fermentation broth containing mycophenolic acid obtained by conventional fermentation of Penicillium Brevicompactum. The specific preparation method is the method disclosed in Example 2 of the specification of a fermentation process of mycophenolic acid in Chinese patent CN109929890B.

[0053] Example 3: A purification process for mycophenolate sodium

[0054] The purification process of mycophenolic acid sodium comprises the following steps:

[0055] S1. Add a 30% sodium hydroxide aqueous solution to the fermentation broth containing mycophenolic acid, adjust the pH to 12.3, and stir at 50° C. for 60 minutes to obtain an alkalized fermentation broth. Take a sample to determine the amount of mycophenolic acid product in the organic phase, 85 g.

[0056] S2, cooling the alkalized fermentation liquid obtained in step S1 to 30°C and filtering it through a plate and frame filter press, collecting 10L of filtrate, adding 10L of toluene at a temperature of 40°C to the filtrate, slowly adding 85% phosphoric acid under stirring to make the pH value reach 4.0, stirring for 1 hour, stopping stirring and standing for 2 hours, separating and discarding the lower aqueous phase, collecting the organic phase, concentrating the organic phase under reduced pressure at 70°C to 1280mL, adding 4.25g of activated carbon, keeping warm at 60°C for 1 hour under stirring, filtering to remove the activated carbon, and collecting 1230mL of the filtrate after impurity removal;

[0057] S3, add 1230mL of water to the impurity-removed filtrate obtained in step S2, adjust the temperature to 30°C, slowly add a 50% sodium hydroxide aqueous solution to make the pH reach 9.0, stir for 1 hour, stop stirring and let stand for 2 hours, separate and collect 1100mL of the lower aqueous phase;

[0058] S4, add 2200mL of toluene at a temperature of 40°C to the aqueous phase obtained in step S3, slowly add 85% phosphoric acid under stirring to make the pH value reach 4.0, stir for 1 hour, stop stirring and let stand for 2 hours, separate and discard the lower aqueous phase, sample and measure the amount of mycophenolic acid product in the organic phase, 79g, add 220mL of drinking water pre-adjusted to pH 4.0 with 85% phosphoric acid to the organic phase, stir for 1 hour, stop stirring and let stand for 2 hours, separate and discard the lower aqueous phase, and collect the organic phase;

[0059] S5. Add 160 mL of purified water to the organic phase obtained in step S4, then slowly add a 50% sodium hydroxide aqueous solution until the pH reaches 8.0, heat and azeotropically remove water from the organic phase, continue to heat and reflux to 110° C. and maintain for 3 hours, then cool to 30° C. and keep warm for 2 hours to precipitate crystals, filter the crystallization liquid to obtain wet crystals of mycophenolic sodium, and dry the wet crystals of mycophenolic sodium under reduced pressure at 55° C. to a drying loss of 0.2%, to obtain 78 g of mycophenolic sodium finished product.

[0060] The fermentation broth containing mycophenolic acid in step S1 is a fermentation broth containing mycophenolic acid obtained by conventional fermentation of Penicillium Brevicompactum. The specific preparation method is the method disclosed in Example 2 of the specification of a fermentation process of mycophenolic acid in Chinese patent CN109929890B.

[0061] Example 4: A purification process for mycophenolate sodium

[0062] The purification process of mycophenolic acid sodium is similar to that of Example 1.

[0063] The difference from Example 1 is that the organic solvent in step S2 and step S4 is butyl acetate, and in step S5, the water in the organic phase is removed by heating and azeotropic distillation, and the mixture is further heated and refluxed to 126° C. for 2 hours, then cooled to 30° C. and kept warm for 2 hours to precipitate crystals. The crystallization liquid is filtered to obtain wet crystals of mycophenolic sodium, and the wet crystals of mycophenolic sodium are dried under reduced pressure at 60° C. to a drying loss of 0.1%.

[0064] Comparative Example 1: A purification process for mycophenolate sodium

[0065] The purification process of mycophenolic acid sodium is similar to that of Example 1.

[0066] The difference from Example 1 is that in step S1, a 50% sodium hydroxide aqueous solution is added to the fermentation culture broth containing mycophenolic acid, the pH is adjusted to 11.0, and the mixture is stirred at room temperature for 60 minutes.

[0067] Comparative Example 2: A purification process for mycophenolate sodium

[0068] The purification process of mycophenolic acid sodium is similar to that of Example 1.

[0069] The difference from Example 1 is that step S4 does not include the operation of "adding 250 mL of drinking water pre-adjusted to a pH value of 3.4 using 85% phosphoric acid to the organic phase, stirring for 1 hour, stopping stirring and standing for 2 hours, separating and discarding the lower aqueous phase, and collecting the organic phase".

[0070] Comparative Example 3: A purification process for mycophenolate sodium

[0071] The purification process of mycophenolic acid sodium is similar to that of Example 1.

[0072] The difference from Example 1 is that step S5 does not include the step of "adding 168 mL of purified water to the organic phase obtained in step S4".

[0073] Comparative Example 4: A purification process for mycophenolate sodium

[0074] The purification process of mycophenolic acid sodium is similar to that of Example 1.

[0075] The difference from Example 1 is that in step S5, a sodium hydroxide aqueous solution with a mass concentration of 50% is added until the pH reaches 8.5.

[0076] Comparative Example 5: A purification process for mycophenolate sodium

[0077] The purification process of mycophenolic acid sodium is similar to that of Example 1.

[0078] The difference from Example 1 is that in step S5, a sodium hydroxide aqueous solution with a mass concentration of 50% is added until the pH reaches 7.2.

[0079] Comparative Example 6: A purification process for mycophenolate sodium

[0080] The purification process of mycophenolic acid sodium is similar to that of Example 1.

[0081] The difference from Example 1 is that step S5 does not include the step of "continuing heating and reflux to 110° C. for 2.5 hours".

[0082] Test Example 1: Determination of the amount of mycophenolic acid produced

[0083] The amount of mycophenolic acid product in step S1 and step S4 of Examples 1 to 4 and Comparative Examples 1 to 6 was determined using the document "HPLC method for determination of the content of mycophenolic acid in samples during production" (Everyone's Health, Issue 12, 2018). Test Example 2: Determination of related substances and crystal form of mycophenolic acid finished product

[0084] The method for detecting the content of related substances in the finished mycophenolate sodium products obtained in step S5 of Examples 1 to 4 and Comparative Examples 1 to 6 was tested by referring to the method described in European Pharmacopoeia 11.0 "Mycophenolate Sodium".

[0085] The finished mycophenolate sodium products prepared in step S5 of Examples 1 to 4 and Comparative Examples 1 to 6 were subjected to crystal form detection using the second method of General Chapter 0451 of Part 4 of the 2020 edition of the Chinese Pharmacopoeia.

[0086] Test Example 3: Calculation Method of Mycophenolate Sodium Yield

[0087] Yield = (mass of the mycophenolic acid sodium product obtained in step S5 / amount of the mycophenolic acid product in step S1) × 100%.

[0088] The test results are shown in Table 1.

[0089] Table 1: Comparison of the test results of the relevant substance content, yield and crystal form of the products obtained in each group

[0090] sample Content of relevant substances Yield Crystal form Example 1 Maximum single impurity: 0.03% 92.2％ M2 crystal form Example 2 Maximum single impurity: 0.04% 91.3％ M2 crystal form Example 3 Maximum single impurity: 0.05% 91.8％ M2 crystal form Example 4 Maximum single impurity: 0.03% 90.8％ M2 crystal form Comparative Example 1 Maximum single impurity: 0.14% 84.4％ M2 crystal form Comparative Example 2 Maximum single impurity: 0.13% 91.6％ M2 crystal form Comparative Example 3 Maximum single impurity: 0.09% 88.3％ Not M2 crystal form Comparative Example 4 Maximum single impurity: 0.13% 92.1％ Not M2 crystal form Comparative Example 5 Maximum single impurity: 0.11% 91.4％ Not M2 crystal form Comparative Example 6 Maximum single impurity: 0.08% 91.4％ Not M2 crystal form

[0091] Note: Pharmacopoeia quality standards require that the maximum single impurity is ≤ 0.10%.

[0092] As can be seen from Table 1, the maximum single impurity of the finished mycophenolic sodium obtained by the purification process of mycophenolic sodium in Examples 1 to 4 of the present invention is ≤0.05%, which meets the requirement of the pharmacopoeia quality standard that the maximum single impurity is ≤0.10%. Moreover, the yield of the finished mycophenolic sodium obtained by the purification process of mycophenolic sodium in Examples 1 to 4 of the present invention is ≥90.8%, all of which are M2 crystal form. Among them, the finished mycophenolic sodium obtained by the purification process of mycophenolic sodium in Example 1 of the present invention has the lowest maximum single impurity content and the highest yield, and is the best embodiment of the present invention. The X-ray powder diffraction pattern of the mycophenolic sodium obtained in Example 1 of the present invention is as follows: Figure 1 As shown, the X-ray powder diffraction pattern of mycophenolate sodium prepared in Comparative Example 3 is as follows Figure 2 As shown. Figure 1 It can be seen that the mycophenolate sodium prepared in Example 1 of the present invention is M2 crystal form; Figure 2 It can be seen that the mycophenolic acid sodium obtained in Comparative Example 3 is not the M2 crystal form. Compared with Comparative Examples 1 to 6, the mycophenolic acid sodium finished product obtained by the purification process of mycophenolic acid sodium in Example 1 of the present invention has the lowest maximum single impurity content and the highest yield, and the obtained mycophenolic acid sodium is the M2 crystal form, which is suitable for use in pharmaceutical preparations.

[0093] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A purification process for mycophenolate sodium, characterized in that: The following steps are involved: S1. adding an alkaline solution to a fermentation culture broth containing mycophenolic acid, adjusting the pH, and stirring the mixture under warm conditions to obtain an alkaline fermentation broth; S2, cooling the alkalized fermentation liquid obtained in step S1, filtering, collecting the filtrate, adding an organic solvent to the filtrate, adjusting the pH, stirring, standing, separating and discarding the lower aqueous phase, concentrating the organic phase under reduced pressure, adding activated carbon, stirring, filtering, and obtaining a filtrate after impurity removal; S3, adding water to the impurity-removed filtrate obtained in step S2, adjusting the temperature, adding an alkaline solution, adjusting the pH, stirring, standing, and separating and collecting the lower aqueous phase; S4, adding an organic solvent to the aqueous phase obtained in step S3, adjusting the pH, stirring, standing, separating and discarding the lower aqueous phase, adding an acidic solution to the organic phase, stirring, standing, separating and discarding the lower aqueous phase, and collecting the organic phase; S5, adding water to the organic phase obtained in step S4, adding an alkaline solution, adjusting the pH, heating to azeotropically remove the water in the organic phase, continuing to heat and reflux, then cooling to precipitate crystals, filtering the crystallization liquid to obtain wet crystals of mycophenol sodium, and drying the wet crystals of mycophenol sodium under reduced pressure to obtain a finished product of mycophenol sodium.

2. The purification process of mycophenolate sodium according to claim 1, characterized in that In step S1, the pH is adjusted to 12.0-13.0, and the mixture is stirred at 50-60° C. for 30-60 minutes.

3. The purification process of mycophenolate sodium according to claim 1, characterized in that The step S2 adjusts the pH to 3.0-4.

0.

4. The purification process of mycophenolate sodium according to claim 1, characterized in that: The alkaline solutions in step S1, step S3 and step S5 are all sodium hydroxide aqueous solutions with a mass concentration of 30-50%.

5. The purification process of mycophenolate sodium according to claim 1, characterized in that: The organic solvent in step S2 and step S4 is toluene or butyl acetate.

6. The purification process of mycophenolate sodium according to claim 1, characterized in that: In step S3, the pH is adjusted to 8.5-9.0 and stirred for 0.5-1.5 hours.

7. The purification process of mycophenolate sodium according to claim 1, characterized in that: The step S4 adjusts the pH to 3.0-4.

0.

8. The purification process of mycophenolate sodium according to claim 1, characterized in that: The pH of the acidic solution in step S4 is 3.0-4.

0.

9. The purification process of mycophenolate sodium according to claim 1, characterized in that: The step S5 adjusts the pH to 7.5-8.

0.

10. The purification process of mycophenolate sodium according to claim 5, characterized in that: When the organic solvent is toluene, the specific operation of heating and azeotropic removal of water in the organic phase in step S5, continuing heating and reflux, and then cooling is: heating and azeotropic removal of water in the organic phase, continuing heating and reflux to 105-110° C. and maintaining for 2-3 hours, then cooling to 25-35° C. and maintaining for 2-4 hours; When the organic solvent is butyl acetate, the specific operation of step S5 of heating and azeotropically removing water from the organic phase, continuing heating and reflux, and then cooling is: heating and azeotropically removing water from the organic phase, continuing heating and reflux to 120-126° C. and maintaining for 2-3 hours, then cooling to 25-35° C. and keeping warm for 2-4 hours.

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